Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials

Diana S Meske, Oluwadolapo D Lawal, Harrison Elder, Valerie Langberg, Florence Paillard, Nathaniel Katz, Diana S Meske, Oluwadolapo D Lawal, Harrison Elder, Valerie Langberg, Florence Paillard, Nathaniel Katz

Abstract

Introduction: Opioids have been used for millennia for the treatment of pain. However, the long-term efficacy of opioids to treat chronic non-cancer pain continues to be debated. To evaluate opioids' efficacy in chronic non-cancer pain, we performed a meta-analysis of published clinical trials for μ-opioid receptor agonists performed for US Food and Drug Administration approval.

Methods: MEDLINE and Cochrane trial register were searched for enriched enrollment randomized withdrawal studies (before June 2016). Selection criteria included: adults, ≥10 subjects per arm, any chronic pain condition, double-blind treatment period lasting ≥12 weeks, and all μ-agonist opioids approved in the USA.

Results: Fifteen studies met criteria. Opioid efficacy was statistically significant (p<0.001) versus placebo for pain intensity (standardized mean difference: -0.416), ≥30% and ≥50% improvement in pain (risk difference: 0.166 and 0.137), patient global impression of change (0.163), and patient global assessment of study medication (0.194). There were minor benefits on physical function and no effect on mental function.

Conclusion: Opioids are efficacious in the treatment of chronic non-cancer pain for up to 3 months in randomized controlled trials. This should be considered, alongside data on opioid safety, in the use of opioids for the treatment of chronic pain.

Keywords: EERW trials; evidence-based medicine; long-term efficacy; non-cancer pain; opioid analgesics; opioid efficacy.

Conflict of interest statement

Disclosure Nathaniel Katz has acted as a consultant for Allergan, Plc, Collegium Pharmaceuticals, Inc., Depomed, Inc., Egalet Corporation, Endo Pharmaceuticals Inc., Janssen Pharmaceuticals, Inc., Mallinckrodt, Inc., Pfizer Inc., and Purdue Pharma, L. P. Diana S Meske was employed by Analagesic Solutions when the work was completed for this manuscript, however at the time of publication she was employed by Collegium Pharmaceutical Inc. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Change in PI from randomization baseline to week 12 with active study opioid drug versus placebo. Notes: The standardized mean difference effect size was −0.416 and p<0.001, with a lower bound estimate of −0.521 and an upper bound −0.312. Abbreviation: PI, pain intensity.
Figure 3
Figure 3
Percentage of patients with ≥30% or ≥50% improvement with active study drug versus placebo. Notes: The graph shows the mean (SD) percent of patients with improvement, from each study that reported these data. A binary random-effects meta-analysis using the restricted maximum likelihood method was performed showing a statistically significant difference between active study drug and placebo for both ≥30% and ≥50%.

References

    1. The use of opioids for the treatment of chronic pain: A consensus statement from the American Academy of Pain Medicine and the American Pain Society [press release] Glenview, IL, USA: 1997.
    1. The use of opioids for the treatment of chronic pain: a consensus statement from the American Academy of Pain Medicine and the American Pain Society [press release] Dallas, TX, USA: 1998.
    1. US Centers for Disease Control and Prevention (CDC) CDC Guideline for Prescribing Opioids for Chronic Pain. 2016.
    1. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a national institutes of health pathways to prevention workshop. Ann Intern Med. 2015;162(4):276–286.
    1. Frieden TR, Houry D. Reducing the risks of relief – The CDC opioid-prescribing guideline. N Engl J Med. 2016;374(16):1501–1504.
    1. Ballantyne JC. Opioid therapy in chronic pain. Phys Med Rehabil Clin N Am. 2015;26(2):201–218.
    1. Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL. Societal costs of prescription opioid abuse, dependence, and misuse in the United States. Pain Med. 2011;12(4):657–667.
    1. Substance Abuse and Mental Health Services Administration . Behavioral health trends in the United States: results from the 2014 national survey on drug use and health. Rockville, MD: SAMHSA; 2015. [Accessed April 16, 2018]. Available from: .
    1. Katz NP, Adams EH, Benneyan JC, et al. Foundations of opioid risk management. Clin J Pain. 2007;23(2):103–118.
    1. Paulozzi LJ, Weisler RH, Patkar AA. A national epidemic of unintentional prescription opioid overdose deaths: how physicians can help control it. J Clin Psychiatry. 2011;72(5):589–592.
    1. Wallace BC, Small K, Brodley CE, Lau J, Trikalinos TA. Deploying an interactive machine learning system in an evidence-based practice center: abstrackr. Proceedings of the 2nd ACM SIGHIT International Health Informatics Symposium; Miami, FL. 28–30 January 2012; New York, NY: ACM; 2012. pp. 819–824.
    1. Johnston BC, Patrick DL, Busse JW, Schunemann HJ, Agarwal A, Guyatt GH. Patient-reported outcomes in meta-analyses – Part 1: assessing risk of bias and combining outcomes. Health Qual Life Outcomes. 2013;11:109.
    1. Wallace BC, Dahabreh IJ, Trikalinos TA, Lau J, Trow P, Schmid CH. Closing the gap between methodologists and end-users: R as a computational back-end. J Stat Software. 2012;49(5):4700.
    1. Hale M, Tudor IC, Khanna S, Thipphawong J. Efficacy and tolerability of once-daily OROS hydromorphone and twice-daily extended-release oxycodone in patients with chronic, moderate to severe osteoarthritis pain: results of a 6-week, randomized, open-label, noninferiority analysis. Clin Ther. 2007;29(5):874–888.
    1. Friedmann N, Klutzaritz V, Webster L. Efficacy and safety of an extended-release oxycodone (Remoxy) formulation in patients with moderate to severe osteoarthritic pain. J Opioid Manag. 2011;7(3):193–202.
    1. Steiner D, Munera C, Hale M, Ripa S, Landau C. Efficacy and safety of buprenorphine transdermal system (BTDS) for chronic moderate to severe low back pain: a randomized, double-blind study. J Pain. 2011;12(11):1163–1173.
    1. Wen W, Sitar S, Kynch S, He E, Ripa SR. A multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of single-entity, once-daily hydrocodone tablets in patients with uncontrolled moderate to severe chronic low back pain. Expert Opin Pharmacother. 2015;16(11):1593–1606.
    1. Katz N, Kopecky EA, O’Connor M, Brown RH, Fleming AB. A phase 3, multicenter, randomized, double-blind, placebo-controlled, safety, tolerability, and efficacy study of Xtampza ER in patients with moderate-to-severe chronic low back pain. Pain. 2015;156(12):2458–2467.
    1. 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(1):117–128.
    1. Vorsanger GJ, Xiang J, Gana TJ, Pascual ML, Fleming RR. Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain. J Opioid Manag. 2008;4(2):87–97.
    1. Hale M, Khan A, Kutch M, Li S. Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain. Curr Med Res Opin. 2010;26(6):1505–1518.
    1. Katz N, Hale M, Morris D, Stauffer J. Morphine sulfate and naltrexone hydrochloride extended release capsules in patients with chronic osteoarthritis pain. Postgrad Med. 2010;122(4):112–128.
    1. Schwartz S, Ertopolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151–162.
    1. Rauck RL, Nalamachu S, Wild JE, et al. Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study. Pain Med. 2014;15(6):975–985.
    1. Vinik AI, Shapiro DY, Rauschkolb C. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care. 2014;37(8):2302–2309.
    1. Hale ME, Laudadio C, Yang R, Narayana A, Malamut R. Efficacy and tolerability of a hydrocodone extended-release tablet formulated with abuse-deterrence technology for the treatment of moderate-to-severe chronic pain in patients with osteoarthritis or low back pain. J Pain Res. 2015;8:623–636.
    1. Hale ME, Zimmerman TR, Eyal E, Malamut R. Efficacy and safety of a hydrocodone extended-release tablet formulation with abuse-deterrence technology in patients with moderate-to-severe chronic low back pain. J Opioid Manag. 2015;11(6):507–518.
    1. Rauck RL, Potts J, Xiang Q, Tzanis E, Finn A. Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain. Postgrad Med. 2016;128(1):1–11.
    1. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ. 2006;174(11):1589–1594.
    1. Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioid therapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manage. 2008;35(2):214–228.
    1. Deshpande A, Furlan A, Mailis-Gagnon A, Atlas S, Turk D. Opioids for chronic low-back pain. Cochrane Database Syst Rev. 2007;3:CD004959.
    1. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of the efficacy and safety. Pain. 2004;112(3):372–380.
    1. Hauser W, Bernardy K, Maier C, et al. Long-term opioid therapy in chronic noncancer pain: a systematic review and meta-analysis of efficacy, tolerability, and safety in open-label extension trials with study duration of at least 26 weeks. Schmerz. 2015;29(1):96–108. German.
    1. Chaparro LE, Furlan AD, Deshpande A, Mallis-Gagnon A, Atlas S, Turk DC. Opioids compared with placebo or other treatments for chronic low back pain: an update of the cochrane review. Spine (Phila Pa 1976) 2014;39(7):556–563.
    1. Dworkin RH, Turk DC, Farrar JT, et al. IMMPACT Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1–2):9–19.
    1. Abdel Shaheed C, Maher CG, Williams KA, Day R, McLachlan AJ. Efficacy, tolerability, and dose-dependent effects of opioid analgesics for low back pain: a systematic review and meta-analysis. JAMA Intern Med. 2016;176(7):958–968.
    1. Katz NP, Paillard FC, Ekman E. Determining the clinical importance of treatment benefits for interventions for painful orthopedic conditions. J Orthop Surg Res. 2015;10:24.
    1. Katz N, Benoit C. Opioids for neuropathic pain. Curr Pain Headache Rep. 2005;9:153–160.
    1. US Food and Drug and Administration (FDA), Center for Drug Evaluation and Research (CDER) Guidance for industry analgesic indications: developing drug biological products. Rockville, MD: FDA, CDER; 2014. [Accessed April 16, 2018]. Available from: .
    1. Dworkin RH, Turk DC, Peirce-Sandner S, et al. Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain. 2012;153(6):1148–1158.
    1. Katz N. Enriched enrollment randomized withdrawal trial designs of analgesics: a focus on methodology. Clin J Pain. 2009;25(9):797–807.
    1. Tayeb BO, Barreiro AE, Bradshaw YS, Chui KK, Carr DB. Durations of opioid, nonopioid drug, and behavioral clinical trials for chronic pain: adequate or inadequate? Pain Med. 2016;17(11):2036–2046.
    1. Wakelee HA, Lee JW, Hanna NH, Traynor AM, Carbone DP, Schiller JH. A double-blind randomized discontinuation phase-II study of sorafenib (BAY 43-9006) in previously treated non-small-cell lung cancer patients: eastern cooperative oncology group study E2501. J Thorac Oncol. 2012;7(10):1574–1582.
    1. Vohringer PA, Ostacher MJ, El-Mallakh RS, et al. Antidepressants in type II versus type I bipolar depression: a randomized discontinuation trial. J Clin Psychopharmacol. 2015;35(5):605–608.
    1. Kemper AR, Van Mater HA, Coeytaux RR, Williams JW, Sanders GD. Systematic review of disease-modifying antirheumatic drugs for juvenile idiopathic arthritis. BMC Pediatr. 2012;15:29.
    1. Ponten J, Biber B, Bjurij T, Henriksson B, Hjalmarson A, Lundberg D. Beta-receptor blockade and spinal anaesthesia withdrawal versus continuation of long-24 term therapy. Acta Anaesth Scand. 1982;76(1):62–69.
    1. McCreadie R, Wiles D, Grant S, et al. The Scottish first episode schizophrenia study. VII Two-year follow-up. Scottish Schizophrenia Research Group. Acta Psychiatr Scand. 1989;80(6):597–602.
    1. Kopec JA, Abrahamowicz M, Esdaile JM. Randomized discontinuation trials: utility and efficiency. J Clin Epidemiol. 1993;46(9):959–971.
    1. Buynak R, Rappaport SA, Rod K, et al. Long-term safety and efficacy of tapentadol extended release following up to 2 years of treatment in patients with moderate to severe, chronic pain: results from an open-label extension trial. Clin Ther. 2015;37(11):2420–2438.
    1. Hale M, Urdaneta V, Kirby MT, Xiang Q, Rauck R. Long-term safety and analgesic efficacy of buprenorphine buccal film in patients with moderate-to-severe chronic pain requiring around-the-clock opioids. J Pain Res. 2017;10:233–240.
    1. Hale ME, Ma Y, Malamut R. Six-month, open-label study of hydrocodone extended release formulated with abuse-deterrence technology: safety, maintenance of analgesia, and abuse potential. J Opioid Manag. 2016;12(2):139–147.
    1. Taber L, Lynch SY, He E, Ripa SR. Long-term safety and effectiveness of once-daily, single entity, extended-release hydrocodone over 76 weeks of an open-label study in patients with chronic noncancer and nonneuropathic pain. Postgrad Med. 2016;128(1):23–33.
    1. Hale ME, Zimmerman TR, Ma Y, Malamut R. Twelve-month, open-label assessment of long-term safety and abuse potential of hydrocodone extended-release formulated with abuse-deterrence technology in patients with chronic pain. J Opioid Manag. 2015;11(5):425–434.
    1. Wen W, Taber L, Lynch SY, He E, Ripa S. 12-month safety and effectiveness of once-daily hydrocodone tablets formulated with abuse-deterrent properties in patients with moderate to severe chronic pain. J Opioid Manag. 2015;11(4):339–356.
    1. Arora S, Setnik B, Michael D, et al. A multicenter, 12-month, open-label, single-arm safety study of oxycodone-hydrochloride/naltrex-one-hydrochloride extended-release capsules (ALO-02) in patients with moderate-to-severe chronic noncancer pain. J Opioid Manag. 2014;10(6):423–436.
    1. Nalamachu S, Rauck RL, Hale ME, Florete OG, Robinson CY, Farr SJ. A long-term, open-label safety study of single-entity hydrocodone bitartrate extended release for the treatment of moderate to severe chronic pain. J Pain Res. 2014;7:669–678.
    1. Friedmann N, Klutzaritz V, Webster L. Long-term safety of Remoxy® (extended-release oxycodone) in patients with moderate to severe chronic osteoarthritis or low back pain. Pain Med. 2011;12(5):755–760.
    1. Wallace M, Thipphawong J. Open-label study on the long-term effi-cacy, safety, and impact on quality of life of OROS hydromorphone ER in patients with chronic low back pain. Pain Med. 2010;11(10):1477–1488.
    1. Webster LR, Brewer R, Wang C, et al. Long-term safety and efficacy of morphine sulfate and naltrexone hydrochloride extended release capsules, a novel formulation containing morphine and sequestered naltrexone, in patients with chronic, moderate to severe pain. J Pain Symptom Manage. 2010;40(5):734–746.
    1. Wild JE, Grond S, Kuperwasser B, et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract. 2010;10(5):416–427.
    1. Wallace M, Moulin DE, Rauck RL, et al. Long-term safety, tolerability, and efficacy of OROS hydromorphone in patients with chronic pain. J Opioid Manag. 2009;5(2):97–105.
    1. Pascual ML, Fleming RR, Gana TJ, Vorsanger GJ. Open-label study of the safety and effectiveness of long-term therapy with extended-release tramadol in the management of chronic nonmaligant pain. Curr Med Res Opin. 2007;23(10):2531–2542.
    1. McIlwain H, Ahdieh H. Safety, tolerability, and effectiveness of oxy-morphone extended release for moderate to severe osteoarthritis pain: a one-year study. Am J Ther. 2005;12(2):106–112.
    1. Moore A, Wiffen PJ, Eccleston C, et al. Systematic review of enriched-enrollment randomized-withdrawal trial designs in chronic pain: a new framework for design and reporting. Pain. 2015;156(8):1382–1395.
    1. US Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH) Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. Rockville, MD: DHHS, FDA, CDER, CBER, CDRH; 2012. [Accessed April 16, 2018]. Available from: .
    1. Furlan A, Chaparro LE, Irvin E, Mailis-Gagnon A. A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain. Pain Res Manag. 2011;16(5):337–351.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren