Chronic widespread pain

The prevalence of chronic pain in the general population is high, seems to increase with age , and is usually assessed by cross-sectional studies utilising screening questionnaires sent to a random sample of subjects . These questionnaires collect information about demographic data, diagnosis, current pain, pain during the previous month, recurring pain, pain duration, location, frequency, intensity, pain at rest or during movement, occupational status, working hours per week, use of health care for pain and disability pensions. Often the respondents also mark the location of their pain on drawings of the human body. Several studies have found that large parts of the general population (34.5–53.7%) report pain of more than 3 months duration regardless of intensity (chronic pain) . The prevalence of chronic pain is consistently higher among women than men and appears to become more prevalent with age . The highest chronic pain prevalence (88%) has been observed in subjects 65–74 years old . By contrast, individuals who have chronic widespread pain (CWP) or fulfil the 1990 classification criteria for fibromyalgia (FM) have more severe symptoms – higher pain intensity, fewer pain-free periods and more pronounced pain-related interference in everyday life – and consequences for daily life. The population prevalence for CWP has been estimated at 10% and for FM at 2.5% . It has been postulated that FM represents the extreme end of the CWP spectrum in the general population. However, only few studies have assessed the similarities and differences in pain experiences between patients fulfilling the American College of Rheumatology (ACR) criteria for FM and those with CWP.

FM syndrome

FM patients encountered in clinical practice are not necessarily representative of patients in the general population because these patients differ in pain severity and lifetime psychiatric diagnoses from FM patients found in the community . Similar findings have been documented for CWP . FM is a chronic pain syndrome, that is defined by widespread pain for more than 3 months and the presence of more than 10 out of 18 tender points . Additionally, almost all FM patients complain of disturbed sleep, distress and pronounced fatigue. The latter features have been included in the preliminary 2010 FM Criteria . FM is a chronic illness that disproportionately affects women (9:1 ratio of women to men affected). Similar to many other syndromes, FM has no single specific feature but represents a symptom complex of self-reported or elicited findings.

FM syndrome

FM patients encountered in clinical practice are not necessarily representative of patients in the general population because these patients differ in pain severity and lifetime psychiatric diagnoses from FM patients found in the community . Similar findings have been documented for CWP . FM is a chronic pain syndrome, that is defined by widespread pain for more than 3 months and the presence of more than 10 out of 18 tender points . Additionally, almost all FM patients complain of disturbed sleep, distress and pronounced fatigue. The latter features have been included in the preliminary 2010 FM Criteria . FM is a chronic illness that disproportionately affects women (9:1 ratio of women to men affected). Similar to many other syndromes, FM has no single specific feature but represents a symptom complex of self-reported or elicited findings.

Pathogenesis of CWP and FM

Similar to CWP, FM pain appears to depend on impulse input from deep tissues, particularly muscles. In genetically susceptible individuals, such tonic impulse input results in peripheral sensitisation as well as neuroplastic changes of the central nervous system (CNS), termed ‘central sensitisation’. During central sensitisation, a cascade of transcriptional and translational events leads to heightened sensitivity (hyperalgesia and/or allodynia) of second- and higher-order neurons and expansion of their receptive fields. It is unclear at this time, why such changes are long lasting or even permanent in FM and CWP patients. One likely mechanism is the abnormal response of chronic pain patients to stressful events. Specifically, altered neuroendocrine and autonomic nervous system (ANS) function appears to play an important role in the pathogenesis of CWP . Disturbances of neuroendocrine and ANS function can trigger many symptoms that are commonly observed in FM and CWP, including pain, fatigue, insomnia, mood disorders, weakness and orthostatic intolerance. A number of studies that have examined coordinated hypothalamic–pituitary–adrenal (HPA) axis and ANS functioning showed hyporeactivity to applied stress in FM . This altered neuroendocrine responsiveness seems to result from changes in hypothalamic function, not from a primary adrenal defect. Thus, neuroendocrine alterations are most likely involved in the pathophysiology of FM and contribute to its ongoing symptomatology. Due to the fact that pain is not only worsened by chronic stress but also an important stressor in its own right, reductions in stress will likely have a positive effect on chronic pain and FM/CWP.

Role of muscle impulse input for CWP

Although there are no detectable nociceptors in muscle fibres muscle stimuli can elicit pain. Nociceptive afferent fibres including A-delta and C-fibres can be found in muscles as dense innervations of vascular structures . Whereas chronic degenerative muscle disorders are not painful, inflammatory myopathies can result in sensitisation of pain receptors that may elicit pain. Hypoxia in combination with muscle activity as well as energy depletion can also cause pain. Thus, if nociceptors in deep tissues of CWP patients are sensitised by inflammatory or non-inflammatory mechanisms, hyperalgesia can occur. Importantly, mechanical hyperalgesia is a characteristic feature of so-called ‘tender points’ which are a hallmark of FM and part of the 1990 classification criteria of the ACR for this syndrome . There is a large body of evidence for a generalised lowering of pressure pain thresholds in FM patients , and the mechanical allodynia of FM patients is not limited to tender points but appears to be widespread . In addition, almost all studies of FM patients have shown abnormalities of pain sensitivity while using different methods of sensory testing.

Not only is the mechanical hyperalgesia of FM patients likely a consequence of abnormal input from sensitised peripheral tissue receptors and resultant central sensitisation, but also the underlying pain mechanisms can be readily evaluated by psychophysical testing. Specifically, if central sensitisation is dependent on peripheral impulse input, it should be short-lived after receptor activation . Infrequently, however, tonic impulse input can change pain pathways and become independent of peripheral input . One particular psychophysical method, temporal summation (TS) of pain, has been used for testing of central pain sensitivity in FM patients . Several studies that used this method seem to indicate that TS is enhanced in FM and that the increased central pain sensitivity of FM patients attenuates much slower than seen in normal subjects . Although direct neurophysiological evidence of tonic input from deep nociceptors is lacking at this time, indirect evidence strongly suggests abnormally sustained impulse input from muscle receptors in FM patients .

Role of myofascial trigger points for overall pain

Local pain of CWP and FM patients is often related to the presence of myofascial trigger points (MTPs) which can be classified as either active or latent. Whereas active MTPs are characterised by spontaneous pain, latent MTPs are clinically silent but usually have all the other clinical characteristics of active MTPs, including taut bands and twitch response . Active MTPs are associated with local and referred pain and a characteristic twitch response after manual or needle stimulation . Both active and latent MTPs show spontaneous electrical activity at rest during needle electromyography , indicating that objective electrophysiological methods can be used to document the existence of MTPs. Unfortunately, there is no pathologic or laboratory test for identifying MTPs. The development of MTPs is often associated with injuries to muscle fibres. Such injury may include traumatic events or repetitive microtrauma to muscles. MTPs cause pain and spasms in the muscle or muscle fibres. Several studies have demonstrated the presence of large numbers of active MTPs in FM patients and one study has shown the ability of active, but not latent, MTP counts to predict overall spontaneous pain intensity in patients with FM . However, highly variable numbers of trigger points in individual patients have been reported between different examiners .

Further support for the important role of muscle abnormalities for CWP is provided by several injection studies of MTP with local anaesthetics . The results of these studies showed that local treatment of peripheral pain generators of CWP patients not only relieved local symptoms but also significantly improved overall pain and tenderness. In addition, local muscle injections increased mechanical and electrical pain thresholds of adjacent as well as remote body areas of CWP patients. This effect was not seen in patients undergoing placebo treatments.

Effects of local pain on generalised pain sensitivity

It is well known that small areas of local pain can have enhancing effects on overall pain sensitivity. This effect, however, depends on several factors including the duration of pain. In contrast to short-lasting dental pains which do not enhance pain sensitivity of distal sites like the arms , chronic pain from myofascial temporomandibular disease can profoundly increase pain sensitivity of remote areas . Generalised hyperalgesia has also been described in patients with local pain syndromes including whiplash injury , irritable bowel syndrome , back pain and pelvic pain . Some of these changes can be explained by increasing recruitment of central neurons that become activated by nociceptive stimulation as well as by enhanced spatial summation . Another local pain mechanism is spatial referral, that is, tonic impulse input from local tissues can result in pain of remote areas and increased pain intensity. Thus, painful input from tonic impulse input can summate with input from acute injuries resulting in widespread pain. Furthermore, spatial summation mechanism seems to be abnormal in FM. Whereas this important pain mechanism appears to be normal during low-grade nociceptive input , spatial summation of pain seems to be unlimited during intense pain stimuli . Spatial summation of pain can be reduced by tissue injections with local anaesthetics. However, the results of local anaesthetics on pain and hypersensitivity of muscle pain are mixed. Whereas injections of local anaesthetics into trigger points attenuated whiplash pain, mechanical hyperalgesia at remote sites was not affected . By contrast, rectal application of lidocaine to irritable bowel syndrome (IBS) patients abolished rectal hyperalgesia and cutaneous pain sensitivity within lumbar dermatomes . Thus, in some chronic pain conditions, such as FM or whiplash pain, generalised hypersensitivity may depend on minimal impulse input from muscles. It is unknown at this time whether central pain mechanisms such as spatial summation and referred pain play important roles for the widespread sensitisation associated with FM. Thus, different pain mechanisms must be considered for the generalised hypersensitivity associated with chronic pain and FM.

Muscle metabolites and pain

A likely source of nociceptive input accounting for FM pain is muscle tissue. Several types of muscle abnormalities have been reported in FM patients including the appearance of ragged red fibres, inflammatory infiltrates and moth-eaten fibres. Possible mechanisms for such muscle changes may include repetitive muscle microtrauma, which could contribute to the postexertional pain, MTP and other painful symptoms experienced by these patients. In addition, prolonged muscle tension and ischaemia have been detected in muscles of FM patients. Investigations using ³¹ P nuclear magnetic resonance (NMR) spectroscopy have shown that FM patients display significantly lower phosphorylation potential and total oxidative capacity in the quadriceps muscle during rest and exercise . FM patients also exhibit significantly lower levels of muscle phosphocreatine and ATP, as well as a lower phosphocreatine/inorganic phosphate ratio.

Changes in muscle pH related to ischaemia can provide powerful mechanisms for the sensitisation of spinal and supraspinal pain pathways. Recent studies have shown that low pH has a profound effect on the initiation and perpetuation of muscle pain . Repeated acid injections into rat muscle produced a bilateral, long lasting, mechanical hyperalgesia that was maintained without continued muscle nociceptive input and did not produce damage to muscle tissue. Furthermore, this secondary mechanical hyperalgesia was maintained by neuroplastic changes in the central nervous system, even after the cessation of nociceptive activity. The initiation of hyperalgesia occurred in response to repeated intramuscular injection of acidic saline, suggesting that this process involves activation of ASICs or the capsaicin-sensitive TRPV1 channel in muscle. Thus, a more acidic milieu may activate ASIC1 or ASIC3 muscle nociceptors, which in turn could produce mechanical hyperalgesia . Because nociceptive input from muscles is very powerful in inducing and maintaining central sensitisation, muscle abnormalities may strongly contribute to this important mechanism of pain amplification.

Role of abnormal muscle microcirculation

The blood flow of muscles, particularly the trapezius, seems to be reduced in FM . Muscle microcirculation can be measured by Doppler ultrasound , xenon-133 clearance or oxygen multipoint electrodes on the muscle surface of FM patients . The trapezius and brachioradialis muscles have been most frequently studied. Tissue oxygen pressures are reported to be abnormal in FM patients compared to normal controls . These results suggest abnormal capillary microcirculation, at least in the upper part of the body. In addition, decreased blood flow in the tender point areas of FM patients has also been reported using intramuscular needle electrodes. These blood flow abnormalities, however, do not appear to result from diminished capillary density. On the contrary, capillary density of trapezius muscles was increased compared to lower extremity muscles including the vastus lateralis . Other reported muscle abnormalities include increased thickness of the capillary endothelium of FM patients . These changes may be either the cause or effect of localised hypoxia. The microcirculation of muscles is regulated by not only locally produced metabolites, humoral factors, but also the ANS. This important role of the ANS for chronic muscle pain was demonstrated by stellate ganglion blockade, which abolished pain and tender points of FM patients, whereas sham blockade was ineffective .

Thus, muscular ischaemia appears to be a relevant mechanism for chronic muscle pain, either focal or generalised. Hypoxia of muscle tissue, exacerbated by contraction, is highly effective in activating unmyelinated muscle nociceptors . Furthermore, muscular blood flow of FM patients cannot only be completely abolished by isometric or isokinetic exercise but also seems to recover very slowly . Such findings may explain why pain is abnormally increased for FM patients during and after exercise . Several lines of evidence support the fact that strenuous or intensive exercise can contribute to FM patients’ hyperalgesia and pain. For example, isometric contractions can increase the mechanical pain sensitivity of FM patients’ exercised muscles (hyperalgesia), but render muscles of normal control subjects hypoalgesic . Similarly, FM patients show increased heat hyperalgesia after exercise, whereas healthy controls become less sensitive . These findings suggest that certain types of exercise can increase the tonic nociceptive input from FM muscles, resulting in peripheral and central sensitisation. Whereas strenuous exercise seems to activate powerful antinociceptive mechanisms in normal control subjects, this stress mechanism appears to be either dysfunctional or insufficient to overcome tonic muscle pain in FM.

Mechanisms of pain in CWP

Pain in CWP is consistently felt in deep tissues and is related to sensitisation of peripheral and CNS pain pathways. Neurotrophins such as nerve growth factor (NGF) and tachykinins such as SP are elevated in the cerebrospinal fluid (CSF) of FM patients . NGF and SP not only enhance the sensitivity of nociceptors but also are associated with inflammatory regulation . Specifically, administration of recombinant human NGF to pain-free volunteers can result in mild-to-moderate back pain . Several neuropeptides, in particular SP, can induce the expression of cytokines which may sensitise peripheral nerve endings . Not surprisingly, elevated levels of cytokines in peripheral blood and skin have been reported in FM patients . These cytokines include IL-1ra, IL-8 and IL-6. Of these cytokines, IL-8 is of particular interest because it not only can increase nociceptive sensitivity but is also involved in the activation of the sympathetic nervous system .

Role of peripheral and central pain mechanisms

Increasing evidence points towards multiple initiating factors for hyperalgesia in FM, in particular psychological and physical stress, including traumatic injuries . Once hyperalgesia has been established little continuous tonic impulse input seems to be required for its maintenance. Several studies have demonstrated abnormalities of pain processing in patients with FM, such as alterations of N -methyl- d -aspartate receptors or monoaminergic modulation in the spinal cord . Furthermore, abnormal increases in TS of pain, expansion of receptive fields and hyperalgesia as well as dysfunctional descending nociceptive modulation have been described in patients with FM and other chronic musculoskeletal pain disorders . These findings suggest that central sensitisation of nociceptive afferent pathways seems to play an important role for the sensory abnormalities of FM/CWP patients .

Many FM studies related to pain and hyperalgesia clearly point to spinal mechanisms, consistent with the observation that FM patients have enhanced responses to somatic and cutaneous stimuli throughout the pain matrix of the brain, including the thalamus . However, on the basis of this evidence, it is not clear whether such enhanced responses are the result of facilitating mechanisms within the brain, spinal sensitisation maintained by tonic impulse input from somatic tissues or abnormal mechanisms of descending facilitation from the brain to the spinal cord and/or somatic tissues. Several neuroimaging studies of FM patients during painful mechanical stimulation showed increased activity of pain processing brain regions such as rostral anterior cingulate cortex (ACC) and prefrontal cortical areas . Such findings, however, do not prove that hyperalgesia in FM is the result of enhanced pain processing at higher cerebral levels. Mostly, because such brain activity may reflect selective cognitive effects, rather than enhanced activity of ascending pain pathways to the brain .