What are the side effects and risks of long‑term gabapentinoid use for neuropathic pain?
Executive summary
Long‑term use of gabapentinoids (gabapentin and pregabalin) for neuropathic pain carries well‑documented central nervous system side effects—dizziness, somnolence, gait instability—and a measurable rate of treatment discontinuation due to adverse effects in trials [1] [2]. Serious harms are uncommon in randomized trials but observational studies and clinical reports raise concerns about respiratory depression, worse outcomes when combined with opioids or benzodiazepines, COPD exacerbations, and potential for misuse—areas where long‑term risk estimates remain uncertain [3] [4] [5] [6].
1. Common central nervous system adverse effects: sedation, dizziness, and unsteadiness
Across systematic reviews and clinical guidance the most frequent problems are CNS‑related—dizziness, sleepiness/somnolence, feeling “intoxicated,” and difficulties with walking or coordination—which may affect roughly 10% or more of patients and contribute to stopping therapy [1] [2] [7]. These effects are particularly important in older adults because gait instability and incoordination raise fall and fracture risk; the AAFP review and multiple analyses explicitly warn about these harms in multimorbid, polypharmacy populations [1] [3].
2. Respiratory and pulmonary risks identified in observational data
Randomized trials have been relatively short and not powered to detect rare but serious events, whereas population studies and case reports implicate gabapentinoids in respiratory depression—especially when combined with opioids or in patients with COPD—with evidence of increased risk for severe COPD exacerbations in some cohort analyses [4] [5] [6]. The safety signal for respiratory compromise is amplified when gabapentinoids are co‑prescribed with benzodiazepines or opioids, a combination shown in reviews to lower respiratory reserve and increase major adverse events [3] [6].
3. Serious adverse events and discontinuation: uncommon in trials but real-world worries remain
Cochrane and randomized‑trial meta‑analyses report that serious side effects are uncommon and not significantly more frequent than placebo in the trial context, but they also note higher overall adverse‑event rates and slightly greater discontinuation with gabapentin [2] [8]. Importantly, these RCTs were typically short (weeks to months), which limits their ability to detect late‑emerging or rare harms relevant to long‑term therapy [9] [10].
4. Misuse, dependence and euphoria: mixed evidence with stronger signals for pregabalin
Systematic RCT evidence to date did not find clear addiction disorders attributable to gabapentinoids, though pregabalin has been associated with euphoria at therapeutic doses in some trials—a potential marker of abuse liability—and observational reports document diversion and misuse, creating a contested but non‑negligible concern [9] [11]. Reviews emphasize that long‑term, real‑world patterns of misuse are harder to quantify because RCTs were short and population studies can be confounded by concurrent substance use [10] [11].
5. Interactions, polypharmacy and off‑label prescribing amplify risk
A recurring theme in clinical reviews is that gabapentinoids are increasingly used off‑label and often substituted for opioids without strong evidence of benefit for many pain types; that practice increases aggregate exposure and the chance for dangerous interactions with opioids or benzodiazepines [1] [3]. Meta‑analyses and narrative reviews call out decreased safety in combination therapy and advise careful medication reconciliation and monitoring [6] [11].
6. Efficacy versus harms and gaps in long‑term evidence
Randomized trials and meta‑analyses confirm that gabapentinoids can be effective for certain neuropathic pain syndromes (diabetic neuropathy, postherpetic neuralgia), with meaningful benefit in a subset of patients, but many do not achieve clinically significant relief and experience side effects instead [9] [2]. Crucially, the evidence base for long‑term safety is limited by short trial durations, heterogeneous off‑label use, and observational confounding—leaving clinicians to weigh modest, individual analgesic benefit against possible long‑term respiratory, cognitive, and misuse risks [10] [11] [2].
7. Journalistic bottom line and unanswered questions
The best available randomized evidence documents common CNS adverse effects and modest benefit in specific neuropathic conditions, while observational studies and clinical reviews add credible warnings about respiratory depression in vulnerable patients, increased COPD exacerbations, interaction risks, and patterns of misuse—especially with pregabalin or in polypharmacy contexts—yet long‑term causal estimates remain uncertain because RCTs were short and real‑world data are confounded [2] [4] [5] [9]. Clinicians and policymakers must therefore balance targeted use for conditions with proven benefit against cautious prescribing, monitoring for respiratory and cognitive harms, avoiding risky drug combinations, and demanding higher‑quality long‑term safety research [1] [6] [10].