At the moment there are four drugs in clinical use that are developed for MS, three beta interferons (Avonex, Betaferon/Betaseron, Rebif) and glatiramer acetate (Copaxone). Together they are known as the ABCRs. They are all expensive, injectable drugs with potentially severe side effects. For almost ten years now they have been recommended as a first line treatment for relapsing-remitting MS by both neurologists and MS-societies around the world. Those recommendations have often been supported with sales promotion material and results from clinical trials funded by the drug companies.

Recently things have been starting to change. There have been doubts about the effectiveness of ABCRs almost as long as they have been used, but within the last two years researchers have been able to demonstrate that even oral drugs commonly used to treat high cholesterol (simvastatin) and acne (minocycline) could be as effective as - or even more effective than - the ABCRs in treating MS. There is also a growing amount of anecdotal evidence on the internet that the opiod antagonist naltrexone taken in low doses (LDN) has relieved MS-symptoms in many individuals. So it is understandable that the manufacturers of the ABCRs and some of the instances funded by them have started to fight back against this kind of development. In doing so they are using three major arguments:

”It doesn’t work in EAE”

EAE is an animal model which is used in testing new MS-drug candidates before clinical trials. The cause of MS is not known, but EAE is supposed to be able to mimic the autoimmune and demyelinating processes of MS. Although it is widely used as a part of MS-research protocol, EAE is not equal to MS. The difference between the two diseases can be described with a single unfortunate example: in 1980s gamma interferon was tested in EAE with very promising results, but when it was given to MS-patients it only made their disease much worse (1, 2). Also a Scottish team of researchers has stated several reasons why EAE doesn’t work as an animal model of MS (3).

However, of the above-mentioned treatments, only LDN has not been tested in EAE. Both cholesterol drug simvastatin and antibiotic minocycline have been able to halt or even reverse EAE in mice. (4, 5)

”Anecdotal evidence only”

Treatment should make people feel better. And if it does, there are always people who want to share their positive experiences with others. The Internet has become a powerful tool for this. After visiting a few sites dedicated to LDN it is easy to come to the conclusion that the amount of satisfied people using it is so large that it just can not be ignored. (6)

Personal experiences and anecdotal evidence are important even for researchers. Actually, a Canadian group of researchers chose to study the antibiotic minocycline in a clinical trial since it anecdotally appeared to improve the condition of MS patients who were using it for acne relief (7). And because there is not that much clinical data available about minocycline and statins as MS-drugs it would be great if there only were people who are using them for MS and would also share their experiences - good or bad - on the internet. But on the other hand, one has to admit that positive results from clinical trials weigh a great deal more than anecdotal evidence only.

”Much more work needs to be done”

This argument belongs to the class ”if you can’t prevent the change, you can always try to delay it”. Authorities that give this kind of statements seem to deliberately forget the fact that minocycline, statins and LDN are all relatively safe drugs and have been used by millions of people for years now. There would be no need for pre-clinical studies or phase I US FDA safety trials with healthy individuals. Minocycline and simvastatin have already been tested in small clinical trials with positive results (8, 9). Dosages used in the trials were not higher than those approved for treating high cholesterol or acne. Also naltrexone is taken in very low dosage, so there probably would not be any major safety concerns related to these drugs.

The only work that really would need to be done is to start open label clinical trials to test minocycline, statins and LDN in practice. It would need patients who would volunteer to try one of them, neurologists who would monitor them as cautiously as those who use ABCRs, and somebody who would organize and analyze the information gathered from different locations.

This is hopeful thinking only, but an expert's comment that the placebo effect can be as high as 30 percent could make expensive double-blinding more or less unnecessary (3). Instead of being able to perform better than placebo to get approved for MS, a drug would for example have to have the ability to reduce the amount and size of active MRI-lesions by over 40 percent during a one year treatment period when compared to pre-treatment level.

Counterarguments

In my opinion it is only fair to use the same arguments against ABCRs and see how well they pass the test. The facts supporting the arguments are - of course - gathered only from unbiased sources:

ABCRs work very well in EAE because they are designed for it. Problem is that similar results have not been achieved in treating humans with MS. That just might be the reason why there is very little spontaneously written anecdotal evidence available on the Internet - or anywhere else - about their ability to relieve MS-symptoms.

There is also a lot of work left to be done before the mechanism of action, long term effectiveness, and safety of ABCRs are proven valid in clinical trials and in practice. So far the results have not been that encouraging. Cochrane review is an unbiased summary of results from clinical trials. It is updated only as necessary. This is how it evaluated beta interferon in the year 2001: "The efficacy of interferon on exacerbations and disease progression in patients with relapsing remitting MS was modest after one and two years of treatment. Longer follow-up and more uniform reporting of clinical and MRI outcomes among these trials might have allowed for a more convincing conclusion” (10). Copaxone received even more criticism in 2003: "Glatiramer acetate did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses. Therefore its routine use in clinical practice is not currently supported. More investigations are needed. Further research should also develop more reliable measures of patient disability over time and include quality of life among primary outcomes” (11).

The most confusing comment concerning the reliability of ABCR-trials is presented in the paper written by professors from Glasgow University: In two different double-blinded studies ”copolymer 1 placebo patients fared better even than the interferon treated group despite the fact that both studies were performed in the same country with patients from an identical population pool” (3).

Finally

Drugs developed for MS have poor cost-effectiveness, and that is a fact we have to live with and accept. What we should not accept is that there could already be cheaper, more effective and safe - oral - drugs available, but we are not able to use them in an organized manner because there are not enough resources and good will to study them further. It is certain that none of them would be a miracle drug. They will not reverse the disease, and they probably are not able to make all existing symptoms disappear. But they might be able to make us feel better and even protect our body from further damage. That should give enough reasons for further studies.

I truly hope that I am wrong, but minocycline, statins and LDN might as well never get an official approval to be used for MS. However, researchers who study them, people who use them, and those who spread the word on the Internet about them are still doing important work. And they give us a reason to question how much are we really ready to pay for hope, if that is the only thing we may get.

REFERENCES:

(1) Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3126227

(2) Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=3110648&dopt=Abstract

(3) The Pathogenesis of Multiple Sclerosis Revisited
http://www.rcpe.ac.uk/publications/articles/journal_32_4/3_pathogenesis_of_MS.pdf

(4) Clinical trial for MS drug follows promising research
http://www.musc.edu/catalyst/co11--3clinical.htm

(5) Inhibition of Autoimmune Encephalomyelitis by a Tetracycline
http://ntp.neuroscience.wisc.edu/faculty/fac-art/Duncan51.pdf

(6) LDN home page
http://lowdosenaltrexone.org

(7) Matrix Metalloproteinases in Multiple Sclerosis
http://www.mmpsinms.ca/research/projects.html

(10) The Myelin Project Progress Report
http://www.myelin.org/06232003.htm

(9) Emerging Therapies for MS
http://www.mult-sclerosis.org/news/May2003/EmergingTherapiesforMS.html

(10) Interferon in relapsing-remitting multiple sclerosis (Cochrane Review)
http://212.49.218.202/abstracts/ab002002.htm

(11) Therapy with glatiramer acetate for multiple sclerosis (Cochrane Review)
http://www.update-software.com/abstracts/AB004678.htm