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GHB-WITHDRAWAL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Gamma hydroxybutyrate (GHB) and its analogs including gamma-butyrolactone (GBL), 1,4-butanediol (1,4-BD) and gamma-valerolactone (GVL) are common drugs of abuse. There is increasing evidence that chronic, frequent (multiple times daily) abuse can lead to physical tolerance. In these patients, abrupt abstinence can be associated with a withdrawal syndrome.
    B) Please refer to the GAMMA HYDROXYBUTYRATE AND RELATED AGENTS management for information regarding acute exposure to GHB and related substances.

Specific Substances

    A) GAMMA HYDROXYBUTYRIC ACID
    1) 4-Hydroxybutyrate
    2) Gamma Hydrate
    3) Gamma Hydroxybutyrate sodium
    4) GHB (withdrawal)(synonym)
    5) Sodium oxybate (Sodium salt)
    6) Sodium oxybutyrate
    7) NSC 84223 (Sodium salt)
    8) Wy-3478 (Sodium salt)
    9) CAS 502-85-2 (Sodium salt)
    GAMMA BUTYROLACTONE
    1) 1,2-butanolide
    2) 2(3H)-furanone, dihydro
    3) 3-hydroxybutyric acid lactone
    4) 4-Butanolide
    5) 4-Butyrolactone
    6) 4-Hydroxybutanoic acid lactone
    7) Butyrolactone
    8) Butyrolactone gamma
    9) Dihydro-2(3H)-furanone
    10) Gamma butyrolactone
    11) Gamma hydroxybutyric acid lactone
    12) GBL
    1,4 BUTANEDIOL
    1) 1,4-B
    2) 1,4-BD
    3) 1,4-butylene glycol
    4) 1,4-dihydroxybutane
    5) 1,4-tetramethylene glycol
    6) 2(3H)-Furanone di-dihydro
    7) BD
    8) butanediol
    9) tetramethylene glycol

Available Forms Sources

    A) FORMS
    1) GHB has been illegally marketed under the following:
    1) 4-Hydroxybutyrate
    2) Gamma Hydrate
    3) Gamma Hydroxybutric Acid
    4) Gamma Hydroxybutyrate Sodium
    5) Gamma-OH
    6) Oxybutyrate
    7) Sodium Oxybate
    8) Somatomax PM
    2) Slang terms that have been used to describe Gamma Hydroxybutyric Acid (Williams, 1998):
    1) Alcover
    2) Cherry menth
    3) Easy lay
    4) Everclear
    5) Fantasy
    6) G
    7) Gamma-OH
    8) GBH
    9) GHB
    10) Georgia home boy
    11) Great hormones at bedtime
    12) Grievous bodily harm
    13) G-riffick
    14) Jolt
    15) Lemons
    16) Liquid E
    17) Liquid Ecstasy
    18) Liquid X
    19) Organic Quaalude
    20) Scoop
    21) Soap
    22) Salty water
    23) Water
    24) Zonked
    3) Gamma butyrolactone is a precursor in the synthesis of gamma hydroxybutyric Acid:
    a) It may be marketed under numerous brand names as a herbal growth hormone stimulator. The brand name Renewtrient has been implicated in one case report of toxicity (LoVecchio et al, 1998).
    b) Products containing gamma butyrolactone are marketed under various brand names and can include the following ((Anon, 1999)) Viswanathan, et al, 2000):
    1) Beta-Tech
    2) Blue Nitro
    3) Blue Nitro Vitality
    4) Firewater
    5) GH Revitalizer
    6) Gamma G
    7) Insom-X
    8) Invigorate
    9) Jolt
    10) Longevity
    11) Re Active
    12) Remforce
    13) Renewtrient
    14) Rest-EZE
    15) Revivarant
    16) Revivarant G
    17) Thunder
    18) Verve
    4) 1,4-butanediol found in a "pine-needle oil" spray was responsible for 2 overdoses in adults with symptoms similar to gamma hydroxybutyrate (GHB) intoxication (Dyer & Andrews, 1997). It is metabolically oxidized to GHB and has a similar clinical course following overdose (Zvosec et al, 2001).
    a) Products containing 1,4-Butanediol (BD) are marketed under various brand names and can include the following (Lindsay, 1999; (Anon, 1999)):
    1) Amino Flex
    2) Biocopia
    3) Borametz
    4) BVM
    5) Cherry FX Bomb
    6) Dormir
    7) Enliven
    8) GHRE
    9) Inner G
    10) Lemon FX Drop
    11) NRG3
    12) Orange FX Rush
    13) Rest-Q
    14) Pine Needle Extract
    15) Promusol
    16) Revitalize Plus
    17) Serenity
    18) SomatoPro
    19) Thunder Nectar
    20) Weight Belt Cleaner
    21) X-12
    22) Zen
    B) SOURCES
    1) GHB
    a) GHB was banned from sale and distribution in the United States in the early 1990's.
    b) Despite the ban on the sale and manufacture of GHB by the USFDA, mail order kits and most recently access through the internet have resulted in easy access to this agent (Henretig et al, 1998). The kits are sold inexpensively and provide detailed instructions to manufacture the drug at home.
    C) USES
    1) GAMMA HYDROXYBUTYRIC ACID
    a) Gamma hydroxybutyric acid (GHB) was originally developed as a general anesthetic, but is being promoted illegally as a growth hormone stimulant, diet aid, anabolic, hypnotic, and euphoriant. Beginning in early 1985, clinical trials were begun to determine the benefits of GHB in the treatment of narcolepsy (Scharf et al, 1985; Scrima et al, 1990; Lammers et al, 1993).
    b) In Europe, GHB has been used experimentally to treat posthypoxic cerebral edema and ethanol withdrawal (Gallimberti et al, 1989; Gallimberti et al, 1992), and as an anesthetic adjunct (CDC, 1990) Addolorato et al, 1997). It has been called "a natural growth hormone" for strength training (Gilmore et al, 1991).
    1) Withdrawal symptoms were reported in a patient after abusing GHB that was prescribed for the treatment of alcohol addiction (Hernandez et al, 1998).
    c) Gamma hydroxybutyrate (sodium oxybate) has been sponsored by Orphan Medical, Inc. as an orphan drug for the treatment of narcolepsy. In July 2002, the United States FDA approved the use of sodium oxybate (Xyrem(R)) to treat cataplexy, a sudden loss of muscle tone associated with narcolepsy ((Anon, 2002)).
    1) Sodium oxybate (Xyrem(R)) is a Schedule III controlled substance. In addition, its distribution is governed by the FDA's Subpart H regulations. The manufacturer has worked closely with the FDA, DEA and law enforcement agencies to develop strict distribution and risk-management controls designed to restrict access to Xyrem(R) to the intended patient population ((Anon, 2002)).
    2) CONSUMER ALERTS/LEGISLATIVE ACTION/USA
    a) GHB
    1) Federal legislation took effect March 13, 2000, making GHB a schedule I agent and GHB under IND or NDA use a schedule III agent (DEA, 2000).
    b) GAMMA BUTYROLACTONE
    1) As of January 1999, the USFDA has alerted consumers NOT to purchase or consume products containing gamma butyrolactone (GBL), which may be labeled as dietary supplements, based on reports of serious health problems associated with its use. The FDA has also asked companies that manufacture these products to voluntarily recall them ((Anon, 1999)). Some products remain available labeled as "solvents".
    c) 1,4 BUTANEDIOL
    1) As of May 1999, the USFDA has alerted consumers of GBL-related products, one of which is 1,4-butanediol (BD) which may cause symptoms similar to GHB or GBL, and the effects are considered as potentially life-threatening (a Class I Health Hazard). Health authorities believe that manufacturers may be relabeling health food products or substituting 1,4-butanediol for GBL ((Anon, 1999a)).
    2) In January 2000, the FDA announced a recall of 1,4 butanediol products. It is uncertain, at the time of this update, whether nutritional supplement manufacturers will comply ((Anon, 2000)). If these products are marketed as "dietary supplements" they are protected under the Dietary Supplement Health and Education Act which was created as a potential loophole for "natural" products. Thus, 1,4-BD may be protected from violation of the Controlled Substance Analogue Enforcement Act (Shannon & Quang, 2000).

Overview

Laboratory Monitoring

    A) GHB levels are not readily available in most laboratories, and are not clinically relevant to the management of GHB withdrawal.
    B) Monitor vital signs and mental status.
    C) Serum electrolytes, renal function, liver enzymes and creatine kinase should be evaluated in patients with evidence of toxicity.
    D) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with toxicity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) GHB withdrawal consists of predominantly symptomatic and supportive care. Anxiety and insomnia may be treated with benzodiazepines as needed.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment for severe toxicity begins with symptomatic and supportive care. Agitation, tachycardia, and hypertension typically respond to treatment with other GABA agonists as needed. Benzodiazepines are considered to be the first-line treatment, although very high doses may be required. Patients who are refractory to treatment with benzodiazepines may require treatment with barbiturates or propofol. Pharmaceutical preparations of GHB have been used to treat resistant withdrawal. Antipsychotics such as droperidol and haloperidol may be considered as adjuncts to treatment, especially in patients where neuropsychiatric symptoms and hallucinations predominate. These agents should be used with caution as they lower the seizure threshold. Patients with hyperthermia and severe agitation may require intubation, sedation, and external cooling, as well as aggressive IV fluid hydration to treat rhabdomyolysis. Seizures are rare. Seizures should be treated with benzodiazepines as needed.
    C) DECONTAMINATION
    1) PREHOSPITAL: There is no role for decontamination in GHB withdrawal.
    2) HOSPITAL: There is no role for decontamination in GHB withdrawal.
    D) AIRWAY MANAGEMENT
    1) Rarely, patients with severe agitation and autonomic instability may require intubation due to the high doses of sedation required.
    E) ANTIDOTE
    1) There is no specific antidote for GHB withdrawal, although symptoms typically resolve if GHB is restarted. In the healthcare setting, symptoms are typically treated with other GABA agonists such as benzodiazepines, barbiturates, and propofol. Pharmaceutical GHB has also been used to treat resistant withdrawal.
    F) ENHANCED ELIMINATION
    1) There is no role for enhanced elimination in the treatment of GHB withdrawal.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management of GHB withdrawal.
    2) OBSERVATION CRITERIA: Patients with GHB withdrawal should be referred to a healthcare facility for evaluation and treatment. Because of the duration of withdrawal symptoms, patients whose symptoms are controlled with ED treatment will need to either be referred to a drug treatment program that can provide tapered benzodiazepine therapy, or provided with tapered benzodiazepine doses that can be carefully supervised in an outpatient setting.
    3) ADMISSION CRITERIA: Patients who develop significant symptoms with tachycardia, hypertension, and severe agitation who require more than a small amount of benzodiazepines for treatment should be admitted to the hospital, especially given the typical duration of withdrawal symptoms lasting several days. Patients with significant autonomic instability including hyperthermia, patients requiring intubation, patients with seizure activity, and patients with severe and refractory symptoms should be admitted to an ICU setting.
    4) CONSULT CRITERIA: Contact your regional poison center for a toxicology consult for any patient with suspected GHB withdrawal and more than mild symptoms. Refer patients for substance abuse counseling.
    H) PHARMACOKINETICS
    1) GHB and its analogs are well absorbed orally, rapidly metabolized, with small volumes of distribution and short elimination half lives. Because of these pharmacokinetics, only patients with prolonged, frequent (multiple times a day) GHB use appear to be at risk for withdrawal.
    I) TOXICOKINETICS
    1) Withdrawal symptoms begin 1 to 6 hours after the last dose of GHB, typically peak in 3 days, and may last up to 15 to 21 days.
    J) PITFALLS
    1) GHB withdrawal generally lasts several days, patients not hospitalized need careful outpatient follow-up and benzodiazepine titration. Severe withdrawal can be resistant to benzodiazepines and barbiturates; pharmaceutical GHB should be considered in these cases.
    K) DIFFERENTIAL DIAGNOSIS
    1) Withdrawal from alcohol, benzodiazepines or barbiturates; intoxication with sympathomimetics or hallucinogens; thyroid storm or sepsis.

Range Of Toxicity

    A) TOXICITY: Prolonged and frequent dosing of GHB and GBL can result in withdrawal. Symptoms can range from mild to severe. Individual variability appears to have some role in the extent and/or severity of withdrawal symptoms reported. In a case series of 57 withdrawal patients (36 cases of GHB, 3 cases of 1,4-BD, and 18 cases of GBL), a common pattern was noted with patients with a history of prolonged daily GHB use (generally more than a year) with frequent dosing up to every 2 hours, and a gradual progression of increased GHB dosing to achieve and maintain the euphoric effects. A death from GHB withdrawal was reported in a patient who died on day 13 after cessation of GHB; the cause of death was unclear.
    B) Chronic administration of therapeutic GHB for the treatment of narcolepsy has NOT been associated with withdrawal symptoms following discontinuation.

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) BACKGROUND: Gamma hydroxybutyrate (GHB) and its analogs including gamma-butyrolactone (GBL), 1,4-butanediol (1,4-BD) and gamma-valerolactone (GVL) are common drugs of abuse. There is increasing evidence that chronic, frequent (multiple times daily) abuse can lead to physical tolerance. In these patients, abrupt abstinence can be associated with a withdrawal syndrome. Please refer to the GAMMA HYDROXYBUTYRATE AND RELATED AGENTS management for information regarding acute exposure to GHB and related substances.
    B) TOXICOLOGY: GHB is thought to function as an inhibitory neurotransmitter in the CNS at GABA-B receptors. GHB temporarily suppresses dopamine release, followed by a release of endogenous opioids and a surge in dopamine release, especially in neurons in the nigrostriatal pathway. Chronic, frequent GHB abuse is thought to be due to decreased endogenous GABAergic tone in the CNS leading to withdrawal when chronic use is abruptly stopped. Withdrawal symptoms are similar to those seen with ethanol withdrawal, as well as with other sedative-hypnotic withdrawal syndromes.
    C) EPIDEMIOLOGY: GHB withdrawal is not common and is generally only seen in patients with escalating daily use (up to every 2 hours) over a period of months to years. Rarely, withdrawal has occurred following brief exposure (ie, 1 to 2 weeks).
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Abrupt abstinence after frequent chronic use may produce a range of effects with symptoms similar to those seen with other sedative-hypnotic agent withdrawal syndromes and ethanol withdrawal syndrome. Mild to moderate effects include anxiety, tremor, insomnia, disorientation and nystagmus. GI effects including nausea, vomiting, and diarrhea may occur.
    2) SEVERE TOXICITY: Severe symptoms of GHB withdrawal include autonomic instability similar to that seen with ethanol withdrawal, including tachycardia, hypertension, and hyperthermia. Severe neuropsychiatric effects include severe anxiety, agitation, paranoia, tremor and visual, auditory and tactile hallucinations. Rarely, rhabdomyolysis and seizures may be seen; seizures are less common with GHB withdrawal than with ethanol withdrawal.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypertension, hyperthermia, and tachycardia have been reported during GHB withdrawal.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: Gamma hydroxybutyrate (GHB) and its analogs including gamma-butyrolactone (GBL), 1,4-butanediol (1,4-BD) and gamma-valerolactone (GVL) are common drugs of abuse. There is increasing evidence that chronic, frequent (multiple times daily) abuse can lead to physical tolerance. In these patients, abrupt abstinence can be associated with a withdrawal syndrome. Please refer to the GAMMA HYDROXYBUTYRATE AND RELATED AGENTS management for information regarding acute exposure to GHB and related substances.
    B) TOXICOLOGY: GHB is thought to function as an inhibitory neurotransmitter in the CNS at GABA-B receptors. GHB temporarily suppresses dopamine release, followed by a release of endogenous opioids and a surge in dopamine release, especially in neurons in the nigrostriatal pathway. Chronic, frequent GHB abuse is thought to be due to decreased endogenous GABAergic tone in the CNS leading to withdrawal when chronic use is abruptly stopped. Withdrawal symptoms are similar to those seen with ethanol withdrawal, as well as with other sedative-hypnotic withdrawal syndromes.
    C) EPIDEMIOLOGY: GHB withdrawal is not common and is generally only seen in patients with escalating daily use (up to every 2 hours) over a period of months to years. Rarely, withdrawal has occurred following brief exposure (ie, 1 to 2 weeks).
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Abrupt abstinence after frequent chronic use may produce a range of effects with symptoms similar to those seen with other sedative-hypnotic agent withdrawal syndromes and ethanol withdrawal syndrome. Mild to moderate effects include anxiety, tremor, insomnia, disorientation and nystagmus. GI effects including nausea, vomiting, and diarrhea may occur.
    2) SEVERE TOXICITY: Severe symptoms of GHB withdrawal include autonomic instability similar to that seen with ethanol withdrawal, including tachycardia, hypertension, and hyperthermia. Severe neuropsychiatric effects include severe anxiety, agitation, paranoia, tremor and visual, auditory and tactile hallucinations. Rarely, rhabdomyolysis and seizures may be seen; seizures are less common with GHB withdrawal than with ethanol withdrawal.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypertension, hyperthermia, and tachycardia have been reported during GHB withdrawal.
    3.3.3) TEMPERATURE
    A) Hyperthermia has occasionally been reported during GHB withdrawal (McDaniel & Miotto, 2001).
    3.3.4) BLOOD PRESSURE
    A) Hypertension is commonly reported during GHB and GHB analog withdrawal (Dyer & Andrews, 1997; Craig et al, 2000; Dyer & Roth, 2001; McDaniel & Miotto, 2001; Wojtowicz et al, 2008).
    3.3.5) PULSE
    A) Tachycardia has been reported in some patients who develop GHB and GHB analog withdrawal (Dyer & Andrews, 1997; Addolorato et al, 1999; Dyer et al, 1999; Craig et al, 2000; Dyer & Roth, 2001; McDaniel & Miotto, 2001; Wojtowicz et al, 2008).

Heent

    3.4.3) EYES
    A) Extraocular motor impairment and nystagmus has been reported to occur during GHB and GHB analog withdrawal (Craig et al, 2000; McDaniel & Miotto, 2001; Wojtowicz et al, 2008).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension has been reported in some patients experiencing moderate to severe withdrawal symptoms from GHB and GHB analogs (Perez et al, 2006; Dyer & Andrews, 1997; Craig et al, 2000; Dyer & Roth, 2001; McDaniel & Miotto, 2001; Wojtowicz et al, 2008).
    b) CASE SERIES
    1) GHB, 1,4-BD, OR GBL
    a) In a case series of 57 withdrawal patients (36 cases of GHB, 3 cases of 1,4-BD, 18 cases of GBL), hypertension was reported in 44% of patients (Wojtowicz et al, 2008).
    B) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has been reported in some patients who develop moderate to severe GHB withdrawal (Perez et al, 2006; Dyer & Andrews, 1997; Addolorato et al, 1999; Dyer et al, 1999; Craig et al, 2000; Dyer & Roth, 2001; McDaniel & Miotto, 2001; Wojtowicz et al, 2008).
    b) CASE REPORTS
    1) GHB
    a) Severe withdrawal occurred in a 33-year-old man who ingested 5 to 6 ounces/day (34 to 41 grams/day) of GHB for 2.5 years. Effects included tachycardia, hypertension, and auditory and visual hallucinations. The patient required a total of 507 milligrams lorazepam over a 90 hour intensive care admission due to ongoing symptoms of confusion and persistent agitation. Toxicological screening was negative for other drugs. The patient was discharged on day 10 without sequelae (Craig et al, 2000).
    c) CASE SERIES
    1) GHB
    a) In a series of 8 patients, all experienced tachycardia at the time of GHB withdrawal secondary to sympathetic stimulation (Dyer et al, 1999).
    GHB, 1,4-BD, OR GBL
    b) In a case series of 57 withdrawal patients (36 cases of GHB, 3 cases of 1,4-BD, 18 cases of GBL), tachycardia was reported in 63% of patients (Wojtowicz et al, 2008).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ANXIETY
    1) WITH POISONING/EXPOSURE
    a) Anxiety is commonly reported, along with insomnia and tremors, by most individuals experiencing withdrawal from GHB and GHB analogs (Choudhuri et al, 2013; Kashyap & Patel, 2011; Perez et al, 2006; Wojtowicz et al, 2008; Galloway et al, 1997; Dyer & Andrews, 1997; Craig et al, 2000; Catalano et al, 2001; McDaniel & Miotto, 2001).
    b) Patients have reported feelings of intense anxiety during periods of attempted abstinence, which usually resulted in drug seeking behavior and frequent (i.e., every few hours) dosing to avoid symptoms (Galloway et al, 1997; Dyer & Andrews, 1997; Craig et al, 2000).
    c) ONSET: Most cases of GHB reported withdrawal symptoms have occurred after months to years of daily use. However, a woman developed significant symptoms of withdrawal after using GHB for only 7 days. She required a continuous infusion of lorazepam (total dose 56 mg) to treat her symptoms and was discharged on a tapered dose of lorazepam (Perez et al, 2006).
    d) CASE SERIES
    1) In a case series of 57 withdrawal patients (36 cases of GHB, 3 cases of 1,4-BD, 18 cases of GBL), anxiety was reported in 46% of patients (Wojtowicz et al, 2008).
    2) In a retrospective database review of all patients presenting with GHB/GBL/1,4-BD withdrawal to a UK hospital between 2008 and 2011, 31 presentations involving 20 different patients with GHB/GBL withdrawal were identified. Of the 31 presentations, 22 (71%) reported using other drugs, in addition to the GHB/analogues, including crystal methamphetamine, cocaine, alcohol, MDMA, mephedrone, ketamine and cannabis. In addition, 6/20 (30%) patients reported pre-existing documented psychiatric disorders other than substance abuse. The most common documented neuropsychiatric withdrawal symptoms included anxiety (61.3%), agitation (48.8%), tremor (38.7%) and hallucinations (35.5%). Withdrawal symptoms were managed with benzodiazepines and baclofen, and only 2 patients required additional antipsychotics such as olanzapine and quetiapine. However, in over half of the cases, psychiatric services were was also needed to address behavioral problems and to manage withdrawal symptoms. Constant observation by a mental health nurse was required along with legal detention under mental health laws (Choudhuri et al, 2013).
    B) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Confusion may occur in patients experiencing severe GHB withdrawal (Hernandez et al, 1998; Craig et al, 2000).
    b) CASE REPORTS
    1) GHB
    a) Confusion along with hypervigilance was reported in a 33-year-old woman who developed severe GHB withdrawal. Neurological effects included short-term and long-term memory deficits. The effects lasted for approximately 4 days before the patient's mental status began to clear; the patient returned to baseline 4 days later (Craig et al, 2000).
    C) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Similar to alcohol withdrawal, tremors (resting and intention) and restlessness are commonly reported during GHB and GHB analog withdrawal (Wojtowicz et al, 2008; LeTourneau et al, 2008; Galloway et al, 1997; Craig et al, 2000; Catalano et al, 2001; McDaniel & Miotto, 2001; Schneir et al, 2001).
    b) CASE SERIES
    1) GHB
    a) A 61-year-old woman with a complex medical history of anxiety, PTSD, depression, fibromyalgia and a recent ankle fracture was started on GHB 18 months prior to admission to treat chronic insomnia and anxiety. She gradually developed tremors so severe she was unable to feed or dress herself. At the time of elective admission for GHB withdrawal treatment, she was taking 4 g of GHB every 3 hours and an additional 1 g every 3 hours as needed. Following admission, she continued GHB and was started on lorazepam. She had 2 witnessed tonic-clonic seizures when GHB was withheld by 1 hour and was transferred to the ICU. Her examination included dysarthric speech and severe tremor affecting her trunk and limbs. Baclofen (5 mg every 8 hours) was added which improved her tremor and speech within hours of starting therapy. She was able to tolerate a gradual withdrawal of GHB and had no further seizure activity and her tremors were minor. The patient was able to complete activities of daily living. Ten weeks later, she continued to do well while continuing baclofen (10 mg 3 times daily) (LeTourneau et al, 2008).
    b) Following chronic use, 8 adult patients (from 22 to 38 years of age) who frequently reported body building (63%) and had a history of GHB use of 2 months up to 3 years, all experienced tremors, auditory and visual hallucinations, delirium (requiring physical restraint) and tachycardia (Dyer et al, 1999).
    2) GBL
    a) A 29-year-old man with a history of polysubstance abuse since the age of 15 and a 10-year history of using GBL of 2 mL at night, was admitted with tremulous, agitation and confusion. Over the next day, he had increasing agitation and bizarre behavior and was sedated with haloperidol, lorazepam and chlorpromazine. He had numerous studies including laboratory analysis, a brain MRI and head CT, lumbar puncture and viral studies which were all negative or within normal limits. He received ongoing supportive care and on day 14 his haloperidol was stopped due to a slight rise in creatinine kinase. By day 17, he was suddenly more calm and able to interact appropriately and feed and drink by himself. He was discharged to home a short time later with no permanent sequelae (Kashyap & Patel, 2011).
    3) GHB, 1,4-BD, OR GBL
    a) In a case series of 57 withdrawal patients (36 cases of GHB, 3 cases of 1,4-BD, 18 cases of GBL), tremor was reported in 67% of patients (Wojtowicz et al, 2008).
    b) In a retrospective database review of all patients presenting with GHB/GBL/1,4-BD withdrawal to a UK hospital between 2008 and 2011, 31 presentations involving 20 different patients with GHB/GBL withdrawal were identified. Of the 31 presentations, 22 (71%) reported using other drugs, in addition to the GHB/analogues, including crystal methamphetamine, cocaine, alcohol, MDMA, mephedrone, ketamine and cannabis. In addition, 6/20 (30%) patients reported pre-existing documented psychiatric disorders other than substance abuse. The most common documented neuropsychiatric withdrawal symptoms included anxiety (61.3%), agitation (48.8%), tremor (38.7%) and hallucinations (35.5%). Withdrawal symptoms were managed with benzodiazepines and baclofen, and only 2 patients required additional antipsychotics such as olanzapine and quetiapine. However, in over half of the cases, psychiatric services were was also needed to address behavioral problems and to manage withdrawal symptoms. Constant observation by a mental health nurse was required along with legal detention under mental health laws (Choudhuri et al, 2013).
    D) DELUSIONAL DISORDER
    1) WITH POISONING/EXPOSURE
    a) Paranoia and delusions have been observed in cases of severe GHB/GBL withdrawal (Choudhuri et al, 2013; Constantinides & Vincent, 2009; Wojtowicz et al, 2008; Sanguineti et al, 1997; Dyer & Andrews, 1997; Chin, 2001) .
    b) CASE REPORTS
    1) Increasing paranoia was reported in a female body builder who took GHB up to 1.5 capfuls every 3 hours around the clock for a year. Primary symptoms of withdrawal consisted of paranoia, agitation, delirium, and hypertension that lasted for 9 days. The patient was successfully treated with benzodiazepines, propranolol, and phenothiazines. At 6 month follow-up, she remained drug free (Dyer & Andrews, 1997).
    2) A 46-year-old man developed paranoid delusions, hallucinations, and depression after abruptly discontinuing daily use of a homemade brew of GHB. The patient had been taking 6 to 7 times the recommended dose of 3 g (dose suggested in the text "The Underground Steroid Handbook for Men and Women, Update 1992") daily as a sleep aid for an unspecified period of time. Recovery was uneventful (Sanguineti et al, 1997).
    E) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Tonic-clonic seizures have been reported infrequently following GHB and GHB analog withdrawal (LeTourneau et al, 2008; Wojtowicz et al, 2008; Catalano et al, 2001; Galloway et al, 1997; Hernandez et al, 1998; Craig et al, 2000; Price, 2000) .
    b) CASE REPORT
    1) A 61-year-old woman with a complex medical history of anxiety, PTSD, depression, fibromyalgia and a recent ankle fracture was started on GHB 18 months prior to admission to treat chronic insomnia and anxiety. She gradually developed tremors so severe she was unable to feed or dress herself. At the time of elective admission for GHB withdrawal treatment, she was taking 4 g of GHB every 3 hours and an additional 1 g every 3 hours as needed. Following admission, she continued GHB and was started on lorazepam. She had 2 witnessed tonic-clonic seizures when GHB was withheld by 1 hour and was transferred to the ICU. Her examination included dysarthric speech and severe tremor affecting her trunk and limbs. Baclofen (5 mg every 8 hours) was added which improved her tremor and speech within hours of starting therapy. She was able to tolerate a gradual withdrawal of GHB and had no further seizure activity and her tremors were minor. The patient was able to complete activities of daily living. Ten weeks later, she continued to do well while continuing baclofen (10 mg 3 times daily) (LeTourneau et al, 2008).
    2) A 29-year-old man who had been ingesting 1,4-BD daily for 5 to 6 years presented to the emergency department with withdrawal symptoms (ie, mental status changes, agitation, hallucinations, and one generalized tonic-clonic seizure). The patient had reportedly run out of 1,4-BD 3 days prior to admission. Other laboratory abnormalities associated with his withdrawal included elevated liver enzymes and rhabdomyolysis. The patient's neurologic symptoms resolved slowly over 6 days with lorazepam and haloperidol therapies (Wojtowicz et al, 2008).
    c) CASE SERIES
    1) In a case series of 57 withdrawal patients (36 cases of GHB, 3 cases of 1,4-BD, 18 cases of GBL), seizure was reported in 7% of patients (Wojtowicz et al, 2008).
    F) WERNICKE'S DISEASE
    1) CASE REPORT: Wernicke-Korsakoff syndrome (described as a triad of clinical signs which include mental, extraoculomotor and gait abnormalities) occurred in a 24-year-old woman after chronic GHB use for a year. GHB was used regularly after stopping alcohol consumption (history of alcoholism starting at age 15). While using GHB she would typically not eat for days at a time. Individual attempts at stopping GHB were unsuccessful and resulted in tremors, restlessness, and severe insomnia along with paranoia.
    a) During this admission, the patient was having visual and auditory hallucinations, a left VI nerve palsy, left beating nystagmus on leftward gaze, and had gait disturbances described as astasia-abasia which prevented her from ambulating. She was treated with daily doses of thiamine, and she was given lorazepam on several occasions, which worsened the psychomotor agitation, and was consequently started on chlorpromazine. By day 5, the patient's status had improved, and one month after admission there was no evidence of nystagmus, ataxia, or memory deficit upon exam (Friedman et al, 1996). It was felt that her Wernicke-Korsakoff syndrome resulted from chronic malnutrition secondary to her GHB abuse.
    G) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: NEUROLEPTIC MALIGNANT SYNDROME-LIKE REACTION: A 31-year-old woman was admitted with a 3-day history of agitation and auditory and visual hallucinations. She reported using 3 bottles of GBL ("Multicleaner" 99.9% GBL) daily for 4 months; no other drugs of abuse were reported. Symptoms included slight delusions and agitation severe enough to require physical restraints. Clorazepate 50 mg and haloperidol 5 mg were started. Two hours after admission, she developed tachycardia, hypertension, diaphoresis, confusion, tremors, hyperthermia and extrapyramidal rigidity. Her creatine kinase was 4240 Units/L and peaked at 22605 Units/L. Lactate dehydrogenase was also elevated (676 Units/L (normal, 220 to 450) and myoglobinemia (4014 mcg/L (normal, 14 to 65)) developed. A sodium bicarbonate infusion was started to treat rhabdomyolysis; antipsychotic therapies were stopped and diazepam and tropatepine were added. Her hallucinations resolved by day 5 and her laboratory abnormalities gradually improved and returned to normal by day 13 (Eiden et al, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH POISONING/EXPOSURE
    a) Sympathetic stimulation has resulted in nausea, vomiting and diarrhea (Price, 2000). Abdominal cramping has been reported during 1,4-BD withdrawal (Mycyk et al, 2001).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Two brothers (22-years-old and 19-years-old) developed symptoms of withdrawal after voluntarily decreasing their daily intake of 1,4-BD, which they had used for approximately one year. General symptoms of insomnia, confusion, agitation, and hallucinations were reported, along with urinary retention in both individuals. Foley catheters were placed with a urine volume of 400 mL and 500 mL, respectively. Both recovered following supportive care. The mechanism for producing this clinical effect was unknown (Su et al, 2001).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis is commonly reported during withdrawal from GHB and GHB analogs (Addolorato et al, 1999; Hutto et al, 2000; McDaniel & Miotto, 2001; Schneir et al, 2001; Wojtowicz et al, 2008).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis has been reported rarely in GHB and GHB analogs withdrawal (van Noorden et al, 2009; Wojtowicz et al, 2008).
    b) CASE REPORT
    1) GHB: An 18-year-old man with a history of drug abuse (ie, cannabis, cocaine, LSD) and possible schizophrenia was admitted after GHB cessation. His routine medications included olanzapine and oxazepam. Initial symptoms, included sedation with an impaired memory and auditory and visual hallucinations. By day 3, he became tachycardic and febrile and had a decreased level of consciousness. Laboratory studies included a creatine kinase (CK) of 3400 Units/L, elevated liver enzymes and an urinalysis was positive for protein and ketones. Over the next 2 days, his temperature rose to 40.2 degrees C and CK increased to 6000 Units/L and the patient became anxious and agitated. A sodium bicarbonate infusion was started for rhabdomyolysis. In addition, olanzapine was stopped due to the risk of neuroleptic malignant syndrome and lorazepam was increased. He gradually improved over the next week and his temperature and CK (830 Units/L) decreased. By the following week, he was transferred back to the psychiatric unit to gradually taper his lorazepam dose (van Noorden et al, 2009).
    2) 1,4 BD: A 29-year-old man with a history of ingesting 1,4-BD daily for 5 to 6 years presented with withdrawal symptoms (ie, mental status changes, agitation, hallucinations, and one generalized tonic-clonic seizure). The patient had reportedly run out of 1,4-BD 3 days prior to admission. Other laboratory abnormalities associated with his withdrawal included elevated liver enzymes and rhabdomyolysis. Five days following his last dose of 1,4-BD, the patient's creatine kinase (CK) level was 24,068 Units/L, and sodium bicarbonate therapy was initiated. By day 6, the patient's CK level had decreased to 2114 Units/L, and he was discharged to home (Wojtowicz et al, 2008).
    c) CASE SERIES
    1) In a case series of 57 withdrawal patients (36 cases of GHB, 3 cases of 1,4-BD, 18 cases of GBL), rhabdomyolysis was reported in 7% of patients (Wojtowicz et al, 2008).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS502-85-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) GHB levels are not readily available in most laboratories, and are not clinically relevant to the management of GHB withdrawal.
    B) Monitor vital signs and mental status.
    C) Serum electrolytes, renal function, liver enzymes and creatine kinase should be evaluated in patients with evidence of toxicity.
    D) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with toxicity.

Methods

    A) CHROMATOGRAPHY
    1) 4-hydroxybutyrate can be extracted from plasma as 4-butyrolactone and subsequently analyzed using gas chromatography (GLC) (Van Der Pol et al, 1975).
    2) Louagie et al (1997) described a method to determine GHB by gas chromatography-mass spectrometry after acetonitrile precipitation and derivation with N-methyl-N-trimethylsilyltrifluoroacetamide, using valproic acid as the internal standard.
    3) LoVecchio et al (1998) described a method to detect butyrolactone (gamma butyrolactone is a precursor in the synthesis of GHB) in urine using a gas chromatography and flame ionization detection.
    4) Kohrs & Porter (1999) reported that the mass spectrometry assay for GHB used in either urine or serum studies is unable to differentiate between GHB and GBL.
    5) Couper & Logan (2000) described a simple liquid-liquid extraction procedure to analyze GHB in biological fluids by GC/MS. This method was able to detect GHB in both blood and urine in several case reports.
    B) URINE SCREENING
    1) Badcock & Zotti (1999) described a qualitative screening test (spot test) for gamma-hydroxybutyric acid in urine which is rapid and sensitive. Results are obtained within 10 minutes, and based on acid conversion to the corresponding butyrolactone and subsequent color formation (intense blue/green color indicates GHB) with nitroprusside in alkaline solution.
    2) Laboratories that analyze urine samples for GHB include: National Medical Services (1-800-522-6671 or www.nmslab.com) and Elsohly Laboratories (662-236-2609 or www.elsohly.com) which tests for both GHB and Rohypnol. In general, samples should be collected as soon as possible in forensically acceptable sampling. Of note, blood (GHB is undetectable in blood after 8 hours) sampling can be done, but is generally more expensive, requires rapid collection, and special handling.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop significant symptoms with tachycardia, hypertension, and significant agitation who require more than a small amount of benzodiazepines for treatment should be admitted to the hospital, especially given the typical duration of withdrawal symptoms lasting several days. Patients with significant autonomic instability including hyperthermia, patients requiring intubation, patients with seizure activity, and patients with severe and refractory symptoms should be admitted to an ICU setting.
    B) Refer patients for treatment for relapse prevention. In a recent review of five cases of withdrawal from GHB and GBL, four relapsed within days of admission (McDaniel & Miotto, 2001).
    6.3.1.2) HOME CRITERIA/ORAL
    A) There is no role for home management of GHB withdrawal.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact your local poison center for a toxicology consult for any patient with suspected GHB withdrawal and more than mild symptoms. Refer patients for substance abuse counseling
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with GHB withdrawal should be referred to a healthcare facility for evaluation and treatment. Because of the duration of withdrawal symptoms, patients whose symptoms are controlled with treatment in the ED will need to either be referred to a drug treatment program that can provide tapered benzodiazepine therapy, or provided with tapered benzodiazepine doses that can be carefully supervised in an outpatient setting.

Monitoring

    A) GHB levels are not readily available in most laboratories, and are not clinically relevant to the management of GHB withdrawal.
    B) Monitor vital signs and mental status.
    C) Serum electrolytes, renal function, liver enzymes and creatine kinase should be evaluated in patients with evidence of toxicity.
    D) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with toxicity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) There is no role for decontamination in GHB withdrawal.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) There is no role for decontamination in GHB withdrawal.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) GHB withdrawal consists of predominantly symptomatic and supportive care. Anxiety and insomnia may be treated with benzodiazepines as needed.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment for severe toxicity begins with symptomatic and supportive care. Agitation, tachycardia, and hypertension typically respond to treatment with other GABA agonists as needed. Benzodiazepines are considered to be the first-line treatment, although very high doses may be required. Patients who are refractory to treatment with benzodiazepines may require treatment with barbiturates or propofol. Pharmaceutical preparations of GHB have been used to treat resistant withdrawal. Antipsychotics such as droperidol and haloperidol may be considered as adjuncts to treatment, especially in patients where neuropsychiatric symptoms and hallucinations predominate. These agents should be used with caution as they lower the seizure threshold. Patients with hyperthermia and severe agitation may require intubation, sedation, and external cooling, as well as aggressive IV fluid hydration to treat rhabdomyolysis. Seizures are rare. Seizures should be treated with benzodiazepines as needed.
    B) AIRWAY MANAGEMENT
    1) Rarely, patients with severe agitation and autonomic instability may require intubation due to the high doses of sedation required.
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Obtain IV access. Hydrate with 0.9% NaCl with 5% dextrose as clinically indicated.
    D) MONITORING OF PATIENT
    1) GHB levels are not readily available in most laboratories, and are not clinically relevant to the management of GHB withdrawal.
    2) Monitor vital signs and mental status.
    3) Serum electrolytes, renal function, liver enzymes and creatine kinase should be evaluated in patients with evidence of toxicity.
    4) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with toxicity.
    E) PSYCHOMOTOR AGITATION
    1) SUMMARY
    a) In a number of case reports, high dose benzodiazepine therapy appears to be a useful first-line therapy in the treatment of GHB withdrawal (Dyer & Andrews, 1997; Craig et al, 2000; Price, 2000; Dyer & Roth, 2001). Lorazepam was used successfully in a patient experiencing moderate to severe agitation and confusion during withdrawal of GHB which he had abused daily (5 to 6 ounces {230 g/L}; initial dose was 0.5 ounces) for 2.5 years (Craig et al, 2000).
    b) Because GHB does not act at the benzodiazepine receptor, the addition of other agents, such as barbiturates, may also be effective in treating severe withdrawal.
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    6) PENTOBARBITAL
    a) Pentobarbital has been successfully used to control the symptoms of withdrawal which were unresponsive to benzodiazepine treatment. Pentobarbital 1 to 2 milligrams/kilogram IV every 30 to 60 minutes markedly improved heart rate, hallucinations, and delusions for 2 to 6 hours (Sivilotti et al, 2001).
    7) PHENOBARBITAL
    a) ADULT LOADING DOSE: This dose has been recommended for use in patients in status epilepticus: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after a loading infusion (Brophy et al, 2012). MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Manno, 2003). Phenobarbital should be considered in patients that do not initially respond or appear resistant to benzodiazepines (Ghio et al, 2014).
    b) MAXIMUM SAFE ADULT DOSE: The total dose should not exceed 600 mg in 24 hours. The effect of large doses must be closely monitored (Prod Info LUMINAL(R)SODIUM powder for IV injection, 2008).
    c) CASE REPORT: A man with a 3 year history of addiction to GBL (up to 180 mL {6 ounces} per day) and daily benzodiazepine use developed grandiose and paranoid delusions, hypersexual behavior, auditory and visual hallucinations several days after the abrupt discontinuation of GBL. Despite initial treatment with diazepam (20 mg IV every 6 hours), followed by olanzapine (up to 15 mg/day), the patient's condition continued to deteriorate and he became verbally and physically aggressive. Olanzapine was stopped and the patient was started on oral phenobarbital (100 mg/day) and diazepam 8 mg/day. Within 20 hours, the patient showed signs of significant clinical improvement; cognitive and psychotic symptoms were completely resolved. The patient was maintained on phenobarbital for several weeks and then it was gradually discontinued. No symptoms or residual effects were reported one month after discharge (Ghio et al, 2014).
    8) PROPOFOL
    a) Propofol has also bee used to treat resistant GHB withdrawal (Dyer & Roth, 2001). The optimal dose is not known. Monitor for hypotension and hypoventilation. Endotracheal intubation should be strongly considered in any patient requiring this level of sedation.
    9) DROPERIDOL
    a) In an anecdotal report of 2 cases of moderate to severe GHB withdrawal, high doses of benzodiazepines (greater than 20 mg lorazepam over 2 hours) were unsuccessful in relieving withdrawal symptoms. Droperidol (2.5 mg) was given with immediate relief of agitation (patients fell asleep) and improved heart rate and blood pressure response was reported. Neither patient required intubation (Personal Communication, 2001).
    b) CAUTION: DROPERIDOL: Based on cases of QT prolongation and/or torsades de pointes in patients receiving droperidol at doses at or below recommended dosing, it should be reserved for use in patients who fail to show an acceptable response to other agents ((Anon, 2001)).
    c) A baseline ECG (repeat as indicated) and continuous cardiac monitoring for 3 hours are recommended for all patients receiving droperidol.
    10) CHLORDIAZEPOXIDE
    a) In a case of severe GHB withdrawal, described as autonomic dysfunction similar to alcoholic delirium tremens, the patient required intensive supportive care for 4 days and received lorazepam, fentanyl and propofol. The patient was discharged to home on day 6 with a tapering dose of chlordiazepoxide (Librium(R)) (Chin, 2001).
    11) CASE REPORTS
    a) GHB
    1) SUMMARY: Based on case reports, benzodiazepines were found to be useful in the treatment of GHB withdrawal.
    2) CASE REPORT: A 33-year-old man who had been using approximately 34 to 41 grams/day of GHB for 2.5 years developed severe symptoms of withdrawal which included agitation, visual and auditory hallucinations and hypertension. The patient required a total of 507 mg lorazepam over a 90-hour period for ongoing symptoms of agitation. Toxicological screening was negative for other drugs. The patient was discharged on day 10 without sequelae (Craig et al, 2000).
    3) CASE REPORT: A 43-year-old man using GHB for 2.5 years was also treated with a titrated dose of diazepam over 11 days; detoxification was uneventful (Price, 2000).
    4) CASE REPORT: A 36-year-old woman started abusing GHB after receiving GHB for alcohol addiction treatment. After 4 months of daily use the patient experienced withdrawal symptoms (i.e., high anxiety, tremor sweating, nausea and tachycardia) within 5 hours of drug removal and was successfully treated with diazepam 20 mg orally (Addolorato et al, 1999).
    5) ALCOHOL/GHB WITHDRAWAL: A 27-year-old who abused alcohol (12 cans of beer daily for an unknown period) and took GHB daily (10 to 15 capfuls of homemade GHB brew) developed withdrawal symptoms (ie diaphoresis, irritability, paranoia, and auditory and visual hallucinations) within 48 hours of GHB cessation and 8 hours of stopping alcohol. The patient required a total of 100 mg of lorazepam over a 6 day period; normal mentation was restored (Bowles et al, 2001).
    b) GBL
    1) CASE REPORT: A woman ingested 10 to 15 cc/day of Invigorate(TM) (3.5 g GBL/ounce) for 90 days and developed acute psychosis after a 48-hour abstinence. Symptoms included thought-blocking, tangential cognition, delusions, and visual and auditory hallucinations. Mental status improved after receiving a single dose of lorazepam (1 mg) and haloperidol (2 mg), with mentation returning to normal within 48 hours of admission. The patient did not develop any symptoms similar to alcohol/benzodiazepine-like withdrawal (Greene et al, 1999).
    2) CASE REPORTS: Two adults developed confusion, agitation, hallucinations and had autonomic instability following the abrupt withdrawal of GBL; both had been treated within the previous 48 hours for GBL toxicity and were discharged in stable condition within 12 hours. The patients required high dose benzodiazepine therapy (followed by a tapered dose) for persistent agitation and confusion. Recovery was uneventful (Sharma et al, 2000).
    F) EXPERIMENTAL THERAPY
    1) DETOXIFICATION BY TITRATION THERAPY
    a) CASE SERIES: In an open-label uncontrolled observational study, 23 patients with a history of chronic, daily GHB (ie, average duration of use of 1.6 years, average dose was 2 to 4.2 g per dose) use desiring detoxification were enrolled in an inpatient treatment center. They were initially stabilized using pharmaceutical GHB (150 mg/mL). The starting dose (70% of the calculated preadmission daily dose) was based on an established titration schedule and followed by a fixed tapered dose each day. The patients were closely monitored along with feedback by the patients to determine if the dose was adequate and withdrawal symptoms were manageable. The "stabilization" dose was then adjusted every 3 hours as needed based on these criteria. As patients became stable, the pharmaceutical GHB dose was tapered by 2 to 3 mL (0.3 to 0.45 g) per dose each day. Again, the patients were evaluated for any undesirable symptoms. If withdrawal symptoms developed, patients were given low doses of metoprolol, diazepam or temazepam as needed. If the patient was taking other psychotropic drugs at the time of admission, those agents were continued; benzodiazepines were replaced with an equivalent dose of diazepam. In this study, there were no reports of delirium or psychosis or the need for intensive supportive care. There was also a gradual decline in withdrawal symptoms as measured by the self-reported Subjective Withdrawal Scale results (de Jong et al, 2012)
    2) OLANZAPINE
    a) CASE REPORT: A 36-year-old man with a 2-year history of taking GHB daily (up to 32 ounces per week) was admitted 4 days after stopping GHB. Upon admission, he was agitated, irritable and tremulous and was complaining of thirst. His initial serum sodium concentration was 126. He was started on diazepam for agitation. The following day he developed increased anxiety and elevated mood and was found wandering the hospital and was incoherent. Forty-eight hours later, he began hearing voices and developed visual hallucinations. Lorazepam and olanzapine were added. Symptoms continued for another 4 days and on day 5 all benzodiazepines were stopped and treatment was continued with olanzapine alone for ongoing psychotic agitation. He started to improve later that day and was discharged on day 8 with no residual symptoms (Bennett et al, 2007).
    G) THIAMINE
    1) THIAMINE has been given to several patients experiencing severe GHB withdrawal (Craig et al, 1999). At the time of this review, its potential role in the treatment of GHB withdrawal remains unclear.
    H) SEIZURE
    1) Seizures are rare, however they should be treated with benzodiazepines as needed.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    I) BUTYROPHENONE
    1) Butyrophenones (e.g., haloperidol) are generally NOT RECOMMENDED in the management of GHB withdrawal, as they lower the seizure threshold (Sharma et al, 2001; Dyer & Roth, 2001).

Enhanced Elimination

    A) SUMMARY
    1) There is no role for enhanced elimination in the treatment of GHB withdrawal.

Abstracts

Case Reports

    A) ADULT
    1) A 29-year-old woman who took 3 ounces of GHB (concentration unknown) every 2 to 3 hours for 7 days, presented with severe withdrawal symptoms after abrupt cessation of GHB. Upon presentation, her blood pressure was 145/95 mmHg, pulse 132 beats/min, respirations 16 breaths/min, and temperature 98.7 degrees F. Over the course of 24 hours, the patient developed increased agitation, delirium, insomnia, and visual hallucinations. After supportive therapy for withdrawal symptoms, the patient recovered and was discharged 2 days after admission (Perez et al, 2006).

Range Of Toxicity

Summary

    A) TOXICITY: Prolonged and frequent dosing of GHB and GBL can result in withdrawal. Symptoms can range from mild to severe. Individual variability appears to have some role in the extent and/or severity of withdrawal symptoms reported. In a case series of 57 withdrawal patients (36 cases of GHB, 3 cases of 1,4-BD, and 18 cases of GBL), a common pattern was noted with patients with a history of prolonged daily GHB use (generally more than a year) with frequent dosing up to every 2 hours, and a gradual progression of increased GHB dosing to achieve and maintain the euphoric effects. A death from GHB withdrawal was reported in a patient who died on day 13 after cessation of GHB; the cause of death was unclear.
    B) Chronic administration of therapeutic GHB for the treatment of narcolepsy has NOT been associated with withdrawal symptoms following discontinuation.

Minimum Lethal Exposure

    A) SUMMARY
    1) Death was reported on day 13 of withdrawal in which the patient was noted to be improving; the mechanism remained unknown (Dyer et al, 1999).

Maximum Tolerated Exposure

    A) SUMMARY
    1) At the time of this review, no permanent sequelae have been reported following GHB withdrawal (Dyer & Andrews, 1997; Galloway et al, 1997; Hernandez et al, 1998; Craig et al, 2000; Price, 2000).
    2) LACK OF EFFECT: In a randomized, placebo-controlled, long-term efficacy trial, chronic daily therapeutic dosing of sodium oxybate (dose range 3 to 9 grams/night for 7 to 44 months) in narcoleptics caused minimal evidence of withdrawal symptoms following abrupt cessation (drug discontinued in 29 of 55 patients). Anxiety (n=2), dizziness (n=1), insomnia (n=1), and somnolence (n=1) were reported during the 2-week trial period. Although these symptoms may be possible symptoms of mild GHB withdrawal, they were also highly consistent with the returning symptoms of narcolepsy (Anon, 2003).
    B) CASE SERIES
    1) In a series of 8 chronic GHB users, the daily intake for each patient was quite variable. In two patients, daily doses of 20 to 25 g were reported, equivalent to 187 mg/kg and 370 mg/kg of GHB, respectively. In comparison, doses of 60 to 70 mg/kg can result in coma for 1 to 2 hours following an acute exposure (Galloway et al, 1997).
    2) Of those patients who desired detoxification, symptoms of insomnia, tremor and feelings of "doom" were described following abstinence; symptoms lasted on average from 3 to 12 days. All patients experienced some degree of withdrawal (Dyer & Roth, 2001).
    C) CASE REPORTS
    1) GHB
    a) A 40-year-old man with chronic GHB and polysubstance abuse and a prior attempt to stop GHB was admitted to the ED with memory deficits, paranoid delusions, and hallucinations. He had been taking 50 to 75 mg of GHB daily at 30 to 90 minute intervals. Despite lorazepam therapy, his symptoms worsened and he required intubation and mechanical ventilation and a lorazepam infusion. He showed signs of rhabdomyolysis (creatine phosphokinase reached 28140) and was paralyzed with vecuronium. His course was complicated by pneumonia, urosepsis, and an ECG showed inferior wall hypokinesis on day 16. By day 14, delirium had resolved and his restraints were removed; he was discharged on day 17. As his mental status cleared, he had no memory of the prior 2 weeks and thought only 1 day had past from the time of admission (Rosenberg et al, 2003).
    b) A 33-year-old man developed persistent agitation, auditory and visual hallucinations and tremors after stopping GHB. The patient had been consuming 5 to 6 ounces of GHB/day in divided doses for 2.5 years (starting dose was 0.5 ounces); a sample of the solution was analyzed and found to contain 230 g/L of GHB. CNS effects and mental status cleared after 8 days of supportive care which included a lorazepam infusion. No permanent sequelae was reported (Craig et al, 1999).
    c) A 35-year-old woman developed visual hallucinations, severe agitation and aggressive behavior during GHB withdrawal. The patient had a history of taking 2 teaspoons of GHB every 2 hours during the day and 2 to 3 teaspoons at night for one year. The patient reported numerous attempts at stopping GHB, but developed visual hallucinations that were relieved only by continued GHB use (Hernandez et al, 1998).
    2) GBL
    a) A 42-year-old man with a 3 year history of addiction to GBL (up to 180 mL {6 ounces} per day) and daily benzodiazepine use developed grandiose and paranoid delusions, hypersexual behavior, auditory and visual hallucinations several days after the abrupt discontinuation of GBL. Despite initial treatment with diazepam (20 mg IV every 6 hours), followed by olanzapine (up to 15 mg/day), the patient's condition deteriorated further with the development of physical and verbal aggression. Olanzapine was stopped and the patient was started on phenobarbital (100 mg/day) and diazepam 8 mg/day. Within 20 hours, the patient was clinically improved and felt remorse for his previous actions; cognitive and psychotic symptoms were completely resolved. The patient was maintained on phenobarbital for several weeks and then it was gradually discontinued. No symptoms or residual effects were reported one month after discharge (Ghio et al, 2014).

Workplace Standards

    A) ACGIH TLV Values for CAS502-85-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS502-85-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS502-85-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS502-85-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) 1,4-BD
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 327 mg/kg (RTECS, 2000)
    B) GHB-
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 4200 mg/kg (RTECS, 2000)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 4500 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Gamma-hydroxybutyrate is a short chain fatty acid derivative of gamma-aminobutyric acid (GABA) (Shannon & Quang, 2000). It is structurally similar to that of GABA and glutamic acid; it occurs naturally in mammalian brain (Craig et al, 2000).
    B) In vivo, GABA is converted to GHB via the enzyme succinic semialdehyde reductase. Metabolic degradation of GHB occurs by oxidation of the enzyme GHB dehydrogenase to succinic semialdehyde which than enters the Kreb cycle. It is thought to function as an inhibitory neurotransmitter in the CNS at GABA-B receptors (Shannon & Quang, 2000).
    C) In Europe, GHB has been used in the treatment of alcohol addiction, and preliminary data suggests that the pharmacologic profile of GHB and alcohol are similar. GHB mimics alcohol in different central actions. In drug discrimination studies with rats symmetrical generalization between alcohol and GHB was found. It has been suggested that GHB may be used in the treatment of alcohol addiction as a substitute therapy similar to methadone therapy for heroin addiction (Beghe & Carpanini, 2000). This may explain some of the similarities observed between the two substances during withdrawal.
    D) The neuropharmacology of GHB indicates that GHB administration temporarily suppresses dopamine release, followed by a surge in dopamine, in particular along the neurons of the nigrostriatal pathway. The release of dopamine is accompanied by a release of endogenous opioids.

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