Chronic inflammation has been implicated in the development of an endless list of disease states. Low-dose Naltrexone (LDN) is being used to decrease inflammation and, therefore, prevent or halt the progression of many of these diseases. This paper explores the pharmacodynamics, or physiological effects, of LDN and some alternative therapies that show promise in achieving similar results.
Inflammation is a biologically important process in which immune and non-immune cells are activated to protect the organism from infection, bacteria, viruses, and toxins by eliminating pathogens and promoting repair of tissue. Normal inflammatory response is transient in nature and ceases once the threat to the organism has been eliminated or resolved. However, there are a host of social, environmental, biological, and psychological influences that can prevent the resolution of acute inflammation and result in a chronic state of low-grade inflammation with deleterious results. These include DNA changes, chronic infections, lifestyle-induced obesity, microbiome dysbiosis, diet, social and cultural changes, and exposure to environmental and industrial toxicants (Furman et al., 2019).
An extremely large percentage of diseases in modern society contain in their etiology some aspect of chronic inflammation and resultant immune dysregulation. It has been reported that over 50% of all deaths are attributable to inflammation-related diseases such as ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease (NAFLD) and autoimmune and neurodegenerative conditions (Roth et al., 2018). Often, chronic inflammation can trace its roots to early development and its effects span into late adulthood and affect health and risks of mortality and morbidity (Furman et al., 2019).
Any treatment found to regulate the inflammatory response and immune system will be an important factor in increasing the health of communities where the diseases resulting from chronic inflammation are rampant. If the treatment also proves to be free of major adverse effects, so much the better. Low-dose Naltrexone is being studied as one such solution.
Naltrexone was approved in 1984 for use in the treatment of opioid and alcohol addiction. The standard dose of 50 mg taken orally acts to block opioid receptors and therefore eliminate the “high” experienced when using opioids and alcohol. At the standard dose, Naltrexone is a permanent and non-selective opioid receptor blocker, meaning that the effects of the drug are longer term, and blocks all opioid receptors. This has ramifications for mental health and well-being that are not commonly discussed when talking about Naltrexone’s approved use, as the opioid system is the primary mechanism through which we feel joy.
Naltrexone is 96% absorbed, is 5-40% bioavailable orally due to first pass metabolism, meaning that the digestive system inactivates between 60-95% of the drug before it even reaches the bloodstream. It has a half-life of 4 hours and is 98% metabolized by the liver, so 2% of the medication is what is left to have an effect on the opioid system. Effects of standard dose Naltrexone include decreased reactivity of immune cells and increased growth of cancer cells (Toljan & Vrooman, 2018).
In the mid-1980s, a doctor by the name of Dr. Bernard Bihari began studying the use of low doses of Naltrexone in the treatment of HIV/AIDS in Brooklyn, New York (Bihari, 2013). The work that he did began research into and treatment of autoimmune diseases using LDN such as Crohn, IBD, ulcerative colitis, fibromyalgia, MS, Grave, Hashimoto, and rheumatoid arthritis. Since that time, research has been conducted on the use of LDN for depression, autism, diabetic neuropathy, dermatological d/o such as pruritis, cancer, and complex regional pain syndrome, as well as further research into its effect on immune dysregulation and inflammation.
Low-dose Naltrexone (LDN) is given in a range of 1-5 mg and falls under the ‘hormetic principle’, by which certain pharmacological or toxicological substances exert qualitatively different pharmacodynamical effects in relation to the applied quantity (Toljan & Vrooman, 2018). What has been found is the duration of opioid receptor blockade, not specifically the dosage, by general opioid antagonists determines the biotherapeutic outcome (McLaughlin & Zagon, 2015). Because the dose of LDN is lower, the length of time it exerts its effect on the opioid system is temporary. This completely changes the pharmacodynamics of the drug. The effects that LDN exerts are precisely opposite that of standard dosed Naltrexone. This means that reactivity of immune cells is increased, cancer cell growth is decreased, and the opioid system is regulated rather than blocked completely. The neurobiological mechanism of this effect is thought to be a result of glial-induced increases in the production of immune factors known as cytokines, which carry signals locally between cells and act to mediate/regulate immunity, hematopoiesis (the production of blood cells), and inflammation (Cooper et al., 2012).
Glia are cells that reside in the nervous system alongside neurons. They do not transmit signals in the way that neurons do, but they play a major role in nervous system development, neurotransmission, disease etiology or progression, and neuronal homeostasis. A stimulus that affects their morphology and function has widespread consequences including changes in neurotransmission, metabolism of neurotransmitters, synaptic plasticity and propagation of action potentials (Cooper et al., 2012)
Two types of glial cells are involved in the cascade of effects stimulated by the presence of opioids (either exogenous or endogenous.) These are microglia and astrocytes.
Microglia have many roles including rapid activation in response to trauma, ischemia, inflammation, hypoxia, neurodegeneration, or viral/bacterial infection, and subsequent release of cytokines in the central nervous system (brain and spinal cord). Microglia also restore tissue homeostasis by destroying dead cells, debris, or infectious agents via phagocytosis and releasing cytotoxic factors, as well as aiding in the repair of damaged cells. Microglia contain structures known as Toll-like receptor 4, found in highest concentration in the spleen and liver, as well as on the microglia. Activation of these receptors by circulating inflammatory cytokines initiates production of more cytokines such as Interleukin 1 (IL-1), tumor necrosis factor-α (TNF-α), interferon-β, and nitric oxide.
Astrocytes provide structural support for nerve cells, modulate the environment around neurons to facilitate neuronal signaling, regulate the production of synapses (where neurons release and take up neurotransmitters), maintain the blood-brain barrier, and release a range of neuronal growth factors. Astrocytes also release cytokines in response to the presence of cytokines from other sources (such as the microglia.)
B-cells are a type of lymphocyte (and white blood cell) at the center of the of the adaptive immune system and are responsible for mediating the production of antibodies in response to specific pathogenic invasions. T-cells are another type of lymphocyte that play important roles in the adaptive immune system and act to regulate cytokines. Regulatory T cells specifically modulate the levels of circulating cytokines in the body to down-regulate the inflammatory response when the threat to the organism has been resolved. Opioid receptors are present on all immune cells, including B and T cells. Because of this, opioids can alter the development, differentiation, and function of immune cells.
Low dosing of Naltrexone produces a transient or temporary blockage of opioid receptors. This stimulates the body to produce more opioids, opioid growth factor, and endorphins. By the time these endogenous opioids reach their receptor sites, the LDN has metabolized out of the body and the receptors are free to accept opioids. The result is a net increase in opioids in the body which serves to function as a check-and-balance system on immune cells such as B- and T-cells. Proliferation of B- and T-cells is suppressed, which not only decreases cytokine production, but also up-regulates endogenous production of serotonin and vasopressin, two chemical messengers in the body that regulate mood and fluid balance, respectively. This helps explain the use of LDN in treating depression and blood pressure regulation. Dysregulation of the opioid growth factor-opioid growth factor receptor (OGF-OGFr) pathway has become clear in the etiology of numerous diseases including diabetes, multiple sclerosis, and cancer (McLaughlin & Zagon, 2015). Regulating this system may prevent or disrupt the progression of these diseases.
LDN also functions as glial cell attenuator, which means that it down-regulates the functions of microglia and astrocytes. One way LDN does this is by blocking Toll-like receptor 4s on the microglia to reduce cytokine production and therefore inflammation.
LDN ➟ binds TLR4 ↛ TLR4 unable to produce IL-1, TNF-α , interferon-β, or nitric oxide
↓
Transient opioid receptor blockade ➟ ↑ reactivity of immune cells, ↓ growth of cancer cells
↓ ↖︎
upregulates opioid signaling in the endogenous opioid system. ↖︎
↓ ↖︎
↑ endorphins, met-enkephalon (opioid growth factor), and opioid growth factor receptors
LDN ➟ Suppression of proliferation of B and T cells ➟ ↓ cytokines, ↑ vasopressin & serotonin
While complete disruption of cytokine production would be disastrous for the body’s ability to eliminate pathogens and heal wounds, temporary interruptions and down-regulation of the cytokine pathways seem to offer the body a normalized immune response and opportunity to heal from systemic chronic inflammation. This is showing to have enormous benefits in the treatment of numerous disease states.
MS, fibromyalgia, complex regional pain syndrome, gastrointestinal tract diseases such as irritable bowel syndrome, inflammatory bowel disease, Crohn disease, and ulcerative colitis, and Haley-Haley disease all show decreased levels of opioid growth hormone and/or increased levels of circulating cytokines (Toljan & Vrooman, 2018). Research into the LDN modulation of the opioid system in these diseases has been promising.
Combining LDN with α-lipoic acid or the opioid growth factor met-enkaphalon has been used in the treatment of pancreatic cancer, follicular lymphoma, and others (Donahue et al., 2011). Extremely positive results warrant further research. LDN has also been used as a primer for increasing the effectiveness of chemotherapy drugs (Toljan & Vrooman, 2018).
Other disease states being researched for the use of LDN include depression, autism, postural orthostatic tachycardia syndrome, mast cell activation syndrome, and amyotrophic lateral sclerosis.
Data on the adverse effects of LDN is scarce and mostly anecdotal in nature. Insomnia, sleep disturbance, vivid dreams, and mild headaches have been observed or reported and seem to be self-resolving after the initial introduction of the medication or are alleviated when dose is decreased to below 3 milligrams. Another strategy utilized to avoid these adverse effects is to start a patient on a dose closer to 1 milligram and then titrate up as necessary (Kresser, 2017).
It seems promising that use of LDN to interrupt chronic inflammation states to bring the body back into a balanced immune state means that long-term use of LDN may be unnecessary. Studies following longer-term use show minimal side-effects even with use as long as 3 years (Toljan & Vrooman, 2018). However, it would be wise to gain a better understanding of the ramifications of the use of LDN over time.
Other considerations for the use if LDN concern drug interactions. Because LDN temporarily blocks opioid receptors which results in a net increase in endogenous opioids, opiate analgesics will be potentiated. This can be a positive strategy in combatting hyperalgesia as well as decreasing the dosage needed of exogenous analgesics. Patients taking medications for thyroid disease should be aware that taking LDN may decrease the need for thyroid medication and should be monitored carefully. Additionally, it is not well understood how LDN may affect patients undergoing immunosuppression in the case of organ transplant. More research is needed in the area of immune modulation in this instance.
Numerous alternatives exist that may, in combination, offer similar treatment strategies as the use of LDN. These include vitamin supplementation, herbal support, dietary changes, and acupuncture.
To upregulate T-cell function and support healthy immune response, supplements to be considered include vitamin D, glutathione, probiotics, selenium, zinc, iodine, and vitamin A or cod liver oil. To decrease inflammatory pathways and the production of cytokines, curcumin derived from turmeric (JiangHuang in Chinese medicine), Boswellia derived from frankincense (RuXiang), fish oil, and dietary changes that include eliminating inflammatory foods are all to be considered (Kresser, 2017).
Another herb that has been shown to decrease cytokines is Tripterigium Wilfordii, common name broad lily root (LeiGongTeng) which is used for relieving pain and swelling in rheumatoid arthritis when proper preparation methods are used. However, there are over one hundred substances in the Chinese pharmacopeia that reduce inflammation (Chen et al., 2004). These are formulated to specifically address the individual pattern that each patient exhibits and could potentially be used for all disease states resulting from chronic inflammation and immune dysregulation.
One medicinal substance from the Chinese pharmacopeia that should be avoided when treating patients with chronic inflammation or immune dysregulation is Ganoderma lucidum, common name reishi mushroom (LingZhi). This mushroom is known to increase the cytokines TNF-α, interleukin, and interferon, as well as immune cells such as T-lymphocytes and macrophages.
As early as the 1970s research suggested that the analgesic properties of acupuncture are mediated by endogenous opioids (Hesselink & Kopsky, 2011). Further research suggests that acupuncture down-regulates inflammation and the immune system through stimulation of the autonomic nervous system via the vagus nerve. Cytokines such as TNF-α in the spleen are down-regulated by vagus nerve stimulation during acupuncture treatment which acts as an immune system regulator (Hennessey, 2018).
Acupuncture has also been shown to induce opioid pathways and increase dopamine production. As outlined previously, increased opioid pathways act to decrease inflammation and regulate immune function. Dopamine also has these effects as it inhibits cytokine production. Studies showing these results all were using electro-acupuncture on either auricular points or ZuSanLi ST36. Patients receiving regular acupuncture may significantly benefit from regulated immune and nervous system functioning and may be able to interrupt chronic inflammation states.
The connection between the opioid system and the immune system has been one of the most important discoveries of modern research and the impact this understanding has on inflammatory states and disease is unquantifiable. The possibility of regulating immune function preventatively using acupuncture, supplements, and dietary therapies is undoubtably fundamental in increasing community health and the health of individuals. The potential that use of low-dose naltrexone exhibits in modern research for some of the most problematic diseases of our time is certainly cause for continued research and treatment. Combining acupuncture with LDN for intractable cases of disease may be a treatment strategy to consider for both practitioners of East Asian medicine and Western doctors.
References
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