A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis

Gironi, Maira; Boneschi, Filippo Martinelli; Sacerdote, Paola; Solaro, Claudio; Zaffaroni, Mauro; Cavarretta, Rosella; Moiola, Lucia; Bucello, Sebastiano; Radaelli, Marta; Pilato, Vincenzo Di; Rodegher, Mariaemma; Cursi, Marco; Franchi, Silvia; Martinelli, Vittorio; Nemni, Raffaello; Comi, Giancarlo; Martino, Gianvito

doi:10.1177/1352458508095828

Cited by 80 publications

(55 citation statements)

References 38 publications

(47 reference statements)

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“…A 6-month phase II multi-center pilot trial with LDN has been carried out in 40 patients with PPMS. A significant reduction of spasticity was observed at the end of the trial [150]. The therapeutic effect of LDN might be explained by the elevated endogenous opioids and opioid receptors due to the temporary blockade of the opioid receptors [151][152][153].…”

Section: Opioid Receptorsmentioning

confidence: 99%

G protein-coupled receptors as therapeutic targets for multiple sclerosis

Xie

2012

Cell Res

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G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spectrum of diseases. Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations. Hopefully some of these findings will lead to the development of novel therapies for MS in the near future.

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Section: Opioid Receptorsmentioning

confidence: 99%

G protein-coupled receptors as therapeutic targets for multiple sclerosis

Xie

2012

Cell Res

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“…These issues have driven patients towards alternative therapies such as low doses of naltrexone (LDN). Although LDN therapy is off-label, it has received widespread use for several autoimmune disorders including fibromyalgia, Crohn's, and MS. [6][7][8][9] Recently, several new clinical trials on LDN are have been initiated nationally and internationally. 10 Whether LDN treats symptomology or is diseasemodifying is unknown.…”

Section: Introductionmentioning

confidence: 99%

Featured Article: Serum [Met⁵]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone

Ludwig

Zagon

McLaughlin

2017

Exp Biol Med (Maywood)

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This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met 5 ]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG 35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. b-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy. AbstractLow-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels.In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met 5 ]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met 5 ]-enkephalin or b-endorphin in normal mice. Thus, [Met 5 ]-enkephalin (i.e. opioid growth factor)...

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“…For MS, it is claimed that LDN may alleviate symptoms and also modify disease by slowing disability progression and reducing the relapse rate. While much of the original information about LDN and MS was based on anecdotal experiences, there are now three published clinical trials in this area [29][30][31]. These trials have produced variable results.…”

Section: Low-dose Naltrexonementioning

confidence: 94%

“…These trials have produced variable results. A study in primary-progressive MS found improvement in spasticity, worsening of pain, and no effect on multiple other outcomes, including depression, quality of life and fatigue [29]. Two other studies used similar crossover trial design in relapsing and progressive MS patients.…”

Section: Low-dose Naltrexonementioning

confidence: 96%

Complementary and alternative treatments

Bowling

2013

Personalized Management of Multiple Sclerosis

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A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis

Cited by 80 publications

References 38 publications

G protein-coupled receptors as therapeutic targets for multiple sclerosis

G protein-coupled receptors as therapeutic targets for multiple sclerosis

Featured Article: Serum [Met⁵]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone

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A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis

Cited by 80 publications

References 38 publications

G protein-coupled receptors as therapeutic targets for multiple sclerosis

G protein-coupled receptors as therapeutic targets for multiple sclerosis

Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone

Complementary and alternative treatments

Contact Info

Product

Resources

About

Featured Article: Serum [Met⁵]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone