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13 Articles in Volume 18, Issue #3
Anger Expression & Chronic Pain
Ask the Expert: Should reliance on gabapentin/pregabalin be limited?
Chronic Pain in Children
Considering Comorbidities When Selecting Medications for Chronic Pain Management
Dousing the Physician Burnout Epidemic: An AMA Perspective
Harnessing the Power of Words
Inside ASRA with David Provenzano, MD
Management of Intrathecal Therapies by Interprofessional Teams
Nurse Burnout in Pediatric Pain Management: A Model and Pilot Intervention
Physician Burnout: An Oldtimer’s View
Reporting Metrics, Media Coverage...Letters from the Minds of Peers and Patients
The Case for Slow-Release Anesthetics
The Impact of Pain Practice

Ask the Expert: Should reliance on gabapentin/pregabalin be limited?

Despite an increase in gabapentinoids, authors suggest curbing usage due to potential abuse.

Despite their therapeutic role in neuropathic pain, gabapentinoids—which include gabapentin and pregabalin—may produce psychoactive effects and have an abuse potential. A recent review of the CDC’s Medical Expenditure Panel Surveys, which included more than 346,000 patient reported medical conditions and their identified prescription, by Michael E. Johansen,1 found that gabapentin and/or pregabalin use increased from 1.2% to 3.9% between 2002 and 2015. The most significant increases of gabapentin took place after 2008 and pregabalin plateaued after that time. Increases were further concentrated among those patients who were older, had diabetes or other chronic diseases, or who were already taking prescribed opioids or benzodiazepines.1

Pregabalin is a Scheduled V controlled substance, which indicates the lowest potential for abuse relative to other scheduled drugs.2 By federal regulation, gabapentin is not considered a controlled substance; however, certain states require pharmacies to report gabapentin prescriptions to the prescription drug monitoring program.3 In Kentucky, gabapentin became a Schedule V controlled substance via state regulation as of July 1, 2017. It is the understanding of the authors that other states are considering legislation to schedule gabapentin as well.

Considering that risk factors for gabapentin abuse include previous opioid use disorder (OUD) as outlined in a systematic review of 59 studies,4 it stands to reason that elevated trends in gabapentinoid misuse and abuse may be a consequence of sophisticated prescription monitoring programs and overall diminished access to prescribed opioids.

Pharmacology

Collectively indicated for neuropathic pain conditions, such as post-herpetic neuralgia and peripheral diabetic neuropathy, and certain seizure disorders, gabapentinoids have also been used off-label in perioperative settings for many years. Gabapentinoids are structurally related to gamma-amino-butyric acid (GABA) and have GABA-mimetic properties. Both agents inhibit alpha-2-delta (α2δ) subunit of N-type voltage gated calcium channels.2,3,5

While gabapentin and pregabalin share the same mechanism of action, there are pharmacologic differences between them. For example, the binding affinity of pregabalin for the α2δ-1 receptor is six times higher than that of gabapentin.3 Gabapentin has nonlinear pharmacokinetics whereas pregabalin has linear pharmacokinetics and is more predictable, with the exception of the branded products Gralise and Horizant.5

The mechanism of gabapentinoid abuse is not completely understood. Thus, it is prudent to explore the pharmacologic characteristics among gabapentinoids that may explain their potential for abuse or dependence. Some believe that, since gabapentinoids are a GABA analogue, they may display addictive behaviors similar to those of benzodiazepines. 6

However, it is important to remember that neither pregabalin nor gabapentin bind to subunits of the GABA receptor complex, GABAA or GABAB. Nevertheless, these agents are postulated to have direct and/or indirect effect on the dopaminergic reward system similar to that of other substances with reward-seeking addiction properties.6 It is thought that the activation of the α2δ subunit plays an important role in neuronal hypersensitization processes. Binding to the α2δ subunit induces inhibition of calcium currents, which, in turn, may reduce the release of neurotransmitters such as glutamate, noradrenaline, serotonin, and dopamine.5

Commonly Abused Dosages & Administration

The therapeutic dosing for gabapentin and pregabalin in neuropathic pain is typically 1800 to 3600 mg/day and 150 to 600 mg/day, respectively, in three divided doses over 24 hours.8,9 The median dose for gabapentin abuse is 3600 mg and for pregabalin is 2100 mg, administered as a single dose.6 Gabapentinoid abuse typically involves doses higher than the therapeutic dose taken as a single dose.7

In a review by Evoy et al, pregabalin 450 mg provided similar drug-liking effects to diazepam 30 mg among 15 drug abusers. Gabapentin 600 mg and 1200 mg produced similar drug-liking to cannabis among eight cannabis users and increased cannabis liking when administered concomitantly.

At therapeutic doses, central nervous system adverse effects may include: drowsiness, somnolence, ataxia, and fatigue.10 Supratherapeutic doses may cause: euphoria, dissociation, relaxation, improved sociability and uninhibited behavior, relaxation, numbness, and hallucination. Abrupt discontinuation of gabapentinoids has been shown to cause withdrawal symptoms that mimic those of alcohol or benzodiazepine withdrawal.7

As noted, the factor most associated with gabapentin abuse is current or previous OUD. It is important to note that alcohol use disorder did not appear to be a risk factor for gabapentin abuse. Additional risk factors for gabapentin and pregabalin abuse, beyond OUD, include:

  • concurrent heroin use
  • past cocaine use
  • concurrent use of cannabis
  • concurrent use of benzodiazepine.

It is unclear why there is a correlation between OUD and gabapentinoid abuse. Since retrospective analysis correlation does not indicate causation, there may be confounders. In one study of 16 healthy volunteers, pregabalin 75 to 150 mg did not alter drug liking of oxycodone.11 However, this study excluded patients with substance use disorder and used therapeutic dosing.

How to Screen and Prescribe

Clinicians may screen patients for the aforementioned risk factors and assess for aberrant drug-related behaviors. Possible red flags may include early refills, mood changes, and requests for rapid dose escalation.

Urine Drug Screenings

Urine drug screenings may be conducted for gabapentin and pregabalin as well, but these generally need to be ordered separately. There are no consensus guidelines on routine urine drug testing for gabapentinoids; however, these tests may be reasonable in high-risk patients to screen for non-compliance, binge use, or diversion. Routine urine drug screening is also recommended to screen for substances that are considered risk factors for gabapentinoid abuse.

Overall, gabapentin and pregabalin represent therapeutic options for certain pain conditions and seizure disorders. However, recent reports of gabapentinoid misuse and abuse call for vigilance among clinicians to identify such behaviors, especially in the current environment where they may be less likely to prescribe opioids and where patients may seek out alternatives.

This article is the sole work of the authors; stated opinions or assertions do not reflect the opinions of employers or employee affiliates listed. The article was not prepared as part of the authors’ duties as federal employees.

Last updated on: May 2, 2018
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