Saturday, February 13, 2010

Do Higher Opioid Doses Increase Overdose Risks?

EBPM Logo Understanding Evidence-Based Pain Management (EBPM)

Along with increased prescribing of long-term opioid therapy for chronic noncancer pain, rates of fatal opioid overdoses have risen. In a large-scale investigation, patients receiving higher opioid doses were 9 times more likely to overdose than were those prescribed lower doses. However, from an evidence-based pain management perspective, this may be an example of making a mountain of publicity out of a statistical molehill.

Reporting in the Annals of Internal Medicine, a research team at the Group Health Research Institute, Seattle, Washington, examined nearly 9,940 patients attending a large Health Maintenance Organization [Dunn et al. 2010]. Each of the selected patients had received 3 or more opioid prescriptions within a 90-day period for chronic noncancer pain, such as back pain and osteoarthritis, between 1997 and 2005. Average daily opioid doses were calculated from an automated pharmacy database, and primary outcomes — nonfatal and fatal overdoses — were identified through diagnostic codes from inpatient and outpatient care records and death certificates. Data for this report were derived from a larger investigation — the Consortium to Study Opioid Risks and Trends (CONSORT).

During the 9 years of collected data, 51 opioid-related overdoses were identified, which included 6 deaths. Compared with patients receiving 1 to 20 mg/day of morphine-equivalent opioids and experiencing a 0.2% annual overdose rate, those taking 50 to 99 mg/d had a 3.7-fold (95% CI, 1.5-9.5) increase in overdose risk (0.7% annual overdose rate). Patients prescribed 100 mg/d or more had an 8.9-fold (CI, 4.0-19.7) increase in overdose risk (1.8% annual overdose rate). The study authors concede that the overall number of overdoses was small and the absolute number of overdoses occurred mostly among patients receiving low to medium doses, because prescriptions at those levels were much more common. Furthermore, the rates may be confounded by patient differences and by misuse of opioids in ways not intended by prescribing physicians. Still, they conclude that, “Patients receiving higher doses of prescribed opioids are at increased risk for overdose, which underscores the need for close supervision of these patients.”

CLINICAL COMMENTARY: Naturally, the medical news media had a heyday with this study report, with headlines broadcasting “new” dangers of opioid analgesics and an implication that prescribers are killing patients with high doses of opioids. However, a close examination of the research report raises important doubts:
  • Based on our own crude hazardous-event-rate analysis, during the 9-year study period the total opioid overdose incidence was only 0.0017% and the fatality rate was 0.0002%. (This takes into account roughly 10,000 patients conservatively taking an estimated 3 doses per day for 90 days, or a total of 2.7-million potentially hazardous opioid exposures). Are these very small incidence rates of greatly alarming proportions?

  • Fewer than a quarter (22%) of overdoses occurred in patients taking >100 mg/d of morphine-equivalent opioids. Properly prescribed opioid therapy, gradually titrated to achieve tolerance, should not pose any greater overdose risk at a higher versus lower ultimate dose. The study authors note that, “Elevated overdose risk was observed in persons recently receiving prescribed opioids in all subgroups [ie, at all dose levels].” Therefore, overdose may have been more a function of improper prescribing with overly rapid titration during early stages of opioid therapy — the induction period, which can be more hazardous — than the final dose.

  • The authors state that, "For every fatal overdose in our study, 7 nonfatal overdoses occurred, and most of the nonfatal overdoses were medically serious." Yet, there are some very interesting clinical aspects of the overdose cases:

    1. Sedative hypnotics had been prescribed in roughly three-quarters of participants (74.4%), including benzodiazepines in approximately 43%. Combined with opioids, at any dose, these agents may have influenced adverse events.

    2. Eight cases involved accidental excess ingestion of opioids, and 6 were suicide attempts.

    3. Three persons obtained additional opioids illicitly, 4 patients applied extra fentanyl patches, and drug abuse was noted in 4 patients.

    4. The largest categories of clinical effects associated with overdose were: delirium, loss of consciousness, or confusion (n=23), respiratory problems (n=15), and falls (n=4). Were some of these side effects rather than overdose?

    5. Overdose rates were higher among persons aged 65 years or older, and among patients with a history of depression or substance abuse. More than a quarter of patients (26.9%) were diagnosed with depression.

    Therefore, it appears that many overdose cases might have been associated with cooccurring conditions or misbehaviors unrelated to opioid dose, while others may have been avoided by better patient education and/or closer monitoring. The overall mean morphine-equivalent opioid dose itself was only 13.3 mg/day, so patients on average may have been receiving inadequate analgesia and this might have motivated opioid misuse leading to overdose in some cases.

  • Most of these patients with chronic pain (90.4%) had been prescribed short-acting opioids (primarily hydrocodone, oxycodone, and codeine combinations). Only 1 in 10 (9.6%) of study participants had been prescribed long-acting opioids, which might be more appropriate for chronic pain. This also raises further questions about why the FDA has such an interest in mandating REMS (Risk Evaluation and Mitigation Strategies) for long-acting opioids and is exempting short-acting formulations that are more frequently prescribed (and more prone to overdose, at least in this study).
A general concern about research of this nature, purely from a quality-of-evidence perspective, is that it is somewhat of an exercise in “data mining.” That is, taking a large accumulated body of facts and figures collected in a preexisting database and using analytical techniques to come up with “significant” statistical outcomes and conclusions of interest. Since such studies are not initiated prospectively — following well-developed protocols for participant inclusion, clinical observations, and data recording to examine the primary outcomes — there can be a high potential for data errors and biases in the reports. Indeed, this current study seems to be rather exploratory, reaching conclusions that appear to have “face validity” but are not fully reflective of objective evidence.

All of this is not to say that opioid overdoses and related deaths are of little or no consequence. According to a recent report from the CDC [MMWR 2009], during 2004 to 2007 in Washington state (where the Dunn et al. study took place) there were 1,668 fatalities due to opioid overdoses (0.006% annual incidence rate in the total population). However, in the CDC data, more than one drug was listed in death certificates for 72.3% of decedents, including a benzodiazepine in 21%, an antidepressant in 32%, and/or an illegal drug in 22% of deaths. Therefore, so-called “opioid related” overdoses and fatalities are actually more complex phenomena in many cases, involving the interface and interaction of multiple factors. While it may be easy to blame opioids and call for broad changes in prescribing practices, such proclamations may be publicity ploys rather than problem solutions.
SIDE NOTE: In a prior blogpost we advocated for the at-home availability of intranasal naloxone, an opioid antagonist and antidote, for preventing or reversing opioid overdose [see blogpost 12/4/09]. We wonder how many overdoses might have been averted and lives saved if the large HMO examined in the Dunn et al. study had invested roughly $25/patient to provide take-home intranasal naloxone, with instructions, for each patient prescribed long-term opioids for chronic pain.
> 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 [
> MMWR [2009;58:1171-1175]. Reported in: Overdose death involving prescription opioids among medicaid enrollees — Washington, 2004-2007. JAMA. 2010;303(1);21-22.