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Gulf War Veterans: Treating Symptoms and Syndromes (2001)

Chapter: 5. Effective Treatments

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Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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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

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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know 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.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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1996; 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.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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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

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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laboratory 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.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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fully 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

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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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.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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CBT 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.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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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

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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pleted; 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

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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reduction 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

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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TABLE 5-3 Diagnostic Criteria for Major Depression

The patient experiences five or more of the following symptoms for at least two weeks during the same two-week period and at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

1. Depressed mood

2. Diminished interest or pleasure in all, or almost all, activities most of the day

3. Weight loss or gain

4. Insomnia or hypersomnia

5. Psychomotor agitation or retardation

6. Fatigue or loss of energy

7. Feelings of worthlessness or excessive guilt

8. Diminished ability to think or concentrate

9. Recurrent thoughts of death or suicidal thoughts

The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning and are not due to the direct effect of a substance (such as alcohol) or a medical condition (such as hypothyroidism).



Manual of Mental Disorders, Fourth Edition (American Psychiatric Association 2000). These include major depression, bipolar disorder depressed type, dysthymic disorder, and minor (or subsyndromal) depression. The diagnostic criteria for major depression are listed in Table 5-3.

Major depression may manifest itself in a single episode, may be recurrent, may be interposed with periods of elated mood (mania or hypomania), may be chronic, and may occur intermittently upon a base of a less severe yet chronic variant of depression, dysthymia. Virtually all studies of treatment efficacy of depression, however, especially of efficacy using randomized clinical trials, have concentrated on major depression (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000). This review, therefore, will focus on evidence for treatment efficacy of major depression.

Evaluation of Therapies

Studies of treatment efficacy of depression in bipolar disorder, depressed type, usually explore the same therapeutic entities as used in major depression. In addition, the actual number of cases of documented bipolar disorder among Gulf War veterans is limited. Though dysthymic disorder and minor depression are more common than major depression, studies of treatment effectiveness and especially efficacy are difficult for at least two reasons. First, the lower level of symptoms responsive to treatment create a “floor effect” that renders comparison of treatment and

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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control groups difficult. Second, most randomized clinical trials of the treatment of depression (whether major depression or a less severe type) exhibit significant placebo effects, further limiting the comparison of treatment and control groups.

Despite the paucity of randomized clinical trials of therapies for less severe forms of depression, the same treatments typically prescribed for major depression are prescribed frequently for the less severe forms. This is especially true for the new-generation antidepressant agents such as the SSRIs which are much more frequently prescribed for less severe forms of depression than for major depression. The likelihood of a person being prescribed an antidepressant medication for major depression, however, is greater than if a person experiences a less severe form of depression.

In other words, in reality depression presents as a spectrum disorder in terms of symptoms and their severity. Psychiatrists have arbitrarily clustered depression into a series of diagnoses for purposes of more reliable diagnosis and clinical trials. Though the more severe depressions are more likely to be caused by biological factors rooted in heredity, virtually all depressions are caused by a combination of biological, psychological, and social factors and for this reason combined therapies for these disorders are intuitive. In addition, at what point along this spectrum a biological therapy is indicated is difficult to establish. It is sufficient to note that the clinical trials of therapies for major depression have not only substantiated the value of certain therapies for major depression but have also led to these therapies being used frequently for less severe forms of depression, often with anecdotal evidence that the therapies are effective.

Beneficial Therapies

  • Tricyclic and heterocyclic antidepressants

  • MOAIs

  • SSRIs and related compounds

  • Cognitive-behavioral therapy

  • Interpersonal psychotherapy

  • Electroconvulsive therapy (in severe/treatment-resistant depression)

  • Maintenance therapy to prevent recurrences

Likely to Be Beneficial

  • St. John's Wort (in mild-to-moderate depression)

  • Exercise

  • Group psychotherapy (especially cognitive-behavioral therapy)

  • Marital and family therapy

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Unknown Effectiveness

  • Antianxiety agents

  • Sedative hypnotic agents

  • Psychoanalysis and insight-oriented therapies (in less severe forms of depression)

  • Other forms of psychotherapy

Interpersonal Psychotherapy(IPT)

Benefits. There is some evidence in RCTs that IPT in controlled studies as a single agent is effective in reducing depressive symptoms in the acute phase of nonmelancholic major depressive episodes of lesser severity. It is thought to be especially valuable in reducing dysfunction in vocational and social aspects of persons experiencing depressive episodes. IPT has also been demonstrated to be effective in reducing the likelihood of relapse.

Harms. There are no known harms associated with IPT or the other psychotherapies frequently prescribed for depression. Patients are informed that the therapy is voluntary, that they may drop out at any time, and that the therapy is time-limited (usually between 12 and 20 sessions). The short duration and educational emphasis virtually eliminate the occasional problems that arise with more insight-oriented psychotherapies, such as intense and potentially pathological transference reactions (feelings for the therapist by the patient that could border on the pathological).

Comment. IPT has become the most frequent psychotherapy for depression studied in randomized clinical trials. The therapy is basically an educational/behavioral therapy with an emphasis on improving interpersonal relations rather than evaluating cognitions associated with depression (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Cognitive Therapy

Benefits. There is evidence that cognitive therapy reduces depressive symptoms during the acute phase of less severe forms of depression. The prophylactic effect of cognitive therapy to reduce the likelihood and severity of relapses of major depression (regardless of severity) has not been firmly demonstrated, as with IPT (see below).

Harms. The committee is aware of no major adverse effects of cognitive therapy, which is generally considered safe.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Comment. Cognitive therapy, as developed by Aaron Beck, has become the model for the educationally oriented, time-limited therapies that for the most part have replaced insight-oriented psychotherapy as the therapy of choice for moderately severe to severe episodes of depression (almost always in conjunction with antidepressant medication in the more severe forms (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

BehavioralTherapies

Benefits. Behavioral therapy has been reported to be effective in the acute treatment of patients with mild to moderately severe depression, especially when combined with pharmacotherapy. There is little evidence that behavioral therapies reduce the likelihood or severity of relapse of major depression. The long-term benefits of behavioral therapy are not well established.

Harms. See “Harms” under “ Interpersonal Psychotherapy.”

Comments. Behavioral therapy for depression is rarely used in isolation for the treatment of major depression, yet elements of behavioral therapy are frequently combined with cognitive therapy, IPT, and marital/family therapy (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Goodle 2000).

Marital/Family Therapy

Benefits. Marital/family therapy, usually directed toward changing behaviors in the marriage or family, along with pyschoeducational approaches to improving the marriage/family relationship may reduce depressive symptoms and the risk of relapse of major depression in patients with marital and family problems.

Harms. See “Harms” under “ Interpersonal Psychotherapy.”

Comments. Marital/family therapy for major depression is usually not prescribed unless marital/family problems are paramount in the presentation of the disorder. Issues in the marriage and family are frequently addressed during IPT and cognitive-behavioral therapy, however. Family members and spouses will occasionally be asked to participate in IPT or cognitive-behavioral therapy sessions (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Group Therapy

Benefits. Group therapy may be of benefit for major depression, especially in the context of bereavement or common stressors such as chronic illness. Medication maintenance groups have also been demonstrated to be effective for some patients who are resistant to taking medications.

Harms. See “Harms” under “IPT.” In addition, group situations may occasionally be threatening to an individual because of comments made by other members of the group, especially if the group therapist is not sensitive to these problems. Individual meetings of group members with the therapist can be useful in decreasing the likelihood of this adverse effect.

Comments. Though evidence for the effectiveness of groups is much less than for individual IPX and cognitive-behavioral therapy, the economy of group sessions coupled with the unique potential benefit of peer support and advice renders groups a potentially valuable form of therapy for major depression (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Psychoanalysis and Insight-Oriented Psychotherapies

Benefits. There is no evidence for the effectiveness of psychoanalysis or insight-oriented psychotherapies in the treatment of major depression. However, some studies that have compared the effectiveness of more educationally oriented therapies and insight-oriented psychotherapies have typically not found a difference between the two forms of therapy.

Harms. See “Harms” under “IPT.” Problems with transference and difficulty terminating therapy due to attachment of the patient to the therapist are more likely to occur in psychoanalysis and insight-oriented psychotherapies than with IPT or cognitive therapies.

Comment. Psychoanalysis and insight-oriented psychotherapy, by their very nature, are not amenable to clinical trials for efficacy. In some loosely designed comparative studies, even over a short period of time, insight-oriented psychotherapy has been as beneficial as cognitive-behavioral therapy (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Tricyclic Antidepressants (TCAs)

Benefits. TCAs have been shown to be effective therapies in many clinical trials for the treatment of major depression. Imipramine, amitriptyline,

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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nortriptyline, doxepin, and desipramine are tricyclic antidepressant therapies that have been demonstrated to be effective and continue to be used today. During the first three weeks, 10% to 15% of patients drop out of RCTs. For those who continue through this initial period, the rate of response is as high as 60% to 70%. These rates apply to each of the drugs listed above. Though patients may show some improvement by the end of the first week, many will not respond fully until six to eight weeks. The rate of placebo response is high in major depression, often reaching 40%.

Harms. Sedation is a common side effect but may be welcomed given the insomnia secondary to depression. Anticholinergic side effects such as dry mouth, fatigue, weight gain, and constipation may occur in up to 20% of patients. In addition, orthostatic hypotension (common) and cardiac toxicity (rare) may occur. 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 much less frequently prescribed for depression today than the newer SSRIs and related compounds primarily due to fewer side effects with the newer agents. For major depression, the efficacy of the TCAs is at least equivalent to these newer agents. TCAs are much less expensive (as virtually all are now manufactured as generic compounds; Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Monoamine Oxidase Inhibitors (MAOIs)

Benefits. MAOIs, including phenelzine, isocarboxazid, selegiline, and tranylcypromine, have been demonstrated to be effective in RCTs for the treatment of major depression. These drugs have been shown to perhaps be of benefit for less severe depressions in open trials. The results are similar in RCTs for TCAs.

Harms. While the MAOIs are not anticholinergic, their side effects often resemble the tricyclic medications. A major concern with 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. In addition, at least two weeks is recommended between discontinuation of the MAO inhibitors and use of the anesthetics for electroconvulsive therapies.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Comment. Because of the dietary restrictions, MAO inhibitors are infrequently used to treat depression today. They should be considered, however, when other agents are not of benefit to the patient (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

SSRIs and Related Compounds

Benefits. All of the currently marketed SSRIs and related compounds have been demonstrated to be effective in RCTs. These include fluoxetine, sertraline, paroxetine, nefazodone, citalopram, mirtazapine, and venlafaxine. Most have been compared to imipramine for effectiveness and have proven equivalent effectiveness. When compared with one another, trials usually show equivalent effectiveness.

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 TCAs. Because elimination of SSRIs involves hepatic metabolism, doses need to be carefully adjusted for patients with liver disease.

Comment. These agents are now considered first-line therapy for major depression in the outpatient setting. They are widely used. As most of these compounds are still under patent, the cost of therapy is not insignificant (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Benzodiazepines (BZPs)

Benefits. No RCTs have demonstrated the benefit of BZPs in treating major depression. These drugs may reduce the anxiety and agitation associated with depression.

Harms. 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 of BZPs can lead to seizures.

Comment. BZPs should never be used as first-line therapy for major depression (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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St. John's Wort (Hypericum Perforatum)

Benefits. St. John's Wort, an herb that can be purchased over the counter, has been demonstrated to be effective in RCTs in Europe and is currently under study in the United States. The drug is considered beneficial primarily for less severe depression.

Harms. The most common adverse effects of St. John's Wort are gastrointestinal symptoms, dizziness/confusion, tiredness, and sedation. Adverse effects of St. John's Wort have been sporadically reported in the literature to date from RCTs. The drug interacts with other medications, and the full extent of these interactions in terms of harm to the patient have yet to be documented completely.

Comment. More studies of this compound are needed before definitive effectiveness is clear. One additional problem is the variation in the preparations and doses marketed to the public. In addition, the potential interactions with other medication should not be overlooked despite the fact that the drug is available over the counter (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Maintenance Therapy

Benefits. RCTs have found that continuing antidepressant drug treatment for four to six months after recovery reduces the risk of relapse. RCTs also find that augmentation of pharmacotherapy with psychotherapy (especially interpersonal therapy) is superior to the use of medications alone in preventing relapse.

Harms. Adverse effects are similar to those reported for the acute treatments listed above.

Comment. Though further large trials are needed to demonstrate the effectiveness of various medications and the combination of psychotherapy and pharmacotherapy in preventing recurrence of depressive episodes, most psychiatrists now recommend continuation of pharmacotherapy for at least six to nine months following response to the medication. A history of multiple or particulary debilitating episodes of depression suggests longer-term maintenance prophylaxis with ongoing antidepressant therapy (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Electroconvulsive Therapy (ECT)

Benefits. ECT has been proven effective in treating severe and/or psychotic depression. The rate of response is similar to antidepressant medications, even among those persons who have previously been treated without success with antidepressants.

Harms. Memory impairment is the major adverse outcome from ECT. It is usually limited to the period of treatment, except in rare cases where longer-term damage may be detected.

Comment. ECT should only be administered to persons with severe (usually psychotic) depression or to persons known to have responded to it in the past. ECT should be administered by a professional with competency in using the treatment, and proper screening for cardiovascular status and possible cerebral masses must precede administration of ECT (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Exercise

Benefits. Exercise has been demonstrated to be effective in RCTs for mildto-moderate depression.

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.

Comment. The type of exercise prescribed and the motivation of the patient to maintain an exercise regime are critical aspects of the use of exercise in the treatment of depression (Depression Guideline Panel 1993; Work Group on Major Depressive Disorder 1993; Godlee 2000).

Summary of Therapies

RCTs have found that many regimens are effective treatment for mild-to-moderate depression, including a variety of medications, psychotherapy, and exercise. There is little evidence that one drug among the prescription drugs is superior to other drugs, and the selection of a drug is usually based on its side effect profile. Maintenance therapy has been demonstrated effective once a subject has recovered from the acute episode of depression.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Practice Issues

The treatment of depression in the offices of primary care physicians and psychiatrists today is generally dominated by the use of medications, specifically the newer and safer medications available during the past 14 years (specifically the SSRIs and related compounds). Relatively few patients receive formal sessions of psychotherapy, though most will receive support and brief counseling from their physicians.

Many persons experiencing depression may seek counseling from professionals other than physicians (and may see these counselors in parallel with physicians, the physicians managing the medications). Counselors range from clinical psychologists through social workers and marriage counselors to pastoral counselors. Pharmacotherapy is usually covered by most insurance plans, but coverage for psychotherapy from physicians is limited and from other counselors even more limited. Considerable evidence has emerged over recent years that depression is a major public health problem (whether that depression is the only problem experienced by the patient or it coexists with other conditions such as a debilitating physical illness). In fact, some have suggested that it will become the most important chronic public health problem worldwide over the next generation.

We have concentrated in this report on major depression for there are very few clinical trials that focus on other depressive diagnoses. Nevertheless, many depressive symptoms of clinical significance that present to practicing physicians do not meet the criteria for major depression as noted earlier in this chapter. These depressive symptoms have been variously categorized as subsyndromal depression, minor depression, and so on. Both psychotherapy and antidepressant medications are frequently prescribed for these patients, most often by primary care physicians.

Though most physicians are more aware of depression today than they were a few years ago, the treatment of depression remains haphazard and evidence exists that depression is untreated or undertreated in most circumstances. Contributing to undertreatment are the discontinuance of medications prematurely or underdosing of medications. In addition, the emerging evidence discussed above for an added benefit from medications being combined with psychotherapy to prevent recurrences of depression has scarcely impacted the general practice of treating depression, in part due to lack of availability of CBT.

The committee recognizes that while other therapies have been demonstrated efficacious, major depression is vastly underrecognized and undertreated in medical care settings.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Recommendation

The committee recommends a combination of antidepressant medication and psychotherapy (either cognitive-behavioral therapy or interpersonal therapy) as the core therapy for major depression.

Uniform implementation of these therapies would vastly improve the treatment of Gulf War veterans diagnosed with major depression (Work Group on Major Depressive Disorder 1993). Nevertheless, Gulf War veterans who experience comorbid major depression and other conditions reviewed in this report clearly may experience improvement in depressive symptoms from therapies such as exercise. Still other Gulf War veterans who experience significant marital and family problems may benefit from marriage and family therapy.

FIBROMYALGIA

Introduction

Fibromyalgia is a disorder of widespread pain, tenderness, fatigue, sleep disturbance, and psychological distress affecting about 2% of the general population (Wolfe et al. 1995). It is up to four times more common in women than in men. Many patients with fibromylagia have concomitant clinical features that include irritable bowel syndrome, paresthesias, chronic headaches, irritable bladder (and/or interstitial cystitis), somatization, and social dysfunction. Emphasizing a sizable overlap with other widespread pain disorders, 20 to 70% of fibromyalgia patients meet classification criteria for chronic fatigue syndrome, although myalgias are significantly more common among those with fibromyalgia (Buchwald and Garrity 1994; Aaron et al. 2000; Bradley et al. 2000).

Difficulties with the classification and diagnosis of fibromyalgia have led to development of a case definition created by a consensus panel of the American College of Rheumatology in 1990 (Wolfe et al. 1990) (see Table 5–4).

Fibromyalgia patients can sometimes be differentiated from patients with other pain disorders by allodynia, a state in which non-noxious stimuli applied to the skin cause pain (IASP 1979), and by hyperalgesia, whereby noxious stimuli result in accentuated painful responses in comparison to the general populace.

Since the major feature distinguishing fibromyalgia from other disorders is tenderness (or heightened sensitivity), this must be carefully assessed on the physical examination. Two methods for measuring tenderness are digital palpation and dolorimetry. The amount of force used in palpation is important because too large a force will elicit pain in persons without fibromyalgia, whereas too little force may lead to underdiagnosis

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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TABLE 5-4 Case Definition of Fibromyalgia

There must be a history of widespread pain. Pain is considered widespread when all of the following are present:

• Pain in the left side of the body,

• Pain in the right side of the body,

• Pain above the waist, and

• Pain below the waist.

In addition, axial skeleton pain (cervical spine or anterior chest or thoracic spine or low back) must be present. Shoulder and buttock pain is considered pain for each involved side. “Low back” pain is considered lower segment pain.

There is pain on digital palpation in 11 of the 18 following sites of tender points:

1. Occiput: bilateral, at the suboccipital muscle insertions.

2. Low cervical: bilateral, at the anterior aspects of the intertransverse spaces at C5–C7.

3. Trapezius: bilateral, at the midpoint of the upper border.

4. Supraspinatus: bilateral, at origins above the scapular spine near the medial border.

5. Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces.

6. Lateral epicondyle: bilateral, 2 cm distal to the epicondyles.

7. Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle.

8. Greater trochanter: bilateral, posterior to the trochanteric prominence.

9. Knee: bilateral, at the medial fat pad proximal to the joint line.



of fibromyalgia. Although the validity of palpation has been questioned, studies have shown that trained examiners can reach high levels of agreement in the identification of patients with and without fibro-myalgia using tender point examination (Wolfe et al. 1992; Okifuji et al. 1997).

Dolorimetry is a more formalized technique to assess tender points utilizing a rubber endplate with a spring-loaded force gauge. Although dolorimetry may be useful in clinical trials as a method to assess exact pain threshold, digital palpation and manual palpation are sufficiently accurate diagnostic approaches for use in the routine clinical setting (Wolfe et al. 1994).

In addition to widespread pain and tender points, there are other signs and symptoms common to patients with fibromyalgia. In a 1990 ACR study of criteria for the classification of fibromyalgia, 81% of patients complained of fatigue and 74% complained of sleep disturbance. Indeed, nonrestorative sleep is traditionally considered one of the key features of fibromyalgia (Moldofsky et al. 1975). Although less than half of patients with fibromyalgia report symptoms of depression (Wolfe et al. 1994), psychological illness is an important cause of comorbidity in

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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fibromyalgia. Although psychological stress is an important precipitator of fibromyalgia (Dailey et al. 1997; Uveges et al. 1990), fibromyalgia is generally not considered a psychiatric illness.

Family members of fibromyalgia patients have a higher-than-expected rate of fibromyalgia. Preliminary results suggest possible genetic linkages (Offenbaecher et al. 1999; Yunus 1999). In addition, trauma, either physical or psychological, may precipitate fibromyalgia (Boisset-Pioro et al. 1994; Taylor et al. 1994).

Many investigators now agree that aberrant central nervous system pain-receptive mechanisms are likely partially involved in the pathogenesis of fibromyalgia. A central nervous system hypothesis would explain not only the high incidence of nonmusculoskeletal symptoms in a wide variety of organs and tissues, but also the affective disorders and neurological features that occur in this condition (Clauw 1995).

Evaluation of Therapies

Limited in part by variable case definition criteria, fibromyalgia treatment studies with both pharmacological and nonpharmacological agents have yielded disparate results. Leventhal (1999) recently summarized the majority of notable English-language investigations. Following an overview of the available treatment options, a compendium of fibromyalgia studies is presented, organized according to the quality of each study. The formatting and nomenclature used are from Clinical Evidence (Enkin et al. 1998). Except as otherwise noted, systematic reviews have not been performed for the vast majority of treatment approaches reviewed. In a review of these studies, the focus is on RCTs. The ability to attribute benefits to any specific treatment is attenuated by a 15 to 30% placebo response in fibromyalgia clinical trials. This finding substantially attenuates enthusiasm for studies not controlled, randomized, and double blinded. However, for therapeutic options where RCTs have been only sparingly performed or are of limited feasibility (e.g., cognitive therapies), studies of lesser methodological rigor are briefly reviewed.

Beneficial

  • No therapy has been well documented to have clear benefits.

Likely to Be Beneficial

  • Multidisciplinary rehabilitation combining education with physical training

  • Tricyclic antidepressants (at least in the short term)

  • Acupuncture

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Unknown Efficacy

The majority of agents and approaches reviewed have been insufficiently investigated, and their true effectiveness is thus unknown. These include other antidepressants (nontricyclic antidepressants), benzodiazepines, local anesthetic injections, tramadol, malic acid/magnesium combination, growth hormone, S-adenylmethionine, 5-hydroxytryptophan (HT), 5-HT3 antagonists, exercise (as single therapy), hypnotherapy, and biofeedback.

While cognitive and behavioral therapies appear efficacious in chronic fatigue syndrome, the literature does not support clear efficacy in fibromyalgia.

Unlikely to Be Beneficial

  • Nonsteroidal antiinflammatory agents

Likely to Be Ineffective or Harmful

  • Opioid analgesics

  • Glucocorticoids

TCAs and Other Amine Salts

Benefits. Seven RCTs were identified that contained a placebo arm. Six examined amitriptyline (Carette et al. 1986; Goldenberg et al. 1986; Scudds et al. 1989; Jaescheke et al. 1991; Carette et al. 1994; Goldenberg et al. 1996) and two cyclobenzabrine (Bennett 1988; Carette et al. 1994). All showed short-term (4- to 12-week) improvement of outcomes such as pain scores, sleep, and tender points in 20 to 30% of subjects. However, longer-term (6-month) benefits are not as well substantiated (Carette et al. 1994). There is evidence that long-term use of tricyclic agents is associated with suppression of HPA axis function, which might explain their loss of efficacy over time (Michelson et al. 1997). No definite differences in efficacy between amitriptyline and cyclobenzaprine have been demonstrated (Carette et al. 1994).

Harms. Anticholinergic side effects such as dry mouth, fatigue, weight gain, constipation, and orthostatic hypotension may occur in up to 20% of patients (Wolfe et al. 1990). There is the potential for cardiac toxicity in older patients and those with underlying heart disease or with long-term use. Caution should be exercised in prescribing TCAs to patients at risk for falls due to the potential for orthostatic hypotension. Due to their

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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potential for lethality with overdose, TCAs should be prescribed in limited quantities in patients who may pose a suicide risk.

Comments. Tricyclic antidepressants are the most commonly used prescription therapy for fibromyalgia. Most patients enrolled in studies of these medications were from outpatient rheumatology clinics and may not be representative of patients with fibromyalgia in the general community. Tachyphylaxis may limit long-term use.

SSRIs and Other Nontricyclic Antidepressants

Benefits. Results of open-label and controlled clinical trials of fluoxetine have been equivocal at best (Geller et al. 1989; Finestone and Ober 1990; Cortet et al. 1992; Wolfe et al. 1994; Goldenberg et al. 1996). Although depression and anxiety scales improved slightly but insignificantly in one fluoxetine study, other parameters, including tender point scores, did not show a favorable response (Wolfe et al. 1994). In a placebo-controlled RCT there was no effect on the number of tender points (Cortet et al. 1992). Venlafaxine, a potent inhibitor of both norepinephrine and serotonin, improved symptoms in one open-label trial (Dwight et al. 1998).

Harms. SSRIs may cause a disruption in sleep, loss of weight, sexual dysfunction, and agitation. In general, however, the side effects are fewer and less severe than with the TCAs. A disruption of sleep by SSRIs has promoted their use in combination with low-dose TCAs. However, this combination must be used carefully due to heightened toxicity.

Comments. These agents seem most appropriate for the 20 to 50% of fibromyalgia patients with concomitant clinical depression (Aaron et al. 1996).

Benzodiazepines

Benefits. Only one RCT was identified of a benzodiazepine currently approved in the United States. An eight-week study demonstrated a 30% improvement in tender point index among patients randomized to alprazolam when given in combination with ibuprofen (Russell et al. 1991).

Harms. The adverse consequences of therapy with the benzodiazepines include dependence, withdrawal seizures, excessive daytime somnolence, and risk of falls and automobile accidents.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Steroidal and Nonsteroidal Antiinflammatory Drugs

Benefits. No significant differences were found between ibuprofen and placebo in one study (Yunus et al. 1989). A cross-over trial of 20 patients showed no improvements with prednisone (Clark et al. 1985). As noted above, combinations of ibuprofen with alprazolam (Russell et al. 1991) and naproxen in combination with amitriptyline (Goldenberg et al. 1986) appeared slightly superior to either drug alone.

Harms. Nonsteroidal antiinflammatory agents (NSAIDs) can cause gastrointestinal ulceration and bleeding, platelet dysfunction, hypertension, fluid retention, and, rarely, allergic reactions. Newer cyclooxgenase-2 (COX-2) selective NSAIDs have a significantly lower gastrointestinal and bleeding toxicity profile but maintain the other NSAID risks. Glucocorticoid toxicity is myriad and includes osteoporosis, weight gain, hypertension, blood sugar elevations, and eye problems.

Comments. There are no data to support a benefit of glucocorticoids in fibromyalgia.

Tramadol

Benefits. One small cross-over trial comparing intravenous tramadol against placebo yielded nearly identical reductions in spontaneous pain and no significant differences in tender point counts (Biasi et al. 1998). A preliminary report of a double-blind RCT showed that fewer tramadol recipients withdrew due to residual pain than placebo recipients (Russell et al. 1997). Tramadol was as effective as acetominophen with codeine on total pain relief score among elderly patients, some of whom had fibromyalgia (Rauck et al. 1994).

Harms. Nausea and dizziness may limit even short-term use. Seizures have been reported in patients with excessive dose or altered drug elimination.

Comments. Limited numbers of patients treated with this agent, poorly generalizable study populations, and symptomatic side effects limit enthusiasm for routine use of tramadol in patients with mild-to-moderate symptoms.

Other Analgesics

Benefits. Studies have not shown a definite benefit of local injections with lidocaine, in contrast to its putative benefits in patients with regional

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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myofascial pain (Hong and Hsueh 1996). There are no RCT data on the use of opioids for fibromyalgia.

Harms. Lidocaine injections at standard dosage are unlikely to produce toxicity other than local injection site pain. Opioids have potential for dependence, tolerance, dulled sensorium, and constipation.

Comments. A placebo effect of “needling” may explain the benefits believed to occur with local anesthetics. On the other hand, needling in general may release endorphins as indicated by reversibility of beneficial effects with naloxone (Fine et al. 1988).

Novel Pharmacological Therapies

Benefits. A tablet containing malic acid and magnesium showed no clear treatment effect in a low-dose blinded trial (Russell et al. 1995). Reductions in severity of pain/tenderness measures were reported, however, in an open-label extension to this trial. Fifty women with fibromyalgia and low insulin-like growth factor 1 levels had significant improvements on the fibromyalgia impact questionnaire and tender point score in comparison to placebo when given growth hormone (GH) (Bennett et al. 1998). The dietary supplement S-adenosylmethionine appeared to improve symptoms and/or signs in two RCTs (Tavoni et al. 1987; Jacobsen et al. 1991) but not in a third (Volkmann et al. 1997). Another dietary supplement, 5-hydroxytrytophan (HT), significantly improved clinical parameters in a double-blind RCT (Caruso et al. 1990). Calcitonin given subcutaneously in a very small double-blind RCT did not result in an appreciable benefit (Bessette et al. 1998). Blockade of the serotonin receptor, 5-HT3, by the commonly used antinausea agent ondansetron decreased pain significantly better than paracetomol in a cross-over trial (Hrycaj et al. 1996). The related compound tropisetron also decreased tender points in an uncontrolled design (Samborski et al. 1996).

Harms. Malic acid and magnesium are both relatively nontoxic at the modest doses used in the study. Diarrhea and nausea can result with higher doses or more prolonged usage. Carpal tunnel syndrome may result from GH administration. The safety of growth hormone in patients without deficiency is unknown. Gastric pain and diarrhea can be caused by 5-HT. Except for occasional rhinitis, calcitonin is generally well tolerated when used nasally. In contrast, the subcutaneous route may more commonly lead to flushing and diarrhea. Ondansetron can cause constipation.

Comments. The frequency of GH deficiency in fibromyalgia is unknown; thus the utility of GH supplementation is unknown based on the single

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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reported investigation. It should be noted that the high cost of GH may make its use as a therapy problematic.

Exercise

Benefits. Compared to a placebo group that continued with usual physical activity level, a 60-minute exercise program twice a week for 20 weeks did not improve pain, coping, or fatigue. However, dynamic work endurance improved significantly (Mengshoel et al. 1992). A Danish study comparing two types of exercise programs to the applications of hot packs detected no differences in pain, fatigue, or other outcomes at 12 weeks in any of the three groups (Norregaard et al. 1997). A cardiovascular exercise program did not show significant improvement in fibromyalgia symptoms or disturbed sleep compared to a flexibility program. However, patient and physician global assessments improved significantly more among those in the cardiovascular exercise group (McCain et al. 1988). Compared to sedentary controls, aerobic walking also had inconclusive effects on pain questionnaire and health-related quality-of-life instruments (Nichols and Glenn 1994).

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. Although symptoms variably improved in some studies, the results do not show consistent improvement in a particular symptom complex with exercise alone.

Biofeedback

Benefits. After a larger, partially favorable experience in an uncontrolled study, a very small RCT suggested that EMG biofeedback significantly improved most variables, compared with sham biofeedback (Ferraccioli et al. 1987). Another open-label study also reported reduction in pain with this modality (Sarnoch et al. 1997). The addition of exercise to biofeedback and relaxation training may result in longer-lasting improvements than with either alone (Buckelew et al. 1998).

Hypnotherapy

Benefits. Only one study was identified. A decrease in fatigue, improved sleep, and less pain were found in those receiving hypnotherapy com

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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pared with a control group assigned to physical therapy. Tender point counts did not differ significantly, however (Haanen et al. 1991).

Acupuncture

Benefits. Compared to a sham procedure, electro-acupuncture significantly improved seven out of eight fibromyalgia outcome measures in an RCT of 70 subjects (Deluze et al. 1992). An older, open-label investigation of an average of slightly over one and a half years showed that 60% of patients had subjective improvements and nearly 70% were taking less medicine at the end of the follow-up period (Waylonis 1977).

Harms. Harms included needle insertion pain and the risk for bloodborne infections if appropriate aseptic technique is not practiced.

Comments. A National Institutes of Health consensus panel has concluded that acupuncture may have benefits in a comprehensive fibromyalgia program (Conference 1998).

CBT and Multidisciplinary Approaches

Benefits. A Cochrane review of multidisciplinary rehabilitation identified only seven studies that met inclusion criteria. Four of these RCTs, graded as low quality, suggested no quantifiable benefits. However, behavioral treatment and stress management and education combined with physical training appeared to show some positive benefits in the long term (Karjalainen et al. 2000). Although a Cochrane review examining CBT for adults with the related (and often overlapping) disorder chronic fatigue syndrome found CBT superior to other treatment approaches (Price and Couper 2000), nearly all CBT studies in fibromyalgia have been uncontrolled or quasi-experimental.

Only three CBT studies in the fibromyalgia literature have appropriate placebo controls or alternative treatments. None of these studies showed clear benefits of behavioral approaches in fibromyalgia (Nicassio et al. 1997; Vlaeyen et al. 1996; Buckelew et al. 1998). Both the Nicassio et al. and the Valeyen et al. studies found that CBT was no more effective than attention placebo. The Buckelew et al. study compared CBT to exercise alone, a combination of CBT and exercise, and to an attention placebo. It was found that all three active treatments produced lower tender point counts than did the attention placebo. However, this effect was likely artifactual since the tender point counts increased in the attention placebo group. There were no other between-group differences in reports of pain or on objective measures of pain behavior.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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The follow-up analysis indicated that change in self-efficacy was significantly correlated with improvement in self-report of pain and the tender point index. No treatment was superior in increasing self-efficacy. Consistent changes were observed in the expected outcome variables in one CBT program (Nielson et al. 1992). At 30 months follow-up, 22 subjects of the original group of 25 had changes in the 10 target variables all in the direction of improvements (White and Nielson 1996). The committee is aware of no major adverse effects of CBT, which is generally considered safe.

Mulitimodal approaches involving education and both physical and behavioral therapy have yielded positive results in several studies. Group treatment (formal lectures, stress reduction, exercise training, and spousal support) showed considerable longitudinal improvement in tender points and on the fibromyalgia impact questionnaire (Bennett et al. 1996). A comparison of integrated group therapy and group relaxation training showed significantly more long-term benefit than a control program consisting of only autogenic training (Keel et al. 1998). In another open-label study of a multidisciplinary program involving cognitive and exercise therapy, somatic pain intensity was significantly reduced compared to baseline (Mengshoel et al. 1995). Group education plus group discussion appeared more successful than a cognitive education intervention alone in another study (Vlaeyen et al. 1996).

Practice Issues

Fibromyalgia treatment studies have been conducted mostly in women and the extrapolation of these findings to the predominantly male Gulf War veterans is unproven. The generally low costs of tricyclic antidepressants and the relatively low toxicity profile of these agents in otherwise healthy individuals have made these drugs of first choice for treating fibromyalgia in many general-practice settings. The use of non-pharmacological approaches, while meriting further study, is limited by availability and cost concerns.

Recommendation

The committee recommends that:

  • Gulf War veterans who meet criteria for fibromyalgia not receive treatment with opioid analgesics or glucocorticoids and

  • In the absence of therapies of generally proven benefit, results of treatment studies of physical training, tricyclic antidepressants, and acupuncture should be further monitored in Gulf War veterans who meet the criteria for fibromyalgia.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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HEADACHE

Introduction

Migraine headache is conservatively estimated to affect about 10% of the population. Other headache types are more prevalent. However, only a small subset of affected individuals seek medical attention for evaluation and treatment. Among these, the majority have primary headaches, with only a few having headaches secondary to structural, inflammatory, or other pathological intracranial processes. Primary headaches can, in turn, be divided into migraine and nonmigraine headaches. Consensus criteria for the diagnosis of migraine are listed below. Headaches that are not of acute onset, that meet criteria 1.1.E and 1.2.C below (i.e., are not suggestive of intracranial disease) but do not meet the other criteria, can be considered primary nonmigrainous headaches, and the same therapeutic and diagnostic approach is applicable. Table 5-5 presents the International Headache Society's diagnostic criteria for migraine headache without and with aura.

Evaluation and treatment of patients with primary headache were recently addressed by the U.S. Headache Consortium, at the request of the American Academy of Neurology. Material in the following sections related to headache is based on the work of the consortium, a complete copy of which can be found online at http://www.aan.com . * The consortium developed practice guidelines for use in the primary practice setting for the management of primary headaches, particularly migraine. Explicitly excluded were new-onset headaches or headaches secondary to identifiable pathology (mass lesions, infections, intracerebral bleeds, etc). No other guidelines are available specifically addressing nonmigrainous primary headaches (e.g., tension headaches), but there is sufficient overlap both in syndromes and in management that these guidelines provide an excellent approach for both types of primary headaches.

All available studies were reviewed by the U.S. Headache Consortium, which graded the aggregated evidence, including the number of studies and the consistency of their findings, thereby implicitly acknowledging that trials of the same treatment sometimes yield conflicting results. Consortium recommendations were graded according to the following scale, adapted from an Agency for Healthcare Research and Quality Research Guideline:

* Neither the U.S. Headache Consortium nor the American Academy of Neurology is resonsible for the text abstraction nor were they requested to verify the text.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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TABLE 5-5 Diagnostic Criteria for Migraine Headache Without and With Aura

1.1 Migraine without aura:

A. At least five attacks fulfilling B–D

B. Headache attacks lasting 4–72 hours a (untreated or unsuccessfully treated).

C. Headache has at least two of the following characteristics:

1. Unilateral location

2. Pulsating quality

3. Moderate or severe intensity (inhibits or prohibits daily activities)

4. Aggravation by walking, stairs, or similar routine physical activity

D. During headache at least one of the following:

1. Nausea and/or vomiting

2. Photophobia and phonophobia

E. At least one of the following:

1. History, physical, and neurological examinations do not suggest headaches secondary to identifiable pathology (e.g., mass lesions, infections, intracerebral bleeds, etc.)

2. History, physical, and/or neurological examinations do suggest such a disorder, but it is ruled out by appropriate investigations

3. Such a disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder

1.2 Migraine with aura:

A. At least two attacks fulfilling B

B. At least three of the following four characteristics:

1. One or more fully reversible aura symptoms b indicating focal cerebral cortical and/or brain stem dysfunction

2. At least one aura symptom develops gradually over more than four minutes or two or more symptoms occur in succession

3. No aura symptom lasts more than 60 minutes. If more than one aura symptom is present, accepted duration is proportionally increased

4. Headache follows aura with a free interval of less than 60 minutes (it may also begin before or simultaneously with the aura)

C. At least one of the following:

1. History, physical, and/or neurological examination do not suggest headaches secondary to identifiable pathology (see 1.1.E.1)

2. History, physical, and/or neurological examination do suggest such a disorder, but it is ruled out by appropriate investigations

3. Such a disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder

a In children under age 15, attacks may last 2–48 hours. If the patient falls asleep and wakes up without migraine, duration of attack is until time of awakening.

b Aura symptoms: A preheadache prodrome, most commonly consisting of perceived flashing lights or other evolving neurological symptoms.

SOURCE: IHS Members Handbook 1997/1998, pp. 54–56. Reprinted with permission of the International Headache Society.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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A. Multiple well-designed randomized clinical trials, directly relevant to the treatment under consideration yielded a consistent pattern of findings.

B. Some evidence from randomized clinical trials supported use of the treatment, but the scientific support was not optimal. For instance, few randomized trials existed, the trials that did exist were somewhat inconsistent, or the trials were not directly relevant. An example of the last point would be the case where trials were conducted using a study group that differed from the target group.

C. The U.S. Headache Consortium achieved consensus on the therapy in the absence of relevant randomized controlled trials.

A key factor in determining appropriate treatment is to identify whether a patient's headaches are primary or secondary, a decision that may require neuroimaging or other evaluation. An abnormal neurological examination increases the likelihood of finding significant intracranial pathology (e.g., brain tumor, arteriovenous malformation, hydrocephalus) on neuroimaging. The absence of any abnormalities on neurological examination reduces the odds of finding a significant abnormality on imaging. Therefore, neuroimaging should be considered in patients with nonacute headache and an unexplained abnormal finding on the neurological examination (Grade B).

Headache worsened by Valsalva maneuver, headache causing awakening from sleep, new headache in the older population, or progressively worsening headache may indicate a higher likelihood of significant intracranial pathology, as reported in several small studies. One study reported that a history of headache worsening with Valsalva maneuver significantly increased the odds of finding a significant intracranial abnormality on neuroimaging. In general, however, the absence of signs and symptoms is less reliable and informative than their presence. The consortium concluded that evidence is insufficient to make specific recommendations regarding neuroimaging in the presence or absence of neurological symptoms (Grade C).

The U.S. Headache Consortium did identify three consensus-based (not evidence-based) general principles of when to perform additional testing:

  • 1. Testing should be avoided if it will not lead to a change in management.
  • 2. Testing is not necessary if the individual is not significantly more likely than anyone else in the general population to have a significant abnormality.
  • 3. Testing that normally may not be necessary as a population policy may make sense at an individual level, resources notwithstanding. For
Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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example, exceptions can be considered for patients who are disabled by their fear of serious pathology or for whom the provider is suspicious even in the absence of known predictors of abnormalities on neuroimaging studies (red flags).

Migraine and Normal NeurologicalExamination

Meta-analysis of studies of patients with migraine and a normal neurological examination found a rate of significant intracranial lesions of 0.18% (2/1000; previously reported rates of finding intracranial lesions with CT and MRI ranged from 0.3 to 0.4%). Neuroimaging is thus unlikely to reveal an abnormality on MRI or CT scanning in patients with migraine and a normal neurological examination.

Therefore, neuroimaging is not usually warranted for patients with migraine and normal neurological examination (Grade B). For patients with atypical headache features or patients who do not fulfill the strict definition of migraine (or have some additional risk factor), a lower threshold for neuroimaging may be applied (Grade C).

Tension-Type Headache and Normal Neurological Examination

In two studies of imaging in patients with tension-type headache (one study specified chronic tension-type headache and normal neurological examinations), no significant lesions were demonstrated. Therefore, data were deemed insufficient to make an evidence-based recommendation regarding the use of neuroimaging for tension-type headache (Grade C).

Based on the limited data in the studies reviewed, MRI appears to be more sensitive in finding white matter lesions and developmental venous anomalies than CT, a result that could be expected based upon the characteristics of the two technologies. The greater resolution and discrimination of MRI, however, appear to be of little clinical importance in the evaluation of patients with nonacute headache. Data were lacking comparing enhanced with unenhanced CT scans. Therefore, data were deemed insufficient to make any evidence-based recommendations regarding the relative sensitivity of MRI compared with CT in the evaluation of migraine or other nonacute headache (Grade C).

Evaluation of Therapies

Consortium evaluations of treatments are presented in Tables 5–6, 5–7, and 5–8. These evaluations are based primarily on findings in patients referred to headache programs. In practice, many patients will respond to simple analgesics such as acetominophen or non-steroidal anti-inflammatories, which should generally be tried first. Patients who fail to

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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TABLE 5-6 Acute Pharmacological Management

Drug Class

Quality of Evidence (A, B, C)

Benefit/ClinicalEffect

Harms

Anti-emetics

(e.g., prochlorperazine)

C

+

Occasional to frequent

IM (e.g., chlorpromazine)

C

++

Infrequent to occasional

IV (e.g., metoclopramide)

B

++

Infrequent to occasional

IV, IM, PR. Prochlorperazine

B

++

Occasional to frequent

Serotonin receptor (5-HT3) antagonists

B

0

Occasional

(as adjunct for nausea)

C

+

Occasional

Butalbital-containing agents

B

+++

Occasional

Ergot alkaloids

Ergotamine PO, PR

B

+

Frequent

DHE IV

B

+++

Frequent

DHE IM, SQ

B

+++

Occasional

DHE IV+antiemetics IV

B

+++

Frequent

DHE nasal spray

A

+++

Occasional

Acetominophen

B

+/−

Infrequent

NSAIDS PO

A

++

Occasional

Ketorolac IM

B

++

Infrequent

Opiates

Butorphanol nasal spray

A

+++

Frequent

Oral (e.g., acetominophen and codeine)

A

++

Occasional

IM/IV

B

++

Frequent

Triptans (serotonin 1B/1D receptor agonists) PO

A

+++

Infrequent to occasional

Nasal, SQ

A

+++

Occasional

Isometheptene

B

+

Occasional

Corticosteroids

C

++

Infrequent

The clinical effect of each drug is indicated on a five-point scale: 0, no evidence of benefit, +/−, equivocal evidence; +, somewhat beneficial; ++, beneficial; +++, highly beneficial.

SOURCE: McCrory et al. 2000.

Reprinted with permission of the American Academy of Neurology.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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TABLE 5-7 Prophylactic Pharmacologic Management I

Drug Class

Quality of Evidence (A, B, C)

Benefit/Clinical Effect

Harms

Alpha 2 agonists

B

+/−

Frequent

Anticonvulsants

Carbamazepine

B

0

Occasional to frequent

Valproate

A

+++

Occasional to frequent

Gabapentin

B

++

Occasional to frequent

Antidepressants

Amitriptyline

A

+++

Frequent

Nortriptyline

C

+++

Frequent

Doxepin, imipramine

C

+

Frequent

SSRIs

B, C (agent specific)

+

Occasional

Beta blockers

Propranolol

A

+++

Infrequent

Atenolol, metoprolol, nadolol, timolol

B

+++

Infrequent

Calcium channel blockers

B, C (agent specific)

+/−

Occasional

NSAIDs

Naproxen

B

++

Infrequent

Others

B

+

Infrequent

The clinical effect of each drug is indicated on a five-point scale: 0 , no evidence of benefit; +/−, equivocal evidence; +, somewhat beneficial; ++, beneficial; +++, highly beneficial.

SOURCE: Ramadan et al. 2000.

Reprinted with permission of the American Academy of Neurology.



respond to these or simple dietary or environmental changes can be treated as indicated. In general, primary headaches can be expected to affect individuals for many years, and this must be taken into consideration in recommending treatment modalities that have potential side effects. Side effects that may be tolerable for a few days or weeks may become far less so if they will be present for years, during pregnancy, or during times when no cognitive compromise is tolerable. It is incumbent on the physician to explore these issues with the patient and decide jointly on the best long-term approach.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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TABLE 5-8 Prophylactic Pharmacological Management II

Group 1

Group 2

Group 3

Group 4

Group 5

Medium-to-high efficacy, good strength of evidence, and a range of severity (mild to moderate) and frequency (infrequent to frequent) of side effects

Lower efficacy than those listed in first column, or limited strength of evidence, and mild-to-moderate side effects

Clinically efficacious based on consensus and clinical experience, but no scientific evidence of efficacy

Medium-to-high efficacy, good strength of evidence, but with side effect

Evidence indicating no efficacy over placebo

Amitriptyline

Aspirin

A. Mild-to-moderate side effects

Methysergide

Acebutolol

Divalproex sodium

Lisuride *

Propranolol

Timolol

Atenolol

Cyclandelate *

Fenoprofen

Feverfew

Flurbiprofen

Fluoxetine(race Mic)

Cyproheptadine

Bupropion

Diltiazem

Doxepin

Fluvoxamine

Ibuprofen

Flunarizine *

Pizotifen *

TR-DHE *

Alprenolol *

Carbamazepine

Clomipramine

Clonazepam

Clonidine DEK *

Femoxetine *

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Gabapentin

Guanfacine

Indobufen *

Ketoprofen

Lornoxicam *

Magnesium

Mefenamic acid

Metoprolol

Nadolol

Naproxen

Naproxen sodium

Nimodipine

Tolfenamic acid *

Verapamil

Vitamin B–2

Imipramine

Mirtazepine

Nortriptyline

Paroxetine

Protriptyline

Sertraline

Tiagabine

Topiramate

Trazodone

Venlafaxine

B. (Side effect concerns)

Methylergonovine (methylergometrine)

Phenelzine

Flumedroone *

Indomethacin

Iprazchrome *

Lamotrigine

Miaserin *

Nabumetone

Nicardipine

Nifedipine

Oxprenolol *

Oxitriptan *

Pindolol

Tropisetron *

Vigabatrin *

* Not available in United States. Reprinted with permission of the American Academy of Neurology.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Acute Pharmacotherapy

Benefits. As summarized in Table 5-6, many classes of agents have been shown to be effective in the acute management of headaches. Selection of specific agents requires a careful consideration of demonstrated efficacy, strength of the data on which this conclusion is based (Classes A and B), and potential side effects.

Harms. Medication side effects vary widely, including cardiovascular and gastrointestinal symptoms with ergots and triptans, sedation with butalbital and opiates, and gastric irritation with NSAIDs.

Prophylactic Pharmacotherapy

Benefits. As summarized in Tables 5-7 and 5-8, many classes of agents have been shown to be effective in the prophylactic management of headaches. Selection of specific agents requires a careful consideration of demonstrated efficacy, strength of the data on which this conclusion is based (Classes A and B), and potential side effects.

Harms. Medication side effects vary widely, including cardiovascular and gastrointestinal symptoms with antidepressants and calcium antagonists, sedation, cardiovascular and mood-related symptoms with beta blockers, gastric irritation with NSAIDs, and so on.

Comment. Prophylactic pharmacotherapy is generally used only in those patients in whom the severity or frequency of headaches is sufficient to warrant the inconvenience and long-term side effects of daily medication.

Behavioral and Physical Therapies

Benefits. Relaxation training with or without thermal biofeedback, EMG biofeedback, and cognitive-behavioral therapy are all somewhat effective in preventing migraines (Classes A and B).

Harms. The committee is aware of no major adverse effects of these modalities.

Relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback, and cognitive-behavioral therapy are all somewhat effective in preventing migraine when compared with controls. Given the evidence reviewed, no conclusions can be made regarding equivalence or superiority among specific behavioral treatments or for specific behavioral treatments relative to other specific preventive

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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pharmacological therapies. Therefore, relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback, and cognitive-behavioral therapy may be considered as treatment options for prevention of migraines (Grade A). Specific recommendations regarding which of these to use for specific patients cannot be made.

Behavioral treatments have been directly compared and integrated with drug treatments as preventive therapy for migraines. The addition of propranolol conferred additional clinical benefits when added to (1) thermal biofeedback plus relaxation plus cognitive-behavioral therapy, (2) thermal biofeedback plus relaxation, and (3) EMG biofeedback (amitriptyline also proved beneficial in a later trial). Therefore, behavioral therapy (i.e., relaxation, biofeedback) may be combined with preventive drug therapy (i.e., propranolol, amitriptyline) for patients to achieve additional clinical improvement for migraine relief (Grade B).

The empirical evidence pertaining to treatment of migraines with acupuncture is limited and the results are mixed. Very limited evidence evaluates hypnosis, TENS, cervical manipulation, occlusal adjustment, and hyperbaric oxygen as preventive or acute therapy for migraine. Therefore, evidenced-based treatment recommendations are not yet possible regarding the use of hypnosis, acupuncture, TENS, cervical manipulation, occlusal adjustment, and hyperbaric oxygen as preventive or acute therapy for migraines. For hyperbaric oxygen treatment, even if further studies confirmed the efficacy results presented above, the lack of availability would limit practical clinical application of this treatment (Grade C).

Practice Issues

A physician's treatment of patients with primary headache includes pharmacological management of acute attacks, prophylactic pharmacological management, and behavioral management. Tables 5-6, 5-7, and 5-8 summarize conclusions regarding relative efficacy and side effects for each class of drug.

Each patient should be actively engaged in his or her own management decisions (e.g., discuss treatment/medication preferences), and in each instance treatment must be tailored to the individual's needs (e.g., based on severity of illness, comorbidity/coexisting conditions, prior response to medications). When creating and maintaining a partnership, realistic patient expectations need to be established. General principles of management include:

  • 1. Educate migraine sufferers about their condition and its treatment and encourage them to participate in their own management.
  • 2. Use migraine-specific agents (triptans, DHE, ergotamine) in patients
Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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with more severe migraine and in those whose headaches respond poorly to NSAIDs or combination analgesics such as aspirin plus acetaminophen plus caffeine. Despite the lack of evidence that headaches of different type and seventy respond to specific agents, strong clinical impression suggests that this is true. Failure to use an effective treatment promptly may increase pain, disability, and the impact of a headache.

  • 3. Select a nonoral route of administration for patients whose migraines present early with nausea or vomiting as a significant component of the symptom complex.
  • 4. Consider a self-administered rescue medication for patients with severe migraine who do not respond well to (or fail) other treatments.
  • 5. Guard against medication-overuse headache. (The terms “rebound headache” or “drug-induced headache” are sometimes used interchangeably with “medication-overuse headache.”)
  • 6. When choosing specific agents, in addition to a consideration of the demonstrated efficacy and side effects of that agent, it is important to consider the strength of the evidence supporting use of that drug (i.e., Class A data). However, for many effective drugs, optimal studies have not been performed, often because closely related agents are known to be effective and there has been little incentive to study these additional agents. Therefore, in many instances (DHE, calcium antagonists, specific tricyclics) agents are widely used and are considered effective, despite the absence of Class A studies.

Recommendations

For Gulf War veterans with chronic headache not associated with underlying pathology (e.g., tumors, vascular abnormalities), the committee recommends the following treatments:

  • pharmacological management of acute episodes, using agents listed in Table 5-6 , taking into consideration the clinical effectiveness and potential side effects, as listed;

  • prophylactic pharmacological management for headaches that occur frequently or are disruptive to the patient's functioning, as listed in Tables 5-7 and 5-8 , taking into consideration the clinical effectiveness and potential side effects, as listed;

  • use of behavioral and physical treatments, including relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback and cognitive-behavioral therapy, or behavioral therapy combined with preventive drug therapy.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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IRRITABLE BOWEL SYNDROME

Introduction

Irritable bowel syndrome (IBS) is a common clinical condition that affects 10–20% of adults. Epidemiological studies indicate a high prevalence in the general population; 14 to 24% of women and 5 to 19% of men (Drossman et al. 1997; Jailwala et al. 2000). Reports indicate that IBS accounts for 12% of visits to primary care providers and 28% of visits to gastroenterologists and that patients with IBS have poorer quality of life and higher health care utilization than persons without the disorder (Drossman 1993; Whitehead et al. 1996; Jailwala et al. 2000). Community-based studies have provided data to demonstrate that patients with IBS have greater disability, threefold higher absenteeism from work, and two-fold higher average health care costs than do healthy controls (Talley et al. 1995a, b; Jailwala et al. 2000).

The Rome II Criteria, revised in 1999 by an international consensus group, is an established standard for the diagnosis of IBS (see Table 5-9).

There are no structural or biochemical markers for IBS. A diagnosis established utilizing the Rome Criteria and thorough physical examination should be followed by further evaluation as appropriate for the specific age group and clinical setting. Performing extensive laboratory, radiological, or endoscopic procedures does not establish a diagnosis of IBS; it is often unnecessary and may be harmful (Functional GI Disorders 2000).




TABLE 5-9 Rome II Diagnostic Criteria for Irritable Bowel Syndrome

Abdominal discomfort or pain that has two of these features:

• Relief with defecation

• Onset associated with change in stool frequency

• Onset associated with change in form (appearance of stool)

• Symptoms for at least 12 weeks in the preceding 12 months (need not be consecutive weeks)

The following symptoms, while not essential, increase the diagnostic confidence with their presence:

• Abnormal stool frequency (>three/day or <three/week)

• Abnormal stool form (lumpy/hard or loose/watery)

• Abnormal stool passage (straining, urgency, feelings of incomplete evacuation)

• Passage of mucus

• Bloating or feeling of abdominal distention

SOURCE: Thompson et al. 1999. Reprinted with permission from BMJ Publishing.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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Evaluation of Therapies

Beneficial

  • Antispasmodic agents, tricyclic antidepressants, and cognitive-behavioral therapy appear to be efficacious in the treatment of IBS.

Likely to Be Beneficial

  • Fiber supplements are likely to be beneficial when constipation is the predominant symptom of IBS. If diarrhea is the predominant symptom, opiates (loperamide, diphenoxylate HC with atropine sulfate) are likely to be beneficial. Loperamide does not cross the blood-brain barrier and is therefore preferable to other narcotics such as codeine or diphenoxylate.

Unknown Efficacy

  • Many pharmacotherapeutic approaches discussed in this report have not been sufficiently investigated, and therefore evidence of their true effectiveness remains unknown. These include SSRIs (selective serotonin reuptake inhibitors), prokinetic agents, oral prostaglandins, complementary alternative medicine approaches, and other newer antidepressants and anxiolytics.

Pharmacological Therapies

Treatment strategies must be individualized and based on the severity of symptoms. A comprehensive electronic search of MEDLINE (1966 to 1999), EMBASE (1980 to 1999), PsycINFO (1967 to 1999), and the Cochrane controlled trials registry was undertaken to identify randomized, double-blind, placebo-controlled, parallel, or cross-over trials of a pharmacological intervention for adult patients who reported outcomes of improvement in global or irritable bowel-specific symptoms in order to evaluate the efficacy of pharmacological agents for IBS (Jailwala et al. 2000) (see Table 5-10). A manual search of the bibliographies from all retrieved publications was also conducted by these same investigators.

A trial had to satisfy the following six criteria for inclusion:

  • address treatment of IBS;

  • study adult patients;

  • administer a pharmacological intervention to more than 10 patients for at least two weeks;

  • include a placebo-control group;

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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TABLE 5-10 Efficacy of Pharmacological Interventions in the Treatment of IBS

Global or Symptom Improvement

Global Improvement

Intervention

Total Trials

Positive Trials

Total Trials

Positive Trials

Balance of Evidence and Recommendations

Bulking agents

All trials

13

4

11

4

Efficacy not clearly established

High-quality trials

7

3

7

3

Smooth-muscle relaxants

All trials

16

13

12

9

Beneficial for abdominal pain

High-quality trials

7

7

5

4

Prokinetic agents

All trials

6

2

5

2

Evidence inconclusive for domperidone; Cisapride removed from market

High-quality trials

4

1

3

1

Loperamide

All trials

4

4

2

2

Beneficial for diarrhea

High-quality trials

2

2

1

1

Psychotropic agents

All trials

7

7

5

5

Evidence inconclusive; more high-quality trials are needed

High-quality trials

1

1

1

1

Peppermint oil

All trials

3

1

2

0

Efficacy not clearly established

High-quality trials

1

1

0

0

5-Hydroxtripta-mine-receptor antagonists

All trials

3

3

3

3

Evidence suggestive; further study required

High-quality trials

2

2

2

2



SOURCE: Jailwala et al. 2000. Reprinted with permission from the American College of Physicians.

Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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  • report an outcome measure of global status or individual symptoms (or both) of IBS; and

  • use a randomized double blind, parallel group or cross-over design.

  • These inclusion criteria were independently applied by all three authors to a subset of studies to assess interrater variation. Criteria for high-quality trials were established. A summary of 28 high-quality trials of pharmacotherapy for IBS was listed, and efficacy of pharmacological interventions in the treatment of IBS was detailed.

    To be noted is that although four smooth-muscle relaxants (cimetroprium, pinaverium, otilonium, and trimetubutine) were consistently shown to be efficacious in high-quality trials, none of these agents is currently approved for treatment of IBS in the United States (Jailwala et al. 2000).

    Antimuscarinic agents are frequently prescribed in the United States for symptoms of IBS specifically for abdominal pain and associated distention. Relief is probably associated with reduction in the contractility of the gut due to precipitating factors such as specific food intake, stress, or other inciting agents. In a study meta-analysis of smooth-muscle relaxants in IBS (Poynard et al. 1994), this class of drugs was significantly better than placebo for global assessment (62 to 35% improvement) and abdominal pain (65 vs. 45%). Similar findings were noted in a 1997 study of IBS. This study reviewed 15 randomized well-controlled studies of at least two weeks' duration (Camilleri and Choi 1997).

    Practice Issues

    Several psychological treatments have been studied in patients with IBS, including psychodynamic/interpersonal psychotherapy, cognitive-behavioral treatment, hypnosis, relaxation, biofeedback, and meditation. “These seem to be effective in reducing abdominal pain and diarrhea but not constipation, and they also reduce anxiety and other psychological symptoms. It is not known whether the improvement in irritable bowel symptoms relates to changes in gastrointestinal physiology or in the psychological interpretation of enteroceptive sensation. A positive response is associated with patients who relate symptom exacerbations to stressors and have a waxing and waning of symptoms rather than chronic pain. There are no comparative data to determine which treatments are superior, and additional studies are needed to determine the relative efficacy of psychological treatments for various subgroups of patients” (Drossman et al. 1997).

    Practice Issues are outlined in Table 5-11. Antidepressants are usually used in smaller doses for IBS patients than for depression. See Table 5-12.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    TABLE 5-11 Practice Issues/Considerations

    Class

    Example

    Principal Use

    Dosage

    Antispasmodics

    Hyoscyamine

    Pain predominant

    0.125–0.250 mg q4 hours

    Dicyclomine

    1–40 mg qid

    Opiates

    Loperamide

    Diarrhea predominant

    2–4 mg qid

    Diphenoxylate HCL with atropine sulfate

    1–2 tablets qid

    Bile acid sequestrant

    Cholestyramine

    Diarrhea predominant

    4–24 gm qd in divided doses

    5-HT3 antagonist

    Alosetron *

    Diarrhea predominant in female patients

    1 mg bid

    Fiber supplement

    Psyllium, methycellulose, Ca polycarbophil

    Constipation predominant

    Titrate to regular BMs (20–30 gm qd)

    Isosmotic electrolyte solution

    PEG 3350

    Constipation predominant

    Titrate to regular BMs (17–34 gm qd-bid)

    Oral prostaglandin

    Misoprostil

    Constipation predominant

    200–400 mg qd-tid

    * Recent voluntary withdrawal from market due to adverse effects.

    SOURCE: Functional GI Disorders: New Visions. 2001. Monograph. Foundation for Digestive Health and Nutrition, created by the American Gastroenterological Association, p. 12. Reprinted with permission of the American Gastroenterological Association.

    A randomized controlled trial supporting the efficacy of psychodynamic psychotherapy appeared in the literature (Guthrie et al. 1993), as did controlled studies generally supportive of cognitive-behavioral therapy (Blanchard et al. 1981; Bennet and Wilkinson 1985; Neff and Blanchard 1987; Lynch and Zamble 1989; Corney et al. 1991; Runsey 1991; Shaw et al. 1991; Greene and Blanchard 1994; Payne and Blanchard 1995; VanDulmen et al. 1996; Toner et al. 1998).

    A randomized double-blind placebo-controlled trial of 116 patients who fulfilled the Rome Criteria was conducted during 1996-1997 utilizing Chinese herbal medicine (Bensonssan et al. 1998). Patients were randomly allocated to one of three treatment groups; individualized Chinese herbal formulations, a standard Chinese herbal formulation, or placebo.

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    TABLE 5-12 Antidepressants for IBS Gastrointestinal Disorders

    Class

    Example

    Principal Use

    Dosage

    TCAs

    Amitriptyline, Desipramine, Doxepin, Imipramine, Nortriptyline

    Treatment of Pain, Nausea, and Nonspecific Symptoms

    Low-Dose Range (e.g., 25–75 mg qd)

    SSRIs

    Fluoxetine, Fluvoxamine, Paroxetine, Sertraline

    Treatment of Symptoms of Concurrent Anxiety and Depression

    Usual Psychiatric Dosage

    Other newer Antidepressants and Anxiolytics

    Amoxapine, Buproprion, Maprotyline, Mirtazapine, Nefazodone, Trazodone, Venlafaxine

    Treatment of Symptoms of Concurrent Anxiety and Depression

    Usual Psychiatric Dosage



    Initially, patients in the active treatment groups had significant improvement in bowel symptom scores as compared to placebo. However, on follow-up 14 weeks after completion of treatment only the individualized complementary and alternative medicine (CAM) treatment group maintained improvement. Further trials designed to study individual herbs in the various manifestations of IBS will be required to demonstrate consistent therapeutic efficacy of CAM therapy.

    The conclusion noted in the American Digestive Health Foundation monograph, Functional GI Disorders (2000), is most useful in treating patients with IBS: “A therapeutic program that concentrates more on ‘health' than on ‘illness,' that teaches coping strategies rather than promises a cure, is, in the end, far more likely to maximize the value (both economic and medical) of the intervention and provide relief for patients suffering from this still mysterious debilitating disorder.”

    Recommendations

    For Gulf War veterans who meet the diagnostic criteria for IBS, the committee recommends that:

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    • cognitive-behavioral therapy, tricyclic antidepressants (TCAs), and smooth-muscle relaxants be considered in appropriate age-specific, carefully selected clinical settings and

    • results of treatment studies should be monitored to clearly establish therapeutic effectiveness of these agents in the various subgroups of patients diagnosed with IBS.

    PANIC DISORDER

    Introduction

    Panic disorder consists of recurrent, unexpected panic attacks accompanied by at least one month or more of persistent concern about having another attack, worry about the implications of having an attack, or significant behavioral change related to the attack. At least four of 13 characteristic symptoms must occur during the attacks, such as shortness of breath, dizziness, palpitations, and trembling or shaking (American Psychiatric Association 2000). The clinician will have determined that the attacks are not induced by a substance (e.g., caffeine) or a medical illness (e.g., hyperthyroidism) and that the anxiety is not better accounted for by another mental disorder. Table 5-13 contains the DSM-IV definition of panic attacks. Table 5-14 provides the DSM-IV criteria for panic disorder without agoraphobia.



    TABLE 5-13 DSM IV-TR Criteria for Panic Attack

    A discrete period of intense fear or discomfort, in which four (or more) of the following symptoms developed abruptly and reached a peak within 10 minutes:

    1. Palpitations, pounding heart, or accelerated heart rate

    2. Sweating

    3. Trembling or shaking

    4. Sensations of shortness of breath or smothering

    5. Feeling of choking

    6. Chest pain or discomfort

    7. Nausea or abdominal distress

    8. Feeling dizzy, unsteady, lighthearted, or faint

    9. Derealization (feelings of unreality) or depersonalization (being detached from oneself)

    10. Fear of losing control or going crazy, fear of dying

    11. Paresthesias (numbness or tingling sensations)

    12. Chills or hot flushes

    SOURCE: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, 1994, Fourth Edition, Text Revision, copyright 2000, American Psychiatric Association, p. 395.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    TABLE 5-14 DSM-IV Criteria for Panic Disorder Without Agoraphobia

    A. Both 1 and 2:

    1. Recurrent unexpected panic attacks.

    2. At least one of the attacks has been followed by at least one month (or more) of one (or more) of the following: (a) persistent concern about having additional attacks; (b) worry about the implications of the attack or its consequences (e.g., losing control, having a heart attack, “going crazy” ); or (c) a significant change in behavior related to the attacks.

    B. Absence of agoraphobia.

    C. The panic attacks are not due to the direct physiological effects of a substance (e.g., drug of abuse, medication) or a general medical condition (e.g., hyperthyroidism).

    D. The panic attacks are not better accounted for by another mental disorder such as social phobia (e.g., occurring on exposure to feared social situations), specific phobia (e.g., on exposure to the phobic situation), obsessive-compulsive disorder (e.g., exposure to dirt in someone with an obsession about contamination), posttraumatic stress disorder (e.g., in response to stimuli associated with a severe stressor), or separation anxiety disorder (e.g., in response to being away from home or close relatives).

    SOURCE: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, copyright 2000. American Psychiatric Association, p. 402.



    It is estimated that 2 to 3% of women and 0.5 to 1.5% of men have panic disorder (Robins et al. 1984). Panic disorder has an onset in the mid-20s, although age of onset may vary. One-third to one-half of panic patients develop agoraphobia, a condition in which they experience anxiety and avoidance of places or situations where escape or help may be unavailable if panic symptoms occur (Weissman et al. 1997). Situations eliciting agoraphobia include traveling on buses, subways, or other public transportation and being on bridges, in tunnels, or far from home.

    Panic attacks vary in frequency and intensity (American Psychiatric Association 1998). They generally have a sudden onset, peak within minutes, and last 5 to 30 minutes. It is not uncommon for individuals to experience numerous moderate attacks for months at a time or to experience frequent attacks daily for a short period, with months separating subsequent periods of attack.

    Among individuals with panic disorder, the lifetime prevalence of major depression is 50 to 60% (Lesser et al. 1989). For individuals with both panic disorder and major depression, the onset of major depression precedes the onset of panic disorder in one-third of cases. Subjects with panic symptoms or disorder are frequent users of emergency medical services and are more likely to be hospitalized for physical problems.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    Patients with panic disorder, especially with comorbid depression, are at higher risk for suicide attempts, impaired social and marital functioning, use of psychoactive medication, and substance abuse.

    Panic disorder is generally considered chronic and lifelong (American Psychiatric Association 1998). Although total remission is uncommon, research suggests that 50 to 70% of patients will show some amount of improvement with time. Family studies show that the risk of panic disorder is eight times as high among first-degree relatives of probands with panic disorder as among relatives of control subjects (Knowles and Weissman 1995).

    Evaluation of Therapies

    The care of patients with panic disorder involves a comprehensive array of approaches designed to reduce the frequency and severity of panic attacks, reduce morbidity, and improve patient functioning (American Psychiatric Association 1998). For most patients, treatment is conducted on an outpatient basis. Once the diagnosis is made, a treatment plan should be developed taking into account the specific needs of the patient and the unique factors that may affect the expression of the patient's panic disorder, including developmental factors, psychosocial stressors and conflicts, social supports, and general living situation.

    According to the American Psychiatric Association (1998), elements of clinical management for patients with panic disorder include (1) establishing and maintaining a therapeutic alliance; (2) educating and reassuring the patient concerning panic disorder; (3) evaluating particular symptoms and monitoring them over time; (4) evaluating types and severity of functional impairment; (5) identifying and addressing comorbid conditions; (6) working with other health professionals; (7) educating family members and enlisting their help when appropriate; (8) enhancing treatment compliance; and( 9) working with the patient to address early signs of relapse.

    There are three classes of medication known to be effective in treating panic disorder: SSRIs, TCAs, and BZPs. Medications from all classes have roughly comparable efficacy (American Psychiatric Association 1998; Sheehan 1999). Most medication studies have focused on the value of the drugs in stopping or reducing the frequency of panic attacks, but medication also reduces anticipatory anxiety, phobic avoidance, and depression and improves global functioning.

    Beneficial Therapies

    • SSRIs

    • TCAs

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    • BZPs

    • CBT

    • Maintenance therapy to prevent reoccurence

    Likely to Be Beneficial

    • MAOIs

    • Newer antidepressants (venlafaxine, nefazodone, trazodone)

    • Valproate

    • Group therapy

    Unknown Effectiveness

    • Beta blockers

    • Psychodynamic psychotherapy

    • Marital and family therapy

    Cognitive-Behavioral Therapy (CBT)

    Benefits. CBT has been found to be effective in RCTs for the treatment of panic disorders. Randomized controlled trials of CBT for panic disorder have been conducted with treatment length varying from 4 to 16 weeks. In a summary of 12 studies, the response rate using an intent-to-treat analysis was 66% (American Psychiatric Association 1998). Using completer analysis, the response rate was 78%. Control treatments produced response rates ranging from 8 to 78%.

    Harms. The committee is aware of no major adverse effects of CBT, which is generally considered safe. Patients are informed that the therapy is voluntary and that they may drop out at any time. The therapy is time limited, typically lasting 12–20 sessions.

    Comment. CBT encompasses a range of treatments each consisting of several elements, including psycho-education, continuous panic monitoring, development of anxiety management skills, cognitive restructuring, and in vivo exposure. The efficacy of CBT for the treatment of panic disorder is supported by extensive evidence (Barlow 1997; Shear and Weiner 1997; American Psychiatric Association 1998).

    CBT requires considerable time and discipline on the part of the patient, as well as the availability of a trained therapist. Exercises must be practiced daily, and monitoring must be done continuously. In addition, patients must be willing to confront feared situations. Approximately 10 to 30% of patients are unwilling or unable to complete these requirements (American Psychiatric Association 1998). CBT is less effective for these patients.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    Group Therapy

    Benefits. There is some evidence for the effectiveness of CBT administered in group settings for the treatment of panic disorder (Telch et al. 1993; Neron et al. 1995). Other types of group therapy have more limited evidence for benefit.

    Harms. Some patients may be uncomfortable in group settings, and maintaining confidentiality may be a concern.

    Comment. Group therapy can be an efficient way to help many patients at once.

    Psychodynamic Therapy

    Benefits. There is no evidence for the effectiveness of psychodynamic psychotherapy in the treatment of panic disorder.

    Harms. Psychodynamic psychotherapy may be associated with difficulty in terminating treatment because of the attachment the patient forms with the therapist.

    Comment. Psychodynamic psychotherapy and related therapies by their very nature are not amenable to clinical trials to assess efficacy.

    Marital/Family Therapy

    Benefits. Marital/family therapy has no demonstrated benefit in treating panic disorder. 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/family therapy.

    Comment. Marital and family therapies are usually not administered for the treatment of panic disorder but may be beneficial when marital/family problems are involved in the presentation of the disorder.

    Selective Serotonin Reuptake Inhibitors (SSRIs)

    Benefits. Five SSRIs are now available in the United States: citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. RCTs show that each is effective in treating panic disorder (American Psychiatric Association

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    1998). Paroxetine and sertraline both have a Food and Drug Administration (FDA) indication for the treatment of panic disorder; it is likely that all of the SSRIs are effective in treating it. The database for SSRI therapy of panic disorder is extensive, and there are sufficient controlled trials to conclude that these medications have demonstrated short-term efficacy in treating panic attacks. A recent analysis of 27 studies involving 2,348 patients in randomized perspective, double-blind, placebo-controlled trials suggested that the effect size for improvement with SSRIs and panic disorder is significantly greater than for alprazolam or imipramine (Boyer 1995).

    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 panic disorder. They are widely used but tend to be expensive.

    Tricyclic Antidepressants (TCAs)

    Benefits. TCAs are effective in treating panic and have been used for nearly 40 years for that purpose (American Psychiatric Association 1998). Controlled trials have been conducted with imipramine, desipramine, and clomipramine. Studies show that following treatment with TCAs, 45 to 70% of patients are panic-free compared to 15 to 50% of those receiving placebo.

    Harms. Adverse effects of TCAs include dry mouth, constipation, urinary hesitancy, sweating, sleep disturbance, orthostatic hypotension, fatigue and weakness, weight gain, and sexual dysfunction. Dosages 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.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    Comment. TCAs are used less frequently for treating panic disorder than the newer SSRIs because of their many side effects, although they are equally efficacious.

    Benzodiazepines (BZPs)

    Benefits. BZPs are effective in reducing the intensity and frequency of panic attacks and anticipatory anxiety (Davidson 1997; American Psychiatric Association 1998). Alprazolam has been studied more extensively than the other BZPs and is FDA approved for the treatment of panic disorder. Controlled trials involving more than 1,000 patients have shown alprazolam to be superior to placebo in the treatment of panic attacks. Other benzodiazepines, including diazepam, clonazepam, and lorazepam, given in equivalent doses, are probably as effective as alprazolam in the treatment of panic disorder.

    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 of BZPs can lead to seizures.

    Comment. BZPs should never be used as first-line therapy for panic disorder due to their tendency to cause habituation.

    Beta Blockers

    Benefits. Beta blockers are widely prescribed in primary care settings to treat panic disorder and other anxiety syndromes. Research suggests that they are probably more effective than placebo but are less effective than antidepressants or BZPs.

    Harms. Beta blockers are well tolerated but provide incomplete symptomatic relief.

    Comment. Beta blockers should not be prescribed as a first-line treatment for panic disorder but may be helpful in alleviating peripheral manifestations of the condition, such as heart palpitations.

    Monoamine Oxidase Inhibitors (MAOIs)

    Benefits. MAOI therapy is probably effective in treating panic disorder, but much of the evidence was collected before the diagnosis was introduced in DSM-III in 1980 (American Psychiatric Association 1998).

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    Harms. While the MAO inhibitors are not anticholinergic, their side effects often resemble the tricyclic medications. A major concern with 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. In addition, at least two weeks is recommended between discontinuation of the MAOIs and use of anesthetics for electroconvulsive therapies.

    Comment. Because of the dietary restrictions involved in their use, MAOIs are infrequently used to treat patients with panic disorder and are considered second-line therapies.

    Newer Antidepressants

    Benefits. Venlafaxine, nefazodone, and trazodone may be effective for persons with panic disorder, based on evidence from open-label or small RTCs (Mavissakalian et al. 1987; De Martinis et al. 1996; Pollack et al. 1996).

    Harms. These medications are generally safe and well tolerated, though venlafaxine carries with it the rare possibility of inducing hypertension.

    Comment. More data are necessary before any specific recommendations can be made about their use.

    Valproate

    Benefits. At least one small open-label trial suggests that valproate may be effective in treating panic disorder (Woodman and Noyes 1994).

    Harms. This mood stabilizer is generally well tolerated, although it may be associated with transient nausea, weight gain, and tremor.

    Comment. More information is needed before specific recommendations can be made about its use.

    Maintenance Therapy

    Benefits. RCTs have found that continuing antidepressant drug treatment for patients with panic disorder reduces the risk of relapse (American Psychiatric Association 1998).

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    Harms. Adverse effects are those reported for the specific treatments listed above.

    Comment. It is unclear from the literature how long maintenance therapy should last, although most psychiatrists recommend continuation of pharmacotherapy for at least 6–12 months following response to medication.

    Practice Issues

    CBT and specific medications have been found to be effective treatments for panic disorder (Barlow 1997; Davidson 1997; Jefferson 1997; Shear and Weiner 1997; American Psychiatric Association 1998; Sheehan 1999;). An emerging body of data suggests that patients do best when receiving a combination of CBT and medication (American Psychiatric Association 1998).

    Recommendation

    For Gulf War veterans who meet the criteria for panic disorder, the committee recommends treatment with antidepressant medication and cognitive-behavioral therapy.

    POSTTRAUMATIC STRESS DISORDER

    Introduction

    Posttraumatic stress disorder (PTSD) occurs in persons who have experienced a traumatic occurrence that has involved experiencing, witnessing, or being confronted with an event that involves actual or threatened death, serious physical injury, or a threat to one's physical integrity. Examples include combat situations, physical assault, rape and other forms of sexual assault, and disasters such as home fires. The three major elements of PTSD are (1) reexperiencing the trauma through dreams or recurrent and intrusive thoughts; (2) emotional numbing, such as feeling detached from others; and (3) symptoms of autonomic hyperarousal such as irritability and exaggerated startle response (American Psychiatric Association 2000). Two subtypes are specified in the DSM-IV: acute, when the duration of symptoms is less than three months, and chronic, when symptoms last three months or longer. Table 5-15 provides the DSM-IV definition of PTSD.

    The prevalence of PTSD in the general population is estimated at about 0.5% in men and 1.2% in women (Helzer et al. 1987). Most men with the disorder have experienced combat situations. For women the most

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    TABLE 5-15 DSM-IV Criteria for Posttraumatic Stress Disorder

    A. The person has been exposed to a traumatic event in which both of the following have been present:

    1. The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of oneself or others.

    2. The person's response involved intense fear, helplessness, or horror. Note: In children, it may be expressed instead by disorganized or agitated behavior.

    B. The traumatic event is persistently reexperienced in at least one of the following ways:

    1. Recurrent and intrusive distressing recollections of the event, including images, thoughts, or perceptions. Note: In young children, repetitive play may occur in which themes or aspects of the trauma are expressed.

    2. Recurrent distressing dreams of the event. Note: In children there may be frightening dreams without recognizable content.

    3. Acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations, and dissociative flashback episodes, including those that occur upon awakening or when intoxicated). Note: In young children, trauma-specific reenactment may occur.

    4. Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event.

    5. Physiological reactivity upon exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event.

    C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by at least three of the following:

    1. Efforts to avoid thoughts, feelings, or conversations associated with the trauma.

    continued



    frequent precipitating stressor is a physical assault or rape. The disorder can occur in persons of any age, and even young children have been observed to develop it (American Psychiatric Association 2000).

    PTSD can begin within hours or days of the stressor but can be delayed for months or years. The disorder is chronic for many. Symptoms fluctuate but typically worsen during stressful periods. Rapid onset of symptoms, good premorbid functioning, strong social support, and the absence of psychiatric or medical comorbidity are factors associated with a good outcome (Choy and de Bosset 1992; Davidson and Conner 1999; American Psychiatric Association 2000). Typically, the more severe the stressor, the greater the likelihood of developing PTSD. In wartime situations certain experiences are linked to the development of PTSD, including witnessing a friend killed in action, witnessing wartime atrocities, or

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    2. Efforts to avoid activities, places, or people that arouse recollections of the trauma.

    3. Inability to recall an important aspect of the trauma.

    4. Markedly diminished interest or participation in significant activities.

    5. Feeling of detachment or estrangement from others.

    6. Restricted range of affect (e.g., unable to have loving feelings).

    7. Sense of a foreshortened future (e.g., does not expect to have a career, marriage, or children, or a normal life span).

    D. Persistent symptoms of increased arousal (not present before the trauma), as indicated by at least two of the following:

    1. Difficulty falling or staying asleep.

    2. Irritability or outbursts of anger.

    3. Difficulty concentrating.

    4. Hypervigilance.

    5. Exaggerated startle response.

    E. Duration of the disturbance (symptoms in B, C, and D) is more than one month.

    F. The disturbance causes clinically significant distress or impairment in social, occuptional, or other important areas of functioning.

    Specify if:

    Acute: If duration of symptoms is less than three months

    Chronic: If duration of symptoms is three months or more

    Specify if:

    With delayed onset: If onset of symptoms is at least six months after the stressor

    SOURCE: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, copyright 2000, American Psychiatric Association, pp. 427-429.



    participating in them (Breslau and Davis 1987). The person's age, history of emotional disturbance, level of social support, and proximity to the stressor are all factors that affect the likelihood of developing PTSD (Smith et al. 1990).

    Many patients with PTSD develop comorbid major depression, other anxiety disorders, alcohol and drug abuse, anger and irritability, and poor impulse control (Mellman et al. 1992; American Psychiatric Association 2000).

    Evaluation of Therapies

    The care of patients with PTSD involves a comprehensive array of approaches designed to reduce the frequency and severity of PTSD symp

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    toms (Davidson and Connor 1999). For most patients with PTSD, treatment can be conducted on an outpatient basis. A careful assessment should precede treatment to rule out medical causes for the symptoms. The assessment should take into account the individual's developmental factors, psychosocial stressors and conflicts, social supports, and general living situation.

    Similar to the clinical management of panic disorder, clinicians working with patients who have PTSD should include:

    • 1. establishing and maintaining a therapeutic alliance to educate and reassure the patient concerning the PTSD,
    • 2. evaluating the particular symptoms and monitoring them over time;
    • 3. evaluating types and severity of functional impairment;
    • 4. identifying and addressing comorbid conditions;
    • 5. working with other health professionals;
    • 6. educating family members and enlisting their help when appropriate;
    • 7. enhancing treatment compliance; and
    • 8. working with the patient to address early signs of relapse.

    Cognitive-behavioral therapy (CBT) and medication have both been shown to be effective treatments for PTSD. The choice between psychotherapy and medication depends upon an individualized assessment of efficacy, benefits, and risks of each modality and the patient's personal preferences.

    Beneficial Therapies

    • SSSRIs

    • CBT

    Likely to Be Beneficial

    • TCAs

    • MAOIs

    • BZPs

    • Group therapy

    • Maintenance therapy to prevent reoccurrence

    Unknown Effectiveness

    • Psychodynamic psychotherapy

    • Marital/family therapy

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    Cognitive-Behavioral Therapy (CBT)

    Benefits. CBT has been found effective in the treatment of PTSD in a randomized clinical trial that compared prolonged exposure and stress innoculation. CBT is symptom oriented and involves psycho-education, anxiety management, cognitive restructuring, and exposure to feared cues. These techniques are effective in the management of PTSD and may ameliorate many of the symptoms associated with it (Foa 1997). Early treatment may prevent the development of chronic PTSD in some patients.

    Harms. The committee is aware of no major adverse effects of CBT, which is generally considered safe. Patients are informed that the therapy is voluntary, they may drop out at any time, and the therapy is time limited, typically lasting 12–20 sessions.

    Comment. CBT requires considerable time and discipline on the part of the patient, as well as the availability of a trained therapist.

    Group Therapy

    Benefits. There is no evidence for the effectiveness of group therapy in the treatment of PTSD.

    Harms. Some patients may be uncomfortable in group settings, and maintaining confidentiality may be a concern.

    Comment. Group therapy can be an efficient way to help many patients at once.

    Psychodynamic Therapy

    Benefits. There is limited evidence for the effectiveness of psychodynamic psychotherapy in the treatment of PTSD (Brom et al. 1989).

    Harms. Psychodynamic psychotherapy may be associated with difficulty in terminating treatment because of the attachment the patient forms to the therapist.

    Comment. Psychodynamic psychotherapy and related therapies by their very nature are not amenable to clinical trials to assess efficacy.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    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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    and 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.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    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

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    unexplained 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.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    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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    patronizing. 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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    patient 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.

    Suggested Citation:"5. Effective Treatments." Institute of Medicine. 2001. Gulf War Veterans: Treating Symptoms and Syndromes. Washington, DC: The National Academies Press. doi: 10.17226/10185.
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    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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    quently 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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    and 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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    psychosocial 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.

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    Ten years after the end of the Gulf War, questions continue to be raised about the health of U.S. service personnel who fought in that war. A primary concern is whether Gulf War veterans are receiving effective treatments for their health problems. Section 105 of the Veterans Program Enhancement Act of 1998 mandates that the Department of Veterans Affairs (VA) ask the Institute of Medicine (IOM) to convene a committee that would identify a method for assessing treatment effectiveness and describe already-validated treatments for Gulf War veterans' health problems, including the problem of medically unexplained symptoms. The specific charge to the committee is to (1) identify and describe approaches for assessing treatment effectiveness; (2) identify illnesses and conditions among veterans of the Gulf War, using data obtained from the VA and the Department of Defense (DoD) Gulf War Registries, as well as information in published articles; and (3) for these identified conditions and illnesses, identify validated models of treatment (to the extent that such treatments exist), or identify new approaches, theories, or research on the management of patients with these conditions if validated treatment models are not available.

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