CR665

Summary

CR665 (also known as FE‑200665) is an investigational peptide that selectively activates kappa‑opioid receptors located on peripheral sensory nerves. Developed to provide analgesia—particularly for visceral and other peripheral pain—its design limits entry into the central nervous system, aiming to avoid typical opioid‑related side effects such as sedation, respiratory depression, and addiction.

Mechanism of Action

CR665 is a tetrapeptide agonist that binds with high affinity to the κ‑opioid receptor (KOR) expressed on peripheral afferent neurons, including those in the gut and visceral tissues. By activating KOR outside the blood‑brain barrier, it inhibits nociceptive signaling locally without engaging central opioid pathways. The peptide’s poor CNS penetration underlies its peripheral selectivity, producing analgesia through reduced neurotransmitter release from peripheral nerve terminals.

What the Research Shows

A randomized, double‑blind, three‑way crossover study in healthy male volunteers compared a single intravenous dose of CR665 (0.36 mg/kg) with oral oxycodone (15 mg) and placebo. CR665 significantly raised the pain‑rating threshold to esophageal distension, indicating selective visceral analgesia, while decreasing skin‑pinch tolerance, suggesting limited somatic effect. A parallel pharmacokinetic/pharmacodynamic analysis showed a two‑compartment disposition and a direct linear relationship between plasma concentration and visceral pain tolerance, supporting peripheral action. Preclinical work demonstrates that CR665 engages KOR with low‑nanomolar potency and >11 000‑fold selectivity over μ and δ receptors; however, the parent peptide is not orally active, prompting development of oral derivatives. Phase‑I data have been completed, and the compound is reported to be in phase‑II trials, but no efficacy data in patient populations are yet published.

Reported Benefits

Human data indicate that CR665 can selectively attenuate visceral pain without the broad somatic analgesia seen with centrally acting opioids, suggesting a lower risk of central side effects such as sedation or respiratory depression. In vitro and animal studies confirm high potency at KOR and strong selectivity over μ/δ receptors, reducing the likelihood of off‑target opioid effects. The peripheral restriction may also limit abuse potential.

Limitations of the Evidence

Evidence is limited to a single‑dose study in healthy volunteers; efficacy in chronic or clinical pain conditions has not been demonstrated. The peptide is inactive when taken orally, restricting convenient administration. Safety data are sparse, with no detailed adverse‑event reporting in the cited trials. Ongoing phase‑II results are not yet available, and long‑term tolerability remains unknown.

Safety Considerations

The published human studies did not report serious adverse events, but the sample size was small and exposure brief. Peripheral selectivity suggests fewer central opioid adverse effects, yet potential peripheral side effects (e.g., gastrointestinal dysmotility) have not been fully characterized. Until comprehensive safety data are released, caution is warranted, especially in patients with compromised renal or hepatic function that could affect peptide clearance.

How It Is Administered

CR665 has been administered intravenously as a 1‑hour infusion (0.36 mg/kg) in clinical studies and is also listed for subcutaneous use in investigational settings. The peptide is not orally bioavailable, and no oral formulations have been approved or reported.

Routes of Administration

Goals & Uses

• Visceral pain (e.g., irritable bowel syndrome)AnalgesiaLow
• Pruritus (itch) modulationSymptom ManagementLow
• Reduced CNS opioid side effectsSafety ProfileModerate
• Acute postoperative painAnalgesiaModerate
• Visceral pain reliefAnalgesiaModerate
• Inflammatory pain reliefAnalgesiaModerate

Contraindications

• Severe hepatic impairmentOrganModerateLiver function concerns
• Severe renal impairmentOrganModerateKidney function concerns
• PregnancyPopulationModeratePotential fetal risk or insufficient safety data
• Hypersensitivity to kappa-opioid agonistsAllergy/ImmunologyHigh

Adverse Effects

• Dysphoria (minimal vs central KOR agonists)NeuropsychiatricRare
• Injection site reactionsLocalUncommon
• ConstipationGastrointestinalUncommonReduced bowel frequency or difficulty passing stool
• DiuresisRenalCommon
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• DizzinessNeurologicCommonFeeling faint, lightheaded, or unsteady

Drug Interactions

• Other opioidsModerate
• CNS depressantsLow
• CNS depressants (e.g., benzodiazepines)Low
• Other opioid agonistsModerate

Population Constraints

• PregnancyReproductive SafetyRelative
• Pediatrics (<12 y)AgeRelative
• Pediatric patientsAgeRelative
• Elderly patientsAgeRelative
• Pregnant womenReproductiveRelative
• Severe hepatic impairmentOrgan ImpairmentRelative

Regulatory Status

• European UnionInvestigationalUnder clinical evaluation; not authorized for marketing.
• United StatesInvestigationalPhase I/II clinical trials; not FDA‑approved.
• United KingdomInvestigationalResearch compound; no MHRA approval.

CR665 has not received regulatory approval in any jurisdiction. It has been studied in early-phase clinical trials (Phase I/II) as an investigational compound. Development has been associated with Janssen and academic research groups.

Evidence & Sources

• 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
  Journal ArticleModerateArendt-Nielsen L, et al.2009-01-01T00:00:00.000000Z
• Development of a Peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain
  Journal ArticleLowHughes FM Jr, et al.2013-01-01T00:00:00.000000Z
• Peripheral opioid receptor agonists for analgesia: a comprehensive review
  Journal ArticleModerateVadivelu N, Mitra S, Hines RL2011-01-01T00:00:00.000000Z
• Targeting Peripheral Kappa Opioid Receptors for the Treatment of Chronic Pain: Review Article
  Journal ArticleLowBeck TC, Dix TA, Reichel CM2019-01-01T00:00:00.000000Z
• Non-addictive orally-active kappa opioid agonists for the treatment of peripheral pain in rats
  Journal ArticleLowBeck TC, et al.2019-01-01T00:00:00.000000Z
• A population pharmacokinetic and pharmacodynamic study of a peripheral κ-opioid receptor agonist CR665 and oxycodone
  Journal ArticleModerateOlesen AE, et al.2013-01-01T00:00:00.000000Z

Frequently Asked Questions