-Original-

Opioid-Related Respiratory Depression in Non-Cancer Patients, as Reported in the Japanese Adverse Drug Event Report Database

Hideki Sugawara^1,8, Mayako Uchida^2,8, Shinya Suzuki^3,8, Yukio Suga^4,8, Yoshihiro Uesawa^5,8, Takayuki Nakagawa^6,8 and Hisamitsu Takase^7,8

¹Department of Pharmacy, Kagoshima University Hospital, Kagoshima, Japan
²Department of Education and Research Center for Pharmacy Practice, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyoto, Japan
³Department of Pharmacy, National Cancer Center Hospital East, Chiba, Japan
⁴Department of Clinical Drug Informatics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical & Health Science, Kanazawa University, Ishikawa, Japan
⁵Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo, Japan
⁶Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
⁷Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan
⁸Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences, Osaka, Japan

Background: Opioid-induced respiratory depression (RD) is a potentially life-threatening adverse drug event. This study used the Japanese Adverse Drug Event Report (JADER) database to investigate the profile of opioid-related RD in non-cancer patients.
Methods: We analyzed data recorded in the JADER database between April 2004 and February 2020, which were downloaded from the Pharmaceutical and Medical Devices Agency website. Reporting odds ratios for RD were calculated for the 20 opioids approved in Japan, and daily dose and onset time were further analyzed for opioids used in chronic non-cancer pain (CNCP).
Results: Among the opioids, RD adverse event signals were detected for 22 combinations of opioids and administration routes in non-cancer patients. Of these combinations, transdermal buprenorphine and oral tramadol/acetaminophen were approved for CNCP and tended to be reported more frequently in elderly patients. The median daily doses of transdermal buprenorphine and oral tramadol/acetaminophen were 10.0 and 22.5 mg of daily oral morphine equivalent doses, respectively, which are within the standard range for starting dosage. The median time-to-onset of transdermal buprenorphine and oral tramadol/acetaminophen was 6.5 and 4.0 days, respectively, and 75% of cases were reported within 20 to 40 days after the start of treatment. The hazard type for both opioids was classified as early failure.
Conclusions: Our findings suggest that elderly CNCP patients should be closely monitored after the start of opioid treatment, especially during the first week and, if possible, for 1 month, even if starting doses are within ranges recommended by the manufacturer and guidelines.

J Nippon Med Sch 2023; 90: 439-448

Keywords
opioid, non-cancer patients, respiratory depression, Japanese Adverse Drug Event Report database, time-to-onset analysis

Correspondence to
Hideki Sugawara, Department of Pharmacy, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima 890-8520, Japan
suu@m2.kufm.kagoshima-u.ac.jp

Received, November 22, 2022
Accepted, May 22, 2023