Fibromyalgia

Fibromyalgia (FM) syndrome is a common and chronic disorder characterized by widespread pain, diffuse tenderness, and a number of other symptoms. It is a disorder of pain regulation and often is classified as a form of central sensitization [Schmidt-Wilcke et al, 2014].

Although fibromyalgia is not a form of arthritis, because it does not cause inflammation or damage to the joints, muscles, or other tissues, however, like arthritis, fibromyalgia can cause significant pain and fatigue, and it can interfere with a person’s ability to carry on daily activities.

It is estimated that fibromyalgia affects 5 million Americans age 18 or older. For unknown reasons, 80% to 90% of those diagnosed with fibromyalgia are women; however, men and children also can be affected. Most people are diagnosed during middle age, although the symptoms often become present earlier in life.

The causes of fibromyalgia are unknown, but there are probably a number of factors involved. Many people associate the development of fibromyalgia with a physically or emotionally stressful or traumatic event, such as an automobile accident. Some connect it to repetitive injuries. Others link it to an illness. For others, fibromyalgia seems to occur spontaneously.

People with certain rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), or ankylosing spondylitis (spinal arthritis) may be more likely to have fibromyalgia. People with fibromyalgia may have a gene or genes that cause them to react strongly to stimuli that most people would not perceive as painful. There have already been several genes identified that occur more commonly in fibromyalgia patients.

Several studies indicate that women who have a family member with fibromyalgia are more likely to have fibromyalgia themselves, but the exact reason for this—whether it be heredity, shared environmental factors, or both—is unknown.

The pathophysiology of FM is not completely clarified, but a number of neuroendocrine, neurotransmitter-related, and neurosensory disturbances, as well as genetic predisposition, have been implicated in its generation.

Neuroendocrine:

• Dysfunction of the hypothalamic-pituitary-adrenal axis, including blunted cortisol responses;
• Abnormal growth hormone regulation

Neurotransmitter:

• Decreased serotonin in the central nervous system;
• Elevated levels of substance P and nerve growth factor in the spinal fluid

Neurosensory:

• Central amplification of pain and/or reduced antinociception (central sensitization, abnormalities of descending inhibitory pain pathways)

Genetic:

• Strong familial aggregation for FM;
• Evidence for a role of polymorphisms of genes in the serotoninergic, dopaminergic, and catecholaminergic systems in the etiology of fibromyalgia

• Rheumatoid arthritis
• SLE
• Osteoarthritis
• Spondyloarthritis
• Polymyalgia rheumatica
• MS
• Depression
• Anxiety
• Hypothyroidism
• hyperparathyroidism
• ushing’s syndrome
• Lyme disease
• Hepatitis C infection
• HIV
• Medications (Statins, bisphosphonates)
• Substance abuse

Fibromyalgia is a syndrome rather than a disease. Unlike a disease that has a specific cause or causes and recognizable signs and symptoms, a syndrome is a collection of signs, symptoms, and medical problems that tend to occur together but are not related to a specific, identifiable cause.

Physical symptoms:

• Chronic and widespread pain in both sides of the body and present above and below the waist
• Arthritis
• Flu-like symptoms
• Fatigue
• Irritable bowel syndrome (IBS)

Neurological manifestations:

Pain that may vary in location and intensity from day to day, and can be modulated by cold and humid weather or stress. (Hagglund et al. 1994; Macfarlane et al. 2010)

• Hypertonic and hypotonic muscles
• Numbness
• Tingling
• Musculoskeletal symmetry and dysfunction involving muscles, ligaments  and  joints
• Atypical patterns of numbnessand tingling
• Abnormal muscle twitch response, muscle cramps, muscle weakness
• Fasciculations
• Headaches
• Migraine headache
• Temporomandibular joint disorder
• Generalized weakness
• Perceptual disturbances
• Spatial instability
• Sensory overload phenomena often occur

Mood disorders:

• Depression and anxiety in up to 75% of FM patients (Epstein et  al. 1999)
• Depression and/or anxiety are present in one-third to one-half of patients at the time of diagnosis [Arnold et al 2006; Chang et al 2015; Soriano-Maldonado et al 2015]. A Canadian study has found that patients with FM were three times more likely to have depression compared with subjects without FM [Fuller-Thomas et al 2012]. Female gender with younger age, unmarried status, food insecurity, number of chronic conditions, and limitations in activities were found to be correlated with diagnosis of depression.

Neurocognitive manifestations: (Canovas  et  al. 2009; Park et al. 2001; Rodriguez-Andreu et al. 2008)

• Concentration and short­term memory consolidation
• Impaired speed of performance
• Inability to multi­task
• Easy distractibility
• Cognitive overload

Fatigue: 

• Reported in over 90% of FM patients (Mease  et al. 2009)
• There is persistent and reactive fatigue accompanied by reduced physical and mental stamina

Sleep disturbance:

• Non-refreshing sleep (Chiu et al. 2005)
• Sleep disturbances (Osorio et al. 2006; Moldofsky 2008)
• Insomnia frequent nocturnal awakenings
• Nocturnal myoclonus
• Restless leg syndrome

Autonomic and/or neuroendocrine manifestations: 

• Cardiac arrhythmias,
• Neutrally medicated  hypotension,
• Vertigo
• Vasomotor instability
• Sicca syndrome
• Temperature instability
• Hot/cold  intolerance,
• Respiratory  disturbances
• Intestinal and bladder motility disturbances with or without irritable bowel or bladder dysfunction, dysmenorrhea
• Loss of adaptability and tolerance for stress,
• Emotional flattening, lability, and/or reactive depression
• Sensitivity to light touch

Stiffness: 

• Generalized or even regional stiffness that is most severe upon awakening and typicallylasts for hours usually occurs, as in active rheumatoid arthritis.
• Stiffness can return during periods of inactivity during the day

Urogenital symptoms: (de  Araujo  et  al. 2008; Dao et al. 1997; Plesh et al. 1996; Poyhia et al. 2001)

• Lower urinary tract symptoms
• Sexual dysfunction

People with fibromyalgia typically see many doctors before receiving the diagnosis. One reason for this may be that pain and fatigue, the main symptoms of fibromyalgia, overlap with those of many other conditions. Therefore, other potential causes of these symptoms have to rule out before making a diagnosis of fibromyalgia. Another challenge is that the symptoms of FM are subjective and assessment is dependent on patient report and no objective laboratory tests exist to confirm the diagnosis.

Because there is no generally accepted, objective test for fibromyalgia, some doctors unfortunately may conclude a patient’s pain is not real, or they may tell the patient there is little they can do.

Diagnosis of fibromyalgia can be made based on criteria established by the American College of Rheumatology (ACR):

• a history of widespread pain lasting more than 3 months, and the presence of diffuse tenderness.
• Pain is considered to be widespread when it affects all four quadrants of the body, meaning it must be felt on both the left and right sides of the body as well as above and below the waist.
• ACR also has designated 18 sites on the body as possible tender points. To meet the strict criteria for a fibromyalgia diagnosis, a person must have 11 or more tender points, but often patients with fibromyalgia will not always be this tender, especially men (see illustration below). People who have fibromyalgia certainly may feel pain at other sites, too, but those 18 standard possible sites on the body are the criteria used for classification.

The questionnaires used for research purposes are not useful for clinical diagnosis of FM in daily practice.

There are currently no diagnostic laboratory tests for fibromyalgia; standard laboratory tests fail to reveal a physiologic reason for pain.

FM is not a diagnosis of exclusion

Simple lab tests should be limited to:

• CBC
• TSH
• ESR, CRP
• 8-11% of patients might have a positive ANA

Fibromyalgia can be difficult to treat. Fibromyalgia treatment often requires a team approach, with patient, primary care physician, a physical therapist, and a nurse all playing an active role.

Non-pharmacologist: (Ang  et al. 2007)

• Cognitive behavioral therapy (CBT)
• Education
• Exercise activities (water based, Tai Chi, Pilates,…)
• Self-management strategies
• Motivational interviewing
• Complementary and alternative medicine: studies has poor quality, small sample size, and mixed results.
• Acupuncture: only immediate pain reduction (Martin-Sanchez et al. 2009; Mayhew et al. 2007; Berman et al. 1999; Langhorst et  2010)

• Chiropractic: no effect (Schneider et al. 2009; Ernest 2009)

Pharmacologic treatments:

Only three medications, duloxetine (Cymbalta®), milnacipran (Savella®), and pregabalin (Lyrica®) are approved by the U.S. Food and Drug Administration (FDA) for the treatment of fibromyalgia.

Cymbalta was originally developed for and is still used to treat depression. Savella is similar to a drug used to treat depression, but is FDA approved only for fibromyalgia. Lyrica is a medication developed to treat neuropathic pain (chronic pain caused by damage to the nervous system).

For a subset of people with fibromyalgia, narcotic medications are prescribed for severe muscle pain. However, there is no solid evidence showing that for most people narcotics actually work to treat the chronic pain of fibromyalgia, and most doctors hesitate to prescribe them for long-term use because of the potential that the person taking them will become physically or psychologically dependent on them.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):  

This drugs work by inhibiting substances in the body called prostaglandins, which play a role in pain and inflammation. These medications, some of which are available without a prescription, may help ease the muscle aches of fibromyalgia. (Guggenheimer et al. 2011; Lynch et al. 2006). NSAIDs can cause renal, cardiovascular, and gastrointestinal toxicity.

Antidepressants:

Perhaps the most useful medications for fibromyalgia are several in the antidepressant class.

These drugs work equally well in fibromyalgia patients with and without depression, because antidepressants elevate the levels of certain chemicals in the brain (including serotonin and norepinephrine) that are associated not only with depression, but also with pain and fatigue. Increasing the levels of these chemicals can reduce pain in people who have fibromyalgia. Doctors prescribe several types of antidepressants for people with fibromyalgia, described below.

Tricyclic antidepressants:  

When taken at bedtime in dosages lower than those used to treat depression, tricyclic antidepressants can help promote restorative sleep in people with fibromyalgia. They also can relax painful muscles and heighten the effects of the body’s natural pain-killing substances called endorphins. Some examples of tricyclic medications used to treat fibromyalgia include amitriptyline hydrochloride (Elavil, Endep), cyclobenzaprine (Cycloflex, Flexeril, Flexiban), doxepin (Adapin, Sinequan), and nortriptyline (Aventyl, Pamelor). Both amitriptyline and cyclobenzaprine have been proven useful for the treatment of fibromyalgia. (Tofferi 2004)

Selective serotonin reuptake inhibitors:

If a tricyclic antidepressant fails to bring relief, doctors sometimes prescribe a newer type of antidepressant called a selective serotonin reuptake inhibitor (SSRI). By promoting the release of serotonin, these drugs may reduce fatigue and some other symptoms associated with fibromyalgia. The group of SSRIs includes fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). Newer SSRIs such as citalopram (Celexa) or escitalopram (Lexapro) do not seem to work as well for pain as the older SSRIs. SSRIs may be prescribed along with a tricyclic antidepressant. Studies have shown that a combination therapy of the tricyclic amitriptyline and the SSRI fluoxetine resulted in greater improvements in the study participants’ fibromyalgia symptoms than either drug alone. (Hauser et al. 2009; Uceyler 2008)

Mixed reuptake inhibitors:

Some newer antidepressants raise levels of both serotonin and norepinephrine and are therefore called mixed reuptake inhibitors. Examples of these medications include venlafaxine (Effexor), duloxetine (Cymbalta), and (Savella). In general, these drugs work better for pain than SSRIs, probably because they also raise norepinephrine, which may play an even greater role in pain transmission than serotonin.

Benzodiazepines

Benzodiazepines can sometimes help people with fibromyalgia by relaxing tense, painful muscles and stabilizing the erratic brain waves that can interfere with deep sleep. Benzodiazepines also can relieve the symptoms of restless legs syndrome, a neurological disorder that is more common among people with fibromyalgia. The disorder is characterized by unpleasant sensations in the legs and an uncontrollable urge to move the legs, particularly when at rest, in an effort to relieve these feelings. Doctors usually prescribe benzodiazepines only for people who have not responded to other therapies because of the potential for addiction. Benzodiazepines include clonazepam (Klonopin) and diazepam (Valium).

Cannabinoids:

In a small trial of 40 patients with FM over a 4 weeks period, nabilone improved pain, functional status and anxiety compared to placebo. (Skrabek et al. 2008)

Opioids:

Tramadol is the only opioid that has been studied in the treatment of FM. It helps with pain control and also improves quality of life. (Biasi 1998, Bennett et al. 2003) Tramadol is metabolized via cytochrome-P450 isoenzyme 2D6.

There are no studies on the potential benefits and safety of NMDA receptor antagonists including ketamine, dextrometorphan, amantadine, memantine, and methadone on treatment of FM.

Other Medications

Carbamazepine, gabapentin, and pregabalin are anticonvulsants and act at a number of sites, including voltage-gated ion channels, NDMA and GABA receptors. An analysis of 127 randomized controlled trials found strong evidence for reduced pain, improved sleep and quality of life for gabapentin and pregabalin.  

What Can I Do to Try to Feel Better?

Fibromyalgia is a chronic condition, meaning it lasts a long time—possibly a lifetime. However, it may be comforting to know that fibromyalgia is not a progressive disease. It is never fatal, and it will not cause damage to the joints, muscles, or internal organs. In many people, the condition does improve over time.

• Use active relaxation strategies.
  • Regular relaxation exercise provides a sense of control over illness
  • Reduced muscular tension
  • Reduces anxiety and worry
  • Increases sense of well-being
  • Regular meditation improves depression and reduces sleep problems.
• Getting enough sleep.
  • Getting enough sleep and the right kind of sleep can help ease the pain and fatigue of fibromyalgia.
  • Stick to a schedule
  • Limit your bed activities
  • Stop daytime napping
• Lessen anger:
  • Identify emotions
  • Stop persistent self-criticism
  • Rethink your view of yourself
  • As a human being you can express your complaints.
• Find relief from worry and guilt
  • Do not worry about symptoms as it will give you any control over what happens
  • Worry does not solve problems
• Easing into pleasant events:
  • Vacation
  • Start with low-effort pleasant activities
• Making changes at work. Most people with fibromyalgia continue to work, but they may have to make big changes to do so. For example, some people cut down the number of hours they work, switch to a less demanding job, or adapt a current job. If you face obstacles at work, such as an uncomfortable desk chair that leaves your back aching or difficulty lifting heavy boxes or files, your employer may make adaptations that will enable you to keep your job.
• Eating well. Although some people with fibromyalgia report feeling better when they eat or avoid certain foods, no specific diet has been proven to influence fibromyalgia.
• Making changes at work. Most people with fibromyalgia continue to work, but they may have to make big changes to do so. For example, some people cut down the number of hours they work, switch to a less demanding job, or adapt a current job. If you face obstacles at work, such as an uncomfortable desk chair that leaves your back aching or difficulty lifting heavy boxes or files, your employer may make adaptations that will enable you to keep your job.
• Eating well. Although some people with fibromyalgia report feeling better when they eat or avoid certain foods, no specific diet has been proven to influence fibromyalgia.

• Abd, T.T. and T.A. Jacobson, Statin-induced myopathy: a review and update. Expert Opin Drug Saf, 2011. 10(3): p. 373-87.
• Al-Allaf, A.W., L. Ottewell, and T. Pullar, The prevalence and significance of positive antinuclear antibodies in patients with fibromyalgia syndrome: 2-4 years’ follow-up. Clinical Rheumatology, 2002. 21(6): p. 472-7.
• Ang, et al., Exercise-based motivational  interviewing for female  patients  with fibromyalgia:  a case  series. Clinical Rheumatology, 2007. 26(11): p. 1843-9.
• Arnold LM, Hudson JI, Keck PE, et al. Comorbidity of fibromyalgia and psychiatric disorders. J Clin Psychiatry 2006; 67:1219.
• Bennett, R.M., et al.,Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. American Journal of Medicine, 2003. 114(7): p. 537-45.
• Berman, B.M., et al., Is acupuncture effective in the treatment of fibromyalgia? Journal of Family Practice, 1999. 48(3): p. 213-8.
• Biasi, G., et al., Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. International Journal of Clinical Pharmacology Research, 1998. 18(1): p. 13-9.
• Canovas, , et al., Virtual reality tasks  disclose  spatial  memory  alterations  in  fibromyalgia. Rheumatology, 2009. 48(10): p. 1273-8.
• Chang MH, Hsu JW, Huang KL, et al. Bidirectional Association Between Depression and Fibromyalgia Syndrome: A Nationwide Longitudinal Study. J Pain 2015; 16:895.
• Chiu, Y.H., et al., Poor sleep and depression are independently associated with a reduced pain threshold. Results of a population based study. Pain, 2005. 115(3): p. 316-21.
• Dao, T.T., W.J. Reynolds, and H.C. Tenenbaum, Comorbidity between myofascial pain of the masticatory muscles and fibromyalgia. J Orofac Pain, 1997. 11(3): p. 232-41.
• de Araujo,  P., et al., Urodynamic  study  and  quality  of  life  in  patients  with  fibromyalgia  and  lower  urinary  tract symptoms. Int Urogynecol J Pelvic Floor Dysfunct, 2008. 19(8): p. 1103-7.
• Epstein, S.A., et al., Psychiatric disorders in patients with A multicenter investigation. Psychosomatics, 1999. 40(1): p. 57-63.
• Ernst, E., Chiropractic treatment for fibromyalgia: a systematic review. Clinical Rheumatology, 2009. 28(10): p. 1175-8.
• Fassbender, K., et al., Tender points, depressive and functional symptoms: comparison between fibromyalgia and major depression. Clinical Rheumatology, 1997. 16(1): p. 76-9.
• Fitzcharles, M.A. and P. Boulos, Inaccuracy in the diagnosis of fibromyalgia syndrome: analysis of referrals.Rheumatology (Oxford), 2003. 42(2): p. 263-7.
• Fuller-Thomson E, Nimigon-Young J, Brennenstuhl S. Individuals with fibromyalgia and depression: findings from a nationally representative Canadian survey. Rheumatol Int 2012; 32:853.
• Guggenheimer, J. and A. Moore, The  therapeutic  applications  of  and  risks  associated  with  acetaminophen  use:  a review and update. Journal of the American Dental Association, 2011. 142(1): p. 38-44.
• Hagglund, K.J., et al., Weather, beliefs about weather, and disease severity among patients with fibromyalgia. Arthritis Care and Research, 1994. 7 (3): p. 130-135.
• Hauser, W., et al., Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis. JAMA,2009. 301(2): p. 198-209.
• Hsu, V.M., S.J. Patella, and L.H. Sigal, “Chronic Lyme disease” as the incorrect diagnosis in patients with fibromyalgia.Arthritis & Rheumatism, 1993. 36(11): p. 1493-500.
• Kotter, I., et al., Is there a predisposition  for  the  development  of  autoimmune  diseases  in  patients  with  fibromyalgia? Retrospective analysis with long term follow-up. Rheumatology International, 2007. 27(11): p. 1031-9.
• Kozanoglu, E., et al., Fibromyalgia syndrome in patients with hepatitis C infection. Rheumatology International, 2003. 23(5): p. 248-251.
• Langhorst, ,  et  al.,  Efficacy  of  acupuncture  in  fibromyalgia  syndrome–a  systematic  review  with  a  meta-analysis  of controlled clinical trials. Rheumatology, 2010. 49(4): p. 778-88.
• Lynch, E. and  C.P. Watson, The  pharmacotherapy of  chronic  pain:  a  review. Pain Research  & Management, 2006. 11(1): p. 11-38.
• Macfarlane, T.V., et al., Whether the weather influences pain? Results from the EpiFunD study in North West England. Rheumatology, 2010. 49(8): p. 1513-20.
• Martin-Sanchez, ,  et  al.,  Efficacy  of  acupuncture  for  the  treatment  of  fibromyalgia:  Systematic  review  and  meta-analysis of randomized trials. Open Rheumatology Journal, 2009. 3: p. 25-29.
• Mayhew, E. and Ernst, Acupuncture  for   fibromyalgia–a systematic  review of  randomized   clinical  trials.Rheumatology (Oxford), 2007. 46(5): p. 801-4.
• Mease, P., et al., Fibromyalgia syndrome module  at  OMERACT  9:  domain construct. Journal of Rheumatology, 2009. 36(10): p. 2318-29.
• Moldofsky, H., The significance of the sleeping-waking brain for the understanding of widespread musculoskeletal pain and fatigue in fibromyalgia syndrome and allied syndromes. Joint Bone Spine, 2008. 75(4): p. 397-402.
• Osorio, C.D., et , Sleep quality  in  patients  with  fibromyalgia  using  the  Pittsburgh  Sleep  Quality  Index. Journal of Rheumatology, 2006. 33(9): p. 1863-5.
• Park, D.C., et al., Cognitive function in fibromyalgia patients. Arthritis & Rheumatism, 2001. 44(9): p. 2125-33.
• Plesh, O., F. Wolfe, and N. Lane, The relationship between fibromyalgia and temporomandibular disorders: Prevalence and symptom severity. Journal of Rheumatology, 1996. 23(11): p. 1948-1952.
• Poyhia, R., D. Da Costa, and M.A. Fitzcharles, Previous pain experience in women with fibromyalgia and inflammatory arthritis and nonpainful controls. Journal of Rheumatology, 2001. 28(8): p. 1888-91.
• Rodriguez-Andreu, J., et al., Cognitive impairment in patients with fibromyalgia syndrome as assessed by the mini-mental state examination. BMC Musculoskeletal Disorders, 2009. 10: p. 162.
• Schmidt-Wilcke T, Kairys A, Ichesco E, et al. Changes in clinical pain in fibromyalgia patients correlate with changes in brain activation in the cingulate cortex in a response inhibition task. Pain Med 2014; 15:1346.
• Schneider, J.,  Tender  points/fibromyalgia  vs.  trigger points/myofascial  pain syndrome: a need  for  clarity  in terminology and differential diagnosis. Journal of Manipulative & Physiological Therapeutics, 1995. 18(6): p. 398-406.
• Schneider, M., et al., Chiropractic management of fibromyalgia syndrome: a systematic review of the literature. Journal of Manipulative & Physiological Therapeutics, 2009. 32(1): p. 25-40.
• Skrabek, R.Q., et al., Nabilone for the treatment of pain in fibromyalgia. Journal of Pain, 2008. 9(2): p. 164-73.
• Soriano-Maldonado A, Amris K, Ortega FB, et al. Association of different levels of depressive symptoms with symptomatology, overall disease severity, and quality of life in women with fibromyalgia. Qual Life Res 2015; 24:2951.
• Tofferi, J.K., J.L. Jackson, and P.G. O’Malley, Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis. Arthritis & Rheumatism, 2004. 51(1): p. 9-13.
• Uceyler, N., W. Hauser, and Sommer,  A systematic  review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome. Arthritis Care and Research, 2008. 59 (9): p. 1279-1298.
• Walitt, B., et al., Automated neuropsychiatric  measurements  of  information processing  in  Rheumatology International, 2008. 28(6): p. 561-6.