What are gabapentinoids?

What Are Gabapentinoids?

Gabapentinoids are a class of medications consisting primarily of gabapentin and pregabalin that bind to the α2δ subunit of voltage-gated calcium channels to reduce neurotransmitter release, originally developed for epilepsy but now widely used for neuropathic pain, with pregabalin also approved for anxiety disorders. 1, 2

Mechanism of Action

• Gabapentinoids bind with high affinity to the α2δ-1 and α2δ-2 subunits of voltage-activated calcium channels, inhibiting cellular calcium influx and attenuating neurotransmission 1, 2
• Despite being structurally related to GABA (gamma-aminobutyric acid), gabapentinoids have no effect on GABA binding, uptake, or degradation and do not act as agonists at GABA receptors 3, 1
• The α2δ-1 protein also functions as a synaptogenic receptor and regulates trafficking of glutamate receptors (NMDA and AMPA receptors) to synapses, which contributes to their efficacy in chronic pain states 4

The Two Main Gabapentinoids

Gabapentin

• FDA-approved for postherpetic neuralgia (nerve pain after shingles) and partial seizures as adjunctive therapy 1
• Typical effective doses range from 900-3600 mg/day divided into 2-3 doses, though bioavailability decreases as dose increases (60% at 900 mg/day down to 27% at 4800 mg/day) 1
• Starting dose should be 100-200 mg/day in older adults due to increased risk of somnolence, dizziness, and mental clouding 5, 6
• Eliminated unchanged by the kidneys with a half-life of 5-7 hours, requiring dose adjustment in renal impairment 1

Pregabalin

• FDA-approved for neuropathic pain, partial seizures, and generalized anxiety disorder 5, 2
• Typical effective doses range from 150-600 mg/day in divided doses 3
• Pregabalin may be preferred for initial trials due to pharmacokinetics that support easier and more rapid titration compared to gabapentin 5
• Has more predictable, linear pharmacokinetics compared to gabapentin's dose-dependent bioavailability 3, 7

Clinical Applications

Evidence-Based Uses

• First-line treatment for diabetic peripheral neuropathy with strong evidence from multiple high-quality studies 5
• Effective for postherpetic neuralgia (gabapentin specifically FDA-approved) 1
• Adjunctive therapy for partial-onset epilepsy 1
• Pregabalin approved for generalized anxiety disorder 5

Common Off-Label Uses

• Increasingly prescribed for chronic non-neuropathic pain, fibromyalgia, and perioperative analgesia despite limited or conflicting evidence 6, 7
• Off-label prescription rates have overtaken on-label use, raising concerns about inappropriate prescribing 7

Critical Safety Concerns

Dependence and Withdrawal Risk

• Approximately 50% of patients prescribed gabapentinoids in England had been treated continuously for at least 12 months, a practice of doubtful efficacy in many cases 5
• Sudden cessation can lead to physical and psychological withdrawal symptoms; patients on long-term therapy should be offered careful tapering and support 5
• History of substance use disorder is a significant risk factor for gabapentinoid abuse, with pregabalin having higher abuse potential than gabapentin 8, 9
• Several countries have reclassified gabapentinoids as controlled substances due to abuse potential 8

Respiratory Depression Risk

• When taken with opioids, gabapentinoids can cause dangerous respiratory depression through cumulative and synergistic effects 5
• This risk is particularly concerning in the context of the opioid crisis and should inform prescribing decisions 7

Common Adverse Effects

• Most frequent side effects include somnolence, dizziness, and mental clouding, which can be particularly problematic in older patients 5, 6
• Pregabalin is associated with peripheral edema, headache, and weight gain 3
• Adverse effects may be more severe in older individuals and those with renal dysfunction, necessitating lower starting doses and slower titration 5

Prescribing Considerations

Dosing Strategy

• Start with the lowest doses (gabapentin 100-200 mg/day; pregabalin 50-75 mg/day) especially in elderly or renally impaired patients 5, 3
• Titrate incrementally at intervals long enough to monitor effects, as effective doses vary widely between patients 5
• Both medications require dose adjustment in renal impairment as they are eliminated unchanged by the kidneys 3, 1

Clinical Pitfalls to Avoid

• Do not use benzodiazepines concurrently when possible, as this increases sedation and fall risk, particularly in older adults 5
• Limit perioperative gabapentinoid use to a single preoperative dose to minimize sedative side effects while maintaining opioid-sparing benefits 5
• Patients may respond to gabapentin, pregabalin, both, or neither—lack of response to one does not predict response to the other 5, 3
• Gabapentin is unlikely to be effective as substitution therapy for pregabalin use disorder despite lower abuse potential 9

When NOT to Use Gabapentinoids

• The American Society of Clinical Oncology guideline does not recommend gabapentinoids for chemotherapy-induced peripheral neuropathy based on negative trial data, despite some insurance companies requiring their use before duloxetine 5
• Avoid in patients with significant risk factors for respiratory depression when combined with opioids 5, 7