Chapter 64. Antiepileptics for Pain

Antiepileptic drugs (AEDs) have been used in the treatment of chronic pain syndromes for more than 50 years.1–4 Phenytoin, in particular, has been extensively used for the treatment of neuropathic pain during that time.5–9 Carbamazepine was the first AED used and extensively studied specifically for the treatment of trigeminal neuralgia.10–12 Since then a variety of neuropathic syndromes have been treated with AEDs, including diabetic neuropathy, postherpetic neuralgia, glossopharyngeal neuralgia, post-sympathectomy neuralgia, and post-thoracotomy pain syndromes.1–4 The AEDs include the older drugs like phenytoin, carbamazepine, and valproic acid, and newer agents such as gabapentin, lamotrigine, felbamate, topiramate, vigabatrin, tiagabine, levetiracetam, zonisamide, and oxcarbazepine.

The individual AEDs are briefly reviewed here, as well as general guidelines for their use in pain control.

Neuropathic pain is defined as pain due to dysfunction of the nervous system in the absence of ongoing tissue damage.13 The pain typically is characterized as sharp, shooting, or burning, and is usually felt in the area of sensory deficit. It is typically worsened by mild stimuli that normally would not produce pain, such as light touch or cool air. The pain tends to be chronic and causes considerable patient discomfort. These symptoms have led to various hypotheses about the pathophysiologic mechanisms of neuropathic pain with relevance to AEDs.14 When peripheral nerves become damaged, axons grow toward the formerly innervated area directed by an intact connective tissue sheath. If this sheath is also damaged, then axon extensions grow without any direction and become tangled into a structure called a neuroma. Neuromas can generate ectopic electrical impulses at the regenerating tips in the damaged primary nociceptive afferents at various levels in the nervous system, from the dorsal root ganglia to demyelinated regions of a root or nerve.15 Since nerves have been damaged, there is a potential disruption in the balance of the excitatory (e.g., glutamate) and inhibitory (e.g., γ-aminobutyric acid, GABA) neurotransmitters. This disruption leads to hyperexcitability of the neuronal membrane sodium channels and voltage-dependent calcium channels, causing rapid ectopic firing. The AEDs have varying mechanisms of action, many of which are directed at sodium and calcium-dependent channels and GABA metabolism.

Although AEDs provide at least partial pain relief in a large percentage of patients with a variety of neuropathic pain syndromes, their use is limited by side effects in a substantial percentage of patients. In addition, older AEDs (phenytoin, carbamazepine, and valproic acid) also require monitoring of blood counts and liver function tests because of their hematologic and hepatic toxicity, leading to poor compliance. Newer AEDs (with the exception of felbamate) generally are not associated with life-threatening side effects and are easier to use.

Phenytoin

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

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

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 occasionally thereafter.

Clonazepam

Clonazepam (5-(o-Chlorophenyl)-1,3-dihidro-7-nitro-2H-1,4-benzodiazepin-2-one) 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 pain.26–28

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 prohibited.

Gabapentin

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.

Lamotrigine

Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) 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

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.

Topiramate

Topiramate (2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose 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

Vigabatrin is a novel AED reported to be effective in the treatment of complex partial seizures; it is not currently marketed in the United States.48

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.

Tiagabine

Tiagabine ((–)-(R)-1-[4,4-Bis(3-methyl-2-thienyl)-3-butenyl]nipecotic 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.

Oxcarbazepine

Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) 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 potassium conductance.

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

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 antiepileptic agents.

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.

Levetiracetam

Levetiracetam ([S]-alpha-ethyl-2-oxo-1-pyrrolidine 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.

Despite the increase in the number of AEDs available, the rule of “old is gold” continues to be applicable in developing a general strategy to treat neuropathic pain syndromes. Phenytoin, the “grandfather” of the modern day antiepileptics, should be tried first for four major reasons:

• Availability in both oral and injectable forms, which could be helpful in providing immediate pain relief
• Lower cost
• Established safety
• Relative ease of use.

The major exception to this rule is in patients with trigeminal neuralgia, a disorder that generally has responded better to carbamazepine than to the other agents. For classic trigeminal neuralgia, carbamazepine followed by lamotrigine, topiramate, gabapentin, and oxcarbazepine should be tried either alone or in combination.

Among the newer AEDs, gabapentin appears to be the most effective and best tolerated. It probably should be considered first after dilantin for most neuropathic pain states other than trigeminal neuralgia. Gabapentin has the added advantage of easy use in combination with other AEDs that have failed as single agents since it does not interact with these agents.

Other AEDs such as valproic acid, lamotrigine, tiagabine, clonazepam, and topiramate should be tried if the above either do not provide adequate pain relief or are not tolerated. In particular, preliminary data indicate topiramate is a promising neuropathic analgesic, but results of randomized, placebo-controlled studies are not yet available. AEDs such as vigabatrin, levetiracetam, zonisamide, and oxcarbazepine have not yet demonstrated proven efficacy in controlled trials of the treatment of neuropathic pain. Felbamate should only be used as a last resort because of its association with aplastic anemia and fulminanent hepatic failure.

An important point to keep in mind is that these medications are AEDs first rather than true analgesics, and are limited by adverse effects, especially when used long term. Their use for neuropathic pain should generally follow the same dosing and monitoring guidelines used for seizure control, although in our experience, many patients benefit from low doses that are considered subtherapeutic in treating epilepsy; monitoring drug levels may not be necessary.