From the Guidelines
Low dose naltrexone (LDN) works by acting as an opioid antagonist for the μ-opioid and κ-opioid receptors, as well as an antagonist to toll-like receptor 4, which is linked to neuropathic pain, reducing the release of pro-inflammatory cytokines and modulating microglial activity. This mechanism of action is supported by a study published in the journal Ophthalmology in 2017 1. The study found that LDN (3–5 mg) was effective in reducing chronic neuropathic pain in patients with conditions such as fibromyalgia, complex regional pain syndrome, low-back pain, and painful diabetic neuropathy.
The recommended dosage of LDN is 1.5 mg at bedtime, with a gradual bi-weekly increase of 1.5 mg to a final maximum dose of 4.5 mg taken at bedtime, as suggested by the study 1. Common side effects of LDN include headache, tachycardia, and vivid dreams. The medication has been shown to be effective in reducing pain and improving satisfaction with life in patients with fibromyalgia, with a significant decrease in pain reported in a randomized controlled trial (RCT) of 31 patients who received LDN 4.5 mg compared to placebo 1.
Key points about LDN include:
- It is an opioid antagonist that reduces the release of pro-inflammatory cytokines and modulates microglial activity
- It is effective in reducing chronic neuropathic pain in patients with conditions such as fibromyalgia and painful diabetic neuropathy
- The recommended dosage is 1.5 mg at bedtime, with a gradual increase to a maximum dose of 4.5 mg
- Common side effects include headache, tachycardia, and vivid dreams
- It has been shown to improve satisfaction with life in patients with fibromyalgia, as reported in a RCT 1.
From the FDA Drug Label
Naltrexone hydrochloride is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids. Naltrexone hydrochloride blocks the effects of opioids by competitive binding (i.e., analogous to competitive inhibition of enzymes) at opioid receptors.
Low-dose naltrexone works by competitively binding to opioid receptors, thereby blocking the effects of opioids. This mechanism of action is due to its properties as a pure opioid antagonist.
- The blockade produced by naltrexone is potentially surmountable, but overcoming full naltrexone blockade by administration of very high doses of opiates has resulted in excessive symptoms of histamine release in experimental subjects 2.
- The exact mechanism of low-dose naltrexone is not explicitly stated in the label, but its action as an opioid receptor antagonist is well described 2.
From the Research
Mechanism of Action
- Low-dose naltrexone (LDN) works by modulating Toll-like receptor 4 signaling, reducing glial inflammatory response, and systemically upregulating endogenous opioid signaling through transient opioid-receptor blockade 3.
- LDN has been shown to inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and anti-inflammatory effect 4.
- The mechanism of LDN appears to be modulation of neuro-inflammation, specifically, the modulation of the glial cells and release of inflammatory chemicals in the central nervous system 5.
Dosage and Effects
- LDN is considered in a daily dose of 1 to 5 mg, and has been shown to reduce symptoms related to chronic pain conditions such as fibromyalgia, inflammatory bowel conditions, and multiple sclerosis 3, 4, 5.
- A dosing range at less than 1 μg per day, termed ultra low-dose naltrexone/naloxone (ULDN), has been used to potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling 3.
- A dosing range between 1 μg and 1 mg, termed very low-dose naltrexone (VLDN), has been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper 3.
Therapeutic Applications
- LDN has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases 4.
- LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders 6.
- There have been anecdotal reports of cancer resolution following the use of LDN, and it has been suggested that LDN may influence cancer progression through various mechanisms, including antagonism of receptors, modulation of immune function, and direct inhibition of signaling pathways involved in cancer cell control 7.