Researchers identify opioids with highest risk of respiratory depression

by Mike Addelman, University of Manchester

edited by Sadie Harley, reviewed by Andrew Zinin

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Fentanyl, combination opioid treatments, oxycodone and morphine are associated with higher risks compared with codeine among patients treated for non-cancer pain. University of Manchester researchers have identified which opioids are most likely to be associated with respiratory depression, in a major new study.

Their findings, published in BMC Medicine, come amid concerns in recent decades over the soaring use of prescribed opioids for non-cancer pain across North America and Europe and NHS England Medicine Optimization targets to reduce high-dose opioid prescribing and harms.

The researchers analyzed electronic health records from 32,909 adult inpatients at a large hospital in northwest England. They evaluated when patients developed respiratory depression using electronic vital signs or were given naloxone, a life-saving medicine used to reverse breathing suppression due to an opioid overdose. Prescribed fentanyl was associated with more than triple the risk of respiratory depression compared with codeine.

Combinations of opioids carried nearly three times the risk of respiratory depression. Oxycodone and morphine were linked to significantly higher risks compared with codeine. When compared directly with morphine, fentanyl still showed almost double the risk, while combination opioids also remained substantially riskier.

Patients receiving 120 morphine milligram equivalents (MME) per day or more had double the risk of respiratory depression compared with those on less than 50 MME. Even moderate doses—as low as 31–60 MME per day—were linked to a measurable increase in the risk of respiratory depression.

Additionally, the combination of opioids and gabapentinoids, such as gabapentin and pregabalin, was associated with a further increased risk of respiratory depression. Fentanyl's high potency and rapid brain uptake help explain why it suppresses breathing more abruptly than other opioids. Oxycodone's role in opioid-related deaths in North America adds further weight to concerns about its respiratory effects.

The study also found that patients with COPD faced even greater risks, with fentanyl linked to a fourfold increase in respiratory depression in this group. These results suggest people with chronic respiratory disease may be especially vulnerable to the effects of potent opioids.

Fatal overdoses associated with opioids, up to 80% of which are unintentional, are most often caused by opioid-induced respiratory depression, where breathing slows to life-threatening levels.

Although all potent opioids act on the same receptor system, they differ in how they affect respiratory control.

First author Carlos Raul Ramirez, a research associate at The University of Manchester, said, "As part of our study we were also able to assess the additional risk associated with other co-administered medications, such as gabapentinoids and benzodiazepines, which may be prescribed for pain, anxiety and sleep problems.

"The use of gabapentinoids with opioids in particular was associated with an increased risk of respiratory depression."

Senior author Dr. Meghna Jani, NIHR Advanced Fellow and senior clinical lecturer at The University of Manchester, said, "Opioids remain important medicines for managing severe acute pain. Our findings show that the risks are not the same across all opioid drugs or doses.

"A key strength of our study was our ability to use detailed hospital electronic health records to accurately capture when opioids were actually administered to patients, alongside routinely collected vital signs to identify changes in breathing."

Jani, who is also a researcher within the Rheumatic and Musculoskeletal Diseases Theme at Manchester BRC, added, "Understanding how different medicines and combinations affect respiratory safety can help clinicians and patients make more informed prescribing decisions together, as well as increasing awareness of what dose thresholds require closer monitoring."

Publication details

Opioid-specific Risk of Respiratory Depression in Non-Cancer Pain: A Retrospective Cohort Study, BMC Medicine (2026).

Journal information: BMC Medicine

Key medical concepts

Depressions, VentilatoryFentanylGabapentinoidsCOPD

Clinical categories

Clinical pharmacologyPulmonary medicine Provided by University of Manchester Who's behind this story?

Sadie Harley

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