Final Report – 2008-09 Research & Creative Works Grants Principal Investigator: Nicholas E. Burgis, Chemistry/Biochemistry Dept. Project Title: Developing a Less Toxic Chemotherapeutic Cocktail to Treat Multiple Myeloma. This report serves to document the scholarly research activities performed by the principal investigator and collaborators during the term of the Faculty Research Grant
Aim 23(3) 121-134.pdfA review of myofascial pain and fibromyalgia
– factors that promote their persistence
Chronic muscle pain (myalgia) is a common problem throughout the world. Seemingly simple, it is actually a difficult problem for the clinician interested in determining the aetiology of the pain, as well as in managing the pain. The two common muscle pain conditions are fibromyalgia and myofascial pain syndrome.
Fibromyalgia is a chronic, widespread muscle tenderness syndrome, associated with central sensitisation. It is often accompanied by chronic sleep disturbance and fatigue, visceral pain syndromes like irritable bowel syndrome and interstitial cystitis. Myofascial pain syndrome is an overuse or muscle stress syndrome characterised by the presence of trigger points in muscle. The problem these syndromes pose lies not in making the diagnosis of muscle pain. Rather, it is the need to identify the underlying cause(s) of persistent or chronic muscle pain in order to develop a specific treatment plan. Chronic myalgia may not improve until the underlying precipitating or perpetuating factor(s) are themselves managed. Precipitating or perpetuating causes of chronic myalgia include structural or mechanical causes like scoliosis, localised joint hypomobility, or generalised or local joint laxity; and metabolic factors like depleted tissue iron stores, hypothyroidism or Vitamin D deficiency. Sometimes, correction of an underlying cause of myalgia is all that is needed to Keywords
Myalgia, hypothyroidism, trigger points, referred pain, fibromyalgia, myofascial pain syndrome. Introduction to fibromyalgia and myofascial
limb, in the same region, in the body wall, or in a pain
visceral organ. Referred pain tends to be segmental, Myalgia is muscle pain or pain of muscular origin, so that referred pain patterns are usually located in irrespective of cause. There are two major types of sites innervated by adjacent or nearby spinal cord non-inflammatory myalgia that are commonly segments. Hence, trigger points in the posterior diagnosed. One is fibromyalgia (FMS). It is a shoulder muscles like the supraspinatus and syndrome in which there is chronic, widespread infraspinatus muscles that are innervated by C5 refer muscle tenderness as a result of central sensitisation.
pain to the shoulder (C4-5 dermatomes) and the arm FMS is denoted as primary when there is no co- and hand (C5-6-7-8 dermatomes). Likewise, upper existent disease that causes widespread muscle pain.
cervical spine muscle trigger points, that have an FMS is considered secondary when myalgia is co- input into the descending (caudal) trigeminal nucleus, morbid with other disorders. Myofascial pain refer pain to the head, because the meninges and the syndrome (MPS), the other common muscle pain face are innervated by the trigeminal nerve. syndrome, is associated with discrete taut bands of Myalgia can be a primary chronic pain state in hardened muscle that contain regions of exquisite muscle tenderness. It, too, may be a central abnormalities that are specific for FMS or MPS.
hypersensitivity syndrome, but little research has Myalgia that lasts for three months or longer is been done on this point in MPS. A striking property considered chronic. It can be a disabling generalised of MPS painful regions is that they generate referred pain that is often associated with disturbed rest and pain that is felt in a different, usually distal, site. The debilitating fatigue. Treatment success may be site of referred pain perception can be in the same limited. Treatment of co-morbid myalgia can also ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm be difficult, especially if a treatable cause of a co- underlying, etiological or co-morbid disorders are applicable to both syndromes. There is always the possibility that muscle pain associated with exercise tenderness, but beyond that common phenomenon intolerance and fatigue can be due to a problem that they differ and form two distinct entities. FMS is a is neither FMS or MPS, such as that seen with a syndrome (not a disease) of central sensitisation and mutation in the cytochrome b gene of mitochondrial musculoskeletal tenderness and pain. MPS is also a deficiency, perhaps myoadenylate deaminase syndrome. It is the result of a local muscle metabolic deficiency, or hypothyroidism. Thus, the diagnosis of stress that is thought to produce an energy crisis that FMS or MPS based on the presence of muscle pain, does not support a specific muscle action. It may fatigue, and exercise intolerance, and the physical develop after one maximal contraction or excessive findings of tenderness or of myofascial trigger points, eccentric contraction in an untrained muscle.1 It is is not sufficient to give primary consideration solely associated with a discrete linear band-like hardness or tautness (trigger points) within one or more muscles, leading to the release of nociceptive Fibromyalgia
substances such as substance P, potassium, and histamine that activate peripheral nociceptive FMS is a chronic, widespread myalgia that by receptors and dorsal horn nociceptive neurons.
definition involves the body above and below the Biochemical changes at the heart of the trigger zone waist, and to the right and left sides of the midline, (elevated levels of calcitonin gene-related peptide, such that three or four quarters of the body are of substance P, norepinephrine, and tumour necrosis involved. Chronic and widespread pain of muscle factor-1D, and of interleukin 1 and 6, and a low pH origin are reflected in the criteria for diagnosis of 3.0 to 4.0) have been identified by Shah et al.2 A region of the taut band is exquisitely tender and can Rheumatology (ACR).4 Using the ACR criteria, refer pain to another, usually distal, region. Sleep 3.5% of women and 0.5% of men in the United disturbance in addition to pain will more likely result States have been estimated to have FMS. The ACR in the diagnosis of FMS. Exercise intolerance can criteria, intended to provide a uniform definition of be seen with either FMS or MPS. Many cases of fibromyalgia for research studies, require that: 1) FMS are in fact cases of MPS that have been symptoms have been present for at least three misdiagnosed as a result of poor muscle palpation months; and 2) 11 sites of a specified 18 sites be techniques that miss the presence of taut bands and tender (Table 1). Diagnosis of FMS in clinical referred pain. Nevertheless, the comments regarding practice was never intended to be as strict as that required for research purposes. Chronic and widespread muscular pain are still required to make the diagnosis, but the extent of muscle tenderness Table 1 The tender points used to diagnose fibromyalgia
may vary over time, and there may be far fewer than 11 tender sites found on examination at any given time. Chronic symptoms including widespread musculoskeletal pain syndromes with a specificity of 81% and a sensitivity of 88%.4 However, they do not distinguish FMS from chronic, widespread MPS or any other chronic condition where there is upper outer quadrant of the gluteal muscles widespread muscle tenderness, since tenderness is the sole significant physical finding specified in the medial knee above the joint line (medial fat pad or ACR criteria. In fact, MPS is the most common condition that must be considered in the differential Each point is examined bilaterally for a total of 18 points.
ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm Any condition associated with myofascial trigger with pelvic floor MPS syndromes. Depression may points will produce tenderness to palpation. Such occur in as many as 30% of FMS patients, but is also conditions include nutritional deficiency states such said to be no more common in FMS than in the as iron insufficiency, vitamin B12 deficiency, hormonal disorders eg hypothyroidism, and trauma eg cervical strain injury (‘whiplash’). Consequently, the physical examination performed for the evaluation Fibromyalgia has been extensively studied to try to of myalgia must include palpation for the taut bands identify an underlying physiological or biochemical of myofascial trigger points (see below), including an basis to explain the fatigue and the muscle tenderness.
attempt to elicit referred pain, as well as for the tender Evidence has accumulated that tenderness in FMS is points of FMS. A comprehensive medical evaluation related to central sensitisation with amplification of is also indicated in order to identify conditions in nociception, resulting in a broad array of stimuli which diffuse myalgia occurs secondarily. A localised perceived as being more painful among FMS patients or regional muscular pain syndrome such as that than they are in control populations.8-11 This is a associated with whiplash is not FMS when there is no fundamental abnormality that is very likely related widespread muscle pain that occurs above and below to the cause of fibromyalgia. Increased substance P in the waist. Even when there is widespread pain, it cerebral spinal fluid may be relevant to the generalised hypersensitivity (which includes ‘hypervigilance’) The acceptance of the ACR criteria fostered a seen in FMS. Sleep disturbance, with lack of sustained virtual explosion in the publication of research studies stage three and four sleep and intrusion of alpha on the nature of fibromyalgia, even though the activity into delta-wave sleep, has been reported in diagnostic criteria were criticised as invalid and based FMS, and patients complain of non-restorative, non- on circular reasoning. Nevertheless, despite the refreshing sleep. Alterations in cardiovascular criticism, the criteria serve a useful purpose as autonomic nervous system function lead to orthostatic similarly established criteria do in other chronic or hypotension, or neurally-mediated orthostatic recurring pain states that lack objective markers, tachycardia,12 further aggravating fatigue and impaired such as non-specific low back pain and migraine ability to function. Neuroendocrine abnormalities in headache without aura. The clinical diagnosis of the hypothalamic-pituitary-adrenal system, and growth FMS continues to be based on the history and hormone deficiency, are hormonal deficiency states physical examination. Laboratory tests and imaging that may tie together the symptoms of fatigue, pain and procedures are not useful for making a positive sleep and mood disturbances.13 Growth hormone is diagnosis, but are required to evaluate the patient secreted during sleep; the deficiency of serotonin in for co-morbid conditions or to identify other reasons FMS leads to sleep disturbances and possibly to the decrease in growth hormone secretion. Interleukin-8 levels are increased in FMS patients and related to pain intensity, suggesting a role for cytokines in the FMS is above all else a chronic muscular pain syndrome,6 but it is associated with a number of other symptoms that include sleep disturbance and fatigue, favourable than initially thought. Symptoms may headache, morning stiffness, irritable bowel persist for years, but patients either learn to cope syndrome (IBS), interstitial cystitis (IC), dyspareunia, with the chronic pain, or the pain does not progress.
and mood disturbance. Some of these symptoms are A substantial percentage of FMS patients reported manifestations of referred muscle pain from some lessening of pain over the years, even though myofascial trigger points (headache, dyspareunia, they were still symptomatic. Functioning improves morning stiffness), and others, like IBS and IC are over the years, particularly in the older population viscerosomatic pain syndromes,7 that occur more (55 to 64 years old), possibly because of more frequently in persons with FMS (up to 70% in FMS effective coping skills. Symptoms decrease with age, patients). The viscerosomatic syndromes are by no and older patients have less pain, depression, illness means unique to FMS, and are usually associated ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm for the use of tramadol, selective serotonin reuptake Treatment of fibromyalgia has included a wide inhibitors, selective serotonin and norepinephrine variety of pharmacological, nutritional, hormonal, reuptake inhibitors, and certain anticonvulsant drugs.
behavioural, cognitive, exercise and physical Moderate evidence also exists for the efficacy of modalities. Extensive experience in the use of strength training, acupuncture, hypnotherapy, antidepressants in the treatment of FMS has biofeedback, massage and warm water baths. Many accumulated over the years. Amitriptyline potentiates commonly used treatments were found not to have the analgesic effect of opioids, and it, as well as other tricyclic antidepressants and the new antidepressants, venlafaxine and duloxetine, inhibit the re-uptake of Myofascial Pain Syndrome
serotonin and norepinephrine at neuronal terminals.
Amitriptyline at 25-50mg at bedtime produces initial MPS is a muscular pain syndrome that arises from a improvement that has not been shown to be sustained primary dysfunction in muscle and yet is associated more than six months.15 The new serotonin and with central sensitisation and a segmental spread norepinephrine reuptake inhibitor duloxetine, and within the spinal cord to give rise to the phenomenon the new anticonvulsant pregabalin have both been of referred pain, or pain that is felt at a distance.18 shown to be effective in reducing the symptoms of The clinical picture of MPS is one of musculoskeletal FMS. Antidepressant treatment improves sleep, pain, limited mobility, weakness and referred pain.19 fatigue, pain and wellbeing, but does not change There may be clumsiness and in-coordination as tender point counts. A problem with the clinical trials well. The specifics of the MPS in a given individual of tricyclic antidepressant therapy is that they are of are dependent on which muscles are involved.
short duration. Only one study lasted 6.5 months, Involvement of the muscles of the head, neck and and it showed no greater effectiveness for shoulders gives rise to headache and neck and shoulder pain. Involvement of the pelvic floor muscles causes pain referred to the viscera (bowel, hormone (GH) replacement in the subset of about bladder and genitourinary tract organs). Hamstring one in three FMS patients who have a demonstrated muscle involvement can impair sitting because of deficiency of GH or insulin-growth-factor-1. The pain felt at the ischial tuberosity, and can also cause treatment is expensive, and is of benefit only as long pain that is felt behind the knee. Pain can be felt at the as the replacement is given. Thyroid hormone site of the muscle dysfunction, called the Myofascial replacement is likewise beneficial in those patients Trigger Point (MTrP), and also in the region of who have demonstrated hypothyroidism, but there referred pain. For example, trigger points in the are no data that suggest that hypothyroidism is more subscapularis muscle can cause both local shoulder common in FMS than in the general population. Graded, progressive exercise programmes provide The features of the trigger point itself comprise both short and long-term improvement in FMS.
both a taut band and pain. This duality of the MTrP Cognitive therapy is effective when combined with emphasises the two main characteristics of the MTrP: exercise. Supplements such as guaiphenesin and a motor or architectural abnormality and a painful sensory dysfunction. The motor abnormality is an magnesium, and S-adenosylmethionine (SAMe) are abnormal hardness in the muscle that is felt on commonly used, but there are few data to show that palpation of the muscle. One or several bands within they are effective in the management of FMS.16 A the muscle are felt to be hard, stiff or taut. The usual committee of the American Pain Society recently description is that of a taut band. It is discrete within reviewed the evidence for effectiveness of currently the muscle, and generally extends the full length of available treatment recommended for fibromyalgia.17 the muscle between tendons or tendinous bands (like They found strong evidence to support the use of low the inscription bands in the rectus abdominis or dose tricyclic antidepressants and cylcobenzaprine, hamstring muscles). The entire muscle is not hard cardiovascular exercise, cognitive behavioural therapy, or cramped, nor is it tender. The exquisite tenderness and patient education. There was moderate evidence ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm Figure 1 This image shows how a taut band in the upper trapezius fibres is palpated and fixed to allow safe dry needling of the trigger point with an acupuncture needle. The taut band is the primary identifiable abnormality times that of normal end plate potential discharges.
accessible to physical examination in the muscle, They are likely to occur as the result of an abnormally and may be present without tenderness. However, excessive, spontaneous release of acetylcholine from tenderness in MPS is not present without a taut band.
the synaptic terminal of the motor nerve fibre. This The clinical diagnosis is made by physical has not been proven, however. The taut band has the characteristic that when it is stimulated mechanically Identification of the trigger point by physical it contracts sharply. Mechanical stimulation, either by examination has good inter-rater reliability.20 A strumming the taut band or by needling it, results in characteristic electromyographic discharge termed a mechanical deformation of the band. A sharp spontaneous electrical activity (SEA) is associated contraction of the muscle in response to needling is with the taut band. The term SEA has been replaced seen on electromyographic recordings as a high by the more accurate term ‘end plate noise’. Low amplitude (1-2mV) polyphasic discharge of up to amplitude (10-50PV) discharges are present in the 250 milliseconds duration. It is maximally elicited taut band, whether painful or not. Intermittent high from the most tender region of the taut band, amplitude (up to 500PV) discharges are seen in diminishes with increasing distance from that point, painful trigger points. The electrical discharges have and is not elicited when recording from normal the characteristics of miniature end plate potentials muscle as little as 10mm from the taut band. Endplate except that they occur with a frequency that is 10-100 noise is reduced by as much as 22% by the infusion of phentolamine – an alpha 2 presynaptic blocker that inhibits adrenergic sympathetic activity.21 Table 2 Essential diagnostic features of myofascial pain
Phentolamine causes an increase in the release of norepinephrine into the synapse by blocking the tenderness in the hardened or taut band of muscle norepinephrine. Beta adrenergic receptors can be reproduction of usual or spontaneous pain stimulated by this action, as for example in the heart.
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www.medical-acupuncture.co.uk/aimintro.htm Thus, the abnormal spontaneous electrical activity Table 3 Causes of persistent myalgia
associated with the taut band is modulated by the sympathetic nervous system, most likely by activity Category
of adrenoreceptors on the motor nerve terminal.
The sensory abnormality is that of muscle tenderness, felt as both local and referred pain.
Experimental models of muscle pain demonstrate that central sensitisation occurs in response to noxious stimulation in the presence of a persistent irritating stimulus, such as an injection of bradykinin into the muscle. This results in lowering the threshold for pain and increasing the number and size of the receptive fields to which a single dorsal horn nociceptive neuron responds (Mense et al Muscle spinal curvature, and to level the eyes with the Pain p 84-98).18 In the human, this is expressed as horizon. The shoulder and neck muscles must level hypersensitivity or allodynia, manifest as tenderness, the head. Chronic muscle contraction to bring the spontaneous pain, or referred pain. The relationship spine back to the midline can produce trigger points between the taut band and pain is explained by the and myofascial pain. Thus, a local or regional integrated hypothesis of Simons (Mense et al Muscle myofascial syndrome can spread through the body Pain p 252-7).18 In this hypothesis, an excess release and become a widespread myofascial syndrome of acetylcholine at the motor end-plate results in the creation of taut bands in the affected muscle that compress capillaries thereby decreasing local blood Non-structural perpetuating factors flow and causing ischemia. Ischemia limits the Medical factors that result in neurological functional availability of oxygen and glucose, thereby creating impairment include vitamin B12, other vitamin an energy crisis in the working muscle. As a result, insufficiency states, iron insufficiency, thyroid potassium, histamine, substance P and other deficiency states, and chronic infections, such as excitatory substances that activate peripheral nerve Lyme disease, and recurrent Candida albicans nociceptive receptors are released, stimulating dorsal horn nociceptive neurons and causing pain.
Vitamin B12 deficiency is a common problem Myofascial pain spreads through the involvement that affects an increasing percentage of persons over of functional muscle units, or muscles that work the age of 65 because the synthesis of intrinsic factor together either as agonists or antagonists. An MTrP decreases with age. As many as 15-20% of persons restricts the range of motion related to a specific over the age of 65 are estimated to be deficient.22;23 muscle, and weakens the muscle. Compensation for Moreover, the pathways of absorption and utilisation the impaired function of the muscle loads other are complex and there are many mutations that can muscles in the functional unit. For example, if the occur that reduce absorption or metabolic activity.
upper trapezius muscle is impaired because of Folic acid corrects the anaemia of B12 deficiency, myofascial trigger points, the levator scapulae muscle but not the neuromuscular deficit. Thus, pernicious will be overloaded in controlling scapular motion, anaemia is a marker of B12 deficiency, but is not and the posterior cervical muscles like the adequate alone because B12 deficiency exists in the semispinalis capitis will be overloaded in extending absence of anaemia. The non-haematological the neck. Myofascial pain can also spread through manifestation of B12 deficiency is nerve dysfunction axial dysfunction. Trigger points in the psoas or in the brain (cognitive impairment), the spinal cord quadratus lumborum muscles can produce a pelvic tilt (combined degeneration of the cord), and in the that looks like a leg-length inequality, causing peripheral nerve (neuropathy). It is likely that the scoliosis. Shoulder tilt occurs to accommodate the peripheral neuropathy is linked to the diffuse myalgia ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm that is sometimes seen in B12 deficiency and that 25ng/ml in 60% of cases, and below 50ng/ml in 83% improves with B12 replacement. If serum B12 of cases studied.26 This suggests that not only are concentration is below 300pg/ml, methylmalonic serum ferritin levels below 20-25ng/ml clinically acid and homocysteine are good markers for significant in restless legs syndrome, but that levels metabolic abnormalities caused by B12 insufficiency.
below 50ng/ml are possibly clinically significant and However, there may be metabolic abnormalities of likely to be suboptimal. One cannot make a direct B12 function even in the absence of elevations of relationship from these data to determine the optimal levels of ferritin in the development of muscle pain, Iron deficiency in muscle occurs when muscle but this gives some general guidance as to what might ferritin is depleted. This occurs at serum ferritin be considered minimally optimal and suboptimal levels of about 15ng/ml. The prevalence of iron deficiency in females age 12-49 is 9-16%. It is higher A deficiency of freely accessible iron in muscle in African-Americans and Hispanics (19-22%). Iron creates an energy crisis in muscle by limiting an is essential for the generation of energy through the energy producing reaction. In this way, iron cytochrome oxidase enzyme system. Iron deficiency deficiency can be a factor in the development or causes fatigue, poor endurance and can cause muscle maintenance of myofascial trigger points. Moreover, pain. Replacement is available both by the oral and with respect to the role that iron plays in contributing to a sleep disorder through producing restless legs Iron deficiency has been generally defined as a syndrome, there is a connection between iron level of iron that is associated with anaemia. Levels deficiency, sleep deprivation and myalgia. Restless vary with age and sex, falling in adolescence with legs syndrome is associated with a sleep disturbance increased growth and, in girls, with the onset of or sleep deprivation, with reduced levels of, or menstrual blood loss. Iron stores rise again in absence of, deep sleep. Thus, iron insufficiency adulthood, and again in post-menopausal women.
associated with restless legs syndrome can be This variation is important in assessing iron stores as indirectly also associated with myalgia. a possible factor contributing to muscle pain, particularly in adolescent girls and in pre-menopausal musculoskeletal pain, loss of type II muscle fibres, women. Iron stores are assessed best by measuring and proximal muscle atrophy.27;28 Plotnikof and serum ferritin. Anaemia is associated with ferritin Quigley found that 89% of subjects with chronic levels below 10ng/ml.24 However, iron loss as musculoskeletal pain were deficient in Vitamin D.29 determined by low ferritin levels does not correlate The diagnosis was made by measuring 25-OH directly with anaemia. The first stage of iron loss is vitamin D. Values above 20ng/ml were considered associated with depletion of freely accessible iron normal. However, other studies suggest that levels stores in muscle, liver and bone marrow when the below 34ng/ml represent vitamin D deficiency.
serum ferritin level is about 15ng/ml. The second Vitamin D deficiency is easily detected by measuring stage of iron deficiency is erythrocyte microcytosis 25-OH vitamin D. The deficiency state is easily without anaemia. The third stage is anaemia, by corrected, but it takes up to six months of replacement which time iron bone marrow stores are undetectable.
to reverse changes caused by deficiency states. People Symptoms such as chronic tiredness, unusual fatigue not exposed to the sun are at great risk, including with exercise, and coldness begin with the first stage those whose clothes leave little skin exposed to the of iron loss. Optimum ferritin levels are unknown sun, and those who spend little time out of doors.
for normal muscle function, but Sun et al reported that in restless leg syndrome, another condition aggravated by iron deficiency or in some cases caused by it, serum ferritin levels below 50ng/ml were Observations of patients with chronic myalgia associated with a worsening of restless legs suggest that hypothyroidism is causally linked to this syndrome.25 In this same condition, but in adolescents condition. There is some evidence to support thyroid and children under the age of 18, the serum ferritin dysfunction in FMS, but little epidemiological level was below 20ng/ml in 50% of cases, below evidence to confirm the clinical impression that thyroid ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm dysfunction is associated with chronic myofascial of T3 is a factor that causes chronic muscle pain such pain syndrome. However, the absence of such data as FMS.32;33 Specifically, the issue is whether reverse may lie in flaws in the studies themselves. T3 blocks the effect of T3 at the cellular level, thereby Underactive thyroid function is a form of creating a peripheral hypothyroidism unrelated to hypometabolism. It can occur as a result of hypothalamic or thyroid gland function. There are insufficient production of T4, either because of conflicting data regarding the metabolic activity of insufficient secretion of thyroid releasing hormone rT3, and its action as an inhibitor of T3, capable of (TRH) as a result of a lack of hypothalamic producing a hypometabolic state. Another view is responsiveness, or because of thyroid disease itself, that rT3 is metabolically inactive, but is a marker such as Hashimoto’s thyroiditis. It also occurs for down regulation of the thyroid axis. In this because of impaired conversion of T4 to T3.
situation, elevation of rT3 signals an impairment of Conversion of inactive to active thyroid hormone is the feedback mechanism in which TSH rises when T3 the result of 5’-deiodination of T4 and occurs in the concentrations fall. These issues are important in liver.30 Peripheral suppression of thyroid hormone both MPS and FMS, because there are reasons to activity also occurs in ‘non-thyroidal illness believe that rT3 is increased in both conditions. syndrome’ (previously call the ‘sick euthyroid syndrome’). Acute and chronic stress also affects the b) Hypothyroidism and chronic and critical hypothalamic-pituitary-adrenal axis, which may in turn have several different effects on thyroid function.
Clinical hypothyroidism with normal levels of These effects include suppression of thyroid T3, T4 and TSH occurs in the so-called sick euthyroid stimulating hormone (TSH) resulting in decreased state often seen in chronic illness or in the Intensive release of T4 from the thyroid gland, and inhibition Care Unit in prolonged critical illness. This condition, of 5’-deiodinase I, thereby decreasing the peripheral also known as non-thyroidal illness, has bearing on conversion of inactive T4 to active T3.31 In addition, the postulated hypothyroid hypometabolic state of reverse T3 (rT3) is increased, at least in the acute FMS, with normal laboratory parameters of thyroid stress response. Chronic stress can also result in function (TSH, T3, T4). This issue has not been hypoactivation or suppression of the hypothalamo- addressed so directly in MPS, but if both MPS and pituitary-adrenal axis, causing a decrease in cortisol FMS, when chronic, have a similar underlying basis releasing hormone (CRH). This in turn results in the of central hypersensitivity, and if both are initiated by decrease in glucocorticoid production and a an acute or recurring energy crisis, then a postulated secondary increase in auto-immune disorders such as hypothyroid hypometabolic state becomes relevant The relationship of hypothyroidism to muscle Tissue thyroid levels are reduced in prolonged pain is complex because there is a controversy over critical illness. Evidence suggests that there is a central the mechanism of so-called hormone resistant neuro-endocrine failure, at least in part at the level of hypothyroidism due to peripheral blocking of T3 activity, and over its relationship to the development responsiveness to other factors such as growth of myalgia. Few would argue about whether hormone.34 On the other hand, non-thyroidal illness hypothyroidism associated with an elevated TSH syndrome with low levels of T3 and T4 can be an should be treated. In normal individuals whose TSH acute response to stress. Possible causes of this levels are under two units, slight elevations of the phenomenon range from a decrease in the deiodination TSH often indicate mild hypothyroidism. These of tetra-iodothyroxine by 5’-deiodinase to make tri- patients often complain of fatigue, feel cold, tend to iodothyroxine, inhibition of T4 and T3 binding be constipated, have dry skin, and muscle pain.
proteins, or the action of circulating cytokines. A study Treatment with a thyroid supplement that reduces of healthy individuals undergoing elective abdominal the TSH level to 1.5 units or less will often improve surgery explored the response of thyroid function to these symptoms, and render the muscle more acute stress. There was a decline of T3 starting 30 responsive to treatment. A controversy exists over minutes before the skin incision was made that whether hypothyroidism responsive to large doses continued throughout the postoperative observation ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm period. An early rise in TSH attenuated the decline This question of the role of rT3 has been looked at in of T3 after eight hours. T4 rose soon after the skin non-myalgic illness. Reverse T3 has been shown to incision and remained elevated. Reverse T3 rose six be a marker for increased mortality after acute hours after surgery and remained elevated. Serum myocardial infarction.38 T3 was slightly reduced in cortisol levels rose rapidly after entering the operating suite and remained high thereafter. Cytokine responses considerably increased, and T4 was slightly were mixed, interleukin-6 (IL-6) rising two hours increased, signifying reduced conversion of T4 to after skin incision and tumour necrosis factor alpha T3. TSH was slightly lower in the MI patients than (TNF-1 alpha) not rising at all. The rapid rise in in the controls. However, only the increased levels of cortisol was hypothesised to cause the fall in T3 in rT3 and T4 correlated with increased mortality.
this acute syndrome.35 In another study of the euthyroid Despite reports that intravenous T3 was beneficial in sick syndrome that was created experimentally by animal studies of myocardial infarction, T3 isolated limb perfusion with TNF-alpha, there was a administration to patients undergoing cardiac bypass rapid fall in T3, rT3, T4 and thyroxine-binding surgery did not improve outcome.38 The authors globulin (TBG), whereas free T4 (fT4) showed a speculated that rT3, usually considered to be an sharp rise. T3 remained low, but rT3 rose over 24 inactive metabolite, has biologic activity, perhaps hours. TSH declined initially, but rose progressively to greater than pre-perfusion levels and remained On the other hand, a study correlating molecular elevated over one week. Cortisol or IL-6 was thought modelling of thyroid hormone metabolites with the to be related to the decline in T3 and T4 levels.
known inhibition of gamma-aminobutyric acidA Recovery was thought to be TSH dependent, because (GABAA) by T3 showed only a weak effect of rT3, its rise preceded the rise of T4 and T3.36 Thus, in the and made the point that the molecular configuration sick euthyroid syndrome, the decline in T3 function of rT3 was less rigid than native T3, so that there is appears to be related to an initial fall in T3 levels, and greater flexibility between the two aromatic rings, a decline in the conversion of T4 to T3, and might be thereby affecting ion channel activity and GABAA a response to a rise in cortisol levels. activity.39 This study suggests that rT3 is biologically inactive at least some of the time. Finally, it is thought that in inflammatory stress conditions, cytokines can The role of rT3 in non-thyroidal illness remains unclear. Changes in rT3 may be a marker of non- The question of the relationship of the factors specific response to acute or chronic stress. For that produce a hypometabolic state to chronic myalgia example, rT3 was elevated in females with ankylosing as a result of stress will now be addressed.
spondylitis, whereas FT3 and FT4 and total T3 were Hypothalamic-pituitary-adrenal axis response to significantly lower. TSH and total T4 were normal.
stress has been well studied in the acute stress state.
Antithyroid antibodies were elevated as well.37 TSH Disorders of this axis have been implicated in the response to thyrotropin releasing hormone (TRH) development of FMS.13 The acute state is associated was normal. It was not stated in this study whether with activation of the hypothalamic-pituitary-adrenal the AS subjects were clinically hypothyroid. The axis and an increase in CRH. Glucocorticoids are controversy is whether rT3 is metabolically active or increased, suppressing the immune system, and by a not, and if it is an inhibitor of T3, thereby producing feedback mechanism, lead to termination of the acute a hypometabolic state. The alternative view is that stress response. Moreover, glucocorticoids also rT3 is metabolically inactive, but is a marker for down- decrease growth hormone secretion and inhibit regulation of the thyroid axis as illustrated in the above somatomedin C, both phenomena known to occur study. In this view, elevation of rT3 indicates that the in FMS, but not really well studied in MPS. The feedback mechanism in which TSH rises in response adrenergic system (locus coeruleus-norepinephrine to lowering of T3 is impaired. This controversy is system) is also activated. Release of beta-endorphins important in both MPS and FMS, because there are from the hypothalamus in the acute stress response reasons to believe that rT3 is increased in both suppresses pain perception. Activation of the hypothalamic-pituitary-adrenal system also centrally ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm suppress TSH production and inhibit the peripheral that nearly 10% of Caucasians had FMS, about 2-3 conversion of T4 to T3, producing the non-thyroidal times the expected prevalence in the general illness syndrome. Cytokines are potent activators of population. The prevalence was much lower in the stress response. Tumour necrosis factor alpha African-Americans and in Hispanics, with an overall (TNF-alpha), IL-6 and interleukin 1 alpha are known prevalence of 5%, a little more than has been reported to stimulate the hypothalamic-pituitary-adrenal in general studies (2-4% prevalence in various system. They have also been implicated in inhibiting studies). FM correlated best with Caucasian ethnicity, anxiety, or affective disorder. It did not correlate with As suggested by the above studies, rT3 elevation SLE clinical activity, specific organ damage, or is a non-specific response to both chronic illness and serologic features.4 Thus, SLE is appropriately acute stress. The question remains unanswered considered in the Caucasian sub-population of FMS whether rT3 is functioning as a blocker to the action patients. However, it is unknown in how many SLE of T3 by competing for T2 receptors at the cellular patients SLE is the presenting manifestation.
level, resulting in hypothyroidism, and whether such Moreover, the course of FMS and SLE do not seem an effect, if present, can be overcome by increasing TSH levels or by T3 supplementation.
Finally, the relation of chronic infection to myalgia (both MPS and FMS) is interesting. The investigation of specific conditions is warranted when the history is compatible with such a diagnosis. This associated with FMS. Measurements of insulin-like concept was dramatically illustrated in a competitive growth factor-1 (IGF-1) show a deficiency in about athlete who swam in ponds and lakes throughout the 30% of FMS patients.42 GH deficiency syndromes United States over a period of time. This athlete share many characteristics with FMS. GH secretion complained of fatigue and diffuse muscle pain. Two may be impaired secondary to a variety of physical protozoan infections, including amoebiasis, and Lyme and psychological stressors. It is a treatable condition, disease were found. Chronic Lyme disease was the and therefore worth investigating in FMS who do specific factor causing muscle pain and fatigue.
not have other identifiable causes or co-morbidities.
Common considerations in the United States include Whether patients with FMS and GH deficiency have parasitic infections, Lyme disease, chronic one disease (GH deficiency), or have FMS made mycoplasma infections, and enteroviruses. worse by GH deficiency, is a moot point. The point made by Bennett is that treatment with GH results in combination of myalgia and arthralgia, fatigue and clinical improvement.42 However, a study of impaired cognition, all features seen with FMS.
premenopausal women showed no association Treatment of such persons is difficult. The chronic between FMS and IGF-1 casting doubt on the validity state, sometimes referred to as Post-Lyme disease of this association in this age group.43 The authors syndrome or Post-treatment Lyme disease syndrome, point out that older age and obese populations have failed to show an improvement in cognition, but did lower activity of the GH-IGF-1 axis, and that these show improvement in fatigue, after prolonged conditions must be considered when studying the treatment with either 30 days intravenous ceftriaxone GH-IGF-1 axis in FMS subjects. Thus, it can be said followed by oral doxycycline, or 28 days of that GH deficiency produces a syndrome much like intravenous ceftriaxone.45;46 However, macrolide FMS, but it is far from clear whether a subset of antibiotics are less active at acidic pH, and poor FMS patients can be said to have FMS as a result of responses such as those just cited, may be due to impaired GH secretion. Moreover, the sub- localisation of the spirochete in an acidic endosome.
populations of FMS patients where this might apply Macrolide antibiotic activity, but not that of the tetracyclines, may be enhanced by alkalinisation with hydroxycholoquine.47 Other diseases that look like Lyme disease, but that are treated differently, A study of the connective tissue disorder systemic like Babesiosis and Ehrlichiosis, should also be lupus erythematosis (SLE) and fibromyalgia showed considered in persistent and difficult cases. ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm Enterovirus infection has been investigated in FMS are necessary to identify metabolic, hormonal or and chronic fatigue syndrome (CFS) patients by nutritional disorders that are important in chronic polymerase chain reaction (PCR) assays of muscle myalgia. Depending on the direction of investigation biopsy tissue. A number of studies have shown a suggested by the history and physical examination, significant increase in the prevalence of PCR positive the laboratory tests in Table 4 are useful in the samples for enterovirus, and positive neutralising evaluation of chronic myalgia, including both MPS antibody for Coxsackie B virus, in patients with chronic and FMS. Generalised or widespread muscle pain is fatigue syndrome, ranging for 20% to 58%, compared more likely to be metabolic, whereas structural or to controls showing 0-9% positive.48;49 In one study of mechanical factors are often seen with focal myalgias.
FMS patients, 13% (4 out of 30) were positive for The exception is hypermobility syndromes that can be enterovirus, compared to none of 29 controls.50 associated with generalised MPS. Iron insufficiency However, another study failed to show evidence to is usually restricted to women, and is generally seen support a role of persistent enteroviral infection in in men only when there has been gastrointestinal CFS patients, but could not exclude the possibility of blood loss from ulcers or cancer, or from taking non- such an infection being an initiating factor.51 This is steroidal anti-inflammatory drugs. Vitamin B12 an interesting etiologic consideration, but as of now, of deficiency is far more prevalent than one might think, little practical clinical use, since muscle biopsy is not and approaches 15 percent of persons with chronic routinely done in FMS patients, and there is no specific MPS. Metabolic abnormalities can be seen at levels treatment for enterovirus infection.
as high as 350pg/ml. Folic acid metabolism is closely linked to that of vitamin B12, and should also be measured. Other vitamin deficiency states such as The history gives clues about structural and metabolic vitamin C and vitamins B1 and B6 can also be or nutritional problems that lead to further, focused associated with widespread myalgia. Vitamin D levels examinations. The physical examination is the place below 32pg/ml have been found to be associated to look for scoliosis, leg length inequality, pelvic with musculoskeletal pain. Hypothyroidism is a major torsion, and hypomobility and hypermobility of joints.
consideration because it produces a hypometabolic Imaging studies are often not necessary for this state thought to promote trigger point formation.
purpose, though they play an important role in Values of thyroid stimulating hormone (TSH) in the identifying co-morbid conditions. Laboratory tests upper half of the normal range (above 2.5 Table 4 Laboratory investigations for chronic FMS and MPS
tissue stores are depleted at levels of 15-20ng/ml impairment at levels as high as 350pg/ml. Follow-up testing includes serum methylmalonic acid and homocysteine.
Either may be elevated in vitamin B12 deficiency folic acid metabolism is closely linked to vitamin B12 action normally generally below 2.5 ISU. Careful history and physical examination often show signs of hypothyroidism inpersons whose TSH level is in the upper normal range levels below 32ng/ml are seen in symptomatic individuals ELISA confirmed by Western blot. Also test for Ehrlichiosis, Babesiosis and Bartonella – may simulate Lyme Disease or co-exist with it ACUPUNCTURE IN MEDICINE 2005;23(3):121-134.
www.medical-acupuncture.co.uk/aimintro.htm international standard units) should lead to careful needle is inserted into subcutaneous tissues about evaluation of possible clinical hypothyroidism.
4mm overlying the trigger point, is another means Infectious diseases can cause widespread pain, whereby the myofascial trigger point can be particularly Lyme disease. Hepatitis C has been inactivated.54;55 Acupuncture has also been used to associated with fibromyalgia. Connective tissue treat myofascial pain syndrome. There are few diseases such as lupus erythematosus have also been controlled or blinded studies to rely upon. However, there is some indication that acupuncture may be effective in treating some myofascial pain Treatment of myofascial pain requires the inactivation of MTrPs, the restoration of normal muscle length, stresses that may cause or aggravate trigger point and the elimination or correction of the factors that formation and activation must also be addressed and created or perpetuated the trigger points in the first corrected or alleviated. Once trigger point pain is place. Manual therapy to do this includes trigger reduced and perpetuating factors are addressed, a point compression, often accompanied by a short physical conditioning programme can strengthen excursion of the appropriate body part actively to muscle, increase endurance, and perhaps reduce the slightly lengthen and shorten the muscle. MTrP pain possibility of reactivating the trigger points.
will usually subside within 20-30 seconds, the referred pain will disappear, and finally the taut band Conclusion
will relax, if not go away, within about a minute.
Patients with myalgia can have many co-morbid The taut band of muscle is stretched locally along conditions that perpetuate or aggravate their muscle its long axis for a distance of a few inches. This local pain. Such conditions may cause myalgia in the first stretch is not across a joint. A myofascial release place, or interfere with the recovery or treatment technique is applied to the muscle to stretch the fascia, process. Identification of such conditions should be moving over the skin away from the trigger point.
undertaken in all chronic cases of myalgia. In some A larger range therapeutic stretch is applied, to stretch cases, an obvious structural abnormality can be the muscle across the joint or joints associated with identified by physical examination. In other cases, the muscle, e.g. the hip and knee for the rectus detailed history-taking and laboratory examination femoris muscle. These stretches must be muscle may be required. Multiple co-morbidities are not uncommon, particularly the combination of a MTrPs can also be inactivated by inserting a structural imbalance and a medical condition.
needle into the trigger zone or point (Figure 1). This can be done with or without the injection of local Reference list
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Material Safety Data Sheet MSDS ID: SK-114 PRODUCT: Spectral-DNCL * * Section 1 - Chemical Product and Company Identification * * * Chemical Name: Spectral.DNC-L Product Use: Hair Growth Stimulating Lotion * * * Section 2 - Composition / Information on Ingredients * * * Component Information/Information on Non-Hazardous Components: This product is non-hazardous and is not