Membrane stabilizers have a growing role in pain management, both acute and chronic. They have been used for many years to treat painful conditions such as trigeminal neuralgia, complex regional pain syndrome, and headaches. In addition to their use in chronic pain conditions, they are seeing increasing use in acute pain situations as well as the perioperative setting. It is important to understand the mechanism of action, titration schedules, and potential side effects of these medications, which will be covered in this chapter. Many of these drugs may have significant side effects that require vigilance on the part of the provider to know when to stop the medication or alter the titration schedule. With proper use these medications can greatly benefit patients with difficult to treat neuropathic pain.
Keywordsanticonvulsants, CRPS, GABA, local anesthetics, neuropathic pain, trigeminal neuralgia
The treatment of neuropathic pain presents a distinct challenge to health care practitioners. A wide range of conditions resulting in chronic neuropathic pain include, but are not limited to, diabetic polyneuropathy, postherpetic neuralgia, central neuropathic pain, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, radiculopathy, complex regional pain syndrome (CRPS), and human immunodeficiency virus (HIV)-associated peripheral neuropathy. Defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system, neuropathic pain is often described as burning, lancinating, or tingling in nature.
Neuropathic pain is the unfortunate consequence of detrimental changes that occur after tissue injury. Pathologic changes after injury result in plasticity or alterations in the way peripheral nerve fibers respond to and deliver input to the central nervous system. The source of neuropathic pain may be related to damage of a peripheral nerve, with or without associated autonomic changes or central nervous system dysfunction. Examples of these changes include prolonged central sensitization, damage to neuronal inhibitory functions, and alterations in the effects of pain on the sympathetic nervous system. When abnormal neural activity persists beyond the expected duration of healing, the pain sensation becomes chronic in nature and continues without ongoing disease.
Following tissue injury, the threshold of activation of A delta and C fibers decreases and an augmented response to a given stimulus occurs. In addition, alterations in ion channels located at the site of injury take place. Sodium and calcium channels play a fundamental role in the propagation of hyperexcitability in central and peripheral neurons. After nerve injury, the number of ion channels accumulates in excess, leading to ectopic, spontaneous firing of sensory nerves and dorsal root ganglion cell bodies. The result of neuronal membrane hyperexcitability is the chronic perception of pain.
Research into the physiologic source and pharmacologic management of neuropathic pain has led to the study of sodium and calcium channel blockade. The pathology leading to epilepsy was extrapolated and studied as a possible source of the development of neuropathic pain. Membrane stabilizers include agents typically used for the treatment of epileptic foci in the brain. As a result of this inferential leap, these agents have been used in patients with neuropathic pain. There are multiple classes of medications that fall under the membrane stabilizer classification, including sodium channel blocking agents (antiepileptics, anticonvulsants, local anesthetics, tricyclic antidepressants, and antiarrhythmics) and calcium channel blocking agents ( Table 49.1 ).
|Membrane Stabilizer||Mechanism||Side Effects||Clinical Comment|
|Carbamazepine||Na channel blockade||Sedation, dizziness, gait abnormalities, hematologic changes||Blood count every 2–4 months|
|Gabapentin/pregabalin||Binds to alpha-2 delta subunit of voltage-gated Ca channel||Dizziness, sedation||Discontinue gradually|
|Lamotrigine||Stabilizes slow Na channel; suppresses release of glutamate from presynaptic neurons||Rash, dizziness, somnolence||Drug interactions a|
|Levetriacetam||Exact mechanism not determined||Asthenia, somnolence||No significant drug interactions|
|Lidocaine cream/TD||Na channel blockade||Skin irritation||—|
|Mexilitine||Na channel blockade||Nausea, blurred vision||Monitor serum level, CBC (for dyscrasias)|
|Oxcarbazepine||Na channel blockade||Hyponatremia, somnolence, dizziness||—|
|Phenytoin||Na channel blockade disturbances||Sedation, motor||—|
|Topiramate||Na channel blockade; potentiates GABA inhibition||Sedation, kidney stones, glaucoma||—|
|Valproic acid||Na channel blockade; increase GABA||Somnolence, dizziness, gastrointestinal upset||Drug interactions a|
|Zonisamide||Calcium and sodium channel blockade||Ataxia, renal calculi||—|
a Amotrigine: Increased efficacy when combined with valproate (reduce dose); decreased efficacy when combined with phenytoin and carbamazepine.
When evaluating the effectiveness of medications for neuropathic pain, outcome measures most commonly include changes in the average daily pain score by a 10-cm (100-mm) visual analog scale (VAS) and on an 11-point Likert scale (0, no pain; 10, worst possible pain), or a numeric rating scale (NRS); patient reported pain relief of 30% or greater (moderate benefit); patient reported pain relief of 50% or greater (substantial benefit). “Numbers needed to treat” (NNT) is used to allow a comparison between different drugs and diseases to better judge the efficacy of an agent more precisely. The NNT is the number of patients treated with a particular drug to obtain one patient with a defined degree of relief. Usually, the parameter of NNT greater than 50% pain relief is used because it is easily understood and seems to be related to relevant clinical effect. The “numbers needed to harm” (NNH) is the number needed to treat with a certain drug before a patient can experience a significant side effect. The NNH of several drugs for pain management is not yet known. The drugs with a low NNT/NNH ratio are superior to the drugs with high NNT/NNH ratio.
Sodium Channel Blockers
These agents include the antiepileptics/anticonvulsants, local anesthetics, tricyclic antidepressants, and antiarrhythmics. As a group, they inhibit the development and propagation of ectopic discharges. The primary agents used for neuropathic pain are antiepileptics/anticonvulsants and local anesthetics. Gabapentin and pregabalin, also anticonvulsants, are discussed separately under calcium channel antagonists, as their mechanism of action differs from other agents that are typically used for epilepsy and convulsions.
Sodium channel blockers are used for primary therapy or adjunctive treatment for processes such as trigeminal neuralgia, CRPS, diabetic neuropathy, radicular extremity pain, chemotherapy-induced peripheral neuropathy, and postherpetic neuralgia. When using these agents, as with all membrane stabilizers, it is crucial to be knowledgeable of the proper dosages, toxicities, and their effects when coadministered with other drugs. As a general rule the dose should be titrated to patient comfort within safety standards.
The initial dosage of phenytoin is 100 mg 2 or 3 times daily ( Table 49.2 ). It is primarily used for the treatment of diabetic neuropathy; however, due to the mixed results of its efficacy and high side effect and medication interaction profile, it has fallen into disuse. Phenytoin provides pain relief by blocking sodium channels, thereby preventing the release of excitatory glutamate and inhibiting ectopic discharges.
|Membrane Stabilizer||Initial Dosage||Titration||Maximum Dosage|
|Carbamazepine||100–200 mg twice daily||Increase by 200-mg increments gradually||1200 mg/day|
|Gabapentin a||100–300 mg at bedtime or 100–300 mg 3 times daily||Increase by 100–300 mg 3 times daily every 1–7 days, as tolerated||3600 mg (1200 3 times daily)|
|Lamotrigine||25–50 mg at bedtime||Increase by 50 mg every 1–2 weeks||300–500 mg/day|
|Levetiracetam||500 mg bid||Increase by 500 mg/week||3000 mg/day|
|Lidocaine cream||2%, 5%, 10%||—||—|
|Lidocaine patch||5%||—||12–18 h on and 6–12 h off|
|Mexilitine||150 mg/day||Increase to 300 mg in 3 days then 600 mg||10 mg/kg per day|
|Oxcarbazepine||600 mg twice daily||Increase by 300 mg||1200–1800 mg every 3 days|
|Phenytoin||100 mg 2 to 3 times daily||—||—|
|Pregabalin a||50 mg 3 times daily or 75 mg twice daily||Increase to 300 mg/day after 3–7 days, then by 150 mg/day every 3–7 days as tolerated||600 mg/day (200 mg 3 times daily or 300 mg twice daily)|
|Topiramate||50 mg daily at bedtime||—||1500 mg twice daily|
|Valproic acid||250 mg twice daily||Increase by 250 mg/week||500 mg twice daily|
|Zonisamide||100 mg/day||Increase by 200 mg/week||600 mg/day|
Studies have been performed in trials regarding the efficacy of phenytoin for diabetic neuropathy, with conflicting results. A recent Cochrane review did not find evidence to routinely use phenytoin in the treatment of neuropathic pain as prior studies have failed to demonstrate effective long-term improvement in pain. Therefore this agent should not be considered first-line therapy for neuropathic pain. Some evidence is present to suggest improvement in acute pain. Intravenous phenytoin has been investigated in the pain management setting. Doses of this agent at 15 mg/kg have provided relief of acute pain when administered over a 2-hour period. Side effects include somnolence and slowing of mentation, with nystagmus and ataxia seen in some patients. Among the antiepileptic drugs, a feature unique to phenytoin is the development of facial alterations, including gum hyperplasia and a coarsening of facial features. Fosphenytoin, an intravenously administered prodrug that is converted to phenytoin, is used by some to avoid long dosing intervals or initial burning at the injection site.
Phenytoin activates the cytochrome P450 enzyme system in the liver, and, hence, careful assessment of cotherapy is warranted. For example, phenytoin decreases the efficacy of methadone, fentanyl, tramadol, mexiletine, lamotrigine, and carbamazepine. As a result, dosages of these medications should be adjusted accordingly. Coadministration with antidepressants and valproic acid could lead to increased blood concentrations of phenytoin, lowering the subsequent doses required for effect. Phenytoin in the treatment of neuropathic pain is considered a therapy of last resort.
The initial dosage of carbamazepine is 100 to 200 mg twice daily, titrated to effect, with typical dose ranges of 300 to 1200 mg/day administered in two divided doses. Common maintenance doses are 600 to 800 mg/day. The chemical structure of this compound is similar to that of the tricyclic antidepressants, although the mechanism of action for analgesia is quite different. This agent is thought to inhibit pain via peripheral and central mechanisms. Carbamazepine selectively blocks active fibers, having no effect on normally functioning A delta and C nociceptive fibers. Major uses of the drug include primary therapy for trigeminal neuralgia (tic doloreux), thalamic-mediated poststroke pain, postherpetic neuralgia, and diabetic neuropathy. Drowsiness, dizziness, and nausea and vomiting are common side effects, which can often be limited by slow titration. Carbamazepine is associated with very deleterious side effects, including pancytopenia (necessitating a complete blood count and monitoring while on this therapy), Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Carbamazepine is considered to be the pharmacologic treatment of choice for trigeminal neuralgia, a sharp severe facial pain in one or more of the distributions supplied by the trigeminal nerve. Although the pathology of this process has not fully been determined, the majority of cases are believed to be caused by compression of the trigeminal nerve at the pontine origin of the nerve by an aberrant loop of an artery or vein.
With an NNT of less than 2, carbamazepine is the most studied treatment for trigeminal neuralgia, and many studies have highlighted its usefulness. One study noted the effect of carbamazepine in 70 patients with trigeminal neuralgia and demonstrated a 68% decrease in pain episodes and a 58% decrease in the severity of pain. Research from other studies noted a verbal response by patients of “excellent” or “good” upon initiation of therapy for 2 weeks. Additionally, the positive effect of carbamazepine on trigeminal neuralgias has been tested by crossover, placebo, and controlled double-blind studies ; yet despite these positive results, trigeminal neuralgia is a disease process that, in many patients, is difficult to treat adequately, often requiring multiple agents.
Carbamazepine has also been investigated for use in pain states caused by diabetes mellitus. Its application in animals resulted in a decrease in hyperalgesia to various stimuli. This agent has been shown to be more beneficial than placebo in the human diabetic patient population. Carbamazepine therapy, when compared with nortriptyline/fluphenazine in patients with painful diabetic neuropathy, was found to be equally effective and with fewer side effects.
Patients on carbamazepine therapy should have blood tests done every 2 to 4 months, as there is an increased risk of developing agranulocytosis and aplastic anemia with this agent. Studies noted that the NNH for severe adverse effects was 24 and for minor adverse effects, such as sedation, was 3. A recent retrospective review study on the use of carbamazepine for the treatment of trigeminal neuralgias showed a high discontinuation rate secondary to adverse effects. In this study of 100 patients, 27% treated with carbamazepine suffered an adverse effect that led to the discontinuation of therapy. The mean time to adverse effect in this review was 8.6 months.
Oxcarbazepine, the keto-analogue of carbamazepine, was developed to preserve carbamazepine’s membrane-stabilizing effects while minimizing minor adverse effects, such as sedation and serious or life-threatening reactions. A major advantage of oxcarbazepine is that monitoring of drug plasma levels and hematologic profiles is generally not necessary. Similar to carbamazepine, oxcarbazepine blocks sodium channels; it does not affect gamma-aminobutyric acid (GABA) receptors.
Significant hyponatremia (sodium < 125 mmol/L) may develop during treatment with oxcarbazepine. This typically occurs during the first 3 months, with normalization of sodium levels within a few days of discontinuing the drug. Monitoring of sodium levels should be performed when instituting oxcarbazepine therapy. Frequently reported adverse effects of oxcarbazepine include dizziness, somnolence, and nausea and vomiting, which are generally well tolerated.
In a randomized placebo-controlled trial over 16 weeks, oxcarbazepine was evaluated in patients with painful diabetic neuropathy. They were treated with 300 mg/day that was titrated to a maximum of 1800 mg/day. Oxcarbazepine-treated patients reported less pain on VAS, global improvement, and less sleep disturbances due to pain.
The superior side-effect profile of oxcarbazepine compared with carbamazepine has led to its increased use. Although it is better tolerated, there is still a significant incidence of adverse effects. In a retrospective review of 100 patients successfully treated for trigeminal neuralgia with oxycarbazepine, there was an 18% discontinuation rate secondary to adverse effects. In several countries oxcarbazepine is now the drug of choice for trigeminal neuralgia. Although a case series reported its efficacy in the treatment of neuropathic pain, prospective randomized controlled studies are lacking at this time.
Valproic Acid (Depakote)
This drug acts at the GABA-A receptor. There are conflicting reports in the literature as to the efficacy of this agent in treating neuropathic pain, although studies have demonstrated that valproic acid was effective in migraine therapy at dosages of 800 mg/day for a period of 3 months in patients with medication overuse headache and a history of migraines following detoxification. Side effects include gastrointestinal upset, somnolence, and dizziness. The exact role of this agent in the armamentarium of the pain practitioner is yet to be elucidated.
The initial dosage is 25 to 50 mg at bedtime, which can be increased to 50 mg twice daily after 2 weeks. Subsequently, it may be increased by 50-mg increments every 1 to 2 weeks as tolerated to a dose of 300 to 500 mg/day in two divided doses. Upon discontinuation, drug administration should be slowly tapered over a 2-week period. Like other agents discussed, lamotrigine is an agent that blocks sodium channels in actively firing nerves. It has no effect on sensation in the native, normally functioning nervous system. Unique to lamotrigine is the fact that, in addition to acting as a sodium channel blocker, it prevents release of the excitatory transmitter glutamate.
A major use for lamotrigine is in the treatment of trigeminal neuralgia. Although carbamazepine has been advocated as the first-line therapy for trigeminal neuralgia, it is not effective in all patients. Lamotrigine has been investigated in this patient model for use as a coadministered drug and as a substitute for carbamazepine. A total of 21 trigeminal neuralgia patients who had received no benefit from carbamazepine therapy were treated with lamotrigine. In a population of 7 men and 14 women, 14 of the patients noted significant to complete relief of their symptoms after the institution of lamotrigine therapy, and the remaining 7 patients had no benefit. The use of lamotrigine may therefore be indicated in carbamazepine-resistant trigeminal neuralgia. This positive result has also been seen in follow-up with a group of 15 patients with trigeminal neuralgia receiving lamotrigine therapy. In this paper, 73% of patients were free of their painful symptoms at the conclusion of the study. Subsequent interval follow-up revealed a continued positive result, with no change in pain scores reported by patients. As a result of these studies, lamotrigine may have a role in the prevention of trigeminal neuralgia in susceptible patients.
Lamotrigine has also been evaluated in the diabetic neuropathy population. Patients suffering from diabetic neuropathy may receive benefit from lamotrigine therapy. In two replicate randomized, double blind, placebo-controlled trials, a total of 360 patients were treated with lamotrigine. In patients receiving 400 mg/day, a reduction in pain-intensity score versus placebo was observed in one of the two studies. Doses of 200 and 300 mg/day did not demonstrate any benefit. A group of 15 patients with peripheral neuropathy induced by diabetes (types I and II combined) were treated in an open study. They were tested with brush and cold stimuli for allodynia and pinprick for hyperalgesia. Upon completion of the study, patients were tested and reported improvement of pain in all settings, and their relief persisted as noted during the subsequent 6-month interval follow-up.
In one randomized controlled trial (RCT), lamotrigine (300 mg/day) was found to significantly reduce pain in distal sensory polyneuropathy (DSP) but not in antiretroviral toxic neuropathy (ATN) associated with HIV disease. HIV-associated neuropathy is believed to be on the rise, concomitant with the increase in the number of patients who become diagnosed with the virus. Patients with distal sensory peripheral neuropathy associated with HIV infection were subjected to a placebo-controlled, randomized double-blind study to identify the benefit of lamotrigine therapy. Although both placebo-treated patients and patients receiving lamotrigine had a decrease in pain, the rate of decrease was more rapid in the lamotrigine group. Patients administered antiretrovirals and lamotrigine, however, were noted to have slower pain relief than those maintained on lamotrigine without the antiretroviral agents. In a subsequent larger trial, lamotrigine was found to be effective for both DSP and ATN HIV-related pain. The effect of lamotrigine as an adjunctive therapy was also studied in 220 patients with a variety of neuropathic pain conditions uncontrolled by monotherapy. This randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of lamotrigine in addition to gabapentin, a tricyclic antidepressant, and a nonopioid analgesic. The study patients suffered from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy. Lamotrigine was generally well tolerated but did not demonstrate effective pain relief as evaluated by pain score or use of rescue medication.
A rash is the most common side effect seen in patients. This can occur in up to 10% of patients. This rash is more likely to develop in pediatric patients, especially when lamotrigine is combined with valproic acid. Stevens-Johnson syndrome has occurred in rare cases. Prescribing physicians should also be aware that when lamotrigine is combined with the CYP450 inhibitor valproate, the initial dose should be reduced to 12.5 mg/day and titration should be done cautiously. Additionally, when combined with anticonvulsants that induce hepatic enzymes, such as phenytoin and carbamazepine, the efficacy of lamotrigine may be diminished and a higher dose required for symptomatic improvement.
In addition to affecting sodium channels and calcium channels, topiramate enhances the action of the GABA (inhibitory) neurotransmitter and inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate (excitatory) receptor. The initial dose is 50 mg at bedtime, increasing to an upper limit of 200 mg thrice daily. Studies have demonstrated that pain relief begins to occur at doses of 200 mg/day.
Topiramate has been assessed for use in patients with diabetic neuropathy. A 12-week, double-blinded study showed that topiramate therapy had more efficacy than placebo in relieving the pain sensed by patients with diabetic neuropathy. A review of other double-blinded studies have not corroborated these results, however. In a double-blinded, randomized crossover trial, topiramate 50 to 400 mg was assessed in patients with chronic, lumbar radicular pain; it resulted in an improved global pain relief score but did not reduce leg pain. The study was limited by frequent side effects and a high dropout rate. The exact role of topiramate is yet to be determined; thus it may best be reserved as an adjunct for pain management with other membrane stabilizing agents. Case reports in the literature have also highlighted the use of this agent for additional forms of neuropathic pain, including postherpetic neuralgia, intercostal neuralgia, and CRPS.
The role of topiramate in migraine prevention is well established and is also approved for migraine prevention in the adolescent population. In a 26-week double-blind, placebo-controlled study, 483 patients were randomized to placebo, topiramate 50, 100, or 200 mg/day. Of this group, 463 patients completed postbaseline efficacy reports. Statistically significant reductions in migraine frequency were seen at the doses of 100 and 200 mg/day. In addition to a reduction in migraine frequency, less rescue medication was reduced at these doses.
The primary side effect seen with topiramate is sedation. Other unique consequences of this agent include the potential for development of kidney stones and ocular glaucoma, since topiramate is an inhibitor of carbonic anhydrase. Weight loss associated with topiramate may be a benefit for some and problematic for others.
Levetiracetam is structurally unrelated to other antiepileptic agents and its mechanism of action has yet to be determined. A starting dose of levetiracetam is 500 mg twice daily, and may be increased to a recommended 3000 mg/day in divided doses. Dosages up to 5000 mg/day have been assessed in the treatment of neuropathic pain. Linear pharmacokinetics allow for predictable effects as the dosage is increased. Levetiracetam is not metabolized by the cytochrome P450 system and thus does not have significant drug interactions.
Levetiracetam was found to be ineffective in the treatment of neuropathic pain secondary to a spinal cord injury and in postmastectomy pain. There is some evidence to support the use of levetiracetam 500 mg/day as prophylaxis therapy for migraine headaches; however studies done to date are small. Adverse effects include asthenia, dizziness, somnolence, and headache.