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McDonagh M, Peterson K, Lee N, et al. Drug Class Review: Antiepileptic Drugs for Indications Other Than Epilepsy: Final Report Update 2 [Internet]. Portland (OR): Oregon Health & Science University; 2008 Oct.
This publication is provided for historical reference only and the information may be out of date.
Drug Class Review: Antiepileptic Drugs for Indications Other Than Epilepsy: Final Report Update 2 [Internet].
Show detailsAntiepileptic drugs have been used beyond treatment of seizure disorders since the 1960s, when they first became available. All antiepileptic drugs can depress abnormal neuronal discharge in the central nervous system. Their exact mechanisms of action, however, remain uncertain. Several mechanisms have been proposed, such as potentiation of gamma-aminobutyric acid–mediated inhibition, inactivation of sodium or calcium channels, and blockade of N-methyl-D-aspartate receptors. Inactivation of sodium channels by antiepileptic drugs may reduce ectopic discharge from injured nerve endings and neurons of dorsal root ganglia.
Conventional pharmacotherapy for bipolar disorder, migraine prophylaxis, chronic pain, and fibromyalgia has typically been suboptimal and limited by drug-related toxicity. Often, multimodal approaches using combinations of pharmacologic and nonpharmacologic therapies are used. For example, in bipolar disorder a combination of antidepressive, antimanic, and mood stabilizing agents is often required to treat and prevent recurrences of mood episodes. And in fibromyalgia syndrome, pharmacotherapy often requires the use of multiple agents to treat the various symptoms associated with the disorder. As new antiepileptic drugs have become available, there has been interest in how their effectiveness, tolerability, and safety compare with existing therapies (carbamazepine, phenytoin, and valproate) used in these populations. The US Food and Drug Administration (FDA) already expanded the indication for some of these drugs beyond treatment of seizure disorders to treatment of bipolar I disorder, prophylaxis of migraine, and management of chronic pain (Table 1). Yet the relative efficacies of the newer and older antiepileptic drugs in the treatment of these disorders, as monotherapy or in combination with another antiepileptic drug or other agent, remain unclear. The objective of this report is to evaluate the comparative effectiveness, safety, tolerability, and response predictors of antiepileptic drugs used for bipolar disorder, fibromyalgia, migraine prophylaxis, and chronic pain.
Table 1
FDA-approved non-epilepsy indications for antiepileptic drugs
Indications Addressed
This report addresses the evidence on benefits and harms associated with the use of antiepileptic drugs for bipolar disorder, fibromyalgia, chronic pain, and migraine prophylaxis, all briefly described below. Earlier versions of the report also addressed the use of antiepileptic drugs to treat neuropathic pain. However, as the Drug Effectiveness Review Project’s “Drug Class Review on Drugs for Neuropathic Pain” (http://www.ohsu.edu/ohsuedu/research/policycenter/customcf/derp/product/NP_Final_Report_Original.pdf) now encompasses evidence for this indication, neuropathic pain was removed from this review of antiepileptic drugs.
Bipolar Disorder
Bipolar disorder is a spectrum of symptoms characterized by cycles of manic or hypomanic episodes. It may include depressive episodes and mood-congruent psychotic features. Dysphoria may also be present. The major types of bipolar disorder are bipolar I disorder (classic manic episodes only or classic manic-depression), bipolar II disorder (hypomania-depression), and bipolar disorder not otherwise specified. About 5% to 15% of individuals with bipolar I disorder have rapid cycling (4 or more episodes per year), which is associated with a poorer prognosis. Manic episodes are marked by abnormally and persistently elevated expansive or irritable moods. Because patients do not necessarily dislike the symptoms of mania, they may be reluctant to receive or continue treatment directed at reducing those symptoms. Major depressive episodes are characterized by depressed mood, severe loss of interest or pleasure in activities, and a constellation of other diagnostic signs and symptoms including recurrent thoughts of death, suicidal ideation, or suicide attempts. In a review of 31 studies of 9389 patients with bipolar disorder, the estimated lifetime prevalence of suicide ranged from 9% to 60% (weighted mean, 18.9%).1
The incidence of bipolar I disorder is estimated to be fairly low, between 2 and 21 per 100 000 per year.2 However, due to its chronic recurrent nature, bipolar I disorder is a highly prevalent condition. The incidence of bipolar II disorder is higher than that of bipolar I disorder.
Fibromyalgia
Fibromyalgia syndrome is a sometimes disabling condition characterized by chronic, widespread musculoskeletal pain. Its estimated worldwide prevalence is 0.5% to 5.0%, with women affected 4 times more often than men.7 It is one of the most common conditions treated by rheumatologists.
The diagnosis of fibromyalgia is based on clinical history and examination; no diagnostic laboratory or radiologic test exists. The American College of Rheumatology’s diagnostic criteria for fibromyalgia require a history of spontaneous pain along the spine and all 4 quadrants of the body for more than 3 months and pain on digital palpation at 11 of 18 tender point sites. Other comorbid conditions are common in patients with fibromyalgia, although they are not part of the American College of Rheumatology diagnostic criteria. These conditions include chronic fatigue syndrome, sleep dysfunction, headaches, mood disorders, irritable bowel syndrome, and neurocognitive disturbances. Under experimental conditions, allodynia and hyperalgesia have been demonstrated in patients with fibromyalgia. These observations of abnormal pain perception support the hypothesis that the etiology of fibromyalgia involves increased central pain sensitization with altered levels or activity of neurotransmitters and neuromodulators, such as substance P. The underlying cause of fibromyalgia remains unknown.
Migraine Prophylaxis
Migraine is a common and disabling neurological disorder affecting approximately 6% of men and 15% to 18% of women in the United States and other industrialized countries; many cases are undiagnosed or undertreated.2–4 It is a chronic condition that usually affects children and young to middle-aged adults, and its repeated acute attacks cause considerable disability, loss of work, and disruption of daily functioning.2, 4
Treatment of migraines includes both preventive and acute drug therapies. Preventive treatment aims to reduce frequency, severity, and duration of attacks and to improve responsiveness to acute treatment, reduce disability, improve patient functioning, and reduce the overall cost of treating migraine.2, 3 Studies suggest that approximately one-third of migraine sufferers ought to use preventive therapy, but only 3% to 13% currently do.3 Preventive treatment should generally be considered for patients (1) who have with frequent migraines (2 or more per month); (2) who have prolonged or severe attacks; (3) who experience intolerable adverse events with acute therapy; (4) in whom acute medication is contraindicated; (5) who have been unresponsive to acute therapy; (6) who are at risk of overusing acute mediations (taken more than twice per week); or (7) who have uncommon migraine conditions, including hemiplegic migraine, migraine with prolonged aura, or migrainous infarction.2, 4 When preventive therapy is prescribed, it should be given an adequate trial of at least 6 weeks at the maximally tolerated dose; however, the full benefit of the medication may not be attained for 6 months on this dose.3
Chronic Pain
Chronic pain is often defined as pain that persists or progresses for longer than 3 to 6 months. Chronic pain may begin as acute pain associated with a specific injury or condition, but it outlasts the expected period needed for the body to heal. Also included in the chronic category is pain associated with cancer, degenerative conditions, neuropathies, and other illnesses. In some cases, chronic pain lacks an identifiable physical cause. Intensity of chronic pain can range from mild to severe and can become a source of significant disability for its sufferers. Chronic pain can also lead to other psychosocial difficulties, including depression, fatigue, poor sleep, and reduced functional capacity and quality of life.
In the United States chronic pain has long been recognized as a major public health concern. According to findings from multiple studies done in North America, Europe, and Australia, the prevalence of chronic pain has been estimated to range from 10% to 55%.5 According to the National Institutes of Health, the American public spends over $100 billion annually on the combined expenses of medical care, lost workdays, and litigation associated with chronic pain.
Scales and Tests Used to Measure Outcomes
In patients with bipolar disorder, migraine, fibromyalgia, and chronic pain, outcomes are measured using a variety of rating scales. For the sake of brevity we reported results using common acronyms for outcomes rating scales. The full names of the rating scales are listed in Appendix A. Terms commonly used in reports produced by the Drug Effectiveness Review Project, such as statistical terms, are defined as they apply to these reports in Appendix B.
Purpose and Limitations of Systematic Reviews
Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. A systematic review focuses on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with a careful formulation of research questions. The goal is to select questions that are important to patients and clinicians, then to examine how well the scientific literature answers those questions.
Systematic reviews emphasize the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are emphasized over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in both groups, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant across groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than the absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat, often referred to as the NNT, is the number of patients who would have to be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.
Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards that reduce the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well-executed, randomized, controlled trials are considered better evidence than results of cohort, case-control, or cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, cohort designs are preferred when conducted well and for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted.
Systematic reviews pay particular attention to the generalizability of efficacy studies performed in controlled or academic settings. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbid diseases, meaning diseases other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that may be impractical in typical practice settings. And these studies often restrict options that are of value in actual practice, such as combination therapies or switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods of time. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.
Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures, such as scores based on psychometric scales.
Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling each study as either an efficacy or an effectiveness study, while convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient.
Studies across the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision-makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how much of it there is, may have limited applicability to practice. Clinicians can judge the relevance of the study results to their practice and should note where there are gaps in the available scientific information.
Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment.
In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice.
Scope and Key Questions
The main goal of this report was to compare the effectiveness and adverse event profiles of antiepileptic drugs in the treatment of bipolar disorder, migraine, chronic pain, and fibromyalgia. The Oregon Evidence-based Practice Center wrote preliminary Key Questions, identifying the populations, interventions, outcomes of interest, and, based on these, the eligibility criteria for studies. A draft of these questions and inclusion and exclusion criteria were posted on the Drug Effectiveness Review Project website for public comment. The draft was reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project, taking into consideration comments received from the public. The participating organizations of Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to clinicians and patients. The participating organizations approved the following Key Questions to guide the review for this updated report:
- For adult outpatients with bipolar disorder, fibromyalgia, migraine, or chronic pain, do antiepileptic drugs differ in effectiveness?
- For adult outpatients with bipolar disorder, fibromyalgia, migraine, or chronic pain, do antiepileptic drugs differ in safety or adverse events?
- Among these patient populations, are there subgroups of patients based on demographics (age, racial groups, and gender), other medications, or comorbidities for which one antiepileptic drug is more effective or associated with fewer adverse events?
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