Phenytoin (5,5-diphenyl-2,4-imidazolidinedione) is an AED used
to control generalized tonic-clonic and complex partial seizures.
For years it was the most commonly used AED for the treatment of
a wide variety of pain syndromes.
Phenytoin has been reported to be effective in the treatment
of diabetic neuropathy, trigeminal neuralgia, neuropathic cancer
pain, postherpetic neuralgia, complex regional pain syndrome (CRPS)
types 1 and 2, and post-sympathectomy neuralgia.5–9 The
proposed mechanism of action is reduction of neuronal hyperexcitability
by decreasing the activity of sodium channels, thereby stabilizing
the neural membrane.16
Dilantin is supplied as 30-mg and 100-mg capsules. The recommended
dose of phenytoin for epilepsy in most patients is 300 mg per day.
An exact dose needed to achieve adequate analgesia has not been
defined. Phenytoin use as a neuropathic analgesic should follow
the guidelines for its use for epilepsy. Phenytoin has the advantage
of once a day dosing and is relatively inexpensive. Absorption orally
is slow and variable; peak concentrations may occur as early as
3 hours or as long as 12 hours. It is about 90% bound to
plasma proteins and is metabolized primarily by the liver. Phenytoin
has a half-life of 20 to 60 hours at therapeutic concentrations.
However, a narrow therapeutic window and its short- and long-term
side effects limit use.
Complete blood counts (CBC), liver function tests (LFTs), and
serum drug levels need to be closely monitored, particularly in
the first 6 months. Long-term use can result in cosmetic side effects
such as gingival hyperplasia, hirsutism, coarsening of the facial
features, and, rarely, cerebellar atrophy and peripheral neuropathy.
Carbamazepine (5H-dibenz(b,f)azepine-5-carboxamide) is considered
to be a primary drug for partial and tonic-clonic seizures. It has
structural similarities to tricyclic antidepressants, making it
a particularly desirable drug for treating chronic pain syndromes.
It has been widely prescribed as the drug of choice for trigeminal
neuralgia,10–12 and is considered the
best neuropathic analgesic for lancinating or electric-like pain.15 Carbamazepine
is effective in other neuropathic pain syndromes such as glossopharyngeal
neuralgia, diabetic neuropathy, and pain syndromes associated with
multiple sclerosis.17–20 It has also been
used for the treatment of migraine headaches in pediatric populations.21
Carbamazepine enhances antidepressant effects and is an effective
mood stabilizer. Its mechanism of action is similar to that of phenytoin
in stabilizing neuronal membranes.
Carbamazepine is available as 100-mg chewable tablets, 100-mg,
200-mg, and 400-mg XR tablets, and 100 mg/5 mL suspension.
The initial starting dose of carbamazepine is between 100 and 200
mg per day; the dose can be slowly increased over several weeks
as needed to a maximum total dose of 1200 mg per day. It is absorbed
slowly orally, and peak concentrations may be observed in 4 to 8
hours but may be delayed 24 hours. It is about 75% bound
to plasma proteins. Carbamazepine is metabolized to 10,11-epoxycarbamazepine,
which is an active metabolite. Its half-life is between 10 and 20
hours depending on induction of hepatic enzymes. Carbamazepine, like
phenytoin, has a narrow therapeutic window. Before initiating therapy,
a baseline CBC and LFTs should be obtained, with frequent monitoring
thereafter, particularly in the first 6 months.
Agranulocytosis and aplastic anemia rarely occur; patients should
be advised to report any episodes of fever while taking the drug
so that a CBC can be checked. Other side effects of concern are
hypersensitivity reactions manifesting as Stevens-Johnson syndrome
with lymphadenopathy and rare cases of liver failure.
Valproic acid (n-dipropylacetic acid) is a broad-spectrum AED
used to treat a number of epileptic syndromes. Although valproic
acid has been used in the management of chronic pain,22 it
has been mainly indicated in the preventive treatment of migraine,
cluster, and tension-type headaches.23,24
Valproic acid has several proposed mechanisms of action, including
increasing GABA brain concentrations by inhibition of GABA-aminotransferase
and succinic semialdehyde dehydrogenase (enzymes involved in the
synthesis and degradation of GABA), selectively enhancing postsynaptic
GABA responses, direct effects on neuronal membranes, and reduction
of excitatory transmission by aspartate.25 Valproic
acid, like carbamazepine, is also an effective mood stabilizer.
Valproic acid is available as 250-mg capsules and 250 mg/5
mL syrup. The starting dose of valproic acid is usually 250 mg per
day; it is titrated slowly upward to a maximum dose of 1000 to 2000
mg per day, usually in divided doses. Valproic acid is absorbed
rapidly orally and peak concentrations are observed in 1 to 4 hours.
It is about 90% bound to plasma proteins. It is metabolized
hepatically with potent antiseizure metabolites. Valproic acid has
an approximately 15-hour half-life.
Limitations for the use of this agent include drug interactions
and drug-related side effects, such as central nervous system depression,
and hepatic and hematologic toxicity. Frequent monitoring of these
parameters should continue during the first year of therapy and
is a benzodiazepine that has been used successfully in providing
relief for both chronic malignant and nonmalignant pain syndromes
such as headaches, temporomandibular joint dysfunction, and phantom limb
Clonazepam acts by enhancing GABA-receptor-mediated chloride
channels. It is particularly effective when used in combination
with other neuropathic analgesics and in patients with prominent
anxiety disorder and insomnia.
Clonazepam is available as 0.5-mg, 1-mg, and 2-mg tablets. The
dose of clonazepam should initially be 0.5 mg at bedtime; the dose
is slowly increased to 0.5 to 1 mg three times per day. Doses of
up to 20 mg/day have been used in epilepsy; 1 to 6 mg per
day is generally successful in treating headache and pain. It is
absorbed rapidly orally with peak concentrations in 1 to 4 hours. Clonazepam
is approximately 85% bound to plasma proteins. It is metabolized
hepatically and has a half-life of about 24 hours.
The most common side effects are drowsiness, dizziness, fatigue,
and sedation. As with other benzodiazepines, clonazepam may produce
physical and psychological dependence; abrupt discontinuation is
Gabapentin (1-(aminomethyl)cyclohexanacetic acid) is one of the
newer AEDs that has been approved for adjunctive treatment of partial
seizures. In recently published anecdotal reports followed by multicenter,
randomized, placebo-controlled studies, the drug was effective in
the treatment of postherpetic neuralgia, diabetic neuropathy, refractory
CRPS type 1, and migraine headaches.29–36 The
efficacy and safety of gabapentin in treating a variety of chronic
pain states has renewed interest and enthusiasm in trying new and
old antiepileptics in the treatment of chronic pain.
The precise mechanism of action of gabapentin is unknown. It
is structurally related to the inhibitory neurotransmitter GABA,
and postulated to increase the level of GABA in the nervous system.
However, gabapentin does not interact with any of the GABA receptors,
nor is it converted to GABA, and it does not affect the metabolism
of GABA in neurons. It does not act at or bind to most receptors
tested, including N-methyl-D-aspartate (NMDA) and kainate receptors,
and does not directly act at the calcium or sodium channels.
Gabapentin is available as 100-mg, 300-mg, 400-mg, 600-mg, 800-mg
capsules and 250 mg/5 mL syrup. Patients have generally
reported adequate relief with gabapentin doses ranging from 900
to 2400 mg/day. It is generally well tolerated at even
higher doses. Gabapentin is well absorbed orally and largely unbound
to plasma proteins. It is not metabolized and is renally excreted.
Gabapentin has a half-life of 5 to 9 hours.
The most common adverse effects include somnolence, diarrhea,
mood swings, ataxia, fatigue, nausea, and dizziness.
is a novel antiepileptic, which is chemically different from other
antiepileptics. It is an adjunctive treatment for partial seizures
in adults. Lamotrigine is approved for children only in the treatment
of Lennox-Gastaut syndrome. There are no published placebo-controlled
studies that have evaluated the efficacy of lamotrigine in treating
neuropathic pain. However, there have been anecdotal reports, including
a large series, of the successful use of lamotrigine in the treatment
of refractory trigeminal neuralgia and facial pain37,38 when
used as adjunctive treatment with carabamazepine or phenytoin.
The precise mechanism of action of lamotrigine is unknown. It
does not affect NMDA or GABA receptors directly. Lamotrigine however,
is thought to stabilize neuronal membranes through the inhibition
of sodium channels39 and reduces the release of
excitatory neurotransmitters such as glutamate and aspartate.
Lamotrigine is available as 25-mg, 100-mg, 150-mg, and 200-mg
tablets. There are also chewable dispersible tablets in 2-mg, 5-mg,
and 25-mg strengths. Lamotrigine doses range from 200 to 500 mg
per day in two divided doses for epilepsy therapy, but there are
no defined doses for the treatment of neuropathic pain. The starting
dose of lamotrigine is 25 to 50 mg per day; it should be increased
slowly to 100 mg twice per day. Caution is required when lamotrigine
is used in a patient on valproic acid because the latter significantly
slows the clearance of lamotrigine. The dose should be cut by at
least 50% in this circumstance and should not exceed 150
mg per day. It is well absorbed after oral administration and peak
serum levels are reached in 1 to 4 hours. It is metabolzied by glucuronic
acid conjugation and primarily excreted in the urine. Lamotrigine
is 55% protein bound and its half-life is 13 to 30 hours.
Rash is the most common side effect associated with lamotrigine
and requires discontinuation of the drug. Patients should be instructed
to inform their physician about any rash or hypersensitivity reaction;
these can result in life-threatening complications such as Stevens-Johnson
syndrome and toxic epidermal necrolysis. Patients also should be
warned of the possibility of dizziness, ataxia, nausea, and vomiting,
which are dose-related side effects. Long-term use of lamotrigine
can lead to its accumulation and binding to melanin-rich tissues
in the body, including the eye, resulting in blurred vision.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) has been successful
in controlling partial seizures in adults and the Lennox-Gastaut
syndrome in children who are unresponsive to other medications.40,41 In
a neurobiologic study in rats, felbamate was found to reduce mechano-allodynia
and hyperalgesia as well as heat-hyperalgesia.42 Because
of the epileptiform nature of certain neuropathic pain states, felbamate
has been reported effective for controlling pain in trigeminal neuralgia.43
Felbamate has multiple mechanisms of action including inhibition
of NMDA and AMPA/kainate receptors, potentiating GABA-receptor-mediated
chloride channels, and inhibiting spontaneous discharges from the
voltage-dependent sodium channels.
Felbamate is available as 400-mg and 600-mg tablets and 600 mg/5
mL suspension. Felbamate provides effective seizure control at doses
of 1200 to 2400 mg per day in three divided doses.
However, felbamate is rarely utilized except for patients who
are refractory to all other AEDs because of its association with
aplastic anemia and fulminant hepatic failure. Patients taking felbamate
should have frequent monitoring with CBCs and LFTs.
sulfamate) is a novel AED approved as adjunctive therapy for partial
seizures and generalized tonic-clonic seizures. There are no published
placebo-controlled trials examining the efficacy of topiramate in
neuropathic pain syndromes. It has, however, been anecdotally reported
to relieve pain in post-thoracotomy pain syndrome, intercostal neuralgia,
headaches, and other neuropathic pain states.44–46 Further
studies are needed to define its role in the treatment of neuropathic
pain and such trials are currently under way.
Pharmacologic studies postulate at least three mechanisms of
action for topiramate: blocking voltage-dependent sodium channels;
potentiating the action of inhibitory GABA transmission; and blocking
excitatory AMPA/glutamate receptors.47
Topiramate is available as 25-mg, 100-mg, and 200-mg tablets.
The usual starting dose of topiramate for the treatment of partial
seizures is 25 to 50 mg/day; the dose can be increased
to 400 mg/day in two divided doses over 8 weeks. However,
the optimal dose for neuropathic pain is unknown.
Side effects of topiramate include anorexia and weight loss.
Patients taking topiramate for prolonged periods may develop kidney
stones due to the inhibition of carbonic anhydrase.
Vigabatrin is a novel AED reported to be effective in the treatment
of complex partial seizures; it is not currently marketed in the
It appears to act by increasing GABA levels thorugh the inhibition
of GABA metabolism in the nervous system. It causes an irreversible
enzyme inhibition of GABA transaminase. Thus, like many of its predecessors
that work through similar mechanisms in controlling neuropathic
pain, vigabatrin can be postulated to be an effective alternative
to other AEDs for patients who fail to achieve adequate analgesia.49 The
precise role of vigabatrin in pain management, however, has yet
to be defined since there are currently no published randomized,
controlled trials reporting its efficacy in neuropathic pain.
Vigabatrin is well tolerated in patients treated for epilepsy
with minimal central nervous system side effects. Unlike the older
antiepileptics, vigabatrin is not metabolized through the liver
and therefore has minimal drug interactions with other medications.
It is available in 500-mg tablets. Vigabatrin has been shown to
be effective in controlling epilepsy in doses ranging between 1
and 4 g/day. It is rapidly absorbed orally with peak plasma
concentrations in 2 hours. Vigabatrin is not extensively bound by
plasma proteins and its half-life is approximately 5 to 8 hours.
Common side effects include drowsiness, tiredness, headaches,
stomach upset, weight gain, and vision problems.
acid hydrochloride), another new AED, is effective as adjunctive
therapy for the treatment of complex partial seizures.50
Tiagabine increases the concentration of GABA by inhibiting the
uptake catabolism pathways in presynaptic neurons and thereby prolonging
the effect of this neurotransmitters.51 This mechanism
of action suggests the drug may be effective for the treatment of
neuropathic pain.52 There are some anecdotal reports
that suggest its effectiveness in this role, and controlled multicenter
trials are currently underway.
Tiagabine is available as 2-mg, 4-mg, 12-mg, 16-mg, and 20-mg
tablets. The adult maintenance dose of tiagabine ranges from 32
to 56 mg/day in 2 to 4 divided doses for the treatment
of epilepsy. It is rapidly absorbed with peak plasma concentrations
occurring at approximately 45 minutes. Tiagabine is 96% bound
to plasma proteins.
Side effects of tiagabine are generalized weakness, binding in
the eye and other melanin-containing tissues, and rash.
is a new antiepileptic, which is chemically similar to carbamazepine
and may prove to be a neuropathic analgesic.53 Oxcarbazepine
is a pro-drug, which means its metabolite is the active substance.
It is indicated for monotherapy or adjunctive therapy in the treatment
of partial seizures.54
Oxcarbazepine blocks voltage-sensitive sodium channels, resulting
in stabilization of hyperexcited neural membranes, inhibition of
repetitive neuronal firing, and diminution of synaptic impulse propagation.55 It
may modulate high-voltage activated calcium channels and increase
A small study demonstrated the efficacy of oxcarbazepine in trigeminal
neuralgia.56 Further controlled studies are under
way to determine its efficacy and optimal dose in the treatment
of neuropathic pain.
Oxcarbazepine is available as 150-mg, 300-mg, and 600-mg tablets.
The starting dose of oxcarbazepine is 150 to 600 mg/day
divided into two doses, up to a maximum of 2400 mg/day.
Monitoring of hepatic enzymes or hematologic parameters is not required
with oxcarbazepine to the same degree as with carbamazepine. It
does not extensively undergo oxidative metabolism and has low protein
binding (40%). Oxcarbazepine is metabolized to 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide
(MHD), which is responsible for the pharmacologic effects of oxcarbazepine.
The peak serum levels of oxcarbazepine and MHD are reached in 4.5
hours after oral administration. The half-life of MHD is 9 hours.
Side effects associated with oxcabazepine are primarily related
to the nervous system and digestive system. The symptoms are somnolence,
headache, dizziness, diplopia, ataxia, nystagmus, abdominal pain,
anorexia, nausea, vomiting, and rash.
Zonisamide (1,2-benzisoxazole 3-methanesulfonamide) is used for
adjuvant therapy for partial seizures.57 It is
chemically classified as a sulfonamide and is unrelated to other
Zonisamide blocks sodium channels and reduces voltage-dependent
T-type calcium currents, stabilizing neuronal membranes and suppressing
neuronal hypersynchronization.58,59 It binds to
the GABA-benzodiazepine receptor and facilitates both dopaminergic
and serotonergic neurotransmission.
There are no published reports of its efficacy in treating headache
and pain, but analgesic efficacy trials are currently under way.
Zonisamide is available in a 100-mg capsule. Its dosing is daily
or twice a day. The starting dose is 100 mg/day and can
be increased up to 400 to 1200 mg/day. Drug interactions
with carbamazepine and phenytoin have been noted. Peak serum levels
are reached in 2 to 6 hours after oral administration. Zonisamide
is metabolized by the liver but does not affect cytochrome P450 metabolism.
It is excreted by the kidneys. Zonisamide is 40% protein
bound but does not affect protein binding of other drugs such as
phenytoin, phenobarbital, or carbamazepine. Zonisamide binds extensively
to erythrocytes, resulting in higher concentrations in red blood
cells (RBCs) than plasma. It has a half-life in plasma of 63 hours
and half-life in RBCs of 105 hours.
Zonisamide is contraindicated in patients with hypersensitivity
to sulfonamides. Side effects experienced with zonisamide are anorexia,
nystagmus, ataxia, abdominal pain, confusion, and fatigue. There
was concern that development of nephrolithiasis was related to zonisamide
but further investigation is required.
acetamide) is indicated for adjunctive therapy for partial seizures
and may be useful for photosensitive epilepsy.60,61 It
was initially developed as a cognition-enhancing agent for the treatment
of Alzheimer’s disease. It possesses antiepileptic, anxiolytic,
and cognitive-enhancing properties.
It has no significant affinity for GABA or benzodiazepine receptors.
Levetiracetam appears to act via an unknown binding site in the
brain. It stimulates several neurochemical systems including glutamatergic,
dopaminergic, and cholinergic neurotransmission. There are no published
reports of its efficacy in treating headache and pain at this time.
Levetiracetam is available in 250-mg, 500-mg, and 750-mg tablets.
The recommended starting dose is 1000 mg/day divided into
two doses; the maximum recommended dose is 3000 mg/day. Levetiracetam
is rapidly absorbed after oral administration. Peak serum concentrations
occur from 0.6 to 1.3 hours after administration. It is transformed
by enzymatic hydrolysis of the acetamide group in the blood to inactive
metabolite and renally excreted. Approximately 66% of levetiracetam
is excreted unchanged. It is largely unbound to plasma protein and
its half-life is about 6 to 8 hours.
Adverse effects include drowsiness, memory impairment, depression,
nausea, and ataxia.