Abstract: Four trials with high risk of bias were included in this review. Two trials evaluated oral nefopam (52 participants) and one trial each evaluated topical capsaicin (31 participants) and oromucosal cannabis (58 participants). The pooled analyses identified a significant reduction in pain levels favouring nefopam over placebo (weighted mean difference (WMD) -21.16, 95% CI -35.61 to -6.71; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5) after two weeks. There were insufficient data to assess withdrawals due to adverse events. Nefopam was associated with significantly more adverse events (RR 4.11, 95% CI 1.58 to 10.69; NNTH 9, 95% CI 2 to 367), which were predominantly nausea and sweating. In a mixed population trial, qualitative analysis of patients with RA showed a significantly greater reduction in pain favouring topical capsaicin over placebo at one and two weeks (MD -23.80, 95% CI -44.81 to -2.79; NNT 3, 95% CI 2 to 47; MD -34.40, 95% CI -54.66 to -14.14; NNT 2, 95% CI 1.4 to 6 respectively). No separate safety data were available for patients with RA, however 44% of patients developed burning at the site of application and 2% withdrew because of this. One small, low quality trial assessed oromucosal cannabis against placebo and found a small, significant difference favouring cannabis in the verbal rating score 'pain at present' (MD -0.72, 95% CI -1.31 to -0.13) after five weeks. Patients receiving cannabis were significantly more likely to suffer an adverse event (risk ratio (RR) 1.82, 95% CI 1.10 to 3.00; NNTH 3, 95% CI 3 to 13). These were most commonly dizziness (26%), dry mouth (13%) and light headedness (10%). There is currently weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis are all superior to placebo in reducing pain in patients with RA. However, each agent is associated with a significant side effect profile. The confidence in our estimates is not strong given the difficulties with blinding, the small numbers of participants evaluated and the lack of adverse event data. In some patients, however, even a small degree of pain relief may be considered worthwhile. Until further research is available, given the relatively mild nature of the adverse events, capsaicin could be considered as an add-on therapy for patients with persistent local pain and inadequate response or intolerance to other treatments. Oral nefopam and oromucosal cannabis have more significant side effect profiles however and the potential harms seem to outweigh any modest benefit achieved.

Plain-language summary: We looked at all the published scientific literature and identified four drug trials that evaluated different neuromodulators. Two small studies with a total of 52 patients tested the drug nefopam (which is only available in some parts of the world). One trial each tested capsaicin cream (31 participants) and a cannabis based mouth spray (58 participants). Note: use of medicinal cannabis is illegal and therefore unavailable in most countries. When patients took nefopam they had a greater improvement in pain levels, on average 21 points on a 100 point scale, than those patients who were given a placebo (an inactive substance that has no treatment value). However, patients on nefopam also developed side effects, which mainly consisted of nausea and sweating. Many patients stopped taking the drug because the symptoms were so bad. These studies were performed in the 1980s when treatment for RA was very different to what it is now. Until further, larger studies are carried out to better assess nefopam, with many other effective pain relieving medications on the market, the risks of harm seem to outweigh the benefit arguing against its routine use. In the one small study testing capsaicin cream (0.025%) in patients with persistent knee pain, patients also had better pain relief with capsaicin cream than for those given a placebo cream. On average, patients receiving the active treatment improved by 34 more points (out of 100) than the control group. The most common side effect was a local burning sensation at the site that the cream was applied. This was usually mild but was moderate to severe in a few patients. About 50% of patients who use capsaicin cream on their skin will develop this local burning but only 2 in 100 will stop treatment because of this. The one small study of the cannabis based mouth spray Setivax also showed reduced pain levels in patients, to a small extent. Pain was measured on a 0 to 5 point scale and there was an improvement in patients receiving Setivax of 0.74 points. About one in every three patients taking this medication developed a side effect, which was commonly dizziness (26%), dry mouth (13%) or light headedness (10%). Although this is only one study, weighing up these side effects and the minimal benefit on pain levels, until further trials are carried out we cannot recommend the use of this medication.