Medication Summary
Medication summary
Always combine pharmacologic approaches with nonpharmacologic therapy in the treatment of fibromyalgia (FM), especially stress management, aerobic exercise, and, in some cases, psychotherapy. Aggressively treat comorbid depression.
Tricyclic antidepressants (TCAs) are of proven benefit. Certain anticonvulsants and antidepressants clearly decrease pain sensitivity. Corticosteroids and nonsteroidal anti-inflammatory medications are useful only as management for coexisting inflammatory processes. 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, is beneficial as adjunctive therapy in patients with fibromyalgia. Topical capsaicin, obtained from red chili peppers, is essentially free of toxicity, other than mild burning at the site of application, and is useful as adjunctive therapy 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. [133]
Patients with fibromyalgia have difficulty tolerating regular doses of most medications and supplements. They are sensitive to medications, and adverse effects are common. To avoid these problems, use the lowest dose available or perhaps one half to one quarter of the lowest recommended dose.
The US Food and Drug Administration (FDA) has approved three drugs for use in fibromyalgia: pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella). [134] 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.
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. [135]
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.
A trial of tramadol may be considered for second-line therapy in patients with moderate to severe pain that is unresponsive to other treatments. [98, 136] 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. [137]
Avoid complications and confusion by providing written instructions and drug information. These instructions need to be easy to understand. Patients should be instructed to consult their physician before starting any over-the-counter (OTC) medications or supplements, to avoid potentially harmful drug interactions.
Integrative medicine
Integrative medicine (complementary and altenative medicine [CAM]) is popular in patients with fibromyalgia, in part due to medical skepticism (ie, doubt in the ability of conventional medical care to appreciably alter health status). [138] Many physicians are ignorant of, if not overtly hostile toward, integrative medicine, and patients are often reluctant to inform their physician about their use of it. This can be dangerous because of unsuspected drug-to-drug interactions.
A practical approach is to inquire about integrative medicine usage, to refrain from expression of negative opinions if a particular integrative treatment is relatively inexpensive and appears to be safe, and to encourage whatever works in the context of the power of the placebo effect and promotion of self-efficacy for pain control.
Analgesics
Nonsteroidal anti-inflammatory drugs (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. [139] 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.
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:
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One prescribing physician
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One dispensing pharmacy
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Acceptance of no new prescription of opioids if the medication runs out early or is lost or stolen
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Agreement for random urine testing
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. [140] Modafinil (Provigil), approved for narcolepsy and shift-work sleep disorder, 100-200 mg in the morning, improves fatigue and cognitive disturbances. [141, 142]
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. [143] Beta-adrenergic antagonists such as pindolol or propranolol (Inderal), given in low doses at bedtime, can also improve pain and agitation. [127]
Other medications used in fibromyalgia may include the following:
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Vitamins and minerals
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Malic acid and magnesium combination
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Antioxidants
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Amino acids
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Herbs and supplements
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). [111] 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), [144] 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.
Currently approved by the FDA for narcolepsy-associated cataplexy and excessive daytime sleepiness, sodium oxybate has been shown in phase III trials in fibromyalgia to be effective for pain relief, fatigue, sleep quality, and patient global improvement. [145] Because of its potential for abuse, dependence, and diversion (date rape), it is available only through a centralized pharmacy (1-866-997-3688).
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)
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)
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)
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
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)
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)
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)
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), [146] or duloxetine (Cymbalta). [147, 148, 149]
Milnacipram has been approved for use in fibromyalgia by the FDA. Duloxetine has been shown to improve pain in fibromyalgia irrespective of comorbid depression [150] 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
Amitriptyline inhibits the reuptake of serotonin and/or norepinephrine at presynaptic neuronal membrane, which increases their concentration in the CNS.
Duloxetine (Cymbalta)
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)
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)
Vanlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake.
Desvenlafaxine (Pristiq)
Desvenlafaxine inhibits neuronal serotonin and norepinephrine reuptake.
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), [124] tiagabine (Gabitril), and the more recently released pregabalin (Lyrica), [151, 152, 153, 118] which has been particularly well-studied in fibromyalgia.
Pregabalin (Lyrica)
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)
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)
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)
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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A neurophysiologist's view of pain. Courtesy of Alan R. Light, PhD.
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Tender points in fibromyalgia.
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Pressure algometer (dolorimeter).
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Biopsychosocial model of fibromyalgia.
