Fosaprepitant, a substance P receptor antagonist used for chemotherapy nausea, reduced the development of morphine tolerance in rats and enhanced pain relief, suggesting a neuropeptide-based strategy to improve opioid therapy.
Tolerance attenuated through day 4While rats on morphine alone lost significant pain relief by day 4 due to tolerance, those receiving the combination of morphine plus fosaprepitant maintained enhanced pain relief through the treatment period.
What the researchers found
In Sprague-Dawley rats treated for 7 days:
- Morphine alone produced pain relief on day 1 that diminished by day 4, indicating tolerance development
- Co-administration of fosaprepitant (30 mg/kg daily) with morphine (10 mg/kg twice daily) attenuated tolerance development (days 1 and 3) and maintained pain relief through days 1-4 compared to controls
- Spinal cord immunohistochemistry showed increased substance P expression in the morphine + fosaprepitant group
- CGRP (calcitonin gene-related peptide) expression was also assessed
- The enhanced analgesia is likely linked to decreased release of substance P from presynaptic terminals in the spinal cord
Why it matters
The opioid crisis has highlighted the urgent need for strategies that improve pain relief while reducing opioid dose escalation. Fosaprepitant is already FDA-approved and widely used for preventing chemotherapy-induced nausea. If it can also slow morphine tolerance development in humans, it could be quickly repurposed as an adjunct to opioid therapy — potentially allowing patients to maintain pain relief at lower opioid doses and reducing the risks of dependence and overdose.
How the study worked
Sprague-Dawley rats received morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) via injection for 7 days. Pain threshold was measured using the hot plate test (measuring how quickly rats respond to a heated surface). Spinal cord tissue was analyzed by immunohistochemistry to measure expression of substance P and CGRP neuropeptides.
What this study cannot tell us
This is an animal study with rats — results may not translate to humans. The sample size per group is not specified in the abstract. The 7-day treatment period is short and may not reflect long-term tolerance patterns. The mechanism (decreased SP release from presynaptic terminals) is proposed but not directly proven. The specific doses used in rats do not directly translate to human dosing. No behavioral tests beyond the hot plate test were used to assess pain.
How to read the evidence
This is a preclinical animal study using a rat model. While it provides interesting mechanistic evidence for a repurposing approach, the small scale, single species, and short duration limit the strength of evidence. Human clinical studies would be needed before any clinical recommendations could be made.
When this study was published
Published in 2016, this study is nearly a decade old. While the fundamental pharmacology of substance P and opioid tolerance remains relevant, newer research may have expanded on or contradicted these findings.
The bigger picture
Substance P (an 11-amino-acid neuropeptide) is one of the key molecules transmitting pain signals in the spinal cord. Blocking its receptor (NK1) has been explored for pain management for decades with mixed results. This study suggests that the real value of NK1 antagonists like fosaprepitant may not be as standalone painkillers but as adjuncts that prevent opioid tolerance — a clinically actionable insight given that fosaprepitant is already approved for another indication.
Questions still open
- Would fosaprepitant attenuate morphine tolerance in human patients with chronic pain?
- Could lower doses of fosaprepitant achieve the same anti-tolerance effect with fewer side effects?
- Does the substance P-mediated anti-tolerance mechanism apply to other opioids beyond morphine?
Common questions
What is substance P and how does it relate to pain?
Could this approach help with the opioid crisis?
Read the original research
Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats.
Indian journal of pharmacology, 48(4), 394-398
Citation
Prasoon, Pranav; Gupta, Shivani; Kumar, Rahul; Gautam, Mayank; Kaler, Saroj; Ray, Subrata Basu. (2016). Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats.. Indian journal of pharmacology, 48(4), 394-398.