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

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

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.
Institute of Experimental Neurology (INSPE) and Department of Neurology, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy; Fondazione Don Carlo Gnocchi, IRCCS, Milan, Italy.

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.

PMID: 18728058 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum

Cherie

Low Dose Naltrexone: Hope for PPMS
New Trial of LDN in Primary Progressive Multiple Sclerosis
© Maija Haavisto

Sep 18, 2008

Low dose naltrexone has been used in the treatment of multiple sclerosis for over 20 years, but only now was the first official study published.

Primary progressive multiple sclerosis (PPMS) is a particularly nasty form of MS affecting about 10-15% of MS patients. Those with PPMS never experience more than minor remissions from their illness with progressive disability from the start. It is generally considered untreatable by current MS drugs. Some doctors even believe PPMS should be considered a separate entity from other forms of MS.

The new study was an Italian open-label trial on 40 patients to evaluate safety and tolerability of LDN in PPMS. It was published in the medical journal Multiple Sclerosis. Open-label means that everyone was receiving the medication; it was not compared with placebo.

LDN
Naltrexone is an opioid antagonist used in the treatment of addiction. In large doses it blocks the effects of endorphins. In very small doses, however, it actually stimulates the production of endorphins, which are not only natural painkillers but important immunomodulators as well. Beta-endorphin levels have been shown to be low in MS and other autoimmune diseases.

What is interesting about LDN is that it is not considered immunosuppressive like most drugs used in the treatment of autoimmunity. Thus it is not expected increase the risk of infections and cancer, as immunosuppressants do.

LDN showed excellent efficacy in a Crohn's disease study published in 2007. It is currently in clinical trials for fibromyalgia, autism, HIV/AIDS and several cancers.

Study Results
LDN markedly reduced spasticity, while pain, fatigue and depression did not improve (or improvement didn't reach statistical significance). The study did not evaluate urinary frequency, a common symptom of MS and often reportedly helped by LDN. It should be noted that LDN is not intended for symptom improvement, but to slow down illness progression, though some patients do experience symptom relief.

During the six-month study neurological disability progressed only in one patient, which is quite a low number considering it was done on people with progressive multiple sclerosis. The study, however, was a preliminary one to assess safety and tolerability, not efficacy.

LDN was also shown to increase blood levels of beta-endorphin. Interestingly the highest levels were measured one month after cessation of the drug. Some of the symptoms were also at their lowest at this point. This raises the question whether LDN should be taken intermittently in PPMS for the best effects, but this is merely speculation.

Adverse Effects
The study abstract lists two "major adverse effects", but this is quite misleading, as they were advanced lung cancer in a 40-cigarette-a-day smoker and kidney failure caused by a urinary tract infection (UTIs are very common in MS due to impaired bladder control). The study authors are obliged to list any such occurrences, even if any connection with the drug is highly unlikely.

Most of the reported adverse effects were mild and could have been caused by MS. Irritability occurred in a few cases. Two patients had elevated liver enzymes and one had elevated bilirubin - but he was also taking methotrexate, though, which should not be taken with LDN anyway. Cholesterol levels increased in six patients.

The study concluded that LDN was safe and well-tolerated. The side effects were negligable compared to current MS drugs. More studies are needed to demonstrate the efficacy of LDN in the treatment of MS, but tens of thousands of patients have already drawn on their conclusions and swear by it.

http://multiple-sclerosis.suite101.c..._hope_for_ppms

Cherie

Hi Cherie,

Those results on PPMS are quite remarkable considering there is virtually nothing out there used to treat that kind of MS. It makes you wonder, though, why PPMS patients were chosen for such a trial and not also RRMS patients who make up about 85% of MS cases.

I would love to see a head to head trial between LDN , the CRABs and Tysabri. Unfortunately, we'll never see such an event because those expensive medications stand a lot to lose.

Harry

Hi Harry,

I think the just completed trial out of the University of California (results pending) is testing PwRRMS, COMBINED with the CRABs (if applicable), so maybe this will give them some information in that regard. I think one of the goals of that trial may be to test whether LDN proves safe, combined with any/all CRABs ... so I'm really not necessarily expecting riveting results on efficacy (unless it DOES prove to work well with the interferons too, which would be GREAT!).

http://clinicaltrials.gov/ct2/show/NCT00501696

I like that they trialed LDN on PPMS, because there can be very little confusion on whether it was possibly only effective ("due to the relapsing nature of RRMS"). If it appears to work and be safe for PPMS, it stands to reason it would probably prove to be even more effective for RRMS.

Cherie