Summary Background Neuropathic pain is difficult to treat. New treatments, clinical trials and standards of quality for assessing evidence justify an update of evidence-based recommendations for its pharmacological treatment. Methods The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain conducted a systematic review of randomised double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including unpublished trials (retrieved from clinicaltrials.gov and pharmaceutical websites). Meta-analysis used Numbers Needed to Treat (NNT) for 50 % pain relief as primary measure and assessed publication bias. Recommendations used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Findings In total 229 studies were included. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-review journals reported greater effects than online studies (R2=9·3%, p<0·01). Trial outcomes were generally modest even for effective drugs : in particular NNTs were 3·6 (95 % CI 3·0–4·4) for tricyclic antidepressants (TCAs), 6·4 (95 % CI 5·2–8·4) for serotonin- noradrenaline reuptake inbibitor (SNRI) antidepressants duloxetine and venlafaxine, 7·7 (95 % CI 6·5–9·4) for pregabalin and 6·3 (95 % CI 5·0–8·3) for gabapentin. NNTs were higher for gabapentin ER/enacarbil and capsaicin high concentration patches, lower for opioids and botulinum toxin A (BTX-A) and undetermined for lidocaine patches. Final quality of evidence was lower for lidocaine patches and BTX-A. Tolerability/safety and values/preferences were high for lidocaine patches and lower for opioids and TCAs. This permitted a strong GRADE recommendation for use and proposal as first line for TCAs, SNRIs, pregabalin, gabapentin and gabapentin ER/enacarbil in neuropathic pain, a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin patches and tramadol, and a weak recommendations for use and proposal as third line for strong opioids (particularly oxycodone and morphine) and BTX-A. Data for cannabinoids, tapentadol, drug combinations, and several other antiepileptics, antidepressants and topical drugs were inconclusive. Interpretation Limited efficacy, large placebo responses, inadequate diagnostic criteria and poor phenotypic profiling probably account for modest trial outcomes and should be taken into account in future studies. Funding This study was funded by NeuPSIG.

A longitudinal cohort study of 100 people with traumatic spinal cord injury (SCI) was performed to determine the prevalence and severity of different types of pain (musculoskeletal, visceral, neuropathic at-level, neuropathic below-level) at 5 years following SCI. Prospective data on the characteristics of pain up to 6 months following injury had been collected previously and allowed comparisons between the presence of pain at different time points. In addition, we sought to determine the relationship between the presence of pain and physical factors related to the injury such as level of lesion, completeness and clinical SCI syndrome. We also obtained information regarding mood, global self-rated health and the impact of pain on function. Of the 100 subjects in the original cohort, 73 were available for follow up. When all types of pain were included, 59 of the 73 subjects (81%) reported the presence of pain. Musculoskeletal pain was the most common type of pain experienced and was present in 43 subjects (59%), at-level neuropathic pain was present in 30 subjects (41%), below-level neuropathic pain was present in 25 subjects (34%) and visceral pain was present in four subjects (5%). Overall, 58% reported their pain as severe or excruciating and those with visceral pain were most likely to rate their pain in these categories. There was no relationship between the presence of pain overall and level or completeness of lesion, or type of injury. However, tetraplegics were more likely to report below-level neuropathic pain. This study prospectively demonstrates the differing time courses of different types of pain over the first 5 years following SCI. There was a strong correlation between the presence of both types of neuropathic pain at 5 years and earlier time points but both visceral pain and musculoskeletal pain demonstrated a poor correlation between time points. Chronic visceral pain occurs in a small percentage of patients and does not correlate with the presence of visceral pain early following injury. Those with neuropathic pain early following their injury are likely to continue to experience ongoing pain and the pain is likely to be severe. In contrast, chronic musculoskeletal pain is more common but less likely to be severe and cannot be predicted by the presence of pain in the first 6 months following injury.

The most obvious impairments associated with spinal cord injury (SCI) are loss of sensation and motor control. However, many subjects with SCI also develop persistent neuropathic pain below the injury which is often severe, debilitating and refractory to treatment. The underlying mechanisms of persistent neuropathic SCI pain remain poorly understood. Reports in amputees describing phantom limb pain demonstrate a positive correlation between pain intensity and the amount of primary somatosensory cortex (S1) reorganization. Of note, this S1 reorganization has also been shown to reverse with pain reduction. It is unknown whether a similar association between S1 reorganization and pain intensity exists in subjects with SCI. The aim of this investigation was to determine whether the degree of S1 reorganization following SCI correlated with on-going neuropathic pain intensity. In 20 complete SCI subjects (10 with neuropathic pain, 10 without neuropathic pain) and 21 control subjects without SCI, the somatosensory cortex was mapped using functional magnetic resonance imaging during light brushing of the right little finger, thumb and lip. S1 reorganization was demonstrated in SCI subjects with the little finger activation point moving medially towards the S1 region that would normally innervate the legs. The amount of S1 reorganization in subjects with SCI significantly correlated with on-going pain intensity levels. This study provides evidence of a link between the degree of cortical reorganization and the intensity of persistent neuropathic pain following SCI. Strategies aimed at reversing somatosensory cortical reorganization may have therapeutic potential in central neuropathic pain.