CDC presents data showing that per capita opioid analgesic sales increased in a roughly parallel manner during that interval.
The authors of the report carefully avoid saying that the increase in opioid-analgesic-related deaths is caused by increased opioid analgesic sales (perhaps because they do not actually test this relationship statistically), but the clear implication is that increased prescribing is leading to increased sales and deaths.
In contrast, an examination of other available data may not be especially supportive of this implication and suggests at least 6 alternative explanations.
Relevant Data: National Survey on Drug Use and Health (NSDUH)
The NSDUH is a national survey conducted every year by the Substance Abuse and Mental Health Services Administration [SAMHSA 2011], an agency of the US Department of Health and Human Services.
Regarding these data, a couple of considerations must be noted
First, nonmedical use, as defined in NSDUH, may represent at least two distinct phenomena:
a) use of opioid analgesics that had been prescribed to someone else by the respondent to treat their own pain (or, “medical misuse”), and
b) use to alter one’s mood or mental status (“recreational use”).
Second, in DSM-IV-TR — or, the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision, from the American Psychiatric Association — opioid abuse and opioid dependence are subtypes of substance use disorders, and are the nearest approximation to what others call “addiction.”
Looking at these data (Figure at right) it seems apparent that rates of NMU and OUD among Americans 12 years old and older are remarkably stable throughout this 9-year time period.
Alternative Explanation #1: Dependent Variable Problems
CDC gathers these data from death certificates filed with state agencies across the country. Three possible difficulties with the quality of these data are immediately obvious:
In the MMWR document, opioid-related overdose deaths are noted to include deaths of any intent, including unintentional, suicide, homicide, or undetermined.
Suicide and homicide are very different from unintentional overdose deaths, and the ‘undetermined’ category undoubtedly includes some combination of the other three in unknown proportions. Thus, we do not know how many were truly unintentional overdoses.
There is no standard definition of an opioid-related overdose death
Many death certificates are completed by county coroners. Qualifications for county coroners vary widely across the United States and, in some jurisdictions, coroners are not even required to be medical professionals
Alternative Explanation #2: Greater Use of Riskier Medications
the explanation for increased mortality most likely lies in some change in patterns of behavior among the roughly 4.8% to 4.9% of Americans 12 or older who are “nonmedical users” of opioids. One possible change is a shift in the specific opioid analgesics used.
Alternative Explanation #3: Lethal Doses of Medications
It is not clear if there are data to support this notion, but perhaps those engaging in NMU are using the same medications, but at higher potency.
If there is a trend away from misusing longer-acting or controlled-release formulations and substituting instead immediate-release versions of the same drugs at roughly the same dose, the effect could be two-fold:
1) shorten the time in which a maximum concentration of drug is reached in the blood (t-max), and
2) increase the maximum total concentration in the blood (c-max) — thus producing greater respiratory depression and a greater likelihood of death.
Alternative Explanation #4: More Frequent Use of Concomitant CNS Depressants
Most fatal overdoses involving opioid analgesics entail the simultaneous use of other central nervous system depressants, such as barbiturates, benzodiazepines, and/or alcohol [Hall et al. 2008], and there could be a greater tendency to use opioid analgesics in conjunction with these other drugs
Alternative Explanation #5: More Frequent Episodic Rather Than Daily Use
All that is known about individuals engaging in NMU of opioid analgesics is that a small proportion (those with an Opioid Use Disorder, or OUD) are likely to be using them on a very regular basis, and are more likely to be opioid tolerant.
It is possible that those engaging in NMU without developing OUD are increasingly “bingeing” in such use, exposing themselves to greater mortality risks because their tolerance to respiratory depression is diminished compared with those who use opioids regularly.
Alternative Explanation #6: Shifts in the Type of NMU
As outlined above, there are two primary types of nonmedical use, or NMU:
- medical misuse and
- recreational use.
Perhaps the observed increases in opioid analgesic prescribing means that more people are having their pain controlled through legitimate means, thereby reducing the number of medical misusers.
If that is true (and it would represent good news), then the stable rate of NMU would suggest that most of those aberrant behaviors are associated with recreational use, and that more people are engaging in recreational use.
All of this suggests that it is recreational users who may be at greatest risk of fatal overdose, and their increasing numbers may be fueling the increased opioid-related death rate.
The Implied Research Agenda
CDC, in the MMWR document that spurred this discussion, proposes a number of policy solutions for the reported problem of increased opioid-related deaths. However, it is unclear that the solutions are based on a clear understanding of what is producing the problem, and it is equally unclear if the solutions would be effective
Just as a physician faced with a patient experiencing elevated blood pressure must work through a differential diagnosis to find the appropriate treatment, CDC and the medical community must work through a differential diagnosis of the overdose mortality problem to find appropriate solutions.
The 6 alternative explanations above comprise a list of alternate “diagnoses,” which must either be ruled out or accepted, and each of those may suggest different policy responses.
Efficient and effective efforts to solve this problem can only be undertaken if we fully understand the nature of the problem. Let’s first get the proper research done, so we can move on with solving the problem.