Chronic pain can be classified as localised, regional or widespread, and its high prevalence in the general population seems to increase with age. The majority of cases present with musculoskeletal pain. The conditions associated with chronic widespread pain (CWP) are highly burdensome as their characteristic symptoms may include multifocal pain, fatigue, insomnia, memory difficulties and a higher rate of concomitant mood disorders. After many years of debate, it is still unclear whether CWP (central sensitisation) is an entirely explainable neurotransmitter-related process or is partially or totally due to individual cognitive experiences and evaluations. The two models (neurochemical and biopsychosocial) also affect our ability to find therapeutic answers.
Chronic pain can be classified as localised, regional or widespread, and its high prevalence in the general population seems to increase with age . The majority of cases presents with musculoskeletal pain. There is still no universally accepted definition of chronic widespread pain (CWP), but it is becoming increasingly accepted that it is manifest by pain involving multiple body regions . When there is no clear anatomical or neuropsychological explanation for persistent pain, different medical specialists have used various names to describe what now seems to be a set of central nervous system (CNS) processes: fibromyalgia (FM), irritable bowel syndrome (IBS), interstitial cystitis and somatisation . All of the conditions associated with CWP are highly burdensome as their characteristic symptoms include multifocal pain, fatigue, insomnia, memory difficulties and a higher rate of concomitant mood disorders , as well as functional problems and difficulties in carrying out the activities of daily living (ADL) . Unlike the acute and ‘peripheral’ pain states that respond to non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, central pain conditions are more responsive to CNS neuromodulating agents, such as serotonin–norepinephrine re-uptake inhibitors (SNRIs) and anticonvulsants .
Many investigators now believe that chronic pain is itself a disease, and that the body region in which it arises may be less relevant than the subject’s genetically determined pain sensitivity combined with neuroplastic changes that increase pain transmission . These heightened states can be associated with hyperalgesia (increased pain in response to normally painful stimuli) and/or allodynia (pain in response to normally non-painful stimuli) , can be triggered by an initial peripheral injury or inflammatory process and may be regional or widespread. Furthermore, concomitant influence of a separate outside stressor (i.e., infection or trauma) may also play a role in the disease’s chronicity .
After many years of debate, it is still unclear whether CWP (central sensitisation) is an entirely explainable neurotransmitter-related process or is partially or totally due to individual cognitive experiences and evaluations. These two models (neurochemical and biopsychosocial) also affect our ability to find therapeutic answers to a number of questions . Why should a physiological mechanism such as pain, which is capable of informing us that potentially dangerous events are internally and externally affecting our bodies, become chronic and therefore a disease in itself? Is it possible that, like depression, anxiety and eating disorders, chronic pain is only abnormal behaviour arising from the brain and related to traumas that affect our tolerance, prevent a well-balanced perception of pain and reduce our quality of life?
In clinical practice, the source of chronic pain is investigated retrospectively by collecting information from the patient concerning traumas, postural problems, affective disorders and family history, which also make it possible to understand how waxing and waning pain have affected our patients’ lives and whether any co-morbid symptoms or syndromes are involved. However, there is no single risk factor or combination of risk factors that can be used to fit all of the clinical syndromes related to central sensitisation. Alternatives are to try to classify our patients on the basis of their pain, physical deconditioning, distress and affective condition, or to use drugs to treat the symptoms we believe to be the most significant for a given patient.
But what makes a local problem become a multifocal pain sensation?
CWP is consistently felt in the deep tissues, and is related to the sensitisation of peripheral and CNS pain pathways. FM patients have high cerebrospinal fluid (SCF) levels of neurotrophins such as nerve growth factor (NGF) and tachykinins such as substance P (SP) . Both NGF and SP enhance the sensitivity of nociceptors and are also associated with inflammatory regulation : the administration of recombinant human NGF to pain-free volunteers can lead to mild-moderate back pain, and various neuropeptides (particularly SP) can induce the expression of cytokines that may sensitise peripheral nerve endings . It is not surprising that high levels of IL-1ra, IL-8, IL-6 and other cytokines have been found in the peripheral blood and skin of FM patients . IL-8 is particularly interesting because it increases nociceptive sensitivity and is also involved in activating the sympathetic nervous system .
Many studies of FM-related pain and hyperalgesia clearly indicate the involvement of spinal mechanisms, which is in line with observations showing that FM patients have enhanced responses to somatic and cutaneous stimuli throughout the pain matrix of the brain, including the thalamus . However, it is not clear whether these are due to facilitating mechanisms within the brain, spinal sensitisation maintained by the input of tonic impulses from somatic tissues, or abnormal mechanisms of descending facilitation from the brain to the spinal cord and/or somatic tissues. A number of neuroimaging studies of FM patients during painful mechanical stimulation have shown increased activity in pain processing brain regions such as the rostral anterior cingulate cortex (ACC) and pre-frontal cortical areas, but these findings do not prove that the hyperalgesia in FM is due to enhanced pain processing at higher cerebral levels because the activity may reflect cognitive effects rather than more activity in the ascending pain pathways .
Depression and anxiety affect the ability to cope with events of everyday life. Both are often more marked in FM than in CWP patients, and affective spectrum disorders (including anxiety) seem to be one reason for the greater disability observed in the former. However, a number of studies have confirmed an association between CWP and depression and anxiety measures .
Distress can lead to dysregulation as a result of spinal sensitisation and sustained arousal, and psychoneuroimmunology has described how subjective experience, emotions, cognitive functions, the nervous system and physiological stress reactions all interact to restore balance by means of complex signalling systems. Responses are affected by emotional and cognitive processes, which depend on individual vulnerability and strength. Phenomenology concentrates on life circumstances and the meaning and interpretation of bodily signals. By acknowledging a patient’s experiences, attention can be switched from shame to coping.
Can risk factors be considered for an early diagnosis and aggressive treatment?
Another way of looking at CWP is to analyse the potential risk factors related to its development. A number of recently published studies have investigated the risk factors that may explain the evolution from local pain to CWP. One hypothesis is that pain hypersensitivity should be considered a bridge between genetics and biopsychosocial patterns. The idea is that somebody predisposed to develop FM may not actually do so unless trauma or the stressful events of mood disorders reach a certain level of intensity. However, there is still no appropriate means of measuring the level at which the change from local to widespread symptoms takes place.
Emerging evidence suggests that a subset of individuals with regional pain subsequently develop widespread pain. Studies investigating this transition have shown that between 10.4% and 17.4% of patients with various regional pain sites develop CWP. One study of subjects with low back pain found that 24.5% of patients developed CWP over 18 years , and studies of subjects with chronic neck pain or whiplash injuries have found that 10–22% develop CWP or FM . It is, therefore, clear that some cases of regional pain can progress to CWP, but the underlying mechanism and the nature of the predisposing risk factors have yet to be discovered. It is known that small areas of local pain enhance overall pain sensitivity, but this depends on various factors, including pain duration: unlike short-lasting dental pains, which do not enhance the pain sensitivity of distal sites such as the arms, chronic pain due to myofascial temporomandibular disease can greatly increase sensitivity in remote areas. Generalised hyperalgesia has also been described in patients with local pain syndromes such as whiplash injuries, IBS, back pain and pelvic pain. The highly predictive nature of intense pain is comparable with the findings of other studies investigating the development of CWP from regional pain.
Contemporary research supports the idea that a persistent high-intensity nociceptive input can increase neuroplastic changes in the central nervous system, expand receptive fields and give rise to more widespread symptoms .
Can risk factors be considered for an early diagnosis and aggressive treatment?
Another way of looking at CWP is to analyse the potential risk factors related to its development. A number of recently published studies have investigated the risk factors that may explain the evolution from local pain to CWP. One hypothesis is that pain hypersensitivity should be considered a bridge between genetics and biopsychosocial patterns. The idea is that somebody predisposed to develop FM may not actually do so unless trauma or the stressful events of mood disorders reach a certain level of intensity. However, there is still no appropriate means of measuring the level at which the change from local to widespread symptoms takes place.
Emerging evidence suggests that a subset of individuals with regional pain subsequently develop widespread pain. Studies investigating this transition have shown that between 10.4% and 17.4% of patients with various regional pain sites develop CWP. One study of subjects with low back pain found that 24.5% of patients developed CWP over 18 years , and studies of subjects with chronic neck pain or whiplash injuries have found that 10–22% develop CWP or FM . It is, therefore, clear that some cases of regional pain can progress to CWP, but the underlying mechanism and the nature of the predisposing risk factors have yet to be discovered. It is known that small areas of local pain enhance overall pain sensitivity, but this depends on various factors, including pain duration: unlike short-lasting dental pains, which do not enhance the pain sensitivity of distal sites such as the arms, chronic pain due to myofascial temporomandibular disease can greatly increase sensitivity in remote areas. Generalised hyperalgesia has also been described in patients with local pain syndromes such as whiplash injuries, IBS, back pain and pelvic pain. The highly predictive nature of intense pain is comparable with the findings of other studies investigating the development of CWP from regional pain.
Contemporary research supports the idea that a persistent high-intensity nociceptive input can increase neuroplastic changes in the central nervous system, expand receptive fields and give rise to more widespread symptoms .
What are the main risk factors for CWP?
Table 1 shows the main risk factors described in the literature .
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