Non-steroidal Anti-inflammatory Drugs for Spinal Pain:
A Systematic Review and Meta-analysis

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM:   Annals of the Rheumatic Diseases 2017 (Jul); 76 (7): 1269–1278 ~ FULL TEXT

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Gustavo C Machado, Chris G Maher, Paulo H Ferreira,
Richard O Day, Marina B Pinheiro, Manuela L Ferreira

The George Institute for Global Health,
Sydney Medical School,
University of Sydney,
Sydney, New South Wales, Australia.

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BACKGROUND:   While it is now clear that paracetamol is ineffective for spinal pain, there is not consensus on the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) for this condition. We performed a systematic review with meta-analysis to determine the efficacy and safety of NSAIDs for spinal pain.

METHODS:   We searched MEDLINE, EMBASE, CINAHL, CENTRAL and LILACS for randomised controlled trials comparing the efficacy and safety of NSAIDs with placebo for spinal pain. Reviewers extracted data, assessed risk of bias and evaluated the quality of evidence using the Grade of Recommendations Assessment, Development and Evaluation approach. A between-group difference of 10 points (on a 0-100 scale) was used for pain and disability as the smallest worthwhile effect, as well as to calculate numbers needed to treat. Random-effects models were used to calculate mean differences or risk ratios with 95% CIs.

RESULTS:   We included 35 randomised placebo-controlled trials. NSAIDs reduced pain and disability, but provided clinically unimportant effects over placebo. Six participants (95% CI 4 to 10) needed to be treated with NSAIDs, rather than placebo, for one additional participant to achieve clinically important pain reduction. When looking at different types of spinal pain, outcomes or time points, in only 3 of the 14 analyses were the pooled treatment effects marginally above our threshold for clinical importance. NSAIDs increased the risk of gastrointestinal reactions by 2.5 times (95% CI 1.2 to 5.2), although the median duration of included trials was 7 days.

CONCLUSIONS:   NSAIDs are effective for spinal pain, but the magnitude of the difference in outcomes between the intervention and placebo groups is not clinically important. At present, there are no simple analgesics that provide clinically important effects for spinal pain over placebo. There is an urgent need to develop new drug therapies for this condition.

KEYWORDS:   Analgesics; Low Back Pain; NSAIDs

Commonly used non-steroidal anti-inflammatory drugs used to treat back pain provide little benefit and may make things worse according to new research from The George Institute for Global Health. The findings of the systematic review, published in the Annals of the Rheumatic Diseases, reveal only one in six patients treated with the pills, also known as NSAIDs, achieve any significant reduction in pain. The study is the latest work from The George Institute questioning the effectiveness of existing medicines for treating back pain. Earlier research has already demonstrated paracetamol does not speed recovery or reduce pain for acute low back pain, and opioids provide minimal benefit over placebo. Lead author Associate Professor Manuela Ferreira says the study highlights an urgent need to develop new therapies to treat back pain which affects 80 per cent of Australians during their lifetime. A/Prof Ferreira, Senior Research Fellow at The George Institute and at the Institute of Bone and Joint Research, said: “Back pain is the leading cause of disability worldwide and is commonly managed by prescribing medicines such as anti-inflammatories. But our results show anti-inflammatory drugs actually only provide very limited short term pain relief. They do reduce the level of pain, but only very slightly, and arguably not of any clinical significance.” A/Prof Ferreira added: “When you factor in the side effects which are very common, it becomes clear that these drugs are not the answer to providing pain relief to the many millions of Australians who suffer from this debilitating condition every year.” The team at The George Institute, which examined 35 trials involving more than 6,000 people, also found patients taking anti-inflammatories were 2.5 times more likely to suffer from gastro-intestinal problems such as stomach ulcers and bleeding. Research Fellow Gustavo Machado, of The George Institute and the School of Medicine at the University of Sydney, said: “Millions of Australians are taking drugs that not only don’t work very well, they’re causing harm. We need treatments that will actually provide substantial relief of these people’s symptoms. “Better still we need a stronger focus on preventing back pain in the first place. We know that education and exercise programs can substantially reduce the risk of developing low back pain.” Most clinical guidelines currently recommend NSAIDs as the second line analgesics after paracetamol, with opioids coming at third choice.

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From the FULL TEXT Article:

INTRODUCTION

Spinal pain (neck or low back pain) is the leading cause of disability worldwide, [1, 2] and commonly managed in general practice by prescription of medicines. [3, 4] Clinical guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) as a second-line analgesic after paracetamol, with third choice being opioids. [5] However, recent meta-analyses have shown that paracetamol is ineffective, [6, 7] and opioids appear only to offer small benefits for this condition. [8] Thus, although the use of NSAIDs has fallen in the past decade, [9] their use could rapidly rise, given the lack of efficacy of paracetamol and increased awareness of risks associated with opioid use. [10, 11]

There is still not consensus on the efficacy of NSAIDs for spinal pain. The most recent meta-analysis excluded participants with acute low back pain or neck pain, [12] and to date no reviews have investigated NSAID injections or topical formulations in this population. Furthermore, previous meta-analyses have reported standardised mean differences (MD) as effect sizes, which are nonintuitive and difficult to interpret; [13] thus better measures of treatment effects, such as numbers needed to treat (NNT), are likely to enhance interpretability for the clinician. There is also concern about the cardiovascular safety of cyclo-oxygenase-2 (COX-2) inhibitors, while serious gastrointestinal adverse reactions are more closely linked to nonselective NSAIDs, [14] although all NSAIDs have been associated with cardiovascular and gastrointestinal risks. [15] Thus, there is far greater need to understand the efficacy and safety of this medicine for spinal pain.

Therefore, the aim of this systematic review was to investigate the efficacy and safety of NSAIDs compared with placebo in patients with spinal pain, with or without radicular pain. We also aimed to evaluate whether trial characteristics or methods are associated with estimates of treatment effect.

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DISCUSSION

Our review of 35 randomised placebo-controlled trials demonstrates that NSAIDs are effective in reducing pain and disability in patients with spinal pain, although treatment effects above those of placebo are small and arguably not clinically important. For every six patients treated with NSAIDs, rather than placebo, only one additional patient would benefit considering a between-group difference of 10 points for clinical importance in the short-term. Furthermore, when looking at different spinal pain, outcomes or time points in only 3 of the 14 analyses were the pooled effects only marginally above our 10-point threshold for clinical relevance. NSAIDs were associated with higher number of patients reporting gastrointestinal adverse effects in the short-term follow-up (ie, <14 days). No data on safety at medium-term or long-term follow-ups were provided by included trials.

The strengths of our review include that it was prospectively registered and followed the PRISMA recommendations, including the use of GRADE to appraise the quality of the evidence. We were able to identify a significantly larger number of trials than past reviews, [12, 62–70] which have often limited their inclusion criteria to a specific language, population or type of NSAID. Including more studies (35 randomised placebocontrolled trials) enabled us to conduct a more thorough evaluation of the effects of NSAIDs for various forms of spinal pain, and to include a range of forms of drug administration. We have also provided valuable information on pooled treatment effects for specific populations, including neck pain, acute/chronic low back pain and sciatica. Furthermore, we have provided clinically interpretable estimates on a 0–100 scale, and compared our effect sizes with a predetermined smallest worthwhile effect of 10 points, which reflects the smallest effect of the intervention on outcomes compared with placebo that patients would consider meaningful or important.22 Given physicians often find the interpretation of effect sizes reported in meta-analysis challenging, [71] we have also presented our results on pain reduction as the NNT for a clinically significant effect of NSAIDs over placebo. Moreover, potential factors that could have influenced our treatment effects, such as risk of bias judegments, class of NSAIDs and route of administration, were investigated through meta-regression analyses. Although COX-2 inhibitors showed larger effects than non-selective NSAIDs on pain reduction, the size of the difference is of arguable clinical relevance. COX-2 inhibitors trials included in our review were fairly recent (all were conducted after 2003) and substantially larger (mean sample size of 280). They were also more likely to report safety outcomes than older trials.

Our review has some limitations. First, we did not find any trials investigating the efficacy and safety of celecoxib versus placebo, a commonly used COX-2 selective drug. Second, some of the trials included in our meta-analysis used drugs that are discontinued or are no longer commercialised in major markets (eg, rofecoxib and valdecoxib), but our meta-regression revealed that this was not a factor that influenced our estimates; discontinued drugs (MD –8.9, 95% CI –10.8 to –7.0) had similar effects as currently marketed NSAIDs (MD –9.3, 95% CI –12.1 to –6.5). Third, there is no evidence on the long-term effects and safety of NSAIDs, as the median follow-up time was 1 week in included trials, with some treatment schedules lasting <1 day. Fourth, our overall pooled estimates resulted in substantial between-trial heterogeneity (I2 ranged from 59% to 87%), which, however, was found considerably reduced in the stratified meta-analyses according to the type of spinal pain (ie, neck pain, acute/ chronic low back pain, or sciatica). Finally, another limitation of our study is that there were very few trials on neck pain, and none on whiplash.

We provide sound evidence that NSAIDs are effective, but do not offer clinically important benefits for spinal pain above those attributable to placebo, given overall pooled estimated differences were <10 points. This is crucially important because we now know paracetamol is ineffective, [6, 7] and opioids only offer small benefits for spinal pain. [8] Thus, given our results and evidence from these recent high-quality meta-analyses, it seems that there are no analgesics with clinically important effects over placebo for spinal pain. This is a problem, as current guidelines for spinal pain endorse these three medicines. [5] For instance, the National Institute for Health and Care Excellence (NICE) guidance on low back pain and sciatica now recommends NSAIDs as first analgesic option and suggests the use of opioids with paracetamol to treat spinal pain. In our review, even when the effects of NSAIDs were analysed for different spinal pain strata (ie, neck pain, acute/chronic low back pain or sciatica), only 3 of the 14 analyses revealed effects that were marginally above our threshold for clinical relevance. The effects observed in trials including participants with neck pain were unexpected, particularly because these trials investigated topical NSAIDs only. Our safety analysis revealed that NSAIDs increased the risk of gastrointestinal adverse effects by 2.5 times compared with placebo, although safety data were limited to trials that used non-selective NSAIDs. However, it is established that all NSAIDs, including COX-2 inhibitors, have been linked to gastrointestinal harms. [15, 72] Our safety results should be interpreted with caution given the short duration of exposure to NSAIDs in included trials.

In summary, compared with placebo, NSAIDs do not provide a clinically important effect on spinal pain, and six patients must be treated with NSAIDs for one patient to achieve a clinically important benefit in the short-term. When this result is taken together with those from recent reviews on paracetamol and opioids, it is now clear that the three most widely used, and guideline-recommended medicines for spinal pain do not provide clinically important effects over placebo. There is an urgent need to develop new analgesics for spinal pain.

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References:

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