Pharmacology

Gabapentin was synthesized because of its structural similarity to GABA and its ability to cross the blood-brain barrier.

Pharmacokinetics. Following a 300 mg oral dose in healthy volunteers, the mean maximum plasma concentration of gabapentin is reached in 2 to 3 hours. Absorption kinetics of gabapentin are dose dependent. The bioavailability of a single oral dose of gabapentin is about 60%, but decreases with increasing dose, suggesting a saturable transport system. Unlike GABA, gabapentin has some lipophilicity, enabling it to readily cross the blood-brain barrier. At therapeutic concentrations, gabapentin is a substrate for the large neutral amino acid transporter (LAT1) across the blood-brain barrier (09). Gabapentin is extensively distributed in body tissues and is not bound to human plasma proteins.

Gabapentin is eliminated almost completely by renal clearance. Renal impairment reduces drug clearance and raises plasma gabapentin concentrations.

The pharmacokinetic parameters of gabapentin are not altered by repeated administration. Clinical effects are seen over the dose range of 600 to 1800 mg. Blood concentrations of gabapentin greater than 2 mg/mL are associated with a clinical response in patients with epilepsy. The dosage of gabapentin, however, should be adjusted according to clinical response. The half-life is 5 to 7 hours, meaning the drug needs to be administered 3 times a day to maintain optimal plasma concentrations.

In healthy subjects, the daily exposure provided by less frequent gabapentin extended-release dosing is not significantly different from same daily dose with gabapentin immediate-release, administered more frequently.

Therapeutic drug monitoring. Because of pharmacokinetic variability, therapeutic drug monitoring is useful for patients under treatment with gabapentin, but challenges in application for indications such as restless legs syndrome include variable dosage regimens that lead to differences in interpretation of serum concentrations (23). A rapid and validated isocratic fluorometric high performance liquid chromatography method is available for the determination of gabapentin in human plasma as well as urine for clinical application and can be used to evaluate pharmacokinetics of gabapentin in humans (39).

Pharmacodynamics. Gabapentin slightly reduces the release of several monoamine neurotransmitters (norepinephrine and serotonin), but not acetylcholine, from mammalian brain tissue. Gabapentin protects against convulsions in standard animal seizure models, and this predicts the clinical efficacy of gabapentin in patients with partial seizures and secondarily generalized tonic-clonic seizures. No tolerance has been noted with respect to the anticonvulsant effects of gabapentin.

Even though it is structurally like GABA, gabapentin does not act through mechanisms related to this neurotransmitter, but rather by events modulated through its interaction with a receptor thought to be present only in the brain. However, some neurons that respond to gabapentin are GABAergic. The specific binding site is a protein of voltage-gated calcium channels and, as a result, modulates the action of calcium channels and neurotransmitter release. Gabapentin is like carbamazepine and phenytoin with respect to effects on excitatory mechanisms and segmental inhibition in the trigeminal complex, but it differs in its effects on inhibitory pathways descending from the reticular formation.

Gabapentin is a neuroprotective agent by inhibition of glutamate synthesis. The mechanism of relief of neuropathic pain is not clear, but gabapentin does not appear to affect the same pathways as opioids or tricyclic antidepressants. Current evidence indicates that it affects a voltage-gated calcium channel in the pain-transmitting nerve cells of the spinal cord.

Gabapentin enacarbil, approved for restless legs syndrome, is an actively transported prodrug of gabapentin that provides sustained dose-proportional exposure to gabapentin and predictable bioavailability (22). In a population pharmacodynamics study, response increased with increasing dose as assessed by Clinical Global Impression of Improvement, whereas the total score on International Restless Legs Scale was similar at all exposures tested.

Mirogabalin besylate (DS-5565) shows greater sustained analgesia due to a high affinity to, and slow dissociation from, the α2δ-1 subunits in the dorsal root ganglion (21). Additionally, it produces a lower level of central nervous systemspecific adverse drug reactions due to a low affinity to, and rapid dissociation from, the α2δ-2 subunits in the cerebellum. Maximum plasma concentration is achieved in less than 1 hour, compared to 1 hour for pregabalin and 3 hours for gabapentin. The plasma protein binding is relatively low, at less than 25%. As with all gabapentinoids, it is also largely excreted via the kidneys in an unchanged form, so the administration dose should also be adjusted according to renal function. The equianalgesic daily dose for 30 mg of mirogabalin is 600 mg of pregabalin and over 1200 mg of gabapentin. The initial adult dose starts at 5 mg, given orally twice a day, and is gradually increased by 5 mg at an interval of at least a week, to 15 mg. In conclusion, mirogabalin is anticipated to be a novel, safe gabapentinoid anticonvulsant with a greater therapeutic effect for neuropathic pain in the dorsal root ganglia and lower adverse reactions in the cerebellum.

Clinical trials

As adjunctive therapy in early trials, gabapentin was reported to have a similar spectrum of activity to valproic acid (ie, being moderately effective against partial seizures and highly effective against tonic-clonic seizures). Initial short-term studies reported a response rate of 25% in patients treated with gabapentin. In open trials, long-term treatment with gabapentin for 2 to 5 years was associated with a high response rate; about 70% of patients showed some improvement in seizure control. Efficacy of gabapentin in controlling seizures in patients with treatment-resistant partial epilepsy may continue to improve during long-term therapy.

In 2 controlled clinical trials in patients with postherpetic neuralgia, the proportion of responders was significantly greater with gabapentin than with placebo (08). Although short-term studies show effectiveness of gabapentin, long-term studies are needed to establish the efficacy in postherpetic neuralgia. High doses used in clinical trials produce adverse effect and the safe optimal dose of gabapentin needs to be determined.

A double-blind study was conducted to evaluate the efficacy and safety of gabapentin 1200 mg per day and 1800 mg per day compared to placebo as an adjunctive therapy in patients with refractory epilepsy (40). Both doses significantly reduced the frequency of refractory seizures compared to placebo.

In a randomized clinical trial, gabapentin maintained improvements in symptoms of moderate to severe primary restless legs syndrome compared with placebo and showed long-term tolerability for up to 9 months of treatment (03). In an open-label, multicenter, 52-week extension study gabapentin enacarbil was well tolerated and improved symptoms in subjects with moderate-to-severe primary restless legs syndrome for up to 64 weeks of treatment (10).

Because of the limitations of multiple daily dosing with gabapentin and high incidences of serious adverse events in the elderly, the efficacy and tolerability of once-daily gastroretentive gabapentin (G-GR) was evaluated by integrating data from 2 phase III, placebo-controlled studies in patients with postherpetic neuralgia and analyzed by age subgroups less than 75 years versus age subgroups greater than or equal to 75 years (16). Results showed that G-GR was as effective as well tolerated for treating pain associated with postherpetic neuralgia in elderly patients as it was in younger patients. Clinical trials have shown that oral gabapentin (1200-3600 mg/d for 4-12 weeks) for moderate or severe neuropathic pain due to postherpetic neuralgia or painful diabetic neuropathy reduces pain of at least 50% in 14% to 17% more patients than placebo (28).

A systematic review of randomized clinical trials has shown that gabapentin is effective as an add-on treatment for drug-resistant focal epilepsy up to a 3-month period, but no information was available about long-term outcome (30).

Indications

Gabapentin is indicated as an add-on therapy for the treatment of partial seizures with or without secondary generalization. It is also approved for the treatment of postherpetic neuralgia and restless legs syndrome. Most of the publications deal with use of gabapentin in all types of pain problems.

Off-label uses

Contraindications

Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Goals and duration of treatment

The aim of gabapentin therapy is to control seizures. Therapy is continued for as long as seizure control is required.

In management of neuropathic pain in a hospice/palliative care setting, 42% of patients experienced benefit at a level that resulted in continued use at 21 days (34). The outcome of at least 50% reduction in pain intensity is regarded as a useful outcome of treatment by patients with neuropathic pain, which is associated with other beneficial effects on sleep interference, fatigue, depression, and quality of life as well as ability to work. A systematic review of controlled clinical trials of gabapentin for neuropathic pain due to postherpetic neuralgia and peripheral diabetic neuropathy showed that 3 or 4 out of 10 participants achieved this degree of pain relief with gabapentin (38).

Dosing

The daily oral dose is 900 to 1800 mg in 3 divided doses with or without food. The dose can be titrated rapidly over a few days. It is not necessary to monitor plasma concentrations of the drug. Because it does not interact with other antiepileptic drugs, its addition to an antiepileptic regimen does not alter the plasma levels of other drugs significantly.

Special considerations

Gabapentin may unmask myasthenia gravis and should be used with caution in this disease.

Pediatric. Safety and efficacy in children under the age of 12 years has not been demonstrated.

Geriatric. No systematic studies have been done in geriatric patients, but dose adjustment may be necessary in elderly patients with renal insufficiency. See the Physicians Desk Reference for details.

Pregnancy. Gabapentin has been shown to be fetotoxic in rodents, but this is not necessarily predictive of human toxicity. It should be used in pregnancy only if the benefits outweigh the potential risks. Review of published pregnancy registries shows that maternal gabapentin use is associated with roughly equivalent rates of premature birth and birth weight after correction for gestational age at delivery and maternal hypertension/eclampsia as those that have been reported in the general population (18). Although these data support the safety of gabapentin use in pregnancy, the number of exposures so far is still small, and further studies are needed.

Withdrawal symptoms from gabapentin, administered to mothers during pregnancy, have been reported in neonates. As in adults, gabapentin should be gradually tapering off in neonates over weeks to months (05).

Transfer of gabapentin to breast milk is extensive, but plasma concentrations appear to be low in suckling infants and no adverse effects have been reported in neonates.

Interactions

Gabapentin does not interact with other antiepileptic drugs. It does not affect the efficacy of oral contraceptives used concomitantly.

Adverse effects

Gabapentin is well tolerated and has a low incidence of adverse events in clinical trials. The most common side effects have included dizziness, fatigue, and headache. No life-threatening idiosyncratic reactions have been reported. Dose-related neurotoxicity is usually mild. Gabapentin can cause dystonic reactions, which are reversible after drug withdrawal.

Gabapentin-associated dose-dependent anorgasmia may be more common in older patients (32).

Adverse events reported during clinical trials along with their frequency are listed in the Physicians Desk Reference. In a postmarketing survey, neurologic-related events were the most frequently reported adverse events and were the most common reasons for discontinuing treatment. Cases of gabapentin addiction have been reported, and most of these involved withdrawal symptoms. A pharmacovigilance study in Japan has confirmed the prevalence of neuropsychiatric adverse drug reactions associated with gabapentin or pregabalin (14).