DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Overview of Products

Opioids are potent analgesics with established therapeutic indications for the management of acute pain, post-surgical pain and cancer-related pain.¹ In Malaysia, prescription opioids are approved for a range of clinical uses, including the management of moderate to severe pain,^2,3 as an adjunct to anaesthesia for analgesia,³ and for the treatment of opioid addiction.⁴

 

Overview of Safety Concern

Opioid-induced oesophageal dysfunction (OIED) is classified as an oesophageal motility disorder and is diagnosed by abnormal manometric testing in individuals who have been receiving daily opioid therapy for a minimum of three (3) months.⁵ This condition is frequently characterised by manometric findings such as Type III achalasia, oesophagogastric junction outflow obstruction, distal oesophageal spasm, and hypercontractile oesophagus. Clinically, affected patients most commonly present with symptoms of dysphagia, gastroesophageal reflux, and chest pain.^6,7

 

Source of Safety Concern

Health Canada has identified a possible link between the risk of oesophageal dysfunction and the long-term use of prescription opioids.⁶ The safety review was triggered by Health Canada following signals identified in published scientific literature on OIED, including cases with diagnoses confirmed by oesophageal pressure testing, and included an assessment of post-marketing reports from the Canadian Vigilance database. In response, Health Canada is working with the product registration holders to update the relevant product safety information accordingly.

In Canada, prescription opioids are authorised for the treatment of certain types of pain, opioid use disorder, and chronic non-productive cough.⁶ The prescription opioids available in Canada include buprenorphine, butorphanol, codeine, diamorphine, fentanyl, hydrocodone, hydromorphone, pethidine, methadone, morphine, nalbuphine, normethadone, oxycodone, tapentadol and tramadol-containing products.

Among the opioids available in Canada, only nine (9) opioids, either as single-ingredient products or fixed-dose combinations, are registered with the Drug Control Authority (DCA) of Malaysia.⁸ These include buprenorphine, codeine, fentanyl, pethidine, methadone, morphine, nalbuphine, oxycodone, and tramadol, accounting for a total of 87 registered prescription opioid products in Malaysia. While the current review focuses on these nine (9) registered opioids, NPRA is continuing to evaluate whether OIED may also be associated with other locally registered opioid-containing products.

 

Background of the Safety Issue

While the precise mechanism underlying OIED remains unclear, one theory suggests that chronic opioid exposure disrupts the inhibitory neural pathways that regulate normal oesophageal motility.^7,9 This disruption leads to functionally unopposed excitatory signaling, which subsequently causes abnormal oesophageal motor activity.⁹ Specifically, this dysregulation manifests as vigorous, rapid, or simultaneous contractions within the oesophageal body. Furthermore, the mechanism often impairs the relaxation of the lower oesophageal sphincter (LES), thereby contributing to the symptoms observed in OIED.

Research by Snyder et al. demonstrated an association between both opioid strength and daily dosage and the prevalence of OIED.⁹ The study indicated that OIED was significantly more prevalent in patients using the stronger opioids, namely oxycodone and hydrocodone (31% and 28% respectively), compared with those using the weaker opioid tramadol (12%). Furthermore, a clear dose-effect relationship was observed, as patients diagnosed with OIED were receiving a significantly higher median 24-hour opioid dose, specifically 45 mg morphine equivalent dose, compared with 30 mg in patients without OIED. Collectively, these findings support a dose-dependent association between opioid exposure and altered oesophageal motor function.

According to Health Canada, reported cases of patients experiencing OIED were administered daily opioid doses ranging from 30 to 300 mg of morphine per day, with a median daily dose of 67.5 mg.⁶ The time to onset of OIED symptoms varied considerably, typically ranging from several weeks to months following the initiation of continuous daily opioid therapy.

 

Local Adverse Drug Reaction Reports¹⁰

The NPRA has received 6,867 reports with 11,676 adverse events suspected to be related to products containing prescription opioids. There have been no local reports of OIED or any oesophageal-related disorders associated with opioid use. OIED-related symptoms such as dysphagia, or chest pain have been reported for fentanyl, pethidine, methadone, nalbuphine, oxycodone and tramadol. However, considering the co-reported adverse events documented in these reports, such as dyspnoea (21), pruritus (7), hypotension (5), respiratory depression (4), syncope (4), and hyperhidrosis (4), these symptoms were not suggestive of oesophageal dysfunction.

 

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware of the risk of OIED when prescribing long-term opioid therapy.
• Educate patients to seek medical advice if they experience the common symptoms of OIED such as difficult swallowing, gastroesophageal reflux, or chest pain.
• If a patient develops symptoms associated with OIED, the first therapeutic measure to be considered is opioid withdrawal, and the clinical response should be assessed.
• Evidence suggests OIED is more common with stronger opioids and higher daily opioid doses. Consider using the lowest effective dose for the shortest duration, and regularly reassess the ongoing need for opioid therapy.
• Report all suspected adverse events associated with opioid-containing products to the NPRA.

 

References:

1. Zin CS, Abdullah NAD, Ramli NA, Khadir N, Zain NS, Rosley NF, Halimah Bux S. A Bibliometric Analysis of Opioid in Malaysia. J Pharm Bioallied Sci. 2020 Nov;12(Suppl 2):S667-S670. Available from: https://doi.org/10.4103/jpbs.jpbs_283_19
2. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Oxynorm 5mg, 10mg Capsules package insert [Internet]. 2024 Mar [cited 2025 Nov 17]. Available from: http://www.npra.gov.my
3. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Intapan Injection 1ml (10mg/ml) Ampoule package insert [Internet]. 2020 Aug 12 [cited 2025 Nov 17]. Available from: http://www.npra.gov.my
4. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Alphadone Syrup 5mg/ml, 10mg/ml package insert [Internet]. 2017 Oct 12 [cited 2025 Nov 17]. Available from: http://www.npra.gov.my
5. Andrew Leopold, Nicol Tugarinov and Guofeng Xie. Opioid-induced esophageal dysfunction masquerading as type I achalasia. J Neurogastroenterol Motil. 2024; 30(4): 517-519. Available from: https://doi.org/10.5056/jnm24088
6. Health Canada. 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. [Internet]. 2025 Nov 17 [cited 2025 Nov 17]. Available from: https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR1750686507938
7. Ortiz V, García-Campos M, Sáez-González E, delPozo P, Garrigues V. A concise review of opioid-induced esophageal dysfunction: is this a new clinical entity? Dis Esophagus. 2018 May 1;31(5). Available from: https://doi.org/10.1093/dote/doy003
8. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 Dec 19]. Available from: https://www.npra.gov.my
9. Snyder DL, Vela MF. Opioid-induced esophageal dysfunction. Curr Opin Gastroenterol. 2020 Jul;36(4):344-350. Available from: https://doi.org/10.1097/mog.0000000000000648
10. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 Nov 18]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wo Wee Kee, Wang Khee Ing

Reviewed/Edited by: Lim Sze Gee, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali