Pregabalin has approval from the United States Food and Drug Administration (FDA) for the treatment of neuropathic pain associated with diabetic peripheral neuropathy, spinal cord injury, and postherpetic neuralgia. Pregabalin is FDA-approved for the treatment of fibromyalgia. Pregabalin is also FDA approved as adjunctive therapy for partial-onset seizures in adults with epilepsy. Off-label uses include generalized anxiety disorder, social anxiety disorder, bipolar disorder, insomnia, and chronic pain conditions not otherwise approved by the FDA. There is significant disagreement regarding the effectiveness of pregabalin for the psychiatric disorders listed above.[1][2][3][4]

Pregabalin is structurally similar to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It has been modified to be a lipophilic analog to enhance diffusion across the blood-brain barrier. However, pregabalin does not directly bind to GABA-A or GABA-B receptors. Additionally, it is not metabolized to a GABA receptor agonist. In animal models, pregabalin binds to presynaptic voltage-gated calcium channels at the alpha-2-delta subunit in central nervous system tissues. Binding of the alpha-2-delta subunit decreases the depolarization-induced influx of calcium into neurons and thus reduces the release of excitatory neurotransmitters. This action may account for the anticonvulsant and analgesic effects of pregabalin. Pregabalin has no known activity at sodium channels, dopamine receptors, serotonin receptors, opiate receptors, and does not modify the activity of cyclooxygenase.

Pregabalin is administered orally and is available in capsules or oral solution. Following oral administration, pregabalin reaches peak plasma concentrations within 1.5 hours and achieves steady state within 24 to 48 hours. The absorption of pregabalin is independent of the dose. Pregabalin readily crosses the blood-brain barrier. Humans cannot significantly metabolize pregabalin. Its elimination is primarily as an unchanged drug (less than 2% metabolized) by renal excretion. In patients with normal renal function, the mean elimination half-life is 6.3 hours. Researchers have studied pregabalin at dosages up to 600 mg/day. However, they did not find 600 mg/day to provide significant additional benefit and was less well tolerated due to side effects.

When discontinuing pregabalin, the recommendation is to taper the drug gradually over one week. In patients with seizure disorders, withdraw pregabalin gradually to minimize the risk of increased seizure.

• Management of Neuropathic Pain Associated with Diabetic Peripheral Neuropathy: The recommended maximum therapeutic dose is 300 mg/day. The suggested starting dose is 50 mg three times per day. The dose can increase up to 300 mg/day within one week of starting treatment.
• Management of Neuropathic Pain Associated with Spinal Cord Injury: The recommended therapeutic dose is 150 mg to 600 mg per day. The recommended starting dose is 75 mg twice per day. The dose may be increased to 150 mg twice per day within one week of initiating treatment. Patients with suboptimal pain relief following 2 to 3 weeks of treatment with 150 mg twice a day may be increased up to 300 mg twice per day. In spinal cord injury, improvement in pain can be seen as early as one week after initiating treatment. However, to evaluate the efficacy of pregabalin, it is recommended to try the medication for 4 to 6 weeks, if tolerated by the patient.
• Management of Postherpetic Neuralgia: The recommended therapeutic dose is 150 mg to 300 mg per day, divided into twice per day or three times per dosing. The recommended starting dose is 75 mg two times per day or 50 mg three times per day. The dose can increase up to 300 mg per day within one week of starting treatment. Patients with suboptimal pain relief after 2 to 4 weeks of treatment with 300 mg per day can be increased to 600 mg per day, divided into twice per day or three times per dosing.  
• Management of Fibromyalgia: The recommended therapeutic dose is 300 mg to 450 mg per day. The recommended starting dose is 150 mg/day divided into twice per day dosing. The dose can increase to 300 mg per day within one week of starting treatment. Patients with suboptimal pain relief on 300 mg per day may be further increased to 450 mg per day, divided into twice per day dosing.
• Adjunctive Therapy for Adults with Partial Onset Seizures: Pregabalin is FDA-approved only as an adjunctive for the treatment of partial-onset seizures. The effective dose is 150 mg to 600 mg per day, divided into twice per day or three times per dosing. The suggested starting dose is no greater than 150 mg per day. The total dose can increase to a maximum of 600 mg per day.  
• Dosing Modifications: Pregabalin is eliminated primarily by renal excretion. Adjust the dose in patients with impaired renal function. Refer to prescription drug manufacturer information for further recommendations on dose reductions for patients with reduced creatinine clearance and those undergoing hemodialysis according to the manufacturer. Although not explicitly studied, because pregabalin is not protein-bound, it is unlikely that patients with hepatic impairment require dosing modifications.

The majority of reported adverse effects caused by pregabalin were of mild to moderate intensity, dose-dependent, and occurred within the first two weeks of initiating treatment. The most common adverse events were those affecting the central nervous system (CNS). Somnolence and dizziness occurred most frequently and were the most common adverse reactions that lead to discontinuation of pregabalin. The most common adverse reactions reported across all patient populations in premarketing controlled trials which occurred in greater than or equal to 5% of patients taking pregabalin and twice the rate reported by patients receiving placebo were: somnolence, dizziness, blurred vision, difficulty with concentration/attention, dry mouth, edema, and weight gain.[5][6][7]

Weight gain associated with pregabalin is dose-dependent and occurred in up to 14% of patients receiving 600 mg per day.

Following rapid or abrupt discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, anxiety, nervousness, irritability, hyperhidrosis, and diarrhea.

Pregabalin is contraindicated in patients who have a known hypersensitivity to pregabalin. Hypersensitivity reactions have occurred in patients receiving pregabalin, including angioedema. There are no adequate studies with pregabalin in pregnant women. Pregabalin may cause fetal harm. Advise patients there is a potential risk to the fetus.

Pregabalin has been detected in the milk of lactating women; thus, breastfeeding is not a recommendation.