Gabapentinoid poisoning and withdrawal

INTRODUCTION — Gabapentin and pregabalin are commonly prescribed medications for the treatment of seizure disorders, neuropathic pain (eg, postherpetic neuralgia), fibromyalgia, anxiety, post-traumatic stress disorder, and restless leg syndrome. Gabapentinoids are commonly ingested in self-harm attempts and often misused for their sedative and euphoric properties. These medications can cause lethargy or agitation in overdose, increase risk of death combined with opioids, and manifest a withdrawal syndrome.

This topic will discuss the evaluation and management of gabapentinoid poisoning and withdrawal. A summary table to facilitate emergency management is provided (table 1). Their therapeutic use and a general discussion of evaluation and management of the poisoned patient are discussed separately.

●(See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

●(See "Nonopioid pharmacotherapy for acute pain in adults".)

●(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 — Nearly 75,000 gabapentin exposures were reported to United States (US) poison control centers from 2013 to 2017 [1]. Seventy percent of these exposures were intentional ingestions, and more than 80 percent of the intentional exposures occurred during attempted suicide. The majority of gabapentin exposures involved other substances, such as sedative-hypnotics, antidepressants, antihypertensives, and opioids. During this five-year period, gabapentin exposures increased by 72 percent.

Misuse and diversion of gabapentin are increasingly recognized [2,3]. Gabapentinoids are often used as part of a multi-modal regimen for chronic pain or misused by individuals with an opioid use disorder (OUD). Among almost 13,000 individuals seeking OUD treatment from 2019 to 2020, 9 percent reported past-month non-medical gabapentin use [4]. In addition to oral intake of pills, increasingly reported routes of misuse include nasal insufflation (crushing the pills and "snorting"), rectal ("plugging"), smoking, and intravenous [5,6]. When used in combination with opioids, gabapentin and pregabalin has been associated with a 50 to 70 percent increased risk of opioid-associated death [7,8]. Based on US post-mortem data from 2019 to 2020, an opioid was found in almost 90 percent of drug overdose deaths in which gabapentin was detected [9].

PHARMACOLOGY — Gabapentin and pregabalin are classified as gabapentinoids because of their structural similarity to gamma aminobutyric acid (GABA). However, their mechanism of action occurs apart from GABA-A receptors. They bind to the alpha-2-delta subunit of a voltage-dependent calcium channel, inhibiting presynaptic calcium influx and release of excitatory neurotransmitters [10]. Gabapentin and pregabalin most likely do not bind the GABA-B receptor [11]. Pregabalin also modulates the release of several neurotransmitters including glutamate, noradrenaline, and substance P [12].

Long term gabapentinoid therapy can lead to the development of tolerance, dependence, and withdrawal symptoms with cessation of therapy [13-16]. (See 'Withdrawal syndromes' below.)

PHARMACOKINETICS — The pharmacokinetics of gabapentin and pregabalin are similar.

●Absorption – Both are rapidly absorbed with oral administration, have high (60-90 percent) oral bioavailability, and reach peak concentrations within one to four hours [17,18].

●Distribution – Both have low plasma protein binding and a low (<1 L/kg) volume of distribution [19].

●Metabolism – Neither undergo metabolism.

●Elimination – Both are eliminated unchanged by the kidneys. The elimination half-life is 4-6 hours but can be significantly prolonged in the setting of overdose or kidney failure [20,21]. Toxic effects are not expected to last beyond 24 hours in a patient with normal kidney function.

Patients with chronic kidney disease require renal dosing adjustments since toxicity can develop from therapeutic dosing, given primarily renal elimination [22,23].

CLINICAL FEATURES OF OVERDOSE

Normal vital signs — Patients with isolated gabapentinoid overdoses usually do not have any significant changes in vital signs. Hypothermia or hyperthermia may reflect downtimes in ambient environments; fever from aspiration pneumonitis can occur in patients who aspirate. Mild tachycardia has been reported, and bradycardia can occur rarely [24]. Blood pressure and respiratory rate are typically within a normal range.

CNS depression — Isolated gabapentinoid overdoses typically cause only mild somnolence. Most patients will remain rousable to voice or tactile stimulation. The most common symptoms reported after gabapentin ingestion include sedation, dizziness, and ataxia [24]. In massive overdose, acute or chronic kidney impairment, or co-ingestion of other sedative (eg, alcohol, benzodiazepines, or opioids), patients may show signs of more pronounced central nervous system (CNS) depression (eg, lethargy, coma). However, massive gabapentin ingestions (up to 50 grams) have been reported with minimal sequelae [25,26].

Patients may have mild miosis after gabapentinoid ingestion, similar to other sedative-hypnotic poisoning.

Myoclonus, seizures — Multifocal and isolated myoclonus have been reported with gabapentin and pregabalin use and overdose and are more likely to occur in patients with impaired kidney function [27-31]. Increased neuromuscular tone (eg, clonus, rigidity, hyperreflexia) would not be expected in a gabapentin or pregabalin overdose.

Isolated seizures can occur following overdose of gabapentin or pregabalin [24,31-34]. Most reports describe a seizure lasting several minutes and resolving without intervention. Recurrent seizures can occur in rare cases.

Agitation, psychosis — Psychotic symptoms such as visual and auditory hallucinations, agitation, and paranoia have been reported with gabapentin and pregabalin use [35,36]. One of these cases was associated with epileptiform discharges on electroencephalography and improved following benzodiazepine administration [35].

Myopathy — There are case reports of gabapentin-induced myopathy and rhabdomyolysis, occasionally requiring renal replacement therapy [37-40].

EVALUATION — As with other suspected overdoses, the clinical approach to a patient with suspected gabapentinoid overdose involves collecting available history, a targeted physical examination, and relevant laboratory and electrocardiogram (ECG) findings.

History — The following are key elements of a clinical history in a suspected gabapentinoid 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)

●Suspected co-ingestants

●Names of other accessible medications

●Last time known well

●Prior history of self-harm attempts

●History of opioid use disorder, chronic renal insufficiency, or seizures

Examination — A targeted physical examination should be performed to assess mental status, airway protection, focal neurologic deficit, evidence of self-injury, and for presence of toxidromes (table 2).

Laboratory studies and ECG — Routine laboratory and diagnostic testing of the patient with somnolence, including when a gabapentinoid ingestion is suspected, is aimed at excluding other diagnoses and includes:

●Fingerstick blood glucose to rule out hypoglycemia as the cause of altered mental status

●Serum chemistries, creatinine, and creatine kinase to assess kidney function and exclude rhabdomyolysis

●Serum acetaminophen, salicylate, and ethanol concentrations to rule out these common co-ingestions

●ECG to screen for poisoning by drugs that affect the QRS or QTc intervals

●Pregnancy test in females of childbearing age

Additional tests are obtained based upon historical and clinical findings.

Gabapentinoid serum concentrations are not routinely useful in the evaluation and management of the somnolent patient, including when a gabapentinoid ingestion is suspected. These assays are not routinely available in the emergency setting, do not reliably correlate with clinical findings since tolerance can develop, and do not aid in acute management due to long turn-around times. Serum concentrations may be helpful confirmatory forensic tests (eg, pediatric patient with altered mental status in whom gabapentinoid poisoning is suspected). Serum concentration can also be helpful in excluding gabapentinoid poisoning as the etiology of unexplained prolonged coma if the serum concentration is <1 mg/L [41].

DIAGNOSIS — Gabapentinoid poisoning is a clinical diagnosis. The diagnosis should be suspected in a somnolent patient whose mental status does not improve after receiving naloxone. In the absence of clear corroborating history (eg, self-report or witnessed ingestion), gabapentinoid 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 — Gabapentinoid poisoning produces a sedative-hypnotic toxidrome characterized by depressed mental status and unremarkable vital signs (table 2). 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. Other common ingestions that present similar to gabapentinoid poisoning include:

●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".)

●Benzodiazepine, zolpidem, zopiclone, trazodone, and phenibut are examples of commonly misused sedatives that can only be excluded by history. (See "Benzodiazepine poisoning".)

●Gamma hydroxybutyrate (GHB) intoxication, which often manifests severe central nervous system 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 as well as tachycardia and anticholinergic delirium. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "Anticholinergic poisoning".)

Sedation and coma (table 3) are found in a wide range of medical and toxicologic conditions. Unless the diagnosis of gabapentinoid poisoning is obvious, other life-threatening, non-toxicologic causes must be considered in the differential diagnosis:

●Hypoglycemia must be excluded in every patient with altered mental status, even if gabapentinoid poisoning is suspected.

●In patients with profound respiratory depression or cardiopulmonary instability, which is rare with isolated gabapentinoid overdoses, the presence of co-ingestants or non-toxicologic etiologies should be investigated [27]. A patient with partial improvement in mental status following naloxone administration may have a gabapentinoid and opioid co-ingestion. (See "Acute opioid intoxication in adults" and "Opioid intoxication in children and adolescents".)

●Altered mental status in association with fever or leukocytosis raises concern for meningitis or other infections and warrants a thorough evaluation, often including assessment of the cerebral spinal fluid. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Bacterial meningitis in children older than one month: Clinical features and diagnosis" and "Viral encephalitis in adults" and "Acute viral encephalitis in children: Pathogenesis, epidemiology, and etiology".)

●Any focal neurologic findings or seizures raise concern for a central nervous system process such as stroke, intracranial hemorrhage, or encephalitis. (See "Overview of the evaluation of stroke".)

●A history of trauma or clinical findings of injuries should prompt obtaining a head computed tomography (CT) scan. (See "Initial management of trauma in adults".)

MANAGEMENT

All patients: supportive care — The initial management begins with rapidly assessing and addressing the patient's airway, breathing, and circulation. In patients who present with anything more than trivial sedation, we suggest establishing intravenous (IV) access and continuous cardiac monitoring.

Tachycardia and/or hypotension, which are unusual from an isolated gabapentinoid ingestion, should initially be managed with boluses of isotonic IV fluids and prompt an exploration for co-ingestant or another process (eg, infection). Vomiting, which commonly occurs following many ingestions, can be treated with ondansetron. (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 do not perform routine gastrointestinal decontamination with activated charcoal (AC) in patients with isolated gabapentinoid ingestion since intoxication will often improve with supportive care and excretion of the gabapentinoid. Administering AC provides no additional benefits but can increase the risk of aspiration and complicate airway management if the patient becomes more sedated. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

Management based on toxicity

CNS depression — Most patients with central nervous system (CNS) depression from gabapentinoid poisoning recover uneventfully without specific intervention. End tidal carbon dioxide (EtCO₂; ie, capnography) is useful to monitor for hypoventilation. Oxygen should be administered as needed. Placing a nasopharyngeal airway (ie, nasal trumpet) may be sufficient to overcome upper airway obstruction from CNS depression and preclude the need for tracheal intubation. (See "Basic airway management in adults", section on 'Nasopharyngeal airway' and "Basic airway management in children", section on 'Nasopharyngeal airway'.)

We do not administer flumazenil to a patient with suspected gabapentinoid poisoning. Flumazenil is a non-specific competitive antagonist of the benzodiazepine receptor on the GABA channel. It would not be expected to improve gabapentinoid intoxication and may precipitate benzodiazepine withdrawal if the patient has a benzodiazepine co-ingestion. Its use in the somnolent patient with benzodiazepine poisoning is discussed elsewhere. (See "Benzodiazepine poisoning", section on 'Role of antidote (flumazenil)'.)

Tracheal intubation may be required if the patient is unable to protect their airway. (See "The decision to intubate", section on 'Is patency or protection of the airway at risk?'.)

Decreased respiratory rate — In a somnolent patient with suspected gabapentinoid poisoning who has a low respiratory rate, we administer a trial of parenteral or intranasal naloxone, given the high rate of opioid co-ingestion. Naloxone would not be expected to reverse the effects of the gabapentinoid itself but may improve mental status or respiration if the patient is also suffering opioid intoxication. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and "Opioid intoxication in children and adolescents", section on 'Naloxone'.)

Tracheal intubation may be required if the respiratory status does not improve following naloxone. (See "The decision to intubate", section on 'Is oxygenation or ventilation failing?'.)

Seizure — Since most gabapentinoid-induced seizures are self-limited and brief, we do not administer antiseizure medication since it could exacerbate gabapentinoid-induced CNS depression. In a patient with recurrent seizures or prolonged seizures (>5 minutes), benzodiazepine administration (eg, adults: lorazepam 4 mg IV; children: 0.1 mg/kg IV, maximum dose 4 mg) is the first-line therapy. If additional medications are needed, phenobarbital or propofol are preferred to phenytoin as the second-line therapy since they have 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'.)

Myoclonus — We suggest symptomatic management of myoclonus since it improves with discontinuation of the gabapentinoid. Dialysis has been reported to improve myoclonus in patients with chronic kidney disease [42].

Patient with kidney impairment — In a patient with severe gabapentinoid poisoning (eg, coma) with severe kidney impairment, we suggest performing extracorporal removal in addition to supportive care. There is no clear definition of severe gabapentinoid poisoning, but the need for mechanical ventilation for depressed mental status or respiratory failure is accepted by most experts. 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 4). The duration of gabapentinoid toxicity is significantly prolonged in patients with severe kidney impairment. Both gabapentin and pregabalin are effectively cleared by hemodialysis [20,21,43]. (See "Enhanced elimination of poisons", section on 'Extracorporeal removal'.)

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 [27].

The evidence for hemodialysis in gabapentin or pregabalin poisoning is based on case reports and measured hemodialysis clearance, which is typically >100 mL/min in pharmacokinetic studies [20,21,27,43]. In patients with kidney failure, hemodialysis has resulted in rapid improvement in mental status and extubation (if the patient required tracheal intubation) [44-50]. Since prolonged mechanical ventilation has potential complications (eg, ventilator-associated pneumonia), significantly shortening the duration outweighs potential complications of hemodialysis, especially in a patient with chronic kidney disease who has established dialysis access.

In a patient with normal kidney function, we think the potential complications of hemodialysis outweigh the benefit of shortening the course of toxicity since most patients will improve within 24 hours without specific interventions.

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 gabapentinoid 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 depression, have resolved. The patient should be able to ambulate safely and without assistance prior to discharge. Patients with persistent signs of intoxication beyond six hours should be admitted to a monitored setting until symptoms resolve.

Since gabapentinoids are frequently ingested in self-harm attempts, a patient with a suspected self-harm attempt should be urgently referred for behavioral health evaluation.

If the patient has an opioid co-ingestion or opioid use disorder, they should be counseled about the risk of respiratory depression from gabapentinoid co-ingestion and offered referral to substance use disorder treatment.

WITHDRAWAL SYNDROMES — Gabapentin and pregabalin withdrawal ranges in severity. Withdrawal can occur following abrupt cessation with misuse or prescribed dosing [51]. Withdrawal symptoms have been reported to start as early as 12 hours after cessation of use, but in most cases start after 24 to 48 hours [14,52].

Common symptoms are anxiety and insomnia, but can also include diaphoresis, gastrointestinal discomfort, diarrhea, tremors, tachycardia, hypertension, agitation, delirium, disorientation, paranoia, hallucinations, and rarely seizures [14,51,53-56].

Reinstitution of the prior dose of gabapentin or pregabalin alleviates withdrawal symptoms [14,52]. This can be followed by a taper if the goal is cessation. An evidence-based taper protocol does not exist. One week is felt to be the minimal duration, but it is important to monitor for recurrence of withdrawal symptoms and extend the taper if needed [57]. Based on anecdotal reports, a reasonable initial approach is decreasing the daily dose by 300 mg every four days to one week. Benzodiazepines are typically ineffective for gabapentin withdrawal. A case series reported three patients who were successfully managed with a diazepam taper [53].

A neonatal gabapentin withdrawal syndrome has been reported [58,59]. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Clinical manifestations of NAS'.)

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 – Gabapentinoids are commonly ingested in self-harm attempts and often misused for their sedative and euphoric properties. They are eliminated unchanged by the kidneys. (See 'Pharmacology' above and 'Pharmacokinetics' above.)

●Clinical features of overdose – Patients with isolated gabapentinoid overdoses typically only develop mild somnolence without significant vital sign derangements. Less common symptoms include myoclonus, agitation, hallucinations, rhabdomyolysis, and isolated seizures, which can occur following overdose and typically resolve after several minutes without intervention. 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, creatine kinase; serum acetaminophen, salicylate, and ethanol concentrations; and electrocardiogram (ECG). (See 'Laboratory studies and ECG' above.)

●Diagnosis – Gabapentinoid poisoning should be suspected in a somnolent patient whose mental status does not improve after receiving naloxone. In the absence of clear corroborating history, it is a diagnosis of exclusion. (See 'Diagnosis' above.)

●Management – Most patients with central nervous system depression from gabapentinoid poisoning recover uneventfully with supportive care without specific intervention. Tracheal intubation may be required if the patient is unable to protect their airway. We do not administer flumazenil since it may precipitate benzodiazepine withdrawal if the patient has a benzodiazepine co-ingestion. We do not routinely administer activated charcoal in a patient with isolated gabapentinoid ingestion since intoxication will often improve with supportive care. (See 'All patients: supportive care' above and 'Limited role for gastrointestinal decontamination' above.)

•Decreased respiratory rate – In a somnolent patient with a low respiratory rate, we administer a trial of parenteral or intranasal naloxone, which would not be expected to reverse the effects of the gabapentinoid itself. Naloxone may improve mental status or respiration if the patient is also suffering opioid intoxication, which are common co-ingestants. (See 'Decreased respiratory rate' above.)

•Seizure – We do not administer antiseizure medication since most seizures are self-limited and brief. In a patient with recurrent or prolonged seizures, we administer benzodiazepines (eg, adults: lorazepam 4 mg IV; children: 0.1 mg/kg IV, maximum dose 4 mg). (See 'Seizure' above.)

•Kidney impairment – In a patient with severe gabapentinoid poisoning with severe kidney impairment (table 4), we suggest hemodialysis in addition to supportive care (Grade 2C). The prolonged duration of gabapentinoid toxicity with severe kidney impairment can be shortened since both gabapentin and pregabalin are effectively cleared by hemodialysis. We define severe poisoning as the need for mechanical ventilation for depressed mental status or respiratory failure. (See 'Patient with kidney impairment' above.)

●Withdrawal syndromes – Abrupt cessation of gabapentinoid use can cause a withdrawal syndrome that may include anxiety, insomnia, diaphoresis, gastrointestinal discomfort, tremors, tachycardia, hypertension, delirium, agitation, paranoia, hallucinations, and rarely seizures. These are treated with reinstitution of the gabapentinoid followed by a gradual taper. (See 'Withdrawal syndromes' above.)