title: Neuromodulators for pain management in rheumatoid arthritis.
abstract: BACKGROUND
  Pain management is a high priority for patients with rheumatoid arthritis (RA). Despite deficiencies in research data, neuromodulators have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain.
  
  
  OBJECTIVE
  The aim of this review was to determine the efficacy and safety of neuromodulators in pain management in patients with RA. Neuromodulators included in this review were anticonvulsants (gabapentin, pregabalin, phenytoin, sodium valproate, lamotrigine, carbamazepine, levetiracetam, oxcarbazepine, tiagabine and topiramate), ketamine, bupropion, methylphenidate, nefopam, capsaicin and the cannabinoids.
  
  
  METHODS
  We performed a computer-assisted search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, 4th quarter), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44, 2010) and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 and 2009 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conference abstracts and performed a handsearch of reference lists of articles.
  
  
  METHODS
  We included randomised controlled trials which compared any neuromodulator to another therapy (active or placebo, including non-pharmacological therapies) in adult patients with RA that had at least one clinically relevant outcome measure.
  
  
  METHODS
  Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of a neuromodulator on pain, depression and function as well as their safety.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Rheumatology and Orthopedics, Royal Prince Alfred Hospital, Camperdown, Australia. brichard@med.usyd.edu.au.
authors.forename: Bethan L
authors.initials: BL
authors.lastname: Richards
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Whittle
authors.forename: Rachelle
authors.initials: R
authors.lastname: Buchbinder
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000627:therapeutic use; D018771:Arthralgia / Q000188:drug therapy* / Q000209:etiology; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000188:drug therapy*; D002186:Cannabinoids / Q000009:adverse effects / Q000627:therapeutic use; D002188:Cannabis / Q000737:chemistry; D002211:Capsaicin / Q000009:adverse effects / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy; D006801:Humans; D009340:Nefopam / Q000009:adverse effects / Q000627:therapeutic use; D018377:Neurotransmitter Agents / Q000009:adverse effects / Q000627:therapeutic use*; D059408:Pain Management / Q000379:methods; D016032:Randomized Controlled Trials as Topic
chemical_list: D018712:Analgesics, Non-Narcotic; D002186:Cannabinoids; D018377:Neurotransmitter Agents; D009340:Nefopam; D002211:Capsaicin