Low-Dose Naltrexone

Naltrexone is an opioid receptor antagonist that is used at high doses to treat drug addiction and dependence1. However, there is a lot of interest in using low-dose naltrexone (LDN) to treat chronic pain and inflammation1,2, and it is used off-label for this purpose. At low doses naltrexone acts as an immune system modulator and increases opioid signalling and pain relief2, and there is some evidence to suggest that it improves quality of life in people with chronic pain2.

Unfortunately, it is not possible to make definite recommendations about the use of LDN because the studies are small and often not high quality2 (not double blinded, placebo controlled). Nonetheless, LDN appears to be safe and well tolerated, and it may have efficacy for treating a range of chronic pain conditions from complex regional pain syndrome, chronic fatigue syndrome, fibromyalgia, inflammatory bowel disease etc.

Typical amounts of LDN range from 0.5 to 4.5 mg daily1,2, with many studies starting at 1 mg per day increasing to 4.5 mg per day2. The low dose and short half-life appear to be essential for the beneficial effects3. At low doses naltrexone is cleared from the body in 4 hours, and this intermittent blockade of opioid receptors is believed to increase the number and sensitivity of opioid receptors3. These effects reduce pain and inflammation and modulate the immune system, and a number of studies have shown that LDN has greater benefits than placebo3. Some papers state that people taking it must be opioid-free2.

We are not aware of any studies investigating the efficacy of LDN for treating arthrofibrosis. Naltrexone is no longer under patent3, and there is little financial incentive for expensive large-scale trials for any condition1, and from existing trials is. With the limited data we cannot draw definitive conclusions at this stage3.

LDN is a compounded medication that can only be supplied by compounding pharmacies1. At higher doses naltrexone may be counterproductive for chronic pain conditions. It is believed to increase cellular proliferation and the number of immune cells that produce inflammatory cytokines, and consequently is likely to increase pain and inflammation.

Go Deeper

LDN has an anti-inflammatory effect on the nervous system. It downregulates Toll-like receptor 4, nitric oxide and inflammatory cytokines including  IL-1, TNF-α1. It also increases endorphins and opioid growth factor levels, upregulating natural opioid signalling and improves mood and the sense of well-being1.    

Chronic pain that persists for longer than 3 months leads to changes in the nervous system2 and hypersensitivity, particularly following traumatic nerve injury from surgery2. These changes can occur in both the local level and in the central nervous system. As a result inflammatory cytokine levels increase 2 as well as substance P4, which further sensitises nerves. Interestingly, some conditions such as chronic myofascial pain are also associated with alterations in the nervous system2. Fascia is made of connective tissue, and this condition likely also involves chronic myofibroblast activation.

References

1      Kim, P. S. & Fishman, M. A. Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review. Curr Pain Headache Rep 24, 64, doi:10.1007/s11916-020-00898-0 (2020).

2       Hatfield, E., Phillips, K., Swidan, S. & Ashman, L. Use of low-dose naltrexone in the management of chronic pain conditions: A systematic review. J Am Dent Assoc 151, 891-902 e891, doi:10.1016/j.adaj.2020.08.019 (2020).

3       Patten, D. K., Schultz, B. G. & Berlau, D. J. The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn’s Disease, and Other Chronic Pain Disorders. Pharmacotherapy 38, 382-389, doi:10.1002/phar.2086 (2018).

4        Ganjaei, K. G., Ray, J. W., Waite, B. & Burnham, K. J. The Fascial System in Musculoskeletal Function and Myofascial Pain. Current Physical Medicine and Rehabilitation Reports 8, 364-372, doi:10.1007/s40141-020-00302-3 (2020).