Opioid receptor agonists in dermatology

For information on opioid receptor antagonists, see: naltrexone and naloxone.

What are opioid receptor agonists?

Opioid receptor agonists (commonly referred to as ‘opioids’) are compounds that bind to and activate opioid receptors. Opioid receptors are G-protein-coupled receptors expressed on cell membranes throughout the body, including the:

• Central and peripheral nervous system
• Skin
• Endocrine system
• Gastrointestinal tract.

The three classical types of opioid receptors are the mu (μ) opioid receptor (MOR), kappa (κ) opioid receptor (KOR), and delta (δ) opioid receptor (DOR).

What are opioid receptor agonists used for?

Opioids are a cornerstone in the management of moderate-to-severe pain. Opioid analgesics used in clinical practice primarily act through MOR agonism eg, morphine, fentanyl, oxycodone, and tramadol.

Other non-dermatological uses include:

• Diarrhoea management eg, loperamide, diphenoxylate
• Management of opioid use disorder eg, buprenorphine, methadone
• Cough suppression eg, codeine, hydrocodone.

Dermatological indications

Kappa-opioid receptor agonists have emerged as a potential therapeutic class for treating refractory pruritus.

Difelikefalin

• Peripherally restricted, selective KOR agonist
• FDA-approved for the treatment of chronic kidney disease-associated pruritus (CKD-aP) in adults undergoing haemodialysis (2021)
  • Korsuva ® — administered as an intravenous bolus injection
• Off-label uses:
  • Pruritus associated with atopic dermatitis (KARE phase II clinical trial)
  • Pruritus associated with notalgia paresthetica (KOMFORT phase II clinical trial).

Nalfurafine

• Centrally penetrating, moderately selective KOR agonist
• Approved in Japan for the treatment of CKD-aP in adults undergoing haemodialysis (2009) and cholestatic pruritus (2015)
  • Remitch ® — administered as an oral tablet

Nalbuphine

• Centrally penetrating, mixed KOR agonist and MOR partial agonist*
• Off-label uses:
  • Prurigo nodularis (PRISM phase II/III clinical trial)
  • CKDaP (phase II/III clinical trial)
  • Opioid-induced pruritus.

Anrikefon

• Peripherally restricted, selective KOR agonist
• Off-label use: CKDaP (phase III clinical trial)

*Partial agonists can act functionally as antagonists by blocking the maximal effect of any full agonist present.

What are the contraindications and precautions for opioid agonists?

Tell me more about the opioid system and skin

Opioid receptors and endogenous ligands are present throughout the skin, including keratinocytes, melanocytes, adnexal structures, skin-resident immune cells, and cutaneous nerve endings.

This cutaneous opioid system is involved in regulating various functions, such as:

• Peripheral pruritus, pain, and inflammation
• Skin cell adhesion, differentiation, and migration in normal skin and wound healing.
• Maintenance of the skin barrier
• Melanin production in melanocytes, hair follicle growth, and lipogenesis in sebocytes.

Pruritus

The balance between MOR and KOR signalling has been implicated in the pathogenesis of pruritus (itch), making the opioid system a target for novel anti-itch treatments.

MOR agonism and KOR antagonism are generally pruritogenic (itch-inducing). This explains why pruritus is a common side effect of opioid analgesics — especially when administered neuraxially eg, epidural morphine. Conversely, MOR antagonism and KOR agonism are generally anti-pruritic (itch-inhibiting).

For information on MOR antagonists, see: naltrexone and naloxone.

What are the benefits and disadvantages of opioid agonists?

Advantages

• KOR agonists lack the euphoric effects of MOR agonists, posing a low risk for misuse and addiction.
• Difelikefalin:
  • In phase III trials (KALM-1 and KALM-2) for uraemic pruritus, a greater proportion of patients achieved a ≥3-point reduction on the mean WI-NRS score (Worst Itching Intensity Numerical Rating Scale) at week 12 compared to placebo (51.1% versus 35.2%, p<0.001).
  • As a peripherally restricted drug, it largely avoids the dysphoric and psychomimetic effects seen with CNS-penetrating KOR agonists.

Disadvantages

• Difelikefalin is approved only as an intravenous injection, limiting its widespread use.
• Nalfurafine is only available in Japan and South Korea.
• Anrikefon and nalbuphine are not approved for the treatment of pruritus or other dermatological conditions.
• The risks of physical tolerance and withdrawal with long-term use of KOR agonists have not yet been evaluated.

What are the adverse effects of opioid agonists?

Centrally acting MOR agonists

• Sedation and respiratory depression
• Dependence and addiction
• Opioid-induced hyperalgesia
• Neonatal opioid withdrawal syndrome (when used during pregnancy)
• Pruritus
• Adrenal insufficiency
• Hypotension
• Dizziness
• Bowel dysfunction eg, constipation, GERD, delayed gastric emptying, bloating
• Nausea and vomiting
• Urinary retention

Centrally acting MOR partial agonists

• Precipitated withdrawal in opioid-dependent patients
• Reversal of analgesia
• Nausea and vomiting

Centrally acting KOR agonists

• Dysphoria and psychomimetic effects eg, hallucinations, perceptual distortions
• Sedation and dizziness
• Nausea and vomiting

Peripherally restricted KOR agonists

• Sedation and dizziness
• Nausea and vomiting
• Headache

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.

We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).