Are new receptors likely to be useful due to concerns about opioids?

As the abuse and abuse of opioids increase, other opioid receptors may be the target for pain relief.

As abuse and abuse of opioids increase and deaths increase from excessive amounts, pain management becomes more and more difficult. One class of potent drugs are opioids, especially those that act on u-opioid receptors (u-OR). However, there are other opioid receptors that can serve as pain relief goals. In animal models, the [delta]-opioid receptor ([delta]-OR) has been shown to increase the likelihood of an [mu]-OR analgesic response, whereas the [kappa]-opioid receptor ([kappa]-OR) has been shown to provide analgesic potential. The potential benefit of these receptors is the lack of effects on u-arrestin-preferred signaling pathways, preventing side effects, while still being able to activate analgesia that produce G-protein coupled receptors.
Investigation of new receptors: research so far
New opioid receptor drugs are being studied for the treatment of pain while minimizing adverse effects through selective binding. CR845 or difelikefalin, a selective u-OR agonist, can be used as an oral and intravenous agent and undergo international pain (including postoperative pain and pruritus) tests. The oral formulations studied have four strengths: 0.25 mg, 0.5 mg, 1 mg and 5 mg, which are usually administered twice daily. The weight of intravenous (IV) formulations used for postoperative pain and pain control was studied to be 0.5 [mu]g/kg, 1.0 [mu]g/kg, and 1.5 [mu]g/kg by weight. Difelikefalin may be arranged as a C-V or unscheduled peripheral opioid and show pain.
The manufacturer Cara Therapeutics (Stamford, CT) has so far not released any research on difelikefalin, but provided a press release to provide information on the trial. At the time of writing, difelikefalin is conducting Phase III IV preparation studies in Korea for the treatment of postoperative pain. Difelikefalin also performed stage II / III postoperative pain tests in the United States and has completed phase II clinical trials of oral pain in the United States.
Due to a potential serious adverse reaction (ie, elevated serum sodium), Phase II / III trials examined IV difelikefalin for postoperative pain at doses of 1 ug / kg, 2ug / kg, and 5 ug / kg, and were discontinuing dose-dependent findings. Asymptomatic. After a safety review, recruiters resumed the recruitment of two low-dose diffelikefalin 0.5 ug/kg and 1 ug/kg with placebo. Interim analysis shows the tolerability and minimal changes in monitoring parameters (including serum sodium).
The effect of osteoarthritis
Phase IIb clinical trials enrolled 480 subjects and evaluated doses in American patients with hip or knee osteoarthritis (OA). The study is a follow-up to the Phase IIa trial, which recruited 80 patients to study drug doses. Phase IIb clinical trials studied the dose of 1 mg, 2.5 mg, or 5 mg of difelikefalin twice daily for 8 weeks in patients with moderate to severe chronic pain compared to placebo. The primary efficacy endpoint was the change in pain intensity using a digital rating scale from baseline to 8 weeks. Secondary endpoints included the effect of Western Ontario and the McMaster Osteoarthritis Index (WOMAC) on pain and stiffness, and the effect on the patient's global impression of change (PGIC). Evaluation of the use of acetaminophen rescued a 41% reduction in patients with 5 mg of hip arthritis compared to placebo.
The trial reduced the average score of patients who used 5 mg after all 8 weeks by 35%. Although results for placebo and other doses have not been published, the 5 mg dose results were statistically significant compared with placebo.6 Difelikefalin tolerates common side effects of constipation (12%) and dry mouth (>5%). No dose-related serum sodium-related adverse events were observed in this study.
Other potential targets include u-OR agonists because they enhance the analgesic effect of u-OR. Currently studied compounds include ligands that have affinity for both [mu]-OR and [delta]-OR. In rats, fentanyl-based mixed ligands showed inhibition of neuropathic pain. Experiments showed signs of lack of motor paralysis and/or sedation. Due to the mixed effects, this may reduce the dose of u-OR agonists and reduce adverse events. Although this may help to reduce the equivalent dose of the total amount of morphine taken daily by the patient, human studies are required.
One of the delta-OR agonists undergoing Phase I clinical trials is TRV250 (Trevena, Chesterbrook, PA), an orally administered drug that can be used to treat refractory refractory migraines that do not benefit from triptan treatment. In preclinical testing, the drug showed no abuse potential or addictive nature. The first phase safety assessment of healthy volunteers showed that the drug was well tolerated and had sufficient bioavailability.
In conclusion
Other subtype opioid receptors contribute to pain management. The adverse effects of u-OR and u-OR are tolerable compared to u-OR drugs and may have less addictive potential. Although more research is needed, these potential drug targets may improve pain management.