Opioid infusions at different times of the day produce varying degrees of opioid-induced hyperalgesia

Bin Shu; Huiting Liu; Xuemei Zheng; Jianrong He; Yingcai Wu; Jie Chen; Yuanjing Chen; Hongni Tian; Dapeng Ju; He Huang; Guangyou Duan

doi:10.1016/j.bja.2023.08.039

Opioid infusions at different times of the day produce varying degrees of opioid-induced hyperalgesia

Br J Anaesth. 2023 Dec;131(6):1072-1081. doi: 10.1016/j.bja.2023.08.039. Epub 2023 Oct 9.

Authors

Bin Shu¹, Huiting Liu², Xuemei Zheng¹, Jianrong He¹, Yingcai Wu¹, Jie Chen¹, Yuanjing Chen¹, Hongni Tian¹, Dapeng Ju¹, He Huang¹, Guangyou Duan³

Affiliations

¹ Department of Anaesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
² Department of Anaesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Department of Anaesthesiology, The Third Affiliated Hospital, Chongqing Medical University, Chongqing, China.
³ Department of Anaesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: duangy@hospital.cqmu.edu.cn.

PMID: 37821342
DOI: 10.1016/j.bja.2023.08.039

Abstract

Background: Opioids are metabolised by enzymes the activities of which vary with the circadian rhythm. We examined whether opioid infusions administered at different times of the day produce varying degrees of opioid-induced hyperalgesia (OIH) in animal experiments and clinical studies.

Methods: Male Sprague-Dawley rats received remifentanil infusions (1 μg kg^-1·min^-1 for 1 h) at Zeitgeber times (ZT) 0, 4, 8, 12, 16, or 20 h. Rhythmicity of mechanical hypersensitivity was assayed after the infusion. Mechanical hypersensitivity, drug concentration, and metabolic enzyme activity of Wistar rats that received sufentanil (10 μg kg^-1; four consecutive i.p. injections at 15-min intervals) or remifentanil infusion at ZT0 or ZT8 were assayed. Sixty patients who underwent abdominal laparoscopic surgery under general anaesthesia received remifentanil infusion (0.15 μg kg^-1 min^-1) and sufentanil injection (0.2 μg kg^-1) at induction and skin incision, respectively. Postoperative pressure pain sensitivity, pain Numeric Rating Scale (NRS), drug concentrations, and nonspecific esterase activity were assessed.

Results: Sprague-Dawley rats that received remifentanil infusion exhibited a robust rhythmic paw withdrawal threshold (JTK_CYCLE: P=0.001, Q=0.001, Phase=26). Wistar rats infused with remifentanil or sufentanil at ZT8 exhibited greater OIH (P<0.001) than those infused at ZT0, with higher blood concentrations (P<0.001) and lower metabolic enzyme activities (P=0.026 and P=0.028, respectively). Patients in the afternoon group exhibited higher pressure pain sensitivity at forearm (P=0.002), higher NRS (P<0.05), higher drug concentrations (sufentanil: P=0.037, remifentanil: P=0.005), and lower nonspecific esterase activity (P=0.024) than the morning group.

Conclusions: Opioid infusions administered at different times of day produced varying degrees of OIH, possibly related to circadian rhythms of metabolic enzyme activities.

Clinical trial registration: NCT05234697.

Keywords: circadian rhythm; cytochrome P450 enzyme; nonspecific esterase; opioid-induced hyperalgesia; remifentanil; sufentanil.

MeSH terms

Analgesics, Opioid*
Animals
Carboxylesterase
Humans
Hyperalgesia* / chemically induced
Male
Pain, Postoperative / drug therapy
Piperidines
Rats
Rats, Sprague-Dawley
Rats, Wistar
Remifentanil / adverse effects
Sufentanil / adverse effects

Substances

Analgesics, Opioid
Remifentanil
Sufentanil
Piperidines
Carboxylesterase

Associated data

ClinicalTrials.gov/NCT05234697