GABAPENTANOIDS – GABAPENTIN and PREGABALIN

Gabapentin (Neurontin®, others) is FDA-approved for partial-onset seizures, post-herpetic neuralgia, and restless leg syndrome; pregabalin (Lyrica®) for fibromyalgia, various painful neuralgias, and partial-onset seizures. Both have myriad off-label uses including chronic cough, migraine prophylaxis, pruritus, bipolar and anxiety disorders, hot flashes, and therapy of substance abuse disorders. They are also increasingly misused and abused as recreational drugs, especially in combination with opioids. Because the gabapentanoids are so broadly dispensed and available, the Missouri Poison Center often handles calls regarding accidental and intentional exposures.

Mechanism of Action & Kinetics

Both medications bind to the alpha-2-delta subunit of N-type calcium channels (found only in the CNS and spinal cord) and impede the release of excitatory neurotransmitters. Although they are GABA analogues, they do not bind to GABA receptors nor enhance GABA action. Pregabalin shows greater CNS effects because of greater potency at the alpha-2-delta site.

Oral overdose of gabapentin is relatively benign, in part because the drug is absorbed only in the upper small bowel and by a specific transporter that is saturable.  In other words, there is a maximum amount that can be absorbed, so as the ingested dose increases the percentage of drug that enters the bloodstream decreases. Extended-release products are less susceptible to this issue due to specific formulation modifications. For example, Gralise is formulated in a gel that expands rapidly in the stomach, so it is retained and only slowly released into the small bowel. Horizant is a prodrug – gabapentin enacarbil – which is absorbed through a different transport mechanism that does not saturate. This leads to an increase in bioavailability and makes it the most potent form of gabapentin.

Gabapentin is eliminated from the systemic circulation by renal excretion as an unchanged drug with no appreciable metabolism. Likewise, pregabalin undergoes very little metabolism and the majority is eliminated in the urine in an unchanged form. As such, dosing adjustments should be made for those with renal insufficiency or who are undergoing dialysis.

Overdose and Abuse

Even in large overdoses, gabapentin and pregabalin are usually well tolerated with only mild CNS depression and hypotension, unless there are co-ingestants involved. The risk of CNS depression is increased with opioids, benzodiazepines, barbiturates, and alcohol. Patients with renal impairment may also be more susceptible to toxic effects due to reduced clearance of the drug through the kidneys.

There has been an accelerating increase in the use of gabapentin and pregabalin for recreational purposes. Sought-after effects of recreational gabapentinoid use include relaxation, sedation, and occasional psychedelic effects, and enhanced euphoria when used together with opioids.

With this rise in recreational use, pregabalin, but not gabapentin, has been classified by the Drug Enforcement Agency as Schedule V. However, some individual states have considered legislation to restrict gabapentin. Several have reclassified it as a Schedule V controlled substance. Others have passed legislation to require mandated reporting into the prescription drug monitoring program. Currently, the MO Bureau of Narcotics and Dangerous Drugs has not reclassified gabapentin as a scheduled drug.

Management of Toxicity

The primary toxic symptoms include CNS depression and/or hypotension, nausea, vomiting, slurred speech, ataxia, dizziness, blurred vision, and nystagmus. In very large overdoses or mixed ingestion, the patient may also experience respiratory depression, hyperkinesia, dyskinesia or seizures.

There is no antidote for gabapentin or pregabalin overdose. Patients have occasionally required mechanical ventilation in very large ingestions or if taken in combination with other CNS depressants. Treatment should be guided by signs and symptoms. Laboratory testing is often unnecessary other than evaluation of renal function to assess the ability to eliminate the medication. Treatment can include:

1. Hypotension: IV fluids with normal saline boluses as needed. Vasopressors as needed.
2. Seizures: The use of fosphenytoin or phenytoin is NOT recommended.
   1. 1^st line: Benzodiazepines – lorazepam or diazepam IV, or midazolam IM if no IV access
   2. 2^nd line: Levetiracetam (Keppra) – 20-30 mg/kg in 100 mL of normal saline or dextrose 5%, over 15 min (most adults will receive 3-4 vials of 500 mg each)
      1. OR phenobarbital loading dose: 15-20 mg/kg, over 15-20 min
      2. OR propofol
   3. 3^rd line: General anesthesia by propofol; if a paralytic is used, bedside continuous EEG monitoring is recommended.
3. Dialysis: Hemodialysis is effective in removing gabapentin and pregabalin, but the majority of patients will recover without dialysis.
   1. May be useful if patient is unresponsive to standard supportive care or in the presence of renal impairment.

Gabapentin and pregabalin overdoses are typically well-tolerated but can become complicated if co-ingestants are present. Our advice is to call the Missouri Poison Center at 1-800-222-1222 where specially trained nurses, pharmacists, and medical toxicologists can provide you with the most up-to-date management advice on common and uncommon exposures.