Acetaminophen (paracetamol, acetyl-para-aminophenol; APAP) was ineffective for low back pain and provided only clinically insignificant relief of hip or knee osteoarthritis (OA) pain while quadrupling the risk for liver function abnormalities, according to a systematic review and meta-analysis published March 31 by Australian researchers in the British Medical Journal. On the basis of this analysis, the researchers suggest that acetaminophen's front-line place in OA and back pain clinical treatment guidelines should be reconsidered.
Edward Michna, MD, director of the Pain Trials Center at Brigham and Women's Hospital, Boston, Massachusetts, and member of the American Pain Society board of directors, told Medscape Medical News that the results are interesting, but subject to the limitations to meta-analysis, which is only as good as the quality of the original studies and may be biased by the limitation of the available studies published.
Dr Michna, who was not involved in the study, said, "I would not place too much importance on these results. There is large variation in response of patients to pain medications, [and] there are subpopulations of patients that do well on APAP and probably should continue to use it as first-line therapy." Dr Michna added that nonresponders should (but sometimes do not) stop taking APAP, as risks may exceed the benefit. "The problem is that patients, out of frustration and anxiety, will continue taking medications even if it doesn't help, just so they feel they are doing something to treat their pain," he said.
However, Raveendhara R. Bannuru, MD, PhD, director, Center for Treatment Comparison and Integrative Analysis; assistant professor of Medicine at Tufts University School of Medicine; and member of the Special & Scientific Staff at the Tufts Center for Arthritis and Rheumatic Diseases, Tufts Medical Center, Boston, Massachusetts, told Medscape Medical News that the Australian study added to a growing body of evidence supporting reconsideration of the role of APAP.
Dr Bannuru, who was not involved in this study, recently reached similar conclusions in a meta-analysis of pharmacologic interventions for knee OA.
"I would definitely expect all the concerned societies involved in developing OA guidelines to take a closer look at this study, as well as our study in reassessing their recommendation on the use of acetaminophen," Dr Bannuru said.
Drugs are the most common first-line approach to treating spinal pain and OA. Acetaminophen is recommended as first-line treatment in major treatment guidelines, including those from the American College of Physicians and the American Pain Society, those from the European League Against Rheumatism, those from the American College of Rheumatology, those from Osteoarthritis Research Society International, and those from the National Institute for Health and Care Excellence.
Little Evidence of APAP Efficacy in Low Back Pain, Knee/Hip OA Found
Gustavo C. Machado, a PhD student at the George Institute for Global Health, University of Sydney, Australia, and colleagues, working with Associate Professor Manuela L. Ferreira, PhD, from the University of Sydney Institute of Bone and Joint Research, analyzed data from 13 randomized controlled trials that compared the efficacy and safety of acetaminophen with placebo in more than 5000 patients with low back pain (n = 1825) or hip or knee OA (n = 3541). Primary outcomes were pain (scale of 0 - 100), disability (scale of 0 - 100), and quality of life. Secondary outcomes were adverse effects, adherence, and use of rescue medications, and the researchers used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate quality of evidence.
In low back pain, the authors found high-quality evidence that acetaminophen was ineffective in the short term for reducing pain, reducing disability, or improving quality of life.
In hip and knee OA, the authors found high-quality evidence that acetaminophen produced a statistically significant reduction in pain, but the difference (−3.7) was far below the −9.0 criterion for minimal clinically important difference. Similarly, the −2.9 reduction in disability did not meet the criterion for clinical importance.
Maurizio Cutolo, MD, director, Research Laboratories and Academic Division of Clinical Rheumatology, University of Genova, Italy, who was not involved in the study, told Medscape Medical News, "At least for back pain, which is a very acute and disabling condition, APAP is not effective as first-line treatment. The severity of the pain and the multitude of possible causes are so intensive that a combination treatment must be started in case of early back pain." Dr Cutolo recommended consideration of local depot steroid injection, physiotherapy, and nonsteroidal anti-inflammatory drugs or major analgesics where needed.
Acetaminophen Liver Toxicity Remains a Concern
Patients who took acetaminophen were 3.8 times more likely to have abnormal liver function tests, but the researchers note that this finding is of uncertain clinical importance. Acetaminophen and placebo groups had similar rates of adverse events, serious adverse events, study withdrawal resulting from adverse events, treatment adherence, and use of rescue medication.
Dr Michna commented that the clinical effects of the liver changes reported in the study are unclear, and that rates of significant liver disease and failure are still relatively small (except in overdose) compared with the gastrointestinal complications that occur in much greater numbers with nonsteroidal anti-inflammatory drugs and the problems of overdose and addiction associated with opioids. Dr Michna also raised the concern that in cases where APAP does not produce adequate pain relief, patients might take even more than the recommended dose in the hope that more might be better, further increasing the risk for liver toxicity.
"If medications are not helping, they need to be stopped. Patients have to have this point reinforced. There is no point taking medications that are not helping that could have harmful effects," Dr Michna said.
Four of the coauthors received research support from GlaxoSmithKline. Machado also received support from GlaxoSmithKline for a PhD scholarship. Dr Michna and Dr Bannuru have disclosed no relevant financial relationships. Dr Cutolo is a member of the advisory board for Horizon Pharma AG.
BMJ. 2015;350:h1225. Full text
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