Interrupting the Fibromyalgia Cycle

An estimated 5 million adults in the United States are affected by fibromyalgia, according to the NIH, with women disproportionately comprising approximately 80% to 90% of those diagnosed. Despite being one of the most common chronic pain conditions, fibromyalgia remains one of the most difficult to diagnose, due in part to the loose confederation of nonspecific symptoms associated with this condition, including fatigue, musculoskeletal pain and insomnia.

Patients with fibromyalgia often find themselves on a merry-go-round of symptoms with prolonged, chronic, widespread pain leading to sleep deprivation, which leads to fatigue. Fatigue consequently makes it difficult for patients to accommodate exercise, a key component of fibromyalgia management. Tired, in pain, and often unable to function in day-to-day life, they are at risk for depression and anxiety, which leads to more sleepless nights, and the cycle begins again.

However, this roundabout is not the only challenge these individuals face: Since these myriad symptoms can present differently from patient to patient, misdiagnosis is common. Before arriving at fibromyalgia, patients may be diagnosed with anything from sleep apnea to lupus, depending on what type of clinician sees them first and where they are in the pain-sleep-fatigue-depression course.

Source: Stanford University

“It’s a vicious circle,” Carmen E. Gota, MD, assistant professor of medicine at Case Western Reserve Lerner School of Medicine, and director of the Fibromyalgia Clinic at the Cleveland Clinic, told Healio Rheumatology in an interview. “The manifestations are constantly contributing to each other.”

Daniel Clauw, MD, director of the Chronic Pain and Fatigue Research Center and professor of medicine in the Division of Rheumatology at Michigan Medicine at the University of Michigan, simplified the discussion somewhat. “What really defines fibromyalgia is a fairly classic clinical widespread pain involving multiple parts of the body,” he said. “Of course, it is accompanied by sleep deprivation, memory loss, fatigue and other symptoms.”

Clauw acknowledged, however, that patients are commonly first diagnosed with ankylosing spondylitis, rheumatoid arthritis or systemic lupus erythematosus. “Around 20% or 30% of patients with any autoimmune disease will present like fibromyalgia,” he said. “But it is important to make the distinction, largely because of the way we treat it. Fibromyalgia is not due to autoimmunity or inflammation, so it won’t respond to the way we treat lupus or RA.”

In 2016, the ACR updated the criteria for fibromyalgia, defining it, firstly, as widespread pain index (WPI) of 7 or greater and symptom severity scale (SSS) score of 5 or greater, or WPI of 4 to 6 and SSS score of 9 or greater. Generalized pain must also be present. The researchers describe this as pain in at least four of five regions, excluding jaw, chest and abdominal pain. Symptoms must have persisted for at least 3 months, according to the next criterion. Yet even with these criteria in place, misdiagnoses remain common.

“It is important to rule out other potential causes of widespread pain that can look like fibromyalgia —but aren’t,” Sean Mackey, MD, PhD, chief of the division of pain medicine at Stanford University, explained. “We do know of many abnormalities that exist in fibromyalgia. We have shown that people with fibromyalgia have brains miswired into a sticky state that amplifies otherwise normal signals from our body, causing them to be felt as painful. We know that cerebrospinal fluid has an increase in neurotransmitters that excite the nerves. We know that there may be abnormalities in the periphery, including the number of small nerve fibers. Patients with fibromyalgia also don’t inhibit pain in the way healthy people do. But if we are talking about the cause or the mechanisms of fibromyalgia, the short answer is: we don’t know.”

It is for this reason that many clinicians recommend first trying to comprehend the exact nature of the pain that their patients are feeling.

Understanding Pain

In a study published in Arthritis Research & Therapy, Claudia M. Campbell, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, and colleagues investigated 57 patients with fibromyalgia who completed catastrophizing, depression and pain questionnaires along with a cold pressor pain assessment at baseline, post-intervention and at 3 months of follow-up. In the first substudy, results showed that catastrophizing ratings prospectively yielded changes in pain ratings over the course of the study duration (P = .005). The findings were validated in a second substudy (P = .014).

“Catastrophizing is negative-thoughts or a mental set characterized by rumination, magnification of pain complaints and feelings of helplessness about pain,” Campbell told Healio Rheumatology. “Unfortunately, there is a negative connotation people have with the term ‘catastrophizing,’ but it isn’t anyone’s fault, and it certainly doesn’t mean the pain is in the patient’s head.”

Campbell acknowledged that there is much to learn about the mechanisms of catastrophizing. “Patients don’t choose to engage in catastrophizing and can’t just stop,” she said. “However, it is important to note that people that have higher levels of catastrophizing don’t just report more pain, but actually experience more pain.”

In a presentation during the 2017 ACR annual meeting, Gota suggested that high pain catastrophizing is associated with a number of fibromyalgia-specific comorbidities, including “higher tender point counts and hyperalgesic response, depression, anxiety, self-reported disability, reduced likelihood of returning to work and poor outcomes of treatment.”

Campbell built on this point. “We have found experimentally that when we apply laboratory pain, increases in catastrophizing thoughts precede increases in pain reports,” she said. “This hints that catastrophizing has an important influence on pain report. Clinically, we have found that reductions in catastrophizing also precede reductions in pain in fibromyalgia patients. When catastrophizing thoughts are reduced, pain perception reduces as well. Others have found that catastrophizing interventions can reduce central sensitization, which is hyper-excitability that occurs in some cases of chronic pain.”

A deeper look at the characteristics of the pain, from all angles, is always useful, according to Gota. “As clinicians, we need to have finesse and pay close attention to determine the nature of pain,” she said. “Is it nocturnal? Does it get better during physical activities, or worse?”

Gota noted that it may be useful for patients to describe their pain in “dramatic” terms. “A patient may tell you that their pain is worse after certain activities, that they have to stay in bed for a day or two,” she said. “They will tell you it’s like an ice pick in their joints and use words like ‘excruciating,’ ‘burning,’ ‘tingling,’ ‘needles’ — this indicates fibromyalgia.”

Cognitive behavioral therapy may yield improvements in pain parameters, Gota suggested, highlighting that it is necessary to educate patients how pain can contribute to stress. “Coping mechanisms work,” she said. “The highest benefit from cognitive behavioral therapy pain interventions are those who achieve highest improvements in pain catastrophizing.”

For Campbell, it is important to legitimize the pain patients are feeling. “Pain affects every aspect of life in those that suffer with chronic pain,” Campbell said. “It can become all-consuming. Unfortunately, treatment options are limited, so the focus has been on how to improve the lives of patients with fibromyalgia and reducing suffering as well as what factors are associated with increases in pain.”

Problematic Diagnosis

In an analysis published in Nature Reviews Rheumatology, Edwards and colleagues wrote that persistent and disabling pain can be observed in patients with osteoarthritis, RA, fibromyalgia and other rheumatic diseases. However, they noted that objective measures of pain and patient-reported measures of pain often fail to sync. Although the results of their analysis indicated that depression and catastrophizing show consistent associations with a number of parameters associated with pain and treatment outcomes, it is also reported that these sequelae may be present in any number of conditions, and not only fibromyalgia.

“Fibromyalgia is not a diagnosis of exclusion, but a diagnosis of inclusion,” Gota said. “Inclusion or exclusion happens when a physician talks to and examines a patient for all of the symptoms we are discussing: Duration of pain, sleep, fatigue and depression.”

Ernest Choy, MD, MB, head of rheumatology and translational research at the Institute of Infection and Immunity and director of the CREATE Centre at the Cardiff University School of Medicine, noted another layer of complication to making a diagnosis. “Fibromyalgia is very common among patients with different rheumatic conditions such as RA, ankylosing spondylitis and lupus,” he said. “It can occur in approximately 20% of those patients and has a significant impact on disease assessment. Therefore, it is crucial that physicians recognize patients with concomitant fibromyalgia to avoid inappropriate treatment.”

Choy recommended that clinicians pay close attention to official guidelines. “The heterogeneity of fibromyalgia has been highlighted in the EULAR recommendations for the management of fibromyalgia,” he said, encouraging rheumatologists to run point on caring for these patients. “Given that concomitant fibromyalgia is so common, ‘handing the patient off to someone who can’ is not an option.”

However, primary care providers and other physicians are often the first clinicians to see these patients, and Gota acknowledged that there can be confusion. “Patients with fibromyalgia sometimes report that their hands swell, or they report every transient rash,” she said. “Primary care will start ordering tests for lupus or RA.”

Gota said that anti-nuclear antibody (ANA) testing is a diagnostic assessment that is positive in patients with lupus but carries very low specificity. She noted that it is often assigned when it should not be and warned of pitfalls with interpretation.

For example, in a 2013 study, Abeles and colleagues reported data for ANA testing among 232 patients referred between 2007 and 2009, largely because they were experiencing widespread pain. Results indicated that no rheumatic disease associated with ANA was observed in individuals with ANA titers less than 1:160. The researchers concluded that more than 90% of positive ANA referrals to rheumatology showed no evidence for ANA-associated rheumatic disease.

“An ANA titer of 140 can be found in up to 37% of the population,” Gota said. “Therefore, it can be a very bad thing for primary care providers to order ANA testing. The vast majority of these referrals are for chronic pain, but doctors should resist the impulse to order the immune test.”

In a patient that is already experiencing a host of symptoms, misdiagnosis can lead to anxiety or panic, according to Gota. “By the time they see a rheumatologist and get the correct diagnosis of fibromyalgia, they don’t trust it,” she said. “This can hinder our management of the patient, and can have serious consequences.”

Individualized Treatment

Although there is no magic bullet for treating fibromyalgia, there is one refrain used by many experts. “Treatments need to be tailored to the individual patients and physicians should assess comorbid symptoms at the time of diagnosis and recommend specific treatment,” Choy said. “Within the EULAR recommendations there is a figure showing how clinicians should assess and manage patients with fibromyalgia.”

For Clauw, individualized management comes down to breaking the vicious circle of symptoms. “It is possible to start with the core symptoms: sleep or pain,” he said. “Draw a circle and one will lead back to the other. Pain leads to poor sleep, poor sleep leads to less exercise, less exercise leads to less sleep, which leads to more pain.”

Clauw suggested that most primary care providers have historically treated the pain because there were obvious pharmacotherapeutic options. “Pain feels like the one thing anyone can treat,” he said. “But it is possible to treat the sleep, the mood, the fatigue; you just have to query the patient and really understand their specific symptoms. The more you understand their symptoms, the more targets for intervention you have.”

Small victories are important, according to Clauw. “Any given patient will have four or five symptoms,” he said. “Some may feel like the depression is most significant, or fatigue. Don’t just be flummoxed by the pain. If you can understand and develop strategies to make one or two of those symptoms better, it helps the patient physically, but it also helps you build trust. ‘That doctor helped my depression. Maybe I’ll listen to that doctor.’”

That said, Clauw warned that attempting to deal with depression first may carry consequences. “Patients may think you think they are crazy,” he said. “Many patients are depressed because they hurt and can’t do what they want to do. It’s a reactive depression, and isn’t likely to improve with drugs.”

The small victories, though, ultimately can lead to improved function. “We tell patients that we may not completely eliminate your pain, but you may be twice as active, or you will be able to visit your grandchildren,” Clauw said.

Sleep Deprivation

Mork and colleagues conducted a longitudinal investigation involving 12,350 women without fibromyalgia, musculoskeletal pain, or physical impairments at baseline assessment between 1984 and 1986. Among the 327 women who developed fibromyalgia during follow-up, sleep problems and fibromyalgia risk were deemed to be associated in a dose-dependent manner (P trend < .001). For women who reported having sleep problems frequently or always, the risk for fibromyalgia was more than tripled (RR = 3.43; 95% CI, 2.26-5.19) compared with women who had no report of sleep problems. Further investigation revealed that this sleep dose-dependent relationship was stronger among women aged 45 years or older (RR = 5.41; 95% CI, 2.65-11.05) than it was among those aged 20 to 44 years (RR = 2.98; 95% CI 1.76-5.05).

“Many people with fibromyalgia have reduced sleep efficiency with an increased number of awakenings, reduced slow wave sleep, restorative sleep and increased alpha-EEG activity,” Mackey said. “Alpha waves are found during wakeful relaxation, and their intrusion is not beneficial when you are trying to get a good night’s sleep. Researchers have also found a clear link between disrupted sleep and increases in whole body pain sensitivity.”

Choy suggested a combination of approaches to dealing with sleep. “I would recommend good sleep hygiene and, if necessary, low-dose amitriptyline, which can improve sleep quality,” he said.

In a similar study, Ablin and colleagues grouped 87 healthy young adults with regular sleep and exercise patterns into four categories: exercise cessation, sleep restriction, both, or neither. The researchers assessed these individuals for symptoms of pain, fatigue, cognitive dysfunction and negative mood before and after the 10-day restriction period. Results indicated that sleep restriction strongly contributed to somatic symptoms, while cessation of exercise led primarily to fatigue.

“Sleep and pain have an interesting bidirectional relationship,” Campbell said. “We all know that when you have pain, your sleep is often impacted and pain can wake you throughout the night. What we are understanding now is that a bad night’s sleep also independently worsens pain. We don’t know the mechanisms, but there are several theories.”

Gota offered an explanation. “Sleep deprivation makes concentration difficult, and decreases the pain threshold,” she said. “A good night’s sleep is important for the pain inhibitor pathways to work, to let that mechanism control the pain.”

Clinicians are encouraged to identify and treat sleep apnea, narcolepsy and restless leg syndrome, according to Gota. She suggested pharmacotherapies such as pregabalin, tricyclic antidepressants, amitriptyline, trazodone, cyclobenzaprine and melatonin may improve sleep parameters, while cognitive behavioral therapy and physical activity also may yield results.

“We have shown low-dose naltrexone reduces symptoms of fibromyalgia and is thought to work to reduce nerve inflammation,” Mackey said. “This can help patients with fibromyalgia feel less pain, sleep better, and have less fatigue. This suggests that fibromyalgia may be a neuroimmune disorder.”

Exercise as Therapy

In a study published in Arthritis Care & Research, Soriano-Maldonado and colleagues examined the impact of physical fitness on a number of parameters in 486 women with fibromyalgia. Associations were observed between higher fitness levels and lower levels of pain, lower pain-related catastrophizing, and higher chronic pain self-efficacy. Pain was associated with both muscle strength and muscle flexibility (P < .05 for both), while pain-related catastrophizing demonstrated associations with both aerobic fitness and flexibility (P < .001 for both).

For many patients, even the idea of exercise can be daunting, according to Clauw. “We get them active as much as possible, as soon as possible,” he said. “Sometimes you say exercise, and the patient looks at you like you are from Mars. But exercise, and education about how exercise can improve everything, from depression to sleep to chronic pain, is critical.”

To examine the effect of exercise on fibromyalgia symptoms, Flodin and colleagues investigated the neurophysiological mechanisms at play when patients with fibromyalgia exercise. Using functional MRI, they assessed resting-state connectivity before and after a 15-week, physical therapist-mediated exercise program. The analysis included 14 patients with fibromyalgia and 11 healthy controls. Symptom severity improved in the patient group, according to the results.

“Although several brain regions showed a treatment-related change in connectivity, only the connectivity between the right anterior insula and the left primary sensorimotor area was significantly more affected by the physical exercise among the fibromyalgia patients compared to healthy controls,” the researchers concluded. “Our results suggest that previously observed aberrant intrinsic brain connectivity patterns in [fibromyalgia] are partly normalized by the physical exercise therapy.”

While the data from Flodin and colleagues begin to paint the picture, they suggested caution in interpreting the findings. “None of the observed normalizations in intrinsic brain connectivity were significantly correlated with symptom changes,” they wrote. “Further studies conducted in larger cohorts are warranted to investigate the precise relationship between improvements in fibromyalgia symptoms and changes in intrinsic brain activity.”

“For instance, when you go for a long run, you get a runner’s high, and feel good,” Mackey said. “People with fibromyalgia just feel worse. One of our treatments is to get people with fibromyalgia engaged in mild aerobic exercise. We find over time that their nervous system will slowly rewire and they will experience that pain reduction.”

Depression and Anxiety

Kudlow and colleagues retrospectively reviewed data for 678 patients from nine studies and found that patients with fibromyalgia carried a seven-fold risk for bipolar disorder (OR= 7.55; 95% CI, 3.9-14.62) compared with controls.

“There is a misconception that all people with fibromyalgia are depressed and anxious,” Mackey said. “This is simply not true. There are other chronic painful conditions, such as chronic low back pain, that have higher rates of associated depression and anxiety. Nevertheless, we know that any increase in depression or anxiety has been shown to also increase chronic pain and its persistence; this is why we need to treat the whole person and improve their physical, psychological and social functioning.”

In a recent study in the International Journal of Rheumatic Diseases, Gota and colleagues investigated 305 patients with fibromyalgia and found that although no depression occurred in 11.4% of the cohort, mild depression was reported in 29.1%, moderate in 27.5%, moderate-severe in 17.7%, and severe depression was observed in 14%. The rate of anxiety was 41.6%, and 21.3% had either an MDQ score of 7 or greater and/or had been previously diagnosed with bipolar disorder.

“Conservatively, the lifetime incidence of depression or anxiety in fibromyalgia patients is 40% to 50%,” Gota said. “To put it in terms of the cycle, if you are depressed, you are going to sleep worse, which will worsen your fibromyalgia. There is also some evidence that depression precedes fibromyalgia.”

Campbell suggested that multiple strategies can be employed to mitigate depression in this patient population. “Combating negative thoughts, improving sleep, scheduling pleasant activities, accepting pain, and doing the things that are important to you anyway, if safe, and trying not to put value judgements on the sensations of pain are all ways to help reduce suffering and potentially reduce the level of pain you are experiencing,” she said.

Choy suggested that sticking to basics may help clinicians deal with depression in their patients. “Not all patients suffer from depression, but in those who have significant depression, antidepressants can improve mood and reduce pain,” he said.

It is important to understand the two-way street of depression/anxiety and pain, according to Mackey. “There are excellent medications used to treat both depression and anxiety that also treat pain at the same time,” he said. “Furthermore, there are well-validated pain psychology treatments for pain associated depression and anxiety that will further empower patients with fibromyalgia.”

Multidisciplinary Intervention

No two patients are alike, according to Gota. “You have to identify the patient’s fibromyalgia fingerprint,” she said. “This can be comprised of a number of factors, including genetic predisposition, trauma, current stressors, lack of exercise, sleep disorder, a maladaptive response to pain.”

Choy built on this point. “This is the reason why, in most patients, treatments targeting multiple issues are necessary,” he said.

A psychiatrist or psychologist is critical to correcting maladaptive behaviors, while a physical therapist can help improve movement, Clauw noted. “We as clinicians understand the experts our patients need,” he said. “Unfortunately, there is not always access to this kind of comprehensive care. You can find it in some major academic centers with clinicians who specialize in the care of pain patients, but not as much in rural communities.”

Campbell highlighted the role of the patient in their own management. “There are some great self-help workbooks out there and different programs,” she said. “There are hints in the literature that reducing psychosocial/behavioral issues like depression, catastrophizing and disturbed sleep do have an impact on pain and can substantially reduce someone’s suffering. I’m all for that and think modifiable risk factors are important to study and understand for the best interest of patients.”

Alternative Therapies

As clinicians become reticent to treat pain pharmacologically in the wake of the opioid epidemic, both patients and practitioners are seeking alternative methods for dealing with the symptoms of fibromyalgia. Meditation, mindfulness, acupuncture, yoga and tai chi are gaining traction. “Opioids became popular because they are easy and they are cheap,” Clauw said. “You just write a script and you don’t have to figure out where to find a yoga class or an exercise program. But we are starting to see that health systems or managed care organizations want to manage pain in this way. Some of this has been moved to the forefront by the opioid epidemic; everyone is cognizant that opioid addiction has killed a lot of people.”

Working with the German Pain Society, Langhorst and colleagues reviewed Cochrane library, MEDLINE, PsycINFO and Scopus databases for studies about such interventions. “Meditative movement therapies (eg, qigong, tai chi and yoga) are strongly recommended,” they concluded. “Acupuncture and weight reduction in cases of obesity can be considered.”

“Alternative or complementary medicine are used commonly by patients in order to reduce pain,” Choy said. “Over the last few years, many studies have been conducted. The risk of side effects is often low, especially for yoga and mindfulness, and there is some evidence to suggest they can be helpful.”

However, more work needs to be done to affirm these findings. In a study published in the International Journal of Yoga, Carson and colleagues found significant improvements in heat pain tolerance, pressure pain threshold, and heat pain after-sensations, along with strength, balance and pain coping strategies in fibromyalgia.

Conversely, in an analysis of 25 systematic reviews, Lauche and colleagues arrived at less definitive conclusions. Although they found consistently positive outcomes for fibromyalgia patients using tai chi, yoga, meditation and mindfulness-based interventions, hypnosis or guided imagery, electromyogram biofeedback, and balneotherapy/hydrotherapy, less consistent results were reported for qigong, acupuncture, chiropractic interventions, electroencephalogram biofeedback, homeopathy, phytotherapy, and nutritional supplements. Moreover, they commonly observed methodological flaws in the studies undergoing analysis.

“As clinicians, we don’t look for whether a therapy is approved or not. We are looking for whether there is evidence that it works,” Clauw said. “The FDA doesn’t have any say over yoga, so what we as clinicians are looking for are good quality studies.”

While Clauw acknowledged that more work needs to be done, he is hopeful for the future of such interventions. “Those things never used to be well studied,” he said. “There was a belief that they didn’t work with the classical biomedical model. But now, with the VA and DOD, along with more progressive health plans, patients are increasingly being covered for acupuncture and yoga because evidence shows that those things will be helpful.”

The next hurdles, then, are more widespread awareness and health insurance coverage, Clauw said. “Awareness can be spotty, depending on the location. I wouldn’t necessarily say that academic hospitals are aware of these options and private practices are not. It’s somewhat random. But awareness that these approaches can have an impact on fibromyalgia could be improved.”

As for the insurance issue, Clauw urged patients to demand coverage. Beyond the movement away from opioids, it may simply come down to money. “If insurance companies see that a patient with back pain gets better after a year of yoga classes instead of a $50,000 surgery, they are going to pay attention,” he said. – by Rob Volansky

• References:
• Abeles AM, et al. Am J Med. 2013;doi:10.1136/annrheumdis-2013-204797.
• Ablin JN, et al. Clin Exp Rheumatol. 2013;6 Suppl 79:S53-9.
• Campbell C, et al. Arthritis Res Ther. 2012; doi:10.1186/ar4073.
• Carson JW, et al. Int J Yoga Therap. 2016;26:93-100.
• Edwards RR, et al. Nat Rev Rheumatol. 2011;doi:10.1038/nrrheum.2011.2.
• Flodin P, et al. Neuroimage Clin. 2015;doi:10.1016/j.nicl.2015.08.004.
• Gota CE, et al. Int J Rheum Dis. 2017;doi:10.1111/1756-185X.12603.
• Kudlow PA, et al. J Affect Disord. 2015;doi:10.1016/j.jad.2015.08.030.
• Langhorst J, et al. Schmerz. 2017;doi: 10.1007/s00482-017-0206-1.
• Lauche R, et al. Evid Based Complement Alternat Med. 2015; doi:10.1155/2015/610615.
• Mork PJ, et al. Arthritis Rheum. 2012;doi:10.1002/art.33346.
• Soriano-Maldonado A, et al. Arthritis Care Res (Hoboken). 2015;doi:10.1002/acr.22610.

• For more information:
• Claudia M. Campbell, PhD, can be reached at 5510 Nathan Shock Drive, Ste. 100, Baltimore, MD 21224; email: ccampb41@jhmi.edu.
• Ernest Choy, MD, can be reached at 1st Floor Tenovus Building, Cardiff University Heath Park Campus, Heath Park Cardiff CF14 4XN; email: ChoyEH@cardiff.ac.uk.
• Daniel J. Clauw, MD, can be reached at U of M Anesthesiology Pain Management, 325 E Eisenhower Pkwy Ste. 100, Burlington Building, Ann Arbor, MI 48108; email: dclauw@med.umich.edu.
• Carmen E. Gota, MD, can be reached at 9500 Euclid Avenue, Cleveland, OH 44195; email: GOTAC@ccf.org.
• Sean Mackey, MD, PhD, can be reached at 1510 Page Mill Road, 2nd floor-Marketing, Palo Alto, CA 94305; email: LiKim@stanfordhealthcare.org.

Disclosures: Clauw reports consulting relationships with Abbott Pharmaceutical Products Division, Cerephex, Eli Lilly and Company, Forest Laboratories, Johnson & Johnson, Merck and Company, Pfizer, Purdue Pharma, Samumed, Theravance, Tonix, UCB, and Zynerba. Campbell, Choy, Gota and Mackey report no relevant financial disclosures.