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. 2019 May 27;5(5):CD005522.
doi: 10.1002/14651858.CD005522.pub3.

Tramadol for osteoarthritis

Karine Toupin April  1 , Jacinthe Bisaillon, Vivian Welch, Lara J Maxwell, Peter Jüni, Anne Ws Rutjes, M Elaine Husni, Jennifer Vincent, Tania El Hindi, George A Wells, Peter Tugwell
Affiliations

Tramadol for osteoarthritis

Karine Toupin April et al. Cochrane Database Syst Rev. .

Abstract

Background: Tramadol is often prescribed to treat pain and is associated physical disability in osteoarthritis (OA). Due to the pharmacologic mechanism of tramadol, it may lead to fewer associated adverse effects (i.e. gastrointestinal bleeding or renal problems) compared to non-steroidal anti-inflammatory drugs (NSAIDs). This is an update of a Cochrane Review originally published in 2006.

Objectives: To determine the benefits and harms of oral tramadol or tramadol combined with acetaminophen or NSAIDs in people with osteoarthritis.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases, as well as the US National Institutes of Health and World Health Organization trial registries up to February 2018. We searched the LILACS database up to August 2015.

Selection criteria: We included randomized controlled trials (RCTs) that evaluated the effect of tramadol, or tramadol in combination with acetaminophen (paracetamol) or NSAIDs versus placebo or any comparator in people with osteoarthritis.

Data collection and analysis: We used standard methodologic procedures expected by Cochrane.

Main results: We included 22 RCTs (11 more than the previous review) of which 21 RCTs were included in meta-analyses for 3871 participants randomized to tramadol alone or tramadol in combination with another analgesic and 2625 participants randomized to placebo or active control. Seventeen studies evaluated tramadol alone and five evaluated tramadol plus acetaminophen. Thirteen studies used placebo controls and eleven studies used active controls (two trials had both placebo and active arms). The dose of tramadol ranged from 37.5 mg to 400 mg daily; all doses were pooled. Most trials were multicenter with a mean duration of two months. Participants were predominantly women with hip or knee osteoarthritis, with a mean age of 63 years and moderate to severe pain. There was a high risk of selection bias as only four trials reported both adequate sequence generation and allocation concealment. There was a low risk for performance bias as most studies blinded participants. There was a high risk of attrition bias as 10/22 trials showed incomplete outcome data. Most of the trials were funded by the pharmaceutical industry.Moderate quality evidence (downgraded due to risk of bias) indicated that tramadol alone and in combination with acetaminophen had no important benefit on pain reduction compared to placebo control (tramadol alone: 4% absolute improvement, 95% confidence interval (CI) 3% to 5%; 8 studies, 3972 participants; tramadol in combination with acetaminophen: 4% absolute improvement, 95% CI 2% to 6%; 2 studies, 614 participants).Fifteen out of 100 people in the tramadol group improved by 20% (which corresponded to a clinically important difference in pain) compared to 10/100 in the placebo group (5% absolute improvement). Twelve out of 100 people improved by 20% in the tramadol in combination with acetaminophen group compared to 7/100 in the placebo group (5% absolute improvement).Moderate quality evidence (downgraded due to risk of bias) indicated that tramadol alone and in combination with acetaminophen led to no important benefit in physical function compared to placebo (tramadol alone: 4% absolute improvement, 95% CI 2% to 6%; 5 studies, 2550 participants; tramadol in combination with acetaminophen: 4% absolute improvement, 95% CI 2% to 7%; 2 studies, 614 participants).Twenty-one out of 100 people in the tramadol group improved by 20% (which corresponded to a clinically important difference in physical function) compared to 16/100 in the placebo group (5% absolute improvement). Fifteen out of 100 people improved by 20% in the tramadol in combination with acetaminophen group compared to 10/100 in the placebo group (5% absolute improvement).Moderate quality evidence (downgraded due to risk of bias) indicated that, compared to placebo, there was a greater risk of developing adverse events with tramadol alone (risk ratio (RR) 1.34, 95% CI 1.24 to 1.46; 4 studies, 2039 participants) and tramadol in combination with acetaminophen compared to placebo (RR 1.91, 95% CI 1.32 to 2.76; 1 study, 308 participants). This corresponded to a 17% increase (95% CI 12% to 23%) with tramadol alone and 22% increase (95% CI 8% to 41%) with tramadol in combination with acetaminophen.The three most frequent adverse events were nausea, dizziness and tiredness. Moderate quality evidence (downgraded due to risk of bias) indicated that there was a greater risk of withdrawing from the study because of adverse events with tramadol alone compared to placebo (RR 2.64, 95% CI 2.17 to 3.20; 9 studies, 4533 participants), which corresponded to a 12% increase (95% CI 9% to 16%).Low quality evidence (downgraded due to risk of bias and inconsistency) indicated that there was a greater risk of withdrawing from the study because of adverse events with tramadol in combination with acetaminophen compared to placebo (RR 2.78, 95% CI 1.50 to 5.16; 2 studies, 614 participants), which corresponded to a 8% absolute improvement (95% CI 2% to 19%).Low quality evidence (downgraded due to risk of bias and imprecision) indicated that there was a greater risk of developing serious adverse events with tramadol alone compared to placebo (110/2459 participants with tramadol compared to 22/1153 participants with placebo; RR 1.78, 95% CI 1.11 to 2.84; 7 studies, 3612 participants), which corresponded to a 1% increase (95% CI 0% to 4%). There were no serious adverse events reported in one small study (15 participants) of tramadol with acetaminophen compared to placebo.

Authors' conclusions: Moderate quality evidence indicates that compared to placebo, tramadol alone or in combination with acetaminophen probably has no important benefit on mean pain or function in people with osteoarthritis, although slightly more people in the tramadol group report an important improvement (defined as 20% or more). Moderate quality evidence shows that adverse events probably cause substantially more participants to stop taking tramadol. The increase in serious adverse events with tramadol is less certain, due to the small number of events.

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Conflict of interest statement

KTA: none.

JB: none.

VW: none.

LM: none.

PJ: Peter Jüni has received research grants from Astra Zeneca, Biotronik, Biosensors International, Eli Lilly and The Medicines Company, that has been paid to the institution. Peter serves as unpaid member of the steering group of trials funded by Astra Zeneca, Biotronik, Biosensors, St. Jude Medical and The Medicines Company.

AWSR: none.

EH: none.

JV: none.

TEH: none.

GW: none.

PT: Travel and accommodation for OMERACT meetings ‐ a registered non‐profit independent medical research organization, OMERACT, whose goal is to improve and advance the health outcomes for patients suffering from musculoskeletal conditions. OMERACT receives unrestriced educational grants from the American College of Rheumatology, European League of Rheumatology and several pharmaceutical companies listed below which is used to support fellows, international patient groups and support a major international bi‐annual conference which results in many peer reviewed publications; Amgen, Astra Zeneca, Bristol Myers Squibb, Celgene, EliLilly, Genentech/Roche, Genzyme/Sanofi, Horizon Pharma Inc, Merck, Novartis, Pfizer, PPD, Quintiles, Regeneron, Savient, Takeda Pharmaceutical, UCB Group, Vertex, Forest, Bioiberica Independent Committee Member for clinical trial Data Safety Monitoring Boards for FDA approved trials being conducted by UCB Biopharma GmbH & SPRL, Parexel International, and Prahealth Sciences. Independent medical consultation professional services for CHEOR Solutions (Canada) Ltd., Innovative Science Solutions LLC. An advisory committee member of the Canadian Reformulary Group Inc., a company that reviews the evidence for health insurance companies employer drug plans.

Figures

1
1
Study flow diagram. OA: osteoarthritis; RCT: randomized controlled trial.
2
2
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.
4
4
Funnel plot of comparison: 1 Tramadol versus placebo, outcome: 1.1 Pain.
See this image and copyright information in PMC

Update of

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