Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic, Nonmalignant Pain Syndromes

Abstract

Pain can have a devastating effect on the quality of life of patients in palliative medicine. Thus far, majority of research has been centered on opioid-based pain management, with a limited empirical evidence for the use of nonopioid medications in palliative care. However, opioid and nonopioid medications such as nonsteroidal anti-inflammatory drugs have their limitations in the clinical use due to risk of adverse effects, therefore, there is a need for more research to be directed to finding an alternative approach to pain management in comfort care setting. The purpose of this article is to discuss a potential new drug that would adequately alleviate pain and enhance quality of life without significant risks of adverse effects that would limit its use. Naltrexone is a reversible competitive antagonist at μ-opioid and κ-opioid receptors, which when used at standard doses of 50 to 150 mg was initially intended for use in opioid and alcohol use disorders. However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response. Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect. Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.

Complex Regional Pain Syndrome: A Comprehensive Review

“…In low doses, naltrexone acts primarily through an alternate pharmacodynamic pathway and inhibits microglial activation, ultimately decreasing the inflammatory response [81]. Low-dose naltrexone has commonly been used for off-label treatment of autoimmune diseases, such as multiple sclerosis and inflammatory bowel disease [81]. Limited data exist, which are primarily case studies, regarding its use in CRPS or other chronic pain syndromes, such as fibromyalgia [81][82][83].…”

Nitric Oxide and Opioids Involvement in Isobolographic Nsaids Antinociception

“…Naltrexone is a reversible competitive antagonist with high affinity for MOR and KOR opioid receptors [29], in doses of 1-5 mg acts as a glial modulator reducing inflammation. In a dosing range at less than 1 μg per day, termed ultra low-dose (ULDN) it has been used for control of analgesia [30].…”

Juvenile primary fibromyalgia syndrome: A Review- Treatment and Prognosis

“…Studies have shown that low-dose naltrexone, an opiate receptor antagonist, may be effective, safe and inexpensive for adults FM [ 65 ]; yet, further large prospective controlled trials are needed before its use can be recommended for JPFS [ 66 ]. To our knowledge, no studies have been published regarding its use for the treatment of JPFS.…”