ABSTRACT: Fibromyalgia syndrome (FMS) is a complex disorder of chronic, widespread pain and tenderness usually accompanied by numerous other symptoms, including fatigue, cognitive dysfunction, nonrestorative sleep, depression, anxiety, and stiffness. Effective FMS treatment requires management of all associated symptoms. Multiple pharmacological agents often are used in combination, but patients with FMS tend to be sensitive to medications and often have difficulty in tolerating therapeutic "cocktails." Also, medications that lessen the severity of one FMS symptom may worsen the severity of others. Information on the use of combination drug therapy in FMS is limited. Although combination pharmacotherapy is a useful approach that can improve FMS management for many patients, such therapy must be given cautiously because it carries increased risks.
The 1990 American College of Rheumatology classification criteria defined fibromyalgia syndrome (FMS) exclusively by the presence of chronic widespread pain and tenderness.1 Because of this exclusivity, treatment typically focuses on pain management. However, effective FMS management requires an individualized treatment regimen that addresses not only pain but also all associated FMS symptoms, including fatigue, cognitive dysfunction ("fibrofog"), nonrestorative sleep, depression, anxiety, and stiffness.2
To improve outcomes, a symptom-based approach has been recommended that uses several pharmacological agents to manage various FMS symptoms.3 However, patients with FMS often have difficulty in tolerating such therapeutic "cocktails," and medications that lessen the severity of one FMS symptom may worsen the severity of others.
Information on combination drug therapy in FMS management is limited. In this article, I review the risks and benefits of combination pharmacotherapy in FMS management and offer treatment recommendations.
COMBINING FMS "ANCHOR" DRUGS
FMS does not respond to the classic analgesics, such as opioids and NSAIDs, because these agents do not address the root cause of FMS—dysfunctional CNS pain processing.4 Drugs that have demonstrated effectiveness in managing FMS pain, the so-called FMS anchor drugs, may work by increasing the activity of descending inhibitory pain pathways that use serotonin and norepinephrine (antidepressants, such as the serotonin-norepinephrine reuptake inhibitors [SNRIs] duloxetine and milnacipran; the tricyclic antidepressants [TCAs] amitriptyline and cyclobenzaprine; and the first-generation selective serotonin reuptake inhibitor [SSRI] fluoxetine). Or, they may decrease the activity of pain pathways by reducing excitatory neurotransmitter release (the anticonvulsant α2δ calcium channel antagonists pregabalin and gabapentin).
However, response to monotherapy usually is incomplete. There is about a 30% reduction of pain for most patients, and these modest pain improvements typically are seen with the use of high drug doses that many patients do not tolerate.
An obvious strategy for improving therapeutic effectiveness is combining anchor drugs that have different mechanisms of action (Table). In a randomized, open-label study of patients with FMS for whom pregabalin monotherapy was not successful, the addition of milnacipran, 50 mg taken twice daily, resulted in significantly more patients "much" or "very much" improved compared with those who received pregabalin maintenance therapy alone (65% vs 25%; P < .001)5; combination-treatment patients also had significantly lower pain scores. Combination therapy also improved the tolerability of adverse effects often seen with monotherapy; 13% of the combination-therapy patients experienced nausea compared with 37% for milnacipran in labeled data, and 8% of the combination-therapy group patients had dizziness compared with 38% in pregabalin registration trials.
Although combination therapy with the indicated medications is preferred, many patients cannot afford the high cost of these drugs. Because generic SNRIs and α2δ calcium channel antagonists are available, combining these agents may improve efficacy and tolerability at lower cost.
In another study, patients with neuropathy for whom gabapentin monotherapy was not successful experienced significant pain reduction and global improvement when the SNRI venlafaxine was added.6 The combination treatment was well tolerated, and patients showed reductions in many symptoms often seen in FMS, including fatigue, insomnia, and mood disturbances. However, all combination-therapy studies to date have been small, and larger studies are needed to better understand the risks and benefits.
Both anticonvulsants and antidepressants carry boxed warnings for suicidality. Therefore, patients who are treated with combination therapy should be monitored for suicidal thoughts, particularly those who have psychiatric disorders.
Goldenberg and associates7 found that the combination of the TCA amitriptyline, 25 mg taken at night, and the SSRI fluoxetine, 20 mg taken in the morning, works better than either drug alone for improving pain, global well-being, and sleep disturbances in patients with FMS; adverse effects were minimal. The synergy between the drugs is thought to be the result of amitriptyline increasing the norepinephrine reuptake inhibition of fluoxetine.
In another small, randomized study, the combination of fluoxetine, 20 mg/d, and cyclobenzaprine, 10 mg/d, was superior to cyclobenzaprine, 10 mg/d, alone in improving FMS pain and morning stiffness.8 Because cyclobenzaprine is a TCA similar to amitriptyline, the synergy with fluoxetine probably is the result of a mechanism similar to that of amitriptyline with fluoxetine. However, patients taking multiple serotonin-active medications are at increased risk for serotonin syndrome.9 Physicians should discuss the risks with patients and monitor them for toxicity.
ADDING MEDICATIONS TO MANAGE SPECIFIC SYMPTOMS
Although some patients have improvement of all FMS symptoms with the use of anchor combination therapy, many continue to have problematic symptoms. Drugs may be added to manage specific FMS symptoms. (Note that medication uses in this section are off-label and published data for the use of these agents in patients with FMS are limited.)
Wakefulness-promoting agents and stimulants for fatigue and fibrofog
Many patients experience fatigue that manifests physically as activity-induced exhaustion and mentally as fibrofog. Although long-term management of fatigue in patients with FMS should be based on improving sleep quality and fitness level, stimulants and wakefulness-promoting agents can improve fatigue symptoms in the short term.10
Modafinil and armodafinil are wakefulness-promoting agents indicated for daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work syndrome. Modafinil has shown effectiveness in improving fatigue associated with multiple disorders, including FMS,11 at doses of 50 to 400 mg given once or twice daily. Because armodafinil is the active R-enantiomer of racemic modafinil, this agent would be expected to have similar efficacy but with the added benefits of once-daily dosing, lower cost, and improved tolerability. However, the only published trial of armodafinil for FMS fatigue did not show efficacy.12
Both modafinil and armodafinil have the potential for drug interactions because they affect multiple cytochrome P-450 isoenzymes and are bound to plasma proteins. Although the adverse effects typically are milder with modafinil and armodafinil, they are similar to those seen with stimulants; patients with insomnia, cardiovascular disease, and psychiatric disorders should be monitored for symptom worsening.13
Stimulants often are used to manage FMS fatigue and fibrofog because they are inexpensive and typically there are few insurance restrictions on their use. Patients with FMS have cognitive deficits similar to those of patients with adult attention-deficit/hyperactivity disorder (ADHD),14 and adult patients who have ADHD with FMS treated with stimulants have shown improvement in multiple FMS symptoms.15
A full discussion of the risks and benefits of stimulants can be found in a recent review.10 However, a "start low and go slow" approach is recommended: a low, short-acting dose is given when the patient awakens, followed by the addition of a second dose at noon, if necessary, before a once-daily, long-acting formulation is used. For example, 5 mg of methylphenidate is taken in the morning for 1 week before adding a second dose at noon for a second week and then increasing to 10 mg twice daily for a third week before switching to a 20-mg once-daily sustained-release pill.
Because wakefulness-promoting agents and stimulants have addiction potential, their use in patients with a history of addiction is discouraged and urine drug screening is encouraged to detect diversion. When wakefulness-promoting agents and stimulants have been added to antidepressant therapy, both have been associated with serotonin syndrome and manic episodes.10
1. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-172.
2. Carville SF, Arendt-Nielsen S, Bliddal H, et al; EULAR. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis. 2008;67:536-541.
3. Boomershine CS, Crofford LJ. A symptom-based approach to pharmacologic management of fibromyalgia. Nat Rev Rheumatol. 2009;5:191-199.
4. Russell IJ, Larson AA. Neurophysiopathogenesis of fibromyalgia syndrome: a unified hypothesis. Rheum Dis Clin North Am. 2009;35:421-435.
5. Farmer M, Dayani N, Trugman JM, et al. Efficacy of milnacipran when added to pregabalin in the management of fibromyalgia: a randomized, open-label, controlled study. Ann Rheum Dis. 2010;69(suppl 3):448.
6. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis. 2001;3:53-62.
7. Goldenberg D, Mayskiy M, Mossey C, et al. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852-1859.
8. Cantini F, Bellandi F, Niccoli L, Di Munno O. Fluoxetine combined with cyclobenzaprine in the treatment of fibromyalgia [in Italian]. Minerva Med. 1994;85:97-100.
9. Nelson LS, Erdman AR, Booze LL, et al. Selective serotonin reuptake inhibitor poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007;45:315-332.
10. Ng B, O’Brien A. Beyond ADHD and narcolepsy: psychostimulants in general psychiatry. Adv Psychiatr Treatment. 2009;15:297-305.
11. Schwartz TL, Rayancha S, Rashid A, et al. Modafinil treatment for fatigue associated with fibromyalgia.
J Clin Rheumatol. 2007;13:52.
12. Schwartz TL, Siddiqui UA, Raza S, Morell M. Armodafinil for fibromyalgia fatigue. Ann Pharmacother. 2010;44:1347-1348.
13. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68:1803-1839.
14. Glass JM. Fibromyalgia and cognition. J Clin Psychiatry. 2008;69(suppl 2):20-24.
15. Young JL, Redmond JC. Fibromyalgia, chronic fatigue, and adult attention deficit hyperactivity disorder in the adult: a case study. Psychopharmacol Bull. 2007;40:118-126.
16. Moldofsky H. The significance, assessment, and management of nonrestorative sleep in fibromyalgia syndrome. CNS Spectr. 2008;13(3 suppl 5):22-26.
17. Hindmarch I, Dawson J, Stanley N. A double-blind study in healthy volunteers to assess the effects of sleep of pregabalin compared with alprazolam and placebo. Sleep. 2005;28:187-193.
18. Samborski W, Lezanska-Szpera M, Rybakowski JK. Open trial of mirtazapine in patients with fibromyalgia. Pharmacopsychiatry. 2004;37:168-170.
19. Calandre EP, Morillas-Arques P, Molina-Barea R, et al. Trazodone plus pregabalin combination in the treatment of fibromyalgia: a two-phase, 24-week, open-label uncontrolled study. BMC Musculoskeletal Disord. 2011;12:95. http://www.biomedcentral.com/1471-2474/12/95. Accessed August 31, 2011.
20. Moldofsky H, Lue FA. The relationship of alpha and delta EEG frequencies to pain and mood in ‘fibrositis’ patients treated with chlorpromazine and L-tryptophan. Electroencephalogr Clin Neurophysiol. 1980;50:71-80.
21. Hidalgo J, Rico-Villademoros F, Calandre EP. An open-label study of quetiapine in the treatment of fibromyalgia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:71-77.
22. Saletu B, Prause W, Anderer P, et al. Insomnia in somatoform pain disorder: sleep laboratory studies on differences to controls and acute effects of trazodone, evaluated by the Somnolyzer 24 × 7 and the Siesta database. Neuropsychobiology. 2005;51:148-163.
23. Moldofsky H, Inhaber NH, Guinta DR, Alvarez-Horine SB. Effects of sodium oxybate on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study. J Rheumatol. 2010;37:2156-2166.
24. Ratcliffe GE, Enns MW, Belik SL, Sareen J. Chronic pain conditions and suicidal ideation and suicide attempts: an epidemiologic perspective. Clin J Pain. 2008;24:204-210.
25. Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of fibromyalgia. Ann Pharmacother. 2003;37:1561-1565.
26. See S, Ginzburg R. Choosing a skeletal muscle relaxant. Am Fam Physician. 2008;78:365-370.
27. Tofferi JK, Jackson JL, O’Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum. 2004;51:9-13.
28. Bennett RM, Schein J, Kosinski MR, et al. Impact of fibromyalgia pain on health-related quality of life before and after treatment with ramadol/acetaminophen. Arthritis Rheum. 2005;53:519-527.
• Boomershine CS, Crofford LJ. A symptom-based approach to pharmacologic management of fibromyalgia. Nat Rev Rheumatol. 2009;5:191-199. This fibromyalgia management approach is based on the symptoms experienced by individual patients; a brief questionnaire that can be used to evaluate symptom severity is included.
• Carville SF, Arendt-Nielsen S, Bliddal H, et al; EULAR. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis. 2008;67:536-541. These evidence-based recommendations for fibromyalgia management include both pharmacological and nonpharmacological treatments.
• Farmer M, Dayani N, Trugman JM, et al. Efficacy of milnacipran when added to pregabalin in the management of fibromyalgia: a randomized, open-label, controlled study. Ann Rheum Dis. 2010;69(suppl 3):448. This article, the only published trial of combination therapy with indicated fibromyalgia drugs, shows that the combination of pregabalin and milnacipran improves efficacy while decreasing adverse effects.
• Nelson LS, Erdman AR, Booze LL, et al. Selective serotonin reuptake inhibitor poisoning: an evidence-based consensus guideline for out-of-hospital man-agement. Clin Toxicol (Phila). 2007;45:315-332. Evidence-based treatment guidelines for the management of serotonin syndrome in the outpatient setting are described here.
• Ng B, O’Brien A. Beyond ADHD and narcolepsy: psychostimulants in general psychiatry. Adv Psychiatr Treat. 2009;15:297-305. This reviews the stimulant therapies; readers should pay particular attention to the section on use in patients with general medical conditions.