Fibromyalgia: A Painful Puzzle

Examining its pathophysiology, diagnosis, and treatment

Watercolor illustration of a crying figure

Fibromyalgia is a chronic and often debilitating condition. It affects around 3 percent of the world’s population, mostly women, and has vexed physicians for centuries.

The syndrome is characterized by widespread pain, fatigue, cognitive fog, and insomnia. Which begets which is unclear. Comorbid maladies may include irritable bowel syndrome, headaches, anxiety, depression, and nondescript bodily sensations … or not. Variable presentation makes fibromyalgia difficult to distinguish from better-understood conditions such as rheumatoid arthritis or lupus. There are no reliable tests for diagnosis — no elevated serum marker, no betraying shadow on a radiograph, no telltale defect of the fingernail.

There is also no cure. This article provides an overview of the pathophysiology, diagnosis, and treatment of fibromyalgia, such as we understand them today.

Pain By Any Other Name

Galen of Pergamum, a fabled Greek physician and proponent of the humoral theory of disease, used rheumatismos to describe the process by which phlegm, one of the four humors, painfully forced its way into joints. Nearly 1,700 years later, the term was resurrected as rheumatism to describe widespread pain in the context of rheumatic fever.

In 1915, Sir William Gower described widespread pain as fibrositis, the prefix implicating connective tissue and the suffix inflammation. Studies so far have failed to confirm the presence of connective tissue inflammation, but the designation remains.

In 1880, neurologist George Beard described a constellation of symptoms approaching those we associate with fibromyalgia today. He called the condition neurasthenia; described as a sort of lassitude of the central nervous system.

There were many more discoveries and missteps, and with each iteration of the syndrome a new name was applied: myogeloses, fibrositis, generalized fibrositis, psychogenic rheumatism, and finally fibromyalgia.

The Shape of Pain

The experience of fibromyalgia is one of pain and fatigue, by definition, but also of frustration at not understanding why one is hurt and tired. The onset is often preceded by physical injury, psychological trauma, or illness — some shock to the system — but patients seldom experience fibromyalgia all at once.

Chart that shows the progression of symptoms that neurologist George Beard attributed to neurasthenia.
This chart from American Nervousness, Its Causes and Consequences by neurologist George Beard (1881) reveals what Beard believed to be the progression of symptoms ascribed to neurasthenia. University of Virginia

The onset is typically insidious and gradually intensifies; for example, a previously pinpoint low back pain begins to bloom, creeping up the back and under the shoulder blade, then switches sides. An old shoulder injury flares for no evident reason. There’s a tingling in the hand that your aunt says is carpal tunnel syndrome, but you’re not sure. You Google it. Sleep becomes more difficult and even when achieved is not restorative. It becomes more difficult to keep track of bills and the kids’ schedules and the new intern’s name.

Such symptoms motivate a trip to the doctor’s office where evaluation and treatment is likely to be focused on one or more of the aforementioned issues in isolation of the rest: physical therapy for the lower back pain, orthopedic referral for the shoulder, and a stern recommendation to quit the afternoon coffee (followed by a silent resolution on your part to do no such thing).

This goes on for months or years as the pain, fatigue, and brain fog become more intrusive. Sleep debt accumulates. Interpersonal relationships begin to deteriorate. Friends and family call to make plans but you, conscious of the volatility of your symptoms, self-isolate. After awhile the calls stop, and isolation is no longer elective. Isolation begets depression, which amplifies pain, which, collectively, result in isolation, which … you get the idea.

A Look Inside

Fibromyalgia is essentially a disorder of pain processing. Problems manifest at the level of the brain, spinal cord, neuron, and even the genome.

The brain of a person with fibromyalgia is wired differently, exhibiting increased connectivity between the default mode network (DMN) and insular cortex (IC). The DMN is a constellation of interconnected brain regions that are more active when the brain is disengaged, not consciously focused on a task. Its interconnectedness with the IC is relevant because the IC plays a critical role in pain perception, with the posterior portion encoding pain intensity and location and the anterior portion imbuing pain with emotion. If the DMN, which may represent the bedrock of self-awareness, becomes hyperconnected to regions of the pain processing network, the brain may become sensitized and predisposed to developing chronic pain.

The delicate balance of signaling within the spinal cord is also tipped in favor of pain. Signals from the periphery will synapse in the dorsal horn of the spinal cord before firing up to the thalamus for processing. The sensitivity of that synapse is constantly modulated with descending inhibitory and facilitatory projections from the brain.

Imagine a tiny Dr. Dre, wearing itty-bitty Beats headphones, standing behind a mixer in your brain. Tiny Dre adjusts the sliders to suit your internal and external environment. He can turn down the volume of incoming signals if they don’t constitute a credible threat. Conversely, he can amplify signals if he thinks doing so will result in a life-saving change of behavior. Fibromyalgia Dre can turn the volume up but has real trouble turning it down. The descending inhibitory network is dysfunctional. As a result, signals are much more likely to be amplified than dampened when they pass through the spinal cord on the way to the brain. This results in hyperalgesia, an exaggerated response to a painful stimulus, and in some cases allodynia, pain in response to a normally innocuous stimulus.

Emerging research suggests that a subset of patients diagnosed with fibromyalgia also have a condition called small fiber sensory neuropathy. This is a condition in which the small nerves of the skin are damaged, leading paradoxically to sensory deficits and diffuse pain. It is not entirely clear whether this is part of fibromyalgia, perhaps a subtype, or if small fiber neuropathy is being misdiagnosed as fibromyalgia.

Imagine a tiny Dr. Dre, wearing itty-bitty Beats headphones, standing behind a mixer in your brain. Tiny Dre adjusts the sliders to suit your internal and external environment. Fibromyalgia Dre can turn the volume up but has real trouble turning it down.

Early research revealed that fibromyalgia tends to aggregate in families and efforts are underway to discover why. Environment doubtless plays a role. Learned behaviors and coping mechanisms may modulate our propensity to develop chronic pain but nurture, as usual, tells only part of the story. Hundreds of genes have been implicated in the regulation of pain. Some of them code for the mu-opioid receptors to which morphine and heroin bind. Others are responsible for sodium channels that facilitate electrical conduction along the length of a nerve. Still others modulate the production of catecholamines (e.g., dopamine, epinephrine/“adrenaline,” and norepinephrine).

There is a great deal of interest in the 5-HT2A gene, which codes for serotonin receptors. Patients with fibromyalgia have exhibited suboptimal serotonin metabolism and neurotransmission. This is relevant because the descending inhibitory system (Dre turning the volume down) is reliant on serotonin to send signals to the spinal cord. Some patients with fibromyalgia respond well to drugs that act on serotonin, and this might be why.


There are agreed upon diagnostic criteria for fibromyalgia. The first iteration was developed and published in 1990 by the American College of Rheumatology and relied on the palpation and provocation of specific tender points. Revisions to the criteria did away with the tender point requirement, as it became evident that those with fibromyalgia hurt everywhere. The most recent criteria considers the number and variety of areas in which a person is experiencing pain as well as the number and severity of associated symptoms (e.g., fatigue, waking unrefreshed, cognitive fog, headaches, abdominal pain, and depression). Symptoms must be present for at least three months for a diagnosis to be made.

Fibromyalgia pain points.
Revisions made to the diagnostic criteria for fibromyalgia in 2016 now recognize that those with fibromyalgia hurt everywhere.

Though the diagnosis of fibromyalgia is considered valid irrespective of other diagnoses, it is critical that other causes for widespread pain be ruled out. Patients who are suspected of having fibromyalgia are often referred to a rheumatologist for this reason. It is not necessarily the case that all rheumatologists are expert in diagnosing and managing fibromyalgia, though some are. Rather, they are expert at identifying inflammatory arthropathies and other rheumatologic disorders that may mimic fibromyalgia. Polymyalgia rheumatica is an inflammatory disease producing diffuse muscle soreness especially in the shoulder and hip girdles. Lupus is an autoimmune disease that causes diffuse joint pain, fatigue, and a general sense of malaise. Such disorders can be treated, but only if they are identified.

As of this writing, there are no reliable, widely available diagnostic tests for fibromyalgia. Still, some promising advances are being made. A 2017 paper published in the journal Pain described the use of functional MRI and machine learning to identify a neural signature discriminative of fibromyalgia. The authors compared 37 patients with fibromyalgia to 35 healthy control subjects, applied painful pressure to their thumbnails, and scanned their brains. Those with fibromyalgia experienced more pain than the controls, and their brains displayed a different pattern of activity, most notably in the insular, posterior cingulate, and medial prefrontal regions — all heavily involved in pain processing. The resulting signature identified by the machine-learning algorithm was 92 percent sensitive and 94 percent specific; overall, it was 93 percent accurate at differentiating between those with a diagnosis of fibromyalgia and those without. Limitations abound, but it is difficult to temper enthusiasm over results like that.


It’s simple enough to stitch a wound or set a broken bone, but how does one soothe a sensitive nervous system? The first order of business is ruling out other bad stuff. Once the physician and patient are satisfied that the condition is not one of the many mimetic of fibromyalgia, they can move forward as a team. Receiving a diagnosis or at least an explanation validates a patient’s experience and reduces healthcare utilization. The second step is setting reasonable expectations. Most people with fibromyalgia will continue to experience chronic pain despite treatment. The goal is not to abolish pain but to reduce the impact of pain on function.

An evidence-based treatment plan for fibromyalgia would include medications but emphasize self-care strategies. Fibromyalgia is often accompanied by insomnia, which contributes to pain sensitivity. That makes sleep a prime treatment target. Cognitive behavioral therapy for insomnia and optimization of sleep hygiene are first-line treatments. One should limit napping, use the bed only for sleep and sex, and reduce exposure to screens around bedtime as bright light may impair the brain’s secretion of melatonin. Self-medication with scotch or craft beer, though scrumptious, is not recommended as alcohol disrupts the architecture of sleep.

Intense or prolonged stress can also amplify pain sensitivity. I say that at the risk of pathologizing stress, which is not my intent. Stress is fundamental to motivation and focus, but too much is, well, too much. Mindfulness-based stress reduction and Cognitive behavioral therapy are two of the better-researched treatment options.

Exercise is the gold-standard treatment for fibromyalgia; however, it must be undertaken deliberately and gradually. Nasty pain flares can be instigated by overactivity. Those with fibromyalgia are constantly navigating between the Scylla of overexertion and Charybdis of deconditioning. The counsel of a well-trained physical therapist could be invaluable. The best exercise is the one the patient will do, but walking and swimming are low impact and easy to increase incrementally in time and intensity. Tai-chi has been demonstrated to be equally or perhaps more effective than aerobic exercise, probably because it integrates elements of mindfulness and stress reduction.

Though three drugs have been FDA approved for fibromyalgia — pregabalin, duloxetine, and milnacipran — they have been only marginally more effective than placebos. Tricyclic antidepressants have been employed to treat associated symptoms, amitriptyline for depression, and cyclobenzaprine for insomnia, with mixed results. Opiates are not recommended.

There is much we don’t know about the causes and effects of fibromyalgia. Right now there is no cure and no reliable diagnostic test. We’ve got a handful of helpful treatments, most of which are just good physiological housekeeping. You are likely to find that unsatisfying. Nonetheless, progress has been made. Most physicians today recognize fibromyalgia as a real condition, and that’s not nothing. We understand, better than ever, fibromyalgia’s neurophysiological underpinnings. We can look our patients in the eye and tell them we have some idea what is wrong and some idea of how to help them. There are miles to go, but we’ve come a long way from Galen.

Source: CASEY OKAMOTO  |  September 26, 2019

Casey Okamoto headshot

Casey practices at the Minneapolis VA Medical Center as a member of the Comprehensive Pain Center team and Pain Medicine Fellowship faculty. He has presented nationally on the evaluation and treatment of complex pain and has authored several peer-reviewed publications. He graduated in 2015 as valedictorian of Palmer College of Chiropractic before completing his residency at the VA Medical Center in Buffalo, N.Y.
Minnesota Mensa | Joined 2018