Research Review By Dr. Brynne Stainsby©


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Date Posted:

November 2022

Study Title:

Similar effects of exercise therapy, nonsteroidal anti-inflammatory drugs, and opioids for knee osteoarthritis pain: A systematic review with network meta-analysis


Thorlund JB, Simic M, Pihl K et al.

Author's Affiliations:

Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark; Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense, Denmark; Discipline of Physiotherapy, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Rehabilitation; Department of General Practice, Erasmus University Medical Center, Rotterdam, the Netherlands

Publication Information:

Journal of Orthopaedic & Sports Physical Therapy 2022; 52(4): 207-216.

Background Information:

Opioids are commonly used in the management of chronic musculoskeletal (MSK) conditions (1), however, the appropriateness of treating conditions such as osteoarthritis (OA) with opioids is widely debated due to the risk of adverse events (AE) and addiction (2-4). The most recent guidelines from the Osteoarthritis Research Society International made a strong recommendation against any opioid use for knee OA, and others suggest they only be used after all other treatment options are exhausted or contraindicated (5-7).

Two other common treatment options for knee OA are exercise therapy and nonsteroidal anti-inflammatory drugs (NSAIDs), however, comparing effects of these interventions is difficult due to a lack of direct statistical comparisons in high quality studies. To account for this, the authors conducted a network meta-analysis (NMA) to provide more valid estimates of the comparative effectiveness of opioids, NSAIDs and exercise therapy for knee OA pain.

Note from the RRS Team: In a network meta-analysis (NMA), researchers can incorporate data from RCTs that do not necessarily have the same comparator group in a virtual ‘network’ of studies. This allows the authors to include studies that tested two or more kinds of treatment, with or without a control and allows for direct comparison of treatment and indirect comparisons with the network. Interestingly, this approach allows researchers to rank interventions as comparably more or less effective, which can be very helpful for clinicians and policy makers!

Pertinent Results:

Results of Systematic Review:
  • The search yielded 7719 independent references (after excluding duplicates). Fifty-eight were considered for full-text review and 13 trials including 1398 patients met the inclusion criteria (8-20).
  • Of the included trials, 11 compared NSAIDs to opioids (8-12, 14-19) and two compared NSAIDs to exercise therapy (13, 20). No trials were identified directly comparing exercise therapy and opioids.
  • Five of the trials comparing NSAIDs to opioids were crossover trials, meaning that 181 of the 1398 patients were exposed to both treatments and acted as their own control (10, 12, 14, 18, 19).
  • The most common pain outcome was Western Ontario and McMaster Universities Osteoarthritis Index – pain (WOMAC) (n = 5), followed by VAS pain (n = 4) and numeric rating scale pain (n = 2).
  • Average patient age ranged from 53 to 69 years, and average baseline pain ranged from 34 to 74 mm on a 0 to 100 mm VAS. Follow-up ranged from 2 days to 52 weeks.
  • The NSAIDs provided were diclofenac (n = 3) (9, 18, 20); naproxen (n = 3) (14, 16, 19); ibuprofen (n = 1) (12); celecoxib (n = 2) (10, 11); etoricoxib (n = 1) (8) and a mix of NSAIDs (n = 3) (13, 15, 17) and were delivered orally and/or topically. The opioids provided were tramadol (n = 7) (9, 11, 14, 16-19); codeine (n = 1) (12); oxycodone (n = 1) (10); tapentadol (n = 1) (8) and a mix of opioids (n = 1) (15); which were predominantly delivered orally, with the exception of one trial that used oral and transdermal delivery (15).
  • In the trials including exercise therapy, one trial delivered a quadriceps home exercise program (13) and the other delivered quadriceps and hamstrings isokinetic exercises using a seated dynamometer (20).
  • The populations were similar with respect to average age, sex distribution, knee OA severity and baseline pain, however, it should be noted that knee OA severity and baseline pain were only reported in a limited number of trials.
  • Adverse events (AEs) were not consistently reported in the included trials, thus precluding a meaningful summary. However, in trials comparing NSAIDs with opioids, a larger proportion of patients who received opioids reported AEs, and a greater number of patients withdrew from studies for this reason.
Results of the Network Meta-Analysis:
  • All treatments showed small to moderate treatment effects (SMD: 0.27-0.45) compared to placebo/control.
  • The treatment effect of NSAIDS was similar to that of opioids (corresponding to 0.3 mm VAS pain scale change) with a low confidence in the estimate.
  • Exercise showed a larger effect compared with NSAIDs (corresponding to 9.1 mm VAS pain scale change) with very low confidence in the estimates due to study limitations, inconsistency and indirectness.
  • Exercise had the highest probability of ranking as the “best” intervention in the NMA, followed by NSAIDs and opioids, and control intervention ranked “worst” (with low confidence in the ranking).
  • In the 11 trials with a direct comparison between opioids and NSAIDs, there was no difference found in the treatment effect on knee OA pain (SMD: 0.03, 95% CI -0.13 to 0.18).
  • In the two trials with a direct comparison between NSAIDs and exercise therapy, there was a large SMD in favour of exercise therapy, however, the confidence intervals were wide and crossed the line of no effect (SMD: 0.80, 95% CI -0.19 to 1.79).
Risk of Bias:
  • One trial had a low risk of bias in all domains (21).
  • Two were considered low on all domains except “other bias”, as these trials were sponsored by pharmaceutical companies or had authors who were employed by pharmaceutical companies (10, 19).
  • Many trials were scored as having high risk of bias or unclear risk of bias for “blinding of participants and personnel” (10, 13-15, 17, 20); “blinding of outcome assessment” (8, 13-15, 17, 20); “incomplete outcome data” (8, 9, 11, 12, 17, 20) and “selective outcome reporting (8, 9, 11-14, 17, 18, 20).

Clinical Application & Conclusions:

Given the general paucity of high-quality evidence, the authors were limited in their ability to draw strong and clinically meaningful conclusions from their review. They caution that estimates should be interpreted carefully and highlight the need for future trials comparing exercise therapy with NSAIDs and opioids for the treatment of knee OA.

With that said, based on very limited data from two studies with high risk of bias, exercise therapy appeared to be superior for pain relief when compared to NSAIDs. It is also noted that exercise was ranked first (again, with low confidence in this estimate based on the available studies), providing encouragement for clinicians when considering treatment options for patients with knee OA. Finally, clinicians should be reassured that exercise therapy for knee OA has minimal or no risk of adverse events (especially compared to opioids and even NSAIDs) - it should be considered as a first-line treatment intervention for all patients with knee OA (7, 22, 23).

Study Methods:

The protocol was preregistered in the PROSPERO database. The study was performed according to the guidelines for NMA using Stata (24). Study findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension statement for reporting systematic reviews incorporating NMA (25). A systematic search strategy was developed in MEDLINE and adjusted for other databases (EMBASE and the Cochrane Central Register of Controlled Trials). There were no restrictions for year of publication or language. Reference lists of included trials and reviews published within the last five years were also reviewed.

Eligibility Criteria:
Randomized controlled trials (RCTs) comparing exercise therapy with NSAIDs, exercise therapy with opioids, or NSAIDs with opioids for knee OA pain were included for review. Trials including mixed populations of both knee and hip OA were included. Trials with patients who had knee replacements or trials with patients who had conditions other than knee OA (unless separate data for knee OA were available) were excluded. Trials that involved combined interventions in which exercise therapy constituted less than 50% of the intervention were also excluded. Exercise therapy was defined as a “regimen or plan of physical activities designed and prescribed for a specific therapeutic goal (i.e. to reduce knee OA pain or to improve muscle function…”.

Two authors then independently appraised each study using the Cochrane Collaboration Risk of Bias Tool (26). Disagreements were resolved by consensus. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the overall quality of the evidence when ranking the treatments from the NMA (27). In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA) guidelines (1), NMA was performed using a five-step approach for statistical analysis and comparative effectiveness ranking.

As a low number of trials with direct comparison between treatments and no trials investigating exercise therapy compared to opioids were identified, an external anchor for the comparison in the NMA was created from trials comparing NSAIDs to placebo, opioids to placebo and exercise therapy to control interventions. The authors then used the same search (filtered for systematic reviews) to identify the most recent and relevant meta-analyses in Cochrane reviews. When no suitable Cochrane reviews were found, they extracted data from the most recent and relevant meta-analysis identified. A qualitative assessment of the clinical similarity of the treatment populations was performed based on mean age, sex distribution, OA severity and baseline pain.

Data Synthesis:
Two reviewers independently extracted relevant data. Data was extracted on outcomes (pain) for the longest follow-up assessment report included in the trial. For each intervention group, additional data relating to patient demographics, adverse events, withdrawals and the definitions of OA were also extracted. The effects from individual trials were expressed as the standardized mean difference (SMD) with a 95% confidence interval (CI). The estimate has a slight bias (especially in smaller studies), and a correction factor was applied to account for this. Results were pooled from individual trials with direct comparison of interventions and then frequentist NMA was performed based on the direct comparison to estimate the effect of the pairwise intervention (i.e., based on direct and indirect comparison). The final NMA was performed including the extracted trials comparing the three interventions to placebo/control intervention given the low number of trials with direct comparison between treatments and no trials investigating exercise therapy compared to opioids identified.

As SMD is often challenging to understand, the authors converted the estimated SMD in the final NMA into pain scores on a visual analog scale (VAS). They considered a change of at least 15 mm to be clinical important.

Study Strengths / Weaknesses:

  • A thorough and systematic search was conducted, not limited by publication date or language, or the type of intervention or comparators.
  • Independent screening of titles and abstracts, and full texts.
  • Assessment of risk of bias was performed with a validated set of criteria.
  • Two authors independently extracted the data from the included articles, and reviewers followed up with authors to access required information.
  • As SMD is often challenging to understand, the authors converted the estimated SMD in the final NMA into pain scores on a visual analog scale (VAS) to improve the clinical utility of their study.
  • Performing a NMA allowed the reviewers to directly compare and rank interventions as comparably more or less effective.
  • The primary limitation of this study relates more to the quality of the body of evidence than the methodology of the review itself. For example, the authors did not identify any trials that compared exercise therapy to opioids.
  • Although the authors used a validated tool to assess risk of bias, the overall low quality of evidence in all included studies mean the findings must be interpreted with caution. The authors did attempt to address this limitation by applying the GRADE approach.
  • Many of the included studies did not report on safety or adverse events, limiting the ability of the authors to draw a meaningful conclusion in this regard.

Additional References:

  1. Han B, Compton WM, Blanco C, et al. Prescription opioid use, misuse, and use disorders in U.S. adults: 2015 National Survey on Drug Use and Health. Ann Intern Med 2017; 167: 293-301.
  2. Cheatle MD. Prescription opioid misuse, abuse, morbidity, and mortality: balancing effective pain management and safety. Pain Med 2015; 16: S3-S8.
  3. Furlan AD, Sandoval JA, Mailis-Gagnon A, et al. Opioids for chronic noncancer pain: a metaanalysis of effectiveness and side effects. CMAJ 2006; 174: 1589-1594.
  4. Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of opioids for nonmalignant pain in older adults. Arch Intern Med 2010; 170: 1979-1986.
  5. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr Cartil 2019; 27: 1578-1589.
  6. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol 2020; 72: 220-233.
  7. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr Cartil 2014; 22: 363-388.
  8. Banerjee M, Mondal S, Sarkar R, et al. Comparative study of efficacy and safety of tapentadol versus etoricoxib in mild to moderate grades of chronic osteorthritis of knee. Ind J Rheumatol 2016; 11: 21-25.
  9. Beaulieu AD, Peloso PM, Haraoui B, et al. Once daily, controlled-release tramadol and sustained release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial. Pain Res Manag 2008; 13: 103-110.
  10. Boyer KA, Angst MS, Asay J, et al. Sensitivity of gait parameters to the effects of anti-inflammatory and opioid treatments in knee osteoarthritis patients. J Orthop Res 2012; 30: 1118-1124.
  11. DeLemos BP, Xiang J, Benson C, et al. Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial. Am J Ther 2011; 18: 216-226.
  12. Doak W, Hosie J, Hossain M, et al. A novel combination of iboprofen and codeine phosphate in the treatment of osteoarthritis: a double-blind placebo controlled study. J Drug Dev 1992; 4: 179-187.
  13. Doi T, Akai M, Fujino K, et al. Effect of home exercise of quadriceps on knee osteoarthritis compared with nonsteroidal anti-inflammatory drugs: a randomized controlled trial. Am J Phys Med Rehabil 2008; 87: 258-269.
  14. Kim SY, Ryou JW, Hur J. Comparison of effectiveness and safety of tramadol/acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of knee osteoarthritis in elderly patients. J Rheum Dis (Korean) 2012; 19: 25-29.
  15. Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA 2018; 319: 872-882.
  16. Ouncharoen T. Tramadol versus naproxen for pain relief in knee osteoarthritis: a pragmatic randomized controlled trial. Clin Academia 2018; 42: 53-64.
  17. Park KS, Choi JJ, Kim WU, et al. The efficacy of tramadol/acetaminophen combination tablets (Ultracet.) as add-on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID). Clin Rheumatol 2012; 31: 317-323.
  18. Pavelka K, Peliskova Z, Stehlikova H, et al. Intraindividual differences in pain relief and functional improvement in osteoarthritis with diclofenac or tramadol. Clin Drug Investig 1998; 16: 421-429.
  19. Peeva E, Beals CR, Bolognese JA, et al. A walking model to assess the onset of analgesia in osteoarthritis knee pain. Osteoarthr Cartil 2010; 18: 646-653.
  20. Yavuz M, Ataoğlu S, Baki AE, et al. Compared effects and effectiveness in applications of isokinetic exercise, laser, and diclophenac iontophoresis in primary osteoarthritis of knee. Duzce Med J 2013; 15: 15-21.
  21. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539-1558.
  22. Niemeijer A, Lund H, Stafne SN, et al. Adverse events of exercise therapy in randomized controlled trials: a systematic review and metaanalysis. Br J Sports Med 2020; 54: 1073-1080.
  23. Quicke JG, Foster NE, Thomas MJ, et al. Is long-term physical activity safe for older adults with knee pain?: a systematic review. Osteoarthr Cartil 2015; 23: 1445-1456.
  24. Shim S, Yoon BH, Shin IS, Bae JM. Network metaanalysis: application and practice using Stata. Epidemiol Health 2017; 39: e2017047.
  25. Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network metaanalyses of health care interventions: checklist and explanations. Ann Intern Med 2015; 162: 777-784.
  26. Higgins JP, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). Oxford, UK: The Cochrane Collaboration; 2011.
  27. Salanti G, del Giovane C, Chaimani A, et al. Evaluating the quality of evidence from a network meta-analysis. PLoS One 2014; 9: e99682.

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