Download Newer Antiepileptic Drugs

CLINICAL THERAPEUTICS® / VOL. 25, NO. 10, 2003
Newer Antiepileptic Drugs: Possible Uses in the
Treatment of Neuropathic Pain and Migraine
Marco Pappagallo, MD
Division of Chronic Pain, Department of Pain and Palliative Medicine, Beth Israel Medical
Center, New York, New York
ABSTRACT
Background: Both neuropathic pain and migraine are now being treated with
a variety of newer antiepileptic drugs (AEDs). The proven efficacy of gabapentin
in postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), and of
divalproex sodium in the prevention of migraine has led to increased clinical investigation of the newer AEDs for these conditions. While basic and clinical research are expanding the knowledge base concerning the fundamental mechanisms of neuropathic pain and migraine, growing recognition of the similarities
in the pathophysiology of epilepsy, migraine, and various chronic pain disorders
has further heightened interest in exploring the newer AEDs in the treatment of
these conditions.
Objective: The goals of this article were to review the empiric basis and scientific rationale for the use of AEDs in the treatment of neuropathic pain and
migraine; summarize available clinical research on the use of 5 newer AEDs
(gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide) in these
conditions; and provide a summary comparison of the dosing, tolerability, and
drug-interaction potential of these agents.
Methods: Relevant English-language articles were identified through searches
of MEDLINE (1990–March 2003), American Academy of Neurology abstracts
(1999–2003), and American Epilepsy Society abstracts (2000–2002). The search
terms were antiepileptic medication or drug, migraine headache, neuropathic pain,
pathophysiology, treatment, mechanism of action, gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide.
Conclusions: The newer AEDs possess the potential advantages of better tolerability and fewer drug–drug interactions compared with standard treatments
such as tricyclic antidepressants or established AEDs. However, with the excepAccepted for publication September 4, 2003.
Printed in the USA. Reproduction in whole or part is not permitted.
2506
0149-2918/03/$19.00
Copyright © 2003 Excerpta Medica, Inc.
M. Pappagallo
tion of data supporting the efficacy of gabapentin in PHN and PDN, there is currently insufficient evidence to determine whether the newer AEDs have equal
or superior efficacy relative to proven pharmacotherapies. (Clin Ther. 2003;25:
2506–2538) Copyright © 2003 Excerpta Medica, Inc.
Key words: neuropathic pain, migraine headache, antiepileptic drugs, anticonvulsant drugs, pain treatment, novel analgesics.
INTRODUCTION
In the early 1990s, a new generation of antiepileptic drugs (AEDs) was introduced
into clinical practice. As a class, these medications had a number of features that
distinguished them from established AEDs; namely, greater tolerability, fewer
drug–drug interactions (largely owing to substantially fewer effects on the cytochrome P450 [CYP] enzyme system), and new mechanisms of action.1 At the
same time, basic scientific research was beginning to unravel the mystery of neuropathic pain and migraine pain,2–5 revealing a striking overlap between the
pathophysiology of these 2 conditions and that of epilepsy. Furthermore, it was
realized that many of the putative mechanisms of action that made the newer
AEDs effective antiseizure medications might also allow them to function as
analgesics.6–10
Gabapentin demonstrated efficacy in 2 randomized, controlled trials published
in 1998—one in patients with postherpetic neuralgia11 (PHN) and the other in
patients with painful diabetic neuropathy12 (PDN). At about the same time, many
uncontrolled studies of the use of AEDs in the treatment of neuropathic pain, as
well as a growing number of pilot studies and case series on the use of these
agents in the prophylaxis of migraine, began to appear in the medical literature
and in presentations at major national meetings.13,14 These developments were
accompanied by a large increase in the prescribing of gabapentin (and of AEDs
released subsequently) for patients whose pain was refractory to the standard
approaches.
The goals of this article were to review the empiric basis and scientific rationale for the use of AEDs in the treatment of neuropathic pain and migraine; summarize available clinical research on the use of the newer AEDs in these conditions; and provide a summary comparison of the dosing, tolerability, and
drug-interaction potential of these agents. The drugs discussed are the newer
AEDs that have been most extensively studied and prescribed in the United
States: gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide.
Relevant English-language articles were identified through searches of MEDLINE
(1990–March 2003), American Academy of Neurology abstracts (1999–2003),
and American Epilepsy Society abstracts (2000–2002). The search terms were
2507
CLINICAL THERAPEUTICS®
antiepileptic medication or drug, migraine headache, neuropathic pain, pathophysiology,
treatment, mechanism of action, gabapentin, lamotrigine, oxcarbazepine, topiramate,
and zonisamide. Only original clinical research was included in the clinical
sections of this article; letters, case reports, and post hoc analyses of preexisting
data were excluded. Articles used for the theoretical sections of the article
were chosen as being timely, clearly written, and supported by experimental
data.
It has been reported that physicians do not receive sufficient education on the
topic of pain in medical school or during residency.15 Therefore, this article begins with a review of the definition, clinical characteristics, and common presentations of neuropathic pain, followed by a similar overview of migraine. The
section closes with a discussion of the current understanding of the basic
neurophysiology of pain perception and a brief summary of some current ideas
concerning the pathophysiology of neuropathic pain and migraine.
NEUROPATHIC PAIN
There are 2 fundamental types of pain: nociceptive and neuropathic. In both
cases, pain (from the Latin poena, a fine or penalty16) arises from nociception
(from the Latin noceo, to injure16); in other words, pain is the price we pay for
consciousness of something injurious happening to us. It can be defined as “an
unpleasant sensory and emotional experience associated with actual or potential
tissue damage or described in terms of such damage.”17 Nociceptive pain, which
can also be thought of as normal, or ordinary, pain, occurs when a pain signal
originates in normally functioning tissue nociceptors—Aδ and C fibers—that
have been activated by a mechanical, chemical, or thermal stimulus.2 Neuropathic
pain, however, occurs when an algogenic (from the Greek algos, pain16) signal
originates within abnormally functioning peripheral or central neurons that have
themselves been damaged or altered in some way.3 Therefore, although the clinical characteristics (intensity, quality, and course) of nociceptive pain are determined primarily by the physical injury causing the pain, the clinical characteristics of neuropathic pain are determined predominantly by the mechanisms,
location, and severity of the neuropathologic process itself.4,5
Neuropathic pain encompasses a heterogeneous group of disorders (Table I).
Some of the more commonly seen syndromes include PHN, PDN, radiculopathy,
and central poststroke pain.18 Trigeminal neuralgia and complex regional pain
syndrome (CRPS) are less prevalent but highly debilitating diseases that account
for a significant proportion of patients seen in specialty settings.19,20 With respect
to their treatment, these illnesses share several critical clinical features: they follow a chronic course; they respond very poorly or not at all to standard analgesic therapies such as nonsteroidal anti-inflammatory drugs and acetaminophen;
and they respond less predictably and less robustly to opioids than do nocicep2508
M. Pappagallo
Table I. Neuropathic pain disorders.
Painful diabetic neuropathy
Postherpetic neuralgia
Trigeminal neuralgia
Complex regional pain syndrome
Radiculopathies
Painful HIV-associated neuropathy
Central poststroke pain
Spinal cord injury
Deafferentation syndromes (eg, phantom limb pain)
Migraine headache
tive pain conditions.21 It is for these reasons that neuropathic pain must be
treated differently from nociceptive pain.
Unlike nociceptive pain, which—apart from the phenomenon of referred
pain—patients can usually describe simply and clearly, neuropathic pain is characterized by a variety of dysesthetic sensations and is therefore reported with difficulty and less precision.18 Often the pain is hard to localize, is spread across a
much larger area, and may not conform to any dermatomal distribution.4
Frequently encountered descriptors include burning, shooting, stabbing, hot, cold,
itching, deep, or sensitive.18 In most cases, patients report that this type of pain is
triggered by benign (nonpainful) stimuli such as light touch, mild heat, or minimal pressure. This characteristic of neuropathic pain is called allodynia. Equally
distressing is the phenomenon of hyperalgesia, which is the experience of severe
pain in response to stimuli that would ordinarily cause only mild pain.4 Patients
may be troubled because their discomfort has no obvious source. As a consequence of these factors, patients with neuropathic pain endure much suffering
and may become demoralized or clinically depressed.22 It is imperative that clinicians not minimize the seriousness of this pain or the “organicity” of its
origins.
In many cases, a patient’s pain has both nociceptive and neuropathic mechanisms. Inflammatory states provide an excellent example.2 Although certain substances released during inflammation (eg, prostaglandins) are responsible for the
sensitization and activation of the nociceptive Aδ and C fibers, some proinflammatory cytokines (eg, tumor necrosis factor–alpha, interleukin-1) can cause central and peripheral neurodegeneration and thereby induce neuropathic pain.23
The combination of inflammatory and neuropathic pain mechanisms is seen most
commonly in patients with cancer.24 The important clinical message is that many
patients present with a combination of pain mechanisms, which often requires a
combination approach to treatment.
2509
CLINICAL THERAPEUTICS®
MIGRAINE
Migraine is a primary headache disorder with a number of syndromic subtypes;
the 2 most common are migraine without aura and migraine with aura. The diagnosis of these subtypes is based on fulfillment of specific criteria concerning
the duration, location, and severity of headache pain, and on the presence or
absence of particular associated symptoms (Table II).25 Migraine is a common
Table II. International Headache Society diagnostic criteria for migraine.25
1.1 Migraine without aura
A. At least 5 attacks fulfilling conditions of B–D
B. Headache attacks lasting 4–72 hours
1. Untreated or unsuccessfully treated
2. If falling asleep with headache and awakening headache free, duration of attack includes
sleep time
C. Headache has at least 2 of the following characteristics:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe intensity (prohibits some daily activities)
4. Exacerbation by routine physical activity (eg, climbing stairs)
D. During headache attack at least 1 of the following:
1. Nausea and/or vomiting
2. Photophobia and phonophobia
E. Any other disorder that causes headache is ruled out by history, physical and neurological
examination, or appropriate investigation
OR
The first headache attacks that fulfill the criteria for migraine in A–D do not occur in
temporal proximity to such a disorder
1.2 Migraine with aura
A. At least 2 attacks fulfilling conditions of B
B. At least 3 of the 4 following characteristics:
1. One or more fully reversible aura symptoms indicating focal cerebral, cortical, and/or
brain-stem dysfunction
2. At least 1 aura symptom develops gradually over >4 minutes, OR ≥2 aura symptoms
occur in succession
3. No aura symptom lasts >60 minutes; if >1 aura symptom is present, accepted duration is
proportionately increased
4. Headache follows aura with a free interval of <60 minutes (it may begin before or simultaneously with aura)
C. Any other disorder that causes headache is ruled out by history, physical and neurological
examination, or appropriate investigation
OR
The first headaches that fulfill the criteria for migraine with aura in A–B do not occur in
temporal proximity to such a disorder
2510
M. Pappagallo
illness, affecting ~11% to 12% of the population of industrialized nations, with
rates in women approximately 3-fold those in men.26–28 In the majority of patients with migraine, the frequency of attacks is low,29 the response to acute treatment is adequate,30–32 and the progression of disease over time is limited.33
A subgroup of patients with migraine, however, experience a more debilitating
illness.34 These patients may have a high frequency or greater severity of migraine
attacks, or they may be unresponsive to or unable to tolerate acute therapies.33 It
is thought that in some patients, overuse of analgesic (narcotic and nonnarcotic)
or abortive medications (primarily triptans) contributes to development of a
chronic form of the disease known as “transformed migraine.”35 Preventive treatment is indicated in these groups of patients.34 Although such treatment may include certain nonpharmacologic modalities, such as relaxation training or cognitive/
behavioral therapy, medications can play a major role in the comprehensive treatment plan.36
PATHOPHYSIOLOGY OF NEUROPATHIC PAIN AND MIGRAINE
Physiology of Nociception
To appreciate the numerous possible etiologies of neuropathic pain, and, more
importantly, understand the putative sites and mechanisms of action of AEDs and
other agents in the treatment of neuropathic pain, it is helpful to review the structure and function of the pain neuraxis. Clinicians should be able to give patients
short, simple explanations of the cause of their symptoms and how the proposed
treatments work. These communications are an essential part of the physician–
patient relationship and are of tremendous value in establishing trust and improving compliance with the prescribed treatment.37 This is particularly true for
such conditions as neuropathic pain, in which the etiology is not obvious and
treatment often takes weeks to begin working and rarely provides complete relief.
Nociception begins when Aδ and C fibers respond to noxious stimulation and
transmit this information via the dorsal root ganglia to the dorsal horn of the
spinal cord.38 These nerve fibers can be activated by a host of biochemical products of tissue damage and inflammation, including prostaglandins, cytokines,
bradykinin, histamine, free radicals, protons, purines, neurotrophins, and others.
The strength of the signal transmitted is proportional to the intensity of the noxious input. Critical membrane components of the dorsal horn nociceptor neurons
(C fibers) are the sensory neuron–specific voltage-gated sodium channels, key ion
channels responsible for the generation and maintenance of action potentials, and
the N-type voltage-gated calcium channels, which, when activated, allow calcium
to flow into the cell and promote excitation.38
Nociceptive signals are processed at the spinal segmental level by the dorsal
horn neurons. Both somatic and visceral afferents terminate on these neurons,
which is probably the physiologic reason for typical pain referral. Interneurons
2511
CLINICAL THERAPEUTICS®
modulate both transmitter release presynaptically and signal intensity postsynaptically. This modulation is primarily inhibitory, and the predominant transmitter is
␥-aminobutyric acid (GABA). Dorsal horn neurons have numerous receptors that
respond to substance P and excitatory amino acids (glutamate and aspartate) as they
are released at the terminals of the afferent inputs. These receptors include
N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and neurokinin-1.38 The dorsal horn neurons project via ascending
pathways to the thalamus, whereas supraspinal modulatory neurons originating in
the brain stem reach the dorsal horn via descending pathways. These neurons are
primarily noradrenergic and exert an inhibitory influence.39
Afferent input from the cranial meninges is conducted through the trigeminal–
vascular pathway, whose cell bodies are in the trigeminal ganglion, and through
synapses on the trigeminal nucleus. Thus, the sensory fibers of the trigeminal nerve
are analogous to the peripheral sensory fibers in the rest of the body, the trigeminal ganglion corresponding to the dorsal root ganglion and the trigeminal nucleus
corresponding to the dorsal horn. The neurochemistry of these corresponding
structures is essentially the same.40
The actual perception of pain is initiated only when the nociceptive signal is
transmitted through the thalamus and neighboring nuclei to the somatosensory cortex, anterior cingular cortex, and amygdala. Whereas the somatosensory cortex is
responsible for pain sensation, it is the other centers that underlie the affective
experience associated with pain. This cortical–limbic–thalamic circuitry is quite
complex and highly individualized, mirroring the dramatic variation in the human
experience of pain.41
Etiologies and Mechanisms of Neuropathic Pain
Anything that causes a structural lesion or a functional change in the peripheral
or central neurons of the pain neuraxis can result in neuropathic pain. Hereditary
abnormalities (eg, Fabry’s disease), traumatic injury, vascular insufficiency, viral infection, toxic/metabolic insult, disk disease, spondylosis, and unremitting nociceptive input are common examples of the etiologies of neuropathic pain disorders
(Table III).18
It is not yet clear which specific neuronal changes are responsible for the aberrant pain sensations associated with neuropathic diseases, but basic science research
is unraveling a host of potential neuropathic pain mechanisms.23,42–45 In particular,
abnormalities in ion channel conductivity45 and receptor function probably play
some role in the majority of these perplexing illnesses. For example, one of the consequences of peripheral nerve injury is an alteration in the expression of adrenergic receptors, resulting in pathologic activation of these nociceptive neurons by noradrenaline. This puzzling process is called sympathetically maintained pain, and
it plays a pathogenic role in some cases of CRPS.19 Several animal models of periph2512
M. Pappagallo
Table III. Etiologies of neuropathic pain.18
Traumatic nerve injury
Peripheral nerve
Dorsal root or trigeminal ganglion
Spinal cord
Viral infection (eg, herpes zoster, HIV)
Connective tissue/autoimmune diseases
Peripheral ischemic disease
Diabetes mellitus types 1 and 2
Cerebrovascular accident
Disk herniation and spinal stenosis
Toxic insult
Metabolic disorders
Hereditary factors
eral neuropathy have shown an increase in both the number and conductivity of
sodium ion channels, which in turn increases the strength of the inward sodium
current and causes persistent aberrant firing of these neurons.2,45
Central neuropathic pain, or central pain, encompasses the entire neuraxis. It is
heuristically useful to separate central pain into 2 processes: (1) the pain-signaling
process, which involves the dorsal horn neurons (the segmental level) and the descending modulatory pathways originating in the brain stem; and (2) the painperception process, which takes place exclusively in the brain. It is only the latter
that generates the subjective experience of pain, whereas the former is responsible
for the intensity of the nociceptive signal.46 It has been amply demonstrated that
central sensitization, a process somewhat like kindling, is an important component
of the neuropathology of central pain. In kindling, the seizure threshold of the postsynaptic neuron progressively decreases, whereas in central sensitization the magnitude of response of the postsynaptic neuron progressively increases. This process
is mediated, at least in part, by the NMDA-receptor complex.47 (Table IV lists the
potential targets of neuropathic pain treatments.2–5,23,42–48)
Etiologies and Mechanisms of Migraine
It is now widely recognized that migraine, as well as other primary headache
disorders such as cluster headache and chronic daily headache, may share several
of the mechanisms known to play a role in neuropathic pain, including peripheral and central sensitization,49 channelopathies,50 and neurogenic inflammation
of the meninges.51 Although the origin of pain in migraine is still a fiercely debated topic, there is general agreement that involvement of the trigeminal nerve
is crucial and that there is an interplay between central and peripheral processes.52
2513
CLINICAL THERAPEUTICS®
Table IV. Potential targets of neuropathic pain treatments.2–5,23,42–48
Target
Peripheral
Segmental
Central
Receptors
Vanilloid
Tyrosine kinase
Purinergic (ATP)
Adrenergic
Serotonergic
Opioid
Cannabinoid
Interleukin
Glutamate
NMDA
AMPA
GABA
Opioid
Alpha2-adrenergic
Neurokinin-1
Adenosine
Glycine
N-nicotinic acetylcholine
Metabotropic glutamate
Cannabinoid
Ion Channels
Sensory neuron–specific
voltage-gated sodium channels
Other types of sodium channels
Acid-sensing ion channels
Nitric oxide synthase*
N-type voltage-gated calcium
channels
Other types of calcium channels
Sensory neuron–specific
voltage-gated sodium channels
Other types of sodium channels
Nitric oxide synthase*
Forebrain-specific NMDA
Alpha2-adrenergic
Serotonergic
N-nicotinic acetylcholine
Cannabinoid
ATP = adenosine triphosphate; NMDA = N-methyl-D-aspartate; AMPA = alpha-amino-3-hydroxy-5-methyl-4isoxazole propionic acid; GABA = ␥-aminobutyric acid.
*Nitric oxide synthase is the key enzyme required for nitric oxide formation.
One theory posits that abnormal activation of the trigeminal nucleus is the primary mechanism in migraine. In this theory, trigeminal nucleus dysfunction is
possibly initiated by hyperactivity in neighboring midbrain structures53 and is
complicated by an antidromic conduction of impulses toward the periphery, promoting both neurogenic inflammation54 and central sensitization.55 Another theory proposes a central role for nitric oxide, which is found in the perivascular
sensory nerve endings as well as in key brain stem structures known to be involved in nociceptive processing. According to this theory, nitric oxide may function as either the trigger for spontaneous migraine attacks, a critical component
2514
M. Pappagallo
of peripheral and central sensitization, or both.56 There are many other theories
of the origin of migraine pain, but a neuropathic etiology is assigned a substantial role in all of them.40
RATIONALE FOR THE USE OF AEDS IN NEUROPATHIC PAIN
AND MIGRAINE
Use of AEDs for the treatment of neuropathic pain is an attractive option, not least
because of the similar pathophysiologies of neuropathic pain and epilepsy.57 One
example of these similarities is provided by the mechanisms of kindling and central sensitization noted in the previous section, and another is provided by the
processes of ectopic neuronal firing common to both epilepsy58 and neuropathic
pain.59 In addition to these closely related pathophysiologic mechanisms, both disorders can be caused by a central nervous system injury, such as head trauma.60
The clinical connection between epilepsy and migraine is also becoming increasingly clear. Several studies have reported that epilepsy and migraine occur as comorbid conditions with greater than random frequency.26,61 The median prevalence
of epilepsy in patients with migraine is 5.9% (range, 1%–17%), compared with
<1.0% in the general population. Similarly, patients with epilepsy have a higher lifetime prevalence of migraine.26 The Epilepsy Family Study61 found that those with
epilepsy had a 2.4 times greater rate of migraine than family members without
epilepsy. The possible explanations for this comorbidity include a shared etiology
(eg, head trauma),60 a shared genetic vulnerability to neuronal hyperexcitability (eg,
channelopathies),62 or some as yet unproved common etiologic factor (eg, particular types of serotonergic dysfunction).63,64
Given the interconnection of these disorders, it is reasonable to speculate that the
mechanisms of action that may be responsible for the therapeutic efficacy of the
newer AEDs in the treatment of epilepsy may also prove beneficial in the treatment
of neuropathic pain65 and migraine.6 Seven mechanisms of action are shared by ≥1
of the newer AEDs that relate directly to the pathophysiology of neuropathic pain
and migraine, any or all of which may account for the effectiveness of the medications discussed in this article: (1) sodium channel blockade10; (2) calcium channel
blockade10; (3) enhancement of GABAergic transmission66; (4) inhibition of glutamatergic transmission66; (5) free radical scavenging67; (6) inhibition of nitric oxide
formation48; and (7) enhancement of serotonergic transmission66 (Table V).
EARLY CLINICAL EXPERIENCE WITH AEDS IN NEUROPATHIC PAIN
AND MIGRAINE
Carbamazepine for Neuropathic Pain
In addition to the foregoing rationale for their use, the AEDs showed some
early clinical promise in the treatment of neuropathic pain. Carbamazepine
emerged as a treatment for trigeminal neuralgia before the discovery of much of
2515
CLINICAL THERAPEUTICS®
Table V. Mechanisms of action of the 5 newer antiepileptic drugs.10,48,66–67
Mechanism
Enhance GABAergic
transmission
L-, N-, or T-type calcium
channel blockade
Inhibit glutamatergic
transmission
Sodium channel
blockade
Free radical scavenger
Enhance serotonergic
transmission
Inhibit formation of
nitric oxide
Gabapentin
Lamotrigine
Oxcarbazepine
Topiramate
Zonisamide
X
X
X
X
X
X
X
X
X
X
X
X
X
GABA = ␥-aminobutyric acid.
what we now know about the neurophysiology of nociception and the neuropathology of neuropathic pain. It first began to be used for trigeminal neuralgia
after the publication in Lancet in 1962 of a report by Blom describing its successful use in a series of patients with this condition.68 Because previous pharmacotherapies for this condition had been almost uniformly unsuccessful, the fact
that carbamazepine worked at all was remarkable. Two double-blind, placebocontrolled, crossover studies69,70 subsequently provided definitive scientific evidence for the efficacy of carbamazepine in the treatment of trigeminal neuralgia.
In these studies, which involved 151 patients, improvement in pain was 2- to 3fold greater with carbamazepine compared with placebo. The dosing was identical to that used for the treatment of epilepsy, ranging from 400 to 1000 mg/d PO,
corresponding to serum levels of 6 to 10 mg/L. Thus, carbamazepine was established as the treatment of choice for trigeminal neuralgia.
The success of carbamazepine in trigeminal neuralgia led to its investigation in
other neuropathic conditions. A small randomized, double-blind, crossover trial
of carbamazepine conducted in the late 1960s in 30 patients with PDN suggested
some benefit, although the outcome measures were not well designed—for example, a standardized pain rating scale was not used.71 Sixty-seven percent of the patients noted “moderate or significant” pain relief with carbamazepine, compared
with 20% with placebo. A subsequent comparison of carbamazepine with the
combination of nortriptyline and fluphenazine in patients with PDN found that
carbamazepine was equivalent in efficacy to the tricyclic antidepressant (TCA)–
neuroleptic combination.72 The clinical experience with carbamazepine in PDN
2516
M. Pappagallo
has not been satisfactory, however, and trigeminal neuralgia is the only neuropathic
pain state for which carbamazepine is considered a first-line agent. One small study
in patients with central pain failed to show efficacy,73 and the results of another
small study in patients with PHN or other neuralgias were inconclusive.74
Clinical studies examining the efficacy of phenytoin in PDN yielded equivocal
results.75,76 With the exception of sodium valproate for the prophylaxis of migraine
(discussed in the following section) and carbamazepine for the treatment of trigeminal neuralgia, none of the other older AEDs were ever demonstrated to be effective in the treatment of any neuropathic pain syndrome or headache disorder.
Thus, little progress has been made in the development of medications for neuropathic pain in the >30 years since the discovery that carbamazepine was efficacious in the treatment of trigeminal neuralgia. TCAs have remained the treatment of choice for most neuropathic pain disorders (except trigeminal neuralgia),77
and beta-blockers and TCAs have continued to be used as first-line treatments
for the prevention of migraine.13 Over the past decade, however, this situation
has been changing, in part because of the introduction of the next generation of
AEDs.
Valproic Acid for the Prophylaxis of Migraine
It was not until the early 1990s that valproic acid was studied as an antimigraine agent. In 2 randomized, controlled trials in patients with migraine,78,79
sodium valproate was found to significantly decrease the frequency of headache
compared with placebo (P = 0.00278 and P < 0.00179). Divalproex sodium, a
slightly different preparation of this agent, was studied in 2 controlled trials and
found to have similar efficacy to sodium valproate.80,81 In the most recent of these
2 trials,81 divalproex given at 500, 1000, and 1500 mg/d reduced the mean frequency of headaches by between 1.7 and 2.0 per month from a baseline value of
4.5 to 4.7 per month. Among patients who received divalproex, 44% had a ≥50%
decrease in migraine occurrence, compared with 21% in the placebo group (P <
0.05). In clinical practice, however, high rates of adverse events (AEs) (eg, nausea, weight gain, tremor); the need for regular monitoring of drug levels, liver enzymes, and blood counts; and the lack of its clear superiority over conventional
treatments have limited the usefulness of this AED as a prophylactic treatment for
migraine. Despite these problems, these studies of sodium valproate indicated the
potential utility of AEDs in the prevention of migraine.
Many migraine patients are candidates for prophylactic therapy, particularly
those with transformed migraine, whose headaches occur on a daily or almostdaily basis.13 Furthermore, excessive use of triptans or other abortive agents (≥3
times per week) can compound the problem by causing medication-overuse, or
rebound, headaches.82 In addition, a sizeable minority of patients do not respond
well to triptans or other abortive agents, and there are those whose headaches are
2517
CLINICAL THERAPEUTICS®
so disabling they prefer to treat them prophylactically, even if this means taking
medication on a daily basis.13 The International Headache Society recognizes all
of these circumstances as medical indications for the use of prophylactic therapy.13 The possibility that AEDs might be effective for this purpose, as suggested
by the experience with sodium valproate, has led to interest in the newer AEDs.
CLINICAL TRIALS OF THE NEWER AEDS IN NEUROPATHIC PAIN
AND MIGRAINE
Gabapentin is the only AED empirically shown to be beneficial in the treatment
of some forms of neuropathic pain.11,12,83 Limited numbers of randomized,
placebo-controlled, double-blind trials have evaluated lamotrigine84–88 and topiramate89–91 in various neuropathic pain states, and gabapentin92 and topiramate93–97 in the prophylaxis of migraine. Much of the clinical research concerning the use of the newer AEDs for neuropathic pain and migraine has been in the
form of open-label, uncontrolled studies in small, nonrandomized samples.13,14
Many of these studies have been presented at the national meetings of professional societies and have been published in abstract form only.95–99 Although the
majority of these open-label, uncontrolled studies have reported positive results,
further randomized, controlled trials are necessary to determine the safety and efficacy of the newer AEDs in the treatment of neuropathic pain and migraine. The
following sections summarize the available literature on the 5 most commonly
prescribed newer AEDs.
Gabapentin
Neuropathic Pain
Clinical interest in the potential role of the newer AEDs in the treatment of neuropathic pain reawakened in 1998 with publication of the results of 2 multicenter, randomized, double-blind, placebo-controlled trials of gabapentin in patients
with PHN11 and PDN12 in the same issue of the Journal of the American Medical
Association. In the PHN study,11 229 patients were randomized to receive gabapentin
or placebo. Gabapentin was titrated over 4 weeks to a maximum of 3600 mg/d,
followed by a 4-week maintenance phase. Patients were allowed to continue stable doses of TCAs and/or opioids. The primary outcome measure was the mean
daily pain score (11-point scale), which decreased from 6.3 to 4.2 in the activetreatment group and from 6.5 to 6.0 in the placebo group (P < 0.001). There was
no significant difference in the rate of withdrawals in the gabapentin group
(13.3%) and the placebo group (9.5%).
In the PDN study,12 165 patients with a ≥1-year history of pain of at least moderate severity were randomized to receive gabapentin or placebo. This study also
employed a 4-week titration phase and a 4-week maintenance phase. In this study,
however, all other medications that could affect the symptoms of PDN were pro2518
M. Pappagallo
hibited from 30 days before randomization throughout the study period. (The only
exceptions were stable doses of a serotonin reuptake inhibitor, low-dose acetylsalicylic acid [up to 325 mg/d], and acetaminophen [up to 3 g/d].) One hundred
thirty-five patients completed the study, with no significant between-group difference in dropout rates (17% gabapentin, 20% placebo). The mean daily pain score
(10-point visual analog scale [VAS]) in the gabapentin group decreased from 6.4
at baseline to 3.9 by the end of the 8-week study, compared with a decrease from
6.5 to 5.1 in the placebo group (P < 0.001). Somnolence, dizziness, ataxia, and
confusion were the most commonly occurring AEs with gabapentin.
A randomized, controlled study directly compared gabapentin with amitriptyline in patients with PDN,100 as did another study employing an open-label design.101 Neither study found a significant difference between the 2 agents in terms
of efficacy or total AE burden. The second study reported numerically greater reductions in pain and paresthesias with gabapentin and less gain in body weight,
although the differences were not statistically significant.101 Although each study
included only 25 patients, the data suggested that gabapentin was at least as efficacious and as well tolerated as the TCA.
A randomized, double-blind, placebo-controlled study of gabapentin in the
treatment of PHN83 confirmed the positive results of the earlier PHN trial.11 This
7-week study in 334 adults evaluated 2 gabapentin regimens—1800 and 2400
mg TID. The active-treatment groups had a 34% decrease in mean daily pain ratings from baseline to the final week of the study, whereas the placebo group had
a 16% decrease (P < 0.01). Subsequent to this confirmation of the drug’s efficacy
in PHN, the US Food and Drug Administration (FDA) added PHN to the indications for gabapentin. This is the only approved indication for a neuropathic pain
disorder for any of the newer AEDs.
The actual improvement in pain scores in those who received gabapentin in the
preceding studies was not dramatic. The magnitude of response to other AEDs
has also been limited—this is partly a reflection of the wide range of responses
in the treatment groups, with some patients experiencing a benefit (≥50% reduction in pain) and others receiving no benefit at all. It must be remembered,
however, that there are few effective treatments for neuropathic pain, and even a
modest benefit is meaningful.
There are published reports suggesting therapeutic benefit for gabapentin in
trigeminal neuralgia,102 multiple sclerosis pain,103,104 and neuropathic head and
neck pain.105 Because none of these studies were prospective or controlled, the
results can be considered only preliminary.
Migraine
Gabapentin was efficacious for the prophylaxis of migraine in a multicenter,
randomized, double-blind, placebo-controlled trial.92 Ninety-eight patients re2519
CLINICAL THERAPEUTICS®
ceived gabapentin and 45 received placebo. Among those who were able to tolerate a stable dosage of 2400 mg/d, 46.4% had a ≥50% reduction in the frequency of migraine, compared with 16.1% in the placebo group (P = 0.02). This
group had a reduction in the frequency of headaches from 4.2 during the 4-week
baseline period to 2.7 during the final 4 weeks of the study (mean reduction, 1.5;
P = 0.006), whereas the placebo group had a reduction from 4.1 to 3.6 (mean reduction, 0.5). Sixteen patients (16.3%) in the gabapentin group dropped out of
the study because of AEs, compared with 4 (8.9%) in the placebo group. These
results have yet to be confirmed by other trials.
Lamotrigine
Neuropathic Pain
Lamotrigine is the only other newer AED to have been evaluated in randomized,
controlled trials involving patients with neuropathic pain. In a multicenter, 14-week,
randomized, double-blind, placebo-controlled trial in 42 patients with painful HIVassociated neuropathy,85 lamotrigine 300 mg reduced pain significantly compared
with placebo (P = 0.03). In descriptive terms, the pain decreased from moderate
to very mild. Interpretation of the results is limited by the small sample size and
the high dropout rate (11/20 lamotrigine, 2/22 placebo). Five patients in the lamotrigine group developed a rash that caused them to discontinue treatment,
although there were no serious medical consequences in any of these cases. Nonetheless, the results of this study are intriguing, as most other treatments for
HIV-associated neuropathy, including amitriptyline, have shown no benefit over
placebo.
In a subsequent randomized, double-blind, placebo-controlled trial in 247 patients with painful HIV-associated neuropathies,84 patients were stratified according to whether or not they were currently receiving neurotoxic antiretroviral therapy. Only those who were receiving antiretroviral therapy had a statistically
significant decrease in scores on a VAS for pain, with a 27.1% reduction in the
lamotrigine group and a 9.0% reduction in the placebo group (P < 0.02).
An 8-week, randomized, double-blind, placebo-controlled trial evaluated
lamotrigine monotherapy in 59 patients with PDN.88 Medication was titrated
slowly to a final dosage of 400 mg/d in the eighth week. The primary outcome
variable was the mean daily pain score (0–10 scale), which decreased from 6.4 to
4.2 in the active-treatment group (lamotrigine 200, 300, and 400 mg/d) and from
6.5 to 5.3 in the placebo group (P < 0.001). There was no difference in rates of
attrition, with 83% of lamotrigine recipients and 73% of placebo recipients completing the study. Twelve of 24 patients (50%) in the lamotrigine group who completed the study reported a ≥50% decrease in pain, compared with 5 of 22 patients (23%) in the placebo group. The efficacy and tolerability results of this
study were comparable to those of the studies of gabapentin in PDN.12,100
2520
M. Pappagallo
In a small randomized, double-blind, placebo-controlled, crossover study in 30
patients with central poststroke pain,86 lamotrigine was titrated to 200 mg/d over
6 weeks and continued at that dosage for the final 2 weeks of treatment. This was
followed by a 2-week washout period and another 8 weeks of double-blind treatment. Lamotrigine reduced the final median weekly pain score compared with
placebo (P = 0.01), as well as the patient’s global assessment of pain (11-point
Likert scale) from strong (4) at baseline to moderate (3) at the end of the study
(P = 0.02). Three patients who received lamotrigine withdrew from the study because of AEs, compared with no placebo recipients. The results were not dramatic, although they suggested potential benefit for lamotrigine. Conversely, an
8-week, randomized, double-blind, placebo-controlled trial of lamotrigine
monotherapy in 100 patients with a variety of neuropathic pain conditions found
no benefit for lamotrigine87; however, the drug was titrated very slowly and the
maximum dosage reached was only 200 mg/d.
Migraine
Lamotrigine has been evaluated as part of combination therapy for the prevention
of migraine in a prospective, open-label trial enrolling 65 patients, most of whom had
transformed migraine.99 Only 35 patients were included in the final analysis; 12
dropped out because of AEs. The primary end point was reduction in the frequency
of severe headaches. By this measure, 17 patients (48.6%) were responders at a mean
dosage of 55 mg/d. Those who had migraine with aura had a better response rate
(12/18 [66.7%]); among these responders were 4 of 8 patients whose headaches were
chronic. This finding was supported by the results of an interesting pilot study that
assessed the impact of lamotrigine on aura itself and reported that the drug significantly reduced both the frequency and duration of aura (both, P < 0.001).106
There are case reports in which lamotrigine is mentioned as having potential
benefit in the treatment of a type of headache known as SUNCT—short-lasting,
unilateral, neuralgiform headache with conjunctival injection and tearing.107,108
Although the relationship of SUNCT to migraine is uncertain, the condition is
thought to be primarily neuropathic in origin.
Oxcarbazepine
Neuropathic Pain
The literature search identified no published randomized, controlled trials of
oxcarbazepine, the 10-keto homologue of carbamazepine, in the treatment of any
neuropathic pain disorder. Reports of several open-label trials of oxcarbazepine
in patients with trigeminal neuralgia that was refractory to carbamazepine suggested that this agent was useful and well tolerated. Twelve of 15 patients responded in one trial,109 13 of 15 in another,110 and 14 of 14 in the third.111 The
titration of oxcarbazepine was rapid (over 7–10 days), and effective dosages
2521
CLINICAL THERAPEUTICS®
ranged from 900 to 2400 mg/d. The AE profile of oxcarbazepine was favorable
relative to carbamazepine in all 3 trials.
An open-label study of adjunctive oxcarbazepine in 36 consecutive patients
with various neuropathic pain disorders that had not responded to treatment with
gabapentin found that the addition of oxcarbazepine 600 to 1200 mg/d was helpful in almost two thirds of patients.112 Excellent results (>70% improvement in
neuropathic symptoms, based on VAS pain score, the Short-Form McGill Pain
Questionnaire, the physician’s global assessment, and physical examination) were
reported in 22.2% of patients, good results (51%–70% improvement) in 41.7%,
and fair or poor results (≤50% improvement) in 38.9%. In the subset of patients
who presented with radiculopathy (n = 18), the proportion of those with excellent or good results was greater than in the sample as a whole (84% vs 64%, respectively). Discontinuation of treatment was more frequently attributed to poor
response than to AEs.
Migraine
The literature search identified no studies examining the use of oxcarbazepine
in the prophylactic treatment of any headache disorder.
Topiramate
Neuropathic Pain
The structurally unique AED topiramate has shown possible efficacy as
monotherapy in 1 small randomized, controlled study in patients with PDN.90
Twenty-six adult patients were randomized to receive placebo or topiramate
titrated over 10 weeks to 400 mg/d or the highest tolerated dose. At the conclusion of the study, the topiramate group had a 35% mean decrease in VAS pain
scores, compared with a 4% mean increase in the placebo group.
Four larger randomized, double-blind, placebo-controlled trials were later conducted, only 1 of which has been published.89 The latter, also the only 1 of the
4 trials to report a significant benefit for topiramate, was a 12-week trial in which
192 patients with PDN received topiramate 400 mg/d (or the maximum tolerated
dose) or placebo. The topiramate group had a mean reduction in pain score of
21.8 mm on a 100-mm VAS, compared with a reduction of 15.1 mm in the
placebo group (P = 0.038). A higher proportion of patients in the topiramate
group reported ≥50% reduction in pain scores compared with the placebo group
(36% vs 21%, respectively; P = 0.005). The authors hypothesized that higher
baseline pain scores or certain design differences may have explained the discrepancy between the results of this study and the other 3.
Use of topiramate for other types of neuropathic pain has been investigated to
a limited extent. One case report of a patient with intercostal neuralgia cited some
benefit,113 and a small case series (N = 6) reported dramatic benefit in patients
2522
M. Pappagallo
with trigeminal neuralgia.114 However, a later placebo-controlled, crossover study
in 3 patients with trigeminal neuralgia failed to show an advantage for topiramate
relative to placebo.91
Migraine
Two randomized, double-blind, placebo-controlled studies of topiramate
monotherapy in the preventive treatment of migraine have been published. One
study enrolled 40 adults with migraine with or without aura (35 completed the
study).93 After a 4-week baseline period, patients were randomized in a 1:1 ratio
to receive topiramate or placebo. Topiramate therapy was titrated to 200 mg/d
over 8 weeks and was maintained at the highest tolerated dose for 8 weeks. The
mean dosage was 125 mg/d. The mean frequency of headaches per 28 days was
reduced from 5.14 at baseline to 3.31 during the maintenance period in the topiramate group, compared with a reduction from 4.37 to 3.83 in the placebo
group (P = 0.003). The second study had essentially the same design,94 with 30
patients randomized in a 1:1 ratio to receive topiramate or placebo, and a similar timetable for the baseline, titration, and maintenance phases. There was a limited group effect, but 7 of 15 patients receiving topiramate had ≥50% reduction
in headaches, compared with only 1 of 15 receiving placebo. This benefit was
counterbalanced by 7 of 15 patients in the topiramate group dropping out of the
study, 4 as a result of AEs.
The results of 2 multicenter, randomized, double-blind, placebo-controlled
studies of topiramate for the prophylactic treatment of migraine were presented
at a national meeting in 2003. In the first study,95 487 patients were randomized
to receive topiramate 50 mg/d (n = 125), 100 mg/d (n = 128), or 200 mg/d (n =
117), or placebo (n = 117). The primary outcome measure was change in headache
frequency from baseline to the end of the double-blind phase. Patients in all 3
treatment groups had significantly greater response rates (defined as a ≥50% reduction in headache frequency) relative to placebo (50 mg: 36%, P = 0.039; 100
mg: 54%, P < 0.001; 200 mg: 52%, P < 0.001; placebo: 23%). Similarly, patients
in the topiramate 100- and 200-mg groups had significantly greater reductions in
the mean monthly frequency of headaches compared with placebo (P < 0.001).
The second study was methodologically identical,96,97 with 483 patients randomized to the same 4 treatment groups as in the first study. The results again
showed a statistically significant benefit for topiramate, whether measured in
terms of response rates (P < 0.001, topiramate 100 and 200 mg vs placebo) or
reduction in mean monthly frequency of headache (100 mg, P = 0.008; 200 mg,
P = 0.001).96 There was no difference in completion rates between the 4 groups
(50 mg, 49%; 100 mg, 52%; 200 mg, 58%; placebo, 52%). A greater proportion
of topiramate recipients dropped out of the study because of AEs compared with
the placebo group (200 mg, 26%; placebo, 12%), whereas a greater proportion
2523
CLINICAL THERAPEUTICS®
of placebo recipients dropped out because of lack of efficacy (100 and 200 mg,
both 10%; placebo, 18%).97
Zonisamide
Neuropathic Pain
Zonisamide has not been evaluated in any randomized, controlled trials in patients with neuropathic pain, but a number of open-label case series and anecdotal reports have been published. In the largest open-label study,115 zonisamide
was added to existing therapy in 50 patients with treatment-refractory neuropathic pain that was primarily associated with cervical or lumbar radiculopathies.
Ten patients had not completed dose titration at the time of publication, so the
analysis included data from 40 patients. At a mean daily dosage of 260 mg/d,
daily pain scores were decreased by >60% in 10 patients (25%) and by 30% to
60% in 8 patients (20%). Only 2 of 40 patients (5%) discontinued therapy because of an AE (drowsiness). Eighteen of 40 patients (45%) were able to discontinue the AED they had been taking at the time of study entry. The initial AED
was gabapentin in 12 of 18 patients, and topiramate in 3 ( J.C. Krusz, MD,
Anodyne PainCare, Dallas, Texas, written communication, November 26, 2002).
A retrospective review of 300 consecutive cases of chronic pain treated at an
outpatient pain clinic included 142 patients with neuropathic pain who received
a prescription for zonisamide.116 Eighty-six of these patients had a diagnosis of
cervical or lumbar radiculopathy, 30 PDN, 19 fibromyalgia, and 7 pelvic pain.
Zonisamide was initiated at 100 mg/d and titrated monthly to the maximal tolerated dose. (Use of concomitant pharmacotherapy was not reported.) Follow-up
data on patients’ subjective assessment of pain were available for 132 of 142 patients. Only 10 patients (7%) discontinued zonisamide because of AEs. At a mean
daily dose of 252 mg, 100 of 142 patients (70%) reported at least moderate reduction in pain; only 9 (6%) felt they received no benefit. Although not the chief
complaint in this population, headache was present in 23 patients, of whom 16
(70%) reported at least moderate improvement in head pain.
In a retrospective case series involving 11 adult patients with various neuropathic
pain diagnoses who received adjunctive zonisamide therapy,117 all 11 reported at
least some benefit from the drug. The mean daily dosage was 275 mg/d. The response was categorized as excellent in 5 patients (45%). No patients discontinued
zonisamide as a result of AEs. In a similar review including 12 adult patients with
neuropathic pain conditions in which the investigator’s assessment was the primary
end point,118 2 patients (17%) were reported to have an excellent result and 5 (42%)
a good result. Two patients dropped out because of AEs (palpitations and decreased
response to opioids), neither of which appeared to be related to zonisamide therapy.
A recent report described the case of a 53-year-old woman with idiopathic
polyneuropathy and severe pain that had responded poorly to several nerve2524
M. Pappagallo
blocking procedures, gabapentin, 2 TCAs, and carbamazepine.119 Addition of topiramate at a dosage of up to 100 mg QID resulted in some diminution of pain.
Addition of alpha2-agonists, first clonidine and then tizanidine, was not helpful.
Zonisamide was then started at 100 mg/d and increased every other week to a
maximum of 400 mg/d, with a reduction in mean daily pain score from 9 at baseline to 5 (on a scale from 0 to 10). This benefit was sustained when the topiramate dosage was decreased to 50 mg BID after the patient experienced shortness
of breath. Another report described the cases of 2 patients with type 1 CRPS who
received low dosages of zonisamide (75 and 125 mg/d) for 10 weeks.120 Pain reduction, as measured on the Neuropathic Pain Scale and the Wisconsin Brief Pain
Scale Inventory, was minimal.
Migraine
Results of 2 retrospective, open-label studies of zonisamide in the preventive
treatment of episodic migraine have been published. In one study,121 34 patients
with treatment-refractory migraine with or without aura received adjunctive treatment with zonisamide at dosages up to 400 mg/d. Headache data were obtained
from patients’ headache diaries and by telephone report. A 40% reduction from
baseline in headache severity, 50% reduction in headache duration, and 25% decrease in headache frequency were reported at 3 months. Four patients (12%) discontinued zonisamide because of AEs, and 9 (26%) discontinued the drug because
they believed it was not working. The other study showed improvement in 14 of
33 patients (42%), with 4 patients dropping out as a result of AEs.98
Zonisamide was examined as prophylactic monotherapy in a prospective, openlabel study in 9 patients with episodic migraine with or without aura.122 The drug
was titrated to a mean dosage of 244 mg/d, and investigator efficacy ratings were made
after therapy had remained at a stable dose for 6 weeks. By this subjective and imprecise standard, the drug was deemed effective or very effective in 6 patients (67%).
Zonisamide was assessed in a population with chronic daily headache, almost
all of them with transformed migraine.123 Patients in this study had failed to respond to ≥2 trials of prophylactic agents (mean no. of agents, 5.9). Sixteen patients received zonisamide, 10 taking 100 mg/d and 6 taking 200 mg/d. After 3
months of treatment, total headache time (frequency × duration) was reduced by
50% in the group as a whole, with the mean number of headache days per month
reduced from 22.0 to 14.5 (34% reduction). These results in a highly treatment
refractory population receiving a relatively low dose of medication suggest benefit for zonisamide.
CLINICAL PROFILE OF THE NEWER AEDS
The first consideration in the decision to use a particular treatment must always
be the evidence base. Most of the published data on the use of the newer AEDs
2525
CLINICAL THERAPEUTICS®
in the treatment of neuropathic pain and migraine suggest that each agent may
be helpful in some patients. With the exception of gabapentin in PHN, however,
the evidence base is insufficient to warrant use of these agents in any pain disorder; this lack of evidence is reflected in the fact that none of the other agents have
obtained FDA approval for the treatment of any neuropathic pain disorder or for
the prophylaxis of any type of migraine. Therefore, the decision to prescribe an
AED for any of these conditions must depend on assessment of the potential risks
and benefits in the individual patient. The following sections summarize what is
known about the AE and drug-interaction profiles of each of the 5 newer AEDs,
and the article concludes with a review of their dosing and titration.
AE Profiles
All medications in the current generation of AEDs have better tolerability than the
established AEDs.1 Table VI summarizes the AEs that have been associated with use
of the 5 AEDs discussed in this article. All of these agents have 2 common AEs: dizziness and somnolence. These AEs are clearly dose related, and most patients develop
some degree of tolerance to them over time. Most other AEs in the clinical trials and
case series were also dose related, did not lead to discontinuation of treatment, and
improved once steady-state levels were achieved and dosing remained constant.124
Investigators and clinicians consistently noted that low initial doses followed by slow
titration reduced the incidence and severity of AEs for most of these drugs. Gabapentin
can be initiated at a higher dose and titrated more quickly than the other 4 AEDs
Table VI. Adverse effects of the 5 newer antiepileptic drugs,* based on data presented in
the double-blind trials reviewed in this article11,12,21,83–97,128 or discussed in the
cited review articles.124,129,138,142
Adverse Effect
Dizziness/ataxia
Somnolence
Fatigue
Cognitive dysfunction
Diplopia
Nausea/vomiting
Anorexia/weight loss
Kidney stones
Rash
*The
Gabapentin
Lamotrigine
Oxcarbazepine
Topiramate
Zonisamide
3
3
2
1
1
1
0
0
0
3
1
1
1
3
3
0
0
3†
3
3
2
1
3
3
0
0
0
2
3
1
3
1
1
3
1
0
2
3
1
1
1
1
3
1
1‡
grading system used in this table is as follows: 0 = same as placebo; 1 = 2%–5% more than placebo; 2 =
6%–10% more than placebo or >2 times placebo; 3 = >10% more than placebo or >3 times placebo.
†<1% Incidence of serious rash.
‡<0.1% Incidence of serious rash.
2526
M. Pappagallo
(see Dosing and Titration section).125 Rates of particular AEs varied depending on
whether the drug was used as monotherapy or as adjunctive therapy, and on whether
patients were naive to AEDs or had received these drugs previously. In general, the
incidence of AEs was lower with monotherapy and in AED-naive patients.124,125
Gabapentin
Gabapentin has gained rapid acceptance among physicians, in part because of its excellent tolerability. Common AEs (occurring in >10% of patients when used adjunctively) are limited to somnolence, dizziness, ataxia, and fatigue.124 In the randomized,
controlled trial in patients with PDN discussed previously,12 the only AEs that occurred
significantly more frequently with gabapentin than with placebo were somnolence
(P = 0.004) and dizziness (P < 0.001), and only 8% of patients in the gabapentin group
withdrew because of AEs. In the PHN study,11 in which gabapentin was used adjunctively in most cases, 13.3% of patients in the gabapentin group dropped out as a result of AEs. Somnolence, dizziness, ataxia, infection, and peripheral edema occurred
more frequently in the gabapentin group than in the placebo group.
Lamotrigine
Lamotrigine is the only drug in this group whose prescribing information contains a “black box” warning, indicating an incidence of severe rash of 3 per 1000
adult patients exposed.126 The total incidence of rash with lamotrigine is ~10%,
and because there is no way of distinguishing clinically between benign and potentially malignant rashes, discontinuation of medication is necessary in all patients who develop a new rash while taking this drug.124 Clinical trials in epilepsy
and bipolar depression have found that the incidence of rash is reduced when lamotrigine is begun at a low dose and titrated very slowly.127,128 In the clinical trials summarized in the present article, rash was more common in patients with
HIV-associated neuropathy (5/20)85 than in those with central poststroke pain
(2/30)86 or PDN (2/29).88 In a meta-analysis of controlled trials of add-on lamotrigine therapy in patients with partial epilepsy,124 the 5 most frequently reported
AEs were nausea, dizziness, ataxia, diplopia, and blurred vision.
Oxcarbazepine
Despite its greater tolerability relative to carbamazepine, oxcarbazepine has
been associated with the highest rates of reported AEs among the newer AEDs
discussed in this article. Oxcarbazepine does not appear to present any risk of serious hepatic or hematologic reaction, and serum monitoring is not required.
Rashes were rarely noted. However, the following AEs were reported at least twice
as often—or with an additional 10 percentage points—in those who received
oxcarbazepine compared with control groups: dizziness, somnolence, ataxia,
nystagmus, diplopia, visual abnormality, vertigo, nausea, vomiting, and fatigue.
2527
CLINICAL THERAPEUTICS®
As noted, the rates of AEs are lower with monotherapy than with adjunctive therapy. Hyponatremia (serum sodium level <125 mmol/L) has been documented in
2.7% of patients who received oxcarbazepine in 14 studies.129
Topiramate
Of the newer AEDs discussed, topiramate has been associated with the highest
rate of cognitive AEs (up to 10%), including psychomotor slowing, confusion,
memory difficulties, and speech- and language-related problems.124 These are
predominantly dose related and may occur less frequently if the drug is started
at a low dose and titrated very slowly.125 Other common AEs associated with the
use of topiramate are dizziness, somnolence, and fatigue. Kidney stones were reported in 1.5% of adults taking part in clinical trials of topiramate.124
Weight loss has been noted with this medication. The most recently reported
study of topiramate in epilepsy included 38 patients who received topiramate as
an adjunct to their existing regimens for the control of refractory partial seizures
and who continued the drug for 1 year.130 Weight loss was noted in 83% of
patients at 3 months (mean weight loss, 3.0 kg) and 86% of patients at 1 year
(mean weight loss, 5.9 kg). Interestingly, patients who were obese at baseline
lost almost twice as much weight as the overall sample (mean weight loss,
10.9 kg).
Zonisamide
As a member of the sulfonamides, zonisamide poses a risk for serious dermatologic or hematologic reactions. However, the incidence of such AEs has been
extremely small (46 cases of toxic dermatologic events per million patient-years
of exposure; 3 cases of serious hematologic events), and the background rate of
rash is 2%.129 Zonisamide is structurally different from sulfonamide antibiotics,
and there is no evidence of cross-reactivity between them.131 It has been used
with caution in patients who report allergy to sulfonamide antibiotics with no occurrence of rash or other allergic reaction.131 Somnolence and dizziness are the
only other AEs occurring with a frequency >10%. Kidney stones were suspected
clinically in 4.0% of patients receiving zonisamide in epilepsy clinical trials and
were symptomatic in 1.4%.129
Weight loss is an unexplained AE that has been associated with the use of
zonisamide. In 3 randomized, placebo-controlled trials of adjunctive zonisamide
therapy for the treatment of partial seizures,132 reliable weight data were available
for 314 of the 493 enrolled patients. In a comparison between the end of
the baseline period and the end of double-blind treatment (3–5 months), 76
zonisamide recipients (28.9%) and 18 placebo recipients (8.4%) lost >5 lb
(P = 0.001), and a respective 17 (6.5%) and 40 (18.6%) gained >5 lb (P =
0.001).
2528
M. Pappagallo
Dosing and Titration
The starting dose, titration schedule, and target dosage range for each of the 5
AEDs are summarized in Table VII.* The initial dosing and titration schedules are
the same for neuropathic pain and migraine prophylaxis, although the effective
dose is generally in the middle of the dosing range for migraine, whereas higher
doses are often necessary in neuropathic pain.88,97
Therapeutic and/or toxic levels of the newer AEDs have not yet been rigorously
defined as they have for standard AEDs, and serum monitoring of plasma levels
is not currently performed on a routine basis.133 However, several studies have
investigated the relationship between serum levels and therapeutic effects for
some of these agents.133–136 Large interindividual and intraindividual differences
were observed, and definitive therapeutic ranges could not be established for any
of the newer AEDs.133–135 Therefore, monitoring of serum drug levels is recommended to assess compliance, determine target levels for individual patients, or
guide dosing in the presence of changes in concomitantly administered medications that could affect serum levels of the AED.134,136
Drug Interactions
The newer AEDs present fewer problems of drug interactions than older
AEDs.137,138 When coadministered, none of the newer AEDs have an effect on lev*References:
11, 12, 84, 88, 89, 97, 112, 115, 121.
Table VII. Dosing and titration of the 5 newer antiepileptic drugs.
Drug
Initial Dose
Titration Schedule
Target Dose
Gabapentin11,12
300 mg/d–300 mg TID
Increase by 300 mg/d,
maintaining TID dosing
1800–3600 mg/d given
TID
Lamotrigine84,88
25 mg/d
Increase to 25 mg BID
for 2 wk, then to 50 mg
BID for 2 wk, then by
100 mg/wk
200–500 mg/d given
BID
Oxcarbazepine112
150–300 mg at
bedtime
Increase by 150–300
mg every 3–5 days
900–1800 mg/d given
BID
Topiramate89,97
25–50 mg/d
Increase by 25–50 mg/wk
50–500 mg/d given BID
Zonisamide115,121
100 mg at bedtime
Increase to 200 mg/d
after 2 wk, then to
300 mg/d for 2 wk,
then by 100 mg/wk
100–500 mg/d given
BID or at bedtime
2529
CLINICAL THERAPEUTICS®
els of any of the others.137–139 The newer AEDs also have much less effect on the
CYP family of enzymes than the standard AEDs. Only topiramate and oxcarbazepine have been documented as having a clinically significant effect on any of
these isozymes.140 Both agents induce CYP3A4, which causes more rapid metabolism of most of the steroid hormones used in oral contraceptives and can lead to
failure of birth control. For that reason, it is recommended that patients taking either of these AEDs not use oral contraceptives.141,142 Oxcarbazepine also inhibits
CYP2C19, which alters levels of commonly used calcium channel antagonists.129
Phenytoin, phenobarbital, and carbamazepine are all potent inducers of CYP
isozymes and will lower serum levels of all AEDs mentioned in this article (except
for gabapentin).137 Valproic acid produces clinically significant decreases in the
clearance of lamotrigine and thus raises lamotrigine levels. Therefore, the dose of
lamotrigine must be reduced in patients taking these medications concomitantly.138
Both zonisamide and topiramate are weak carbonic anhydrase inhibitors, and
combining them may increase the risk for kidney stones. In clinical practice,
however, these 2 agents have generally been combined safely.143,144
CONCLUSIONS
The study of the pathophysiology of neuropathic pain and migraine is developing
rapidly and is beginning to shed light on the underlying disease processes. This
research should help direct the development of increasingly specific therapies—
for example, sensory neuron–specific sodium channel blockers or more selective
NMDA antagonists. Scientific study of the clinical effectiveness of the newer AEDs
in the treatment of these diseases is beginning to provide the evidence needed to
determine how well each may work.
The primary clinical advantages of newer AEDs relative to the established AEDs
are their greater tolerability, potential for fewer drug–drug interactions, and, in
some instances, greater pain relief. Randomized, double-blind, placebo-controlled
trials of the newer AEDs in neuropathic pain and migraine are needed to yield a
broader evidence base.
ACKNOWLEDGMENTS
This article was sponsored by Elan Pharmaceuticals, San Diego, California. The author acknowledges the assistance of William A. Kadish, MD, Market Development
Group, Inc., Chester, New Jersey, in the development and writing of this article.
Dr. Pappagallo has been the primary investigator in several research projects and
clinical trials supported by the following: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; Pfizer Inc,
New York, New York; Elan Pharmaceuticals, San Diego, California; GlaxoSmithKline, Research Triangle Park, North Carolina; Endo Pharmaceuticals, Chadds
Ford, Pennsylvania; and Ortho-McNeil Pharmaceutical Inc., Raritan, New Jersey.
2530
M. Pappagallo
REFERENCES
1. Asconape JJ. Some common issues in the use of antiepileptic drugs. Semin Neurol.
2002;22:27–39.
2. Bolay H, Moskowitz MA. Mechanisms of pain modulation in chronic syndromes.
Neurology. 2002;59(Suppl 2):S2–S7.
3. Chung JM, Chung K. Importance of hyperexcitability of DRG neurons in neuropathic
pain. Pain Pract. 2002;2:87–97.
4. Baron R. Peripheral neuropathic pain: From mechanisms to symptoms. Clin J Pain.
2000;16(Suppl 2):S12–S20.
5. Costigan M, Woolf CJ. Pain: Molecular mechanisms. J Pain. 2000;1(Suppl):35–44.
6. Cutrer FM, Limmroth V, Waeber C, et al. New targets for antimigraine drug development. In: Goadsby PJ, Silberstein SD, eds. Blue Books of Practical Neurology. Vol 17.
Boston, Mass: Butterworth-Heinemann; 1997:59–72.
7. Cutrer FM. Antiepileptic drugs: How they work in headache. Headache. 2001;41(Suppl
1):S3–S10.
8. Chong MS, Libretto SE. The rationale and use of topiramate for treating neuropathic
pain. Clin J Pain. 2003;19:59–68.
9. Nicholson B. Gabapentin use in neuropathic pain syndromes. Acta Neurol Scand.
2000;101:359–371.
10. Wallace M. Calcium and sodium channel antagonists for the treatment of pain. Clin J
Pain. 2000;16(Suppl 2):S80–S85.
11. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic
neuralgia: A randomized controlled trial. JAMA. 1998;280:1837–1842.
12. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment
of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial.
JAMA. 1998;280:1831–1836.
13. Silberstein SD, Goadsby PJ. Migraine: Preventive treatment. Cephalalgia. 2002;22:
491–512.
14. Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology.
2002;59(Suppl 2):S14–S17.
15. Benedetti C, Dickerson ED, Nichols LL. Medical education: A barrier to pain therapy
and palliative care. J Pain Symptom Manage. 2001;21:360–362.
16. Stedman’s Medical Dictionary. 22nd ed. Baltimore, Md: Williams & Wilkins; 1972.
17. Merskey H, Bogduk N. International Association for the Study of Pain (IASP). Classification of Chronic Pain. 2nd ed. Seattle, Wash: IASP Press; 1994:210.
18. Dworkin RH. An overview of neuropathic pain: Syndromes, symptoms, signs, and
several mechanisms. Clin J Pain. 2002;18:343–349.
19. Wasner G, Schattschneider J, Binder A, Baron R. Complex regional pain syndrome—
diagnostic, mechanisms, CNS involvement and therapy. Spinal Cord. 2003;41:61–
75.
20. Burchiel KJ. Trigeminal neuropathic pain. Acta Neurochir Suppl. 1993;58:145–149.
2531
CLINICAL THERAPEUTICS®
21. Serpell MG, for the Neuropathic Pain Study Group. Gabapentin in neuropathic pain
syndromes: A randomised, double-blind, placebo-controlled trial. Pain. 2002;99:
557–566.
22. Haythornthwaite JA, Benrud-Larson LM. Psychological aspects of neuropathic pain.
Clin J Pain. 2000;16(Suppl 2):S101–S105.
23. Cunha JM, Cunha FQ, Poole S, Ferreira SH. Cytokine-mediated inflammatory hyperalgesia limited by interleukin-1 receptor antagonist. Br J Pharmacol. 2000;130:
1418–1424.
24. Kocoglu H, Pirbudak L, Pence S, Balat O. Cancer pain, pathophysiology, characteristics and syndromes. Eur J Gynaecol Oncol. 2002;23:527–532.
25. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.
Cephalalgia. 1988;8(Suppl 7):1–96.
26. Lipton RB, Newman LC. Epidemiology, impact, and comorbidities of migraine
headache in the United States. Neurology. 2003;60(Suppl 2):S3–S8.
27. Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of headache in a general
population—a prevalence study. J Clin Epidemiol. 1991;44:1147–1157.
28. Stewart WF, Shechter A, Rasmussen BK. Migraine prevalence. A review of populationbased studies. Neurology. 1994;44(Suppl 4):S17–S23.
29. Lipton RB, Stewart WF. The epidemiology of migraine. Eur Neurol. 1994;34(Suppl 2):
6–11.
30. Lipton RB, Baggish JS, Stewart WF, et al. Efficacy and safety of acetaminophen in the
treatment of migraine: Results of a randomized, double-blind, placebo-controlled,
population-based study. Arch Intern Med. 2000;160:3486–3492.
31. Codispoti JR, Prior MJ, Fu M, et al. Efficacy of nonprescription doses of ibuprofen for
treating migraine headache. A randomized controlled trial. Headache. 2001;41:665–
679.
32. Diener HC, Jansen JP, Reches A, et al. Efficacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: A
multicentre, randomised, double-blind, placebo-controlled comparison. Eur Neurol.
2002;47:99–107.
33. Rapoport AM. Pharmacological prevention of migraine. Clin Neurosci. 1998;5:55–
59.
34. Silberstein SD, Freitag FG. Preventive treatment of migraine. Neurology. 2003;60
(Suppl 2):S38–S44.
35. Mathew NT. Transformed migraine, analgesic rebound, and other chronic daily
headaches. Neurol Clin. 1997;15:167–186.
36. Silberstein SD, Winner PK, Chmiel JJ. Migraine preventive medication reduces resource utilization. Headache. 2003;43:171–178.
37. Edmeads J. Communication issues in migraine diagnosis. Can J Neurol Sci. 2002;
29(Suppl 2):S8–S10.
2532
M. Pappagallo
38. Doubell TP, Mannion RJ, Woolf CJ. The dorsal horn: State-dependent sensory processing, plasticity and the generation of pain. In: Wall PD, Melzack R, eds. Textbook
of Pain. 4th ed. London: Churchill Livingstone; 1999:165–182.
39. Craig AD, Dostrovsky JO. Medulla to thalamus. In: Wall PD, Melzack R, eds. Textbook of Pain. 4th ed. London, Churchill Livingstone; 1999:183–214.
40. Ebersberger A. Pathophysiology of migraine: Models to explain the generation of migraine headache [in German]. Anaesthesist. 2002;51:661–667.
41. Rome HP, Rome JD. Limbically augmented pain syndrome—LAPS. Pain Med. 2000;1:9–
21.
42. Mamet J, Baron A, Lazdunski M, Voilley N. Proinflammatory mediators, stimulators
of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci. 2002;22:10662–10670.
43. Hohmann AG. Spinal and peripheral mechanisms of cannabinoid antinociception: Behavioral, neurophysiological and neuroanatomical perspectives. Chem Phys Lipids.
2002;121:173–190.
44. Decker MW, Meyer MD, Sullivan JP. The therapeutic potential of nicotinic acetylcholine receptor antagonists for pain control. Expert Opin Investig Drugs. 2001;10:
1819–1830.
45. Waxman SG. Acquired channelopathies in nerve injury and MS. Neurology. 2001;56:
1621–1627.
46. Lidbeck J. Central hyperexcitability in chronic musculoskeletal pain: A conceptual
breakthrough with multiple clinical implications. Pain Res Manag. 2002;7:81–92.
47. Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur
J Pain. 2000;4:5–15.
48. Noda Y, Mori A, Packer L. Zonisamide inhibits nitric oxide synthase activity induced
by N-methyl-D-aspartate and buthionine sulfoximine in the rat hippocampus. Res
Commun Mol Pathol Pharmacol. 1999;105:23–33.
49. Malick A, Burstein R. Peripheral and central sensitization during migraine. Funct Neurol. 2000;15(Suppl 3):28–35.
50. Ptacek LJ. The place of migraine as a channelopathy. Curr Opin Neurol. 1998;11:217–226.
51. Williamson DJ, Hargreaves RJ. Neurogenic inflammation in the context of migraine.
Microsc Res Tech. 2001;53:167–178.
52. Buzzi MG. Trigeminal pain pathway: Peripheral and central activation as experimental models of migraine. Funct Neurol. 2001;16(Suppl 4):77–81.
53. Strassman AM, Raymond SA, Burstein R. Sensitization of meningeal sensory neurons
and the origin of headache. Nature. 1996;384:560–564.
54. Dimitriadou V, Buzzi MG, Theoharides TC, Moskowitz MA. Ultrastructural evidence
for neurogenically mediated changes in blood vessels of the rat dura mater and tongue
following antidromic trigeminal stimulation. Neuroscience. 1992;48:187–203.
55. Goadsby PJ. New aspects of the pathophysiology of migraine and cluster headache. In:
Max M, ed. Pain 1999—An Updated Review. Seattle, Wash: IASP Press; 1999:181–191.
2533
CLINICAL THERAPEUTICS®
56. Thomsen LL, Olesen J. Nitric oxide theory of migraine. Clin Neurosci. 1998;5:28–33.
57. Finnerup NB, Gottrup H, Jensen TS. Anticonvulsants in central pain. Expert Opin
Pharmacother. 2002;3:1411–1420.
58. Engelborghs S, D’Hooge R, De Deyn PP. Pathophysiology of epilepsy. Acta Neurol Belg.
2000;100:201–213.
59. Chaplan SR, Guo HQ, Lee DH, et al. Neuronal hyperpolarization–activated pacemaker channels drive neuropathic pain. J Neurosci. 2003;23:1169–1178.
60. Sakas DE, Whittaker KW, Whitwell HL, Singounas EG. Syndromes of posttraumatic
neurological deterioration in children with no focal lesions revealed by cerebral imaging: Evidence for a trigeminovascular pathophysiology. Neurosurgery. 1997;41:661–
667.
61. Ottman R, Lipton RB. Comorbidity of migraine and epilepsy. Neurology. 1994;44:
2105–2110.
62. Terwindt GM, Ophoff RA, Haan J, et al, for the Dutch Migraine Genetics Research
Group. Migraine, ataxia and epilepsy: A challenging spectrum of genetically determined calcium channelopathies. Eur J Hum Genet. 1998;6:297–307.
63. Eggers AE. New neural theory of migraine. Med Hypotheses. 2001;56:360–363.
64. Giroud M, Couillault G, Arnould S, et al. Epilepsy with rolandic paroxysms and
migraine, a non-fortuitous association. Results of a controlled study [in French].
Pediatrie. 1989;44:659–664.
65. Backonja MM. Anticonvulsants (antineuropathics) for neuropathic pain syndromes.
Clin J Pain. 2000;16(Suppl 2):S67–S72.
66. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain
syndromes: Mechanisms of action and place in therapy. Drugs. 2000;60:1029–1052.
67. Mori A, Noda Y, Packer L. The anticonvulsant zonisamide scavenges free radicals.
Epilepsy Res. 1998;30:153–158.
68. Blom S. Trigeminal neuralgia: Its treatment with a new anticonvulsant drug. Lancet.
1962;1:839–840.
69. Campbell FG, Graham JG, Zilkha KJ. Clinical trial of carbazepine (Tegretol) in trigeminal neuralgia. J Neurol Neurosurg Psychiatry. 1966;29:265–267.
70. Nicol CF. A four year double-blind study of Tegretol in facial pain. Headache.
1969;9:54–57.
71. Rull JA, Quibrera R, Gonzalez-Millan H, Lozano Castaneda O. Symptomatic treatment
of peripheral diabetic neuropathy with carbamazepine (Tegretol): Double blind
crossover trial. Diabetologia. 1969;5:215–218.
72. Gomez-Perez FJ, Choza R, Rios JM, et al. Nortriptyline-fluphenazine vs. carbamazepine
in the symptomatic treatment of diabetic neuropathy. Arch Med Res. 1996;27:525–529.
73. Leijon G, Boivie J. Central post-stroke pain—a controlled trial of amitriptyline and
carbamazepine. Pain. 1989;36:27–36.
74. Killian JM, Fromm GH. Carbamazepine in the treatment of neuralgia. Use and side
effects. Arch Neurol. 1968;19:129–136.
2534
M. Pappagallo
75. Saudek CD, Werns S, Reidenberg MM. Phenytoin in the treatment of diabetic symmetrical polyneuropathy. Clin Pharmacol Ther. 1977;22:196–199.
76. Chadda VS, Mathur MS. Double blind study of the effects of diphenylhydantoin
sodium on diabetic neuropathy. J Assoc Physicians India. 1978;26:403–406.
77. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain:
An update and effect related to mechanism of drug action. Pain. 1999;83:389–400.
78. Jensen R, Brinck T, Olesen J. Sodium valproate has prophylactic effect in migraine without aura: A triple-blind, placebo-controlled crossover study. Neurology. 1994;44:647–
651.
79. Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: A
double-blind study versus placebo. Cephalalgia. 1992;12:81–84.
80. Klapper JA. An open label crossover comparison of divalproex sodium and propranolol HCl in the prevention of migraine headaches. Headache Q. 1994;5:50–53.
81. Klapper JA. Divalproex sodium in migraine prophylaxis: A dose-controlled study.
Cephalalgia. 1997;17:103–108.
82. Limmroth V, Katsarava Z, Fritsche G, et al. Features of medication overuse headache
following overuse of different acute headache drugs. Neurology. 2002;59:1011–1014.
83. Rice AS, Maton S, for the Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: A randomised, double blind, placebo controlled study. Pain. 2001;
94:215–224.
84. Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for HIV-associated painful
sensory neuropathies: A placebo-controlled trial. Neurology. 2003;60:1508–1514.
85. Simpson DM, Olney R, McArthur JC, et al. A placebo-controlled trial of lamotrigine
for painful HIV-associated neuropathy. Neurology. 2000;54:2115–2119.
86. Vestergaard K, Andersen G, Gottrup H, et al. Lamotrigine for central poststroke pain:
A randomized controlled trial. Neurology. 2001;56:184–190.
87. McCleane G. 200 mg daily of lamotrigine has no analgesic effect in neuropathic pain:
A randomised, double-blind, placebo controlled trial. Pain. 1999;83:105–107.
88. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: A randomized, controlled study. Neurology. 2001;57:505–509.
89. Vinik A, Hewitt D, Xiang J, et al. Topiramate in the treatment of painful diabetic neuropathy: Results from a multicenter, randomized, double-blind, placebo-controlled
trial. Neurology. 2003;60(Suppl 1):A154–A155. Abstract.
90. Edwards KR, Glanz MJ, Button J, et al. Efficacy and safety of topiramate in the treatment of painful diabetic neuropathy: A double-blind, placebo-controlled study.
Neurology. 2000;54:A81. Abstract.
91. Gilron I, Booher SL, Rowan JS, Max MB. Topiramate in trigeminal neuralgia: A randomized, placebo-controlled multiple crossover pilot study. Clin Neuropharmacol.
2001;24:109–112.
92. Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41:119–128.
2535
CLINICAL THERAPEUTICS®
93. Storey JR, Potter DL, Hart DE, Calder CS. A double blind, randomized, placebocontrolled, parallel study to determine the efficacy of topiramate in the prophylactic treatment of migraine. Neurology. 2000;54:A267–A268. Abstract.
94. Edwards KR, Glanz MJ, Shea P, et al. A double blind, randomized trial of topiramate
versus placebo in the prophylactic treatment of migraine headache with and without aura. Cephalalgia. 2000;20:S16. Abstract.
95. Mathew NT, Dodick DW, Schmitt J, et al. Topiramate in migraine prevention (MIGR001): Effect on migraine frequency. Neurology. 2003;60(Suppl 1):A336. Abstract
S42.001.
96. Brandes JL, Jacobs D, Neto W, Bhattacharaya S. Topiramate in the prevention of migraine headache: A randomized, double-blind, placebo-controlled, parallel study
(MIGR-002). Neurology. 2003;60(Suppl 1):A238. Abstract P03.155.
97. Rothrock JF, Jacobs D, Neto W, Bhattacharaya S. Safety and tolerability of topiramate
in migraine prevention: Results from a multicenter, randomized, double-blind, placebocontrolled study (MIGR-002). Neurology. 2003;60(Suppl 1):A238. Abstract P03.156.
98. Krusz JC. Zonisamide in the treatment of headache disorders. Cephalalgia. 2001;
21:374–375. Abstract.
99. Wheeler SD. Lamotrigine efficacy in migraine prevention. Cephalalgia. 2001;21:374.
Abstract.
100. Candis MM, Susan GL, Carol PS. Effects of gabapentin compared to amitriptyline on
pain in diabetic neuropathy. Diabetes. 1998;47:A374. Abstract.
101. Dallocchio C, Buffa C, Mazzarello P, Chiroli S. Gabapentin vs. amitriptyline in
painful diabetic neuropathy: An open-label pilot study. J Pain Symptom Manage.
2000;20:280–285.
102. Cheshire WP Jr. Defining the role for gabapentin in the treatment of trigeminal neuralgia: A retrospective study. J Pain. 2002;3:137–142.
103. Samkoff LM, Daras M, Tuchman AJ, Koppel BS. Amelioration of refractory dysesthetic limb pain in multiple sclerosis by gabapentin. Neurology. 1997;49:304–
305.
104. Solaro C, Uccelli MM, Guglieri P, et al. Gabapentin is effective in treating nocturnal
painful spasms in multiple sclerosis. Mult Scler. 2000;6:192–193.
105. Sist TC, Filadora VA II, Miner M, Lema M. Experience with gabapentin for neuropathic pain in the head and neck: Report of ten cases. Reg Anesth. 1997;22:473–478.
106. Lampi C, Buzath A, Klinger D, Neumann K. Lamotrigine in the prophylactic treatment of migraine aura—a pilot study. Cephalalgia. 1999;19:58–63.
107. D’Andrea G, Granella F, Ghiotto N, Nappi G. Lamotrigine in the treatment of SUNCT
syndrome. Neurology. 2001;57:1723–1725.
108. Leone M, Rigamonti A, Usai S, et al. Two new SUNCT cases responsive to lamotrigine. Cephalalgia. 2000;20:845–847.
109. Lindstrom P. The analgesic effect of carbamazepine in trigeminal neuralgia. Pain.
1987;28(Suppl 4):S85. Abstract.
2536
M. Pappagallo
110. Remillard G. Oxcarbazepine and intractable trigeminal neuralgia. Epilepsia. 1994;35
(Suppl 3):S28–S29. Abstract.
111. Lopez MR, Santiago ER, Ramos RR, Zenteno JS. Symptomatic treatment of trigeminal neuralgia with oxcarbazepine. J Neurol Sci. 1997;150(Suppl 1):S34–S35.
112. Jensen MG, Royal MA, Ward S, et al. An open-label trial of oxcarbazepine in patients
with radiculopathy refractory to gabapentin. Pain Clin. 2002:11–14.
113. Bajwa ZH, Sami N, Warfield CA, Wootton J. Topiramate relieves refractory intercostal neuralgia. Neurology. 1999;52:1917.
114. Zvartau-Hind M, Din MU, Gilani A, et al. Topiramate relieves refractory trigeminal
neuralgia in MS patients. Neurology. 2000;55:1587–1588.
115. Krusz JC. Zonisamide in the treatment of pain and headache disorders. J Neurol Sci.
2001;187(Suppl 1):S107. Abstract.
116. Kaplan M. Zonisamide—Benefits in chronic pain patients. Arch Phys Med Rehabil.
2002;83:1671. Abstract.
117. Royal M, Jensen M, Gunyea I, et al. Retrospective case series of zonisamide in the
treatment of neuropathic pain. Poster presented at: Annual Meeting of the American
Epilepsy Society; November 30–December 5, 2001; Philadelphia, Pa.
118. Cochran JW. Efficacy of zonisamide in the treatment of neuropathic pain. J Pain.
2002;3(Suppl 1):39. Abstract 752.
119. Bernstein CD, Diaz JH, Gould HJ. A possible role for zonisamide in treating neuropathic pain: A case of idiopathic polyneuropathy. Pain Pract. 2002;2:134–136.
120. Wallace MS. Zonisamide for complex regional pain syndrome. J Pain. 2002;3(Suppl
1):42. Abstract.
121. Drake ME, Greathouse NI, Armenthright AD, Renner JB. Zonisamide in the prophylaxis of migraine headache. Cephalalgia. 2001;21:374. Abstract.
122. Cochran JW. Efficacy of zonisamide in prophylactic treatment of migraine headaches with
or without aura: Open-label experience in 7 patients. J Pain. 2002;3(Suppl 1):39. Abstract.
123. Smith TR. Treatment of refractory chronic daily headache with zonisamide: A case
series. Poster presented at: Annual Meeting of the American Epilepsy Society;
November 30–December 5, 2001; Philadelphia, Pa.
124. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: A
systematic review of their efficacy and tolerability. Epilepsia. 1997;38:859–880.
125. Ferrendelli JA. Concerns with antiepileptic drug initiation: Safety, tolerability, and
efficacy. Epilepsia. 2001;42(Suppl 4):28–30.
126. Physicians’ Desk Reference. 56th ed. Montvale, NJ: Medical Economics Company;
2002:1559.
127. Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotriginerelated skin rash. Ann Pharmacother. 1999;33:1037–1042.
128. Calabrese JR, Bowden CL, Sachs GS, et al, for the Lamictal 602 Study Group. A double blind placebo-controlled study of lamotrigine monotherapy in outpatients with
bipolar I depression. J Clin Psychiatry. 1999;60:79–88.
2537
CLINICAL THERAPEUTICS®
129. Leppik IE. Three new drugs for epilepsy: Levetiracetam, oxcarbazepine, and zonisamide. J Child Neurol. 2002;17(Suppl 1):S53–S57.
130. Ben-Menachem E, Axelsen M, Johanson EH, et al. Predictors of weight loss in adults
with topiramate-treated epilepsy. Obes Res. 2003;11:556–562.
131. Ritter FJ, Gustafson MC, Karney V, Penovich PE. Do allergic reactions to sulfonamide
antibiotics predict allergy to zonisamide? Poster presented at: Annual Meeting of the
American Epilepsy Society; November 30–December 5, 2001; Philadelphia, Pa.
132. Welty TE, Kuzniecky RI, Limdi N, Faught E. Weight loss associated with use of zonisamide in European and US clinical trials. Poster presented at: American Epilepsy
Society Annual Meeting; November 30–December 5, 2001; Philadelphia, Pa.
133. Armijo JA, Adin-Ibarra J, Sanchez-Baglietto N, Vega-Gil N. Monitoring serum levels
of new antiepileptics [in Spanish]. Rev Neurol. 2002;35(Suppl 1):S116–S134.
134. Tomson T, Johannessen SI. Therapeutic monitoring of the new antiepileptic drugs.
Eur J Clin Pharmacol. 2000;55:697–705.
135. Perucca E. Is there a role for therapeutic drug monitoring of new anticonvulsants?
Clin Pharmacokinet. 2000;38:191–204.
136. Chong E, Dupuis LL. Therapeutic drug monitoring of lamotrigine. Ann Pharmacother.
2002;36:917–920.
137. Hachad H, Ragueneau-Majlessi I, Levy RH. New antiepileptic drugs: Review on drug
interactions. Ther Drug Monit. 2002;24:91–103.
138. Natsch S, Hekster YA, Keyser A, et al. Newer anticonvulsant drugs: Role of pharmacology, drug interactions and adverse reactions in drug choice. Drug Saf. 1997;
17:228–240.
139. Berry DJ, Besag FM, Pool F, et al. Lack of an effect of topiramate on lamotrigine
serum concentrations. Epilepsia. 2002;43:818–823.
140. Benedetti MS. Enzyme induction and inhibition by new antiepileptic drugs: A review of human studies. Fundam Clin Pharmacol. 2000;14:301–319.
141. Crawford P. Interactions between antiepileptic drugs and hormonal contraception.
CNS Drugs. 2002;16:263–272.
142. Gatti G, Bonomi I, Jannuzzi G, Perucca E. The new antiepileptic drugs: Pharmacological and clinical aspects. Curr Pharm Des. 2000;6:839–860.
143. Rosenfeld WE. Safety and tolerability of zonisamide used concurrently with topiramate. Poster presented at: Annual Meeting of the American Epilepsy Society;
November 30–December 5, 2001; Philadelphia, Pa.
144. Vazquez B, Ghacigeh G, Hopkins M, Devinsky O. Zonisamide and topiramate combination therapy: Safety and tolerability. Epilepsia. 2001;42(Suppl 7):261. Abstract.
Address correspondence to: Marco Pappagallo, MD, Director, Division of Chronic
Pain, Department of Pain and Palliative Medicine, Beth Israel Medical Center, 1st
Avenue at 16th Street, New York, NY 10003. E-mail: [email protected]
2538