Gabapentin

Gabapentin was initially approved by the U.S. Food and Drug Administration (FDA) as an anticonvulsant (partial seizure) and is currently extensively used for the treatment of neuropathic pain conditions. Although gabapentin’s mechanism of action is unclear, it does block voltage-gated calcium channels by binding to the α ₂ -δ subunit, thereby reducing calcium influx. By blocking calcium influx, gabapentin reduces the release of glutamate and substance P from primary nociceptive afferents, thereby modulating nociceptive transmission. Gabapentin has been used to treat painful diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, and painful peripheral neuropathies caused by human immunodeficiency virus (HIV), cancer, multiple sclerosis, and spinal cord injury.

Painful diabetic neuropathy is a debilitating condition commonly seen in patients with diabetes mellitus. Up to 25% of patients with diabetes may suffer from spontaneous pain, allodynia, hyperalgesia, paresthesias, and other pain symptoms. Postherpetic neuralgia is another common neuropathic pain condition. The incidence of postherpetic neuralgia is estimated to be 9% to 34%, which increases significantly with age. Multiple classes of drugs have been tried to treat pain associated with painful diabetic neuralgia and postherpetic neuralgia, including tricyclic antidepressants (TCAs) such as amitriptyline, nortriptyline, imipramine, and desipramine. Because of the significant side effects of TCAs, gabapentin has been increasingly used in the treatment of these pain conditions.

Gabapentin is effective in reducing several salient symptoms of neuropathic pain such as burning and shooting pain, allodynia, and hyperalgesia. The number needed to achieve at least 50% pain relief with antidepressants and gabapentin are 3.4 and 2.7, respectively. Although both antidepressants and gabapentin may provide moderate pain relief, antidepressants may have more major side effects.

The recommended gabapentin dose range is 1800 to 3600 mg/day, starting at 100 to 300 mg/day and increasing 100 to 300 mg every 1 to 3 days. Adverse effects are usually mild to moderate and typically subside within 7 to 10 days after the treatment is started; however, serious side effects can occur including mood swing, edema, and suicidality. In general, a slow titration process can significantly reduce some otherwise intolerable side effects, such as dizziness. In addition to its use as a monotherapy, gabapentin has been extensively used in multimodal drug therapy in conjunction with TCAs and other anticonvulsants. Multimodal drug therapy provides better pain control, requiring a smaller dose range for each drug included in the regimen. Gabapentin also can treat complex regional pain syndrome, phantom pain, trigeminal neuralgia, cancer-related neuropathic pain, multiple sclerosis, spinal cord injury, HIV-associated painful sensory neuropathy, and glossopharyngeal neuralgia.

The role of gabapentin in acute postoperative pain management remains unclear.

Pregabalin

Pregabalin is an anticonvulsant that has a high affinity to the α ₂ -δ subunit of voltage-sensitive calcium channels. The mechanism of action of pregabalin is similar to that of gabapentin. Pregabalin decreases calcium influx, thereby reducing the release of excitatory neurotransmitters, including glutamate, substance P, and calcitonin gene–related peptide. Pregabalin has no activity on GABA or benzodiazepine receptors; therefore it has no significant drug-drug interactions with such agents.

Pregabalin has been used to treat painful diabetic neuropathy and postherpetic neuralgia, with a significant therapeutic effect. It has a quick onset, and, in some cases, pain reduction can be expected on the first day of treatment with pregabalin (300 mg/day). Sustainable sleep improvement is also observed 1 week after the therapy is initiated. Common side effects are dizziness, somnolence, and mild to moderate peripheral edema. Other concerns over pregabalin include behavioral changes such as mood swing and suicidality. Before starting pregabalin, it is recommended to check the baseline creatinine level. Moreover, pregabalin (at an average dose of 450 mg/day) is effective in patients with fibromyalgia, who often have clinical presentations including diffuse musculoskeletal pain, sleep disturbance, and fatigue.

Zonisamide

Zonisamide blocks both voltage-sensitive sodium channels and N-type calcium channels. Studies suggest that zonisamide may be used to treat mania, Parkinson disease, and poststroke central pain or to provide migraine prophylaxis. Its possible mechanisms of action include modulation of monoamine neurotransmitter release and free radical scavenging. Zonisamide is effective for the treatment of painful diabetic neuropathy (540 mg/day). The tolerability of zonisamide is difficult to assess because it is often used in multimodal drug therapy. Thus the data on the effectiveness and side effects of zonisamide remain limited.

Ziconotide

Ziconotide is a synthetic peptide analogue of omega conotoxin derived from a marine snail, Conus magus . Ziconotide potently and selectively blocks N-type voltage-sensitive calcium channels. This drug is approved only for intrathecal use in patients with severe pain who are refractory to other treatment options, including intrathecal morphine. In early clinical trials, ziconotide exhibited severe central nervous system and psychiatric adverse effects with an initial intrathecal infusion rate of 0.4 μg/h and frequent dosing titration. More recently, ziconotide has been shown to be effective for chronic pain conditions resulting from cancer, acquired immunodeficiency syndrome, and trigeminal neuralgia. The role of ziconotide in postoperative pain management is less clear. Given ziconotide’s significant side effects and restrictive delivery route, its routine use in acute postoperative pain management is not well justified.

The initial infusion rate of ziconotide should start at 0.1 μg/h intrathecally, with a slow titration of no more than 2 to 3 times the initial dose per week. An implanted intrathecal infusion system is required for the long-term use of this therapy if the initial ziconotide trial is effective. Patients with severe psychiatric disorders may not be proper candidates for this therapy. On the other hand, ziconotide may be advantageous over intrathecal morphine because patients do not develop tolerance after a prolonged use of ziconotide. However, adverse neurologic effects associated with ziconotide therapy will require careful patient selection and monitoring. Using a smaller dose increment may help to avoid systemic toxicity.

Levetiracetam

Levetiracetam is an anticonvulsant approved by the FDA for treatment of epilepsy. Its mechanisms of action are less clear because it may have effects on several neurotransmitter systems, including dopaminergic, glutamatergic, and GABAergic systems. But at least one of its mechanisms of action is due to inhibition of N-type voltage-sensitive calcium channels. Levetiracetam improves neoplastic plexopathies, painful peripheral neuropathy, and postherpetic neuralgia. It also has been used in migraine headache prophylaxis. The dose range is 500 to 2000 mg/day. At this dose range, levetiracetam is well tolerated in clinical trials. Common adverse effects are dry eyes and dizziness.

Lidocaine

Lidocaine is a local anesthetic and cardiac antiarrhythmic. Since the 1980s, intravenous administration of lidocaine has been used as a diagnostic tool and, in some cases, a therapeutic tool for intractable neuropathic pain. This treatment modality has been shown to improve chronic pain conditions induced by neurologic diseases, including stroke, neurogenic facial pain, and myofascial pain. Up to 78% of cases are associated with a positive outcome when intravenous lidocaine is used. A major pitfall of intravenous lidocaine treatment is its short duration, which requires frequent treatment sessions.

Topical 5% lidocaine patch and over-the-counter topical lidocaine gel or cream provide a local analgesic effect with a minimum systemic effect. Lidocaine patch has been used in patients with neuropathic pain conditions such as painful diabetic neuropathy, postherpetic neuralgia, and peripheral neuropathies. It reduces allodynia and hyperalgesia associated with such conditions. Although the evidence remains weak and unclear, lidocaine patch has been used to treat chronic lower back pain. In some cases, lidocaine patch has become a part of multimodal drug therapy, such as a combination of topical lidocaine patch and gabapentin.

Mexiletine

Mexiletine is an oral lidocaine congener. It may be used to overcome the shortcoming of transient pain relief with intravenous lidocaine. In many cases, intravenous lidocaine is used as a test to determine whether the intended lidocaine treatment is effective. When a positive response is achieved, oral mexiletine is administered to maintain the therapeutic effect. This treatment regimen reduces pain due to painful diabetic neuropathy refractory to other therapies. Mexiletine alone has been used to treat phantom pain and pain after spinal cord injury.

Fibromyalgia and myofascial pain are other clinical conditions that may be responsive to a lidocaine and mexiletine treatment regimen. In addition, anecdotal reports suggest that oral mexiletine may be used to treat primary erythromelalgia, metastasis bone pain, and headaches.

Carbamazepine

A primary mechanism of action of carbamazepine is sodium channel blockade, which decreases spontaneous firing of Aδ-fibers and C-fibers. Carbamazepine has been approved to treat trigeminal neuralgia, a neuropathic pain condition characterized by episodic lightning, lancinating, or shooting pain along the trigeminal nerve distribution. Carbamazepine has been used for decades and was superior to placebo in a number of clinical trials. It was once considered a “gold standard” and remains a treatment of choice for trigeminal neuralgia, with a response rate of 89% within 5 to 14 days after the treatment is initiated. However, carbamazepine has significant drug-drug interactions and a long list of adverse effects, including central nervous system side effects. In the United States the FDA has issued black box warnings about this drug, including aplastic anemia and agranulocytosis. Therefore its clinical utility is rather limited considering that newer anticonvulsants are available with fewer and less severe side effects.

Oxcarbazepine

Oxcarbazepine is an analogue of carbamazepine, which acts as a sodium channel blocker and stabilizes neuronal membrane. In contrast to carbamazepine, oxcarbazepine has fewer drug-drug interactions and side effects, particularly severe blood dyscrasias. The most common side effects of oxcarbazepine are dizziness, drowsiness, hypotension, nausea, and asymptomatic mild hyponatremia. Oxcarbazepine has been used to treat intractable trigeminal neuralgia refractory to other anticonvulsants. With a median dose of 750 mg/day, this novel drug appears to have the same efficacy as carbamazepine in the treatment of trigeminal neuralgia but a much lower incidence of side effects.

Oxcarbazepine also reduces pain associated with painful diabetic neuropathy and complex regional pain syndrome. For patients with postherpetic neuralgia that is unresponsive to carbamazepine and gabapentin, oxcarbazepine, starting at 150 mg/day and titrating up to a maintenance dose of 900 mg/day, may be a promising drug because it significantly reduces allodynia related to postherpetic neuralgia. Oxcarbazepine appears to be well tolerated and may serve as a reasonable alternative to other sodium channel blockers.

Lamotrigine

Lamotrigine has multiple mechanisms of action, although it also blocks both sodium and calcium channels. Lamotrigine is effective in the treatment of trigeminal neuralgia, neuralgia after nerve section, and pain related to HIV neuropathy. With a daily lamotrigine dose of 75 to 300 mg, the intensity of burning and shooting pain is relieved by 33% to 100%, and the frequency of shooting pain attack is reduced by 80% to 100%. In patients with spinal cord injury, lamotrigine decreases overall pain sensation to less than the level of injury in patients with incomplete spinal cord injury but has little effect on spontaneous and evoked pain in patients with complete spinal cord injury.

A typical starting dose for lamotrigine is 25 to 50 mg/day, which can be slowly titrated up over 2 to 3 weeks to 250 to 500 mg/day in divided doses. Tolerability is usually low at high doses (>300 mg/day). Up to 10% of patients may have rashes after taking this medication, with a 3 in 1000 incidence of Stevens-Johnson syndrome. Other side effects are mild dizziness, somnolence, nausea, and constipation.

Topiramate

Topiramate is another drug that has multiple mechanisms of action. However, at least one of its actions is to block voltage-sensitive sodium channels. It also may potentiate GABA inhibitory action, block voltage-sensitive calcium channels, and inhibit subtypes of glutamate receptors (non-NMDA receptors). Topiramate can cause significant weight loss (up to 7%), a side effect that could be beneficial for certain patient populations with chronic pain conditions. Topiramate, at a daily dose of 400 mg or greater, attenuates neuropathic pain, improves sleep quality, and reduces body weight. When used to treat chronic lumbar radicular pain, the effect of topiramate is inconclusive because of a high dropout rate and frequent side effects in clinical trials. However, topiramate 30 to 80 mg/day is superior to placebo for the treatment of chronic tension, migraine, and cluster headaches with a substantial tolerability.