Focus on Gabapentin

Ivan Goldberg, M.D. and

Ben Green MB, ChB, MRCPsych

1346 Lexington Avenue
New York, NY 10128

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Fax: + 212 737 0473

ben@priory.com

Halton Hospital,
Runcorn, Cheshire, UK.

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Introduction

Dosages

Efficacy

Tolerability

Side Effects

Interactions

Cautions

Gabapentin for Mood Disorders

References

Introduction

Gabapentin is an anticonvulsant that is chemically unrelated to any other anticonvulsant or mood regulating medication. Gabapentin received final approval for marketing in the USA on 30 December 1993 and is labeled for use as an anticonvulsant. There is no generic gabapentin as the manufacturer has patent protection. Gabapentin is currently available in about 45 countries worldwide.

Gabapentin is an antiepileptic drug indicated as add-on therapy for partial seizures with or without secondary generalisation in patients who have not achieved satisfactory control with, or who are intolerant to, standard anticonvulsants.

There are two major reasons why physicians prescribe and patients take gabapentin rather than conventional, better established drugs. Firstly, not everyone benefits from treatment with the older, better known drugs, and secondly some patients find the side effects of the established drugs to be unacceptable.

US Prices

As of 12 April 1997, the per tablet cost of gabapentin, when ordered in lots of 100 tablets from a national US mail-order pharmacy was:

100 mg $0.40
300 mg $.092

Package quantities und basic NHS price:

22.86 for pack of 1 00 x 100mg capsules
53.00 for pack of 100 x 300mg capsules
61.33 for pack of 1 00 x 400mg capsules

Dosages

For epileptic control: Titration of dose to 900 - 1200mg daily in divided doses; 300mg once a day on day 1; 300mg twice a day on day 2; and 300mg three times a day on day 3. On day ,4 the dose may be increased to 1 200mg given in three equally divided doses. If necessary, further titration can occur using increments of 300mg per day given in three equally divided doses up to a maximum of 2400mg/day. It is not necessary to rnonitor gabapentin plasma concentrations to optimize gabapentin therapy. If there is a need for dose reduction, discontinuation or substitution of an alternative anticonvulsant, this should be done gradually over a minimum of one week.

Efficacy

There are at least four parallel studies in which supplementary gabapentin was compared with placebo. These studies tested doses of 600, 900, 1200, and 1800 mg gabapentin a day and included a total of 750 patients. The overall odds ratio (95% confidence interval) for 50% responders across all studies was 2.29 (1.53 to 3.43). There were indications of increasing efficacy with increasing doses, with no suggestion of plateauing effects at the doses used in these studies.

Tolerability

Tolerability is a major issue in the panoply of advantages that the newer antiepileptic drugs have over old favourites such as phenytoin, carbamazepine and valproate.Evidence suggests that gabapentin and lamotrigine mat be better tolerated than tiagapine, topiramate, vigabatrin and zonisamide.

Side Effects

Here is a listing of gabapentin's side effects that affected 5% or more of the 543 people taking the drug during clinical trials and the frequency of those side effects in the 378 people treated with placebo in those trials:

 

Adverse Reactions (%)
Adverse Reaction Gabapentin Placebo
Sleepiness 19 9
Dizziness 17 7
Unsteadiness 13 6
Nystagmus 8 4
Tremor 7 3
Double Vision 6 2

 

Side-effects are most noticeable the few days after an increase in dose and then usually fade.

The side effects most often associated with discontinuation of gabapentin are sleepiness (1.2%), unsteadiness (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%).

Other side effects include headache, tremor, diplopia, nausea and/or vomiting, rhinitis, and amblyopia. Gabapentin may affect the patient's ability to drive or operate machinery. Less common side effects are pharyngitis, dysarthria, weight increase, dyspepsia, amnesia, nervousness and myalgia. As with other AEDs there have been rare reports of pancreatitis, elevated liver function tests, erythema multiforme, Stevens Johnson Syndrome and sudden unexplained deaths where a causal relationship to treatment has not been established,

Among the other rarely reported side effects of gabapentin are depersonalization, mania, agitation, paranoia, and increased or decreased libido.

Interactions

Only a few interactions between gabapentin and other drugs have been identified. Aluminium and magnesium containing antacids given at the same time may decrease the bioavailability of gabapentin and lower the blood level by 20% Gabapentin may increase the concentration of some oral contraceptives by 13%. This probably is not clinically significant.

There is no anticipated pharmacokinetic interaction between gabapentin and phenytoin, sodium valproate, carbamazepine or phenobcirbitone.

Alcohol may increase the severity of the side-effects of gabapentin.

Cautions

Gabapentin is has been placed in the FDA pregnancy Category C:

"Animal studies have shown an adverse effect on the fetus but there are no adequate studies in humans; The benefits from the use of the drug in pregnant women may be acceptable despite its potential risks . . . ."

UK cautions/warnings include pregnancy, lactation and abrupt withdrawal of the drug.

Hypersensitivity is a contraindication.

Gabapentin has been used with children and young adolescents in other countries other than the USA. In the USA gabapentin is only approved for use in those over the age of 12.

Older people seem to handle gabapentin similarly to younger ones.

Gabapentin for Mood Disorders

In various countries Gabapentin is only approved for the treatment of people with seizures. There are no systematic studies that establish the safety or efficacy of gabapentin as a treatment for people with mood disorders. While such studies are in the planning stages, what is currently known about the use of gabapentin for the control of mood disorders comes from uncontrolled case reports.

Gabapentin differs from other mood stabilizing drugs in two major ways:

1. Gabapentin's frequent effectiveness for patients who have failed to respond to antidepressants or mood stabilizers;

2. Gabapentin's relatively benign side-effect profile.

Gabapentin has had been successful in controlling rapid cycling and mixed bipolar states in people who have not received adequate relief from carbamazepine and/or valproate. It also appears that gabapentin has significantly more antianxiety and antiagitation potency than either carbamazepine or valproate.

It is too early to be very specific about which mood disorders are most likely to respond to treatment with gabapentin. There are very few published reports on gabapentin's use in psychiatry. Patients with hard-to-treat bipolar syndromes seem to have been treated more often than patients with "treatment-resistant" unipolar disorders, although some people with such hard to treat unipolar depressions have been treated with good results. It is possible that gabapentin will prove to be a useful treatment for people with other disorders.

The initial use of gabapentin was to treat people with depressed, manic and mixed states that did not respond to existing medications. Some patients are now being maintained on gabapentin on a long term basis in an attempt to prevent future episodes. The effectiveness of gabapentin as a long-term prophylactic agent is currently being established.

 

Gabapentin seems to be effective in about two-thirds of people with bipolar mood disorders that have not responded to lithium or other mood-stabilizers. Some people who have not been able to tolerate any antidepressant because of switches to mania or increased speed or intensity of cycling, or because of the development of mixed states, have been able to tolerate therapeutic doses of anti- depressants when taking gabapentin.

For most people, gabapentin has minimal side effects.

As gabapentin has only been available for a relatively short time, it was first marketed in 1990, there is no information about long term side-effects. As its use with people with mood disorders started even more recently, it is not known if people who initially do well on gabapentin continue to do so after many years of treatment. The short half-life of gabapentin makes it necessary for it to be taken in divided doses over the course of the day.

Before gabapentin is prescribed the patient should have a thorough medical evaluation, including blood and urine tests, to rule out any medical condition, such as thyroid disorders, that may cause or exacerbate a mood disorder.

Gabapentin is usually started at a dose of 300 mg once a day, usually at bed time. Every three to five days the dose is increased. In some people a response is seen with 600 mg/day . . . other people must increase the dose as high as 3,600 mg/day. When used as an antidepressant or as a mood-stabilizing agent the final dose of gabapentin is most often between 900 and 2,000. Some people require doses as high as 3.200 mg/day to achieve a good results.

No interactions between gabapentin and lithium, carbamazepine or valproate have been reported.

While some people notice the antimanic and antidepressant effects within a week or two of starting treatment, others have to take a therapeutic amount of gabapentin for up to a month before being aware of a significant amount of improvement.

There are no specific symptoms that have been described following the abrupt discontinuation of gabapentin, other than the seizures that sometimes follow the rapid discontinuation of any anticonvulsant. Only when necessary because of a serious side effect, should gabapentin be suddenly discontinued.

Data on overdoses are scarce. Overdoses of up to 49,000 mg of gabapentin have been survived without sequelae.

Gabapentin has been taken along with MAO inhibitors and the combination has been used without any special problems.

 

References

 

Anhut H, Ashman P, Feuerstein Tj, Sauermann W, Samden M, Schmidt B. (1994) Gabapentin (Neurontin) as add-on therapy in patients with partial seizures: a double-blind, placebo-controlled study. 7he International Gabapentin Study Group. Epilepsia ;35:795-80 1.

Regan WM & Gordon SM (1997) Gabapentin for behavioral agitation in Alzheimer's Disease. J Clin Psychopharmacol , 17, 59-60.

Ryback R & Ryback L (1995) Gabapentin for behavioral dyscontrol. Amer J Psychiat , 152, 1399.

Schaffer C & Schaffer L (1997) Gabapentin in the treatment of bipolar disorder. Amer J. Psychiat , 154, 291-292.

Short C & Cooke L (1995) Hypomania induced by gabapentin. Br J Psychiat , 166, 679-680.

Sivenius J, Kalviainen R, Ylinen A, Piekkinen P.(1991) Double blind study of gabapentin in the treatment of partial seizures. Epilepsia 32:539-42.

Stanton SP Keck PE McElroy SL (1997) Treatment of acute mania with gabapentin. Amer J Psychiat , 154, 287.

UK Gabapentin Study Group.(1990) Gabapentin in partial epilepsy. Lancet ;335:1114-7.

US Gabapentin Study Group No 5. (1993) Gabapentin as add-on therapy in refractory partial epilepsy: a double-blind, placebo-controlled, parallelgroup study. Neurology 43:2292-8.

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Form and CGI Copyright 1997 Priory Lodge Education Ltd.

Priory Lodge Education Ltd., 1997. Focus on Gabapentin
First published May 1997. Version 1.0 Last amended: 18/02/00