ineffectiveness of gabapentinoids for pain or radiculopathy

 there has been a major increase in prescribing gabapentinoids (gabapentin and pregabalin) for chronic pain and neuropathic pain, despite many studies finding no or minimal effect. there is an impressive list of associated adverse events including very serious ones, however.

    -- a study done on gabapentinoid utilization in 72 countries from 2012 o 2023 found annual sale increase by 114.5% from 2012 to 2022, with a 180.9% increase in developing countries and a 110.0% increase in developed countries: see graph below from gabapentinoid and opiate utilization 2012 to 2023 Pharmicoepidem2025 in dropbox, or doi.org/10.1002/pds.70149

    -- gabapentinoids, however, have substantial side effects like dizziness, somnolence, and gait disturbance, with the number of patients needed to take gabapentinoids in order for one of them to experience adverse effects ranging from 3 to 11 depending on the adverse effect, with approximately 33% of patients experiencing somnolence and dizziness with higher dosages

    -- but there is a large literature finding that gabapentinoids are ineffective for both chronic pain and neuropathic/radicular pain overall:

        -- gabapentin was found to be ineffective in women with chronic pelvic pain: https://gmodestmedblogs.blogspot.com/2020/10/chronic-pelvic-pain-gabapentin.html

        -- gabapentinoids have no clear benefit but potential harm in patients with nerve injury; this orthopedic study also found no benefit for either pain or sleep: https://gmodestmedblogs.blogspot.com/2025/04/pain-and-gabapentinoids-no-clear.html

            -- there is a bidirectional relationship between pain and sleep: pain can lead to poor sleep quality in up to 80% of patients, and poor sleep quality can lead to reduced pain tolerance

        -- gabapentinoids have no significant benefit in treating low back pain or lumbar radicular pain: https://gmodestmedblogs.blogspot.com/2018/07/gabapentinoids-still-not-help-low-back.html , and the prior blog https://gmodestmedblogs.blogspot.com/2017/08/gabapentinoids-not-indicated-for.html

        -- for diabetic neuropathy, there was a systematic review in the journal Neurology that found no benefit with gabapentin and a small one with pregabalin but with low strength-of-evidence. Venlafaxine and duloxetine were the big winners, finding significant benefit (see http://gmodestmedblogs.blogspot.com/2017/04/diabetic-peripheral-neuropathy-and-more.html  and https://gmodestmedblogs.blogspot.com/2022/03/painful-diabetic-neuropathy-meds.html)

    -- a Cochrane review and FDA statement , however, do support using gabapentinoids specifically for neuropathy associated with zoster infection and diabetes (though, again, there do seem to me to be better meds, such as duloxetine as per above). UpToDate recommends duloxetine, venlafaxine, amitriptyline and other tricyclic drugs as well as the gabapentinoids; lidocaine patches and capsaicin 8% cream also help (but we should NOT use capsaicin if zoster is associated with open breaks in the skin)

        -- the Cochrane review's actual conclusions were more muted: Gabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 or 4 out of 10 participants achieved this degree of pain relief with gabapentin, compared with 1 or 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief but may experience adverse events. Conclusions have not changed since the previous update of this review: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007938.pub4/full

        -- by the way, it seems that amitriptyline and doxepin are the most anticholinergic of the tricyclics. though direct comparisons of different tricyclics for efficacy are wanting, it seems that they all work well in clinical practice; one study comparing desipramine to  amitriptyline did find equivalence. my approach has been to use desipramine for some patients but nortriptyline at night in those with sleep disturbances, both achieving impressive effects in those with diabetic neuropathies

-- and there is a one-page summary that elaborates the effects of "gabapentin misuse": https://www.cmaj.ca/content/cmaj/191/2/E47.full.pdf

    -- in fact the FDA's 2026 warning was (https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9a05f0c-b5f0-422c-9d67-6d0efc921a74):

        -- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS: ie, Multiorgan hypersensitivity): Discontinue the gabapentin if alternative etiology is not established

        -- Anaphylaxis and Angioedema: Discontinue and evaluate patient immediately

        -- Driving Impairment; Somnolence/Sedation and Dizziness: Warn patients not to drive until they have gained sufficient experience to assess whether their ability to drive or operate heavy machinery will be impaired

        -- Suicidal Behavior and Ideation: Monitor for suicidal thoughts/behavior 

        -- Abrupt or rapid discontinuation may increase the risk for seizures. Withdrawal symptoms, or suicidal behavior and ideation have been observed after discontinuation

        -- Respiratory Depression: May occur with gabapentin when used with concomitant central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate

            -- the FDA issued a warning about gabapentinoids and respiratory depression, esp in combo with other respiratory depressants: https://gmodestmedblogs.blogspot.com/2020/01/fda-warning-gabapentinoids-and.html

            -- i would add: gabapentinoids are associated with increased risk of asthma and copd, as well as heart failure: https://gmodestmedblogs.blogspot.com/2020/01/fda-warning-gabapentinoids-and.html ; and they are associated with severe COPD exacerbations: https://gmodestmedblogs.blogspot.com/2024/01/gabapentinoids-association-with-severe.html, or gabapentin assoc severe COPD AnnIntMed2024 in dropbox, or doi:10.7326/M23-0849.

                -- a recent study found that gabapentinoids were associated with an increased risk of corticosteroid-requiring asthma exacerbations versus tricyclic antidepressants or SNRIs: https://pubmed.ncbi.nlm.nih.gov/40850791/

                -- heart failure: there was increased risk for both non-cardiogenic edema and acute heart failure frequently after a gabapentinoid dose escalation: see gabapentinoids heart failure BoimedPharmacoth2022 in dropbox, or https: doi.org/10.1016/j.biopha.2022.112807

        -- Neuropsychiatric Adverse Reactions in Children 3 to 12 Years of Age: Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of CNS related adverse reactions. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the gabapentin-treated patients, most of the reactions were mild to moderate in intensity

        -- Tumorigenic Potential: in an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell tumors in rats. The clinical significance of this finding is unknown. Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.

            -- In clinical studies in adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment. this really should be evaluated in big studies, especially as the use of gabapentinoids is increasing so rapidly....

    -- there was also a recent article delineating the risks of gabapentinoids (gabapentinoids adverse effects Pain2024 in dropbox, or doi.org/10.1097/j.pain.0000000000003239) that includes general comments as well as in the FDA statements that adding gabapentinoids to respiratory depressants is associated with increased respiratory risk

        -- for respiratory depressants, alcohol,  especially with consumption of large quantities, is a known respiratory depressant, suggesting not using gabapentinoids in patients with significant alcohol use disorder

        -- a study in Finland found that alcohol in combination with gabapentinoids was associated with 15% of their gabapentinoid-related fatalities: gabapentinoid misuseDrugs2016 in dropbox, or DOI 10.1007/s40263-016-0359-y

        -- gababentinoids and benzos with alcohol are associated with increased somnolence and even fatal respiratory depression

so, as an unusual blog for me, this one is not a review/critique of a medical study, but instead is a review of a lot of information finding that gabapentinoids are not good for chronic pain and/or neuropathic pain, despite their pretty strikingly increasing popularity:

-- these medications are loaded with both minor and major adverse events

-- the major adverse events are often associated with concomitant meds such as opiates, benzos, alcohol and other respiratory depressants

-- it certainly happens that some individuals do feel they help a lot. is it because the meds do actually help some people?? is it because the meds are so frequently associated with minor adverse effects, and those effects convince some people that they are really taking a strong medication, thereby encouraging a placebo effect???

-- the various studies mentioned above do support the use of SNRIs, tricyclics, etc as better alternatives overall for chronic and radicular pain

-- and to top off the above arguments: in 1998, JAMA published a trial of gabapentin for neuropathy and chose a very high dose of gabapentin of up to 3600mg/d (https://jamanetwork.com/journals/jama/fullarticle/188226); this study found benefit for patients with postherpetic neuralgia, resulting in many clinicians jumping on the gabatpentin bandwagon for neuropathy (beyond postherpetic neuropathy). however, a subsequent and larger study sponsored by the same drug company found no benefit. BUT this study was suppressed by the drug company and never published, as revealed in a blistering review: https://www.nejm.org/doi/full/10.1056/NEJMsa0906126

geoff

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