Fibromyalgia: Treatment Approaches

Overview

Since the exact etiology of fibromyalgia is unknown, treatment at this time must remain empirical. It also should be multidisciplinary. Viewed as a biopsychosocial model, the current feeling is that fibromyalgia is a disease of central sensitization. There are certain variables which are non-modifiable such as genetics and gender and others, which appear modifiable including sleep disturbance, psychological distress and external triggers.

Genetic analysis appears to implicate an association between major mood disorders and fibromyalgia. However, this does not lead to any obvious treatments modalities at this time. In similar fashion, the marked preponderance of females does not lead to any obvious remediation. However, external factors are known to exacerbate symptoms of fibromyalgia. Noises commonly known to worsen fibromyalgia symptoms and many patients also complained of cold intolerance and report worsening symptoms in the fall and winter. Weather changes, specifically, barometric changes, rather than temperature changes seem to produce problems. Too little or too much physical activity can also worsen symptoms. (1) Nonrestorative sleep occurs an almost 100% of fibromyalgia patients. The nonrestorative sleep is largely a result of pain and may underlie, at least in part, the pervasive fatigue seen in fibromyalgia. (2)

Geriatric and pediatric fibromyalgia present different problems, are not covered in this review and will be the subject of future reviews.
Psychological distress: A variety of abnormal cognitive-behavioral aberrations may play a role in fibromyalgia. These include posttraumatic stress disorder, depression, and anxiety, and to a lesser extent, personality disorders. The fixed belief system of some fibromyalgia patients sometimes interferes with recovery. Some fibromyalgia patients believe that minor traumatic events, infections, chemical exposure or other physical and emotional agents are the proximate and competent cause of their condition. Since these beliefs are unproven and suggest no therapeutic opportunities, they may serve as an impediment to recovery. Treatment starts with recognition that the patient is suffering valid distress. A thorough history, physical examination, review of records and comprehensive discussion with the patient leads to a therapeutic environment which is an important therapeutic agent. It should be stressed to the patient that amelioration, rather than cure is a realistic therapeutic goal. A rush to therapy with medications without a consideration of the patient's overall life situation and recourse to non-pharmacologic measures is a disservice to the patient. Many treatments in the past have been predicated on putative and unproven theories of fibromyalgia. These include such concepts as the leaking gut theory, occult infection and disturbances of the pituitary-hypothalamic-adrenal axis.

It should be stated at the outset of that there is a plethora of studies on multiple treatments, but a dearth of controlled, double-blind studies. Various reasons for this exist, including the heterogeneity of fibromyalgia patients, small sample size in various series, short durations of trials and placebo effect. Two meta-analyses are available, but they do suffer from their remote origin in time. (3) (4).
Co-morbidities and associated symptoms

Multiple comorbidities and associated medical conditions abound in fibromyalgia:

Frequency of associated symptoms in FM (5)

• Widespread pain and tender points 100%
• Generalized weakness and aching joints 80%
• Non-restorative sleep 80-86%
• Fatigue 70-96%
• Tilt table response 70%
• Stiffness 60%
• Tension type headache 53-60%
• Irritable bowel 40%
• Painful periods or dysmenorrhea 40%
• Paresthesias 35-52%
• Leg cramps and restless legs 42-56%
• Significant cognitive dysfunction 20-40%
• Severe depression 20%

In addition, there is a high incidence of association with chronic disease states (6,7,8)

• Chronic fatigue syndrome ~70%
• Irritable bowel syndrome ~ 60%
• Sjögren’s syndrome ~ 50%
• Systemic lupus erythematosis ~ 30%
• Irritable bladder syndrome ~ 30%
• Restless legs syndrome ~ 30%
• Rheumatoid arthritis ~ 25%
• Osteoarthritis ~ 0 – 60%

Addressing these conditions is mandatory.

Treatment Approaches

Gaining empathy
An empathetic approach is mandatory in the treatment of fibromyalgia. The uncertainty of the diagnosis often presents the most difficult period of time for the patient. (9) patients with a chronic illness, such as fibromyalgia, face, permanent changes in lifestyle, threats to dignity in self-esteem, disruption of normal life transitions and decreasing resources. Their families face financial, social, and psychological challenges. Living with chronic and painful illnesses is a highly subjective experience, filtered through the lens of each individual’s life circumstances. A variety of coping strategies, such as information seeking, direct action and turning to others may be employed effectively to positively influence function and well-being. (10)

Education
As indicated above, patient beliefs may be a real detriment to effective treatment of fibromyalgia. Patient and family education is a highly therapeutic measure. There are a variety of excellent resources available for patient education.

National Fibromyalgia Association
http://fmaware.org

Fibromyalgia-Mayo Clinic.com
http://www mayoclinic.com/invoke.cfm?id=DS00079

Nonpharmacologic Intervention
In many ways, nonpharmacological treatments have been more effective than pharmacologic treatments. They may include exercise biofeedback and stress management, counseling and support groups. Some have advocated Yoga and meditation. In particular, aerobic exercise, has been of benefit on reducing pain threshold increasing physical ability and encouraging global well-being. (11) The exercise is best if mild. (12). Psychological counseling may be helpful for many patients, but there are no controlled studies available.

Pharmacological Treatment

There are 3 FDA approved treatments for fibromyalgia: Duloxetine,Pregabalin and Milnacipran.

Duloxetine (Cymbalta)
Duloxetine hydrochloride was originally developed as an antidepressant for the treatment of major depressive disorder including both the emotional and physical symptoms. Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor for oral administration. Its chemical designation is (+)-(S)-N-methyl-gamma-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. A randomized, double-blind, placebo-controlled trial showed that duloxetine was effective and safe in the treatment of fibromyalgia in female patients with or without major depressive disorder. (13) This was a 12-week, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in 354 female patients with primary fibromyalgia, with or without current major depressive disorder. The treatment effect of duloxetine on pain reduction was independent of the effect on mood and the presence of major depressive disorder. Compared with patients on placebo, patients treated with duloxetine 60 mg QD or duloxetine 60 mg BID had significantly greater improvement in remaining Brief Pain Inventory pain severity and interference scores, Fibromyalgia Impact Questionnaire, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and several quality-of-life measures. Both doses of duloxetine were safely administered and well tolerated. Both duloxetine 60 mg QD and duloxetine 60 mg BID were effective and safe in the treatment of fibromyalgia. (14).

Pregabalin (Lyrica)
The chemical name of pregabalin(15) is: CI-1008 or (S)-3-isobutyl GABA, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid. It is an alpha2delta-ligand that has been found effective in a variety of animal models of neuropathic and nociceptive pain. The mode of action of pregabalin is similar to that of gabapentin which had often been used previously off-label for fibromyalgia.. Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma aminobutyric acid (GABA), it does not bind directly to GABA and has no effects on GABA uptake or degradation. Pregabalin selectively binds to the alpha2delta-subunit protein of voltage-gated calcium channels in various regions of brain and in the superficial dorsal horn of the spinal cord. It acts as a presynaptic inhibitor of the release of excitatory neurotransmitters in stimulated neurons. It reduces influx of calcium into isolated synaptic endings. A multicenter, double-blind, 8-week, randomized clinical trial compared the effects of placebo with those of 150, 300, and 450 mg/day pregabalin on pain, sleep, fatigue, and health-related quality of life in 529 patients with FMS. The primary outcome variable was the comparison of end point mean pain scores, derived from daily diary ratings of pain intensity, between each of the pregabalin treatment groups and the placebo group. Pregabalin at 450 mg/day significantly reduced the average severity of pain in the primary analysis compared with placebo. Improvement in pain at the end point was29%, versus 13% in the placebo group. Pregabalin at 300 and 450 mg/day was associated with significant improvements in sleep quality, fatigue, and global measures of change. Pregabalin, at 450 mg/day, improved several domains of health-related quality of life. Dizziness and somnolence were the most frequent adverse events. Rates of discontinuation due to adverse events were similar across all 4 treatment groups. (16).

Milnacipran HCl (Savella)
Milnacipran HCl belongs to a class of drugs called serotonin and norepinephrine reuptake inhibitors (SNRIs), which include some of the other antidepressants. It is the latest drug to be approved by the FDA for the treatment of fibromyalgia and was approved in January 2 009.
Milnacipran compared with placebo produced at least a 30% reduction in pain and a similar percentage of patients rated themselves as being "very much improved" or "much improved" in terms of their fibromyalgia, Milnacipran HCl is administered in two divided doses per day. The dosage is gradually increased over the course of the first week to get to the recommended dose of 100 mg/day. Some patients may require 200 mg/day -- and some may require a lower dose if they have renal (kidney) impairment.Milnacipran is contraindicated in patients with uncontrolled narrow-angle glaucoma. Savella should also not be used by patients taking MAOIs (monoamine oxidase inhibitors), typically used for depression.It is not approved for use in children.

Other Drugs used for Fibromyalgia
Antidepressant drugs not approved by the FDA include try cyclic antidepressants. Amitriptyline is a very common choice for treating fibromyalgia and has met with some success. It tends to facilitate sleep, but its anti-cholinergic of effects as well as the sedative effects and weight gain are usually a poorly tolerated. The usual dose is 10 to 50 mg at bedtime. The other SSRIs and SNRIs have been used but there efficacy is not proven. Skeletal muscle relaxants such as cyclobenzaprine, tizanidine, and baclofen, have also been used. Botox, trigger point injections, as well as ultrasound, laser and regional blocks have also been used. Their efficacy remains unproven. Ibuprofen and other NSAIDs have been used. For fatigue, Modafinil may be useful, especially in the early stages of treatment. Sleep disturbances, may be treated with tricyclic a, trazodone antidepressants or benzodiazepines. A better choice may be the melatonin receptor agonist ramelteon.Trazadone is also a reasonable option. Drugs, with addictive potential, such as opioids, and benzodiazepines or best avoided.

Complementary and alternative treatments have been used, mostly self prescribed by the patients. Various diets, acupuncture, and magnetic therapy have also been used.

Conclusion:
Fibromyalgia is a chronic, incurable condition, which has far-reaching effects on the patient and the family. Treatment begins with an empathetic recognition of the disease and the patient’s suffering. Realistic goals must be set. Education is of great value, especially in dispelling barriers to treatment, such as the patient's self perceived etiological basis for their condition. Nonpharmacologic treatment is of proven efficacy and aerobic exercise is of value in improving the quality of life and decreasing pain. Comorbid conditions, such as chronic fatigue, irritable bowel syndrome, depression, and migraine headaches, all of which occur in a much higher proportion than in the general population require conscientious attention. Psychological counseling, when indicated, for patient, and family, alike, may be most useful. While many drugs have been used for fibromyalgia, at this time there are only 3 FDA approved drugs which have been reviewed above. Prudence dictates that these should be the initial drugs of choice.

References

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