Neuropathic pain, which is caused by nerve damage, is increasing in prevalence worldwide. This may reflect improved diagnosis, or it may be due to increased incidence of diabetes‐associated neuropathy, linked to increasing levels of obesity. Other types of neuropathic pain include post‐herpetic neuralgia, trigeminal neuralgia, and neuralgia caused by chemotherapy. Antidepressant drugs are sometimes used to treat neuropathic pain; however, their analgesic efficacy is unclear. A previous Cochrane review that included all antidepressants for neuropathic pain is being replaced by new reviews of individual drugs examining chronic neuropathic pain in the first instance. Venlafaxine is a reasonably well‐tolerated antidepressant and is a serotonin reuptake inhibitor and weak noradrenaline reuptake inhibitor. Although not licensed for the treatment of chronic or neuropathic pain in most countries, it is sometimes used for this indication.
To assess the analgesic efficacy of, and the adverse effects associated with the clinical use of, venlafaxine for chronic neuropathic pain in adults.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via The Cochrane Library, and MEDLINE and EMBASE via Ovid up to 14 August 2014. We reviewed the bibliographies of any randomised trials identified and review articles, contacted authors of one excluded study and searched www.clinicaltrials.gov to identify additional published or unpublished data. We also searched the meta‐Register of controlled trials (mRCT) (www.controlled‐trials.com/mrct) and the WHO International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) for ongoing trials but did not find any relevant trials.
We included randomised, double‐blind studies of at least two weeks' duration comparing venlafaxine with either placebo or another active treatment in chronic neuropathic pain in adults. All participants were aged 18 years or over and all included studies had at least 10 participants per treatment arm. We only included studies with full journal publication.
Data collection and analysis
Three review authors independently extracted data using a standard form and assessed study quality. We intend to analyse data in three tiers of evidence as described by Hearn 2014, but did not find any first‐tier evidence (ie evidence meeting current best standards, with minimal risk of bias) or second‐tier evidence, that was considered at some risk of bias but with adequate participant numbers (at least 200 in the comparison). Third‐tier evidence is that arising from studies with small numbers of participants; studies of short duration, studies that are likely to be of limited clinical utility due to other limitations, including selection bias and attrition bias; or a combination of these.
We found six randomised, double‐blind trials of at least two weeks' duration eligible for inclusion. These trials included 460 participants with neuropathic pain, with most participants having painful diabetic neuropathy. Four studies were of cross‐over design and two were parallel trials. Only one trial was both parallel design and placebo‐controlled. Mean age of participants ranged from 48 to 59 years. In three studies (Forssell 2004, Jia 2006 and Tasmuth 2002), only mean data were reported. Comparators included placebo, imipramine, and carbamazepine and duration of treatment ranged from two to eight weeks. The risk of bias was considerable overall in the review, especially due to the small size of most studies and due to attrition bias. Four of the six studies reported some positive benefit for venlafaxine. In the largest study by Rowbotham, 2004, 56% of participants receiving venlafaxine 150 to 225 mg achieved at least a 50% reduction in pain intensity versus 34% of participants in the placebo group and the number needed to treat for an additional beneficial outcome was 4.5. However, this study was subject to significant selection bias. Known adverse effects of venlafaxine, including somnolence, dizziness, and mild gastrointestinal problems, were reported in all studies but were not particularly problematic and, overall, adverse effects were equally prominent in placebo or other active comparator groups.
We found little compelling evidence to support the use of venlafaxine in neuropathic pain. While there was some third‐tier evidence of benefit, this arose from studies that had methodological limitations and considerable risk of bias. Placebo effects were notably strong in several studies. Given that effective drug treatments for neuropathic pain are in current use, there is no evidence to revise prescribing guidelines to promote the use of venlafaxine in neuropathic pain. Although venlafaxine was generally reasonably well tolerated, there was some evidence that it can precipitate fatigue, somnolence, nausea, and dizziness in a minority of people.
Helen C Gallagher, Ruth M Gallagher, Michelle Butler, Donal J Buggy, Martin C Henman
Plain language summary
Venlafaxine for neuropathic pain in adults
Neuropathic pain is pain that arises from damaged nerves. It is different in nature than pain that arises from damaged tissue, such as a cut, although that type of pain is also carried along nerves. Drugs that are commonly used to treat pain, such as paracetamol, ibuprofen, or morphine, are not very good at treating neuropathic pain. However, other drugs, such as gabapentin, which are also used to prevent or treat epilepsy (fits), do appear to be of some benefit in treating neuropathic pain. There is also a great deal of interest in using antidepressant drugs to treat neuropathic pain. This does not imply that the person with neuropathic pain is depressed, but simply that these drugs may have benefits in neuropathic pain. However, while some doctors prescribe antidepressants in people with neuropathic pain, their benefits have not been confirmed in large clinical trials.
Here we reviewed clinical trials for one antidepressant drug, venlafaxine, to see if robust evidence exists that it is effective in treating neuropathic pain.
In detailed searches of the medical literature, we found six trials that were suitable for inclusion in our analysis, that together included 460 adults.
Key results and quality of the evidence
All six trials were conducted in an approved statistical manner (randomised and double‐blinded); however, all had limitations that could lead to an overestimation of efficacy in treating this type of pain. Four were of very small size and five were of short duration, both of which can bias the results of chronic pain trials. Although it was not possible to combine the results of all trials to make an overall conclusion, individually they did all show some, albeit moderate, benefit for venlafaxine in treating neuropathic pain. Usually this benefit was achieved at doses of 75 to 225 mg per day. Known side effects of venlafaxine, including sleepiness, dizziness, and mild gastrointestinal problems, were reported by some studies, but were not particularly problematic.
Overall, there is currently an inadequate amount of information available to warrant any change in current prescribing practice and we cannot recommend venlafaxine as a first‐line treatment for neuropathic pain. However, it is a reasonably well‐tolerated drug and may be of some benefit in people who cannot tolerate other antidepressants or anticonvulsant drugs that are more widely prescribed to people with neuropathic pain. Larger clinical trials may provide more robust evidence for the effectiveness of venlafaxine in treating neuropathic pain.
Helen C Gallagher, Ruth M Gallagher, Michelle Butler, Donal J Buggy, Martin C Henman
Implications for practice
Implications for people with neuropathic pain
This review is unlikely to change clinical practice in a manner that will improve outcomes for people with neuropathic pain. Our results suggested that, for the vast majority of people with neuropathic pain, there is insufficient evidence to support the use of a venlafaxine‐based intervention in the current standard of care.
Implications for clinicians
There is little compelling evidence to support the use of venlafaxine in neuropathic pain except by experienced clinicians in exceptional circumstances.
Implications for practice for policy makers
Any evidence for venlafaxine's benefit in treating neuropathic pain is not sufficiently robust to warrant any change in policy regarding its licensed indications.
Implications for practice for funders
Although this review found some evidence to support the use of venlafaxine in treating neuropathic pain, overall this evidence was of low quality. From a pharmacoeconomic perspective, there is insufficient evidence to support a change in reimbursement practice.
Implications for research
Larger, prospective well‐designed studies are required to provide more definitive conclusions on the efficacy of venlafaxine for treating neuropathic pain. While we hope these will be performed, there is no guarantee that this will occur
Double‐blind, randomised, placebo‐controlled trials with over 200 participants per treatment arm and treatment period of at least eight weeks would be more conclusive if further evidence for the efficacy of venlafaxine in treating neuropathic pain is to be obtained. We believe that there is little value in the conduct of future small trials or case series.
Current best standards, where studies report the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation methods for drop‐out, should be adopted to provide first‐tier evidence in future trials. Furthermore, in future clinical studies it would be most beneficial if mean data were not reported so that proper estimates can be made of the proportion of participants benefiting from venlafaxine treatment.
Further research studies on the mechanism of action of venlafaxine in treating neuropathic pain are also warranted.Get full text at The Cochrane Library
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