¹Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
²Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
³Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
⁴Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, Ontario, Canada
⁵Chinese Cochrane Centre, West China Hospital, Sichuan University, Chengdu
⁶Faculty of Medicine, Ain Shams University, Cairo, Egypt
⁷Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada
⁸Krembil Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
⁹Now with the Canadian Agency for Drugs and Technologies in Health (CADTH), Toronto, Ontario, Canada
¹⁰Pharmaceutical Science, University of Sorocaba, Sao Paulo, Brazil
¹¹Leonardo Hirslanden Klinik Birshof, Münchenstein, Switzerland
¹²Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
¹³Department of Internal Medicine, Hospital Alemán de Buenos Aires, Buenos Aires, Argentina
¹⁴Department of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, Ontario, Canada
¹⁵Department of Anesthesiology, Perioperative and Pain Medicine, University of Calgary, Calgary, Alberta, Canada
¹⁶Department of Family Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
¹⁷Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
¹⁸Department of Medicine, University of Toronto, Toronto, Ontario, Canada
¹⁹Accident and Emergency Department, Queen Mary Hospital, Pokfulam, Hong Kong, China
²⁰Accident and Emergency Department, Tuen Mun Hospital, Hong Kong, China
²¹Department of Medicine, Gjøvik, Innlandet Hospital Trust, Norway
²²Department of Hygiene and Dietetics, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
²³Institute for Clinical Epidemiology and Biostatistics, University of Basel Hospital, Basel, Switzerland
²⁴Department of Clinical Research, University of Basel Hospital, Basel, Switzerland.
²⁵Department of Anesthesiology, Operative Intensive Care, Preclinical Emergency Medicine and Pain Management, University of Basel Hospital, Basel, Switzerland
²⁶Isfahan Medical Education Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran
²⁷Canadian Academy of Osteopathy, Hamilton, Ontario, Canada
²⁸Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
²⁹Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada
³⁰Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio

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Key Points

Question Is the use of opioids to treat chronic noncancer pain associated with greater benefits or harms compared with placebo and alternative analgesics?

Findings In this meta-analysis that included 96 randomized clinical trials and 26 169 patients with chronic noncancer pain, the use of opioids compared with placebo was associated with significantly less pain (−0.69 cm on a 10-cm scale) and significantly improved physical functioning (2.04 of 100 points), but the magnitude of the association was small. Opioid use was significantly associated with increased risk of vomiting.

Meaning Opioids may provide benefit for chronic noncancer pain, but the magnitude is likely to be small.

Abstract

Importance Harms and benefits of opioids for chronic noncancer pain remain unclear.

Objective To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain.

Data Sources and Study Selection The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control.

Data Extraction and Synthesis Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence.

Main Outcomes and Measures The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting.

Results Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], −0.69 cm [95% CI, −0.82 to −0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low- to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, −0.60 cm [95% CI, −1.54 to 0.34 cm]; physical functioning: WMD, −0.90 points [95% CI, −2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, −0.13 cm [95% CI, −0.99 to 0.74 cm]; physical functioning: WMD, −5.31 points [95% CI, −13.77 to 3.14 points]), and anticonvulsants (pain: WMD, −0.90 cm [95% CI, −1.65 to −0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, −5.77 to 6.66 points]).

Conclusions and Relevance In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.

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Article Information

Corresponding Author: Jason W. Busse, DC, PhD, Department of Anesthesia, Michael G. DeGroote School of Medicine, McMaster University, HSC-2V9, 1280 Main St W, Hamilton, ON L8S 4K1, Canada (bussejw@mcmaster.ca).

Accepted for Publication: October 30, 2018.

Author Contributions: Drs Busse and Wang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Busse, Schandelmaier, Johnston, Buckley, Sessler, Guyatt.

Acquisition, analysis, or interpretation of data: Busse, Wang, Kamaleldin, Craigie, Riva, Montoya, Mulla, Lopes, Vogel, Chen, Kirmayr, De Oliveira, Olivieri, Kaushal, Chaparro, Oyberman, Agarwal, Couban, Tsoi, Lam, Vandvik, Hsu, Bala, Schandelmaier, Scheidecker, Ebrahim, Ashoorion, Rehman, Hong, Sun, Buckley, Guyatt.

Drafting of the manuscript: Busse, Craigie, Kirmayr, Oyberman, Ebrahim, Johnston.

Critical revision of the manuscript for important intellectual content: Busse, Wang, Kamaleldin, Craigie, Riva, Montoya, Mulla, Lopes, Vogel, Chen, De Oliveira, Olivieri, Kaushal, Chaparro, Agarwal, Couban, Tsoi, Lam, Vandvik, Hsu, Bala, Schandelmaier, Scheidecker, Ebrahim, Ashoorion, Rehman, Hong, Sun, Buckley, Sessler, Guyatt.

Statistical analysis: Wang.

Obtained funding: Busse, Johnston, Buckley.

Administrative, technical, or material support: Kamaleldin, Craigie, Riva, Lopes, Vogel, Kirmayr, De Oliveira, Olivieri, Kaushal, Chaparro, Oyberman, Agarwal, Couban, Lam, Vandvik, Hsu, Ebrahim, Rehman, Hong.

Supervision: Busse, Craigie, Vandvik, Buckley.

Conflict of Interest Disclosures: Dr Buckley reported receiving personal fees from Purdue Pharma and Nova Scotia College of Physicians and Surgeons. No other disclosures were reported.

Funding/Support: This study was supported by grant 119801 from the Canadian Institutes of Health Research and grant 1516-HQ-000017 from Health Canada. Dr Riva is supported by a PhD training award from the NCMIC Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Wichor Bramer, BSc (Erasmus University Medical Center), Brian Alper, MD, MSPH, FAAFP (DynaMed Plus, EBSCO Health), and Neera Bhatnagar, BSc, MLiS (McMaster University Health Sciences Library), for peer review of the MEDLINE search strategy. We thank Yaping Chang, PhD (Department of Health Research Methods, Evidence, and Impact, McMaster University), Yvgeniy Oparin, BHSc (Michael G. DeGroote School of Medicine, McMaster University), Kayli Culig, BHSc (Faculty of Medicine, University of Toronto), Raad Yameen, MD (Institute of Medical Sciences, University of Toronto and Department of Family Medicine, University of Manitoba), Curtis May, BKin (Faculty of Medicine, University of British Columbia), Anna Goshua, BHSc (Faculty of Health Sciences, McMaster University), Annie Lok, HBA, MHE (Faculty of Health Sciences, McMaster University), and Regina Li, HBA, MSc (Faculty of Health Sciences, McMaster University) for screening citations. We thank Norman Buckley, MD (Department of Anesthesia, McMaster University), Dwight Moulin, MD (Department of Clinical Neurological Sciences, Western University), David Juurlink, MD, PhD (Departments of Medicine and Pediatrics, University of Toronto), Sol Stern, MD (Argus Medical Centre, Oakville), and Lydia Hatcher, MD (Department of Family Medicine, St Joseph’s Healthcare Hamilton), for review and feedback regarding the morphine equianalgesic table. We thank Linn Brandt, MD (Department of Internal Medicine, Gjøvik Sykehus, Sykehuset Innlandet Hospital Trust), Jan Brozek, MD, PhD (Department of Health Research Methods, Evidence, and Impact, McMaster University), Eva Dobos, MD (Szeged University of Medicine), Toshiaki A. Furukawa, MD, PhD (Departments of Health Promotion and Human Behavior and of Clinical Epidemiology, Kyoto University Graduate School of Medicine/School of Public Health), Andrea Rita Horvath, MD, PhD (Department of Clinical Chemistry and Endocrinology, New South Wales Health Pathology), Roman Jaeschke, MD, MSc (Department of Medicine, McMaster University), Annette Kristiansen, MD (Department of Health and Science, University of Oslo), Frances LeBlanc, DC (New Brunswick Chiropractic Association), Giovanna Lurati Buse, MD, MSc (Basel University Hospital), Irene Marzona, Pharmacy DR, MSc (IRCCS-Istituto di Ricerche Farmacologiche Mario Negri), Marek Nemec, MD (Department of Emergency Medicine, Basel University Hospital), Josef Prazak MD, PhD (Bern University Hospital), Dmitry Shiktorov, MD (Canadian Centre for Clinical Trials), Aran Tajika, MD (Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health), Brian Younho Hong, BHSc (Department of Medicine, University of Ottawa), and Konstantin Tikhonov, MD (University Health Network, Toronto), for screening the full texts of non-English articles. No financial compensation was provided to any of these individuals.

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