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Executive Summary

INTRODUCTION

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.

IDENTIFYING HEALTH PROBLEMS

The committee reviewed Gulf War veterans' symptoms and complaints as described in published literature, data from the VA and the



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Page 1 Executive Summary INTRODUCTION 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. IDENTIFYING HEALTH PROBLEMS The committee reviewed Gulf War veterans' symptoms and complaints as described in published literature, data from the VA and the

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Page 2DoD, and testimony from veterans and other interested individuals. Gulf War veterans are more likely than nondeployed veterans to report symptoms, illness, and functional impairment, although no study has been able to identify a single accepted condition or group of diagnoses that explains the symptoms experienced (IOM 1999a). Reported symptoms experienced by Gulf War veterans include fatigue, joint and muscle pain, headache, memory loss, depression, anxiety, respiratory problems, and diarrhea (Perconte et al. 1993; Southwick et al. 1993; Stretch et al. 1995; Sostek et al. 1996; Iowa Persian Gulf Study Group 1997; Pierce 1997; Fukuda et al. 1998; Proctor et al. 1998; Wolfe et al. 1998; Coker et al. 1999; Department of Veterans Affairs 1999; IOM 1999a; Kang et al. 2000). Almost 80% of Gulf War veterans examined by the VA and DoD have readily identifiable medical conditions. However, about 20% of symptomatic veterans report multiple symptoms for which no diagnosis has been identified (Department of Veterans Affairs 1999). The committee examined the most commonly reported symptoms and grouped them into (1) established and accepted symptom-based conditions experienced by people in the general population who have recognized diagnoses of unknown etiology and (2) individuals who fall into no clear diagnostic category. In this report, conditons of unknown etiology for which treatments are examined include chronic fatigue syndrome (fatigue, headache, cognitive dysfunction, and other symptoms), depression (fatigue, loss of memory and other general symptoms, cognitive dysfunction, and sleep disturbances), fibromyalgia (muscle pain, sleep disturbances, fatigue), and irritable bowel syndrome (diarrhea, constipation, abdominal pain, nausea, vomiting, and other gastrointestinal symptoms). Other diagnoses such as headache and panic disorder are included in the report because they involve symptoms similar to those reported by Gulf War veterans. Posttraumatic stress disorder (PTSD) is included because of its increased prevalence in veteran populations. 1 The committee examined treatments for these recognized diagnoses to determine what might be learned and borrowed from the management of these conditions to apply to the treatment of Gulf War veterans. There is, however, a group of veterans with symptoms that do not fit any of the above diagnostic categories. For those veterans, the committee reviewed relevant literature and described practice approaches currently being researched. Chapter 5 provides detailed information evaluating individual treatments for each of these conditions. 1 The committee acknowledges that the VA has significant expertise in the area of PTSD. The diagnosis is included here, however, because of its prevalence in this as well as other veteran populations.

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Page 3 TREATMENT EFFECTIVENESS Prior to recommending treatments, the committee reviewed and analyzed information on evaluating treatment effectiveness. Treatment effectiveness is defined as the benefit produced by a given treatment in day-to-day clinical practice in unselected patient populations that do not receive extra tests, education, or visits because of participation in a study. There is little formal evidence of treatment effectiveness for any medical treatment because relatively few true effectiveness studies have been conducted. There are, however, efficacy studies. Treatment efficacy is the benefit produced by a given treatment in tightly controlled, perhaps artificial, study conditions in which patients are carefully selected and may be more frequently observed, tested, and monitored than is typically the case in routine practice. A number of study designs can provide varying levels of evidence of treatment efficacy. They include, from strongest to weakest: Multiple well-designed randomized controlled trials (RCTs); Single well-designed RCTs or multiple small RCTs; Cohort study, particularly one with “multiple on/off” features; Case-control study; and Series of clinical observations or anecdotes. In addition to the above designs, there is the technique of meta-analysis. Meta-analysis was developed to fit the situation in which study results are not fully consistent or there are multiple studies of differing degrees of design rigor. In meta-analysis the results of multiple studies are combined to yield an overall cross-study estimate of effectiveness. In its review of clinical studies, the U.S. Preventive Health Services Task Force (USPHSTF) used strict criteria for selecting admissible evidence of effectiveness in grading the quality of evidence (see Table ES-1). The task force gave greater weight to those study designs that, for methodological reasons, are less subject to bias and inferential error (USPHSTF 1996). In evaluating treatments for Gulf War veterans, the committee chose to recommend as effective only those treatments with demonstrated efficacy using the highest level of evidence—the randomized controlled trial (Level I of the USPHSTF scale). However, in responding to its charge to identify and describe approaches to assessing treatment effectiveness, the committee has explored other alternatives. From the perspective of evaluating treatment effectiveness, there are two general classes of studies, each with strengths and weaknesses: Treatment efficacy studies, including prospective randomized tri

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Page 4 TABLE ES-1 Quality of Evidence Level Evidence I Evidence obtained from at least one properly randomized controlled trial. II-1 Evidence obtained from well-designed controlled trials without randomization. II-2 Evidence obtained from well-designed cohort or case-control analytical studies, preferably from more than one center or research group. II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. III Opinions of respected authorities, based on clinical experience, descriptive studies, and case reports, or reports of expert committees. als, emphasize internal validity at the expense of external validity. That is, the sampling, data collection, and data analysis procedures are designed to support the strongest possible inferences about associations between independent and dependent variables (i.e., cause and effect) in a tightly controlled context. The best, strongest studies in tightly controlled situations may, however, lack generalizability to routine medical practice. Treatment effectiveness studies, including the largest and most comprehensive outcomes studies, emphasize external validity often at the expense of internal validity. They may involve very large samples that are fully representative of the patients seen in routine clinical practice, but the studies may include confounding factors that weaken the inferences about cause-and-effect relationships. The committee believes the results of a single, well-designed outcomes study (e.g., a cohort study or variation of care and outcome study) should be considered to be as compelling as the results of a single, well-controlled randomized trial in determining treatment effectiveness. An outcomes study will have few concerns about the generalizability of its findings to real-world settings (external validity) but perhaps some concerns about internal validity; RCTs will have the opposite pattern of strengths and weaknesses. For a detailed discussion of the various types of studies, see Chapter 3. If there were studies of both types available with similar results, the combined evidence would be quite powerful. Studies of the two types with conflicting findings would essentially cancel each other out and no conclusion could be drawn. Table ES-2 is organized to

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Page 5 TABLE ES-2 Hierarchy of Evidence Emphasis on Efficacy Emphasis on Effectiveness Level I Systematic Review (e.g., metaanalysis) of Several Well-Controlled Randomized Trials—consistent results Systematic Review (e.g., meta-analysis) of Several Well-Designed Outcome Studies or “Effectiveness RCTs”— consistent results Level II Single, Well-Controlled Randomized Trial Single, Well-Designed Outcomes Study or “Effectiveness RCT” Level III Consistent Findings from Multiple Cohort, Case-Control, or Observational Studies * Level IV Single Cohort, Case-Control, or Observational Study Level V Uncontrolled Experiment, Unsystematic Observation, Expert Opinion, or Consensus Judgments * It is not clear in many cases whether an observational or case-control study is an efficacy study or an effectiveness study. In principle, the label or definition depends on the extent to which the study sample and study procedures reflect the complexities and realities of daily clinical practice. For any one study, though, this may not be clear; however, when it is, more credence should be given to those truly reflecting effectiveness. suggest that types of studies at the same vertical position in the two columns should be seen as equally powerful for demonstrating treatment effectiveness. The above hierarchy implies that when the focus of evaluation is on treatment effectiveness, and in the absence of RCTs specifically designed to assess effectiveness in real-world settings, evidence from well-designed outcomes studies may provide Level I or Level II evidence and serve as the basis for clinical policies and treatment guidelines. Therefore, in conducting treatment effectiveness research, the committee recommends that the VA: use a hierarchy of evidence structure that includes effectiveness studies as well as efficacy studies for any future treatment guidelines it develops for symptoms or illnesses of Gulf War veterans; design future studies of treatment effectiveness that include outcomes research and effectiveness randomized clinical trials; and develop a standard language for describing Gulf War veterans' symptoms, including their severity and temporal patterns, and that this

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Page 6 standard language be used in conducting treatment effectiveness studies and developing treatment guidelines. Further, the committee recommends that those conducting ongoing cohort studies of veterans' health (e.g., the national VA study, the Iowa follow-up study on Gulf War veterans, and the Millennium Cohort Study being implemented by DoD) include collection of data on treatments and health-related quality of life. The committee also recommends that current VA and DoD Gulf War registries be used as one way to identify patient samples and serve as a sampling frame for future treatment effectiveness studies. CONDITION-SPECIFIC TREATMENTS Results of studies on conditions with unknown etiology may not generalize directly to Gulf War veterans whose similar symptoms may have a different etiology. However, given currently available diagnostic information and the lack of effectiveness studies conducted on Gulf War veterans, identification of effective treatments for such conditions as these may offer the best opportunity for alleviating the health problems of Gulf War veterans. Because there are no true effectiveness studies for the conditions chosen for study, however, the committee determined that recommended treatments would be required to demonstrate efficacy through at least one randomized controlled trial. However, there may be situations in which other approaches to treatment are taken. While the committee has chosen to recommend only those therapies with RCT-demonstrated efficacy, it is important to continue to evaluate these other therapies. Committee members reviewed clinical practice guidelines, major literature reviews, and published studies of treatments for these conditions. Randomized controlled trials were given the greatest weight in making recommendations about specific treatments; other types of published studies were evaluated using the levels-of-evidence concepts discussed above and described in detail in Chapter 3. The approaches presented here are not clinical guidelines. Rather, this report is an effort to extrapolate from what is known about other existing diseases and apply it to the problems suffered by Gulf War veterans. Chapter 5 contains a detailed discussion of each condition, including diagnostic criteria; evaluation of therapies describing benefits, harms, and comments; practice issues; and recommendations. Table ES-3 summarizes the committee's recommendations for each identified condition. In addition to the condition-specific treatments recommended above, the committee determined that there are general principles of a patient-centered approach to medicine that form part of the effective evaluation

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Page 7and treatment of any patient. This patient-centered approach, intended to foster excellent communication between the provider and the patient, is explored in detail in Chapter 4. It involves caring, investigation of all complaints, respect for the patient's perspective, avoidance of excessive testing, and joint decision-making regarding treatment to the extent possible. Daltroy (1993) has identified three primary communication goals and nine tasks (see Table ES-4) for the health care provider that are critical components of patient-centered care. The goals are to elicit the patient's problems and history with an eye toward making a diagnosis, to negotiate a treatment regimen that the patient will accept and that is congruent with recognized medical practice, and to teach the patient about managing his/her disease and treatment regimen so that it may be effectively implemented. Therefore, the committee recommends that the VA: provide specific training to health care providers caring for Gulf War veterans to ensure that they are skilled in the principles and practice of patient-centered care and ensure that health care practitioners serving Gulf War veterans are allowed sufficient time with patients to provide patient-centered care. CONCLUSION Most Gulf War veterans have not experienced the troubling and sometimes debilitating symptoms that plague some who fought in that conflict. The national survey conducted by the VA surveyed 30,000 veterans, 15,000 of whom had been deployed to the Gulf War and another 15,000 who had not. About 75% of Gulf War veterans who responded to the survey described their health as good to excellent, while the remaining 25% rated their health as fair or poor. Ninety percent of responding nonGulf deployed veterans rated their health as good to excellent, with the remaining 10% reporting fair or poor health (Kang et al. 2000). For those Gulf War veterans who have been evaluated in the VA and DoD Gulf War registries (about 120,000 individuals), about 80% have received readily identifiable diagnoses that explain their symptoms (DVA 1999). For 20% of registry participants, however, no diagnosis has been found. In this report the committee has attempted to extrapolate from what is known about treating patients in other circumstances who experience symptoms similar to Gulf War veterans with unexplained symptoms and to apply that knowledge to the veteran population. Many capable providers may take other valid approaches to the management of these problems based on their clinical experience or on patient preferences. In fulfilling its charge to identify already validated treatments for ill Gulf War

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Page 8 TABLE ES-3 Recommendations for Condition-Specific Treatments Conditions Recommendations Chronic fatigue syndrome (CFS) 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 The committee recommends a combination of antidepressant medication and psychotherapy (either cognitive behavioral therapy or interpersonal therapy) as the core therapy for major depression. Fibromyalgia The committee recommends that: Gulf War veterans who meet criteria for fibromyalgia not receive treatment with opioid analgesics or glucocorticoids. 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 Headache For Gulf War veterans with chronic headaches, 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.

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Page 9 Irritable bowel syndrome (IBS) For Gulf War veterans who meet the diagnostic criteria for IBS, the committee recommends that: 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 be monitored to clearly establish therapeutic effectiveness of these agents in the various subgroups of patients diagnosed with IBS. Panic disorder For Gulf War veterans who meet criteria for panic disorder, the committee recommends treatment with antidepressant medication and cognitive behavioral therapy. Post-traumatic stress disorder (PTSD) For Gulf War veterans who meet the criteria for PTSD and with no contraindications, the committee recommends treatment with antidepressant medication and cognitive behavioral therapy. Medically unexplained symptoms 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 medically unexplained symptoms. TABLE ES-4 Nine Steps in Patient-Centered Care 1 The patient must express all of his or her concerns during the clinical encounter. 2 The physician addresses all of the patient's concerns. 3 The physician and the patient share models of disease and symptoms. 4 The physician and patient must share goals for treatment. 5 The physician and the patient should agree on treatment goals, state them explicitly, and set priorities. 6 The physician and the patient should share their respective ideas about the purpose and course of treatments. 7 The physician and patient should identify potential difficulties in the care plan. 8 The physician and the patient should plan how to overcome anticipated compliance difficulties. 9 The physician should provide written information on the disease and treatment regimen.

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Page 10veterans, the committee developed an approach to evaluating treatments that could be consistently applied across diagnoses. Recommendations for treatment are based on efficacy as demonstrated through RCTs, the highest level of evidence available. Much has yet to be learned about ways to prevent, or at least mitigate, health problems associated with deployment. While research into consequences of war-related illnesses and deployment-related health effects proceeds, we are faced with the task of providing effective treatments to those who are suffering from difficult-to-diagnose, ill-defined, or unexplained illnesses. It is hoped that the work of this committee will contribute to the understanding and treatment of such health problems.