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Opioids Compared With Placebo or Other Treatments for Chronic Low Back Pain An Update of the Cochrane Review Luis Enrique Chaparro, MD,* Andrea D. Furlan, MD, PhD,t Amol Deshpande, M D , i Angela Mailis-Gagnon, MD, MSc, FRCPC,§ Steven Atlas, MD,1 and Dennis C. Turk, PhD|l
Study Design. Systematic review and meta-analysis. Objective. To assess the efficacy of opioids in adults with chronic low back pain (CLBP). Summary of Background Data. Opioids for CLBP has increased dramatically. However, the benefits and risks remain unclear. Methods. We updated a 2007 Cochrane Review through October 2012 of randomized controlled trials from multiple databases. Use of noninjectable opioids in CLBP for at least 4 weeks was compared with placebo or other treatments; comparisons with different opioids were excluded. Outcomes included pain and function using standardized mean difference (SMD) or risk ratios with 95% confidence intervals (CIs), and absolute risk difference with 95% CI for adverse effects. Study quality was evaluated using Grading of Recommendations Assessment, Development, and Evaluation criteria. Results. Fifteen trials (5540 participants), including twelve new, met the criteria. Tramadol was better than placebo for pain (SMD, -0.55; 95% CI, -0.66 to -0.44) and function (SMD, -0.18; 95% CI, -0.29 to -0.07). Compared with placebo, transdermal buprenorphine decreased pain (SMD, -2.47; 95% CI, -2.69 to -2.25), but not function (SMD, -0.14; 95% CI, -0.53 to 0.25). Strong opioids (morphine, hydromorphone, oxycodone, oxymorphone. From the *Department of Anesthesiology, Hospital Pablo Tobon Uribe, Medellin, Colombia; tlnstitute for Work and Health, Toronto, Canada; ^Toronto Western Hospital, Comprehensive Rain Program, University Health Network, Toronto, Canada; §Department of Medicine, Toronto Western Hospital, Comprehensive Pain Program, Toronto, Canada; 1 Medical Practices Fvaluation Center, Massachusetts General Hospital, Boston, MA; and ||Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA. Acknowledgment date: November 14, 2013. Acceptance date: November 18,2013. The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication. No funds were received in support of this work. Relevant financial activities outside the submitted work: board membership, payment for lecture, travel/accommodations/meeting expenses, employment, royalties, consultancy, grants, payment for manuscript preparation, payment for development of educational presentations. Address correspondence and reprint requests to Luis Enrique Chaparro, MD, Department of Anesthesioiogy, Hospital ftiblo Tobon Uribe, Medellin, Colombia; E-mail: [email protected] DOI: 10.1097/BRS.0000000000000249 556
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and tapentadol), were better than placebo for pain (SMD, -0.43; 95% CI, -0.52 to -0.33) and function (SMD, -0.26; 95% Cl, -0.37 to -0.15). One trial demonstrated little difference with tramadol compared with celecoxib for pain relief. Two trials (272 participants) found no difference between opioids and antidepressants for pain or function. Reviewed trials had low to moderate quality, high drop-out rates, short duration, and limited interpretability of functional improvement. No serious adverse effects, risks (addiction or overdose), or complications (sleep apnea, opioid-induced hyperalgesia, hypogonadism) were reported. Conclusion. There is evidence of short-term efficacy (moderate for pain and small for function) of opioids to treat CLBP compared with placebo. The effectiveness and safety of long-term opioid therapy for treatment of CLBP remains unproven. Key words: analgesics, opioid/adverse effects, opioid/ therapeutic use, buprenorphine/therapeutic use, Cochrane Review, hydromorphone/therapeutic use, low back pain/drug therapy, metaanalysis, morphine/therapeutic use, oxycodone/therapeutic use, oxymorphone/therapeutic use, sciatica/drug therapy, systematic review, tramadol/therapeutic use. Level of Evidence: 1 Spine 2014;39:556-563
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ow back pain (LBP) is a major cause of pain, disability costs, and the largest cause of disability-adjusted years worldwide.''^ Almost one quarter of North Americans are estimated to have experienced an episode of LBP within the previous 3 months.^ Although 80% to 90% of people with chronic low back pain (CLBP) improve by 12 weeks,"* 6% to 1 1 % continue to report symptoms for more than 3 months.' Among individuals with CLBP, one-third continued to be symptomatic after 12 months.^ Fewer than 50% of individuals with CLBP who missed work for more than 12 weeks returned to work, and an absence of 2 years from employment was associated with little chance of ever returning to work.'^ Medications play an important role in the management of CLBP and generally fall into 4 broad categories: nonsteroidal anti-inflammatory drugs, antidepressants, muscle relaxants, and opioids. The use of opioids have increased markedly, but April 2014
CocHRANE COLLABORATION remains in the management of chronic non-cancer pain,^ and CLBP in particular.* Our primary objective is to update a previous Cochrane Review'' to determine whether opioids are effective in improving pain, function, or both, in individuals with CLBP. Our secondary objectives are to determine the effectiveness of opioids in patients with CLBP with or without prior spinal surgery; with or without radicular symptoms; and specifically the effectiveness of tramadol, or transdermal buprenorphine, or strong opioids.
MATERIALS AND METHODS We included published randomized controlled trials with a blinded assessment of outcomes that compared any opioid to placebo or any other drug with analgesic properties for a period of 1 month or longer in an outpatient setting. We had no restriction on the language of publication. Trials included participants aged 18 years or older, who had persistent low back pain for at least 12 weeks, with or without radiating symptoms to the legs or prior low back surgery. LBP was defined as pain occurring below the lower ribs and above the gluteal folds. We excluded trials involving patients with cancer, infections, infiammatory arthritic conditions, compression fractures, and trials where less than 50% of participants had CLBP, or study authors failed to report cohorts separately. We considered trials with opioids administered by oral, transdermal, mucosal (nasal or rectal), or intramuscular routes, either alone or in combination with other interventions, such as: pharmacological therapy (e.g., anti-infiammatory drugs, antidepressants, and sedatives), physical modalities {e.g., transcutaneous electrical nerve stimulation), exercise, or alternative pain management techniques {e.g., acupuncture). We excluded trials that examined opioids administered by intravenous route, including implantable pumps as this has been discussed elsewhere.'" We considered the following comparator groups: (1) placebo, (2) no treatment, (3) nonpharmacological treatments, (4) other pharmacological agents, and (5) opioids in combination with other pharmacological or nonpharmacological treatments compared with other pharmacological or nonpharmacological treatments, either alone or in combination. We excluded trials where comparisons were made between opioids.
Opioids for Chronic Low Back Pain • Chaparro et al
Digital Content available at http://links.lvirw.com/BRS/A860), and was adapted to search the other databases (see Supplemental Digital Content Appendix 2, available at http://links. lww.com/BRS/A860). Additional studies were identified through examination of references from identified trials and systematic reviews.
Selection of Studies Two authors independently screened titles, abstracts, and key words of identified trials to determine if references met inclusion criteria. We obtained the full text of trials that either seemed to meet criteria or for which inclusion was uncertain. We screened these articles for inclusion and resolved any disagreements through discussion.
Data Extraction and Management Three authors independently extracted data, using the standardized forms developed by the Cochrane Back Review Group," on characteristics of participants, intervention group, clinical setting, method of recruitment, interventions, primary and secondary outcomes, opioid abuse or addiction, side effects, country of study, and sponsorship of study. If data were not available in a format for data extraction, we contacted the authors of the trial for clarification.
Data Synthesis We pooled data from trials comparing opioids to placebo using Review Manager (Revman 5.2) and performed metaanalyses (both fixed-effect and random-effects methods) on pain, function, and adverse effects (AEs). We reported the results of pain and function from the pooled data as standardized mean difference (SMD) with a 95% confidence interval (CI) and AEs using absolute risk differences with a 95% CI. We used the approach'^ to categorize the quality of evidence as follows: high (further research is very unlikely to change the confidence in the estimate of effect); moderate (further research is likely to have important impact); low (further research very likely to have an important impact); or very low (any estimate of effect very uncertain). We graded trials on 5 specific domains: (1) risk of bias, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias.
Primary Outcomes
Risk of Bias
Trials must have reported on at least 1 of 4 primary outcome measures: pain, function, global improvement, or proportion of patients reporting 30% or 50% pain relief. We grouped outcome measures according to the timing of postrandomization follow-up: very short term (3 but < 6 mo), and long term (>6 mo).
Search Methods for Identification of Studies
We defined high-quality studies as fulfilling 6 or more of the 12 internal validity criteria and with no major methodological flaws (see Supplemental Digital Content Appendix 3, available at http://links.lww.com/BRS/A860). When trials were judged as "low risk of bias" for all 5 categories, we did not downgrade the evidence. We downgraded the evidence by 1 point when fewer than 3 categories were judged "high or unclear. " We downgraded the evidence by 2 points when 4 or more categories were judged "high or unclear."
We searched: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials 2012, Issue 10, PsycINFO, and CINAHL for relevant trials up to October 2012. The search strategy for MEDLINE is presented in Appendix 1 (see Supplemental
We downgraded the quality of evidence by 1 point when heterogeneity was large {P> 80%), and by 2 points when the
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CocHRANE COLLABORATION heterogeneity was large and there was inconsistency arising from populations, interventions, or outcomes.
Opioids for Chronic Low Back Pain • Chaparro et al
Records included from the original review: 4
Indirectness We assessed whether the question being addressed in this systematic review was different from the available evidence regarding the population, intervention, comparator, or an outcome. Imprecision Results were imprecise when trials included relatively few patients and few events and thus had wide CIs around the estimate of the effect. Publication Bias We downgraded the quality of the evidence by one point when the funnel plot suggested publication bias. We prepared the summary of findings tables following published guidelines from the Cochrane Collaboration.'^ We used GRADEprofiler 3.6 to prepare the Grading of Recommendations Assessment, Development, and Evaluation tables and Summary of Findings Tables. RESULTS We identified 2201 references, obtained full-text articles for 91 studies with 12 RCTs meeting the inclusion criteria. In addition, 3 of the 4 trials from the original review were included and the fourth was excluded^^ because it was not bhnded. In total, we included 15 trials (5540 participants) in this review (Figure 1).
Included Studies Six trials evaluated either tramadol alone'''"'^ or the combination tramadol/acetaminophen'**'' 1 tapentadol,^" 2 morphine,^''^-^ 2 oxymorphone,^^'^"* 2 transdermal buprenorphine,^^'^^ 2 oxycodone^^ or hydromorphone.^* All trials were placebo-controlled, except for one that reported 2 trials with identical methodology and used celecoxib in the control arm.''' Thirteen trials were conducted in the United 1 in Canada,^^ and 1 in Germany.»*^
Description of Studies Tramadol Five RCTs, including 1378 participants, examined the use of tramadol compared with placebo.'^"^' One study used tramadol as the active control arm and evaluated the efficacy of flupirtine (a centrally acting, nonopioid agent).^* All trials excluded patients with pain other than in the low back and with a history of substance abuse. In 2 RCTs, tramadol was combined with acetaminophen (paracetamol).**'" The average dose of tramadol was approximately 150'"''' to 300 mg/day.'^ The included trials did not allow initiation of other treatments during the follow-up periods, although 2 trials permitted continuation of physiotherapy started prior to inclusion in the trial.'^''^ None of the trials documented 558
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Records identified through database searching (January 2006 to October 16 2012): 2201
No of records after duplicates removed: 2039
No of records screened: 2039
Nooffuil-text articles assesseri for eligib Ity: 91
No.of records excluded: 1948
No. of full-text articles excluded: 76
No of studies included in quantitative analysis: 15 Figure 1. Study flow diagram.
the number of people receiving concurrent treatments or the types of concurrent treatment. Buprenorphine Two RCTs compared transdermal buprenorphine with placebo.^^'^* Gordon et aF^ used a crossover design, and each period included a 4-week follow-up. Steiner et aP'' used a 15-week enrichment design including 3 weeks of open-label titration followed by 12-week randomized and double-blind phase. Gordon et al used buprenorphine patches of 10 or 20 meg/hour, up to a maximum dose of 40 meg/hour. Steiner et al titrated the dose of buprenorphine from 5 meg/hour to 20 meg/hour during the run-in period and maintained a maximum dose of 20 meg/hour during the double-blind phase. Gordon et al allowed participants to use rescue analgesic with acetaminophen and to use nonopioid analgesics (antidepressants or anticonvulsants). Steiner et al allowed participants to use acetaminophen plus ibuprofen and oxycodone immediate release during the first 6 weeks of the double-blind phase.
Strong Opioids There were 7 RCTs in this category: Buynak et aF° used tapentadol; 2 used morphine^''^^; 2 evaluated oxymorphone"'-"*; April 2014
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£ o 20%). Although the reasons were clearly documented, the implications on final outcomes could be significant. Substantial dropouts reduce the power of the study, compromising the ability to detect a significant difference and interpretation of the study outcomes. In addition, several studies failed to perform a proper intention-to-treat analysis. The method of handling absent data for patients lost to follow-up was documented through the use of last observation carried forward. This method has been criticized given the potential overestimation of the effect.^"
CONCLUSIONS Implications for Practice There is evidence that the use of tramadol (a weak atypical opioid) or strong opioids results in improved pain and moderate changes in function in the short term in people with CLBP when compared with placebo. However, the general applicability of this treatment to the clinical setting is questionable. Several factors, including the strict inclusion criteria of the original studies, high drop-out rates, and the poor description of the study population, concurrent treatments, work status, and compensation, limit the reported results. Notably, a number of important outcomes that capture patient function were absent (such as return-to-work outcome). Finally, there is strong evidence that nausea is more common in patients with CLBP being treated with opioids when compared with placebo. Implications for Research This review highlights the need for high-quality RCTs for (1) the "long-term benefits" and risks of opioid therapy for CLBP; (2) inclusion of different subgroups of CLBP {e.g., failed back surgery syndrome, CLBP with radicular symptoms); (3) opioid effectiveness relative to other conventional physical and www.spinejournaLcom
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medical treatments; (4) subgroups of patients who are most likely to respond to long-term opioid therapy; and (5) the predictors of opioid side effects, abuse, and misuse among patients with CLBP.
Key Points •
^
An updated systematic review assessed the efficacy of opioids for CLBP in adults.
D Fifteen randomized trials were included (N: 5540 participants); 12 (80%) had a low risk of bias. Q This review provides some support for the effectiveness of several opioids for CLBP relief and function in the short term. Side effects are more common with opioids but non-life threatening. Ü We have no information from randomized trials supporting the efficacy and safety of opioids used for more than 4 months. Ü The literature does not support that opioids are more effective than other groups of analgesics for LBP such as anti-inflammatory drugs or antidepressants.
Acknowledgments This review is adapted from the Cochrane Review: Chaparro LE, Eurlan AD, Deshpande A, et al. Opioids compared to placebo or other treatments for chronic low back pain. Cochrane Database Syst Rev 2013;8:CD004959. doi: 10.1002/14651858.CD004959.pub4. PMID: 23983011. Copyright Cochrane Library, reproduced with permission. Supplemental digital content is available for this article. Direct URL citations appearing in the printed text are provided in the HTML and PDE version of this article on the journal's web site (www.spinejournal.com). References 1. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lawcei 2012;380:2163-96. 2. Volinn E, Fargo JD, Fine PG. Opioid therapy for nonspecific low back pain and the outcome of chronic work loss. Pain 2009;142:194-201. 3. Deyo RA, Mirza SK, Martin BL Back pain prevalence and visit rates: estimates from US National Surveys, 2002. Spine (Phila Pa Î976; 2006;31:2724-7. 4. Shekelle PG, Markovicb M, Louie R. An epidemiologic study of episodes of back pain care. Spine (Phila Pa 1976) 1995;20: 1668-73. 5. Thomas F, Silman AJ, Croft PR, et al. Predicting who develops chronic low back pain in primary care: a prospective study. BM] 1999;318:1662-7. 6. Anonymous. Scientific approach to the assessment and management of activity-related spinal disorders. A monograph for clinicians. Report of the Quebec Task Force on Spinal Disorders. Spine (Phila Pa 1976) 1987;12:Sl-59. 7. Furlan AD, Reardon R, Weppler C. Opioids for chronic noncancer pain: a new Canadian practice guideline. CAlA/2010;182:923-30. 562
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8. Turk DC, Wilson HD, Cahana A. Treatment of chronic noncancer pain. Lafîcet 2011;377:2226-35. 9. Deshpande A, Furlan A, Mailis-Gagnon A, et al. Opioids for chronic low back pain. Cochrane Database Syst Rev 2007;CD004959. 10. Noble M, Tregear SJ, Treadwell JR, et al. Long-term opioid therapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety. / Pain Symptom Manage 2008;35:214-28. 11. Furlan AD, Pennick V, Bombardier C, et al. 2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine (Phila Pa 1976) 2009;34:1929-41. 12. Higgins JPT, Green SCochrane Collaboration. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken, NJ: Wiley-Blackwell; 2008. 13. Jamison RN, Raymond SA, Slawsby FA, et al. Opioid therapy for chronic noncancer back pain. A randomized prospective study. Spine (Phila Pa 1976) 1998;23:2591-600. 14. O'Donnell JB, Ekman EF, Spalding WM, et al. The effectiveness of a weak opioid medication versus a cyclo-oxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug in treatingflare-upof chronic low back pain: results from two randomized, double-blind, 6-week studies. / Int Med Res 2009;37:1789-802. 15. Schnitzer TJ, Gray WL, Paster RZ, et al. Efficacy of tramadol in treatment of chronic low back pain. / Rheumatol 2000;27: 772-8. 16. überall MA, Mueller-Schwefe GH, Terhaag B. Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo- and active-controlled parallelgroup phase IV study. Curr Med Res Opin 2012;28:1617-34. 17. Vorsanger GJ, Xiang J, Gana TJ, et al. Extended-release tramadoi (tramadol ER) in the treatment of chronic low back pain. / Opioid Manag 2008;4:87-97. 18. Peloso PM, Fortin L, Beaulieu A, et al. Analgesic efficacy and safety of tramadol/ acetaminophen combination tablets (Ultracet) in treatment of chronic low back pain: a multicenter, outpatient, randomized, double blind, placebo controlled trial. / Rheumatol 2004;31:2454-63. 19. Ruoff GE, Rosentbal N, Jordan D, et al. Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicenter, randomized, double-blind, placebo-controlled outpatient study. Clin Ther 2003;25:l 123-41. 20. Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother 2010;l 1:1787-804. 21. Chu LF, D'Arcy N, Brady C, et al. Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low back pain. Pain 2012;153:1583-92. 22. Khoromi S, Cui L, Nackers L, et al. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain 2007;130:66-75. 23. Hale ME, Ahdieh H, Ma T, et al. Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe chronic low back pain in opioid-experienced patients: a 12-week, randomized, double-blind, placebo-controlled study. / Pain 2007;8:175-84. 24. Katz N, Rauck R, Ahdieh H, et al. A 12-week, randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain. Curr Med Res Opin 2007;23:l 17-28. 25. Gordon A, Callaghan D, Spink D, et al. Buprenorphine transdermal system in adults with chronic low back pain: a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. Clin Ther 2010;32:844-60. 26. Steiner DJ, Sitar S, Wen W, et al. Efficacy and safety of the sevenday buprenorphine transdermal system in opioid-naive patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study. / Pain Symptom Manage 20n;42:903-17. April 2014
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27. Webster LR, Butera PG, Moran LV, et al. Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain, j Pain 2006;7:937-46. 28. Hale M, Khan A, Kutcb M, et al. Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain. Curr Med Res Opin 2010;26: 1505-18. 29. Furlan A, Chaparro LE, Irvin E, et al. A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain. Pain Res Manag 2011;16:337-51. 30. Kuijpers T, van Middelkoop M, Rubinstein SM, et al. A systematic review on the effectiveness of pharmacological interventions for chronic nonspecific low back pain. Eur Spine / 2011;20:40-50. 31. Martell BA, O'Connor PG, Kerns RD, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med 2007;146:l 16-27.
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32. Eurlan AD, Clarke J, Esmail R, et al. A critical review of reviews on the treatment of chronic low back pain. Spine (Phila Pa 1976) 2001;26:E155-62. 33. Jadad AR, Cook DJ, Browman GP. A guide to interpreting discordant systematic reviews. CMAJ 1997;156:1411-6. 34. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl} Meíí2003;349:1943-53. 35. Andersson GB. Epidemiological features of chronic low back pain. La«ceil999;354:581-5. 36. Greenough CG. Recovery from low back pain. 1-5 year follow-up of 287 injury-related cases. Acta Orthop Scand Suppl 1993;254:l-34. 37. Sander RA, Meyers JE. The relationship of disability to compensation status in railroad workers. Spine (Phila Pa 1976) 1986;ll:141-3. 38. Moore RA, Sträube S, Eccleston C, et al. Estimate at your peril: imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses. Pain 2012;153:265-8.
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SPINE Volume 39, Number 7, pp 556-563 ©2014, Lippincott Williams & Wilkins
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Opioids Compared With Placebo or Other Treatments for Chronic Low Back Pain An Update of the Cochrane Review Luis Enrique Chaparro, MD,* Andrea D. Furlan, MD, PhD,t Amol Deshpande, M D , i Angela Mailis-Gagnon, MD, MSc, FRCPC,§ Steven Atlas, MD,1 and Dennis C. Turk, PhD|l
Study Design. Systematic review and meta-analysis. Objective. To assess the efficacy of opioids in adults with chronic low back pain (CLBP). Summary of Background Data. Opioids for CLBP has increased dramatically. However, the benefits and risks remain unclear. Methods. We updated a 2007 Cochrane Review through October 2012 of randomized controlled trials from multiple databases. Use of noninjectable opioids in CLBP for at least 4 weeks was compared with placebo or other treatments; comparisons with different opioids were excluded. Outcomes included pain and function using standardized mean difference (SMD) or risk ratios with 95% confidence intervals (CIs), and absolute risk difference with 95% CI for adverse effects. Study quality was evaluated using Grading of Recommendations Assessment, Development, and Evaluation criteria. Results. Fifteen trials (5540 participants), including twelve new, met the criteria. Tramadol was better than placebo for pain (SMD, -0.55; 95% CI, -0.66 to -0.44) and function (SMD, -0.18; 95% CI, -0.29 to -0.07). Compared with placebo, transdermal buprenorphine decreased pain (SMD, -2.47; 95% CI, -2.69 to -2.25), but not function (SMD, -0.14; 95% CI, -0.53 to 0.25). Strong opioids (morphine, hydromorphone, oxycodone, oxymorphone. From the *Department of Anesthesiology, Hospital Pablo Tobon Uribe, Medellin, Colombia; tlnstitute for Work and Health, Toronto, Canada; ^Toronto Western Hospital, Comprehensive Rain Program, University Health Network, Toronto, Canada; §Department of Medicine, Toronto Western Hospital, Comprehensive Pain Program, Toronto, Canada; 1 Medical Practices Fvaluation Center, Massachusetts General Hospital, Boston, MA; and ||Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA. Acknowledgment date: November 14, 2013. Acceptance date: November 18,2013. The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication. No funds were received in support of this work. Relevant financial activities outside the submitted work: board membership, payment for lecture, travel/accommodations/meeting expenses, employment, royalties, consultancy, grants, payment for manuscript preparation, payment for development of educational presentations. Address correspondence and reprint requests to Luis Enrique Chaparro, MD, Department of Anesthesioiogy, Hospital ftiblo Tobon Uribe, Medellin, Colombia; E-mail: [email protected] DOI: 10.1097/BRS.0000000000000249 556
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and tapentadol), were better than placebo for pain (SMD, -0.43; 95% CI, -0.52 to -0.33) and function (SMD, -0.26; 95% Cl, -0.37 to -0.15). One trial demonstrated little difference with tramadol compared with celecoxib for pain relief. Two trials (272 participants) found no difference between opioids and antidepressants for pain or function. Reviewed trials had low to moderate quality, high drop-out rates, short duration, and limited interpretability of functional improvement. No serious adverse effects, risks (addiction or overdose), or complications (sleep apnea, opioid-induced hyperalgesia, hypogonadism) were reported. Conclusion. There is evidence of short-term efficacy (moderate for pain and small for function) of opioids to treat CLBP compared with placebo. The effectiveness and safety of long-term opioid therapy for treatment of CLBP remains unproven. Key words: analgesics, opioid/adverse effects, opioid/ therapeutic use, buprenorphine/therapeutic use, Cochrane Review, hydromorphone/therapeutic use, low back pain/drug therapy, metaanalysis, morphine/therapeutic use, oxycodone/therapeutic use, oxymorphone/therapeutic use, sciatica/drug therapy, systematic review, tramadol/therapeutic use. Level of Evidence: 1 Spine 2014;39:556-563
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ow back pain (LBP) is a major cause of pain, disability costs, and the largest cause of disability-adjusted years worldwide.''^ Almost one quarter of North Americans are estimated to have experienced an episode of LBP within the previous 3 months.^ Although 80% to 90% of people with chronic low back pain (CLBP) improve by 12 weeks,"* 6% to 1 1 % continue to report symptoms for more than 3 months.' Among individuals with CLBP, one-third continued to be symptomatic after 12 months.^ Fewer than 50% of individuals with CLBP who missed work for more than 12 weeks returned to work, and an absence of 2 years from employment was associated with little chance of ever returning to work.'^ Medications play an important role in the management of CLBP and generally fall into 4 broad categories: nonsteroidal anti-inflammatory drugs, antidepressants, muscle relaxants, and opioids. The use of opioids have increased markedly, but April 2014
CocHRANE COLLABORATION remains in the management of chronic non-cancer pain,^ and CLBP in particular.* Our primary objective is to update a previous Cochrane Review'' to determine whether opioids are effective in improving pain, function, or both, in individuals with CLBP. Our secondary objectives are to determine the effectiveness of opioids in patients with CLBP with or without prior spinal surgery; with or without radicular symptoms; and specifically the effectiveness of tramadol, or transdermal buprenorphine, or strong opioids.
MATERIALS AND METHODS We included published randomized controlled trials with a blinded assessment of outcomes that compared any opioid to placebo or any other drug with analgesic properties for a period of 1 month or longer in an outpatient setting. We had no restriction on the language of publication. Trials included participants aged 18 years or older, who had persistent low back pain for at least 12 weeks, with or without radiating symptoms to the legs or prior low back surgery. LBP was defined as pain occurring below the lower ribs and above the gluteal folds. We excluded trials involving patients with cancer, infections, infiammatory arthritic conditions, compression fractures, and trials where less than 50% of participants had CLBP, or study authors failed to report cohorts separately. We considered trials with opioids administered by oral, transdermal, mucosal (nasal or rectal), or intramuscular routes, either alone or in combination with other interventions, such as: pharmacological therapy (e.g., anti-infiammatory drugs, antidepressants, and sedatives), physical modalities {e.g., transcutaneous electrical nerve stimulation), exercise, or alternative pain management techniques {e.g., acupuncture). We excluded trials that examined opioids administered by intravenous route, including implantable pumps as this has been discussed elsewhere.'" We considered the following comparator groups: (1) placebo, (2) no treatment, (3) nonpharmacological treatments, (4) other pharmacological agents, and (5) opioids in combination with other pharmacological or nonpharmacological treatments compared with other pharmacological or nonpharmacological treatments, either alone or in combination. We excluded trials where comparisons were made between opioids.
Opioids for Chronic Low Back Pain • Chaparro et al
Digital Content available at http://links.lvirw.com/BRS/A860), and was adapted to search the other databases (see Supplemental Digital Content Appendix 2, available at http://links. lww.com/BRS/A860). Additional studies were identified through examination of references from identified trials and systematic reviews.
Selection of Studies Two authors independently screened titles, abstracts, and key words of identified trials to determine if references met inclusion criteria. We obtained the full text of trials that either seemed to meet criteria or for which inclusion was uncertain. We screened these articles for inclusion and resolved any disagreements through discussion.
Data Extraction and Management Three authors independently extracted data, using the standardized forms developed by the Cochrane Back Review Group," on characteristics of participants, intervention group, clinical setting, method of recruitment, interventions, primary and secondary outcomes, opioid abuse or addiction, side effects, country of study, and sponsorship of study. If data were not available in a format for data extraction, we contacted the authors of the trial for clarification.
Data Synthesis We pooled data from trials comparing opioids to placebo using Review Manager (Revman 5.2) and performed metaanalyses (both fixed-effect and random-effects methods) on pain, function, and adverse effects (AEs). We reported the results of pain and function from the pooled data as standardized mean difference (SMD) with a 95% confidence interval (CI) and AEs using absolute risk differences with a 95% CI. We used the approach'^ to categorize the quality of evidence as follows: high (further research is very unlikely to change the confidence in the estimate of effect); moderate (further research is likely to have important impact); low (further research very likely to have an important impact); or very low (any estimate of effect very uncertain). We graded trials on 5 specific domains: (1) risk of bias, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias.
Primary Outcomes
Risk of Bias
Trials must have reported on at least 1 of 4 primary outcome measures: pain, function, global improvement, or proportion of patients reporting 30% or 50% pain relief. We grouped outcome measures according to the timing of postrandomization follow-up: very short term (3 but < 6 mo), and long term (>6 mo).
Search Methods for Identification of Studies
We defined high-quality studies as fulfilling 6 or more of the 12 internal validity criteria and with no major methodological flaws (see Supplemental Digital Content Appendix 3, available at http://links.lww.com/BRS/A860). When trials were judged as "low risk of bias" for all 5 categories, we did not downgrade the evidence. We downgraded the evidence by 1 point when fewer than 3 categories were judged "high or unclear. " We downgraded the evidence by 2 points when 4 or more categories were judged "high or unclear."
We searched: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials 2012, Issue 10, PsycINFO, and CINAHL for relevant trials up to October 2012. The search strategy for MEDLINE is presented in Appendix 1 (see Supplemental
We downgraded the quality of evidence by 1 point when heterogeneity was large {P> 80%), and by 2 points when the
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Records included from the original review: 4
Indirectness We assessed whether the question being addressed in this systematic review was different from the available evidence regarding the population, intervention, comparator, or an outcome. Imprecision Results were imprecise when trials included relatively few patients and few events and thus had wide CIs around the estimate of the effect. Publication Bias We downgraded the quality of the evidence by one point when the funnel plot suggested publication bias. We prepared the summary of findings tables following published guidelines from the Cochrane Collaboration.'^ We used GRADEprofiler 3.6 to prepare the Grading of Recommendations Assessment, Development, and Evaluation tables and Summary of Findings Tables. RESULTS We identified 2201 references, obtained full-text articles for 91 studies with 12 RCTs meeting the inclusion criteria. In addition, 3 of the 4 trials from the original review were included and the fourth was excluded^^ because it was not bhnded. In total, we included 15 trials (5540 participants) in this review (Figure 1).
Included Studies Six trials evaluated either tramadol alone'''"'^ or the combination tramadol/acetaminophen'**'' 1 tapentadol,^" 2 morphine,^''^-^ 2 oxymorphone,^^'^"* 2 transdermal buprenorphine,^^'^^ 2 oxycodone^^ or hydromorphone.^* All trials were placebo-controlled, except for one that reported 2 trials with identical methodology and used celecoxib in the control arm.''' Thirteen trials were conducted in the United 1 in Canada,^^ and 1 in Germany.»*^
Description of Studies Tramadol Five RCTs, including 1378 participants, examined the use of tramadol compared with placebo.'^"^' One study used tramadol as the active control arm and evaluated the efficacy of flupirtine (a centrally acting, nonopioid agent).^* All trials excluded patients with pain other than in the low back and with a history of substance abuse. In 2 RCTs, tramadol was combined with acetaminophen (paracetamol).**'" The average dose of tramadol was approximately 150'"''' to 300 mg/day.'^ The included trials did not allow initiation of other treatments during the follow-up periods, although 2 trials permitted continuation of physiotherapy started prior to inclusion in the trial.'^''^ None of the trials documented 558
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Records identified through database searching (January 2006 to October 16 2012): 2201
No of records after duplicates removed: 2039
No of records screened: 2039
Nooffuil-text articles assesseri for eligib Ity: 91
No.of records excluded: 1948
No. of full-text articles excluded: 76
No of studies included in quantitative analysis: 15 Figure 1. Study flow diagram.
the number of people receiving concurrent treatments or the types of concurrent treatment. Buprenorphine Two RCTs compared transdermal buprenorphine with placebo.^^'^* Gordon et aF^ used a crossover design, and each period included a 4-week follow-up. Steiner et aP'' used a 15-week enrichment design including 3 weeks of open-label titration followed by 12-week randomized and double-blind phase. Gordon et al used buprenorphine patches of 10 or 20 meg/hour, up to a maximum dose of 40 meg/hour. Steiner et al titrated the dose of buprenorphine from 5 meg/hour to 20 meg/hour during the run-in period and maintained a maximum dose of 20 meg/hour during the double-blind phase. Gordon et al allowed participants to use rescue analgesic with acetaminophen and to use nonopioid analgesics (antidepressants or anticonvulsants). Steiner et al allowed participants to use acetaminophen plus ibuprofen and oxycodone immediate release during the first 6 weeks of the double-blind phase.
Strong Opioids There were 7 RCTs in this category: Buynak et aF° used tapentadol; 2 used morphine^''^^; 2 evaluated oxymorphone"'-"*; April 2014
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£ o 20%). Although the reasons were clearly documented, the implications on final outcomes could be significant. Substantial dropouts reduce the power of the study, compromising the ability to detect a significant difference and interpretation of the study outcomes. In addition, several studies failed to perform a proper intention-to-treat analysis. The method of handling absent data for patients lost to follow-up was documented through the use of last observation carried forward. This method has been criticized given the potential overestimation of the effect.^"
CONCLUSIONS Implications for Practice There is evidence that the use of tramadol (a weak atypical opioid) or strong opioids results in improved pain and moderate changes in function in the short term in people with CLBP when compared with placebo. However, the general applicability of this treatment to the clinical setting is questionable. Several factors, including the strict inclusion criteria of the original studies, high drop-out rates, and the poor description of the study population, concurrent treatments, work status, and compensation, limit the reported results. Notably, a number of important outcomes that capture patient function were absent (such as return-to-work outcome). Finally, there is strong evidence that nausea is more common in patients with CLBP being treated with opioids when compared with placebo. Implications for Research This review highlights the need for high-quality RCTs for (1) the "long-term benefits" and risks of opioid therapy for CLBP; (2) inclusion of different subgroups of CLBP {e.g., failed back surgery syndrome, CLBP with radicular symptoms); (3) opioid effectiveness relative to other conventional physical and www.spinejournaLcom
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medical treatments; (4) subgroups of patients who are most likely to respond to long-term opioid therapy; and (5) the predictors of opioid side effects, abuse, and misuse among patients with CLBP.
Key Points •
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An updated systematic review assessed the efficacy of opioids for CLBP in adults.
D Fifteen randomized trials were included (N: 5540 participants); 12 (80%) had a low risk of bias. Q This review provides some support for the effectiveness of several opioids for CLBP relief and function in the short term. Side effects are more common with opioids but non-life threatening. Ü We have no information from randomized trials supporting the efficacy and safety of opioids used for more than 4 months. Ü The literature does not support that opioids are more effective than other groups of analgesics for LBP such as anti-inflammatory drugs or antidepressants.
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