New Recommendations for Drug Treatment of Inflammatory Arthritis

In March, the journal Rheumatology (http://bit.ly/M7kTis) published the results of a systematic literature review conducted by rheumatologists participating in the 3e (Evidence, Expertise, Exchange) Initiative, a “multinational collaboration aimed at promoting evidence-based practice in rheumatology by developing practical recommendations that address important clinical problems.” The participants sought to develop recommendations for the use of pharmacotherapy in the management of pain in patients with inflammatory arthritis (IA), defined for the review as including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and spondyloarthropathy (SpA).

The literature review was conducted to provide evidence to support recommendations surrounding 11 clinically relevant questions regarding pain management in IA identified by an international panel of rheumatologists. The participants also developed an algorithm for the pharmacotherapy management of pain in patients with IA based on the review findings and recommendations. The recommendations are summarized below.

1) Measure IA pain regularly, using the visual analogue scale (VAS), the numerical rating scale (NRS), or the verbal rating scale (VRS).

Most of the studies identified in the literature search focused primarily on the use of these instruments to evaluate pain associated with RA. The VAS for measuring overall pain intensity has the strongest evidence backing its efficacy.

2) Treat persistent IA pain with acetaminophen.

Data from 12 controlled trials provided weak evidence showing that acetaminophen was more effective than placebo in reducing pain associated with IA. The experts stated that acetaminophen is “generally a safe and effective analgesic in IA, both alone and in combination with other pain pharmacotherapies,” although they noted that “no evidence exists regarding the preferred formulation or dosing interval.”

3) Do not use systemic glucocorticoids for routine IA pain management in patients with no signs of inflammation.

The authors found no studies that supported the use of systemic glucocorticoids as an analgesic therapy in patients with IA, especially in light of the “well recognized” effects of long-term glucocorticoid use. The authors also “strongly agreed that there is no role for steroids in the treatment of IA pain when inflammation is adequately suppressed.”

4) Consider the use of tricyclic antidepressants and neuromodulators as adjuvant treatment, not muscle relaxants and benzodiazepines.

The authors reported mixed evidence regarding the analgesic efficacy of tricyclic antidepressants in patients with IA. They also found “insufficient evidence regarding the role of newer antidepressants in patients with IA to warrant a recommendation at this time.” Although there is little data on the use of neuromodulators (defined here as “substances that alter nerve transmission,” including topical capsaicin), the experts agreed that these medications (along with anticonvulsants such as pregabalin and gabapentin) “may be considered as adjuvant therapies in individual patients.” Limited clinical trial evidence showed no improvement in pain outcomes in patients treated with benzodiazepines and non-benzodiazepine muscle relaxants. The data did show that these medications were associated with a significant increase in the risk of adverse events compared with placebo.

5) Use weak opioids for short-term pain treatment only when other therapies fail or are contraindicated. Use caution and review frequently when prescribing long-term. Strong opioids should be used only in exceptional cases, by experienced clinicians.

The authors noted that “no consensus classification system exists” for distinguishing between “weak” and “strong” opioids. Analysis of data from clinical trials involving the use of weak opioids in patients with IA found “treatment with weak oral opioids resulted in superior patient-reported global impression of clinical change,” but was associated with higher risk of adverse events. Citing “the lack of evidence regarding the use of strong opioids in IA pain and the significant potential for harm,” the authors recommended caution when considering the use of these medications, advising they should be prescribed only when other treatments have failed and only by clinicians experienced in their use in patient care.

6) In patients whose pain is refractory to acetaminophen or NSAID, consider adding a drug with a different mode of action. Do not combine two or more NSAIDs.

Although analysis of more than 20 trials that compared combination analgesic therapy with monotherapy in patients with RA produced “inconclusive evidence,” the authors advised that “clinicians could choose to trial an alternative drug from a different class, or a combination of drugs with different modes of action,” as part of a tailored treatment plan.

7) Use NSAIDs at the lowest effective dose.

There is very little evidence on the relative risks and benefits of continuous vs. on-demand use of NSAIDs in patients with IA. NSAIDs should be prescribed at the lowest effective dose and for the shortest duration that produces adequate analgesia, and should be “tailored to the individual patient’s clinical circumstances.”

8) Use existing guidance on pain pharmacotherapy safety in patients with IA who are pregnant and/or lactating.

The authors found little strong data on the safety of analgesics in pregnant and/or lactating women with IA, opting to create a general recommendation acknowledging that, while acetaminophen is generally considered to be safe in pregnant women and NSAIDs may be used with caution before the third trimester, decision regarding pain pharmacotherapy in pregnant and lactating women “should be made jointly by the rheumatologist, obstetrician and patient.”

9) Combination treatment with methotrexate and acetaminophen or NSAIDs is safe in patients with IA.

The authors identified 17 studies in which patients with RA were treated with methotrexate plus acetaminophen or methotrexate plus NSAIDs, finding no effect on the rate of methotrexate- related adverse events. Methotrexate plus low-dose aspirin may impair liver and renal function; data suggest that “aspirin at daily doses of ≥650 mg has different pharmacokinetic properties and is more likely to increase risk” when combined with methotrexate.

10) Acetaminophen should be used as first-line therapy in patients with IA and gastrointestinal comorbidities. Use caution when prescribing non-selective NSAIDs or COX-2 selective inhibitors in combination with proton-pump inhibitors.

The authors found safety and efficacy data only for NSAIDs in patients with IA and gastrointestinal (GI) and/or hepatic complications. In patients with RA, treatment with NSAIDs was associated with “an increased risk of GI events in individuals with prior uncomplicated GI events or a history of upper GI symptoms.” Several trials involving patients with OA treated with NSAIDs found an increased risk of GI complications in patients with a history of gastro-duodenal ulceration. The experts recommended the use of either non-selective NSAIDs plus protonpump inhibitors, or COX-2 selective inhibitors (alone or in combination with PPI) while closely monitoring patients for potential GI events. Because the authors found “little evidence regarding the efficacy and safety of analgesic drugs in patients with IA and comorbid hepatic disease,” they recommend that clinicians should exercise a “similar level of caution” when prescribing acetaminophen, NSAIDs, or opioids in patients with IA as they would with other patient populations.

11) Use acetaminophen as first-line analgesic therapy in patients with IA and pre-existing hypertension, cardiovascular, or kidney disease. Exercise caution when prescribing NSAIDs and COX-2 selective inhibitors in this population.

Again, the authors found little data on the risk associated with the use of analgesic drugs in patients with IA and co-morbid renal or cardiovascular disease. One trial found that patients with RA and cardiovascular disease treated with either etoricoxib or diclofenac faced “a 3-fold increase in the risk of thrombotic events” compared with patients without cardiovascular disease. Because “there is as yet no convincing epidemiological evidence to suggest that [acetaminophen] contributes to increased vascular risk in a manner comparable with NSAIDs,” the authors recommended that “the most reasonable approach would be to use [acetaminophen] as the primary analgesic in this setting.”

Recommendation-based algorithm

The algorithm developed by the panel based on these recommendations assumes that “the clinician’s first goal is to optimally control inflammation with DMARDs according to current practice (including the use of biologic DMARDs and glucocorticoids).” The algorithm is intended to help “guide the choice of medications for individuals with IA who experience pain despite optimal management of inflammation,” as part of a treatment strategy that is “tailored to the individual patient” and reflects “the relative risks and benefits in the individual circumstances, as well as the patient’s values.”

The algorithm recommends treatment first with acetaminophen or an NSAID. If these prove ineffective or are contraindicated, clinicians are advised to switch to an alternate NSAID or treat with acetaminophen plus an NSAID. If that approach does not produce adequate analgesia, the algorithm recommends treatment with a weak opioid and/or acetaminophen and/or an NSAID, pursuant to the relevant recommendations above. The algorithm does not cover the use of strong opioids, which (as per recommendation #5) may be used “with caution under exceptional circumstances.” Adjuvant therapy with tricyclic antidepressants or neuromodulators “may be introduced at any point in the algorithm, where appropriate.” Considerations regarding the type of pain experienced by the patient, the form of IA, residual inflammation, comorbidities, the patient’s medication preference, and the addiction risk of this particular patient/drug combo should inform all treatment decisions.

“I was disturbed by the panel’s recommendation that strong opioids be used only in exceptional cases. They don’t describe what they mean by ‘exceptional,’ nor do they address that the more potent opioids are often safer than drugs like codeine or tramadol.”

—Scott Strassels, PharmD, PhD, BCPS Assistant Professor, Division of Pharmacy Practice University of Texas at Austin, College of Pharmacy

Although the authors of these recommendations noted that there was a high level of agreement among the expert panelists regarding the final recommendations and algorithm (so much so that nearly one in five rheumatologists surveyed for this process “reported that the algorithm would change their practice”), there are several caveats that should inform the application of these recommendations in clinical practice. Foremost is the relative lack of quality data available to support the recommendations. The authors noted that “Many of the included studies were performed in an era that pre-dates the current practice of early intensive therapy, and the use of novel DMARDs, including the biologic drugs, which may limit applicability to patients in the modern era.”

Scott Strassels, PharmD, PhD, BCPS, Assistant Professor, Division of Pharmacy Practice; Adjunct Assistant Professor of Public Health, University of Texas at Austin, College of Pharmacy; (and Pain Management advisory board member), says that because of some of the these shortcomings, he is unsure of the recommendations’ usefulness. He says “We must still treat people as best we can. Nonetheless, I was disturbed by the panel’s recommendation that strong opioids be used only in exceptional cases. They don’t describe what they mean by ‘exceptional,’ nor do they address that the more potent opioids are often safer than drugs like codeine or tramadol.”

Despite these shortcomings, the authors wrote that the recommendations “represent the integration of the best available evidence and multinational clinical expertise” and are potentially a valuable tool for physicians and other clinicians who are treating patients with IA for pain.