In 1984, Bernard Bihari, MD, a Harvard University physician and researcher, observed that while naltrexone successfully blocked heroin’s ability to bind the opioid receptors, the complete blockage led to such severe side effects that the former addicts would not comply with continued use.

With his knowledge of naltrexone’s effect on the immune system, he turned his research attention in that direction. Realising that naltrexone’s effects included increasing endorphins and that this action raises immune competence, Bihari and others began testing innate endorphin levels in individuals with HIV/AIDS and found they were low in endorphin production compared to patients who did not have HIV/AIDS.

The first clinical use of low-dose naltrexone (LDN) was in 1985 by Bihari. He compared various doses of LDN and found that 3.0 mg stimulated the body’s own production of endorphins but also the immune system. In an effort to find the minimal dose of naltrexone needed to raise endorphins, Bihari and his colleagues did a dose-ranging study comparing 50, 20, 10, 5, 3, and 1 mg of naltrexone. They found that while all these doses raised endorphins equally, a dose as low as 1.0 mg had no effect on endorphins. He then compared various doses of LDN between 1.75 and 4.5 mg and verified that a dose of 3.0 mg of LDN increased levels of endorphins during the night and even throughout the next day.

Bihari stated in his research that endogenous endorphins were released in the body between 2:00 am and 4:00 am; however, other research has shown that beta (β)-endorphins are released in healthy adults between 4:00 am and 10:00 am. 

Most LDN is prescribed at bedtime, but if patients report nightmares, taking the dose in the morning is an alternative. Vivid dreams are the most commonly reported side effect in clinical trials, but this seems to decrease after a few nights. Another less common side effect is headaches, but these are reported as mild in severity. No side effects of stomach ulcers, renal impairment, or interference with anticlotting medications have been reported in research.

Perhaps one of the most common uses of LDN is to reduce inflammation and manage autoimmune diseases. 

The increase of β-endorphins has been shown to help reduce pain levels, especially when the source of the pain is related to an inflammatory process. It has been shown that LDN reduces inflammation by reducing multiple pro-inflammatory cytokines. Cytokines are chemical messengers, often made by immune cells, whose net effect can be to either increase or decrease immune function. The coordination of the immune system rests on the body’s ability to keep a balance between cytokines that promote inflammation and those that reduce it. Tumour necrosis factor alpha (TNF-α) is also associated with both increased inflammation and neuroprotection when the body is presented with an insult such as nerve damage. Excess synthesis or upregulation of TNF-α is associated with certain conditions such as cerebral ischaemia, Alzheimer disease, and atherosclerosis; reducing levels of TNF-α may be beneficial in treatment. There are well-documented studies on positive results when treating autoimmune conditions such as Crohn disease and rheumatoid arthritis.

A more complex case involves individuals presenting with symptoms that involve both physical and emotional features; this gives the practitioner the opportunity to explore a monotherapy as an alternative to adding numerous pharmaceuticals and/or natural supplements. Fibromyalgia is a very common condition that fits this picture, and it also has been well-studied with LDN as a therapy.

Fibromyalgia is a generalised muscular pain syndrome. In addition to complaints of pain, patients with fibromyalgia also report symptoms of sleep disturbance and fatigue. In an 8-week, single-blinded pilot study involving 4.5 mg of LDN each night, serum levels of numerous proinflammatory cytokines, including interleukin 2 (IL-2) and TNF-α, were significantly reduced when compared to baseline in patients suffering from fibromyalgia (P<0.001). 

When practitioners recommend LDN for conditions as complex as fibromyalgia, it is important to work with the patient as a whole person, not just the pain. Patients with fibromyalgia also have complaints of fatigue, depression, anxiety, and insomnia. Pharmaceutical treatment of fibromyalgia includes muscle relaxants, gabapentin, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors. These medications may be used in combination in an attempt to treat multiple concerns. The use of LDN as a monotherapy may offer the person suffering from fibromyalgia a solution for several concerns, including pain relief. 

Conclusion

Treating patients with too low of a dose of opioid medications will not provide relief from pain and may result in hyperalgesia. Treating patients with higher doses on a chronic basis can lead to a tolerance to the inhibitory actions of opioids, thus resulting in an increased sensitivity to pain, opioid tolerance, and hyperalgesia.Investigators continue to research the use of naltrexone in medicine to assist practitioners in treating a variety of situations including autoimmune diseases, neurodegenerative diseases, and pain management. Adjustable dosing of naltrexone can serve as a valuable alternative to opioid medications and as an adjunctive measure to reduce the need for higher doses of opioids, to reduce or eliminate the side effects of these drugs, or to work synergistically to avoid opioid tolerance and chronic hyperalgesia.

References

Srivastava AB, Gold MS. Naltrexone: A history and future directions. Cerebrum. 2018;2018:cer-13-18.
Substance Abuse and Mental Health Services Administration. Chapter 3C: Naltrexone. In: Medications for Opioid Use Disorder: For Healthcare and Addiction Professionals, Policymakers, Patients, and Families [Internet]. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2018.
Comer SD, Sullivan MA, Yu E, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence, a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2006;63(2):210-218.
Schwaiger T. The uses of low-dose naltrexone in clinical practice; potential benefits for a wide range of conditions. Nat Med J. 2018;