Some serious risks of long-term opioid therapy may be dose-dependent

Long-term opioid therapy is associated with increased risk for serious harms such as overdose, opioid abuse, fractures, and myocardial infarction, and some of the effect may be dose-dependent, according to a systematic review.

Researchers considered 39 randomized trials and observational studies (cohort studies with concurrent controls, cross-sectional studies, and case-control studies) of adults with chronic pain for more than 3 months who were prescribed long-term opioid therapy. Results appeared online Jan. 13 at Annals of Internal Medicine.

One large, fair-quality retrospective cohort study of 9,940 people found that, compared with nonuse, recent opioid use was associated with an increased risk for any overdose events (adjusted hazard ratio [HR], 5.2; 95% CI, 2.1 to 12.5) and serious overdose events (adjusted HR, 8.4, 95% CI, 2.5 to 28). The annual overdose rate was 256 per 100,000 person-years among patients who had recently been prescribed opioids versus 36 per 100,000 person-years among those who had not. Higher doses were associated with increased risk. Compared with a morphine-equivalent dose (MED) of 1 to 19 mg/d, the adjusted HRs for overdose ranged from 1.44 (95% CI, 0.57 to 3.62) for an MED of 20 to 49 mg/d to 8.87 (95% CI, 3.99 to 19.72) for an MED of at least 100 mg/d.

No randomized trial evaluated rates of opioid abuse, addiction, or related outcomes with long-term opioid therapy compared to placebo or no opioid therapy, but 1 fair-quality study determined that opioid therapy for more than 90 days was associated with increased risk for a diagnosis of opioid abuse or dependence. Rates of abuse or dependence ranged from 0.7% with low-dose therapy (MED of 1 to 36 mg/d) to 6.1% with high-dose therapy (MED of ≥120 mg/d) compared with 0.004% with no opioid prescription; adjusted odds ratios (ORs) ranged from 14.9 (95% CI, 10.4 to 21.5) for low-dose therapy to 122.5 (95% CI, 72.8 to 206.0) for high-dose therapy.

Ten fair-quality uncontrolled studies found that estimates of opioid abuse, addiction, and related outcomes varied substantially, even after stratification by setting. In primary care settings, prevalence of opioid abuse ranged from 0.6% to 8% and prevalence of dependence ranged from 3% to 26%. Prevalence of aberrant drug-related behaviors (such as aberrant urine drug test results, medication agreement violations, or other behaviors indicative of misuse) ranged from 6% to 37%.

A fair-quality cohort study of 2,341 adults age 60 or older found a higher fracture rate among current opioid users (6%) than among nonusers (4%) after a mean follow-up of 33 months, but the difference was not statistically significant. A good-quality case-control study of 21,739 case-patients found that current opioid use was associated with increased risk for hip, humerus, or wrist fracture versus nonuse (adjusted OR, 1.27; 95% CI, 1.21 to 1.33).

One fair-quality cohort study of 297,314 adults found that a cumulative opioid supply of at least 180 days over a 3.5-year period was associated with an increased risk for myocardial infarction versus no long-term opioid therapy (adjusted incidence rate ratio, 2.66; 95% CI, 2.30 to 3.08). Compared with a cumulative MED of 0 to 1,350 mg over 90 days, the adjusted incidence rate ratio for myocardial infarction was 1.21 (95% CI, 1.02 to 1.45) for an MED of 1,350 to 2,700 mg and ranged from 1.42 to 1.89 for MEDs of at least 2,700 mg. A good-quality case-control study among 11,693 case-patients found that current opioid therapy versus nonuse was associated with increased odds of myocardial infarction (adjusted OR, 1.28; 95% CI, 1.19 to 1.37).

Researchers found insufficient evidence to determine the effectiveness of long-term opioid therapy for improving pain and function and noted that serious harms of long-term therapy seemed to increase at higher opioid doses. Limitations of the systematic review include that a meta-analysis could not be done and publication bias could not be assessed. No placebo-controlled trials met inclusion criteria, evidence was lacking for many comparisons and outcomes, and observational studies were limited in their ability to address potential confounding.

The authors wrote, “Despite these limitations, the lack of scientific evidence on effectiveness and harms of long-term opioid therapy for chronic pain is clear and is in striking contrast to its widespread use for this condition.”

In a second paper based on this review and also published Jan. 13 by Annals of Internal Medicine, the National Institutes of Health Pathways to Prevention Workshop identified key evidence gaps and research priorities that must be addressed so that physicians can make informed decisions when prescribing opioids for chronic pain. According to the report, lack of research and inadequate knowledge about the best approaches to treating various types of pain leave clinicians to rely on their own clinical experience. Until research is done, a better approach is for clinicians to follow guidelines issued by professional societies and for systems of care to facilitate this practice.