NIHR DC Discover

NIHR Signal Diclofenac or etoricoxib, but not paracetamol, is effective for treating osteoarthritis

Published on 26 May 2016

doi: 10.3310/signal-000245

This review aimed to identify the most effective drugs for pain relief in hip or knee osteoarthritis. High dose diclofenac or etoricoxib were the most effective non-steroidal anti-inflammatory drugs (NSAID) for treating pain and function. They were superior to other commonly used NSAIDs such as ibuprofen. Paracetamol, when used alone, had no meaningful effect on pain symptoms.

The authors point out that prescribers need to balance these findings with the safety profile of each drug when selecting the preparation and dose for individual patients. The current recommendation from NICE is that paracetamol is a drug of first-choice. Future guideline updates are anticipated in the light of new evidence and a review commissioned by the Medicines and Healthcare products Regulatory Agency.

The trials included in this review were of a relatively short duration and safety information was not reported. There was no information on the effectiveness of paracetamol when prescribed along with NSAID, nor on intermittent use of NSAID compared with regular use.

The original version of this review has been retracted and republished after the authors drew attention to two missed trials and a duplicate publication. This has not changed the overall message.

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Why was this study needed?

Osteoarthritis is the most common type of arthritis in the UK and the leading cause of pain in older adults. The severity of pain and functional disability can vary from person to person, from mild symptoms that come and go to more continuous and severe problems.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat symptoms of osteoarthritis. In the USA, about 65% of patients with osteoarthritis are prescribed NSAIDs. In England, each month, £5-6 million is spent in general practice prescribing NSAIDs.

A wide variety of NSAIDs is available and little is known about how these preparations or doses compare to each other, so clinicians are faced with difficult treatment decisions. Therefore, this review aimed to compare them in a network meta-analysis, pooling not only direct evidence from “head-to-head” trials but also comparing findings indirectly across trials.

What did this study do?

This network meta-analysis included 76 randomised controlled trials (58,451 participants) up to February 2015, comparing non-steroidal anti-inflammatory drugs, paracetamol or placebo for the treatment of hip or knee osteoarthritis pain.

The study was mostly interested in effects on pain, which was assessed on pain scales at various time-points ranging from one week to 12 months and/or the end of the trial. Function was the second outcome of interest, which was assessed at weeks one and two and at the end of the trial. Based on other studies of osteoarthritis, an effect size of 0.37 was considered the minimum for a clinically meaningful improvement in symptoms. This corresponds to a 9mm difference on a 100mm visual pain scale.

The main source of bias in the included trials was incomplete data collection for all participants. The majority of trials (92%) were also reported to have commercial funding, representing an uncertain potential for conflict of interest.

What did it find?

  • Irrespective of dose, all non-steroidal anti-inflammatory drugs and paracetamol improved reported osteoarthritis pain compared to placebo, but only three drugs gave a clinically significant improvement: diclofenac, etoricoxib and rofecoxib. Rofecoxib has been withdrawn from the market due to safety concerns.
  • Diclofenac at a dose of 150 mg/day was the most effective drug for pain relief compared with placebo (effect size -0.57 95% credibility interval [CI] -0.69 to -0.45). It also significantly improved physical function.
  • Etoricoxib at a dose of 60 mg/day was as effective as diclofenac 150 mg/day for osteoarthritis pain compared with placebo (effect size 0.58 95%CI), but its effect on physical function was unclear.
  • Paracetamol at any dose, including the maximum daily dose, did not have a clinically meaningful effect on osteoarthritis pain.
  • No results were given for adverse effects.

What does current guidance say on this issue?

Current NICE guidance on osteoarthritis (2014) recommends paracetamol and topical non-steroidal anti-inflammatory drugs (NSAIDs) as the first-line treatment options for pain, partly because they have a very low risk of adverse effects. If symptoms are not controlled then NSAIDs or the COX-2 inhibitor etoricoxib are considered.

These recommendations date from 2008 and NICE note that a later evidence review showed paracetamol may be less effective than previously thought. The Medicines and Healthcare products Regulatory Agency plan to commission a full review on the drug management of osteoarthritis: NICE advise that until this is published the possible limitations of paracetamol are kept in mind.

When prescribing an oral NSAID/COX-2 inhibitor, it is recommended that the lowest effective dose is used for the shortest possible time. Choice of drug is guided by individual patient risk factors due to the variation in potential side effects.

What are the implications?

This review found paracetamol, irrespective of dose, had no meaningful effect on osteoarthritis symptoms, so its use in clinical practice is not supported by this evidence.

The current guideline recommendations to consider paracetamol as the first-choice pain relief medication are being reviewed. Diclofenac at the maximum daily dose was the most effective non-steroidal anti-inflammatory drug (NSAID) for improving pain and function and was superior to the maximum doses of other frequently used NSAIDs, including ibuprofen and naproxen. Etoricoxib, a COX-2 inhibitor, was also an effective choice but is more costly than diclofenac.

The benefit of NSAIDs must be weighed against their potential side effects, including cardiovascular events. Diclofenac and etoricoxib have similar rates of cardiovascular events. The trials in this review were mostly of short to medium duration (three months or less) so longer-term effectiveness is unknown.

Given that currently about £5-6 million is spent on community prescribing of NSAIDs each month in England, this is an important area of prescribing practice.

Citation and Funding

Da Costa BR, Riechenbach S, Keller N, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet. 2016. [Epub ahead of print].

This project was funded by the Swiss National Science Foundation and the Swiss Arco Foundation.

Retraction and republication on 8th July 2017:

Explanation can be found here.

The final version can be found here.

Bibliography

Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-79.

Cannon CP, Curtis SP, FitzGerald GA, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2006;368(9549):1771-81.

McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22(3):363-88.

NHS Choices. Osteoarthritis. London: Department of Health; 2014.

NICE. Osteoarthritis: care and management. CG177. London: National Institute of Health and Care Excellence; 2014.

 

Why was this study needed?

Osteoarthritis is the most common type of arthritis in the UK and the leading cause of pain in older adults. The severity of pain and functional disability can vary from person to person, from mild symptoms that come and go to more continuous and severe problems.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat symptoms of osteoarthritis. In the USA, about 65% of patients with osteoarthritis are prescribed NSAIDs. In England, each month, £5-6 million is spent in general practice prescribing NSAIDs.

A wide variety of NSAIDs is available and little is known about how these preparations or doses compare to each other, so clinicians are faced with difficult treatment decisions. Therefore, this review aimed to compare them in a network meta-analysis, pooling not only direct evidence from “head-to-head” trials but also comparing findings indirectly across trials.

What did this study do?

This network meta-analysis included 76 randomised controlled trials (58,451 participants) up to February 2015, comparing non-steroidal anti-inflammatory drugs, paracetamol or placebo for the treatment of hip or knee osteoarthritis pain.

The study was mostly interested in effects on pain, which was assessed on pain scales at various time-points ranging from one week to 12 months and/or the end of the trial. Function was the second outcome of interest, which was assessed at weeks one and two and at the end of the trial. Based on other studies of osteoarthritis, an effect size of 0.37 was considered the minimum for a clinically meaningful improvement in symptoms. This corresponds to a 9mm difference on a 100mm visual pain scale.

The main source of bias in the included trials was incomplete data collection for all participants. The majority of trials (92%) were also reported to have commercial funding, representing an uncertain potential for conflict of interest.

What did it find?

  • Irrespective of dose, all non-steroidal anti-inflammatory drugs and paracetamol improved reported osteoarthritis pain compared to placebo, but only three drugs gave a clinically significant improvement: diclofenac, etoricoxib and rofecoxib. Rofecoxib has been withdrawn from the market due to safety concerns.
  • Diclofenac at a dose of 150 mg/day was the most effective drug for pain relief compared with placebo (effect size -0.57 95% credibility interval [CI] -0.69 to -0.45). It also significantly improved physical function.
  • Etoricoxib at a dose of 60 mg/day was as effective as diclofenac 150 mg/day for osteoarthritis pain compared with placebo (effect size 0.58 95%CI), but its effect on physical function was unclear.
  • Paracetamol at any dose, including the maximum daily dose, did not have a clinically meaningful effect on osteoarthritis pain.
  • No results were given for adverse effects.

What does current guidance say on this issue?

Current NICE guidance on osteoarthritis (2014) recommends paracetamol and topical non-steroidal anti-inflammatory drugs (NSAIDs) as the first-line treatment options for pain, partly because they have a very low risk of adverse effects. If symptoms are not controlled then NSAIDs or the COX-2 inhibitor etoricoxib are considered.

These recommendations date from 2008 and NICE note that a later evidence review showed paracetamol may be less effective than previously thought. The Medicines and Healthcare products Regulatory Agency plan to commission a full review on the drug management of osteoarthritis: NICE advise that until this is published the possible limitations of paracetamol are kept in mind.

When prescribing an oral NSAID/COX-2 inhibitor, it is recommended that the lowest effective dose is used for the shortest possible time. Choice of drug is guided by individual patient risk factors due to the variation in potential side effects.

What are the implications?

This review found paracetamol, irrespective of dose, had no meaningful effect on osteoarthritis symptoms, so its use in clinical practice is not supported by this evidence.

The current guideline recommendations to consider paracetamol as the first-choice pain relief medication are being reviewed. Diclofenac at the maximum daily dose was the most effective non-steroidal anti-inflammatory drug (NSAID) for improving pain and function and was superior to the maximum doses of other frequently used NSAIDs, including ibuprofen and naproxen. Etoricoxib, a COX-2 inhibitor, was also an effective choice but is more costly than diclofenac.

The benefit of NSAIDs must be weighed against their potential side effects, including cardiovascular events. Diclofenac and etoricoxib have similar rates of cardiovascular events. The trials in this review were mostly of short to medium duration (three months or less) so longer-term effectiveness is unknown.

Given that currently about £5-6 million is spent on community prescribing of NSAIDs each month in England, this is an important area of prescribing practice.

Citation and Funding

Da Costa BR, Riechenbach S, Keller N, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet. 2016. [Epub ahead of print].

This project was funded by the Swiss National Science Foundation and the Swiss Arco Foundation.

Retraction and republication on 8th July 2017:

Explanation can be found here.

The final version can be found here.

Bibliography

Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-79.

Cannon CP, Curtis SP, FitzGerald GA, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2006;368(9549):1771-81.

McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22(3):363-88.

NHS Choices. Osteoarthritis. London: Department of Health; 2014.

NICE. Osteoarthritis: care and management. CG177. London: National Institute of Health and Care Excellence; 2014.

 

Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis

Published on 22 March 2016

da Costa, B. R.,Reichenbach, S.,Keller, N.,Nartey, L.,Wandel, S.,Juni, P.,Trelle, S.

Lancet , 2016

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone of osteoarthritis pain management. We aimed to assess the effectiveness of different preparations and doses of NSAIDs on osteoarthritis pain in a network meta-analysis. METHODS: For this network meta-analysis, we considered randomised trials comparing any of the following interventions: NSAIDs, paracetamol, or placebo, for the treatment of osteoarthritis pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the reference lists of relevant articles for trials published between Jan 1, 1980, and Feb 24, 2015, with at least 100 patients per group. The prespecified primary and secondary outcomes were pain and physical function, and were extracted in duplicate for up to seven timepoints after the start of treatment. We used an extension of multivariable Bayesian random effects models for mixed multiple treatment comparisons with a random effect at the level of trials. For the primary analysis, a random walk of first order was used to account for multiple follow-up outcome data within a trial. Preparations that used different total daily dose were considered separately in the analysis. To assess a potential dose-response relation, we used preparation-specific covariates assuming linearity on log relative dose. FINDINGS: We identified 8973 manuscripts from our search, of which 74 randomised trials with a total of 58 556 patients were included in this analysis. 23 nodes concerning seven different NSAIDs or paracetamol with specific daily dose of administration or placebo were considered. All preparations, irrespective of dose, improved point estimates of pain symptoms when compared with placebo. For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] -0.37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES -0.57, 95% credibility interval [CrI] -0.69 to -0.46) and etoricoxib 60 mg/day (ES -0.58, -0.73 to -0.43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for celecoxib (p=0.030), diclofenac (p=0.031), and naproxen (p=0.026). We found no evidence that treatment effects varied over the duration of treatment. Model fit was good, and between-trial heterogeneity and inconsistency were low in all analyses. All trials were deemed to have a low risk of bias for blinding of patients. Effect estimates did not change in sensitivity analyses with two additional statistical models and accounting for methodological quality criteria in meta-regression analysis. INTERPRETATION: On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients. FUNDING: Swiss National Science Foundation (grant number 405340-104762) and Arco Foundation, Switzerland.

Expert commentary

This review indicates a need to reduce our reliance on paracetamol and effective non-steroidal anti-inflammatory drugs (NSAIDs) as symptomatic treatment for osteoarthritis. Many of those with osteoarthritis will be older people with multiple morbidities and will be on multiple medications increasing the risk of harms from both paracetamol, which may not be as safe as previously thought, and NSAIDs. The use of opioid drugs as an alternative analgesic will bring its own problems. Individual patients may benefit from these drugs and accept the potential harms.

The challenge for health professionals and commissioners is how to promote exercise and weight loss that is effective for osteoarthritis.

Professor Martin Underwood, Director, Warwick Clinical Trials Unit, Warwick Medical School, The University of Warwick