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17 Articles in Volume 20, Issue #3
20/20 with Dr. Suzanne Amato Nesbit: Clinical Pharmacy Roles and Disparities
A Clinician’s Guide to Treating Chronic Overuse Injuries
Adhesive Arachnoiditis: No Longer a Rare Disease
Analgesics of the Future: Cebranopadol as an Opioid Alternative
Ask the PharmD: What role do vitamin D supplements play in treating dysmenorrhea?
Behavioral Pain Medicine: Managing the Affective Components of Pain
Chronic Fatigue Syndrome: Naltrexone as an Alternative Treatment
Chronic Pain and Coronavirus
Connecting the Dots: How Adverse Childhood Experiences Predispose to Chronic Pain
Editorial: Why Are ER Opioids Out of Favor?
Fibromyalgia as a Neuropathic Pain Disorder: The Link to Small Fiber Neuropathy
How the COVID-19 Pandemic Is Transforming Pain Care
Hydroxychloroquine Use and Risk in the Management of Systemic Lupus Erythematosus
Management of Trigeminal Neuralgia in Multiple Sclerosis
Optimizing Care Using a Trauma-Informed Approach
Pediatric Pain Management: A Review of Clinical Diagnosis and Management
The Use of Low Dose Naltrexone in the Management of Chronic Pain

Chronic Fatigue Syndrome: Naltrexone as an Alternative Treatment

At low doses, naltrexone is thought to disrupt the inflammatory process and restore the impaired cation channel functioning associated with chronic fatigue. Inside the latest data.
Pages 63-64

Chronic fatigue syndrome, also known as myalgic encephalomyelitis, is a long-term complicated illness with unknown causes that is characterized by at least six months of pain and fatigue. There is currently no cure for the illness and diagnosis can be difficult due to lack of testing with adequate sensitivity and specificity. However, there is evidence of underlying abnormalities in the nervous, immune, and metabolic systems in affected patients. Because the illness is poorly understood, it has been difficult to treat. Prior research has focused on immunosuppressive treatments, anti-viral agents, later followed by cognitive behavioral theory and antidepressants.1

The efficacy of these treatment regimens has not been consistent. A new perspective is emerging with research looking at low dose naltrexone (LDN), defined as doses about one-tenth the size of the normal dose, as a potential alternative treatment for chronic fatigue.

Naltrexone is an opioid antagonist (particularly at the mu receptor) formulated as a tablet that is indicated for the treatment of ethanol or opioid addiction in a dose of roughly 50 mg to 100 mg per day. At this dosage, naltrexone is believed to block the euphoric effects of endorphins which act to sustain addiction.

Naltrexone has been proposed to be helpful in other chronic inflammatory conditions, including multiple sclerosis, Crohn’s disease, and fibromyalgia. Could it also help manage chronic fatigue? (Image: iStock)

Anti-inflammatory and Hyperalgesia Effects

At a much lower dosage of 3.0 mg to 4.5 mg per day, it is the non-opioid antagonist path that is more active, which is believed to exert the anti-inflammatory and hyperalgesia effects.2 In this path, naltrexone simultaneously has an antagonist effect on non-opioid receptors, including toll-like receptor 4 (TLR 4), that are found on macrophages such as microglia.2 Microglia are central nervous system immune cells that are activated by a wide range of triggers.3

Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as fatigue, pain sensitivity, sleep disorders, mood disorders, cognitive disruption and general malaise.4 When chronically activated, the resulting pro-inflammatory release of cytokines and interleukins may become neurotoxic, causing several damaging effects. Naltrexone is thought to disrupt this process as it blocks TLR 4 from becoming activated and, therefore, inhibits microglia activation.

The hypothesis of this microglial pathway producing the hyperalgesia effects is best supported by a stereoisomer of naltrexone called dextro-naltrexone. Dextro-naltrexone has been shown to have no activity on opioid receptors but is active on microglia receptors.5 The analgesic, anti-inflammatory, and neuroprotective effects of naltrexone do not appear to be dependent on opioid receptors as dextro-naltrexone has analgesic effects.6 This stereoisomer could be the source of future research as there might be fewer side effects because only one pathway is activated and therefore translates into higher tolerated doses.

Restoring TRPM3 Ion Channel Function

In addition to this perspective, and more recently, there has been an association found between abnormal cation channel functioning and chronic fatigue. Transient receptor potential melastatin 3 (TRPM3) is a calcium permeable nonselective channel that is activated by a vast array of stimuli in the environment, ranging from temperature, natural chemicals, and toxins or synthetic compounds. As it tightly controls the influx of calcium ions, this channel is essential in maintaining natural killer cell functioning and cytokine production. A significant reduction in both TRPM3 surface expression and intracellular calcium mobilization in natural killer cells has been found in chronic fatigue patients compared with healthy controls.7

When administered, LDN restored the impaired TRPM3 ion channel function in natural killer cells of patients.8 Polo, et al, also tested the use of LDN further clinically with 218 patients with a diagnosis of chronic fatigue syndrome.9 Low dose naltrexone was administered during an average follow-up time of 1.7 years. A reduction in pain symptoms was found in 73.9% of patients with most patients experiencing improved alertness, physical and cognitive performance.

Other Chronic Inflammatory Conditions

For similar reasons as previously discussed, naltrexone has been proposed to be helpful in other chronic inflammatory conditions, including multiple sclerosis, Crohn’s disease, and fibromyalgia.10 In the initial pilot study of low dose naltrexone in fibromyalgia, baseline erythrocyte sedimentation rate (a commonly employed clinical test that is sensitive to both chronic and acute inflammatory processes) was a significant predictor of clinical response to the medication.11

Of note, the pathophysiology of the above diseases may be similar as many of the symptoms including chronic fatigue are often seen. This may serve as an explanation as to why naltrexone may be effective.


The concept of having a paradoxical hyperalgesia effect produced at significantly reduced doses of medications has been demonstrated before. The most notable example is that of morphine. The hyperalgesia effect can be seen at roughly one-tenth of the dose than that would typically produce reduced pain. This suggests that there is a small window at which opioid analgesics produce the opposite effects than those typically expected.12 Therefore, this same principle may explain the effects as seen with the hyperalgesia nature of greatly reduced doses of naltrexone.

In summary, naltrexone is a very low-cost medication that has been widely available since 1984. The high frequency of treatment response and good overall safety profile observed confirms the feasibility of low dose naltrexone in alleviating chronic fatigue symptoms. Additionally, naltrexone does not appear to exert any euphoric or reinforcing effects, and therefore offers a minimal risk of misuse. However, as research is still in its infancy, more insight is needed before this treatment may be widely accepted.

Last updated on: June 18, 2020
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