Friday, 6 July 2012

Modafinil and Progression

Bibani RH et al. Reduced EDSS progression in multiple sclerosis patients treated with modafinil for three years or more compared to matched untreated subjects Multiple Sclerosis and Related Disorders 1:131-135, July 2012

Background: Modafinil is a wakefulness-promoting drug used to treat narcolepsy, obstructive sleep apnoea, and shift-work sleep disorder. Modafinil has also been used for the treatment of fatigue and excessive sleepiness in other neurological disorders including multiple sclerosis, psychiatric disorders, and for cognitive enhancement. Recent preclinical studies suggest a potential neuroprotective effect of modafinil in neurodegenerative diseases. Therefore, we investigated its neuroprotective potential in multiple sclerosis.

Objective: To retrospectively assess disease progression in a group of MS patients that had received treatment with modafinil, and a matched group that received no treatment with modafinil.
Methods: We assessed the expanded disability status scale (EDSS) score change, over at least three years, in 30 patients with MS treated with modafinil, and in 90 patients who did not receive modafinil. The two groups were matched for initial EDSS, age, sex, type of disease, disease duration, duration of follow-up, and concomitant disease modifying therapies. 

Results: In relapsing-remitting (RR) patients treated with modafinil there was no significant EDSS change over the follow-up period. In RR patients not treated with modafinil, the mean EDSS increased significantly (0.94; p=0.0001) over the follow-up period. Independent of modafinil treatment status, our model indicated an additional mean EDSS increase of 1.1 point (p=0.0002) for progressive patients i.e. mean EDSS change was 1.1 point for modafinil treated, and 1.1+0.94=2.04 points for modafinil-untreated patients.
 
Conclusion: Our results support the hypothesis that modafinil has neuroprotective potential, and may play a role in the treatment of multiple sclerosis. A prospective study will need to confirm this finding.


Modafinil is a drug which really has a undefined mechanism of action that has been used off-label to allay symptoms of the neurological fatigue. The study suggests that progression of EDSS is slower in people with MS on modafinil for 3 years or more and that the effect is more pronounced at lower EDSS levels i.e. less disability, but was not dependent on disease modifying treatment. Modafinil is not without its side effects are therefore we need to see this this data can be repeated in a proper clinical study. 


This also suggests that we need combination therapies in RRMS neuroprotectives and anti-inflammatories just as we have suggested will be important in progressiveMS 

14 comments:

  1. This is a hugely important post and I am very worried that it will be ignored by the medics and the MS community at large. THIS NEEDS TO BE LOOKED AT!

    I posted about this on this site the other week before Mouse Doc published it.

    http://www.msard-journal.com/article/S2211-0348(12)00042-9/abstract

    This ( I think) shows a neuro-protective impact of Modafinil. So why isn't this prescribed as a matter of course? What is stopping the NHS from just giving all MS patients a pill a day to reduce progression?

    I know: you need more trials. But until you come up with a cure, or a treatment that stops progression... why NOT? My doctor won't give me this. So I'll buy it online instead.

    For me we need the following approach to MS:

    1. A strong anti-inflammatory
    2. A neuroprotective
    3. An anti viral
    4. Vitamin D supplementation

    All of these posts seem to suggest a one pill cure all approach to such a systemic and complicated disease.

    Why not combine Vitamin D, modafinil (neuroprotection), Interferon B (for it's antiviral and antiinflammatory impact), minocycline (neuroprotective) as a first course treatment for all with MS... and then when other drugs emerge replace?

    Why are all drug trials seeming single drug trials. Adding minocycline to GA reduces relapses by a further 60% - and yet... do we get offered this on the NHS? Not unless you are informed and scream for it.

    Prof G - will you start prescribing Modafinil as a standard therapy to all MS patients? If not, when not?

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  2. "This ( I think) shows a neuro-protective impact of Modafinil. So why isn't this prescribed as a matter of course? What is stopping the NHS from just giving all MS patients a pill a day to reduce progression?"

    You need to prove they work in clinical trials first.

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  3. I agree wholeheartedly. I started using Modafinil and it has helped me enormously. The effects are immediate and clean. I simply feel more awake, more able to do the things I couldn't do because of Multiple Sclerosis symptoms, such as a creeping, low-level fatigue, that dreadful kind of amorphous weariness that's almost impossible to describe. Before Multiple Sclerosis I was a furiously active and hyper-driven type, nothing I couldn't do. Multiple Sclerosis cut that out. Modafinil is clean and efficacious and it's a shambles, an utter failure of common sense that the NHS won't prescribe it - especially, now that there's much evidence (although, admittedly not trialled evidence) which shows that the use of Modafinil not only makes Multiple Sclerosis patients feel better, it gives them back a whole lot that the droopy symptoms take away. A full trial needs to begin, or, we take the approach taken in the USA and get the NHS to remove the incredibly strict and illogical off-licence inhibitors for this very useful drug. It's even sadder still, that I need to take dumb risks with buying Modafinil on line. That's a dodgy undertaking and will, sooner or later, lead to trouble. M.J Hyland

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  4. "Why are all drug trials seeming single drug trials"

    Because combinations are very difficult to do.

    You could have toxicity from a combination and then you have the issue of competing companies.
    Prof G spent alot of time investigating a polypill It is a tough ask to get a number of things tested at once, add-ons are easier

    "Why not combine.."
    Where is the evidence?

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  5. Mouse Doctor,

    "Where is the evidence?"

    There have been some combination trials for Minocycline:

    When combined with Glatiramer acetate it reduced the total number of new and enlarging T2 lesions by 65% above just application of GA alone:
    http://msj.sagepub.com/content/15/10/1183.short

    It can improve outcomes in mice when combined with interferon-B
    http://www.jni-journal.com/article/S0165-5728(05)00164-5/abstract

    Combining GA with Minocycline affects phenotype expressioon of blood monocyte-derived dentritic cells:
    http://www.jni-journal.com/article/S0165-5728(08)00129-X/abstract

    Doxyccline when combined with Interferon Beta-1a resulted in reductions in contrast-enhancing lesion numbers and posttreatment Expanded Disability Status Scale values (P < .001 for both). Only 1 patient relapsed.
    http://archneur.jamanetwork.com/article.aspx?articleid=795219

    The first is by far the most important.

    So why has the add-on of an antibiotic to GA in the UK not been discussed?

    I know, it needs Phase III trials. But Mino is off label. Sigh.

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    Replies
    1. Can Doxycycline be used instead of Minocycline? What are your thoughts?

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  6. I endose the comments of M J Hyland. Modafinil certainly improves my quality of life, I feel that the dimmer switch has been switched off and my 'normal brain' has returned. Fatigue has disappeared and my social life is back, able to do more work at gym. I have noticed improvement in my memory, am finding my ability to get through my academic reading substantially improved. There have been a few trials with mixed results - I don't believe it has been seriously pursued as a potential source of fatigue relief, and given that fatigue is one of the most debilitating symptoms of MS, you would think that someone should encourage the drug's manufacturer to pursue a large untapped market.

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  7. Re: "Prof G - will you start prescribing Modafinil as a standard therapy to all MS patients? If not, when not?"

    I use off license for severe MS-related mental fatigue; about 30-40% of MSers with mental fatigue find some benefit. However, not all GPs are prepared to prescribe and continue the medication as MS-related fatigue is an off license indication for modafinil. The phase 3 trials of modafinil in MS were disappointing.

    As drug is now off patent this should not be a big issue for GPs in the future.

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  8. Then you lead the way - good on you Prof!
    I think the interesting thing to ask is this: what, if any, is the mechanism. Not just on fatigue but on the issue of progression (if the findings of the American recent trial are to be taken seriously)?

    This article suggests evidence of mitochondrial issues following EBV infection.
    http://www.biomedcentral.com/1471-2334/6/15/

    This suggests that EBV causes "a dramatic reorganization of mitochondria accompanied by a significant alteration of mitochondrial membrane potential and a rapid and transient increase in the microtubular cytoskeleton."
    http://www.ncbi.nlm.nih.gov/pubmed/15950179

    This article references a body of work that shows MS to be an immune-mediated loss of myelin and that mitochondrial dysfunction is associated with the disease. It goes on to suggests that Mitochondrial dysfunction leading to excessive production of ROS and RNS plays a significant role in the pathogenesis of MS, particularly in loss of myelin/oligodendrocyte complex.
    http://www.ncbi.nlm.nih.gov/pubmed/17981781

    Engber et al (1998) measured glucose utilization with 2-deoxyglucose autoradiography in the brains of rats given modafinil, and they found that modafinil increased glucose utilization in the thalamus, hippocampus, subiculum, and the amygdala. They noted that much of the glucose utilization in the brain may be in the mitochondria of axons and dendrites.

    And this article suggests that "modafinil could intracellularly inhibit CYP2C9 in the brain, thereby reducing reactive oxygen species levels and promoting better mitochondrial function".
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654794

    Any mechanism involving improved mitochondrial function or free-radical scavenging could, therefore, explain how modafinil enhances neurocognitive function and bolsters serotonin release without stimulating serotonin release on its own (Ferraro et al 2000, 2001, 2005).

    I reiterate a strong belief. That you are right Prof when you say there is a viral causality of MS.
    And that the impact of that virus is to impair energy levels.

    This is why I believe more works should be done on MITOCHONDRIA in MS and its link to EBV. More should be done on what can boost mitochondria. There is a trial for Idebenone in the US for MSers with PPMS. Idebenone boosts mitochondria across the BBB.

    For me, taking 2gram a day of idebenone has helped immensely. But my current neuro looked at me like I had an extra head when I mentioned it. He had never heard of it.

    Terry Whal's diet has caused much noise. But, as far as I can see, she is just boosting her own mitochondria.

    Is MS a virus-triggered mitochondrial disease?

    I believe it is, in part. It also causes inflammation and other neuron death.

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  9. Many sceintists would agree that mitochondria are very important in the course of MS.

    This is an area undergoing very active investigation.

    Whther it is the cause or consequence of inflammation is open to debate but mitochondiral problems are not going to be good for oligodendrocyes or nerves and this will be an area of "Watch this space"

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  10. Re using off-license modafinil for severe MS-related mental fatigue :
    how bad must fatigue be before you consider modafinil?

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    Replies
    1. Not bad at all; the drug is relatively safe and if an MSer is having problems functioning why not have a trial. The problem in the UK is that some GPs are not willing to pay for the drug.

      Delete
  11. Not quite the same, but I have IST (Inappropriate Sinus Tachycardia).
    Due to the IST, I developed severe mental fog that I've struggled with on and off for the last couple of years. I finally decided to speak to my doctor about trying Modafinil a few days ago - taking 200mg first thing in the morning has made such a huge difference. I find it a lot easier to keep focused on tasks at work now. I'm just hoping the effect from the pills will keep helping.

    I only found out today that I have had EBV in the past which according to the doctor may have triggered my IST in the first place and certainly would have contributed to my fatigue.

    I would say that if you find your mental fatigue is interfering significantly with your daily tasks, then it's more than worth a try.

    ReplyDelete

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