Commentary in British Medical Journal

Cohort study finds nine times increased overdose risk (fatal plus non-fatal) in patients receiving 100 mg/day for 90 days compared with 1–20 mg/day opioids for chronic non-cancer pain, but wide CI and possibility of unmeasured confounders
Joel Simon Hochman1, Joe Pergolizzi
British Medical Journal, Evid Based Nurs 2010;13:55-56 doi:10.1136/ebn1062

+ Author Affiliations
National Foundation for the Treatment of Pain, Houston, Texas, USA
Department of Anesthesiology, Georgetown University School of Medicine, Washington, District of Columbia, USA
Naples Anesthesia and Pain Associates, Naples, Florida, USA
Correspondence to: Joel Simon Hochman
Executive Director, National Foundation for the Treatment of Pain, 1714 White Oak Drive, Houston, TX 770099, USA; jfshmd@gmail.com

Commentary on:
Dunn KM, Saunders KW, Rutter CM, et al
Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med 2010;152:85–92.

Dunn and colleagues are employed at Group Health Research Institute, the Arthritis Research Campaign National Primary Care Centre and Kaiser Permanent, with affiliations at the University of Washington and the University of California in San Francisco, and with funding from the National Institute of Drug Abuse. From their website (http://www.grouphealthresearch.org/aboutus/aboutghri.html) we note that “Group Health Research Institute (GHRI) is a non-proprietary, public-domain research institution within Group Health, a health care system based in Seattle, Washington. Group Health Cooperative is a consumer-governed, nonprofit health care system that coordinates care and coverage. Based in Seattle, Group Health and its subsidiary health carriers, Group Health Options, Inc. and KPS Health Plans, serve nearly 600,000 residents of Washington State and Idaho. More than 70% of members receive care in Group Health-owned medical facilities.”

This study addressed the increasing frequency of long-term opioid treatment for chronic pain and the doubling of hospitalisations for overdose in Washington, DC. The authors noted a study in West Virginia which found that fewer than 44% of people who died of unintentional prescription drug overdose had received opioids from a physician, which suggests that overdose typically resulted from drug diversion. They then explained that “the overdose risk in patients receiving medically prescribed opioids has not been studied.” This is the focus of their research and report.
Their objectives were to estimate the overall overdose rates (non-fatal and fatal) among people receiving long-term opioid therapy for chronic non-cancer pain from medical sources and to compare the risks for opioid overdoses of long-term opioid therapy.

Their study was based on data obtained from the Consortium to Study Opioid Risks and Trends, which was conducted within the Group Health Cooperative. The cohort they studied consisted of 9940 people from the 600 000 insured by Group Health Incorporated who had received opioid therapy for non-cancer pain, followed for a mean of 42 months (range <1 to 119 months). Two-thirds of the cohort had received a diagnosis of back or extremity pain. The mean daily dosage of opioids prescribed was 13.3 mg (morphine equivalents). Among 46% of the cohort, hydrocodone was the most commonly prescribed opioid, and 10% of the cohort had received predominantly long-acting opioids. During the observation period 51.2% were using opioids, 40.1% at the lowest dosage (1 to <20 mg/day of morphine equivalents), 6.7% at 20–49 mg/day, 6% at 50–99 mg/day and 1.8% at ≥100 mg/day.

During the study the authors identified 6 fatal and 74 non-fatal overdoses. Of the 74 non-fatal overdoses, 2 were identified as definitely not opioid overdoses, 17 as probably not and 10 as uncertain. So, a total of 45 non-fatal opioid overdoses were studied. Of the 51 cases studied in total, 40 (78%) were fatal or serious overdoses, and 11 (21.6%) were non-serious overdose events. Accidental excess ingestion of opioids occurred in eight patients, suicide attempts were made by six people, three people had obtained additional opioid from non-medical sources, and drug abuse was noted for four patients. Four patients had overdosed by applying extra fentanyl patches without medical authorisation or by sucking a patch.
The authors concluded that the annual rate of overdose for the total sample was 148 per 100 000 person years, and 116 per 100 000 person years for serious overdose. The rate for patients who had only recently been prescribed opioid therapy was 256 per 100 000 person years. Overdose rates were somewhat higher for patients older than 65 years and among patients with a history of depression and substance abuse. The overall rate of fatal overdose (6 patients of 9940 studied) was 17 per 100 000 person years.

The authors reported that people receiving <20 mg/day of opioids had an annual overdose rate of 160 per 100 000 person years, whereas patients receiving >100 mg/day had a rate of 1791 per 100 000 person years (“a ninefold increase compared to people receiving the lowest dose”). Also, “persons receiving the highest doses were more often men, smokers, had a history of depression treatment and had a history of substance abuse treatment”.

The authors concluded that, “in our study, patients receiving higher doses of medically prescribed opioids for chronic non-cancer pain were at increased risk for overdose relative to patients receiving lower doses.” However, they added, “because few events were observed in the sample, we could not assess overdose risk for specific opioids or risk differences for long-acting versus short-acting opioids.”

Conclusions

The use of statistics sometimes clouds understanding rather than improves it. The simplest conclusion from this study should have been that the rate of fatal overdose is 6/9940 (1 out of every 1656 patients over a 42-month period, or 1 per 5796 patients per year). The non-fatal overdose rate was 45/9940 (1 out of 148 patients over a 42-month period, or 1 out of 516 per year). Calculations of rates per 100 000 person years are not clarifying or particularly useful.

The reported statistical associations between dosage and overdose rates are also not clarifying. Less than 20 mg/day of morphine equivalents is an insignificant dosage for most chronic opioid patients, particularly in the form of hydrocodone. A dosage of >100 mg/day of morphine equivalents is fivefold greater and obviously associated with more profound pain and therefore an increased likelihood of substance abuse, depression and suicide (all of which were reported by the authors).
If one calculates that chronic pain patients take four doses of opioid per day, and that 9940 patients were studied, the annual number of doses of opioid consumed would be 14 512 000. On the basis of this calculation, the rate of fatal overdose would be 1.71 per 14 512 000 doses, or 1.2e−7%; the rate of non-fatal overdose would be 45 per 14 512 000 doses, or 3.1−6%.

Finally, the significance of the statistical association between dosage and overdose rates is questionable. One would ordinarily assume that patients suffering from the greatest pain, and thus requiring the highest dosages of opioid, would also be at much higher risk for depression, suicide and substance abuse. Therefore, any attempt to associate overdose rates and dosage statistically would likely be an artefact of a post hoc error in logic. The causes of an overdose are far more likely to be the extent and duration of pain, depression and suicidality, the extent to which the pain is relieved or naiveté about the use of opioids, rather than the milligram dosage consumed.
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Footnotes
Competing interests None.