Opioids in postoperative pain treatment: Studies on analgesic efficacy and reduction of opioid-induced side effects

Opioids have an important role in the treatment of postoperative pain, making them essential drugs in the field of anesthesiology. However, opioids have common side effects such as nausea, vomiting, constipation and respiratory depression. Recently there has also been focus on a less known side effect, opioid-induced hyperalgesia, when paradoxical lowering of the pain threshold increases pain after opioid use. In her thesis, «Opioids in postoperative pain treatment. Studies on analgesic efficacy and reduction of opioid-induced side effects» Marlin Comelon has conducted three randomized controlled trials on the analgesic effect and side effects of opioids with relevance in the postoperative setting. In the first study, no effect on constipation was found from adding peripherally acting naloxone to the opioid oxycodone after hysterectomy. Naloxone did, however, not antagonize the analgesic effect of oxycodone. The second study focused on tapentadol which combines effects from µ-opioid receptors and noradrenaline reuptake inhibition for analgesia. Similar analgesic effects from tapentadol and oxycodone after hysterectomy were found, but the patients receiving tapentadol had less nausea and need for antiemetics. The third study was an experimental crossover study on healthy volunteers. It demonstrated that gradual withdrawal of remifentanil infusion, as opposed to abrupt withdrawal, could prevent opioid-induced hyperalgesia. The two clinical studies in the thesis contribute to the evidence on which patients may have benefits from these drugs over standard treatment. Oxycodone-naloxone is not likely to have effect in patients with normal risk of postoperative constipation but can be an alternative for long-term use in patients with a high risk of constipation. Tapentadol is an option for patients with previous postoperative nausea and vomiting. The study on opioid-induced hyperalgesia helps increase awareness of adverse postoperative effects from perioperative opioids

Determination of equi-analgesic doses of inhaled methoxyflurane versus intravenous fentanyl using the cold pressor test in volunteers: a randomised, double-blinded, placebo-controlled crossover study

Background Inhaled methoxyflurane for acute pain relief has demonstrated an analgesic effect superior to placebo. Data comparing methoxyflurane to an opioid are needed. The aim of this study was to determine the equi-analgesic doses of inhaled methoxyflurane vs i.v. fentanyl. Both drugs have an onset within minutes and an analgesic effect of 20–30 min. Methods Twelve subjects were included in a randomised, double-blinded, placebo-controlled crossover study with four treatments: placebo (NaCl 0.9%), fentanyl 25 μg i.v., fentanyl 50 μg i.v., or inhaled methoxyflurane 3 ml. The subjects reported pain intensity using the verbal numeric rating scale (VNRS) from 0 to 10 during the cold pressor test (CPT). The CPT was performed before (CPT 1), 5 min (CPT 2), and 20 min (CPT 3) after drug administration. Results Inhaled methoxyflurane and fentanyl 25 μg reduced VNRS scores significantly compared with placebo at CPT 2 (–1.14 [estimated difference in VNRS between treatment groups with 95% confidence interval {CI}: –1.50 to –0.78]; –1.15 [95% CI: –1.51 to –0.79]; both P<0.001) and CPT 3 (–0.60 [95% CI: –0.96 to –0.24]; –0.84 [95% CI: –1.20 to –0.47]; both P<0.001). There were no significant differences between the two drugs. Methoxyflurane had significantly higher VNRS scores than fentanyl 50 μg at CPT 2 (0.90 [95% CI: 0.54–1.26]; P<0.001) and CPT 3 (0.57 [95% CI: 0.21–0.94]; P<0.001). Conclusions Inhaled methoxyflurane 3 ml was equi-analgesic to fentanyl 25 μg i.v. at CPT 2. Both resulted in significantly less pain than placebo. Fentanyl 50 μg i.v. demonstrated analgesia superior to methoxyflurane. Clinical trial registration NCT0389480

Haemodynamic effects of methoxyflurane versus fentanyl and placebo in hypovolaemia: a randomised, double-blind crossover study in healthy volunteers

Background: Methoxyflurane is approved for relief of moderate to severe pain in conscious adult trauma patients: it may be self-administrated and is well suited for use in austere environments. Trauma patients may sustain injuries causing occult haemorrhage compromising haemodynamic stability, and it is therefore important to elucidate whether methoxyflurane may adversely affect the haemodynamic response to hypovolaemia. Methods: In this randomised, double-blinded, placebo-controlled, three-period crossover study, inhaled methoxyflurane 3 ml, i.v. fentanyl 25 μg, and placebo were administered to 15 healthy volunteers exposed to experimental hypovolaemia in the lower body negative pressure model. The primary endpoint was the effect of treatment on changes in cardiac output, while secondary endpoints were changes in stroke volume and mean arterial pressure and time to haemodynamic decompensation during lower body negative pressure. Results: There were no statistically significant effects of treatment on the changes in cardiac output, stroke volume, or mean arterial pressure during lower body negative pressure. The time to decompensation was longer for methoxyflurane compared with fentanyl (hazard ratio 1.9; 95% confidence interval 0.4–3.4; P=0.010), whereas there was no significant difference to placebo (hazard ratio −1.3; 95% confidence interval −2.8 to 0.23; P=0.117). Conclusions: The present study does not indicate that methoxyflurane has significant adverse haemodynamic effects in conscious adults experiencing hypovolaemia. Clinical trial registration: ClinicalTrials.gov (NCT04641949) and EudraCT (2019-004144-29) https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004144-29/NO

Toll-like receptor 4 deficient mice do not develop remifentanil-induced mechanical hyperalgesia

Background: Drugs with antagonistic actions on the Toll-like receptor 4 (Tlr4), such as naloxone at ultra low doses, have been used to inhibit opioid-induced hyperalgesia in rodents suggesting the involvement of this receptor and pathway on opioid-induced hyperalgesia. Objective: The aim of this study was to determine whether mice without the Tlr4 gene (Tlr4) would not develop remifentanil-induced hyperalgesia. Design: An experimental randomised animal study. Setting: Experimental Unit, Complutense University of Madrid, Madrid, Spain. Animals: Twelve adult female wild-type mice and 12 adult Tlr4 mice. Interventions: Under sevoflurane anaesthesia, a 1-h, constant rate subcutaneous infusion of remifentanil (4 μg kg min) or 0.9% saline. Main outcome measures: Mechanical nociceptive thresholds were evaluated using a von Frey hair test before (baseline) and on days 5, 6 and 7 after treatment. Hyperalgesia was considered to be a decrease in the mechanical nociceptive threshold. Changes in mechanical nociceptive thresholds in the different groups were compared with one-sided paired t tests. Results: Baseline mechanical nociceptive thresholds were similar in all groups (2.2 ± 0.1 g). Remifentanil produced a 24% decrease in mechanical nociceptive thresholds in the wild-type mice (1.7 ± 0.0 g, averaged over 3 days, P = 0.00021), whereas the nociceptive thresholds were not changed in Tlr4 mice (2.2 ± 0.1 g, P = 0.857) or in mice receiving 0.9% saline (Tlr4, 2.2 ± 0.1 g, P = 0.807; wild-type, 2.2 ± 0.1 g, P = 0.962). Conclusion: Tlr4 receptor involvement is suggested in the development of remifentanil-induced hyperalgesia in mice. Trial registration: CEA-UCM 107/2012.Instituto de Salud Carlos IIIUniversidad Complutense de MadridDepto. de Medicina y Cirugía AnimalFac. de VeterinariaTRUEpu