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Current Concepts in the Pathophysiology ofAbnormal Pain Perception In Fibromyalgia
Current Concepts in the Pathophysiology of Abnormal Pain Perception In Fibromyalgia DOUGLAS A. WEIGENT, PHD, GRACIELA S. ALARCON
LAURENCE A. BRADLEY, PHD,
ABSTRACT: Fibromyalgia is a noninflammatory rheumatic disorder characterized by chronic widespread musculoskeletal pain. Although many studies have described the pain and other clinical symptoms associated with this disorder, the primary mechanisms underlying the etiology of fibromyalgia remain elusive. This article reviews recent data supporting the links among each of three systemsthe musculoskeletal system, the neuroendocrine system, and the central nervous system (CNS), all of which appear to play major roles in fibromyalgia pathophysiology-and pain in fibromyalgia, and concludes by presenting a model of the pathophysiology of abnormal pain perception in fibromyalgia which integrates the research findings described. KEY INDEXING TERMS: Fibromyalgia; Abnormal pain perception; Musculoskeletal system; Neuroendocrine system; Central nervous system. [Am J Med Sci 1998;315(6):405-412.]
F
ibromyalgia (FM) is a noninflammatory rheumatic disorder characterized by chronic, widespread musculoskeletal pain. Although many studies have described the pain and other clinical symptoms associated with this disorder, the primary mechanisms underlying the etiology of FM remain elusive. 1 ,2 Nevertheless, the contributors to this issue of the Journal have identified three areas-the musculoskeletal system, the neuroendocrine system, and the central nervous system (CNS)-that appear to play major roles in the pathophysiology of FM. We will now review the recent data supporting the From the Department of Medicine, Division of Clinical Immu· nology and Rheumatology, and the Departments of Physiology and Biophysics, The University of Alabama at Birmingham, Bir· mingham, Alabama. Correspondence: Laurence A. Bradley, PhD, 615 MEB, UAB, Birmingham, AL 35294. Email: [email protected] THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
J.
EDWIN BLALOCK, PHD,
links among each of these three systems and pain in FM, and conclude by presenting a model of the pathophysiology of abnormal pain perception in FM which integrates the research findings described below. Musculoskeletal System
Because muscle pain is the primary symptom of FM, early investigators thought it logical to assess whether the musculoskeletal system might be the origin of the disorder (see articles in this issue by Olsen and Park and by Simms). Indeed, several studies produced evidence that patients with FM exhibit abnormalities in muscle energy metabolism and muscle tissue oxygenation. 3 ,4 Other investigations found significant decreases in high-energy phosphate compounds as well as the appearance of ragged red fibers in the tender areas ofthe trapezius muscle of FM patients. 5 Together, these data have led to the hypothesis that local tissue hypoxia might contribute to the perceived weakness and pain associated with FM. Recent investigations with better experimental controls generally have failed to demonstrate differences between FM patients and sedentary control subjects in adenosine triphosphate levels, lactate levels, muscle tension or hypoxia, or intracellular pH. 6 ,7 Nevertheless, Olsen and Park described in this issue ofthe Journal the results of a study involving P-31 magnetic resonance spectroscopy (MRS) which showed that FM patients, compared to appropriately matched controls, exhibited significantly lower resting levels of phosphocreatine and adenosine triphosphate, as well as significantly higher levels of adenosine diphosphate, both of which are indicative of an abnormal bioenergetic status. These findings were not associated with evidence of inflammation, which suggests that biochemical abnormalities in the muscles of FM patients may playa role in the perceptions of weakness and fatigue of FM. In addition, European investigators have observed a pattern oflatent tetany and a reduced ability of the muscle to relaxs as well as a reduced blood level of calcium in a small number of patients with
405
Pathophysiology of Abnormal Pain Perception
Table 1. Endocrine Hormone Alterations in Fibromyalgia Hormone
Result
Reference
Plasma cortisol, peak (AM) Plasma cortisol, through (PM) Free cortisol (24 h urine) Circadian change ACTH (CRH stimulation) Cortisol response (CRH stimulation) Free T g , T. TSH
Normal Elevated Low Blunted Elevated Blunted Reduced Reduced Reduced Reduced High
10, 12, 13 12,13 12, 13 14 12,13 12,13 9
GH IGF-1
Prolactin
11
22 20 9
ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; TSH = thyroid-stimulating hormone; GH = growth hormone axis; IGF-l = insulin-like growth factor 1.
FM.9 The ongm of hypocalcemia in FM patients, however, was not elucidated. In summary, most of the well-controlled studies of muscle tissue in FM do not show strong evidence that defects in this tissue are a primary cause of the disorder. Nevertheless, a small number ofinvestigations suggest that biochemical abnormalities or alterations in muscle function may contribute to FM symptoms. These intriguing findings must be replicated, however, in independent and larger samples before they can be considered to be reliable. Neuroendocrine System
Over the past few years, several studies have indicated that a functional disturbance in the neuroendocrine system may contribute to the development of FM symptoms. This functional disturbance is characterized by a blunting of the stress response in patients with FM and involves the hypothalamicpituitary-adrenal axis (HPA) and its reciprocal interactions with the hypothalamic-pituitary-gonadal axis (HPG), the locus ceruleuslnorepinephrine (LCI NE) sympathetic nervous system, the hypothalamicpituitary-thyroid axis (HPT), and the growth hormone axis (GH).lO Table 1 summarizes the relevant findings produced by these studies. All investigations of the HPA axis in FM patients have produced evidence of primary adrenal insufficiency.ll,12 Thus, there is decreased production of cortisol in response to corticotropin-releasing hormone (CRH) or corticotropin (ACTH) and an exaggerated ACTH response to hypothalamic CRH. 13 ,14 The blunted cortisol levels are associated with a flattened diurnal secretion pattern. However, abnormalities in the HPA axis are also found in other stress-related disorders. 12 Indeed, in this issue of the Journal, Crofford suggests that FM may be part of a spectrum of stress-related disorders which also includes irritable bowel syndrome, chronic fatigue syndrome, and dysmenorrhea. 15
406
Similarly, studies of HPT axis function have shown that patients with FM display blunted secretion ofthyroid-stimulating hormone (TSH) and thyroid hormones in response to thyrotropin-releasing hormone (TRH), suggestive of a blunted pituitary response. 9 The secretion offree triiodothyronine (T3) and free thyroxine (T4) to TRH is poor,10 which suggests that the thyroid hormone profile might be due to a failure to deiodinate T4 to T3 in peripheral tissues or within the pituitary. Glucocorticoids may also be involved since they have been shown to inhibit the conversion of T4 to T3 and decrease the response of TSH to TRH.16 Finally, several studies have produced evidence of changes in the GHlIGF-I axis in FM patients. Growth hormone, which is involved in muscle homeostasis maintenance, is maximally secreted during stage 4 of REM sleep. However, as noted by Harding in this issue ofthe Journal, many FM patients display stage 4 sleep anomalies such as alpha wave intrusions during slow wave sleep.17,18 BennettI9 hypothesized that the sleep anomalies could disrupt the secretion of GH and indirectly confirmed this by showing low levels of IGF-I in patients with FM.20 Two subsequent reports 21 ,22 confirmed this finding; another did not. 23 Recently, Bennett et al produced evidence that the low IGF-I levels in patients with FM are a secondary phenomenon associated with hypothalamic-pituitary-GH dysfunction. 24 This dysfunction may be produced by chronic stress and low thyroid hormone levels in addition to sleep disturbances. 25 ,26 The clinical significance ofGH deficiency is that it may contribute to poor healing of muscle microtrauma and thereby to nociceptive transmission 27 by its influence on muscle metabolism. 28 ,29 In conclusion, it appears that in FM the pituitary release patterns of ACTH, TSH, and GH are altered and that the subsequent abnormalities in hormone levels may contribute to the spectrum of symptoms observed in patients. Although alterations in the neuroendocrine system are also found in other stress-related disorders,I5 the pattern of exaggerated ACTH response to CRH and the subsequent blunting of the cortisol response is unique to FM. It is necessary to determine how the HPA and GH axes are interrelated in FM and whether these interactions may contribute to the pain, fatigue, and other symptoms associated with this disorder. Central Nervous System NeurotransmiHer Abnormalities. Several investiga-
tors have evaluated differences between patients with FM and healthy controls in levels of neurotransmitters, brain hormones, and neuropeptides related to pain transmission or pain inhibition (Table 2). The earliest studies in this area focused on serotonin, given that this neurotransmitter is involved in both stage 4 sleep and pain modulation. 30 Russell et June 1998 Volume 315 Number 6
Weigent et 01
Table 2. Neuromediator Perturbations in Fibromyalgia Variable
Result
Calcium Serotonin Substance P Nerve growth factor Dynorphin A Calcitonin generelated peptide
Low Low Elevated (CSF) Elevated (CSF) Elevated (CSF)
41
Elevated (CSF)
42
CSF
=
Reference 9
31 35 40
cerebrospinal fluid.
aI, for example, found decreased levels of serotonin in the sera of FM patients and increased numbers of reuptake receptors for serotonin on platelets. 3l ,32 These investigators also reported that the cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-HIAA were significantly lower in FM patients than in controls; the same findings were observed in several serum amino acids including tryptophan, alanine, histidine, lysine, proline, serine, and threonine. 3l ,33 In a recent report by the same group, however, the serum levels of serotonin were not correlated with any clinical variables. 34 Investigators have devoted substantial attention to CSF levels of substance P (SP) in persons with FM, given that it serves as a nociceptive neurotransmitter at the dorsal horn level. Several studies have found that both patients with FM and community residents who meet diagnostic criteria for FM but who have not consulted physicians for pain (ie, who are non patients) exhibit significantly higher levels ofCSF SP than healthy controls. 35 - 37 Indeed, the SP levels in persons with FM are two to three times higher than those of controls. Substance P levels, however, are normal in serum and urine of FM patients. 35 Recent data produced by Russell's laboratory suggest that stress may potentiate the nociceptive effects of SP release in persons with FM; that is, it has been shown that activation of the CNS by stress stimulates mammotroph cells in the anterior pituitary to secrete nerve growth factor (NGF) and prolactin. 38,39 Consistent with these findings, Russell's group reported elevated CSF levels of NGF in patients with FM.40 Given that NGF regulates SP expression in sensory nerves and may inhibit the antinociceptive effect of SP metabolites,40 it is possible that stress may contribute to pain perception in individuals with FM through its effects on NGF. Russell has reported in this issue of the Journal that patients with FM also exhibit elevated CSF levels of calcitonin gene-related peptide (CGRP) and dynorphin A. 4l ,42 These findings are consistent with changes in CNS function that have been observed following injury. Under these circumstances, a series of events can occur which produce allodynia, a pheTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
nomenon by which formerly innocuous stimuli such as light touch or mild heat are perceived as painful. 43 One event is that new axon sprouts that are sensitive to stimulation often develop in the injured area of tissue. Spontaneous firings of these damaged nerves, as well as from the dorsal root ganglion, increase the neuronal barrage into the CNS and contribute to the perception of pain. Similarly, spinal dorsal horn neurons also show an increased excitability after injury which is characterized by an enlargement of their peripheral receptive fields and greater responsiveness to mechanical, thermal, and chemical stimuli. This process of central sensitization, which also leads to increased neural input, is mediated by the activation of neurons with Nmethyl-D-aspartate (NMDA) receptor sites by excitatory amino acids and enhanced by neuropeptides such as dynorphin, SP, and CGRP (Figure 1).43 Functional changes in peripheral or dorsal horn neurons have not been documented in patients with FM. However, Sprott et al recently observed collagen cuffs around the preterminal nerve fibers in skin samples obtained from the trapezius region in FM patients. 29 These collagen cuffs, which might lower the firing thresholds of the nerves, may have been produced by remodeling of the extracellular matrix by injury-related stimulation of local nociceptors which, in turn, stimulated the release of proinflammatory cytokines (eg, IL-1, IL-6, TNFa) by macrophages. It is possible, however, that the alterations in collagen metabolism mark an intrinsic defect in systemic crosslinking of collagen which renders individuals susceptible to the development ofFM. 28 We recently produced behavioral evidence of increased neural input in persons with FM that is consistent with the phenomenon of central sensitization. We administered standardized pain perception tasks under controlled laboratory conditions to patients and non patients with FM as well as healthy controls, and found a similar pattern of results. 44 Both FM subject groups, relative to the controls, exhibited significantly lower pain thresholds in response to mechanical stimulation at 10 tender points included in the diagnostic criteria for FM 45 and 10 control points. Moreover, both FM groups produced significantly higher scores than controls on an index of sensory discrimination derived from their intensity ratings of a wide range of standardized mechanical stimuli applied to the tender and control points. These findings suggest that stimulation of both sets of points produced substantially higher levels ofneural input in the patients and nonpatients with FM compared to the controls. 46 Moreover, given that FM patients tend to have much higher levels ofpsychiatric morbidity than nonpatients, our findings suggest that abnormal pain perception in FM cannot be explained solely by psychiatric illness. 47
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Pathophysiology of Abnormal Pain Perception
Tissue or Nerve Injury
Increased Neural Activity at Site of Injury
1
Excitatory amino acid release neuropeptide release (Dynorphin, SP, CGRP)
Increased Depolarization at NMDA Receptor Sites in Dorsal Horn Excessive Depolarization
t
Excitotoxicity
tI
Cell Dysfunction
_ _-I~~
Expanded Receptive Fields and Hyperexcitability
Figure 1. Changes in the nervous system after injury. The hyperexcitability involves activation of neurons at N-methyl-Daspartate (NMDA) receptor sites by excitatory amino acids. The release of excitatory amino acids from presynaptic sites and their effects on dorsal horn neurons are enhanced by neuropeptide transmitters such as dynorphin, substance P (SP), and calcitonin gene-related peptide (CGRP). (Reprinted with permission from Pillemer SR, Bradley LA, Crofford LJ, Moldofosky H, Chrousos GP. The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum 1997;40:1928-39.)
Loss of Inhibition
Increased Pain
Functional Brain Activity Abnormalities. Our laboratory has produced evidence that abnormalities occur in the functional activity of the brain as well as in neurotransmitter levels among persons with FM. As documented by Mountz et al in this issue ofthe Journal, we have consistently found abnormally low levels of regional cerebral blood flow (rCBF) in the thalamus and caudate nucleus of patients with FM during resting conditions. 48 The low level of caudate rCBF has been replicated in nonpatients with FM.37 We believe that low levels of functional activity (as measured by rCBF) in these brain structures probably represent a response to high levels of nociceptive neural input. As a consequence, the modulating actions of these structures on nociceptive transmission are compromised, thereby contributing to the low pain thresholds and other abnormal pain perceptions exhibited by persons with FM. We currently are examining functional activity levels in the thalamus and caudate nucleus as well as in several other brain structures which process the affective-motivational dimension of pain (eg, cingulate cortex) in patients with FM, chronic fatigue syndrome, or major depression. We are performing the evaluations un-
408
der resting conditions and during painful stimulation in order to determine to what extent these disorders overlap with one another with regard to abnormalities in brain function. eNS Interactions with the Immune System. It has been proposed that viral infections may lead to persistent pathological changes in neuron metabolism, even when the infection itself is no longer present. 49 This is consistent with the report that as many as 55% of patients with FM attribute the initiation of their symptoms to a flulike febrile illness. 50 Several cytokines, including IL-l and TNFa, that are released after infection induce increased sleep, activate the HPA axis, and contribute to hyperalgesia. 51 Nevertheless, the possible role of the immune system in the pain ofFM has not been thoroughly investigated. Wallace et al reported that CD4+ cell numbers were higher in 60% of the FM patients compared to controls; circulating levels of IL-2 were elevated in 53% of the patients with FM.52 No study, however, has convincingly demonstrated a correlation between immune system parameters and disease severity. 53 The levels of CSF IL-l and TNFa, which are known to stimulate the release of NGF, have not been deJune 1998 Volume 315 Number 6
Weigent et al
~ectable among FM patients in very preliminary studies in our laboratory. Nevertheless, it has been shown that NGF synthesis in astrocytes can be stimulated by calcitriol and cytokines IL-l and TGF-,B.54 rhus, it remains necessary to determine whether ~he elevated CSF levels ofNGF and SP are initiated primarily by nociception-induced changes within the CNS, or if they may also be induced by alterations in peripheral IL-l or TNFa. The immune system also may be involved in endogenous pain control mechanisms. Using a rat model, it has been shown that during stress, CRH induces the release of opioid peptides within inflamed tissue. The opioid peptides bind to opioid receptors on sensory nerves and inhibit pain. 55 The mechanism does not involve IL-l,B, circulating CRH, or anti-inflammatory agents. Thus, it appears that pain can be diminished by local paracrine interactions of the immune system with peripheral sensory nerves. The results suggest that CRH originates from the inflammatory site and are consistent with previous data demonstrating the synthesis of CRH56 and endorphins 57 by cells ofthe immune system. 58 It remains to be determined if and how this peripheral defense mechanism may be linked to the perception of pain in patients with FM.
Etiopathogenesis of Abnormal Pain Perception in Fibromyalgia
We recently developed a preliminary model of the etiopathogenesis of abnormal pain perception in FM.59 Given the research efforts described above and in the other articles in this issue of the Journal, it is possible to refine our model (Figure 2). We propose that, consistent with the evidence described by Crofford in this issue, there is probably a genetic susceptibility to the neuroendocrine abnormalities associated with FM. These neuroendocrine abnormalities may also be influenced by infections and emotional trauma or other stressful events. The blunted neuroendocrine responses found in FM patients may be responsible for select symptoms such as fatigue and mood disturbances. However, these neuroendocrine responses, along with the stress-related sleep abnormalities described by Harding, also influence the activity of the GH axis and thus contribute to poor healing of muscle microtrauma and nociceptive transmission from peripheral nerve fibers to dorsal horn spinal neurons. There also may be a genetic susceptibility to the development of some structural defects of the CNS and the musculoskeletal system, such as Chiari malformation,60 which may result in nociceptive transmission. Physical trauma, stressful events, and infectious agents are environmental factors which also contribute to increased nociceptive transmission. Physical trauma directly stimulates peripheral nociceptors and, through release of cytokines, may contribute to THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
the development of altered collagen metabolism of peripheral nerve endings as well as muscle microtrauma resulting in nociceptive transmission. Physical trauma, such as cervical spinal injury, also may produce structural defects which activate peripheral nociceptors. 61 In contrast, infectious agents and stressful events appear to have indirect effects on nociception. Both of these environmental factors stimulate the production of NGF which regulates SP expression in sensory nerves. Thus, they may contribute to the hyperexcitability of dorsal horn spinal neurons (ie, central sensitization) by SP and other neuropeptides. It is clear from the preceding discussion that there are multiple endogenous and exogenous factors which may contribute to nociceptive transmission in persons with FM. Figure 2 suggests that the final common pathway for the actions of all of these precipitating factors is the process of central sensitization. We propose that in persons with FM, one or more of the precipitating factors contribute to the development of muscle microtrauma or other tissue injury which enhances nociceptive transmission from the periphery to the dorsal horn spinal neurons. Activation of neurons with NMDA receptor sites by excitatory amino acids, and the release of SP, CGRP, and dynorphin, leads to functional alterations in the dorsal horn spinal neurons which greatly increase nociceptive transmission to the brain. We also propose that, over time, functional alterations occur in the brain structures which are involved in modulating nociceptive input (eg, thalamus) and in processing the sensory-discriminative (eg, thalamus, caudate nucleus) and affective-motivational (eg, prefrontal cortex, anterior cingulate cortex) dimensions of pain. Moreover, the function of the latter structures, which are part of the brain limbic system, are influenced by alterations in the HPA axis. Indeed, we propose that the high level of perceived aversiveness which is generally associated with FM pain represents an emotional stressor which may contribute to the maintenance of HPA axis abnormalities. The endpoints of all of these processes are the abnormal pain thresholds found at multiple anatomic sites and the widespread pain ofFM. Clinical Implications of the Model. Although the above model does not account for all symptoms associated with FM (eg, those of irritable bowel syndrome), it does enhance our understanding of the difficulties involved in the attempts of patients and physicians to reduce the pain which characterizes this disorder. First, nociceptive transmission from the periphery may be initiated by more than one precipitating factor which then interact with each other. Careful medical and psychosocial evaluations of FM patients, therefore, are required to provide optimal treatment planning. For example, physical
409
Pathophysiology of Abnormal Pain Perception
Genetic Susceptibility
Infections.
Emotional Trauma.
'" cytokines
Stress
~
.--------.
Sleep Abnormalities
HPT
HPG
.-
AxIs
AxIs
....
+
HPA AxIs
1
Muscle Microtrauma
Physical Trauma
1,
'" cytokinas
r.=;;;;Ollagen Metabolism at Peripheral Nerve Endings
~-
Structural Defects
:
,
GH Axis
I.....r-.-T"I
~----------------~ LCINE Sympathetic NS
,L __________________________ ,L
B-G ,,"'CGRP, ~
'" Peripheral Nociceptive Transmission
, ~
__ J
'" Dorsal Hom Spinal Neuron ExcltabOity (CENTRAL SENSITIZATION'
1
'" Excitetory Amino Acids
'" rCBF Prefrontal Cortex '" rCBF Anterior Cingulate Cortex
Abnonnal Pain Thresholds and Generalized Persistent Pain
Figure 2. Model of the pathophysiology of abnormal pain perception in FM. Genetic factors, as well as several precipitating factors (eg, physical trauma, emotional trauma or stress, and infections), may contribute to abnormalities in the neuroendocrine axes, muscle tissue, peripheral nerve endings, and sleep. These abnormalities lead to hyperexcitability of dorsal horn spinal neurons through increased nociceptive transmission from the periphery to the dorsal horn or through stimulation of SP production. This produces a barrage of nociceptive input to the brain which eventually alters the function of brain structures that process the sensory-discriminative and affective-motivational dimensions of pain. The function of the latter structures is also influenced by and may influence alterations in HPA axis function. The endpoint of this process is abnormal pain thresholds and widespread persistent pain. In this model, solid lines between variables indicate relationships for which there is reliable empirical evidence; dotted lines indicate relationships for which there is only prelimiJ?-ary evidence.
trauma such as an assault upon a woman may directly induce nociceptive transmission and influence NGF production and neuroendocrine abnormalities through the emotional stress (eg, posttraumatic stress disorder) which can persist for extended periods after the assault. The emotional stress may be particularly severe among women whose coping resources have been compromised by the presence of psychiatric disorders which developed before the onset ofFM. Indeed, 50% to 75% ofFM patients studied 410
in our university-based rheumatology clinic reported that symptoms of their mood and anxiety disorders began before the onset of their pain. 47 Thus, recovery from the precipitating physical trauma may not produce a positive alteration in function ofthe HPA axis or growth hormone axis, and both psychological and medical intervention may be necessary for many women with FM who have been assaulted. The second difficulty in attempts to alleviate the pain of FM is that it is difficult to attenuate the June 1998 Volume 315 Number 6
Weigent et al
dorsal horn neuron excitability associated with the central sensitization process with present pharmacologic, behavioral, or surgical interventions. Further development of NMDA receptor antagonists and SP antagonists may lead to improved pain control in the future. 43 However, given the primary role that central sensitization may play in the production ofFM pain, it is not surprising that current pharmacologic treatments tend to show moderate effectiveness. These are largely psychotropic medications which alter levels of brain neuropeptides involved in endogenous pain control mechanisms and symptoms of depression or anxiety, but do not act at the dorsal horn level. Similarly, our model suggests that behavioral and cognitive-behavioral interventions often may help patients cope with or modify the intensity and aversiveness of their pain through reduction of emotional distress. However, these interventions should not be expected to greatly modifY the excitability of dorsal horn spinal neurons in most individuals (see review of treatment efficacy by Alarcon and Bradley in this issue). Finally, our model suggests that attempts to surgically correct structural defects in patients with FM for pain relief should be considered with great caution. Correction of these structural defects may not have a great effect on dorsal horn spinal neuron excitability, given the multiple factors which contribute to this phenomenon. More important, induction of additional trauma through surgery will alter sensory input and actually may contribute to the enhancement of the central sensitization process over time. Conclusion
Our knowledge regarding the pathophysiology of abnormal pain perception in FM has been greatly enhanced by the efforts of many investigators from diverse disciplines. The pathophysiologic model of abnormal pain perception presented in this article will certainly require revision as additional research findings are produced. At present, however, it offers a mechanism for generating testable hypotheses that may contribute to our understanding of pain in FM. It also provides a strong empiric basis for explaining to patients and healthcare professionals the causes of the persistent and unusual pain perceptions associated with this disorder. Finally, the model may help physicians and other scientists to develop improved treatments for pain that are based on our current understanding of nociceptive transmission and pain perception and which may be evaluated by appropriate scientific methods. Acknowledgments
Preparation of this article was supported by NIAMS Grant l-ROI-AR-43136-04, NIH Center Grant P60-AR-20164, and NCCR Grant 5 MOI00032, and THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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Pathophysiology of Abnormal Pain Perception
24.
25. 26. 27.
28.
29. 30. 31.
32.
33. 34. 35. 36.
37.
38.
39.
40. 41.
42.
aek NE. A controlled study on serum insulin-like growth factor-I and urinary excretion of growth hormone in fibromyalgia. J Rheumatol. 1995;22:1138-40. Bennett RM, Cook DM, Clark SR, Burckhardt CS, Campbell SM. Hypothalamic-pituitary-insulin-like growth factor-I axis dysfunction in patients with fibromyalgia. J Rheumatol. 1997;24:1384-9. Daughaday WHo The anterior pituitary gland. In: Wilson JD, Foster DW, eds. Williams Textbook of Endocrinology. Philadelphia: WB Saunders; 1992;568-613. Lowe JC, Cullum ME, Graf JrLH, Yellin J. Mutations in the c-erbAB 1 gene: do they underlie euthyroid fibromyalgia? Med Hypothesis. 1997;48:125-35. Bennett RM. The origin ofmyopain: an integrated hypothesis of focal muscle changes and sleep disturbance in patients with the fibromyalgia syndrome. J Musculoskeletal Pain. 1993; 1:95-112. Jacobsen S, Jensen LT, Foldager M, DanneskioldSamsoe B. Primary fibromyalgia: clinical parameters in relation to serum procollagen type III aminoterminal peptide. Br J Rheumatol. 1990;29:174-7. Sprott H, Muller A, Heine H. Collagen crosslinks in fibromyalgia. Arthritis Rheum. 1997;40:1450-4. Moldfosky H, Warsh J. Plasma tryptophan and musculoskeletal pain in non-articular rheumatism ("fibrositis syndrome"). Pain. 1978;5:65-71. Russell IJ, Vaeroy H, Javors M, Nyberg F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgialfibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992; 35:550-6. Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Javors MA, Bowden CA Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgialfibrositis syndrome. J Rheumatol. 1992; 19:104-9. Russell IJ, Michalek JE, Vipraio GA. Serum amino acids in fibrositis/fibromyalgia syndrome. J Rheumatol. 1989; 19: 158-63. Wolfe F, Russell IJ, Vipraio G, Ross K, Anderson J. Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J Rheumatol. 1997;24:555-9. Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum. 1994;37:1593-1601. Vaeroy H, Helle R, Forre 0, Kass E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud's phenomenon in patients with fibromyalgia: new features for diagnosis. Pain. 1988;32:21-6. Bradley LA, Alberts KR, Alarcon GS, Alexander MT, Mountz JM, Weigent DA, et al. Abnormal brain regional cerebral blood flow and cerebrospinal fluid levels of substance P in patients and nonpatients with fibromyalgia. Arthritis Rheum. 1996;39:S212. Aloe L, Bracci-Laudiero L, Alleva E, Lambiase A, Mic· era A, Tirassa P. Emotional stress induced by parachute jumping enhances blood nerve growth factor levels and the distribution of nerve grow.th factor receptors in lymphocytes. Proc Natl Acad Sci USA. 1994;91:10440-4. Missale C, Toroni F, Sigala S, et al. Nerve growth factor in the anterior pituitary: localization in mammotroph cells and cosecretion with prolactin by a dopamine-regulated mechanism. Proc Natl Acad Sci USA. 1996;93:4240-5. Giovengo SL, Russell IJ, Larson AA Increases in nerve growth factor concentrations in cerebrospinal fluid (CSF) of fibromyalgia patients (abstract). Pain. 1996; 66(suppl):225. Vaeroy H, Nyberg F, Terenius L. No evidence for endorphin deficiency in fibromyalgia following investigation of cerebrospinal fluid (CSF) dynorphin A and Met-enkephalinArg6-Phe7. Pain. 1991;46:139-43. Vaeroy H, Sakurada T, Forre 0, Kass E, Terenius L. Modulation of pain in fibromyalgia (fibrositis syndrome): ce-
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43. 44.
45. 46.
47.
48.
49. 50.
51. 52. 53. 54.
55.
56. 57.
58. 59. 60. 61.
rebrospinal fluid (CSF) investigation of pain-related neuropeptides with special reference to calcitonin gene-related peptide (CGRP). J Rheumatol. 1989; 19(suppl):94-7. Pillemer SR, Bradley LA, Crofford LJ, Moldofsky H, Chrousos GP. The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum. 1997;40:1928-39. Bradley LA, Alberts KR, Alarcon GS, et al. Abnormal neurosensory processing of dolorimeter stimuli in patients with fibromyalgia (FM): two-year reliability at tender and control points. Arthritis Rheum. 1997;40:S42. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Arthritis Rheum. 1990; 33: 160-72. Clark WC. The psyche in the psychophysics of pain: an introduction to sensory decision theory. In: Boivie J, Hansson P, Lindblom U, eds. Touch, Temperature, and Pain in Health and Disease: Mechanisms and Assessments. Seattle: IASP Press; 1994:41-62. Aaron LA, Bradley LA, Alarcon GS, Alexander MT, et al. Psychiatric diagnoses are related to health care seeking behavior rather than illness in fibromyalgia. Arthritis Rheum. 1996;39:436-45. Mountz JM, Bradley LA, Modell JG, et al. Fibromyalgia in women: abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels. Arthritis Rheum. 1995;38:926-38. Old stone MB, Sinha YN, Blount P, et al. Virus-induced alterations in homeostasis: alterations in differentiated functions of infected cells in vivo. Science. 1982;218:1125-7. Buchwald D, Goldenberg DL, Sullivan JL, Komaroff AL. The "chronic, active Epstein-Barr virus infection" syndrome and primary fibromyalgia. Arthritis Rheum. 1987; 30:1132-6. DunnAJ. The role ofinterleukin-1 and tumor necrosis factor alpha in the neurochemical and neuroendocrine responses to endotoxin. Brain Res Bull. 1992; 29:807 -12. Wallace DJ, Bowman RL, Wormsley SB, Peter JB. Cytokines and immune regulation in patients with fibrositis. Arthritis Rheum. 1989;32:1334-5. Clauw DJ. The pathogenesis of chronic pain and fatigue syndromes, with special reference to fibromyalgia. Med Hypothesis. 1995; 44:369-78. Hahn M, Lorez H, Fischer G. Effect of calcitriol in combination with corticosterone, interleukin-1 beta, and transforming growth factor-beta 1 on nerve growth factor secretion in an astroglial cell line. J Neurochem. 1997;69:102-9. Schafer M, Mousa SA, Zhang Q, Carter L, Stein C. Expression of corticotropin-releasing factor in inflamed tissue is required for intrinsic peripheral opioid analgesia. Proc N atl Acad Sci USA. 1996;93:6096-100. Aird F, Clevenger CV, Prystowsky MB, Redei E. Corticotropin-releasing factor mRNA in rat thymus and spleen. Proc Natl Acad Sci USA. 1993;90:7104-8. Harbour-McMenamin D, Smith EM, Blalock JE. B lymphocyte-enriched populations produce immunoreactive endorphin that binds to delta opiate receptors and may playa role in endotoxic shock (lCSU Short Reports). Adv Gene Technol Mol BioI Endocrinol Syst. 1986;4:378-9. Blalock JE. The syntax of immune-neuroendocrine communication. Immunology Today. 1994; 15:504-11. Bradley LA, Alarcon GS. Fibromyalgia. In: Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook ofRheumatology. Baltimore: Williams & Wilkins; 1997:1619-40. Alarcon GS, Bradley LA, Hadley MN, et al. Does Chiari malformation contribute to fibromyalgia (FM) symptoms? Arthritis Rheum. 1997;40:S190. Buskila D, Neumann L, Vaisberg G, Alkalay D, Wolfe F. Increased rates of fibromyalgia following cervical spine injury: a controlled study of 161 cases of traumatic injury. Arthritis Rheum. 1997;40:446-52.
June 1998 Volume 315 Number 6
LAURENCE A. BRADLEY, PHD,
ABSTRACT: Fibromyalgia is a noninflammatory rheumatic disorder characterized by chronic widespread musculoskeletal pain. Although many studies have described the pain and other clinical symptoms associated with this disorder, the primary mechanisms underlying the etiology of fibromyalgia remain elusive. This article reviews recent data supporting the links among each of three systemsthe musculoskeletal system, the neuroendocrine system, and the central nervous system (CNS), all of which appear to play major roles in fibromyalgia pathophysiology-and pain in fibromyalgia, and concludes by presenting a model of the pathophysiology of abnormal pain perception in fibromyalgia which integrates the research findings described. KEY INDEXING TERMS: Fibromyalgia; Abnormal pain perception; Musculoskeletal system; Neuroendocrine system; Central nervous system. [Am J Med Sci 1998;315(6):405-412.]
F
ibromyalgia (FM) is a noninflammatory rheumatic disorder characterized by chronic, widespread musculoskeletal pain. Although many studies have described the pain and other clinical symptoms associated with this disorder, the primary mechanisms underlying the etiology of FM remain elusive. 1 ,2 Nevertheless, the contributors to this issue of the Journal have identified three areas-the musculoskeletal system, the neuroendocrine system, and the central nervous system (CNS)-that appear to play major roles in the pathophysiology of FM. We will now review the recent data supporting the From the Department of Medicine, Division of Clinical Immu· nology and Rheumatology, and the Departments of Physiology and Biophysics, The University of Alabama at Birmingham, Bir· mingham, Alabama. Correspondence: Laurence A. Bradley, PhD, 615 MEB, UAB, Birmingham, AL 35294. Email: [email protected] THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
J.
EDWIN BLALOCK, PHD,
links among each of these three systems and pain in FM, and conclude by presenting a model of the pathophysiology of abnormal pain perception in FM which integrates the research findings described below. Musculoskeletal System
Because muscle pain is the primary symptom of FM, early investigators thought it logical to assess whether the musculoskeletal system might be the origin of the disorder (see articles in this issue by Olsen and Park and by Simms). Indeed, several studies produced evidence that patients with FM exhibit abnormalities in muscle energy metabolism and muscle tissue oxygenation. 3 ,4 Other investigations found significant decreases in high-energy phosphate compounds as well as the appearance of ragged red fibers in the tender areas ofthe trapezius muscle of FM patients. 5 Together, these data have led to the hypothesis that local tissue hypoxia might contribute to the perceived weakness and pain associated with FM. Recent investigations with better experimental controls generally have failed to demonstrate differences between FM patients and sedentary control subjects in adenosine triphosphate levels, lactate levels, muscle tension or hypoxia, or intracellular pH. 6 ,7 Nevertheless, Olsen and Park described in this issue ofthe Journal the results of a study involving P-31 magnetic resonance spectroscopy (MRS) which showed that FM patients, compared to appropriately matched controls, exhibited significantly lower resting levels of phosphocreatine and adenosine triphosphate, as well as significantly higher levels of adenosine diphosphate, both of which are indicative of an abnormal bioenergetic status. These findings were not associated with evidence of inflammation, which suggests that biochemical abnormalities in the muscles of FM patients may playa role in the perceptions of weakness and fatigue of FM. In addition, European investigators have observed a pattern oflatent tetany and a reduced ability of the muscle to relaxs as well as a reduced blood level of calcium in a small number of patients with
405
Pathophysiology of Abnormal Pain Perception
Table 1. Endocrine Hormone Alterations in Fibromyalgia Hormone
Result
Reference
Plasma cortisol, peak (AM) Plasma cortisol, through (PM) Free cortisol (24 h urine) Circadian change ACTH (CRH stimulation) Cortisol response (CRH stimulation) Free T g , T. TSH
Normal Elevated Low Blunted Elevated Blunted Reduced Reduced Reduced Reduced High
10, 12, 13 12,13 12, 13 14 12,13 12,13 9
GH IGF-1
Prolactin
11
22 20 9
ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; TSH = thyroid-stimulating hormone; GH = growth hormone axis; IGF-l = insulin-like growth factor 1.
FM.9 The ongm of hypocalcemia in FM patients, however, was not elucidated. In summary, most of the well-controlled studies of muscle tissue in FM do not show strong evidence that defects in this tissue are a primary cause of the disorder. Nevertheless, a small number ofinvestigations suggest that biochemical abnormalities or alterations in muscle function may contribute to FM symptoms. These intriguing findings must be replicated, however, in independent and larger samples before they can be considered to be reliable. Neuroendocrine System
Over the past few years, several studies have indicated that a functional disturbance in the neuroendocrine system may contribute to the development of FM symptoms. This functional disturbance is characterized by a blunting of the stress response in patients with FM and involves the hypothalamicpituitary-adrenal axis (HPA) and its reciprocal interactions with the hypothalamic-pituitary-gonadal axis (HPG), the locus ceruleuslnorepinephrine (LCI NE) sympathetic nervous system, the hypothalamicpituitary-thyroid axis (HPT), and the growth hormone axis (GH).lO Table 1 summarizes the relevant findings produced by these studies. All investigations of the HPA axis in FM patients have produced evidence of primary adrenal insufficiency.ll,12 Thus, there is decreased production of cortisol in response to corticotropin-releasing hormone (CRH) or corticotropin (ACTH) and an exaggerated ACTH response to hypothalamic CRH. 13 ,14 The blunted cortisol levels are associated with a flattened diurnal secretion pattern. However, abnormalities in the HPA axis are also found in other stress-related disorders. 12 Indeed, in this issue of the Journal, Crofford suggests that FM may be part of a spectrum of stress-related disorders which also includes irritable bowel syndrome, chronic fatigue syndrome, and dysmenorrhea. 15
406
Similarly, studies of HPT axis function have shown that patients with FM display blunted secretion ofthyroid-stimulating hormone (TSH) and thyroid hormones in response to thyrotropin-releasing hormone (TRH), suggestive of a blunted pituitary response. 9 The secretion offree triiodothyronine (T3) and free thyroxine (T4) to TRH is poor,10 which suggests that the thyroid hormone profile might be due to a failure to deiodinate T4 to T3 in peripheral tissues or within the pituitary. Glucocorticoids may also be involved since they have been shown to inhibit the conversion of T4 to T3 and decrease the response of TSH to TRH.16 Finally, several studies have produced evidence of changes in the GHlIGF-I axis in FM patients. Growth hormone, which is involved in muscle homeostasis maintenance, is maximally secreted during stage 4 of REM sleep. However, as noted by Harding in this issue ofthe Journal, many FM patients display stage 4 sleep anomalies such as alpha wave intrusions during slow wave sleep.17,18 BennettI9 hypothesized that the sleep anomalies could disrupt the secretion of GH and indirectly confirmed this by showing low levels of IGF-I in patients with FM.20 Two subsequent reports 21 ,22 confirmed this finding; another did not. 23 Recently, Bennett et al produced evidence that the low IGF-I levels in patients with FM are a secondary phenomenon associated with hypothalamic-pituitary-GH dysfunction. 24 This dysfunction may be produced by chronic stress and low thyroid hormone levels in addition to sleep disturbances. 25 ,26 The clinical significance ofGH deficiency is that it may contribute to poor healing of muscle microtrauma and thereby to nociceptive transmission 27 by its influence on muscle metabolism. 28 ,29 In conclusion, it appears that in FM the pituitary release patterns of ACTH, TSH, and GH are altered and that the subsequent abnormalities in hormone levels may contribute to the spectrum of symptoms observed in patients. Although alterations in the neuroendocrine system are also found in other stress-related disorders,I5 the pattern of exaggerated ACTH response to CRH and the subsequent blunting of the cortisol response is unique to FM. It is necessary to determine how the HPA and GH axes are interrelated in FM and whether these interactions may contribute to the pain, fatigue, and other symptoms associated with this disorder. Central Nervous System NeurotransmiHer Abnormalities. Several investiga-
tors have evaluated differences between patients with FM and healthy controls in levels of neurotransmitters, brain hormones, and neuropeptides related to pain transmission or pain inhibition (Table 2). The earliest studies in this area focused on serotonin, given that this neurotransmitter is involved in both stage 4 sleep and pain modulation. 30 Russell et June 1998 Volume 315 Number 6
Weigent et 01
Table 2. Neuromediator Perturbations in Fibromyalgia Variable
Result
Calcium Serotonin Substance P Nerve growth factor Dynorphin A Calcitonin generelated peptide
Low Low Elevated (CSF) Elevated (CSF) Elevated (CSF)
41
Elevated (CSF)
42
CSF
=
Reference 9
31 35 40
cerebrospinal fluid.
aI, for example, found decreased levels of serotonin in the sera of FM patients and increased numbers of reuptake receptors for serotonin on platelets. 3l ,32 These investigators also reported that the cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-HIAA were significantly lower in FM patients than in controls; the same findings were observed in several serum amino acids including tryptophan, alanine, histidine, lysine, proline, serine, and threonine. 3l ,33 In a recent report by the same group, however, the serum levels of serotonin were not correlated with any clinical variables. 34 Investigators have devoted substantial attention to CSF levels of substance P (SP) in persons with FM, given that it serves as a nociceptive neurotransmitter at the dorsal horn level. Several studies have found that both patients with FM and community residents who meet diagnostic criteria for FM but who have not consulted physicians for pain (ie, who are non patients) exhibit significantly higher levels ofCSF SP than healthy controls. 35 - 37 Indeed, the SP levels in persons with FM are two to three times higher than those of controls. Substance P levels, however, are normal in serum and urine of FM patients. 35 Recent data produced by Russell's laboratory suggest that stress may potentiate the nociceptive effects of SP release in persons with FM; that is, it has been shown that activation of the CNS by stress stimulates mammotroph cells in the anterior pituitary to secrete nerve growth factor (NGF) and prolactin. 38,39 Consistent with these findings, Russell's group reported elevated CSF levels of NGF in patients with FM.40 Given that NGF regulates SP expression in sensory nerves and may inhibit the antinociceptive effect of SP metabolites,40 it is possible that stress may contribute to pain perception in individuals with FM through its effects on NGF. Russell has reported in this issue of the Journal that patients with FM also exhibit elevated CSF levels of calcitonin gene-related peptide (CGRP) and dynorphin A. 4l ,42 These findings are consistent with changes in CNS function that have been observed following injury. Under these circumstances, a series of events can occur which produce allodynia, a pheTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
nomenon by which formerly innocuous stimuli such as light touch or mild heat are perceived as painful. 43 One event is that new axon sprouts that are sensitive to stimulation often develop in the injured area of tissue. Spontaneous firings of these damaged nerves, as well as from the dorsal root ganglion, increase the neuronal barrage into the CNS and contribute to the perception of pain. Similarly, spinal dorsal horn neurons also show an increased excitability after injury which is characterized by an enlargement of their peripheral receptive fields and greater responsiveness to mechanical, thermal, and chemical stimuli. This process of central sensitization, which also leads to increased neural input, is mediated by the activation of neurons with Nmethyl-D-aspartate (NMDA) receptor sites by excitatory amino acids and enhanced by neuropeptides such as dynorphin, SP, and CGRP (Figure 1).43 Functional changes in peripheral or dorsal horn neurons have not been documented in patients with FM. However, Sprott et al recently observed collagen cuffs around the preterminal nerve fibers in skin samples obtained from the trapezius region in FM patients. 29 These collagen cuffs, which might lower the firing thresholds of the nerves, may have been produced by remodeling of the extracellular matrix by injury-related stimulation of local nociceptors which, in turn, stimulated the release of proinflammatory cytokines (eg, IL-1, IL-6, TNFa) by macrophages. It is possible, however, that the alterations in collagen metabolism mark an intrinsic defect in systemic crosslinking of collagen which renders individuals susceptible to the development ofFM. 28 We recently produced behavioral evidence of increased neural input in persons with FM that is consistent with the phenomenon of central sensitization. We administered standardized pain perception tasks under controlled laboratory conditions to patients and non patients with FM as well as healthy controls, and found a similar pattern of results. 44 Both FM subject groups, relative to the controls, exhibited significantly lower pain thresholds in response to mechanical stimulation at 10 tender points included in the diagnostic criteria for FM 45 and 10 control points. Moreover, both FM groups produced significantly higher scores than controls on an index of sensory discrimination derived from their intensity ratings of a wide range of standardized mechanical stimuli applied to the tender and control points. These findings suggest that stimulation of both sets of points produced substantially higher levels ofneural input in the patients and nonpatients with FM compared to the controls. 46 Moreover, given that FM patients tend to have much higher levels ofpsychiatric morbidity than nonpatients, our findings suggest that abnormal pain perception in FM cannot be explained solely by psychiatric illness. 47
407
Pathophysiology of Abnormal Pain Perception
Tissue or Nerve Injury
Increased Neural Activity at Site of Injury
1
Excitatory amino acid release neuropeptide release (Dynorphin, SP, CGRP)
Increased Depolarization at NMDA Receptor Sites in Dorsal Horn Excessive Depolarization
t
Excitotoxicity
tI
Cell Dysfunction
_ _-I~~
Expanded Receptive Fields and Hyperexcitability
Figure 1. Changes in the nervous system after injury. The hyperexcitability involves activation of neurons at N-methyl-Daspartate (NMDA) receptor sites by excitatory amino acids. The release of excitatory amino acids from presynaptic sites and their effects on dorsal horn neurons are enhanced by neuropeptide transmitters such as dynorphin, substance P (SP), and calcitonin gene-related peptide (CGRP). (Reprinted with permission from Pillemer SR, Bradley LA, Crofford LJ, Moldofosky H, Chrousos GP. The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum 1997;40:1928-39.)
Loss of Inhibition
Increased Pain
Functional Brain Activity Abnormalities. Our laboratory has produced evidence that abnormalities occur in the functional activity of the brain as well as in neurotransmitter levels among persons with FM. As documented by Mountz et al in this issue ofthe Journal, we have consistently found abnormally low levels of regional cerebral blood flow (rCBF) in the thalamus and caudate nucleus of patients with FM during resting conditions. 48 The low level of caudate rCBF has been replicated in nonpatients with FM.37 We believe that low levels of functional activity (as measured by rCBF) in these brain structures probably represent a response to high levels of nociceptive neural input. As a consequence, the modulating actions of these structures on nociceptive transmission are compromised, thereby contributing to the low pain thresholds and other abnormal pain perceptions exhibited by persons with FM. We currently are examining functional activity levels in the thalamus and caudate nucleus as well as in several other brain structures which process the affective-motivational dimension of pain (eg, cingulate cortex) in patients with FM, chronic fatigue syndrome, or major depression. We are performing the evaluations un-
408
der resting conditions and during painful stimulation in order to determine to what extent these disorders overlap with one another with regard to abnormalities in brain function. eNS Interactions with the Immune System. It has been proposed that viral infections may lead to persistent pathological changes in neuron metabolism, even when the infection itself is no longer present. 49 This is consistent with the report that as many as 55% of patients with FM attribute the initiation of their symptoms to a flulike febrile illness. 50 Several cytokines, including IL-l and TNFa, that are released after infection induce increased sleep, activate the HPA axis, and contribute to hyperalgesia. 51 Nevertheless, the possible role of the immune system in the pain ofFM has not been thoroughly investigated. Wallace et al reported that CD4+ cell numbers were higher in 60% of the FM patients compared to controls; circulating levels of IL-2 were elevated in 53% of the patients with FM.52 No study, however, has convincingly demonstrated a correlation between immune system parameters and disease severity. 53 The levels of CSF IL-l and TNFa, which are known to stimulate the release of NGF, have not been deJune 1998 Volume 315 Number 6
Weigent et al
~ectable among FM patients in very preliminary studies in our laboratory. Nevertheless, it has been shown that NGF synthesis in astrocytes can be stimulated by calcitriol and cytokines IL-l and TGF-,B.54 rhus, it remains necessary to determine whether ~he elevated CSF levels ofNGF and SP are initiated primarily by nociception-induced changes within the CNS, or if they may also be induced by alterations in peripheral IL-l or TNFa. The immune system also may be involved in endogenous pain control mechanisms. Using a rat model, it has been shown that during stress, CRH induces the release of opioid peptides within inflamed tissue. The opioid peptides bind to opioid receptors on sensory nerves and inhibit pain. 55 The mechanism does not involve IL-l,B, circulating CRH, or anti-inflammatory agents. Thus, it appears that pain can be diminished by local paracrine interactions of the immune system with peripheral sensory nerves. The results suggest that CRH originates from the inflammatory site and are consistent with previous data demonstrating the synthesis of CRH56 and endorphins 57 by cells ofthe immune system. 58 It remains to be determined if and how this peripheral defense mechanism may be linked to the perception of pain in patients with FM.
Etiopathogenesis of Abnormal Pain Perception in Fibromyalgia
We recently developed a preliminary model of the etiopathogenesis of abnormal pain perception in FM.59 Given the research efforts described above and in the other articles in this issue of the Journal, it is possible to refine our model (Figure 2). We propose that, consistent with the evidence described by Crofford in this issue, there is probably a genetic susceptibility to the neuroendocrine abnormalities associated with FM. These neuroendocrine abnormalities may also be influenced by infections and emotional trauma or other stressful events. The blunted neuroendocrine responses found in FM patients may be responsible for select symptoms such as fatigue and mood disturbances. However, these neuroendocrine responses, along with the stress-related sleep abnormalities described by Harding, also influence the activity of the GH axis and thus contribute to poor healing of muscle microtrauma and nociceptive transmission from peripheral nerve fibers to dorsal horn spinal neurons. There also may be a genetic susceptibility to the development of some structural defects of the CNS and the musculoskeletal system, such as Chiari malformation,60 which may result in nociceptive transmission. Physical trauma, stressful events, and infectious agents are environmental factors which also contribute to increased nociceptive transmission. Physical trauma directly stimulates peripheral nociceptors and, through release of cytokines, may contribute to THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
the development of altered collagen metabolism of peripheral nerve endings as well as muscle microtrauma resulting in nociceptive transmission. Physical trauma, such as cervical spinal injury, also may produce structural defects which activate peripheral nociceptors. 61 In contrast, infectious agents and stressful events appear to have indirect effects on nociception. Both of these environmental factors stimulate the production of NGF which regulates SP expression in sensory nerves. Thus, they may contribute to the hyperexcitability of dorsal horn spinal neurons (ie, central sensitization) by SP and other neuropeptides. It is clear from the preceding discussion that there are multiple endogenous and exogenous factors which may contribute to nociceptive transmission in persons with FM. Figure 2 suggests that the final common pathway for the actions of all of these precipitating factors is the process of central sensitization. We propose that in persons with FM, one or more of the precipitating factors contribute to the development of muscle microtrauma or other tissue injury which enhances nociceptive transmission from the periphery to the dorsal horn spinal neurons. Activation of neurons with NMDA receptor sites by excitatory amino acids, and the release of SP, CGRP, and dynorphin, leads to functional alterations in the dorsal horn spinal neurons which greatly increase nociceptive transmission to the brain. We also propose that, over time, functional alterations occur in the brain structures which are involved in modulating nociceptive input (eg, thalamus) and in processing the sensory-discriminative (eg, thalamus, caudate nucleus) and affective-motivational (eg, prefrontal cortex, anterior cingulate cortex) dimensions of pain. Moreover, the function of the latter structures, which are part of the brain limbic system, are influenced by alterations in the HPA axis. Indeed, we propose that the high level of perceived aversiveness which is generally associated with FM pain represents an emotional stressor which may contribute to the maintenance of HPA axis abnormalities. The endpoints of all of these processes are the abnormal pain thresholds found at multiple anatomic sites and the widespread pain ofFM. Clinical Implications of the Model. Although the above model does not account for all symptoms associated with FM (eg, those of irritable bowel syndrome), it does enhance our understanding of the difficulties involved in the attempts of patients and physicians to reduce the pain which characterizes this disorder. First, nociceptive transmission from the periphery may be initiated by more than one precipitating factor which then interact with each other. Careful medical and psychosocial evaluations of FM patients, therefore, are required to provide optimal treatment planning. For example, physical
409
Pathophysiology of Abnormal Pain Perception
Genetic Susceptibility
Infections.
Emotional Trauma.
'" cytokines
Stress
~
.--------.
Sleep Abnormalities
HPT
HPG
.-
AxIs
AxIs
....
+
HPA AxIs
1
Muscle Microtrauma
Physical Trauma
1,
'" cytokinas
r.=;;;;Ollagen Metabolism at Peripheral Nerve Endings
~-
Structural Defects
:
,
GH Axis
I.....r-.-T"I
~----------------~ LCINE Sympathetic NS
,L __________________________ ,L
B-G ,,"'CGRP, ~
'" Peripheral Nociceptive Transmission
, ~
__ J
'" Dorsal Hom Spinal Neuron ExcltabOity (CENTRAL SENSITIZATION'
1
'" Excitetory Amino Acids
'" rCBF Prefrontal Cortex '" rCBF Anterior Cingulate Cortex
Abnonnal Pain Thresholds and Generalized Persistent Pain
Figure 2. Model of the pathophysiology of abnormal pain perception in FM. Genetic factors, as well as several precipitating factors (eg, physical trauma, emotional trauma or stress, and infections), may contribute to abnormalities in the neuroendocrine axes, muscle tissue, peripheral nerve endings, and sleep. These abnormalities lead to hyperexcitability of dorsal horn spinal neurons through increased nociceptive transmission from the periphery to the dorsal horn or through stimulation of SP production. This produces a barrage of nociceptive input to the brain which eventually alters the function of brain structures that process the sensory-discriminative and affective-motivational dimensions of pain. The function of the latter structures is also influenced by and may influence alterations in HPA axis function. The endpoint of this process is abnormal pain thresholds and widespread persistent pain. In this model, solid lines between variables indicate relationships for which there is reliable empirical evidence; dotted lines indicate relationships for which there is only prelimiJ?-ary evidence.
trauma such as an assault upon a woman may directly induce nociceptive transmission and influence NGF production and neuroendocrine abnormalities through the emotional stress (eg, posttraumatic stress disorder) which can persist for extended periods after the assault. The emotional stress may be particularly severe among women whose coping resources have been compromised by the presence of psychiatric disorders which developed before the onset ofFM. Indeed, 50% to 75% ofFM patients studied 410
in our university-based rheumatology clinic reported that symptoms of their mood and anxiety disorders began before the onset of their pain. 47 Thus, recovery from the precipitating physical trauma may not produce a positive alteration in function ofthe HPA axis or growth hormone axis, and both psychological and medical intervention may be necessary for many women with FM who have been assaulted. The second difficulty in attempts to alleviate the pain of FM is that it is difficult to attenuate the June 1998 Volume 315 Number 6
Weigent et al
dorsal horn neuron excitability associated with the central sensitization process with present pharmacologic, behavioral, or surgical interventions. Further development of NMDA receptor antagonists and SP antagonists may lead to improved pain control in the future. 43 However, given the primary role that central sensitization may play in the production ofFM pain, it is not surprising that current pharmacologic treatments tend to show moderate effectiveness. These are largely psychotropic medications which alter levels of brain neuropeptides involved in endogenous pain control mechanisms and symptoms of depression or anxiety, but do not act at the dorsal horn level. Similarly, our model suggests that behavioral and cognitive-behavioral interventions often may help patients cope with or modify the intensity and aversiveness of their pain through reduction of emotional distress. However, these interventions should not be expected to greatly modifY the excitability of dorsal horn spinal neurons in most individuals (see review of treatment efficacy by Alarcon and Bradley in this issue). Finally, our model suggests that attempts to surgically correct structural defects in patients with FM for pain relief should be considered with great caution. Correction of these structural defects may not have a great effect on dorsal horn spinal neuron excitability, given the multiple factors which contribute to this phenomenon. More important, induction of additional trauma through surgery will alter sensory input and actually may contribute to the enhancement of the central sensitization process over time. Conclusion
Our knowledge regarding the pathophysiology of abnormal pain perception in FM has been greatly enhanced by the efforts of many investigators from diverse disciplines. The pathophysiologic model of abnormal pain perception presented in this article will certainly require revision as additional research findings are produced. At present, however, it offers a mechanism for generating testable hypotheses that may contribute to our understanding of pain in FM. It also provides a strong empiric basis for explaining to patients and healthcare professionals the causes of the persistent and unusual pain perceptions associated with this disorder. Finally, the model may help physicians and other scientists to develop improved treatments for pain that are based on our current understanding of nociceptive transmission and pain perception and which may be evaluated by appropriate scientific methods. Acknowledgments
Preparation of this article was supported by NIAMS Grant l-ROI-AR-43136-04, NIH Center Grant P60-AR-20164, and NCCR Grant 5 MOI00032, and THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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June 1998 Volume 315 Number 6