LDN and MS

Trials and studies for LDN and multiple sclerosis

Multiple Sclerosis:  LDN and MS Papers

  • 'Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis',  Mult Scler J Exp Transl Clin. 2016 Jan-Dec; 2: 2055217316672242. Published online 2016 Sep 29
  • Holmøy: 'Research on low dosage naltrexone', Letter to the Editor, Journal Nor Legeforen 2011:131:1277-8.  Published online doi: 10.4045 / times.11.0578
  • Holmøy: 'Development of new treatment for multiple sclerosis', Journal Nor Legeforen 2011;131:832. Norwegian. Published online doi: 10.4045 / times.10.0077


Abstract

Rahn KA, McLaughlin PJ, Zagon IS. Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis. Brain Res. 2011;1381:243‐253. doi:10.1016/j.brainres.2011.01.036  http://www.ncbi.nlm.nih.gov/pubmed/21256121

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Endogenous opioids inhibit the onset and progression of experimental autoimmune encephalomyelitis (EAE) with 30days of treatment. This study examined the long term effects of the opioid growth factor (OGF, [Met(5)]-enkephalin) and a low dose of the opioid antagonist naltrexone (LDN) on expression of myelin oligodendrocyte glycoprotein (MOG)-induced EAE. C57BL/6 mice began receiving daily injections of 10mg/kg OGF (MOG+OGF), 0.1mg/kg naltrexone (MOG+LDN), or saline (MOG+Vehicle) at the time of EAE induction and continuing for 60days. In contrast to 100% of the MOG+Vehicle group with behavioral symptoms of EAE, 63% and 68% of the MOG+OGF and MOG+LDN mice expressed disease. Both severity and disease indices of EAE in OGF- and LDN-treated mice were notably decreased from MOG+Vehicle cohorts. By day 60, 6- and 3-fold more animals in the MOG+OGF and MOG+LDN groups, respectively, had a remission compared to MOG+Vehicle mice. Neuropathological studies revealed i) astrocyte activation and neuronal damage as early as day 10 (prior to behavioral symptoms) in all MOG-injected groups, ii) a significant reduction of activated astrocytes in MOG+OGF and MOG+LDN groups compared to MOG+Vehicle mice at day 30, and iii) no demyelination on day 60 in mice treated with OGF or LDN and not displaying disease symptoms. These results indicate that treatment with OGF or LDN had no deleterious long-term repercussions and did not exacerbate EAE, but i) halted progression of disease, ii) reversed neurological deficits, and iii) prevented the onset of neurological dysfunction across a considerable span of time.

Abstract

Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010;68(2):145‐150. doi:10.1002/ana.22006 http://www.ncbi.nlm.nih.gov/pubmed/20695007

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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 nightly naltrexone (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.

Abstract

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):964‐969. doi:10.1177/1352458510366857. https://pubmed.ncbi.nlm.nih.gov/20534644/

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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.

Abstract

Zagon IS, Rahn KA, Turel AP, McLaughlin PJ. Endogenous opioids regulate expression of experimental autoimmune encephalomyelitis: a new paradigm for the treatment of multiple sclerosis. Exp Biol Med (Maywood). 2009;234(11):1383‐1392. doi:10.3181/0906-RM-189 https://www.ncbi.nlm.nih.gov/pubmed/19855075

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Preclinical investigations utilizing murine experimental auto-immune encephalomyelitis (EAE), as well as clinical observations in patients with multiple sclerosis (MS), may suggest alteration of endogenous opioid systems in MS. In this study we used the opioid antagonist naltrexone (NTX) to invoke a continuous (High Dose NTX, HDN) or intermittent (Low Dose NTX, LDN) opioid receptor blockade in order to elucidate the role of native opioid peptides in EAE. A mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced EAE was employed in conjunction with daily treatment of LDN (0.1 mg/kg, NTX), HDN (10 mg/kg NTX), or vehicle (saline). No differences in neurological status (incidence, severity, disease index), or neuropathological assessment (activated astrocytes, demyelination, neuronal injury), were noted between MOG-induced mice receiving HDN or vehicle. Over 33% of the MOG-treated animals receiving LDN did not exhibit behavioral signs of disease, and the severity and disease index of the LDN-treated mice were markedly reduced from cohorts injected with vehicle. Although all LDN animals demonstrated neuropathological signs of EAE, LDN-treated mice without behavioral signs of disease had markedly lower levels of activated astrocytes and demyelination than LDN- or vehicle-treated animals with disease. These results imply that endogenous opioids, evoked by treatment with LDN and acting in the rebound period from drug exposure, are inhibitory to the onset and progression of EAE, and suggest that clinical studies of LDN are merited in MS and possibly in other autoimmune disorders.

Abstract 

Gironi M, Martinelli-Boneschi F, Sacerdote P, et al. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008;14(8):1076‐1083. doi:10.1177/1352458508095828 https://www.ncbi.nlm.nih.gov/pubmed/18728058

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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. 

Abstract 

Agrawal YP. , Low dose naltrexone therapy in multiple sclerosis., Med Hypotheses. 2005;64(4):721-4.  https://www.ncbi.nlm.nih.gov/pubmed/15694688

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The use of low doses of naltrexone for the treatment of multiple sclerosis (MS) enjoys a worldwide following amongst MS patients. There is overwhelming anecdotal evidence, that in low doses naltrexone not only prevents relapses in MS but also reduces the progression of the disease. It is proposed that naltrexone acts by reducing apoptosis of oligodendrocytes. It does this by reducing inducible nitric oxide synthase activity. This results in a decrease in the formation of peroxynitrites, which in turn prevent the inhibition of the glutamate transporters. Thus, the excitatory neurotoxicity of glutamate on neuronal cells and oligodendrocytes via activation of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid class of glutamate receptor is prevented. It is crucial that the medical community respond to patient needs and investigate this drug in a clinical trial.