Tolerance Development with SR17018 Opioid Use
Yes, tolerance does develop with SR17018 use, as with all opioids. An important characteristic of all opioids is that both the direct physical and perceptual effects diminish significantly with repeated administrations, resulting in tolerance, physical dependence, and hyperalgesia 1.
Mechanisms of Opioid Tolerance
- Tolerance develops through molecular and circuit-level adaptations in opioid receptors and their intracellular signaling cascades 1, 2
- These adaptations can emerge after even a few administrations of opioids 1
- The decreased sensitivity to opioid effects typically necessitates increasingly larger doses to achieve the initial level of analgesia or reward 1
Differential Development of Tolerance
- Tolerance to different opioid effects develops at varying rates and to different extents 1
- Tolerance to analgesia and reward appears to develop faster than tolerance to respiratory depression, increasing overdose risk 1
- While tolerance develops to respiratory and CNS depressive effects, it does not develop to constipating effects 1
SR17018 Specific Considerations
- SR17018 exhibits a distinctive μ-opioid receptor phosphorylation profile that differs from other opioids, but this does not prevent tolerance development 3, 4
- SR17018 stimulates a μ-opioid receptor phosphorylation pattern similar to full agonists, but with unique dephosphorylation kinetics that persist for hours 3
- Despite its unique pharmacological properties, SR17018 would still be subject to the fundamental neuroadaptive processes that lead to tolerance 3, 4
Clinical Implications
- Tolerance development necessitates dose escalation to maintain analgesic efficacy, which increases the risk of overdose and potentially addiction 1
- Cross-tolerance between opioids means that patients may require higher doses of other opioids as well 1
- Tolerance generally resolves relatively rapidly (within 3-7 days) after opioid discontinuation, depending on the specific opioid, dose, and treatment duration 1, 2
Associated Phenomena
- Physical dependence develops alongside tolerance, manifesting as withdrawal symptoms upon abrupt discontinuation 1
- Opioid-induced hyperalgesia can develop with repeated exposure, resulting in increased pain sensitivity that may be mistaken for tolerance 1
- Unlike tolerance and physical dependence, addiction does not resolve promptly after discontinuation 1
Clinical Management Considerations
- Monitoring for signs of tolerance development is essential for safe opioid prescribing 5
- Dose escalation should be approached cautiously due to the differential development of tolerance to analgesia versus respiratory depression 1
- When patients complain of pain despite increasing doses, clinicians must determine whether to increase the dose (for tolerance) or decrease it (for hyperalgesia) 1
Understanding the development of tolerance with SR17018, as with all opioids, is crucial for appropriate pain management and minimizing risks of overdose, addiction, and other adverse outcomes 1, 5.