Medications and the Mitochondria in ME/CFS (& FM)

Discussion in 'Fibromyalgia Main Forum' started by tansy, Aug 28, 2008.

  1. tansy

    tansy New Member

    Medication and ME/CFS?

    Margaret Williams

    27th August 2008

    Mitochdondria are the powerhouses of the cells. They are responsible for
    generating energy as adenosine triphosphate (ATP) and are involved in the
    apoptosis signalling pathway (apoptosis being programmed cell death).

    There is a significant literature suggestive of mitochondrial defects (both
    structural and functional) in ME/CFS from 1984 to date and it is accepted by
    informed ME/CFS clinicians and researchers that there is actual biopsy
    evidence of mitochondrial damage in ME/CFS, for example:

    Behan WM et al, Acta Neuropathol 1991:83(1):61-65 ("Mitochondrial
    degeneration was obvious in 40 of the biopsies, with swelling, vacuolation,
    myelin figures and secondary lysosomes. The pleomorphism of the
    mitochondria in the patients' muscle biopsies was in clear contrast to the
    findings in the normal control biopsies. Diffuse or focal atrophy of type
    II fibres has been reported, and this does indicate muscle damage and not
    just muscle disuse")

    Pizzigallo E et al, JCFS 1996:2 (2/3):76-77 ("We performed histochemical and
    quantitative analysis of enzymatic activities and studies of mitochondrial
    DNA deletions. All specimens showed hypotrophy, fibres fragmentation, red
    ragged fibres, and fatty and fibrous degeneration. Electron microscopy
    confirmed these alterations, showing degenerative changes, and allowed us to
    detect poly/pleomorphism and cristae thickening of the mitochondria. The
    histochemical and quantitative determination of the enzymatic activity
    showed important reduction, in particular of the cytochrome-oxydase and
    citrate-synthetase. The 'common deletion' of 4977 bp of the mitochondrial
    DNA was increased as high as 3,000 times the normal values in three
    patients. Our results agree with those of Behan et al 1991 and Gow et al
    1994. The alterations are compatible with a myopathy of probable
    mitochochondrial origin (which) could explain the drop in functional
    capability of the muscle")

    Cheney P, Orlando Workshop, International Congress of Bioenergetic Medicine
    1999, audio tape #2 ("The most important thing about exercise is not to have
    then do aerobic exercise. If you have a defect in the mitochondrial
    function and you push the mitochondria by exercise, you kill the DNA").
    Cheney's findings were supported by Benjamin Natelson, Professor of
    Neurology at New Jersey Medical School - in his 1999 lecture at the Fatigue
    2000 Conference in London, Natelson discussed his work on muscle metabolism
    using NMR testing the muscle of patients with ME/CFS after exercise, in
    which his team demonstrated a problem with mitochondrial recovery; this
    Conference was reported in the ME Association Newsletter Perspectives,
    Summer 1999:18

    Klimas NG et al, Curr Rheumatol Rep 2007:9(6):482-487 ("Gene microarray data
    have led to better understanding of pathogenesis. Research has evaluated
    genetic signatures (and) described biologic subgroups. Genomic studies
    demonstrate abnormalities of mitochondrial function").

    Nestadt P: ("These
    results show that a significant proportion of patients diagnosed with
    (ME)CFS have elevated ventricular lactate levels, suggesting anaerobic
    energy conversion in the brain and / or mitochondrial dysfunction").
    (Elevated blood lactate levels after mild exercise are considered to be a
    sign of mitochondrial damage)

    Bell DS:
    ("I agree that ME/CFS is a mitochondrial disease (but) ME/CFS is a
    mitochondrial disease like no other. There are lots of studies that
    implicate mitochondrial problems: Dr Hirohiko Kuratsune and carnitine; Dr
    Suzanne Vernon and genomics; Dr Kenny DeMeirlier (Brussels); Dr Martin Pall
    (New York); Dr Paul Cheney and many others").
    That there is evidence of disrupted apoptosis in ME/CFS cannot be disputed
    (Increased neutrophil apoptosis in Chronic Fatigue Syndrome. Kennedy G et
    al. J Clin Pathol 2004:57(8):891-893)

    Attention is therefore drawn to a paper by Neustadt and Pieczenik which
    reviews the evidence that medications have now emerged as a major cause of
    mitochondrial damage (Medication-induced mitochondrial damage and disease.
    Mol Nutr Food Res 2008:52:780-788).

    In addition to medication-induced systemic dysfunction, systems most
    affected are listed as being the muscles, brain, nerves, kidneys, heart,
    liver, eyes and pancreas.

    Acquired conditions in which mitochondrial dysfunction has been implicated
    include (ME)/chronic fatigue syndrome and fibromyalgia.

    The mechanisms of mitochondrial-induced injury and the damage caused by
    medication-induced production of free radicals are explained in detail by
    the authors.

    Medications documented to induce mitochrondial damage include analgesics;
    anti-inflammatories; anaesthetics; angina medications; antibiotics;
    antidepressants; anxiolytics; barbiturates; cholesterol-lowering medications
    (statins); chemotherapy; and the mood-stabiliser lithium, amongst others,
    including medications for Parkinson's Disease, diabetes, cancer and

    It is a matter of record that psychiatrist Professor Simon Wessely advises
    the prescription of lithium for patients with ME/CFS: "There is no doubt
    that at least half of CFS patients have a disorder of mood. The management
    of affective disorders is an essential part of the treatment of CFS/ME.
    Numerous trials attest to the efficacy of tricyclic antidepressants in the
    treatment of fatigue states. Patients who fail to respond should be treated
    along similar lines to those proposed for treatment-resistant depression.
    Adding a second antidepressant agent, especially lithium, may be beneficial"
    (The chronic fatigue syndrome - myalgic encephalomyelitis or postviral
    fatigue. S Wessely PK Thomas. In: Recent Advances in Clinical Neurology
    (ed): Christopher Kennard. Churchill Livingstone 1990: pp 85-131).

    In addition to lithium, specific medications listed that are known to induce
    mitochondrial damage include aspirin; acetaminophen (paracetamol / Tylenol);
    fenoprofen (Nalfon); indomethacin (Indocin, Indocid); naproxen (Naprosyn);
    lidocaine; amiodarone (Cordarone); tetracycline; amtitriptyline; citalopram
    (Cipramil); fluoxetine (Prozac); chlorpromazine (Largactil); diazepam
    (Valium); galantamine (Reminyl) and the statins, amongst others.

    The authors state that damage to mitochondria may explain the side effects
    of many medications: "Recently it has become known that iatrogenic
    mitochondrial (damage) explains many adverse reactions from medicines".

    It was in 1994 at the Dublin International Meeting on ME/CFS (held under the
    auspices of the World Federation of Neurology) that Charles Poser, Professor
    of Neurology at Harvard, confirmed that adverse reactions to medication is
    virtually "pathognomonic" of ME/CFS, and that a paradoxical or inappropriate
    reaction to medications is one of the most important criteria in ME/CFS.

    As Neustadt and Pieczenik state that mitochondrial dysfunction has been
    implicated in fibromyalgia (FM) as well as in (ME)CFS, and as FM has been
    recognised as an additional burden of suffering in many patients with ME/CFS
    (Buchwald D et al. Rheum Dis Clin N Am 1996:22:2:219-243), it is of interest
    that a 2007 paper estimated the prevalence and number of FM patients in ten
    countries, looking specifically at FM patients' AAT (alpha-1 antitrypsin)
    phenotypic distribution worldwide. Those countries were Canada, the USA,
    Denmark, Finland, Germany, Italy, the Netherlands, Spain, Sweden and
    Pakistan. The authors noted that during the last few years, clinical,
    epidemiological and pathological evidence suggests that alpha-1 antitrypsin
    (AAT) deficiency may play a role in the development of FM. Studies on AAT
    gene frequencies and FM were retrieved from all ten countries. Results
    showed that a severe deficiency Z allele was found in all these countries,
    with very high frequencies in Denmark and Sweden; high frequencies in Italy
    and Spain; intermediate frequencies in Germany, the Netherlands, Canada and
    the USA, and a low frequency in Pakistan. The authors conclude that AAT
    phentotype characterisation should be recommended in all FM patients, and
    that the possible efficacy of AAT replacement therapy in severely deficient
    FM patients warrants further study.

    This is evidence that argues robustly against the Wessely School belief
    that, together with "CFS/ME", FM is a single somatoform disorder (S Wessely
    et al. Lancet 1999:354:936-939).

    It also adds to the existing evidence that demonstrates the lack of
    scientific rigour accepted by the Medical Research Council (MRC) in
    permitting the Wessely School investigators (who are in charge of the PACE
    trials on cognitive behaviour therapy and graded exercise therapy in
    "CFS/ME") intentionally to include people with FM in those trials.
    Including different patient populations from the outset will inevitably skew
    the results, and under the WHO taxonomic principles, FM is classified
    separately from ME/CFS at ICD-10 M79, whereas ME/CFS is classified at G93.3.

    Of further concern is the fact --- confirmed by the then Minister of State
    Dr Stephen Ladyman in July 2004 at the All Party Parliamentary Group of
    Fibromyalgia (now disbanded) ---that doctors were offered financial
    inducements to persuade those who do not have ME/CFS (but who have FM) to
    take part in the MRC trials.

    In a separate paper by Professor Julia Newton et al comparing mitochondrial
    function in patients with primary biliary cirrhosis (PBC), patients with
    primary sclerosing cholangitis, patients with ME/CFS and normal controls
    (Pilot Study of Peripheral Muscle Function in Primary Biliary Cirrhosis:
    Potential Implications for Fatigue Pathogenesis. Hollingsworth KG, Newton JL
    et al. Clin Gastroenterol Hepatol; in press, September 2008) the authors
    state that PBC is characterised in 95% of patients by autoantibody responses
    directed against the mitochondrial antigen pyruvate dehydrogenase complex
    (PDC). To define mitochondrial function in peripheral muscle during
    exercise, (31)P magnetic resonance spectroscopy was used.

    Whilst the paper is chiefly concerned with mitochondrial dysfunction in
    patients with primary biliary cirrhosis (and the results clearly indicate
    mitochondrial dysfunction in patients with PBC, who showed excess muscle
    acidosis at higher levels of exercise), the authors state about ME/CFS
    patients: "Interestingly, prolonged time to maximum proton efflux was also
    seen in the (ME)CFS control group, indicating that there are aspects of
    muscle pH handling that are abnormal in this important clinical group".

    Professor Newton is Lead Clinician in the internationally renowned
    Cardiovascular Investigations Unit at the University of Newcastle, UK, which
    is the largest autonomic function testing laboratory in Europe; her work
    focuses on the role of the autonomic nervous system in the development of
    fatigue, specifically in primary biliary cirrhosis, but also in the
    pathogenesis of fatigue in ME/CFS. In her Conference pack for the ME
    Research UK International Research Conference held at the University of
    Cambridge on 6th May 2008, Professor Newton said: "Recent results from a
    series of MR scans have shown impaired proton removal from muscle during
    exercise in patients with ME/CFS compared to matched controls. This has led
    us to hypothesise that fatigue arises due to impaired pH run off from muscle
    during exercise which is influenced by the degree of autonomic dysfunction".

    Despite the irrefutable evidence of mitochondrial dysfunction and damage in
    patients with ME/CFS, the NICE Guideline on "CFS/ME" proscribes
    mitochondrial testing and recommends only behavioural modification in the
    form of cognitive behavioural therapy, together with incremental aerobic
    exercise, and refers to "perceived exertion" (52 page version, page 30). It
    claims that it "offers the best practice advice on the care of people with
    CFS/ME" (52 page version, page 6) and that its advice is "evidence-based".
    It is notable that the alleged evidence-base upon which the Guideline
    Development Group relied specifically states: "If patients complained of
    increased fatigue, they were advised to continue at the same level of
    exercise" (Fulcher and White, BMJ 1997:314:1647-1652). Given the evidence
    of mitochondrial damage, such advice cannot conceivably qualify as "best
    practice advice".
    [This Message was Edited on 08/28/2008]
  2. simonedb

    simonedb Member

    good article tansy.
    but what do you think of the fact that part of Dr Cheney's first line of defense is doxepin and klonopin?
  3. tansy

    tansy New Member

    Hi Simone

    I believe Cheney uses these to protect the brain. In the UK ME/CFS specialists have for decades Rx very low doses of tricyclic ADS to patients who can tolerate them. If Cheney also uses very low doses it may be that this avoids further damage to the mitochondria.

    Having had both short and long term problems with many of these meds and anaesthesia I avoid them if possible; when I do need meds like NSAIDs and pain killers I discontinue them as soon as possible.

    tc, Tansy
    [This Message was Edited on 08/28/2008]
  4. Jayna

    Jayna New Member

    Way back in the late 1990's, I was clumsily searching on the internet for research on exactly this connection, to support my determination to my physical therapist that I would be safer doing light weight-training than cardio workouts.

    As it was, I could only do half the reps on her starter routine, was not able to increase any reps, and was terribly sick for a couple of days after each time.

    I did lose several pounds, regained a lot of core strength, and retained my muscle strength for a couple of years after i quite working out... quite good benefits for only 10 weeks of twice weekly workouts/PEM, although, in retrospect, I may have done permanent damage to my mitochondria by doing it at all.

    I wouldn't try it now for anything in the world.
  5. victoria

    victoria New Member

    Tansy & Grammy!

    A friend of mine had a special mitochondria test about 8 years ago that showed they were not functioning properly. Of course they had nothing to offer her... and of course it still took her 5 years to get her SSD!

    She was lucky she was still able to work at the time of the test, or at least was on leave, as her insurance covered this test, cost about $20K at the time! NOT something most of us can afford - or that anyone's health insurance would pay for nowadays.

    Very interesting about what all can affect the mitochondria... I'm not surprised about ANY of it. I think we've helped poison ourselves unwittingly trying to heal other things and allowed some new strains of bugs (viral or bacterial) to take the opportunity offered.

    all the best,