Guide to YKHC Medical Practices - User contributions [en]

Fishhook Removal

2020-10-09T19:36:05Z

TravisN:

(''written by Dr. Travis Nelson'')

Not surprisingly, this is a common procedure at YKHC and is often addressed via RMT.

There are multiple strategies for removing fishhooks.
*'''push-through method:''' This is my preferred method of removal, it is a simple technique that does not require technical proficiency and can be performed by CHAs.
*# use lidocaine to numb an area adjacent to the fishhook
*# push the hook through the anesthetized region until the barb is visible
*# cut the barb off with nail scissors or bone cutters
*# back the fishhook through the entrance wound.
[[file: Push-through_method.png|400px]]
*'''string-yank technique''', in which a line is attached to the hook to guide removal,
*'''needle-cover technique''', in which an 18-gauge hypodermic needle is used to cover the barb of the fishhook.
*'''retrograde technique''', in which the fishhook is simply backed out in-plane to its angle of entry
[[file: Fishhook_removal.png|400px]]

===Resources/References===
*Gammons et al. [https://www.aafp.org/afp/2001/0601/p2231.html Fishhook Removal]. Am Fam Physician. 2001 Jun 1;63(11):2231-2237

[[Common ED Procedures]]

Digital Block

2020-10-09T17:20:34Z

TravisN:

[[file:Digital_Block.jpg|right|400px]]
Digital block is a safe and effective form of regional anesthesia. It is indicated for analgesia of laceration, fracture, infection or nail injury.

Complications include damage to digital vasculature or nerves.

The digital nerves run in the four corners of the finger. There are two methods of digital block:
#insert needle at 12 o’clock position and angle towards digital nerves, then at 6 o’clock and angle towards inferior digital nerves
#insert needle directly superior to lateral nerves and inject both nerves then repeat on medial nerves.

Neither method is superior, though the first method has less theoretical risk of vascular damage. Traditionally anasthetic preparations with epinephrine were avoided due to risk of digital ischemia. A recent literature review of 2800 cases of digital block concluded that epinephrine is safe to use in digital blocks as epinephrine-induced vasoconstriction rarely occurred, and was transient if present.

===Resources/References===
*Latham, J. and Martin, S. [https://www.aafp.org/afp/2014/0615/p956.html Infiltrative Anesthesia in Office Practice]. Am Fam Physician. 2014 Jun 15;89(12):956-962.

Ilicki J. Safety of Epinephrine in Digital Nerve Blocks: A Literature Review. J Emerg Med. 2015 Nov;49(5):799-809. doi: 10.1016/j.jemermed.2015.05.038. Epub 2015 Aug 4. PMID: 26254284.

[[Common ED Procedures]]

Category:Medevacs and Transport

2020-10-09T17:13:27Z

TravisN: /* Activate the Medevac */

'''OVERVIEW'''

Weather, patient acuity, commercial plane availability and limited medevac resources can make routine, urgent and emergency medical transportation a tremendous challenge on a daily basis. Health aides and more experienced providers can give you ideas on how to get non-emergency patients into Bethel based on weather, plane schedules and sometimes alternative travel options. YKHC also operates LifeMed, a medevac company that provides services statewide. There is a dedicated Bethel-based crew for local Medevacs and Anchorage/Fairbanks based crews for transporting patients to Anchorage 24/7. Emergency Medevacs require careful coordination and collaboration with LifeMed dispatch, activating physicians and ER physicians. Emergency medevacs are a limited resource and patient acuities in the hospital units and in the villages need to be considered, weighed and prioritized on an ongoing basis.

YKHC owns a medevac service called LifeMed. This is the service that is used for both village to Bethel medevacs and Bethel to Anchorage medevacs. You have to activate the medevac for all patients traveling to Anchorage via LifeMed because ANMC has a different contract for all other sites in Alaska (Guardian.) It is very important that you document very well about why you chose to “roll over” the medevac to Guardian if Lifemed is not available.

'''''Always Consult an experienced provider before you make the decision to transfer or medevac a patient until you become familiar with our system. Generally it requires about 6 months of getting advice before medevacs, unless the medevac is obvious (GSW, trauma, sepsis, respiratory failure, etc.)'''''

==Medevac Activation Process==
* [[media:Medevac_Bethel_to_Anchorage.pdf|Medevac Activation Bethel to Anchorage YKHC Clinical Guideline]]
* [[Media:Medevac_village_to_Bethel.pdf|Medevac Activation Village to Bethel YKHC Clinical Guideline]]

Activate Medevacs as soon as possible to avoid delays in patient’s getting to the higher level of care they need. If you are too busy to activate…get someone else to do it for you.

===Obtain an Accepting Physician===
*When activating from the village, the accepting physician is usually the Emergency Department Physician (E1/E2)
*For Native (beneficiary) patient’s you must obtain an ANMC accepting physician—even if the patient is going to another facility (during the weekday this is via the ANMC transfer center (*97 or page Transfer Center Coordinator) and on evenings / weekends contact your accepting provider directly and they can contact the house supervisor).
*For non-native patients you must obtain an accepting physician from a Providence or Alaska Regional ER physician or an on-call specialist.
* Communicate clearly with the receiving physician the reason for transfer ie deterioration of clinical status, potential surgical intervention, need for diagnostic and specialty care not available in Bethel or need for a higher level of care that is not available in Bethel (this may be nursing).
* Let the accepting physician know you are calling to transfer the patient to their facility (You are not calling to ask for advice on managing them in Bethel).

NOTE: If you think the patient needs to be transferred to a higher level of care, the on call specialist should not refuse the transfer. If there is any issue with obtaining an accepting physician, page the Clinical Director (CD) on call for assistance.

===Complete a [[media:ptos.pdf|Patient Transport Form (PTO)]]===
*Once you have an accepting provider / facility, complete a [https://intranet.ykhc.org/mdocs-posts/patient-transport-order-memorandum-of-transfer/ PTO] and [https://intranet.ykhc.org/mdocs-posts/consent-to-transfer-transfer-recommended/ consent the patient for travel]. Both of these forms are available on the intranet document library.
*Send a copy of the completed PTO to the ER (this can be done by walking it over, sending it through the tube system, or scan emailing it to the charge nurse) with pertinent patient information
*'''''It is important to notify the Emergency Department Physician (E1/E2) about ALL medevacs (Village to Bethel and Bethel to Anchorage) as they help to coordinate all medevac flights.'''''

===Activate the Medevac===
*Call Lifemed (*96) and press 1 to get to dispatch. Dispatch will require the following information:
**patient name, date of birth and weight in kilograms
**patient diagnosis / reason for transfer
**your name and facility (transferring facility)
**patient location (ER, outpatient clinic, Northwing)
**accepting provider and facility (receiving facility)
**whether the patient has any special equipment (intubated, NIPPV, pressors)
**location in receiving facility to deliver patient (e.g. ER, L&D, ICU, etc.)
**escort information (name and weight in kilos) if applicable

This sounds like a lot of information but it goes quick e.g. “Hello, this is (activating provider), I am calling from the Bethel (ER/ Northwing/ L&D). I am transferring John Doe, date of birth 00/00/00 to Anchorage for (diagnosis). His weight is (kg). He (does / does) not have an escort. He (does / does not) have any special equipment. He will be going to (recieving hospital and unit), care of (accepting provider).”

You will then send the PTO form to Lifemed dispatch. Lifemed dispatch will relay this information to their flight crew who will check on weather. You may or may not receive a call from the flight crew— if it is fairly straightforward (e.g. stable hip fracture), the flight crew may just contact you to report their ETA and not require further patient information. If the patient is complicated you may be directing flight crew with management advice. Once Lifemed lands and leaves YKHC with the patient, update the accepting provider with an ETA as a courtesy, though this is not required.

===Provider===
'''Village to Bethel Medevacs'''
* sign out to ER doc
* ER doc will place the medevac on the ER white board
* ER doc will assume medical control except for OB patients and for some pediatric patients where the pediatrician keeps medical control until the patient arrives in the ER OR the patient has been stabilized and is turned back over to the ER physician for medical control

'''Bethel to Anchorage Medevacs''' (stable outpatient/inpatient/OB/ER patients)
* Talk to med control doctor
* Write a detailed transfer note
* Make sure patient records and health summary are copied and that x-rays are teleraded to ANMC (unless going to another facility) and a disk is made to go with the patient
* Stay in touch with the medical control physician if needed. Update them on the condition of the patient prior to LifeMed team assuming care if patient’s status has changed.

===RN===
Once the patient leaves YKHC, the RN taking care of the patient is responsible for calling report to the accepting unit.

===Tech===
The tech is responsible for putting together a transfer packet. This packet can be found on all inpatient units and in the ER. The things that need to go in the packet are conveniently listed on the outside of the packet. All of these items are related to current visit only! They don’t need to see the last 5 years of labs. The things that need to go in the packet are:
*provider notes
*nursing notes
*CHAP notes
*lab results
*vital signs
*imaging results ; both printout of radiologist read and CD of images made by radiology tech
*EKGs (copies, not originals)
*3 copies of the PTO form
*3 copies of patient demographic information
This packet is given to Lifemed on arrival to YKHC.

==Village to Bethel Medevacs==
[[Media:Medevac_village_to_Bethel.pdf|Medevac Activation Village to Bethel Guideline]]

If LifeMed is unable to complete a medevac, the RCC can help find a military medevac aircraft ([[media:Activating_emergency_military_transport.pdf|Activating Emergency Military Transport]]). If the Bethel Based Army National Guard is available, the Bethel Lifemed Med Crew may fly with them on their aircraft to complete the medevac. If the Bethel Guard Helicopter is not available, RCC will dispatch an aircraft from somewhere else in the state, usually from the 210 or 211 Rescue Squadron based in Anchorage. LifeMed Dispatch will take care of all of those transportation arrangements for you.

NOTE: If Lifemed cannot travel due to weather then Lifemed and YK staff cannot travel with the National Guard. If a patient needs surgical intervention or care that cannot be provided in the village ie compartment syndrome or fracture related vascular compromise, then the risks and benefits must be carefully weighed, CD on call should be consulted and there must be good documentation about the decision

An OB patient in a village will require a medevac to Bethel if she is in labor that can not be stopped and if the gestational age is <34 weeks (or unknown), there is a high-risk pregnancy, or there are concerning maternal/fetal signs. A family practitioner and a pediatrician will accompany the LifeMed team if there is a considered risk of the patient delivering in the village or on the plane. The LifeMed team has a full premature/full term delivery kit and a baby warmer for resuscitation and transportation. The family medicine physician must pick up the OB delivery kit and supplies from OB before leaving the hospital. For more details see [[Village Delivery Orientation|pediatric and family medicine village delivery protocols]] and [[preterm delivery RMT]]
Note: OB medical control remains with the family medicine physician on the flight or the FP that activates the medevac.

Sick and preterm newborns that deliver in the village and require transfer to ANMC or Providence will benefit from early activation of an Anchorage based PNP/neonatal team to pick up the baby in the village (this occasionally can be arranged) or to meet the team in Bethel to assume care in our nursery or for a ramp transfer if appropriate.

==Bethel to Anchorage Medevacs==
[[media:Medevac_Bethel_to_Anchorage.pdf|Medevac Activation Bethel to Anchorage Guideline]]

Anchorage and Fairbanks Medevac teams are comprised of two paramedics on a Lear jet. Thismight be a paramedic and a nurse pair. It takes 1.5 to 3 hours (or longer due to weather or resource availability) to get a plane to Bethel so activate as soon as you know you need to medevac a patient.

If LifeMed is not able to dispatch a LifeMed crew in a timely fashion, they will make arrangements to send another medevac company’s team out to pick up a patient if appropriate.

OB medevacs to Anchorage are possible when a patient is not in active labor and the benefit of a transport outweighs the risk of a possible delivery en route. YKHC does not have a nursery, therefore all high risk OB patients and possible preterm deliveries would benefit from being delivered at a higher level of care for both mother and baby. The FP and the pediatrician can consult with the high risk OB doctor on call, accepting OB physician and the peri-natologist if needed in extremely difficult cases.

Newborn medevacs from YKHC to ANMC or Providence may be done by regular medevac if the baby is very stable and is not expected to require resuscitation, intubation or any specialty care. For babies that are unstable in any way, a NICU PNP with accompany the medevac team to Bethel

'''ANMC to Bethel Inpatient Unit and Bethel Inpatient Unit to village Medevacs.''' These are unusual occurrences and they must be evaluated and approved on a case-by-case basis. Occasionally ANMC will request a patient return to YKHC inpatient unit to finish up a prolonged course of treatment or an end-of-life YKHC inpatient may want to return to a village and is not able to travel commercially. If this request is made by ANMC or a YKHC inpatient physician, the medevac request will have to be reviewed and pre-approved by YKHC and LifeMed administrators. These medevacs do not require emergency care and are not eligible for reimbursement.

'''Lifemed Detailed Information for medevac roadblocks and alternative options:'''
Lifemed Dispatch, the crew and experienced providers may work together to get patients directly from a village or Subregional Clinic (SRC) to Anchorage without coming to the Bethel ER. In some cases the Bethel-based team will fly to the village and care for the patient until an Anchorage team gets to the village OR a ramp transfer may be arranged at a SRC or Bethel airport. Below are some options and limitations…

*'''Runway Lights''': Most of the villages in the YK Delta have runway lights, which are pilot-controlled. Kwigillingok and Newtok do not have pilot-controlled runway lights, however they do have portable runway lights that are FAA approved for fixed wing aircraft. Legally, we are no longer allowed to land our aircraft in the dark at an airport that does not have FAA approved runway lights. Crooked Creek, Lime Village, Red Devil and Stony River do not have any form of FAA approved runway lights, so we can land our aircraft there only during daylight hours.

*'''Rescue Coordination Center''': If LifeMed is unable to complete a medevac the RCC can help find a military medevac aircraft. If the Bethel Based Army National Guard is available, the Bethel Lifemed Med Crew may fly with them on their aircraft to complete the medevac. NOTE: If the National Guard helicopter is activated due to poor weather conditions, Lifemed crew, health aides and providers are not allowed to fly with the patient. In cases such as this, it is best to keep the patient in the village If the Bethel Guard Helicopter is not available, RCC will dispatch an aircraft from somewhere else in the state, usually from the 210 or 211 Rescue Squadron based in Anchorage. LifeMed Dispatch can take care of all of those transportation arrangements for you.

*'''Helicopter Destinations:''' When a military helicopter transports the patient to Anchorage, they can land only at Providence, Alaska Regional, Elmendorf AFB, and Mat-Su Regional Medical Center. ANMC does not have a helipad, therefore a helicopter cannot land on the ANMC campus. It is an EMTALA violation to have the patient transported directly from the helicopter to ANMC via ground transportation without the receiving hospital doing an initial evaluation of the patient. Therefore, if a patient is sent from the YK Delta to Anchorage on a helicopter, the patient must be seen initially by the hospital the helicopter landed at. Arrangements can then be made between the receiving hospital and ANMC to have the patient transferred to ANMC via ground transportation.

*'''LifeMed Pilots''': LifeMed Pilots make the decision to fly based solely on aviation, weather and runway condition factors. They are not provided any information about the patients in order to prevent them from feeling any pressure to fly based on a patient’s condition. They know only the pick-up point, weight and destination of the patient. The dispatchers will not allow you to speak with a pilot regarding the medevac. If you want to know the reason for a pilot’s decision (i.e. weather, runway condition, etc.), the dispatcher can provide you with that information.

*'''Medical Crews on Standby:''' There are times when either the Bethel-based Caravan crew or the requesting physician place the Anchorage-based Lear Jet on standby. This moves the pilots and medical crew to the hangar to prepare at that time. The pilot can check weather and determine how much fuel will be needed and the medical crew can assemble any additional medical supplies they will need for that medevac. The crew will then be standing by awaiting the call to launch or cancel. Putting the crew on standby will decrease response time by 40-60 minutes because the crew has the aircraft ready to go. Putting the Lear Jet crew on standby allows more patients to be ramp transferred and transported directly to Anchorage without having to be seen at YKHC.

*'''Contacting Medical Crews Directly''': Please contact the medical crews thru Dispatch. They know where the crews are in their sleep cycle and whether they are on crew rest. For non-urgent communications, you can contact the crews on the Base Quarter’s phone at 543-5036. The crews turn the ringer off when they are on crew rest.

==Medevacs for the ER Provider==
#The ED doc is the med control for all medevacs that arrive in Bethel from the surrounding villages. This is often 2-3 per day.
#The exception to this is our OB medevacs when we send a Family Med doc and a pediatrician along. Med control is then with the doc on the plane.
#The ED doc should also know about every single medevac that is going out of Bethel to Anchorage, regardless of the location of the patient. For example, if OB is medevacing an OB patient, the ED doc needs to know about the medevac and at least a cursory clinical knowledge of the patient. This is for purposes of triage. If a sicker patient comes into the ED, the plane may need to be diverted to get the sicker patient.
#Once the inpatient doc tells you about the patient being medevac’s in from the village, you assume medical control. This means that you talk to the Health Aide when he/she calls and you document in the record any interventions and changes in condition. You can either start your own note or add to the RMT note already started by the CHA and the inpatient doc. Just right click and modify the document.
#All weather delays must be clearly documented in the patient’s chart, as well as all other delays. For example if another medevac is already underway in another village, this should be noted in the chart (not the details obviously, just that the medevac team and plane are in another village and unavailable.)
#Our hard-working medics will occasionally time out because of too many hours of continuously flying. They will then go on “red” status meaning they can’t fly for at least 8 hours. If they are on “yellow” status, it generally means that whatever flight you send them on is the last flight before they go on “red.” When this happens, sometimes LifeMed can put another plane and team in Bethel to perform the village flights and sometimes the plane from Anchorage can go directly to the village to pick up the patients. Creative problem solving is key in these situations. Clear documentation in the chart as to what is going on is key in these situations as well.
#In general, do not activate a medevac for CPR in progress in a village. The CHAs can only do BLS and return of spontaneous circulation is rare. The exception to this is cold water drowning in a child with high-quality CPR on-going since they were taken out of the water. It may be appropriate to send the plane out in these situations. Consult with peds in these cases.
#If you transfer a meningitis patient to ANMC, send an extra tube of CSF with the patient to ANMC for faster turnaround on identification of the causative agent.

==Pediatrician Medevacs==
The only medevacs the pediatricians go out on are for high risk or premie (less than 36 week) village deliveries. There is limited space on these medevacs so only one pediatrican can go out at a time. This makes it difficult to orient new staff for this part of your job. It is important to review the links below and talk with other pediatricians about their experiences on medevacs. Your assigned back up pediatrician during orientation (or any pediatrician at any time will be happy to help you) can talk to you before you go out and after you get to the village to help coach and help you.

Medevacs are one of the scariest things we do. We don’t do them often; we can’t have another pediatrician by our side and there are limited resources in the village. BUT the medevac crews are great. We have phone and video conferencing capability and even new pediatricians will be surprised at how well they can do with good preparation ☺

You need to review the following information before going on your first medevac. It would be good to have a copy of these handouts available to review or print when you go out on your first medevac.

===Resources===
*[[Village Delivery Orientation|Pediatric Village Delivery Orientation]]
*[[Premie Warm Welcome Protocol]]
*[[Curosurf Administration]]
*[[media:Village OB Patient in Possible Labor.pdf|Village OB Patient in Possible Labor]] (FM reference, but good for the pediatricians to review)

NOTE: Pediatricians '''do not''' go on any Anchorage medevacs. Our medevac crews are good and can handle very sick pediatric patients and infants.

[[:category:Pediatrics]]

==Transportation/Transports==
Stable patients, that do not require a medevac, can usually be transferred from villages, outpatient clinics, ER, the inpatient unit and the OB/Newborn unit to a higher level of care via commercial flights. These transfers are often needed to obtain diagnostic evaluations not available in a village, SRC or Bethel and to be closer to surgical and intensive care resources if needed.

'''Commercial Flights From Village to Bethel:''' Patients can be sent to Bethel via regular commercial flights. These flights are expensive. Only patients who are covered by Medicaid or Denali Kid Care have their travel, meals and housing covered. Some patients have medical insurance, but often they have to get reimbursed for travel and there is no coverage for meals and housing. The CHAs and village clinic office staff complete patient travel from village to Bethel. Remember to have CHAs remind patients to bring money, extra cloths, diapers, medications, neb machines, ID etc. in case they have a prolonged stay in Bethel.

If a patient is sick but stable, they must pay their own way in or be managed in the village. If a patient is sick and you feel the patient needs to get to Bethel, the administrator on call may be paged to authorize one-way travel to Bethel. If admin approves travel, the patient will need money for food, cabs and the hostel (or have a place to stay).

If urgent or emergency travel is required (and the patient is stable enough for a commercial flight), the inpatient or ER physician may approve one way travel to the ER without paging the administrator on call.

'''Commercial Flights From ER/Inpatient to Anchorage:''' Patients may need to take a commercial flight from Bethel to Anchorage after being discharged from the ER, OB or the inpatient unit. The patient may be going to a specialist f/u appt. the next day, to ANMC ER for re-admission or for further evaluation or the patient might be a direct admission to the pediatric unit, etc. These patients have been discharged from our facility, but YKHC has assisted in the patient’s travel and there is an accepting physician at the next facility expecting the patient with an agreed upon plan of care.

For patients traveling commercially to Anchorage without Medicaid, the travel payment and authorization protocol is the same as it is for the village patients. YKHC travel makes the travel arrangements. Patients will still need funds for cabs plus food and lodging if they are not admitted. Sometimes ANMC can assist the patient with housing on campus once they arrive.

'''Behavioral Health''': The Behavioral Health department and clinicians will arrange for patients who are medically stable to travel from village to Bethel and from Bethel to Anchorage. BH inpatients that require psychiatric hospitalization will be transferred with a BH escort, via a commercial flight, to Alaska Psychiatric Institute (API) after they are medically cleared.

'''Creative Alternative Transports:''' When weather is down or there are no flights available, a stable patient might come in to Bethel or an SRC by boat, snow machine, snowmobile, river cab or private vehicle on the ice highway. In extreme situations, a CHA may accompany a very sick patient to another close-by village for more help/supplies/medevac access OR bring them to Bethel if able. Having a CHA leave the village to accompany a patient requires approval of the Community Health Aide Administrator on call (a CHA must not leave the village without appropriate health aide coverage)

'''Urgent Charters:'''
Urgent Charters should only be considered when a patient is stable, there are no commercial flights available, transport is urgent and there are no reasonable options for transporting a patient into an SRC, Bethel or Anchorage. This is an option when the patient needs to be evaluated by a higher level of care within 12-24 hours but there are no other options.

'''Process for obtaining an urgent charter'''
# Contact the Administrator On Call for payment approval.
# Let CHA know a charter has been admin approved
# CHA will work with Medicaid/patient travel to arrange the charter using Medicaid or [[YK pay]]
# Ask CHA to let you know if and when the charter has been arranged and approximate time of arrival at destination
# Make sure patient is stable before getting on charter
# Make sure the patient is expected at destination and there is good documentation of why the patient is being transported.
# Ask CHA to notify the provider if the patient is not able to get a charter, the charter is held up by weather, the patient does not make to charter or if the patient gets worse before getting on charter.

Urgent charters can only be arranged on weekdays and weekends, but not holidays or after hours. Usually they are arranged from village to Bethel or SRC, but occasionally they can be arranged from Bethel or SRC to Anchorage.

==Medevac Ride Along/Observers==
Ride-a-longs are scheduled on a first-come first-serve basis. A [https://www.lifemedalaska.com/copy-of-ride-along-program Medevac Ride-along Release Form] must be filled out prior to a medevac.

Fill out the form online and someone from Lifemed will contact you within 2 weeks.

The medevac team will call you when they get a call and you have 15-20 minutes to make it to the hangar. You must be ready to get in a cab and go the first time to the hangar without going home for rain gear or other gear. After you know where it is, you can drive out there and leave your truck there during the medevac. They will not wait if you are not there when they are ready for takeoff since by definition, the patient waiting is in an emergency situation.

If you are in the ED this process is much easier and you may get a ride from one of the techs.

The most important tip is to come prepared. You may be riding in a boat, snow machine or ATV from the village airport to the clinic. You may also have to spend lots of time outside and so if it is cold, bring the gear. A headlamp is helpful.

Category:Emergency Room

2019-09-23T00:00:24Z

TravisN:

==Overview==
This department is open 24 hours a day/7 days a week and is responsible for the management of all emergent and urgent patients in our region. The primary ER doc serves as medical control for all medevacs in and out of our region. The Emergency Department is designated a Level IV Trauma Center.

===Unit Description (facility)===
The Emergency Department contains 9 beds and 2 trauma bays. We have approximately 25,000 patient encounters per year, about 50 percent of them are for pediatric patients. The coverage of the ED is physicians 8 a.m.– 8 p.m. and 8 p.m.– 8 a.m., a second physician 10 a.m.– 10 p.m. (sometimes this physician is a pediatrician), a PA/NP from noon to midnight and a Fast Track NP/PA from 1 p.m.–11 p.m..

===Job Description/Duties===
*[[Emergency Room Job Description|Emergency Room Providers]]
*[[Pediatric Hospitalist Job Description|Pediatric Provider]]

===ER Documentation===
All patient encounters must be documented in RAVEN, our electronic medical record. There are standard pre-completed notes to choose from and modify for your own use.

'''All notes should include the following elements:'''
#Chief complaint – can be pulled in from the nursing chief complaint
#HPI- this should be free-texted in narrative format
#Review of Systems – can be from pre-completed notes, auto-text or macros
#Past Medical History – can be pulled in from the record
#Past Surgical History – can be pulled in from the record, if completed
#Social History – use the SH smart template for this by entering ..ykSocialHistoryMostRecent
#Allergies – can pull in from record
#Medication list – make sure the list is accurate if you are pulling in from record, may need to compete the meds rec first.
#Physical Exam – including pertinent vital signs
#Summary of diagnostic studies (lab, imaging, EKGs, etc)
#Description of any procedures – can use precompleted templates in RAVEN or free-text
#Emergency Department course/Medical Decision Making – make sure this includes differential diagnosis if appropriate.
#Impression and Plan – this should be free-texted
#Follow up – include from your depart summary

'''To discharge a patie'''nt:
#Click on the Depart button in the grey section at the top of the screen
#Complete the top 5 sections
#*Diagnosis
#*Patient Education/Follow up
#*Prescriptions (if any)
#*Medication Reconciliation – this MUST be completed on every patient
#*Charges
#Under “Charges” click on discharge order
#Remember to complete E&M charges at this time.

==[[Common ER Encounters]]==

==[[Common ED Procedures]]==

==[[Special ED Situations/Protocols]]==

==[[Emergency Guidelines/Protocols]]==

==Admissions to Inpatient Unit==
*We have 24-hour inpatient Family Medicine hospitalists who will admit all patients who require admission to the inpatient unit. They write the admission orders.
*When you determine that a patient would benefit from inpatient admission, have the med tech page the on-call inpatient provider for the appropriate village. Once the decision has been made for admission the inpatient provider assumes the responsibility of disposition; if they feel on reviewing the case that the patient is not ill enough to warrant admission they are responsible for discharging the patient from the emergency room.

==[[:Category:Consults|Consults]]==

==Transfers==
#Call ANMC when you need to transfer a patient and ask for the appropriate service to consult for the transfer. For example, the surgeons take all trauma patients, the intensivists take all intubated patients, etc.
#All patients who require medevac to ANMC go by LifeMed, the air ambulance service that is 50% owned by YKHC and 50% by Providence Hospital in Anchorage. You have to activate this service as soon as you have an accepting doc at ANMC. ANMC uses Guardian for their air ambulance service, but you must use LifeMed, unless the LifeMed service is busy and you believe that delaying the transport until a LifeMed flight is available would be unsafe for the patient.
#You must complete a paper consent for transfer, signed by you and the patient.
#You must complete a paper PTO – Patient Transfer Order.
#You must complete your transfer note – usually right before the team gets there so that the med tech can print out the chart to send along with the patient.
#If the patient’s condition changes, call and update the accepting doc, for example if you have to intubate the patient, let them know because this affects where the patient can go.
#For patients who are traveling via commercial flight to Anchorage, the ER doc can authorize this travel if the patient does not have Medicaid or a means to pay for travel. [[Media:YK pay.pdf|See Preauthorized Travel]]

==Referrals==
#Occasionally you will need to place a referral on a patient that you see in the ED. For example, a non-emergency hernia repair will need an order placed in the chart for the referral to surg.
#Type in the search order window the word “refer” and hit enter or the binoculars. The list of services that you can refer to come up and you will need to choose the correct service and complete the order (yellow parts are required.)
#Once you sign the order, it goes to a queue for the case managers to review and forward the appropriate documentation.

==ED follow up appointments==
#The ED is allotted a certain number of appointments for patients who need follow up in the ambulatory clinic the next day.
#To obtain one of these appointments, our current work flow is to ask the med tech to make the actual appointment for the patient in the computer. The patient is then given a letter with the appointment time on it. You also need to indicate this in your discharge paperwork under the follow up tab.

==Medevacs==
[[:Category:Medevacs and Transport|See Medevacs and Transport]]

#YKHC owns a medevac service called LifeMed. This is the service that is used for both village to Bethel medevacs and Bethel to Anchorage medevacs. You have to activate the medevac for all patients traveling to Anchorage via LifeMed because ANMC has a different contract for all other sites in Alaska (Guardian.) It is very important that you document very well about why you chose to “roll over” the medevac to Guardian.
#The ED doc is the med control for all medevacs that arrive in Bethel from the surrounding villages. This is often 2-3 per day.
#The exception to this is our OB medevacs when we send a Family Med doc and a pediatrician along. Med control is then with the doc on the plane.
#The ED doc should also know about every single medevac that is going out of Bethel to Anchorage, regardless of the location of the patient. For example, if OB is medevacing an OB patient, the ED doc needs to know about the medevac and at least a cursory clinical knowledge of the patient. This is for purposes of triage. If a sicker patient comes into the ED, the plane may need to be diverted to get the sicker patient.
#Once the inpatient doc tells you about the patient being medevac’s in from the village, you assume medical control. This means that you talk to the Health Aide when he/she calls and you document in the record any interventions and changes in condition. You can either start your own note or add to the RMT note already started by the CHA and the inpatient doc. Just right click and modify the document.
#All weather delays must be clearly documented in the patient’s chart, as well as all other delays. For example if another medevac is already underway in another village, this should be noted in the chart (not the details obviously, just that the medevac team and plane are in another village and unavailable.)
#Our hard-working medics will occasionally time out because of too many hours of continuously flying. They will then go on “red” status meaning they can’t fly for at least 8 hours. If they are on “yellow” status, it generally means that whatever flight you send them on is the last flight before they go on “red.” When this happens, sometimes LifeMed can put another plane and team in Bethel to perform the village flights and sometimes the plane from Anchorage can go directly to the village to pick up the patients. Creative problem solving is key in these situations. Clear documentation in the chart as to what is going on is key in these situations as well.
#In general, do not activate a medevac for CPR in progress in a village. The CHAs can only do BLS and return of spontaneous circulation is rare. The exception to this is cold water drowning in a child with high-quality CPR on-going since they were taken out of the water. It may be appropriate to send the plane out in these situations. Consult with peds in these cases.
#If you transfer a meningitis patient to ANMC, send an extra tube of CSF with the patient to ANMC for faster turnaround on identification of the causative agent.

==RMT (Radio Medical Traffic)==
#There are 2 types of RMT: emergency/urgent and routine.
#Emergency/Urgent are cases where the CHA sends in an RMT document to the message center proxy called NW emergency/urgent RMT. The CHA then calls the on-call inpatient doc for that village and they talk about the patient and what to do for the patient. These calls can sometimes end up in a medevac, sometimes the patient is sent to the ED via commercial flight and sometimes the patient is treated and sent home.
#Routine RMT is handled by ambulatory providers and the CHA sends in a document and the provider responds is electronically.
#Sometimes the CHA will call the ED and ask to talk to the ED doc, usually because they are doing CPR on a patient and haven’t had time to start any documentation. See above about activating medevac for CPR in progress (generally don’t.) You will be expected to talk the CHA through the case. These are highly stressful situations for the CHA – remember this is certainly someone they know and often a relative. There is often chaos in the background and it can be hard to hear the CHA or determine what is going on. Please be very patient at these times. The CHA will want you to make the determination when to stop resuscitative efforts. Generally speaking, we don’t have them do CPR for more than an hour. So at about the 45 minute mark, ask them to start thinking about stopping CPR. Sometimes they don’t want to and we let them keep doing CPR longer. This is especially true if it is a baby or a child. If it is a child, get the pediatrician on the phone if you think that will help. Link to [[:category:Radio Medical Traffic (RMT)#Emergency RMT|code resuscitation section of Emergency RMT]].
#If you get other calls from CHAs regarding other emergencies (strokes, seizures, village deliveries, etc) re-direct CHAs to the NW doc on call for that village. Peds on call can also be contacted for any pediatric patient.

==Ancillary Services==
#'''Lab''': YKHC has a lab staffed 24/7 by lab techs. At night there is a single tech on. If you need blood products or have a massive transfusion at night, they will need to call in help. Have the charge nurse let them know to do that as soon as you know you will need lots of blood or blood products.
#'''Radiology''': YKHC has 24/7 in house radiology services with the exception of ultrasound which is available only Mon-Friday 9-5.
#'''Pharmacy''': YKHC has 24 hour pharmacy available, usually in house but sometimes on call from home. They come to all critically ill patient bedsides and help with meds. We have wonderful, highly competent clinical pharmacists who will answer your questions and help you make good choices about meds. Use them and listen to them.
#'''Respiratory Therapy''': YKHC has in house RT from 7a-7p and on call from 7p-7a. They come in for all intubated patients who need to be placed on a ventilator.
#'''Physical Therapy''': YKHC has several PTs. If you want a patient to have a PT appointment, make a referral within RAVEN. During the day, feel free to call them. They also provide our wound care services and can be enlisted to help with complicated wound care. They are not on call and not available on the weekends. If you need splints like wrist or ankle splints, or crutches, the ER charge nurse has a key to their supply room.
#'''Diabetes''': YKHC has a robust and well-staffed diabetes team. They educated and manage all of our diabetics. They can be reached during the day by calling their number or having them paged. The med techs know the number.
#'''Tobacco Cessation''': YKHC has a very strong tobacco cessation department as well. You can provide the patient with the number to call if they are ready to quit.
#'''Dietary''': YKHC ED has food available around the clock for patients, the kitchen can bring trays during the day or sandwiches and crackers available at night.
#'''Community Relations/Translation''': YKHC has 24 hour Yupik language translators available.
#'''Specialty Clinic''': YKHC has multiple visiting specialists from ANMC. The list of when they are coming is published and posted in the ED. If you would like to refer a patient to be seen at one of these clinics, place an order for referral (type in the word refer in the search order window and the list of specialists will pop up.) Choose the one that says “internal” to indicate that the patient can wait until the visiting specialist arrives from Anchorage.

Phenobarbital for Alcohol Withdrawal

2019-09-22T23:52:58Z

TravisN:

[https://en.wikipedia.org/wiki/Phenobarbital Phenobarbital] (PB) is a non-competitive [https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid gamma-Aminobutyric acid] (GABA) agonist which is an equally effective and safe alternative to benzodiazepines (BZD) for the treatment of alcohol withdrawal syndrome (AWS).<ref name="Mo2016">Mo Y, Thomas MC, Karras GE. Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2016;32:101-107. doi:[https://www.doi.org/10.1016/j.jcrc.2015.11.022 10.1016/j.jcrc.2015.11.022]</ref> Though its use for AWS has waned and consequently many clinicians are now unfamiliar with this regimen, PB has both mechanistic and pharmacokinetic properties which make it more suitable for outpatient monotherapy than BZD.
 
IV/IM titrated PB is the first-line outpatient medication used for treatment of AWS at the Yukon-Kuskokwim Delta Regional Hospital (YKDRH). Its use is favored because substantial experience at this institution has shown that it is safe, it is effective, it minimizes return visits, and it eliminates the need to dispense abuse-prone medications (i.e. BZD) to abuse-prone patients while in the midst of a substance abuse crisis. Indeed, minimizing high-risk dispensing of abuse-prone medication is important for improving the health of our community.
 
The treatment of AWS with phenobarbital (or barbiturates [BBT] in general) is not new, but it has fallen so out of favor that many clinicians are unfamiliar with this use. However, there is ample published evidence, both old and new, indicating that phenobarbital is ''at least'' equally safe and effective compared with benzodiazepines.
 
 
__TOC__ 
 
 
== '''Treatment Principles and Pearls''' ==
=== Sub-sedative dosing ===
: Alcohol withdrawal is a ''hyper''-alert and/or ''hyper''-autonomic state. The goal of outpatient treatment of alcohol withdrawal is ''normalization'' of alertness (i.e. level of consciousness) and autonomic function, not sedation. If a sedative level of [any] medication is required for AWS symptom control, then admission is often indicated.
 

=== Dose titration ===
: Patients’ individual medication requirements are unpredictable. Therefore no standard PB dose is expected to be effective for all patients. Rather, an initial IV (or IM) PB dose of 260 mg is given, and then every 30 minutes (or 60 minutes for IM) an additional 130mg are given until the desired effect is achieved. Using this regimen, many patients will require repeat doses, but none should end up “sedated.”
 
: The standard 260mg/130mg regimen works well for average size patients. This regimen yields weight-based doses of 3.7 mg/kg and 1.9 mg/kg in a 70 kg patient. However, for patients substantially below or above 70 kg, clinicians should consider administering 4 mg/kg with subsequent doses of 2 mg/kg. For convenience, these doses can be rounded to the nearest 130 mg increment (i.e. the amount in a single vial). For example, weight-based doing for a 125 kg patient would yield 500 mg and 250 mg doses, and these can be safely rounded to 520mg and 260mg for ease of administration. Weight-based dosing prevents sedating unusually small patients while preventing excessively long visits for unusually large patients. Dosing in whole-vial increments minimizes the risk of dosing errors and eliminates the effort required to precisely dose from a 1mL vial.
 
=== Dosing interval ===
:In pharmacokinetic studies of rapid PB boluses, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982">Paulson OB, Györy A, Hertz MM. Blood-brain barrier transfer and cerebral uptake of antiepileptic drugs. Clin Pharmacol Ther. 1982;32(4):466-477. doi:[https://doi.org/10.1038/clpt.1982.190 10.1038/clpt.1982.190]</ref> Yet clinical judgment must still be used. At 30 minutes after a PB dose, if the patient has “almost” complete symptom relief, the clinician should appreciate the possibility of a small amount of biological variability and consider reevaluating after another 10 minutes, as it is possible that a small additional effect may become apparent. But if the dose is clearly inadequate at 30 minutes, further waiting is very unlikely to reveal any substantial further effect.
 
=== Sleep after symptom control ===
: When patients’ hyper-alert/hyper-autonomic state is normalized, many will lightly nap. But such patients easily awaken to voice or light touch and they easily meet all discharge criteria. Rather than being “sedated,” such patients are merely exhibiting the normal physiologic response in the absence of discomfort to a 24-48 hour sleep deficit (which is the norm for patients in this situation). Any concern for sedation can usually be answered by asking oneself if the patient’s post-treatment behavior would be considered '''ab'''normal for a patient in the ED with a normal mental status, with a substantial sleep deficit, whose discomfort had been relieved. If the answer is “no”, then the patient is not “sedated,” but rather has been returned to a normal level of alertness.
 
=== Post-infusion dizziness/nystagmus/ataxia ===
:Post-infusion dizziness/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.
 
=== Isolated withdrawal hallucinosis ===
: A subset of AWS patients will present as soon as 12 hours after alcohol cessation with classic withdrawal hallucinations but without any signs of hyper-alertness, clouding of consciousness, confusion, or autonomic hyper-stimulation. This is a well documented variant of AWS, and it should be neither under-treated (i.e. dismissed as fake) nor over-treated (i.e. managed as delirium tremens). Hallucinations are one of the many manifestations of AWS, and they can occur in isolation or in combination with other signs. Primary management is a therapeutic level of GABA agonist (i.e. PB or a BZD). The use of anti-psychotic medications is contraversial. If hallucinations are refractory to an appropriate level of GABA agonist then an anti-psychotic medication can be added. However, caution is advised because there have been reports of increased mortality associated with these medications due to arrhythmias (due to QT prolongation) and lowering the seizure threshold. The risk/benefit must be carefully weighted in these situations, especially in the first 48 hours when the seizure risk is highest. Anti-psychotic medications should never be the first-line or sole therapy for hallucinosis or other withdrawal symptoms.<ref>Jesse S, Bråthen G, Ferrara M, et al. Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurol Scand. 2017;135(1):4-16. doi:[https://doi.org/10.1111/ane.12671 10.1111/ane.12671].</ref>
 
 

=== Alcoholic Hallucinosis ===

: Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations without other strong evidence of alcohol withdrawal or alcohol delirium. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

: As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing gaba agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

: A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.

[[media:Barkat_et_al_2017.pdf|Treatment of Alcohol Induced Psychotic Disorder]]

== '''Evidence of Effectiveness and Safety''' ==
=== Systematic Review / Meta-analysis ===
* A 2016 systematic review by '''Mo et al'''. in the ''Journal of Critical Care''<ref name="Mo2016" /> concluded that "''barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS.''" This review included three randomized controlled trials (RCT's) and four observational studies. Importantly, the authors observed that "''none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS.''" While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.<ref name="Hendey2011">Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382-385. doi:[https://doi.org/10.1016/j.ajem.2009.10.010 10.1016/j.ajem.2009.10.010]</ref>) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.
* Other systematic reviews<ref name = "Minozzi2010">Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064. doi:[https://doi.org/10.1002/14651858.CD005064.pub3 10.1002/14651858.CD005064.pub3]</ref><ref>Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537. doi:[https://doi.org/10.1002/14651858.CD008537.pub2 10.1002/14651858.CD008537.pub2]</ref> have only indirectly assessed the effectiveness of PB for AWS. These reviews have grouped all studies which compared any anti-convulsant to a BZD, and then concluded that anti-convulsants (as a group) are inferior to BZDs for treatment of AWS. This grouping of PB with other anti-convulsants badly biases the results against PB and does not seem justified. The mechanism of action of both PB and BZDs is non-competitive agonism of the GABAA ion channel and both of these medication have been long known to display cross-tolerance with each other and alcohol. Conversely, the other anti-convulsants work via different mechanisms. Therefore grouping PB with the other anti-convulsants is inappropriate and seems to merely reflect how the authors think about the drugs rather than their pharmacological properties.

=== Studies of ED/Outpatient Treatment ===
* '''Young et al'''. (1987, prospective uncontrolled study, n=62)<ref name = "Young1987">Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987;16(8):847-850. doi:[https://doi.org/10.1016/s0196-0644(87)80520-6 10.1016/s0196-0644(87)80520-6]</ref> 
::62 patients received IV PB loading dose in the emergency department. The protocol was an initial 260mg which was followed by 130mg increments, but the dosing interval is unclear. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experienced minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention. All patients were discharged from the ED and none returned for further care during the following week.

* '''Hendey et al'''. (2011, RCT of PB vs lorazepam, n=25/19)<ref name="Hendey2011" /> 
::44 ED patients were randomized (25 to IV-PB, 19 to LZ). PB patients received a 230 mg initial dose followed by 130mg subsequent doses (dosing interval was "''at the discretion of the treating physician''"). Mean PB dose was 509 mg (range 260-910 mg); mean number of doses was 2.9 (range 1-6). There were no outcome differences at 48 hours, and importantly, there was no significant difference in length of ED stay (267 min for PB versus 256 min for LZ). Fewer PB patients required admission (12 vs. 16). The authors concluded that "''phenobarbital and LZ were similarly effective in the treatment of mild/moderate alcohol withdrawal in the ED and at 48 hours.''"

* '''Nelson et al'''. (2019, retrospective cohort study)<ref>Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019;37(4):733-736. doi:[https://doi.org/10.1016/j.ajem.2019.01.002 10.1016/j.ajem.2019.01.002]</ref> 
::300 ED patients: 100 received IV-PB alone, 100 received IV-PB + lorazepam, and 100 received diazepam alone. Initial PB dose was 260mg and subsequent doses were 130mg (dosing interval is not specified). Authors' conclusions: "''Incorporating phenobarbital into a benzodiazepine based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department''."

=== Historical Reports ===
:PB has long been used for treatment of delirium tremens (DT). Though it has fallen out of favor in most places, a minority of countries and institutions have continued to use it as first line treatment of AWS.
::* A 2010 study by Michaelsen in the ''Danish Medical Bulletin''<ref>Michaelsen IH, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens--a retrospective study. Dan Med Bull. 2010;57(8):A4169.</ref> states BBTs have been used for treatment of DT in Denmark "for over 100 years."
::* A 2006 RCT of gabapentin for AWS<ref>Mariani JJ, Rosenthal RN, Tross S, Singh P, Anand OP. A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal. Am J Addict. 2006;15(1):76-84. doi:[https://doi.org/10.1080/10550490500419110 10.1080/10550490500419110]</ref> compared it to a control group which received PB. The authors gave the following explanation in the methods section:
::::''Those randomized to the experimental group received a protocol using gabapentin, while those in the control group received a phenobarbital protocol that is customary in our inpatient detoxification service. Phenobarbital was used in this study rather than benzodiazepines because it is the detoxification medication that the clinical staff is most familiar with.''
::* A 1995 United States nationwide survey of inpatient alcohol treatment centers<ref>Saitz R, Friedman LS, Mayo-Smith MF. Alcohol withdrawal: a nationwide survey of inpatient treatment practices. J Gen Intern Med. 1995;10(9):479-487. doi:[https://doi.org/10.1007/bf02602395 10.1007/bf02602395]</ref> reported that approximately 10% primarily used PB for treatment of AWS.

=== EVIDENCE SUMMARY ===
:In landmark studies by Kaim and Klett in 1969<ref>Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969;125(12):1640-1646. doi:[https://doi.org/10.1176/ajp.125.12.1640 10.1176/ajp.125.12.1640]</ref> and 1972,<ref>Kaim SC, Klett CJ. Treatment of delirium tremens. A comparative evaluation of four drugs. Q J Stud Alcohol. 1972;33(4):1065-1072.</ref> both BBTs and BZDs were shown to be equally effective in treatment of AWS. Both of these drug classes had been previously known to exhibit cross dependance with each other as well as alcohol, and the subsequent discovery that these structurally unrelated compounds are both GABA agonists was critical to understanding the pathophysiology of AWS. 
 
:Though BZDs have become the standard of care, this seems mostly attributable to a larger movement away from inpatient treatment and toward outpatient treatment with oral medications. Dispensing BZDs to patients is clearly safer than dispensing PB/BBTs. Yet when the dose is titrated to effect by a physician and patients are not dispensed medication, there is ample evidence that PB is equally safe and effective compared to BZD. 
 
:Numerous articles advise caution with regard to PB by alluding to concerns about respiratory depression, but no evidence of adverse effects is ever presented or cited. Therefore these concerns seem to originate more from the authors' lack of familiarity with the use of IV-PB in this setting than from documented outcomes. However, it must be pointed out that PB should '''''never''''' be dispensed to a patient for symptom-triggered dosing, as this would present an '''extreme risk''' of unintentional lethal overdose. PB use for AWS ''must'' be limited to titrating the dose to the desired effect, and then discharging the patient without additional medication. There have been no reports of iatrogenic overdoses using this protocol, and the drug packaging is a strong mitigating factor to prevent drug errors: At YKDRH, PB is only available in 130mg vials. Therefore the initial dose is two vials and the subsequent doses are one vial. A dangerous overdose (i.e. one yielding respiratory depression) would require accidentally drawing up 20-30 vials, which would be very labor intensive and very likely produce questions prior to administration. ''(PB is also marketed in 65mg vials, but that would require even more vials to produce an overdose.)''
 
 

== '''Regulatory Information and Packaging''' ==
*PB is not approved by the U.S. FDA; this is likely due its use preceding the creation of the FDA (in 1938).
*DEA Schedule: IV
*Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert">Phenobarbital sodium [[https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 package insert]]. Eatontown, NJ: West-Ward Pharmaceuticals Corporation; 2018.</ref>.
*How Supplied:
:::Phenobarbital Sodium Injection, 65 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0476-25) 
:::Phenobarbital Sodium Injection, 130 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0477-25) 
 
 

== '''Pharmacology''' ==
 
The following are some of the important properties of PB with regard to outpatient treatment of AWS. 
 
=== Classification ===
:; Chemical Class
::PB belongs to the chemical class ''barbiturate''.
:; Clinical Class
:# Like all barbiturates, PB is a ''sedative/hypnotic''.<ref name = "Harvey1979">Harvey SC. Hypnotics and Sedatives: The Barbiturates. In: Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 5th ed. New York: MacMillan Publishing Co., Inc.; 1975:124-136.</ref> However, it is almost never used for this purpose.
:# PB is also classified as an ''anti-convulsant''. 
::::::''In anesthetic doses, all BBTs have an anti-convulsant effect. However, PB is the only BBT which has an anti-convulsant effect at sub-sedative doses. (Historically, two closely related derivatives [mephobarbital and metharbital] also had an anti-convulsant effect at sub-sedative doses).''<ref name="Harvey1979" />
 

=== Mechanism of Action ===
:; GABA agonist
::The binding of GABA to its receptor inhibits nerve depolarization. Like all barbiturates, PB's sedative/hypnotic effect occurs primarily via noncompetitive agonism of the GABAA receptor on the GABA-mediated ion channel. Like BZDs, PB/BBTs do not themselves open the channel and thus GABA is still required. PB/BBTs bind at a different site on the GABAA receptor than BZDs.<ref name = "Hobbs1996">Hobbs WR, Rall TW, Verdoorn TA. Ch 17: Hypnotics and Sedatives; Ethanol. In: Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:361-398.</ref> 
::When PB/BBTs bind to the GABAA receptor, three effects occur: 
::::::# Enhancement of the binding of GABA<ref name="Hobbs1996" /> 
::::::# Enhancement of the binding of BZDs<ref name="Hobbs1996" /> 
::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /> 
::Both 2 and 3 indicate a potential synergistic effect when co-administered with BZDs. Studies have shown that dual therapy is superior to either PB or BZDs alone,(insert refs) indicating at least an additive effect.
:; Glutamate antagonist
::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>
 
 

=== Distribution ===

:Volume of distribution is X(ref).

:Plasma protein binding has been estimated as X percent, predominantly to albumin.(ref)
 
==== Venous concentration versus infused dose ====
{| class="wikitable" style="float:right;font-size: 85%; border: 1px solid black;"
|+ style="caption-side:top; text-align:center;" |Table-1. PB dose, concentration, and ratio for [nonexclusive] subgroups reported in Young (1987).<ref name = "Young1987" />
|-
! scope="col"| Group
! scope="col"| PB Dose (mg/kg)
! scope="col" style="width: 50px;"| Serum Concentration (μ/mL)
! scope="col" style="width: 70px;"| Conc : Dose Ratio
|-
| scope="row"| Tremulous (n=48)
| style="text-align:center;" | 8.5
| style="text-align:center;" | 14.0
| style="text-align:center;" | 1.65
|-
| scope="row"| Seizures (n=38)
| style="text-align:center;" | 8.3
| style="text-align:center;" | 13.8
| style="text-align:center;" | 1.66
|-
| scope="row"| Alcoholic liver disease (n=21)
| style="text-align:center;" | 8.2
| style="text-align:center;" | 13.7
| style="text-align:center;" | 1.67
|-
| scope="row"| ALL (n=62)
| style="text-align:center;" | 8.4
| style="text-align:center;" | 13.9
| style="text-align:center;" | 1.65
|}
::Young (1987)<ref name = "Young1987"/> compared infused PB doses to post-infusion serum PB concentrations in adults presenting to the ED for AWS, and reported that the serum PB level rose 1.65 μg/mL for each mg/kg of PB infused. Though no standard deviation is reported, the similarity of outcomes in different subgroups (including those with alcoholic liver disease) is indicative of very minimal variability of the final serum concentration versus the infused dose (see Table-1).
 
 

==== Venous concentration versus time ====
:: Following rapid bolus injection in adults, PB quickly distributes in the blood, achieving peak venous concentration at about 3 minutes and settling into a relatively steady concentration by 5 minutes.<ref>Bøjholm S, Paulson OB, Flachs H. Arterial and venous concentrations of phenobarbital, phenytoin, clonazepam, and diazepam after rapid intravenous injections. Clin Pharmacol Ther. 1982;32(4):478-483. doi:[https://doi.org/10.1038/clpt.1982.191 10.1038/clpt.1982.191]</ref>
 
==== Brain concentration versus time====
:: Paulson et al. showed that after rapid bolus injection, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982"/>
[[File:PB_CSF_pharmacokinetics_01.PNG|center|thumb|500px|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]
 
However, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>
 
 
=== Bioavailability ===
Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).
 
 
=== Dosing ===
==== Infused dose, Venous concentration, and Clinical Effect ====
::Figure-2 is a nomagram illustrating the expected serum PB levels based on infusion dose (in mg/kg) and it also shows expected effects at particular concentrations as well as the dose ranges reported in applicable studies. 
[[File:PB Dose-Level NOMOGRAM DRAFT.png|center|thumb|500px|'''Fig-1. Phenobarbital weight-based infused dose with associated serum levels and clinical effects'''. Copyright: Andrew W. Swartz, MD (Sept 2019).]]
 

==== Recommended Dosing ====
:;Intravenous
:: '''Initial''': 260mg (or approximately 4 mg/kg) over 10 minutes
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) over 10 minutes, repeat every '''30''' minutes until adequate symptom relief
:: '''Infusion Rate''': ≤ 60 mg/min (adults)<ref name = "PBpkginsert"/>
 
:;Intramuscular
:: '''Initial''': 260mg (or approximately 4 mg/kg)
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) every '''60-90''' minutes until adequate symptom relief
 
:;Dosing Pearls:
:* Weight-based dosing should be considered for patients who are particularly under or overweight.
:* It is convenient to save two orders (i.e. one for 260mg and one for 130mg) which specify administration "over 10 minutes via infusion pump." This provides standardization, safety, and efficient use of nursing time.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* If adequate symptom relief cannot be obtained with a sub-sedative dose of PB, then the patient should be admitted for dual-treatment with a BZD. These patients warrant consideration for transfer for ICU care.
 
:;Oral Dosing
:* Oral dosing information is for hypothetical purposes only. There is no standard indication for this regimen at YKDRH, but in highly unusual circumstances this information might be useful.
:* Oral PB has 95-100% bioavailability.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* Three uncontrolled observational studies have reported results of an orally titrated PB loading regimen for treatment of "sedative/hypnotic" withdrawal.<ref name = "Robinson1981">Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther. 1981;30(1):71-76. doi:[https://doi.org/10.1038/clpt.1981.129 10.1038/clpt.1981.129]</ref><ref name = "Janecek1987">Janecek E, Kapur BM, Devenyi P. Oral phenobarbital loading: a safe method of barbiturate and nonbarbiturate hypnosedative withdrawal. CMAJ. 1987;137(5):410-412. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1492801/ PMID: 3621099/]</ref><ref>1. Loder E, Biondi D. Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache. 2003;43(8):904-909. doi:[https://doi.org/10.1046/j.1526-4610.2003.03171.x 10.1046/j.1526-4610.2003.03171.x]</ref> The three studies involved a total of 87 patients, and they administered PB 120mg orally each hour until the desired therapeutic affect was achieved. There were zero occurrences of adverse effects or over-sedation despite minimal monitoring (nursing contact once per hour). The average final doses were 1440mg, 1315mg, and 1180, respectively. The authors concluded the regimen is safe, effective, and efficient (i.e. requires minimal nursing resources). The caveat to consider is that these patients were withdrawing from barbiturates, therefore they had developed tolerance. If used for alcohol withdrawal, lower final doses should be anticipated.
 

=== Elimination ===
:The half-life of PB is frequently reported as 100 hours or as 80-120 hours.<ref>Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979;26(2):256-264. doi:10.1002/cpt1979262256</ref> This is an accurate generalization, but the generalization hides the variation among different populations.
:::* Non-barbiturate-habituated adults: approximately 80-85 hours.
:::* Barbiturate-habituated adults: approximately 55-60 hours.
:25-50% of PB is excreted unchanged in the urine. Alkalinization of the urine enhances elimination. Hepatic metabolism produces only inactive metabolites which are excreted in the urine and feces.
:Renal insufficiency has little effect upon elimination half-life, but severe renal failure likely prolongs elimination.<ref name = "Asconapé">Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 2014;119:417-432. doi:[https://doi.org/10.1016/B978-0-7020-4086-3.00027-8 10.1016/B978-0-7020-4086-3.00027-8]</ref>
:Hepatic cirrhosis has been shown to prolong elimination whereas acute viral hepatitis does not.<ref>Kutt H, Winters W, Scherman R, Mcdowell F. Diphenylhydantoin and Phenobarbital Toxicity. The Role of Liver Disease. Arch Neurol. 1964;11:649-656. doi:[https://doi.org/10.1001/archneur.1964.00460240081011 10.1001/archneur.1964.00460240081011]</ref>
 
 

=== Adverse Effects ===
:;Common
::Transient post-infusion dizziness, ataxia, and/or nystagmus
::Injection-site reactions
:;Uncommon
::Allergic reactions
:;Very uncommon
::Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermic necrolysis
:;With overdose
::Coma
::Respiratory depression
::Vomiting
:;With severe overdose
::Apnea
::Cardiovascular collapse
:;Cardiac conduction
::Neither the manufacturer package insert nor Lexicomp report cardiac conduction effects (such as QT prolongation) or increased risk of arrhythmias.
 

=== Cautions ===
:Acute or chronic pain
:Airway obstruction
:Respiratory distress
 
 

=== Contraindications ===
:History of porphyria
 
 

=== Pregnancy ===
:;Pregnancy Risk Factor
::Injection: Category '''D'''
 
:PB readily crosses placenta and yields fetal blood levels similar to maternal levels. Data from retrospective, case-controlled studies suggest an association with increased fetal abnormalities and malformations; however, this data has risk of confounding from the seizure disorder and other co-prescribed seizure medications. The manufacturer recommends that ''Phenobarbital should be used during pregnancy only when clearly indicated''.<ref name = "PBpkginsert"/> During labor, PB does not effect uterine contractions, but it does cause newborn respiratory depression.<ref name ="lexidrugs">Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019; Sept. 17, 2019.</ref>
 
 
=== Lactation ===
:PB readily passes into breast milk. The major effect is infant drowsiness but there are several reports of severe infant sedation. PB does not effect milk production.
:See [http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+401 TOXNET/LACTMED: PHENOBARBITAL] for details.
 
 

=== Toxicology ===
:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref>Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>
 
 

== '''Abbreviations''' ==
:'''AWS''': Alcohol Withdrawal Syndrome
:'''BBT''': Barbiturate[s]
:'''BZD''': Benzodiazepine[s]
:'''GABA''': Gamma-aminobutyric acid
:'''PB''': Phenobarbital
:'''YKDRH''': Yukon-Kuskokwim Delta Regional Hospital
 
 

== '''External Links''' ==
PubMed (all settings):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>)]
PubMed (ED/outpatient):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D)+AND+(%22emergency+department%22%5BTitle%2FAbstract%5D+OR+outpatient*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>) AND ("emergency department"[Title/Abstract<nowiki>]</nowiki> OR outpatient*[Title/Abstract<nowiki>]</nowiki>)]
 
Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert"/>.
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7478?searchUrl=%2Flco%2Faction%2Fsearch%3Bjsessionid%3Daf83d0252408d9273a5e3a8ac007%3Forigin%3Dapi%26t%3Dglobalid%26q%3D6763%26nq%3Dtrue#monograph-tab-content Lexicomp/Lexi-Drugs: Phenobarbital] 
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/lexier/1231760 Lexicomp/Lexi-Tox: Phenobarbital]
 
 
== '''Contributors''' ==
''Authors''
:Andrew W. Swartz, MD 
''Reviewers:''
:Travis Nelson, MD (suggestions incorporated)
:Megan Young, MD
:Tara Lathrop, MD
 
 

== '''References''' ==
<references />

Phenobarbital for Alcohol Withdrawal

2019-09-22T23:50:54Z

TravisN:

[https://en.wikipedia.org/wiki/Phenobarbital Phenobarbital] (PB) is a non-competitive [https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid gamma-Aminobutyric acid] (GABA) agonist which is an equally effective and safe alternative to benzodiazepines (BZD) for the treatment of alcohol withdrawal syndrome (AWS).<ref name="Mo2016">Mo Y, Thomas MC, Karras GE. Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2016;32:101-107. doi:[https://www.doi.org/10.1016/j.jcrc.2015.11.022 10.1016/j.jcrc.2015.11.022]</ref> Though its use for AWS has waned and consequently many clinicians are now unfamiliar with this regimen, PB has both mechanistic and pharmacokinetic properties which make it more suitable for outpatient monotherapy than BZD.
 
IV/IM titrated PB is the first-line outpatient medication used for treatment of AWS at the Yukon-Kuskokwim Delta Regional Hospital (YKDRH). Its use is favored because substantial experience at this institution has shown that it is safe, it is effective, it minimizes return visits, and it eliminates the need to dispense abuse-prone medications (i.e. BZD) to abuse-prone patients while in the midst of a substance abuse crisis. Indeed, minimizing high-risk dispensing of abuse-prone medication is important for improving the health of our community.
 
The treatment of AWS with phenobarbital (or barbiturates [BBT] in general) is not new, but it has fallen so out of favor that many clinicians are unfamiliar with this use. However, there is ample published evidence, both old and new, indicating that phenobarbital is ''at least'' equally safe and effective compared with benzodiazepines.
 
 
__TOC__ 
 
 
== '''Treatment Principles and Pearls''' ==
=== Sub-sedative dosing ===
: Alcohol withdrawal is a ''hyper''-alert and/or ''hyper''-autonomic state. The goal of outpatient treatment of alcohol withdrawal is ''normalization'' of alertness (i.e. level of consciousness) and autonomic function, not sedation. If a sedative level of [any] medication is required for AWS symptom control, then admission is often indicated.
 

=== Dose titration ===
: Patients’ individual medication requirements are unpredictable. Therefore no standard PB dose is expected to be effective for all patients. Rather, an initial IV (or IM) PB dose of 260 mg is given, and then every 30 minutes (or 60 minutes for IM) an additional 130mg are given until the desired effect is achieved. Using this regimen, many patients will require repeat doses, but none should end up “sedated.”
 
: The standard 260mg/130mg regimen works well for average size patients. This regimen yields weight-based doses of 3.7 mg/kg and 1.9 mg/kg in a 70 kg patient. However, for patients substantially below or above 70 kg, clinicians should consider administering 4 mg/kg with subsequent doses of 2 mg/kg. For convenience, these doses can be rounded to the nearest 130 mg increment (i.e. the amount in a single vial). For example, weight-based doing for a 125 kg patient would yield 500 mg and 250 mg doses, and these can be safely rounded to 520mg and 260mg for ease of administration. Weight-based dosing prevents sedating unusually small patients while preventing excessively long visits for unusually large patients. Dosing in whole-vial increments minimizes the risk of dosing errors and eliminates the effort required to precisely dose from a 1mL vial.
 
=== Dosing interval ===
:In pharmacokinetic studies of rapid PB boluses, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982">Paulson OB, Györy A, Hertz MM. Blood-brain barrier transfer and cerebral uptake of antiepileptic drugs. Clin Pharmacol Ther. 1982;32(4):466-477. doi:[https://doi.org/10.1038/clpt.1982.190 10.1038/clpt.1982.190]</ref> Yet clinical judgment must still be used. At 30 minutes after a PB dose, if the patient has “almost” complete symptom relief, the clinician should appreciate the possibility of a small amount of biological variability and consider reevaluating after another 10 minutes, as it is possible that a small additional effect may become apparent. But if the dose is clearly inadequate at 30 minutes, further waiting is very unlikely to reveal any substantial further effect.
 
=== Sleep after symptom control ===
: When patients’ hyper-alert/hyper-autonomic state is normalized, many will lightly nap. But such patients easily awaken to voice or light touch and they easily meet all discharge criteria. Rather than being “sedated,” such patients are merely exhibiting the normal physiologic response in the absence of discomfort to a 24-48 hour sleep deficit (which is the norm for patients in this situation). Any concern for sedation can usually be answered by asking oneself if the patient’s post-treatment behavior would be considered '''ab'''normal for a patient in the ED with a normal mental status, with a substantial sleep deficit, whose discomfort had been relieved. If the answer is “no”, then the patient is not “sedated,” but rather has been returned to a normal level of alertness.
 
=== Post-infusion dizziness/nystagmus/ataxia ===
:Post-infusion dizziness/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.
 
=== Isolated withdrawal hallucinosis ===
: A subset of AWS patients will present as soon as 12 hours after alcohol cessation with classic withdrawal hallucinations but without any signs of hyper-alertness, clouding of consciousness, confusion, or autonomic hyper-stimulation. This is a well documented variant of AWS, and it should be neither under-treated (i.e. dismissed as fake) nor over-treated (i.e. managed as delirium tremens). Hallucinations are one of the many manifestations of AWS, and they can occur in isolation or in combination with other signs. Primary management is a therapeutic level of GABA agonist (i.e. PB or a BZD). The use of anti-psychotic medications is contraversial. If hallucinations are refractory to an appropriate level of GABA agonist then an anti-psychotic medication can be added. However, caution is advised because there have been reports of increased mortality associated with these medications due to arrhythmias (due to QT prolongation) and lowering the seizure threshold. The risk/benefit must be carefully weighted in these situations, especially in the first 48 hours when the seizure risk is highest. Anti-psychotic medications should never be the first-line or sole therapy for hallucinosis or other withdrawal symptoms.<ref>Jesse S, Bråthen G, Ferrara M, et al. Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurol Scand. 2017;135(1):4-16. doi:[https://doi.org/10.1111/ane.12671 10.1111/ane.12671].</ref>
 
 

=== Alcoholic Hallucinosis ===

Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations without other strong evidence of alcohol withdrawal or alcohol delirium. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing gaba agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.

[[media:Barkat_et_al_2017.pdf|Treatment of Alcohol Induced Psychotic Disorder]]

== '''Evidence of Effectiveness and Safety''' ==
=== Systematic Review / Meta-analysis ===
* A 2016 systematic review by '''Mo et al'''. in the ''Journal of Critical Care''<ref name="Mo2016" /> concluded that "''barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS.''" This review included three randomized controlled trials (RCT's) and four observational studies. Importantly, the authors observed that "''none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS.''" While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.<ref name="Hendey2011">Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382-385. doi:[https://doi.org/10.1016/j.ajem.2009.10.010 10.1016/j.ajem.2009.10.010]</ref>) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.
* Other systematic reviews<ref name = "Minozzi2010">Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064. doi:[https://doi.org/10.1002/14651858.CD005064.pub3 10.1002/14651858.CD005064.pub3]</ref><ref>Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537. doi:[https://doi.org/10.1002/14651858.CD008537.pub2 10.1002/14651858.CD008537.pub2]</ref> have only indirectly assessed the effectiveness of PB for AWS. These reviews have grouped all studies which compared any anti-convulsant to a BZD, and then concluded that anti-convulsants (as a group) are inferior to BZDs for treatment of AWS. This grouping of PB with other anti-convulsants badly biases the results against PB and does not seem justified. The mechanism of action of both PB and BZDs is non-competitive agonism of the GABAA ion channel and both of these medication have been long known to display cross-tolerance with each other and alcohol. Conversely, the other anti-convulsants work via different mechanisms. Therefore grouping PB with the other anti-convulsants is inappropriate and seems to merely reflect how the authors think about the drugs rather than their pharmacological properties.

=== Studies of ED/Outpatient Treatment ===
* '''Young et al'''. (1987, prospective uncontrolled study, n=62)<ref name = "Young1987">Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987;16(8):847-850. doi:[https://doi.org/10.1016/s0196-0644(87)80520-6 10.1016/s0196-0644(87)80520-6]</ref> 
::62 patients received IV PB loading dose in the emergency department. The protocol was an initial 260mg which was followed by 130mg increments, but the dosing interval is unclear. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experienced minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention. All patients were discharged from the ED and none returned for further care during the following week.

* '''Hendey et al'''. (2011, RCT of PB vs lorazepam, n=25/19)<ref name="Hendey2011" /> 
::44 ED patients were randomized (25 to IV-PB, 19 to LZ). PB patients received a 230 mg initial dose followed by 130mg subsequent doses (dosing interval was "''at the discretion of the treating physician''"). Mean PB dose was 509 mg (range 260-910 mg); mean number of doses was 2.9 (range 1-6). There were no outcome differences at 48 hours, and importantly, there was no significant difference in length of ED stay (267 min for PB versus 256 min for LZ). Fewer PB patients required admission (12 vs. 16). The authors concluded that "''phenobarbital and LZ were similarly effective in the treatment of mild/moderate alcohol withdrawal in the ED and at 48 hours.''"

* '''Nelson et al'''. (2019, retrospective cohort study)<ref>Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019;37(4):733-736. doi:[https://doi.org/10.1016/j.ajem.2019.01.002 10.1016/j.ajem.2019.01.002]</ref> 
::300 ED patients: 100 received IV-PB alone, 100 received IV-PB + lorazepam, and 100 received diazepam alone. Initial PB dose was 260mg and subsequent doses were 130mg (dosing interval is not specified). Authors' conclusions: "''Incorporating phenobarbital into a benzodiazepine based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department''."

=== Historical Reports ===
:PB has long been used for treatment of delirium tremens (DT). Though it has fallen out of favor in most places, a minority of countries and institutions have continued to use it as first line treatment of AWS.
::* A 2010 study by Michaelsen in the ''Danish Medical Bulletin''<ref>Michaelsen IH, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens--a retrospective study. Dan Med Bull. 2010;57(8):A4169.</ref> states BBTs have been used for treatment of DT in Denmark "for over 100 years."
::* A 2006 RCT of gabapentin for AWS<ref>Mariani JJ, Rosenthal RN, Tross S, Singh P, Anand OP. A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal. Am J Addict. 2006;15(1):76-84. doi:[https://doi.org/10.1080/10550490500419110 10.1080/10550490500419110]</ref> compared it to a control group which received PB. The authors gave the following explanation in the methods section:
::::''Those randomized to the experimental group received a protocol using gabapentin, while those in the control group received a phenobarbital protocol that is customary in our inpatient detoxification service. Phenobarbital was used in this study rather than benzodiazepines because it is the detoxification medication that the clinical staff is most familiar with.''
::* A 1995 United States nationwide survey of inpatient alcohol treatment centers<ref>Saitz R, Friedman LS, Mayo-Smith MF. Alcohol withdrawal: a nationwide survey of inpatient treatment practices. J Gen Intern Med. 1995;10(9):479-487. doi:[https://doi.org/10.1007/bf02602395 10.1007/bf02602395]</ref> reported that approximately 10% primarily used PB for treatment of AWS.

=== EVIDENCE SUMMARY ===
:In landmark studies by Kaim and Klett in 1969<ref>Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969;125(12):1640-1646. doi:[https://doi.org/10.1176/ajp.125.12.1640 10.1176/ajp.125.12.1640]</ref> and 1972,<ref>Kaim SC, Klett CJ. Treatment of delirium tremens. A comparative evaluation of four drugs. Q J Stud Alcohol. 1972;33(4):1065-1072.</ref> both BBTs and BZDs were shown to be equally effective in treatment of AWS. Both of these drug classes had been previously known to exhibit cross dependance with each other as well as alcohol, and the subsequent discovery that these structurally unrelated compounds are both GABA agonists was critical to understanding the pathophysiology of AWS. 
 
:Though BZDs have become the standard of care, this seems mostly attributable to a larger movement away from inpatient treatment and toward outpatient treatment with oral medications. Dispensing BZDs to patients is clearly safer than dispensing PB/BBTs. Yet when the dose is titrated to effect by a physician and patients are not dispensed medication, there is ample evidence that PB is equally safe and effective compared to BZD. 
 
:Numerous articles advise caution with regard to PB by alluding to concerns about respiratory depression, but no evidence of adverse effects is ever presented or cited. Therefore these concerns seem to originate more from the authors' lack of familiarity with the use of IV-PB in this setting than from documented outcomes. However, it must be pointed out that PB should '''''never''''' be dispensed to a patient for symptom-triggered dosing, as this would present an '''extreme risk''' of unintentional lethal overdose. PB use for AWS ''must'' be limited to titrating the dose to the desired effect, and then discharging the patient without additional medication. There have been no reports of iatrogenic overdoses using this protocol, and the drug packaging is a strong mitigating factor to prevent drug errors: At YKDRH, PB is only available in 130mg vials. Therefore the initial dose is two vials and the subsequent doses are one vial. A dangerous overdose (i.e. one yielding respiratory depression) would require accidentally drawing up 20-30 vials, which would be very labor intensive and very likely produce questions prior to administration. ''(PB is also marketed in 65mg vials, but that would require even more vials to produce an overdose.)''
 
 

== '''Regulatory Information and Packaging''' ==
*PB is not approved by the U.S. FDA; this is likely due its use preceding the creation of the FDA (in 1938).
*DEA Schedule: IV
*Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert">Phenobarbital sodium [[https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 package insert]]. Eatontown, NJ: West-Ward Pharmaceuticals Corporation; 2018.</ref>.
*How Supplied:
:::Phenobarbital Sodium Injection, 65 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0476-25) 
:::Phenobarbital Sodium Injection, 130 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0477-25) 
 
 

== '''Pharmacology''' ==
 
The following are some of the important properties of PB with regard to outpatient treatment of AWS. 
 
=== Classification ===
:; Chemical Class
::PB belongs to the chemical class ''barbiturate''.
:; Clinical Class
:# Like all barbiturates, PB is a ''sedative/hypnotic''.<ref name = "Harvey1979">Harvey SC. Hypnotics and Sedatives: The Barbiturates. In: Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 5th ed. New York: MacMillan Publishing Co., Inc.; 1975:124-136.</ref> However, it is almost never used for this purpose.
:# PB is also classified as an ''anti-convulsant''. 
::::::''In anesthetic doses, all BBTs have an anti-convulsant effect. However, PB is the only BBT which has an anti-convulsant effect at sub-sedative doses. (Historically, two closely related derivatives [mephobarbital and metharbital] also had an anti-convulsant effect at sub-sedative doses).''<ref name="Harvey1979" />
 

=== Mechanism of Action ===
:; GABA agonist
::The binding of GABA to its receptor inhibits nerve depolarization. Like all barbiturates, PB's sedative/hypnotic effect occurs primarily via noncompetitive agonism of the GABAA receptor on the GABA-mediated ion channel. Like BZDs, PB/BBTs do not themselves open the channel and thus GABA is still required. PB/BBTs bind at a different site on the GABAA receptor than BZDs.<ref name = "Hobbs1996">Hobbs WR, Rall TW, Verdoorn TA. Ch 17: Hypnotics and Sedatives; Ethanol. In: Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:361-398.</ref> 
::When PB/BBTs bind to the GABAA receptor, three effects occur: 
::::::# Enhancement of the binding of GABA<ref name="Hobbs1996" /> 
::::::# Enhancement of the binding of BZDs<ref name="Hobbs1996" /> 
::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /> 
::Both 2 and 3 indicate a potential synergistic effect when co-administered with BZDs. Studies have shown that dual therapy is superior to either PB or BZDs alone,(insert refs) indicating at least an additive effect.
:; Glutamate antagonist
::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>
 
 

=== Distribution ===

:Volume of distribution is X(ref).

:Plasma protein binding has been estimated as X percent, predominantly to albumin.(ref)
 
==== Venous concentration versus infused dose ====
{| class="wikitable" style="float:right;font-size: 85%; border: 1px solid black;"
|+ style="caption-side:top; text-align:center;" |Table-1. PB dose, concentration, and ratio for [nonexclusive] subgroups reported in Young (1987).<ref name = "Young1987" />
|-
! scope="col"| Group
! scope="col"| PB Dose (mg/kg)
! scope="col" style="width: 50px;"| Serum Concentration (μ/mL)
! scope="col" style="width: 70px;"| Conc : Dose Ratio
|-
| scope="row"| Tremulous (n=48)
| style="text-align:center;" | 8.5
| style="text-align:center;" | 14.0
| style="text-align:center;" | 1.65
|-
| scope="row"| Seizures (n=38)
| style="text-align:center;" | 8.3
| style="text-align:center;" | 13.8
| style="text-align:center;" | 1.66
|-
| scope="row"| Alcoholic liver disease (n=21)
| style="text-align:center;" | 8.2
| style="text-align:center;" | 13.7
| style="text-align:center;" | 1.67
|-
| scope="row"| ALL (n=62)
| style="text-align:center;" | 8.4
| style="text-align:center;" | 13.9
| style="text-align:center;" | 1.65
|}
::Young (1987)<ref name = "Young1987"/> compared infused PB doses to post-infusion serum PB concentrations in adults presenting to the ED for AWS, and reported that the serum PB level rose 1.65 μg/mL for each mg/kg of PB infused. Though no standard deviation is reported, the similarity of outcomes in different subgroups (including those with alcoholic liver disease) is indicative of very minimal variability of the final serum concentration versus the infused dose (see Table-1).
 
 

==== Venous concentration versus time ====
:: Following rapid bolus injection in adults, PB quickly distributes in the blood, achieving peak venous concentration at about 3 minutes and settling into a relatively steady concentration by 5 minutes.<ref>Bøjholm S, Paulson OB, Flachs H. Arterial and venous concentrations of phenobarbital, phenytoin, clonazepam, and diazepam after rapid intravenous injections. Clin Pharmacol Ther. 1982;32(4):478-483. doi:[https://doi.org/10.1038/clpt.1982.191 10.1038/clpt.1982.191]</ref>
 
==== Brain concentration versus time====
:: Paulson et al. showed that after rapid bolus injection, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982"/>
[[File:PB_CSF_pharmacokinetics_01.PNG|center|thumb|500px|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]
 
However, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>
 
 
=== Bioavailability ===
Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).
 
 
=== Dosing ===
==== Infused dose, Venous concentration, and Clinical Effect ====
::Figure-2 is a nomagram illustrating the expected serum PB levels based on infusion dose (in mg/kg) and it also shows expected effects at particular concentrations as well as the dose ranges reported in applicable studies. 
[[File:PB Dose-Level NOMOGRAM DRAFT.png|center|thumb|500px|'''Fig-1. Phenobarbital weight-based infused dose with associated serum levels and clinical effects'''. Copyright: Andrew W. Swartz, MD (Sept 2019).]]
 

==== Recommended Dosing ====
:;Intravenous
:: '''Initial''': 260mg (or approximately 4 mg/kg) over 10 minutes
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) over 10 minutes, repeat every '''30''' minutes until adequate symptom relief
:: '''Infusion Rate''': ≤ 60 mg/min (adults)<ref name = "PBpkginsert"/>
 
:;Intramuscular
:: '''Initial''': 260mg (or approximately 4 mg/kg)
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) every '''60-90''' minutes until adequate symptom relief
 
:;Dosing Pearls:
:* Weight-based dosing should be considered for patients who are particularly under or overweight.
:* It is convenient to save two orders (i.e. one for 260mg and one for 130mg) which specify administration "over 10 minutes via infusion pump." This provides standardization, safety, and efficient use of nursing time.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* If adequate symptom relief cannot be obtained with a sub-sedative dose of PB, then the patient should be admitted for dual-treatment with a BZD. These patients warrant consideration for transfer for ICU care.
 
:;Oral Dosing
:* Oral dosing information is for hypothetical purposes only. There is no standard indication for this regimen at YKDRH, but in highly unusual circumstances this information might be useful.
:* Oral PB has 95-100% bioavailability.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* Three uncontrolled observational studies have reported results of an orally titrated PB loading regimen for treatment of "sedative/hypnotic" withdrawal.<ref name = "Robinson1981">Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther. 1981;30(1):71-76. doi:[https://doi.org/10.1038/clpt.1981.129 10.1038/clpt.1981.129]</ref><ref name = "Janecek1987">Janecek E, Kapur BM, Devenyi P. Oral phenobarbital loading: a safe method of barbiturate and nonbarbiturate hypnosedative withdrawal. CMAJ. 1987;137(5):410-412. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1492801/ PMID: 3621099/]</ref><ref>1. Loder E, Biondi D. Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache. 2003;43(8):904-909. doi:[https://doi.org/10.1046/j.1526-4610.2003.03171.x 10.1046/j.1526-4610.2003.03171.x]</ref> The three studies involved a total of 87 patients, and they administered PB 120mg orally each hour until the desired therapeutic affect was achieved. There were zero occurrences of adverse effects or over-sedation despite minimal monitoring (nursing contact once per hour). The average final doses were 1440mg, 1315mg, and 1180, respectively. The authors concluded the regimen is safe, effective, and efficient (i.e. requires minimal nursing resources). The caveat to consider is that these patients were withdrawing from barbiturates, therefore they had developed tolerance. If used for alcohol withdrawal, lower final doses should be anticipated.
 

=== Elimination ===
:The half-life of PB is frequently reported as 100 hours or as 80-120 hours.<ref>Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979;26(2):256-264. doi:10.1002/cpt1979262256</ref> This is an accurate generalization, but the generalization hides the variation among different populations.
:::* Non-barbiturate-habituated adults: approximately 80-85 hours.
:::* Barbiturate-habituated adults: approximately 55-60 hours.
:25-50% of PB is excreted unchanged in the urine. Alkalinization of the urine enhances elimination. Hepatic metabolism produces only inactive metabolites which are excreted in the urine and feces.
:Renal insufficiency has little effect upon elimination half-life, but severe renal failure likely prolongs elimination.<ref name = "Asconapé">Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 2014;119:417-432. doi:[https://doi.org/10.1016/B978-0-7020-4086-3.00027-8 10.1016/B978-0-7020-4086-3.00027-8]</ref>
:Hepatic cirrhosis has been shown to prolong elimination whereas acute viral hepatitis does not.<ref>Kutt H, Winters W, Scherman R, Mcdowell F. Diphenylhydantoin and Phenobarbital Toxicity. The Role of Liver Disease. Arch Neurol. 1964;11:649-656. doi:[https://doi.org/10.1001/archneur.1964.00460240081011 10.1001/archneur.1964.00460240081011]</ref>
 
 

=== Adverse Effects ===
:;Common
::Transient post-infusion dizziness, ataxia, and/or nystagmus
::Injection-site reactions
:;Uncommon
::Allergic reactions
:;Very uncommon
::Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermic necrolysis
:;With overdose
::Coma
::Respiratory depression
::Vomiting
:;With severe overdose
::Apnea
::Cardiovascular collapse
:;Cardiac conduction
::Neither the manufacturer package insert nor Lexicomp report cardiac conduction effects (such as QT prolongation) or increased risk of arrhythmias.
 

=== Cautions ===
:Acute or chronic pain
:Airway obstruction
:Respiratory distress
 
 

=== Contraindications ===
:History of porphyria
 
 

=== Pregnancy ===
:;Pregnancy Risk Factor
::Injection: Category '''D'''
 
:PB readily crosses placenta and yields fetal blood levels similar to maternal levels. Data from retrospective, case-controlled studies suggest an association with increased fetal abnormalities and malformations; however, this data has risk of confounding from the seizure disorder and other co-prescribed seizure medications. The manufacturer recommends that ''Phenobarbital should be used during pregnancy only when clearly indicated''.<ref name = "PBpkginsert"/> During labor, PB does not effect uterine contractions, but it does cause newborn respiratory depression.<ref name ="lexidrugs">Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019; Sept. 17, 2019.</ref>
 
 
=== Lactation ===
:PB readily passes into breast milk. The major effect is infant drowsiness but there are several reports of severe infant sedation. PB does not effect milk production.
:See [http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+401 TOXNET/LACTMED: PHENOBARBITAL] for details.
 
 

=== Toxicology ===
:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref>Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>
 
 

== '''Abbreviations''' ==
:'''AWS''': Alcohol Withdrawal Syndrome
:'''BBT''': Barbiturate[s]
:'''BZD''': Benzodiazepine[s]
:'''GABA''': Gamma-aminobutyric acid
:'''PB''': Phenobarbital
:'''YKDRH''': Yukon-Kuskokwim Delta Regional Hospital
 
 

== '''External Links''' ==
PubMed (all settings):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>)]
PubMed (ED/outpatient):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D)+AND+(%22emergency+department%22%5BTitle%2FAbstract%5D+OR+outpatient*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>) AND ("emergency department"[Title/Abstract<nowiki>]</nowiki> OR outpatient*[Title/Abstract<nowiki>]</nowiki>)]
 
Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert"/>.
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7478?searchUrl=%2Flco%2Faction%2Fsearch%3Bjsessionid%3Daf83d0252408d9273a5e3a8ac007%3Forigin%3Dapi%26t%3Dglobalid%26q%3D6763%26nq%3Dtrue#monograph-tab-content Lexicomp/Lexi-Drugs: Phenobarbital] 
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/lexier/1231760 Lexicomp/Lexi-Tox: Phenobarbital]
 
 
== '''Contributors''' ==
''Authors''
:Andrew W. Swartz, MD 
''Reviewers:''
:Travis Nelson, MD (suggestions incorporated)
:Megan Young, MD
:Tara Lathrop, MD
 
 

== '''References''' ==
<references />

Phenobarbital for Alcohol Withdrawal

2019-09-22T23:47:50Z

TravisN:

[https://en.wikipedia.org/wiki/Phenobarbital Phenobarbital] (PB) is a non-competitive [https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid gamma-Aminobutyric acid] (GABA) agonist which is an equally effective and safe alternative to benzodiazepines (BZD) for the treatment of alcohol withdrawal syndrome (AWS).<ref name="Mo2016">Mo Y, Thomas MC, Karras GE. Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2016;32:101-107. doi:[https://www.doi.org/10.1016/j.jcrc.2015.11.022 10.1016/j.jcrc.2015.11.022]</ref> Though its use for AWS has waned and consequently many clinicians are now unfamiliar with this regimen, PB has both mechanistic and pharmacokinetic properties which make it more suitable for outpatient monotherapy than BZD.
 
IV/IM titrated PB is the first-line outpatient medication used for treatment of AWS at the Yukon-Kuskokwim Delta Regional Hospital (YKDRH). Its use is favored because substantial experience at this institution has shown that it is safe, it is effective, it minimizes return visits, and it eliminates the need to dispense abuse-prone medications (i.e. BZD) to abuse-prone patients while in the midst of a substance abuse crisis. Indeed, minimizing high-risk dispensing of abuse-prone medication is important for improving the health of our community.
 
The treatment of AWS with phenobarbital (or barbiturates [BBT] in general) is not new, but it has fallen so out of favor that many clinicians are unfamiliar with this use. However, there is ample published evidence, both old and new, indicating that phenobarbital is ''at least'' equally safe and effective compared with benzodiazepines.
 
 
__TOC__ 
 
 
== '''Treatment Principles and Pearls''' ==
=== Sub-sedative dosing ===
: Alcohol withdrawal is a ''hyper''-alert and/or ''hyper''-autonomic state. The goal of outpatient treatment of alcohol withdrawal is ''normalization'' of alertness (i.e. level of consciousness) and autonomic function, not sedation. If a sedative level of [any] medication is required for AWS symptom control, then admission is often indicated.
 

=== Dose titration ===
: Patients’ individual medication requirements are unpredictable. Therefore no standard PB dose is expected to be effective for all patients. Rather, an initial IV (or IM) PB dose of 260 mg is given, and then every 30 minutes (or 60 minutes for IM) an additional 130mg are given until the desired effect is achieved. Using this regimen, many patients will require repeat doses, but none should end up “sedated.”
 
: The standard 260mg/130mg regimen works well for average size patients. This regimen yields weight-based doses of 3.7 mg/kg and 1.9 mg/kg in a 70 kg patient. However, for patients substantially below or above 70 kg, clinicians should consider administering 4 mg/kg with subsequent doses of 2 mg/kg. For convenience, these doses can be rounded to the nearest 130 mg increment (i.e. the amount in a single vial). For example, weight-based doing for a 125 kg patient would yield 500 mg and 250 mg doses, and these can be safely rounded to 520mg and 260mg for ease of administration. Weight-based dosing prevents sedating unusually small patients while preventing excessively long visits for unusually large patients. Dosing in whole-vial increments minimizes the risk of dosing errors and eliminates the effort required to precisely dose from a 1mL vial.
 
=== Dosing interval ===
:In pharmacokinetic studies of rapid PB boluses, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982">Paulson OB, Györy A, Hertz MM. Blood-brain barrier transfer and cerebral uptake of antiepileptic drugs. Clin Pharmacol Ther. 1982;32(4):466-477. doi:[https://doi.org/10.1038/clpt.1982.190 10.1038/clpt.1982.190]</ref> Yet clinical judgment must still be used. At 30 minutes after a PB dose, if the patient has “almost” complete symptom relief, the clinician should appreciate the possibility of a small amount of biological variability and consider reevaluating after another 10 minutes, as it is possible that a small additional effect may become apparent. But if the dose is clearly inadequate at 30 minutes, further waiting is very unlikely to reveal any substantial further effect.
 
=== Sleep after symptom control ===
: When patients’ hyper-alert/hyper-autonomic state is normalized, many will lightly nap. But such patients easily awaken to voice or light touch and they easily meet all discharge criteria. Rather than being “sedated,” such patients are merely exhibiting the normal physiologic response in the absence of discomfort to a 24-48 hour sleep deficit (which is the norm for patients in this situation). Any concern for sedation can usually be answered by asking oneself if the patient’s post-treatment behavior would be considered '''ab'''normal for a patient in the ED with a normal mental status, with a substantial sleep deficit, whose discomfort had been relieved. If the answer is “no”, then the patient is not “sedated,” but rather has been returned to a normal level of alertness.
 
=== Post-infusion dizziness/nystagmus/ataxia ===
:Post-infusion dizziness/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.
 
=== Isolated withdrawal hallucinosis ===
: A subset of AWS patients will present as soon as 12 hours after alcohol cessation with classic withdrawal hallucinations but without any signs of hyper-alertness, clouding of consciousness, confusion, or autonomic hyper-stimulation. This is a well documented variant of AWS, and it should be neither under-treated (i.e. dismissed as fake) nor over-treated (i.e. managed as delirium tremens). Hallucinations are one of the many manifestations of AWS, and they can occur in isolation or in combination with other signs. Primary management is a therapeutic level of GABA agonist (i.e. PB or a BZD). The use of anti-psychotic medications is contraversial. If hallucinations are refractory to an appropriate level of GABA agonist then an anti-psychotic medication can be added. However, caution is advised because there have been reports of increased mortality associated with these medications due to arrhythmias (due to QT prolongation) and lowering the seizure threshold. The risk/benefit must be carefully weighted in these situations, especially in the first 48 hours when the seizure risk is highest. Anti-psychotic medications should never be the first-line or sole therapy for hallucinosis or other withdrawal symptoms.<ref>Jesse S, Bråthen G, Ferrara M, et al. Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurol Scand. 2017;135(1):4-16. doi:[https://doi.org/10.1111/ane.12671 10.1111/ane.12671].</ref>
 
 

=== Alcoholic Hallucinosis ===

Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations without other strong evidence of alcohol withdrawal or alcohol delirium. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing gaba agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.

[[media:Barkat_et_al_2017.pdf|Treatment of Alcohol Induced Psychotic Disorder]]

Alcoholic hallucinosis. Bhat PS et al. Ind Psychiatry J. 2012 Jul;21(2):155-7.

Phenomenology and Course of Alcoholic Hallucinosis. Narasimha VL, et al. J Dual Diagn. 2019 Jul-Sep;15(3):172-176.

Alcohol-induced psychotic disorder: a review. Jordaan GP, Emsley R. Metab Brain Dis. 2014 Jun;29(2):231-43.

== '''Evidence of Effectiveness and Safety''' ==
=== Systematic Review / Meta-analysis ===
* A 2016 systematic review by '''Mo et al'''. in the ''Journal of Critical Care''<ref name="Mo2016" /> concluded that "''barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS.''" This review included three randomized controlled trials (RCT's) and four observational studies. Importantly, the authors observed that "''none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS.''" While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.<ref name="Hendey2011">Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382-385. doi:[https://doi.org/10.1016/j.ajem.2009.10.010 10.1016/j.ajem.2009.10.010]</ref>) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.
* Other systematic reviews<ref name = "Minozzi2010">Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064. doi:[https://doi.org/10.1002/14651858.CD005064.pub3 10.1002/14651858.CD005064.pub3]</ref><ref>Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537. doi:[https://doi.org/10.1002/14651858.CD008537.pub2 10.1002/14651858.CD008537.pub2]</ref> have only indirectly assessed the effectiveness of PB for AWS. These reviews have grouped all studies which compared any anti-convulsant to a BZD, and then concluded that anti-convulsants (as a group) are inferior to BZDs for treatment of AWS. This grouping of PB with other anti-convulsants badly biases the results against PB and does not seem justified. The mechanism of action of both PB and BZDs is non-competitive agonism of the GABAA ion channel and both of these medication have been long known to display cross-tolerance with each other and alcohol. Conversely, the other anti-convulsants work via different mechanisms. Therefore grouping PB with the other anti-convulsants is inappropriate and seems to merely reflect how the authors think about the drugs rather than their pharmacological properties.

=== Studies of ED/Outpatient Treatment ===
* '''Young et al'''. (1987, prospective uncontrolled study, n=62)<ref name = "Young1987">Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987;16(8):847-850. doi:[https://doi.org/10.1016/s0196-0644(87)80520-6 10.1016/s0196-0644(87)80520-6]</ref> 
::62 patients received IV PB loading dose in the emergency department. The protocol was an initial 260mg which was followed by 130mg increments, but the dosing interval is unclear. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experienced minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention. All patients were discharged from the ED and none returned for further care during the following week.

* '''Hendey et al'''. (2011, RCT of PB vs lorazepam, n=25/19)<ref name="Hendey2011" /> 
::44 ED patients were randomized (25 to IV-PB, 19 to LZ). PB patients received a 230 mg initial dose followed by 130mg subsequent doses (dosing interval was "''at the discretion of the treating physician''"). Mean PB dose was 509 mg (range 260-910 mg); mean number of doses was 2.9 (range 1-6). There were no outcome differences at 48 hours, and importantly, there was no significant difference in length of ED stay (267 min for PB versus 256 min for LZ). Fewer PB patients required admission (12 vs. 16). The authors concluded that "''phenobarbital and LZ were similarly effective in the treatment of mild/moderate alcohol withdrawal in the ED and at 48 hours.''"

* '''Nelson et al'''. (2019, retrospective cohort study)<ref>Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019;37(4):733-736. doi:[https://doi.org/10.1016/j.ajem.2019.01.002 10.1016/j.ajem.2019.01.002]</ref> 
::300 ED patients: 100 received IV-PB alone, 100 received IV-PB + lorazepam, and 100 received diazepam alone. Initial PB dose was 260mg and subsequent doses were 130mg (dosing interval is not specified). Authors' conclusions: "''Incorporating phenobarbital into a benzodiazepine based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department''."

=== Historical Reports ===
:PB has long been used for treatment of delirium tremens (DT). Though it has fallen out of favor in most places, a minority of countries and institutions have continued to use it as first line treatment of AWS.
::* A 2010 study by Michaelsen in the ''Danish Medical Bulletin''<ref>Michaelsen IH, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens--a retrospective study. Dan Med Bull. 2010;57(8):A4169.</ref> states BBTs have been used for treatment of DT in Denmark "for over 100 years."
::* A 2006 RCT of gabapentin for AWS<ref>Mariani JJ, Rosenthal RN, Tross S, Singh P, Anand OP. A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal. Am J Addict. 2006;15(1):76-84. doi:[https://doi.org/10.1080/10550490500419110 10.1080/10550490500419110]</ref> compared it to a control group which received PB. The authors gave the following explanation in the methods section:
::::''Those randomized to the experimental group received a protocol using gabapentin, while those in the control group received a phenobarbital protocol that is customary in our inpatient detoxification service. Phenobarbital was used in this study rather than benzodiazepines because it is the detoxification medication that the clinical staff is most familiar with.''
::* A 1995 United States nationwide survey of inpatient alcohol treatment centers<ref>Saitz R, Friedman LS, Mayo-Smith MF. Alcohol withdrawal: a nationwide survey of inpatient treatment practices. J Gen Intern Med. 1995;10(9):479-487. doi:[https://doi.org/10.1007/bf02602395 10.1007/bf02602395]</ref> reported that approximately 10% primarily used PB for treatment of AWS.

=== EVIDENCE SUMMARY ===
:In landmark studies by Kaim and Klett in 1969<ref>Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969;125(12):1640-1646. doi:[https://doi.org/10.1176/ajp.125.12.1640 10.1176/ajp.125.12.1640]</ref> and 1972,<ref>Kaim SC, Klett CJ. Treatment of delirium tremens. A comparative evaluation of four drugs. Q J Stud Alcohol. 1972;33(4):1065-1072.</ref> both BBTs and BZDs were shown to be equally effective in treatment of AWS. Both of these drug classes had been previously known to exhibit cross dependance with each other as well as alcohol, and the subsequent discovery that these structurally unrelated compounds are both GABA agonists was critical to understanding the pathophysiology of AWS. 
 
:Though BZDs have become the standard of care, this seems mostly attributable to a larger movement away from inpatient treatment and toward outpatient treatment with oral medications. Dispensing BZDs to patients is clearly safer than dispensing PB/BBTs. Yet when the dose is titrated to effect by a physician and patients are not dispensed medication, there is ample evidence that PB is equally safe and effective compared to BZD. 
 
:Numerous articles advise caution with regard to PB by alluding to concerns about respiratory depression, but no evidence of adverse effects is ever presented or cited. Therefore these concerns seem to originate more from the authors' lack of familiarity with the use of IV-PB in this setting than from documented outcomes. However, it must be pointed out that PB should '''''never''''' be dispensed to a patient for symptom-triggered dosing, as this would present an '''extreme risk''' of unintentional lethal overdose. PB use for AWS ''must'' be limited to titrating the dose to the desired effect, and then discharging the patient without additional medication. There have been no reports of iatrogenic overdoses using this protocol, and the drug packaging is a strong mitigating factor to prevent drug errors: At YKDRH, PB is only available in 130mg vials. Therefore the initial dose is two vials and the subsequent doses are one vial. A dangerous overdose (i.e. one yielding respiratory depression) would require accidentally drawing up 20-30 vials, which would be very labor intensive and very likely produce questions prior to administration. ''(PB is also marketed in 65mg vials, but that would require even more vials to produce an overdose.)''
 
 

== '''Regulatory Information and Packaging''' ==
*PB is not approved by the U.S. FDA; this is likely due its use preceding the creation of the FDA (in 1938).
*DEA Schedule: IV
*Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert">Phenobarbital sodium [[https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 package insert]]. Eatontown, NJ: West-Ward Pharmaceuticals Corporation; 2018.</ref>.
*How Supplied:
:::Phenobarbital Sodium Injection, 65 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0476-25) 
:::Phenobarbital Sodium Injection, 130 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0477-25) 
 
 

== '''Pharmacology''' ==
 
The following are some of the important properties of PB with regard to outpatient treatment of AWS. 
 
=== Classification ===
:; Chemical Class
::PB belongs to the chemical class ''barbiturate''.
:; Clinical Class
:# Like all barbiturates, PB is a ''sedative/hypnotic''.<ref name = "Harvey1979">Harvey SC. Hypnotics and Sedatives: The Barbiturates. In: Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 5th ed. New York: MacMillan Publishing Co., Inc.; 1975:124-136.</ref> However, it is almost never used for this purpose.
:# PB is also classified as an ''anti-convulsant''. 
::::::''In anesthetic doses, all BBTs have an anti-convulsant effect. However, PB is the only BBT which has an anti-convulsant effect at sub-sedative doses. (Historically, two closely related derivatives [mephobarbital and metharbital] also had an anti-convulsant effect at sub-sedative doses).''<ref name="Harvey1979" />
 

=== Mechanism of Action ===
:; GABA agonist
::The binding of GABA to its receptor inhibits nerve depolarization. Like all barbiturates, PB's sedative/hypnotic effect occurs primarily via noncompetitive agonism of the GABAA receptor on the GABA-mediated ion channel. Like BZDs, PB/BBTs do not themselves open the channel and thus GABA is still required. PB/BBTs bind at a different site on the GABAA receptor than BZDs.<ref name = "Hobbs1996">Hobbs WR, Rall TW, Verdoorn TA. Ch 17: Hypnotics and Sedatives; Ethanol. In: Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:361-398.</ref> 
::When PB/BBTs bind to the GABAA receptor, three effects occur: 
::::::# Enhancement of the binding of GABA<ref name="Hobbs1996" /> 
::::::# Enhancement of the binding of BZDs<ref name="Hobbs1996" /> 
::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /> 
::Both 2 and 3 indicate a potential synergistic effect when co-administered with BZDs. Studies have shown that dual therapy is superior to either PB or BZDs alone,(insert refs) indicating at least an additive effect.
:; Glutamate antagonist
::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>
 
 

=== Distribution ===

:Volume of distribution is X(ref).

:Plasma protein binding has been estimated as X percent, predominantly to albumin.(ref)
 
==== Venous concentration versus infused dose ====
{| class="wikitable" style="float:right;font-size: 85%; border: 1px solid black;"
|+ style="caption-side:top; text-align:center;" |Table-1. PB dose, concentration, and ratio for [nonexclusive] subgroups reported in Young (1987).<ref name = "Young1987" />
|-
! scope="col"| Group
! scope="col"| PB Dose (mg/kg)
! scope="col" style="width: 50px;"| Serum Concentration (μ/mL)
! scope="col" style="width: 70px;"| Conc : Dose Ratio
|-
| scope="row"| Tremulous (n=48)
| style="text-align:center;" | 8.5
| style="text-align:center;" | 14.0
| style="text-align:center;" | 1.65
|-
| scope="row"| Seizures (n=38)
| style="text-align:center;" | 8.3
| style="text-align:center;" | 13.8
| style="text-align:center;" | 1.66
|-
| scope="row"| Alcoholic liver disease (n=21)
| style="text-align:center;" | 8.2
| style="text-align:center;" | 13.7
| style="text-align:center;" | 1.67
|-
| scope="row"| ALL (n=62)
| style="text-align:center;" | 8.4
| style="text-align:center;" | 13.9
| style="text-align:center;" | 1.65
|}
::Young (1987)<ref name = "Young1987"/> compared infused PB doses to post-infusion serum PB concentrations in adults presenting to the ED for AWS, and reported that the serum PB level rose 1.65 μg/mL for each mg/kg of PB infused. Though no standard deviation is reported, the similarity of outcomes in different subgroups (including those with alcoholic liver disease) is indicative of very minimal variability of the final serum concentration versus the infused dose (see Table-1).
 
 

==== Venous concentration versus time ====
:: Following rapid bolus injection in adults, PB quickly distributes in the blood, achieving peak venous concentration at about 3 minutes and settling into a relatively steady concentration by 5 minutes.<ref>Bøjholm S, Paulson OB, Flachs H. Arterial and venous concentrations of phenobarbital, phenytoin, clonazepam, and diazepam after rapid intravenous injections. Clin Pharmacol Ther. 1982;32(4):478-483. doi:[https://doi.org/10.1038/clpt.1982.191 10.1038/clpt.1982.191]</ref>
 
==== Brain concentration versus time====
:: Paulson et al. showed that after rapid bolus injection, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982"/>
[[File:PB_CSF_pharmacokinetics_01.PNG|center|thumb|500px|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]
 
However, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>
 
 
=== Bioavailability ===
Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).
 
 
=== Dosing ===
==== Infused dose, Venous concentration, and Clinical Effect ====
::Figure-2 is a nomagram illustrating the expected serum PB levels based on infusion dose (in mg/kg) and it also shows expected effects at particular concentrations as well as the dose ranges reported in applicable studies. 
[[File:PB Dose-Level NOMOGRAM DRAFT.png|center|thumb|500px|'''Fig-1. Phenobarbital weight-based infused dose with associated serum levels and clinical effects'''. Copyright: Andrew W. Swartz, MD (Sept 2019).]]
 

==== Recommended Dosing ====
:;Intravenous
:: '''Initial''': 260mg (or approximately 4 mg/kg) over 10 minutes
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) over 10 minutes, repeat every '''30''' minutes until adequate symptom relief
:: '''Infusion Rate''': ≤ 60 mg/min (adults)<ref name = "PBpkginsert"/>
 
:;Intramuscular
:: '''Initial''': 260mg (or approximately 4 mg/kg)
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) every '''60-90''' minutes until adequate symptom relief
 
:;Dosing Pearls:
:* Weight-based dosing should be considered for patients who are particularly under or overweight.
:* It is convenient to save two orders (i.e. one for 260mg and one for 130mg) which specify administration "over 10 minutes via infusion pump." This provides standardization, safety, and efficient use of nursing time.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* If adequate symptom relief cannot be obtained with a sub-sedative dose of PB, then the patient should be admitted for dual-treatment with a BZD. These patients warrant consideration for transfer for ICU care.
 
:;Oral Dosing
:* Oral dosing information is for hypothetical purposes only. There is no standard indication for this regimen at YKDRH, but in highly unusual circumstances this information might be useful.
:* Oral PB has 95-100% bioavailability.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* Three uncontrolled observational studies have reported results of an orally titrated PB loading regimen for treatment of "sedative/hypnotic" withdrawal.<ref name = "Robinson1981">Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther. 1981;30(1):71-76. doi:[https://doi.org/10.1038/clpt.1981.129 10.1038/clpt.1981.129]</ref><ref name = "Janecek1987">Janecek E, Kapur BM, Devenyi P. Oral phenobarbital loading: a safe method of barbiturate and nonbarbiturate hypnosedative withdrawal. CMAJ. 1987;137(5):410-412. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1492801/ PMID: 3621099/]</ref><ref>1. Loder E, Biondi D. Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache. 2003;43(8):904-909. doi:[https://doi.org/10.1046/j.1526-4610.2003.03171.x 10.1046/j.1526-4610.2003.03171.x]</ref> The three studies involved a total of 87 patients, and they administered PB 120mg orally each hour until the desired therapeutic affect was achieved. There were zero occurrences of adverse effects or over-sedation despite minimal monitoring (nursing contact once per hour). The average final doses were 1440mg, 1315mg, and 1180, respectively. The authors concluded the regimen is safe, effective, and efficient (i.e. requires minimal nursing resources). The caveat to consider is that these patients were withdrawing from barbiturates, therefore they had developed tolerance. If used for alcohol withdrawal, lower final doses should be anticipated.
 

=== Elimination ===
:The half-life of PB is frequently reported as 100 hours or as 80-120 hours.<ref>Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979;26(2):256-264. doi:10.1002/cpt1979262256</ref> This is an accurate generalization, but the generalization hides the variation among different populations.
:::* Non-barbiturate-habituated adults: approximately 80-85 hours.
:::* Barbiturate-habituated adults: approximately 55-60 hours.
:25-50% of PB is excreted unchanged in the urine. Alkalinization of the urine enhances elimination. Hepatic metabolism produces only inactive metabolites which are excreted in the urine and feces.
:Renal insufficiency has little effect upon elimination half-life, but severe renal failure likely prolongs elimination.<ref name = "Asconapé">Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 2014;119:417-432. doi:[https://doi.org/10.1016/B978-0-7020-4086-3.00027-8 10.1016/B978-0-7020-4086-3.00027-8]</ref>
:Hepatic cirrhosis has been shown to prolong elimination whereas acute viral hepatitis does not.<ref>Kutt H, Winters W, Scherman R, Mcdowell F. Diphenylhydantoin and Phenobarbital Toxicity. The Role of Liver Disease. Arch Neurol. 1964;11:649-656. doi:[https://doi.org/10.1001/archneur.1964.00460240081011 10.1001/archneur.1964.00460240081011]</ref>
 
 

=== Adverse Effects ===
:;Common
::Transient post-infusion dizziness, ataxia, and/or nystagmus
::Injection-site reactions
:;Uncommon
::Allergic reactions
:;Very uncommon
::Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermic necrolysis
:;With overdose
::Coma
::Respiratory depression
::Vomiting
:;With severe overdose
::Apnea
::Cardiovascular collapse
:;Cardiac conduction
::Neither the manufacturer package insert nor Lexicomp report cardiac conduction effects (such as QT prolongation) or increased risk of arrhythmias.
 

=== Cautions ===
:Acute or chronic pain
:Airway obstruction
:Respiratory distress
 
 

=== Contraindications ===
:History of porphyria
 
 

=== Pregnancy ===
:;Pregnancy Risk Factor
::Injection: Category '''D'''
 
:PB readily crosses placenta and yields fetal blood levels similar to maternal levels. Data from retrospective, case-controlled studies suggest an association with increased fetal abnormalities and malformations; however, this data has risk of confounding from the seizure disorder and other co-prescribed seizure medications. The manufacturer recommends that ''Phenobarbital should be used during pregnancy only when clearly indicated''.<ref name = "PBpkginsert"/> During labor, PB does not effect uterine contractions, but it does cause newborn respiratory depression.<ref name ="lexidrugs">Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019; Sept. 17, 2019.</ref>
 
 
=== Lactation ===
:PB readily passes into breast milk. The major effect is infant drowsiness but there are several reports of severe infant sedation. PB does not effect milk production.
:See [http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+401 TOXNET/LACTMED: PHENOBARBITAL] for details.
 
 

=== Toxicology ===
:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref>Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>
 
 

== '''Abbreviations''' ==
:'''AWS''': Alcohol Withdrawal Syndrome
:'''BBT''': Barbiturate[s]
:'''BZD''': Benzodiazepine[s]
:'''GABA''': Gamma-aminobutyric acid
:'''PB''': Phenobarbital
:'''YKDRH''': Yukon-Kuskokwim Delta Regional Hospital
 
 

== '''External Links''' ==
PubMed (all settings):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>)]
PubMed (ED/outpatient):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D)+AND+(%22emergency+department%22%5BTitle%2FAbstract%5D+OR+outpatient*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>) AND ("emergency department"[Title/Abstract<nowiki>]</nowiki> OR outpatient*[Title/Abstract<nowiki>]</nowiki>)]
 
Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert"/>.
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7478?searchUrl=%2Flco%2Faction%2Fsearch%3Bjsessionid%3Daf83d0252408d9273a5e3a8ac007%3Forigin%3Dapi%26t%3Dglobalid%26q%3D6763%26nq%3Dtrue#monograph-tab-content Lexicomp/Lexi-Drugs: Phenobarbital] 
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/lexier/1231760 Lexicomp/Lexi-Tox: Phenobarbital]
 
 
== '''Contributors''' ==
''Authors''
:Andrew W. Swartz, MD 
''Reviewers:''
:Travis Nelson, MD (suggestions incorporated)
:Megan Young, MD
:Tara Lathrop, MD
 
 

== '''References''' ==
<references />

Phenobarbital for Alcohol Withdrawal

2019-09-22T23:45:27Z

TravisN:

[https://en.wikipedia.org/wiki/Phenobarbital Phenobarbital] (PB) is a non-competitive [https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid gamma-Aminobutyric acid] (GABA) agonist which is an equally effective and safe alternative to benzodiazepines (BZD) for the treatment of alcohol withdrawal syndrome (AWS).<ref name="Mo2016">Mo Y, Thomas MC, Karras GE. Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2016;32:101-107. doi:[https://www.doi.org/10.1016/j.jcrc.2015.11.022 10.1016/j.jcrc.2015.11.022]</ref> Though its use for AWS has waned and consequently many clinicians are now unfamiliar with this regimen, PB has both mechanistic and pharmacokinetic properties which make it more suitable for outpatient monotherapy than BZD.
 
IV/IM titrated PB is the first-line outpatient medication used for treatment of AWS at the Yukon-Kuskokwim Delta Regional Hospital (YKDRH). Its use is favored because substantial experience at this institution has shown that it is safe, it is effective, it minimizes return visits, and it eliminates the need to dispense abuse-prone medications (i.e. BZD) to abuse-prone patients while in the midst of a substance abuse crisis. Indeed, minimizing high-risk dispensing of abuse-prone medication is important for improving the health of our community.
 
The treatment of AWS with phenobarbital (or barbiturates [BBT] in general) is not new, but it has fallen so out of favor that many clinicians are unfamiliar with this use. However, there is ample published evidence, both old and new, indicating that phenobarbital is ''at least'' equally safe and effective compared with benzodiazepines.
 
 
__TOC__ 
 
 
== '''Treatment Principles and Pearls''' ==
=== Sub-sedative dosing ===
: Alcohol withdrawal is a ''hyper''-alert and/or ''hyper''-autonomic state. The goal of outpatient treatment of alcohol withdrawal is ''normalization'' of alertness (i.e. level of consciousness) and autonomic function, not sedation. If a sedative level of [any] medication is required for AWS symptom control, then admission is often indicated.
 

=== Dose titration ===
: Patients’ individual medication requirements are unpredictable. Therefore no standard PB dose is expected to be effective for all patients. Rather, an initial IV (or IM) PB dose of 260 mg is given, and then every 30 minutes (or 60 minutes for IM) an additional 130mg are given until the desired effect is achieved. Using this regimen, many patients will require repeat doses, but none should end up “sedated.”
 
: The standard 260mg/130mg regimen works well for average size patients. This regimen yields weight-based doses of 3.7 mg/kg and 1.9 mg/kg in a 70 kg patient. However, for patients substantially below or above 70 kg, clinicians should consider administering 4 mg/kg with subsequent doses of 2 mg/kg. For convenience, these doses can be rounded to the nearest 130 mg increment (i.e. the amount in a single vial). For example, weight-based doing for a 125 kg patient would yield 500 mg and 250 mg doses, and these can be safely rounded to 520mg and 260mg for ease of administration. Weight-based dosing prevents sedating unusually small patients while preventing excessively long visits for unusually large patients. Dosing in whole-vial increments minimizes the risk of dosing errors and eliminates the effort required to precisely dose from a 1mL vial.
 
=== Dosing interval ===
:In pharmacokinetic studies of rapid PB boluses, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982">Paulson OB, Györy A, Hertz MM. Blood-brain barrier transfer and cerebral uptake of antiepileptic drugs. Clin Pharmacol Ther. 1982;32(4):466-477. doi:[https://doi.org/10.1038/clpt.1982.190 10.1038/clpt.1982.190]</ref> Yet clinical judgment must still be used. At 30 minutes after a PB dose, if the patient has “almost” complete symptom relief, the clinician should appreciate the possibility of a small amount of biological variability and consider reevaluating after another 10 minutes, as it is possible that a small additional effect may become apparent. But if the dose is clearly inadequate at 30 minutes, further waiting is very unlikely to reveal any substantial further effect.
 
=== Sleep after symptom control ===
: When patients’ hyper-alert/hyper-autonomic state is normalized, many will lightly nap. But such patients easily awaken to voice or light touch and they easily meet all discharge criteria. Rather than being “sedated,” such patients are merely exhibiting the normal physiologic response in the absence of discomfort to a 24-48 hour sleep deficit (which is the norm for patients in this situation). Any concern for sedation can usually be answered by asking oneself if the patient’s post-treatment behavior would be considered '''ab'''normal for a patient in the ED with a normal mental status, with a substantial sleep deficit, whose discomfort had been relieved. If the answer is “no”, then the patient is not “sedated,” but rather has been returned to a normal level of alertness.
 
=== Post-infusion dizziness/nystagmus/ataxia ===
:Post-infusion dizziness/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.
 
=== Isolated withdrawal hallucinosis ===
: A subset of AWS patients will present as soon as 12 hours after alcohol cessation with classic withdrawal hallucinations but without any signs of hyper-alertness, clouding of consciousness, confusion, or autonomic hyper-stimulation. This is a well documented variant of AWS, and it should be neither under-treated (i.e. dismissed as fake) nor over-treated (i.e. managed as delirium tremens). Hallucinations are one of the many manifestations of AWS, and they can occur in isolation or in combination with other signs. Primary management is a therapeutic level of GABA agonist (i.e. PB or a BZD). The use of anti-psychotic medications is contraversial. If hallucinations are refractory to an appropriate level of GABA agonist then an anti-psychotic medication can be added. However, caution is advised because there have been reports of increased mortality associated with these medications due to arrhythmias (due to QT prolongation) and lowering the seizure threshold. The risk/benefit must be carefully weighted in these situations, especially in the first 48 hours when the seizure risk is highest. Anti-psychotic medications should never be the first-line or sole therapy for hallucinosis or other withdrawal symptoms.<ref>Jesse S, Bråthen G, Ferrara M, et al. Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurol Scand. 2017;135(1):4-16. doi:[https://doi.org/10.1111/ane.12671 10.1111/ane.12671].</ref>
 
 

=== Alcoholic Hallucinosis ===

Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations without other strong evidence of alcohol withdrawal or alcohol delirium. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing gaba agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.

[[Media:Barkat_et_al_2017.pdf]]

Alcoholic hallucinosis. Bhat PS et al. Ind Psychiatry J. 2012 Jul;21(2):155-7.

Phenomenology and Course of Alcoholic Hallucinosis. Narasimha VL, et al. J Dual Diagn. 2019 Jul-Sep;15(3):172-176.

Alcohol-induced psychotic disorder: a review. Jordaan GP, Emsley R. Metab Brain Dis. 2014 Jun;29(2):231-43.

== '''Evidence of Effectiveness and Safety''' ==
=== Systematic Review / Meta-analysis ===
* A 2016 systematic review by '''Mo et al'''. in the ''Journal of Critical Care''<ref name="Mo2016" /> concluded that "''barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS.''" This review included three randomized controlled trials (RCT's) and four observational studies. Importantly, the authors observed that "''none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS.''" While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.<ref name="Hendey2011">Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382-385. doi:[https://doi.org/10.1016/j.ajem.2009.10.010 10.1016/j.ajem.2009.10.010]</ref>) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.
* Other systematic reviews<ref name = "Minozzi2010">Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064. doi:[https://doi.org/10.1002/14651858.CD005064.pub3 10.1002/14651858.CD005064.pub3]</ref><ref>Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537. doi:[https://doi.org/10.1002/14651858.CD008537.pub2 10.1002/14651858.CD008537.pub2]</ref> have only indirectly assessed the effectiveness of PB for AWS. These reviews have grouped all studies which compared any anti-convulsant to a BZD, and then concluded that anti-convulsants (as a group) are inferior to BZDs for treatment of AWS. This grouping of PB with other anti-convulsants badly biases the results against PB and does not seem justified. The mechanism of action of both PB and BZDs is non-competitive agonism of the GABAA ion channel and both of these medication have been long known to display cross-tolerance with each other and alcohol. Conversely, the other anti-convulsants work via different mechanisms. Therefore grouping PB with the other anti-convulsants is inappropriate and seems to merely reflect how the authors think about the drugs rather than their pharmacological properties.

=== Studies of ED/Outpatient Treatment ===
* '''Young et al'''. (1987, prospective uncontrolled study, n=62)<ref name = "Young1987">Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987;16(8):847-850. doi:[https://doi.org/10.1016/s0196-0644(87)80520-6 10.1016/s0196-0644(87)80520-6]</ref> 
::62 patients received IV PB loading dose in the emergency department. The protocol was an initial 260mg which was followed by 130mg increments, but the dosing interval is unclear. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experienced minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention. All patients were discharged from the ED and none returned for further care during the following week.

* '''Hendey et al'''. (2011, RCT of PB vs lorazepam, n=25/19)<ref name="Hendey2011" /> 
::44 ED patients were randomized (25 to IV-PB, 19 to LZ). PB patients received a 230 mg initial dose followed by 130mg subsequent doses (dosing interval was "''at the discretion of the treating physician''"). Mean PB dose was 509 mg (range 260-910 mg); mean number of doses was 2.9 (range 1-6). There were no outcome differences at 48 hours, and importantly, there was no significant difference in length of ED stay (267 min for PB versus 256 min for LZ). Fewer PB patients required admission (12 vs. 16). The authors concluded that "''phenobarbital and LZ were similarly effective in the treatment of mild/moderate alcohol withdrawal in the ED and at 48 hours.''"

* '''Nelson et al'''. (2019, retrospective cohort study)<ref>Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019;37(4):733-736. doi:[https://doi.org/10.1016/j.ajem.2019.01.002 10.1016/j.ajem.2019.01.002]</ref> 
::300 ED patients: 100 received IV-PB alone, 100 received IV-PB + lorazepam, and 100 received diazepam alone. Initial PB dose was 260mg and subsequent doses were 130mg (dosing interval is not specified). Authors' conclusions: "''Incorporating phenobarbital into a benzodiazepine based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department''."

=== Historical Reports ===
:PB has long been used for treatment of delirium tremens (DT). Though it has fallen out of favor in most places, a minority of countries and institutions have continued to use it as first line treatment of AWS.
::* A 2010 study by Michaelsen in the ''Danish Medical Bulletin''<ref>Michaelsen IH, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens--a retrospective study. Dan Med Bull. 2010;57(8):A4169.</ref> states BBTs have been used for treatment of DT in Denmark "for over 100 years."
::* A 2006 RCT of gabapentin for AWS<ref>Mariani JJ, Rosenthal RN, Tross S, Singh P, Anand OP. A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal. Am J Addict. 2006;15(1):76-84. doi:[https://doi.org/10.1080/10550490500419110 10.1080/10550490500419110]</ref> compared it to a control group which received PB. The authors gave the following explanation in the methods section:
::::''Those randomized to the experimental group received a protocol using gabapentin, while those in the control group received a phenobarbital protocol that is customary in our inpatient detoxification service. Phenobarbital was used in this study rather than benzodiazepines because it is the detoxification medication that the clinical staff is most familiar with.''
::* A 1995 United States nationwide survey of inpatient alcohol treatment centers<ref>Saitz R, Friedman LS, Mayo-Smith MF. Alcohol withdrawal: a nationwide survey of inpatient treatment practices. J Gen Intern Med. 1995;10(9):479-487. doi:[https://doi.org/10.1007/bf02602395 10.1007/bf02602395]</ref> reported that approximately 10% primarily used PB for treatment of AWS.

=== EVIDENCE SUMMARY ===
:In landmark studies by Kaim and Klett in 1969<ref>Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969;125(12):1640-1646. doi:[https://doi.org/10.1176/ajp.125.12.1640 10.1176/ajp.125.12.1640]</ref> and 1972,<ref>Kaim SC, Klett CJ. Treatment of delirium tremens. A comparative evaluation of four drugs. Q J Stud Alcohol. 1972;33(4):1065-1072.</ref> both BBTs and BZDs were shown to be equally effective in treatment of AWS. Both of these drug classes had been previously known to exhibit cross dependance with each other as well as alcohol, and the subsequent discovery that these structurally unrelated compounds are both GABA agonists was critical to understanding the pathophysiology of AWS. 
 
:Though BZDs have become the standard of care, this seems mostly attributable to a larger movement away from inpatient treatment and toward outpatient treatment with oral medications. Dispensing BZDs to patients is clearly safer than dispensing PB/BBTs. Yet when the dose is titrated to effect by a physician and patients are not dispensed medication, there is ample evidence that PB is equally safe and effective compared to BZD. 
 
:Numerous articles advise caution with regard to PB by alluding to concerns about respiratory depression, but no evidence of adverse effects is ever presented or cited. Therefore these concerns seem to originate more from the authors' lack of familiarity with the use of IV-PB in this setting than from documented outcomes. However, it must be pointed out that PB should '''''never''''' be dispensed to a patient for symptom-triggered dosing, as this would present an '''extreme risk''' of unintentional lethal overdose. PB use for AWS ''must'' be limited to titrating the dose to the desired effect, and then discharging the patient without additional medication. There have been no reports of iatrogenic overdoses using this protocol, and the drug packaging is a strong mitigating factor to prevent drug errors: At YKDRH, PB is only available in 130mg vials. Therefore the initial dose is two vials and the subsequent doses are one vial. A dangerous overdose (i.e. one yielding respiratory depression) would require accidentally drawing up 20-30 vials, which would be very labor intensive and very likely produce questions prior to administration. ''(PB is also marketed in 65mg vials, but that would require even more vials to produce an overdose.)''
 
 

== '''Regulatory Information and Packaging''' ==
*PB is not approved by the U.S. FDA; this is likely due its use preceding the creation of the FDA (in 1938).
*DEA Schedule: IV
*Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert">Phenobarbital sodium [[https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 package insert]]. Eatontown, NJ: West-Ward Pharmaceuticals Corporation; 2018.</ref>.
*How Supplied:
:::Phenobarbital Sodium Injection, 65 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0476-25) 
:::Phenobarbital Sodium Injection, 130 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0477-25) 
 
 

== '''Pharmacology''' ==
 
The following are some of the important properties of PB with regard to outpatient treatment of AWS. 
 
=== Classification ===
:; Chemical Class
::PB belongs to the chemical class ''barbiturate''.
:; Clinical Class
:# Like all barbiturates, PB is a ''sedative/hypnotic''.<ref name = "Harvey1979">Harvey SC. Hypnotics and Sedatives: The Barbiturates. In: Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 5th ed. New York: MacMillan Publishing Co., Inc.; 1975:124-136.</ref> However, it is almost never used for this purpose.
:# PB is also classified as an ''anti-convulsant''. 
::::::''In anesthetic doses, all BBTs have an anti-convulsant effect. However, PB is the only BBT which has an anti-convulsant effect at sub-sedative doses. (Historically, two closely related derivatives [mephobarbital and metharbital] also had an anti-convulsant effect at sub-sedative doses).''<ref name="Harvey1979" />
 

=== Mechanism of Action ===
:; GABA agonist
::The binding of GABA to its receptor inhibits nerve depolarization. Like all barbiturates, PB's sedative/hypnotic effect occurs primarily via noncompetitive agonism of the GABAA receptor on the GABA-mediated ion channel. Like BZDs, PB/BBTs do not themselves open the channel and thus GABA is still required. PB/BBTs bind at a different site on the GABAA receptor than BZDs.<ref name = "Hobbs1996">Hobbs WR, Rall TW, Verdoorn TA. Ch 17: Hypnotics and Sedatives; Ethanol. In: Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:361-398.</ref> 
::When PB/BBTs bind to the GABAA receptor, three effects occur: 
::::::# Enhancement of the binding of GABA<ref name="Hobbs1996" /> 
::::::# Enhancement of the binding of BZDs<ref name="Hobbs1996" /> 
::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /> 
::Both 2 and 3 indicate a potential synergistic effect when co-administered with BZDs. Studies have shown that dual therapy is superior to either PB or BZDs alone,(insert refs) indicating at least an additive effect.
:; Glutamate antagonist
::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>
 
 

=== Distribution ===

:Volume of distribution is X(ref).

:Plasma protein binding has been estimated as X percent, predominantly to albumin.(ref)
 
==== Venous concentration versus infused dose ====
{| class="wikitable" style="float:right;font-size: 85%; border: 1px solid black;"
|+ style="caption-side:top; text-align:center;" |Table-1. PB dose, concentration, and ratio for [nonexclusive] subgroups reported in Young (1987).<ref name = "Young1987" />
|-
! scope="col"| Group
! scope="col"| PB Dose (mg/kg)
! scope="col" style="width: 50px;"| Serum Concentration (μ/mL)
! scope="col" style="width: 70px;"| Conc : Dose Ratio
|-
| scope="row"| Tremulous (n=48)
| style="text-align:center;" | 8.5
| style="text-align:center;" | 14.0
| style="text-align:center;" | 1.65
|-
| scope="row"| Seizures (n=38)
| style="text-align:center;" | 8.3
| style="text-align:center;" | 13.8
| style="text-align:center;" | 1.66
|-
| scope="row"| Alcoholic liver disease (n=21)
| style="text-align:center;" | 8.2
| style="text-align:center;" | 13.7
| style="text-align:center;" | 1.67
|-
| scope="row"| ALL (n=62)
| style="text-align:center;" | 8.4
| style="text-align:center;" | 13.9
| style="text-align:center;" | 1.65
|}
::Young (1987)<ref name = "Young1987"/> compared infused PB doses to post-infusion serum PB concentrations in adults presenting to the ED for AWS, and reported that the serum PB level rose 1.65 μg/mL for each mg/kg of PB infused. Though no standard deviation is reported, the similarity of outcomes in different subgroups (including those with alcoholic liver disease) is indicative of very minimal variability of the final serum concentration versus the infused dose (see Table-1).
 
 

==== Venous concentration versus time ====
:: Following rapid bolus injection in adults, PB quickly distributes in the blood, achieving peak venous concentration at about 3 minutes and settling into a relatively steady concentration by 5 minutes.<ref>Bøjholm S, Paulson OB, Flachs H. Arterial and venous concentrations of phenobarbital, phenytoin, clonazepam, and diazepam after rapid intravenous injections. Clin Pharmacol Ther. 1982;32(4):478-483. doi:[https://doi.org/10.1038/clpt.1982.191 10.1038/clpt.1982.191]</ref>
 
==== Brain concentration versus time====
:: Paulson et al. showed that after rapid bolus injection, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982"/>
[[File:PB_CSF_pharmacokinetics_01.PNG|center|thumb|500px|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]
 
However, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>
 
 
=== Bioavailability ===
Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).
 
 
=== Dosing ===
==== Infused dose, Venous concentration, and Clinical Effect ====
::Figure-2 is a nomagram illustrating the expected serum PB levels based on infusion dose (in mg/kg) and it also shows expected effects at particular concentrations as well as the dose ranges reported in applicable studies. 
[[File:PB Dose-Level NOMOGRAM DRAFT.png|center|thumb|500px|'''Fig-1. Phenobarbital weight-based infused dose with associated serum levels and clinical effects'''. Copyright: Andrew W. Swartz, MD (Sept 2019).]]
 

==== Recommended Dosing ====
:;Intravenous
:: '''Initial''': 260mg (or approximately 4 mg/kg) over 10 minutes
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) over 10 minutes, repeat every '''30''' minutes until adequate symptom relief
:: '''Infusion Rate''': ≤ 60 mg/min (adults)<ref name = "PBpkginsert"/>
 
:;Intramuscular
:: '''Initial''': 260mg (or approximately 4 mg/kg)
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) every '''60-90''' minutes until adequate symptom relief
 
:;Dosing Pearls:
:* Weight-based dosing should be considered for patients who are particularly under or overweight.
:* It is convenient to save two orders (i.e. one for 260mg and one for 130mg) which specify administration "over 10 minutes via infusion pump." This provides standardization, safety, and efficient use of nursing time.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* If adequate symptom relief cannot be obtained with a sub-sedative dose of PB, then the patient should be admitted for dual-treatment with a BZD. These patients warrant consideration for transfer for ICU care.
 
:;Oral Dosing
:* Oral dosing information is for hypothetical purposes only. There is no standard indication for this regimen at YKDRH, but in highly unusual circumstances this information might be useful.
:* Oral PB has 95-100% bioavailability.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* Three uncontrolled observational studies have reported results of an orally titrated PB loading regimen for treatment of "sedative/hypnotic" withdrawal.<ref name = "Robinson1981">Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther. 1981;30(1):71-76. doi:[https://doi.org/10.1038/clpt.1981.129 10.1038/clpt.1981.129]</ref><ref name = "Janecek1987">Janecek E, Kapur BM, Devenyi P. Oral phenobarbital loading: a safe method of barbiturate and nonbarbiturate hypnosedative withdrawal. CMAJ. 1987;137(5):410-412. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1492801/ PMID: 3621099/]</ref><ref>1. Loder E, Biondi D. Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache. 2003;43(8):904-909. doi:[https://doi.org/10.1046/j.1526-4610.2003.03171.x 10.1046/j.1526-4610.2003.03171.x]</ref> The three studies involved a total of 87 patients, and they administered PB 120mg orally each hour until the desired therapeutic affect was achieved. There were zero occurrences of adverse effects or over-sedation despite minimal monitoring (nursing contact once per hour). The average final doses were 1440mg, 1315mg, and 1180, respectively. The authors concluded the regimen is safe, effective, and efficient (i.e. requires minimal nursing resources). The caveat to consider is that these patients were withdrawing from barbiturates, therefore they had developed tolerance. If used for alcohol withdrawal, lower final doses should be anticipated.
 

=== Elimination ===
:The half-life of PB is frequently reported as 100 hours or as 80-120 hours.<ref>Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979;26(2):256-264. doi:10.1002/cpt1979262256</ref> This is an accurate generalization, but the generalization hides the variation among different populations.
:::* Non-barbiturate-habituated adults: approximately 80-85 hours.
:::* Barbiturate-habituated adults: approximately 55-60 hours.
:25-50% of PB is excreted unchanged in the urine. Alkalinization of the urine enhances elimination. Hepatic metabolism produces only inactive metabolites which are excreted in the urine and feces.
:Renal insufficiency has little effect upon elimination half-life, but severe renal failure likely prolongs elimination.<ref name = "Asconapé">Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 2014;119:417-432. doi:[https://doi.org/10.1016/B978-0-7020-4086-3.00027-8 10.1016/B978-0-7020-4086-3.00027-8]</ref>
:Hepatic cirrhosis has been shown to prolong elimination whereas acute viral hepatitis does not.<ref>Kutt H, Winters W, Scherman R, Mcdowell F. Diphenylhydantoin and Phenobarbital Toxicity. The Role of Liver Disease. Arch Neurol. 1964;11:649-656. doi:[https://doi.org/10.1001/archneur.1964.00460240081011 10.1001/archneur.1964.00460240081011]</ref>
 
 

=== Adverse Effects ===
:;Common
::Transient post-infusion dizziness, ataxia, and/or nystagmus
::Injection-site reactions
:;Uncommon
::Allergic reactions
:;Very uncommon
::Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermic necrolysis
:;With overdose
::Coma
::Respiratory depression
::Vomiting
:;With severe overdose
::Apnea
::Cardiovascular collapse
:;Cardiac conduction
::Neither the manufacturer package insert nor Lexicomp report cardiac conduction effects (such as QT prolongation) or increased risk of arrhythmias.
 

=== Cautions ===
:Acute or chronic pain
:Airway obstruction
:Respiratory distress
 
 

=== Contraindications ===
:History of porphyria
 
 

=== Pregnancy ===
:;Pregnancy Risk Factor
::Injection: Category '''D'''
 
:PB readily crosses placenta and yields fetal blood levels similar to maternal levels. Data from retrospective, case-controlled studies suggest an association with increased fetal abnormalities and malformations; however, this data has risk of confounding from the seizure disorder and other co-prescribed seizure medications. The manufacturer recommends that ''Phenobarbital should be used during pregnancy only when clearly indicated''.<ref name = "PBpkginsert"/> During labor, PB does not effect uterine contractions, but it does cause newborn respiratory depression.<ref name ="lexidrugs">Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019; Sept. 17, 2019.</ref>
 
 
=== Lactation ===
:PB readily passes into breast milk. The major effect is infant drowsiness but there are several reports of severe infant sedation. PB does not effect milk production.
:See [http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+401 TOXNET/LACTMED: PHENOBARBITAL] for details.
 
 

=== Toxicology ===
:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref>Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>
 
 

== '''Abbreviations''' ==
:'''AWS''': Alcohol Withdrawal Syndrome
:'''BBT''': Barbiturate[s]
:'''BZD''': Benzodiazepine[s]
:'''GABA''': Gamma-aminobutyric acid
:'''PB''': Phenobarbital
:'''YKDRH''': Yukon-Kuskokwim Delta Regional Hospital
 
 

== '''External Links''' ==
PubMed (all settings):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>)]
PubMed (ED/outpatient):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D)+AND+(%22emergency+department%22%5BTitle%2FAbstract%5D+OR+outpatient*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>) AND ("emergency department"[Title/Abstract<nowiki>]</nowiki> OR outpatient*[Title/Abstract<nowiki>]</nowiki>)]
 
Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert"/>.
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7478?searchUrl=%2Flco%2Faction%2Fsearch%3Bjsessionid%3Daf83d0252408d9273a5e3a8ac007%3Forigin%3Dapi%26t%3Dglobalid%26q%3D6763%26nq%3Dtrue#monograph-tab-content Lexicomp/Lexi-Drugs: Phenobarbital] 
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/lexier/1231760 Lexicomp/Lexi-Tox: Phenobarbital]
 
 
== '''Contributors''' ==
''Authors''
:Andrew W. Swartz, MD 
''Reviewers:''
:Travis Nelson, MD (suggestions incorporated)
:Megan Young, MD
:Tara Lathrop, MD
 
 

== '''References''' ==
<references />

Phenobarbital for Alcohol Withdrawal

2019-09-22T23:44:41Z

TravisN:

[https://en.wikipedia.org/wiki/Phenobarbital Phenobarbital] (PB) is a non-competitive [https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid gamma-Aminobutyric acid] (GABA) agonist which is an equally effective and safe alternative to benzodiazepines (BZD) for the treatment of alcohol withdrawal syndrome (AWS).<ref name="Mo2016">Mo Y, Thomas MC, Karras GE. Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2016;32:101-107. doi:[https://www.doi.org/10.1016/j.jcrc.2015.11.022 10.1016/j.jcrc.2015.11.022]</ref> Though its use for AWS has waned and consequently many clinicians are now unfamiliar with this regimen, PB has both mechanistic and pharmacokinetic properties which make it more suitable for outpatient monotherapy than BZD.
 
IV/IM titrated PB is the first-line outpatient medication used for treatment of AWS at the Yukon-Kuskokwim Delta Regional Hospital (YKDRH). Its use is favored because substantial experience at this institution has shown that it is safe, it is effective, it minimizes return visits, and it eliminates the need to dispense abuse-prone medications (i.e. BZD) to abuse-prone patients while in the midst of a substance abuse crisis. Indeed, minimizing high-risk dispensing of abuse-prone medication is important for improving the health of our community.
 
The treatment of AWS with phenobarbital (or barbiturates [BBT] in general) is not new, but it has fallen so out of favor that many clinicians are unfamiliar with this use. However, there is ample published evidence, both old and new, indicating that phenobarbital is ''at least'' equally safe and effective compared with benzodiazepines.
 
 
__TOC__ 
 
 
== '''Treatment Principles and Pearls''' ==
=== Sub-sedative dosing ===
: Alcohol withdrawal is a ''hyper''-alert and/or ''hyper''-autonomic state. The goal of outpatient treatment of alcohol withdrawal is ''normalization'' of alertness (i.e. level of consciousness) and autonomic function, not sedation. If a sedative level of [any] medication is required for AWS symptom control, then admission is often indicated.
 

=== Dose titration ===
: Patients’ individual medication requirements are unpredictable. Therefore no standard PB dose is expected to be effective for all patients. Rather, an initial IV (or IM) PB dose of 260 mg is given, and then every 30 minutes (or 60 minutes for IM) an additional 130mg are given until the desired effect is achieved. Using this regimen, many patients will require repeat doses, but none should end up “sedated.”
 
: The standard 260mg/130mg regimen works well for average size patients. This regimen yields weight-based doses of 3.7 mg/kg and 1.9 mg/kg in a 70 kg patient. However, for patients substantially below or above 70 kg, clinicians should consider administering 4 mg/kg with subsequent doses of 2 mg/kg. For convenience, these doses can be rounded to the nearest 130 mg increment (i.e. the amount in a single vial). For example, weight-based doing for a 125 kg patient would yield 500 mg and 250 mg doses, and these can be safely rounded to 520mg and 260mg for ease of administration. Weight-based dosing prevents sedating unusually small patients while preventing excessively long visits for unusually large patients. Dosing in whole-vial increments minimizes the risk of dosing errors and eliminates the effort required to precisely dose from a 1mL vial.
 
=== Dosing interval ===
:In pharmacokinetic studies of rapid PB boluses, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982">Paulson OB, Györy A, Hertz MM. Blood-brain barrier transfer and cerebral uptake of antiepileptic drugs. Clin Pharmacol Ther. 1982;32(4):466-477. doi:[https://doi.org/10.1038/clpt.1982.190 10.1038/clpt.1982.190]</ref> Yet clinical judgment must still be used. At 30 minutes after a PB dose, if the patient has “almost” complete symptom relief, the clinician should appreciate the possibility of a small amount of biological variability and consider reevaluating after another 10 minutes, as it is possible that a small additional effect may become apparent. But if the dose is clearly inadequate at 30 minutes, further waiting is very unlikely to reveal any substantial further effect.
 
=== Sleep after symptom control ===
: When patients’ hyper-alert/hyper-autonomic state is normalized, many will lightly nap. But such patients easily awaken to voice or light touch and they easily meet all discharge criteria. Rather than being “sedated,” such patients are merely exhibiting the normal physiologic response in the absence of discomfort to a 24-48 hour sleep deficit (which is the norm for patients in this situation). Any concern for sedation can usually be answered by asking oneself if the patient’s post-treatment behavior would be considered '''ab'''normal for a patient in the ED with a normal mental status, with a substantial sleep deficit, whose discomfort had been relieved. If the answer is “no”, then the patient is not “sedated,” but rather has been returned to a normal level of alertness.
 
=== Post-infusion dizziness/nystagmus/ataxia ===
:Post-infusion dizziness/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.
 
=== Isolated withdrawal hallucinosis ===
: A subset of AWS patients will present as soon as 12 hours after alcohol cessation with classic withdrawal hallucinations but without any signs of hyper-alertness, clouding of consciousness, confusion, or autonomic hyper-stimulation. This is a well documented variant of AWS, and it should be neither under-treated (i.e. dismissed as fake) nor over-treated (i.e. managed as delirium tremens). Hallucinations are one of the many manifestations of AWS, and they can occur in isolation or in combination with other signs. Primary management is a therapeutic level of GABA agonist (i.e. PB or a BZD). The use of anti-psychotic medications is contraversial. If hallucinations are refractory to an appropriate level of GABA agonist then an anti-psychotic medication can be added. However, caution is advised because there have been reports of increased mortality associated with these medications due to arrhythmias (due to QT prolongation) and lowering the seizure threshold. The risk/benefit must be carefully weighted in these situations, especially in the first 48 hours when the seizure risk is highest. Anti-psychotic medications should never be the first-line or sole therapy for hallucinosis or other withdrawal symptoms.<ref>Jesse S, Bråthen G, Ferrara M, et al. Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurol Scand. 2017;135(1):4-16. doi:[https://doi.org/10.1111/ane.12671 10.1111/ane.12671].</ref>
 
 

=== Alcoholic Hallucinosis ===

Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations without other strong evidence of alcohol withdrawal or alcohol delirium. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing gaba agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.

[[Media:Barkat_et_al_2017.ogg]]

Alcoholic hallucinosis. Bhat PS et al. Ind Psychiatry J. 2012 Jul;21(2):155-7.

Phenomenology and Course of Alcoholic Hallucinosis. Narasimha VL, et al. J Dual Diagn. 2019 Jul-Sep;15(3):172-176.

Alcohol-induced psychotic disorder: a review. Jordaan GP, Emsley R. Metab Brain Dis. 2014 Jun;29(2):231-43.

== '''Evidence of Effectiveness and Safety''' ==
=== Systematic Review / Meta-analysis ===
* A 2016 systematic review by '''Mo et al'''. in the ''Journal of Critical Care''<ref name="Mo2016" /> concluded that "''barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS.''" This review included three randomized controlled trials (RCT's) and four observational studies. Importantly, the authors observed that "''none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS.''" While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.<ref name="Hendey2011">Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382-385. doi:[https://doi.org/10.1016/j.ajem.2009.10.010 10.1016/j.ajem.2009.10.010]</ref>) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.
* Other systematic reviews<ref name = "Minozzi2010">Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064. doi:[https://doi.org/10.1002/14651858.CD005064.pub3 10.1002/14651858.CD005064.pub3]</ref><ref>Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537. doi:[https://doi.org/10.1002/14651858.CD008537.pub2 10.1002/14651858.CD008537.pub2]</ref> have only indirectly assessed the effectiveness of PB for AWS. These reviews have grouped all studies which compared any anti-convulsant to a BZD, and then concluded that anti-convulsants (as a group) are inferior to BZDs for treatment of AWS. This grouping of PB with other anti-convulsants badly biases the results against PB and does not seem justified. The mechanism of action of both PB and BZDs is non-competitive agonism of the GABAA ion channel and both of these medication have been long known to display cross-tolerance with each other and alcohol. Conversely, the other anti-convulsants work via different mechanisms. Therefore grouping PB with the other anti-convulsants is inappropriate and seems to merely reflect how the authors think about the drugs rather than their pharmacological properties.

=== Studies of ED/Outpatient Treatment ===
* '''Young et al'''. (1987, prospective uncontrolled study, n=62)<ref name = "Young1987">Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987;16(8):847-850. doi:[https://doi.org/10.1016/s0196-0644(87)80520-6 10.1016/s0196-0644(87)80520-6]</ref> 
::62 patients received IV PB loading dose in the emergency department. The protocol was an initial 260mg which was followed by 130mg increments, but the dosing interval is unclear. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experienced minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention. All patients were discharged from the ED and none returned for further care during the following week.

* '''Hendey et al'''. (2011, RCT of PB vs lorazepam, n=25/19)<ref name="Hendey2011" /> 
::44 ED patients were randomized (25 to IV-PB, 19 to LZ). PB patients received a 230 mg initial dose followed by 130mg subsequent doses (dosing interval was "''at the discretion of the treating physician''"). Mean PB dose was 509 mg (range 260-910 mg); mean number of doses was 2.9 (range 1-6). There were no outcome differences at 48 hours, and importantly, there was no significant difference in length of ED stay (267 min for PB versus 256 min for LZ). Fewer PB patients required admission (12 vs. 16). The authors concluded that "''phenobarbital and LZ were similarly effective in the treatment of mild/moderate alcohol withdrawal in the ED and at 48 hours.''"

* '''Nelson et al'''. (2019, retrospective cohort study)<ref>Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019;37(4):733-736. doi:[https://doi.org/10.1016/j.ajem.2019.01.002 10.1016/j.ajem.2019.01.002]</ref> 
::300 ED patients: 100 received IV-PB alone, 100 received IV-PB + lorazepam, and 100 received diazepam alone. Initial PB dose was 260mg and subsequent doses were 130mg (dosing interval is not specified). Authors' conclusions: "''Incorporating phenobarbital into a benzodiazepine based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department''."

=== Historical Reports ===
:PB has long been used for treatment of delirium tremens (DT). Though it has fallen out of favor in most places, a minority of countries and institutions have continued to use it as first line treatment of AWS.
::* A 2010 study by Michaelsen in the ''Danish Medical Bulletin''<ref>Michaelsen IH, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens--a retrospective study. Dan Med Bull. 2010;57(8):A4169.</ref> states BBTs have been used for treatment of DT in Denmark "for over 100 years."
::* A 2006 RCT of gabapentin for AWS<ref>Mariani JJ, Rosenthal RN, Tross S, Singh P, Anand OP. A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal. Am J Addict. 2006;15(1):76-84. doi:[https://doi.org/10.1080/10550490500419110 10.1080/10550490500419110]</ref> compared it to a control group which received PB. The authors gave the following explanation in the methods section:
::::''Those randomized to the experimental group received a protocol using gabapentin, while those in the control group received a phenobarbital protocol that is customary in our inpatient detoxification service. Phenobarbital was used in this study rather than benzodiazepines because it is the detoxification medication that the clinical staff is most familiar with.''
::* A 1995 United States nationwide survey of inpatient alcohol treatment centers<ref>Saitz R, Friedman LS, Mayo-Smith MF. Alcohol withdrawal: a nationwide survey of inpatient treatment practices. J Gen Intern Med. 1995;10(9):479-487. doi:[https://doi.org/10.1007/bf02602395 10.1007/bf02602395]</ref> reported that approximately 10% primarily used PB for treatment of AWS.

=== EVIDENCE SUMMARY ===
:In landmark studies by Kaim and Klett in 1969<ref>Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969;125(12):1640-1646. doi:[https://doi.org/10.1176/ajp.125.12.1640 10.1176/ajp.125.12.1640]</ref> and 1972,<ref>Kaim SC, Klett CJ. Treatment of delirium tremens. A comparative evaluation of four drugs. Q J Stud Alcohol. 1972;33(4):1065-1072.</ref> both BBTs and BZDs were shown to be equally effective in treatment of AWS. Both of these drug classes had been previously known to exhibit cross dependance with each other as well as alcohol, and the subsequent discovery that these structurally unrelated compounds are both GABA agonists was critical to understanding the pathophysiology of AWS. 
 
:Though BZDs have become the standard of care, this seems mostly attributable to a larger movement away from inpatient treatment and toward outpatient treatment with oral medications. Dispensing BZDs to patients is clearly safer than dispensing PB/BBTs. Yet when the dose is titrated to effect by a physician and patients are not dispensed medication, there is ample evidence that PB is equally safe and effective compared to BZD. 
 
:Numerous articles advise caution with regard to PB by alluding to concerns about respiratory depression, but no evidence of adverse effects is ever presented or cited. Therefore these concerns seem to originate more from the authors' lack of familiarity with the use of IV-PB in this setting than from documented outcomes. However, it must be pointed out that PB should '''''never''''' be dispensed to a patient for symptom-triggered dosing, as this would present an '''extreme risk''' of unintentional lethal overdose. PB use for AWS ''must'' be limited to titrating the dose to the desired effect, and then discharging the patient without additional medication. There have been no reports of iatrogenic overdoses using this protocol, and the drug packaging is a strong mitigating factor to prevent drug errors: At YKDRH, PB is only available in 130mg vials. Therefore the initial dose is two vials and the subsequent doses are one vial. A dangerous overdose (i.e. one yielding respiratory depression) would require accidentally drawing up 20-30 vials, which would be very labor intensive and very likely produce questions prior to administration. ''(PB is also marketed in 65mg vials, but that would require even more vials to produce an overdose.)''
 
 

== '''Regulatory Information and Packaging''' ==
*PB is not approved by the U.S. FDA; this is likely due its use preceding the creation of the FDA (in 1938).
*DEA Schedule: IV
*Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert">Phenobarbital sodium [[https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 package insert]]. Eatontown, NJ: West-Ward Pharmaceuticals Corporation; 2018.</ref>.
*How Supplied:
:::Phenobarbital Sodium Injection, 65 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0476-25) 
:::Phenobarbital Sodium Injection, 130 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0477-25) 
 
 

== '''Pharmacology''' ==
 
The following are some of the important properties of PB with regard to outpatient treatment of AWS. 
 
=== Classification ===
:; Chemical Class
::PB belongs to the chemical class ''barbiturate''.
:; Clinical Class
:# Like all barbiturates, PB is a ''sedative/hypnotic''.<ref name = "Harvey1979">Harvey SC. Hypnotics and Sedatives: The Barbiturates. In: Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 5th ed. New York: MacMillan Publishing Co., Inc.; 1975:124-136.</ref> However, it is almost never used for this purpose.
:# PB is also classified as an ''anti-convulsant''. 
::::::''In anesthetic doses, all BBTs have an anti-convulsant effect. However, PB is the only BBT which has an anti-convulsant effect at sub-sedative doses. (Historically, two closely related derivatives [mephobarbital and metharbital] also had an anti-convulsant effect at sub-sedative doses).''<ref name="Harvey1979" />
 

=== Mechanism of Action ===
:; GABA agonist
::The binding of GABA to its receptor inhibits nerve depolarization. Like all barbiturates, PB's sedative/hypnotic effect occurs primarily via noncompetitive agonism of the GABAA receptor on the GABA-mediated ion channel. Like BZDs, PB/BBTs do not themselves open the channel and thus GABA is still required. PB/BBTs bind at a different site on the GABAA receptor than BZDs.<ref name = "Hobbs1996">Hobbs WR, Rall TW, Verdoorn TA. Ch 17: Hypnotics and Sedatives; Ethanol. In: Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:361-398.</ref> 
::When PB/BBTs bind to the GABAA receptor, three effects occur: 
::::::# Enhancement of the binding of GABA<ref name="Hobbs1996" /> 
::::::# Enhancement of the binding of BZDs<ref name="Hobbs1996" /> 
::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /> 
::Both 2 and 3 indicate a potential synergistic effect when co-administered with BZDs. Studies have shown that dual therapy is superior to either PB or BZDs alone,(insert refs) indicating at least an additive effect.
:; Glutamate antagonist
::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>
 
 

=== Distribution ===

:Volume of distribution is X(ref).

:Plasma protein binding has been estimated as X percent, predominantly to albumin.(ref)
 
==== Venous concentration versus infused dose ====
{| class="wikitable" style="float:right;font-size: 85%; border: 1px solid black;"
|+ style="caption-side:top; text-align:center;" |Table-1. PB dose, concentration, and ratio for [nonexclusive] subgroups reported in Young (1987).<ref name = "Young1987" />
|-
! scope="col"| Group
! scope="col"| PB Dose (mg/kg)
! scope="col" style="width: 50px;"| Serum Concentration (μ/mL)
! scope="col" style="width: 70px;"| Conc : Dose Ratio
|-
| scope="row"| Tremulous (n=48)
| style="text-align:center;" | 8.5
| style="text-align:center;" | 14.0
| style="text-align:center;" | 1.65
|-
| scope="row"| Seizures (n=38)
| style="text-align:center;" | 8.3
| style="text-align:center;" | 13.8
| style="text-align:center;" | 1.66
|-
| scope="row"| Alcoholic liver disease (n=21)
| style="text-align:center;" | 8.2
| style="text-align:center;" | 13.7
| style="text-align:center;" | 1.67
|-
| scope="row"| ALL (n=62)
| style="text-align:center;" | 8.4
| style="text-align:center;" | 13.9
| style="text-align:center;" | 1.65
|}
::Young (1987)<ref name = "Young1987"/> compared infused PB doses to post-infusion serum PB concentrations in adults presenting to the ED for AWS, and reported that the serum PB level rose 1.65 μg/mL for each mg/kg of PB infused. Though no standard deviation is reported, the similarity of outcomes in different subgroups (including those with alcoholic liver disease) is indicative of very minimal variability of the final serum concentration versus the infused dose (see Table-1).
 
 

==== Venous concentration versus time ====
:: Following rapid bolus injection in adults, PB quickly distributes in the blood, achieving peak venous concentration at about 3 minutes and settling into a relatively steady concentration by 5 minutes.<ref>Bøjholm S, Paulson OB, Flachs H. Arterial and venous concentrations of phenobarbital, phenytoin, clonazepam, and diazepam after rapid intravenous injections. Clin Pharmacol Ther. 1982;32(4):478-483. doi:[https://doi.org/10.1038/clpt.1982.191 10.1038/clpt.1982.191]</ref>
 
==== Brain concentration versus time====
:: Paulson et al. showed that after rapid bolus injection, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982"/>
[[File:PB_CSF_pharmacokinetics_01.PNG|center|thumb|500px|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]
 
However, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>
 
 
=== Bioavailability ===
Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).
 
 
=== Dosing ===
==== Infused dose, Venous concentration, and Clinical Effect ====
::Figure-2 is a nomagram illustrating the expected serum PB levels based on infusion dose (in mg/kg) and it also shows expected effects at particular concentrations as well as the dose ranges reported in applicable studies. 
[[File:PB Dose-Level NOMOGRAM DRAFT.png|center|thumb|500px|'''Fig-1. Phenobarbital weight-based infused dose with associated serum levels and clinical effects'''. Copyright: Andrew W. Swartz, MD (Sept 2019).]]
 

==== Recommended Dosing ====
:;Intravenous
:: '''Initial''': 260mg (or approximately 4 mg/kg) over 10 minutes
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) over 10 minutes, repeat every '''30''' minutes until adequate symptom relief
:: '''Infusion Rate''': ≤ 60 mg/min (adults)<ref name = "PBpkginsert"/>
 
:;Intramuscular
:: '''Initial''': 260mg (or approximately 4 mg/kg)
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) every '''60-90''' minutes until adequate symptom relief
 
:;Dosing Pearls:
:* Weight-based dosing should be considered for patients who are particularly under or overweight.
:* It is convenient to save two orders (i.e. one for 260mg and one for 130mg) which specify administration "over 10 minutes via infusion pump." This provides standardization, safety, and efficient use of nursing time.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* If adequate symptom relief cannot be obtained with a sub-sedative dose of PB, then the patient should be admitted for dual-treatment with a BZD. These patients warrant consideration for transfer for ICU care.
 
:;Oral Dosing
:* Oral dosing information is for hypothetical purposes only. There is no standard indication for this regimen at YKDRH, but in highly unusual circumstances this information might be useful.
:* Oral PB has 95-100% bioavailability.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* Three uncontrolled observational studies have reported results of an orally titrated PB loading regimen for treatment of "sedative/hypnotic" withdrawal.<ref name = "Robinson1981">Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther. 1981;30(1):71-76. doi:[https://doi.org/10.1038/clpt.1981.129 10.1038/clpt.1981.129]</ref><ref name = "Janecek1987">Janecek E, Kapur BM, Devenyi P. Oral phenobarbital loading: a safe method of barbiturate and nonbarbiturate hypnosedative withdrawal. CMAJ. 1987;137(5):410-412. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1492801/ PMID: 3621099/]</ref><ref>1. Loder E, Biondi D. Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache. 2003;43(8):904-909. doi:[https://doi.org/10.1046/j.1526-4610.2003.03171.x 10.1046/j.1526-4610.2003.03171.x]</ref> The three studies involved a total of 87 patients, and they administered PB 120mg orally each hour until the desired therapeutic affect was achieved. There were zero occurrences of adverse effects or over-sedation despite minimal monitoring (nursing contact once per hour). The average final doses were 1440mg, 1315mg, and 1180, respectively. The authors concluded the regimen is safe, effective, and efficient (i.e. requires minimal nursing resources). The caveat to consider is that these patients were withdrawing from barbiturates, therefore they had developed tolerance. If used for alcohol withdrawal, lower final doses should be anticipated.
 

=== Elimination ===
:The half-life of PB is frequently reported as 100 hours or as 80-120 hours.<ref>Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979;26(2):256-264. doi:10.1002/cpt1979262256</ref> This is an accurate generalization, but the generalization hides the variation among different populations.
:::* Non-barbiturate-habituated adults: approximately 80-85 hours.
:::* Barbiturate-habituated adults: approximately 55-60 hours.
:25-50% of PB is excreted unchanged in the urine. Alkalinization of the urine enhances elimination. Hepatic metabolism produces only inactive metabolites which are excreted in the urine and feces.
:Renal insufficiency has little effect upon elimination half-life, but severe renal failure likely prolongs elimination.<ref name = "Asconapé">Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 2014;119:417-432. doi:[https://doi.org/10.1016/B978-0-7020-4086-3.00027-8 10.1016/B978-0-7020-4086-3.00027-8]</ref>
:Hepatic cirrhosis has been shown to prolong elimination whereas acute viral hepatitis does not.<ref>Kutt H, Winters W, Scherman R, Mcdowell F. Diphenylhydantoin and Phenobarbital Toxicity. The Role of Liver Disease. Arch Neurol. 1964;11:649-656. doi:[https://doi.org/10.1001/archneur.1964.00460240081011 10.1001/archneur.1964.00460240081011]</ref>
 
 

=== Adverse Effects ===
:;Common
::Transient post-infusion dizziness, ataxia, and/or nystagmus
::Injection-site reactions
:;Uncommon
::Allergic reactions
:;Very uncommon
::Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermic necrolysis
:;With overdose
::Coma
::Respiratory depression
::Vomiting
:;With severe overdose
::Apnea
::Cardiovascular collapse
:;Cardiac conduction
::Neither the manufacturer package insert nor Lexicomp report cardiac conduction effects (such as QT prolongation) or increased risk of arrhythmias.
 

=== Cautions ===
:Acute or chronic pain
:Airway obstruction
:Respiratory distress
 
 

=== Contraindications ===
:History of porphyria
 
 

=== Pregnancy ===
:;Pregnancy Risk Factor
::Injection: Category '''D'''
 
:PB readily crosses placenta and yields fetal blood levels similar to maternal levels. Data from retrospective, case-controlled studies suggest an association with increased fetal abnormalities and malformations; however, this data has risk of confounding from the seizure disorder and other co-prescribed seizure medications. The manufacturer recommends that ''Phenobarbital should be used during pregnancy only when clearly indicated''.<ref name = "PBpkginsert"/> During labor, PB does not effect uterine contractions, but it does cause newborn respiratory depression.<ref name ="lexidrugs">Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019; Sept. 17, 2019.</ref>
 
 
=== Lactation ===
:PB readily passes into breast milk. The major effect is infant drowsiness but there are several reports of severe infant sedation. PB does not effect milk production.
:See [http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+401 TOXNET/LACTMED: PHENOBARBITAL] for details.
 
 

=== Toxicology ===
:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref>Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>
 
 

== '''Abbreviations''' ==
:'''AWS''': Alcohol Withdrawal Syndrome
:'''BBT''': Barbiturate[s]
:'''BZD''': Benzodiazepine[s]
:'''GABA''': Gamma-aminobutyric acid
:'''PB''': Phenobarbital
:'''YKDRH''': Yukon-Kuskokwim Delta Regional Hospital
 
 

== '''External Links''' ==
PubMed (all settings):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>)]
PubMed (ED/outpatient):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D)+AND+(%22emergency+department%22%5BTitle%2FAbstract%5D+OR+outpatient*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>) AND ("emergency department"[Title/Abstract<nowiki>]</nowiki> OR outpatient*[Title/Abstract<nowiki>]</nowiki>)]
 
Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert"/>.
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7478?searchUrl=%2Flco%2Faction%2Fsearch%3Bjsessionid%3Daf83d0252408d9273a5e3a8ac007%3Forigin%3Dapi%26t%3Dglobalid%26q%3D6763%26nq%3Dtrue#monograph-tab-content Lexicomp/Lexi-Drugs: Phenobarbital] 
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/lexier/1231760 Lexicomp/Lexi-Tox: Phenobarbital]
 
 
== '''Contributors''' ==
''Authors''
:Andrew W. Swartz, MD 
''Reviewers:''
:Travis Nelson, MD (suggestions incorporated)
:Megan Young, MD
:Tara Lathrop, MD
 
 

== '''References''' ==
<references />

Phenobarbital for Alcohol Withdrawal

2019-09-22T23:44:12Z

TravisN:

[https://en.wikipedia.org/wiki/Phenobarbital Phenobarbital] (PB) is a non-competitive [https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid gamma-Aminobutyric acid] (GABA) agonist which is an equally effective and safe alternative to benzodiazepines (BZD) for the treatment of alcohol withdrawal syndrome (AWS).<ref name="Mo2016">Mo Y, Thomas MC, Karras GE. Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials. J Crit Care. 2016;32:101-107. doi:[https://www.doi.org/10.1016/j.jcrc.2015.11.022 10.1016/j.jcrc.2015.11.022]</ref> Though its use for AWS has waned and consequently many clinicians are now unfamiliar with this regimen, PB has both mechanistic and pharmacokinetic properties which make it more suitable for outpatient monotherapy than BZD.
 
IV/IM titrated PB is the first-line outpatient medication used for treatment of AWS at the Yukon-Kuskokwim Delta Regional Hospital (YKDRH). Its use is favored because substantial experience at this institution has shown that it is safe, it is effective, it minimizes return visits, and it eliminates the need to dispense abuse-prone medications (i.e. BZD) to abuse-prone patients while in the midst of a substance abuse crisis. Indeed, minimizing high-risk dispensing of abuse-prone medication is important for improving the health of our community.
 
The treatment of AWS with phenobarbital (or barbiturates [BBT] in general) is not new, but it has fallen so out of favor that many clinicians are unfamiliar with this use. However, there is ample published evidence, both old and new, indicating that phenobarbital is ''at least'' equally safe and effective compared with benzodiazepines.
 
 
__TOC__ 
 
 
== '''Treatment Principles and Pearls''' ==
=== Sub-sedative dosing ===
: Alcohol withdrawal is a ''hyper''-alert and/or ''hyper''-autonomic state. The goal of outpatient treatment of alcohol withdrawal is ''normalization'' of alertness (i.e. level of consciousness) and autonomic function, not sedation. If a sedative level of [any] medication is required for AWS symptom control, then admission is often indicated.
 

=== Dose titration ===
: Patients’ individual medication requirements are unpredictable. Therefore no standard PB dose is expected to be effective for all patients. Rather, an initial IV (or IM) PB dose of 260 mg is given, and then every 30 minutes (or 60 minutes for IM) an additional 130mg are given until the desired effect is achieved. Using this regimen, many patients will require repeat doses, but none should end up “sedated.”
 
: The standard 260mg/130mg regimen works well for average size patients. This regimen yields weight-based doses of 3.7 mg/kg and 1.9 mg/kg in a 70 kg patient. However, for patients substantially below or above 70 kg, clinicians should consider administering 4 mg/kg with subsequent doses of 2 mg/kg. For convenience, these doses can be rounded to the nearest 130 mg increment (i.e. the amount in a single vial). For example, weight-based doing for a 125 kg patient would yield 500 mg and 250 mg doses, and these can be safely rounded to 520mg and 260mg for ease of administration. Weight-based dosing prevents sedating unusually small patients while preventing excessively long visits for unusually large patients. Dosing in whole-vial increments minimizes the risk of dosing errors and eliminates the effort required to precisely dose from a 1mL vial.
 
=== Dosing interval ===
:In pharmacokinetic studies of rapid PB boluses, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982">Paulson OB, Györy A, Hertz MM. Blood-brain barrier transfer and cerebral uptake of antiepileptic drugs. Clin Pharmacol Ther. 1982;32(4):466-477. doi:[https://doi.org/10.1038/clpt.1982.190 10.1038/clpt.1982.190]</ref> Yet clinical judgment must still be used. At 30 minutes after a PB dose, if the patient has “almost” complete symptom relief, the clinician should appreciate the possibility of a small amount of biological variability and consider reevaluating after another 10 minutes, as it is possible that a small additional effect may become apparent. But if the dose is clearly inadequate at 30 minutes, further waiting is very unlikely to reveal any substantial further effect.
 
=== Sleep after symptom control ===
: When patients’ hyper-alert/hyper-autonomic state is normalized, many will lightly nap. But such patients easily awaken to voice or light touch and they easily meet all discharge criteria. Rather than being “sedated,” such patients are merely exhibiting the normal physiologic response in the absence of discomfort to a 24-48 hour sleep deficit (which is the norm for patients in this situation). Any concern for sedation can usually be answered by asking oneself if the patient’s post-treatment behavior would be considered '''ab'''normal for a patient in the ED with a normal mental status, with a substantial sleep deficit, whose discomfort had been relieved. If the answer is “no”, then the patient is not “sedated,” but rather has been returned to a normal level of alertness.
 
=== Post-infusion dizziness/nystagmus/ataxia ===
:Post-infusion dizziness/nystagmus/ataxia is a common, transient effect of IV PB administration. Both experience and published reports reveal that this resolves spontaneously in 15-30 minutes. Given PB's exceptionally long half-life, this seems to be attributable to the rapidity of the drug level increase rather than the level itself. After resolution, this is not a contraindication for more PB, but further doses should be infused much more slowly (such as over 30-45 minutes). Importantly, this is not an allergic reaction nor a reaction which warrants a chart alert. This reaction can be thought of as similar to the "red man" effect of vancomycin: it merely requires adjustment of the administration speed and possibly the dosing interval. This effect occurs more frequently when infusing larger doses (such as 390mg or 520mg) over 10 minutes; such larger doses (such as in a very large patient or one with a well-established dose requirement) should be infused over 30-45 minutes.
 
=== Isolated withdrawal hallucinosis ===
: A subset of AWS patients will present as soon as 12 hours after alcohol cessation with classic withdrawal hallucinations but without any signs of hyper-alertness, clouding of consciousness, confusion, or autonomic hyper-stimulation. This is a well documented variant of AWS, and it should be neither under-treated (i.e. dismissed as fake) nor over-treated (i.e. managed as delirium tremens). Hallucinations are one of the many manifestations of AWS, and they can occur in isolation or in combination with other signs. Primary management is a therapeutic level of GABA agonist (i.e. PB or a BZD). The use of anti-psychotic medications is contraversial. If hallucinations are refractory to an appropriate level of GABA agonist then an anti-psychotic medication can be added. However, caution is advised because there have been reports of increased mortality associated with these medications due to arrhythmias (due to QT prolongation) and lowering the seizure threshold. The risk/benefit must be carefully weighted in these situations, especially in the first 48 hours when the seizure risk is highest. Anti-psychotic medications should never be the first-line or sole therapy for hallucinosis or other withdrawal symptoms.<ref>Jesse S, Bråthen G, Ferrara M, et al. Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurol Scand. 2017;135(1):4-16. doi:[https://doi.org/10.1111/ane.12671 10.1111/ane.12671].</ref>
 
 

=== Alcoholic Hallucinosis ===

Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations without other strong evidence of alcohol withdrawal or alcohol delirium. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing gaba agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved. Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.

[[Media:Barkat_et_al_2017.ogg]]

Alcoholic hallucinosis. Bhat PS et al. Ind Psychiatry J. 2012 Jul;21(2):155-7.

Phenomenology and Course of Alcoholic Hallucinosis. Narasimha VL, et al. J Dual Diagn. 2019 Jul-Sep;15(3):172-176.

Alcohol-induced psychotic disorder: a review. Jordaan GP, Emsley R. Metab Brain Dis. 2014 Jun;29(2):231-43.

== '''Evidence of Effectiveness and Safety''' ==
=== Systematic Review / Meta-analysis ===
* A 2016 systematic review by '''Mo et al'''. in the ''Journal of Critical Care''<ref name="Mo2016" /> concluded that "''barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS.''" This review included three randomized controlled trials (RCT's) and four observational studies. Importantly, the authors observed that "''none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS.''" While this review firmly establishes PB's similar pharmacological effectiveness compared to BZD's, only one of the included studies (an RCT by Hendey et al.<ref name="Hendey2011">Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011;29(4):382-385. doi:[https://doi.org/10.1016/j.ajem.2009.10.010 10.1016/j.ajem.2009.10.010]</ref>) focused solely upon outpatient treatment. Though its sample size was small (25 in PB group, 19 in BZD group), Hendey et al. reported statistically nonsignificant trends toward better outcomes in the PB group.
* Other systematic reviews<ref name = "Minozzi2010">Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064. doi:[https://doi.org/10.1002/14651858.CD005064.pub3 10.1002/14651858.CD005064.pub3]</ref><ref>Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;(6):CD008537. doi:[https://doi.org/10.1002/14651858.CD008537.pub2 10.1002/14651858.CD008537.pub2]</ref> have only indirectly assessed the effectiveness of PB for AWS. These reviews have grouped all studies which compared any anti-convulsant to a BZD, and then concluded that anti-convulsants (as a group) are inferior to BZDs for treatment of AWS. This grouping of PB with other anti-convulsants badly biases the results against PB and does not seem justified. The mechanism of action of both PB and BZDs is non-competitive agonism of the GABAA ion channel and both of these medication have been long known to display cross-tolerance with each other and alcohol. Conversely, the other anti-convulsants work via different mechanisms. Therefore grouping PB with the other anti-convulsants is inappropriate and seems to merely reflect how the authors think about the drugs rather than their pharmacological properties.

=== Studies of ED/Outpatient Treatment ===
* '''Young et al'''. (1987, prospective uncontrolled study, n=62)<ref name = "Young1987">Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987;16(8):847-850. doi:[https://doi.org/10.1016/s0196-0644(87)80520-6 10.1016/s0196-0644(87)80520-6]</ref> 
::62 patients received IV PB loading dose in the emergency department. The protocol was an initial 260mg which was followed by 130mg increments, but the dosing interval is unclear. The mean loading dose was 598 mg (8.4 mg/kg) and the subsequent mean serum PB level was 13.9 mcg/mL. Four patients experienced minor, self-limited adverse reactions (asymptomatic hypotension, ataxia, or lethargy) which resolved without intervention. All patients were discharged from the ED and none returned for further care during the following week.

* '''Hendey et al'''. (2011, RCT of PB vs lorazepam, n=25/19)<ref name="Hendey2011" /> 
::44 ED patients were randomized (25 to IV-PB, 19 to LZ). PB patients received a 230 mg initial dose followed by 130mg subsequent doses (dosing interval was "''at the discretion of the treating physician''"). Mean PB dose was 509 mg (range 260-910 mg); mean number of doses was 2.9 (range 1-6). There were no outcome differences at 48 hours, and importantly, there was no significant difference in length of ED stay (267 min for PB versus 256 min for LZ). Fewer PB patients required admission (12 vs. 16). The authors concluded that "''phenobarbital and LZ were similarly effective in the treatment of mild/moderate alcohol withdrawal in the ED and at 48 hours.''"

* '''Nelson et al'''. (2019, retrospective cohort study)<ref>Nelson AC, Kehoe J, Sankoff J, Mintzer D, Taub J, Kaucher KA. Benzodiazepines vs barbiturates for alcohol withdrawal: Analysis of 3 different treatment protocols. Am J Emerg Med. 2019;37(4):733-736. doi:[https://doi.org/10.1016/j.ajem.2019.01.002 10.1016/j.ajem.2019.01.002]</ref> 
::300 ED patients: 100 received IV-PB alone, 100 received IV-PB + lorazepam, and 100 received diazepam alone. Initial PB dose was 260mg and subsequent doses were 130mg (dosing interval is not specified). Authors' conclusions: "''Incorporating phenobarbital into a benzodiazepine based protocol or as sole agent led to similar rates of ICU admission, length of stay, and need for mechanical ventilation in patients treated for alcohol withdrawal in the emergency department''."

=== Historical Reports ===
:PB has long been used for treatment of delirium tremens (DT). Though it has fallen out of favor in most places, a minority of countries and institutions have continued to use it as first line treatment of AWS.
::* A 2010 study by Michaelsen in the ''Danish Medical Bulletin''<ref>Michaelsen IH, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens--a retrospective study. Dan Med Bull. 2010;57(8):A4169.</ref> states BBTs have been used for treatment of DT in Denmark "for over 100 years."
::* A 2006 RCT of gabapentin for AWS<ref>Mariani JJ, Rosenthal RN, Tross S, Singh P, Anand OP. A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal. Am J Addict. 2006;15(1):76-84. doi:[https://doi.org/10.1080/10550490500419110 10.1080/10550490500419110]</ref> compared it to a control group which received PB. The authors gave the following explanation in the methods section:
::::''Those randomized to the experimental group received a protocol using gabapentin, while those in the control group received a phenobarbital protocol that is customary in our inpatient detoxification service. Phenobarbital was used in this study rather than benzodiazepines because it is the detoxification medication that the clinical staff is most familiar with.''
::* A 1995 United States nationwide survey of inpatient alcohol treatment centers<ref>Saitz R, Friedman LS, Mayo-Smith MF. Alcohol withdrawal: a nationwide survey of inpatient treatment practices. J Gen Intern Med. 1995;10(9):479-487. doi:[https://doi.org/10.1007/bf02602395 10.1007/bf02602395]</ref> reported that approximately 10% primarily used PB for treatment of AWS.

=== EVIDENCE SUMMARY ===
:In landmark studies by Kaim and Klett in 1969<ref>Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry. 1969;125(12):1640-1646. doi:[https://doi.org/10.1176/ajp.125.12.1640 10.1176/ajp.125.12.1640]</ref> and 1972,<ref>Kaim SC, Klett CJ. Treatment of delirium tremens. A comparative evaluation of four drugs. Q J Stud Alcohol. 1972;33(4):1065-1072.</ref> both BBTs and BZDs were shown to be equally effective in treatment of AWS. Both of these drug classes had been previously known to exhibit cross dependance with each other as well as alcohol, and the subsequent discovery that these structurally unrelated compounds are both GABA agonists was critical to understanding the pathophysiology of AWS. 
 
:Though BZDs have become the standard of care, this seems mostly attributable to a larger movement away from inpatient treatment and toward outpatient treatment with oral medications. Dispensing BZDs to patients is clearly safer than dispensing PB/BBTs. Yet when the dose is titrated to effect by a physician and patients are not dispensed medication, there is ample evidence that PB is equally safe and effective compared to BZD. 
 
:Numerous articles advise caution with regard to PB by alluding to concerns about respiratory depression, but no evidence of adverse effects is ever presented or cited. Therefore these concerns seem to originate more from the authors' lack of familiarity with the use of IV-PB in this setting than from documented outcomes. However, it must be pointed out that PB should '''''never''''' be dispensed to a patient for symptom-triggered dosing, as this would present an '''extreme risk''' of unintentional lethal overdose. PB use for AWS ''must'' be limited to titrating the dose to the desired effect, and then discharging the patient without additional medication. There have been no reports of iatrogenic overdoses using this protocol, and the drug packaging is a strong mitigating factor to prevent drug errors: At YKDRH, PB is only available in 130mg vials. Therefore the initial dose is two vials and the subsequent doses are one vial. A dangerous overdose (i.e. one yielding respiratory depression) would require accidentally drawing up 20-30 vials, which would be very labor intensive and very likely produce questions prior to administration. ''(PB is also marketed in 65mg vials, but that would require even more vials to produce an overdose.)''
 
 

== '''Regulatory Information and Packaging''' ==
*PB is not approved by the U.S. FDA; this is likely due its use preceding the creation of the FDA (in 1938).
*DEA Schedule: IV
*Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert">Phenobarbital sodium [[https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 package insert]]. Eatontown, NJ: West-Ward Pharmaceuticals Corporation; 2018.</ref>.
*How Supplied:
:::Phenobarbital Sodium Injection, 65 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0476-25) 
:::Phenobarbital Sodium Injection, 130 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0477-25) 
 
 

== '''Pharmacology''' ==
 
The following are some of the important properties of PB with regard to outpatient treatment of AWS. 
 
=== Classification ===
:; Chemical Class
::PB belongs to the chemical class ''barbiturate''.
:; Clinical Class
:# Like all barbiturates, PB is a ''sedative/hypnotic''.<ref name = "Harvey1979">Harvey SC. Hypnotics and Sedatives: The Barbiturates. In: Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 5th ed. New York: MacMillan Publishing Co., Inc.; 1975:124-136.</ref> However, it is almost never used for this purpose.
:# PB is also classified as an ''anti-convulsant''. 
::::::''In anesthetic doses, all BBTs have an anti-convulsant effect. However, PB is the only BBT which has an anti-convulsant effect at sub-sedative doses. (Historically, two closely related derivatives [mephobarbital and metharbital] also had an anti-convulsant effect at sub-sedative doses).''<ref name="Harvey1979" />
 

=== Mechanism of Action ===
:; GABA agonist
::The binding of GABA to its receptor inhibits nerve depolarization. Like all barbiturates, PB's sedative/hypnotic effect occurs primarily via noncompetitive agonism of the GABAA receptor on the GABA-mediated ion channel. Like BZDs, PB/BBTs do not themselves open the channel and thus GABA is still required. PB/BBTs bind at a different site on the GABAA receptor than BZDs.<ref name = "Hobbs1996">Hobbs WR, Rall TW, Verdoorn TA. Ch 17: Hypnotics and Sedatives; Ethanol. In: Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:361-398.</ref> 
::When PB/BBTs bind to the GABAA receptor, three effects occur: 
::::::# Enhancement of the binding of GABA<ref name="Hobbs1996" /> 
::::::# Enhancement of the binding of BZDs<ref name="Hobbs1996" /> 
::::::# Increased duration of channel opening. This contrasts with the effect of BZDs, which is increased frequency of channel opening.<ref name="Hobbs1996" /> 
::Both 2 and 3 indicate a potential synergistic effect when co-administered with BZDs. Studies have shown that dual therapy is superior to either PB or BZDs alone,(insert refs) indicating at least an additive effect.
:; Glutamate antagonist
::The binding of glutamate to its receptor stimulates nerve depolarization. At sub-sedative doses PB/BBTs also inhibit the AMPA subtype of glutamate receptors; however, PB/BBT do not effect the NMDA subtype.<ref name="Hobbs1996" /> This glutamate antagonism is an anti-convulsive effect which is separate from PB's GABAergic effect.<ref>Nardou R, Yamamoto S, Bhar A, Burnashev N, Ben-Ari Y, Khalilov I. Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus. Front Cell Neurosci. 2011;5:16. doi:[https://doi.org/10.3389/fncel.2011.00016 10.3389/fncel.2011.00016]</ref>
 
 

=== Distribution ===

:Volume of distribution is X(ref).

:Plasma protein binding has been estimated as X percent, predominantly to albumin.(ref)
 
==== Venous concentration versus infused dose ====
{| class="wikitable" style="float:right;font-size: 85%; border: 1px solid black;"
|+ style="caption-side:top; text-align:center;" |Table-1. PB dose, concentration, and ratio for [nonexclusive] subgroups reported in Young (1987).<ref name = "Young1987" />
|-
! scope="col"| Group
! scope="col"| PB Dose (mg/kg)
! scope="col" style="width: 50px;"| Serum Concentration (μ/mL)
! scope="col" style="width: 70px;"| Conc : Dose Ratio
|-
| scope="row"| Tremulous (n=48)
| style="text-align:center;" | 8.5
| style="text-align:center;" | 14.0
| style="text-align:center;" | 1.65
|-
| scope="row"| Seizures (n=38)
| style="text-align:center;" | 8.3
| style="text-align:center;" | 13.8
| style="text-align:center;" | 1.66
|-
| scope="row"| Alcoholic liver disease (n=21)
| style="text-align:center;" | 8.2
| style="text-align:center;" | 13.7
| style="text-align:center;" | 1.67
|-
| scope="row"| ALL (n=62)
| style="text-align:center;" | 8.4
| style="text-align:center;" | 13.9
| style="text-align:center;" | 1.65
|}
::Young (1987)<ref name = "Young1987"/> compared infused PB doses to post-infusion serum PB concentrations in adults presenting to the ED for AWS, and reported that the serum PB level rose 1.65 μg/mL for each mg/kg of PB infused. Though no standard deviation is reported, the similarity of outcomes in different subgroups (including those with alcoholic liver disease) is indicative of very minimal variability of the final serum concentration versus the infused dose (see Table-1).
 
 

==== Venous concentration versus time ====
:: Following rapid bolus injection in adults, PB quickly distributes in the blood, achieving peak venous concentration at about 3 minutes and settling into a relatively steady concentration by 5 minutes.<ref>Bøjholm S, Paulson OB, Flachs H. Arterial and venous concentrations of phenobarbital, phenytoin, clonazepam, and diazepam after rapid intravenous injections. Clin Pharmacol Ther. 1982;32(4):478-483. doi:[https://doi.org/10.1038/clpt.1982.191 10.1038/clpt.1982.191]</ref>
 
==== Brain concentration versus time====
:: Paulson et al. showed that after rapid bolus injection, on average, PB reaches 90% of peak brain concentration by 19 minutes, 95% by 22 minutes, and 100% by 30 minutes.<ref name = "Paulson1982"/>
[[File:PB_CSF_pharmacokinetics_01.PNG|center|thumb|500px|'''Fig-1. Adult phenobarbital brain concentration versus time after a rapid bolus injection'''. Y-axis is fractional concentration compared to the initial serum concentration (which has been removed for clarity). Adapted from Fig-3 of Paulson 1982<ref name = "Paulson1982"/>]]
 
However, the manufacturer package insert (updated 12-10-2018) states that peak brain concentration is reached within 15 minutes of IV administration.<ref name = "PBpkginsert"/>
 
 
=== Bioavailability ===
Intramuscular bioavailability is 75-80% (based upon a 1978 study of five young adult males<ref>Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2-3):100-105. PMID:[https://www.ncbi.nlm.nih.gov/pubmed/624773 624773]</ref>).
 
 
=== Dosing ===
==== Infused dose, Venous concentration, and Clinical Effect ====
::Figure-2 is a nomagram illustrating the expected serum PB levels based on infusion dose (in mg/kg) and it also shows expected effects at particular concentrations as well as the dose ranges reported in applicable studies. 
[[File:PB Dose-Level NOMOGRAM DRAFT.png|center|thumb|500px|'''Fig-1. Phenobarbital weight-based infused dose with associated serum levels and clinical effects'''. Copyright: Andrew W. Swartz, MD (Sept 2019).]]
 

==== Recommended Dosing ====
:;Intravenous
:: '''Initial''': 260mg (or approximately 4 mg/kg) over 10 minutes
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) over 10 minutes, repeat every '''30''' minutes until adequate symptom relief
:: '''Infusion Rate''': ≤ 60 mg/min (adults)<ref name = "PBpkginsert"/>
 
:;Intramuscular
:: '''Initial''': 260mg (or approximately 4 mg/kg)
:: '''Subsequent''': 130mg (or approximately 2 mg/kg) every '''60-90''' minutes until adequate symptom relief
 
:;Dosing Pearls:
:* Weight-based dosing should be considered for patients who are particularly under or overweight.
:* It is convenient to save two orders (i.e. one for 260mg and one for 130mg) which specify administration "over 10 minutes via infusion pump." This provides standardization, safety, and efficient use of nursing time.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* If adequate symptom relief cannot be obtained with a sub-sedative dose of PB, then the patient should be admitted for dual-treatment with a BZD. These patients warrant consideration for transfer for ICU care.
 
:;Oral Dosing
:* Oral dosing information is for hypothetical purposes only. There is no standard indication for this regimen at YKDRH, but in highly unusual circumstances this information might be useful.
:* Oral PB has 95-100% bioavailability.
:* Patients '''must never''' be discharge with a supply of oral PB for symptom-triggered dosing due to an '''extreme risk''' of unintended lethal overdose.
:* Three uncontrolled observational studies have reported results of an orally titrated PB loading regimen for treatment of "sedative/hypnotic" withdrawal.<ref name = "Robinson1981">Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther. 1981;30(1):71-76. doi:[https://doi.org/10.1038/clpt.1981.129 10.1038/clpt.1981.129]</ref><ref name = "Janecek1987">Janecek E, Kapur BM, Devenyi P. Oral phenobarbital loading: a safe method of barbiturate and nonbarbiturate hypnosedative withdrawal. CMAJ. 1987;137(5):410-412. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1492801/ PMID: 3621099/]</ref><ref>1. Loder E, Biondi D. Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache. 2003;43(8):904-909. doi:[https://doi.org/10.1046/j.1526-4610.2003.03171.x 10.1046/j.1526-4610.2003.03171.x]</ref> The three studies involved a total of 87 patients, and they administered PB 120mg orally each hour until the desired therapeutic affect was achieved. There were zero occurrences of adverse effects or over-sedation despite minimal monitoring (nursing contact once per hour). The average final doses were 1440mg, 1315mg, and 1180, respectively. The authors concluded the regimen is safe, effective, and efficient (i.e. requires minimal nursing resources). The caveat to consider is that these patients were withdrawing from barbiturates, therefore they had developed tolerance. If used for alcohol withdrawal, lower final doses should be anticipated.
 

=== Elimination ===
:The half-life of PB is frequently reported as 100 hours or as 80-120 hours.<ref>Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979;26(2):256-264. doi:10.1002/cpt1979262256</ref> This is an accurate generalization, but the generalization hides the variation among different populations.
:::* Non-barbiturate-habituated adults: approximately 80-85 hours.
:::* Barbiturate-habituated adults: approximately 55-60 hours.
:25-50% of PB is excreted unchanged in the urine. Alkalinization of the urine enhances elimination. Hepatic metabolism produces only inactive metabolites which are excreted in the urine and feces.
:Renal insufficiency has little effect upon elimination half-life, but severe renal failure likely prolongs elimination.<ref name = "Asconapé">Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol. 2014;119:417-432. doi:[https://doi.org/10.1016/B978-0-7020-4086-3.00027-8 10.1016/B978-0-7020-4086-3.00027-8]</ref>
:Hepatic cirrhosis has been shown to prolong elimination whereas acute viral hepatitis does not.<ref>Kutt H, Winters W, Scherman R, Mcdowell F. Diphenylhydantoin and Phenobarbital Toxicity. The Role of Liver Disease. Arch Neurol. 1964;11:649-656. doi:[https://doi.org/10.1001/archneur.1964.00460240081011 10.1001/archneur.1964.00460240081011]</ref>
 
 

=== Adverse Effects ===
:;Common
::Transient post-infusion dizziness, ataxia, and/or nystagmus
::Injection-site reactions
:;Uncommon
::Allergic reactions
:;Very uncommon
::Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermic necrolysis
:;With overdose
::Coma
::Respiratory depression
::Vomiting
:;With severe overdose
::Apnea
::Cardiovascular collapse
:;Cardiac conduction
::Neither the manufacturer package insert nor Lexicomp report cardiac conduction effects (such as QT prolongation) or increased risk of arrhythmias.
 

=== Cautions ===
:Acute or chronic pain
:Airway obstruction
:Respiratory distress
 
 

=== Contraindications ===
:History of porphyria
 
 

=== Pregnancy ===
:;Pregnancy Risk Factor
::Injection: Category '''D'''
 
:PB readily crosses placenta and yields fetal blood levels similar to maternal levels. Data from retrospective, case-controlled studies suggest an association with increased fetal abnormalities and malformations; however, this data has risk of confounding from the seizure disorder and other co-prescribed seizure medications. The manufacturer recommends that ''Phenobarbital should be used during pregnancy only when clearly indicated''.<ref name = "PBpkginsert"/> During labor, PB does not effect uterine contractions, but it does cause newborn respiratory depression.<ref name ="lexidrugs">Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019; Sept. 17, 2019.</ref>
 
 
=== Lactation ===
:PB readily passes into breast milk. The major effect is infant drowsiness but there are several reports of severe infant sedation. PB does not effect milk production.
:See [http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+401 TOXNET/LACTMED: PHENOBARBITAL] for details.
 
 

=== Toxicology ===
:PB blood levels above 80 μg/mL are considered "potentially" lethal, whereas lethal overdose is usually associated with levels of 100-200 μg/mL.<ref name = "PBpkginsert"/> For a 70 kg person, these levels would result from ingestions of 3,394mg, 4,242mg, and 8,485mg, respectively. Six to ten grams is a commonly cited lethal ingestion dose range.<ref>Lindberg MC, Cunningham A, Lindberg NH. Acute phenobarbital intoxication. South Med J. 1992;85(8):803-807. doi:[https://doi.org/10.1097/00007611-199208000-00004 10.1097/00007611-199208000-00004]</ref><ref>Hoyland K, Hoy M, Austin R, Wildman M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013;2013. doi:[https://doi.org/10.1136/bcr-2013-010011 10.1136/bcr-2013-010011]</ref>
 
 

== '''Abbreviations''' ==
:'''AWS''': Alcohol Withdrawal Syndrome
:'''BBT''': Barbiturate[s]
:'''BZD''': Benzodiazepine[s]
:'''GABA''': Gamma-aminobutyric acid
:'''PB''': Phenobarbital
:'''YKDRH''': Yukon-Kuskokwim Delta Regional Hospital
 
 

== '''External Links''' ==
PubMed (all settings):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>)]
PubMed (ED/outpatient):
:[https://www.ncbi.nlm.nih.gov/pubmed/?term=%22alcohol+withdrawal%22%5BTitle%2FAbstract%5D+AND+(phenobarb*%5BTitle%2FAbstract%5D+OR+barbiturat*%5BTitle%2FAbstract%5D)+AND+(%22emergency+department%22%5BTitle%2FAbstract%5D+OR+outpatient*%5BTitle%2FAbstract%5D) "alcohol withdrawal"[Title/Abstract<nowiki>]</nowiki> AND (phenobarb*[Title/Abstract<nowiki>]</nowiki> OR barbiturat*[Title/Abstract<nowiki>]</nowiki>) AND ("emergency department"[Title/Abstract<nowiki>]</nowiki> OR outpatient*[Title/Abstract<nowiki>]</nowiki>)]
 
Manufacturer's package insert ([https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214 electronic], [https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display printable], [https://web.archive.org/web/20190918234645/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ffcaa218-ed6a-4557-9645-b9a91128a214&type=display archived printable])<ref name = "PBpkginsert"/>.
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7478?searchUrl=%2Flco%2Faction%2Fsearch%3Bjsessionid%3Daf83d0252408d9273a5e3a8ac007%3Forigin%3Dapi%26t%3Dglobalid%26q%3D6763%26nq%3Dtrue#monograph-tab-content Lexicomp/Lexi-Drugs: Phenobarbital] 
 
[http://online.lexi.com/lco/action/doc/retrieve/docid/lexier/1231760 Lexicomp/Lexi-Tox: Phenobarbital]
 
 
== '''Contributors''' ==
''Authors''
:Andrew W. Swartz, MD 
''Reviewers:''
:Travis Nelson, MD (suggestions incorporated)
:Megan Young, MD
:Tara Lathrop, MD
 
 

== '''References''' ==
<references />

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===Alcoholic Hallucinosis===

Alcoholic hallucinosis (AH), also known as Alcohol Induced Psychotic Disorder, is described as persistent hallucinations without other strong evidence of alcohol withdrawal or alcohol delirium. Hallucinations are predominantly auditory though can be visual and can be accompanied by delusions and suicidality. AH is a heterogeneous disorder with variable presentation and clinical course. Hallucinosis typically lasts 2-7 days, though persistent hallucinosis lasting weeks to months is possible.

As AH is a relatively rare phenomenon there is not consensus in the literature regarding treatment. Two approaches are generally utilized. The first approach considers alcoholic hallucinosis as a symptom of alcohol withdrawal, with treatment utilizing gaba agonists. The second approach considers alcoholic hallucinosis as a primary psychotic disorder treated with either first or second generation antipsychotics. Both approaches appear equally efficacious, though data is limited by a lack of single studies comparing treatments via a randomized approach.

A reasonable approach is to treat for alcohol withdrawal as long as symptoms of withdrawal persist, then adjunct treatment with a second generation antipsychotic if hallucinosis persists after other withdrawal symptoms have improved.
Providers are cautioned against the use of anti-psychotics during DTs as these are associated with increased mortality, likely via QT prolongation and lowering of seizure threshold.

[[Media:Barkat_et_al_2017.ogg]]

Alcoholic hallucinosis. Bhat PS et al. Ind Psychiatry J. 2012 Jul;21(2):155-7.

Phenomenology and Course of Alcoholic Hallucinosis. Narasimha VL, et al. J Dual Diagn. 2019 Jul-Sep;15(3):172-176.

Alcohol-induced psychotic disorder: a review. Jordaan GP, Emsley R. Metab Brain Dis. 2014 Jun;29(2):231-43.

File:Barkat et al 2107.pdf

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