Medication and ME/CFS?

[Guest guest]

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 disuseâ€)

 

 

* 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 muscleâ€)

 

 

* 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 DNAâ€).

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

functionâ€).

 

 

* Nestadt P: _http://www.cfids.org/cfidslink/2007/neurobiological.asp_

(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 dysfunctionâ€).

(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

_

(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 othersâ€). 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 medicinesâ€.

 

 

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/MEâ€, 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/MEâ€) 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 groupâ€.

 

 

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 dysfunctionâ€.

 

 

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-basedâ€. 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 adviceâ€.

 

 

 

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