Complete Detail about Fibromyalgia Signs,Symptoms ,Management ,Treatments and Medication.Must Read

Fibromyalgia is a disorder of chronic, widespread pain and tenderness (see the image below). It typically presents in young or middle-aged women but can affect patients of either sex and at any age.

Research has shown that fibromyalgia patients typically see several different doctors before receiving their diagnosis. The symptoms of fibromyalgia often mimmick other health issues, which can make it hard to diagnose. Understanding the symptoms can help a patient identify their diagnosis sooner, so they can find a way to manage their pain.

a Critical Images slideshow, for more information on strategies for accurately diagnosing and treating fibromyalgia.

Signs and symptoms

Fibromyalgia is a syndrome that consists of the following signs and symptoms [1] :

  1. Persistent (≥3 mo) widespread pain (pain/tenderness on both sides of the body, above and below the waist, including the axial spine [usually the paraspinus, scapular, and trapezius muscles])
  2. Stiffness
  3. Fatigue; disrupted and unrefreshing sleep
  4. Cognitive difficulties

Multiple other unexplained symptoms, anxiety and/or depression, and functional impairment of activities of daily living (ADLs)

  •  Body Stiffness

The majority of patients who suffer from fibromyalgia experience body stiffness. This usually occurs in the morning. The stiff feeling is similar to those who suffering from arthritis. It may fade within 10-15 minutes, or it may last most of the day.

  • Abnormal Digestion

Symptoms of fibromyalgia can include constipation, diarrhea and bloating. About 40-70% of patients who are suffering from fibromyalgia experience symptoms similar to Irritable Bowel Syndrome, Acid Reflux and GERD.

  • Numbness, Swelling Or Tingling

Many fibromyalgia sufferers experience a pins and needles sensation. This often occurs in the arms, feet, hands and legs – a condition known as paraesthesia. For some patients, these sensations might only last a few minutes. For other patients, the sensations can last much longer.

  • Head To Toe Pain
 Approximately 97% of patients suffering from fibromyalgia experience pain across their entire body. Fibromyalgia pain is often described as “deep, sharp, throbbing or aching.” This type of pain is often constant, and unresponsive to over-the-counter pain medication.
  • Finger Spasms And Toe Spasms

Arterial spasms of the hands or toes is a fairly common symptom of fibromyalgia. It can result from exposure to the cold or stress. The areas that are affected will develop a blue or pale tint. Arterial spasms are also accompanied by pain.

  • Poor Sleep Quality

Fibromyalgia can make it difficult for a patient to get quality sleep. Studies have shown erratic brain activity in fibromyalgia patients during rest. This irregular brain activity, along with pain or stiffness, can cause poor quality sleep.

  • Fibromyalgia Fog

Fibromyalgia sufferers may experience a brain fog. Trouble concentrating and difficulty with short term memory can be symptoms of fibromyalgia. General feelings of confusion, forgetfulness and lack of mental clarity may also arise.

  • Sensitivity To Temperature

Patients with fibromyalgia often have a difficult time regulating their body temperature. They may feel extreme heat or extreme cold when the temperature hasn’t changed drastically.

Diagnosis

Fibromyalgia is a diagnosis of exclusion and patients must be thoroughly evaluated for the presence of other disorders that could be the cause of symptoms before a diagnosis of fibromyalgia is made. The clinical assessment may reveal objective evidence for a discrete or comorbid illness, such as the following:

  1. Hypothyroidism
  2. Rheumatoid arthritis
  3. Systemic lupus erythematosus
  4. Polymyalgia rheumatic
  5. Other inflammatory or autoimmune disorders
  6. Serious cardiac conditions in those with chest pain, dyspnea, and palpitations

Laboratory testing

Although patients with fibromyalgia do not have characteristic or consistent abnormalities on laboratory testing, routine laboratory and imaging studies can help to rule out diseases with similar manifestations and to assist in diagnosis of certain inflammatory diseases that frequently coexist with fibromyalgia. Such tests include the following:

  1. Complete blood count with differential
  2. Metabolic panel
  3. Urinalysis
  4. Thyroid-stimulating hormone level
  5. 25-hydroxy vitamin D level
  6. Vitamin B12 level
  7. Iron studies, including iron level, total iron binding capacity, percent saturation, and serum ferritin level
  8. Magnesium level
  9. Erythrocyte sedimentation rate
  10. Antipolymer antibody assay: May provide conclusive evidence for a subgroup of people with fibromyalgia; about 50% of fibromyalgia patients have antipolymer antibodies

Patient self-report forms, clinical psychometric testing

 Self-report forms, for assessing patients’ pain, fatigue, and overall status, include the following:
  1. Modified Health Assessment Questionnaire
  2. Fibromyalgia Impact Questionnaire
  3. Checklist of current symptoms
  4. Scales for helplessness and cognitive performance
  5. The Physician Health Questionnaire–9 for depression
  6. The Generalized Anxiety Disorder–7 questionnaire for anxiety
  7. The Mood Disorder Questionnaire to screen for bipolar disease

Psychometric testing provides a more comprehensive assessment and includes the following:

  1. Minnesota Multiphasic Personality Inventory
  2. Social Support Questionnaire
  3. Sickness Impact Profile
  4. Multidimensional Pain Inventory

Management

There is no cure for fibromyalgia, but education, lifestyle changes, and proper medications can help the individual to regain control and achieve significant improvement.

Models of pain behavior that interrelate biologic, cognitive, emotional, and behavioral variables form the basis for cognitive-behavioral and operant-behavioral approaches to adult pain management. Fibromyalgia in children responds to a combination of psychotherapy, exercise, relaxation techniques, and education. Pharmacotherapy is generally not indicated in children.

 Nonpharmacotherapy

  1. Diet (eg, promote good nutrition, vitamin supplementation, bone health, weight loss)
  2. Stress management
  3. Aerobic exercise (eg, low-impact aerobics, walking, water aerobics, stationary bicycle)
  4. Sleep therapy (eg, education/instruction on sleep hygiene)
  5. Psychologic/behavioral therapy (eg, cognitive-behavioral, operant-behavioral)

Pharmacotherapy

 Always combine pharmacologic and nonpharmacologic therapy in the treatment of fibromyalgia. Aggressively treat comorbid depression.
 Medications used in the management of fibromyalgia include the following:
  1. Analgesics (eg, tramadol)
  2. Antianxiety/hypnotic agents (eg, alprazolam, clonazepam, zolpidem, zaleplon, trazodone, buspirone, temazepam, sodium oxybate)
  3. Skeletal muscle relaxants (eg, cyclobenzaprine)
  4. Antidepressants (eg, amitriptyline, duloxetine, milnacipran, venlafaxine, desvenlafaxine)
  5. Anticonvulsants (eg, pregabalin, gabapentin, tiagabine)
  6. Alpha 2 agonists (eg, clonidine)

Medications that may prove helpful for sleep problems that do not respond to nonpharmacotherapy include the following:

  1. Antidepressants (eg, trazodone, SSRIs, SNRIs, tricyclic antidepressants)
  2. Anticonvulsants (eg, clonazepam, gabapentin, tiagabine)
  3. Nonbenzodiazepine hypnotics (eg, zolpidem, zaleplon, eszopiclone)
  4. Muscle relaxants (eg, cyclobenzaprine, tizanidine)
  5. Dopamine agonists (eg, pramipexole)

Other agents used in fibromyalgia may include the following:

  1. Vitamins and minerals
  2. Malic acid and magnesium combination
  3. Antioxidants
  4. Amino acids
  5. Herbs and supplements

Treatment

Fibromyalgia Treatment & Management

Approach Considerations

The physician should inform the patient that no cure exists for fibromyalgia but that education, lifestyle changes including regular physical activity, and proper medications can help the individual to regain control and achieve significant improvement. [99] When patients with fibromyalgia fully understand the nature of the disease, they are more likely to comply with treatment and to take an active role in managing the disease.

European League Against Rheumatism (EULAR) 2016 guidelines recommend that initial management of fibromyalgia involve patient education and focus on nonpharmacological therapies. Patients whose condition fails to respond should receive treatment tailored to their specific needs, such as psychological therapies for mood disorders and unhelpful coping strategies, pharmacotherapy for severe pain or sleep disturbance, and/or a multimodal rehabilitation program for severe disability. EULAR noted that most treatments have only a relatively modest effect. [100]

At the initial visit, give patients educational materials about fibromyalgia, including a list of resources, such as Web sites, books, videotapes, newsletters, and brochures, related to the disease. Some authors recommend encouraging patients to attend their local fibromyalgia support group. Provide education and support to the patient’s significant family members.

Therapeutic recommendations for fibromyalgia can now be based almost entirely on evidence from well-designed randomized controlled trials. Models of pain behavior that interrelate biologic, cognitive, emotional, and behavioral variables form the basis for cognitive-behavioral and operant-behavioral approaches to pain management. Wood published a useful summary of therapeutic approaches to central sensitivity syndrome (CSS) comorbidities in fibromyalgia. [101]

The first crucial element in the treatment of pain, fatigue, and other diverse symptoms in patients with fibromyalgia is for the clinician to validate the patient’s illness through empathetic listening and acknowledgment that the patient is indeed experiencing pain. [27, 34, 102, 103, 104, 105, 106, 107, 108] Comments such as “it’s all in your mind” or “I cannot find anything wrong with you” only add to the patient’s frustration.

Avoid excessive use of physical therapy modalities after minor trauma, excessive activity limitation, and overly liberal work release. Be aware of confounders to recovery, such as pending litigation or compensation claims.

The overall approach for chronic pain in fibromyalgia involves a multifaceted treatment plan that incorporates various adjuvant medicines, aerobic and resistance exercise, and psychological and behavioral approaches to reduce distress and promote self-efficacy and self-management (eg, relaxation training, activity pacing, visual imagery, distraction).

If significant nociceptive pain coexists with the diffuse chronic pain of fibromyalgia, manage it pharmacologically with non-narcotic medications such as antidepressants, anticonvulsants, or muscle relaxers. For associated regional chronic pain syndromes (eg, temporomandibular disorder), referral to an experienced specialist who advocates nonsurgical approaches is recommended.

In a systematic review by Häuser of 1119 patients in 9 randomized controlled trials, multicomponent treatment (at least 1 form of educational or other psychological therapy plus at least 1 form of exercise therapy) yielded short-term benefits for the symptoms of pain, fatigue, depression, and quality of life. They found no evidence that these symptomatic benefits were durable in the long term, but strong evidence suggested that multicomponent therapy conferred a long-term benefit to maintenance of physical fitness. [109]

Poor sleep is virtually universal in fibromyalgia and contributes importantly to pain, depression, and fatigue. Accurate diagnosis and pharmacologic and nonpharmacologic management are essential. [110, 111, 112]

Trigger point injections, acupuncture, chiropractic manipulation, and myofascial release are usually well received by patients and can be beneficial, but results are not long lasting. In addition, patients may not be able to afford long-term therapy since these are sometimes not covered by insurance.

A possible etiologic link between Chiari malformation and fibromyalgia has been suggested. However, no generally accepted evidence indicates that skull surgery for correction of Chiari malformation is of benefit in patients with fibromyalgia, and screening all fibromyalgia patients for Chiari formation is not recommended.

Treatment of Children

Fibromyalgia in children responds to a combination of psychotherapy, exercise, relaxation techniques, and education. Pharmacotherapy is generally not indicated or recommended. Stephens et al conducted a 12-week randomized controlled trial of exercise intervention in children with fibromyalgia and found that both aerobics and qigong yielded benefits in terms of fibromyalgia symptoms, pain, and quality of life in this population. Aerobics were found to be advantageous in several measures. [113]

Juvenile-onset fibromyalgia in adolescents is unlikely to resolve spontaneously. A prospective longitudinal study found that more than 80% of adolescents with juvenile-onset fibromyalgia continued to have symptoms into adulthood. At a mean age of 21 years, approximately half met American College of Rheumatology criteria for adult fibromyalgia. [114, 115

Managing Flare-ups

Patients should learn to identify the factors that trigger flare-ups (although, on occasion, no trigger can be identified) and what measures to take to decrease their symptoms. [107] Tips for avoiding and managing flare-ups include the following:

  1. Treat infections quickly
  2. Avoid changes in diet
  3. Exercise as prescribed (ask patients not to increase their routine without consulting a physician)
  4. Moderate changes in activity
  5. Avoid unnecessary life changes
  6. Treat changes in mood or sleep early and aggressively
  7. Always start new medications at the lowest possible dose
  8. Prepare for unavoidable situations that have caused flare-ups in the past (eg, arrange for an increase in sleep medication or for help with housework and child care)
  9. Encourage patients to pace their activities and know their limits

Psychological and Behavioral Therapy

Depression, anxiety, stress, sleep disturbance, pain beliefs and coping strategies, and self-efficacy all are central to the pain experience in many patients and frequently determine the outcome of chronic pain. Depression must be treated aggressively.

Unless psychosocial and behavioral variables are recognized and approached, strictly pharmacologic interventions are of limited benefit. Cognitive-behavioral therapy (CBT) and operant-behavioral therapy (OBT) both effect clinically meaningful improvements in pain intensity and physical impairment in approximately one third to one half of patients with fibromyalgia. [116]

Pretreatment patient characteristics are important predictors of response to nonpharmacologic therapies. [117] High levels of affective distress, poor coping skills, few pain behaviors, and unsolicitous spouse behavior predict response to CBT. Prominent pain behaviors, high levels of physical impairment, catastrophizing, and solicitous spouse behavior predict response to OBT.

Other useful strategies include the following:

  1. Relaxation training
  2. Activity pacing
  3. Guided imagery
  4. Written emotional disclosure
  5. Distraction strategies
  6. Instruction in proper sleep hygiene
Depression in fibromyalgia may be treated with a regimen that includes nonpharmaceutical therapies. Treating depression alone does not cure fibromyalgia. Antidepressants may help, but the clinician also should address other symptoms, such as fatigue or pain. Modifying diet and practicing good sleep hygiene are crucial. Starting a rehabilitation exercise program is important. Behavioral modification techniques and stress management may also be used.
A meta-analysis by Häuser et al of randomized controlled clinical trials found strong evidence that antidepressants reduced pain, fatigue, depressed mood, and sleep disturbances and improved health-related quality of life in patients with fibromyalgia. [118] The study included analysis of tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors in 1427 participants.
In a study of patients with fibromyalgia who were taking an SSRI or an SNRI for comorbid depression, Arnold et al reported that the addition of pregabalin significantly improved pain, anxiety, and depression and improved sleep quality, compared with placebo. [119]

Physical Therapy/Physical Modalities

Because many patients with chronic pain fear that activity will worsen their pain and fatigue, they become deconditioned. In fact, limitations on activity, including work release, should generally be avoided. Graded aerobic exercise (eg, low-impact aerobics, walking, water aerobics, stationary bicycle) is an integral part of optimum treatment in patients with fibromyalgia.

However, exercise programs should start gently and progress gradually to endurance and strength training. Patients should avoid prolonged, overly strenuous physical exercise before reconditioning is established.

The benefits of exercise for patients with fibromyalgia include improvement in subjective and objective measures of pain and in an overall sense of well-being. [108, 120, 121]

In a randomized controlled trial, Munguía-Izquierdo and Legaz-Arrese found that unfit women with severe fibromyalgia symptoms benefitted from aquatic therapy (in a warm pool) 3 times per week for 16 weeks. This approach also resulted in greatly improved adherence to exercise in the study participants. [122]

Qigong, a traditional Chinese practice that is currently characterized as meditative movement, has demonstrated benefit in fibromyalgia. However, the best outcomes require diligent practice. Four trials in 201 subjects who practiced qigong for 30-45 minutes daily over 6-8 weeks found significant and consistent benefits in pain, sleep, impact, and physical and mental function, with benefits maintained at 4-6 months. [123]

Heat, massage, and other treatments are useful. Diffuse and regional pain is improved by strategies such as saunas, hot baths and showers, hot mud, and massage. However, excessive dependence on administration of physical therapy and modalities by another person may confound the patient’s efforts to achieve self-efficacy for pain control.

Encouragement and positive reinforcement can improve compliance. Obesity, poor posture, and overloading activities at work and at home should be addressed.

Pharmacologic Therapy

The treatment of fibromyalgia (FM) should always combine pharmacologic approaches with nonpharmacologic therapy, especially stress management, aerobic exercise, and, in some cases, psychological counseling. Aggressively treat comorbid depression and anxiety.

Patients with fibromyalgia have difficulty tolerating regular doses of most medications and supplements. They are sensitive to medications, and often experience adverse effects. To avoid those problems, use the lowest dose available or perhaps one half to one quarter of the lowest recommended dose.

Many fibromyalgia patients have cognitive dysfunction that limits their ability to understand and process verbal information. Avoid complications and confusion by providing easily understandable written instructions on medication use. Patients should be instructed to consult their physician before starting any over-the-counter (OTC) medications or supplements to avoid potentially harmful drug interactions.

The US Food and Drug Administration (FDA) has approved three drugs for use in fibromyalgia: pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella). [124]  Pregabalin is used to reduce pain and improve sleep. The antidepressants duloxetine and milnacipran, which are used to relieve pain, fatigue, and sleep problems, are generally prescribed at lower doses than for treatment of depression.

In randomized, controlled trials, a significantly higher proportion of patients have experienced >30% improvement from baseline in pain with pregabalin, duloxetine, or milnacipran, compared with placebo. However, a meta-analysis found no significant difference in the efficacy and tolerability of the three drugs, when given at the recommended doses. [125]

Other anticonvulsants and antidepressants are often used off-label to treat fibromyalgia and there is evidence that many can decrease pain sensitivity. In particular, tricyclic antidepressants (TCAs) have proven benefit but anticholinergic side effects often limit their use. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are useful only for management of coexisting inflammatory processes and are not recommended as first-line therapies. Pharmacologic and nonpharmacologic treatment of poor sleep is crucial for improving the patient’s overall sense of well-being.

Anecdotally, dextromethorphan, an N-methyl-D-aspartate (NMDA) receptor antagonist available as an over-the-counter (OTC) antitussive, and naltrexone, an opioid receptor antagonist, have been used to treat fibromyalgia, but placebo-controlled trial data is lacking. Topical capsaicin, obtained from red chili peppers, is essentially free of toxicity, other than mild burning at the site of application, and can be a useful adjunct in combination with gentle massage.

Beta-blockers and/or increased fluid and sodium/potassium intake may benefit a subset of patients with fibromyalgia who have orthostatic hypotension, palpitation, and vasomotor instability. Growth hormone and cytokine therapies are still experimental. [126]

Several medications should be avoided or used carefully. Opioids, hypnotics, anxiolytics, and certain skeletal-muscle relaxants must be used with caution because of the potential for abuse and the risk of worsening fatigue and cognitive dysfunction.

 Analgesics

NSAIDs and acetaminophen are of limited efficacy in reducing pain due to fibromyalgia but are important adjuncts for nociceptive pain generators, such as osteoarthritis and degenerative spondylosis. [127]  Topical anesthesia with lidocaine (5% Lidoderm patch) can also be helpful in this regard.

 Tramadol, a weak opioid agonist with additional effects on serotonin and norepinephrine receptors, improves pain associated with fibromyalgia. A trial of tramadol may be considered for second-line therapy in patients with moderate to severe pain that is unresponsive to other treatments.  [99] [128]   In a 12-month observational study of opioid use in 1700 adult patients with fibromyalgia, tramadol proved superior to other opioids for improving pain-related interference with daily living, functioning, depression, and insomnia.  [129]
 Opioid analgesics with more potency (eg, hydrocodone, oxycodone, fentanyl, morphine), although frequently prescribed in patients with fibromyalgia, appear to be of limited efficacy in most patients with this disorder and are generally not recommended. However, in addition to utility in the treatment of severe nociceptive pain (eg, radicular pain, advanced osteoarthritis of the knee), opioid analgesics may reduce pain, improve quality of life, and occasionally restore function in a patient with fibromyalgia who has severe allodynia and who has not responded to other approaches.
 More often, rheumatologists discover that patients with fibromyalgia are already taking very high doses of opioids prescribed by their family physician. The task is then to gradually withdraw opioids, if possible, or perhaps switch therapy to reasonable doses of methadone (eg, 5-10 mg tid). Tapering takes 2-3 weeks; clonidine, 0.2-0.4 mg/day, is helpful for controlling withdrawal symptoms. Remember that opioid-induced hyperalgesia can be a paradoxical complication of high-dose opioid therapy.
 Monitoring of patients receiving opioid medications requires frequent reevaluation for efficacy, improvement in daily functioning, and adverse effects during initiation, titration, and maintenance therapy, especially in older patients. The patient should sign a “narcotics contract” that specifies the following:
  1. One prescribing physician
  2. One dispensing pharmacy
  3. Acceptance of no new prescription of opioids if the medication runs out early or is lost or stolen
  4. Agreement for random urine testing

Antianxiety agents

Agents of varying durations of action are used frequently for anxiety and panic and as sleep aids (poor sleep is nearly universal in fibromyalgia). [112]  Antianxiety agents are often used in combination with antidepressants and anticonvulsant drugs (both of which also have efficacy for anxiety and insomnia) and include benzodiazepines (eg, alprazolam [Xanax, Niravam; half-life, < 12 h], temazepam [Restoril; half-life, 10-15 h], clonazepam [Klonopin; half-life, 25-100 h], buspirone, trazodone [Oleptro]).

 In considering the choice of an anxiolytic drug, remember that many antidepressants also have indications for anxiety. The short-acting nonbenzodiazepine hypnotics zolpidem (Ambien) and zaleplon (Sonata), along with careful attention to optimum sleep hygiene, are useful in the treatment of insomnia but have no effect on pain in fibromyalgia.
 An effective combination is zolpidem at bedtime as needed, plus zaleplon (5 mg)—which has a very short half-life—for awakenings in the middle of the night. Patients who do not experience improved sleep with the above and with careful attention to good sleep hygiene should be referred for polysomnography.
 Sodium oxybate (Xyrem), [130]  a sedative hypnotic, prolongs stage III/IV restorative sleep, which is essential to feeling rested and refreshed on awakening. Such deep sleep is usually disrupted in patients with fibromyalgia, leaving the patient stiff, sore, and exhausted upon awakening.
 Sodium oxybate is currently approved by the FDA for narcolepsy-associated cataplexy and excessive daytime sleepiness. In phase III trials, it has proved effective for relief of pain and fatigue and for sleep quality and patient global improvement. [131]  Because of its potential for abuse, dependence, and diversion (date rape), it is available only through a centralized pharmacy (1-866-997-3688).

Antidepressants

Low-dose TCAs have proved to have short-term efficacy for pain control, improved sleep, and improved sense of well-being in patients with fibromyalgia. However, adverse anticholinergic effects (eg, dry mouth, drowsiness, weight gain) often limit patient acceptance/tolerance.

 First-generation selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and paroxetine (Paxil, Pexeva), improve symptoms in fibromyalgia but the high doses required often cause adverse effects that are poorly tolerated. For this reason, the SSRIs have largely been replaced as a treatment for fibromyalgia by dual serotonin/norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine (Effexor), desvenlafaxine (Pristiq), levomilnacipran (Fetzima), milnacipran (Savella), [132] or duloxetine (Cymbalta). [133, 134, 135]
 Milnacipran has been approved for use in fibromyalgia by the FDA. Duloxetine has been shown to improve pain in fibromyalgia irrespective of comorbid depression [136] and is currently approved by the FDA for pain in fibromyalgia. SNRIs can cause nausea, so they should be taken with food.
 A useful combination is a TCA (eg, amitriptyline, nortriptyline) in low dosage at bedtime plus a first-generation SSRI (eg, fluoxetine, paroxetine), which allows for improved efficacy with lower dosing that can help prevent adverse effects. [137] However, patients taking combinations of serotonin-active drugs should be closely monitored for the development of serotonin syndrome, [138] and all patients taking antidepressants should be carefully monitored for worsening depression or the emergence of suicidal thoughts.
 While many patients find relief with the above-mentioned antidepressants, some fail to tolerate them. For those patients, antidepressants that work via alternative mechanisms are reasonable options. Animal studies have shown that 5-HT1A receptor activation can induce analgesia. [139, 140]
Currently available drugs with 5-HT1a receptor agonist activity include buspirone (Buspar), vilazodone (Viibryd), and vortioxetine (Brintellix). Buspirone is indicated as an anti-anxiety agent and is also used off-label to augment antidepressant activity, while vilazodone and vortioxetine are both indicated only for the treatment of depression. The most common side effect of both vilazodone and vortioxetine is nausea, so both should be taken with food. All three medications should be started in the morning, since they can cause activation.
 Bupropion is structurally different from other antidepressants and its ability to reduce pain is due to its inhibition of the neuronal reuptake of norepinephrine and dopamine. [139, 140] While bupropion is available in an extended release (ER) preparation that allows for once daily dosing, it is activating and can cause or worsen insomnia, so patients should start with immediate-release tablets in the morning with gradual up-titration, or switch to the ER preparation as tolerated. The activating aspect of bupropion can be particularly helpful for fatigue, which is common in fibromyalgia.

Anticonvulsants

Anticonvulsants are useful for chronic pain states, including fibromyalgia and related syndromes and various types of neuropathic pain, and serve as adjunctive medications for disturbed sleep and anxiety. While multiple choices are available, the most studied options for fibromyalgia are gabapentin [141] and pregabalin (Lyrica). [142, 143, 119]  Other options include the following:

  1. Tiagabine
  2. Levetiracetam
  3. Topiramate
  4. Zonisamide
  5. Oxcarbazepine

Anticonvulsants often cause sedation, so they should be started using low doses at night with gradual up-titration and/or use during the day. One option for improving tolerability and efficacy of anticonvulsants is by combining them with antidepressants. Studies have shown benefits from combining pregabalin with milnacipran [144]  as well as gabapentin with venlafaxine, [145]  and the author’s personal experience has shown that other combinations of anticonvulsants and antidepressants can result in augmentation.

Other medications

The selective estrogen receptor modulator raloxifene (Evista), 60 mg every other day, is effective in improving pain, improving fatigue, reducing tender-point count, and improving daily functioning in postmenopausal women with fibromyalgia. [146]  Modafinil (Provigil), approved for narcolepsy and shift-work sleep disorder, 100-200 mg in the morning, can improve fatigue and cognitive disturbances. [147, 148]

 Preliminary data suggest that the synthetic cannabinoid nabilone (Cesamet), in doses escalating from 0.5 mg daily to 1 mg twice daily, improves pain and anxiety in fibromyalgia. [149]  Beta-adrenergic antagonists such as pindolol or propranolol (Inderal), given in low doses at bedtime, can also improve pain and agitation. [150}

Fibromyalgia Medication

Medication Summary

Medication use in patients with fibromyalgia should always be combined with nonpharmacologic therapy. Japanese and German guidelines recommend that pediatric patients receive nonpharmacologic treatment exclusively. [160, 161]

The US Food and Drug Administration (FDA) has approved three drugs for use in fibromyalgia: pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella). [124] Pregabalin is used to reduce pain and improve sleep. The antidepressants duloxetine and milnacipran, which are used to relieve pain, fatigue, and sleep problems, are generally used at lower doses than for treatment of depression.

Other anticonvulsants and antidepressants are often used off-label to treat fibromyalgia and there is evidence that many can decrease pain sensitivity. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are useful only for management of coexisting inflammatory processes and are not recommended as first-line therapies. Pharmacologic and nonpharmacologic treatment of poor sleep is crucial for improving the patient’s overall sense of well-being.

Several medications should be avoided or used carefully. Opioids, hypnotics, anxiolytics, and certain skeletal-muscle relaxants must be used with caution because of the potential for abuse and the risk of worsening fatigue and cognitive dysfunction.

Analgesics

Class Summary

Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties, which are beneficial for patients who experience pain.

Tramadol (Ultram, Ryzolt, Rybix

Tramadol is a centrally acting analgesic indicated for moderately severe pain. This agent inhibits ascending pain pathways, altering the perception of and response to pain. Tramadol also inhibits reuptake of norepinephrine and serotonin.

Antianxiety Agents

Class Summary

Agents of varying durations of action are used frequently for anxiety and panic and as sleep aids (poor sleep is nearly universal in fibromyalgia). [112] Antianxiety agents are often used in combination with antidepressants and anticonvulsant drugs.

Alprazolam (Xanax, Niravam)

Alprazolam binds receptors at several sites within the central nervous system (CNS), including the limbic system and reticular formation. Effects may be mediated through the gamma-aminobutyric acid (GABA) receptor system. It has a short half-life (< 12 h).

Clonazepam (Klonopin

Clonazepam suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. It has a long half-life (25-100 h).

Zolpidem (Ambien)

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Zolpidem is indicated for insomnia. It is structurally dissimilar to benzodiazepines but similar in activity, with the exception of having reduced effects on skeletal muscle and seizure threshold.

Zaleplon (Sonata)

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Zaleplon interacts selectively with the GABA receptor. It binds to the omega-1 receptor situated on the alpha subunit of the GABA-A receptor complex in the brain.

Trazodone (Oleptro)

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Trazodone is useful as an alternative to improve sleep and to treat anxiety and panic disorders that may be associated with fibromyalgia. It is an antagonist at the 5-HT2 receptor and inhibits the reuptake of 5-HT. It also has negligible affinity for cholinergic and histaminergic receptors. In animals, trazodone selectively inhibits serotonin uptake by brain synaptosomes and potentiates behavioral changes induced by the serotonin precursor 5-hydroxytryptophan.

Buspirone

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This agent is a 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in the CNS. It has an anxiolytic effect but may take as long as 2-3 wk for full efficacy.

Temazepam (Restoril)

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Temazepam is indicated for insomnia. It depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Sodium Oxybate (Xyrem)

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Sodium oxybate acts as an inhibitory chemical transmitter in the brain through specific receptors for gamma hydroxybutyrate (GHB) and GABA.

Skeletal Muscle Relaxants

Class Summary

These agents have modest short-term benefit as adjunctive therapy for nociceptive pain associated with muscle strains and, used intermittently, for diffuse and certain regional chronic pain syndromes. With the exception of cyclobenzaprine, long-term improvement over placebo has not been established for muscle relaxants in fibromyalgia, and they are not recommended. Cyclobenzaprine can be helpful for sleep and pain control as a single nighttime dose in combination with an anxiolytic/hypnotic agent.

Cyclobenzaprine (Flexeril, Flexmid)

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Cyclobenzaprine acts centrally and reduces motor activity of tonic somatic origins, influencing both alpha and gamma motor neurons. This agent is structurally related to tricyclic antidepressants (TCAs) and, thus, carries some of the same liabilities.

Antidepressants

Class Summary

Low-dose TCAs have proven to have short-term efficacy for pain control, improved sleep, and improved sense of well-being in patients with fibromyalgia. However, adverse effects (eg, dry mouth, drowsiness, weight gain) limit patient acceptance.

Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac), citalopram (Celexa), escitalopram (Lexapro), fluvoxamine, paroxetine (Paxil, Pexeva), and sertraline (Zoloft), improve symptoms in fibromyalgia but have largely been replaced as a treatment for pain by dual serotonin/norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine (Effexor), desvenlafaxine (Pristiq), milnacipram (Savella), [132] or duloxetine (Cymbalta). [133, 134, 135]

Milnacipram has been approved for use in fibromyalgia by the FDA. Duloxetine has been shown to improve pain in fibromyalgia irrespective of comorbid depression [136] and is currently approved by the FDA for pain in fibromyalgia.

A useful combination is a TCA (eg, amitriptyline or cyclobenzaprine in low dosage at bedtime) and an SNRI. Patients taking either SSRIs or SNRIs should be carefully monitored for worsening depression or emergence of suicidal thoughts.

Amitriptyline

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Amitriptyline inhibits the reuptake of serotonin and/or norepinephrine at presynaptic neuronal membrane, which increases their concentration in the CNS.

Duloxetine (Cymbalta)

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Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake. Its antidepressive action is theorized to be due to serotonergic and noradrenergic potentiation in CNS.

Milnacipran (Savella)

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Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Its exact mechanism of central pain inhibitory action and ability to improve symptoms of fibromyalgia remain unknown. It is indicated for fibromyalgia.

Venlafaxine (Effexor, Effexor XR)

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Vanlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake.

Desvenlafaxine (Pristiq)

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Desvenlafaxine inhibits neuronal serotonin and norepinephrine reuptake.

Levomilnacipran (Fetzima)

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A potent inhibitor of neuronal serotonin and norepinephrine reuptake, levomilnacipran inhibits norepinephrine uptake with ~3-fold higher potency in vitro than serotonin, without directly affecting the uptake of dopamine or other neurotransmitters

anticonvulsants

Class Summary

These agents are useful for chronic pain states, including fibromyalgia and related syndromes and various types of neuropathic pain, and serve as adjunctive medications for disturbed sleep and depression. Multiple choices are available, including gabapentin (Neurontin), [141] tiagabine (Gabitril), and the more recently released pregabalin (Lyrica), [142, 167, 143, 119] which has been particularly well-studied in fibromyalgia.

Pregabalin (Lyrica)

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Pregabalin is a structural derivative of GABA. Its mechanism of action is unknown. Pregabalin binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, it reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. This agent is FDA approved for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, or fibromyalgia. It is also indicated as adjunctive therapy in partial-onset seizures.

Gabapentin (Neurontin)

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Gabapentin is effective for pain and associated depressed mood and anxiety. It has anticonvulsant properties and antineuralgic effects; however, its exact mechanism of action is unknown. Gabapentin is structurally related to GABA but does not interact with GABA receptors. Titration to effect can take place over several days to weeks.

Tiagabine (Gabitril)

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This drug enhances GABA activity by inhibiting uptake in neurons and astrocytes.

Alpha2 Agonists

Class Summary

Clonidine is helpful in controlling withdrawal symptoms during tapering of opioids, which may take 2-3 weeks or longer.

Clonidine (Catapres, Kapvay)

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Clonidine stimulates alpha-2 adrenoreceptors in the brain stem, activating an inhibitory neuron, which, in turn, results in reduced sympathetic outflow. These effects result in a decrease in vasomotor tone and heart rate.

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