Dose-Related Side Effects

Dieter Schmidt

Steven C. Schachter

Introduction

Most antiepileptic drugs (AEDs) block seizure generation by altering membrane excitability, increasing postsynaptic inhibition, or modifying the synchronization of neuronal networks.³⁴ At therapeutic doses, this may also cause dysfunction of the central nervous system (CNS) and other organ systems, resulting in adverse effects that may be life threatening in rare cases.² Not surprisingly, adverse effects significantly impair health and well being, particularly in patients with refractory epilepsy.¹⁶ Accordingly, the goal of treatment should be seizure freedom with no or a minimum of side effects. The patient should not suffer more from the side effects of treatment than from the epilepsy itself. Fortunately, most side effects of AEDs are predictable, dose dependent, and resolve with dose reduction. Furthermore, a number of unpredictable and idiosyncratic side effects of AEDs are also characterized by a dose–response relationship.²¹ As a consequence, one major strategy to minimize dose-dependent side effects is to avoid overtreatment.³³^,³⁸ Overtreatment is broadly defined as unnecessary or excessive drug load in the management of epilepsy leading to a suboptimal risk-to-benefit balance.⁴⁰ The second major strategy is to recognize patients at increased risk for host-dependent side effects. In this chapter, we give an overview of dose-related side effects of drug treatment for epilepsy. Furthermore, we describe clinical scenarios that often lead to side effects and outline specific strategies to minimize or prevent dose-related side effects of AEDs.

The Scope of Dose-Related Side Effects

The scope of dose-related side effects ranges from rare serious and irreversible adverse events to common reversible side effects.³⁶ In a survey of >5,000 patients living in Europe, 88% of patients currently treated with AEDs reported at least one side effect, and 44% of respondents said they worried “a lot” or “some” about the possible side effects of their medication.³ In different studies, the proportion of patients with side effects from AED therapy range from <10% to >70% depending on ascertainment procedures, definitions and measurements of side effects, characteristics of patients, AED dose, and duration of follow-up.¹⁹^,³⁰ Important methodologic differences between studies hamper the comparison of side effects among AEDs.¹²^,¹⁹ Although no AED is free of adverse effects, some AEDs have fewer side effects than others, and there are clearly differences in the spectrum of adverse effects produced by specific agents (Table 1). These specific adverse effects influence drug selection in the individual patient. For example, AEDs causing weight gain may not be the best choice for overweight patients. On the other hand, agents that cause weight loss may not be ideal for an anorectic patient trying to gain weight. Finally, it has been suggested that some of the newer AEDs are better tolerated in clinical use than some of the older agents (Table 1).¹⁶ When used appropriately, some of the newer AEDs undoubtedly offer relevant advantages in tolerability, in particular, less sedation and fewer metabolic changes, including fewer drug interactions.¹⁹^,³⁸ However, when all newer AEDs were compared in a critical review of 80 randomized, controlled trials reporting adverse events of AEDs, there was no consistent or convincing evidence for better relative safety and tolerability of newer AEDs.⁴⁸ For full details of individual side effects and contraindications of each AED, see Summary of Product Characteristics of each AED and respective chapters of this and other books (e.g., Levy et al.²⁴).

Irreversible Side Effects

Dose-related side effects may be irreversible and life threatening in some patients. Such cases include severe bradyarrhythmia after rapid intravenous phenytoin, pneumonia with nitrazepam treatment in young children, and respiratory arrest following high-dose intravenous benzodiazepines.⁷ In addition, the serious Stevens-Johnson syndrome or the Lyell syndrome may be dose related. The highest incidence of Stevens-Johnson syndrome (1:50 to 1:300) is observed in association with use of lamotrigine in children, particularly when a high starting dose is used or valproate is given as comedication, which increases the serum concentration of lamotrigine by inhibition of its metabolism.³⁰ The incidence seems to be decreasing following introduction of a slower dose escalation and the wider use of lamotrigine monotherapy.³⁰ Further examples of irreversible side effects that may be dose related are malformations in the offspring following maternal exposure to AEDs, which is discussed in detail elsewhere in this book. For other irreversible and often severe side effects, a dose relationship is not well documented. This group, as shown in Table 1, includes concentric visual field defects following exposure to vigabatrin and cases of rare phenytoin-associated cerebellar degeneration or Dupuytren contracture and Ledderhose syndrome during chronic treatment with phenobarbital or primidone.³⁶

Table 1 Overview of adverse effects of antiepileptic drugs

	CBZ	CLB	ESM	FBM	GBP	LEV	LTG	OXC	PGB	PHB	PHT	TGB	TPM	VPA	VGB	ZNS
Early-onset adverse events
Somnolene		++			+	+	+		+	++		++	++		+	++
Dizziness^a		++	+		+	+	+	++			++	++	++		+	+
Seizure aggravation^a	+	+			+				+		+	+			++
Gastrointestinal	+		++	+	(+)	(+)		+						+		+
Liver failure^b				+										+
Hypersensitivity^a	+			+			++	+		+	+		+
Late-onset adverse events
Sedation^a		++	+							++			(+)
Encephalopathy^a											+			+	++
Dyskinesia, tics, parkinsonism	+		+	(+)	+		+			(+)	+	(+)		+	(+)
Depression^b			+							+	+	+			+
Language dysfunction													+
Behavioral problems^a					+	+				++	+	+	++		++	+
Psychotic episodes^b	(+)		++	(+)	+	(+)				(+)	(+)		(+)	(+)	++
Leucopenia^b	++		+	+						+	+
Aplastic anemia^b	+		+	++						+	+
Thrombopenia^a				+										++
Megaloblastic anemia^a										+	+
Pancreatitis^b					(+)									+
Nephrolithiasis^b													(+)			+
Osteoporosis^b	(+)									+	+			(+)
Hyponatremia^b	(+)							+
Weight gain^a	+				+				++					+	+	+
Weight loss^a				+									+			+
Cognition impaired^a	+	+								++	+		+			+
Teratogenicity^b														++
Summary (all +)	9	8	10	8	7	3	5	5	4	14	13	7	10	10	12	9
The incidence of many early adverse events shown here may vary significantly from patient to patient, depending on individual susceptibility, development of tolerance, titration, and drug load. The list summarizes the adverse event potential of a given compound, in the authors’ view. In our view, representing evidence class IV, (+) denotes minimally increased risk at effective dose in clinical use, + denotes a risk higher than for AEDs without a + sign, and ++ denotes the highest risk among AEDs. CBZ, carbamazepine; CLB, clobazam; FBM, felbamate; GBP, gabapentin; LEV, levetiracetam, LTG, lamotrigine; OXC, oxcarbazepine: PGB, pregabalin; PHB, phenobarbital; PHT, phenytoin; TGB, tiagabine; TPM, topiramate; VPA, valproate; VGB, vigabatrin; ZNS, zonisamide. ^aDose-related side effect. ^bDose relationship not proven or controversial. Source: Modified from refs. 3, 7, 14, 15, 19, 24, 30, 36, 49, and 50.

Reversible Side Effects

A number of CNS side effects such as dizziness, ataxia, or somnolence emerging early in the course of treatment with AEDs are transient despite continued therapy.²⁴^,²⁵^,³⁶ The mechanism underlying the resolution of early CNS side effects without dose reduction is the rapid development of functional tolerance to adverse effects within weeks.²⁸ Functional tolerance to early side effects such as dizziness and gastrointestinal adverse effects was elegantly demonstrated for several first-generation AEDs in a well-controlled comparison of carbamazepine, phenytoin, phenobarbital, and primidone.²⁸ Although serum
concentrations were similar at weeks 1 and 12, the proportion of patients with dizziness and gastrointestinal complaints was much lower at week 12.²⁸ For newer antiepileptic drugs such as gabapentin, lamotrigine, pregabalin, topiramate, vigabatrin, and zonisamide, resolution of early CNS side effects during continued therapy has also been noted in many patients.²⁴^,²⁵

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