Defensive and repair processes, of which inflammation is a part, are more active between roughly 10pm and the following 10am. For example, Sutherland (2005) reports that as many as 75% of asthmatic subjects are awakened by asthma symptoms, at least once per week, with approximately 40% experiencing nocturnal symptoms on a nightly basis. A great deal of research demonstrates that nocturnal symptoms of cough and dyspnea accompany circadian (i.e. chrononbiological) variations in airway inflammation and physiologic variables.

Monro (2001) reports that: ‘A natural cycling between the defensive and repair modes of aspects of the immune system is disturbed in ill-health and a chronic cytokine shift may lock the body into a pro-inflammatory state’.

These patterns are, therefore, capable of being disrupted. Various events and circumstances, which can largely be described as ‘stressful events’, seem capable of altering the diurnal rhythms, so that the inflammatory phase can stay ‘switched on’ for most of the time, not just at night. When this happens the defensive phase of the cycle is relatively weakened, creating a greater likelihood of infection. This can occur because of:

• multiple vaccinations

• exposure to carbamate and organophosphate insecticides, which inhibit interleukin-2, essential for Th1 function

• intake of steroids, such as cortisone

• ‘Stress, both psychological and physical. Stress activates the hypothalamo–pituitary–adrenal axis and leads to increased production of cortisol. Excessive exercise and deprivation of food or sleep also result in a falling ratio of DHEA to cortisol and an increase in a Th1 to Th2 shift. It is known that Epstein-Barr virus antibody titers rise amongst students facing examinations and that this virus is usually controlled by a Th1 response. Stress causes increased viral replication and hence antibody production’ (Monro 2001).

• Cancer. ‘Many of the risk factors for cancer, such as carcinogenic chemicals or tobacco smoke also cause long-term inflammation and lower Th1 levels’ (Monro 2001).

Sleep and pain

Additional to these influences, disturbed sleep patterns can produce negative effects on pain and recovery from injury. Any disruption of stage 4 sleep results in reduction in growth hormone production by the pituitary gland, leading to poor repair of irritated, inflamed and damaged tissues and longer recovery times (Griep 1994, Moldofsky & Dickstein 1999).

‘The interaction of the circadian sleeping-waking brain and the cytokine-immune-endocrine system is integral to preserving homeostasis. … there may be host defense implications for altered immune and endocrine functions in sleep-deprived humans. Activation of cytokines and sleepiness occur during the acute phase response to bacterial or viral disease. There are disturbances in sleep and cytokine-immune functions in chronic protozoal and viral disease… Sleep-related physiological disturbances may play a role in autoimmune diseases, primary sleep disorders and major mental illnesses.’ (Monro 2001)

The stress factors listed by Monro, as well as awareness of the cyclical nature of inflammation, are both important informational features of which patients should be made aware. In addition, nutritional tools that may allow a degree of influence over inflammatory processes (without switching them off!) can offer the patient a sense of control over pain, a powerful empowerment, especially in chronic conditions.

Pain and inflammation: allergic, dietary and nutritional factors

Two major antiinflammatory nutritional methods are useful in most pain situations – the dietary approach and the enzyme approach – and both or either can be used, if appropriate.

Inflammation is a natural and mostly useful physical response to irritation, injury and infection. To drastically alter or reduce it may be counterproductive and, therefore, a mistake, as has been shown in the treatment of arthritis using non-steroidal antiinflammatory drugs (NSAIDs) over the past 30 years or so. Apart from the toxic nature of NSAIDs, untreated joints have commonly been shown to remain in better condition than those treated with NSAIDs (Pizzorno 1996, Werbach 1996).

Nutritional approaches for modulating inflammation (Bakker et al 2010, Sanders 2007)

The reasoning behind the importance of antiinflammatory dietary protocols for patients is given below. The advice for the patient (guidelines that can be copied for the patient’s use) is found in Chapter 7 and in the Appendix.

1. Reduce consumption of animal fats. Pain/inflammation processes involve particular prostaglandins and leukotrienes, which are (to a great extent) dependent upon the presence of arachidonic acid, which humans manufacture mainly from animal fats. Reducing animal fat intake cuts down access to the enzymes that help to produce arachidonic acid and, therefore, lowers the levels of the inflammatory substances released in tissues that contribute so greatly to pain (Donowitz 1985, Ford-Hutchinson 1985).

• The first priority in an antiinflammatory dietary approach is to cut down or eliminate dairy fat.

• Fat-free or low-fat milk, yogurt and cheese should be eaten in preference to full-fat varieties and butter avoided altogether.

• Meat fat should be completely avoided and since much fat in meat is invisible, meat itself can be left out of the diet for a time (or permanently).

• Poultry skin should be avoided.

• Hidden fats in products such as biscuits and other manufactured foods should be looked for on packages and avoided.

2. Eating fish or taking fish oil helps ease inflammation (Moncada 1986). Fish deriving from cold water areas such as the North Sea or Alaskan waters contain the highest levels of eicosapentanoic acid (EPA), which reduces levels of arachidonic acid in tissues and therefore helps to produce fewer inflammatory precursors. Fish oil provides these antiinflammatory effects without interfering with those prostaglandins, which protect the stomach lining and maintain the correct level of blood clotting. Over-the-counter drugs, such as NSAIDs, which reduce inflammation, commonly cause new problems by interfering with prostaglandin function as well as encouraging gut dysfunction, which may lead to intolerance or allergic reactions (see below).

Research has shown that the use of EPA in rheumatic and arthritic conditions offers relief from swelling, stiffness and pain, although benefits do not usually become evident until supplementation has been taken for 3 months, reaching their most effective level after about 6 months (Werbach 1991a).

Patients (unless intolerant to fish) should be advised to:

• eat fish such as herring, sardine, salmon and mackerel at least twice weekly, more if desired

• take EPA capsules (5–10 daily) regularly when inflammation is at its worst until relief appears and then a maintenance dose of 3–6 daily.

3. Antiinflammatory (proteolytic) enzymes, derived from plants, have a gentle but substantial antiinflammatory influence. These include bromelaine, which comes from the pineapple stem (not the fruit), and papain from the papaya plant. Around 2–3 g of one or other should be taken (bromelaine seems to be more effective) spread through the day, away from meal times as part of an antiinflammatory, pain-relieving strategy (Cichoke 1981, Taussig 1988).

Intolerances, allergies and musculoskeletal dysfunction

Specific individualized pathophysiological responses to particular foods and liquids account for a significant amount of symptom production, including pain and discomfort (Brostoff 1992). In order to make sense of a patient’s presenting symptoms, remain alert to the possibility that at least some of the pain, stiffness, fatigue, etc. may be deriving from, or being aggravated by, what is being consumed.

Two different responses seem to be involved: true food allergy, which is an immunological event (involving immunoglobulin E or IgE), and the less well-understood phenomenon of food intolerance, which involves adverse physiological reactions of unknown origin, without immune system intervention. It is possible that food intolerance may include an element of actual food toxicity or a very individual reaction to foods, probably related to enzyme deficiency (Anderson 1997).

Unfortunately, the terms food allergy (hypersensitivity) and food intolerance seem to have become the source of much confusion and little certainty.

Mitchell (1988) states:

The Royal College of Physicians … has directly addressed the problem of terminology. They recommend that the general term of food intolerance be used and that other terms such as food allergy and hypersensitivity be reserved for those situations where a pathogenetic mechanism is known or presumed.

By definition (Royal College of Physicians 1984), food intolerance is a reproducible, unpleasant (i.e. adverse) reaction to a specific food or food ingredient that is not psychologically based (food aversion). Classification of adverse reactions (Ortolani & Vighi 1995) is divided into toxic and non-toxic, with toxic implying general human toxicity, not individual susceptibility. Non-toxic divisions include immune mediated (food allergy) and non-immune mediated (food intolerance). Provocation and other tests help to determine the level of reaction and whether desensitization might be attempted or if total avoidance should be recommended. (Figure 6.1)

Figure 6.1 A classification of adverse reactions to foods.

(Drawn after Ortolani & Vighi 1995)

Mechanisms

Food reaching the digestive system is usually processed enzymatically to molecular size (short-chain fatty acids, peptides and disaccharides) so that absorption or elimination can take place after the nutrients have been transferred across the mucous membrane into the bloodstream.

Unfortunately, in many instances food antigens and immune complexes also find their way across this mucosal barrier. How fast and in what quantity such undesirable substances enter the bloodstream from the gut seem to be directly linked to the quantity of antigenic material in the gut lumen (Mitchell 1988, Walker 1981).

Mitchell states:

The presence of specialised membranous epithelial cells… appears to allow active transport of antigen across the mucosa even when concentrations of antigen are low. Permeability is retarded by defensive mechanisms, including enzyme and acid degradation, mucus secretion and gut movement and barriers, which reduce absorption and adherence.

If permeability across the barrier to the bloodstream is compromised this signifies a failure of the defensive mechanisms, so the question arises as to what leads to this failure.

• Drugs (antibiotics, steroids, alcohol, NSAIDs – see discussion earlier in this chapter) (Bjarnason 1984, Jenkins 1991)

• Advancing age (Hollander 1985)

• Specific genetically acquired intolerances (allergies)

• Infections and overgrowths in the intestine, e.g. bacterial, yeast (Isolauri 1989)

• Chemicals contaminating ingested food (pesticides, additives, etc.) (O’Dwyer 1988)

• Maldigestion, constipation (leading to gut fermentation, dysbiosis, etc.) (Iacano 1995)

• Emotional stress that alters the gut pH, negatively influencing normal flora

• Major trauma, such as burns (possibly due to loss of blood supply to traumatized area) (Deitch 1990)

• Toxins that are not excreted or deactivated may end up in the body’s fat stores (O’Dwyer 1988)

All or any of these or other factors can irritate the gut wall and allow an increase in the rate of transportation of undesirable molecules into the bloodstream – the so-called leaky gut syndrome.

Research suggests that the relative health and efficiency of the individual’s liver, along with the age of first exposure, the degree of antigenic load and the form in which the antigen is presented, all play roles in deciding how the body responds, with some degree of adaptive tolerance being a common outcome (Mitchell 1988, Roland 1993). Early feeding patterns are one key factor in determining the way the body later responds to antibodies delivered via food and which foods are most involved, with eggs, milk, fish and nuts being among those most likely to produce problems (Brostoff 1992, Mitchell 1988).

Most people exhibit some degree of serum antibody responses to food antigens. Antibodies assist in elimination of food antigens by forming immune complexes, which are subsequently eliminated by the immune system. However, failure to remove such complexes may result in them being deposited in tissues, leading to subsequent inflammation (Brostoff 1992). Sometimes the immune response to food antigens involves IgE and sometimes it does not, in which case the response would attract a label of ‘food intolerance’.

Mast cells, immune responses and inflammation

Mast cells in the lungs, intestines, connective tissues and elsewhere in the body are critical to the allergic response. Mast cells in connective tissue play a role in the regulation of the composition of ground substance. They contain heparin, histamine and eosinophilic chemotactic factor and are involved in immediate hypersensitivity reactions. Mast cells have surface receptors with a high affinity for IgE, but they can also interact with non-immunological stimuli, including food antigens.

The violence of any reaction between mast cells and IgE (or other stimuli) depends on the presence in the tissues of a variety of biological substances, such as histamine and arachidonic acid (and its derivatives such as leukotrienes), all of which augment inflammatory processes (Holgate 1983, Wardlaw 1986). Histamine is secreted by mast cells during exposure to allergens and the result is local inflammation and edema as well as bronchiole constriction. This last effect is especially relevant to asthmatics but can affect anyone to some degree, creating breathing difficulties.

At times the response to ingested and absorbed antigens is very fast – a matter of seconds, however, it is also possible for hours or days to elapse before a reaction occurs (Mitchell 1988).

Muscle pain and allergy/intolerance

Copious evidence exists linking allergy and food intolerance to muscle pain, chronic fatigue, fibromyalgia syndrome and a host of other mysterious and complex symptoms. Lactose intolerance produced temporal pain, blurred vision, dizziness and tachycardia in one patient that lasted 26 years before diagnosis. (Matthews & Campbell 2000). Many people suffering perplexing symptoms are often labeled as psychosomatic patients, with the symptoms described as ‘somatoform’ – i.e. symptoms that cannot be traced to a specific physical cause. Rief et al (2001) report that the most frequent somatoform symptoms were back pain, joint pain, pain in the extremities, and headache, as well as abdominal symptoms (bloating or intolerance of several foods) and cardiovascular symptoms (palpitation). The question as to the validity of ‘intolerance’ as a non-psychosomatic condition continues to rage in medical circles. (Nettleton et al 2009) Answers other than ‘somatoform’ or ‘psychosomatic’ are emerging. For example, Fruhauf (2009) notes that:

More than 20% of the population in industrialized countries suffers from food intolerance or food allergy. The majority of cases of food intolerance are due to non-immunological causes. These causes range from pseudo-allergic reactions to enzymopathies, chronic infections and psychosomatic reactions that are associated with food intolerance. The prevalence of true food allergy, i.e., immunologically mediated intolerance reactions, is only 2% to 5% in adults and 5% to 10% in children.

The manifestation and severity of allergic rhinitis symptoms exhibit marked 24 hour variations; in most people symptoms are worse overnight, or early in the morning, and often compromise nighttime sleep, resulting in poor daytime quality of life, disturbed school and work performance, irritability and moodiness (Smolensky et al 2007).

A study evaluated the frequency of major symptoms as well as allergic symptoms, such as rhinitis, in a group of more than 30 patients with a diagnosis of ‘primary fibromyalgia’ compared with matched (age and sex) controls (Tuncer 1997). Symptom prevalence in the FMS group (apart from pain, which was 100%) was migraine 41%, irritable bowel syndrome (IBS) 13%, sleep disturbance 72% and morning stiffness 69%. There was a frequent finding of allergy history in the FMS group, with elevated (though not significantly) IgE levels. Sixty-six percent of the FMS patients tested were positive for allergic skin tests.

A study at the school of medicine of East Carolina University in 1992, involving approximately 50 people with hay fever or perennial allergic rhinitis, found that approximately half those tested fitted the American College of Rheumatology criteria for fibromyalgia (Cleveland et al 1992).

Four patients diagnosed with fibromyalgia syndrome for between 2 and 17 years, who had all undergone a variety of treatments with little benefit, all had complete, or nearly complete, resolution of their symptoms within months after eliminating monosodium glutamate (MSG), or MSG plus aspartame, from their diet. All patients were women with multiple co-morbidities prior to elimination of MSG. All have had recurrence of symptoms whenever MSG is ingested. The researchers note that excitotoxins are molecules, such as MSG and aspartame, that act as excitatory neurotransmitters and can lead to neurotoxicity when used in excess. They proposed that these four patients may represent a subset of fibromyalgia syndrome that is induced or exacerbated by excitotoxins or, alternatively, may comprise an excitotoxin syndrome that is similar to fibromyalgia (Werbach 1993).

Simons et al (1999) note that patients with active symptoms of allergic rhinitis as well as myofascial trigger points receive only temporary relief when specific therapy is given for the trigger points. ‘When the allergic symptoms are controlled, the muscle response to local TrP therapy usually improves significantly. Hyper-sensitivity to allergens, with histamine release, seems to act as a perpetuating factor for myofascial trigger points.’ They note that food allergies should be considered as a perpetuating factor for myofascial TrPs and that although the ‘shock organs for allergic reactions’ in most people are the upper respiratory tract, eyes, bronchi, skin or joints, ‘in other patients, the skeletal muscles appear to serve as the shock organ for allergies’.

Dr Anne Macintyre, medical adviser to ME Action, an active UK support group for patients with myalgic encephalomyelitis, fibromyalgia and chronic fatigue conditions, supports an ‘immune dysfunction’ model as the underlying mechanism for FMS. She states: ‘The immune dysfunction in ME may be associated with increased sensitivities to chemicals and/or foods, which can cause further symptoms such as joint pain, asthma, headache and IBS’ (Macintyre 1993).

For many years, Dr Theron Randolph recorded clinical changes as an individual passes through stages of ‘reaction’ to chemicals (in food or in the environment) (Randolph 1976). He divides these reactions into those that relate to the active stimulation of an immune reaction by the allergen and those that relate to withdrawal from it. During some of the stages, most notably ‘systemic allergic manifestations’, most of the major symptoms associated with FMS may become apparent, including widespread pain, fatigue, mental confusion, insomnia and irritable bowel. Where particular food allergens are consumed daily, reactions are usually not acute but may be seen to be chronically present. The clinical ecology model suggests that the individual may by then have become ‘addicted’ to the substance and that the allergy is then ‘masked’ by virtue of regular and frequent exposure to it, preventing the withdrawal symptoms that would appear if exposure was stopped. Feingold (1973) states:

If a reacting individual associates the stimulatory effect [of an allergen] with a given exposure, he tends to resort to this agent as often as necessary ‘to remain well’. The coffee addict for example who requires coffee to get started in the morning, tends to use it through the day as often as necessary and in the amount sufficient to keep going. Over a period of time, a person so adapting tends to increase the frequency of intake and the amount per dose to maintain the relatively desirable effect. The same holds true for other common foods.

Allergy-hyperventilation ‘masqueraders’

Blood chemistry can be dramatically modified (increased alkalosis) by a tendency to hyperventilation and this has profound effects on pain perception and numerous other symptoms including anxiety, sympathetic arousal, paresthesia and sustained muscular tonus (Lum 1981, Macefield & Burke 1991, Timmons & Ley 1994).

Brostoff (1992) states that some experts are actually dismissive of the concept of food intolerance and believe that many individuals so diagnosed are actually hyperventilators. He considers that: ‘Hyperventilation is relatively uncommon and can masquerade as food sensitivity’. Barelli (1994) has shown that a tendency to hyperventilation increases circulating histamines, making allergic reactions more violent and more likely.

So we have two phenomena – allergy and hyper-ventilation – both of which can produce symptoms reminiscent of the other (including many associated with chronic muscle pain), each of which can aggravate the effects of the other (hyperventilation by maintaining high levels of histamine and allergy by provoking breathing dysfunction, such as asthma), and both of which commonly co-exist in individuals with fibromyalgia and other forms of chronic pain.

Defining food intolerances

In the 1920s and 1930s, Dr A.H. Rowe demonstrated that widespread chronic muscular pains, often associated with fatigue, nausea, gastrointestinal symptoms, weakness, headaches, drowsiness, mental confusion and slowness of thought, as well as irritability, despondency and widespread bodily aching, commonly had an allergic etiology. He called the condition ‘allergic toxemia’ (Rowe 1930, 1972).

Randolph (1976) has described what he terms ‘systemic allergic reaction’, which is characterized by a great deal of pain, either muscular and/or joint related, as well as numerous symptoms common in FMS. Randolph says:

The most important point in making a tentative working diagnosis of allergic myalgia is to think of it. The fact remains that this possibility is rarely ever considered and is even more rarely approached by means of diagnostico-therapeutic measures capable of identifying and avoiding the most common environmental incitants and perpetuents of this condition – namely, specific foods, addictants, environmental chemical exposures and house dust.

Randolph points out that when a food allergen is withdrawn from the diet it may take days for the ‘withdrawal’ symptoms to manifest: ‘During the course of comprehensive environmental control [fasting or multiple avoidance] as applied in clinical ecology, myalgia and arthralgia are especially common withdrawal effects, their incidence being exceeded only by fatigue, weakness, hunger and headache’. The myalgic symptoms may not appear until the second or third day of avoidance of a food to which the individual is intolerant, with symptoms starting to recede after the fourth day. He warns that in testing for (stimulatory) reactions to food allergens (as opposed to the effects of withdrawal), the onset of myalgia and related symptoms may not take place for between 6 and 12 hours after ingestion (of an allergen-containing food), which can confuse matters as other foods eaten closer to the time of the symptom exacerbation may then appear to be at fault. Other signs that can suggest that muscle pain is allied to food intolerance include the presence of restless legs, a condition that also commonly co-exists with FMS and contributes to insomnia (Ekbom 1960).

When someone has an obvious allergic reaction to a food this may well be seen as a causal event in the emergence of other symptoms. If, however, the reactions occur many times every day and responses become chronic, the cause and effect link may be more difficult to make.

If symptoms such as muscular pain may at times be seen to be triggered by food intolerance or allergy, the major question remains – what is the cause of the allergy? (Box 6.1) As discussed earlier in this chapter, one possibility is that the gut mucosa may have become excessively permeable, so allowing molecules to enter the bloodstream where a defensive immune response is both predictable and appropriate. ‘Leaky gut’ can be seen to be a cause of some people’s allergy (Paganelli 1991, Troncone 1994). The trail does not stop there, however, because it is necessary to ask: what caused the leaky gut?

Box 6.1 Biological synchronicity

There are both linear and spatial ways of interpreting what happens in life in general and to the body in particular. Cause and effect represent the way many people in the West understand the relationships between events (causality), i.e. one thing causes or is caused, or at least strongly influenced, by another.

A different way of viewing two events is to see them as being part of a complex continuum, each being part of the same (larger) process but with neither event dependent on the other, linked by a synchronistic connective principle. The words ‘synchronicity’ or ‘simultaneity’ are used to describe this way of viewing patterns and events (Jung 1973).

For example: