Fibromyalgia: Combining Pharmacological and Nonpharmacological Approaches to Treating the Person, Not Just the Pain

The Journal of Pain, Vol 9, No 2 (February), 2008: pp 99-104 Available online at www.sciencedirect.com

Case Reviews in Pain Fibromyalgia: Combining Pharmacological and Nonpharmacological Approaches to Treating the Person, Not Just the Pain Dennis C. Turk, Charles J. Vierck, Elizabeth Scarbrough, Leslie J. Crofford, and Nathan J. Rudin

Editor’s Note: This article is one in a series of “Case Reviews in Pain” to be presented by The Journal, designed to share scientific and clinical knowledge in a case review format. This report presents a discussion of a 42-year-old woman with fibromyalgia after 18 months of severe pain that followed an automobile accident.

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42-year-old woman experienced 18 months of severe pain after an automobile accident. Her car was rear-ended and she received a whiplash injury. The location of the pain spread from her neck to multiple areas of her body, and she had been diagnosed with fibromyalgia. She also reported frequent headaches, tingling in her fingers and toes, difficulty sleeping, trouble concentrating, and chronic fatigue even when she had a good night’s sleep. Almost any activity made her pain worse. She had no history of any chronic medical conditions, nor a history of psychiatric treatment. She had numerous diagnostic evaluations for her current symptoms, but no positive findings were identified. Prior treatments included oxycodone for pain initiated 2 days after the accident and a series of physical therapy treatments that consisted primarily of heat and massage. She took fluoxetine for depression for the last 8 months. She walks slowly and in a very stiff fashion. Her head movements are limited and she pivots her body rather than turning her head to talk. She reports that she has gained about 17 pounds since the accident and has become very inactive because movements make her pain worse. She states that her pain ranges from 5 to 10 on an 11-point scale. Physical examination revealed significant restriction in cervical range of motion and some general physical deconditioning. No joint swelling or tenderness was ob-

Address correspondence to Judith A. Paice, PhD, RN, Editor, Case Reviews in Pain; Director, Cancer Pain Program, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611. E-mail: J-Paice@ northwestern.edu 1526-5900/$34.00 © 2008 by the American Pain Society doi:10.1016/j.jpain.2007.08.006

served. The results of all imaging procedures were unremarkable. Laboratory tests did not identify any positive rheumatological findings. On the manual tender point survey, she had 16 positive tender points and was positive on the 3 control points. Her total pain severity score was 138 (range: 18 –180) and the average tender point severity was 8.6. Indications of the regions of pain on the “figure drawing” were in all 4 quadrants and axial. She met the 2 American College of Rheumatology criteria for the diagnosis of fibromyalgia. The pain had been severe enough to disrupt all aspects of her life (occupational, social, familial, and recreational) and she stated that her life had “collapsed.” She was spending her days lying down and reported that pain does not permit her to get a good night’s sleep. Consequently, she never feels rested and is fatigued most of the time. The expenses of her medication and medical treatments have drained the family’s finances and eliminated vacations and other pleasurable family activities. She has no interest in any previously enjoyed activities or sex. She just wants to be “left alone.” Dennis C. Turk, PhD John and Emma Bonica Professor of Anesthesiology and Pain Research Department of Anesthesiology University of Washington Seattle, WA

Mechanism-Based Therapeutic Considerations for Fibromyalgia Pain Whiplash injury often results in pain localized to traumatized tissue and then, with chronicity, symptoms of the fibromyalgia syndrome (FMS) develop. There is substantial experimental evidence for bidirectional interactions between the periphery and the central nervous system that can establish FMS in this manner.33 Chronic focal pain of peripheral origin sensitizes central nociceptive projection systems and activates limbic circuits, 99

100 which drive the hypothalamic-pituitary-adrenal axis (HPA) and sympathetic nervous system as part of the stress reaction. Stress has central hyperalgesic effects22 and generates sympathetic output, which acts back on the periphery to produce widespread peripheral vasoconstriction and eventuate in widespread muscular ischemia. Nociceptors in deep tissues are sensitized and can even be activated by ischemia, generating hyperalgesia and muscular pain that extend well beyond the distribution of the whiplash pain. This peripheral sensitization can be demonstrated by palpation of deep tissues in the standard tender point examination for FMS. Sensitized muscular nociceptors respond to mild trauma, including exercise, accounting for referral of FMS pain to deep tissues in regions that differ in time in relation to recent activity or muscular tension. Tonic peripheral vasoconstriction and muscular ischemia are particularly robust for females, and FMS predominates among women. Raynaud’s syndrome, involving signs of peripheral vasoconstriction, is similarly prevalent among women and often is associated with FMS. Within deep tissues, not only nociceptors but also ergoreceptors are sensitized by ischemia. Ergoreceptor activation provides the sense of muscular fatigue, which is exaggerated for most FMS patients. Loss of sleep can be explained by the arousing effect of chronic nociceptive input and stress effects on sleep regulation. Also, depression is a predictable consequence of chronic pain and stress. These are the essential characteristics of FMS that must be dealt with therapeutically. A principal option for treatment of FMS has involved administration of an antidepressant (AD). Beneficial AD effects have been reported for mood and sleep,5,17 which are important therapeutic goals, improving active attempts of a patient to deal with their pain and overcome fatigue. However, ratings of pain are less often reduced by ADs, and hypersensitivity to tender point palpation has been reported to be spared in studies reporting attenuation of FMS pain.5,12,26 Meta-analyses have concluded that ADs have a moderate effect on FMS pain,5 but a statistical expression of efficacy has estimated that 4 patients must be treated to significantly attenuate FMS pain in one.26 A consideration for these studies is that knowledge by subjects of AD reception, based on altered mood, drowsiness with improved sleep, and agent-specific side effects is likely to affect ratings of pain and could account for differences in effect from placebo administration, regardless of double-blinding procedures. Also, beneficial effects of AD medication on FMS pain appear not to appreciably exceed effects of nonpharmacological programs of education, exercise and stress management.17 Furthermore, when moderate improvement in pain ratings occurs, it may be transient. An investigation of long-term AD administration found that differences in ratings of pain relative to placebo disappeared over months for FMS subjects.12 Antidepressants have complex effects throughout the neuraxis.25 Their principal AD effect is achieved by inhibition of reuptake of noradrenaline and/or serotonin and prolonging receptor occupancy by these transmit-

Fibromyalgia ters. However, understanding mechanisms of any AD on pain processing are obscure because 1) serotonin and noradrenaline activate numerous receptors (at least 10 for serotonin and 8 for noradrenaline) within complex central systems of influence over mood, stress, sympathetic tone, and pain sensitivity, 2) occupation of postsynaptic receptors and presynaptic autoreceptors by each transmitter can exert opposite effects within different components of these systems, 3) most ADs activate receptors other than noradrenaline and serotonin (eg, GABA and dopamine), either directly or indirectly, and 4) complex patterns of receptor up- and downregulation inevitably occur with chronic administration of ADs. Therefore, known mechanisms of AD actions do not uniformly predict that pain would be attenuated by these agents. For example, a central stress circuit includes the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus, where ␣1 adrenoreceptor activation is especially potent for females and during chronic stress.23 ␣1 influences of ADs on this system probably reinforce activation of the HPA by sources of stress such as chronic focal pain. However, ␣2 adrenoreceptor activation should oppose this effect,25 and chronic AD administration increases glucocorticoid receptor expression, enhancing negative feedback onto the HPA.27 Thus, adrenergic effects (and similar serotonergic influences) within cerebral stress systems both excite and inhibit the HPA, suggesting that the net effect of ADs is not to substantially excite the HPA. In addition to influences on the HPA, stress-related actions of noradrenaline and serotonin extend throughout the sympathetic nervous system, in the brain stem,20 spinal cord,16 and periphery.14,28,30,36 However, effects of AD administration on sympathetic outflow to the periphery have been neglected, relative to central effects of these agents on the HPA. A full understanding of peripheral influences is particularly important for longterm use of ADs by FMS patients who characteristically exhibit tonic sympathetic activation.32 Reduction of noradrenergic and serotonergic reuptake may not be advantageous in relation to the peripheral vasoconstriction and muscular ischemia that are commonly associated with sympathetic activation by stress, focal pain, and FMS pain.33 Effects of chronic AD administration on peripheral blood flow of chronic pain patients should be investigated thoroughly. Charles J. Vierck, PhD Department of Neuroscience University of Florida College of Medicine Gainesville, FL

Pharmacological Considerations The patient under discussion probably will need improved pharmacologic management but will also need to employ nonpharmacologic treatments to achieve symptomatic improvement (see following commentary). In evaluating effectiveness of pharmacologic treatment, one can use drugs that treat “the syndrome,” that is, use drugs that are effective across more than one of the key

CASE REVIEWS IN PAIN/Turk et al symptom domains of pain: Tenderness, fatigue, sleep disturbance, mood disorders, and other common symptoms. An alternative approach is to target a specific symptom like pain with analgesics. Drugs used to treat FMS generally target central neurotransmitters and are of the antidepressant (see above) or anticonvulsant class. However, adverse effects associated with drugs in these classes often pose treatment limitations.18

Antidepressants As noted in the previous commentary, antidepressants are the primary pharmacologic therapies used to treat FMS, despite studies that demonstrate varying degrees of efficacy. Given the lack of clarity in study outcomes, the challenge for the clinician is selecting the most appropriate agent: Tricyclic, selective serotonin reuptake inhibitors, or mixed agents. Arnold et al5 in a meta-analysis of tricyclic AD drugs found moderate effectiveness in patients with FMS. Sleep quality, tenderness, and stiffness were the most affected measures. A significant response was found in 25% to 36% of patients studied. Evidence supporting the use of selective serotonin reuptake inhibitors (SSRIs) in FMS is inconsistent. In a study of 42 patients with fibromyalgia treated over a 6-week period with fluoxetine (20 mg), no significant effect was found over placebo.35 In contrast, a randomized, placebo-controlled, double-blinded, dose-optimization trial with FMS patients found a significant difference in the Fibromyalgia Impact Questionnaire (FIQ) total score, pain score, fatigue score, and depression score when conducted over a 12-week period with doses of fluoxetine ranging between 10 and 80 mg (45 ⫾ 25 mg/d). The McGill Pain Questionnaire also differed significantly between the fluoxetine and placebo groups. Tender point and myalgic scores did not differ between the 2 treatment groups.4 Studies using even more highly selective SSRIs have not been beneficial.35 Dual-acting serotonin and noradrenaline reuptake inhibitors have been studied in patients with FMS with varying results. Ninety patients were studied in a randomized controlled trial (RCT) of venlafaxine (75 mg) versus placebo. No significant difference was found between the 2 treatment groups.37 In contrast, a doubleblinded RCT of 125 patients treated for 8 weeks with up to 200 mg twice daily of milnacipran, another dual-acting drug, found a significant difference in overall improvement compared with placebo. Twice-daily dosing also resulted in a significant decrease in pain intensity.34 Similarly, 2 multicenter RCTs comparing another dualacting agent, duloxetine, reported significant improvement in female patients in FIQ total score, FIQ stiffness, Brief Pain Inventory pain score, and number of tender points.6,7 Men were found to receive no significant effect from treatment.6 For the patient under discussion, it appears that the fluoxetine dose she is taking is insufficient to control mood or to provide adequate analgesia. With her sleep difficulties, she may benefit from changing to a tricyclic AD or adding a tricyclic AD to her SSRI. An alternative would be to replace fluoxetine with a more balanced

101 reuptake inhibitor, though the patient may still require pharmacologic treatment that improves sleep.

Anticonvulsants If patients are unable to tolerate or symptoms are insufficiently controlled by AD drugs, anticonvulsants may be used. In a recent RCT, gabapentin was shown to be effective in the treatment of FMS in daily doses between 1200 and 2400 mg, with a median dose of 1800 mg/d.3 A multicenter, double-blinded RCT of pregabalin, a drug targeting the ␣2-␦ subunit of calcium channels, 3 doses (150, 300, and 450 mg/d) were studied in an 8-week trial in 529 patients. At 450 mg/d, pregabalin had a significant effect on pain, fatigue, sleep, and health-related quality of life when compared with placebo. Side effects included dizziness, somnolence, and rarely, peripheral edema.13 A follow-up open-label, dose-optimization study examined the durability of response to pregabalin in patients who had 50% reduction of pain and described themselves as much or very much improved: Two-thirds of pregabalin responders maintained this benefit for 6 months.1 Pregabalin was recently approved by the FDA for treatment of FMS. Other anticonvulsants have not been specifically studied in FMS. In the patient under discussion, adding either gabapentin or pregabalin to her antidepressant therapy may be helpful in managing her pain as well as improving sleep.

Other Drugs A double-blinded, placebo-controlled, RCT of pramipexole, a dopamine-3 receptor agonist used in the treatment of Parkinson’s disease, reported a significant improvement in measures of pain, FIQ global status score, FIQ fatigue score, and FIQ function score when compared with placebo. Sixty patients with fibromyalgia were included in the trial using a study dose of pramipexole at 4.5 mg. A washout period was not included in the trial, and no medications were excluded from use.21 Additional medications, including atypical antipsychotic drugs and other psychoactive drugs, have been studied but the results of these trials are limited by small sample size or open designs. Analgesics have been studied in only a limited way in FMS. There is no evidence to support the use of antiinflammatory drugs in FMS, though these drugs may be helpful for management of musculoskeletal pain generators.19 There is also no evidence to support the use of opioid analgesics in patients with FMS.18 However, the centrally acting ␮-opioid agonist tramadol (which also is an inhibitor of serotonin and noradrenalin reuptake) in combination with acetaminophen was tested in a double-blinded RCT in 315 FMS patients. Tramadol-acetaminophen was reported to provide significantly better pain relief on a visual analog scale and FIQ scores of physical functioning, role-physical, body pain, health transition, and physical component summary versus a placebo-treated group.10 Nevertheless, these agents are best reserved for “as needed” use rather that routine use. A single study reported a positive effect of sodium

102 oxybate in FMS patients in a randomized, controlled trial.29 There are concerns regarding abuse liability with this drug. The patient under discussion clearly requires changes to her overall management. Given her symptoms of concomitant depression, using an effective AD regimen is essential. However, it is unlikely that controlling depression without addressing the pain and sleep complaints will be effective. For these reasons, selecting an AD regimen that provides improved analgesia and potentially adding a second AD or anticonvulsant with beneficial effects on sleep would be recommended as well. Once improved, it is essential to incorporate increased physical activity into the treatment regimen. Elizabeth Scarbrough, ARNP Leslie J. Crofford, MD Division of Rheumatology University of Kentucky Lexington, KY

Beyond Pharmacologic Therapy: Interdisciplinary Care Few people have “pure” fibromyalgia (FM), and this patient is a good example. Besides diffuse pain, her symptoms also include neck pain, headache, and limited neck motion, all likely sequelae of cervical whiplash injury. She suffers from depression, fatigue, nonrestorative sleep, and deconditioning. Potential non-FM causes of widespread pain have been appropriately excluded. While all FM sufferers report widespread pain and are diffusely tender on examination, most have musculoskeletal, psychological, or other comorbidities, necessitating comprehensive assessment and individualized treatment for each patient. This patient unfortunately has not had access to such services. She is involved in modality based physical therapy that does not address her limited motion or deconditioning. She is taking opioid analgesics despite a lack of any apparent pain relief or functional benefit. While she is appropriately taking an antidepressant, she lacks counseling or other behavioral health services. No specific treatment goals have been defined. The American Pain Society’s evidence-based FM guideline11 recommends a program including education, appropriate medications, exercise, and cognitive-behavioral treatments. Interdisciplinary pain treatment programs, which deliver this combination of interventions after comprehensive assessment, produce durable improvements in pain, function, quality of life and coping for FM patients.2,31 An interdisciplinary program would be ideal.

Education and Goal Setting Education and careful goal-setting are crucial. The patient and her family should be educated about FM and the planned treatment approach. It is important to acknowledge and accept the patient’s suffering and its impact on her life, while still reinforcing that she must be-

Fibromyalgia come actively involved in her own rehabilitation; simply being “left alone” will accomplish nothing. This is a good time to establish concrete treatment goals. There is as yet no cure for FM, and patients expecting complete pain relief are most often disappointed.15 Restoration of lost function is the primary goal of interdisciplinary pain treatment. Pain reduction is also a major goal, and should certainly be possible, but should not be promised. Specific functional goals may include reduced medication use, increased ability to perform household or work tasks, improved mood, or others.

Comprehensive Examination This patient should have further workup for her postwhiplash neck pain and motion limitation, much of which can be accomplished by an expanded physical examination. The neck should be carefully palpated with the patient both erect and supine (the latter position facilitates deactivation of the erector spinae and allows more accurate palpation of spinal structures, especially posteriorly). Facet joint or other ligamentous trauma is common in cervical whiplash9,24 but may not be detected on imaging studies. Localized facet tenderness reproducing neck pain may indicate joint trauma. Cervical traction may help alleviate neck symptoms and facilitate rehabilitation, as may image-guided medial branch block at the level of the painful facet, which can be of both diagnostic and therapeutic benefit.8 Short courses of both traditional and adjuvant analgesics may help reduce cervical pain and muscle spasm sufficiently to improve participation in rehab. Ineffective analgesics should be discontinued.

Treatment Exercise is the most highly recommended physical treatment for FM, but the best type of exercise remains controversial; both light aerobic activity and light strengthening programs have shown benefit.11 The patient should begin with basic neck range-of-motion and postural correction exercises to reduce her neck and head complaints. Light whole-body strengthening and aerobic conditioning can then be gradually introduced. (Starting at too high an exercise intensity can lead to pain flares and decreased motivation.) Heat, massage, TENS, and other therapeutic modalities are generally of short-term benefit and should be used mainly to facilitate exercise. As conditioning and function improve, simulation of home and work activities can be introduced to help return the patient toward normal function. Behavioral therapy should begin at the same time as exercise. The patient’s mood, coping style, activity, and level of interpersonal support should be carefully assessed. Cognitive-behavioral therapy helps patients identify maladaptive behaviors and develop more effective strategies. Activity diaries are helpful tools for tracking daily activity patterns and monitoring the effects of interventions. Family members should be enlisted as active partners in behavioral therapy. Members of the treatment team should communicate regularly to assess progress toward goals, adjust the

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treatment plan, and ensure delivery of consistent messages to the patient and her family. Interdisciplinary treatment ends when the patient has achieved treatment goals, has made the best possible progress toward them, or has proven unable or unwilling to achieve them despite appropriate adjustment of the treatment plan. Even after formal treatment ends, she should continue to exercise and draw upon the other skills she has learned, working in partnership with her family and her primary care provider. Reduced depression, enhanced

coping skills and better physical condition should help her to enjoy a more comfortable, satisfying and functional life.

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Nathan J. Rudin, MD, MA Orthopedics and Rehabilitation Medicine Pain Treatment and Research Center University of Wisconsin School of Medicine and Public Health Madison, WI

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