Intended for healthcare professionals

Rapid response to:

Education And Debate Complexity science

Complexity and clinical care

BMJ 2001; 323 doi: (Published 22 September 2001) Cite this as: BMJ 2001;323:685

Rapid Response:

Complexity, Nitric Oxide and Chronic Fatigue

While it is important to hear Prof. Ian Reid’s caution (BMJ Letters,
19th January 2002) about misusing the language of complexity as metaphor
without mathematical modelling, I hope the rather dismissive style of his
letter will not hinder the way we develop theories of disease, nor of ‘un-
learning’ as a form of therapy. Chronic Fatigue Syndrome (CFS) provides a
useful illustration. The Chief Medical Officer’s Report of January 2002
recognised CFS to be a genuine condition. But what sort of genuine
condition could it be? This case example from primary care illustrates an
interesting new disease paradigm.

A 42 year old family man, social class 1employed, had experienced
this syndrome for two years. His condition had started following a viral
chest infection that put him off work three months after his father had
died. He continued to experience tiredness, muscle aches and episodes of
profound weakness that suddenly and unexpectedly forced him to lie down.
When he became anxious about the unpredictable amount of time he needed
off work, I offered a trial of a beta-blocker because he was also getting
episodes of tachycardia. Nebivolol had recently come onto the market, and
he agreed to try this. It unfortunately made his symptoms acutely and
profoundly worse. He recovered over a week or two sufficiently to return
to work, but sadly the condition deteriorated with a fluctuating course

Nebivolol is marketed as a highly cardio-selective beta-blocker that
also produces vaso-dilatation via nitric oxide modulation. The role of
nitric oxide as an intra-endothelial mediator of rapid vasodilatation has
been extensively researched. Massive release is associated with
cardiogenic shock. Its mode of action on small vessels, including those of
muscles and the brain, takes effect over about two seconds. This is about
the time it takes for an episode of profound weakness to affect a sufferer
of CFS. Pall and Satterlee have recently presented evidence suggesting
elevated nitric oxide as a possible mechanism for the fatigue of CFS. The
CSM has on record twelve adverse reaction reports of fatigue on nebivolol,
by far the largest single side-effect to be reported, and proportionally
much higher than is reported for labetolol, another cardio-selective beta-

But this is not a simple issue reducible to biochemistry. The new
disease paradigm in question is a complex adaptive systems that includes
whole people experiencing loss emotions within networks of relationships.
The science of psychoneuroimmunology (PNI) is detailing how emotional
states affect the immune system through the hypothalamic-pituitary-adrenal
system. The theory proposed by Hyland , for example, is that co-incidental
timing of events within such a system can generate maladaptive emergent
properties, an ‘extended network learning error’. It has been known since
1977 that lymphocyte function is depressed after bereavement, and fatigue
is a common ‘psychological’ feature of bereavement. Reduced killer cell
activation detectable in CFS is also mediated by increased nitric oxide.
Sufferers of CFS vigorously reject the suggestion that ‘depression’
(identified by questionnaires designed to diagnose it) is a predisposing
factor. Perhaps bereavement, or even ‘unrecognised grieving’ may be the
confounding, timely, dynamically significant, and much less stigmatising,
psycho-social feature of the physical, and therefore (sic) genuine,
condition of CFS.

Hyland’s ‘extended network learning error’ model for CFS is one
possibility that allows the complex interplay of social attachments,
emotional states, and hypothalamic hormonal or mediator chemistry to
produce a pattern of emergent conditions. His model predicts just the
response my patient had - deterioration, improvement and then slow
deterioration again - to the challenge of an iatrogenic chemical
interference. But, in response to Prof. Reid, at the ‘whole human’ level
word ‘interference’ is important to making, and un-learning, errors.
Therefore metaphors must have their place alongside statistics in this new
paradigm of genuine illness.

1. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite
mechanism for the common aetiology of multiple chemical sensitivity,
chronic fatigue syndrome and post-traumatic stress disorder. Annals of the
New York Academy of Sciences 2001; 933: 323-329.

2. Hyland M. Extended Network Learning Error: A new way of
conceptualising chronic fatigue syndrome. Psychology and Health 2001; 16:

3. Bartrop RW, Lazarus L, et al. Depressed lymphocyte function after
bereavement. Lancet 1977; 1: 834-836.

4. Ogawa M, Nishiura T, et al. Decreased nitric oxide-mediated
natural killer cell activation in chronic fatigue syndrome. European
Journal of Clinical Investigation 1998; 28(11): 937-943.

5. Griffiths TN. Lost and Then Found: Turniong life’s disappointments
into hidden treasures. Carlisle: Paternoster, 1999.

Editorial note
The patient whose case is described has given his signed informed consent to publication.

Competing interests: No competing interests

06 March 2002
Trevor N Griffiths
GP Principal
Highlands Health Centre, Fore Street, Ivybridge, S Devon. PL21 9AE