Version May 2024
INTRODUCTION — Baclofen is used for the management of muscle spasticity, dystonia, substance use disorders, and hiccups. Baclofen is sometimes delivered as a continuous infusion via intrathecal pump; malfunction can lead to withdrawal or, less commonly, overdose. Phenibut was developed as an anxiolytic and cognition enhancer (nootropic). It is a controlled substance in some countries. Although it can be purchased from internet vendors, it has not been reviewed by the US Food and Drug Administration and thus has not been approved for any medical indication or use as a supplement. Both are recreationally misused. These medications can cause lethargy and respiratory depression or paradoxical agitation in overdose. Sudden cessation of baclofen or phenibut after chronic use can manifest a life-threatening withdrawal syndrome that requires aggressive treatment.
This topic will discuss the evaluation and management of baclofen and phenibut poisoning and withdrawal. A summary table to facilitate emergency management is provided (table 1). The therapeutic use of baclofen and the general evaluation and management of the poisoned patient are discussed separately.
●(See "Cerebral palsy: Treatment of spasticity, dystonia, and associated orthopedic issues".)
●(See "Treatment of dystonia in children and adults".)
●(See "High-risk dietary supplements: Patient evaluation and counseling".)
●(See "General approach to drug poisoning in adults".)
●(See "Approach to the child with occult toxic exposure".)
●(See "Initial management of the critically ill adult with an unknown overdose".)
EPIDEMIOLOGY
●Baclofen – Approximately 5000 baclofen exposures are reported annually to United States regional poison control centers, producing between 2 and 12 deaths yearly [1-5]. In 2020, baclofen was reported to United States regional poison control centers as the sole agent in overdoses in 2112 cases, including more than 1100 intentional exposures, nearly 700 unintentional exposures, and 110 adverse medication reactions [2]. In baclofen-associated fatalities, frequent co-ingestants included opioids, benzodiazepines, and gabapentin.
●Phenibut – Among 1320 exposure calls involving phenibut to United States poison control centers from 2009 to 2019, there were three fatalities reported, two of which involved a co-ingestant [6]. The number of exposures rose sharply between 2015 and 2018, possibly due to increased marketing, popularity, and availability.
PHARMACOLOGY — Baclofen and phenibut are structurally similar to gamma aminobutyric acid (GABA), the predominant inhibitory neurotransmitter. They are agonists at GABA-B receptors, which are ubiquitously located both pre- and postsynaptically in the central nervous system (CNS). GABA-B receptors are G protein-coupled receptors; depending on location, activation can inhibit adenylyl cyclase, gate ion channels, or open G protein-gated inwardly rectifying potassium channels (and hyperpolarize neuronal membranes) [7]. GABA-B receptors are implicated in many disease processes, including epilepsy, anxiety, depression, schizophrenia, obsessive-compulsive disorder, addiction, and pain. In contrast, the GABA-A receptor is a ligand-gated chloride channel located primarily postsynaptically in the CNS and has binding sites for many sedative-hypnotic agents (eg, benzodiazepines, barbiturates, etomidate) in addition to GABA [8].
●Baclofen – Baclofen reduces muscle spasticity by acting on the spinal cord. It is occasionally delivered in low doses (25 to 1000 mcg/day) intrathecally via a surgically implanted, computer-programmed infusion pump, which achieves high spinal concentrations and good spasmolytic effects without adverse effects (eg, sedation) associated with higher oral doses [9]. Pump malfunction is a rare complication that can cause baclofen withdrawal or overdose. Other complications of intrathecal baclofen pumps are discussed elsewhere. (See "Cerebral palsy: Treatment of spasticity, dystonia, and associated orthopedic issues", section on 'Intrathecal baclofen' and "Chronic complications of spinal cord injury and disease", section on 'Intrathecal baclofen'.)
●Phenibut – Phenibut (beta-phenyl-gamma-aminobutyric acid) was developed in Russia in the 1960s for anxiolysis and as a cognition enhancer (nootropic) [10]. It is approved for medical use in Russia and various Eastern European countries, can be purchased from internet vendors in the United States, and is found in some cognitive enhancement supplements [11,12]. In addition to acting as a GABA-B receptor agonist, phenibut may share a mechanism with gabapentin in binding to the alpha-2-delta subunit of the voltage-dependent calcium channel. The gabapentin-like action inhibits presynaptic calcium influx and release of excitatory neurotransmitters [12,13].
Phenibut users report dose-dependent effects with physical and mental stimulation, wakefulness, and euphoria at lower doses; at higher doses, sedation, anxiolysis, and muscle relaxation predominate [12].
Daily use of baclofen or phenibut can lead to the development of tolerance, dependence, and life-threatening withdrawal symptoms with abrupt cessation of therapy [12,14,15]. (See 'Withdrawal syndromes' below.)
PHARMACOKINETICS
●Oral baclofen administration
•Absorption – Baclofen is rapidly absorbed after oral administration, reaching peak concentrations within one to three hours [16,17]. Bioavailability is high (>70 percent) and similar between oral tablets and suspension [16,18].
•Distribution – Baclofen has low plasma protein binding and a low (<1.2 L/kg) volume of distribution [19-21]. Baclofen is lipophilic and rapidly distributes into cerebral spinal fluid (CSF). However, only a small portion of baclofen crosses into the CSF; thus, large oral doses or direct intrathecal delivery are needed to achieve a therapeutic effect [9].
•Metabolism – Approximately 15 percent of baclofen is hepatically deaminated [22].
•Elimination – Baclofen is mostly eliminated unchanged by the kidneys (70 percent) [12,19,20]. The elimination half-life is two to seven hours in therapeutic dosing with normal kidney function, but can be significantly prolonged in the setting of overdose or kidney impairment [20,23,24]. The elimination half-life lengthens from 10 hours in overdose with normal kidney function to 80 hours in therapeutic dosing in patients with stage IV or V chronic kidney disease, with large inter-individual variability [19,22].
A renal dosing adjustment for baclofen is required to prevent toxicity during therapeutic dosing, given primarily renal elimination [25]. Patients with chronic kidney disease can develop toxicity within three days of starting baclofen [26].
●Intrathecal baclofen administration – After an intrathecal baclofen bolus, the onset of action is approximately 30 to 60 minutes, with a peak action and duration of four and eight hours, respectively. During continuous infusion, the maximal effect occurs at 24 to 48 hours. Plasma baclofen concentrations are expected to be low (<5 ng/mL) in adults; in a cohort of six pediatric patients, concentrations were near or less than 10 ng/mL [27].
Elimination likely occurs due to CSF turnover. After a single intrathecal bolus, the CSF elimination half-life was 1.5 hours during the first four hours then two to five hours afterward, but it shows large inter-individual variability [28].
●Phenibut – There is little published regarding the pharmacokinetics of phenibut [10]. It is mostly eliminated unchanged by the kidneys (65 percent). The elimination half-life is approximately six hours in therapeutic dosing with normal kidney function, but can be significantly prolonged in the setting of overdose or kidney impairment [12].
CLINICAL FEATURES OF OVERDOSE
Overview and vital sign abnormalities — Baclofen and phenibut overdose cause a wide range of manifestations that typically involve the central nervous system (CNS). Common vital sign abnormalities include hypothermia, hypoventilation, bradycardia, and hypotension.
●Baclofen – Mild symptoms following baclofen overdose include nausea, vomiting, and somnolence. More severe manifestations include myoclonus, hypotonia, hypothermia, bradycardia, hypotension, respiratory depression/failure, seizure, and/or coma. One-third to one-half of patients with baclofen toxicity have been reported to require tracheal intubation and mechanical ventilation [19]. Marked hypothermia with the presence of Osborn waves has been reported after baclofen ingestion [29]. Both mydriasis and miosis have been reported following baclofen overdose.
Intrathecal pump malfunction causing baclofen overdose has been reported, although pump malfunction more frequently results in withdrawal. Intrathecal baclofen overdose can rapidly cause severe toxicity similar to oral overdose; the hypotonia often progresses in a rostral direction [30,31].
●Phenibut – Toxicity ranges from nausea, vomiting, and sedation to severe and life-threatening respiratory depression. In a systematic review, almost half of patients who presented with phenibut toxicity required tracheal intubation [12]. Most patients (90 percent) develop altered mental status (either sedation or agitation/psychosis) and some (<15 percent) will develop disordered movements. Phenibut ingestion can cause hypothermia and bradycardia but can also produce paradoxical diaphoresis, tachycardia, and/or hypertension [6,12,32].
CNS depression, movement disorders
●Baclofen – Baclofen toxicity causes central nervous system (CNS) depression ranging from sedation to coma, frequently requiring tracheal intubation for airway protection. In a case series of 23 patients presenting after baclofen overdose, eight required mechanical ventilation; of these patients, seven had a reported ingestion greater than 200 mg [33]. A common manifestation of phenibut misuse and ingestion is CNS depression, often described as drowsiness, lethargy, confusion, and occasionally coma [6,32,34,35].
Severe baclofen toxicity can mimic anoxic brain injury or brain death with loss of brain stem reflexes and burst suppression pattern on electroencephalogram [36-40]. Patients with baclofen overdose have nearly undergone premature organ harvest and cessation of life-supporting treatment [39]. Although most patients improve within 48 to 72 hours, baclofen toxicity can last longer than five elimination half-lives, which is the commonly used criteria for establishing brain death during drug intoxication (table 2) [40]. (See "Diagnosis of brain death", section on 'Brain death mimics'.)
Baclofen can cause myoclonus, hypotonia, hyporeflexia, and/or areflexia [41].
●Phenibut – Phenibut toxicity can produce various movement disorders, including tremor, myoclonus, dystonia, and rigidity [12].
Agitation, psychosis, seizures — Both baclofen and phenibut, in either misuse or overdose, can produce paradoxical agitation; erratic behavior, delirium, paranoia, psychosis, and auditory and visual hallucinations have been reported [6,32,34,42-45]. Occasionally, the agitation is sufficiently severe that tracheal intubation is required to provide adequate pharmacologic sedation [32,43].
Baclofen overdose can cause single or multiple seizures [46]. In a case series of 23 patients presenting after baclofen overdose, four had witnessed or reported seizures [33]. All four patients with seizures had a reported ingestion of greater than 200 mg. Isolated seizures have been reported following overdose of phenibut [6,32].
Since GABA is an inhibitory neurotransmitter, it is counterintuitive that overdose of a GABA-agonist would cause psychomotor agitation, psychosis, and seizures. However, baclofen and phenibut overdose can actually decrease CNS inhibitory tone depending on the location (presynaptic versus postsynaptic) of the GABA-B receptor, distinguishing their toxicity from CNS depression caused by GABA-A agonist overdose [45].
EVALUATION — As with other suspected overdoses, the evaluation of a patient with suspected baclofen or phenibut overdose involves collecting available history, performing a targeted physical examination, and obtaining relevant ancillary studies.
History — The following are key elements of a clinical history in a suspected baclofen or phenibut overdose:
●Reasons to suspect overdose (eg, suicide note, witnessed, reported to bystanders)
●Time of ingestion or last dose
●Intent behind use (self-harm versus misuse)
●Presence of intrathecal pump (if baclofen is suspected) and any recent pump manipulation
●Suspected co-ingestants
●Names of other accessible medications
●Last time patient was seen without signs of toxicity
●Prior history of self-harm attempts
●History of substance use disorder, chronic kidney disease, or seizures
Examination — We perform a targeted physical examination assessing vital signs, mental status, ability to protect airway, focal neurologic deficits, muscle tone, clonus, evidence of self-injury, and presence of specific toxidromes (table 3). Patients with an unknown downtime should be evaluated for signs of compartment syndrome or traumatic myositis (eg, palpation of muscle compartments, including paraspinal and gluteal muscles).
If the patient has an intrathecal pump, listen for an audible low battery/low reservoir volume alarm and inspect the surrounding tissue for a fluid collection. If a history cannot be obtained but the patient is suspected to be taking baclofen, the anterior abdominal wall should be examined for an implanted device.
Laboratory studies and electrocardiograms — Routine laboratory and diagnostic testing of the patient with somnolence, including when baclofen or phenibut ingestion is suspected, is aimed at excluding other diagnoses and includes:
●Fingerstick blood glucose to rule out hypoglycemia
●Serum chemistries, creatinine
●Serum acetaminophen, salicylate, and ethanol concentrations to rule out these common co-ingestions
●Complete blood count
●Electrocardiogram (ECG) to screen for poisoning by drugs that affect the QRS or QTc intervals
●Pregnancy test in females of childbearing age
We obtain additional tests based upon historical and clinical findings. In a patient with a fever, in addition to obtaining studies to identify a source of infection (eg, urinalysis, chest radiograph), we also obtain creatine kinase, liver enzymes, and coagulation studies as these can be elevated if the patient has a severe withdrawal syndrome. (See 'Withdrawal syndromes' below.)
Baclofen or phenibut serum concentrations are not useful in the evaluation and management of the somnolent patient, even when an ingestion is suspected. These assays are not routinely available in the emergency setting and do not aid in acute management due to long turnaround times. Serum concentrations may be helpful confirmatory forensic tests (eg, pediatric patient with altered mental status in whom poisoning is suspected) or when a brain death declaration is considered in a patient with suspected baclofen overdose [39]. When obtained, concentrations correlate with duration of mechanical ventilation [47]. Serum concentration can also be helpful in excluding baclofen or phenibut poisoning as the etiology of unexplained prolonged coma. A therapeutic anti-spasticity serum baclofen concentration is 0.08 to 0.4 mg/L [19].
Patients with an intrathecal baclofen pump — In a patient with a baclofen pump and concerns for toxicity or withdrawal, the clinician who manages the pump should be contacted. In a patient with signs of baclofen toxicity, the pump may need interrogation to ensure active dosing is consistent with the prescribed dosing and to check the pump’s residual volume [30]. Premature reservoir emptying may not trigger the pump’s low reservoir volume alarm, which is often based on calculated remaining volume instead of actual measured volume.
In a patient with signs of baclofen withdrawal, pump interrogation may reveal rotor stall, programming error, or other issues. Pump interrogation alone does not confirm proper function. If interrogation does not identify malfunction, confirming the pump reservoir volume and/or diagnostic aspiration of the catheter access port may be required and should only be performed by clinicians experienced with these procedures [30]. If the catheter is radiopaque, radiographs (typically abdominal anteroposterior and lumbar/thoracic spine lateral) may identify disconnection, fracture, or migration from the spinal canal. Development of tolerance to baclofen should be a diagnosis of exclusion after the pump has been thoroughly evaluated. A full discussion on evaluation of baclofen pump malfunction is beyond the scope of this topic.
DIAGNOSIS — Baclofen or phenibut poisoning is a clinical diagnosis that should be suspected in a somnolent patient known to take one of these agents and/or with a corroborating history (eg, report of ingestion) or who has an implanted intrathecal pump. In the absence of clear corroborating history, poisoning should be considered a diagnosis of exclusion. Non-toxicologic and other toxicologic etiologies must be ruled out, especially conditions in which diagnostic delay will hold up critical interventions and definitive care.
DIFFERENTIAL DIAGNOSIS — Baclofen or phenibut poisoning can produce either a sedative-hypnotic toxidrome characterized by depressed mental status or delirium and agitation (table 3). In any suspected ingestion when the patient cannot provide a history, an exploration of alternative sources of information is warranted, including but not exclusive to emergency medical services, family members, pill bottles when available, medical records, and pharmacy information. Unless the diagnosis of baclofen or phenibut poisoning is obvious, other life-threatening non-toxicologic causes must be investigated.
The differential diagnosis varies according to the primary clinical features:
●Central nervous system (CNS) depression – Sedation and coma (table 4) are found in a wide range of medical and toxicologic conditions.
•Hypoglycemia must be excluded in every patient with altered mental status, even if baclofen or phenibut poisoning is suspected.
•Ethanol and phenobarbital intoxication, which can be assessed by obtaining serum concentrations. (See "Ethanol intoxication in adults" and "Ethanol intoxication in children: Clinical features, evaluation, and management" and "Barbiturate (phenobarbital) poisoning".)
•Gabapentin, pregabalin, benzodiazepine, zolpidem, zopiclone, and trazodone are examples of commonly misused sedatives that can only be excluded by history. (See "Benzodiazepine poisoning" and "Gabapentinoid poisoning and withdrawal".)
•Gamma hydroxybutyrate (GHB) intoxication, which often manifests severe CNS depression followed by abrupt awakening. GHB intoxication is difficult to distinguish from other causes of obtundation without a clear history. (See "Gamma hydroxybutyrate (GHB) intoxication".)
•Atypical antipsychotic agents (eg, quetiapine), which are commonly misused and intentionally ingested, can cause sedation but also miosis and anticholinergic toxicity. (See "Second-generation (atypical) antipsychotic medication poisoning".)
•A patient with partial improvement in mental status following naloxone administration may have an opioid co-ingestion. (See "Acute opioid intoxication in adults" and "Opioid intoxication in children and adolescents".)
•Any focal neurologic findings or seizures raise concern for a CNS process such as stroke, intracranial hemorrhage, or encephalitis. (See "Overview of the evaluation of stroke".)
●Agitation, delirium, confusion – These are found in a wide range of medical and toxicologic conditions.
•Anticholinergic poisoning typically causes an agitated delirium with tachycardia, dry lips and axilla, and mumbling speech. (See "Anticholinergic poisoning".)
•The mnemonic FIND ME (functional [ie, psychiatric], infectious, neurologic, drugs, metabolic, endocrine) may be helpful to organize a diagnostic search for the etiology of delirium and agitation (table 5). (See "Diagnosis of delirium and confusional states".)
•A history of trauma or evidence of injuries should prompt obtaining a head computed tomography scan to exclude CNS injury (eg, subdural hematoma). (See "Initial management of trauma in adults".)
●Fever, tachycardia, hypotension, altered mental status, and rigidity – In addition to baclofen withdrawal, this constellation of signs and symptoms can be found in various medical conditions.
•Neuroleptic malignant syndrome is associated with the use of antipsychotic agents. (See "Neuroleptic malignant syndrome".)
•Malignant hyperthermia occurs when a susceptible individual is exposed to a volatile anesthetic agent. (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)
•Altered mental status in association with fever or leukocytosis raises concern for meningitis, sepsis, or other infections and warrants a thorough evaluation, often including assessment of the cerebral spinal fluid (CSF). (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Viral encephalitis in adults" and "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)
•Autonomic dysreflexia, a manifestation of the loss of coordinated autonomic responses in patients with spinal cord injury above T6, can present with attacks typically triggered by noxious stimuli. (See "Chronic complications of spinal cord injury and disease", section on 'Autonomic dysreflexia'.)
●Intrathecal pump and CNS depression – Patients with an intrathecal pump are usually receiving either baclofen, morphine, fentanyl, hydromorphone, ziconotide, bupivacaine, clonidine, or cancer chemotherapy (eg, methotrexate, thiotepa, cytarabine). (See "Treatment of leptomeningeal disease from solid tumors", section on 'Intrathecal therapy' and "Interventional therapies for chronic pain".)
MANAGEMENT
All patients: supportive care — Rapidly assess and address the patient's airway, breathing, and circulation. In a patient with suspected baclofen or phenibut toxicity, establish intravenous (IV) access and continuous cardiac monitoring. In a patient with tachycardia or hypotension, we administer bolus volumes (10 to 20 mL/kg) of isotonic IV fluids (0.9% sodium chloride or lactated Ringer solution). An anti-emetic (eg, ondansetron) is administered for vomiting. (See "General approach to drug poisoning in adults", section on 'Supportive care' and "Initial management of the critically ill adult with an unknown overdose", section on 'Systematic evaluation: The "ABCDE" approach'.)
Limited role for gastrointestinal decontamination — We suggest not performing routine gastrointestinal decontamination with activated charcoal (AC) in patients with isolated baclofen or phenibut ingestion since intoxication often improves with supportive care. Administering AC provides no additional benefits but can increase the risk of aspiration and complicate airway management. In a patient who presents within 30 to 60 minutes of a reported large ingestion and is asymptomatic, AC may limit absorption and prevent onset of severe toxicity. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)
Toxicity-based management
CNS depression — Most patients with central nervous system (CNS) depression from baclofen or phenibut poisoning recover uneventfully, but many will require tracheal intubation for airway protection or ventilatory support. Administer oxygen as needed. A nasopharyngeal airway (ie, nasal trumpet) may be sufficient to overcome upper airway obstruction from CNS depression and preclude the need for tracheal intubation. End-tidal carbon dioxide (EtCO2; ie, capnography) is useful to monitor for hypoventilation. (See "Basic airway management in adults", section on 'Nasopharyngeal airway' and "Basic airway management in children", section on 'Nasopharyngeal airway' and "The decision to intubate", section on 'Is patency or protection of the airway at risk?'.)
In a patient with CNS depression and a low respiratory rate (ie, <12 breaths/minute after stimulation), we suggest a trial of parenteral or intranasal naloxone. Naloxone would not be expected to reverse the effects of baclofen or phenibut but may improve mental status or respiration if the patient has concomitant opioid intoxication. Tracheal intubation may be required if the respiratory status does not improve following naloxone. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and "Opioid intoxication in children and adolescents", section on 'Naloxone'.)
We suggest not administering flumazenil to a patient with suspected baclofen or phenibut poisoning. Flumazenil is a nonspecific competitive antagonist of the benzodiazepine receptor on the GABA-A channel. It would not be expected to improve intoxication with these agents and may precipitate benzodiazepine withdrawal if the patient has a benzodiazepine co-ingestion. Its use in somnolent patients with benzodiazepine poisoning is discussed elsewhere. (See "Benzodiazepine poisoning", section on 'Role of antidote (flumazenil)'.)
Seizure — In a patient with a prolonged baclofen- or phenibut-induced seizure (>5 minutes) or recurrent seizures, first-line therapy is benzodiazepines (eg, adults: lorazepam 4 mg IV; children: 0.1 mg/kg IV, maximum dose 4 mg). If additional medications are needed, phenobarbital or propofol is preferred to phenytoin as second-line therapy given their greater efficacy for toxin-induced seizures. (See "Initial management of the critically ill adult with an unknown overdose", section on '"D": Disability and neurological stabilization' and "Convulsive status epilepticus in adults: Management", section on 'In-hospital treatment' and "Management of convulsive status epilepticus in children", section on 'In-hospital treatment'.)
Agitation — In a patient with baclofen- or phenibut-induced agitation that requires pharmacologic sedation, we prefer benzodiazepines (eg, lorazepam 2 to 4 mg IV or intramuscularly [IM]).
A patient who is not adequately sedated following benzodiazepine administration may require tracheal intubation to facilitate escalation of pharmacologic sedation (eg, propofol, phenobarbital, dexmedetomidine). (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Initiating sedative-analgesics'.)
Patients with kidney impairment — In a patient with severe baclofen poisoning (eg, coma) and severe kidney impairment, we suggest extracorporeal removal in addition to supportive care. We define kidney impairment as acute kidney injury stage 2 or 3 using the Kidney Disease: Improving Global Outcomes (KDIGO) or stages III-V chronic kidney disease (table 6). The duration of baclofen toxicity is significantly prolonged in patients with severe kidney impairment, and baclofen is effectively cleared by hemodialysis [19]. We expect that phenibut is also cleared by hemodialysis since it is excreted unchanged in the urine and has a chemical structure similar to baclofen; specific supporting evidence does not exist. (See "Enhanced elimination of poisons", section on 'Extracorporeal removal'.)
There is no standard definition of severe baclofen or phenibut poisoning, but the need for mechanical ventilation for airway protection or respiratory failure is accepted by most experts. The preferred extracorporeal removal modality is intermittent hemodialysis, which should be continued until the patient's clinical status improves. Our recommendations are in agreement with those of the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup [19].
The evidence for hemodialysis in baclofen poisoning is based on cohort studies, case reports, and measured hemodialysis clearance, which is typically >120 mL/min in toxicokinetic studies [19]. The EXTRIP workgroup reviewed published studies and cases of patients with kidney impairment and therapeutic dosing toxicity and found those who received extracorporeal removal had a shorter duration of mental status alteration (51 patients, two versus three days) and hospital length of stay (23 patients, three versus eight days), although the findings did not achieve statistical significance [19]. In patients with kidney impairment, especially those with chronic kidney disease and established dialysis access, the benefit of potentially shortening the duration of toxicity (and preventing complications of prolonged mechanical ventilation) outweighs the risks of hemodialysis.
In a patient with baclofen toxicity and normal kidney function, hemodialysis has not been found to reduce the duration of mechanical ventilation or improve mortality [19]. Most patients will improve within two to three days with supportive care alone.
Patients with intrathecal overdose — The clinician who manages the pump should be contacted to reprogram the pump to reduce the dose or temporarily stop the infusion [30]. In addition to supportive care, an optional strategy that has been described is withdrawal of 30 mL cerebrospinal fluid ([CSF]; via catheter access port, lumbar puncture, or lumbar drain) [48]. Since most patients with baclofen toxicity recover with access to ventilatory support, CSF aspiration likely has a role limited to patients with life-threatening toxicity not improving with available supportive measures. In patients with suspected baclofen toxicity due to intrathecal administration, extracorporeal removal would not be expected to provide benefit since intrathecal baclofen pumps produce relatively low plasma concentrations [19].
DISPOSITION — Patients who have significant respiratory depression (eg, require mechanical ventilation), hypotension, or have been exposed to a hazardous co-ingestant should be admitted to a critical care setting.
Most patients with an isolated baclofen or phenibut ingestion can be safely discharged or cleared for psychiatric evaluation following an observation period of four to six hours, provided that any concerning symptoms, such as central nervous system (CNS) depression, have resolved. The patient should be able to ambulate safely and without assistance prior to discharge. We admit patients with persistent signs of intoxication beyond six hours to a monitored setting until symptoms resolve.
A patient with a suspected self-harm attempt, which is a common reason for baclofen or phenibut ingestion, should be referred for urgent behavioral health evaluation.
WITHDRAWAL SYNDROMES
Baclofen — Maintain a high degree of suspicion for baclofen withdrawal in patients with chronic baclofen use who present with hyperthermia, altered mental status, and increased muscle tone (spasticity or rigidity). The treatment goal of baclofen withdrawal is emergent baclofen administration via the same route as that prior to cessation [49]. While administration of other sedative agents is a helpful temporizing measure, treatment may remain incomplete until baclofen is reinstituted.
●Oral dosing – Abrupt cessation of oral baclofen causes a potentially life-threatening withdrawal syndrome. Common manifestations are hyperthermia, pruritus, and increased spasticity [50]. Other manifestations can include tachycardia, hypertension, anxiety, insomnia, tremor, visual changes, confusion, agitation, psychosis, delusions, hallucinations, and seizures. Untreated rigidity can cause hyperthermia, acidemia, and rhabdomyolysis. Reinstitution of the prior dose of baclofen alleviates withdrawal symptoms and can be followed by a taper if cessation is the goal.
●Intrathecal administration – Withdrawal from abrupt cessation of intrathecal baclofen is typically more severe compared with oral baclofen withdrawal [51]. Symptoms start within hours to two days. Return of baseline spasticity and pruritus without a rash are commonly reported early symptoms [30]. In addition to symptoms seen with oral withdrawal, intrathecal baclofen withdrawal causes muscle rigidity; without treatment, progressive rigidity can lead to severe hyperthermia, tachycardia, acidemia, rhabdomyolysis, and hypotension. Seizures, dysrhythmias, disseminated intravascular coagulation, multiorgan failure, coma, and death have been reported to occur from intrathecal baclofen withdrawal [50].
Intrathecal baclofen withdrawal can occur because of pump malfunction, programming error, battery failure, baclofen refill errors, or catheter migration, kinking, or fracture. The clinician who manages the pump should be contacted to evaluate the pump. (See 'Patients with an intrathecal baclofen pump' above.)
Treatment is to reinstate baclofen, ideally with intrathecal baclofen (either via pump or lumbar puncture) at the precessation dose if known; otherwise, 50 mcg baclofen intrathecally improves spasticity in most patients and can be redosed as needed [30,51]. It is often difficult to obtain adequate cerebrospinal fluid (CSF) concentrations with solely oral dosing; high oral doses (eg, ≥240 mg/day) have been required. If intrathecal delivery cannot be promptly reinstated, high-dose oral baclofen combined with intravenous benzodiazepines, barbiturates, or propofol (in a patient with a secure airway) can be temporizing measures.
Phenibut — Abrupt cessation of phenibut use can precipitate a complex withdrawal syndrome similar to baclofen withdrawal. Commonly reported symptoms include anxiety and insomnia [12]. Patients may develop nausea, hyperthermia, agitation, visual or auditory hallucinations, delusions, paranoia, tremor, myoclonus, rigidity, catatonia, seizures, and rhabdomyolysis. A case report describes a patient who developed dependence after only 10 days of daily self-treatment of restless leg syndrome; after abruptly stopping use, withdrawal symptoms included nervousness, irritability, palpitations, nausea, and insomnia [52]. Neonatal withdrawal from in-utero exposure to phenibut has also been reported [53].
Management often requires aggressive treatment since signs and symptoms can be refractory to standard treatment of a sedative-hypnotic withdrawal (eg, benzodiazepines) [12]. In patients with severe phenibut withdrawal, tracheal intubation has been required for airway protection to facilitate adequate sedation and muscle relaxation [14]. In a case report, phenibut withdrawal was successfully managed by gradually substituting 10 mg of baclofen for each gram of phenibut that the patient had used daily, followed by a taper [15].
ADDITIONAL RESOURCES
Regional poison centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)
SUMMARY AND RECOMMENDATIONS
●Pharmacology – Baclofen and phenibut (GABA-B receptor agonists) are recreationally misused and can accumulate and cause toxicity in patients with kidney impairment. (See 'Pharmacology' above.)
●Clinical features of overdose – Common vital sign abnormalities include hypothermia, hypoventilation, hypotension, and bradycardia. Symptoms of mild toxicity include somnolence, nausea, and vomiting. More severe toxicity can include myoclonus, hypotonia, respiratory depression/failure, seizures, and/or coma. Severe baclofen toxicity can mimic brain death with loss of brain stem reflexes. Baclofen and phenibut misuse or overdose can produce paradoxical agitation. A summary table to facilitate emergency management is provided (table 1). (See 'Clinical features of overdose' above.)
●Evaluation – Routine laboratory and diagnostic testing is aimed at excluding other diagnoses and includes serum chemistries, creatinine, complete blood count, serum acetaminophen, salicylate, and ethanol concentrations, and ECG. Examine the anterior abdominal wall for the presence of an implanted intrathecal pump and inspect the surrounding tissue for fluid collection (baclofen can be infused intrathecally via an implanted pump). In a patient with a fever, in addition to obtaining studies to identify a source of infection (eg, urinalysis, chest radiograph), we also obtain a creatine kinase, liver enzymes, and coagulation studies, as these can be elevated if the patient has a severe withdrawal syndrome. (See 'Evaluation' above.)
●Patient with intrathecal baclofen pump – Pump or catheter malfunction can cause either baclofen toxicity or withdrawal. The clinician who manages the pump should be contacted for pump interrogation and possibly other testing or reprogramming. (See 'Patients with an intrathecal baclofen pump' above.)
●Diagnosis – Baclofen or phenibut poisoning is a clinical diagnosis that should be suspected in a somnolent patient with a corroborating history (eg, report of ingestion), who is known to take one of these agents, or who has an implanted intrathecal pump. It should be a diagnosis of exclusion in the absence of clear corroborating history. (See 'Diagnosis' above.)
●Management – All patients should receive supportive care. (See 'Management' above.)
•Central nervous system (CNS) depression – Most patients with CNS depression from baclofen or phenibut poisoning recover uneventfully, but many will require tracheal intubation and mechanical ventilation. (See 'CNS depression' above.)
In a patient with a low respiratory rate and CNS depression, we administer a trial of parenteral or intranasal naloxone. Naloxone may improve mental status or respiration if the patient has concomitant opioid intoxication.
•Seizure, agitation – In a patient with a prolonged baclofen or phenibut-induced seizure (>5 minutes), recurrent seizures, or agitation, first-line therapy is benzodiazepines (eg, adults: lorazepam 4 mg intravenous [IV]; children: 0.1 mg/kg IV, maximum dose 4 mg). (See 'Seizure' above and 'Agitation' above.)
•Kidney impairment – In a patient with severe baclofen poisoning with severe kidney impairment (table 6), we suggest hemodialysis in addition to supportive care (Grade 2C). The prolonged duration of baclofen toxicity with severe kidney impairment can be shortened since it is effectively cleared by hemodialysis. We define severe poisoning as the need for mechanical ventilation for airway protection or respiratory failure. (See 'Patients with kidney impairment' above.)
●Withdrawal syndromes – Abrupt cessation of baclofen (oral or intrathecal) or phenibut use can cause a withdrawal syndrome that may include anxiety, insomnia, pruritus, hyperthermia, tachycardia, hypertension, confusion, agitation, psychosis, delusions, hallucinations, myoclonus, hypertonia, and seizures. Intrathecal baclofen withdrawal is more likely to be life threatening and cause severe hyperthermia, severe tachycardia, hypotension, rhabdomyolysis, disseminated intravascular coagulation, multiorgan failure, coma, and death. The treatment goal of baclofen withdrawal is emergent baclofen administration via the same route as that prior to cessation. Phenibut withdrawal can be treated with benzodiazepines, baclofen, barbiturates, or propofol (if secure airway). (See 'Withdrawal syndromes' above.)
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