Neurontin (gabapentin) is a household name to home care clinicians who care for patients with chronic neuropathy from shingles, phantom limb pain, diabetes, or cancer. Neurontin for the treatment of neuropathy, other than that caused by shingles (postherpetic), is considered an "off-label" use of the drug.

Soon, Pfizer will lose its Neurontin patent, and lower-cost generic gabapentin will become available. Pfizer will be replacing Neurontin with its new drug Lyrica (pregabalin) which, although more expensive, has an improved side effect profile.

Currently, the only Food and Drug Administration (FDA)-approved Neurontin (gabapentin) indications are for:

* seizures (French et al., 2004) and

* postherpetic neuropathy (Mellegers et al., 2001)

However, off-label uses of Neurontin account for more than 70% of Neurontin sales and include

* diabetic neuropathy (Mellegers et al., 2001),

* phantom limb pain (Bone et al., 2002),

* neuropathic pain from cancer (Bennett & Simpson, 2004),

* fibromyalgia (use not supported by clinical trials), and

* anxiety (use not supported by clinical trials).

Although off-label uses are allowed to be prescribed, the FDA forbids manufacturers from marketing drugs for off-label uses. In May 2004, the Warner-Lambert division of Pfizer pleaded guilty to illegally marketing Neurontin for off-label uses and defrauding Medicaid. The company paid a $430 million fine.

Off-label uses of Neurontin account for more than 70% of its sales. Soon, Pfizer will lose its Neurontin patent, and lower-cost generic gabapentin will become available.

Despite this problem, Neurontin sales increased by 32% in the first quarter of 2004, with annual sales of more than $2.7 billion. Neurontin was the tenth most widely prescribed brand-name drug by retail dollars in 2004 (Drug Topics, 2005).

Most state Medicaid programs continue to pay for the drug. The patent on Neurontin was supposed to expire in 2001, but Pfizer obtained a production patent to protect the drug until 2014, a move that generic manufacturers have been challenging in the courts. Meanwhile, rather than apply to the FDA for approval of new indications for Neurontin, Pfizer sought FDA approval of pregabalin for both the on- and off-label uses of Neurontin.

Pregabalin and gabapentin have structures similar to gamma-aminobutyric acid (GABA) and have similar mechanisms of action, modulating calcium influx in calcium channels. As a result, they both have analgesic, anxiolytic, and anticonvulsant activity. The primary differences between the two drugs are that:

* Pregabalin is more potent than gabapentin, so smaller doses are required;

* Because smaller doses are used, patients taking pregabalin experience fewer dose-related side effects, such as fatigue, dizziness, somnolence, dry mouth, peripheral edema, and blurred vision; and

* Pregabalin binds more tightly to pain receptors than does gabapentin, but it is unknown whether this results in better pain relief

Late in 2004, the FDA approved pregabalin for:

* postherpetic neuropathy (Dubinsky et al., 2004;Sabatowski et al., 2004) and

* diabetic neuropathy (Lesser et al., 2004;Rosenstock et al., 2004).

Lyrica is available in 150-, 300-, and 600-mg capsules. Dosing is titrated, starting with 150 mg/day, followed by 300 mg/day after 3 to 7 days, and is increased to 600 mg/day after an additional 7 days. Because Lyrica is more potent than Neurontin, side effects occur less frequently. However, approximately 6% of patients with diabetic neuropathy gained weight during clinical trials of Lyrica.

Patients with diabetes should have their glucose and Hb1AC levels closely monitored while taking the drug. Some patients may need adjustments in diabetes medication.

Clinical trials are in various stages for the following (currently off-label) uses of pregabalin:

* Anticonvulsant adjunct for patients with partial seizures (the FDA is currently reviewing the application for this indication) (Arroyo et al., 2004;Brodie, 2004);

* Fibromyalgia syndrome (Phase III trials are ongoing); and

* Generalized anxiety (the FDA refused approval for this indication in 2004) (Van Amerigen et al., 2004)

Additional study is needed to evaluate whether long-term use of Lyrica results in tolerance or dependence and whether discontinuance leads to withdrawal reactions. It remains to be seen whether Lyrica will replace most uses of Neurontin as generic gabapentin becomes available.

For patients with dose-related side effects, Lyrica may offer more patient acceptance. For patients currently experiencing good response to Neurontin, the generic formulation could significantly reduce costs.

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