Acute phenibut withdrawal : A comprehensive literature review and illustrative case report

Phenibut is a glutamic acid derivative with activity on the γ-aminobutyric acid (GABA)B, A, and B-phenethylamine receptors. It is prescribed in former Communist Bloc countries for anxiolysis and related psychiatric disorders. It can be easily obtained in Western countries and is thought to have abuse potential. Abrupt discontinuation has been reported to precipitate an abstinence syndrome. A review of the literature identified 22 reported cases, many of which were notable for severe psychomotor agitation and requirements for aggressive pharmacologic treatment. Neurologic and autonomic signs and symptoms may mimic serotonin or neuroleptic malignant syndrome. Patients were typically younger and had coexisting substance abuse disorders to other drugs. Also presented is a case of a 23-year-old male with an acute phenibut abstinence syndrome. This patient exhibited severe psychomotor agitation requiring physical restraints, dexmedetomidine, lorazepam, haloperidol, diphenhydramine, cyproheptadine, melatonin, olanzapine, and baclofen for symptom control.

PHB is prescribed in former Communist Bloc countries to treat anxiety and insomnia, as well as other psychiatric conditions (motor tics, alcohol withdrawal, restless leg syndrome, and post-traumatic stress disorder) [1,7,8].While PHB is unavailable as a prescription in Western countries, it can be obtained via the internet or vitamin and supplement suppliers [9][10][11].At this time, it is unclear how widespread the use of PHB is within the United States, and there is no laboratory or blood test to confirm its presence.As a central nervous system (CNS) depressant, PHB can be abused to induce euphoria and anxiolysis.It is also widely used as a nootropic agent [1,7,[11][12][13][14].Chronic PHB use results in tolerance, and abrupt discontinuation can lead to abstinence syndromes, some of which have been reported to be severe [3,10,11,13,[15][16][17][18].
To better understand the presentations and severity of PHB abstinence syndromes as well as therapeutic approaches, we conducted a thorough review of the literature.In addition, we present an illustrative case from our institution of a 23-yearold male who required intensive care to manage withdrawal symptoms associated with acute, severe PHB abstinence.

CASE REPORT
A 23-year-old male with an extensive polysubstance abuse history (cannabis, cocaine, opioids, amphetamines, benzodiazepines, and hallucinogens) and anxiety/depression managed with the selective serotonin reuptake inhibitor, sertraline, presented to the emergency department with progressive hallucinations and psychomotor agitation.A year prior, he had completed a drug rehabilitation program, but relapsed after a few months by abusing PHB.At the time of his emergency department presentation, he was using 4000 mg of PHB every six hours.He abruptly discontinued PHB two days prior.He denied other current drug abuse.
His urine toxicology panel (PHB screening was not included) was negative.He was admitted to the psychiatry service with the differential diagnosis of PHB withdrawal and substance-induced psychosis.However, his symptoms were recalcitrant to multiple pharmacological treatments including lorazepam, haloperidol, diphenhydramine, melatonin, and olanzapine.His physical symptoms worsened and he developed tachycardia, increased muscular tone, and inducible clonus.Laboratory evaluation revealed elevated creatine kinase at 867 U/L, though he remained afebrile.He was subsequently transferred to the intensive care unit for worsening agitation.Physical restraints, a dexmedetomidine infusion, and additional doses of lorazepam were required for severe agitation.Out of concern he was developing rhabdomyolysis, baclofen was administered and aggressive intravenous hydration begun; however, his kidney function was not adversely affected (creatinine levels remained between 0.7 mg/dl and 0.8 mg/dl throughout hospital stay).Cyproheptadine, a first-generation antihistamine with anticholinergic and antiserotonergic properties, was administered to empirically treat serotonin syndrome (patient was on sertraline) or neuroleptic malignant syndrome, without improvement.
The patient spent three days in intensive care where the dexmedetomidine infusion was slowly discontinued and gabapentin initiated and titrated.Baclofen and lorazepam were continued as needed for ongoing tremulousness, insomnia, nausea/vomiting, anxiety, and psychomotor agitation.After his acute episode of withdrawal resolved, he was transferred to the psychiatry service for further management of anxiety and insomnia.The patient was discharged from the psychiatry service six days later with scheduled outpatient follow-up.

DISCUSSION
Our case illustrates the serious nature of PHB withdrawal as well as complex management needed to prevent potentially life-threatening sequelae.In our patient, PHB withdrawal posed substantial management challenges and protracted treatment in the intensive care unit.Further, our case also demonstrates the diagnostic conundrum related to similarity between PHB withdrawal and serotonin syndrome.Only a few cases of PHB withdrawal are available in the literature (Table 1).However, patients were consistently reported to display signs of psychomotor agitation, oftentimes severe [3,10,11,13,[15][16][17][18][19]21,23].Two reports of withdrawal described patients who required such degree of sedation that mechanical ventilation was required [10,23].In addition, the patient demographics including young to middle age adults and concomitant substance abuse were typically present [10,11,[15][16][17][18][19].

Treatment of PHB intoxication
Management of intoxication is largely supportive with focus on respiratory drive, airway protection, and providing sedation if paradoxical agitation, seizures and delirium are present [7,8,[10][11][12]15,16,20,[24][25][26][27].PHB is minimally metabolized in the liver and secreted largely unchanged in the urine, according to animal models.Little is known about the potential drug-drug interactions or alterations in metabolism in humans [1].
Our patient manifested with tachycardia, increased muscular tone and rigidity, and inducible clonus.PHB intoxication, as well as withdrawal, can result in rhabdomyolysis leading to acute kidney injury [25].As seen in our case, despite aggressive and prompt anxiolytic and antipsychotic treatment, the patient developed a moderate increase of serum creatine kinase but did not develop kidney impairment, as assessed from unchanged serum creatinine concentrations.Severe hypertension requires aggressive blood pressure management and agitation and rebound anxiety requires anxiolytic therapy [3,10,11,13,[15][16][17][18][19].In extreme situations, these patients may harm self and/or others [3,16].

Treatment of PHB withdrawal
The pharmacologic treatment of PHB withdrawal is largely directed towards the management of withdrawal symptoms (Table 2).In cases of severe agitation, both chemical and physical restraints may be required [25], as well as admission to the intensive care unit.During the acute withdrawal, sedatives including dexmedetomidine, benzodiazepines, olanzapine, phenobarbital and haloperidol have been used; although it remains unclear which agent is optimal [3,10,11,13,[15][16][17][18][19].Once Chlordiazepoxide, baclofen.
Concomitant anabolic steroid use.
Not reported.
Not reported.
CIWA: Clinical Institute Withdrawal Assessment for Alcohol; HR: Heart rate the patient is able to take oral medications, clonidine, gabapentin, baclofen, benzodiazepines, phenobarbital and pregabalin may be used.Gabapentin, baclofen, benzodiazepines, and pregabalin may be particularly useful due to their similar interaction with GABAB and A receptors as PHB [2,6].Patients who take PHB will often need continued outpatient management of underlying psychiatric and substance abuse issues with the transition to safer medications.

CONCLUSION
The clinical presentation of our patient suggests that severe PHB withdrawal can be difficult to manage and refractory to multiple standard interventions.Neurologic and autonomic signs and symptoms may mimic serotonin or neuroleptic malignant syndrome.Medical providers must be familiar with the complex mechanisms by which PHB may affect various CNS receptors in order to treat patients with PHB withdrawal.

DECLARATION OF INTERESTS
Dr. Weingarten serves as a consultant to Medtronic in the role as chairman of the Clinical Endpoint Committee for the Prodigy Trial and has received unrestricted investigator-initiated grants from Merck for research unrelated to the current study.The other authors declare no conflict of interests.

Baclofen
GABAB receptor antagonist that inhibits neurotransmitter release.Phenobarbital GABAA receptor agonist resulting in increased chloride channel opening duration and reduced membrane excitability.

TABLE 1 .
Reported cases of phenibut withdrawal

TABLE 2 .
Mechanisms of action of medications used for phenibut withdrawal treatmentExtended sedation with intravenous infusions Dexmedetomidine A2 receptor agonist with sedative, amnestic, and analgesic effects.Phenobarbital GABAA receptor agonist resulting in increased chloride channel opening duration and reduced membrane excitability.PropofolPotentiates GABAA receptor by increasing the binding affinity of GABAA leading to inhibition of excitatory neurotransmission.Immediate-acting abortive therapy Haloperidol Dopaminergic antagonist that leads to depression of the reticular activating system.