Monir Bertayli 1,2, Wouter Bakker 2, Geert Jan Groeneveld 2,3, Jeroen Elassaiss-Schaap 1
1 PD-value (Utrecht, the Netherlands), 2 Centre for Human Drug Research (Leiden, the Netherlands), 3 Leiden University Medical Center (Leiden, the Netherlands)
Introduction:
Chronic pain is a major burden for patients and is highly prevalent. In Europe and the US 21% and 24.3% of the adult population have chronic pain respectively.[1,2] Opioids are currently the most effective class of analgesics, but lead to many adverse effects such as cognitive impairment, sedation and even risk of death due to opioid overdose. There is a strong need for improved treatments. One avenue is to identify novel analgesic drug combinations that are complementary or synergistic with each other allowing dose reduction because of an increased analgesic response relative to the side effects.
Previously we designed a cold pain tolerance threshold (ColdPTT) PK-PD model of the individual and combined morphine and pregabalin analgesic responses in healthy subjects showing synergistic effects [3,4]. Here we also modelled CNS side effects representing sedation (reduction in saccadic peak velocity (SacPV)), alertness (Bond-Lader VAS-alertness), alertness (reduction in reaction time in the N-back (zero back)), sustained attention and psychomotor function (adaptive tracking test (TrackPer)) and body stability (body sway test).
We used a Clinical Utility Index (CUI) model (a quantitative Benefit-Risk assessment framework) to weigh the side effects against the analgesic effect. An interactive CUI model can be used in both treatment and dose selection based on clinician and patient perspective and preferences.
Objectives:
• Describe the clinical trial results by PK-PD models of outcomes representing analgesia, sedation, attention/alertness, attention and coordination and posterior stability.
• To determine if the combined treatment effects are antagonistic, additive or synergistic.
• Identify appropriate morphine dose reduction taking both analgesic and side effects into account using a CUI model.
Methods:
Clinical trial:
Clinical trial design and power analysis based simulations were previously provided [5]. Combined treatment effect of morphine and pregabalin was assessed in a double-blind, placebo controlled clinical trial in 12 healthy male and 15 female volunteers. In four identical study periods with 7 days wash-out in-between, subjects (20-64years) received a single oral dose of 300mg pregabalin, 3mg + 7mg morphine as a bolus infused intravenously, a combination of these two (double-dummy) or placebo in randomized order.
Model development:
NONMEM 7.6.0 was used for PK-PD model development. Between occasion variability (BOV) was examined for both PK and PD models. Model selection was based on objective function value (OFV), diagnostic plots, model stability and relative standard error (RSE), among others. CUI initial draft weights were set after consulting clinicians.
Results:
The previous reported 2 compartment morphine PK model [3] was updated to a 3 compartment model with the pregabalin PK and ColdPTT PD models remaining the same. All new PD endpoints were best described by a turnover model. With regards to the combined treatment, we estimated the modulation of the pregabalin effect when morphine and pregabalin were present within the system. The estimated modulation of the ColdPTT indicates an approximate 50% improvement over the additive (1+1) case in healthy subjects. Whereas the modeled side effects were either non-additive/antagonistic (up to -20%) or additive/slight synergy (up to 20%). With ColdPTT, SacPV and N-back set on the basis of preliminary CUI weights of 1, 0.5 and 0.2 respectively, a dose of 10mg morphine can be reduced to 6.5mg when combined with 300mg pregabalin based on the AUC of the CUI score in the first 3 hours. When only looking at the analgesic ColdPTT AUC, it predicted that a 3.5mg morphine dose in combination with 300mg pregabalin is approximately equivalent to 10mg of morphine over the first 3 hours.
Conclusions:
In conclusion, here we present PK-PD models of endpoints representing analgesia, sedation, attention/alertness, attention/coordination and posterior stability. The models indicate analgesic synergy of the combined morphine and pregabalin treatment, resulting in an approximate 50% improvement over the additive (1+1) case in healthy subjects. When the analgesic (ColdPTT), sedative (SacPV) and alertness (N-back) endpoints were combined in a CUI model, the model indicated that a 10mg morphine can be reduced to 6.5mg when combined with 300mg pregabalin based on the AUC of that composite CUI score in the first 3 hours (arbitrary). Limitations apply, such as possible transformation functions to endpoints have not been thoroughly investigated. Currently, an online clinical trial is ongoing to determine patient preference weights.
References:
[1] Rometsch, Caroline, et al. “Chronic pain in European adult populations: a systematic review of prevalence and associated clinical features.” Pain 166.4 (2025): 719-731.
[2] Lucas, Jacqueline W., and Inderbir Sohi. “Chronic pain and high-impact chronic pain in US adults, 2023.” (2024).
[3] Bertayli, Monir, et al. PAGE 32 (2024) Abstr 11143 [www.page-meeting.org/?abstract=11143]
[4] Bakker, Wouter Alexander, et al. “Application of a Nociceptive Test Battery to Assess Potential Synergy between Two Analgesics in Healthy Subjects.” ACS Pharmacology & Translational Science (2025).
[5] Bertayli, Monir, et al. PAGE 30 (2022) Abstr 10216 [www.page-meeting.org/?abstract=10216]
Reference: PAGE 34 (2026) Abstr 12051 [www.page-meeting.org/?abstract=12051]
Poster: Drug/Disease Modelling - CNS