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Possible Causes of Fibromyalgia

Because many fibromyalgia patients appear well upon physical examination, the diagnosis of fibromyalgia was historically considered controversial and, unfortunately, written off by many conventional physicians as a psychosomatic condition (Goldenberg 2011; Goldenberg 1999).

Insulin Resistance

Despite years of research, the etiology of fibromyalgia has remained incompletely understood. Consequently, consistently effective therapies are not available. But there may now be some hope: an article published in May 2019 provided compelling support for the hypothesis that insulin resistance may cause fibromyalgia (Pappolla 2019).

Insulin resistance has been shown to cause dysfunction of brain blood vessels, leading to cerebral hypoperfusion (inadequate blood supply) (Frosch 2017). Similar abnormalities have been observed in patients with fibromyalgia (Mountz 1995). This similarity was the basis for the recent study. To test their theory, researchers compared levels of glycated hemoglobin A1c (HbA1c—a biomarker of insulin resistance) (Goldstein 2003) in fibromyalgia patients with levels in age-matched healthy controls. The age-matching is important, as what is considered “normal” for HbA1c levels changes with age (Pani 2008). They found that compared with healthy subjects in the same age group, patients with fibromyalgia had much higher HbA1c levels.

The most intriguing part of the study is how fibromyalgia patients responded to treatment with the insulin-sensitizing drug metformin: all 16 patients treated with metformin saw a dramatic reduction in pain. Half of the patients even experienced complete resolution of pain, a degree of improvement never before accomplished in people with fibromyalgia. The fact that there were no non-responders could indicate that this is a disease-modifying therapy.

Further studies are necessary to explore the relationship between insulin resistance and fibromyalgia. This finding, if confirmed by future studies, could lead to a “radical paradigm shift” in the management of fibromyalgia.

More strategies to overcoming insulin resistance are detailed in Life Extension’s Diabetes and Glucose Control protocol.

Pain Hypersensitivity

Evidence from functional magnetic resonance imaging (fMRI) studies of the brain has demonstrated that patients with fibromyalgia are more sensitive to pain than their healthy counterparts (Gracely 2002). Therefore, fibromyalgia is thought to be a result of some type of neurosensory disorder that perturbs the central nervous system’s ability to process painful stimuli (Dadabhoy 2008; Braz 2011).This dysfunction appears to be a result of neurochemical imbalances that cause the brain to amplify pain through two different mechanisms: (1) allodynia (i.e., a heightened sensitivity to stimuli that are not normally painful); and (2) hyperalgesia (an increased response to painful stimuli) (Clauw 2011). Although no one knows exactly how or why this central sensitization develops, researchers have identified several possible theories.

Hormonal Influences and Stress

Although a causal link has yet to be established, some evidence suggests a role for sex hormones in the etiology of fibromyalgia. For example, fibromyalgia predominantly affects middle aged women; a population whose hormones have begun to decline or fall out of youthful balance (Lawrence 2008; Terhorst 2011). Furthermore, the fluctuating hormone levels caused by endocrine dysfunction commonly produce symptoms that are similar to those of fibromyalgia (e.g., muscle pain/tenderness, exhaustion, and reduced exercise capacity) (Geenen 2002). In one clinical trial, taking the selective estrogen receptor modulator (SERM) raloxifene every other day for 16 weeks led to significant improvements in pain and fatigue scores; reduced tender points and sleep disturbances; and greater recovery of usual activities compared to placebo among 49 women (Sadreddini 2008). These findings implicate estrogen signaling in fibromyalgia etiology.

Likewise, perturbations in the hypothalamic-pituitary-adrenal (HPA) axis have been demonstrated in fibromyalgia patients, indicating a possible therapeutic role for dehydroepiandrosterone (DHEA) supplementation and stress management strategies (Sarac 2006). It is thought that stress functions to cause alterations in corticotropin-releasing hormone (CRH), with associated effects on the neuroendocrine axis. More information is available in the Stress Management protocol.

This evidence is consistent with recent data indicating a relatively high prevalence of growth hormone deficiency among patients with severe fibromyalgia. This deficiency is linked to increased levels of blood cytokines and pain severity (Cuatrecasas 2010; Terry 2012).Therefore, fibromyalgia patients may benefit from hormone level testing in order to identify, and subsequently treat any underlying imbalances or insufficiencies (Cuatrecasas 2010). In the case of growth hormone (GH)-deficient fibromyalgia patients, GH replacement therapy has been associated with significant improvements in symptoms and quality of life (Cuatrecasas 2009).

For more information on hormone testing and natural hormone replacement, refer to the Female Hormone Restoration Therapy protocol.

Neurotransmitter Imbalances

Symptoms of fibromyalgia might be caused by a disruption in the communication between peripheral nerves and the brain. This theory is supported by evidence indicating that fibromyalgia patients often have lower-than-normal amounts of neurotransmitters (i.e., serotonin, norepinephrine, and dopamine) (Becker 2012) and frequently suffer from mood disorders like depression and anxiety. A low level of serotonin is particularly significant to fibromyalgia patients as an imbalance can contribute to pain sensitivity, sleep disturbances, and mood alterations. This supports the use of antidepressants for treating fibromyalgia, since antidepressants often increase the circulating amounts of these important neurotransmitters. The problem with antidepressants is that they often come with undesirable side effects, and thus are not a very attractive option for many patients. Fortunately, supplementation with a natural building block of serotonin called 5-HTP (5-Hydroxytryptophan) may improve the fibromyalgia symptoms of pain, depression, anxiety, and insomnia (Birdsall 1998). 5-HTP supplementation is well tolerated, and generally starts to take effect within the first 30 days of use (Sarac 2006).


Although fibromyalgia is not generally believed to be an inflammatory condition (Goldenberg 2011), there is evidence suggesting that some type of inflammatory process may be contributing to its onset and/or progression (Kadetoff 2012). While classic inflammatory processes are not observed in fibromyalgia patients, these individuals do exhibit some inflammation-related abnormalities (Lucas 2006). For instance, the cerebro-spinal fluid (CSF) of fibromyalgia patients commonly contains higher-than-normal levels of the inflammatory mediators substance P and corticotropin releasing hormone (CRH). Likewise, the serum of fibromyalgia patients commonly contains higher-than-normal levels of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and substance P, while the skin of fibromyalgia patients commonly contains higher-than-normal amounts of mast cells, which can produce IL-6 and IL-8.

In addition, fibromyalgia often occurs simultaneously with other chronic inflammatory conditions, such as arthritis, systemic lupus erythematosus, or chronic hepatitis C infection (Buskila 2003; Thompson 2003; Wolfe 1984). It is possible that inflammation arising from co-occurring medical conditions could play a role in the pathology of fibromyalgia. Therefore, some individuals with fibromyalgia, especially those who have been diagnosed with other medical conditions, may respond to supplementation with natural anti-inflammatory agents such as omega-3 fatty acids, curcumin and boswellia serrata (Calder 2010; Basnet 2011; Sengupta 2011).

Sleep Dysfunction

Although sleep disturbance is an obvious consequence/symptom of fibromyalgia, some researchers believe that non-restorative sleep (NRS) may actually cause and/or contribute to fibromyalgia-related pain (Moldofsky 2010). This bi-directional relationship is further supported by studies of fibromyalgia patients showing that improvement in sleep quality is linked to significant reductions in fibromyalgia symptom intensity (Prados 2012). Since serotonin is involved in pain signaling and sleep regulation, some researchers have suggested that abnormally low serotonin levels (common among fibromyalgia patients) may be one possible explanation for this connection (Arnold 2010). Clinical studies have also found that fibromyalgia patients may have low circulating levels of melatonin, which can lead to disruptions in sleep cycles (Hussain 2011). Among these patients, melatonin supplementation has been shown to improve sleep and fatigue-related symptoms (Reiter 2007).

As with pain, fibromyalgia-related sleep dysfunction should be managed in a step-wise fashion, starting with the least risky treatment. For many of those with fibromyalgia, improving sleep hygiene is enough to make a significant difference (Spaeth 2011). The sleep environment should be dark, cool, and quiet, and external distractions should be minimized. The sleep cycle should be normal (e.g., consistent bedtime and morning awakening time), and healthy lifestyle considerations (e.g., adequate exercise, smoking cessation, and avoiding nighttime alcohol use) may also help improve sleep quality (Leger 2010).

Patients who continue to have problems sleeping may require pharmacotherapy with agents such as zolpidem (Ambien®) and eszopiclone (Lunesta®). However, these medications can be habit forming and are not associated with subsequent pain relief (Spaeth 2011). On the other hand, natural supplements such as 5-HTP and melatonin are not only associated with improvements in sleep quality and pain score, but are also less likely to produce negative side effects (Reiter 2007; Sarac 2006).

Mitochondrial Dysfunction

Mitochondria are cellular components responsible for the generation of the energy necessary for proper cellular function. Evidence indicates that fibromyalgia symptoms may arise as a result of mitochondrial dysfunction (Gardner 2011; Pieczenik 2007; Le Goff 2006). For example, case reports of two patients with fibromyalgia revealed impaired mitochondrial function and deficiency in coenzyme Q10 (a critical compound necessary for proper mitochondrial function) in blood and skin cells (Cordero 2010a). Similarly, in another case report, a 41-year-old woman diagnosed with fibromyalgia, but who had been unresponsive to a variety of conventional treatments, was later found to have significant mitochondrial dysfunction (Abdullah 2012). Her symptoms improved dramatically when treated four times daily with a cocktail of mitochondrial nutrients including coenzyme Q10 (200 mg), creatine (1,000 mg), L-carnitine (200 mg) and folic acid (1,000 mcg). Moreover, dysfunctional mitochondria contribute to increased oxidative stress. In a study involving 20 fibromyalgia patients and 10 healthy controls, the fibromyalgia patients had greater levels of a mitochondria-derived free radical (superoxide) in their blood cells and increased lipid peroxidation compared to the healthy subjects (Cordero 2010b).

Fibromyalgia and Obesity

While the relationship between obesity and chronic pain has been common knowledge for decades, more recent evidence suggests that this association is particularly true for fibromyalgia patients. For example:

  • In 2008, researchers demonstrated significant improvement in pain scores and tender point frequency among fibromyalgia patients who underwent gastric bypass surgery (Saber 2008). This suggests that weight loss should be an important treatment goal for obese patients diagnosed with fibromyalgia.
  • In 2009, researchers reported that 71% of fibromyalgia patients enrolled in their study were either overweight or obese and exhibited common laboratory findings associated with obesity such as elevated levels of IL-6, catecholamines, cortisol, and CRP (Okifuji 2009). The authors also pointed out that both obese patients and those with fibromyalgia presented with reduced sleep duration and quality, concluding that excess weight and obesity may play a significant role in fibromyalgia and its related dysfunction(s).
  • In 2010, a study of 215 fibromyalgia patients reported that nearly 80% of participants were either overweight or obese. These same patients exhibited greater tender point sensitivity, reduced physical strength, reduced lower-body flexibility, shorter sleep duration, and greater restlessness during sleep (Okifuji 2010).
  • A 2011 review article concluded that fibromyalgia patients are 40% more likely to be obese and 30% more likely to be overweight (Ursini 2011). In addition to concluding that obesity is highly prevalent among fibromyalgia patients, the authors also proposed the following possible mechanisms that might explain this link:
    • Alterations in the endogenous opioid system (painkilling mechanisms naturally occurring in the body)
    • Endocrine system dysfunction (e.g., thyroid and sex hormone imbalances)
    • Systemic inflammation (e.g., cytokine imbalance)
    • Too little physical activity
    • Cognitive and sleep disturbances
    • Psychiatric conditions (e.g., depression)
    • Dysfunction of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis