And other concise reviews of studies on pain management in rheumatology
March 2015, Vol 3, No 3 - Inside Pain Management

In This Article

Acetaminophen Lacks Effectiveness in Knee Osteoarthritis

Despite being the most common over-the-counter treatment for pain related to knee osteoarthritis (OA), acetaminophen was found inferior to other commonly used pain medications in a large network meta-analysis.

Intra-articular (IA) treatments were superior to oral nonsteroidal anti-inflammatory drugs (NSAIDs) for pain relief in this study.

Lead author Raveendhara R. Bannuru, MD, and colleagues at Tufts Medical Center in Boston, MA, noted that the superiority of IA treatments may be associated with the placebo effect. “The information from this study, along with the safety profiles and relative costs of included treatments, should be helpful to clinicians when making care decisions tailored to individual patient needs,” they explained.

In the absence of definitive head-to-head trials of medications used to treat knee OA, the authors conducted a large meta-analysis to assess the comparative effectiveness of commonly used drugs in this setting. They reviewed a total of 33,243 participants in 137 randomized controlled trials published between 1980 and 2014; each trial compared 2 or more treatments for knee OA and reported at least 1 measure of pain, function, or stiffness. Studies were drawn from searches of MEDLINE, EMBASE, Web of Science, Google, Scholar, and Cochrane Central Register of Controlled Trials, as well as unpublished data. Treatments studied included acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, IA corticosteroids, IA hyaluronic acid, oral placebo, and IA placebo. An absolute change of 20 points on a scale from 0 to 100 on the OA Research Society International Outcome Measures in Rheumatology responder criteria was deemed clinically significant.

Reported outcomes differed in these trials; 129 trials with 32,129 participants contributed to the analyses of pain-related outcomes, 76 trials (24,059 participants) contributed to the analyses of physical function outcomes, and 55 trials (18,267 participants) contributed to the analyses of stiffness outcomes. Age of participants ranged from 45 to 76 years, and the proportion of women ranged from 3% to 100%.

All interventions were statistically superior to placebo for pain-related outcomes. The most efficacious pain relief occurred with IA hyaluronic acid and the least was acetaminophen; effect sizes (standard mean differences) were 0.63 and 0.18, respectively. All treatments except acetaminophen met the prespecified criteria for clinically significant improvement. All active treatments except celecoxib were statistically superior to acetaminophen; IA treatments were more effective than oral treatments.

All interventions were significantly superior to oral placebo for function, except IA corticosteroids. Naproxen, ibuprofen, diclofenac, and celecoxib were statistically significantly better than acetaminophen for functional outcomes. IA hyaluronic acid was significantly better than IA placebo and IA corticosteroids. In addition, all oral treatments were significantly superior to acetaminophen for stiffness. IA hyaluronic acid was significantly better than IA placebo for stiffness.

Traditional nonselective NSAIDs were associated with more gastrointestinal (GI) adverse events and withdrawals compared with oral placebo and acetaminophen; GI adverse events were similar between acetaminophen and celecoxib. The short exposure time of 2 to 3 months probably affected reporting on adverse cardiovascular events, the authors noted. Transient local reactions were the most commonly reported adverse events related to IA treatments, and the frequency was similar among IA therapies. The network meta-analysis did not investigate combination therapies, even though these are commonly used to treat knee OA. “The large number of possible therapy combinations and scarcity of trials comparing these treatments prompted us to restrict our analysis to monotherapies,” the authors wrote.

Bannuru RR, Schmid CH, Kent DM, et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162:46-54.

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Patient Descriptions Deepen Understanding of Fibromyalgia Flares

Fibromyalgia flares are associated with intense pain, flulike aches and exhaustion, and other phenomena such as “brain fog,” as confirmed by the first-ever qualitative analysis of these periods of symptom exacerbation. Furthermore, according to the 44 people who responded to the survey, the patients tried many coping techniques, from medications to massage and from meditation to humor.

One of the most common coping strategies described by the respondents was to avoid all forms of activity, which surprised the investigators. “Avoiding everything may indicate a lack of knowledge of or ability to use healthy coping strategies, and therefore, future research could evaluate the potential effects of teaching patients healthy coping strategies as one method to deal with symptom flare,” according to Ann Vincent, MD, Associate Professor of Medicine, Mayo Clinic, Rochester, MN, and colleagues. The team administered the survey to Mayo Clinic patients with fibromyalgia at a ratio of 4:1 of women:men to reflect the gender proportion of the illness; 77% of the respondents were women, and 93% were non-Hispanic white.

“This is a qualitative study and this [the survey results] is what patients reported they do,” Dr Vincent explained when asked about the specific clinical implications of optimizing coping strategies. Future research could include a larger, more diverse patient population to assess the characteristics of fibromyalgia flares quantitatively, the study authors added.

The 7 items in the qualitative questionnaire were designed to probe the unique characteristics of flares. The questions included, “Do you experience any new symptoms during a fibromyalgia flare that are not typical of your everyday fibromyalgia symptoms?” and “How do you cope with a fibromyalgia flare?”

In the respondents’ descriptions of flare triggers, the most common theme was “stress, stress, stress” related to work and life in general. They also said “overdoing it” can cause flares; this included physical exercise and variations in normal activity such as attending social events. Inadequate or poor-quality sleep and weather changes were the other most common triggers. Sleep is particularly problematic for patients because flare-ups reduce sleep quality, causing a continuing feedback loop.

A key characteristic of flares is an intensification of symptoms to the point of being disabling. Many survey respondents described full-body aching and exhaustion, similar to having the flu, and also severe pain, which could be so intense that, as one patient described, it made them not want to move or be touched. Respondents also described severe and disabling fatigue and other symptoms such as “fogginess in my head,” severe headaches or migraines, and difficulty with emotional regulation.

Among the respondents, 77% turned to medications as treatment—principally acetaminophen and ibuprofen—and 22.7% reported using massage. Many also reported using meditation, breathing exercises, and hot or cold therapy. Three other major coping strategies were getting more rest or staying home, avoiding all activities including social interactions, and “waiting it out.”

Vincent A, Whipple MO, Rhudy LM. Fibromyalgia flares: a qualitative analysis. Pain Med. 2015 Jan 13. [Epub ahead of print]

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Adverse Events on Biologics Common in Juvenile Idiopathic Arthritis

The occurrence of adverse events (AEs), including serious adverse events (SAEs), is more common in children with juvenile idiopathic arthritis (JIA) on biologic therapy than has been previously reported. More than 90% of children experienced at least 1 AE on biologics, and more than one-third suffered an SAE over long-term follow-up in a retrospective, observational study reported in Rheumatology. Although AEs and SAEs were more frequent than assumed, these events seldom led to drug discontinuation.

“Our data show a wide spectrum of AEs during biologic therapy as they appear in a real-life setting,” explained Maarit Tarkiainen, MD, Children’s Hospital, University of Helsinki, Finland, and colleagues. “One of the strengths of the study is that we included all AEs, whether known to be related to the biologic agent or not, regardless of how many times or when they appeared in a single patient. Moreover, we did not rely on surveys or survey-based registries, but assessed all the available information in patient records, which seemed to be a more reliable method of collecting information.”

Other strengths of the study included long-term follow-up of more than 4 years in the majority of patients. The main limitation was the retrospective nature of the study and not defining causality of AEs with accuracy.

The study included 348 consecutive patients with JIA treated at 3 different tertiary centers in Finland. This amounted to 1516 patient-years: 710 patient-years on etanercept, 591 on infliximab, 188 on adalimumab, 8 on rituximab, 5.3 on anakinra, 6 on abatacept, 4 on tocilizu­mab, and 1 on golimumab. Median follow-up of an individual patient on biologics was 50.5 months (range, 1-154.7 months). Median age at end of follow-up was 15.9 years (range, 3.8-29 years). Ninety-five percent (n = 330) were on disease-modifying antirheumatic drugs (DMARDs) prior to biologics, and 97% received DMARDs during treatment with biologics.

Ninety-two percent (n = 319) reported at least 1 AE. Patients without an AE had a significantly shorter median follow-up compared with those who had an AE: 18.8 months versus 52.3 months, respectively (P <.0001). AEs totaled 2902 and 169/100 patient-years. Infections were the most common AE, reported in 274 patients (79%). Other common AEs included infusion or injection site reactions (n = 105, 30.2%), flare of uveitis (n = 43, 12.4%), and mild elevation of alanine aminotransferase (ALT) <3 times upper limit of normal (n = 49, 14.1%).

SAEs were reported in 121 patients (35%) during follow-up, with a total of 173 events and 11.4/100 patient-years. A total of 44 patients (12.6%) had a serious infectious AE. The occurrence of serious infections was significantly higher with ritixumab compared with all other antitumor necrosis factors, with a relative risk of 6.16 (P = .008). A total of 32 patients had more than 1 SAE. Drug therapy was continued unchanged in 150 patients (87%) despite an SAE. In some of these cases, there was a short pause in therapy. No cases of malignancies or tuberculosis were found. New-

onset uveitis was reported in 9 patients, psoriasis or psoriasiform lesions in 13 patients, and inflammatory bowel disease in 6 patients.

These data support the use of biologics in juvenile patients, Dr Tarkiainen stated. “Most common SAEs were leucopenias and ALT elevations. After these, drug therapy could most often be continued after a short pause. SAEs during treatment with biologics in juvenile patients can mostly be controlled by experienced pediatric rheumatologists,” she added.

Tarkiainen M, Tynjälä P, Vähäsalo P, Lahdenne P. Occurrence of adverse events in patients with JIA receiving biologic agents: long-term follow-up in a real-life setting. Rheumatology (Oxford). 2014 Dec 10. [Epub ahead of print]

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