Introduction

Fibromyalgia is a disorder of the central nervous system characterized by the presence of chronic widespread pain. It affects at least 2% of the general population, primarily women.^[1] Additional symptoms associated with fibromyalgia include fatigue, insomnia, nonrefreshing sleep, and cognitive "fogginess" (known as fibrofog). Patients with fibromyalgia are also likely to experience 1 or more co-occurring regional chronic pain syndromes, such as irritable bowel syndrome (IBS), interstitial cystitis, temporomandibular joint disorder, and tension headaches, over their lifetime.^[2-4] For example, it has been estimated that between 32% and 70% of individuals with fibromyalgia also meet criteria for IBS.^[5,6] Patients who experience multiple syndromes and/or comorbid conditions present a more complex clinical scenario that requires special consideration, and such patients tend to have worse outcomes.

This review focuses on the current knowledge regarding similarities and overlap between fibromyalgia and IBS and their treatment approaches as a basis for understanding the pathophysiology of pain.

Chronic Pain Syndromes Comorbidities

Chronic pain syndromes can co-occur with other diseases; for example, fibromyalgia has been observed in about 1 in 4 patients with rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus.^[7] Wolfe^[8] characterizes these patients as having varying degrees of "fibromyalgianess," characterized by varying degrees of multifocal pain, fatigue, insomnia, and memory difficulties that cannot be explained on the basis of the current understanding of the pathogenesis of their rheumatologic disorders. Similarly, IBS has been estimated to co-occur in 10%-20% of patients with inflammatory bowel disease, while 5%-33% of patients with enteric infections will subsequently go on to have chronic IBS symptoms (a condition known as postinfectious IBS).^[9-11] Psychological factors such as depression and anxiety are associated with the presence of IBS-like symptoms in these patients.^[12]

Psychiatric comorbidities, especially depression and anxiety, are common in chronic pain conditions, including fibromyalgia and IBS. In fibromyalgia, depression and/or anxiety are present in approximately 25% of patients,^[13,14] while lifetime estimates of depression are well over 60%.^[13-16] Similarly, psychiatric disorders have been identified in up to 50% of patients with functional abdominal pain.^[17] The presence of psychiatric comorbidities, inadequate response to treatment, and a lack of objective evidence of disease (eg, positive lab tests and identification of a peripheral cause of pain) contributed to the belief that these pain syndromes are somatization disorders -- psychiatric in nature and a "fashionable" expression of psychological distress.^[18] Terms such as "functional somatic syndromes" or "medically unexplained syndromes" have only reinforced the dualism that restricts research and treatment and can be stigmatizing for individuals affected by these illnesses.

Over the past decade, innovative research inspired by advances in the neuroscience of pain has markedly contributed to the understanding of the pathophysiology of conditions like fibromyalgia and IBS. These advances have allowed us to reliably demonstrate augmented central processing of pain and sensory information in fibromyalgia, IBS, interstitial cystitis, and temporomandibular joint disorder, resulting in new and more integrative ways of conceptualizing these conditions (characterized as "central sensitivity syndromes" or "central pain syndromes") and their treatment.^[19]

Fibromyalgia and Irritable Bowel Syndrome: Understanding the Central Augmentation of Pain and Sensory Processing

There is a growing consensus among experts in the pain field that chronic pain is a disease and that the underlying mechanisms may be similar to those of fibromyalgia, regardless of whether pain is present throughout the body or localized to a specific area.^[20,21] Realizing that the underlying pain was not caused by peripheral damage or inflammation, but was likely the product of central nervous system dysfunction, further increased our understanding of these disorders.

Experimental pain testing studies in fibromyalgia and IBS have also enhanced our understanding of the pathophysiology of pain and sensory processing. Although early fibromyalgia dolorimetry studies found that pain thresholds correlated with distress, expectancy, and hypervigilance,^[1,22,23] recent studies using sophisticated experimental paradigms demonstrated that: (1) unlike tender-point and dolorimetry exams, the random measures of pressure pain threshold were not influenced by levels of distress of the individual; (2) patients with fibromyalgia were much more sensitive to pressure, even when these more sophisticated paradigms were used; (3) patients with fibromyalgia were not more "expectant" or "hypervigilant" than controls; and (4) pressure pain thresholds at any 4 points in the body highly correlated with the average tenderness at all 18 tender points and 4 "control points."^[24,25]

In addition to heightened sensitivity to pressure, individuals with fibromyalgia and IBS also display decreased somatic thresholds to heat, cold, electrical, and sensory information other than somatic stimuli, such as auditory tones.^[26-29] The notion that fibromyalgia and related syndromes like IBS might represent biological amplification of all sensory stimuli also has significant support from functional neuroimaging studies. In a seminal study using functional magnetic resonance imaging to evaluate neural processing in fibromyalgia, Gracely and colleagues^[30] found that stimuli of equal pressure magnitude resulted in significant increases in the blood oxygen level-dependent signal in patients with fibromyalgia compared with control individuals. Affected areas included the primary and secondary somatosensory cortices, insula, and anterior cingulate. This finding has been replicated in fibromyalgia, and similar findings of a hyperalgesic state (including hyperreactivity of the insula) have been noted in a variety of chronic pain states, including IBS.^[31] The insula plays a critical role in sensory integration; while the posterior insula is associated with sensory processing, the anterior insula is linked to the emotional processing of sensations.^[32-34]

Besides the common observance of diffuse hyperalgesia/allodynia, attenuated activity of descending analgesic pathways (sometimes referred to as diffuse noxious inhibitory control [DNIC]) has been reported in several of these conditions and may contribute to pain sensitivity.^[35-37] In animals and healthy humans, the repeated administration of an acutely painful stimulus typically results in a subsequent increase in pain threshold (ie, decrease of tenderness).^[38] This phenomenon is known as DNIC because it involves the recruitment of descending analgesic pathways to address the painful stimulus. Diffuse noxious inhibitory control has been shown to be attenuated or absent in both fibromyalgia and IBS patients, suggesting a deficiency in descending analgesic systems.^[35-37] Furthermore, in fibromyalgia and comorbid depression, the deficit in pain inhibition has been shown to be more pronounced.^[39] A relative deficiency in DNIC thus appears to be one of the mechanisms of central pain augmentation and may eventually serve to help characterize subgroups of patients who might be differentially responsive to various treatment modalities.

Role of Neurotransmitters

Studies from a variety of sources support the analogy of an increased "volume control" or "gain" setting on pain and sensory processing.^[20] Like essential hypertension, for which a variety of causes can result in elevated systemic blood pressure, these disorders can be characterized as "essential hypertension of pain and sensory processing pathways". As depicted in the Figure, in central pain syndromes elevated levels of neurotransmitters tend to be pro-nociceptive (left side of figure), while reduced levels of neurotransmitters that inhibit pain transmission have a tendency to increase volume control (right side of figure). To date, the endogenous opioid system is the only neurotransmitter system not found to be "out of line" in a direction that would cause augmented pain transmission. Drugs that block neurotransmitters or increase their activity typically are effective treatments for individuals with central pain syndromes.

Figure. Neural influences on pain and sensory processing. GABA = gamma-aminobutyric acid

Genetic and Environmental Factors

Several lines of evidence support a stress-diathesis etiology for the development of central pain syndromes. Family studies have shown that first-degree biological relatives of individuals with fibromyalgia display an 8-fold greater risk of developing fibromyalgia compared with the general population,^[6] while family members of individuals with IBS have almost 3 times the odds of developing IBS.^[40] Furthermore, compared with controls, family members of individuals with fibromyalgia tend to be more sensitive to pain and are more likely to have other central pain disorders, such as IBS, temporomandibular joint disorder, and headaches.^[41] Findings from twin studies suggest that approximately half of the risk of developing chronic widespread pain is genetic, while the other half is environmental.^[42]

Environmental factors may predispose and/or trigger central pain syndromes in some individuals. Although the retrospective analysis of childhood traumatic events is fraught with pitfalls, numerous studies have found elevated rates of these events reported in patients with central pain syndromes.^[43] The reported presence of a history of early trauma has been associated with poor outcomes, including physiologic dysfunction.^[44,45] Central pain syndromes can be triggered in approximately 5%-10% of individuals who experience peripheral pain syndromes, infections (eg, parvovirus, Epstein-Barr virus, Lyme disease, bacterial gastroenteritis), physical trauma (eg, automobile accidents), psychological trauma/distress, hormonal alteration, or catastrophic events.^[46] Environmental factors have also been implicated in triggering fibromyalgia and related conditions.

Psychological and Behavioral Factors

As previously noted, depression and anxiety are common in central pain syndromes. In addition to psychiatric comorbidities, other psychological variables associated with poor outcomes have been frequently described in fibromyalgia and IBS, including pain catastrophizing and somatosensory amplification.^[47-50] Similar to what is observed in almost every medical condition, psychological factors significantly contribute to symptom severity and treatment outcome in central pain syndromes. For example, in addition to the presence of mucosal inflammation, psychological distress at the time of enteric infection best predicted those who later developed postinfectious IBS.^[51]

In fibromyalgia, such psychological factors occur on a continuum, from a high incidence of personality disorders in tertiary care patients^[13] to psychological resilience, whereby patients have no psychiatric comorbidity and exhibit high levels of positive affect and significantly better functional outcomes.^[52] Years of psychopathology-oriented research in fibromyalgia and IBS have shown that no single psychological factor accounts for the symptoms or behaviors of all individuals with these conditions in any given sample. It is possible that within subgroups of resilient patients, positive psychological and/or cognitive characteristics may buffer neurobiologic factors that result in pain and other symptoms.^[52-54] Subgroups of patients may also present differently, respond differently to treatment, and/or require specific or "tailored" treatment strategies

Treatment of Fibromyalgia and Irritable Bowel Syndrome

The diagnosis, evaluation, and effective management of individuals with chronic pain is a complex process, due to tremendous heterogeneity with respect to the underlying cause of any given pain symptoms. Individuals with chronic pain can have varying involvement of peripheral nociceptive factors (eg, tissue damage and inflammation) and central non-nociceptive factors (eg, pain amplification and psychiatric comorbidity) contributing to their pain (Table 1).^[55] Differential diagnosis of chronic pain involves identifying the degree to which these factors are present in a given individual so that the appropriate pharmacologic, procedural, and psychological therapies can be administered. The treatment strategies discussed below predominantly focus on addressing pain (most of the approved pharmacologic therapies for IBS are more effective at treating motility than pain). For management of IBS-specific symptoms, mainly diarrhea or constipation, the recommendations of the American College of Gastroenterology Task Force on IBS should be considered.^[56]

Table 1. Mechanistic Characterization of Pain (any combination may be present in a given individual)

NSAIDs = nonsteroidal anti-inflammatory drugs; TCAs = tricyclic antidepressants

Pharmacologic Treatment

Tricyclic antidepressants (TCAs). TCAs generally increase concentrations of serotonin and/or norepinephrine by directly blocking their reuptake. The efficacy of TCAs in treating pain, poor sleep, and fatigue in fibromyalgia patients is supported by several randomized controlled trials.^[57] Furthermore, they have been found to be effective in a broad range of chronic pain states, including IBS.^[57,58] Although tolerability can represent a problem, this issue can be improved by initiating treatment at very low doses.

Selective serotonin reuptake inhibitors (SSRIs). Given that they exhibit a better side-effect profile than TCAs, SSRIs have been evaluated in randomized, placebo-controlled trials in fibromyalgia^[59-62] and IBS.^[63-66] In general, the results of these studies paralleled those evaluating other pain conditions. Newer, highly selective SSRIs (eg, citalopram) seem less efficacious than the older SSRIs, which have some noradrenergic activity at higher doses.^[67]

Serotonin norepinephrine reuptake inhibitors (SNRIs). SNRIs are pharmacologically similar to TCAs in their ability to inhibit the reuptake of serotonin and norepinephrine but lack significant activity at other receptor systems, resulting in diminished side effects and enhanced tolerability. Data on venlafaxine, the first agent of this class available for clinical investigation, support its use in the management of neuropathic pain and in the prophylaxis of migraine and tension headaches.^[68] Although venlafaxine was ineffective in the management of fibromyalgia at 75 mg/day in a randomized controlled trial, it appeared effective at higher doses in 2 case reports.^[59]

Duloxetine is an SNRI that was recently approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia. Recent clinical trials have shown that duloxetine is effective in the management of pain and other symptom domains of fibromyalgia, as well as a number of other chronic pain states (eg, osteoarthritis and chronic low back pain), further supporting the involvement of central nervous system factors in these conditions.^[69,70] To date, only 1 small open pilot study of duloxetine has been conducted in IBS, showing a significant reduction of pain.^[71]

Milnacipran, another SNRI, may preferentially inhibit norepinephrine reuptake over serotonin, in contrast to duloxetine and other SNRIs.^[72] In recent large, multicenter trials, milnacipran showed efficacy in the management of pain and other symptom domains of fibromyalgia, such as fatigue and physical functioning.^[73] The benefits of milnacipran and duloxetine in fibromyalgia management have been shown to be independent of their effect on mood, suggesting that the analgesic and other beneficial effects of this class of drugs are not simply due to their antidepressant effects.^[69,74]

Antiepileptic drugs. Several antiepileptic drugs are widely used in the treatment of various chronic pain conditions.^[75] Pregabalin, an alpha(2)delta calcium channel ligand approved for the treatment of neuropathic pain, was the first pharmacologic agent approved by the FDA for the treatment of fibromyalgia. Recent randomized, double-blinded, placebo-controlled trials demonstrated efficacy of pregabalin against pain, sleep disturbances, and fatigue in fibromyalgia patients compared with placebo.^[76-78] Similarly, in a small but thorough study, pregabalin was found to increase visceral pain threshold in IBS compared with placebo.^[72] Gabapentin is a compound with similar pharmacology to pregabalin that has been indicated for the treatment of postherpetic neuralgia and studied in a variety of pain states, including fibromyalgia, IBS, and headache prophylaxis.^[75,79,80]

Sedative-hypnotic compounds. Sedative-hypnotic compounds are widely used by fibromyalgia patients. A number of studies published on the use of nonbenzodiazepine hypnotics (ie, zopiclone and zolpidem) have suggested that although these agents can improve lack of sleep and possibly fatigue in fibromyalgia patients, they do not have significant effects on improving pain.^[81,82] However, gamma-hydroxybutyrate (also known as sodium oxybate), a precursor of gamma-aminobutyric acid (GABA) with powerful sedative properties, was recently shown to be useful in improving fatigue, pain, and sleep architecture in fibromyalgia patients.^[81] It is important to note that this agent is a scheduled substance due to its abuse potential.

Opioids. There have not been adequate randomized controlled clinical trials of opiates in fibromyalgia and IBS, and many practitioners in the field have not found this class of compounds to be effective. In fact, there is anecdotal evidence that some individuals with central pain states may develop opioid-induced hyperalgesia, and thus this class of drugs may make some individuals' conditions worse. Tramadol, a compound that exhibits opioid activity combined with serotonin/norepinephrine reuptake inhibition, appears to be somewhat efficacious in the management of fibromyalgia, both as monotherapy and as a fixed-dose combination with acetaminophen.^[83]

Nonpharmacologic Treatment

For both fibromyalgia and IBS, multidisciplinary treatment is recommended.^[84,85] Central to this approach is taking into consideration the unique characteristics of each patient and adding adjunctive nonpharmacologic interventions to the evidence-based use of medication. The importance of including exercise, patient education, and cognitive-behavioral therapy in the treatment of fibromyalgia and IBS has been substantiated in a number of studies.^[86-89] Balneotherapy, hypnotherapy, and various forms of biofeedback have also demonstrated some degree of benefit.^[90]

Exercise. Jones and Liptan^[86] noted that over 80% of patients with fibromyalgia have below-average fitness levels and do not engage in aerobic exercise. Exercise studies conducted in central-pain populations almost always exhibit high attrition rates; however, they consistently demonstrate benefit for participants.^[89,91] Persistence with an exercise regimen can be improved by participation in low-intensity, nonrepetitive exercise (eg, aquatic exercise), "starting slow and going slow" (eg, 15 minutes of exercise a day twice a week), and making it fun (eg, exercise with friends, walk in pleasant surroundings, engage in dance or yoga).

Education. Psychoeducation is viewed by most experts as useful, if not necessary, for the treatment of fibromyalgia.^[84] A recent study in IBS also found a structured patient education program to be particularly effective for patients with this condition.^[92] These educational programs aim to improve the understanding of the complex interactions between neurobiological processes, behavior, stress, and symptoms. Such programs have varied foci but typically target the stigma often attached to fibromyalgia, IBS, and similar disorders.

Cognitive-behavioral therapy. Cognitive-behavioral therapy interventions for fibromyalgia and IBS should target modification of maladaptive thoughts and expectations, how to better cope with pain, mood, perceived stress, and problem-solving, while including behavioral interventions (eg, activity pacing, sleep hygiene, and relaxation training) that address symptoms. The main goal of cognitive-behavioral therapy for chronic pain syndromes is to increase self-management and level of functioning.

For daily clinical practice, the principles of comprehensive nonpharmacologic pain management represented by the acronym ExPRESS (Table 2) can help guide intervention.^[90] Many of the ExPRESS domains can be addressed by using a self-paced education, exercise, and cognitive-behavioral therapy program known as FibroGuide (www.knowfibro.com).

Table 2. ExPRESS Approach to Adjunctive, Nonpharmacologic Treatment for Patients With Chronic Pain Syndromes

Summary

Data from various types of studies show a significant overlap between fibromyalgia and IBS in terms of symptom profile, underlying pathophysiologic processes, and response to treatment. A hallmark of both of these conditions is an "increased gain" in pain processing due in large part to central nervous system mechanisms. This phenomenon, also termed hyperalgesia, is being identified in a subset of individuals with nearly any chronic pain state, including conditions such as osteoarthritis, for which pain previously was thought to be due exclusively to peripheral nociceptive factors.^[93,94] The most appropriate treatment for these hyperalgesic states includes choosing the appropriate pharmacologic therapy (ie, drugs that modify neurotransmitters involved in setting the gain on pain transmission rather than nonsteroidal anti-inflammatory drugs or opioids, which are more appropriate for treating peripheral pain) and combining it with the aggressive use of nonpharmacologic therapies, such as education, cognitive-behavioral therapy, and exercise.

Supported by independent educational grants from Forest Laboratories and Pfizer, Inc.