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Low Dose Naltrexone: Is it Really Worth the Hype?

Nov 6, 2023, 01:00 AM by Priyanka Singla, MD, Yasmin Sritapan, DO, and Bhavana Yalamuru, MD

Cite as: Singla P, Sritapan Y, Yalamuru B. Low dose naltrexone: is it really worth the hype?. ASRA Pain Medicine News 2023;48.


Chronic pain affects over 50 million people in the United States,1 presenting significant challenges in treatment. As we grapple with the current opioid epidemic, there has been a renewed focus on discovering effective non-opioid alternatives to treat chronic pain with minimal adverse effects. Naltrexone is an FDA approved opioid antagonist for treatment of opioid use disorder and alcohol use disorder.2 There is emerging evidence for use of a low dose form of this medication to treat chronic pain conditions. This review will discuss the pharmacology and current evidence for use of Low Dose Naltrexone (LDN) for treating chronic pain.

Pharmacology: Mechanism of Action

Neuropathic pain occurs due to nerve damage, which results in activation of glial cells and subsequent release of proinflammatory mediators leading to peripheral and central sensitization, contributing to the chronic pain experience.3,4 LDN offers a potent therapeutic strategy for mitigating this chronic inflammation and central sensitization via its anti-inflammatory and immunomodulating properties.5-7

Naltrexone is a mu-opioid receptor antagonist.5,8-10 However, it has multiple dose-dependent pharmacological dynamics with different respective effects8,9 and can be a versatile tool to treat and manage chronic pain. At low doses, LDN reduces glial inflammatory response by antagonism of Toll-like receptor 4 in both the central and peripheral nervous system, thereby reversing neuropathic pain.8-11 Additionally, LDN competitively inhibits binding of Opioid Growth Factor to Opioid Growth Factor Receptor for a short duration and therefore results in inhibition of cellular proliferation.5,8 This may have a potential role in cancer treatment as well.5,8

An Important Tool in the Pain Physician’s Armamentarium: Indications and Evidence

LDN has been utilized in the management of a number of chronic inflammatory and central pain sensitization conditions.5 These include fibromyalgia, Crohn’s disease, multiple sclerosis (MS), complex regional pain syndrome (CRPS), Hailey-Hailey disease, and cancer.7,8 In a recent case series, there was a pronounced therapeutic effect of LDN in patients diagnosed with neuropathic pain in comparison to those presenting with arthritic conditions.12 This has been particularly evident in patients afflicted with painful neuropathic conditions, such as diabetic peripheral neuropathy and CRPS, wherein LDN implementation has yielded successful results.5,12,24,25 However, the broadest research has been conducted in patients with MS and Crohn’s disease. These studies have demonstrated the tangible benefits of LDN therapy in managing and mitigating the often-debilitating effects of these conditions (Table 1).

Table 1: Evidence for Use of LDN in Pain Medicine.
Author Study Type Year Published Indication Key Finding
Smith et al13 Pilot study 2007 Crohn’s disease 4.5 mg for 12 weeks, improved quality of life, effective in controlling symptoms of Crohn’s disease
Gironi et al14 Phase II pilot trial 2008 Multiple sclerosis Minor adverse effects, improvement in spasticity
Cree et al15 Randomized placebo cross over trial 2010 Multiple sclerosis 4.5mg for 8 weeks, improved mental health quality of life indices and symptomatic pain
Sharafaddinzade et al16 Randomized placebo cross over trial 2010 Multiple sclerosis No significant difference in quality of life, safe option
Smith et al17 Randomized control trial 2011 Crohn’s disease 4.5 mg for 12 weeks, improvement in clinical and inflammatory activity of disease compared to placebo
Younger et al18 Randomized control trial 2013 Fibromyalgia 4.5 mg, greater reduction in pain compared to placebo
Turel et al5,19 Retrospective review 2015 Multiple sclerosis At 3.5 mg, 60% patients reported reduction in fatigue; 75% reported improved or stable quality of life.
Ludwig et al20 Retrospective review 2016 Multiple sclerosis Safe, inexpensive treatment option
Parkitny et al21 Pilot trial 2017 Fibromyalgia 4.5 mg for 10 weeks, decreased plasma levels of proinflammatory cytokines, better pain control
Metyas et al22 Open label trial 2018 Fibromyalgia 90 days, 40% improvement in symptoms
Peters et al23 Randomized control trial 2022 High grade glioma 4.5 mg for 16 weeks, no improvement in quality of life and fatigue

Concerns with LDN Therapy

In a retrospective review of 215 patients diagnosed with MS, LDN was deemed safe with negligible adverse effects.5,19 Multiple other studies tout the safety profile of LDN.15,16 The most common side effects reported with LDN therapy are sleep disturbances, vivid dreams, fatigue, and headaches.13,17,18 Authors reported resolution of vivid dreams and headaches by decreasing the dose to 3 mg or altering the time of administration from night to day time.12,18

Unfortunately, at the time of writing this review, several insurance carriers in the United States do not pay for or cover the cost of LDN prescriptions.12,19 LDN is specially prepared, which limits its availability to select compounding pharmacies. 12 In a retrospective review of cases, McKenzie-Brown et al noted about 1-3 months of lag period of symptom relief in patients who responded after the initiation of therapy.12

Perioperative Concerns for Patients on LDN

When managing patients on LDN, recommendations from the Low Dose Naltrexone Research Trust26,27 suggest stopping LDN 2 days prior to the procedure and restarting 2 days after the patient has stopped taking opioids completely. This recommendation is grounded in the understanding that opioids should be individualized with cautious monitoring, as there can be significant variation in response to narcotics given baseline upregulation of opioid receptors. Most hospital pharmacies don’t carry LDN on formulary and have varying policies on patients bringing their own home medications. Given these circumstances, it may be considered more practical to advise patients to discontinue LDN during the perioperative period of their hospitalization.

Most hospital pharmacies don't carry LDN on formulary and have varying policies on patients bringing their own home medications

How We Do It: Our Practice at the University of Virginia Medical Center

In our practice, we prescribe LDN for patients with fibromyalgia and neuropathic pain conditions such as Complex Regional Pain Syndrome, which are refractory to first- and second-line medications commonly used to treat neuropathic pain and Ehlers Danlos Syndrome. Since patients must pay out of pocket, we reserve it as a last resort when all indicated medications and therapy options have been exhausted.

We initially started patients on LDN at 1.5 mg for a month with subsequent titration to 3 mg in the following month. The objective of this regimen was to attain the target dose of 4.5 mg once daily, which was typically achieved after 2 months of initiating the therapy. We have seen a very low incidence of adverse effects within this protocol and have now changed our practice to start patients at 4.5 mg daily dosage, thereby eliminating the need for a titration period. We follow up with patients in 3 months after starting the medication and thereafter every 6-12 months.

Priyanka Singla
Priyanka Singla, MD, is an assistant professor in the department of anesthesiology at the University of Virginia in Charlottesville.
Yasmin Sritapan, DO, is an assistant professor of anesthesiology at Johns Hopkins University in Baltimore, MD.
Bhavana Yalamuru, MD, is an assistant professor in the department of anesthesiology at the University of Virginia in Charlottesville.


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