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      Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study

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          The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown.

          Methods and Findings

          We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy.


          Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated.

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          Most cited references 32

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          Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.

          Use of chronic opioid therapy for chronic noncancer pain has increased substantially. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on chronic opioid therapy for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations. Although evidence is limited, the expert panel concluded that chronic opioid therapy can be an effective therapy for carefully selected and monitored patients with chronic noncancer pain. However, opioids are also associated with potentially serious harms, including opioid-related adverse effects and outcomes related to the abuse potential of opioids. The recommendations presented in this document provide guidance on patient selection and risk stratification; informed consent and opioid management plans; initiation and titration of chronic opioid therapy; use of methadone; monitoring of patients on chronic opioid therapy; dose escalations, high-dose opioid therapy, opioid rotation, and indications for discontinuation of therapy; prevention and management of opioid-related adverse effects; driving and work safety; identifying a medical home and when to obtain consultation; management of breakthrough pain; chronic opioid therapy in pregnancy; and opioid-related policies. Safe and effective chronic opioid therapy for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion. Although evidence is limited in many areas related to use of opioids for chronic noncancer pain, this guideline provides recommendations developed by a multidisciplinary expert panel after a systematic review of the evidence.
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            Patterns of abuse among unintentional pharmaceutical overdose fatalities.

             Aron Hall (2008)
            Use and abuse of prescription narcotic analgesics have increased dramatically in the United States since 1990. The effect of this pharmacoepidemic has been most pronounced in rural states, including West Virginia, which experienced the nation's largest increase in drug overdose mortality rates during 1999-2004. To evaluate the risk characteristics of persons dying of unintentional pharmaceutical overdose in West Virginia, the types of drugs involved, and the role of drug abuse in the deaths. Population-based, observational study using data from medical examiner, prescription drug monitoring program, and opiate treatment program records. The study population was all state residents who died of unintentional pharmaceutical overdoses in West Virginia in 2006. Rates and rate ratios for selected demographic variables. Prevalence of specific drugs among decedents and proportion that had been prescribed to decedents. Associations between demographics and substance abuse indicators and evidence of pharmaceutical diversion, defined as a death involving a prescription drug without a documented prescription and having received prescriptions for controlled substances from 5 or more clinicians during the year prior to death (ie, doctor shopping). Of 295 decedents, 198 (67.1%) were men and 271 (91.9%) were aged 18 through 54 years. Pharmaceutical diversion was associated with 186 (63.1%) deaths, while 63 (21.4%) were accompanied by evidence of doctor shopping. Prevalence of diversion was greatest among decedents aged 18 through 24 years and decreased across each successive age group. Having prescriptions for a controlled substance from 5 or more clinicians in the year prior to death was more common among women (30 [30.9%]) and decedents aged 35 through 44 years (23 [30.7%]) compared with men (33 [16.7%]) and other age groups (40 [18.2%]). Substance abuse indicators were identified in 279 decedents (94.6%), with nonmedical routes of exposure and illicit contributory drugs particularly prevalent among drug diverters. Multiple contributory substances were implicated in 234 deaths (79.3%). Opioid analgesics were taken by 275 decedents (93.2%), of whom only 122 (44.4%) had ever been prescribed these drugs. The majority of overdose deaths in West Virginia in 2006 were associated with nonmedical use and diversion of pharmaceuticals, primarily opioid analgesics.
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              Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects.

              Chronic noncancer pain (CNCP) is a major health problem, for which opioids provide one treatment option. However, evidence is needed about side effects, efficacy, and risk of misuse or addiction. This meta-analysis was carried out with these objectives: to compare the efficacy of opioids for CNCP with other drugs and placebo; to identify types of CNCP that respond better to opioids; and to determine the most common side effects of opioids. We searched MEDLINE, EMBASE, CENTRAL (up to May 2005) and reference lists for randomized controlled trials of any opioid administered by oral or transdermal routes or rectal suppositories for CNCP (defined as pain for longer than 6 mo). Extracted outcomes included pain, function or side effects. Methodological quality was assessed with the Jadad instrument; analyses were conducted with Revman 4.2.7. Included were 41 randomized trials involving 6019 patients: 80% of the patients had nociceptive pain (osteoarthritis, rheumatoid arthritis or back pain); 12%, neuropathic pain (postherpetic neuralgia, diabetic neuropathy or phantom limb pain); 7%, fibromyalgia; and 1%, mixed pain. The methodological quality of 87% of the studies was high. The opioids studied were classified as weak (tramadol, propoxyphene, codeine) or strong (morphine, oxycodone). Average duration of treatment was 5 (range 1-16) weeks. Dropout rates averaged 33% in the opioid groups and 38% in the placebo groups. Opioids were more effective than placebo for both pain and functional outcomes in patients with nociceptive or neuropathic pain or fibromyalgia. Strong, but not weak, opioids were significantly superior to naproxen and nortriptyline, and only for pain relief. Among the side effects of opioids, only constipation and nausea were clinically and statistically significant. Weak and strong opioids outperformed placebo for pain and function in all types of CNCP. Other drugs produced better functional outcomes than opioids, whereas for pain relief they were outperformed only by strong opioids. Despite the relative shortness of the trials, more than one-third of the participants abandoned treatment.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                20 August 2015
                : 10
                : 8
                [1 ]Department of Medicine, University of Toronto, Toronto, Ontario, Canada
                [2 ]Chronic Disease and Pharmacotherapy Research Program, Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
                [3 ]Department of Pharmacy, University of Toronto, Toronto, Ontario, Canada
                University of British Columbia, CANADA
                Author notes

                Competing Interests: The authors have read the journal's policy and have the following conflicts: Dr. Muhammad Mamdani has received honoraria from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Bayer. Dr. Mamdani has served as an Advisory Board member for the following pharmaceutical companies: Astra-Zeneca, Bristol-Meyers Squibb, Eli Lilly and Company, Glaxo Smith Kline, Hoffman La Roche, Novartis, Novo Nordisk, Pfizer. Irfan A. Dhalla serves in a voluntary capacity on the National Advisory Committee on Prescription Drug Misuse, which is organized by the Canadian Centre for Substance Abuse, a non-governmental organization funded by the Canadian federal government. Irfan A. Dhalla also serves in a voluntary capacity on the Board of Directors of Physicians for Responsible Opioid Prescribing.

                Conceived and designed the experiments: EK TG XC IAD MM DJ. Analyzed the data: XC.


                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 2, Tables: 3, Pages: 11
                This study was supported by a grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC) Drug Innovation Fund and the Institute for Clinical Evaluative Sciences (ICES), a non-profit research institute sponsored by the Ontario MOHLTC. The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Custom metadata
                Data cannot be made publicly available due to the ethical and legal requirements implemented by the Institute for Clinical Evaluative Sciences and Ontario's Information and Privacy Commissioner (IPC). Public availability of ICES data would compromise patient privacy. More information can be found here: http://www.ices.on.ca/Data-and-Privacy/Privacy%20at%20ICES. Requests to access data may be submitted to Data & Analytic Services at das@ 123456ices.on.ca or via the following link http://www.ices.on.ca/Data-Services.



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