Description

Pregabalin, sold under brand names such as Lyrica®, is an anticonvulsant and analgesic medication. It is a structural analog of the neurotransmitter gamma-aminobutyric acid (GABA), but like gabapentin, it does not act directly on GABA receptors. Instead, it has a distinct mechanism of action and is primarily used to treat neuropathic pain, seizures, and anxiety. Pregabalin is a Schedule V controlled substance in the U.S. due to its potential for abuse and dependence.

Indications

Pregabalin is a versatile medication with several FDA-approved and off-label uses. The main indications include:

• Diabetic Peripheral Neuropathy (DPN): Management of nerve pain associated with diabetes.

• Postherpetic Neuralgia (PHN): Management of the chronic nerve pain that can persist after shingles.

• Fibromyalgia: Management of the widespread pain, stiffness, and fatigue characteristic of this condition.

• Adjunctive Therapy for Partial-Onset Seizures: Used as an add-on medication for the treatment of certain types of partial seizures in adults with epilepsy.

• Generalized Anxiety Disorder (GAD): In some countries, it is approved for the treatment of GAD.

Mechanism of Action

The mechanism by which pregabalin exerts its therapeutic effects is centered on its high-affinity binding to a specific subunit of voltage-gated calcium channels.

1. Binding to the Alpha-2-Delta Protein: Pregabalin works by binding with high affinity to the alpha-2-delta (α2​δ) subunit of voltage-gated calcium channels. These channels are found on the surface of neurons, particularly in the presynaptic terminal.
2. Inhibition of Neurotransmitter Release: By binding to theα2​δ subunit, pregabalin reduces the influx of calcium into the presynaptic neuron. This reduction in calcium flow decreases the release of several key excitatory neurotransmitters, including glutamate, norepinephrine, and substance P.
3. Analgesic and Anxiolytic Effect: This reduction in excitatory neurotransmitter release is believed to be the primary mechanism for its pain-relieving and anti-anxiety effects. By dampening the release of pain-signaling molecules, pregabalin modulates and suppresses the transmission of pain signals. In anxiety, it reduces the hyperexcitability of neurons in brain regions associated with fear and worry.
4. Anticonvulsant Effect: By reducing the release of excitatory neurotransmitters, pregabalin helps to stabilize neuronal membranes and prevent the abnormal, rapid electrical firing that causes seizures.

Similar to gabapentin, it is important to note that pregabalin does not directly bind to GABA receptors, nor does it affect GABA uptake or metabolism. Its primary action is through its modulation of calcium channel activity, which in turn reduces the release of excitatory neurotransmitters.