Influence of STR-324, a Dual Enkephalinase Inhibitor, on Postoperative Pain Scores: A Proof-of-Concept Trial in Patients after Laparoscopic Surgery

STR-324 is the chemically stable analog of opiorphin, a human pentapeptide (Gln-Arg-Phe-Ser-Arg), that inhibits two enkephalinases, aminopeptidase-N and neutral endopeptidase. These enkephalinases break down met-enkephalin into inactive metabolites.1 Both opiorphin and STR-324 are naturally present in humans, because opiorphin rapidly cycles into STR-324 under physiologic conditions.2 Experimental studies demonstrated the strong analgesic properties of STR-324 in a rodent model of plantar-incision pain.3 Potentiation of endogenous opioid peptides represents a novel approach to pain treatment and offers several advantages, including a reduced likelihood of side effects associated with exogenous µ-opioids and dependency on µ-opioid receptor activation, because met-enkephalin, in particular, has higher affinity for the δ-opioid receptor.4 One additional advantage of STR-324 is that, in rats, high-dose STR-324 was devoid of respiratory depression or hemodynamic effects, and there are indications that δ-opioid receptor activation reverses opioid-induced respiratory depression.1,5We conducted an exploratory, double-blind, randomized study to determine whether STR-324 is a viable and safe option for treatment of postoperative pain in patients after laparoscopic abdominal or pelvic surgery. The protocol was approved by the local ethics committee and conducted from January 2021 to March 2023. The participants provided written informed consent before enrollment. The protocol was registered at https://www.clinical.trials.gov (October 5, 2020; identifier NCT04582786).After surgery, 81 patients received a 20-min fixed dose-escalating infusion with STR-324 (ALAXIA-SAS, France); for blinding reasons, 26 others received a 20-min fixed dose-escalating infusion with morphine. Doubling of the infusion rate, starting at 1.3 mg/h, could occur at 5-min intervals until an absolute pain score decrease of 2 numerical rating scale (NRS) points or a pain score of 3 or less. If these endpoints were met, infusion continued for 2 h, if they were not met within the 20-min infusion period, patients were transitioned to standard pain management. Half of the patients received an initial bolus dose of 4 ml, which corresponds to 1 mg STR-324 or morphine. During the surgical procedure, all patients received propofol for induction and maintenance, sufentanil (last dose given at least 1 h before the end of surgery), rocuronium, and 1 g acetaminophen before surgery.The primary endpoint of the study was the number of treatment responders; a responder was defined by a change in pain intensity by 2 NRS points (on an 11-point scale ranging from 0, no pain, to 10, most severe pain imaginable) or to an NRS level of 3 or less during the 20-min drug infusion (table 1). A 90% CI of success proportion between STR-324 and morphine was calculated with limits set to ±0.2 to evaluate equivalence between groups. Second, the study aimed to determine the maximum decrease in NRS after the initiation of dosing.The number of patients that responded were 28 (35%; 95% CI, 24 to 46) in the STR-324 group versus 12 (46%; 27 to 67) in the morphine group (chi-square test, P = 0.29; fig. 1); there was a lack of equivalence between groups because the 90% CI of the difference in responder rates was –0.30 to 0.07. The largest decrease in numerical rating scale was 0.9 ± 1.3 (STR-324) and 1.0 ± 1.2 (morphine; analysis of covariance, P = 0.65). No safety issues were observed in any of the patients. The switch to standard pain medication occurred at 20 ± 1 min (STR-324) and 20 ± 0 min (morphine, P = 0.89). The presence or absence of the bolus dose had no effect on responder rate or maximum decrease in NRS.This exploratory study on the enkephalinase inhibitor STR-324 in postoperative patients showed promising results. Enhancing the availability of enkephalins at the µ-opioid receptor represents a novel approach in the management of pain.4 It is important to note that, in this paradigm, the effect of STR-324 is only possible when endogenous pain modulation is active (and enkephalins are produced), which occurs during the central processing of afferent nociceptive input.6,7 Additionally, we would like to mention that our initial protocol was designed to compare STR-324 to placebo (saline) and not intended for a noninferiority analysis. This comparator was, however, deemed unacceptable and, hence, the current comparison to morphine, an opioid with a very different mode of action compared to STR-324.In conclusion, STR-324, administered at a fixed dose for a maximum duration of 20 min, produced a successful analgesic response in 35% of patients. Notably, no safety issues were observed in any of the patients. These findings suggest that using a drug like STR-324, which potentiates and/or extends the activity of endogenous opioid peptides, particularly met-enkephalin, represents a viable alternative for the treatment of moderate to severe pain.This study was supported by departmental and institutional funds and by ALAXIA-SAS (Lyon, France).Dr. Juarez-Perez is an employee of ALAXIA-SAS (Lyon, France). Dr. Dahan received consultancy fees from Enalare Therapeutics Inc. (Princeton, New Jersey), Trevena Inc. (Chesterbrook, Pennsylvania), and Takeda Pharmaceuticals International AG (Opfikon, Switzerland). The Department of Anesthesiology at Leiden University Medical Center (Leiden, The Netherlands) is supported by awards/grants to Dr. Dahan from the U.S. Food and Drug Administration (Silver Spring, Maryland), the Netherlands Organization for Health Research and Development (ZonMW, The Hague, The Netherlands; project 848120001), and the Dutch Research Council (NWO, The Hague, The Netherlands; NWA.1160.18.300). The other authors declare no competing interests.