Fibromyalgia Except for Tenderness Over Her Upper Back Neurologic and Hips

Fib romyalgia

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Repeated pain signals in the periphery may sensitize spinal cord neurons, resulting in amplifi ed and prolonged signals traveling to the brain

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36_CPSY0309 36 2/13/09 10:56:44 AM Fib romyalgia romyalgia Fib 37_CPSY0309 37 romyalgia romyalgia

KEN ORVIDAS FOR CURRENT PSYCHIATRY Cincinnati, OH College ofMedicine University ofCincinnati HealthResearch Program Assistant director, Women’s andfamilymedicine Assistant professor ofpsychiatry Stanford, MD Sharon B. (Shay) Psychiatric drugs target CNS-linked symptoms rhea, debilitating fatigue, andsleepdisturbance. stressful situations. Shealsoexperiences nauseaandintermittent diar- an intense ache, “like having thefl u,” andin that worsens withactivity thighs, whichsherates painscale. as7to 8ona0-to-10 Shedescribes “Nothinghelps” shoulders, thepersistent and paininherback, her dent left day.” sore thenext “very deteriorating moodover 6months, beginningwhenaminorcaracci- physician for evaluationprimary ofdepression andanxiety. Shereports Ms. D, ofmigraineheadachesandisreferred age50,has ahistory by her ‘Just too tired’ REPORT CASE cations—are likelytoplayalarger role intreating fi bromyalgia. phenomena andmanagingantidepressant andanticonvulsantmedi- sue. As aresult, psychiatrists—becauseofourexperiencewithCNS rather thananinfl ammatoryprocess inthemusclesorconnectivetis- condition, a CNS of understanding as fl revised bromyalgia fi a ect Thesemedications—pregabalin, duloxetine,andmilnacipran—re- pressants formanagingfi bromyalgia symptoms. with therecent FDA approval ofananticonvulsantand2antide- diagnosis ortreat theirsymptoms.Thissituationmaybechanging “Is itfi bromyalgia orsomatization disorder?” Web audio atCurrentPsychiatry.com physicians whoseemunableorunwillingtoprovide a many describeacommonexperience:seeingmultiple atients withfi bromyalgia are aheterogeneous group, yet Current Psychiatry Vol. 8,No.3 ONLY ONLINE 2/17/09 11:21:25 AM 2/17/09 11:21:25 AM continued 37 Table 1 Ms. D reports she is depressed because Medical and cognitive she feels “just too tired” after work to keep up symptoms related to with social activities or housework. Her physician’s referral notes a normal physical exam fibromyalgia except for tenderness over her upper back Neurologic and hips. Laboratory testing is negative. Tension/migraine headache Fibromyalgia Psychiatric Memory and cognitive diffi culties Making the diagnosis Mood disturbance American College of Rheumatology (ACR) Anxiety disorders criteria for fi bromyalgia require wide- Ear, nose, throat spread pain for at least 3 months. “Wide- Sicca symptoms spread” is defi ned as pain in the axial Vasomotor rhinitis Vestibular complaints skeleton, left and right sides of the body, and above and below the waist. Pain must Cardiovascular Neurally mediated hypotension be found in at least 11 of 18 tender point Clinical Point Mitral valve prolapse sites on digital palpation using a force of Musculoskeletal Noncardiac chest pain approximately 4 kg/cm2.1 For many fi bro- pain is not the Gastrointestinal myalgia patients, however, musculosk- Esophageal dysmotility eletal pain is not their most problematic most problematic Irritable bowel syndrome symptom (Table 1). They may suffer: symptom for many Urological • migraine and tension headaches (10% patients with Interstitial cystitis to 80% of patients) fi bromyalgia Gynecological • irritable bowel syndrome (32% to Vulvodynia 80%)2 Chronic pelvic pain • mood disorders (major depressive dis- Oral/dental order [62%], bipolar disorder [11%]) Temporomandibular joint syndrome • anxiety disorders (panic disorder Other (general) [29%], posttraumatic stress disorder Chronic fatigue syndrome [21%], social phobia [19%]).3 Sleep disturbances ACR criteria are useful in research but Idiopathic low back pain Multiple chemical sensitivity lack many common symptoms and comor- bidities. A structured interview that follows the DSM-IV-TR format incorporates other Table 2 symptoms into the diagnosis (Table 2).4 Fibromyalgia: Structured Because patients with fi bromyalgia interview for diagnosis often meet criteria for somatization or somatoform disorders, how to classify A. Generalized pain affecting the axial, plus upper and lower segments, plus left and them—as medically or psychiatrically rights sides of the body ill—is controversial. Some patients believe their mood or anxiety problem stems from Either B or C: the diffi culty they experience dealing with B. At least 11 of 18 reproducible tender their physical symptoms, and if they could ONLINE points ONLY feel better physically they would not be C. At least 4 of the following symptoms: depressed or anxious. Others believe their • Generalized fatigue Download a form psychiatric symptoms impede their ability for patients to report • Headaches to help themselves feel better. fi bromyalgia symptoms. • Sleep disturbance Saves time, structures • Neuropsychiatric complaints Consider fi bromyalgia in any patient offi ce visits. • Numbness, tingling sensations with widespread pain of unknown cause. • Irritable bowel symptoms CurrentPsychiatry.com Before making the diagnosis, rule out oth- D. It cannot be established that disturbance er illnesses that present with similar symp- was due to another systematic condition toms (Table 3). Because many patients Current Psychiatry Source: Reference 4 38 March 2009 newly diagnosed with fi bromyalgia worry

38_CPSY0309 38 2/17/09 11:21:35 AM Table 3 Diff erentiating fibromyalgia from illnesses with similar symptoms

Illness Tests to differentiate from primary ﬁ bromyalgia Rheumatic diseases Osteoarthritis Radiographs Spondyloarthropathies, Rheumatic markers (antinuclear antibody, rheumatoid arthritis rheumatoid factor, antibodies) Systemic lupus erythematosus, Infl ammatory markers (ESR, C-reactive protein) polymyalgia rheumatica Osteomalacia Vitamin D level Myopathy CPK Neurologic Multiple sclerosis, Chiari’s MRI malformation, spinal stenosis, radiculopathy Clinical Point Neuropathy EMG Fibromyalgia Endocrine Hypothyroidism TSH patients show lower Diabetes Basic chemistry panel with fasting glucose levels of serotonin, Other norepinephrine, Infectious CBC and dopamine Lyme disease Lyme titer metabolites in Hepatitis Hepatitis antibody panel, liver function tests cerebrospinal ﬂ uid Anemia Hemoglobin/hematocrit Cancers Routine cancer screening tests, bone scan, blood chemistries specifi c for suspected primary cancer

ESR: erythrocyte sedimentation rate; CPK: creatine phosphokinase; EMG: electromyography; TSH: thyroid-stimulating hormone; CBC: complete blood count

that something “more serious” may be go- Fibromyalgia affects 3.5% of women and ing on, confi rm the diagnosis with appro- 0.5% of men.5 It runs in families with his- priate testing and physical examination, tories of fi bromyalgia and major mood usually by a rheumatologist or primary and anxiety disorders, suggesting ge- care physician. netic links.6 Defects in genes controlling serotonin and norepinephrine have been CASE CONTINUED implicated.7-9 Central pain sensitization Fibromyalgia patients show lower lev- As you elicit more details about Ms. D’s mood, els of serotonin, norepinephrine, and do- she continues to focus on her physical symp- pamine metabolites in cerebrospinal fl uid toms. She states that some days she wishes (CSF), compared with controls.10 These to die because her pain gets so bad, but she neurotransmitters may inhibit descending denies any plan or intent to harm herself. She pain pathways in the CNS, and low levels worries that her symptoms will worsen and in the brain and spinal cord may inhibit that she will become completely disabled. CNS regulation of pain impulses from the Her primary physician attempted to relieve periphery.11 Ms. D’s pain with multiple trials of nonsteroidal Although many patients describe mus- anti-inﬂ ammatory drugs (NSAIDs) and cyclo- cle pain, evidence suggests central pain benzaprine. She says she gained no beneﬁ t augmentation rather than an abnormality from the NSAIDs and discontinued the muscle of muscle or connective tissue.12 Some stud- Current Psychiatry relaxant because it made her too sleepy. ies have found evidence of “windup,” in Vol. 8, No. 3 39 continued on page 46

39_CPSY0309 39 2/13/09 10:56:59 AM continued from page 39 Box Managing unrealistic expectations of fi bromyalgia patients

BELIEF: ‘A magic pill exists that will resolve BELIEF: ‘You (the psychiatrist) can make all my symptoms and have no side effects’ me feel better’ Clinical evidence: Most medications that Clinical evidence: Psychiatrists can have been studied were effective in 30% to help by prescribing appropriate medications, Fibromyalgia 50% of patients and reduced pain scores by but much of the burden falls on the patient 30% to 50%. to maintain a healthy, active lifestyle and to Patient education: Explain to the patient manage stressors in an adaptive manner. with a pain rating of 7 at the fi rst visit that Patient education: A fi bromyalgia achieving a pain level of 3 to 4 may be patient may fi nd relief with a medication, but possible with treatment. Even with successful symptoms may fl are if they ‘overdo’ and take treatment, symptoms may fl are intermittently. on too many physical or emotional stressors. As with any treatment, adverse effects may A consistent, healthy routine is ideal. occur. Discuss these, so the patient is not BELIEF: ‘I will eventually become disabled surprised. by ﬁ bromyalgia’ Clinical Point BELIEF: ‘I can’t exercise’ Clinical evidence: Despite little long- Clinical evidence: Most patients term research on fi bromyalgia patients, most Many patients experience more fatigue and pain with evidence points to a chronic, fl uctuating expect to resume an physical activity, but exercise is important to syndrome that does not worsen with age. maintain physical function. Factors that may worsen symptoms include energetic, pain-free Patient education: When discussing an uncontrolled comorbid conditions, chronic life, which usually exercise program, focus on what the patient opiate use, inactivity, and deconditioning. can do. Most patients attempt too much, too Patient education: Discourage long-term is not the case soon; advise them to start at a tolerable level physical disability; exercise and maintaining with ﬁ bromyalgia (such as 2 to 3 minutes of aerobic activity an active daily routine helps patients avoid daily for the fi rst week) and gradually increase focusing in a nonadaptive manner on their as tolerated. dysfunction and symptoms.

Source: Sharon B. (Shay) Stanford, MD

which second-order neurons in the spinal degree of overlap was seen in brain ar- cord become sensitized by repeated signals eas responsible for pain processing. This from fi rst-order neurons in the periphery, indicates that fi bromyalgia patients and resulting in amplifi ed and prolonged pain controls were experiencing the pain they signals traveling to the brain.13 reported in the same way.15 Levels of substance P—a primary trans- mitter of pain impulses—are signifi cantly higher in CSF of fi bromyalgia patients Treating the whole patient compared with controls.14 This fi nding, As a clinician who specializes in fi bromyal- in addition to low levels of serotonin and gia, I counteract my patients’ and my own norepinephrine, indicates that pain signals frustration with this condition by structur- are ascending unchecked to be processed ing offi ce visits, determining realistic treat- by the brain. ment goals, and treating all symptoms as Neuroimaging studies confi rm this part of a common syndrome rather than observation. In a study using functional individual illnesses. magnetic resonance imaging (fMRI), re- searchers applied pressure to the thumb- Structure oﬃ ce visits. Before every visit, nails of fi bromyalgia patients and controls have patients rate each symptom domain until each subject reported pain: and write their top 2 or 3 concerns for that • Twice as much pressure was required day (for a sample form, see this article at before controls rated their pain at a level CurrentPsychiatry.com). Focusing on the similar to that of fi bromyalgia patients. patient’s most troublesome symptoms can • When controls and fi bromyalgia pa- help both of you feel greater satisfaction Current Psychiatry 46 March 2009 tients reported similar pain, a very high with treatment.

46_CPSY0309 46 2/17/09 11:21:40 AM Educate patients. Ask them to discuss their beliefs about fi bromyalgia; 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, page 50).

Set realistic expectations. Many patients expect to resume an energetic and pain-free life, Your search is over! which usually is not the case with fi bromyalgia (Box). Most medications are considered success- DISCOVER CURRENT PSYCHIATRY’S ful 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 fi rst weeks. Ñ PSYCHIATRYFindit.com deﬁ ned: Cognitive-behavioral therapy (CBT) for fi - PSYCHIATRYFindit.com is a custom vertical search tool that allows visitors to perform targeted searches of Web bromyalgia incorporates relaxation techniques, sites most relevant to psychiatrists and related clinicians. helping patients view symptoms as manage- PSYCHIATRYFindit.com covers hundreds of carefully able, reinforcing adaptive coping skills, and selected Web sites containing information directly related teaching them how to monitor thoughts, feel- to psychiatric practice. ings, and behavior to change the view that they are helpless victims. A modest course of Ñ PSYCHIATRYFindit.com delivers results from: 6 weekly group CBT sessions signifi cantly im- •Peer-reviewed psychiatric journals proved physical functioning in 25% of fi bro- •Psychiatric professional associations •Government agencies myalgia patients (n=76) compared with 12% •Patient advocacy sites in a standard-care group (n=69), even though patients’ pain severity did not improve.16 Ñ Beneﬁ ts to psychiatrists are: • Targeted and relevant searches Recommend exercise, lifestyle changes. • Time-saving tool Aerobic exercise can signifi cantly improve • Trusted source: CURRENT PSYCHIATRY well-being and physical functioning in fi bro- Ñ PSYCHIATRYFindit.com provides 3 convenient myalgia patients.17 Low-impact aerobics, such search options: as done in warm water, usually are well tol- • “CURRENT PSYCHIATRY” allows searches of current and erated, although any low-impact exercise can archived issues. help. Because fi bromyalgia symptoms often • “Psychiatry sites” includes hundreds of the most increase with physical activity, counsel pa- relevant sites selected by CURRENT PSYCHIATRY’s editors and Editorial Board. tients to begin with a few minutes daily and increase very slowly each week. • “PubMed” includes 18 million citations from life science journals. Lifestyle changes are as important as medications in controlling fi bromyalgia symptoms. In Visit us online at www.PSYCHIATRYFindit.com today! addition to exercise, recommend that patients: • follow a daily routine • pace activity to avoid exacerbating symptoms • reduce stress. SYCHIATRY CURRENTPSYCHIATRY.com Sometimes, I use the analogy of diabetes: treating fi bromyalgia with medication but

47_CPSY0309 47 2/17/09 12:04:49 PM Table 4 Off -label medications shown to benefi t patients with fi bromyalgia

Drug Comment Amitriptyline27,28 Considered fi rst-line because of studies supporting its use, low cost, and wide availability; may be associated with more side effects than newer medications Fibromyalgia 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

without changing lifestyle is like pre- brain and spinal cord. This SNRI was Clinical Point scribing medication for a diabetic patient fi rst FDA-approved for diabetic periph- Pregabalin may be without changing diet. Follow up on this eral neuropathic pain and major depres- a benefi cial fi rst “homework” at each visit to reinforce that sive disorder. Approval for fi bromyalgia patients helping themselves is an impor- at 60 mg/d in June 2008 was based on 2 choice for patients tant part of treatment. placebo-controlled, double-blind, 12-week who report pain and trials comprising 874 patients.23,24 For de- sleep as major issues tailed fi ndings of these studies and a 6- New direction with medications month fi xed-dose trial,25 see this article at Pregabalin is an anticonvulsant that binds CurrentPsychiatry.com. to the alpha-2-delta subunits of neurons’ In clinical trials, duloxetine dosages of voltage-gated calcium channels. This ac- 60 mg/d and 120 mg/d were signifi cantly tivity reduces calcium infl ux at nerve ter- more effective than placebo. The most com- minals and inhibits release of excitatory mon side effects were nausea, constipation, neurotransmitters, such as substance P excessive sweating, and somnolence.23-25 and glutamate.18 In June 2007, pregabalin was the fi rst medication FDA-approved Milnacipran is an SNRI that was approved for fi bromyalgia. for treating fi bromyalgia in January 2009 Two placebo-controlled trials19,20 showed at dosages of 50 mg bid and 100 mg bid. that pregabalin at 150 mg bid, 225 mg bid, Like other SNRIs, milnacipran is thought or 300 mg bid signifi cantly reduced weekly to work by inhibiting pain signals through mean pain scores in fi bromyalgia patients. increasing serotonin and norepinephrine For details of these trials, see this article at in the brain and spinal cord. Milnacipran CurrentPsychiatry.com. The most common has a higher selectivity for norepineph- side effects—dizziness, somnolence, pe- rine reuptake compared with duloxetine, ripheral edema, blurred vision, and weight which may mean these medications will gain—were regarded as mild to moderate have different effects in different patients. in 87% of patients.21 Although milnacipran is approved as an ONLINE ONLY Although a dosage of 300 mg bid also antidepressant in other countries, the FDA was studied, the FDA approved pregaba- has not approved it for treating depression Details of clinical lin at dosages of 150 mg bid and 225 mg in the United States. trials that supported bid for fi bromyalgia.22 For details of a 15-week, double-blind, fi bromyalgia indications for 3 CNS medications. placebo-controlled trial of milnacipran in CurrentPsychiatry.com Duloxetine is a serotonin/norepineph- patients with fi bromyalgia, see this article rine reuptake inhibitor (SNRI) thought at CurrentPsychiatry.com. Side effects in to inhibit dorsal horn neurons’ response clinical trials were similar to those of du- to peripheral pain signals by increas- loxetine, with nausea, constipation, and in- Current Psychiatry 48 March 2009 ing serotonin and norepinephrine in the creased sweating being most prominent.26

48_CPSY0309 48 2/17/09 12:04:57 PM Other medications, such as the fi rst-line CASE CONTINUED agent amitriptyline, have shown benefi cial Not as hopeless effects in fi bromyalgia but are not FDA- Ms. D’s primary care physician confi rms your approved for this indication (Table 4).27-32 presumptive diagnosis of fi bromyalgia. He prescribes a trial of amitriptyline, which she Choosing medications. When prescribing does not tolerate well because of sedation and one of the FDA-approved medications to weight gain. At her next psychiatric visit, she treat fi bromyalgia, consider their benefi ts tells you she remains very frustrated about her and side effects. physical symptoms and reports that her doc- Pregabalin may be a benefi cial fi rst choice tor “has given up on me.” for patients who report pain and sleep as You discuss what a fi bromyalgia diagnosis major issues. Although the medication’s means to her and educate her about the syn- label recommends starting with twice-daily drome. You refer her to a colleague who does dosing, patients might better tolerate an ini- CBT with chronic pain patients and start her tial dose of 50 to 75 mg in the evening, with on a low dose of duloxetine (30 mg once daily) the morning dose added later. Pregabalin to minimize side eff ects. You discuss possible can be useful in patients taking multiple side eff ects and that she may need a higher Clinical Point medications because of its renal clearance, dose to notice improvement in her pain. She Milnacipran’s more seems receptive to starting a graded exercise resulting in low risk of interactions with selective eff ect on drugs metabolized by liver enzymes. It also program, and you encourage her to reduce can be useful in patients who have not toler- physical and emotional stress in her life. norepinephrine ated antidepressants in the past or in whom When she returns, she reports her pain could be benefi cial antidepressants are contraindicated. is somewhat improved and medication side for patients with If a patient has a history of depression eff ects have subsided. She is not as hopeless excessive fatigue or discontinuing medications because of and tells you she is up to 10 minutes of walk- sedating side effects, an antidepressant ing daily. You increase duloxetine to 60 mg/d such as duloxetine or milnacipran may be and reinforce her ability to exercise and man- more successful than starting with prega- age her stress. balin. In general, if a patient does not respond to one of these SNRIs, moving on to References 1. Wolfe F, Smythe HA, Yunus MB, et al. The American College the other might help. Milnacipran’s more of Rheumatology 1990 criteria for the classifi cation of selective effect on norepinephrine could fi bromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33(2):160-172. be benefi cial for some patients, especially 2. Aaron LA, Buchwald D. Chronic diffuse musculoskeletal pain, fi bromyalgia and co-morbid unexplained clinical conditions. those with excessive fatigue. Others, es- Best Prac Res Clin Rheumatol. 2003;17(4):563-574. pecially those with a high level of anxiety, 3. Arnold LM, Hudson JI, Keck PE, et al. Comorbidity of fi bromyalgia and psychiatric disorders. J Clin Psychiatry. might respond better to a more balanced 2006;67(8):1219-1225. SNRI such as duloxetine. 4. Pope HG Jr, Hudson JI. A supplemental interview for forms

Bottom Line Consider ﬁ bromyalgia in patients with pain, depression, sleep problems, fatigue, and cognitive dysfunction beyond what is expected for a primary mood disorder. Two antidepressants and an anticonvulsant that target the CNS are FDA-approved for ﬁ bromyalgia, although other medications may help. Encourage patients to share in symptom management by exercising and making lifestyle changes. Cognitive/ Current Psychiatry behavioral techniques can help patients manage frustration and hopelessness. Vol. 8, No. 3 49

49_CPSY0309 49 2/17/09 12:05:02 PM of “affective spectrum disorder.” Int J Psychiatry Med. 1991; 21(3):205-232. Related Resources 5. Wolfe F, Ross K, Anderson J, et al. The prevalence and characteristics of fi bromyalgia in the general population. • Arthritis Foundation. Fibromyalgia. www.arthritis.org/ Arthritis Rheum. 1995;38(1):19-28. disease-center.php?disease_id=10. 6. Arnold LM, Hudson JI, Hess EV, et al. Family study of • National Fibromyalgia Association. www.fmaware.org. fi bromyalgia. Arthritis Rheum. 2004;50(3):944-952. 7. Bondy B, Spaeth M, Offenbaecher M, et al. The T102C • Self-management program for patients with fi bromyalgia, polymorphism of the 5-HT2A-receptor gene in fi bromyalgia. cosponsored by the National Fibromyalgia Association and Neurobiol Dis. 1999;6(5):433-439. Eli Lilly and Company. www.knowfi bro.com. 8. Offenbaecher M, Bondy B, de Jonge S, et al. Possible asso- Drug Brand Names Fibromyalgia ciation of fi bromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum. 1999; Amitriptyline • Elavil, Endep Milnacipran • Savella 42(11):2482-2488. Cyclobenzaprine • Flexeril Pregabalin • Lyrica 9. Gürsoy S, Erdal E, Herken H, et al. Signifi cance of catechol- Duloxetine • Cymbalta Tramadol • Ultram, Ultracet O-methyltransferase gene polymorphism in fi bromyalgia Fluoxetine • Prozac Venlafaxine • Eff exor, Eff exor syndrome. Rheumatol Int. 2003;23(3):104-107. Gabapentin • Neurontin XR 10. Russell IJ, Vaeroy H, Javors M, et al. Cerebrospinal fl uid biogenic amine metabolites in fi bromyalgia/fi brositis Disclosure syndrome and rheumatoid arthritis. Arthritis Rheum. Dr. Stanford receives grant/research support from Eli Lilly and 1992;35(5):550-556. Company, Pfi zer Inc., Cypress Bioscience, and Allergan. 11. Fields HL, Basbaum AI. In: Wall PD, Melzack R, eds. Textbook of pain. 4th ed. New York, NY: Churchill Livingstone; 1999: 309-329. Clinical Point 12. Clauw DJ, Crofford LJ. Chronic widespread pain and two randomized, placebo-controlled clinical trials. J Womens fi bromyalgia: what we know, and what we need to know. Best Health (Larchmt). 2007;16(8):1145-1156. Other patients may Pract Res Clin Rheumatol. 2003;17(4):685-701. 24. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, 13. Staud R, Cannon RC, Mauderli AP, et al. Temporal summation multicenter trial comparing duloxetine with placebo in the respond better to a of pain from mechanical stimulation of muscle tissue in treatment of fi bromyalgia patients with or without major normal controls and subjects with fi bromyalgia syndrome. depressive disorder. Arthritis Rheum. 2004;50(9):2974-2984. more balanced SNRI Pain. 2003;102(1-2):87-95. 25. Russell IJ, Mease PJ, Smith TR, et al. Effi cacy and safety of 14. Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal such as duloxetine, duloxetine for treatment of fi bromyalgia in patients with or fl uid levels of substance P in patients with the fi bromyalgia without major depressive disorder: results from a 6-month, syndrome. Arthritis Rheum. 1994;37(11):1593-1601. especially those with randomized, double-blind, placebo-controlled, fi xed-dose 15. Gracely RH, Petzke F, Wolf JM, et al. Functional magnetic trial. Pain. 2008;136(3):432-444. high levels of anxiety resonance imaging evidence of augmented pain processing in 26. Clauw DJ, Mease P, Palmer RH, et al. Milnacipran for the fi bromyalgia. Arthritis Rheum. 2002;46(5):1333-1343. treatment of fi bromyalgia in adults: a 15-week, multicenter, 16. Williams DA, Cary MA, Groner KH. Improving physical randomized, double-blind, placebo-controlled, multiple-dose functional status in patients with fi bromyalgia: a brief clinical trial. Clin Ther. 2008;30(11):1988-2004. cognitive behavioral intervention. J Rheumatol. 2002;29:1280- 27. Goldenberg DL, Felson DT, Dinerman H. A randomized, 1286. controlled trial of amitriptyline and naproxen in the 17. Busch AJ, Schachter CL, Overend TJ, et al. Exercise for fi bro- treatment of patients with fi bromyalgia. Arthritis Rheum. myalgia: a systematic review. J Rheumatol. 2008;35(6):1130- 1986;29(11):1371-1377. 1144. 28. Hannonen P, Malminiemi K, Yli-Kerttula U, et al. A 18. Field MJ, Cox, PJ, Stott E. Identifi cation of the alpha2-delta-1 randomized, double-blind, placebo-controlled study subunit of voltage-dependent calcium channels as a molecular of moclobemide and amitriptyline in the treatment of target for pain mediating the analgesic actions of pregabalin. fi bromyalgia in females without psychiatric disorder. Br J Proc Natl Acad Sci USA. 2006;103(46):17537-17542. Rheumatol. 1998;37:1279-1286. 19. Arnold LM, Russel IJ, Diri EW, et al. A 14-week, randomized, 29. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin double-blind, placebo-controlled, monotherapy trial of pre- in the treatment of fi bromyalgia: a randomized, double- gabalin in patients with fi bromyalgia. J Pain. 2008;9(9):792- blind, placebo-controlled, multicenter trial. Arthritis Rheum. 805. 2007;56:1336-1344. 20. Mease PJ, Russel IJ, Arnold LM, et al. A randomized, double- 30. Bennett RM, Schein J, Kosinski MR, et al. Impact of blind, placebo-controlled, phase III trial of pregabalin in fi bromyalgia pain on health-related quality of life before the treatment of patients with fi bromyalgia. J Rheumatol. and after treatment with tramadol/acetaminophen. Arthritis 2008;35(3):502-514. Rheum. 2005;53:519-527. 21. Crofford LJ, Mease J, Simpson SL, et al. Fibromyalgia relapse 31. Arnold LM, Hess EV, Hudson JI, et al. Randomized, placebo- evaluation and effi cacy for durability of meaningful relief controlled, double-blind, fl exible-dose study of fl uoxetine (FREEDOM): a 6-month, double-blind, placebo-controlled in the treatment of women with fi bromyalgia. Am J Med. trial with pregabalin. Pain. 2008;136(3):419-431. 2002;112:191-197. 22. Pregabalin [package insert]. New York, NY: Pfi zer, Inc.; 2004. 32. Dwight MM, Arnold LM, O’Brien H, et al. An open clinical 23. Arnold LM, Pritchett YL, D’Souza DN, et al. Duloxetine for trial of venlafaxine treatment of fi bromyalgia. Psychosomatics. the treatment of fi bromyalgia in women: pooled results from 1998;39:14-17.

Current Psychiatry 50 March 2009

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