The 3e (evidence, expertise, exchange) initiative, a 17-nation collaboration that promotes evidence-based practice in rheumatology, recently published recommendations for pharmacologic pain management for inflammatory arthritis patients [41••
]. The authors highlighted six factors to consider when making a decision regarding pharmacologic pain management:
- type of pain
- type of inflammatory arthritis
- the presence of residual inflammation
- patient preference; and
- the addictive potential of the medication and the patient.
The main treatment options included:
- non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen as first line therapy;
- NSAIDs+acetaminophen or an alternative NSAID second line therapy; and
- weak opioids when NSAIDs and acetaminophen have failed or are contraindicated ().
Medications for treatment of pain in inflammatory arthritis
The authors also advocated the use of adjuvant therapy, for example tricyclic antidepressants and neuro-modulators, when appropriate. Of note, the authors specifically advised against the use of systemic glucocorticoids to treat pain in inflammatory arthritis patients who did not have signs or symptoms of active inflammation. No data exist regarding the use of systemic glucocorticoids for pain, whereas substantial data exist regarding the adverse effects of glucocorticoids [42
Many of the 3e recommendations were based upon a series of Cochrane Database Systematic Reviews, published in 2011–2012, regarding pain management in inflammatory arthritis and, more specifically, RA. A systematic review of 11 randomized or quasi-randomized controlled trials comparing opioids with placebo or an active analgesic agent concluded there was weak evidence for use of weak opioids (codeine, dextropropoxyphene, pentazosine, tilidine, tramadol) for RA patients [43
]. However, side effects, such as constipation, dizziness, nausea, and vomiting, were common. The risk ratio for study withdrawal because of side effects was 2.7 among participants taking opioids compared with those on placebo. In addition to these adverse effects, opioid use may also lead to opioid-induced hyperalgesia, which is associated with heightened pain sensitivity and increased clinical pain intensity. Given these effects, it is generally recommended that long-term opioid prescriptions be minimized and, when opioids are necessary, use should be regularly and judiciously monitored [44
A Cochrane systematic review also found weak evidence for the use of neuromodulators in the treatment of pain in RA [45
]. This review, however, included only four small, randomized controlled trials. Two trials compared nefopam, a centrally-acting analgesic used in Europe (but not the United States), with placebo. One trial compared topical capsaicin with placebo, and one study compared oromucosal cannabis with placebo. The authors concluded that topical capsaicin could be regarded as adjuvant therapy for pain for RA patients. However, because of the side effect profiles of nefopam (nausea, sweating) and cannabis (dizziness, dry mouth, light headedness), the authors did not recommend use of these agents. Of note, this review did not identify any randomized controlled trials of gabapentin or pregabalin, neuromodulators commonly used to treat pain in the United States, for pain in RA. On the basis of the 3e recommendations, gabapentin and pregabalin are included as potential adjuvant treatment options for pain in inflammatory arthritis. These recommendations are mainly based on their efficacy in studies of pain in fibromyalgia, a non-inflammatory, chronic widespread pain condition [41••
The use of antidepressants as analgesic therapy in inflammatory arthritis remains controversial. A Cochrane systematic review of eight randomized controlled trials comparing antidepressant therapy with placebo or an active intervention found insufficient evidence to advocate the use of antidepressants to treat pain in RA [49
], whereas the 3e recommendations include antidepressants, specifically tricyclic antidepressants, as a potential adjuvant treatment for pain patients with inflammatory arthritis [41••
]. However, the 3e investigators specifically note that these medications should only be considered for a subset of patients (not all patients with pain), stating very clearly that the data remain unclear.
Neither expert opinion from the 3e initiative nor combined data from a Cochrane systematic review supported the use of muscle relaxants to treat the pain of inflammatory arthritis patients [41••
]. Most studies included in the review were small, short-term (≤2 week) studies of benzodiazepines. Compared with placebo, muscle relaxants were significantly associated with an increased risk of adverse effects, particularly drowsiness and dizziness. The number needed to harm was 3 (95 % confidence interval 2–7).
The use of combination therapy to treat pain in inflammatory arthritis has not been well-studied. A Cochrane systematic review recently summarized the existing literature, but a meta-analysis was not performed because of substantial heterogeneity among studies [51
]. Eighteen of 23 studies reported no significant difference in a standardized pain outcome between monotherapy and combination therapy groups. However, the generalizability of these results was unclear. Almost all studies were performed before 1990. Most of the subjects were not taking any disease-modifying antirheumatic drugs (DMARDs), and no subjects were taking biologic DMARDs. Based largely on expert opinion, the 3e initiative supported the use of combination therapy to treat pain among inflammatory arthritis patients who did not achieve adequate response to monotherapy [41••
]. However, because of increased risk of side effects, the 3e investigators warned against the concomitant use of two drugs with the same mechanism of action. New studies are needed to investigate the use of combination analgesic therapy to treat pain in patients with inflammatory arthritis.
Few studies have examined the use of pain medications among inflammatory arthritis patients with medical comorbidities. A Cochrane systematic review found no studies that met inclusion criteria to assess the safety and efficacy of analgesic medications among RA patients with renal or cardiovascular comorbidities [52
]. A Cochrane review examining the safety and efficacy of analgesic medications among inflammatory arthritis patients with gastrointestinal and/or hepatic comorbidities identified only one study that fulfilled inclusion criteria [53
]. This small study (N
=58), published in 1975, concluded that naproxen, at doses of 500 to 750 mg daily, was safe for patients with gastrointestinal and hepatic comorbidities [54
]. However, none of the study participants were using modern DMARDs. Results from more recent studies of other patient populations (e.g., osteoarthritis, combination of rheumatic conditions) were indicative of increased risk of gastrointestinal side effects among patients with a history of gastrointestinal comorbidity, treated with NSAIDs [55
]. Ultimately, the Cochrane review concluded there was “scant evidence” of appropriate use of pain medications by patients with inflammatory arthritis and gastrointestinal and hepatic comorbidities.
Studies to examine the safety of analgesics among patients taking DMARDs are particularly needed, because many common DMARDs have adverse effects that may be potentiated by specific analgesic medications. A Cochrane systematic review examining the safety of NSAIDs among inflammatory arthritis patients concluded that the use of NSAIDs with methotrexate was generally safe when appropriate monitoring was performed [57
]. However, the use of high-dose aspirin (e.g., 2 g daily) was associated with increased risk of kidney and liver toxicity.