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17 Articles in Volume 19, Issue #4
Analgesics of the Future: Inside the Potential of Nerve Growth Factor Antagonists
Best Practices Are Still Largely Undefined in Task Force Report
Brief Behavioral Interventions for Chronic Pain
Cervicogenic Headache: Diagnosis and Management
Chronic Headache and Central Pain Conditions
Considering Comorbidities When Selecting Medications for Pain (Part 4)
For APPs: How to Contribute to Clinical Research
Gabapentin and Suicidal Ideation: Is There a Link?
Intranasal Ketamine for the Relief of Cluster Headache
Letters: Slipping Rib Syndrome; Burning Leg Pain; CGRP Complications
Pain Assessment Tools for Malingering in Patients with Chronic Pain
Refractory Chronic Migraine: Mild, Moderate, or Severe
Should Probuphine be considered for MAT?
Special Report: The Abuse Potential of Gabapentin & Pregabalin
Tension-Type Headache: Evidence for Trigger Points
Treatment Alternatives for Migraine
Trigeminal Neuralgia: Current Diagnosis and Treatment Options

Special Report: The Abuse Potential of Gabapentin & Pregabalin

Despite their inherent abuse potential, gabapentinoids may be safer than presumed and offer prescribers an effective opioid-alternative treatment for certain types of neuropathic pain.
Pages 50-53

Update: On July 19, 2019, the FDA approved multiple applications for first generics of pregabalin for the management of neuropathic pain associated with diabetic peripheral neuropathy, for the management of postherpetic neuralgia, as an adjunctive therapy for the treatment of partial onset seizures in patients 17 years of age and older, for the management of fibromyalgia, and for the management of neuropathic pain associated with spinal cord injury.

In an attempt to reduce the practice of opioid overprescribing and the potential for subsequent opioid abuse or misuse, gabapentinoids have been used as an alternative treatment in cases where the pain type is consistent with a neuropathy. Gabapentinoids include gabapentin and pregabalin. Both medications have FDA-approved indications for post-herpetic neuralgia (PHN) and as an adjunct for partial seizures.1,2 Pregabalin has additional FDA-approved indications, including for fibromyalgia, renal impairment, and for the management of neuropathic pain associated with diabetic peripheral neuropathy and spinal cord injury.2 In the European Union, pregabalin has also been indicated for generalized anxiety disorder.

From 2012 to 2016 in the United States, gabapentin prescribing increased by 64%.3 In 2017, 68 million prescriptions of gabapentin were dispensed, making gabapentin the 10th most commonly prescribed medication. Notwithstanding, gabapentinoids have their own inherent abuse potential.4 Pregabalin has been classified as a Schedule V controlled substance since its release to the market in 2005, indicating that it has potential for abuse. The first marketed medication in this class, gabapentin, is not currently classified as a controlled substance in most states, however, its abuse potential is still being investigated. In fact, Kentucky, Michigan, and Tennessee have reclassified gabapentin as a Schedule V controlled substance.5,6

In addition to their approved indications, both pregabalin and gabapentin are frequently prescribed off-label for restless legs syndrome and diabetic neuropathy.3,7 Gabapentinoid use for patients with these indications is currently supported only by small studies.3 Gabapentin has also been found to significantly reduce the number of alcoholic drinks a person has in a week, leading to its off-label use in alcohol use disorder.8 However, the limited data on the use of gabapentinoids for these conditions should be weighed against their risk of abuse.

Millennium Health, a specialty laboratory, reported on its collection of urine drug tests taken between 2014 and 2018 which looked specifically at gabapentin and pregabalin use.9 While the rate of prescriptions for both of these medications increased during this four-year period, the rate of urine drug tests positive for non-prescribed gabapentin decreased from 11% in 2014 to 10% in 2018. The frequency of positives for non-prescribed gabapentinoids varied greatly by state. (Read the full report, "National Drug Use and Abuse Trends" in the April/May 2019 issue of PPM).

Gabapentin and pregablin may be best used before opioid therapy, or in patients who have been safely rehabilitated off them. (Source: 123RF)

The Pharmacology of Gabapentinoids

Gabapentinoids are structurally similar to gamma-aminobutyric acids (GABA), however, they do not act on GABA receptors and have no effect on GABA synthesis or metabolism.10 Gabapentin and pregabalin act on the alpha-2-delta-1 subunit of calcium channels in the central nervous system (CNS). Binding to these calcium channels, which are located on the presynaptic neurons, reduces calcium efflux and ultimately reduces the release of excitatory neurotransmitters into the synapse. This explains the use of gabapentinoids in blocking nerve pain and treating seizures. Therapeutic doses of gabapentinoids have a moderate dose-dependent increase in GABA extracellular concentrations, which is why some individuals experience relaxation and euphoria when taking the medication.4

There are differences between gabapentin and pregabalin as well. Pregabalin has been found to have a much higher binding affinity for the alpha-2-delta-1 subunit compared to gabapentin, by about six times.4 In addition, absorption differs between the two gabapentinoids. Gabapentin is saturable in terms of absorption, which is why it follows non-linear pharmacokinetics. In addition, there are two brand-name extended-release versions of gabapentin – Horizant and Gralise – that may be taken only once or twice daily.11,12 Pregabalin, on the other hand, follows linear pharmacokinetics, meaning that absorption increases proportionally as the dose increases. The bioavailability of gabapentin is 60% for a 300-mg dose and 35% for a 1600-mg dose.1 In comparison, the bioavailability of pregabalin is 90% regardless of the dose being used.2 For neuropathic pain, gabapentin is usually initiated at 300 mg given by mouth three times daily.1 This may be titrated up to 600 mg given by mouth three times daily if pain is not controlled at lower dosages. On the other hand, pregabalin is usually initiated at 50 mg given by mouth three times daily; this dose may be titrated up to 200 mg given by mouth three times daily.2

Abuse Potential
Why, How Gabapentinoids May Be Abused

Gabapentin and pregabalin abuse has been seen primarily in patients with a history of substance use disorder (SUD), particularly in those who abuse opioids.10 Effects from gabapentinoid abuse may include euphoria, dissociation, relaxation, sedation, and sometimes psychedelic effects. Gabapentinoids are commonly abused using supratherapeutic doses in combination with alcohol, cannabis, selective serotonin reuptake inhibitors (SSRIs), amphetamines, LSD, gamma-hydroxybutyrate (GHB, or “liquid ecstasy”), and heroin.13

Gabapentinoid abuse may also be used to lessen the effects of opioid withdrawal and to potentiate opioid-induced “highs.”13 It is speculated that the “GABA-mimetic” properties of gabapentinoids cause these effects at doses well above those prescribed.13 Another reason that gabapentin, specifically, may be abused is because it is relatively easy to obtain large quantities undetected; since the drug is not a controlled substance, it does not need to be reported to a prescription drug monitoring program (PDMP) in most states in the US. Moreover, the street values of gabapentin and pregabalin are fairly low, with gabapentin running around $1 per 100-mg capsule and pregabalin around $5 per capsule.14

Are Gabapentinoids Actually Addictive?

Snellgrove, et al, conducted face-to-face interviews regarding pregabalin use in a ward for qualified detoxification.15 The team found that 7% of subjects (n = 253) had a 24-month prevalence rate of pregabalin dependence. Dependence was defined as the proportion of subjects who had taken pregabalin in the past 24 months. Of the total participants, 6% of those who reported pregabalin use also met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) dependency criteria. DSM-IV criteria are utilized to determine substance abuse or dependence based on behavioral and physiological effects. Included in the dependence criteria are: tolerance to the abused drug, presence of withdrawal symptoms, and continued use despite knowledge of adverse consequences among other factors. However, all patients were also found to be dependent on at least one other substance, including opioids or benzodiazepines. (See also: "Gabapentin and Suicidal Ideation").

In a systematic review by Bonnet, et al, symptoms of dependence were assessed.16 Using the PubMed and Scopus electronic databases, the reviewers searched for articles focusing on gabapentinoids and their relationship to misuse, addiction, and overdose. They searched for articles with a starting date of when each drug was introduced into the market (around 1994 for gabapentin and around 2005 for pregabalin) up to March 31, 2017. Articles were included in the review if they reported rewarding behavior of gabapentinoids, self-administration of gabapentinoids, overdoses of and death due to gabapentinoids. The authors looked for clinical studies as well as case reports.

Overall, 36 case presentations regarding gabapentin and 19 studies regarding pregabalin were identified and assessed based on the International Classification of Diseases (ICD-10) dependence criteria. Dependence syndrome is defined in ICD-10 based on behavioral, physiological, and cognitive effects. Researchers found that tolerance and withdrawal symptoms occurred commonly with gabapentin (75%, 27 out of 36) and pregabalin (84%, 16 out of 19). Withdrawal symptoms were similar to those observed for benzodiazepines, including withdrawal seizures, insomnia, and anxiety. Behavioral dependence symptoms were also measured between the two gabapentinoids, which typically include craving, loss of control, and drug-seeking behavior. Behavioral dependence was more common in the pregabalin group (79%, 15 out of 19) compared to the gabapentin group (8%, 3 out of 36). Out of all of the case studies reviewed, only four patients were observed who showed symptoms of a behavioral dependence without a history of addiction to another substance according to ICD-10. Pregabalin was the cause of behavioral dependence in all four of these cases. The review found no reports of anyone seeking treatment for gabapentinoid abuse indicating that the causative factor of abuse may be more strongly associated with other substance use disorders.

How Dangerous is Gabapentinoid Abuse?

Gabapentinoid overdoses can range from exhibiting benign symptoms to resulting in death. A review by Evoy, et al, observed six cases of pregabalin overdose and 31 cases of gabapentin overdose.17 One patient who overdosed on pregabalin and lamotrigine experienced seizures and reduced consciousness after taking a dose of 11,500 mg of pregabalin; the patient eventually recovered. Another patient who overdosed on gabapentin (a 91,000-mg dose) with co-ingestion of valproic acid and alcohol experienced symptoms of drowsiness, dizziness, and slurred speech. Two cases of pregabalin overdose resulted in death due to pregabalin poisoning involving co-ingestants. In the first case, the patient was found dead with elevated levels of pregabalin (110 mg/L) in addition to therapeutic levels of oxazepam (0.30 mg/L) and temazepam (0.15 mg/L), traces of quetiapine and levomepromazine, and an alcohol level of 0.24%. Similarly, the second patient was found with elevated levels of pregabalin (48 mg/L) in addition to therapeutic levels of buprenorphine (0.86 μg/L), norbuprenorphine (1.2 μg/L), temazepam (0.75 mg/L), nordazepam (0.63 mg/L), diazepam (0.17 mg/L), oxazepam (0.17 mg/L), and traces of tetrahydrocannabinol.

The main cause of death for both patients was listed as pregabalin toxicity but the dose taken and determined cause of death was not reported. In the case of gabapentin, two of the three recorded fatal overdoses were due to gabapentin alone. One of these patients was found to have consumed up to 15.6 grams of gabapentin, while the amount the second patient consumed was unknown. Both were found unresponsive due to cardiorespiratory compromise as a result of gabapentin toxicity.

Recent Regulations on Gabapentin

As noted, gabapentin, unliked pregabalin, is not currently considered a federally controlled substance in the United States. However, some states have added legislation to limit its misuse.5 In addition to Kentucky and Tennessee reclassifying all gabapentinoid drugs as Schedule V controlled substances5,6 Minnesota, Ohio, Virginia, Wyoming, West Virginia, Massachusetts, North Dakota, Nebraska, and New Jersey have added mandates that gabapentin prescriptions be reported to their state PDMP.5,18 New York has proposed similar legislation, creating a Schedule VI class for such controlled substances.19 This would not limit the amount of gabapentin a pharmacy can dispense but rather would require practitioners to report it to their PDMP.

Key Takeaways

Gabapentinoid abuse may rise as the prescribing and use of opioids decreases, but the biggest concern may come when these agents are combined with other prescribed medications or illicit street drugs. Gabapentinoid use has been associated with an amplification of a “high” feeling when used in combination with opioids.19 Therefore, the use of gabapentinoids in a population already receiving opioids may lead to a greater risk of abuse for both substances. Gabapentin and pregabalin may be used more safely as alternatives after a patient has been rehabilitated off of opioids or before they start using them in the first place. Because gabapentin has a higher potential for abuse in patients with a history of SUD and patients concurrently taking opioids, it is prudent to be cautious when prescribing gabapentin or pregabalin in this population.

There are a few precautions healthcare providers can take to identify possible abuse. Prescribers can monitor patients for changes in mood, frequent requests for early refills, and requests for rapid increases in doses.4 They can also include gabapentinoids in urine monitoring to ascertain whether their patient is actually taking the prescribed medications. Pharmacists can watch for patients taking multiple doses and/or and receiving prescriptions from multiple prescribers, and counsel patients. Another sign to watch for is frequent early refill requests and asking to pay out of pocket instead of billing insurance. Reporting gabapentin to prescription drug monitoring programs may be useful in identifying patients who may be abusing or diverting gabapentin. By increasing awareness of abuse potential and reporting to prescription monitoring programs, healthcare providers may help to prevent and/or reduce overall abuse of gabapentinoids.

Last updated on: July 23, 2019
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