Medication and ME/CFS?
Margaret Williams
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 'commondeletion'
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 them 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:
http://www.cfids.org/cfidslink/2007/neurobiological.asp
("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:
http://dfwcfids.net/index.php?option=com_content&task=view&id=2007&Itemid=754
("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 HIV/AIDS.
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".
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