Researchers at the University of Manchester have identified which opioids are most likely to be associated with respiratory depression in a major new study.
Fentanyl, opioid combination therapy, oxycodone, and morphine are associated with a higher risk compared to codeine in patients treated for non-cancer pain.
This research was funded by a National Institute for Health and Care Research (NIHR) Advanced Fellowship and supported by the NIHR Manchester Biomedical Research Center (BRC) and the Northern Care Alliance NHS Foundation Trust.
Their findings were published in BMC Medicine on August 7, 2026. It was announced amid concerns that the use of prescription opioids for non-cancer pain has skyrocketed in recent decades across North America and Europe, and the UK NHS Healthcare Optimization Goal to reduce high-dose opioid prescribing and harm.
Researchers analyzed electronic health records from 32,909 adult inpatients at a large hospital in the northwest of England.
They used electronic vital signs to assess when patients developed respiratory depression or were given naloxone, a life-saving drug used to reverse respiratory depression caused by opioid overdose.
Prescription fentanyl was associated with more than three times the risk of respiratory depression compared to codeine.
Concomitant use of opioids nearly tripled the risk of respiratory depression.
Oxycodone and morphine were associated with a significantly higher risk compared to codeine.
When compared directly to morphine, fentanyl still showed almost twice the risk, but combination opioids also remained significantly riskier.
Patients receiving 120 or more morphine milligram equivalents (MME) per day had twice the risk of respiratory depression compared to patients receiving less than 50 MME.
Even moderate doses (as low as 31 to 60 MME per day) were associated with 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 depresses breathing more rapidly than other opioids.
Oxycodone’s role in opioid-related deaths in North America further heightens concerns about its respiratory effects.
The study also found that COPD patients faced an even greater risk, with fentanyl associated with a four-fold increase in respiratory depression in this group.
These results suggest that people with chronic respiratory diseases may be particularly vulnerable to the effects of strong opioids.
Although up to 80% of fatal opioid-related overdoses are unintentional, most are caused by opioid-induced respiratory depression, which slows breathing to life-threatening levels.
All strong opioids act on the same receptor system, but differ in how they affect respiratory control.
As part of the study, we were also able to assess the additional risks associated with the co-administration of other medications that may be prescribed for pain, anxiety, and sleep disorders, such as gabapentinoids and benzodiazepines.
In particular, the concomitant use of gabapentinoids and opioids was associated with an increased risk of respiratory depression. ”
Carlos Raul Ramírez, first author and researcher, University of Manchester
Senior author Dr Meghna Jani, NIHR Senior Research Fellow and Senior Clinical Lecturer at the University of Manchester, said: “Opioids remain important drugs for managing severe acute pain. Our findings show that the risks are not the same for all opioid drugs or doses.
“The main strengths of our study were the use of detailed hospital electronic health records to know exactly when opioids were actually administered to patients, and the availability of regularly collected vital signs to identify changes in breathing.”
Dr Jani, who is also a rheumatology and musculoskeletal disease theme researcher at Manchester BRC, added: “Understanding how different drugs and combinations affect respiratory safety can help clinicians and patients make more informed prescribing decisions together and increase awareness of which dose thresholds require close monitoring.”
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University of Manchester
