Efficacy and safety of paracetamol for spinal pain and osteoarthritis
Systematic review and meta-analysis of randomised placebo controlled trials
“Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials” by G C Machado and colleagues (BMJ 2015;350:h1225)
Objective—To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee.
Design—Systematic review and meta-analysis.
Data sources—Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014.
Eligibility criteria for selecting studies—Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee.
Data extraction—Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration’s tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions.
Results—12 reports (13 randomised trials) were included. There was “high quality” evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference −0.5, 95% confidence interval −2.9 to 1.9) and disability (0.4, −1.7 to 2.5) or improving quality of life (0.4, −0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was “high quality” evidence that paracetamol provides a significant, although not clinically important, effect on pain (−3.7, −5.5 to −1.9) and disability (−2.9, −4.9 to −0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. “High quality” evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain.
Conclusions—Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines.
Why do the study?
Back pain and osteoarthritis are extremely common, accounting for 10-15% of all primary care consultations. Paracetamol is a popular treatment that people worldwide have relied on for decades. But there are still doubts about its effectiveness and safety. Two new trials have been published since researchers last reviewed the evidence supporting paracetamol for back pain or osteoarthritis, so Machado and colleagues conducted a systematic review and meta-analysis to bring the evidence base up to date and to inform the ongoing debate about how best to treat these conditions. Meta-analysis is a mathematical way of combining findings from individual trials. Done well, it can add power and precision to previous estimates of the effects of treatments, and help resolve inconsistencies in results from individual trials.
What did the authors do?
They searched systematically through multiple research databases and trial registers to find all randomised controlled trials reporting the effects of paracetamol on important outcomes such as pain, disability, quality of life and side effects. They selected trials comparing paracetamol with a placebo, and included trials in any language, conducted at any time, anywhere, whether published or not. The authors then conducted a series of meta-analyses to combine results from groups of individual trials. Each meta-analysis was designed to answer a specific research question such as: does paracetamol reduce arthritic pain more than a placebo, in the short term? Does paracetamol reduce the disability associated with arthritis more than a placebo, in the immediate term?
The authors converted all measures of pain and disability from individual trials in to a simple scale running from 0 to 100 (the lower the better) to harmonise results across trials and make the combined results easier to understand.
They worked from a protocol, which was registered in a publicly accessible register called PROSPERO. We can check the entry in PROSPERO to make sure their review was carried out faithfully. They also reported their review using a respected guideline called PRISMA. Reporting guidelines help authors report studies completely, transparently, and in an unbiased way so readers get the full picture and can trust the results.
The box below lists the key elements to look for in the methods of any systematic review and meta-analysis of randomised trials. All are present in Machado and colleagues review.
Key elements to look out for in the methods of any systematic review and meta-analysis of randomised trials
- Inclusion of unpublished studies, and studies in any language
- An assessment of the likelihood of bias in included trials
- Clearly defined primary and secondary outcomes—preferably outcomes that matter to patients, such as quality of life
- A test for publication bias. (A skewness in the visible literature caused by non publication of certain trials—for example, those that didn’t find the expected result)
- A test for heterogeneity. Heterogeneity is a measure of the variation among the results of individual trials. High heterogeneity (study results vary in magnitude or direction or both) needs further investigation and may suggest that the trials are too different to be combined in a meaningful way
- Selection of studies by at least two authors, and extraction of data for pooling by at least two authors, with disagreements resolved by consensus
- An indication that the reviewers asked the authors of included studies for any missing data items. Or at least tried to contact them
- Sensitivity analyses testing the robustness of the reviews findings
Machado and colleagues also did a post hoc analysis to predict whether future trials could change their findings. Post hoc or exploratory analyses are legitimate but should be clearly labelled and treated with caution.
What did they find?
The authors found 13 relevant randomised trials, and conducted 14 separate meta-analyses of different groups of trials. Together, the 13 trials included 5366 patients with mostly chronic pain. Ten of the trials tested paracetamol for osteoarthritis of the hip or knee. Three tested paracetamol for lower back pain. The authors found no suitable trials of paracetamol for neck pain.
In meta-analyses of no more than two trials, paracetamol had no significant effects on pain or disability among people with lower back pain. The one trial reporting quality of life also found no effect. The authors judged these findings to be “high quality” evidence using the well respected GRADE system (grading of recommendations assessment, development and evaluation).
In meta-analyses of between three and seven trials, paracetamol had statistically significant effects on pain and disability caused by osteoarthritis of the hip or knee. But the improvements were too small to be noticeable to patients. For example, paracetamol improved pain scores by 3.7 points (95% confidence interval 5.5 to 1.9) on a scale running from 0 to 100, and reduced disability by 2.9 points (4.9 to 0.9). Machado and colleagues identified nine points as the minimum improvement likely to be noticed by patients. This evidence was also judged to be “high quality.”
Patients taking paracetamol were nearly four times more likely than controls to have abnormal results on liver function tests (risk ratio 3.8, 1.9 to 7.4). They were no more likely to report adverse events, adhere to treatment, or drop out of a trial due to adverse events.
Sensitivity analyses confirmed the authors’ main findings. The post hoc analysis suggested that future trials were unlikely to change them.
Eyeballing Forest plots is a quick and easy way to see the results of meta-analyses. For each outcome, look for the diamond shape or “pooled effect.” If the whole diamond is one side or other of the vertical line, you can see instantly that the active treatment was significantly better or worse than the control treatment. If even the tip of the diamond touches or crosses the line, the two comparators were not significantly different from each other. The figure, for example, shows the results of eight different meta-analyses. In three of them, the diamond is wholly to the left of the vertical line. Paracetamol improved these outcomes significantly. But when we look at the size of the improvement in the right hand column, it’s clear that these significant differences were too small to matter to patients. The mean difference between groups (paracetamol v placebo) is always much less than the “minimum clinically important difference” of nine points. 1
What are the study’s strengths and weaknesses?
This is a well conducted and clearly reported systematic review and meta-analysis. The findings are secure enough to influence clinical practice, and inform treatment guidelines. The authors used a strong systematic search of multiple research databases, looked for unpublished work, and made few exclusions. So this is an inclusive review of largely high quality evidence that helps to answer common clinical questions (“doctor, will paracetamol improve the pain in my back/hip/ knee?”).
The main weakness is the relatively small number of trials overall, which meant that some meta-analyses included only a handful. The headline finding reporting no effect on low back pain come from meta-analyses of just two trials. Only one trial reported quality of life. All included studies lasted three months or less. The long term effects of paracetamol are unknown.
What do the findings mean?
Paracetamol alone is an ineffective treatment for low back pain, or for osteoarthritis of the hip or knee. It may even be harmful, although the authors stress that the isolated biochemical abnormalities they found may or may not be important clinically.
We don’t know, however, whether paracetamol would work better if combined with physical exercise, a recommended and evidence based treatment for back pain and osteoarthitis. Pending further research, what should patients use instead? Non steroidal anti-inflammatory drugs and opioids are effective but associated with serious side effects, according to the linked editorial. Topical non-steroidal creams are another possibility, along with exercise based treatments. Managing musculoskeletal pain without pills isn’t easy and may not be popular says the editorial. Doctors should still encourage people to go down this route, supported by the high quality evidence in this new review.
The findings may also prompt a re-evaluation of some clinical guidelines, including recent guidance from NICE (National Institute for Health and Care Excellence) which recommended paracetamol, among other things, for arthritic pain.Alison Tonks, associate editor
Correspondence to: firstname.lastname@example.org
Competing interests: Alison Tonks is an associate editor at the BMJ and helps select research for publication.
Provenance and peer review: Commissioned; not externally peer reviewed.
- Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ 2015;350:h1225.
- PROSPERO. International Prospective Register of Systematic Reviews. www.crd.york.ac.uk/PROSPERO/.
- PRISMA. Transparent Reporting of Systematic Reviews and Meta-analysis. www.prisma-statement.org/.
- Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-6.
- Mallen C, Hay E. Managing back pain and osteoarthritis without paracetamol. BMJ 2015;350:h1352.
- National Institute for Health and Care Excellence. Osteoarthritis: care and management in adults. NICE, 2014.www.nice.org.uk/guidance/cg177.
Cite this as: Student BMJ 2015;23:h2859