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.
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.
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.
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.
Antiepileptic drugs such as pregabalin may increase the risk of suicidal thoughts or behavior. Monitor patients under treatment with pregabalin for symptoms of new or worsening depression, suicidal ideation or behavior, and other changes in behavior or mood.
There is limited information regarding overdose with pregabalin. The highest known accidental overdose of pregabalin during clinical development was 8000 mg, and this was without significant clinical consequences. There is no specific antidote for overdose with pregabalin.
Pregabalin is a widely used medication for the management of seizures and pain disorders. While the drug is relatively safe, the primary care provider, pharmacist, nurse practitioner, and internist must monitor the patient regularly. The drug is known to cause depression and suicidal thoughts, so a mental assessment is advisable at each visit. Patients should be educated about the other side effects and told not to drive when taking the drug or combine it with other anti-seizure medications or alcohol. The patient should have a neurologist consult before making a change in the dose. [Level II]
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