Conventional (immediate-release) preparations of gabapentin are used in the management of seizure disorders. Conventional preparations also are used in the treatment of postherpetic neuralgia (PHN). Gabapentin also is commercially available as a gastroretentive tablet formulation (Gralise) for once-daily administration in the treatment of PHN. Because of differences in pharmacokinetic properties, gabapentin gastroretentive tablets are not interchangeable with other gabapentin preparations.
Gabapentin enacarbil, a prodrug of gabapentin, is commercially available as an extended-release tablet formulation (Horizant) for once-daily administration in the treatment of PHN and primary restless legs syndrome. Because of differences in pharmacokinetic properties, gabapentin enacarbil extended-release tablets are not interchangeable with other gabapentin preparations.
Gabapentin (as conventional preparations) is used in combination with other anticonvulsant agents in the management of partial seizures with or without secondary generalization. The anticonvulsant potential of gabapentin has been established in studies in which gabapentin or placebo was administered as adjunctive therapy in adults and children 3 years of age or older with refractory partial seizures; comparative efficacy of therapeutically effective dosages of gabapentin versus other anticonvulsants remains to be established.
In several placebo-controlled clinical studies, gabapentin (as conventional preparations) was effective in reducing seizure frequency, including that of secondarily generalized tonic-clonic seizures, in 17-26% of patients with partial seizures refractory to therapy with conventional anticonvulsant drugs (e.g., phenytoin, carbamazepine, phenobarbital, valproic acid). Patients in these studies had a history of at least 4 partial seizures (with or without secondary tonic-clonic generalization) per month despite optimum therapy with one or more anticonvulsants and were eligible for study entry if they continued to have at least 2-4 seizures per month during a 12-week baseline period while receiving their established anticonvulsant regimen. Efficacy of gabapentin in these studies was evaluated principally in terms of the percentage of patients with a reduction in seizure frequency of 50% or greater compared with baseline values (i.e., responder rate) and the change in seizure frequency associated with the addition of gabapentin or placebo to existing anticonvulsant treatment (i.e., response ratio, calculated as treatment seizure frequency minus baseline seizure frequency divided by the sum of the treatment and baseline seizure frequencies). Combined analysis of these response parameters in patients receiving various dosages of gabapentin (600, 900, 1200, or 1800 mg in 3 divided doses daily as conventional preparations) or placebo indicated a dose-related reduction in the frequency of partial seizures with gabapentin, although a dose-response relationship was not consistently found in the individual studies. The efficacy of adjunctive therapy with gabapentin for the management of partial seizures does not appear to be affected by patient gender or age, although the influence of these characteristics on efficacy has not been studied systematically.
Efficacy of gabapentin (as conventional preparations) in children 3-12 years of age with partial seizures was established in a multicenter randomized controlled trial. Response ratios were substantially better in patients receiving gabapentin 25-35 mg/kg daily (as conventional preparations) compared with those receiving placebo; for the same population, the responder rate for the drug (21%) was not substantially different from placebo (18%). Another study in children 1 month to 3 years of age reported no substantial difference in either the response ratio or responder rate for those receiving gabapentin compared with those receiving placebo.
Safety and efficacy of gabapentin gastroretentive tablets (Gralise) and gabapentin enacarbil (Horizant) have not been established in patients with seizure disorders.
Gabapentin (as conventional preparations or gastroretentive tablets) and gabapentin enacarbil are used in the management of postherpetic neuralgia (PHN) in adults. Gabapentin is considered one of several first-line therapies for the management of neuropathic pain associated with PHN; other options include tricyclic antidepressants, pregabalin, opiate analgesics, and topical lidocaine patches. When selecting an appropriate regimen, clinicians should consider the relative efficacy and safety of the specific drugs as well as individual patient-related factors (e.g., age, preference, tolerance, contraindications, comorbid conditions, concomitant medications).
Efficacy of conventional (immediate-release) preparations of gabapentin for the management of PHN was established in 2 placebo-controlled studies of 7-8 weeks' duration in patients who were continuing to experience pain for longer than 3 months after healing of their herpes zoster rash. In these studies, gabapentin was titrated over several weeks up to a target dosage of 1.8, 2.4, or 3.6 g daily (administered in 3 divided doses as conventional preparations). Gabapentin substantially reduced weekly mean pain scores from baseline compared with placebo (assessed by an 11-point numeric rating scale); improvement was noted at 1 week and maintained throughout the duration of these studies. In addition, a greater proportion of patients receiving gabapentin compared with placebo achieved at least a 50% reduction in pain from baseline, and this was observed at all dosages evaluated.
Efficacy of gabapentin gastroretentive tablets (Gralise) for the management of PHN was established in an 11-week double-blind, placebo-controlled study in patients who were experiencing persistent pain for at least 6 months after healing of their herpes zoster rash. Gabapentin (at a dosage of 1.8 g once daily as gastroretentive tablets) was substantially more effective than placebo in improving average pain scores from baseline; the extent of improvement was similar to that achieved with the conventional (immediate-release) formulation of the drug. In this study, the proportion of patients who experienced at least a 50% reduction in pain with gabapentin (29.5%) was not substantially different from placebo (22.6%).
Efficacy of gabapentin enacarbil for the management of PHN was established in a 12-week randomized, double-blind, placebo-controlled multicenter study that evaluated 3 different dosages of the drug (600 mg, 1.2 g, or 1.8 g twice daily as extended-release tablets) in patients who were experiencing persistent pain for at least 3 months after healing of their herpes zoster rash. Compared with placebo, treatment with gabapentin enacarbil substantially reduced mean pain scores and increased the proportion of patients with at least a 50% reduction in pain intensity from baseline; improvements were noted as early as 1 week following initiation of therapy and were maintained throughout the duration of the study. Although benefits of gabapentin enacarbil were observed at all dosages evaluated, the 1.2-g daily dosage (administered as 600 mg twice daily) appeared to provide the greatest benefit-to-risk ratio.
Other Types of Neuropathic Pain
Gabapentin is used for the treatment of pain associated with diabetic neuropathy. In an 8-week controlled clinical study in patients with diabetic neuropathy, gabapentin was more effective than placebo in improving pain (based on an 11-point numeric rating scale), sleep, and mood during weeks 2-8 of the study. Most patients in this study (67%) received gabapentin in dosages of 3.6 g daily. In addition, 2 comparative studies reported that gabapentin was at least as effective as amitriptyline in relieving pain associated with diabetic neuropathy. Analysis of data from randomized studies in patients with pain associated with diabetic neuropathy indicates that 40% of patients who received gabapentin for neuropathic pain obtained good pain relief.
Gabapentin also has been used with some evidence of benefit for the relief of chronic neurogenic pain in a variety of conditions including trigeminal neuralgia, pain and control of paroxysmal symptoms of multiple sclerosis, complex regional pain syndromes (CRPS), HIV-related peripheral neuropathy, and neuropathic pain associated with cancer. Additional study and experience are needed to further elucidate the precise role of gabapentin in the management of these conditions. Limited evidence indicates that gabapentin is not effective for the management of acute pain.
Restless Legs Syndrome
Gabapentin enacarbil is used for the symptomatic treatment of moderate-to-severe primary restless legs syndrome in adults. The drug is not recommended in patients who are required to sleep during the daytime and remain awake at night.
Restless legs syndrome (also known as Ekbom syndrome) is a sensorimotor disorder characterized by a distressing urge to move the legs accompanied by sensations deep in the limbs that have been variously described as tingling, pulling, itching, aching, or jittering. These symptoms are present at rest, especially in the evening and at night, and are relieved by movement. Dopamine receptor agonists (e.g., pramipexole, ropinirole) traditionally have been considered the drugs of choice for patients with restless legs syndrome, particularly those with symptoms that occur nightly. Current evidence from randomized placebo-controlled studies also supports the use of gabapentin enacarbil for this condition. Although direct comparison studies have not been conducted to date, efficacy of gabapentin enacarbil appears to be comparable to that of the dopamine receptor agonists.
Efficacy of gabapentin enacarbil for the management of restless legs syndrome was established in 2 randomized, placebo-controlled studies of 12 weeks' duration in adults with moderate-to-severe restless legs syndrome (defined as a score of at least 15 on the International Restless Legs Syndrome [IRLS] scale, and a history of symptoms for at least 15 days in the month prior to screening). The primary measure of efficacy in these studies was a composite of the change from baseline in IRLS total score and the proportion of patients considered to be responders (i.e., those with a ''much improved'' or ''very much improved'' rating on the Clinical Global Impression-Global Improvement [CGI-I] scale) at 12 weeks. Gabapentin enacarbil (600 mg or 1.2 g once daily as extended-release tablets) substantially improved both measures of efficacy compared with placebo; improvements were noted as early as 1 week and were maintained throughout the duration of the studies. At 12 weeks, the mean change in IRLS score was a reduction of 13-13.8 with gabapentin enacarbil (versus a reduction of 8.8-9.8 with placebo), and 73-77% of patients receiving gabapentin enacarbil compared with 39-45% of those receiving placebo were described as responders. The 1.2-g daily dosage of gabapentin enacarbil appeared to provide no additional benefit over the 600-mg daily dosage, and was associated with an increased incidence of adverse effects.
Gabapentin also has been used in the treatment of restless legs syndrome; however, the drug currently is not labeled by the FDA for this use. Although evidence supporting the use of gabapentin for restless legs syndrome alone generally is insufficient, some experts state that the analgesic effects of the drug may provide some benefit in patients with both restless legs syndrome and pain.
Gabapentin has been used for the management of vasomotor symptoms in women with breast cancer and in postmenopausal women. Therapy with the drug has improved both the frequency and severity of vasomotor symptoms (e.g., hot flushes or flashes) in these women.
Most women receiving systemic antineoplastic therapy for breast cancer experience vasomotor symptoms, particularly those receiving tamoxifen therapy. In a randomized, double-blind, placebo-controlled study in 420 women with breast cancer (68-75% were receiving tamoxifen) who were experiencing 2 or more episodes of hot flushes daily, the percentage reductions in hot flush severity score at 4 and 8 weeks of treatment were 21 and 15%, respectively, for placebo; 33 and 31%, respectively, for gabapentin 300 mg daily (100 mg 3 times daily), and 49 and 46%, respectively, for gabapentin 900 mg daily (300 mg 3 times daily). Comparisons among treatment groups showed that only the 900-mg daily dosage was associated with a statistically significant reduction in hot flush frequency and severity. Whether higher dosages will provide further reductions in vasomotor symptoms remains to be determined. The role of gabapentin in managing vasomotor symptoms in women with breast cancer relative to other nonhormonal therapies (e.g., selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs]) remains to be determined. Well-designed, comparative studies are needed to establish optimum nonhormonal therapy, both in terms of efficacy and patient tolerance of adverse effects, in these women.
Because of the risks associated with hormone replacement therapy (HRT) for vasomotor symptoms in perimenopausal and postmenopausal women, alternative nonhormonal therapies are being investigated. In a randomized, double-blind, placebo-controlled study in 59 postmenopausal women who were experiencing 7 or more hot flushes daily, intent-to-treat analysis revealed that 12 weeks of gabapentin 900 mg daily (300 mg 3 times daily) was associated with a 45% reduction in hot flush frequency and a 54% reduction in composite hot flush score (frequency and severity). In a continuation open-label phase in which patients were permitted upward titration of dosage as needed to a maximum of 2.7 g daily (25% received 900 mg or less daily, 61% received 900 mg-1.8 g daily, 14% received 1.8-2.7 g daily), the associated reductions in hot flush frequency and composite score were 54 and 67%, respectively. The role of gabapentin therapy relative to other nonhormonal therapies (e.g., SSRIs, SNRIs) for postmenopausal vasomotor symptoms, both in terms of efficacy and safety, as well as the optimum dosage remain to be established.
Current evidence indicates that gabapentin is effective and well tolerated in the short-term treatment of vasomotor symptoms associated with breast cancer treatment and with menopause. The principal adverse effects associated with gabapentin therapy in women with vasomotor symptoms have been somnolence, fatigue, dizziness, and rash (with or without peripheral edema). Additional study and experience are needed to further elucidate the role of gabapentin relative to other nonhormonal therapies, and to establish longer-term (i.e., beyond 17 weeks) efficacy and safety.
The possible role of gabapentin in the management of vasomotor symptoms associated with antiandrogenic therapy in men with prostate cancer remains to be established. Current evidence of efficacy is limited; well-designed, controlled studies are under way in this population.