Antidepressants May Curb Opioid Overdose

Batya Swift Yasgur, MA, LSW

July 14, 2022

Patients with a history of depression who are also being treated with opioid analgesics have a lower risk for overdose and self-harm after taking antidepressants, new research suggests.

Investigators analyzed insurance claims for more than 200,000 adults with a history of depression. Of these, 8200 experienced adverse events (AEs) during the year after initiation of opioid therapy.

However, the risk for an AE such as overdose and other forms of self-harm was reduced among patients who had been treated with antidepressants for at least 6 weeks.

The take-home message is that clinicians and health systems need to be more aware that individuals in pain are more likely to be depressed and at higher risk for AEs ― so the depression should be treated "more liberally," corresponding author Bradley Stein, MD, PhD, a practicing psychiatrist in Pittsburgh, Pennsylvania, and director of the Rand Corporation Opioid Policy Center, told Medscape Medical News

"If you are treating someone with pain, particularly chronic pain, it's critically important to better assess their depression and not to attribute depressive symptoms only to pain," Stein said.

The findings were published online June 30 in Psychiatric Services.

Promising Approach?

Opioid treatment for pain "complicates the interactions among pain, depression, and self-harm," the investigators write. Individuals with depression receiving long-term opioid therapy are two to three times more likely to misuse opioids, compared with individuals who do not have depression.

Although comorbid depression "substantially increase overdose and suicide risk, it remains underdiagnosed and undertreated among individuals with chronic pain," the researchers note. They add that increasing access to depression treatment may be a "potentially promising approach to preventing overdoses and suicide" in these patients.

"We know that individuals using opioids who have a history of depression are more likely to have negative outcomes, such as overdoses and self-harm events," Stein said. "We wanted to see whether antidepressants, which would treat depression in these individuals, would help with that."

The researchers assessed a database of commercial insurance claims of adults with a history of depression who received opioids between 2007 and 2017 (n = 283,374). The data included 336,599 opioid treatment episodes.

To be included in the study, patients had to have been diagnosed with depression before they filled their first opioid prescription.

The "outcome of interest" was time from the beginning of an opioid episode until an adverse event, such as opioid poisoning, overdose of nonopioid controlled or illicit substances, or self-harm unrelated to overdose.

Participants were followed from the onset of the opioid episode until an AE occurred, loss to follow-up, or week 52, whichever came first.

The "key independent variable" was filling an antidepressant prescription. The patient's sex and age were considered to be independent variables as well.

Teasing Out Antidepressant Effect

Of participants with a history of depression treatment, 8203 experienced at least one AE during the 12 months after treatment initiation (n = 47,486 AEs). Approximately half (50.8%) filled an antidepressant prescription at least once during the 12 months after the opioid episode began.

AEs were more likely among men than among women. The highest risk was in patients aged 18 – 24 years.

After adjusting for age and sex, participants who had received antidepressants had a greater risk for all adverse outcomes during the first 6 weeks of antidepressant treatment. However, those who had received antidepressants for 6 weeks or longer were at reduced risk for all adverse outcomes.

Outcome Adjusted OR, <6 weeks of treatment (95% CI) Adjusted OR, ≥6 weeks of treatment (95% CI)
Any adverse event 1.19 (1.03 – 1.37) .79 (.65 - .97)
Opioid overdose 1.18 (1.02 – 1.37) .78 (.64 - .96)
Overdoses from nonopioid controlled substances 1.18 (1.02 – 1.37) .76 (.62 - .94)
Overdoses from other substances 1.18 (1. 02 – 1.36) .79 (.65 - .97)
Other self-harm events 1.16 (1.00 – 1.34) .82 (.67 – 1.00)


"We took advantage of the fact that, for most people, antidepressants take a while to work and aren't immediately effective, so we were able to use that difference in our research," Stein said.

"We wouldn't expect to see an immediate effect of antidepressants, so the difference between what we saw immediately after the person had started treatment and the time it took for the antidepressant to be effective enabled us to tease out the effect of the antidepressant," he added.

Consider CBT?

Commenting for Medscape Medical News, Andrew Saxon, MD, professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, said clinicians "tend to think categorically and give people diagnoses that are clear-cut." But neurobiologically, "it may be hard to distinguish where chronic pain ends and depression begins, or whether there's some commonality."

For patients with chronic pain and those taking opioids, "we need to be very attuned to the possibility or likelihood that they have major depression and other psychiatric diagnoses, like PTSD and anxiety disorders, which are very common," said Saxon, who is also the director of the Center of Excellence in Substance Abuse Treatment and Education at the VA Puget Sound Health Care System. He was not involved with the current research.

He noted that treating those disorders "is a very important component of managing chronic pain." However, "patients just starting antidepressants need to be carefully monitored when they're getting stabilized on their antidepressants because they can have side effects, particularly early on, that can destabilize them."

Saxon added that beyond pharmacotherapy, cognitive-behavioral therapy (CBT) for pain might be an even better intervention for addressing both pain and depression.

Also commenting for Medscape Medical News, Brian Hurley, MD, an addiction medicine specialist and the medical director of the Division of Substance Abuse Prevention and Control for the Los Angeles County Department of Public Health, California, said: "In the context of the largest wave of overdose mortality in US history, we know comparatively little about the impact of mental health interventions that mitigate overdose risks."

This study "contributes important new information that treating depression with antidepressant medications reduces overdose and self-harm risks for people who are prescribed opioids," said Hurley, who is also the president-elect of the American Society of Addiction Medicine.

It also "underscores the general importance of integrated mental health and substance use disorder treatment in both primary care and in mental health settings," added Hurley, who was not involved with the study.

The study was funded by the National Institute on Drug Abuse. The investigators and commenters reported no relevant financial relationships.

Psychiatr Serv. Published online June 30, 2022. Abstract

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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