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The “No Oh No" Cycle

Dr Martin Pall, a professor of biochemistry and basic medical sciences at Washington State University in America, is proposing that the illnesses chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity and post-traumatic stress disorder could all share the same underlying cause. We all know that there is plenty of overlap between these conditions and if you are diagnosed with one you are more than likely to have symptoms of another; just like many people have fibromyalgia with many of the symptoms of multiple chemical sensitivity.

Dr Pall's main research interests focus around a chemical called nitric oxide and what are known as free radicals: supercharged chemicals resulting from biological reactions that can cause havoc in the body.

He is suggesting that the underlying cause of these multisystem illnesses is elevated levels of nitric oxide and its companion peroxynitrite.

His theory goes like this:

  • Some kind of trigger like an infection, physical trauma, or emotional upset activates a sequence ofevents that stimulates the enzyme nitric oxide synthase.
  • Nitric oxide synthase responds by increasing levels of nitric oxide and peroxynitrite. 
  • These elevated levels initiate a vicious cycle which feeds off itself to keep the levels of nitric oxide and peroxynitrite high.
  • It is this chronic elevation and the effects it has on other chemicals in the body that cause the multisystem illnesses like fibromyalgia to take hold.

Dr Pall calls this vicious cycle the NO/ONOO- cycle, which is pronounced "no oh no", somewhat accurately portraying the common reaction by both medical professionals and patients to this group of illnesses! Dr Pall believes that all the symptoms of these illnesses can be explained by some aspect of the cycle and suggests that this proposed mechanism is the only one that explains all four of them.

His ideas are supported by different clinical and experimental observations of patients as well as evidence from animal models. Reports also link individual components of the NO/ONOO- cycle with the symptoms described by people with these illnesses.  

For example:

  • Fatigue: peroxynitrite, nitric oxide and super oxide all disrupt energy production in all cells in the body. 
  • Cognitive Difficulties: could be caused by elevated brain nitric oxide and low energy production in the brain. 
  • Dizziness & Light-headedness: nitric oxide can cause blood vessels to become dilated reducing blood pressure and can influence autonomic nervous activity.
  • Pain: every element of the NO/ONOO- cycle has a role for increasing pain. For example, nitric oxide and peroxynitrite stimulate N-methyl d-aspartate (NMDA) receptors directly involved in transmitting pain signals.

Another interesting point about the NO/ONOO-cycle is that its main components, nitric oxide and peroxynitrite, tend to only act locally as they do not survive very long once they have been released. This means that they can only affect the body locally where they have been released, meaning that one body tissue might be quite badly affected whereas another body tissue nearby is not affected at all. This could explain the myriad of different symptoms the individual patients with these illnesses describe. There is an almost infinite variation of symptoms and signs that could be produced depending on which body tissues are affected.

However, in fibromyalgia we experience widespread pain that affects the whole body. Dr Pall proposes that this widespread excessive pain is due to the impact of the NO/ONOO- cycle on the thalamus in the brain. The thalamus is responsible for controlling a special pathway that descends from the brain to the spinal cord. The job of this pathway is to interrupt incoming pain signals from throughout the body and reduce their intensity before they reach the brain. So, if the thalamus is affected by the NO/ONOO- cycle this pathway will not work as effectively to regulate pain and incoming pain signals will be felt at a much higher intensity: basically, we will experience widespread excessive pain. The role of the thalamus in fibromyalgia is well documented by several research groups and it is known that the descending pathway is not as effective as it should be.

The Pall/Ziem Treatment Protocol

  • Vitamin B12 & B6
  • Natural tocopherols
  • Vitamin C
  • Magnesium malate
  • Flavonoids: Inca biloba, cranberry extract, bilberry extract and silymarin
  • Selenium
  • Coenzyme Q10
  • Folic acid
  • Carotenoids: lycopene, lutein and beta-carotene
  • Alpha-lipoic acid
  • Zinc, manganese and copper-low doses
  • Riboflavin
  • Betaine
  • N-acetyl carnitine
  • Taurine
  • Green tea extract

Dr Pall's therapy focuses on reducing the levels of nitric oxide and peroxynitrite by decreasing the activity of the NO/ONOO- cycle. In this way he sees it as treating the cause of these illnesses rather than simply treating the symptoms. He lists 30 agents, both medications and nutritional supplements, which are predicted to lower one or more elements of the NO/ONOO- cycle. Some of these agents have already been reported to be helpful in the treatment of these multisystem illnesses from clinical trial data, clinical observations or anecdotal evidence.

Dr Pall also points out the various specialists, like Dr Jacob Teitelbaum, who already use a multiagent approach with good success and many of the agents used reduce the activity of the NO/ONOO- cycle. Dr Pall and his colleague Dr Ziem have put together a group of agents they believe have the most beneficial effects (see above).

The main problem with this kind of therapy is the required financial commitment which many patients simply cannot sustain. It is possible that some of the nutritional supplements could be prescribed on the NHS if shown to be effective, but the majority would have to be purchased regularly. Some patients simply take an ad hoc selection from the list, but according to Dr Ziem, those on the complete protocol see a much greater improvement than those on only part of it.

Basically more clinical trial data is needed to support Dr Pall's proposals, but he argues whether it is right to wait for the data to arrive when people are suffering now. He hopes to change the perception of medical professionals to the treatability of these diseases and hopes this will lead to more rapid diagnosis, more effective treatment and an improved prognosis.

Dr Pall’s Book

If you are interested in finding out more Dr Pall has recently published a book entitled, Explaining 'Unexplained Illnesses'.

In this book Dr Pall sets out a well structured and clearly explained argument, from the point of view of the sceptic. Each chapter begins with a summary of the salient points entitled ‘take home lessons’, so it is possible to obtain a good overview of his ideas by simply reading these summaries. The argument for his theory is clearly constructed over four sequential chapters with suitable reference to supporting research, clinical and anecdotal evidence. These are followed by individual chapters dedicated to the five named multisystem illnesses allowing the reader to focus on their particular area of interest. The text is clear and easy to follow often with simple translations of any scientific jargon. It certainly makes an interesting read.

Available in paperback from the NUTRI

CENTRE priced £24.99. (www.nutricentre.com)

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