Gamma-hydroxybutyric acid (GHB) withdrawal: a case report.
Keywords--abuse, delerium, dependence, Gamma-hydroxybutyric acid (GHB), withdrawal
Gamma-hydroxybutyric acid (GHB), an increasingly popular drug of illicit use, is a four carbon fatty acid endogenous metabolite of gamma amino butyric acid, a central nervous system depressant. Present in the brain as a neurotransmitter, it increases the level of dopamine in the substantia nigra and mesolimbic system (Wong et al. 2004; Nicholson & Balster 2001; Galloway et al. 1997). It is somewhat unique in light of its multiple therapeutic uses, narrow dose range, popularity among recreational users, and potential use as a date-rape drug (Hernandez et al. 1998; Schwartz 1998). It is FDA approved in the United States for treatment of narcolepsy, is used in anesthesia outside of the United States, and is under study for the treatment of alcohol dependence (Fuller et al. 2004; Wong et al. 2004; Gallimberti et al. 2000; Addolorato et al. 1996).
GHB's initial popularity arose in the United States among bodybuilders, who believed that the increase in slow wave sleep induced by GHB would increase the body's natural production of growth hormone (Van Cauter et al. 2004; Nicholson & Balster 2001). The unique euphoric effects, increased libido, and disinhibition quickly made it popular among rave, dance and circuit party crowds, often used in conjunction with other club drugs such as Ecstasy (MDMA), and methamphetamine. Its use is widespread, perhaps underreported in many populations, and undetected by current drug toxicology screens (Anonymous 2005; Lettieri & Fung 1978). At higher doses (more than 30 mg/kg) GHB produces a trancelike state and amnesia (Schwartz 1998). Overdose manifests with vomiting, sedation, muscle spasms and clouded consciousness. Respiratory depression occurs with loss of consciousness (Medical Letter 1991).
Previously published work has established the risk, frequency and management of overdose of GHB, highlighting the absence of detection on drug toxicology screens in emergency departments and the lack of necessary treatment protocols (Miglani et al. 2000; Lettieri & Fung 1978). However, little is known about GHB dependence and the management of its withdrawal. The 39 published cases indicate diverse clinical presentations of withdrawal including seizures (Chew & Fernando 2004), agitation (Zvosec & Smith 2005), and psychosis and delirium (McDonough et al. 2004). Two clinical studies using GHB in the treatment of alcohol dependence found a 10% to 15 % prevalence of GHB abuse or dependence (Gallimberti et al. 2000; Addolorato et al. 1996). A recently proposed protocol for management of GHB withdrawal (McDonough et al. 2004) recommends use of high dose benzodiazepines, but the utility of this approach has not been supported by other reports.
The authors report here a case of GHB withdrawal delirium with psychosis to illustrate that high-dose benzodiazepines may not be effective in cases of severe GHB withdrawal. Consistent with a previous report of three severe "benzodiazepine resistant" cases of GHB withdrawal (McDonough et al. 2004), our case indicates possible exacerbation of withdrawal delirium and psychosis by continued use of lorazepam after delirium had already cleared. These symptoms resolved promptly with discontinuation of all benzodiazepines and the use of a second generation antipsychotic.
The patient was a 36-year-old Caucasian male who had been using gamma-hydroxybutyric acid (GHB) to alleviate insomnia and for its body building properties for about two years.
Six months before admission, he had an acute onset of vomiting, diminished level of consciousness and decreased breathing, requiring intubation and respiratory support, with negative urine toxicology screen and blood alcohol level of zero, and was diagnosed by emergency room physicians as having overdosed on GHB. One and one-half months prior to admission, he again required emergency medical attention, with intubation for respiratory support, urine toxicology screens positive for alcohol and cocaine, and blood alcohol level of 50, again attributed to a GHB overdose. One week before admission he came to the emergency room twice with complaints of shaking, light headedness and general malaise in the course of trying to decrease and discontinue his GHB use, which he had managed to decrease in frequency to every 24 hours to prevent "getting shaky and weak." Urine toxicology screens were negative and blood alcohol levels were zero at both visits. On the last ER visit he was treated with diazepam.
On the day of admission, the patient was brought to the ER agitated, irritable, hyperventilating, and tremulous, with palpitations and shortness of breath. He gave a two-year history of using about 32 capfuls or ounces of GHB per week, (one ounce = about 2 g, range 0.5-5.0 g, depending on the source of GHB; see Miotto et al. 2001; Nicholson & Balster 2001) every two hours, until he stopped his usage in the four days before admission. He said he'd been extremely thirsty since trying to stop and had been drinking "a lot" of water each day. His only current medications were cetirizine for seasonal allergies and albuterol for asthma. He reported that he had stopped drinking alcohol and stopped using cocaine and marijuana four weeks prior to hospitalization. Prior to the previous month, he described drinking a few beers per night and using cocaine and marijuana on a once weekly basis.
Urine toxicology screen was negative and his blood alcohol level was zero. He was found to have low serum sodium of 126 and was diagnosed as being in GHB withdrawal with hyponatremia secondary to primary polydipsia (urine maximally dilute indicating no ADH activity), that is he had succeeded by drinking copious amounts of water in lowering his serum sodium. He was begun on diazepam 5 mg to 20 mg p.o. (orally) every 30 minutes to two hours as needed for anxiety, and was closely observed for possible seizures while hyponatremia was corrected with free water restriction of four liters per 24 hours.
On the day after admission, the patient showed increased energy and anxiety and an elevated mood. He was found in the hospital lobby, partially disrobed and incoherent. He was taken back to the ward and placed under close nursing observation. His vital signs for that day were blood pressure of 108-129/ 47-66, pulse 67-85 and respirations of 16-19. He received 20 mg of Valium and 2 mg of Ativan. There was no prior history of mania but a history of mild to moderate depression previously treated with antidepressants. Two days after admission, the patient began hearing voices and reported that he saw "advertising trucks" in his room. He had tangential thinking and loose associations. Blood pressure and respirations were higher than on previous days (114-148/59-79 and 18-28), but his pulse was similar at 59-85. Diazepam was changed to lorazepam 2 mg po/iv every six hours, and 1 mg po every four hours as needed for agitation with haloperidol 1 mg po/im every two hours as needed for severe agitation. Olanzapine 5 mg at bedtime was begun for the psychotic symptoms. He received 15 mg of lorazepam, 3 mg of haloperidol and 5 mg of olanzapine.
On the third day, the patient became even more agitated and confused and again began wandering off the neurology ward. Blood pressure (118-133/63-84), pulse (79-117), and respirations (18-20) continued to be elevated. Increased lorazepam doses IV along with haloperidol were given as needed. He received 2 mg of haloperidol, 8 mg of lorazepam and 5 mg of olanzapine. On the fourth day, the patient was transferred to the psychiatric unit, where he was cooperative but had increasing auditory hallucinations, visual hallucinations, and severely disorganized thought. He was found wandering the ward partially disrobed. Vital signs were blood pressure 119-140/58-75 and pulse 72-113 (respirations not recorded). He received 2 mg of haloperidol, 10 mg of lorazepam and 5 mg of olanzapine. On day ve, because of continuing confusion and disorganization, all benzodiazepines were discontinued and olanzapine was continued alone to treat the psychotic agitation. Later on day five he became coherent, less pressured, complaining only of slight tremor and "weak eyes" and began eating and drinking well. Vital signs were blood pressure of 129-141/62 and pulse of 70-98. On day six, he had a brief episode of increased temperature (39.1[degrees] C) and some "cold symptoms" with headache and shakiness, but slept better, with less scattered thought process and no voices or visions. His temperature returned to normal and he continued to have slightly rapid speech but was oriented and the clinical picture was that of a resolving delirium. Later on day six, the patient denied any racing thoughts, his speech was near normal rate, he said he felt "almost normal," and denied voices, visions or fears. The olanzapine was lowered to 2.5 mg per day and discontinued at discharge on the eighth hospital day.
This case highlights the unusual occurrence of delirium, psychosis and bizarre behavior developing in the context of acute withdrawal from GHB dependence. Treatment with benzodiazepines did not help the syndrome and may even have exacerbated it, although the resolution of the syndrome with reduction in benzodiazepines may have been a coincidence related to the natural course of this kind of withdrawal syndrome. The one reported case of a GHB withdrawal seizure describes a patient who had violent agitation following treatment with IV diazepam, biting staff while in the postictal phase (Chew & Fernando 2004). McDonough's (2004) proposed protocol for the management of withdrawal from GHB dependence describes the use of benzodiazepines, as it is the current standard of care in treatment of sedative-hypnotic withdrawal. However he notes that benzodiazepines in some cases do not adequately sedate the patient in severe GHB withdrawal, describing "benzodiazepine resistant cases." A review of cases finds that authors often comment on extremely large doses being required (Mason & Kerns 2002; Sivilotti, Burns et al. 2001; Schneir et al. 2001; Craig et al. 2000)--as high as 1138 mg of lorazepam over four days. Some suggest using pentobarbital; others note benefit from Risperdal and chlorpromazine. We raise the question: should large dose benzodiazepines be the sole first line agent for treatment of GHB withdrawal? We propose consideration for the use of adjuvant agents in severe cases of GHB dependence withdrawal, such as the second generation antipsychotic olanzapine.
Olanzapine has a spectrum of actions at multiple receptors. It is known that GHB acts primarily on GABA-B receptors, whereas benzodiazepines and ethanol act on GABA-A receptors (McDonough et al. 2004). Although it has become common practice to use benzodiazepines in sedative-hypnotic withdrawal (e.g. alcohol withdrawal), clearly different receptor subtypes are involved in the case of GHB. Even in the case of treating withdrawal from one benzodiazepine by using another, such as treating alprazolam dependence with clonazepam, problems can arise. Complex interactions at the level of cortical pyramidal cells between serotonin receptors and GABAergic interneurons (which contain both GABA-A & GABA-B receptors) provide a possible neuronal mechanism for causing psychosis. Studies in normal humans (D'Souza et al. 2006) demonstrate that pharmacologic reduction in GABA-ergic tone lowers vulnerability to psychosis in the face of stimulation of serotonin 2 receptors. It is reasonable to postulate that restimulation of GABA-A receptors might not be sufficient to counteract severe loss of GABA-B tone from GHB withdrawal, and that olanzapine, by blocking serotonin 2 receptors, might have more effectively improved our patient's psychotic delirium.
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W. R. Murray Bennett, M.D., FRCPC * Lawrence G. Wilson, M.D. ** Peter P. Roy-Byrne M.D. ***
* Assistant Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Seattle WA.
** Associate Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Seattle, WA.
*** Professor and Vice-Chair, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Seattle, WA.
Please address correspondence and reprint requests to W. R. Murray Bennett, M.D., Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Box 359930 325 Ninth Ave, Seattle WA 98104; Phone 206-731-1190, Fax 206-731-5109; email firstname.lastname@example.org
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|Title Annotation:||Short Communication|
|Author:||Bennett, W.R. Murray; Wilson, Lawrence G.; Roy-Byrne, Peter P.|
|Publication:||Journal of Psychoactive Drugs|
|Article Type:||Case study|
|Date:||Sep 1, 2007|
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