Definition

Gabapentin is an anti-seizure medication. It is sold in the United States under the trade name Neurontin.

Purpose

Gabapentin is used in combination with other antiseizure (anticonvulsant) drugs to manage partial seizures with or without generalization in individuals over the age of 12. Gabapentin can also be used to treat partial seizures in children between the ages of three and 12. Off-label uses (legal uses not specifically approved by the United States Food and Drug Administration [FDA]) include treatment of severe, chronic pain caused by nerve damage (such as occurs in shingles, diabetic neuropathy, multiple sclerosis, or post-herpetic neuralgia). Studies are also looking at using gabapentin to treat bipolar disorder (also known as manic-depressive disorder).

Description

Brain cells normally transmit nerve impulses from one cell to another by secreting chemicals known as neurotransmitters.

Gabapentin is chemically related to a naturally occurring neurotransmitter called GABA (gamma-amino butyric acid). The actual mechanism of action by which gabapentin acts in the brain to control seizures and treat pain is not known, although it appears to alter the action of nerve cells.

Gabapentin was approved for use in the United States in 1993. A liquid formulation was approved for use in 2000. Use in children ages three to 12 was also approved by the FDA in 2000.

Gabapentin is available in 100-, 300-, and 400-mg capsules; in 600- and 800-mg tablets; and in a liquid solution containing 250 mg per 5 ml.

Recommended dosage

People over the age of 12 should be started on 300 mg gabapentin taken three times a day. The dose can be increased up to a total of 1,800 mg per day. In some instances, doses of up to 3,600 mg per day have been tolerated.

Children should receive a dosage of 10–15 mg per kg of body weight per day, divided into three equal doses.

Chronic pain may be treated with 300–3,600 mg per day, divided into three equal doses.

When gabapentin is used for bipolar disorder, the starting dose is usually 300 mg taken at bedtime. Depending on the patient's response, the dose can be increased every four to seven days. Many people receive maximum therapeutic benefit at 600 mg per day, although some people have required up to 4,800 mg per day.

Precautions

Women who are breast-feeding and people who have decreased kidney functioning should discuss the risks and benefits of this drug with their physician. Women who are or wish to become pregnant will also require a careful assessment of the risks and benefits of gabapentin.

Patients should not suddenly discontinue gabapentin, as this can result in an increased risk of seizures. If the medication needs to be discontinued, the dosage should be reduced gradually over a week.

Until an individual understands the effects that gabapentin may have, he or she should avoid driving, operating dangerous machinery, or participating in hazardous activities. Alcohol should be avoided while taking gabapentin.

Side effects

Patients who experience the following side effects of gabapentin should check with their doctor immediately. These include more common side effects, such as unsteadiness, clumsiness, and uncontrollable back-and-forth eye movements or eye rolling. Less common side effects include depression, irritability, other mood changes or changes in thinking, and decreased memory. Rare side effects include pain in the lower back or side, difficulty urinating, fever and/or chills, cough, or hoarseness.

Children under age 12 who have the following more common side effects should also check with their doctor immediately: aggressive behavior, irritability, anxiety, difficulty concentrating and paying attention, crying, depression, mood swings, increased emotionality, hyperactivity, suspiciousness or distrust.

Multiple side effects often occur when a patient starts taking gabapentin. While these side effects usually go away on their own, if they last or are particularly troublesome, the patient should consult a doctor. More common side effects that occur when first starting to take gabapentin include blurred or double vision, muscle weakness or pain, swollen hand, feet, or legs, trembling or shaking, and increased fatigue or weakness. Less common side effects that occur when initiating gabapentin treatment include back pain, constipation, decreased sexual drive, diarrhea, dry mouth and eyes, frequent urination, headache, indigestion, low blood pressure, nausea, ringing in the ears, runny nose, slurred speech, difficulty thinking and sleeping, weight gain, twitching, nausea and/or vomiting, weakness.

Interactions

Antacids can decrease gabapentin levels in the blood. They should be taken at least two hours before taking gabapentin.

Resources

BOOKS

Ellsworth, Allan J. Mosby's Medical Drug Reference. St. Louis, MO: Mosby, Incorporated, 1999.

Mosby's Drug Consult. St. Louis, MO: Mosby, Incorporated, 2002.

Rosalyn Carson-DeWitt, M.D.

Gabapentin (brand name Neurontin) is a medication originally developed for the treatment of epilepsy. Presently, gabapentin is widely used to relieve pain, especially neuropathic pain. Gabapentin is well tolerated in most patients, has a relatively mild side-effect profile, and passes through the body unmetabolized.

Gabapentin was initially synthesized to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid (GABA), but is not believed to act on the same brain receptors. Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is thought to involve voltage-gated N-type calcium ion channels. It is thought to bind to the α2δ subunit of the voltage-dependent calcium channel in the central nervous system.

Clinical uses

Gabapentin has been found to be effective in prevention of frequent migraine headaches, neuropathic pain and nystagmus, and is prescribed off-label (that is, without formal regulatory agreement) for these conditions.

Gabapentin has also been used in the treatment of bipolar disorder. However, its off-label use for this purpose is increasingly controversial. Some claim gabapentin acts as a mood stabilizer and has the advantage of having fewer side-effects than more conventional bipolar drugs such as lithium and valproic acid. Some small, non-controlled studies in the 1990s, most sponsored by gabapentin's manufacturer, suggested that gabapentin treatment for bipolar disorder may be promising. However, more recently, several larger, controlled, and double-blind studies have found that gabapentin was no more effective (and in one study, slightly less effective) than placebo. Despite this scientific evidence that gabapentin in the treatment of bipolar disorder is not an optimal treatment, many psychiatrists continue to prescribe it for this purpose.

Gabapentin has limited usefulness in the treatment of anxiety disorders such as social anxiety disorder and obsessive-compulsive disorder, in treatment-resistant depression, and for insomnia. Gabapentin may be effective in reducing pain and spasticity in multiple sclerosis. Gabapentin has also had success in treating certain instances of Complex Regional Pain Syndrome.

Gabapentin has also been found to help patients with post-operative chronic pain (usually caused by nerves that have been severed accidentally in an operation and when grown back, have reconnected incorrectly). Symptoms of this include a tingling sensation near or around the area where the operation was performed, sharp shooting pains, severe aches after much movement, constant 'low ache' all day and sometimes a general 'weak' feeling. These symptoms can appear many months after an operation, and therefore the condition can go unnoticed.

Gabapentin is also prescribed to patients being treated with anti-androgenic compounds to reduce the incidence and intensity of the accompanying hot flushes.

Gabapentin (administered orally) is one of two medications (the other being flumazenil, which is administered intravenously) used in the expensive Prometa Treatment Protocol for methamphetamine, cocaine and alcohol addiction. Gabapentin is administered at a dosage of 1200 mg taken at bedtime for 40–60 days. Though the combination of flumazenil infusions and gabapentin tablets is a licensed treatment, there is no prohibition against a physician prescribing gabapentin outside the Prometa protocol. There have been reports by methamphetamine addicts that gabapentin alone in doses of 1200 mg at bedtime taken for 40–60 days has been effective in reducing the withdrawal symptoms and almost eliminating cravings or desire to use methamphetamine.

Gabapentin has occasionally been prescribed for treatment of idiopathic subjective tinnitus, but a double blind, randomized controlled trial found it ineffective.

Gabapentin is best known under the brand name Neurontin manufactured by Pfizer subsidiary Parke-Davis. A Pfizer subsidiary named Greenstone markets generic Gabapentin.

In December 2004, the FDA granted final approval to a generic equivalent to Neurontin made by Israeli firm Teva.

Neurontin is one of Pfizer’s best-selling drugs, and was one of the 50 most-prescribed drugs in the United States in 2003. However, in recent years, Pfizer has come under heavy criticism for its marketing of Neurontin, facing allegations that, behind the scenes, Parke-Davis marketed the drug for at least a dozen supposed uses for which the drug had not been FDA approved.

By some estimates, so-called off-label prescriptions account for roughly 90% of Neurontin sales. While off-label prescriptions are common for a number of drugs and are perfectly legal (if not always appropriate), marketing of off-label uses of a drug is strictly illegal. In 2004, Warner-Lambert agreed to plead guilty and pay $430 million in fines to settle civil and criminal charges regarding the illegal marketing of Neurontin for off-label purposes, and further legal action is pending. The courts of New York State, for example, have refused to certify a class of injured parties who took Neurontin for off-label use, finding that they had failed to state that they had had any injury.

The University of California, San Francisco (UCSF) has archived and studied the documents made public by this case, which opens a unique window into pharmaceutical marketing and their illegal promotion. However, Pfizer maintains that the illegal activity originated in 1996, well before it acquired Parke-Davis (through its acquisition of Warner-Lambert) in 2000. Several lawsuits are underway after people prescribed gabapentin for off-label treatment of bipolar disorder attempted or committed suicide.

Pfizer has developed a successor to gabapentin, called pregabalin (being marketed as Lyrica). Related in structure to gabapentin, pregabalin is effective for neuropathic pain associated with diabetes, fibromyalgia, and shingles, as well as for the treatment of epilepsy and seizures.

In 2004, a generic version of neurontin was released.

Side-effects

Gabapentin's most common side-effects in adult patients include dizziness, drowsiness, and peripheral edema (swelling of extremities); these mainly occur at higher doses, in the elderly. Also, children 3–12 years of age were observed to be susceptible to mild-to-moderate mood swings, hostility, concentration problems, and hyperactivity. Although rare, there are several cases of hepatotoxicity reported in the literature. Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.

An increase in formation of adenocarcinomas was observed in rats during preclinical trials, however the clinical significance of these results remains undetermined. Gabapentin is also known to induce pancreatic acinar cell carcinomas in rats through an unknown mechanism, perhaps by stimulation of DNA synthesis; these tumors did not affect the lifespan of the rats and did not metastasize.

Abuse potential

Though gabapentin is not a controlled substance, it does produce psychoactive effects that could lead to abuse of the drug. However, it is widely regarded as having little or no abuse potential. Pregabalin, a gabapentinoid with higher potency marketed for neuropathic pain, is a controlled substance, under Schedule V of the United States' Controlled Substances Act.

References

External links

• Gabapentin information from MedlinePlus
• News Article regarding Neurontin settlement and off-label marketing/use
• Website for the Greenstone subsidiary of Parke-Davis
• Website for the pending Class Action Lawsuit against Pfizer