The effectiveness of drugs for neuropathic pain – what do we know?

Neuropathic pain (NP) – that is pain arising from identifiable damage or disease affecting the somatosensory nervous system is common and frequently severe and life-changing. It is also notoriously difficult to treat effectively. Indeed we know that for many people with NP treatment is inadequate. The International Association for the Study of Pain (IASP) have a special interest group “NeuPSIG” focused explicitly on understanding the mechanisms, assessment, prevention and treatment of NP. They have just published an up to date systematic review on the effectiveness of pharmacotherapy in Lancet Neurology. Better still it has now been made available beautifully open access. You can download it for free here.

This is a comprehensive review, containing 229 trials of the full range of pharmacological agents using robust methods, to synthesize, summarise and make value judgements about the quality of the available evidence. So what are the take home messages?

Using a primary outcome of achieving at least 50% pain relief trial outcomes were described as “generally modest”. The number of patient needed to treat with the drug compared to a placebo for one more person to achieve this outcome ranged from a relatively rosy 3.6 (95% confidence interval 3 to 4.4) for tricyclic antidepressants such as amitryptiline, 4.3 (95%CI 3.4 to 5.80 for strong opioids to a less impressive 7.2 (95%CI 5.9 to 9.21) for gabapentin, and 7.7 (6.5 to 9.4) for pregabalin (often sold under the brand-name Lyrica). It’s interesting, at least to me, how much better the older more traditional agents seem to have fared compared on effectiveness to the more modern (and commonly more expensive) agents although the safety and tolerability of gabapentin seems superior.

The spectre of publication bias also raises its head. The reviewers carefully took a number of routes to try to unpick this notoriously difficult issue and estimate that there has been overall a 10% overstatement of treatment effects. Published studies reported larger effect sizes than did unpublished studies. This is not a problem restricted to the field of pain trials. It is a burning issue across the world of clinical trials. It is very important because if we fail to base our clinical recommendations on the totality of relevant evidence (because some data are hidden from us) we are in danger of mis-estimating the benefits and the harms and as a result patients are put at risk. If you think that is pretty important then there are ways that you can help. Check out the All-Trials campaign.

Overall what does this mean? Many drugs are effective but not as effective as we would wish them to be. No pharmacological agent really impresses and for any drug the most probable outcome is failure to produce 50% pain relief. There are various potential reasons for this. The first is that the drugs may only be moderately or marginally effective, another is that neuropathic pain includes quite a mixed bag and our ability to accurately diagnose and to target drugs to specific mechanisms in the clinic is currently fairly poor.

The NeuPSIG review team formulate a number of recommendations for revision of their clinical guideline for managing NP pain, balancing the benefits, harms, costs and strength of the evidence:

  • a strong recommendation for use and proposal as a first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin;
  • a weak recommendation for use and proposal as a second line treatment for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.

Neil O’Connell

Neil O'Connell 2As well as writing for Body in Mind, Dr Neil O’Connell, (PhD, not MD) is a lecturer and researcher in the College of Health and Life Sciences (Department of Clinical Sciences) at Brunel University London,  UK. He divides his time between research and training new physiotherapists and previously worked extensively as a musculoskeletal physiotherapist.
He also tweets! @NeilOConnell

Neil’s main research interests are chronic low back pain and chronic pain more broadly with a focus on evidence based practice. He has conducted numerous systematic reviews and is a member of the editorial board of the Cochrane Collaboration’s Pain Palliative and Supportive Care Group (PaPaS). He also makes a mean Yorkshire pudding despite being a child of Essex. Link to Neil’s published research here. Downloadable PDFs here.

References

Finnerup NB, Attal N, Haroutounian S et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73.