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12 Articles in Volume 18, Issue #4
A New Frontier in Migraine Management: Inside CGRP Inhibitors & Migraine Prevention
Assessment of Patients with Rheumatoid Arthritis or Osteoarthritis
Biosimilars in Rheumatology: How Popular Will They Be?
Case Studies in Regenerative Cellular Therapy: Tendinopathy and Osteoarthritis
Commentary: Make the Easy Choice for Care
Editorial: The Emergence of Trackable Pill Technology: Hype or Hope?
Editorial: The Practicality of Pain Acceptance
How to Avert Government Scrutiny When Prescribing Opioids
Letters to the Editor: DEA and Prescribing, the War on Statistics, Failing Treatments, Patients' Options
Meet the Migraine Game-Changers
Platelet-Rich Plasma and Stem Cell-Rich Prolotherapy for Musculoskeletal Pain
With concerns over opioids, could novel receptors be useful?

With concerns over opioids, could novel receptors be useful?

With opioid misuse and abuse on the rise, other opioid receptors may be targeted for pain relief.

With opioid misuse and abuse on the rise and death counts increasing from overdoses, pain management is becoming more difficult.1 One effective class of medication is opioids, especially those that act on the mu-opioid receptor (µ-OR).2 However, there are other opioid receptors that can be targeted for pain relief. In animal models, delta-opioid receptors (δ-OR) have shown potential to increase µ-OR analgesic response, while kappa-opioid receptors (κ-OR) have shown a potential in providing an analgesic effect.3 The potential benefit of these receptors is the lack of effects on β-arrestin-biased signaling pathway, preventing adverse effects, while still being able to activate G-protein coupled receptor producing analgesia.1,3

Investigations into Novel Receptors: Research to Date

Novel opioid receptor drugs are being investigated for treatment of pain while minimizing adverse effects via selective binding. CR845, or difelikefalin, a selective κ-OR agonist that is available as oral and intravenous formulation, which undergone trials internationally for pain, including postoperative pain, and pruritus. Oral formulations studied have four strengths: 0.25 mg, 0.5 mg, 1 mg, and 5 mg, which are generally administered twice daily. Intravenous (IV) formulations being studied for postoperative pain and pain management are dosed by weight in strengths of 0.5 µg/kg, 1.0 µg/kg, and 1.5 µg/kg. Difelikefalin could possibly be scheduled as a C-V, or non-scheduled peripheral opioid with indication of pain.

Cara Therapeutics (Stamford, CT), the manufacturer, has not published any studies to date for difelikefalin but has provided press release statements providing information about trials. At the time of this writing, difelikefalin was undergoing a Phase III study of its IV formulation in South Korea for treatment of postoperative pain. Difelikefalin is also in Phase II/III trials for post-operative pain in the United States, and has completed a phase II trial for pain in an oral formulation in the US.4

The Phase II/III trial examining IV difelikefalin for postoperative pain with doses of 1 µg/kg, 2 µg/kg, and 5 µg/kg, was halted due to a potentially serious adverse effect (ie, increased serum sodium), which was found to be dose-dependent and asymptomatic. After a safety review, recruitment resumed with two lower doses of difelikefalin of 0.5 µg/kg, and 1 µg/kg versus placebo. Interim analysis showed tolerance and minimal changes to monitored parameters, including serum sodium. 4

Osteoarthritis Impact

The Phase IIb trial enrolled 480 subjects and evaluated dosing in patients with osteoarthritis (OA) of the hip or knee in the US. The study was a follow-up to a Phase IIa trial, which enrolled 80 patients to study drug dosing. The Phase IIb trial studied difelikefalin doses of 1 mg, 2.5 mg, or 5 mg twice daily compared to placebo for eight weeks in patients with moderate-to-severe chronic pain.4,5 The primary efficacy endpoint was a change in pain intensity using a numerical rating scale from baseline to eight weeks. Secondary endpoints included efficacy for pain and stiffness in the Western Ontario and McMaster Osteoarthritis Index (WOMAC) and effects on Patient Global Impression of Change (PGIC). The use of rescue acetaminophen was evaluated and the 5 mg group with OA of the hip had a 41% reduction compared to placebo.5

The trial resulted a mean score reduction of 35% in all patients using 5 mg after eight weeks. Results for the 5 mg dose were found to be statistically significant compared to placebo although results for placebo and other doses have not been published.6 Difelikefalin was tolerable with common adverse effects of constipation (12%), and dry mouth (> 5%).4 No adverse effects related to serum sodium was noted with doses in this study.5

Other potential targets include δ-OR agonists, as they may enhance analgesic effect of the µ-OR. Compounds being studied currently include ligands that have affinity to both µ-OR and δ-OR. In rats, fentanyl-based mixed ligands demonstrate inhibition of neuropathic pain. Experiments demonstrated a lack of motor paralysis and/or signs of sedation. With mixed effects, this could potentially lower doses of µ-OR agonist and decrease adverse events. Although this could be beneficial in decreasing patient total daily morphine equivalent doses, human studies need to be conducted.7

One δ-OR agonist undergoing Phase I trials is TRV250 (Trevena, Chesterbrook, PA), an oral medication that could be used in treatment-refractory migraines that do not benefit from triptan therapy. In preclinical trials, the drug showed it did not have abuse potential or addictive properties. Phase I safety assessments in healthy volunteers have shown the drug to be well tolerated with adequate bioavailability.8


There is a potential for other subtypes of opioid receptors to aid with pain management. Adverse effects of δ-OR and κ-OR are tolerable with possibly less addiction potential than µ-OR medications. Although more research is necessary, these potential drug targets could improve pain management going forward.

Last updated on: April 12, 2019
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