Roland Staud Twaddle MD
Essentials of Diagnosis
Fibromyalgia syndrome (FM) is a chronic pain syndrome, characterized by generalized pain, tender points, disturbed sleep, and pronounced fatigue. Pain in FM is consistently felt in the musculature and is related to sensitization of central nervous system (CNS) pain pathways. The pathogenesis of FM is unknown, although abnormal concentration of CNS neuropeptides and alterations of the hypothalamic-pituitary-adrenal axis have been described. There is a large body of evidence for a generalized lowering of pressure pain thresholds in FM patients. Importantly, this mechanical allodynia in patients with FM is not limited to tender points but appears to be widespread. In addition, almost all studies of patients with FM have shown abnormalities of pain sensitivity while using different methods of neurosensory testing.
By definition, FM encompasses the extreme end of chronic widespread pain in the general population and is a chronic illness that disproportionately affects women (9:1). Like many other syndromes, FM has no single specific feature but represents a symptom complex of self-reported or elicited findings. In 1990, the American College of Rheumatology (ACR) published diagnostic criteria for FM that include chronic widespread pain (>3 months) and mechanical allodynia in at least 11 of 18 tender points. Most tender point sites are located at tendon insertion areas and have shown few detectable tissue abnormalities. Besides musculoskeletal pain and mechanical tenderness, most FM patients also complain of insomnia, fatigue, and distress. The familial coaggregation and frequent comorbidity of FM with major mood disorders also suggests a role for neuroendocrine and stress-response abnormalities.
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Patients with FM, which is a pain amplification syndrome, are highly sensitive to painful and nonpainful stimuli, including touch, heat, cold, and chemical stimuli. However, it should be noted that the hypersensitivity of these patients is not limited to pain, but also includes light, sound, and smell. The cause for the heightened sensitivity of patients with FM is unknown, but CNS pain processing abnormalities have been reported in several studies. Most of these studies found evidence of central sensitization indicating lowered nociceptive thresholds at the dorsal horn of the spinal cord and the brain. Although peripheral nociceptive input is required for pain in FM,
an important characteristic of central sensitization is that it requires very little sustained nociceptive input from peripheral tissues for the maintenance of the sensitized state and chronic pain.
There is increasing evidence of a familial aggregation for FM, although these data often are inferential rather than definitive. Several prospective studies have suggested that relatives of patients with FM display higher than expected rates of FM. Family members of patients with FM also display a high frequency of a number of conditions related to FM, including irritable bowel syndrome, chronic fatigue syndrome, migraine headaches, and mood disorders. Many of these allied conditions, such as migraine headaches and major depression, have also been noted independently to have a familial predilection.
The onset of FM has frequently been associated with certain triggers. Like many illnesses, the start of FM symptoms may occur when genetically predisposed individuals become exposed to certain environmental triggers that can initiate the development of symptoms. Most environmental exposures that have been described as triggers for FM can be categorized as “stressors” including physical trauma; infections; emotional distress; endocrine disorders; and immune activation, which sometimes result in autoimmune disorders.
These stressors seem to result in high degrees of pain, disability, life interference, and affective distress as well as decreasing levels of physical activity. Some of the strongest evidence supporting the association of trauma and FM symptoms was obtained during prospective studies of adults with neck injuries. Compared with adults with lower extremity fractures or ankle injury, neck trauma carried a more than 10-fold increased risk of developing FM within 1 year of injury. Additional evidence supporting such an association include sleep abnormalities postinjury, local injury sites as a source of chronic distal regional pain, and recent evidence of extensive CNS neuroplasticity in FM. Chronic pain after neck injury raises several important questions about the role that injury location plays in long-term outcome. Obviously, there is something different between neck and leg trauma. One important fact may be related to the difference in local pain sensitivity, with neck and upper chest area showing decreased mechanical pain thresholds compared with the lower extremities. Further prospective studies, however, are needed to confirm this association and to identify whether trauma plays a causal role in FM pain.
The biologic response to stressors appears predictable in animals and humans. Particularly, events that are perceived as inescapable or unavoidable, or which appear unpredictable, evoke the strongest adverse biologic responses. This may explain why trauma victims appear to develop much higher rates of FM than injured persons who are responsible for the incident. In addition, early life stressors can have a permanent and profound impact on subsequent biologic responses to stress, which may explain the higher than expected incidence of traumatic childhood events in persons in whom chronic pain later develops.
More than 50% of patients with FM have been found to suffer from posttraumatic stress disorder (PTSD) in the United States and Israel. Compared with the prevalence of PTSD in the general population (6%), patients with FM show a greatly increased rate of PTSD that is similar to Vietnam veterans and victims of natural disasters or motor vehicle accidents. PTSD often occurs after a significant traumatic event and is characterized by behavioral, emotional, functional, and physiologic symptoms.
Relevant traumatic events related to PTSD are usually perceived by the person as threatening his or her life or physical integrity and can lead to emotional responses including horror, helplessness, or intense fear. The psychological symptoms of PTSD include reexperience of the traumatic event, avoidance, and increased arousal. It has been shown that the experience of trauma is associated with increased somatic and physical complaints, including pain. Not surprisingly, the incidence of FM is increased in patients with PTSD (21%); the combination of FM and PTSD is often associated with increased pain ratings, more distress, and higher functional impairment. As with several other disorders, however, it is unclear whether PTSD is the cause or consequence of FM.
Numerous studies have reported that FM and major depressive disorder are comorbidities. The outcome of a recent large family study of FM probands was consistent with the hypothesis that FM and major depressive disorder are characterized by shared, genetically mediated risk factors. Although the findings of this study should not be interpreted to mean that major depressive disorder and FM represent different forms of the same syndrome, they strongly suggest that FM and major depressive disorder share important CNS mechanisms.
Tissue sensitization after injury has long been recognized as an important contribution to pain and may play an important role in FM pain. This form of sensitization is related to changes of the properties of primary nociceptive afferents (peripheral sensitization), whereas
central sensitization requires functional changes in the CNS (neuroplasticity). Such CNS changes may result in central sensitization, which manifests itself as the following:
Figure 15-1. Windup of healthy persons. Twenty identical heat stimuli (52°C) were applied to the hand. With increasing stimulus frequency (1 tap every 3-6 seconds), the pain ratings progressively increased.
Behaviorally, centrally sensitized patients, like FM sufferers, report abnormal or heightened pain sensitivity; this hypersensitivity spreads to uninjured sites and pain is generated by low threshold mechanoreceptors that are normally silent in pain processing. Thus, tissue injury may not only cause pain but also an expansion of dorsal horn receptive fields and central sensitization.
There are several important points that are relevant for clinical practice. When central sensitization has occurred in patients with chronic pain (eg, in those with FM), very little additional nociceptive input is required to maintain the sensitized state. Thus, seemingly innocuous daily activities may contribute to the maintenance of chronic pain states. In addition, the decay of painful sensations is prolonged in FM, and therefore, patients should not expect drastic changes of their pain levels during brief therapeutic interventions. Many analgesic medications do not seem to improve central sensitization, and some medications (including opioids) have been shown to maintain or even worsen this central phenomenon.
The noninvasive method of summation of second pain or windup can be used in FM patients for evaluation of central sensitization. This technique reveals sensitivity to input from unmyelinated (C) afferents and the status of the N-methyl-D-aspartate (NMDA) receptor systems that are implicated in a variety of chronic pain conditions (Figure 15-1). Thermal, mechanical, or electrical windup stimuli can be easily applied to the skin or musculature of patients. Commercial neurosensory stimulators are readily available that can be used for windup testing. Patients with FM show excessive summation of C-fiber mediated pain. Temporal summation depends on activation of NMDA transmitter systems by C nociceptors, and chronic central pain states like FM can result from excessive temporal summation of pain.
-Repetitive C-fiber stimulation can result in a progressive increase of electrical discharges from second order neurons in the spinal cord. This important mechanism of pain amplification in the dorsal horn neurons of the spinal cord is related to temporal summation of second pain or windup. First pain is conducted by myelinated Aδ pain fibers and is often described as sharp or lancinating and can be readily distinguished from second pain by most persons. Second pain(transmitted by unmyelinated C fibers) is strongly related to chronic pain states and is most frequently reported as dull, aching, or burning. Second pain increases in intensity when painful stimuli are applied more often than once every 3 seconds. This progressive increase represents temporal summation (termed “windup”) and has been demonstrated to result from CNS rather than peripheral nervous system mechanisms. Importantly, windup and second pain can be inhibited by application of NMDA receptor antagonists, including dextromethorphan and ketamine.
-Abnormal windup and central sensitization may be relevant for FM pain because this chronic pain syndrome is often associated with extensive secondary hyperalgesia and allodynia. Several recent studies have obtained
psychophysical evidence that input to central nociceptive pathways is abnormally processed in patients with FM.
Figure 15-2. Predictors of clinical pain intensity in patients with fibromyalgia. A statistical model consisting of windup aftersensations, pain-related negative affect (PRNA), and tender point (TP) count, accounts for 50% of patients' variance in clinical pain intensity.
When windup pain is evoked both in healthy persons and persons with FM, the perceived magnitude of the experimental stimuli (heat, cold, electricity) is greater among persons with FM, as is the amount of temporal summation within a series of stimuli. Following a series of stimuli, after-sensations are greater in magnitude, last longer and are more frequently painful in persons with FM. These results indicate both augmentation and prolonged decay of nociceptive input in patients with FM and provide convincing evidence for the presence of central sensitization.
-The important role of central pain mechanisms for clinical pain is also supported by their usefulness as predictors of clinical pain intensity in patients with FM. Thermal windup ratings correlate well with clinical pain intensity (Pearson's r = 0.529), thus emphasizing the important role of these pain mechanisms for FM. In addition, statistical prediction models that include tender point count, pain-related negative affect, and windup ratings have been shown to account for 50% of the variance in FM clinical pain intensity (Figure 15-2).
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FM is a clinical syndrome that encompasses patients at the extremes of chronic musculoskeletal pain in the general population. Although the 1990 ACR diagnostic criteria for FM have shown 85% specificity for this illness, they do not mean that FM exists only in persons fulfilling these definitions. Similar to systemic lupus or rheumatoid arthritis criteria, FM criteria were narrowly defined
for study purposes. For clinical use, FM should be considered in all patients who have widespread pain and tenderness but who do not have structural or inflammatory tissue abnormalities. However like many chronic pain syndromes, FM becomes clinically relevant frequently after significant dysfunction or affective distress has occurred. At this crucial point, FM sufferers often become patients and seek medical care. However, epidemiologic research has clearly shown that secondary gain or malingering do not seem to play a major role for FM patients' health care seeking.
Most important for the diagnosis of FM is widespread chronic musculoskeletal pain of unknown origin that has led to functional impairment or distress. Pain has to be reported in all four quadrants of the body as well as the lower back. However, the pain does not have to be in all body quadrants at the same time. Pain is considered to be chronic when it has been present for at least 3 months. Other physical findings include the following:
Besides chronic widespread pain, patients with FM need to show evidence of widespread mechanical tenderness. So-called tender points are used to evaluate mechanical allodynia. Tender points are located in areas of tendon insertion sites (Figure 15-3) and can be tested with an algometer or by thumb pressure. A tender point is present when pain threshold is detectable at pressures of ≤ 4 kg applied to these sites. Similarly, when thumb pressure is applied to a tender point site and pain threshold is reached at or before the thumb nail blanches, a tender point has been verified. The locations of tender points are listed in Table 15-1.
There are no specific laboratory abnormalities detectable in patients with FM. Elevated levels of substance P (more than three times normal) and nerve growth factor in the cerebrospinal fluid of FM patients have been reported in three different studies. Conversely, decreased concentrations of serotonin and noradrenalin have been found in the cerebrospinal fluid of FM patients. Otherwise, patients with FM have normal laboratory examinations.
Figure 15-3. Location of 18 tender points.
Elevated erythrocyte sedimentation rates or C-reactive protein concentrations should raise suspicion for chronic inflammatory or neoplastic diseases. Thyroid function studies, including thyroid-stimulating hormone and free T4 levels are helpful in ruling out thyroid dysfunction. Because the differential diagnosis for FM includes inflammatory and metabolic myopathies, screening for elevated creatine kinase levels and aldolase is useful. Chronic infections such as tuberculosis, HIV, or hepatitis B and C should always be excluded in high-risk populations. Laboratory evaluations of unproven value for the diagnosis of FM include autoimmune
antibodies, antipolymer antibodies, Epstein-Barr virus antibodies, Lyme disease antibodies, yeast antibodies, and serotonin antibodies.
Table 15-1. Locations of Tender Points in Patients with Fibromyalgia.
Although brain imaging studies of patients with FM have not identified structural changes, more specific brain imaging protocols using functional MRI can be used to show increased activation of pain-related brain areas in patients with FM. In patients with high likelihood for multiple sclerosis, brain imaging is indicated and necessary for making the diagnosis. Otherwise, radiologic evaluation of the spine and painful joints may help in identifying major pain generators, such as osteoarthritis and inflammatory arthritis.
Quantitative neurosensory testing with mechanical, thermal, and electrical stimuli to the skin and muscles has shown profound pain processing abnormalities, including hyperalgesia, allodynia, and central sensitization, in patients with FM. Specifically, testing of temporal summation of second pain (windup) and R-III nociceptive reflex measurements have demonstrated abnormalities consistent with central sensitization in FM.
Besides a manual tender point examination, a body pain diagram completed by the patient is clinically useful. The number of pain areas shaded on a body pain diagram shares a linear relationship with clinical pain intensity and can be easily obtained in clinical practice.
Pain can be measured using pain rating scales. Table 15-2 lists the pain rating scales and their useful-ness in evaluating patients with FM. The Visual Analogue Scale is superior to the Numerical Pain Scale because of its ratio scaling properties. Validated pain scales often use end points such as “no pain at all” and “most intense pain sensation imaginable.” However, to obtain clinically relevant pain ratings, pain occurring within a specific time period should be measured (eg, the usual pain during the previous day or the previous week).
Table 15-2. Pain Rating Scales and Their Usefulness in Evaluating Patients with Fibromyalgia.
In addition, testing for major mood disorders should be obtained using validated questionnaires like the Beck Depression Inventory (a score of ≥21 indicates clinical depression).
Staud R et al. Body pain area and pain-related negative affect predict clinical pain intensity in patients with fibromyalgia. J Pain. 2004;5:338.
Many systemic illnesses can present with diffuse pain similar to FM, including myofascial pain syndrome, polymyalgia rheumatica, rheumatoid arthritis, Sjögren syndrome, inflammatory myopathies, systemic lupus erythematosus, multiple sclerosis, and joint hypermobility syndrome. Furthermore, several infectious diseases, including hepatitis C, Lyme disease, coxsackie B infection, HIV, and parvovirus infection, have been described as a trigger for chronic pain. Although most patients with FM report the insidious onset of pain and fatigue, approximately half of all patients describe the start of chronic pain after a traumatic event. Because a large epidemiologic study provided recent evidence for increased cancer mortality in patients with widespread pain, this differential diagnosis needs to be considered in many patients with FM.
Myofascial pain or regional musculoskeletal pain is commonly encountered in clinical practice. Myofascial pain syndrome is defined as a chronic pain syndrome accompanied by trigger points in one or more muscles or groups of muscles and is a common cause of neck and shoulder pain, tension headaches, and lower back pain. Similar to FM, it is found more frequently in women than in men and is often associated with limitation of movement, weakness, and autonomic dysfunction as well as the trigger points and referred pain.
Trigger points represent areas of local mechanical hyperalgesia that can be found in myofascial pain syndrome and several chronic pain conditions, including FM, osteoarthritis, and rheumatoid arthritis. Trigger points are
specific areas of hyperirritability in muscle but can also be detected in ligaments, tendons, periosteum, scar tissue, or skin. Trigger points are located in palpable “taut bands” and produce local and referred pain, which is specific for the particular muscle. When trigger points are mechanically stimulated, the “taut bands” within a muscle, rather than the entire muscle, will contract. Trigger points are often associated with a local muscle “twitch response,” which can easily be elicited by needling or palpation of the trigger point. Latent trigger points are similar to active trigger points, but they are not associated with spontaneous pain and no referral of pain occurs. However, latent trigger points are painful when palpated.
Pain and FM
Approximately 70% of patients with FM have trigger points. A tender point is considered to be different than a trigger point because of the absence of referred pain, local twitch response, and a taut band in the muscle. The distinction between a tender point and a trigger point requires careful physical examination. Trigger points, however, are frequently located in areas of muscular tender points of patients with FM suggesting that some muscular tender points in patients with FM may actually be trigger points.
The presence of trigger points in most if not all patients with FM represents evidence for local muscle abnormalities in this chronic musculoskeletal pain syndrome. Although it is unclear whether trigger points are the cause or effect of muscle injury, they represent abnormally contracted muscle fibers. This muscle contraction can lead to accumulation of histamine, serotonin, tachykinins, and prostaglandins, which may result in the activation of local nociceptors. Prolonged muscle contractions may also result in local hypoxemia and energy depletion.
Many patients with chronic arthritis (up to 25%) also have chronic widespread pain similar to FM. These patients may also have the following symptoms: chronic fatigue, impaired memory and concentration, and mood abnormalities. However, most of these patients will have findings suggestive of inflammation (including joint pain and swelling, rashes, and muscle weakness) as well as laboratory abnormalities, including elevated erythrocyte sedimentation rate, C-reactive protein, anemia, and autoantibodies (rheumatoid factor, cyclic citrullinated peptide antibodies, antinuclear antibodies).
Thus, a detailed clinical examination and laboratory testing may be necessary to exclude inflammatory connective tissue diseases in chronic pain patients with arthritis or rash.
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Treatment of patients with chronic widespread pain needs to be individually tailored. This includes the assessment of biopsychosocial abnormalities, which are readily detectable in most patients with FM. Importantly, the identification of pain generators is essential for an effective treatment plan. Thus, patients with arthritis, particularly osteoarthritis of the spine, will benefit from muscle relaxants, physical therapy, and massage. In addition, these patients may respond well to therapy with cyclooxygenase (COX) inhibitors. Identification and treatment of mood abnormalities is crucial because affective spectrum disorders seem to share important mechanisms with FM.
Pharmacotherapy for FM has been most successful with antidepressant, muscle relaxant, or anticonvulsant drugs. These drugs affect the release of various neurochemicals (eg, serotonin, norepinephrine, substance P) that have a broad range of activities in the brain and spinal cord, including modulation of pain sensation and tolerance. However, none of these drugs are currently approved by the US Food and Drug Administration for the treatment of FM.
Most patients with FM respond to low-dose tricyclic antidepressants, such as amitriptyline, and to cyclobenzaprine as well as cardiovascular exercise, cognitive-behavioral therapy, patient education, or a combination of these therapies. Also tramadol, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and anticonvulsants have been found to be moderately effective. There is some evidence for the efficacy of strength training exercise, acupuncture, hypnotherapy, biofeedback, massage, and warm water baths. However, many commonly used FM therapies like guaifenesin have been found to be ineffective.
Based on published evidence, a stepwise FM management approach can be recommended. Confirmation of the diagnosis is crucial and relevant FM pain mechanisms, including the important role of pain generators, must be explained to the patient and family. This often
alleviates concerns about the nature of chronic musculoskeletal pain. Any comorbid illnesses, such as mood disturbances or primary sleep disturbances, need to be identified and treated. It is important to refer patients with high levels of depression or anxiety to a psychologist or psychiatrist. First-line medications for FM pain are low doses of tricyclic antidepressants or cyclobenzaprine (Table 15-3). These medications provide dual benefits including improvement of mood and central sensitization. All patients with FM should begin a cardiovascular exercise program. In addition, treatment often needs to include cognitive-behavioral therapy or stress reduction with relaxation training. A multidisciplinary approach combining each of these modalities may be most beneficial.
Table 15-3. Medications for Treating Patients with Fibromyalgia.
Patients with FM not responding to these steps should be referred to a rheumatologist, physiatrist, psychiatrist, or pain management specialist. It is important to remember that FM is not a homogenous illness with several subgroups based on psychosocial status and biological response to pain. The ability of patients with FM to manage their pain seems to correlate with their functional status. Brain imaging and psychological profiles have identified at least three FM subgroups:
Such studies provide an explanation why some treatments seem to be differentially effective in individual patients. Thus, optimal FM management will require a combination of pharmacologic and nonpharmacologic therapies with patients and health care professionals working as a team.
-Several trials have demonstrated effectiveness of amitriptyline (25 to 50 mg) and cyclobenzaprine in trials lasting 6 to 12 weeks. The effective dose of cyclobenzaprine for FM pain has been 10 to 40 mg/d. Tricyclic antidepressants are effective for pain, mood, function, and quality of sleep.
Less strong evidence is available for the effectiveness of selective serotonin reuptake inhibitors, such as fluoxetine, in managing FM pain. Serotonin and norepinephrine re-uptake inhibitors, such as venlafaxine (150 to 300 mg/d) and duloxetine (60 mg/d), demonstrated improvement of pain, sleep, and function in FM patients.
-Tramadol, with or without acetaminophen, has been effective in patients with FM. There is, however, no evidence that nonsteroidal antiinflammatory drugs (NSAIDs) improve FM pain, although they may be useful when combined with tricyclic antidepressants. There is no good evidence to recommend opioids for FM pain. However, opioid analgesics should be considered after all other medicinal and non-medicinal therapies have failed.
-Gabapentin is frequently used for the treatment of chronic pain but has not yet been studied in FM. However, the second-generation anticonvulsant pregabalin (450 mg/d), which has been found to be effective in FM, significantly improves pain, sleep, fatigue, and health-related quality of life.
-Several small trials have shown that tropisetron, a 5-hydroxytryptamine-3 (5HT-3) receptor antagonist, and 5-hydroxytryptophan, an intermediate metabolite of L-tryptophan, are effective for FM pain. Although benzodiazepines or similar sedatives are effective for insomnia and anxiety they do not seem to affect FM pain.
-A study of corticosteroids showed that prednisone (10 mg/d) was ineffective for FM pain. Growth hormone supplementation moderately improves function of patients with FM who have low hormone levels. At this time the usefulness of thyroid hormone, dehydroepiandrosterone (DHEA), melatonin, or calcitonin is unproven for the treatment of FM. Other treatments, such as dietary modifications, nutritional supplements, magnesium, herbal, and vitamin
therapy have not been adequately evaluated in FM. Although frequently used, guaifenesin has shown no significant effects on pain over the long term.
-Cardiovascular aerobic exercise is one of the most effective treatments for FM. This therapeutic benefit was first recognized 20 years ago and has been subsequently confirmed in multiple trials. Pool exercise is usually well tolerated and especially helpful. In addition, aerobic exercise including cycling, dance, and walking in-doors significantly improves FM pain and function. The combination of aerobic exercise with education can significantly improve physical function, globalwell-being, fatigue, and sleep.
-There is strong evidence that psychological and behavioral therapy, especially cognitive-behavioral therapy, is effective in man aging FM pain. In addition, meditation, relaxation, and stress management seem to be useful. Multi-disciplinary treatment including education, cognitive-behavioral therapy, or both, combined with exercise showed beneficial effects on patient self-efficacy, significant decreases in pain, and improvements on a 6-minute walk. Importantly, improvements in the treatment out comes were maintained over a long time in patients receiving combination therapy.
-There is some evidence to support the use of acupuncture in patients with FM because it can decrease pain ratings and medication use. Similarly, chiropractic spinal manipulation, soft-tissue massage, ultrasound, and inferential current seem to have positive effects on patients with FM.
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FM can be mild or disabling but often has substantial emotional and social consequences. About 50% of all patients have difficulty with or are unable to perform routine daily activities. Estimates of patients who have had to stop work or change jobs range from 30% to 40%. Patients with FM suffer job losses and social abandonment more often than people with other conditions that cause pain and fatigue. Although FM symptoms seem to remain stable over extended periods of time, several long-term studies indicate that physical function and pain worsen. Significant life stressors often result in a poor outcome, including diminished capacity to work, poor self-efficacy, increased pain sensations, disturbed sleep, fatigue, and depression.
FM, like many other chronic illnesses, is treatable, and remission can occur in many patients who actively participate in effective disease management programs. When FM is perceived to be the consequence of an injury, patients often have a more severe condition than those without a history of injury. A recent study reported higher mortality rates in patients with widespread pain compared with those without chronic pain. Although this study did not specifically look at FM subgroups, the findings may be relevant for patients with chronic pain conditions such as FM. The higher mortality rate was mostly associated with cancer, although the cause for this association is currently unknown.