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5 Effective Treatments

Using the levels of evidence discussed in Chapter 3 as a guide for assessing effective treatments, the committee evaluated available evidence regarding the effectiveness of treatments for chronic fatigue syndrome, depression, fibromyalgia, headache, irritable bowel syndrome, panic disorder, posttraumatic stress disorder, and medically unexplained physical symptoms. Committee members reviewed clinical practice guidelines, major literature reviews, and published studies of treatments for these conditions. Randomized controlled trials were given greatest weight in making recommendations about specific treatments; other types of published studies were evaluated using the levels-of-evidence concepts described in Chapter 3.

The following material is organized by condition studied. Each provides a definition of the condition and diagnostic criteria, describes any unique factors or difficulties related to the condition, summarizes available therapies and rates them in terms of benefit, describes practice issues and approaches that are generally recognized as acceptable by the medical community, and presents committee recommendations. In the “Harms” section of each therapy, the discussion provided is not exhaustive nor is it a substitute for reading a thorough documentation of the treatment's nature.

The approaches presented here are not clinical guidelines. The Institute of Medicine (IOM) defines clinical practice guidelines as “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” (IOM 1990: 39). Rather, this chapter is an effort to extrapolate from what we



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Page 51 5 Effective Treatments Using the levels of evidence discussed in Chapter 3 as a guide for assessing effective treatments, the committee evaluated available evidence regarding the effectiveness of treatments for chronic fatigue syndrome, depression, fibromyalgia, headache, irritable bowel syndrome, panic disorder, posttraumatic stress disorder, and medically unexplained physical symptoms. Committee members reviewed clinical practice guidelines, major literature reviews, and published studies of treatments for these conditions. Randomized controlled trials were given greatest weight in making recommendations about specific treatments; other types of published studies were evaluated using the levels-of-evidence concepts described in Chapter 3. The following material is organized by condition studied. Each provides a definition of the condition and diagnostic criteria, describes any unique factors or difficulties related to the condition, summarizes available therapies and rates them in terms of benefit, describes practice issues and approaches that are generally recognized as acceptable by the medical community, and presents committee recommendations. In the “Harms” section of each therapy, the discussion provided is not exhaustive nor is it a substitute for reading a thorough documentation of the treatment's nature. The approaches presented here are not clinical guidelines. The Institute of Medicine (IOM) defines clinical practice guidelines as “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” (IOM 1990: 39). Rather, this chapter is an effort to extrapolate from what we

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Page 52know about other existing diseases and apply it to the problems suffered by Gulf War veterans. In extrapolating from specific clinical entities to the problems of Gulf War veterans, the committee chose to recommend only those specific therapies for which efficacy has been demonstrated through one or more randomized controlled trials. However, there may be situations where other approaches are used to manage these conditions. Some of these approaches are described in the “Practice Issue” sections included with each condition. While the committee has chosen to recommend only those therapies whose efficacy has been demonstrated through randomized controlled trials (RCTs), it is important to continue to evaluate these other therapies. As indicated in Chapter 3, the committee believes that it is essential to demonstrate treatment effectiveness using other approaches to study design. The committee found, however, that there are essentially no strong effectiveness studies of treatments for the selected conditions. The best currently available evidence for potential effectiveness in a population of Gulf War veterans, therefore, is strong evidence of efficacy through RCTs. CHRONIC FATIGUE SYNDROME Introduction Chronic fatigue syndrome (CFS) is a clinically defined condition characterized by severe, disabling fatigue that persists for at least six months and has a definite onset (Fukuda et al. 1994). Appendix C provides a discussion of unique considerations in CFS. The symptoms include self-reported problems in concentration, short-term memory, sleep, and musculoskeletal pain. A diagnosis is made only after alternative medical and psychiatric causes of fatiguing illness are excluded. There are no laboratory tests that can confirm its diagnosis, no pathognomonic physical examination findings, and no treatment that alleviates the symptoms for all patients (Buchwald and Komaroff 1991; Komaroff and Buchwald 1991, 1998). A major question regarding the diagnosis of CFS is whether it is a discrete entity as opposed to the most severe manifestation of a spectrum of fatigue, or a debilitating but nonspecific symptom complex shared by many different clinical entities. No single cause of CFS has been identified, but many avenues of investigation have been undertaken. Since about 80% of patients diagnosed with CFS report that their condition started with a virus-like illness (Buchwald and Komaroff 1991; Komaroff and Buchwald 1991), infections were the focus of early studies. Over the last decade, many infectious agents have been suspected and investigated, including Epstein-Barr virus, but none has been found to be causative for CFS (Buchwald et al.

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Page 531996; Komaroff and Buchwald 1998). Other studies have noted that 60% to 70% of CFS patients reported allergies, compared to 20% of the general population, and CFS has been associated with heightened reactivity to allergens (Straus et al. 1988). Since allergies are immunological phenomena, scientists have examined other immunological parameters and found decreased natural killer cell number and activity, altered lymphocyte sub-set numbers and percentage, and increased expression of activation markers on lymphocyte subsets (Buchwald and Komaroff 1991; Straus et al. 1993; Komaroff and Buchwald 1998). Other areas have also been investigated, including neuroendocrine, especially hypothalamic-pituitary-adrenal abnormalities and psychiatric illness (Demitrack et al. 1991; Manu et al. 1988). More recently, autonomic nervous system dysfunction has been hypothesized to be associated with CFS because the symptoms of neurally mediated hypotension can overlap with those of CFS (Bou-Holaigah et al. 1995). However, no finding was ultimately found to be adequately reproducible and reliable to warrant its use as a diagnostic marker. Although many abnormalities exist in CFS, they are not observed in many patients and may not correlate with clinical status, leading to disagreement over their etiological relevance. Diagnosis In 1994 the Centers for Disease Control and Prevention convened the International Chronic Fatigue Syndrome Study Group to develop a conceptual framework and a set of research guidelines for use in studies of CFS (Fukuda et al. 1994). This group developed diagnostic criteria for CFS (see Table 5-1). TABLE 5-1 Diagnostic Criteria for Chronic Fatigue Syndrome A person must meet both of the following criteria in order to be diagnosed with CFS: 1. Clinically evaluated, unexplained, persistent, or relapsing fatigue of new or definite onset that is not due to ongoing exertion, is not substantially relieved by rest, and results in a substantial reduction in previous levels of occupational, educational, social, or personal activities; and 2. Concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred for at least six months: • Impaired short-term memory or concentration severe enough to cause substantial reduction in previous levels of activity; • Sore throat; • Tender cervical or axillary lymph nodes; • Muscle pain, multijoint pain without joint swelling or redness; • Headaches of a new type or severity; • Unrefreshing sleep; • Postexertional malaise lasting more than 24 hours.

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Page 54 There are many medical and psychiatric conditions that cause severe fatigue and, therefore, often preclude the diagnosis of CFS. These include: 1. Active medical condition that may explain the chronic fatigue, such as untreated hypothyroidism, sleep apnea, or narcolepsy; 2. Previously diagnosed medical conditions that have not fully resolved, such as previously treated malignancies or unresolved cases of hepatitis B or C virus infection; 3. Any past or current major depressive disorder with psychotic or melancholic features, including bipolar affective disorders, schizophrenia, delusional disorders, dementias, anorexia nervosa, or bulimia nervosa; 4. Alcohol or other substance abuse within two years before the onset of chronic fatigue and at any time afterward. It is important to note that the following comorbid conditions do not exclude CFS: 1. Any condition defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests (e.g., fibromyalgia, anxiety disorders, somatoform disorders, nonpsychotic or nonmelancholic depression, neurasthenia, panic disorder, and multiple chemical sensitivity disorder). 2. Any condition under specific treatment sufficient to alleviate all symptoms related to the condition for which the adequacy of treatment has been well documented (e.g., hypothyroidism in which the adequacy of replacement hormone has been verified by normal thyroid-stimulating hormone levels and asthma in which the adequacy of treatment has been determined by pulmonary function and other testing). 3. Any condition that was previously treated with definitive therapy before the development of chronic symptomatic sequelae. 4. Any isolated and unexplained physical examination finding or laboratory or imaging test abnormality that is insufficient to strongly suggest the existence of an exclusionary condition (e.g., an elevated anti-nuclear antibody titer that is inadequate to strongly support the diagnosis of a discrete connective tissue disorder without other laboratory or clinical evidence). To confirm the absence of underlying disease, the case definition requires that patients with suspected CFS have a minimum laboratory evaluation that includes a complete blood count with differential, electrolytes, blood urea nitrogen, creatinine, calcium, glucose, and thyroid function tests; erythrocyte sedimentation rate; antinuclear antibodies; and urinalysis. Although CFS patients may have abnormalities on such routine

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Page 55laboratory tests, the lack of consistency precludes the use of routine laboratory tests in determining whether a patient has CFS. That is, there are no dignostic markers available to establish a diagnosis of CFS (Bates et al. 1994). Components of Fatigue 1 A literature on the elements or components of fatigue dates back 100 years. Please see Appendix C for a discussion of the unique considerations of fatigue. Fatigue is thought to have four components, each of which may be important in constructing outcome measures or designing tests. The first component is behavior, by which is meant the physical manifestations of fatigue, or a decline in performance, such as making more errors, or an inability to complete a race or clean the house. A second element is the sensation or perception of the fatigued state. This may occur in the absence of any actual physical or mental effort, or it may occur in, or out, of proportion to a particular task. Furthermore, the sensation of fatigue may coexist with psychological symptoms (even in the absence of a psychiatric disorder) and cognitive assessments that result in behaviors (e.g., the belief that exertion is harmful and the consequent avoidance of exercise). The third element is the mechanisms of fatigue. Mechanisms, as examined in the literature, have tended to focus on a single explanatory model (e.g., infections, psychiatric disorders), a perspective unlikely to be useful in the vast majority of cases. Physiological mechanisms of fatigue are thought to reflect either peripheral (i.e., in the muscles or nerves) or central (i.e., in the brain) processes. In the realm of psychological mechanisms, beliefs, perceptions, expectations, and symptom amplification have all been invoked. The final component of fatigue is contextual. This includes an appraisal of the personal, social, occupational, cultural, and physical environments in which the symptom occurs. Here one may observe the influence of temperature, noise, family, and stressors on the experience of fatigue. Measurementof Fatigue The measurement strategy should be closely linked to one or more of the four components of fatigue described above. With few exceptions, even the basic measurement methods currently available are, at best, not 1 The sections “Components of Fatigue,” “Measurement of Fatigue,” and “Physical Fatigue” are from a consultant's report prepared by Dedra Buchwald for the IOM Committee on Multiple Sclerosis.

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Page 56fully evaluated. Thus, this leaves open to discussion the utility of more quantitative, and typically sophisticated, tools. The operating characteristics for many of these measures are not well established for fatigued populations. Moreover, the “gold standards,” even when they exist, are often poor. Nonetheless, if carefully selected, some currently available measures are adequate for clinical trials. These are primarily self-report measures such as the Short Form-36. For most medical conditions, a suitable biological measure or marker of fatigue has not yet been identified. Disease-specific instruments may offer the advantage of greater sensitivity to change since they incorporate measurements of phenomena more likely to be experienced by persons with a particular condition (e.g., swollen joints in rheumatoid arthritis). On the other hand, comparability and generalizability are sacrificed. In general, standard instruments are preferable unless a floor or ceiling effect has suggested the need for alternative measures. Physical Fatigue Many physical health problems are associated with fatigue. For most, although several potential mechanisms may come to mind, a single unifying mechanism is often lacking. Nonetheless, given the distinction made above between “central” and “peripheral” fatigue, the problem of muscle fatigue has been placed in the central nervous system, the spinal cord, or the various components of the muscle. In other conditions a more disease-specific mechanism may be invoked. Nonetheless, one curious and disturbing finding across heterogeneous physical disorders has been that fatigue severity rarely correlates well with measures of disease activity (e.g., in rheumatoid arthritis, hepatitis C). Functioning is often more closely tied, even in physical conditions, to psychological factors and stressors. In addition, activity reduces fatigue and is well tolerated in most medical conditions, and inactivity results in fatigue. These observations suggest that fatigue, even in clear-cut medical disorders with plausible mechanisms, is likely to be multifactorial. Evaluation of Therapies CFS treatment trials have been limited by changing case definition criteria and lack of adjusting for psychiatric illness, as well as other factors, and have therefore yielded somewhat disparate results. In addition, many agents have only been evaluated in a single study. Reid et al. (2000) have recently summarized the majority of notable English-language randomized, controlled trials that met clinical evidence criteria. Following a brief overview, the efficacy of each therapy was rated. It is important to

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Page 57 TABLE 5-2 Benefit Ratings for Chronic Fatigue Syndrome Treatment Interventions Class of Treatment Benefit Rating Cognitive-behavioral therapy Likely to be beneficial Exercise Likely to be beneficial Antidepressants other than SSRIs Unknown efficacy Oral NADH Unknown efficacy Dietary supplements Unknown efficacy Corticosteroids Unlikely to be beneficial SSRIs Unlikely to be beneficial Immunotherapy Likely to be ineffective Antiviral therapy Likely to be ineffective note that for most modalities used in treating CFS, randomized controlled trials have been performed infrequently, if at all. In Table 5-2, therapies for CFS that have been tested in a clinical trial are reviewed and rated as being beneficial, likely to be beneficial, of unknown efficacy, unlikely to be beneficial, or likely to be ineffective or harmful. The detailed discussion of each therapy is based on Reid et al. (2000). Cognitive-Behavioral Therapy (CBT) Benefits. Two recent controlled trials found that approximately 70% of patients receiving several months of weekly CBT versus only 20% of the placebo group (who received visits or relaxation therapy) demonstrated functional improvement. Another more complicated study design involving an immunotherapy arm, and having a high dropout rate, did not show an effect of CBT. Harms. The committee is aware of no major adverse effects of CBT, which is generally considered safe. Comments. The use of CBT derives from the belief that CFS may be perpetuated by ineffective coping and unhelpful health beliefs and its success in other illnesses such as depression, chronic low back pain, and atypical chest pain. The effect may be dependent, to some degree, on the therapist. Of importance, improvements are sustained and continue over 6-12 months of follow-up. Although encouraging, the exact content and duration of the CBT require careful scrutiny. All RCTs conducted on CBT did not involve the same number of sessions or duration of follow-up.

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Page 58CBT was associated with little benefit in earlier studies that used shorter durations and different composition of therapy than the recent trials conducted in the United Kingdom. Exercise Benefits. Two randomized controlled trials have compared exercise with and without fluoxetine to appointments or flexibility training. CFS patients appear to experience short- and long-term subjective and objective functional benefits from a graded aerobic exercise program. Harms. Exercise is generally considered safe, and most patients can perform modest exercise without negative consequences. Exercise should be undertaken at a slow and gradual pace given that most patients are considerably deconditioned and may often experience severe postexertional symptoms. Comments. In one trial CFS patients were included only if they did not have psychiatric disease and sleep disturbances. It remains to be confirmed whether the benefits of exercise can be generalized to those with comorbid affective and sleep difficulties. Antidepressants Benefits. Two controlled trials have shown that selective serotonin reuptake inhibitors (SSRIs) have not shown consistent and clinically important benefits such as improvements in fatigue or mood, even in those CFS patients with concurrent depression. A small randomized controlled trial of a Monoamine Oxidase Inhibitor (MAOI) failed to show a significant effect on symptoms. Harms. SSRIs may cause a disruption in sleep, weight loss, sexual dysfunction, and agitation. In general, however, the side effects are fewer and less severe than with the tricyclic antidepressants. Because elimination of SSRIs involves hepatic metabolism, doses need to be carefully adjusted for patients with liver disease. Comments. No randomized controlled trials of tricyclics, bupropion, or venlafaxine have been conducted. Because of their effects on sleep, SSRIs are frequently used in conjunction with tricyclic antidepressants. When used together, SSRIs can dramatically increase the serum concentrations of tricyclics. SSRIs are unlikely to be of benefit; other antidepressants are of unknown effectiveness.

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Page 59 Corticosteroids Benefits. Three randomized controlled trials, including one cross-over design, have been conducted with mixed results. One used fludro-cortisone, and two used hydrocortisone. Improvements, when noted, were modest and not consistent across measurement modalities. Harms. There is the potential for adrenal suppression even with low doses, as well as osteoporosis, weight gain, hypertension, diabetes, and many other therapy-related complications, especially with higher doses. With higher doses, 40% of CFS patients experienced adrenal suppression; even with lower doses, 10% had minor adverse effects. Comments. Any benefit appears to be relatively transient. OralNicotinamide Adenine Dinucleotide (NADH) Benefits. Only a single short-term, randomized, cross-over trial has been reported. About a third of treated patients improved by 10%. Harms. Minor gastrointestinal side effects such as loss of appetite and dyspepsia were noted but did not result in cessation of treatment. Comments. Larger trials are needed to confirm or refute these early modest findings. Dietary Supplements Benefits. There have been several clinical trials of dietary supplements, including magnesium (one study) and evening primrose oil (two studies). Magnesium had a significant benefit. The evening primrose oil studies yielded mixed results. Harms. No adverse effects were reported in the trials above; however, nutraceuticals have documented side effects that clinicians and patients should be aware of. Comments. Subsequent studies failed to reproduce the intracellular magnesium deficiency reported to be associated with CFS. One study of evening primrose oil had a poorly designed placebo. Immunotherapy Benefits. A modest number of trials of immunotherapy have been com

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Page 60pleted; these include four of IgG, one of alpha interferon, one of dialysable leukocyte extract, and one of terfenadine. Two trials found IgG to be of benefit; the other studies of immunotherapy did not demonstrate a positive treatment effect. Harms. The side effects in the IgG trials were considerable and included gastrointestinal problems, headaches, arthralgias, and worsening symptoms in up to 80% of participants. Neutropenia developed in 15% of the interferon-treated patients. Comments. Different doses and dosing schedules make comparisons of IgG trials difficult. Of importance, outcomes in at least two of the IgG trials were physician, not patient, ratings. Antiviral Therapy Benefits. One double-blinded placebo-controlled trial has been performed of acyclovir, and it did not demonstrate a positive treatment effect. Of the 24 patients who completed the trial, similar numbers improved with acyclovir therapy and with placebo. Harms. Three patients had acyclovir-induced nephrotoxicity and were withdrawn from the study. Each course of treatment consisted of intravenous placebo or acyclovir administered every eight hours for seven days followed by an oral regimen. Comments. Neither acyclovir treatment nor clinical improvement correlated with alterations in laboratory findings or levels of circulating immune complexes or of leukocyte 2′,5′-oligoadenylate synthetase. Subjective improvement correlated with various measures of mood. Practice Issues Because the cause of CFS is still uncertain and few well-designed trials have been conducted to evaluate treatment modalities, therapy is generally directed toward relieving symptoms and improving function. Initial therapy includes education. The physician offers supportive counseling, symptom acceptance, and patient teaching about the current understanding of CFS. Specifically, the physician provides reassurance that CFS carries no excessive mortality; symptoms often improve with time, although relapse may occur; and that even though there is no specific cure, several therapeutic options can provide benefit. It is necessary for the practitioner to acknowledge that the patient's suffering is real. Patients need to establish realistic goals for managing their lives, apply stress

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Page 61reduction techniques, and restructure their activities to better accommodate their needs and condition. The basic tenets of treatment are to establish a good patient-provider relationship in which the patient's illness is validated and reassurance is provided. Additionally, as described in Chapter 4, it is important to take a global approach to care and to develop a treatment plan that is approved by both the provider and the patient. Frequent visits are important, at least initially and no more than one to two medications at low doses should be used. Physical therapy and/or an exercise program, counseling, diet modification, and acupuncture form an important part of current practice approaches. Finally, current practice calls for the treatment of comorbid psychiatric disorders. Some investigators have found that the longer a patient has been ill with CFS, the less likely he or she is to get better. Therefore, early diagnosis and treatment are important. In summary, current practice dictates that successful therapy for CFS is built on patient-physician respect and advocacy. Specific treatment regimens are individualized, reflecting the heterogeneity of the CFS population. Recommendations For Gulf War veterans who meet the criteria for diagnosis of CFS, the committee recommends: use of cognitive-behavioral therapy and exercise therapies because they are likely to be beneficial; monitoring the results of studies of the efficacy and effectiveness of NADH, dietary supplements, corticosteroids, and antidepressants other than SSRIs; because immunotherapy and prolonged rest are unlikely to be beneficial, they should not be used as treatments; SSRIs are unlikely to be beneficial and are not recommended unless they are used as treatment for persons with concurrent major depression; and treatments effective for CFS should be evaluated in Gulf War veterans who meet the criteria for CFS. DEPRESSION Introduction Depression is one of the most common complaints among persons with psychological distress. Cases of depression are typically categorized into one of the mood disorders according to the Diagnostic and Statistical

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Page 112 Marital/Family Therapy Benefits. Marital/family therapy has no demonstrated benefit in treating PTSD. These therapies are usually directed toward changing behaviors in the marriage or family to improve these relationships, which may, as a by-product, reduce symptoms of anxiety. Harms. The committee is not aware of adverse consequences associated with marital and family therapies. Comment. Marital and family therapies are usually not administered for the treatment of PTSD but may be beneficial when marital/family problems are involved in the presentation of the disorder. Selective Serotonin Reuptake Inhibitors (SSRIs) Benefits. Sertraline was recently approved by the FDA for the treatment of PTSD and is safe and effective in reducing its symptoms (Brady et al. 2000). It is currently the only FDA-approved medication for PTSD. A small RCT of fluoxetine showed a marked reduction in overall PTSD symptoms (van der Kolk 1994) compared to placebo. Open-label trials and case reports have also shown benefit for fluoxetine, sertraline, and fluvoxamine (Friedman 1998). These drugs have a broad range of effects and reduce hyperarousal symptoms, anxiety, insomnia, and depression. Harms. SSRIs may cause a disruption of sleep, loss of weight, sexual dysfunction, and agitation. In general, however, the side effects are fewer and less severe than with the tricyclic antidepressants. Because elimination of SSRIs involves hepatic metabolism, doses need to be carefully adjusted for patients with liver disease. Comment. SSRIs are safe and effective; they are not lethal in overdose and have few serious effects on cardiovascular function. These agents are now considered first-line therapy for PTSD. They tend to be expensive. Tricyclic Antidepressant (TCAs) Benefits. There have been several case reports, open-label trials, and small RCTs in the treatment of PTSD, producing statistically significant but generally modest benefits with TCAs (Friedman 1998). Drugs studied include amitriptyline, amitriptyline, imipramine, and desipramine. Harms. Adverse effects of TCAs include dry mouth, constipation, urinary hesitancy, sweating, sleep disturbance, orthostatic hypotension, fatigue

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Page 113and weakness, weight gain, and sexual dysfunction. Doses must be carefully titrated, and higher doses are associated with greater dropout rates. Overdoses can lead to significant cardiac toxicity and fatality. TCAs should not be prescribed to patients with narrow-angle glaucoma or significant prostatic hypertrophy. Caution should be exercised in prescribing TCAs to patients at risk for falls due to the potential for orthostatic hypotension. Due to their potential for lethality with overdose, TCAs should be prescribed in limited quantities to patients who may pose a suicide risk. Comment. TCAs are used less frequently for treating PTSD than the newer SSRIs. Benzodiazepines (BZPs) Benefits. BZPs are effective in reducing symptoms of anxiety. Their effectiveness in treating PTSD is uncertain, although a small RCT of alprazolam and open-label trials of alprazolam and clonazepam suggest benefit (Friedman 1998). Harms. The adverse effects of BZPs include sedation, fatigue, ataxia, slurred speech, memory impairment, and weakness. BZPs have a potential to induce drug dependency and should be avoided in patients with substance abuse disorders. Discontinuation of these drugs can be difficult. Abrupt discontinuation can lead to seizures. Comment. BZPs may be helpful as an adjunctive therapy for short-term treatment of anxiety associated with PTSD but should not be used as a first-line therapy. Monoamine Oxidase Inhibitors (MAOIs) Benefits. Phenelzine produced reduction of PTSD symptoms in a small RCT (Kosten et al. 1991), but results have been mixed in other studies (Friedman 1998). Harms. A major concern of MAOIs is the risk of hypertensive crisis secondary to ingestion of tyramine. Patients taking MAOIs must adhere to a low-tyramine diet. Persons unable to follow the diet should not take MAOIs. Potentially serious drug-drug interactions can occur with SSRIs, sympathomimetic amines, decongestants, dextromethorphan, and meperidine. These drugs should not be used with MAOIs.

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Page 114 Comment. Because of the dietary restrictions involved in their use, MAOIs are rarely used to treat patients with PTSD. Maintenance Therapy Benefit. Patients with PTSD may benefit from continuing antidepressant drug treatment. Harms. Adverse effects are those for the specific treatments listed above. Comment. It is unclear how long maintenance therapy should last, but it is generally continued for 12 months following improvement (Davidson and Connor 1999). Practice Issues CBT and SSRIs have been found to be effective treatments for PTSD (Foa 1997; Davidson and Connor 1999; Brady et al. 2000). An emerging consensus among clinicians is that patients do best when they receive a combination of CBT and medication (Foa et al. 1999; Ballenger et al. 2000). Recommendation For Gulf War veterans who meet the criteria for PTSD and with no contraindications, the committee recommends treatment with anti-depressant medication and cognitive-behavioral therapy. MEDICALLY UNEXPLAINED PHYSICAL SYMPTOMS Introduction As described in Chapter 2, many Gulf War veterans experience symptoms that correspond closely to symptoms experienced by people in other populations that have recognized diagnoses of unknown etiology, such as chronic fatigue syndrome. The committee recognizes that studies of the treatment of persons with these diagnoses could inform veterans and their health care providers regarding effective treatments for their symptoms. The major focus of this report has, therefore, been upon these conditions. Yet, in addition to those veterans whose symptoms are similar to conditions with unknown etiologies, there remain a number of Gulf War veterans with symptoms for which there is no readily identifiable diagnosis. These individuals have been categorized as experiencing medically

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Page 115unexplained physical symptoms or MUPS (Engel and Katon 1999). Many who experience MUPS visit health care providers. A 1987 IOM report noted, “[F]or the patient and the health professional, such encounters can be frustrating because the symptom is often so very difficult to diagnose and treat. The absence of a diagnosable disease does not mean the absence of abnormalities, disturbances, or alterations in bodily functions. Thus, severe illness, illness behavior, and suffering can exist in the absence of a diagnosable disease. Effective treatment of patients with chronic pain [symptoms] requires that health care professionals view illness broadly and not only in terms of a narrow disease model” (IOM 1987: 3). Engel and Katon described MUPS as arising from a four-part process. First, an individual must experience the symptom. Second, the person having the symptom must believe it has medical significance. Third, the symptomatic and concerned individual must behave in a way that indicates his or her suspicion of serious illness or disease (e.g., he or she seeks health care). Fourth, the clinician must determine that the symptoms are unexplained or partly explained by medical problems. Of course, persons who qualify for the diagnosis of chronic fatigue syndrome or fibromyalgia, for example, would meet the criteria for MUPS. Yet others who do not fall into the diagnosis categories reviewed previously in this report also fall into this category. As noted by Wessley et al. (1999), patients seek help from doctors for symptoms and doctors diagnose diseases to explain them. One common way to explain these symptoms is to disaggregate them into a series of diagnostic categories. Wessley et al. argue, that the existence of specific syndromes such as chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome is largely an artifact of medical specialization and that similarities between these syndromes outweigh the differences. They suggest, instead, a dimensional classification. The intricacies of the debate between investigators who propose to aggregate these medically unexplained physical symptoms and those who propose to disaggregate them is beyond the scope of this report. Nevertheless, the debate is relevant because, to the degree that overlap across these diagnoses exists, the way is opened to more general strategies and services for their management. The evidence of efficacy of some of the therapies for diagnoses reviewed previously may also be applicable to MUPS. Because there are no published reports to date of RCTs for the treatment of MUPS, however, direct evidence of efficacy is currently lacking. Despite the absence of RCTs for MUPS (apart from the above diagnoses), a general approach to the patient, as developed by health care providers who work with these patients, has evolved.

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Page 116 Practice Approach 2 Conservative diagnostic testing. Clinicians are often aware at the time of initial history and physical that diagnostic testing offers a low yield or that anxiety or depression are important exacerbating factors. Most evidence suggests that ordering medically unnecessary tests to reassure patients does not work (Kidd et al. 1993; McDonald et al. 1996). It may also promote a passive patient mindset (e.g., “the doctor's in charge” and will “find it and fix it”) that is counter to behavioral activation goals and the shifting of responsibility for wellness to the patient. One alternative to running new tests is for doctor and patient to carefully review past testing together, an approach that promotes clinician-patient collaboration and patient understanding. It is important, however, that both the clinician and the patient recognize that MUPs is not a diagnosis and that they continue to explore, without excessive testing at each visit, the possibility that new evidence indicates the emergence of a specific disease entity. Judicious medication use. Medications are no substitute for person-centered care that addresses patient concerns and disability. Central nervous system depressants such as sedative-hypnotics, “muscle relaxers,” and anxiolytics are usually inappropriate unless insomnia is acute, related to a clearly identifiable stressor, and expected to abate within a short time. These medications and narcotic analgesics usually do more harm than good, since they typically slow cognition, cause sedation, and reduce overall functioning and levels of physical activity. In contrast, antidepressants may reduce MUPS among patients with chronic pain, panic disorder, dysthymic disorder, and major depressive disorder and can result in improved activity levels among depressed or anxious patients. It is important to carefully explain the rationale for psychotropic medications prescribed for MUPS or else patients may assume “the doctor thinks that the symptoms are in my head.” All patients with MUPS should receive a complete and careful explanation of medication side effects, so that if they occur the clinician's credibility is enhanced and the chance of continued adherence is maximized. Reassurance strategies. Comforting patients with MUPS often entails reassurance. This means more than simply telling them that their symptoms are not serious, a strategy that many patients will experience as 2 The section is taken from a report prepared for the committee by Charles C. Engel, Jr., M.D., M.P.H., and Wayne J. Katon, M.D.

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Page 117patronizing. Reassurance involves elucidation of the patient's beliefs about their illness (beliefs about cause, prognosis, and treatment) and providing education and advice that address those beliefs. Clinicians can learn the phrases that people with MUPS find belittling and avoid them. Similarly, they can learn some phrases that “join” the clinician and patient in a collaborative dialogue. For example, most individuals with MUPS describe their distress as secondary to symptoms. It is best to adopt the patient's words and views regarding causation, no matter how faulty the clinician may think they are. Patients with MUPS understandably react negatively to physician statements such as “There's nothing physiologically wrong.” This is an unempathetic statement that runs contrary to the patient experience of physical distress. It is important to convey that the clinician believes that the patient is hurting and will work collaboratively with them to maximize functioning and quality of life. The clinician may have to prepare the patient for a shift in emphasis from a solely diagnostic and curative approach to a rehabilitative emphasis. Collaborative goal setting. Reducing disability requires specific changes in patient behavior. It requires patients to take an active, collaborative role in their treatment. Clinician-patient collaboration and negotiation of behavioral goals will usually prove to be more rewarding than striving for elusive cures. Goals must be specific, incremental, realistic, and achievable, and they should center on observable or reportable behaviors. First and foremost, goals must be negotiated with the patient to provide the patient with a feeling of ownership of his or her goals. Productive goal-setting areas include occupational, household, or social tasks, physical activation, sleep hygiene, or medication adherence. Clinicians should shift the responsibility for change to the patient but avoid blaming the patient for his or her predicament. Physical and role reactivation. Regular exercise in tolerable doses helps patients with MUPS discharge distress, increase stamina, and improve functioning. A physical therapist is seldom necessary to initiate reactivation strategies. Instead, activation goals can be negotiated in the primary care setting. The goal here is to start at low levels of exertion and gradually increase exercise in a stepwise fashion to build aerobic capacity and functional reserve. Patients may also need encouragement to remain gainfully employed and active in supportive relationship roles. This reduces dependence and improves morale, self-confidence, and ability to meet expectations. Involvement of social supports. Clinicians should encourage participation of support systems in nearly all aspects of care, provided that the

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Page 118patient approves of this. Involving family or friends can enhance rapport and help clarify concerns, illness beliefs, symptoms, and deficits in functioning. Coordination of care. In the absence of well-coordinated and centralized care, patients with multiple MUPS are likely to bounce from specialist to specialist, receive many unnecessary diagnostic procedures, and end up on multiple unnecessary medications. The key elements of coordinated care include: 1. establishment of a relationship with a single primary care provider; 2. appointments at regular, time-contingent intervals of about every four to six weeks; 3. a brief physical examination at each visit to address new physical concerns; and 4. limits on patient-initiated visits for an exacerbation of otherwise chronic symptoms. Introducing specialty mental health consultation. Psychiatric referral is frequently appropriate for those with MUPS, especially for patients who request it, have suffered a recent stressor, have a treatment-refractory psychiatric disorder, or describe suicidal or other clinically worrisome issues. However, most patients with MUPS do not require psychiatric treatment or psychological testing. Some patients may be alienated by a psychiatric referral and become less cooperative. Evidence suggests that a surprisingly large proportion of patients with MUPS receive mental health referrals without an adequate explanation as to why they are needed (Kouyanau et al. 1997). In some cases, there is little doubt that a clinician desires psychiatric referral primarily in order to reject a difficult patient. Not surprisingly, this message is seldom lost on the patient. Clinicians should not wait until potential medical causes are “ruled out” before introducing psychiatric referral to patients with MUPS. To prevent patients from experiencing mental health referral as rejection, it is usually best for clinicians to anticipate the potential need and introduce it early in a nonthreatening way. Clinicians should see patients again after completion of mental health consultation to reduce any patient concerns over personal rejection or abandonment. Primary care clinicians can ask patients how they experienced the consultation and contact the consultant directly for recommendations if possible. Close collaboration between the primary care physician and the mental health consultant is optimal to decrease misunderstandings and support treatment goals.

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Page 119 Collaborative Primary Care Management Collaborative, behaviorally oriented health care programs that are based in primary care settings are the next step in an appropriate continuum of population-based health care for MUPS. Such programs can enhance patient adherence to behavioral approaches initiated in primary care. In addition, on-site consultation reduces stigma by presenting it as a routine part of the primary care experience rather than something mysterious and remote. On-site collaboration also provides primary care providers with satisfying opportunities to work closely with specialists. Several groups have looked at primary care-based psychosocial interventions for persons with MUPS, psychiatric disorders, or both. Strategies have most commonly involved screening (Ormel and Giel 1990; Ormel et al. 1990, 1991), physician and patient education (Andersen and Harthorn 1990), primary care-based mental health consultation (Kates 1988), interdisciplinary treatment teams (NIH 1979), and psychotherapy techniques adapted for primary care use (Catalan et al. 1991). Researchers (Smith et al. 1990; Kashner et al. 1992; Rost et al. 1994) have found replicable reductions in the cost of care and even small improvements in health-related quality of life for patients with the most severe forms of MUPS (i.e., patients with somatization disorder) simply by sending a set of short, codified recommendations to patients' primary care providers with advice on how to manage them. Katon and colleagues (1992b) completed a randomized trial of psychiatric consultation for “distressed high utilizers of primary care” at a health maintenance organization. Distressed high utilizers (the top 10% of ambulatory care utilizers over the year prior to study who were identified as distressed either by their primary care physicians or by high scores on a validated paper-and-pencil measure) accounted for approximately one-third of all outpatient visits, 26% of all prescriptions, and one-half of all inpatient hospital days. The intervention consisted of a structured psychiatric research interview followed by a 30-minute collaborative patient interview and treatment planning session involving the generalist, psychiatrist, and patient. Patients in the control group received usual primary care. Improvements in mental status or service utilization of intervention patients over that of controls could not be demonstrated. In retrospect, the intensity of the intervention was low, perhaps serving notice that MUPS involve many complex factors that are not responsive to a brief one-time intervention that targets mainly psychiatric disorders. Prescription practices were marginally better for the intervention group, but subsequent antidepressant regimen adherence was generally poor for patients in both groups. There was no formalized mechanism for interdisciplinary collaboration after the initial consultation and no way of subse

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Page 120quently enhancing primary care clinicians' effectiveness or their adherence to the original collaborative care plan (Katon et al. 1992b). More recently, primary care approaches to physically symptomatic and distressed primary care patients have focused on “multimodal” or “multifaceted” interventions. These are best administered in steps, so that the most intensive, expensive, or burdensome treatments are held in reserve for those who are otherwise treatment refractory. Components have included screening; on-site mental health consultation; cognitive-behavioral and problem-solving therapies aimed at medication adherence, depression, MUPS, physical activation, and relapse prevention; videotapes, pamphlets, and other educational materials on self-care; structured follow-up strategies; and standardized written primary care instructions. Other efforts to enhance primary care clinicians' ability to tackle the multiple needs of their patients have employed “academic detailing,” feedback to clinicians from their patients' automated pharmacy or health care utilization records, and case management. Katon and colleagues (1996) used a multifaceted approach to assist depressed primary care patients, an approach that can serve as a model for similar primary care-based MUPS interventions. Elements of their intervention targeted the patient, the physician, and the process of health care delivery. Elements that targeted patients were reading materials on depression, antidepressants, simple self-administered cognitive-behavioral techniques for managing depression, and a videotape on similar topics for viewing with spouses. Elements that targeted primary care physicians were didactics on antidepressants and behavioral treatment of depression, case-based consultation for each depressed patient, and ongoing interaction and feedback between the psychologist and primary care physicians. Elements that targeted the process of care were extensive and manualized. These included behavioral therapy conducted in the primary care setting and aimed at teaching patients depression self-management skills, improving medication regimen adherence, and preventing future relapses. Psychologist contacts were scheduled and occurred in the primary care setting. These contacts involved skills training, education, and homework. Relaxation training, assertiveness training, problem-solving training, and collaborative psychologist-patient development of a relapse prevention plan were done. Additional telephone contacts with the psychologist occurred after completion of primary care-setting contacts. Symptom monitoring occurred by a standardized measure and a checklist. The psychologist screened and documented antidepressant side effects, dosing, and adherence. During weekly interdisciplinary team meetings, a psychiatrist reviewed antidepressant-related information and overall treatment progress. The psychiatrist would advise medication alterations as indicated,

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Page 121and the psychologist communicated these recommendations to the primary care physician, who would carry them out. This integrated process of care was carefully monitored for integrity by using a numerical rating system. These integrity ratings were monitored and used to provide regular clinician feedback. Katon and co-workers (1996) compared this collaborative interdisciplinary intervention to usual care for depressed primary care patients using a randomized controlled design. As long as four months after completion of the intervention, intervention patients with major depression reported greater satisfaction with care, adherence to the medication regimen, and improvement in depressive symptoms than major depression patients receiving usual care. The results of the intervention were less clearly favorable among patients with minor depression (significantly improved antidepressant regimen adherence and perceived antidepressant helpfulness, but there were no significant differences between the groups regarding depression symptoms or satisfaction with depression care; Katon et al. 1996). Other analyses of these data have found evidence of improvements in physical symptoms. Analyses of cost-effectiveness found that the intervention was more costly than usual care for patients with both major and minor depression. However, for the major depression patients, the multifaceted intervention offered significantly greater cost-effectiveness than usual primary care (Von Korff et al. 1998). Given the added expense associated with collaborative models, it may be that they are best focused on patients for whom routine primary care management strategies for MUPS fail. When a patient's symptoms reach some threshold of extended duration, more intensive collaborative efforts may be proactively introduced. For example, Katon et al. (1999) found that compared to usual care, an intensified collaborative approach for primary care patients with persistent symptoms of depression significantly improved adherence to antidepressant therapy, satisfaction with care, depressive symptoms, and the likelihood of full recovery at three-and six- month follow-up (Katon et al. 1999). A similar stepped intensity of care may also benefit people at elevated risk of poor outcomes due to MUPS. Specialized Intensive Multimodal Care There are several examples on which to model tertiary prevention programs for patients with MUPS who fail to improve in response to collaborative primary care approaches. These programs are multimodal and multidisciplinary, occur in specialized (i.e., nonprimary care) settings, and involve either a three- to four-week inpatient or intensive out-patient program or a 10- to 15-week program of weekly or biweekly individual or group visits. These programs emphasize carefully planned

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Page 122psychosocial elements that address the chronic nature of reduced functioning and the factors that reinforce it. Evidence-based criteria for these programs have yet to be applied. Usually, psychosocial and medical care is combined with a highly structured and generally supervised physical activation or exercise plan. These programs view disability as a behavior amenable to modification regardless of its biomedical etiology. Engel and colleagues (1998) have described such a program for Gulf War veterans with MUPS. The intervention, called the Specialized Care Program (SCP), is a three-week intensive outpatient program modeled directly after the University of Washington's Multidisciplinary Pain Center (Loeser and Egan 1989). Preliminary data suggest that treated patients make mild-to-moderate gains in multiple domains, including functional status and health-related quality of life, psychosocial distress, physical symptoms, and physical health concerns (Engel et al. 2000). Bonica at the University of Washington was among the first to apply a multidisciplinary approach to the treatment of chronic pain patients in the late 1950s (Loeser and Egan 1989). Since then, the approach has gained relatively wide acceptance for work-impaired chronic pain patients, especially those with back pain and fibromyalgia. A recent meta-analysis of 65 controlled studies of multidisciplinary interventions for chronic pain patients noted improvements in return-to-work rates, pain, mood, and health care utilization (Flor-H. et al. 1992). The authors were cautious in their conclusions, noting that the level of methodological rigor for most studies was low. Recommendations Given the lack of efficacy and effectiveness studies focused on treatments for patients with MUPS, the committee is unable to recommend specific treatments. However, research conducted to date and described above has demonstrated that there are approaches to treating MUPS that show promise and should be further researched. Therefore, for Gulf War veterans with unexplained symptoms, the committee recommends that: for the purposes of treatment efficacy and effectiveness studies, explicit criteria for medically unexplained physical symptoms (apart from chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome) be developed and used uniformly in treatment studies and treatment studies of antidepressant medications, cognitive-behavioral therapy, and a stepped intensity-of-care program be implemented for MUPS.