Antiepileptic Drugs, 5th Edition

Gabapentin

33

Adverse Effects

Eugene R. Ramsay MD^*

Flavia M. Pryor RN, BSN^**

* Professor of Neurology and Psychiatry, Department of Neurology, University of Miami School of Medicine, Miami, Florida

** Nurse Researcher, Department of Neurology Service, Miami Veterans Affairs Medical Center, Miami, Florida

Gabapentin is a chemical derivative of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). It was originally developed to be a GABA analog that would penetrate the blood-brain barrier.

ANIMAL STUDIES

Preclinical toxicology studies showed gabapentin to be well tolerated in mice and rats in acute doses up to 8,000 mg/kg and with chronic dosing up to 3,000 mg/kg (1). Signs of toxicity (e.g., ataxia and sedation) were noted only at the higher doses. No toxicity was noted in monkeys in doses up to 1,250 mg/kg. Efficacy was evident in rats and mice in doses of 25 to 100 mg/kg. Thus, the studies suggested a very favorable toxicity-to-efficacy ratio.

Pancreatic Tumors

In chronic preclinical studies, a statistically significant increase in the incidence of pancreatic acinar cell tumors was found in male Wistar rats receiving 2,000 mg/kg of gabapentin, but not with lower doses (1,2,3). These tumors were not observed in female rats or mice of either sex. The tumors were low-grade malignancies, did not metastasize, were similar to those seen in concurrent control animals, and did not affect survival (1,2,3). Cellular hyperplasia, carcinoma in situ, and locally invasive tumors became evident after the same duration of drug exposure. This is not the pattern of occurrence seen with carcinogenic drugs, where hyperplasia is evident early, followed by carcinoma in situ, and then invasive tumors. The rat is not a generally accepted model for human pancreatic cancer and no pancreatic tumors have been reported in patients taking gabapentin (3). The relevance of these tumors to humans is questionable given the characteristics of the pancreatic tumors in male rats and the circumstances under which they develop. As a result of the animal studies, clinical trials were halted in the United States in August 1990 while this issue was reviewed further. A National Institutes of Health Advisory Committee reviewed the available information and recommended that the clinical trials be restarted. Trials were restarted in October 1991.

Teratogenesis

Clinical studies of gabapentin in pregnant women have not been conducted. In rats and mice given up to 2,000 mg/kg of gabapentin, delayed skeletal ossification was found; however, fetal weight and subsequent growth and development were unaffected. Doses 25 to 50 times those used in humans resulted in an increased occurrence of hydroureter and hydronephrosis. In these animals, the incidence of major malformations (e.g., clefting and congenital heart, gastrointestinal, or neural tube defects) was the same as in control animals. Maternal toxicity resulted when rabbits were given 1,500 mg/kg. However, no malformations were observed and skeletal ossification was not affected. Gabapentin was not mutagenic in vitro in standard assays using bacterial or mammalian cells (1).

CLINICAL ADVERSE EVENTS

Gabapentin's adverse event profile has been compiled from results from clinical trials and long-term follow-up studies (1,3, 4, 5, 6, 7, 8, 9, 10, 11, 12). Doses up to 1,800 mg/day were used in the controlled trials and up to 3,600 mg/day in open studies. Since gabapentin has been marketed, doses above 7,000 mg/day have been prescribed. However, the typical upper dosage limit has been 3,600 to 4,800 mg/day. In the controlled clinical trials, gabapentin was used mainly as add-on therapy, and hence a direct causal relationship between the adverse events reported and gabapentin therapy has not

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been established. The most common adverse events reported were those affecting the central nervous system (CNS) and included somnolence, dizziness, and ataxia (Table 33.1). The median time to onset of the first side effect of any type was 14 days in gabapentin-treated patients and 20 days for those receiving placebo (1,9). In those patients reporting CNS symptoms, the median time of onset was 3 days after initiating gabapentin treatment, compared with a 14-day median onset of CNS symptoms in patients receiving placebo (1,9). Although most patients experienced one or more adverse events, the events were of mild to moderate severity and usually transient, resolving within 2 weeks of onset during continued treatment (1,1,13, 14, 15). The median duration of symptoms in the gabapentin treatment group was 14 days, versus 13 days with placebo groups (1). Long-term gabapentin therapy did not result either in an increase in number or in new types of adverse events (1). Although overall, side effects were reported more often in the groups treated with gabapentin, a clear dose-effect relationship was not evident (Figure 33.1). The incidence of somnolence was higher in the placebo than in the 900 mg/day gabapentin group, whereas the incidence of dizziness was higher in the 900 mg/day than in the 1,200 or 1,800 mg/day gabapentin groups (1,1,9,16). Results from 59 healthy patients older than 65 years of age revealed no evidence for increased frequency of adverse events in this age group compared with younger patients (1).

Few patients withdrew from the controlled clinical trials with gabapentin as a result of side effects (9). Overall, approximately 7% of patients receiving gabapentin withdrew, compared with approximately 3% of those receiving placebo (1,14, 15, 16). The most common reason for the gabapentin-treated patients to withdraw was development of CNS symptoms (1,3,5,14,15) (Table 33.2). To evaluate the relative incidence of side effects, Marson et al. (17) collected outcomes on all the placebo-controlled trials involving the new antiepileptic drugs (AEDs). The side effect odds ratios (ratio of outcomes on therapy compared with placebo) ranged across all the drugs from 1.19 to 4.23. Gabapentin's odds ratio of 1.36 was second lowest of all the new AEDs, indicating a low incidence of side effects.

Gabapentin has been compared with carbamazepine (18) and lamotrigine (19) in controlled clinical trials involving patients with newly diagnosed epilepsy. The dropout rate was 0% to 14% for gabapentin (doses of 300, 900, and 1,800 mg/day), compared with 24% for carbamazepine. The dropout rate was similar comparing the outcome of gabapentin and lamotrigine (600 mg/day) (19).

Cognitive effects of AEDs always are of concern. In the controlled clinical trials, anecdotal reports of a feeling of well-being were encountered in patients taking gabapentin. In normal subjects, gabapentin manifests a psychotropic effect compared with placebo (20). This was characterized by improvement in concentration, numerical memory, complex reaction, and reaction time test. A blinded, controlled study was performed in healthy young adults using

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topiramate, gabapentin, and lamotrigine (21). Neurocognitive performance was established before and after 2 and 4 weeks of chronic dosing. Gabapentin-treated subjects had no alteration in performance at any testing period. Similar results were reported by Leach et al. (22) comparing 1,200, 1,800, and 2,400 mg/day of gabapentin with placebo added to the existing AED regimen in patients with uncontrolled seizures. Gabapentin has been compared with carbamazepine for their effects on cognitive testing in healthy senior adults (≥65 years of age) (23). Most (15 of 19) of the subjects who dropped out before study's end were taking carbamazepine. A mild effect was evident with both drugs, but performance with gabapentin was better than with carbamazepine in 9 of 11 cognitive measures. A similar comparison was made in healthy young subjects, and the results favored gabapentin over carbamazepine in 22 of the 31 cognitive measures studied (24).

Mood Changes

Gabapentin-induced mood and behavioral changes have been reported in both adults and children (25, 26, 27, 28, 29). In children, behavioral changes are characterized by acute onset of aggression, hyperactivity, and impulsive behavior (25, 26, 27). All children had chronic epilepsy and static encephalopathy, and many were multiply handicapped. In all cases, these behaviors were reversible either with dose reduction or discontinuation of gabapentin. These side effects, however, are not unique to gabapentin and have been reported with other AEDs, including carbamazepine, valproate, clonazepam, and phenobarbital (30, 31, 32, 33). Mood changes characterized by euphoria and behavioral disinhibition have been reported in adults being treated for epilepsy or paresthesias (28,29). In each case, the severity of the mood change has been mild and self-limiting or reversible.

Seizure Exacerbation

Gabapentin has been reported to aggravate seizures in some epileptic patients (34, 35, 36). This side effect is not unique to gabapentin. In fact, virtually all AEDs can produce similar effect(s). Specifically, gabapentin may increase typical and atypical absences and worsen or produce myoclonus (36,37). In reviewing 104 consecutive patients started on gabapentin, 13 cases of myoclonus were found (37). Multifocal myoclonus developed in 10 patients; focal myoclonus contralateral to the epileptic focus developed in 3 of these patients. Exacerbation of preexisting myoclonus was observed in two patients. In all cases, the myoclonus was of mild intensity and did not significantly interfere with daily living. The myoclonus resolved when gabapentin was discontinued. There have been no reports of gabapentin aggravating partial-onset seizures.

Weight Gain

Early clinical trials did not report weight gain associated gabapentin therapy. However, changes in body weight have subsequently been reported with long-term, high-dose gabapentin therapy (38). Of 44 patients [23 men and 21 women; 18 to 54 years of age (mean, 27.2 years)] treated with gabapentin for 12 months, 10 patients gained more than 10% of their baseline weight; 15 patients gained 5% to 10% of baseline; 16 patients had no change; and 3 patients lost 5% to 10% of baseline weight. All patients were receiving at least 1,800 mg/day; 28 of the 44 were receiving dosages 3,000 mg/day. Weight gain also was reported in a retrospective study of 121 epileptic patients (62 men and 59 women; mean age, 36 years) receiving gabapentin for at least 3 months (39). The average gabapentin dose was 2,291 mg/day. Seventy-eight (64%) of patients gained 10 lbs. The greatest weight gain (average, 20.1 lbs.) occurred in those patients discontinuing felbamate (n = 72) compared with those on concomitant valproate (n = 15; average weight gain, 14.7 lbs.). Patients receiving other AEDs (n = 34) gained an average of 7 lbs.

Pedal Edema

In the authors' clinical experience, gabapentin therapy has been associated with pedal edema. This often occurs with relatively low doses (900 to 1,800 mg/day) and improves or resolves with dosage reduction or discontinuing the drug. Pedal edema occurs with approximately the same frequency as with valproate therapy (40,41). Cotherapy with gabapentin and valproate does not seem to increase the frequency with which this side effect is encountered. The mechanism is unclear, and it occurs without evidence for congestive heart failure or low serum protein.

Sexual Dysfunction

Ejaculatory failure and anorgasmia have been reported in patients treated with gabapentin for psychiatric disorders or pain management (42, 43, 44). These adverse events are rare and have been reported in men receiving doses as low as 900 mg/day. In each case, symptoms resolved after gabapentin therapy was discontinued. In all cases, the

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patients were receiving other psychotropic medications. No clear pharmacokinetic or pharmacodynamic drug interaction associated with gabapentin resulting in ejaculatory difficulty has been identified.

SERIOUS ADVERSE EVENTS

Very few potentially serious adverse events requiring discontinuation of gabapentin therapy have been reported in over 2,000 patient exposures in randomized, controlled clinical trials. Those events reported include rash (0.54%), decreased white blood cell counts (WBC; 0.19%), increased blood urea nitrogen (0.09%), decreased platelets (0.09%), and angina or electrocardiographic changes (0.04%) (1). The low incidence of rash compares favorably with an average 5% to 10% incidence of rash requiring discontinuation of therapy with traditional AEDs (45). No patient has experienced a Stevens-Johnson reaction or other severe allergic reaction to gabapentin during clinical trials. Subsequently, only two verified skin reactions from gabapentin have been published (see later).

Systemic Toxicities

Only four patients discontinued therapy owing to low WBC counts, and they were all receiving concurrent AEDs. The overall incidence of WBC <3,000 cells/mm³ was 8% in patients treated with gabapentin, versus 7% in those patients receiving placebo (1). As might be expected from a drug that does not undergo hepatic metabolism, hepatotoxicity has not been observed (9). No changes in liver function have been observed that required termination of gabapentin therapy (1).

Overdose

Five cases of overdose with gabapentin have occurred. The largest dose was 48.9 g in a 16-year-old, otherwise healthy girl (46). She presented to an emergency department with complaints of dizziness and lethargy. Her highest plasma level was 62 µg/mL, which is approximately three times the level being achieved in clinical use. The patient's symptoms had cleared by 18 hours postingestion. A case of sustained massive overdose also was reported without serious side effects (47). Because of the dose-dependent absorption of gabapentin, overdosing appears unlikely to occur.

Allergic Reactions

Only two verified cases of serious skin reactions from gabapentin have been published (48,49). These patients had significant skin rashes to other AEDs and the reaction to gabapentin was milder than they had previously experienced (48). Considering that over 5 million patients have been treated with this drug and given the rarity of reported skin reactions, gabapentin appears to have the lowest incidence of allergic reactions of all the AEDs.

OTHER ADVERSE EVENTS

Other case reports of side effects have included choreoathetosis (50,51), dystonia (52), isolated ataxia (53), reversible acute renal allograft dysfunction (54), and worsening of myasthenia gravis (55). A causal relationship with gabapentin therapy is more difficult to determine when there is only a single or very few reported cases of each of these effects.

PHARMACODYNAMIC INTERACTIONS

Few pharmacodynamic interactions have been described with concomitant use of gabapentin. In the authors' clinical experience, visual disturbances consisting oscillopsia and diplopia may be encountered when gabapentin is administered to patients with high plasma levels of carbamazepine. Neurologic examination when the patient is symptomatic reveals the presence of a prominent nystagmus with a downbeat component at the extremes of horizontal gaze and an ataxic gait. This possibly represents a pharmacodynamic interaction between gabapentin and carbamazepine resulting in carbamazepine toxicity. This interaction is similar to that reported with concurrent use of carbamazepine and lamotrigine (56). Morris et al. (57) also noted an increase in fatigue when gabapentin was added to carbamazepine therapy.

TERATOGENESIS

As of March 1997, 38 pregnancies have been verified in women taking gabapentin during their first trimester. All the infants were normal in the eight monotherapy exposures. Pregnancies were electively terminated with no evidence of malformations in the fetuses. Two malformations have been reported—pyloric stenosis and a sixth digit. A third infant was delivered at 26 weeks of gestation and did not survive. Additional clinical experience is needed, but these data suggest a relative lack of teratogenic potential.

SUMMARY

The safety profile of an anticonvulsant is an important consideration. The older AEDs have a significant incidence of side effects that either limit the dosage that can be used or, in some cases, are life threatening. The differences in the usefulness of AEDs often are related to their relative toxicities

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(58, 59, 60). Gabapentin is very well tolerated, with the CNS symptoms of somnolence, dizziness, and ataxia the most frequently encountered. A very low incidence of potentially serious side effects has been encountered, and no fatalities have been reported that can be attributed to this drug. The adverse effects encountered are dose related and usually transient. The use of a higher dose does produce a somewhat greater incidence of side effects. These usually are transient and tolerated by the patient. The safety and tolerability of gabapentin, along with the absence of pharmacokinetic interactions, are strong advantages in using this drug.

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