Summary Safety Review - Prescription Opioids (buprenorphine, butorphanol, codeine, diamorphine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, nalbuphine, normethadone, oxycodone, tapentadol and tramadol) - Assessing the Potential Risk of Esophageal Dysfunction With Long-term Use

Prescription opioids (buprenorphine-, butorphanol-, codeine-, diamorphine-, fentanyl-, hydrocodone-, hydromorphone-, meperidine-, methadone-, morphine-, nalbuphine-, normethadone-, oxycodone-, tapentadol- and tramadol-containing products)

Esophageal dysfunction (impaired function of the esophagus) with long-term use (daily for a few weeks) of prescription opioids

• Health Canada’s review found a possible link between the long-term use of prescription opioids and the risk of esophageal dysfunction.

• Health Canada will work with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for prescription opioids to include the risk of esophageal dysfunction with long-term use.

Health Canada reviewed the potential risk of esophageal dysfunction with the long-term use of prescription opioids. The safety review was triggered by Health Canada’s identification of several scientific studies reporting a possible association between the long-term use of opioids and esophageal dysfunction, confirmed by tests measuring how well the esophagus is working (esophageal pressure testing). Health Canada’s review did not include non-prescription opioid-containing products since this risk has not been reported with these products.

• Prescription opioids are authorized in Canada for the treatment of various conditions including certain types of pain, opioid use disorder and chronic non-productive cough.

• Prescription opioids are widely used and have been marketed in Canada for over 50 years. The prescription opioids included in this safety review are: buprenorphine, butorphanol, codeine, diamorphine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, nalbuphine, normethadone, oxycodone, tapentadol and tramadol. These opioids are available in various formulations and combinations under different brand names. Generic versions are also available.

• While the number of prescriptions dispensed for the majority of opioids has decreased from 2018 to 2023, the overall number of prescriptions remains high.

• Health Canada reviewed the available information from searches of the Canada Vigilance database^a and the scientific literature.

• At the time of the review, Health Canada had received 28 Canadian reports of esophageal dysfunction in patients taking prescription opioids. However, none of these cases met the criteria for further assessment to determine if there was a link due to several contributing factors, such as: incomplete information in the reports, lack of information about when or how long the opioid was taken relative to the esophageal dysfunction, or the reported diagnosis was not confirmed by esophageal pressure testing.

• Health Canada reviewed 14 international cases of esophageal dysfunction in patients taking prescription opioids. Of the 14 cases, 3 were found to be probably linked to the use of prescription opioids and 11 were found to be possibly linked. One death occurred among the 3 cases found to be probably linked, although the death was unlikely to be linked to the use of prescription opioids.

• The patients in the 14 cases were taking doses equivalent to between 30 and 300 mg of morphine per day, with a midrange daily dose of 67.5 mg. Esophageal dysfunction was more likely to occur in patients taking a higher daily opioid dose. The time to onset of symptoms ranged from several weeks to months, with the most common symptoms reported being difficulty swallowing, gastroesophageal reflux and chest pain.

• Health Canada also reviewed articles published in the scientific literature, which identified potential biological mechanisms that may explain how the long-term use of prescription opioids could lead to esophageal dysfunction.

• Health Canada’s review found a possible link between the long-term use of prescription opioids and the risk of esophageal dysfunction.

• Health Canada will work with the manufacturers to update the CPM for prescription opioids to include the risk of esophageal dysfunction with long-term use.

• Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of prescription opioids, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information for prescription opioids, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of prescription opioids both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Canadian reports can be accessed through the Canada Vigilance Online Database.