*Low-Dose Naltrexone for Chronic Pain

I will preface this with a word of personal experience. I tried LDN 1.5 mg, orally, and found it reduced my pain by 80%. My doctor and I decided then to increase the dose to 4.5 mg daily, which immediately caused stomach pain, cramping and diarrhea. We should have left well-enough alone. We consequently tried lowering the dose, and then tried an oral very-low-dose, 0.01 mg, which helped control pain but still irritated my digestive tract. In a last-ditch attempt we tried a low-dose, then a very-low dose trans-dermal cream, all to no avail. I don’t know whether to blame this in my extraordinary sensitivity to medications, combination of genetic disorders, or plain bad luck, but if you can talk your doctor into allowing you into trying Naltrexone, I’d suggest the transdermal route and a beginning with a very-low-dose. You can always increase the dose, but it may be impossible to back down successfully. – Deb C-G  

Naltrexone was synthesized in 1963 as an opioid receptor antagonist. It is structurally and functionally similar to the opioid antagonist naloxone, but it has greater oral bioavailability and a longer biologic half-life. Naltrexone is used primarily in the management of alcohol and opioid dependence; the FDA approved naltrexone in 1984 at 50 mg. The typical daily dosage for opioid addiction is 50.0–100.0 mg daily, and 50.0-mg tablets are available commercially.  

Oral naltrexone in a dosage range from 1.5 mg to 4.5 mg is referred to as low-dose naltrexone (LDN). Low-dose naltrexone use is “off label” and has been successfully used as therapy in a wide range of conditions including Crohn’s disease, fibromyalgia, major depressive disorder, cancer, chronic pain, Charcot-Marie-Tooth, systemic sclerosis, sarcoidosis, Hailey-Hailey Disease, lichen planopilaris, atopic dermatitis, and guttate psoriasis. 

Low-dose naltrexone is a viable treatment option for chronic pain because other agents for chronic pain increase risk of confusion, hypoxia, addiction, gastrointestinal bleeding, renal injury, myocardial infarction or stroke. LDN has minimal adverse effects, no drug-drug interactions, and is relatively inexpensive compared with other options for chronic pain.  

The periodic paralyses are hereditary muscle diseases that cause both episodic and permanent weakness. Permanent weakness is caused by fibrosis and fatty replacement. Both episodes and the ongoing process of muscle degeneration are accompanied by moderate to severe pain in over 80% of patients. Opioid medications are often a poor choice for these patients due to their decreased respiratory capacity, slow bowel transit time, and sedentary life style, making LDN a potential viable option for pain relief.  

As an opioid antagonist, naltrexone is used as a treatment for substance abuse. It does not exert any euphoric or reinforcing effects, and there have been no reported cases of LDN misuse or abuse. Patients do not develop dependence on or tolerance to the medication. In reported studies, the cessation of LDN is generally followed by a slow return of symptoms to baseline levels.  

Very-low-dose naltrexone, doses which range less than 1 mg, can be successfully combined with opiates to enhance and prolong the analgesia of the opiate alone and prevent or attenuate opioid tolerance or dependence. Patients require reduced doses of opioid medication in combination with very-low-dose naltrexone. 

Although no formal studies have been done on LDN use in the elderly, side effects are generally very mild, with the most common side effect observed being transient insomnia and vivid dreams. A double-blind study involving children with moderate to severe  Crohn’s Disease aged 8-17 found oral LDN safety and tolerability equal to placebo. No abnormalities occurred in regards to bone marrow toxicity, electrolyte disturbances, or renal dysfunction. At the end of the eight-week study 25% those treated were in remission, and a further 67% had improved to ‘mild disease activity’.

Mechanisms of Naltrexone

The mechanism of action of naltrexone is still being researched, but there are theories that explain why LDN works on both autoimmune diseases and cancers, as well as inflammatory disease and in chronic pain. Naltrexone not only blocks the reception of opiates, but also the body’s own endogenous opioids-endorphins. However, when Naltrexone is administered in low doses it is believed that it only briefly (for 3-4 hours) obstructs the effects of endorphins in what is called ‘the rebound effect.’ The rebound effect results in three things:

  • Production of endorphins is increased in order to compensate for the perceived shortage
  • Opioid receptor production increases
  • Opioid receptors sensitivity increases

Once LDN is metabolized by the liver and eliminated from the body (after 3-4 hours) the elevated levels of endorphins produced now interact and bind with the more sensitive and more plentiful opioid receptors. These elevated levels of endorphins will usually last around 18-20 hours. During this time they up-regulate vital elements of the body’s immune system. 

  • Down regulating inflammatory cytokines
  • Reducing inflammation and oxidative stress
  • Facilitating tissue repair and wound healing
  • Restoring T-helper/CD4 levels
  • Restoring the balance between Th1 & Th2 lymphocytes
  • Increasing cytotoxic T cells and natural killer (NK) cells
  • Regulating cell growth & inhibiting tumor growth
  • Reducing excitotoxicity and microglial activation
  • Reducing apoptosis of the myelin-producing oligodendrocytes
  • Stimulating mucosal healing  (lining of bowel)

Glial cells are immune cells located in the central nervous system (brain, spinal cord)/ They are involved in dysregulation of pain systems, neuro-inflammation, and some neurological diseases. 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. 

  1. Because LDN blocks opioid receptors throughout the body for three or four hours, patients using any narcotic medicine – such as Ultram (tramadol), morphine, Percocet, Duragesic patch or codeine-containing medication – should go through a gradual two-week washout period before beginning LDN. Non-opioid analgesics may be substituted during this period. 
  2. Patients who are taking thyroid hormone replacement for Hashimoto’s thyroiditis should begin LDN at the lowest range (1.5 mg for an adult). LDN may lead to a prompt decrease in the autoimmune disorder, which then may require a rapid reduction in thyroid hormone replacement in order to avoid symptoms of hyperthyroidism. [This is very important for patients with HypoKPP!] 
  3. LDN sensitizes delta-opioid receptors in the gut. A very few patients may react with experience loose stool and gut cramping. If this effect persists after the 1st week or two then it’s best to discontinue the drug for a week or two to allow the gut to settle, and then resume treatment with the drug compounded as a transdermal cream.  
  4. Patients who have received organ transplants and who therefore are taking immunosuppressive medication on a permanent basis are cautioned against the use of LDN because it may act to counter the effect of those medications.

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