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Supplemental Digital Content is Available in the Text.Long-term opioid use decreased from 2011, but the proportion of more potent opioids prescribed increased. Ongoing review of effectiveness and need for discontinuation is important.

Background Long‐term opioid prescribing for musculoskeletal pain is controversial due to uncertainty regarding effectiveness and safety. This study examined the risks of a range of adverse events in a large cohort of patients prescribed long‐term opioids using the UK Clinical Practice Research Datalink. Methods Patients with musculoskeletal conditions starting a new long‐term opioid episode (defined as ≥3 opioid prescriptions within 90 days) between 2002 and 2012 were included. Primary outcomes: major trauma and intentional overdose (any). Secondary outcomes: addiction (any), falls, accidental poisoning, attempted suicide/self‐harm, gastrointestinal pathology and bleeding, and iron deficiency anaemia. “Control” outcomes (unrelated to opioid use): incident eczema and psoriasis. Results A total of 98,140 new long‐term opioids users (median age 61, 41% male) were followed for (median) 3.4 years. Major trauma risk increased from 285 per 10,000 person‐years without long‐term opioids to 369/10,000 for a long‐term opioid episode (<20 mg MED), 382/10,000 (20–50 mg MED), and 424/10,000 (≥50 mg MED). Adjusted hazard ratios were 1.09 (95% CI; 1.04, 1.14 for <20 mg MED vs. not being in an episode of long‐term prescribing), 1.24 (95% CI; 1.16, 1.32: 20–50 mg MED) and 1.34 (95% CI; 1.20, 1.50: ≥50 mg MED). Significant dose‐dependent increases in the risk of overdose (any type), addiction, falls, accidental poisoning, gastrointestinal pathology, and iron deficiency anaemia were also found. Conclusions Patients prescribed long‐term opioids are vulnerable to dose‐dependent serious adverse events. Opioid prescribing should be reviewed before long‐term use becomes established, and periodically thereafter to ensure that patients are not being exposed to increased risk of harm, which is not balanced by therapeutic benefit. Significance Long‐term opioid use is associated with serious adverse events such as major trauma, addiction and overdose. The risk increases with higher opioid doses. Opioid prescribing should be reviewed before long‐term use becomes established, and periodically thereafter to assess ongoing effectiveness.