Naltrexone and naloxone

For information on opioid receptor agonists, see opioid receptor agonists in dermatology.

What are naltrexone and naloxone?

Naltrexone and naloxone are both competitive antagonists of opioid receptors, binding with high affinity to the mu (μ) opioid receptors. They also exhibit affinity for kappa (κ) and delta (δ) opioid receptors, but to a lesser extent.

What are naltrexone and naloxone used for?

Naltrexone is used to maintain abstinence in alcohol and opioid use disorders through its suppressive effects on cravings. When given in fixed combination with bupropion, naltrexone is also an FDA-approved weight loss drug called Contrave®.

There has been growing interest in the use of low-dose naltrexone (LDN) in inflammatory and chronic pain conditions. LDN refers to a dosage of around 1-5 mg daily. For comparison, the standard dose used in alcohol or opioid use disorders is 50-100 mg daily, orally.

Off-label uses for LDN include:

• Crohn disease
• Sjögren syndrome
• Multiple sclerosis
• Rheumatoid arthritis
• Fibromyalgia
• Long COVID.

Naloxone is used for the rapid reversal of opioid toxicity or overdose.

Dermatological uses (off-label)

Naltrexone

At standard doses (50-100 mg/day orally):

• Pruritus associated with atopic dermatitis, psoriasis, lichen simplex, and nodular prurigo
• Aquagenic pruritus
• Cholestatic pruritus
• Burn injury pruritus.

At low doses (1-5 mg/day orally):

• Hailey-Hailey disease
• Lichen planopilaris
• Psoriasis
• Systemic sclerosis
• Dermatomyositis
• Frontal fibrosing alopecia.

Naloxone

• Hailey-Hailey disease
• Pruritus associated with cutaneous T-cell lymphoma
• Brachioradial pruritus
• Cholestatic and renal pruritus

Axillary Hailey-Hailey disease - low-dose naltrexone can help this condition 

Prurigo may improve with standard dose naltrexone 

What are the contraindications and precautions for naltrexone and naloxone?

Naltrexone

Contraindications:

• Concurrent opioid use or anticipated need for opioid analgesia eg, post-operative period
  • Patients can experience uncontrolled pain and exceedingly high opioid requirements, risking respiratory depression.
  • Low-dose naltrexone may be continued on a case-by-case basis.
• Opioid dependence
  • Naltrexone can precipitate acute opioid withdrawal, which can be severe and rarely life-threatening.
  • Medically supervised opioid withdrawal is necessary before initiating naltrexone.
• Acute opioid withdrawal
• Hypersensitivity reactions to naltrexone or its excipients
• Acute hepatitis or liver failure
  • Hepatotoxic effects have been observed at five times the standard dose.

Precautions:

• Pregnancy and breastfeeding — lack of safety data
• Pediatric populations — lack of safety data in patients younger than 18 years old
• Active liver disease, including compensated cirrhosis — requires monitoring of liver function
• Renal impairment
• Increased sensitivity to opioids after cessation of naltrexone
  • Patients must be warned that they may respond to opioids at doses lower than what was previously tolerated.
  • Increased sensitivity may put them at risk of opioid intoxication with respiratory depression.

Naloxone

Contraindications:

There are no absolute contraindications for naloxone in emergency use. The only relative contraindication is hypersensitivity to naloxone or its excipients.

Precautions:

• Concurrent opioid analgesic use
• Opioid dependence
  • Naloxone can precipitate acute opioid withdrawal, though effects tend to resolve in 30-60 minutes due to its short half-life.
• Cardiovascular disease or concurrent use of potentially cardiotoxic drugs
• History of seizures
• Renal or hepatic impairment — dose adjustments are not required
• Nasal mucosa damage or septal defects — intranasal absorption may be impaired.

Naloxone is considered compatible for use in pregnancy and breastfeeding.

Tell me more about naltrexone and naloxone

Naltrexone is typically given orally and has a half-life of 5 hours. Its active metabolite, 6β-naltrexone, has a half-life of 15 hours. The half-life of naltrexone can be extended by administering it as an implant or intramuscular injection (depot).

Naloxone is administered parenterally (intravenously, subcutaneously, or intramuscularly) or by nasal spray, and it has a short half-life of 30 to 90 minutes.

While regulatory approval for dermatological conditions is lacking, emerging evidence from case series and small trials supports their off-label use. Larger, robust clinical trials are needed to establish standardised dosing, efficacy, and long-term safety for these indications.

Low-dose naltrexone (LDN)

LDN is proposed to exert its effects through the transient blockade of opioid receptors, binding for only 4-6 hours compared to 24-48 hours with standard dosing. This intermittent blockade promotes a paradoxical upregulation in endogenous opioid production and opioid receptor expression.

Moreover, LDN also antagonises Toll-like receptor 4 (TLR4) on microglial cells, which are the primary immune cells in the central nervous system. This action inhibits the release of pro-inflammatory cytokines. Together, enhanced opioid signalling and microglial modulation produce anti-inflammatory and anti-nociceptive effects.

(For information on opioid receptors, see: opioid receptor agonists in dermatology).

What are the benefits of naltrexone and naloxone?

• Both agents have an excellent safety profile and are generally well-tolerated.
• Drug tolerance and dependence do not develop with continued use.
• Naltrexone is a relatively inexpensive drug.

What are the disadvantages of naltrexone and naloxone?

• Regulatory approval and standardised dosing for their use in dermatological conditions have not been established.
• Low-dose naltrexone is not commercially available and must be compounded by a pharmacist.

What are the side effects and risks of naltrexone and naloxone?

In non-opioid dependent patients, serious adverse effects are rare, and most side effects are mild and transient.

Naltrexone

Side effects of low-dose naltrexone are usually milder and fewer in number than those observed with standard doses. They include:

• Gastrointestinal cramping, nausea, and diarrhoea
• Fatigue and dizziness
• Insomnia and vivid dreams.

In rare cases, naltrexone has been reported to paradoxically exacerbate itch in cholestatic and mycosis fungoides-associated pruritus.

Naloxone

In the context of acute opioid reversal, there have been reports of ventricular tachycardia, atrial fibrillation, pulmonary oedema, and cardiac arrest occurring after naloxone administration in postoperative patients, most of whom had pre-existing cardiovascular disorders or received potentially cardiotoxic drugs. A causal relationship has not been established.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

If you are not based in New Zealand, we suggest you refer to your national drug approval agency for further information about medicines (eg, the Australian Therapeutic Goods Administration and the US Food and Drug Administration or a national or state-approved formulary (eg, the New Zealand Formulary and New Zealand Formulary for Children and the British National Formulary and British National Formulary for Children).