The management of chronic pain in most cases involves the prescribing of opioids or non-steroidal anti-inflammatory drugs. These classes of drugs often have undesirable adverse effects and drug interactions. There is a significant need to find ways to treat pain that have less adverse effects and less risk of addiction. A promising treatment for pain that is being studied is low dose naltrexone, an opioid antagonist that was first used to manage addiction. It was discovered that lower doses of naltrexone exhibited paradoxical effects that had a beneficial impact for a variety of conditions, including those associated with chronic pain.

What is Low Dose Naltrexone?

Naltrexone was first approved by the FDA in 1984 for managing opioid addiction. The doses that are prescribed for addiction range from 50mg to 150mg daily. At a dose that is 1/10^th of the lowest daily dose of the commercial product, naltrexone produces different effects. There are a few explanations as to how LDN treats pain, and it is possible they are all correct to some degree. One explanation is that the short duration of action of low dose naltrexone compared to the regular dose encourages an up-regulation of endogenous opioids and opioid receptors. This has been called a “rebound” effect because the body is compensating after a temporary blockade of receptors.

Another explanation involves the anti-inflammatory actions of low dose naltrexone. At lower doses, naltrexone does not just affect opioid receptors but also non-opioid receptors that are found on macrophages like microglia. These include Toll-like receptors that are implicated in inflammatory reactions throughout the body. This method of action may describe the beneficial effects found when treating fibromyalgia and other conditions associated with diverse symptoms that seem to be either related to inflammation or an immune disorder. It may also be the reason for LDN’s effectiveness at treating inflammatory conditions like Crohn’s disease.

Chronic Pain and LDN

LDN has been shown to be an effective treatment for fibromyalgia in several studies. Fibromyalgia is a chronic condition that is most common in women, and is associated with musculoskeletal pain throughout the body, fatigue, memory issues, and more. At the end of one double-blind, crossover, counterbalanced study, 57% of women with fibromyalgia were observed to exhibit a significant reduction in pain while using LDN.  Over half of the women reported that their symptoms were “much improved” or “very much improved.” Other studies have confirmed that low dose naltrexone is more effective than placebo at treating fibromyalgia pain. It is thought the effectiveness of LDN for fibromyalgia is related to a reduction of inflammation in the CNS as well as its ability to increase endogenous opioid production.

Complex regional pain syndrome (CRPS) is also being treated with LDN. A study is being conducted now with CRPS patients to investigate its effectiveness. CRPS is characterized by chronic pain in particular areas of the body like limbs, hands, and feet. It also can cause stiffness, swelling, weakness, and sensitivity to hot or cold. The hope is low dose naltrexone will be effective at reducing pain for patients with CRPS as it has been for patients with other chronic pain conditions with unspecific or complex etiologies. Some case studies have demonstrated benefits of reduced pain and remission of dystonia for patients with CRPS who were given LDN.

Diabetic neuropathy is a condition characterized by burning pain in the legs and feet related to nerve damage from diabetes. Case studies have demonstrated that low dose naltrexone can effectively reduce this type of chronic pain. In one case study, the patient reported pain on the VAS to be 5% after LDN treatment compared to 90% before therapy. This was a significant change in quality-of-life for this patient, who had previously tried numerous other medications with little improvement.

LDN Side Effects and Contraindications

LDN is considered to be non-toxic with almost no adverse effects reported in studies to-date. The most common adverse effects that have been reported include insomnia, vivid dreams, and headaches, although all of these are still rare. There are also few documented contraindications for using low dose naltrexone to treat chronic pain. The major exception is combining naltrexone with opioid analgesics. When combined with an opioid like morphine, naltrexone will reduce its effectiveness significantly. Embeda is a morphine capsule that contains naltrexone at the center strictly for the purpose of preventing misuse of the medication. If the capsule is crushed to be ingested or inhaled recreationally, the naltrexone is released and diminishes the euphoric effects of the morphine. However when the capsule is taken orally as intended without being crushed, the naltrexone is not activated. If a patient is taking opioid medications they should not take low dose naltrexone simultaneously.

Compounded Low Dose Naltrexone

Naltrexone is FDA approved in 50mg tablets and in combination with other medications like Contrave and Embeda. There is no commercially available version that allows for dosing in the 1.5 to 4.5mg range. A compounding pharmacy is needed to make capsules that contain the lower dosages. Studies have shown that compounded low dose naltrexone, when stored at room temperature and away from sunlight, can maintain its potency for up to one year, although most prescriptions are only for 30, 60, or 90-day supplies. One filler, microcrystalline cellulose, is used but no other additives are needed. It is possible that low dose naltrexone will become available commercially sometime in the future. However in the meantime, many healthcare providers are prescribing low dose naltrexone from a compounding pharmacy to help their patients with chronic pain that is refractory to other treatments.

Research

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain – Clinical Rheumatology

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

The Use and Utility of Low-dose Naltrexone Capsules for Patients with Fibromyalgia. – International Journal of Pharmaceutical Compounding

Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis – BMC Medicine

Low‐dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double‐blind, placebo‐controlled, counterbalanced, crossover trial assessing daily pain levels – Wiley Online Library

Off-Label, Low-Dose Naltrexone for Refractory Painful Diabetic Neuropathy – Pain Medicine