How Do Kappa Opioid Receptor Agonists Work?

Kappa opioid receptor agonists are medications that are newly being developed to treat chronic pain and itching. The first kappa-opioid receptor agonist, difelikefalin (Korsuva) is in clinical trials for safety and efficacy in pain relief (analgesia) and itching (pruritus). Kappa opioid receptor agonists work by selectively activating peripheral kappa opioid receptors.

Opioid receptors are protein molecules on nerve cell (neuron) membranes in the central and peripheral nervous system and immune cells. Opioid receptors mediate the body’s response to most hormones and some of their functions include modulating pain, stress response, respiration, mood, and emotion.

The five different opioid receptors discovered in the human body are:

• Mu receptor (MOR)
• Kappa receptor (KOR)
• Delta receptor (DOR)
• Nociceptin receptor (NOR)
• Zeta receptor (ZOR)

Most of the opioid receptor agonists currently in use activate opioid receptors in the central nervous system (CNS), which are effective for analgesia but also have serious side effects such as respiratory depression, sedation, dependence, euphoria, and/or dysphoria (feeling of unease).

Kappa opioid receptor agonists selectively activate peripheral kappa opioid receptors, and consequently, they can effectively block the transmission of pain signals in the peripheral sensory nerves with minimal adverse effects on the CNS. Peripheral kappa-opioid receptor agonists can also help reduce inflammation by activating kappa receptors on immune cells.

The peripheral kappa opioid receptor agonist difelikefalin has been developed as oral and intravenous formulations. Difelikefalin is currently in clinical trials and 

• Moderate to severe pruritus induced by hemodialysis.

Other potential uses for difelikefalin being studied include:

• Pruritus from dermatitis 
• Acute postoperative pain
• Chronic pain

Completed studies on kappa-opioid receptor agonists have not yet been published, but studies indicate that some of the common side effects may include:

• Nausea
• Vomiting
• Diarrhea
• Dizziness
• Nasopharyngitis (inflammation of nasal passage and pharynx)
• Paresthesia (prickling sensation)
• Somnolence (drowsiness)
• Increased sodium and chloride
• Hypotension (low blood pressure)
• Headache
• Dry mouth
• Constipation

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand name of a kappa-opioid receptor agonist drug pending FDA approval is:

• difelikefalin 
• Korsuva