By John Neill, PharmD Candidate 2018, and Courtney Kominek, PharmD, BCPS, CPE
Gabapentin and pregabalin are widely prescribed in chronic pain. Food and Drug Administration (FDA)-approved indications for gabapentin and pregabalin include post-herpetic neuralgia and epilepsy.1,2 In addition, pregabalin is FDA-approved for neuropathic pain (diabetic or spinal cord injury) and fibromyalgia.2 These gabapentinoids are frequently prescribed off-label for various reasons including post-operative pain, hot sweats, generalized anxiety disorder, and substance use disorders.3,4 Per the Controlled Substance Act, pregabalin is a Schedule V drug indicating it has the least likelihood for abuse among the 5 classes of controlled substances. Pregabalin was classified as a controlled substance based on the data from clinical trials. These trials showed that pregabalin causes positive psychic effects similar to alprazolam and diazepam, as well as acute euphoric effects seen at a higher proportion than expected.5 Gabapentin is not a controlled substance.3 Up until recently, gabapentin and pregabalin have been regarded as having low levels of abuse and being safe. This thought is rapidly changing and the reasoning behind this change will be described in this article.
Many drugs of abuse including alcohol, benzodiazepines, and non-benzodiazepine hypnotics display effects on gamma-aminobutyric acid (GABA) receptors.3 Gabapentinoids have structures that are similar to GABA, but they do not directly interact with GABA receptors or impact GABA uptake or production.6 It has been proposed that gabapentin may interfere with GABA metabolism, as well as cause the release of GABA allowing it to interact with its receptors.4 Gabapentinoids also reduce neurotransmitter release and the influx of calcium by binding to the alpha-2-delta subunit of voltage-gated calcium channels potentially causing their anticonvulsant, anxiolytic, and antinociceptive effects. It is believed, that not only do gabapentinoids cause euphoric effects most commonly attributed to GABA moderating drugs, but they may also cause dissociative effects through their interaction with the dopaminergic system.3 This dopaminergic relationship may also be the cause for the addictive potential of these drugs with the reward system being activated through this interaction. These dopaminergic effects are not typically seen with the other GABA modifying medications.3,4 In addition to the above effects associated with gabapentinoid abuse, other unexpected effects have been reported by abusers. These effects include relaxation and a high described as being similar to a high from marijuana, ‘zombie-like’ effects, and enhanced sociability.4
Gabapentinoid abuse is most common among the younger population, generally occurring in the 30s, on average. Risk factors for abusing gabapentinoids include a history of cocaine use, combination marijuana and benzodiazepine use at high rates, psychiatric patients, prisoners, and opioid abusers. The data for abuse rates for males vs. females is conflicting, with some studies showing higher rates in males, while others show higher rates in females. The prevalence of gabapentinoid abuse is much higher in this patient population and this problem has been on the rise in recent years. U.S. opioid abusers misused gabapentin and pregabalin as much as clonazepam and 2 times more than amphetamines. Gabapentinoid abuse is of particular concern in patients who currently abuse opioids or have a history of opioid abuse. Studies that have been done that have specifically assessed people with opioid use disorders and gabapentinoid abuse show pregabalin being abused at rates ranging from 3-68%, and gabapentin being abused at rates ranging from 15-22%. When comparing this to a study that showed the general population in the United Kingdom abusing pregabalin and gabapentin at rates of 1.1 and 0.5%, it shows you the alarming difference in rates of abuse between opioid use disorder patients and the general population.3Gabapentin dosing for post-herpetic neuralgia starts with 300 mg on day 1, 300 mg twice daily on day 2, and 300 mg three times daily on day 3, titrating up as needed to a max of 1800 mg/day; however, gabapentin may be dosed up to 3600 mg/day in divided doses for other conditions. Pregabalin dosing is recommended to start at 150 mg/day for all indications. This is typically divided into 2 to 3 doses per day. The general titration schedule is to increase to the max dose per indication based on tolerability and efficacy within 1 week. Max doses for pregabalin vary from 300 mg/day to 600 mg/day based on indication.2 Both medications require dosage adjustments for reduced renal function when creatinine clearance is below 60 mL/min.1,2.
Per individual case reports for gabapentinoid abusers, pregabalin abuse ranged anywhere between 800 to 7,500 mg per dose, with the median dose being 2,100 mg; and gabapentinoid abuse was anywhere between 1,000 and 12,000 mg per dose, with the median dose being 3,600 mg. These are typically single supratherapeutic doses when abused. Tachyphylaxis develops rapidly, so repeat abusers commonly increase the dose as they continue to abuse. U.S. poison centers have reported doses ranging up to 96,000 mg of gabapentin and 9,000 mg of pregabalin. No deaths occurred due to these high doses and outcomes were mostly mild to moderate. These reports indicate an advantageous adverse effect profile for these drugs; however, they are being seen on toxicology reports on an increasing basis. When pregabalin and gabapentin are used in conjunction with other central nervous system depressants, overdose deaths are more frequent.3
Typical abuse occurs via oral route, but intravenous routes, rectal plugging, smoking, and parachuting have been reported. Often times gabapentinoids are abused in conjunction with other drugs like alcohol, benzodiazepines, marijuana, opioids, lysergic acid diethylamide (LSD), selective-serotonin reuptake inhibitors, and quetiapine.3,4 People who abuse gabapentinoids typically acquire them with a legal prescription, from their family members or friends, or may purchase them online. Gabapentin on the black market ranges from $1 to $7 per pill.3
A concern related to gabapentinoid abuse is physical dependence and withdrawal symptoms. Withdrawal symptoms can be caused by sudden discontinuation of gabapentin or pregabalin. Withdrawal with gabapentinoids are very similar to what is seen with alcohol and benzodiazepine withdrawal, likely due to their effects on GABA.3 Symptoms that can result from alcohol and benzodiazepine withdrawal include anxiety, tremors, sweating, irritability, cognitive dysfunction, psychosis, and seizures, which can be life-threatening.7 Treatment for benzodiazepine and alcohol withdrawal involves using primarily benzodiazepines to help relieve symptoms. Benzodiazepine treatment for gabapentinoid withdrawal is ineffective, but fast relief can be attained by the administration of gabapentinoids. Re-administering gabapentinoids and slowly tapering the dose is the ideal way to treat gabapentinoid withdrawal.3
Some states have taken their own action to address this issue. The State Board of Pharmacy in Ohio made a rule effective on December, 1st 2016 requiring pharmacies, wholesalers, and prescribers to submit the specified dispensing, personal furnishing, or wholesale sale information on gabapentin to the Ohio Automated Rx Reporting System.8 In addition to the changes to gabapentin in Ohio, a rule went into effect in Kentucky on July 1, 2017 making gabapentin a Schedule V controlled substance resulting in the requirement of the administering and dispensing of gabapentin to be reported to Kentucky All Schedule Prescription Electronic Reporting (KASPER).9 It is highly likely that as time goes on more states will continue to adopt similar rules to help reduce the misuse and abuse of gabapentin.
Pharmacists are in a critical position to help reduce the spread of the abuse and misuse of pregabalin and gabapentin. Pharmacists can help raise awareness to this problem and make sure these medications are being used for legitimate purposes and that the doses are appropriate and do not exceed the maximum recommended dosages. It is important that pharmacists are aware of the warning signs of abuse such as frequent early refill request, patients requesting to pay out of pocket when they have insurance, multiple prescriptions for the same medication from different doctors, frequent transfers for that medication, and patients wanting their prescription early because it was ‘stolen or misplaced.’ We also need to pay particular attention to patients taking gabapentinoids who have substance abuse disorders, specifically people using opioids or with psychiatric issues.3