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Despite a large body of new evidence, our best treatments for neuropathic pain continue to provide only modest benefits.
Neuropathic pain is a common and disabling condition caused by injury or disease of the nervous system. Affecting almost 10% of the general population, it is estimated that over two million Australians live with neuropathic pain. Neuropathic pain arises secondary to a range of causes, including diabetic neuropathy, nerve lesions, infection, disc herniation, multiple sclerosis, spinal cord injury, and stroke. Presenting as severe shooting or burning pain, numbness, and altered sensation, neuropathic pain often leads to psychological distress, sleep disturbance, impaired physical function, and reduced quality of life.
Neuropathic pain is difficult to manage. Effective care requires early and accurate diagnosis, comprehensive biopsychosocial assessment, and treatments that meaningfully alleviate symptoms. The Special Interest Group on Neuropathic Pain (NeuPSIG) of the International Association for the Study of Pain (IASP) first published international guidelines for the pharmacological management of neuropathic pain in 2007, followed by an update in 2015. While these guidelines have been widely adopted by primary care and specialist clinicians, modest treatment effects, growing concerns about treatment-related harms, and development of non-drug interventions highlighted the need for updated, evidence-based guidelines.
What we did
Our international working group of 43 experts, including two patient partners, conducted a systematic review and meta-analysis to update recommendations. We expanded the scope and methods of the 2015 review to assess emerging invasive and non-invasive neuromodulation treatments (devices that provide targeted electrical or magnetic stimulation of the nervous system) and incorporate the views of people with lived experience of neuropathic pain. Our recommendations were developed through a series of consensus meetings, and considered the GRADE certainty of evidence, effect size, cost, and harms (including frequency, severity, and prevalence) and availability of treatments, including in low-income and middle-income countries.
What we found
We identified 313 randomised trials that enrolled 48 789 adult participants with a range of neuropathic pain conditions. Included trials evaluated 89 pharmacological interventions and 9 neuromodulation interventions.
Three drug classes — α-2-delta ligands (eg, pregabalin, gabapentin), serotonin noradrenaline reuptake inhibitors, and tricyclic antidepressants — remain strongly recommended for first-line use, notwithstanding important caveats. New data showed that the effects of these classes are smaller than previous estimates, and benefits are accompanied by substantial risks and adverse effects: α-2-delta ligands have been linked with misuse and overdose, and tricyclic antidepressants are contraindicated for older adults because of risk of sedation and falls. Prescribers are advised to balance these risks against potential benefits when proposing first-line treatments.
Capsaicin creams and patches, previously supported by inconclusive evidence, now have a weak recommendation for second-line use. The small benefits of these treatments are offset by favourable safety and tolerability, appropriate for older adults who have comorbidities or are taking multiple medicines.
In light of the ongoing impacts of the opioid crisis, opioids (whether weak or strong) are now proposed as third-line options supported by a weak recommendation. This recommendation is specific to patients with worsening pain that has not been adequately relieved by other treatments. Opioid therapy should involve the shortest possible duration of use, and early and ongoing review.
Almost a third of the new evidence evaluated invasive and non-invasive neuromodulation interventions. Data supported the use of repetitive transcranial magnetic stimulation in select patients. Although the benefits of this intervention appeared greater than many drug treatments, the low certainty of evidence, limited availability, and high cost reduced our strength of recommendation. Critically, our review identified just a single sham-controlled trial of spinal cord stimulation for neuropathic pain despite endorsement by other national bodies, resulting in an inconclusive recommendation.
Limited data meant we were unable to provide condition- or dose-specific recommendations, or advise which therapies can be prescribed in combination. Our guidance applies to all adult patients with neuropathic pain, irrespective of aetiology. Recommended daily dosages and dose regimens are based on manufacturer guidance, while decisions on when and how to combine treatments should be guided by clinical judgement.
Where to from here?
Despite the inclusion of a large body of new evidence, our revised recommendations have only changed slightly. Even our best treatments provide modest benefits and have risks that limit use. A step-change is needed in the way we investigate and treat neuropathic pain.
Underwhelming trial results have been proposed to arise from averages: by testing therapies in neuropathic pain with varied mechanisms, we are diluting the effects in subpopulations where treatments perform dramatically. Therefore, matching treatments to individual patient phenotypes (“personalised medicine”) could improve the efficacy of current therapies. However, methods to evaluate individual responses are limited, often unable to separate true response from random fluctuation in symptoms. While there is some evidence to support that drugs are more effective in neuropathic pain patients stratified by sensory phenotype (ie, how they feel pain), results are inconsistent. The shift to personalised medicine remains largely aspirational despite its promise.
There is a critical need for effective, targeted treatments. However, until we fully unravel the mechanisms that lead to the development of neuropathic pain, this possibility remains uncertain. With few promising treatments on the horizon and declining industry investment in analgesic therapies, national resources might be well placed in implementing effective preventive strategies. These include medical and behavioural interventions to improve management of diabetes, and vaccination to prevent herpes zoster infection in at-risk groups. Such approaches have the potential to meaningfully reduce the development of neuropathic pain at the population level.
We need to recalibrate expectations: our current treatments are not curative. Clinicians and patients might explore other non-pharmacological (eg, exercise and psychology) interventions despite limited evidence of effectiveness, considering their favourable safety profiles. Shared decision making and honest discussions about likely benefits and harms must remain central to care.
Michael Ferraro is a doctoral researcher at the Centre for Pain IMPACT, Neuroscience Research Australia and the School of Health Sciences, University of New South Wales. His research focuses on the evaluation of treatments for chronic pain.
Dr Nadia Soliman is a research fellow at the Evidence for Policy and Practice Information Centre (EPPI Centre) at the University College London. Her research interests focus on automation tools and methods for evidence synthesis and systematic reviewing. She has a background in pharmacology and experience conducting systematic reviews and meta-analyses to narrow the translation gap between preclinical and clinical research of chronic pain.
The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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This article summarises both my professional and personal experiences. I do have concerns that patients are frequently given false hope, and invasive treatments with little to no benefit that are expensive and can have significant complications. My mother used to tell me a quote she had heard, “the road to hell is paved with good intentions “, and I have frequently seen the consequences of naive well intentioned doctors adding to the suffering of their patients. Education was lacking when I trained many years ago but this issue should be an important part of modern medical education, particularly in view of the high prevalence in the community.
Having practiced as a consultant physician (largely non-interventionalist pain; MSK injuries; whole body pain fibromyalgia; public health; occupational/environmental medicine) for some 40years, I counsel against iatrogenesis in favour of two hour personalised clinical information sessions, light aerobic activity, Pilates and core stability, and combination of paracetamol/anti-inflammatories; and some 20% pain patients having a pain specialising clinical psychologist therapy – with some reasonable success.
More elaborate programmes for chronic pain management having largely failed, most patients saying that clinicians dont explain anything… other than it is ‘nerve pain’ which means little to the majority of the population…….
Two important facts about neuropathic pain are that it does not respond to normal analgesics and that neural modulating dug treatments like gabapentin are variably effective but cause brain fog and and are difficult to come off, typically requiring gradual dose reduction over many weeks. These drugs are not the answer. My experience with neuropathic pain was in treating patients post-inguinal hernia surgery , where this can be an occasional but sometimes disabling complication. The best approach was early intervention with local anaesthetic blocks, but too many cases were fobbed off ( ‘its nothing to do with the surgery’ ) or “it will get better’ , until the pain was well established and pretty much impossible to treat. Recognition of neuropathic pain vs normal postoperative pain is important. . Re-operation to divide the responsible w sensory nerves ( exchanging pain with numbness ) was only effective if done within a few weeks of the repair, and when local anaesthetic blocks had been temporarily effective.
Recognition, validation of the patients symptoms and early interventions are the only hope.