A Randomized Placebo-Controlled, Crossover-Design Study of the Effects of Low Dose Naltrexone
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 3

Summary: 
      This is a randomized placebo-controlled, parallel-group study, crossover-design of the
      effects of low dose naltrexone on the multiple sclerosis quality of life inventory (MSQLI54)

      This study will assess the impact of LDN compared to placebo on quality of life as measured
      by the composite score of the MSQOL54 in adult subjects with MS.

      Also we plan:

        1. To compare the 10 scales of the MSQOL54 during the active treatment and placebo cycles
           between active treatment and placebo groups

        2. To compare each individual's composite response to LDN versus placebo during the active
           treatment and placebo cycles

        3. To compare each individual on the 10 scales of the MSQOL54 during the active treatment
           and placebo cycles
    

Detailed description: 
      Immunomodulatory and immunosuppressive therapies are known to modify the course of the
      disease. Interferon beta-1a, interferon beta-1b and glatiramer acetate are immunomodulators
      whereas mitoxantrone and natalizumab are immunosuppressants

      The disease modifying therapies decrease the frequency of relapses and are associated with
      improved neurological outcomes relative to placebo. However, these medications are only
      partially effective, are expensive, require either frequent self injections or intravenous
      infusion and have significant side effects. None are proven in the progressive forms of MS
      and none of alleviate the symptoms associated with MS.

      Endogenous Opioid peptides and Naltrexone:

      Low dose naltrexone (LDN) is proposed to adjust the level of endorphins in the body thereby
      enhancing immune function and is anecdotally beneficial in MS. LDN is inexpensive, easily
      administered (one capsule a day at bedtime), and virtually has no serious side effect (during
      the first weeks of LDN use, some patients complain of some difficulty sleeping, that rarely
      persists after the first week). Although use of LDN is popular within the MS community
      efficacy is not proven because clinical trials have not been performed.

      Naltrexone, is an opioid antagonist approved by the FDA in 1984 in a 50mg dose for the
      treatment of opioid and alcohol abuse. By blocking opioid receptors, naltrexone also blocks
      reception of the endogenous opioid peptides: beta-endorphin, metenkephalin and dynorphin.
      Virtually every cell of the immune system has receptor for these mediators. These peptides
      regulate a wide range of biological activities, including immune responses through
      interaction with G-protein coupled transmembrane opioid receptors.

      In 1985, Bernard Bihari, MD, described the effects of low dose Naltrexone (1.5-4.5 mg
      Naltrexone) on the body's immune system. He discovered that people with HIV had less than
      twenty percent of the normal level of endorphins. He began looking for ways to raise
      endorphin without blocking its receptors and found that 1.75-4.5 mg Naltrexone (Low Dose
      Naltrexone, LDN) at bed time raises the endorphin level up to 100 to 300 percent during the
      night. Dr. Bihari has reported beneficial effects of LDN on a variety of diseases such as
      cancers (e.g. Multiple Myeloma, Lymphoma, Hodgkin's disease, breast cancer, GI cancers, non
      small cell cancer of lung, malignant melanoma, neuroblastoma, ovarian cancer, prostate
      cancer, renal cell carcinoma, and uterine cancer), amyotrophic lateral sclerosis, Alzheimer's
      disease, Behçet's disease, celiac disease, chronic fatigue syndrome, Crohn's disease,
      emphysema, fibromyalgia, HIV/AIDS, Irritable bowel syndrome, Parkinson's disease, pemphigoid,
      psoriasis, multiple sclerosis, rheumatoid arthritis, systemic Lupus erythematosus, ulcerative
      colitis and Wegner's granulomatosis . Despite these anecdotal claims there are no published
      studies demonstrating efficacy of LDN in any disease state.

      Because of its low cost and ease of administration and anecdotal reports of efficacy LDN has
      gained a significant gross-roots following among patients and doctors. There are some
      striking reports about beneficial effects of LDN on relapse reduction and disability and in
      general patients treated with LDN report improvements in a sense of well being, fatigue, as
      well as bowel, bladder and sexual function.

      Immunological Mechanisms Involved in MS and effects of LDN β-endorphin is an opioid peptide,
      synthesized by cells of the central nervous system (arcuate nucleus) and immune system
      (lymphocytes, thymocytes, monocytes and splenocytes). This peptide is decreased in
      concentration in peripheral blood mononuclear cells (PBMC) of MS patients, with the lowest
      concentrations linked to the progressive forms of the disease. Furthermore increased
      concentrations of β-endorphin are found during interferon beta treatment and following
      clinical relapses. In the animal model of MS, experimental autoimmune encephalitis,
      β-endorphin blockade worsens disability.

      Lesions in MS may be the result of oligodendroglial apoptosis and microglial activation
      rather than neuroinflammatory processes. Activated microglia secrete proinflammatory and
      neurotoxic factors (nitric oxide and peroxynitrites) that could cause neurodegeneration. In
      theory, inhibition of microglia would be protective in MS. Naltrexone, is capable of reducing
      microglial cytokine (IL-1β) and nitric oxide in glial cultures. If naltrexone is beneficial
      in MS, a possible mechanism of action is through reduction in microglial nitric oxide
      synthase activity resulting in decreased peroxynitrites production. Peroxynitrites are
      thought to inhibit glutamate transporters thereby increasing the synaptic concentrations of
      glutamate resulting in excitatory neurotoxicity.
    

Intervention name(s): 4.5 mg Naltrexone; Naltrexone
Intervention type(s): Drug; Drug
Intervention description(s): low dose naltrexone 4,5mg on the multiple sclerosis quality of life inventory (MSQLI54); 4,5mg low dose naltrexone on the multiple sclerosis quality of life inventory (MSQLI54)
Other intervention name(s): Naltrexon(4.5mg) or placebo , crossover-design; Naltrexone(4.5mg) or placebo , crossover-design
Intervention MeSH terms: Naltrexone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment