Fibromyalgia Medication: Analgesics, Antianxiety Agents, Skeletal Muscle Relaxants, Antidepressants, Anticonvulsants, Alpha2 Agonists

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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.^{[165, 166]}

The US Food and Drug Administration (FDA) has approved three drugs for use in fibromyalgia: pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella).^[128]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.

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)

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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.

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).^[114]Antianxiety agents are often used in combination with antidepressants and anticonvulsant drugs.

Alprazolam (Xanax, Niravam)

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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)

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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.

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.

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),^[136]or duloxetine (Cymbalta).^{[137, 138, 139]}

Milnacipram has been approved for use in fibromyalgia by the FDA. Duloxetine has been shown to improve pain in fibromyalgia irrespective of comorbid depression^[140]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. It is indicated for fibromyalgia in adults and adolescents aged 13-17 y.

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

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),^[145]tiagabine (Gabitril), and the more recently released pregabalin (Lyrica),^{[146, 172, 147, 122]}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.

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.

Questions

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Media Gallery

A neurophysiologist's view of pain. Courtesy of Alan R. Light, PhD.
Tender points in fibromyalgia.
Pressure algometer (dolorimeter).
Biopsychosocial model of fibromyalgia.

of 4

Author

Chad S Boomershine, MD, PhD, CPI, CPT Assistant Clinical Professor, Department of Medicine, Vanderbilt University School of Medicine; Principal Investigator, Clinical Research Solutions; Medical Director, Boomershine Wellness Centers, Elite Healthcare Alliance, Platinum Medical Group, and Spectrum Pain Clinic

Chad S Boomershine, MD, PhD, CPI, CPT is a member of the following medical societies: American College of Rheumatology, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Pfizer;<br/>Serve(d) as a speaker or a member of a speakers bureau for: Pfizer;.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Acknowledgements

Lawrence H Brent, MD Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, and American College of Rheumatology

Disclosure: Genentech Honoraria Speaking and teaching; Genentech Grant/research funds Other; Amgen Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Abbott Immunology Honoraria Speaking and teaching; Takeda Honoraria Speaking and teaching; UCB Speaking and teaching; Omnicare Consulting fee Consulting; Centocor Consulting fee Consulting

Kristine M Lohr, MD, MS Professor, Department of Internal Medicine, Center for the Advancement of Women's Health and Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

John Buckner Winfield, MD Herman and Louise Smith Distinguished Professor of Medicine in Arthritis Emeritus, Department of Medicine, Senior Member, Neurosensory Disorders Center, University of North Carolina at Chapel Hill; Consulting Rheumatologist, Appalachian Regional Rheumatology

John Buckner Winfield, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Immunologists, American Clinical and Climatological Association, American College of Rheumatology, American Federation for Clinical Research, American Pain Society, American Society for Clinical Investigation, Association of American Physicians, and North Carolina Medical Society

Disclosure: Pfizer Honoraria Speaking and teaching; Forest Honoraria Speaking and teaching

Fibromyalgia Medication

Medication Summary

Analgesics

Class Summary

Tramadol (Ultram, Ryzolt, Rybix)

Antianxiety Agents

Class Summary

Alprazolam (Xanax, Niravam)

Clonazepam (Klonopin)

Zolpidem (Ambien)

Zaleplon (Sonata)

Trazodone (Oleptro)

Buspirone

Temazepam (Restoril)

Sodium Oxybate (Xyrem)

Skeletal Muscle Relaxants

Class Summary

Cyclobenzaprine (Flexeril, Flexmid)

Antidepressants

Class Summary

Amitriptyline

Duloxetine (Cymbalta)

Milnacipran (Savella)

Venlafaxine (Effexor, Effexor XR)

Desvenlafaxine (Pristiq)

Levomilnacipran (Fetzima)

Anticonvulsants

Class Summary

Pregabalin (Lyrica)

Gabapentin (Neurontin)

Tiagabine (Gabitril)

Alpha2 Agonists

Class Summary

Clonidine (Catapres, Kapvay)

References

Tables

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