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4 Treatment for Chronic Multisymptom Illness This chapter assesses the evidence on interventions for treatment for symptoms associated with, or that define, chronic multisymptom illness (CMI). The 38 studies and nine systematic reviews (described in 51 manu- scripts) reviewed were found in the systematic search detailed in Chapter 3 for treatments of multiple physical symptoms associated with CMI. A nar- rative synthesis of the evidence is presented here by type of treatment: phar- macologic treatments and other biologic interventions, psychotherapies, mind–body approaches (including biofeedback, cognitive rehabilitation therapy, and complementary and alternative therapies), and exercise inter- ventions. The committee looked for evidence of efficacy or effectiveness1 of interventions in alleviating symptoms and improving quality of life in all populations affected by multiple symptoms or syndromes similar to CMI. This chapter also includes the committee’s evaluation of the body of evidence on each treatment on the basis of the Agency for Healthcare Research and Quality (AHRQ) strength-of-evidence grading (Owens et al., 2010) and conclusions about the effectiveness of the evaluated treatments. The committee did not limit its investigation to particular types of treatments but rather chose to evaluate all treatments on which there was evidence. The treatments considered varied widely and included non- traditional medicine, such as complementary and alternative medicine, 1  Efficacy is benefit from an intervention under the best possible conditions, such as in a randomized controlled trial in which a selected sample of a specific population is carefully monitored by physicians, whereas effectiveness is benefit in real life as shown by many types of research studies (Agency for Healthcare Research and Quality, 2011). 37

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38 GULF WAR AND HEALTH psychologic therapies, and stress-management techniques. The committee also considered various outcomes, including symptoms, functioning, qual- ity of life, health care use, and harms. Although the symptoms of CMI are physical, the committee embraced the need for a “whole-person” approach because of the complexity of CMI and its potential comorbidities. The nontraditional treatments were included in an effort to identify potentially effective pathways for treatment of the whole person instead of focusing on each specific symptom. Only three studies that were identified were conducted in samples of veterans. Each reported the effects of a different intervention: cognitive rehabilitation therapy (Jakcsy, 2002), doxycycline (Donta et al., 2004), and cognitive behavioral therapy (CBT) and exercise (Donta et al., 2003; Guarino et al., 2001; Mori et al., 2006). The veteran populations were generally male (85% in Donta et al., 2003, and Mori et al., 2006; 86% in Donta et al., 2004, and 50% in Jakcsy, 2002), and the average age ranged from 37.5 years (Jakcsy, 2002) to 40.7 years (Donta et al., 2004). The committee considers those studies with others of similar interventions but different populations below. The committee believed it necessary to consider additional evidence so that it could offer recommendations about the best treatment and man- agement approaches for veterans who have CMI. Thus, the recommen- dations presented in Chapter 8 result from careful consideration of the evidence presented in the present chapter, evidence on the best treatments for comorbid and related conditions in Chapter 5, and issues surrounding ­ patient care and communication in Chapters 6 and 7. PHARMACOLOGIC INTERVENTIONS People who have many of the conditions described in this report are treated with pharmacologic agents that are also used to treat for other con- ditions. Often, the mechanisms of action of the pharmacologic agents are unknown. For example, patients who have fibromyalgia may benefit from duloxetine, which works independently of depression (which duloxetine ­ is often prescribed for). Such agents include selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors (for example, duloxetine), tricyclic medications (for example, amitriptyline), mono- amine oxidase inhibitors (for example, phenelzine), dopaminergic blockers (for example, haloperidol), anxiolytics (for example, ­ enzodiazepines), b and medications that potentiate gaba-ergic transmission (for example, g ­abapentin), potentiate binding of voltage-gated calcium channels (for example, pregabalin), and potentiate voltage-dependent sodium channels (for example, topiramate). Analgesic medications include nonsteroidal anti- inflammatory analgesics, acetaminophen, opioid analgesics, and tramadol,

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TREATMENT FOR CHRONIC MULTISYMPTOM ILLNESS 39 which is serotonergic and partially binds to the mu-opiate receptor. Because of the variety of effects of these pharmacologic agents and their varied biologic targets, the committee considered the evidence on specific agents rather than broad classes. The committee reviewed 11 studies: nine clinical studies and two sys- tematic reviews. Of the clinical trials, five were randomized (Donta et al., 2004; Han et al., 2008a; Kroenke et al., 2006; Muller et al., 2008; Volz et al., 2000), six were blinded (Altamura et al., 2003; Donta et al., 2004; Han et al., 2008a; Kroenke et al., 2006; Muller et al., 2008; Volz et al., 2000), and three were pre–post2 studies (Garcia-Campayo and S ­ anz-Carrillo, 2002; Han et al., 2008b; Menza et al., 2001). Six of the clini- cal trials included agents typically known as antidepressants (­ irtazapine, m venlafaxine, nefazodone, escitalopram, paroxetine, and opipramol), one an anti­ sychotic (sulpiride), one an anticonvulsant (topiramate), and one p an antibiotic (doxycycline). Most of the pharmacologic studies were limited by a high number of dropouts in both treatment and placebo arms. Only one study involved the veteran population (Donta et al., 2004); it was the only study that used a nonpsychopharmacologic intervention (doxycycline), and it did not demonstrate efficacy. The other eight studies enrolled people in the general population, most of them female, who had somatoform disorder variously described as multisomatoform disorder, undifferentiated somatoform dis- order, and somatization disorder. Two studies excluded patients who had comorbid major depressive disorder, social anxiety disorder, or generalized anxiety disorder but used anxiolytics, alprazolam, or lorazepam in over 50% of the subjects in addition to the medications being assessed (Han et al., 2008a,b). The generalizability of studies of nonveteran populations to the veteran population is unclear. In all the studies except the doxycycline study (Donta et al., 2004), the authors concluded that there may be benefit from specific drug interventions but that future research should include larger cohorts of patients and fixed doses of medications. The evidence is limited by small sample sizes, high dropout rates, and potentially confounding effects of depression and anxiety. The influence of pharmaceutical manufacturers, who funded or employed the authors of several of the clinical trials, may have affected the reported results (Altamura et al., 2003; Donta et al., 2004; Han et al., 2008a; Kroenke et al., 2006; Menza et al., 2001). Publication bias may also be an issue if it limited the evidence available for consideration by the committee. Regarding the risk of bias in each study, the committee judged four of the studies (Donta et al., 2004; Kroenke et al., 2006; Muller et al., 2008; 2  Pre–post is used to describe clinical study designs where pre-intervention measures are compared to post-intervention measures.

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40 GULF WAR AND HEALTH Volz et al., 2000) to be at low risk for bias and five to be at high risk (Altamura et al., 2003; Garcia-Campayo and Sanz-Carrillo, 2002; Han et al., 2008a,b; Menza et al., 2001). The two systematic reviews were of relatively good quality. A review by Sumathipala et al. (2007) was particularly relevant in that the studies reviewed focused on adults who had medically unexplained symptoms and excluded symptom syndromes such as chronic fatigue syndrome (CFS), fibro- myalgia, and irritable bowel syndrome (IBS). The studies that were reviewed were limited by high dropout rates, focus on short-term outcomes, and use of varied methods but did indicate support for antidepressants. A review by Kroenke (2007) noted that pharmacologic studies were limited by short follow-up and included drugs that are not available in the United States. On the basis of guidance provided by AHRQ (Owens et al., 2010), the committee rated the strength of evidence as shown in Table 4-1 and concluded that • There is insufficient strength of evidence to determine the effective- ness of paroxetine, nefazodone, and opipramol in people who have somatoform disorders. • There is low strength of evidence that venlafaxine, escitalopram, levosulpiride, and topiramate improved symptoms in people who had somatoform disorders. • There is high strength of evidence that doxycycline is not effective in improving symptoms and functioning in veterans who have CMI (referred to as Gulf War illnesses in Donta et al., 2004). Each of the studies on pharmacologic interventions is summarized in Table 4-2. Clinical trials are presented first, followed by systematic reviews. OTHER BIOLOGIC INTERVENTIONS Fontani et al. (2011) studied the use of noninvasive radioelectric asym- metric conveyer brain stimulation (REAC-BS) to treat for pain and physical problems related to stress. REAC-BS is a series of painless electric pulses applied to specific reflex auricular points. The authors found that patients treated with REAC-BS reported fewer pain and physical symptoms after treatment after a 4-week treatment cycle than those treated with a placebo. The study was limited because there was a lack of follow-up and because the dose was not standardized but varied on the basis of patient response. Patients may have been able to sense the stimulations and deduce their allocation to the treatment or placebo group. The clinical significance of pre–post score change from 122 to 96 on the psychologic stress measure questionnaire is unclear (Fontani et al., 2011).

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TREATMENT FOR CHRONIC MULTISYMPTOM ILLNESS 41 TABLE 4-1  Strength of Evidence on Pharmacologic Interventions No. Studies Strength of (No. Subjects) RoB Consistency Directness Precision Evidence Venlafaxine   RCT: 2 (207)a High Consistent Indirect Imprecise Low Paroxetine   Pre–post: 1 (22)b High N/A Indirect Imprecise Insufficient Nefazodone   Pre–post: 1 (15)c High N/A Indirect Imprecise Insufficient Escitalopram   RCT: 1 (31)d Low N/A Indirect Imprecise Low Opipramol   RCT: 1 (208)e Unclear N/A Indirect Imprecise Insufficient Levosulpiride   RCT: 1 (74)f High N/A Indirect Imprecise Low Topiramate   Pre–post: 1 (35)g High N/A Direct Imprecise Low Doxycycline   RCT: 1 (491)h Low N/A Direct Precise Highi NOTES: RCT = randomized controlled trial; RoB = risk of bias. aHan et al., 2008a; Kroenke et al., 2006. bHan et al., 2008b. cMenza et al., 2001. dMuller et al., 2008. eVolz et al., 2000. fAltamura et al., 2003. gGarcia-Campayo and Sanz-Carrillo, 2002. hDonta et al., 2004. iNo beneficial effect was found in the study. On the basis of guidance provided by AHRQ (Owens et al., 2010), the committee rated the strength of evidence as shown in Table 4-3 and found that there was insufficient evidence to draw conclusions about the effective- ness of REAC-BS in treating for CMI. Details of Fontani et al. (2011) are summarized in Table 4-4. PSYCHOTHERAPIES Cognitive Behavioral Interventions The committee reviewed five individual CBT studies and five group CBT studies that assessed CBT for patients who presented with somatic symptoms. Somatic-focused CBT, reviewed below, is not general CBT but rather targets somatic symptoms directly and includes relaxation and activ- ity components.

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42 GULF WAR AND HEALTH TABLE 4-2  Pharmacologic Interventions Study Type Intervention Population Altamura et al., 2003 RCT, Levosulpiride 50 mg/ 64.9% female, mean age crossover day vs placebo for 4 38.1 years Somatoform disorders weeks. N levosulpiride = 37 Italy N placebo = 37 Donta et al., 2004 RCT Doxycycline 200 mg/ 14% female, mean age day vs identically 41 years Veterans with Gulf matched placebo War veterans illness capsules for 12 N screened = 2,712 and positive for months. N doxycycline = 245 mycoplasma DNA N placebo = 246 US VA and DOD medical centers Garcia-Campayo and Pre–post Topiramate starting 68.6% female, mean age Sanz-Carrillo, 2002 at 50 mg, increased 41.8 years by 50 mg every 4 Multisomatoform days to a maximum N screened = 84 disorder of 300–400 mg N enrolled = 35 (150–200 mg bi-daily) Zargoza, Spain or until adverse event occurred; trial lasted 6 months; dose averaged 365.7 mg (range 300–400 mg). Han et al., 2008a RCT Venlafaxine vs 61% female, mean age mirtazapine. 45 years Undifferentiated Venlafaxine starting at somatoform disorder 37.5 mg/day, increased N venlafaxine = 45 each week by 37.5–75 N mirtazapine = 50 Ansan, Korea mg/day to maximum of 225 mg/day. Mirtazapine starting at 15 mg/day, increased by 15 mg/ day to maximum of 60 mg/day. Both were adjusted for tolerability and clinical response. Conducted over 12 weeks.

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TREATMENT FOR CHRONIC MULTISYMPTOM ILLNESS 43 Outcomes and Results After treatment, levosulpiride patients reported fewer symptoms (measured by CISSD-SDS) compared with baseline (1,709 vs 1,205 symptoms, p = 0.007) and compared with placebo at 4 weeks (1,205 vs 1,597 symptoms, p < 0.001). No difference between treatments in anticholinergic or neuroendocrine side effects reported; extrapyramidal system involvement was reported more frequently by levosulpiride-treated patients (9 vs 2 patients, p < 0.03). After treatment, treatment and placebo groups did not differ significantly in any outcome measured. In primary outcome, physical health functioning (SF-36), treatment and placebo groups’ average scores were 30.2 and 30.1 (physical) and 37.4 and 36.2 (mental), respectively, at baseline; at 12 months, treatment and placebo groups’ average scores were 32.0 and 30.9 (physical) and 37.6 and 36.7 (mental). No differences in pain (MPQ), fatigue (MFI), or cognition (Cognitive Failures Questionnaire). After 12 months, 154 of 200 doxycycline and 159 of 211 placebo patients were negative for mycoplasma DNA. Increased adverse events considered related to study drug were myalgia in placebo group (4.5% vs 1.2%, p = 0.05), nausea in doxycycline group (37.1% vs 10.2%, p < 0.001), and photosensitivity in doxycycline group (14.7% vs 6.1%, p = 0.002); all other reported events were in the two groups. Blood doxycycline concentrations were undetectable in 38.9% of treatment-group patients and 98% of placebo-group patients at 12 months (adherence). From baseline to 6-month follow-up, improvements in severity (CGI, 3.8 to 3.3, p < 0.001) and functioning (GAF, 52.4 to 58.5, p < 0.001) were significant; no significant changes were seen in pain (pain VAS, 68.8 to 68.7; MPQ, 36.6 to 36.2) or anxiety and depression (HADS, 9.5 to 9.6). Most frequently reported side effects were somnolence (25.7%), fatigue (20%), paresthesia (14.2%), nervousness (8.5%), and nausea (5.7%). After treatment, mean somatic symptom severity scores (PHQ-15) decreased significantly for mirtazapine (–8.4, p < 0.0001) and venlafaxine (–6.1, p < 0.0001) over 12 weeks; between- group difference was significant (p = 0.046) in favor of mirtazapine. For mirtazapine, scores for psychologic distress (GHQ-12) and depression (BDI) decreased significantly between baseline and end of study (–4.9, p < 0.0001 and –13.5, p < 0.0001, respectively); for venlafaxine, psychologic distress and depression scores also decreased significantly (–4.3, p = 0.001 and –9.02, p < 0.0001) with no significant difference between groups. Adverse effects reported by participants were dry mouth in both groups; somnolence, yawning, and dizziness in mirtazapine group; and nausea in venlafaxine group. continued

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44 GULF WAR AND HEALTH TABLE 4-2  Continued Study Type Intervention Population Han et al., 2008b Pre–post Paroxetine 59% female, mean age Immediate Release 37.4 years Undifferentiated (IR) administered somatoform disorder starting at 10 mg/ N screened = 43 day and increased N enrolled = 22 Ansan, Korea to a maximum of 40 mg/day on basis of patient’s response over 8 weeks; average dose was 19.5 mg/day (range 10–40 mg/day). Kroenke et al., 2006 RCT Venlafaxine ER vs 80% female, mean age placebo. Capsules 47 years Multisomatoform given once a day in disorder following doses: week N screened = 231 1 = 75 mg; week 2 = N venlafaxine ER = 55 USA 150 mg; weeks 3–12 = N placebo = 57 225 mg. Dose was decreased to tolerable level for participants who experienced intolerance. Conducted over 12 weeks, with up to 2 weeks of taper. Menza et al., 2001 Pre–post Nefazodone 86% female, mean age administered starting 48.6 years Somatization disorder at 50 mg bi-daily, increased to 100 mg N screened = 46 Piscataway, bi-daily after first N enrolled = 15 New Jersey week, increased to 150 mg bi-daily in weeks 2–8.

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TREATMENT FOR CHRONIC MULTISYMPTOM ILLNESS 45 Outcomes and Results After treatment, average symptom severity (PHQ-15) score dropped significantly, by 75%, from 17.2 to 4.3 (p = 0.001) between baseline and 8 weeks. Average depression (BDI) scores also decreased significantly, 50.8% (p < 0.001), and average psychologic distress (GHQ-12) scores decreased by 13%, but difference was not significant. Most common adverse events reported were nausea, dry mouth, and somnolence. After treatment, both treatment and placebo groups had significant (p < 0.0001) decrease in somatic symptoms (PHQ-15 change of –8.3 and –6.6 respectively) but no significant difference between groups (p = 0.097). From baseline to 12 weeks, greater improvement was seen in Venlafaxine ER participants than in those who received placebo for pain (PHQ- 15 pain subscale, –3.3 and –2.6, respectively, p = 0.03), psychic anxiety (HAM-A, –8.6 and –5.9, respectively, p = 0.02), clinical improvement (CGI-Improvement, –1.8 and –1.4, respectively, p = 0.009), physical symptoms (MQOL Physical symptoms, –11.7 and –6.0, respectively, p = 0.01), mental health (SF-36, 28.6 and 16.8, respectively, p = 0.03), bodily pain (SF-36, 26.1 and 14.5, respectively, p = 0.03), and concentration (MOS-CS, 30.1 and 15.3, respectively, p = 0.007). Significant (p ≤ 0.001) improvement from baseline to week 12 was noted for several measures without difference between groups (depression, HAM-D; HAM-A total score and HAM-A somatic anxiety score; CGI-Severity score; and SF-36 physical health score). Percentage of patients reporting bothersome headache and stomach pain symptoms decreased significantly more in venlafaxine ER than in placebo-treated patients (both p = 0.03). Venlafaxine ER–treated participants reported more adverse effects than placebo; more than 10% of venlafaxine ER patients reported nausea, headache, fatigue, dizziness, constipation, and tremor. 11 of 15 patients who completed study showed nonsignificant improvement by 24% in symptom severity on VAS after 8 weeks of treatment compared with baseline. From baseline to week 8, 73% of participants showed improvement on CGI (significance not noted), and 73% showed significant improvement in functioning (SF-36, p < 0.025). Significant improvement in depression (p < 0.005) and cognitive and somatic subscales (both p < 0.025) of HAM-D and HAM-A were reported, but there was no correlation with VAS, CGI, or SF-36 score. Most common adverse effects were sedation, GI discomfort, anxiety, and dry mouth. continued

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46 GULF WAR AND HEALTH TABLE 4-2  Continued Study Type Intervention Population Muller et al., 2008 RCT Escitalopram vs 90% female, mean age placebo. Administered 40 years Multisomatoform at 10 mg/day and disorder could be increased to N screened = 60 20 mg/day after week N escitalopram = 25 Cape Town, South 4 (dose decreased N placebo = 26 Africa to 10 mg/day for intolerance). Dosage was constant for weeks 8–12; after 12 weeks, dosage was tapered and stopped over 1 week. Entire study took place over 18 months. Volz et al., 2000 RCT Opipramol vs placebo. 64% female, mean age Started at 50 mg/day, 46 years Somatoform disorders increased by 50–200 (ICD-10 codes F45.0, mg/day on day 4. N opipramol = 104 F45.1, F45.3) Number of placebo N placebo = 104 capsules was identical Germany with number of opipramol capsules. Treatment lasted 6 weeks. Systematic Reviews Kroenke, 2007 Systematic Multiple N RCTs = 34 review Somatoform disorders Sumathipala, 2007 Systematic Multiple N abstracts screened review = 368 Somatoform disorders N systematic reviews =6 N RCTs = 14

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TREATMENT FOR CHRONIC MULTISYMPTOM ILLNESS 47 Outcomes and Results After treatment, symptom severity (PHQ-15) scores in treatment group decreased significantly more than in placebo group (14.6 vs 17.3 at baseline and 5.6 vs 12.5 at 12 weeks, respectively, p < 0.0001). Clinical improvement (CGI-Improvement, treatment: 3.0 to 1.6 vs placebo: 3.4 to 3.2, at baseline and 12 weeks, respectively) and severity (CGI- Severity, treatment: 4.5 to 2.6 vs placebo: 4.7 to 4.1, at baseline and 12 weeks, respectively) also showed significant improvement in treatment subjects (p < 0.05). Likewise, escitalopram showed improvement on somatic anxiety (HAM-A somatic subscore, p < 0.0001, and HAM-A psychic subscore, p = 0.0002), depression (MADRS, p = 0.017), and disability (SDS, p = 0.015) scores after 12 weeks compared with placebo. No difference between treatment and placebo in illness behavior (SAIB) was detected. After 12 weeks, 80% of treatment and 26.9% of placebo subjects met criteria for being responsive to treatment, and 52% of treatment and 3.8% of placebo subjects met criteria for remission. Most common adverse events were headache, nausea, and abdominal discomfort in first 2 weeks and headache, nasopharyngitis, and diarrhea in weeks 2–12, with no significant differences between treatment and placebo groups in reported adverse events. Average dose was 14.4 mg of escitalopram per day and 18.1 mg of placebo per day. After treatment, anxiety scores decreased significantly more in opipramol group than in placebo group for somatic anxiety (HAM-A somatic subscore, 16.8 to 7.3 vs 16.9 to 9.1, p = 0.013) and total anxiety (HAM-A, 25.1 to 11.8 vs 25.3 to 14.5, p = 0.013), and decrease in psychic anxiety score was nearly significant (HAM-A psychic subscore, 8.3 to 4.5 vs 8.4 to 5.4, p = 0.052). Scores followed same trend with greater decrease in opipramol group and in placebo group for depression (HAM-D, 14.6 to 8.0 vs 14.3 to 9.5, p = 0.006) and for symptoms (SCLR-90-R, 0.95 to 0.57 vs 0.77 to 0.55, p = 0.041), including somatic symptoms (1.61 to 0.93 vs 1.40 to 0.98, p = 0.043) and anxiety symptoms (1.15 to 0.63 vs 0.94 to 0.64, p = 0.049). Adverse events were reported by 37% of opipramol patients and 38% of placebo patients— gastrointestinal complaints in 7.1% of opipramol patients and 20.8% of placebo patients and musculoskeletal complaints in 14% of opipramol patients and 7% of placebo patients. Tiredness occurred more frequently in opipramol group than in placebo group (9% vs 2%). Positive results for at least one outcome (symptoms, functional, or psychologic) were noted in 11 of 13 CBT studies and 4 of 5 antidepressants studies, and 8 of 16 studies of other interventions reported improvement—consultation letter to primary care physician (4 studies), primary care physician training (2 studies), and non-CBT psychotherapies (2 studies), hypnosis (2 studies), and one study each investigating multicomponent nurse-care management, aerobic exercise, writing disclosure, paradoxic intention, and explanatory therapy. CBT is most effective for variety of somatoform disorders and outcomes. Studies assessed interventions with antidepressants (1 review and 3 RCTs), CBT (5 reviews and 2 RCTs), psychiatric consultation (3 RCTs), other forms of psychotherapy (3 RCTs), exercise (2 RCTs), and collaborative care (1 RCT). Studies have many limitations and varied methods, so interventions cannot be compared. Authors note support for antidepressants and CBT and limited evidence on other interventions. continued

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82 GULF WAR AND HEALTH TABLE 4-12  Continued Study Type Intervention Population Payne and Stott, 2010; Pre–post BMA with DMP. 83% of participants Payne, 2009 Four parts comprising female, mean age 48 4 sessions lasting 2 years MUS hours each for 12 weeks. N screened = 31 United Kingdom N enrolled = 18 Volz et al., 2002 RCT SJW vs control. 72% of treatment group Participants received female, mean age 46.9 Somatoform disorders placebo or SJW years; 62% of placebo tablets twice daily for group female, mean age Germany 6 weeks. SJW was 48.6 years administered as 300- mg tablets. N treatment = 75 N control = 74 Yamada et al., 2005 Pre–post Kampo (with 74% of participants supportive female, mean age 47.1 USD and CD psychotherapy). years; 94 met criteria Duration of treatment for USD, 26 criteria Japan 3 months. for CD N = 120 NOTES: BE = bioenergetic exercise; BMA = body–mind approach; CD = conversion dis­ order; CGI = Clinical Global Impressions Scale; CORE-OM = Counseling Outcome Routine­ E ­ valuation–Outcome Measure; DMP = dance-movement psychotherapy; EQ-5D = EuroQol ­ health status questionnaire; ES = effect size; HAM-A = Hamilton Anxiety Rating Scale; MUPS = medically unexplained physical symptoms; MUS = medically unexplained symptoms; MYMOP = Measure Yourself Medical Outcome Profile; SCL-90-R = Symptom Checklist-90-­ Revised; SJW = St. John’s wort (Hypericum); SOMS-7 = Screening for ­ omatoform ­ ymptoms-7; S S STAXI = State-Trait Anger Expression Inventory; USD = undifferentiated somatiform disorder; ­ W-BQ12 = 12-Item Well-Being Questionnauire; WHOQoL-BREF = World Health Organization Quality of Life Scale Brief Version.

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TREATMENT FOR CHRONIC MULTISYMPTOM ILLNESS 83 Outcomes and Results At 3-month follow-up, significant mean changes (CORE-OM, baseline to follow-up) were reported for well-being –0.76 (95% CI –1.15 to –0.38), p < 0.001, ES = 0.72; problems –0.70 (95% CI –1.13 to –0.26), p < 0.004, ES = 0.65; function –0.54 (95% CI –0.93 to –0.14), p < 0.011, ES = 0.58; risk –0.15 (95% CI –0.38 to 0.09), p < 0.204, ES = 0.31; all nonrisk –0.64 (95% CI –1.03 to –0.25), p < 0.003, ES = 0.66; all items –0.56 (–0.90 to –0.21), p < 0.003, ES = 0.66. Significant improvements for specific symptoms were also shown (MYMOP, baseline to follow-up) for symptom one –1.7 (95% CI –2.6 to –0.8), p < 0.001, ES = 0.71; activity –2.1 (95% CI –3.4 to –0.9), p < 0.003, ES = 0.66; well-being –1.7 (95% CI –2.6 to –0.8), p < 0.001, ES = 0.71; symptom two –1.8 (95% CI –3.2 to –0.5), p < 0.012, ES = 0.67. Facilitator and participant perceptions were compared and found to be largely congruent; participants learned how their emotions are linked to physical well-being and how to avoid or cope with symptoms in different ways. At end of treatment, statistically significant differences were reported between treatment and control groups from day 0 to day 42 with regard to somatic anxiety (HAM-A somatization subscale SJW 15.39–6.64 vs placebo 15.55–11.97, p = 0.001), anxiety (HAM-A SJW 22.09–10.0 vs placebo 22.47–17.0, p = 0.0001), psychic anxiety (HAM-A psychic subscale SJW 6.71–3.36 vs placebo 6.92–5.03, p = 0.0001), depression (HAM-D SJW 10.59–5.43 vs placebo 10.80–8.08, p = 0.0001), psychic symptoms (SCL-90-R SJW 61.65–29.39 vs placebo 66.37–50.50, p = 0.0001), somatic symptoms (SCL-90-R somatization subscale SJW 15.57–6.84 vs placebo 15.95–12.50, p = 0.0001). 9 adverse events were observed in 8 participants in treatment group and 5 adverse events in 4 participants in control group. After treatment, 13 participants were “very much improved,” 37 “much improved,” 39 “minimally improved,” 9 “no change,” 1 “minimally worse,” and 1 “much worse.” Quality-of-life (WHOQoL-BREF) score improved from 3.08 at baseline to 3.21 after 3 months (p = 0.0001). Subscores also showed significant improvement in “physical health” (p = 0.0004) and “psychological health” (p = 0.0006), and nonsignificant changes were found in “social relationships” and “environment.” Adverse events were reported in 6 patients.

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84 GULF WAR AND HEALTH TABLE 4-13  Strength of Evidence on Exercise Interventions No. Studies Strength of (No. Subjects) RoB Consistency Directness Precision Evidence RCT: 2 (1,320)a Intermediate Inconsistent Indirect Imprecise Insufficient NOTES: RCT = randomized controlled trial; RoB = risk of bias. aDonta et al., 2003/Mori et al., 2006; Peters et al., 2002. TABLE 4-14  Exercise Interventions Study Type Intervention Population Donta et al., 2003; RCT CBT vs CBT + Gulf War Veterans Mori et al., 2006 exercise. deployed August 1990 CBT was 60–90 min to August 1991; 15% Gulf War Veterans’ long; groups met female, mean (SD) age Illnesses weekly for 12 weeks. 40.7 (8.7) years; 24% Aerobic exercise was with disability claim 18 VA and 2 DOD one 1-hour session medical centers per week with an N screened = 2,793 exercise therapist for N CBT + exercise = 266 12 weeks and 2 or 3 N CBT only = 286 independent sessions N exercise only = 269 per week for 12 N usual care = 271 weeks. Peters et al., 2002 RCT Aerobic exercise vs 53% female, mean age stretching, 1-hour 44 years (range 9–73), PUPS sessions twice weekly 46% employed for 10 weeks. Liverpool, United Homework: exercise N screened = 323 Kingdom or stretch for 20 min N aerobic training = 3 times weekly. 114 N stretching training = 114 NOTES: CBT = cognitive behavioral therapy; GP = General Practitioner; HADS = Hospital Anxiety and Depression Scale; MSPQ = Modified Somatic Perception Questionnaire; PUPS = persistent unexplained physical symptoms; RCT = randomized controlled trial; SD = standard ­ deviation; V/SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey for Veterans.

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TREATMENT FOR CHRONIC MULTISYMPTOM ILLNESS 85 Outcomes and Results At 12-month follow-up, physical functioning (V/SF-36): CBT + exercise adj OR = 1.84 (95% CI 0.95–3.55); CBT adj OR = 1.72 (95% CI 0.91–3.23); exercise adj OR = 1.07 (95% CI 0.63–1.82); CBT vs no CBT OR = 1.71 (95% CI 1.21–2.41); exercise vs no exercise adj OR = 1.07 (95% CI 0.76–1.50). Mean change from baseline: CBT 0.59, CBT + exercise 1.03, exercise 0.97. Exercise alone or in combination with CBT significantly improved fatigue, cognitive symptoms, mental health functioning; CBT alone significantly improved cognitive symptoms and mental health functioning, p < 0.025. Neither had significant impact on pain. In treatment phase, 44.9% in exercise group and 40.2% in CBT + exercise group complied (p = 0.28); in maintenance phase, 24.9% of exercise and 21.1% of CBT + exercise patients complied (p = 0.29). 6 months after training, aerobic exercise and stretching resulted in improvement from baseline with fewer symptoms recorded by GP; fewer GP consultations; fewer prescriptions; fewer secondary-care contacts; and fewer new referrals to secondary care (all p < 0.01). Anxiety and depression (HADS) and somatization (MSPQ) declined from start of program to 6-month follow-up (all p < 0.01). Reported life interference, energy, mental health, and social function improved from randomization to 6-month follow-up (all p < 0.001). No significant changes were noted in SF-36 scores. Most improvement occurred during training and did not continue in 6 months after. No significant difference between effects of stretching and aerobic exercise on any variable. Regression models show that treatment attendance significantly reduced visits to GPs (p < 0.001), number of prescriptions (p < 0.01), number and type of prescription refills (p < 0.001) from start of treatment to 6-month follow-up but was not related to measures of symptoms and somatization.

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86 GULF WAR AND HEALTH evidence had methodologic limitations and biases that may have masked true treatment effects, and there was great diversity in study populations, types of interventions conducted, controls used, and types of outcomes assessed and measures used. Study quality was generally poor, and samples were small (from 10 to 1,092 participants, median 87, mean 150), and many studies had high dropout rates. Most of the studies reviewed were subject to multiple sources of bias or did not clearly describe methods, and this resulted in a high pro- portion of studies at high or unclear risk of bias. Confounding diagnoses, such as depression and anxiety, may affect the magnitude of treatment effect and were not examined. For example, using an antidepressant to treat patients who have CMI with minor depression may improve symptoms because of changes in mood rather than changes in CMI symptoms. Some of the studies attempted to avoid that problem by excluding people who met diagnostic criteria for some psychiatric disorders or medical illnesses, but subsyndromal or undiagnosed conditions may have remained in study samples. The heterogeneous nature of the literature limited the committee’s abil- ity to compare the efficacy of different interventions. With the exception of CBT, each intervention was the subject of only a few studies that evaluated its efficacy. The study populations were defined in different ways; some studies examined only a few symptoms not explained by medical illness, and others required diagnosis of a specific disorder for various durations and of various degrees of severity. Methods differed greatly as well: there were few blinded RCTs, and many clinical trials were influenced by varied sources of bias. The literature also used a variety of outcomes to define treatment success—such as number of symptoms, severity of symptoms, health care use, functional improvement, and changes in mood—and this made comparison difficult in that different studies used different outcomes. In addition, the numerous outcomes were measured in different ways with different tools, so comparability of studies was limited further. Generalizability among the populations studied is questionable. Only three studies were conducted in military or veteran populations. Almost all the other study samples were dominated by middle-aged women. Thus, it is difficult to extrapolate the efficacy and acceptability of an intervention to the veteran population of interest, which is slightly younger on the average and mostly male. Adverse effects of pharmaceuticals are typically reported, but other types of interventions may have harmful effects that are not identified or investigated. The method of adverse-event reporting may be important; use of a standardized list of adverse events may cause study participants who are suggestible (such as people who are seeking psychologic health

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TREATMENT FOR CHRONIC MULTISYMPTOM ILLNESS 87 care) to report more events than they would have otherwise (Kroenke and Rosmalen, 2006). Length of follow-up was variable, although generally short, ranging from 1 week to 18 months (median 3 months) between the start of a study and the last assessment. Many studies collected data only immediately after treatment, whereas others assessed the effect of treatment many months after treatment had ceased. The committee’s recommendations—based on the weight of the evi- dence described above, treatments for comorbid and other related condi- tions (Chapter 5), and issues related to patient care and communication (Chapters 6 and 7)—are presented in Chapter 8. REFERENCES Abbass, A., S. Campbell, K. Magee, and R. Tarzwell. 2009a. Intensive short-term dynamic psychotherapy to reduce rates of emergency department return visits for patients with medically unexplained symptoms: Preliminary evidence from a pre-post intervention study. Canadian Journal of Emergency Medical Care 11(6):529-534. Abbass, A., S. Kisely, and K. Kroenke. 2009b. Short-term psychodynamic psychotherapy for somatic disorders: Systematic review and meta-analysis of clinical trials. Psychotherapy and Psychosomatics 78(5):265-274. AHRQ (Agency for Healthcare Research and Quality). 2011. Effective Health Care Pro- gram. Glossary of Terms. http://effectivehealthcare.ahrq.gov/index.cfm/glossary-of-terms/ ( ­accessed July 1, 2012). Aiarzaguena, J. M., G. Grandes, I. Alonso-Arbiol, J. L. del Campo Chavala, M. B. Oleaga Fernandez, and J. Marco De Juana. 2002. Bio-psychosocial treatment approach to s ­ omatizing patients in primary care: A pilot study. Atencion Primaria 29(9):558-561. Allen, L. A., J. I. Escobar, P. M. Lehrer, M. A. Gara, and R. L. Woolfolk. 2002. Psychosocial treatments for multiple unexplained physical symptoms: A review of the literature. ­ sychosomatic Medicine 64(6):939-950. P Allen, L. A., R. L. Woolfolk, J. I. Escobar, M. A. Gara, and R. M. Hamer. 2006. Cognitive- behavioral therapy for somatization disorder: A randomized controlled trial. Archives of Internal Medicine 166(14):1512-1518. Altamura, A. C., A. Di Rosa, A. Ermentini, G. P. Guaraldi, G. Invernizzi, N. Rudas, G. T ­ acchini, R. Pioli, M. T. Coppola, V. Tosini, E. Proto, E. Bolognesi, and B. Marchio. 2003. Levosulpiride in somatoform disorders: A double-blind, placebo-controlled cross- over study. International Journal of Psychiatry in Clinical Practice 7:155-159. Arnold, I. A., M. W. de Waal, J. A. Eekhof, W. J. Assendelft, P. Spinhoven, and A. M. van Hemert. 2009. Medically unexplained physical symptoms in primary care: A controlled study on the effectiveness of cognitive-behavioral treatment by the family physician. Psychosomatics: Journal of Consultation Liaison Psychiatry 50(5):515-524. Barrios-Choplin, B., R. McCraty, and B. Cryer. 1997. An inner quality approach to reduc- ing stress and improving physical and emotional wellbeing at work. Stress Medicine 13(3):193-201. Bleichhardt, G., B. Timmer, and W. Rief. 2004. Cognitive-behavioural therapy for patients with multiple somatoform symptoms: A randomised controlled trial in tertiary care. Journal of Psychosomatic Research 56:449-454.

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