Low-dose naltrexone

Purported Benefits, Side Effects & More
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Low-dose naltrexone

Common Names

  • LDN

For Patients & Caregivers

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What is it?

Naltrexone is an older drug that was developed in the 1960s and approved for medical use by the FDA in the 1980s. It is used clinically to treat opioid and alcohol addictions.

More recently, low-dose naltrexone (LDN) has been promoted as a safe and inexpensive way to treat various conditions.

What are the potential uses and benefits?

Low-dose naltrexone is used to:

  • Treat various types of unresolved lingering pain
  • Relieve pain caused by fibromyalgia (chronic widespread pain, fatigue, and tenderness)

LDN has other uses, but doctors haven’t studied them to see if they work.

Talk with your healthcare provider before taking LDN. It may interact with some medications and affect how they work. For more information, read the “What else do I need to know?” section below.

What are the side effects?

Generally well tolerated in a few small studies

Side effects of using low-dose naltrexone appear to be mild, but may include:

  • Diarrhea (loose or watery bowel movements)
  • Nausea (feeling like you’re going to throw up)
  • Stomach pain
  • Altered mood
  • Headache
  • Joint pain
What else do I need to know?
  • Talk with your healthcare provider if you’re undergoing chemotherapy. It is unclear whether using LDN during treatment may affect how these drugs work.
  • Talk with your healthcare provider if you’re taking tamoxifen (such as Nolvadex® or Soltamox™). It is unclear whether using LDN during treatment may affect how these drugs work.
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For Healthcare Professionals

Clinical Summary

Naltrexone is an opioid antagonist that was originally developed in the 1960s and approved for medical use by the FDA in the 1980s. It has been used clinically to treat opioid and alcohol addictions (1). More recently, low-dose naltrexone (LDN) has been promoted for off-label use as a safe and inexpensive option to treat myriad conditions including pain, inflammation, immune dysfunction, gastrointestinal, neurological, and psychological conditions, and even cancer. However, studies are quite limited.

Small placebo-controlled trials suggest benefit with LDN for patients with fibromyalgia (2) (3). LDN efficacy for diabetic neuropathy appears to be similar to amitriptyline, but with fewer adverse effects (4). In a proof-of concept study of patients with major depressive disorder who relapsed on antidepressants, LDN-augmented treatment reduced depression severity (5). Other pilot RCTs suggest benefit for patients with moderate to severe Crohn’s disease (6) (7). However, results from studies in patients with multiple sclerosis are equivocal (8) (9), and anecdotal claims of efficacy with LDN for cancer have not been examined in clinical trials.

Although it is thought to be well-tolerated, larger well-designed clinical trials are needed to understand the conditions for which LDN may be safe and effective before it can be recommended.

Purported Uses and Benefits
  • Fibromyalgia
  • Pain
  • Cancer
  • Numerous other ailments
Mechanism of Action

Naltrexone is a semi-synthetic opioid with structural similarity to other opioid agonists and competitive antagonist activity at mu opioid receptors (10), neuromodulators with functions that include nociception, or identifying and responding to painful stimuli.

The phenomenon of paradoxical hyperalgesia discovered with morphine in animal studies, where the opposite effect occurs at about one-tenth of the dose used to relieve pain has been proposed as the mechanism by which LDN may actually reduce pain (11). Anti-inflammatory effects have been attributed to additional antagonist effects on toll-like receptor 4, nonopioid receptors found on macrophages such as microglial cells (11) (12).

Contraindications

Contraindications associated with standard doses of naltrexone include (13):

  • Patients receiving opioid analgesics.
  • Patients currently dependent on opioids, including those currently maintained on opiate agonists such as methadone or partial agonists like buprenorphine.
  • Patients in acute opioid withdrawal.
  • Any individual who has failed the naloxone challenge test or who has a positive urine screen for opioids.
  • Any individual with a history of sensitivity to naltrexone or any other components of this product. It is not known if there is any cross-sensitivity with naloxone or the phenanthrene containing opioids.
Adverse Reactions

Generally well tolerated in small studies (2) (6)
Mild: Diarrhea (4); nausea, epigastric pain, altered mood, headache, and joint pain (9)

Herb-Drug Interactions

Chemotherapy drugs: Preclinical data suggest that naltrexone can interact with several CYP enzymes (14). Clinical relevance, including for low doses, has yet to be determined.

CYP450 substrates: Preclinical data show that naltrexone can interact with several CYP enzymes, and particularly 2C9 and 2D6 (14). Clinical relevance, including for low doses, has yet to be determined.

Dosage (OneMSK Only)
References
  1. The Substance Abuse and Mental Health Services Administration (SAMHSA), U.S. Department of Health & Human Services. Naltrexone. Available at https://www.samhsa.gov/medication-assisted-treatment/medications-counse…. Accessed April 13, 2022.
  2. Younger J, Noor N, McCue R, et al. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. Feb 2013;65(2):529-538.
  3. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. May-Jun 2009;10(4):663-672.
  4. Srinivasan A, Dutta P, Bansal D, et al. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active-control, crossover clinical trial. J Diabetes. Oct 2021;13(10):770-778.
  5. Mischoulon D, Hylek L, Yeung AS, et al. Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. J Affect Disord. Jan 15 2017;208:6-14.
  6. Smith JP, Field D, Bingaman SI, et al. Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn’s disease: a pilot study. J Clin Gastroenterol. Apr 2013;47(4):339-345.
  7. Smith JP, Bingaman SI, Ruggiero F, et al. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial. Dig Dis Sci. Jul 2011;56(7):2088-2097.
  8. Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. Aug 2010;68(2):145-150.
  9. Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, et al. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. Aug 2010;16(8):964-969.
  10. Sudakin D. Naltrexone: Not Just for Opioids Anymore. J Med Toxicol. Mar 2016;12(1):71-75.
  11. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. Apr 2014;33(4):451-459.
  12. Hutchinson MR, Zhang Y, Brown K, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci. Jul 2008;28(1):20-29.
  13. REVIA®(naltrexone hydrochloride tablets USP). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018932s017lbl…. Accessed April 13, 2022.
  14. AlRabiah H, Ahad A, Mostafa GAE, et al. Effect of Naltrexone Hydrochloride on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activity in Human Liver Microsomes. Eur J Drug Metab Pharmacokinet. Dec 2018;43(6):707-713.
  15. Bruun-Plesner K, Blichfeldt-Eckhardt MR, Vaegter HB, et al. Low-Dose Naltrexone for the Treatment of Fibromyalgia: Investigation of Dose-Response Relationships. Pain Med. Oct 1 2020;21(10):2253-2261.
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