Fibromyalgia: Psychiatric drugs target CNS-linked symptoms

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"Is fibromyalgia a somatoform disorder?

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Patients with fibromyalgia are a heterogeneous group, yet many describe a common experience: seeing multiple physicians who seem unable or unwilling to provide a diagnosis or treat their symptoms. This situation may be changing with the recent FDA approval of an anticonvulsant and 2 antidepressants for managing fibromyalgia symptoms.

These medications—pregabalin, duloxetine, and milnacipran—reflect a revised understanding of fibromyalgia as a CNS condition, rather than an inflammatory process in the muscles or connective tissue. As a result, psychiatrists—because of our experience with CNS phenomena and managing antidepressant and anticonvulsant medications—are likely to play a larger role in treating fibromyalgia.

CASE REPORT: ‘Just too tired’

Ms. D, age 50, has a history of migraine headaches and is referred by her primary physician for evaluation of depression and anxiety. She reports deteriorating mood over 6 months, beginning when a minor car accident left her “very sore the next day.”

“Nothing helps” the persistent pain in her back, shoulders, and thighs, which she rates as 7 to 8 on a 0-to-10 pain scale. She describes an intense ache, “like having the flu,” that worsens with activity and in stressful situations. She also experiences nausea and intermittent diarrhea, debilitating fatigue, and sleep disturbance.

Ms. D reports she is depressed because she feels “just too tired” after work to keep up with social activities or housework. Her physician’s referral notes a normal physical exam except for tenderness over her upper back and hips. Laboratory testing is negative.

Making the diagnosis

American College of Rheumatology (ACR) criteria for fibromyalgia require widespread pain for at least 3 months. “Widespread” is defined as pain in the axial skeleton, left and right sides of the body, and above and below the waist. Pain must be found in at least 11 of 18 tender point sites on digital palpation using a force of approximately 4 kg/cm².¹ For many fibromyalgia patients, however, musculoskeletal pain is not their most problematic symptom (Table 1). They may suffer:

• migraine and tension headaches (10% to 80% of patients)
  
• irritable bowel syndrome (32% to 80%)²
  
• mood disorders (major depressive disorder [62%], bipolar disorder [11%])
  
• anxiety disorders (panic disorder [29%], posttraumatic stress disorder [21%], social phobia [19%]).³
  

ACR criteria are useful in research but lack many common symptoms and comorbidities. A structured interview that follows the DSM-IV-TR format incorporates other symptoms into the diagnosis (Table 2).⁴

Because patients with fibromyalgia often meet criteria for somatization or somatoform disorders, how to classify them—as medically or psychiatrically ill—is controversial. Some patients believe their mood or anxiety problem stems from the difficulty they experience dealing with their physical symptoms, and if they could feel better physically they would not be depressed or anxious. Others believe their psychiatric symptoms impede their ability to help themselves feel better.

Consider fibromyalgia in any patient with widespread pain of unknown cause. Before making the diagnosis, rule out other illnesses that present with similar symptoms (Table 3). Because many patients newly diagnosed with fibromyalgia worry that something “more serious” may be going on, confirm the diagnosis with appropriate testing and physical examination, usually by a rheumatologist or primary care physician.

Table 1

Medical and cognitive symptoms related to fibromyalgia

Neurologic Tension/migraine headache
Psychiatric Memory and cognitive difficulties Mood disturbance Anxiety disorders
Ear, nose, throat Sicca symptoms Vasomotor rhinitis Vestibular complaints
Cardiovascular Neurally mediated hypotension Mitral valve prolapse Noncardiac chest pain
Gastrointestinal Esophageal dysmotility Irritable bowel syndrome
Urological Interstitial cystitis
Gynecological Vulvodynia Chronic pelvic pain
Oral/dental Temporomandibular joint syndrome
Other (general) Chronic fatigue syndrome Sleep disturbances Idiopathic low back pain Multiple chemical sensitivity

Table 2

Fibromyalgia: Structured interview for diagnosis

A. Generalized pain affecting the axial, plus upper and lower segments, plus left and rights sides of the body
Either B or C:
B. At least 11 of 18 reproducible tender points
C. At least 4 of the following symptoms: Generalized fatigue Headaches Sleep disturbance Neuropsychiatric complaints Numbness, tingling sensations Irritable bowel symptoms
D. It cannot be established that disturbance was due to another systematic condition
Source: Reference 4

Table 3

Differentiating fibromyalgia from illnesses with similar symptoms

Illness	Tests to differentiate from primary fibromyalgia
Rheumatic diseases Osteoarthritis Spondyloarthropathies, rheumatoid arthritis Systemic lupus erythematosus, polymyalgia rheumatica Osteomalacia Myopathy	Radiographs Rheumatic markers (antinuclear antibody, rheumatoid factor, antibodies) Inflammatory markers (ESR, C-reactive protein) Vitamin D level CPK
Neurologic Multiple sclerosis, Chiari’s malformation, spinal stenosis, radiculopathy Neuropathy	MRI EMG
Endocrine Hypothyroidism Diabetes	TSH Basic chemistry panel with fasting glucose
Other Infectious   Lyme disease   Hepatitis Anemia Cancers	CBC Lyme titer Hepatitis antibody panel, liver function tests Hemoglobin/hematocrit Routine cancer screening tests, bone scan, blood chemistries specific for suspected primary cancer
ESR: erythrocyte sedimentation rate; CPK: creatine phosphokinase; EMG: electromyography; TSH: thyroid-stimulating hormone; CBC: complete blood count

 

CASE CONTINUED: Central pain sensitization

As you elicit more details about Ms. D’s mood, she continues to focus on her physical symptoms. She states that some days she wishes to die because her pain gets so bad, but she denies any plan or intent to harm herself. She worries that her symptoms will worsen and that she will become completely disabled.

Her primary physician attempted to relieve Ms. D’s pain with multiple trials of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclobenzaprine. She says she gained no benefit from the NSAIDs and discontinued the muscle relaxant because it made her too sleepy. Fibromyalgia affects 3.5% of women and 0.5% of men.⁵ It runs in families with histories of fibromyalgia and major mood and anxiety disorders, suggesting genetic links.⁶ Defects in genes controlling serotonin and norepinephrine have been implicated.^7-9

Fibromyalgia patients show lower levels of serotonin, norepinephrine, and dopamine metabolites in cerebrospinal fluid (CSF), compared with controls.¹⁰ These neurotransmitters may inhibit descending pain pathways in the CNS, and low levels in the brain and spinal cord may inhibit CNS regulation of pain impulses from the periphery.¹¹

Although many patients describe muscle pain, evidence suggests central pain augmentation rather than an abnormality of muscle or connective tissue.¹² Some studies have found evidence of “windup,” in which second-order neurons in the spinal cord become sensitized by repeated signals from first-order neurons in the periphery, resulting in amplified and prolonged pain signals traveling to the brain.¹³

Levels of substance P—a primary transmitter of pain impulses—are significantly higher in CSF of fibromyalgia patients compared with controls.¹⁴ This finding, in addition to low levels of serotonin and norepinephrine, indicates that pain signals are ascending unchecked to be processed by the brain.

Neuroimaging studies confirm this observation. In a study using functional magnetic resonance imaging (fMRI), researchers applied pressure to the thumbnails of fibromyalgia patients and controls until each subject reported pain:

• Twice as much pressure was required before controls rated their pain at a level similar to that of fibromyalgia patients.
  
• When controls and fibromyalgia patients reported similar pain, a very high degree of overlap was seen in brain areas responsible for pain processing. This indicates that fibromyalgia patients and controls were experiencing the pain they reported in the same way.¹⁵
  

Treating the whole patient

As a clinician who specializes in fibromyalgia, I counteract my patients’ and my own frustration with this condition by structuring office visits, determining realistic treatment goals, and treating all symptoms as part of a common syndrome rather than individual illnesses.

Structure office visits. Before every visit, have patients rate each symptom domain and write their top 2 or 3 concerns for that day (Click here for a sample form). Focusing on the patient’s most troublesome symptoms can help both of you feel greater satisfaction with treatment.

Educate patients. Ask them to discuss their beliefs about fibromyalgia; many know others with this condition or have researched diagnosis and treatment. Before developing a treatment plan, explain that their symptoms are chronic and all part of the same syndrome. Describe their pain as a complex phenomenon with possible peripheral and CNS components. Guide them to reputable Web sites and resources (see Related Resources).

Set realistic expectations. Many patients expect to resume an energetic and pain-free life, which usually is not the case with fibromyalgia (Box). Most medications are considered successful if they reduce pain by 30% to 50%, and side effects can be problematic. Discuss side effects before treatment begins to reduce patients’ anxiety and improve compliance in the first weeks.

Cognitive-behavioral therapy (CBT) for fibromyalgia incorporates relaxation techniques, helping patients view symptoms as manageable, reinforcing adaptive coping skills, and teaching them how to monitor thoughts, feelings, and behavior to change the view that they are helpless victims. A modest course of 6 weekly group CBT sessions significantly improved physical functioning in 25% of fibromyalgia patients (n=76) compared with 12% in a standard-care group (n=69), even though patients’ pain severity did not improve.¹⁶

Recommend exercise, lifestyle changes. Aerobic exercise can significantly improve well-being and physical functioning in fibromyalgia patients.¹⁷ Low-impact aerobics, such as done in warm water, usually are well tolerated, although any low-impact exercise can help. Because fibromyalgia symptoms often increase with physical activity, counsel patients to begin with a few minutes daily and increase very slowly each week.

 

Lifestyle changes are as important as medications in controlling fibromyalgia symptoms. In addition to exercise, recommend that patients:

• follow a daily routine
  
• pace activity to avoid exacerbating symptoms
  
• reduce stress.
  

Sometimes, I use the analogy of diabetes: treating fibromyalgia with medication but without changing lifestyle is like prescribing medication for a diabetic patient without changing diet. Follow up on this “homework” at each visit to reinforce that patients helping themselves is an important part of treatment.

Box

New direction with medications

Pregabalin is an anticonvulsant that binds to the alpha-2-delta subunits of neurons’ voltage-gated calcium channels. This activity reduces calcium influx at nerve terminals and inhibits release of excitatory neurotransmitters, such as substance P and glutamate.¹⁸ In June 2007, pregabalin was the first medication FDA-approved for fibromyalgia.

Two placebo-controlled trials^19,20 showed that pregabalin at 150 mg bid, 225 mg bid, or 300 mg bid significantly reduced weekly mean pain scores in fibromyalgia patients. Click here for details of these trials. The most common side effects—dizziness, somnolence, peripheral edema, blurred vision, and weight gain—were regarded as mild to moderate in 87% of patients.²¹

Although a dosage of 300 mg bid also was studied, the FDA approved pregabalin at dosages of 150 mg bid and 225 mg bid for fibromyalgia.²²

Duloxetine is a serotonin/norepinephrine reuptake inhibitor (SNRI) thought to inhibit dorsal horn neurons’ response to peripheral pain signals by increasing serotonin and norepinephrine in the brain and spinal cord. This SNRI was first FDA-approved for diabetic peripheral neuropathic pain and major depressive disorder. Approval for fibromyalgia at 60 mg/d in June 2008 was based on 2 placebo-controlled, double-blind, 12-week trials comprising 874 patients.^23,24Click here for detailed findings of these studies and a 6-month fixed-dose trial.²⁵

In clinical trials, duloxetine dosages of 60 mg/d and 120 mg/d were significantly more effective than placebo. The most common side effects were nausea, constipation, excessive sweating, and somnolence.^23-25

Milnacipran is an SNRI that was approved for treating fibromyalgia in January 2009 at dosages of 50 mg bid and 100 mg bid. Like other SNRIs, milnacipran is thought to work by inhibiting pain signals through increasing serotonin and norepinephrine in the brain and spinal cord. Milnacipran has a higher selectivity for norepinephrine reuptake compared with duloxetine, which may mean these medications will have different effects in different patients. Although milnacipran is approved as an antidepressant in other countries, the FDA has not approved it for treating depression in the United States.

Click here for details of a 15-week, double-blind, placebo-controlled trial of milnacipran in patients with fibromyalgia. Side effects in clinical trials were similar to those of duloxetine, with nausea, constipation, and increased sweating being most prominent.²⁶

 

Other medications, such as the first-line agent amitriptyline, have shown beneficial effects in fibromyalgia but are not FDA-approved for this indication (Table 4).^27-32

Choosing medications. When prescribing one of the FDA-approved medications to treat fibromyalgia, consider their benefits and side effects.

Pregabalin may be a beneficial first choice for patients who report pain and sleep as major issues. Although the medication’s label recommends starting with twice-daily dosing, patients might better tolerate an initial dose of 50 to 75 mg in the evening, with the morning dose added later. Pregabalin can be useful in patients taking multiple medications because of its renal clearance, resulting in low risk of interactions with drugs metabolized by liver enzymes. It also can be useful in patients who have not tolerated antidepressants in the past or in whom antidepressants are contraindicated.

If a patient has a history of depression or discontinuing medications because of sedating side effects, an antidepressant such as duloxetine or milnacipran may be more successful than starting with pregabalin. In general, if a patient does not respond to one of these SNRIs, moving on to the other might help. Milnacipran’s more selective effect on norepinephrine could be beneficial for some patients, especially those with excessive fatigue. Others, especially those with a high level of anxiety, might respond better to a more balanced SNRI such as duloxetine.

Table 4

Off-label medications shown to benefit patients with fibromyalgia

Drug	Comment
Amitriptyline27,28	Considered first-line because of studies supporting its use, low cost, and wide availability; may be associated with more side effects than newer medications
Gabapentin29	Possible alternative to pregabalin but may not be as well tolerated
Tramadol30	May help with breakthrough pain; use with extreme caution in patients taking antidepressants because of serotonin syndrome risk
Fluoxetine31	Dosages of 40 to 60 mg/d may help patients who do not tolerate SNRIs
Venlafaxine32	Dosages of 150 to 225 mg/d may be an alternative to other SNRIs
SNRIs: serotonin/norepinephrine reuptake inhibitors

CASE CONTINUED: Not as hopeless

Ms. D’s primary care physician confirms your presumptive diagnosis of fibromyalgia. He prescribes a trial of amitriptyline, which she does not tolerate well because of sedation and weight gain. At her next psychiatric visit, she tells you she remains very frustrated about her physical symptoms and reports that her doctor “has given up on me.”

You discuss what a fibromyalgia diagnosis means to her and educate her about the syndrome. You refer her to a colleague who does CBT with chronic pain patients and start her on a low dose of duloxetine (30 mg once daily) to minimize side effects. You discuss possible side effects and that she may need a higher dose to notice improvement in her pain. She seems receptive to starting a graded exercise program, and you encourage her to reduce physical and emotional stress in her life.

When she returns, she reports her pain is somewhat improved and medication side effects have subsided. She is not as hopeless and tells you she is up to 10 minutes of walking daily. You increase duloxetine to 60 mg/d and reinforce her ability to exercise and manage her stress.

Related Resources

• Arthritis Foundation. Fibromyalgia. www.arthritis.org/disease-center.php?disease_id=10.
  
• National Fibromyalgia Association. www.fmaware.org.
  
• Self-management program for patients with fibromyalgia, cosponsored by the National Fibromyalgia Association and Eli Lilly and Company. www.knowfibro.com.
  

Drug Brand Names

• Amitriptyline • Elavil, Endep
  
• Cyclobenzaprine • Flexeril
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Milnacipran • Savella
  
• Pregabalin • Lyrica
  
• Tramadol • Ultram, Ultracet
  
• Venlafaxine • Effexor, Effexor XR
  

Disclosure

Dr. Stanford receives grant/research support from Eli Lilly and Company, Pfizer, Cypress Bioscience, and Allergan.

WEB AUDIO
Listen to Dr. Stanford discuss,
"Is fibromyalgia a somatoform disorder?

Comment on this article

Patients with fibromyalgia are a heterogeneous group, yet many describe a common experience: seeing multiple physicians who seem unable or unwilling to provide a diagnosis or treat their symptoms. This situation may be changing with the recent FDA approval of an anticonvulsant and 2 antidepressants for managing fibromyalgia symptoms.

These medications—pregabalin, duloxetine, and milnacipran—reflect a revised understanding of fibromyalgia as a CNS condition, rather than an inflammatory process in the muscles or connective tissue. As a result, psychiatrists—because of our experience with CNS phenomena and managing antidepressant and anticonvulsant medications—are likely to play a larger role in treating fibromyalgia.

CASE REPORT: ‘Just too tired’

Ms. D, age 50, has a history of migraine headaches and is referred by her primary physician for evaluation of depression and anxiety. She reports deteriorating mood over 6 months, beginning when a minor car accident left her “very sore the next day.”

“Nothing helps” the persistent pain in her back, shoulders, and thighs, which she rates as 7 to 8 on a 0-to-10 pain scale. She describes an intense ache, “like having the flu,” that worsens with activity and in stressful situations. She also experiences nausea and intermittent diarrhea, debilitating fatigue, and sleep disturbance.

Ms. D reports she is depressed because she feels “just too tired” after work to keep up with social activities or housework. Her physician’s referral notes a normal physical exam except for tenderness over her upper back and hips. Laboratory testing is negative.

Making the diagnosis

American College of Rheumatology (ACR) criteria for fibromyalgia require widespread pain for at least 3 months. “Widespread” is defined as pain in the axial skeleton, left and right sides of the body, and above and below the waist. Pain must be found in at least 11 of 18 tender point sites on digital palpation using a force of approximately 4 kg/cm².¹ For many fibromyalgia patients, however, musculoskeletal pain is not their most problematic symptom (Table 1). They may suffer:

• migraine and tension headaches (10% to 80% of patients)
  
• irritable bowel syndrome (32% to 80%)²
  
• mood disorders (major depressive disorder [62%], bipolar disorder [11%])
  
• anxiety disorders (panic disorder [29%], posttraumatic stress disorder [21%], social phobia [19%]).³
  

ACR criteria are useful in research but lack many common symptoms and comorbidities. A structured interview that follows the DSM-IV-TR format incorporates other symptoms into the diagnosis (Table 2).⁴

Because patients with fibromyalgia often meet criteria for somatization or somatoform disorders, how to classify them—as medically or psychiatrically ill—is controversial. Some patients believe their mood or anxiety problem stems from the difficulty they experience dealing with their physical symptoms, and if they could feel better physically they would not be depressed or anxious. Others believe their psychiatric symptoms impede their ability to help themselves feel better.

Consider fibromyalgia in any patient with widespread pain of unknown cause. Before making the diagnosis, rule out other illnesses that present with similar symptoms (Table 3). Because many patients newly diagnosed with fibromyalgia worry that something “more serious” may be going on, confirm the diagnosis with appropriate testing and physical examination, usually by a rheumatologist or primary care physician.

Table 1

Medical and cognitive symptoms related to fibromyalgia

Neurologic Tension/migraine headache
Psychiatric Memory and cognitive difficulties Mood disturbance Anxiety disorders
Ear, nose, throat Sicca symptoms Vasomotor rhinitis Vestibular complaints
Cardiovascular Neurally mediated hypotension Mitral valve prolapse Noncardiac chest pain
Gastrointestinal Esophageal dysmotility Irritable bowel syndrome
Urological Interstitial cystitis
Gynecological Vulvodynia Chronic pelvic pain
Oral/dental Temporomandibular joint syndrome
Other (general) Chronic fatigue syndrome Sleep disturbances Idiopathic low back pain Multiple chemical sensitivity

Table 2

Fibromyalgia: Structured interview for diagnosis

A. Generalized pain affecting the axial, plus upper and lower segments, plus left and rights sides of the body
Either B or C:
B. At least 11 of 18 reproducible tender points
C. At least 4 of the following symptoms: Generalized fatigue Headaches Sleep disturbance Neuropsychiatric complaints Numbness, tingling sensations Irritable bowel symptoms
D. It cannot be established that disturbance was due to another systematic condition
Source: Reference 4

Table 3

Differentiating fibromyalgia from illnesses with similar symptoms

Illness	Tests to differentiate from primary fibromyalgia
Rheumatic diseases Osteoarthritis Spondyloarthropathies, rheumatoid arthritis Systemic lupus erythematosus, polymyalgia rheumatica Osteomalacia Myopathy	Radiographs Rheumatic markers (antinuclear antibody, rheumatoid factor, antibodies) Inflammatory markers (ESR, C-reactive protein) Vitamin D level CPK
Neurologic Multiple sclerosis, Chiari’s malformation, spinal stenosis, radiculopathy Neuropathy	MRI EMG
Endocrine Hypothyroidism Diabetes	TSH Basic chemistry panel with fasting glucose
Other Infectious   Lyme disease   Hepatitis Anemia Cancers	CBC Lyme titer Hepatitis antibody panel, liver function tests Hemoglobin/hematocrit Routine cancer screening tests, bone scan, blood chemistries specific for suspected primary cancer
ESR: erythrocyte sedimentation rate; CPK: creatine phosphokinase; EMG: electromyography; TSH: thyroid-stimulating hormone; CBC: complete blood count

 

CASE CONTINUED: Central pain sensitization

As you elicit more details about Ms. D’s mood, she continues to focus on her physical symptoms. She states that some days she wishes to die because her pain gets so bad, but she denies any plan or intent to harm herself. She worries that her symptoms will worsen and that she will become completely disabled.

Her primary physician attempted to relieve Ms. D’s pain with multiple trials of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclobenzaprine. She says she gained no benefit from the NSAIDs and discontinued the muscle relaxant because it made her too sleepy. Fibromyalgia affects 3.5% of women and 0.5% of men.⁵ It runs in families with histories of fibromyalgia and major mood and anxiety disorders, suggesting genetic links.⁶ Defects in genes controlling serotonin and norepinephrine have been implicated.^7-9

Fibromyalgia patients show lower levels of serotonin, norepinephrine, and dopamine metabolites in cerebrospinal fluid (CSF), compared with controls.¹⁰ These neurotransmitters may inhibit descending pain pathways in the CNS, and low levels in the brain and spinal cord may inhibit CNS regulation of pain impulses from the periphery.¹¹

Although many patients describe muscle pain, evidence suggests central pain augmentation rather than an abnormality of muscle or connective tissue.¹² Some studies have found evidence of “windup,” in which second-order neurons in the spinal cord become sensitized by repeated signals from first-order neurons in the periphery, resulting in amplified and prolonged pain signals traveling to the brain.¹³

Levels of substance P—a primary transmitter of pain impulses—are significantly higher in CSF of fibromyalgia patients compared with controls.¹⁴ This finding, in addition to low levels of serotonin and norepinephrine, indicates that pain signals are ascending unchecked to be processed by the brain.

Neuroimaging studies confirm this observation. In a study using functional magnetic resonance imaging (fMRI), researchers applied pressure to the thumbnails of fibromyalgia patients and controls until each subject reported pain:

• Twice as much pressure was required before controls rated their pain at a level similar to that of fibromyalgia patients.
  
• When controls and fibromyalgia patients reported similar pain, a very high degree of overlap was seen in brain areas responsible for pain processing. This indicates that fibromyalgia patients and controls were experiencing the pain they reported in the same way.¹⁵
  

Treating the whole patient

As a clinician who specializes in fibromyalgia, I counteract my patients’ and my own frustration with this condition by structuring office visits, determining realistic treatment goals, and treating all symptoms as part of a common syndrome rather than individual illnesses.

Structure office visits. Before every visit, have patients rate each symptom domain and write their top 2 or 3 concerns for that day (Click here for a sample form). Focusing on the patient’s most troublesome symptoms can help both of you feel greater satisfaction with treatment.

Educate patients. Ask them to discuss their beliefs about fibromyalgia; many know others with this condition or have researched diagnosis and treatment. Before developing a treatment plan, explain that their symptoms are chronic and all part of the same syndrome. Describe their pain as a complex phenomenon with possible peripheral and CNS components. Guide them to reputable Web sites and resources (see Related Resources).

Set realistic expectations. Many patients expect to resume an energetic and pain-free life, which usually is not the case with fibromyalgia (Box). Most medications are considered successful if they reduce pain by 30% to 50%, and side effects can be problematic. Discuss side effects before treatment begins to reduce patients’ anxiety and improve compliance in the first weeks.

Cognitive-behavioral therapy (CBT) for fibromyalgia incorporates relaxation techniques, helping patients view symptoms as manageable, reinforcing adaptive coping skills, and teaching them how to monitor thoughts, feelings, and behavior to change the view that they are helpless victims. A modest course of 6 weekly group CBT sessions significantly improved physical functioning in 25% of fibromyalgia patients (n=76) compared with 12% in a standard-care group (n=69), even though patients’ pain severity did not improve.¹⁶

Recommend exercise, lifestyle changes. Aerobic exercise can significantly improve well-being and physical functioning in fibromyalgia patients.¹⁷ Low-impact aerobics, such as done in warm water, usually are well tolerated, although any low-impact exercise can help. Because fibromyalgia symptoms often increase with physical activity, counsel patients to begin with a few minutes daily and increase very slowly each week.

 

Lifestyle changes are as important as medications in controlling fibromyalgia symptoms. In addition to exercise, recommend that patients:

• follow a daily routine
  
• pace activity to avoid exacerbating symptoms
  
• reduce stress.
  

Sometimes, I use the analogy of diabetes: treating fibromyalgia with medication but without changing lifestyle is like prescribing medication for a diabetic patient without changing diet. Follow up on this “homework” at each visit to reinforce that patients helping themselves is an important part of treatment.

Box

New direction with medications

Pregabalin is an anticonvulsant that binds to the alpha-2-delta subunits of neurons’ voltage-gated calcium channels. This activity reduces calcium influx at nerve terminals and inhibits release of excitatory neurotransmitters, such as substance P and glutamate.¹⁸ In June 2007, pregabalin was the first medication FDA-approved for fibromyalgia.

Two placebo-controlled trials^19,20 showed that pregabalin at 150 mg bid, 225 mg bid, or 300 mg bid significantly reduced weekly mean pain scores in fibromyalgia patients. Click here for details of these trials. The most common side effects—dizziness, somnolence, peripheral edema, blurred vision, and weight gain—were regarded as mild to moderate in 87% of patients.²¹

Although a dosage of 300 mg bid also was studied, the FDA approved pregabalin at dosages of 150 mg bid and 225 mg bid for fibromyalgia.²²

Duloxetine is a serotonin/norepinephrine reuptake inhibitor (SNRI) thought to inhibit dorsal horn neurons’ response to peripheral pain signals by increasing serotonin and norepinephrine in the brain and spinal cord. This SNRI was first FDA-approved for diabetic peripheral neuropathic pain and major depressive disorder. Approval for fibromyalgia at 60 mg/d in June 2008 was based on 2 placebo-controlled, double-blind, 12-week trials comprising 874 patients.^23,24Click here for detailed findings of these studies and a 6-month fixed-dose trial.²⁵

In clinical trials, duloxetine dosages of 60 mg/d and 120 mg/d were significantly more effective than placebo. The most common side effects were nausea, constipation, excessive sweating, and somnolence.^23-25

Milnacipran is an SNRI that was approved for treating fibromyalgia in January 2009 at dosages of 50 mg bid and 100 mg bid. Like other SNRIs, milnacipran is thought to work by inhibiting pain signals through increasing serotonin and norepinephrine in the brain and spinal cord. Milnacipran has a higher selectivity for norepinephrine reuptake compared with duloxetine, which may mean these medications will have different effects in different patients. Although milnacipran is approved as an antidepressant in other countries, the FDA has not approved it for treating depression in the United States.

Click here for details of a 15-week, double-blind, placebo-controlled trial of milnacipran in patients with fibromyalgia. Side effects in clinical trials were similar to those of duloxetine, with nausea, constipation, and increased sweating being most prominent.²⁶

 

Other medications, such as the first-line agent amitriptyline, have shown beneficial effects in fibromyalgia but are not FDA-approved for this indication (Table 4).^27-32

Choosing medications. When prescribing one of the FDA-approved medications to treat fibromyalgia, consider their benefits and side effects.

Pregabalin may be a beneficial first choice for patients who report pain and sleep as major issues. Although the medication’s label recommends starting with twice-daily dosing, patients might better tolerate an initial dose of 50 to 75 mg in the evening, with the morning dose added later. Pregabalin can be useful in patients taking multiple medications because of its renal clearance, resulting in low risk of interactions with drugs metabolized by liver enzymes. It also can be useful in patients who have not tolerated antidepressants in the past or in whom antidepressants are contraindicated.

If a patient has a history of depression or discontinuing medications because of sedating side effects, an antidepressant such as duloxetine or milnacipran may be more successful than starting with pregabalin. In general, if a patient does not respond to one of these SNRIs, moving on to the other might help. Milnacipran’s more selective effect on norepinephrine could be beneficial for some patients, especially those with excessive fatigue. Others, especially those with a high level of anxiety, might respond better to a more balanced SNRI such as duloxetine.

Table 4

Off-label medications shown to benefit patients with fibromyalgia

Drug	Comment
Amitriptyline27,28	Considered first-line because of studies supporting its use, low cost, and wide availability; may be associated with more side effects than newer medications
Gabapentin29	Possible alternative to pregabalin but may not be as well tolerated
Tramadol30	May help with breakthrough pain; use with extreme caution in patients taking antidepressants because of serotonin syndrome risk
Fluoxetine31	Dosages of 40 to 60 mg/d may help patients who do not tolerate SNRIs
Venlafaxine32	Dosages of 150 to 225 mg/d may be an alternative to other SNRIs
SNRIs: serotonin/norepinephrine reuptake inhibitors

CASE CONTINUED: Not as hopeless

Ms. D’s primary care physician confirms your presumptive diagnosis of fibromyalgia. He prescribes a trial of amitriptyline, which she does not tolerate well because of sedation and weight gain. At her next psychiatric visit, she tells you she remains very frustrated about her physical symptoms and reports that her doctor “has given up on me.”

You discuss what a fibromyalgia diagnosis means to her and educate her about the syndrome. You refer her to a colleague who does CBT with chronic pain patients and start her on a low dose of duloxetine (30 mg once daily) to minimize side effects. You discuss possible side effects and that she may need a higher dose to notice improvement in her pain. She seems receptive to starting a graded exercise program, and you encourage her to reduce physical and emotional stress in her life.

When she returns, she reports her pain is somewhat improved and medication side effects have subsided. She is not as hopeless and tells you she is up to 10 minutes of walking daily. You increase duloxetine to 60 mg/d and reinforce her ability to exercise and manage her stress.

Related Resources

• Arthritis Foundation. Fibromyalgia. www.arthritis.org/disease-center.php?disease_id=10.
  
• National Fibromyalgia Association. www.fmaware.org.
  
• Self-management program for patients with fibromyalgia, cosponsored by the National Fibromyalgia Association and Eli Lilly and Company. www.knowfibro.com.
  

Drug Brand Names

• Amitriptyline • Elavil, Endep
  
• Cyclobenzaprine • Flexeril
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Milnacipran • Savella
  
• Pregabalin • Lyrica
  
• Tramadol • Ultram, Ultracet
  
• Venlafaxine • Effexor, Effexor XR
  

Disclosure

Dr. Stanford receives grant/research support from Eli Lilly and Company, Pfizer, Cypress Bioscience, and Allergan.

WEB AUDIO
Listen to Dr. Stanford discuss,
"Is fibromyalgia a somatoform disorder?

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Patients with fibromyalgia are a heterogeneous group, yet many describe a common experience: seeing multiple physicians who seem unable or unwilling to provide a diagnosis or treat their symptoms. This situation may be changing with the recent FDA approval of an anticonvulsant and 2 antidepressants for managing fibromyalgia symptoms.

These medications—pregabalin, duloxetine, and milnacipran—reflect a revised understanding of fibromyalgia as a CNS condition, rather than an inflammatory process in the muscles or connective tissue. As a result, psychiatrists—because of our experience with CNS phenomena and managing antidepressant and anticonvulsant medications—are likely to play a larger role in treating fibromyalgia.

CASE REPORT: ‘Just too tired’

Ms. D, age 50, has a history of migraine headaches and is referred by her primary physician for evaluation of depression and anxiety. She reports deteriorating mood over 6 months, beginning when a minor car accident left her “very sore the next day.”

“Nothing helps” the persistent pain in her back, shoulders, and thighs, which she rates as 7 to 8 on a 0-to-10 pain scale. She describes an intense ache, “like having the flu,” that worsens with activity and in stressful situations. She also experiences nausea and intermittent diarrhea, debilitating fatigue, and sleep disturbance.

Ms. D reports she is depressed because she feels “just too tired” after work to keep up with social activities or housework. Her physician’s referral notes a normal physical exam except for tenderness over her upper back and hips. Laboratory testing is negative.

Making the diagnosis

American College of Rheumatology (ACR) criteria for fibromyalgia require widespread pain for at least 3 months. “Widespread” is defined as pain in the axial skeleton, left and right sides of the body, and above and below the waist. Pain must be found in at least 11 of 18 tender point sites on digital palpation using a force of approximately 4 kg/cm².¹ For many fibromyalgia patients, however, musculoskeletal pain is not their most problematic symptom (Table 1). They may suffer:

• migraine and tension headaches (10% to 80% of patients)
  
• irritable bowel syndrome (32% to 80%)²
  
• mood disorders (major depressive disorder [62%], bipolar disorder [11%])
  
• anxiety disorders (panic disorder [29%], posttraumatic stress disorder [21%], social phobia [19%]).³
  

ACR criteria are useful in research but lack many common symptoms and comorbidities. A structured interview that follows the DSM-IV-TR format incorporates other symptoms into the diagnosis (Table 2).⁴

Because patients with fibromyalgia often meet criteria for somatization or somatoform disorders, how to classify them—as medically or psychiatrically ill—is controversial. Some patients believe their mood or anxiety problem stems from the difficulty they experience dealing with their physical symptoms, and if they could feel better physically they would not be depressed or anxious. Others believe their psychiatric symptoms impede their ability to help themselves feel better.

Consider fibromyalgia in any patient with widespread pain of unknown cause. Before making the diagnosis, rule out other illnesses that present with similar symptoms (Table 3). Because many patients newly diagnosed with fibromyalgia worry that something “more serious” may be going on, confirm the diagnosis with appropriate testing and physical examination, usually by a rheumatologist or primary care physician.

Table 1

Medical and cognitive symptoms related to fibromyalgia

Neurologic Tension/migraine headache
Psychiatric Memory and cognitive difficulties Mood disturbance Anxiety disorders
Ear, nose, throat Sicca symptoms Vasomotor rhinitis Vestibular complaints
Cardiovascular Neurally mediated hypotension Mitral valve prolapse Noncardiac chest pain
Gastrointestinal Esophageal dysmotility Irritable bowel syndrome
Urological Interstitial cystitis
Gynecological Vulvodynia Chronic pelvic pain
Oral/dental Temporomandibular joint syndrome
Other (general) Chronic fatigue syndrome Sleep disturbances Idiopathic low back pain Multiple chemical sensitivity

Table 2

Fibromyalgia: Structured interview for diagnosis

A. Generalized pain affecting the axial, plus upper and lower segments, plus left and rights sides of the body
Either B or C:
B. At least 11 of 18 reproducible tender points
C. At least 4 of the following symptoms: Generalized fatigue Headaches Sleep disturbance Neuropsychiatric complaints Numbness, tingling sensations Irritable bowel symptoms
D. It cannot be established that disturbance was due to another systematic condition
Source: Reference 4

Table 3

Differentiating fibromyalgia from illnesses with similar symptoms

Illness	Tests to differentiate from primary fibromyalgia
Rheumatic diseases Osteoarthritis Spondyloarthropathies, rheumatoid arthritis Systemic lupus erythematosus, polymyalgia rheumatica Osteomalacia Myopathy	Radiographs Rheumatic markers (antinuclear antibody, rheumatoid factor, antibodies) Inflammatory markers (ESR, C-reactive protein) Vitamin D level CPK
Neurologic Multiple sclerosis, Chiari’s malformation, spinal stenosis, radiculopathy Neuropathy	MRI EMG
Endocrine Hypothyroidism Diabetes	TSH Basic chemistry panel with fasting glucose
Other Infectious   Lyme disease   Hepatitis Anemia Cancers	CBC Lyme titer Hepatitis antibody panel, liver function tests Hemoglobin/hematocrit Routine cancer screening tests, bone scan, blood chemistries specific for suspected primary cancer
ESR: erythrocyte sedimentation rate; CPK: creatine phosphokinase; EMG: electromyography; TSH: thyroid-stimulating hormone; CBC: complete blood count

 

CASE CONTINUED: Central pain sensitization

As you elicit more details about Ms. D’s mood, she continues to focus on her physical symptoms. She states that some days she wishes to die because her pain gets so bad, but she denies any plan or intent to harm herself. She worries that her symptoms will worsen and that she will become completely disabled.

Her primary physician attempted to relieve Ms. D’s pain with multiple trials of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclobenzaprine. She says she gained no benefit from the NSAIDs and discontinued the muscle relaxant because it made her too sleepy. Fibromyalgia affects 3.5% of women and 0.5% of men.⁵ It runs in families with histories of fibromyalgia and major mood and anxiety disorders, suggesting genetic links.⁶ Defects in genes controlling serotonin and norepinephrine have been implicated.^7-9

Fibromyalgia patients show lower levels of serotonin, norepinephrine, and dopamine metabolites in cerebrospinal fluid (CSF), compared with controls.¹⁰ These neurotransmitters may inhibit descending pain pathways in the CNS, and low levels in the brain and spinal cord may inhibit CNS regulation of pain impulses from the periphery.¹¹

Although many patients describe muscle pain, evidence suggests central pain augmentation rather than an abnormality of muscle or connective tissue.¹² Some studies have found evidence of “windup,” in which second-order neurons in the spinal cord become sensitized by repeated signals from first-order neurons in the periphery, resulting in amplified and prolonged pain signals traveling to the brain.¹³

Levels of substance P—a primary transmitter of pain impulses—are significantly higher in CSF of fibromyalgia patients compared with controls.¹⁴ This finding, in addition to low levels of serotonin and norepinephrine, indicates that pain signals are ascending unchecked to be processed by the brain.

Neuroimaging studies confirm this observation. In a study using functional magnetic resonance imaging (fMRI), researchers applied pressure to the thumbnails of fibromyalgia patients and controls until each subject reported pain:

• Twice as much pressure was required before controls rated their pain at a level similar to that of fibromyalgia patients.
  
• When controls and fibromyalgia patients reported similar pain, a very high degree of overlap was seen in brain areas responsible for pain processing. This indicates that fibromyalgia patients and controls were experiencing the pain they reported in the same way.¹⁵
  

Treating the whole patient

As a clinician who specializes in fibromyalgia, I counteract my patients’ and my own frustration with this condition by structuring office visits, determining realistic treatment goals, and treating all symptoms as part of a common syndrome rather than individual illnesses.

Structure office visits. Before every visit, have patients rate each symptom domain and write their top 2 or 3 concerns for that day (Click here for a sample form). Focusing on the patient’s most troublesome symptoms can help both of you feel greater satisfaction with treatment.

Educate patients. Ask them to discuss their beliefs about fibromyalgia; many know others with this condition or have researched diagnosis and treatment. Before developing a treatment plan, explain that their symptoms are chronic and all part of the same syndrome. Describe their pain as a complex phenomenon with possible peripheral and CNS components. Guide them to reputable Web sites and resources (see Related Resources).

Set realistic expectations. Many patients expect to resume an energetic and pain-free life, which usually is not the case with fibromyalgia (Box). Most medications are considered successful if they reduce pain by 30% to 50%, and side effects can be problematic. Discuss side effects before treatment begins to reduce patients’ anxiety and improve compliance in the first weeks.

Cognitive-behavioral therapy (CBT) for fibromyalgia incorporates relaxation techniques, helping patients view symptoms as manageable, reinforcing adaptive coping skills, and teaching them how to monitor thoughts, feelings, and behavior to change the view that they are helpless victims. A modest course of 6 weekly group CBT sessions significantly improved physical functioning in 25% of fibromyalgia patients (n=76) compared with 12% in a standard-care group (n=69), even though patients’ pain severity did not improve.¹⁶

Recommend exercise, lifestyle changes. Aerobic exercise can significantly improve well-being and physical functioning in fibromyalgia patients.¹⁷ Low-impact aerobics, such as done in warm water, usually are well tolerated, although any low-impact exercise can help. Because fibromyalgia symptoms often increase with physical activity, counsel patients to begin with a few minutes daily and increase very slowly each week.

 

Lifestyle changes are as important as medications in controlling fibromyalgia symptoms. In addition to exercise, recommend that patients:

• follow a daily routine
  
• pace activity to avoid exacerbating symptoms
  
• reduce stress.
  

Sometimes, I use the analogy of diabetes: treating fibromyalgia with medication but without changing lifestyle is like prescribing medication for a diabetic patient without changing diet. Follow up on this “homework” at each visit to reinforce that patients helping themselves is an important part of treatment.

Box

New direction with medications

Pregabalin is an anticonvulsant that binds to the alpha-2-delta subunits of neurons’ voltage-gated calcium channels. This activity reduces calcium influx at nerve terminals and inhibits release of excitatory neurotransmitters, such as substance P and glutamate.¹⁸ In June 2007, pregabalin was the first medication FDA-approved for fibromyalgia.

Two placebo-controlled trials^19,20 showed that pregabalin at 150 mg bid, 225 mg bid, or 300 mg bid significantly reduced weekly mean pain scores in fibromyalgia patients. Click here for details of these trials. The most common side effects—dizziness, somnolence, peripheral edema, blurred vision, and weight gain—were regarded as mild to moderate in 87% of patients.²¹

Although a dosage of 300 mg bid also was studied, the FDA approved pregabalin at dosages of 150 mg bid and 225 mg bid for fibromyalgia.²²

Duloxetine is a serotonin/norepinephrine reuptake inhibitor (SNRI) thought to inhibit dorsal horn neurons’ response to peripheral pain signals by increasing serotonin and norepinephrine in the brain and spinal cord. This SNRI was first FDA-approved for diabetic peripheral neuropathic pain and major depressive disorder. Approval for fibromyalgia at 60 mg/d in June 2008 was based on 2 placebo-controlled, double-blind, 12-week trials comprising 874 patients.^23,24Click here for detailed findings of these studies and a 6-month fixed-dose trial.²⁵

In clinical trials, duloxetine dosages of 60 mg/d and 120 mg/d were significantly more effective than placebo. The most common side effects were nausea, constipation, excessive sweating, and somnolence.^23-25

Milnacipran is an SNRI that was approved for treating fibromyalgia in January 2009 at dosages of 50 mg bid and 100 mg bid. Like other SNRIs, milnacipran is thought to work by inhibiting pain signals through increasing serotonin and norepinephrine in the brain and spinal cord. Milnacipran has a higher selectivity for norepinephrine reuptake compared with duloxetine, which may mean these medications will have different effects in different patients. Although milnacipran is approved as an antidepressant in other countries, the FDA has not approved it for treating depression in the United States.

Click here for details of a 15-week, double-blind, placebo-controlled trial of milnacipran in patients with fibromyalgia. Side effects in clinical trials were similar to those of duloxetine, with nausea, constipation, and increased sweating being most prominent.²⁶

 

Other medications, such as the first-line agent amitriptyline, have shown beneficial effects in fibromyalgia but are not FDA-approved for this indication (Table 4).^27-32

Choosing medications. When prescribing one of the FDA-approved medications to treat fibromyalgia, consider their benefits and side effects.

Pregabalin may be a beneficial first choice for patients who report pain and sleep as major issues. Although the medication’s label recommends starting with twice-daily dosing, patients might better tolerate an initial dose of 50 to 75 mg in the evening, with the morning dose added later. Pregabalin can be useful in patients taking multiple medications because of its renal clearance, resulting in low risk of interactions with drugs metabolized by liver enzymes. It also can be useful in patients who have not tolerated antidepressants in the past or in whom antidepressants are contraindicated.

If a patient has a history of depression or discontinuing medications because of sedating side effects, an antidepressant such as duloxetine or milnacipran may be more successful than starting with pregabalin. In general, if a patient does not respond to one of these SNRIs, moving on to the other might help. Milnacipran’s more selective effect on norepinephrine could be beneficial for some patients, especially those with excessive fatigue. Others, especially those with a high level of anxiety, might respond better to a more balanced SNRI such as duloxetine.

Table 4

Off-label medications shown to benefit patients with fibromyalgia

Drug	Comment
Amitriptyline27,28	Considered first-line because of studies supporting its use, low cost, and wide availability; may be associated with more side effects than newer medications
Gabapentin29	Possible alternative to pregabalin but may not be as well tolerated
Tramadol30	May help with breakthrough pain; use with extreme caution in patients taking antidepressants because of serotonin syndrome risk
Fluoxetine31	Dosages of 40 to 60 mg/d may help patients who do not tolerate SNRIs
Venlafaxine32	Dosages of 150 to 225 mg/d may be an alternative to other SNRIs
SNRIs: serotonin/norepinephrine reuptake inhibitors

CASE CONTINUED: Not as hopeless

Ms. D’s primary care physician confirms your presumptive diagnosis of fibromyalgia. He prescribes a trial of amitriptyline, which she does not tolerate well because of sedation and weight gain. At her next psychiatric visit, she tells you she remains very frustrated about her physical symptoms and reports that her doctor “has given up on me.”

You discuss what a fibromyalgia diagnosis means to her and educate her about the syndrome. You refer her to a colleague who does CBT with chronic pain patients and start her on a low dose of duloxetine (30 mg once daily) to minimize side effects. You discuss possible side effects and that she may need a higher dose to notice improvement in her pain. She seems receptive to starting a graded exercise program, and you encourage her to reduce physical and emotional stress in her life.

When she returns, she reports her pain is somewhat improved and medication side effects have subsided. She is not as hopeless and tells you she is up to 10 minutes of walking daily. You increase duloxetine to 60 mg/d and reinforce her ability to exercise and manage her stress.

Related Resources

• Arthritis Foundation. Fibromyalgia. www.arthritis.org/disease-center.php?disease_id=10.
  
• National Fibromyalgia Association. www.fmaware.org.
  
• Self-management program for patients with fibromyalgia, cosponsored by the National Fibromyalgia Association and Eli Lilly and Company. www.knowfibro.com.
  

Drug Brand Names

• Amitriptyline • Elavil, Endep
  
• Cyclobenzaprine • Flexeril
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Milnacipran • Savella
  
• Pregabalin • Lyrica
  
• Tramadol • Ultram, Ultracet
  
• Venlafaxine • Effexor, Effexor XR
  

Disclosure

Dr. Stanford receives grant/research support from Eli Lilly and Company, Pfizer, Cypress Bioscience, and Allergan.