|| Checking for direct PDF access through Ovid
To the Editors:Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that afflicts 400,000 people in the United States and more than 4 million individuals worldwide.1,2 The most common form of MS is relapsing remitting multiple sclerosis (RRMS), characterized by alternating relapses and remissions for a period of 10 to 15 years followed by steadily progressive deterioration transitioning into secondary progressive MS.1,3 Multiple sclerosis is characterized by neurodegeneration of the spinal cord and brain, resulting in a reduction in mobility, reduced quality of life, and increased medical expenditures.4–6 Of the Food and Drug Administration-approved therapies, many such as interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab require daily or weekly injections,5,6 whereas some of the oral medications such as fingolimod have unproven long-term efficacy. Nearly all of the therapies are costly and have side effects that reduce compliance.1,2 There remains an unmet medical need for safe, inexpensive therapies that delay MS progression and improve its clinical course.A potential alternative or adjunctive therapy for MS is related to knowledge about the endogenous opioid system and its ability to modulate autoimmune diseases using animal models of MS.7–10 This novel biological pathway involves an endogenous opioid growth factor, chemically termed methionine enkephalin, and its nuclear-associated receptor, Opioid growth factor receptor.11 Modulation of this pathway by exogenous administration of opioid antagonists such as naltrexone (NTX) has been shown to mediate cell replication including T lymphocytes, astrocytes, and other glia that are associated with MS inflammation and degeneration.9 The magnitude and direction of change in cell proliferation is dependent on the duration of opioid receptor blockade.12 Low dosages of NTX (LDN), given once daily, block the receptor intermittently and result in inhibited cell replication. The LDN treatment of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, improves the course of progressive EAE.8,9 Mice immunized with myelin oligodendrocytic glycoprotein to establish EAE and treated daily with 0.1 mg/kg NTX (LDN) beginning at the time of disease induction show delayed onset of clinical disease and reduced behavioral deficits.8,9 Pathology of the spinal cord from these mice revealed significant reductions in the number of activated astrocytes and area of demyelination.8,9 The LDN treatment of mice with established relapsing-remitting EAE revealed that endogenous opioids inhibited progression of the disease as well.10Three clinical trials of LDN in MS have been conducted and report that LDN increases the quality of life of MS patients.13–15 Cree et al14 concluded from a trial of 8 weeks that 4.5 mg LDN daily was a safe therapy that improved quality of life, whereas Sharafaddinzadeh et al13 reported safety after 17 weeks of treatment and recommended that longer trials be conducted to evaluate efficacy. Gironi et al15 studied primary progressive MS patients treated with LDN for 6 months and reported increased endogenous opioid levels in the patients and improved MS. The LDN treatment of patients with other autoimmune diseases including Crohn's disease and fibromyalgia has demonstrated safety and efficacy of the therapy.16,17 A major symptom of MS is fatigue,18 which is one of the many characteristics that patients seek to alleviate. Improvement in fatigue was cited in these clinical studies after LDN therapy, which suggests that there is a potential link between upregulated endogenous opioid systems and fatigue. Gironi et al15 reported elevated β-endorphin levels at 1, 3, and 6 months after the onset of treatment, with β-endorphin levels remaining elevated for an additional month after LDN was discontinued. A return to pretreatment levels was not reported.