Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain

Anesthesiology. 2009 Sep;111(3):616-24. doi: 10.1097/ALN.0b013e3181af6356.


Background: Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid).

Methods: The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing.

Results: Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007).

Conclusion: CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology*
  • Cross-Over Studies
  • Double-Blind Method
  • Electric Stimulation
  • Esophagus / drug effects
  • Esophagus / physiology
  • Hot Temperature
  • Humans
  • Male
  • Monitoring, Physiologic
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / physiology
  • Opioid Peptides / adverse effects
  • Opioid Peptides / pharmacology*
  • Oxycodone / pharmacology*
  • Pain / drug therapy*
  • Pain Measurement / drug effects
  • Receptors, Opioid, kappa / agonists*
  • Skin Physiological Phenomena / drug effects
  • Young Adult


  • Analgesics, Opioid
  • Opioid Peptides
  • Receptors, Opioid, kappa
  • D-argininamide, D-phenylalanyl-D-phenylalanyl-D-norleucyl-N-(4-pyridinylmethyl)-
  • Oxycodone