The cause of fibromyalgia remains unknown but appears to be multifactorial. Engel’s biopsychosocial model of chronic illness (ie, health status and outcomes in chronic illness are influenced by the interaction of biologic, psychologic, and sociologic factors) is a useful way to approach fibromyalgia.

• Biologic variables: Certain biologic variables may contribute to the development and persistence of fibromyalgia. None of the variables, as single elements, explains all facets of fibromyalgia. Some of the variables (eg, trauma) are highly controversial, and additional evidence is required before an etiologic role can be assigned.

  • Inheritance: With regard to inheritance, altered serotonin metabolism in at least one subgroup of patients with fibromyalgia has been linked to a genotype of the promoter region of the serotonin transporter gene.
  • Sex
    • Sex-related effects are important with fibromyalgia, which has a female-to-male ratio of 9:1, and with pain in general.
    • Central pain modulatory systems in females are influenced by phasic alterations in reproductive hormone levels.
    • Aversive stimuli and stressful tasks more likely evoke SNS, HPA axis, and psychologic responses in females compared to males.
  • Age
  • Sleep: Almost all patients with fibromyalgia sleep poorly, and the frequent complaint that a night of poor sleep is followed by a more painful day is supported in the research. Although not the proximate cause of fibromyalgia, abnormal sleep affects both limbs of the stress response system and contributes to negative mood and cognitive difficulties.
  • Trauma and tissue injury
    • Trauma as a trigger of fibromyalgia has been a highly contentious and medicolegally charged issue in American society today. Until very recently, physical trauma as a causative factor in the development of fibromyalgia was an open question because properly designed prospective studies had not been performed and little experimental evidence explained the presence of pain in the absence of tissue injury. Setting aside case series and other anecdotal observations that do not provide valid evidence concerning causation, a number of controlled investigations bearing on this issue are now available.
    • In addition, clinical neurophysiological investigations have begun to clarify, at least potentially, how physical injury could result in central sensitization (induced functional alterations in the brain that disrupt normal mechanisms of pain control).
    • At the clinical level, patients who attribute their fibromyalgia to trauma have more perceived disability, self-reported pain, life interference, and affective distress than patients with idiopathic onset.
  • Physical conditioning
  • Stress/neuroendocrine and autonomic dysregulation
    • A large body of data suggests that fibromyalgia, chronic fatigue syndrome, regional chronic pain syndromes, and certain emotional disorders that frequently coexist with fibromyalgia all involve central dysregulation of the stress response system. Here, various forms of stress function as initiators or perpetuators of functional alterations in the corticotropin-releasing hormone (CRH) neuron, with associated effects on the HPA axis, other neuroendocrine axes, and the SNS.
    • Subtle abnormalities in the stress response system, which cannot be detected by routine clinical and laboratory assessments, may contribute to the diverse clinical manifestations in this spectrum of illnesses. Although incomplete, the emerging evidence is beginning to clarify how the brain, endocrine, and immune systems (especially proinflammatory cytokines) interact in the pathophysiology of pain, fatigue, neurally mediated hypotension, depression, anxiety, and poor sleep.
    • The extremely high prevalence of stress-related disorders in society may reflect maladaption of the stress response system in the face of chronic unrelieved stress and distress in modern life.
    • Both neurally mediated hypotension and fibromyalgia are female-associated disorders and exhibit similar symptomatology; however, exercise and emotional distress can precipitate these conditions. Neurally mediated hypotension is demonstrated in patients with fibromyalgia by tilt-table testing, which, in turn, provokes pain. Although still poorly understood, current investigations are focusing on a role for inhibition of arterial baroreceptors in the setting of hypotension, or some other type of baroreceptor dysfunction, in the genesis of increased pain and anxiety. Consistent with this idea is evidence that arterial baroreceptor activation by increased blood pressure results in a decreased pain threshold, pain tolerance, and anxiety.
  • Neurotransmitter abnormalities/neuronal activation leading to central sensitization, low calcium levels, low serotonin levels, elevated levels of substance P, elevated levels of cerebrospinal fluid (CSF) nerve growth factor, elevated levels of CSF dynorphin A, elevated levels of CSF calcitonin gene-related peptide, and various other antinociceptive molecules
  • Functional brain activity abnormalities (decreased regional blood flow in thalamus and caudate nucleus): These variables (eg, those involved in abnormal central nociceptive processing and functional brain abnormalities) may also be part of the pathophysiology of fibromyalgia but likely are derivative or secondary.
  • Neurally mediated hypotension
  • Viruses or other infections: While considered unlikely to be sole triggers, they may contribute to exacerbation of symptomatology via cytokine-vagus nerve stimulation of the CRH neuron/stress response system in bidirectional brain-immune system communication.
  • Decreased collagen cross-linking, hypermobility, Chiari malformation, environmental chemicals: These variables are conjectural, of limited significance, or just plain wrong.
• Cognitive-behavioral variables: Cognitive-behavioral variables may be pivotal in the development and maintenance of persistent pain and functional disability. The repertoire of cognitive-behavioral variables that are operant in adults may have antecedents in earlier life (eg, childhood abuse, parental alcoholism, learned behaviors from living as children with dysfunctional or chronically ill parents). By early adulthood, a failure in goal-oriented behavior may develop, leading to lower self-efficacy, the inability to achieve goals, and a fear of failure. In turn, this may presage reporting of chronic pain as a socially acceptable excuse for failure to achieve goals in later life.
  • Meaning structures
    • Qualitative research shows that patients with fibromyalgia exhibit meaning structures that facilitate their invisible and capricious illness, for which they cannot be blamed.
    • Unwittingly, this may serve as an excuse for not meeting the demands and challenges of life, with accompanying strong rejection of any notion that fibromyalgia could have psychologic antecedents.
    • Rather, patients with fibromyalgia need their physicians and family to confirm that they are ill and that their symptoms are explained as being organically based rather than psychologically based. Therefore, physicians should assist patients with somatic symptoms to not choose illness as a way to deal with difficult personal life situations.
  • Pain beliefs and attributions
    • Negative beliefs (eg, self-blame for the mysterious enduring pain) are associated with increased subjective pain intensity, reduced compliance with treatment, low self-esteem, somatization, and psychologic distress. In patients with chronic pain, the expected tolerance to stimuli or activities that evoke pain or fatigue predicts actual tolerance. Expected danger (damage) predicts avoidance.
    • Self-assessed inability to work, helplessness, low perceived control over pain, and maladaptive coping all affect pain severity and the overall impact of fibromyalgia. Thus, patients with fibromyalgia perceive that they are using excessive effort during formal exercise testing of muscle, even though their actual muscle function is electrophysiologically normal. Similarly, the discordance between disability by self-report versus observed functional disability is high in patients with fibromyalgia but low or absent in patients with other rheumatic diseases, such as ankylosing spondylitis and RA.
  • Hypervigilance
    • Certain data support a hypervigilance model of pain in patients with fibromyalgia. Heightened sensitivity to pain occurs, at least in part, because of increased attention to external stimuli and a preoccupation with pain sensations.
    • Here, pain is amplified by hypervigilance to pain. Patients with fibromyalgia become what they perceive themselves to be.
  • Self-efficacy and coping
    • Perceived self-efficacy is the level of confidence that the patient requires to control pain effectively. People with high self-efficacy beliefs engage in coping behaviors until success is achieved. People with low self-efficacy beliefs anticipate failure and stop using effective coping strategies. Higher coping self-efficacy is associated with less negative mood and pain conditions associated with pain generally. Treatments that improve coping reduce pain and enhance a positive mood, although the use of active coping actually may be detrimental in patients with fibromyalgia who have low self-efficacy for pain control.
    • Self-efficacy may be a significant determinant of pain itself, particularly with respect to its emotional arousal and unpleasant effects. In a study of patients with osteoarthritis, those scoring high for self-efficacy about arthritis pain control exhibited higher thresholds and tolerance for thermal pain compared to those with low scores. Conversely, maladaptive coping strategies, such as catastrophizing about pain, make the pain experience worse, especially with respect to the development of depression.
  • Mood, depression, and anxiety
    • Mood encompasses sadness, fear, anger, joy, interest, and surprise. Depression and anxiety are emotional disorders. A consensus is emerging that depression is a common denominator in chronic pain and fatigue. In addition, unrelieved stress is believed to be the underlying element linking depression, pain, and fatigue. As discussed above, neurohumoral dysfunction consequent to chronic stress provides, at least in part, a biologic explanation for mood disorders and subjective pain and fatigue in patients with fibromyalgia and related disorders.
    • fibromyalgia and major depressive disorder are similar with respect to symptomatology, lifetime prevalence of depression, patterns of comorbidity in individual patients, family history, and response to antidepressant medications. However, chronic pain is not simply a manifestation of depression. Despite frequent complaints of pain and other somatic symptoms, patients with pure major depression actually have increased pain thresholds and more stoical responses to pain stimuli. Similarly, patients with major depression have markedly fewer tender points compared to patients with fibromyalgia.
  • Personality traits and disorders: Personality traits have the largest effect on the cognitive processes by which people attach meanings and implications to their pain. For example, neuroticism, which is associated with hypochondriasis, irritability, and emotional disturbance, has no influence on the discrimination of thermal pain but exerts powerful influences in the delayed, reflective stage of pain (ie, at the level of emotions related to suffering, including depression, anxiety, and, especially, frustration).
  • Pain behaviors
    • At one level, pain behaviors are the various signals that serve to communicate the pain experience to the outside world and include nonverbal expressions of pain (eg, grimacing, bracing, sighing, rubbing, groans, histrionic behavior). Increased pain behaviors are associated with more depression, reduced self-efficacy for pain control, and more negative thoughts. Pain behaviors can be important perpetuators of illness through reinforcement of the responses that the patients induce as a means to get attention, obtain medication, or avoid work or activity. This can lead to limited physical and social activity, dependence on narcotics and alcohol, and unemployment.
    • A common pain behavior in patients with fibromyalgia is excessive use of medical services. Care seekers exhibit lower pain thresholds and greater psychiatric morbidity compared to patients without fibromyalgia who do not have chronic pain, an observation consistent with the idea that care seeking reduces the emotional distress consequent to symptoms and life stressors.
    • Models of pain behavior that interrelate biologic, cognitive, emotional, and behavioral variables form the basis for cognitive-behavioral approaches to pain management.

• Environmental and sociocultural variables: Multiple experiences and forces in a person’s environment and social culture influence the pain experience, either positively (eg, job satisfaction in a person who strains his or her back at work) or negatively (eg, physician who medicalizes a minor injury by diagnostic waffling and inappropriate diagnostic testing). Environmental and sociocultural variables include (1) psychosocial experiences during childhood, (2) spousal and family support, (3) ethnological factors, (4) focus on definable causes, (5) media hype, and (6) primary and secondary gain.

  • Developmental variables
    • These include the psychosocial experiences during childhood, including school stress, role models, unhappy families, and abuse, that shape the cognitive, affective, and behavioral aspects of pain in adults.
    • Some studies show that two thirds of patients with chronic pain have first-degree relatives with chronic pain, one third have a family member with an affective illness, and one third have a family member with alcohol abuse.
    • Childhood physical, emotional, or sexual abuse appears to be a common antecedent of anxiety, somatization, and chronic pain in many adults.
    • In this regard, biologic vulnerability may derive from persisting effects of early life stresses on the stress response system.
  • Interpersonal variables
    • Spousal and family support can either mitigate or adversely impact the various dimensions of chronic pain.
    • Training of spouses to enhance their ill partner’s coping skills improves self-efficacy for pain control and reduces pain and psychologic distress. Spousal reinforcement of pain behaviors can lower experimentally determined pain thresholds.
  • Work environment and job satisfaction
    • Job satisfaction and a healthy work environment lessen the emotional distress associated with chronic pain.
    • Conversely, job dissatisfaction strongly predicts the progression of acute back pain to chronic low back pain. Similarly, workers’ compensation and disability benefits can be significant disincentives for recovery from chronic pain.
  • Sociocultural factors
    • Pain tolerance may be profoundly influenced by culture (eg, greater emotional and behavioral responses to pain in Jewish and Italian patients in New York City relative to native-born Anglo-Saxons). The prevalence of widespread chronic pain is zero in Pima Indians but is approximately 10% for white populations on both sides of the Atlantic.
    • The current epidemic of fibromyalgia, chronic fatigue syndrome, sick building syndrome, and multiple chemical sensitivity syndrome arguably is, at least in part, due to media hype, fear, suggestibility, and a focus on definable causes by patients and physicians.