The aim of this commentary is to discuss in a rehabilitation perspective the published Cochrane review “Gabapentin for chronic neuropathic pain in adults”1 by Wiffen et al. (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007938.pub4/full), under the direct supervision of the Cochrane Pain, Palliative, and Supportive Care Group. This Cochrane Corner is produced in agreement with the AJPM&R by Cochrane Rehabilitation.
Neuropathic pain is caused by lesion or disease of the somatosensory nervous system.2 It can be a result of a series of different pathologic mechanisms, including metabolic disorders (e.g., peripheral diabetic neuropathy [PDN]), viral infections (e.g., post-herpetic neuralgia [PHN], HIV), autoimmune disorders that affect central nervous system (e.g., multiple sclerosis), chemotherapy, trauma, inflammation, hereditary neuropathies, and channelopathies.3
The incidence and prevalence of neuropathic pain in global population are difficult to estimate because of a lack of consensus about the definition of neuropathic pain. In 2014, a systematic review about neuropathic pain in general population reported that its prevalence was between 3% and 17%.4
In addition to being highly prevalent, neuropathic pain is problematic because it is difficult to treat, and only a minority of patients report adequate pain relief with currently available treatment modalities.5
GABAPENTIN FOR CHRONIC NEUROPATHIC PAIN IN ADULTS (Wiffen et al., 2017)
What Is the Aim of the Cochrane Review?
The objective of this Cochrane review1 was to analyze analgesic efficacy and harms of gabapentin in chronic neuropathic pain in adults.
What Was Studied in the Cochrane Review?
The review included only randomized controlled trials (RCTs) following patients for 2 wks of treatment or longer. The population analyzed in this study was adults 18 yrs or older, experiencing one or more chronic neuropathic pain disorders. Intervention was gabapentin, regardless of the dose or route of administration. Eligible comparators were placebo or any other active comparator. Primary outcomes were participant-reported pain intensity reduction of 30%, and 50% or greater, and patient-reported global impression of clinical change much or very much improved. Secondary outcomes were any other pain-related outcomes, withdrawals (because of lack of efficacy, adverse events, or any cause), experiencing any adverse event, and experiencing any serious adverse event, somnolence, and dizziness. Substantial benefit was defined as at least 50% pain relief or a patient-reported global impression of clinical change of very much improved, whereas moderate benefit was defined as at least 30% pain relief or a patient-reported global impression of clinical change of much or very much improved.
What Were the Main Results of the Cochrane Review?
The review included 37 RCTs with a total of 5914 participants, although not all of the participants took all the study medication and not all the participants were included in results. Most RCTs used oral gabapentin or extended-release prodrug gabapentin encarbil at doses of 1200 mg or more daily in different neuropathic pain disorders, predominantly PHN (11 RCTs) and PDN (9 RCTs). Most of the RCTs were 4 to 13 wks in duration. Not all RCTs reported relevant outcomes.
Substantial benefit was reported in 32% of participants who took gabapentin at 1200 mg or more daily compared with 17% of those who took placebo (risk ratio [RR], 1.8 [95% confidence interval (CI), 1.5–2.1]; number needed to treat [NNT], 6.7 [5.4–8.7]; eight studies, 2260 participants, moderate-quality evidence). Moderate benefit was reported in more participants who took gabapentin at 1200 mg daily or more (46%) compared with those who took placebo (25%) (RR, 1.8 [95% CI, 1.6–2.0]; NNT, 4.8 [4.1–6.0]; eight studies, 2260 participants, moderate-quality evidence).
Peripheral Diabetic Neuropathy
Substantial benefit was reported in 38% of participants who took gabapentin compared with 23% of those who took placebo (RR, 1.7 [95% CI, 1.4–2.0]; NNT, 6.6 [5.0–10]; six studies, 1331 participants, moderate-quality evidence). Moderate benefit was reported in 52% of participants who took gabapentin compared with 37% in placebo group (RR, 1.4 [95% CI, 1.3–1.6]; NNT, 6.6 [4.9–9.9]; seven studies, 1439 participants, moderate-quality evidence).
All Neuropathic Pain Disorders Included in the Review
Withdrawals due to adverse event were more frequent in participants who took gabapentin (11%) compared with placebo group (8.2%) (RR, 1.4 [95% CI, 1.1–1.7]; NNH, 30 [20–65]; 22 studies, 4346 participants, high-quality evidence). Frequency of serious adverse events was similar in both groups: 3.2% with gabapentin and 2.8% with placebo (RR, 1.2 [95% CI, 0.8–1.7]); 19 studies, 3948 participants, moderate-quality evidence). The number of participants who experienced at least one adverse event was higher among those who took gabapentin (63%) compared with the placebo group (49%) (RR, 1.3 [95% CI, 1.2–1.4]; NNH, 7.5 [6.1–9.6]; 18 studies, 4279 participants, moderate-quality evidence).
Somnolence, drowsiness, or sedation were reported in 14% of participants taking gabapentin and 5.2% of those who took placebo (RR, 2.8 [95% CI, 2.3–3.5]; NNH, 11 [95% CI, 9.4–14]; 20 studies, 4288 participants).
What Were the Authors’ Conclusions?
The authors concluded that gabapentin at doses ranging from 1800 to 3600 mg daily (1200 to 3600 mg gabapentin encarbil) provides substantial or moderate pain relief to some patients with PHN and PDN, whereas evidence for other types of neuropathic pain was very limited. Based on the results of this review, more than half of patients experiencing chronic neuropathic pain who are treated with gabapentin will not have worthwhile pain relief. The level of efficacy reported for gabapentin in this review is in line with efficacy estimates for other medicines in analyzed neuropathic pain conditions.
Future studies should explore combination therapy for neuropathic pain, for example, a combination of gabapentin with tricyclic antidepressants and opioids. Studies of timing and sequencing of these medicines with gabapentin would be worthwhile. For multiple chronic neuropathic pain disorders, this review did not find sufficient information; therefore, further trials about the benefits and harms of gabapentin in patients suffering from those conditions are needed.
What Are the Implications of the Cochrane Evidence for Rehabilitation?
The Cochrane Review1 summarized in this Cochrane Rehabilitation Corner addresses analgesic efficacy and harms of gabapentin for adults experiencing chronic neuropathic pain.
The rehabilitation implications are that gabapentin achieves substantial or moderate beneficial effect in more patients with PHN and PDN compared with placebo, but it is effective in less than half of patients. The review was open to including participants with various chronic neuropathic pain disorders, but for most of those conditions, the evidence was scarce.
The rehabilitation implications are that gabapentin can be offered to patients experiencing chronic neuropathic pain, but with the expectations that the therapy may need to be combined with or replaced with other nonpharmacologic interventions, such as physical therapy and transcutaneous electrical nerve stimulation.6
Thanks to Cochrane Rehabilitation and the Cochrane Pain, Palliative and Supportive Care Group for reviewing the contents of the Cochrane Corner.
1. Wiffen PJ, Derry S, Bell RF, et al.: Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev
2. International Association for the Study of Pain (IASP): Pain Terminology. Neuropathic pain. Available at: https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698
. Accessed December 22, 2019
3. Colloca L, Ludman T, Bouhassira D: Neuropathic pain. Nat Rev Dis Primers
4. Van Hecke O, Austin SK, Khan RA: Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain
5. Moore RA, Derry S, Taylor RS, et al.: The costs and consequences of adequately managed chronic non-cancer pain and chronic neuropathic pain. Pain Pract
6. Gibson W, Wand BM, O’Connell NE: Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults. Cochrane Database Syst Rev