Low-dose naltrexone for treatment of multiple sclerosis Are clinical trials needed. Will they happen?

Every time I talk about complementary/alternative medicine to MSers someone tells me of a good luck story about low dose naltrexone. Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. Naltrexone should not be confused with naloxone (which is used in emergency cases of opioid overdose) nor nalorphine. Using naloxone in place of naltrexone can cause acute opioid withdrawal symptoms; conversely, using naltrexone in place of naloxone in an overdose can lead to insufficient opioid antagonism and fail to reverse the overdose. Low Dose Naltrexone or LDN as it known has been hitting the news recently. However the problem is is that there is simple not enough good data to support this use. 

Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G.A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008;14(8):1076-83.

A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.

Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, Majdinasab N, Shalbafan B. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010;16(8):964-9.
BACKGROUND: Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire.
METHODS: A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing-remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups.
RESULTS: Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study.
CONCLUSION: The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.


Cree BA, Kornyeyeva E, Goodin DS Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010;68(2):145-50. doi: 10.1002/ana.22006.OBJECTIVE: To evaluate the efficacy of 4.5mg nightly naltrexone on the quality of life of multiple sclerosis (MS) patients.
METHODS: This single-center, double-masked, placebo-controlled, crossover study evaluated the efficacy of 8 weeks of treatment with 4.5mg nightlynaltrexone (low-dose naltrexone, LDN) on self-reported quality of life of MS patients.
RESULTS: Eighty subjects with clinically definite MS were enrolled, and 60 subjects completed the trial. Ten withdrew before completing the first trial period: 8 for personal reasons, 1 for a non-MS-related adverse event, and 1 for perceived benefit. Database management errors occurred in 4 other subjects, and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial's statistical power. LDN was well tolerated, and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05).
INTERPRETATION: LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.

So the same odd addage...Further studies are warranted. 

However, this is the perennial problem...neuros and charities tend to fund small scale trials, which are invariably too small to give definitive answers and not large enough to make a compelling case for moving things forward

Pharma aren't really interested cos they can't make any money out of this in the present climate. 

Should we be doing small trials that need another in the hope that pharma will work out how to repurpose the drug or only support stuff that gives a definitive answer. Or should we keep the Status Quo going? often with false hope peddling.

Can pharma be incentivised to do these studies? 

Is it another fad treatment? 

What are your views?

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