Oliceridine Safety Profile Favorable Compared With Morphine

Oliceridine has a favorable safety profile compared with morphine in terms of analgesia benefit and respiratory depression harms, according to research published in Anesthesiology.

To further understand respiratory behaviors associated with oliceridine, researchers compared oliceridine with morphine, hypothesizing that it would be associated with less respiratory depression. Investigators conducted a reanalysis of 3 previously published data sets from a previous trial comparing the 2 drugs in terms of analgesic efficacy and respiratory depression in order to measure and compare benefits and harms. Results were then extrapolated in a utility analysis for patients in clinical practice.

The initial study included 29 healthy volunteers (100% men aged 19-50 years; body mass index, 19-32 kg/m²). Dose-dependent increase in plasma concentration for oliceridine was identified from 8.7 to 11 minutes after dosing (56.8 ng/ml for 1.5 mg, 96.6 ng/ml for 3.0 mg, and 145.1 ng/ml for 4.5 mg); for morphine, mean peak concentration was observed at 3.5 minutes (209.6 ng/ml for 10 mg).

In a pharmacokinetic data analysis, overall between-participant variance for all parameters was 0.08 (±0.03) and 0.04 (±0.01) for oliceridine and morphine, respectively. A pharmacodynamic data analysis found that baseline hand withdrawal latency (46±6 seconds) increased to 94 plus or minus 19 seconds, 120 plus or minus 19 seconds, and 129 plus or minus 18 seconds after 1.5 mg, 3.0 mg, and 4.5 mg oliceridine, respectively, within 10 minutes of dosing.

With 10 mg morphine, peak latency occurred at 30 minutes (89±20 seconds). With morphine dosing, patient return to baseline hypercapnia values was “considerably slower” and was not reached during the course of the experiment.

Oliceridine and morphine were equianalgesic, with C100 values of 27.9 (±4.9) ng/ml and 34.3 (±9.7) ng/ml, respectively (potency ratio, 0.81; 95% CI, 0.39-1.56). Morphine had a 2.48-fold higher respiratory potency compared with oliceridine (95% CI, 1.65-3.72), with a 50% reduction of ventilatory response to hypercapnia reduction of 33.7 (±4.8) ng/ml vs oliceridine (25% at 27.4±3.5 ng/ml).

Utility functions indicated a “marked difference” between oliceridine and morphine, with a positive function for oliceridine, indicating a higher probability of analgesia than respiratory depression. Comparatively, morphine utility is predominantly negative, and morphine is more likely to result in respiratory depression than in analgesia.

In an extrapolation of these utility functions, patients undergoing bunionectomy under sciatic nerve block and patients undergoing abdominoplasty under general anesthesia were treated via either drug using patient-controlled analgesia (oliceridine, n=309 at 3 doses vs morphine, n=159). Utility function over time was calculated for each patient and utility values at respiratory depression events were noted.

In total, 96 respiratory events were observed: 60 with oliceridine administration (combined including all 3 doses) and 36 with the single regimen of morphine. Measured utility values indicate that most events (86%) occurred at utility values of 0.2 or less.

Study limitations include methodologic issues allowing for the comparison of 2 opioids with standardized endpoints and without confounding factors, limiting generalizability; the use of arbitrary analgesia and respiratory depression thresholds; and significant differences in anesthesia techniques in the clinical trials.

“The utility functions demonstrate that oliceridine better separates analgesia from respiratory depression than morphine, within the clinically relevant concentration range,” the researchers concluded. “Prediction of respiratory depression events based on the utility function should currently be considered exploratory, and further studies are needed to confirm our approach and results.”

Disclosure: This clinical trial was supported by Trevena Inc. Please see the original reference for a full list of authors’ disclosures.

Reference

Dahan A, van Dam CJ, Niesters M, et al. Benefit and risk evaluation of biased µ-receptor agonist oliceridine versus morphine. Anesthesiology. 2020;133(3):559-568. doi:10.1097/ALN.0000000000003441