Reappraisal of Polytherapy in Epilepsy: A Critical Review of Drug Load and Adverse Effects

Summary: Purpose: We reviewed the literature to determine whether an analysis of published data could clarify the relationship between antiepileptic drug (AED) polytherapy and adverse affects (AE). We highlight the problems encountered. Methods: We made a Medline-search for articles published between 1974 and 1994 reporting the number of AE and doses or serum levels of every AED, per patient or treatment group, and used the PDD/DDD ratio to calculate AED load per patient from doses or the OSL/AToxL ratio to do so from serum levels of individual drugs. The PDD/DDD is the sum of ratios of the actual prescribed daily doses divided by the published average therapeutic dose of each drug. The OSL/AToxL is the sum of each observed serum level divided by its average toxic level. Results: We retrieved 118 trial reports. Most had to be excluded because of incomplete reporting of concomitant medication or AE. The data of the 15 articles selected for further analysis indicate a relationship between drug load and number of AE. We noted no relationship between the number of AEDs administered and AE. In add-on studies, the difference in neurotoxicity between the active and placebo arm may be obscured if the relative increase in drug load is small, as exemplified by the study of McGuire et al. (35). Conclusions: Articles reporting add-on trials of new AEDs generally do not provide detailed information about the basic medication to which the new AED is added, which makes calculation of total drug load impossible. Furthermore, often only frequency of AE is reported, not severity or development of tolerance, making it difficult to judge the impact of AE. However, despite the paucity of available information, we present some evidence that toxicity in AED polytherapy may be related to total drug load, rather than to the number of drugs administered. Therefore, the present trend to reject polytherapy for fear of increased toxicity is not warranted, which removes one of the objections to initiating specific research to prove or disprove the value of AED combinations as long as the drug load is appropriate.     

Side-effects of antiepileptic drugs: The economic burden

PurposeAntiepileptic drugs are a potentially effective treatment for epilepsy. Side-effects are, however, common and the negative consequences necessitate treatment ranging from minor interventions to very expensive hospitalization. This analysis has been conducted to provide insight into the costs of side-effects due to antiepileptic drugs in The Netherlands from a societal perspective.MethodResources allocated to care (grouped according to health, patient and family and other) for five different categories of side-effect were measured using a questionnaire. Standard cost prices were derived from the Dutch costing manual. Chronic epilepsy patients were invited to complete the questionnaire if they had experienced side-effects during the previous 12 months.ResultsBased on data from 203 patients, the total societal costs of common side-effects in 2012 are estimated to be €20,751 CI:15,049–27,196 (US$26,675 CI:19,345–34,960) per patient per year. These consist of: health care costs (mean €4458; US$5731), patient and family costs (i.e. informal care, mean €10,526; US$13,531) and other costs (i.e. productivity losses, mean €5761; US$7406). Examining the different categories of side-effects separately, ranging from the most to the least expensive category, the cost estimates per patient per year were as follows: other (mean €13,228; US$17,005), behavioral (mean €9689; US$12,455), general health (mean €7454; US$9582), cognitive (mean €7285; US$9365) and cosmetic side-effects (mean €2845; US$3657). Subgroup analyses showed significant differences in costs between patients using monotherapy and those using polytherapy when looking at cognitive and cosmetic side-effects.ConclusionThese estimates should be considered in the overall assessment of the economic impact of a pharmacotherapy.     

Determinants of health-related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments

Purpose: To evaluate the relative contribution of demographic and epilepsy‐related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health‐related quality of life (HRQOL) in adults with pharmacoresistant epilepsy. Methods: Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory‐31 (QOLIE‐31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory‐II (BDI‐II). Multivariate linear regression models were used to identify variables associated with QOLIE‐31 total score and subscale scores. Key Findings: Of 933 enrolled individuals aged 16 years or older, 809 (87%) were able to complete the self‐assessment instruments and were included in the analysis. Overall, 61% of the variance in QOLIE‐31 scores was explained by the final model. The strongest predictors of HRQOL were AEP total scores (β = −0.451, p < 0.001) and BDI‐II scores (β = −0.398, p < 0.001). These factors were also the strongest predictors of scores in each of the seven QOLIE‐31 subscales. Other predictors of HRQOL were age (β = −0.060, p = 0.008), lack of a driving license (β = −0.053, p = 0.018), pharmacoresistance grade, with higher HRQOL in individuals who had failed only one AED (β = 0.066, p = 0.004), and location of the enrolling center. Epilepsy‐related variables (seizure frequency, occurrence of tonic–clonic seizures, age of epilepsy onset, disease duration) and number of AEDs had no significant predictive value on HRQOL. The AEP total score was the strongest negative predictor of HRQOL in the subgroup of 362 patients without depressive symptoms (BDI‐II score <10), but even in this subgroup the BDI‐II score was retained as a significant predictor. Significance: In individuals with pharmacoresistant epilepsy, AEs of medication and depressive symptoms are far more important determinants of HRQOL than seizures themselves. When seizure freedom cannot be achieved, addressing depressive comorbidity and reducing the burden of AED toxicity is likely to be far more beneficial than interventions aimed at reducing the frequency of seizures.     

Safety Profile of Levetiracetam

Summary: Levetiracetam was approved in November 1999 as add-on therapy for the treatment of partial-onset seizures in adults (age 16 years and older). This review focuses on recently published data from four well-controlled studies in patients with partial-onset seizures with or without secondary generalization. When levetiracetam was given along with other antiepileptic drugs (AEDs), the most frequently reported adverse events were central nervous system related. Adverse events were usually mild to moderate in intensity, with the most frequently reported events occurring predominantly during the first 4 weeks of treatment. No relationship was apparent between the dose of levetiracetam and the most commonly reported adverse events in well-controlled clinical trials within the recommended dose range of 1,000–3,000 mg/day. Levetiracetam is a Pregnancy Category C drug. Overall, when used in combination with other AEDs, levetiracetam was generally well tolerated as add-on treatment for partial-onset seizures.     

The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials

Purpose: Despite the widespread use of antiepileptic drugs (AEDs) across different neurologic and psychiatric disorders, no study has systematically reviewed all available randomized controlled trials (RCTs) of a given AED to fully uncover its tolerability profile. We aimed at identifying treatment emergent adverse events (AEs) associated with pregabalin through a systematic review and meta‐analysis of all available RCTs. We also assessed the association between serious AEs and pregabalin, and investigated whether pregabalin AEs display a dose–response relationship. Methods: We searched MEDLINE, EMBASE, and Cochrane CENTRAL to February 2010 for RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo‐controlled, double‐blind RCTs investigating the therapeutic effects of pregabalin in adults with any condition. Studies had to include at least 20 subjects per arm and have a duration of at least 4 weeks. AEs were assessed for their association with pregabalin after identification/exclusion of synonyms, rare AEs, and nonassessable AEs due to methodologic limitations. We used relative risks (RRs) to assess the association of any [99% confidence intervals (CIs)] or serious AEs (95% CIs) with pregabalin, and risk differences (RDs, 95% CIs) to investigate dose–response relationships of pregabalin AEs. Key findings: Thirty‐eight RCTs were included in our study. Of 39 AEs, 20 (51%) were significantly associated with pregabalin (dizziness, vertigo, incoordination, balance disorder, ataxia, diplopia, blurred vision, amblyopia, tremor, somnolence, confusional state, disturbance in attention, thinking abnormal, euphoria, asthenia, fatigue, edema, peripheral edema, dry mouth, constipation). The highest RRs were found for cognition/coordination AEs. There was no significant association between serious AEs and pregabalin. There was a selective dose–response pattern in the onset of pregabalin AEs, with certain AEs appearing at lower doses than others. Significance: Individuals starting treatment with pregabalin are at increased risk for several AEs, particularly those affecting cognition/coordination. Pregabalin AEs appear according to a selective dose–response pattern, possibly reflecting the severity of dysfunction of distinct anatomic structures. These findings may aid clinicians in providing better patient management, and support the value of including in meta‐analyses of AED tolerability profiles RCTs performed in different conditions.     

The adverse event profile of lacosamide: A systematic review and meta‐analysis of randomized controlled trials

Purpose: Defining the tolerability and safety profile of recently marketed antiepileptic drugs, such as lacosamide (LCM), is a prerequisite for their optimal utilization in clinical practice. We aimed to identify any adverse event (AE) associated with LCM treatment by conducting a systematic review and meta‐analysis of all available randomized controlled trials (RCTs). We also evaluated the association of serious AEs with LCM, the proportion of study withdrawals due to intolerable AEs at different LCM doses, and whether the tolerability profile of LCM differs according to the disorder in which it was investigated. Methods: We searched MEDLINE and Cochrane CENTRAL to May 2011 for LCM RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo‐controlled, double‐blind RCTs and investigated the therapeutic effects of oral LCM in adults with any condition. AEs were assessed for their association with LCM after identification/exclusion of synonyms, rare AEs, and non‐assessable AEs. We used risk differences to evaluate the association of any (99% confidence intervals [CIs]) or serious AEs (95% CIs) with LCM and to investigate dose–response relationships of identified AEs. Key Findings: Ten RCTs (three in pharmacoresistant epilepsy, four in neuropathic pain, one in migraine, one in fibromyalgia, and one in knee osteoarthritis) were included in our study. Their duration varied from 12–18 weeks. The total number of patients included was 3,148. No serious AE was significantly associated with LCM treatment. Of 21 identified AEs, 11 (52%) were found to be significantly associated with LCM. The number of AEs significantly associated with LCM increased with increasing dose: one at 200 mg/day (dizziness); six at 400 mg/day (dizziness, vertigo, abnormal coordination, abnormal vision, nausea, and vomiting); nine at 600 mg/day (dizziness, vertigo, ataxia, balance disorder, diplopia, fatigue, nausea, vomiting, and tremor). The proportion of AE‐related study withdrawals also significantly increased with increasing dose. LCM AEs tended to occur more frequently in patients with drug‐resistant epilepsy compared with patients with other disorders. Significance: A range of AEs suggestive of vestibulocerebellar dysfunction is significantly associated with LCM treatment and their incidence increases with increasing doses.     

Idiosyncratic adverse reactions to antiepileptic drugs

Idiosyncratic drug reactions may be defined as adverse effects that cannot be explained by the known mechanisms of action of the offending agent, do not occur at any dose in most patients, and develop mostly unpredictably in susceptible individuals only. These reactions are generally thought to account for up to 10% of all adverse drug reactions, but their frequency may be higher depending on the definition adopted. Idiosyncratic reactions are a major source of concern because they encompass most life-threatening effects of antiepileptic drugs (AEDs), as well as many other reactions requiring discontinuation of treatment. Based on the underlying mechanisms, idiosyncratic reactions can be differentiated into (1) immune-mediated hypersensitivity reactions, which may range from benign skin rashes to serious conditions such as drug-related rash with eosinophilia and systemic symptoms; (2) reactions involving unusual nonimmune-mediated individual susceptibility, often related to abnormal production or defective detoxification of reactive cytotoxic metabolites (as in valproate-induced liver toxicity); and (3) off-target pharmacology, whereby a drug interacts directly with a system other than that for which it is intended, an example being some types of AED-induced dyskinesias. Although no AED is free from the potential of inducing idiosyncratic reactions, the magnitude of risk and the most common manifestations vary from one drug to another, a consideration that impacts on treatment choices. Serious consequences of idiosyncratic reactions can be minimized by knowledge of risk factors, avoidance of specific AEDs in subpopulations at risk, cautious dose titration, and careful monitoring of clinical response.     

The relation between anger management style, mood and somatic symptoms in anxiety disorders and somatoform disorders

The objective of this study was to examine the relationship between anger management style, depression, anxiety and somatic symptoms in anxiety disorder and somatoform disorder patients. The subjects comprised 71 patients with anxiety disorders and 47 with somatoform disorders. The level of anger expression or anger suppression was assessed by the Anger Expression Scale, the severity of anxiety and depression by the Symptom Checklist-90-Revised (SCL-90-R) anxiety and depression subscales, and the severity of somatic symptoms by the Somatization Rating Scale and the SCL-90-R somatization subscale. The results of path analyses showed that anger suppression had only an indirect effect on somatic symptoms through depression and anxiety in each of the disorders. In addition, only anxiety had a direct effect on somatic symptoms in anxiety disorder patients, whereas both anxiety and depression had direct effects on somatic symptoms in somatoform disorder patients. However, the anxiety disorder group showed a significant negative correlation between anger expression and anger suppression in the path from anger-out to anger-in to depression to anxiety to somatic symptoms, unlike the somatoform disorder group. The results suggest that anger suppression, but not anger expression, is associated with mood, i.e. depression and anxiety, and somatic symptoms characterize anxiety disorder and somatoform disorder patients. Anxiety is likely to be an important source of somatic symptoms in anxiety disorders, whereas both anxiety and depression are likely to be important sources of somatic symptoms in somatoform disorders. In addition, anger suppression preceded by inhibited anger expression is associated with anxiety and somatic symptoms in anxiety disorders.     

Monotherapy or Polytherapy for Epilepsy Revisited: A Quantitative Assessment

Summary: Some investigators argue that treating epilepsy with several antiepileptic drugs (AEDs) simultaneously (polytherapy) may give rise to more adverse effects than monotherapy, but this argument lacks supporting quantitative data. To reexamine this issue, we recruited a cohort of patients from the outpatients of the Special Centres for Epilepsy in The Netherlands and from the outpatients of the Department of Neurology, Nijmegen University, The Netherlands. Two tools were used for analysis. All daily doses of antiepileptic drugs (AEDs) were standardized by the ratio of prescribed daily dose to defined daily dose (PDD/DDD). The DDD is the assumed average effective daily dose for a drug used for its main indication in adults. The assignment of DDD Values is the task of the World Health Organization (WHO) Collaborating Centre for Drugs Statistics Methodology and Nordic Council on Medicines, which regularly publishes Guidelines for Defined Daily Doses. The severity of adverse effects (AE) was assessed by using the Neurotoxicity Index and the Systemic Toxicity Index as developed by the VA Cooperative Study Group for their recent studies comparing the efficacy and tolerability of AEDs. One hundred sixty-one patients received monotherapy; all had a PDD/DDD ratio ≤2/day; 128 of 262 patients receiving polytherapy also had ≤2 PDD/DDD ratios/day. The mono- and polytherapy groups were stratified according to the PDD/DDD ratio. The prevalence of neurological AE for patients with similar PDD/DDD ratios was 50–80% for monotherapy patients and 50–80% for polytherapy patients. The difference between the mono- and polytherapy groups was not significant. The prevalence of neurological AE for patients receiving polytherapy with a PDD/DDD ratio >2.0 was 71–100%, whereas all patients with a PDD/DDD ratio >4.0 had neurological AE. This difference between patients with a PDD/DDD ratio ≤2.0 and those with >2.0 was statistically significant; p < 0.05. The severity of neurological AE also increased with dose, but appeared to peak at ～3.5 PDD/DDD ratio. Our study underscores the usefulness of applying quantitative methods to the analysis of drug AE. Comparison of monotherapy and polytherapy showed no difference for equipotent doses. Because distribution of the AED doses was uneven between the groups receiving mono- and polytherapy, our study permits only a tentative statement that the frequency and severity of AE is independent of the use of either. In addition, frequency and intensity of AE apparently are not very sensitive to changes in dose. An experimental prospective study is planned to verify or refute the conclusions of this observational pilot study.     

Are Psychiatric Adverse Events of Antiepileptic Drugs a Unique Entity? A Study on Topiramate and Levetiracetam

PURPOSE: To investigate the hypothesis that some patients with epilepsy are generally prone to develop psychiatric adverse events (PAEs) during antiepileptic drug (AED) therapy irrespective of the mechanism of action of the drugs. METHODS: From a large case registry of patients prescribed topiramate (TPM) and levetiracetam (LEV), data of patients who had a trial with both drugs were analyzed. Demographic and clinical variables of those who developed PAEs with both drugs (group 1) were compared with those who did not (group 2). Subsequently, from the whole case registry, psychopathological features, demographic, and clinical variables of patients developing PAEs with TPM were compared with those of patients developing PAEs with LEV. RESULTS: The case registry included over 800 patients. Among 108 patients having a trial with both drugs, we identified 9 patients in group 1 and 71 in group 2. Previous psychiatric history, family psychiatric history and history of febrile convulsions showed to be significant clinical correlates. Comparing patients who developed PAEs with LEV with those who developed PAEs with TPM, there were no differences in epilepsy related variables. Well-defined DSM-IV disorders were more frequent with TPM than with LEV. Seizure freedom was associated with psychosis. Conclusions: This study suggests that a subgroup of patients is generally prone to develop PAEs during AED therapy, despite different pharmacological properties of the AEDs. A particular clinical profile and relevant variables have been identified.     

Safety of Topiramate: Adverse Events and Relationships to Dosing

Summary: To date, 1,809 individuals have been exposed to topiramate (TPM), primarily adults with partial-onset seizures. Of this total, 665 patients have been treated for more than 1 year, 177 for more than 3 years, and 67 for more than 5 years. The profile of treatment-emergent adverse reactions (TEAEs) observed with TPM at various dosages is based primarily on data from five double-blind, placebo-controlled trials in which 360 patients received TPM at target doses of 200–1,000 mg/day. Long-term safety is assessed on the basis of 1,001 patients treated with TPM in controlled and open trials for up to 5.3 years. Most of the commonly reported TEAEs were related to the central nervous system and were observed with greater frequency at dosages above the 200–600-mg/day range found to be optimal in dose ranging trials. Nephro-lithiasis not requiring surgery was seen in 1.5% of patients, and mild, dose-related weight loss was associated with TPM therapy. No clinically significant treatment-related abnormalities were observed in clinical laboratory parameters or in neurologic, electrocardiographic, oph-thalmologic, or audiologic tests.     

Relationship between adverse effects of antiepileptic drugs,number of coprescribed drugs,and drug load in a large cohort of consecutive patients with drug‐refractory epilepsy

Purpose: To evaluate the adverse effects (AEs) of antiepileptic drugs (AEDs) in adults with refractory epilepsy and their relationship with number of coprescribed AEDs and AED load. Methods: Patients with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers. AEs were assessed through unstructured interview and the Adverse Event Profile (AEP) questionnaire. AED loads were calculated as the sum of prescribed daily dose (PDD)/defined daily dose (DDD) ratios for each coprescribed AED. Results: Of 809 patients enrolled, 709 had localization‐related epilepsy and 627 were on polytherapy. AED loads increased with increasing number of AEDs in the treatment regimen, from 1.2 ± 0.5 for patients on monotherapy to 2.5 ± 1, 3.7 ± 1.1, and 4.7 ± 1.1 for those on two, three, and ≥4 AEDs, respectively. The number of spontaneously reported AEs correlated with the number of AEs identified by the AEP (r = 0.27, p < 0.0001). AEP scores did not differ between patients with monotherapy and patients with polytherapy (42.8 ± 11.7 vs. 42.6 ± 11.2), and there was no correlation between AEP scores and AED load (r = ?0.05, p = 0.16). Conclusions: AEs did not differ between monotherapy and polytherapy patients, and did not correlate with AED load, possibly as a result of physicians’ intervention in individualizing treatment regimens. Taking into account the limitations of a cross‐sectional survey, these findings are consistent with the hypothesis that AEs are determined more by individual susceptibility, type of AEDs used, and physicians’ skills, than number of coprescribed AEDs and AED load.