Impact of High-Dose Opioids on Overdoses

Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality | Pain Medicine | Oxford AcademicJanuary 2016


Previous studies examining opioid dose and overdose risk provide limited granularity by milligram strength and instead rely on thresholds.

We quantify dose-dependent overdose.

Spoiler: there is no linear or incremental increase in overdose risk by dosage.  The 90MME limit proposed by the CDC Guideline isn’t based on science, but more like a consensus “best guess” by addiction doctors. 

mortality over a large spectrum of clinically common doses. We also examine the contributions of benzodiazepines and extended release opioid formulations to mortality.

Design. Prospective observational cohort with one year follow-up.

Setting. One year in one state (NC) using a controlled substances prescription monitoring program, with name-linked mortality data.

Subjects. Residential population of North Carolina (n = 9,560,234), with 2,182,374 opioid analgesic patients.

Methods. Exposure was dispensed prescriptions of solid oral and transdermal opioid analgesics; person-years calculated using intent-to-treat principles. Outcome was overdose deaths involving opioid analgesics in a primary or additive role. Poisson models were created, implemented using generalized estimating equations.


Opioid analgesics were dispensed to 22.8% of residents.

Among licensed clinicians, 89.6% prescribed opioid analgesics, and 40.0% prescribed ER formulations.

There were 629 overdose deaths, half of which had an opioid analgesic prescription active on the day of death.

Of 2,182,374 patients prescribed opioids, 478 overdose deaths were reported (0.022% per year).

Mortality rates increased gradually across the range of average daily milligrams of morphine equivalents.

80.0% of opioid analgesic patients also received benzodiazepines.

This just shows how the symptoms of anxiety and stress are unleashed by chronic pain, making the co-prescribing of pain relievers (opioids) and anxiety relievers (benzodiazepines) a common and appropriate medical practice.

Rates of overdose death among those co-dispensed benzodiazepines and opioid analgesics were ten times higher (7.0 per 10,000 person-years, 95 percent CI: 6.3, 7.8) than opioid analgesics alone (0.7 per 10,000 person years, 95 percent CI: 0.6, 0.9).

This is easily explained by the increasing anxiety that comes along with increasing intractable pain.

Not being able to earn a living and having pain limit almost all activities, both necessary and enjoyable, is a powerful stressor in itself.


Dose-dependent opioid overdose risk among patients increased gradually and did not show evidence of a distinct risk threshold.

There is urgent need for guidance about combined classes of medicines to facilitate a better balance between pain relief and overdose risk.


This study reports findings from the largest known prospective cohort study of opioid analgesic use in routine medical practice.

While there may be a place for high-dose opioid formulations in modern medicine, previous research provided little insight on risks above 100 MME.

These results extended the knowledge of the relationship between opioid analgesic use and mortality by clarifying dose-specific risks at higher doses.

The dose-dependent relationship between opioid analgesic dose and overdose mortality is strongly influenced by concurrent benzodiazepine exposure, especially in the presence of higher opioid doses.

Overdose mortality rates rose gradually at lower doses, and increased gradually at doses greater than 200 mg average daily MME.

Like previous studies, a dose–response relationship between MME and mortality risk was observed, but there is new evidence that the shape of the curve is not linear. Unlike previous studies, there was no meaningful inflection of the incidence rate at 100 mg/day average daily MME.

However, there appeared to be relatively small additional risk of overdose death after patients reach 200 mg average daily MME, relative to the lowest strata, on the log-linear scale. Theoretically, opioid tolerance may be part of the explanation. Increased opioid tolerance results in a rightward shift of the median effective dose, which may be accompanied by a corresponding shift in the median toxic dose, resulting in a broader or shifted therapeutic window where medication errors may be less likely to lead to respiratory depression.

A surprising finding was that benzodiazepines had been prescribed in the previous year to eight-out-of-ten patients receiving opioid analgesics, despite widespread clinical knowledge of the risk of respiratory depression and electronic access to a controlled substances prescription monitoring program. This is in comparison to 5% of the adult US population receiving benzodiazepines

This isn’t surprising at all, considering that chronic pain causes muscle spasms and becoming disabled is anxiety-inducing. Drugs like Valium are not just anti-anxiety medications, but also powerful muscle spasm relaxants.

However since so many studies like this ignore the pain that motivates opioid prescribing, and this blindness makes for results that researchers find surprising but patients find validating.

This situation differs considerably from opioid analgesic efficacy clinical trials that exclude patients with psychiatric diagnoses for conditions routinely treated with benzodiazepines (e.g., anxiety, etc.) in the United States.

While “access to care” is a commonly described concern in pain management, there is no accepted way to quantify it.

While increased prescribing by primary care doctors has led to wider access to pain treatment, a general concern is that non-specialized clinicians may not have been adequately trained to prescribe these medications safely.

Many ER opioid analgesics have approved single unit doses greater than 100 mg/day MME. There is limited information from general practice settings to guide clinical decisions at these higher doses.

The increase in the 160–179.9 mg/day MME interval represents risk from the most commonly prescribed dose strengths of the fentanyl patch.

Methods for calculating MME which do not take into account overlapping prescriptions (e.g., total mg MME for all prescriptions divided by the sum of days supply) underestimate the risk in this specific category. Therefore, it is critical to account for overlapping prescriptions, and justifies taking a person-time approach to MME calculation with intent-to-treat principles.

This is far from the only thing that justifies individualized prescribing

It is important to consider that patients at higher doses, especially those on stable for long periods of time, may be chronic pain patients under the care of a physician.

Being on stable high doses of opioids indicates the person is a chronic pain patient. It’s hard to imagine that any illicit opioid user would ever be considered stable and on high doses.

Given that 24% of decedents had no prescription opioid analgesic history in the year preceding death, it is clear that some of the drugs used in overdose deaths are obtained through social sharing outside of sanctioned medical use.

This is similar to the 26% and 16% of methadone and other opioids overdose decedents, respectively, not having opioid prescriptions in a Washington state Medicaid study

The findings suggest that history of opioid analgesic prescription is neither necessary nor causal to experience an overdose, but that opioid availability from a licensed clinician is one factor in a likely complex individual risk environment.

If merely access to opioids correlated with overdoses, anyone who has ever had a tooth extraction or a minor cosmetic surgery would be dead.

The greatest limitation of this study stems from the inherent question of exchangeability when comparing patients at different doses of the same medication in observational studies.

Patients receiving higher doses are more likely to have more serious illnesses which may necessitate higher doses.

This is the first time I’ve seen a statement about high opioid doses correlating with severity of illness that I’ve seen in these studies.

Deaths involving opioid analgesics result from physiologic, genetic, and behavioral factors, compounded by broader social determinants such as health literacy, poverty, access to healthcare, and further upstream causes of painful conditions from injuries, cancer and violence.

These characteristics may also influence the likelihood of receiving a prescription for an opioid analgesic.

Data on these potential confounders are not routinely available at an individual level in large population-based studies, and were thus not controlled for in this study.


Higher doses of opioid analgesics were associated with increased overdose risk, however, there were smaller incremental increases in risk above 200 mg average daily MME.

Much of the risk at higher doses appears to be associated with co-prescribed benzodiazepines.

10 thoughts on “Impact of High-Dose Opioids on Overdoses

  1. canarensis

    I love you. I’m gonna print this out & take it to my next appointment…it just moved to #1 on the list. In fact, I think I’ll take this one only. Given the state I’m stuck in it won’t do any good, but it’s lovely to have something so clear & straightforward showing the truth.

    Liked by 2 people

  2. louisva

    My, my. I have to be the poster boy of high dose patients that also took Benzos. Last time I checked I seem to be alive. Yes, eight beautiful years of low pain and high QOL. It’s good to be here; in fact, it’s good to be just about anywhere? I’m dreaming about low pain.

    Liked by 2 people


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