Prescribed Dose and Unintentional Opioid Overdose Mortality

In the past 10 years, the rate of overdose mortality has had a sharp increase in the United States, creating an urgent health problem, according to researchers. From 1999 through 2007, the rate of unintentional overdose death increased by 124%, largely due to increases in overdoses of prescription opioids. The researchers noted that there is some evidence that higher prescribed doses increase the risk of overdose among patients treated with opioids for noncancer chronic pain; the risk of drug-related adverse events is higher among patients prescribed morphine at doses ≥50 mg/day. The association of opioid prescribing patterns with the risk of overdose may vary across groups of patients, the researchers said. However, potential subgroup differences in overdose risk related to opioid prescribing have not been examined, they added. The researchers recently conducted a case-cohort study designed to examine the relationship between opioid prescribing patterns and risk of opioid-related deaths over 5 years among diagnostic subgroups of patients (chronic pain, cancer, acute pain, and substance use disorders) in a national sample of Veterans Health Administration (VHA) patients. They reported study results in the Journal of the American Medical Association [2011;305(13):1315-1321]. In a case-cohort study design, all incident cases in a defined cohort are sampled in addition to a random sample from this same cohort. This study included two 5% random samples of VHA patients (one each for fiscal year [FY] 2004 and FY2005) as well as all FY2004 and FY2005 VHA patients who died of an opioid overdose prior to the end of FY2008 (“cases”). Exclusion criteria included patients not treated with opioids and those with indications of palliative care consultations or hospice care in their VHA medical records. The final study cohort comprised all unintentional prescription opioid overdose decedents (n=750) and a random sample of patients (n=155,434) among individuals who used medical services in 2004 or 2005 and received opioid therapy for pain. The study’s primary outcome measure was associations of opioid regimens (dose and schedule) with death by unintentional prescription overdose in subgroups defined by clinical diagnoses, adjusting for age group, sex, race, ethnicity, and comorbid conditions. The researchers estimated the frequency of fatal overdose over the study period among patients treated with opioids as 0.04%. Opioid overdose decedents were statistically significantly more likely to be middle-aged, white, and have chronic or acute pain. They were also more likely to have substance use disorders and other psychiatric diagnoses and less likely to have cancer. Adjusted analyses found that the risk of overdose death was directly related to the maximum prescribed daily dose of opioid medication. The overdose death rate was higher at higher maximum daily doses compared with lower daily doses across all subgroups examined. The adjusted hazard ratios (HRs) associated with a maximum prescribed daily dose of ≥100 mg/day, compared with the dose category 1 mg/day to <20 mg/day, were: among patients with substance use disorders, adjusted HR=4.54 (95% confidence interval [CI], 2.46-8.37; absolute risk difference approximation [ARDA]=0.14%); among those with chronic pain, adjusted HR=7.18 (95% CI, 4.85-10.65; ARDA=0.25%); among those with acute pain, adjusted HR=6.64 (95% CI, 3.31-13.31; ARDA, 0.23%); and among those with cancer, adjusted HR=11.99 (95% CI, 4.42-32.56; ARDA=0.45%). There was no association between receiving both as-needed and regularly scheduled doses and overdose death. In conclusion, the researchers said that this study “documents a relationship between opioid prescribing and opioid overdose in a large, national, prospective cohort of individuals receiving opioid therapy for a variety of medical conditions. The risk of opioid overdose should continue to be evaluated relative to the need to reduce pain and suffering and be considered along with other risk factors.”