From the Guidelines
Pregabalin works primarily by binding to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system, reducing the influx of calcium into nerve terminals and subsequently decreasing the release of excitatory neurotransmitters like glutamate, norepinephrine, and substance P, as supported by the most recent evidence from 2023 1.
Mechanism of Action
The mechanism of action of pregabalin involves binding to the alpha-2-delta subunit of voltage-gated calcium channels, which reduces the influx of calcium into nerve terminals. This reduction in calcium influx decreases the release of excitatory neurotransmitters like glutamate, norepinephrine, and substance P. By inhibiting these neurotransmitters, pregabalin reduces neuronal excitability and pain signaling in the brain and spinal cord.
Comparison to Gabapentin
Unlike gabapentin, pregabalin has greater binding affinity for the alpha-2-delta subunit, making it more potent. Pregabalin does not directly interact with GABA receptors despite its structural similarity to GABA.
Pharmacokinetics
Pregabalin is rapidly absorbed after oral administration, with high bioavailability (approximately 90%) that is not affected by food. It undergoes minimal metabolism and is primarily excreted unchanged through the kidneys.
Therapeutic Effects
The drug's therapeutic effects include pain reduction, anxiolysis, and anticonvulsant activity, making it useful for neuropathic pain, fibromyalgia, generalized anxiety disorder, and as adjunctive therapy for partial seizures. Its mechanism explains both its therapeutic effects and common side effects like dizziness, somnolence, and peripheral edema, as noted in studies from 2011 1 and 2010 1.
Key Points
- Pregabalin binds to the alpha-2-delta subunit of voltage-gated calcium channels
- Reduces the influx of calcium into nerve terminals
- Decreases the release of excitatory neurotransmitters
- Reduces neuronal excitability and pain signaling
- Has greater binding affinity for the alpha-2-delta subunit than gabapentin
- Rapidly absorbed with high bioavailability
- Undergoes minimal metabolism and is primarily excreted unchanged through the kidneys
- Useful for neuropathic pain, fibromyalgia, generalized anxiety disorder, and as adjunctive therapy for partial seizures.
From the FDA Drug Label
Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord
The mechanism of action of pregabalin involves binding to the alpha2-delta site of voltage-gated calcium channels in the central nervous system, which may be responsible for its anti-nociceptive and antiseizure effects. Pregabalin may also reduce calcium-dependent release of pro-nociceptive neurotransmitters and interact with descending noradrenergic and serotonergic pathways to modulate pain transmission 2.
- Key points:
- Binds to alpha2-delta site of voltage-gated calcium channels
- May reduce calcium-dependent release of pro-nociceptive neurotransmitters
- Interacts with descending noradrenergic and serotonergic pathways
- Does not bind directly to GABAA, GABAB, or benzodiazepine receptors
- Does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation
From the Research
Mechanism of Action of Pregabalin
- Pregabalin is a potent ligand for the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system, exhibiting anticonvulsant, analgesic, and anxiolytic activity 3, 4, 5, 6, 7.
- The binding of pregabalin to the alpha-2-delta subunit reduces depolarization-induced calcium influx, resulting in a modulation of excitatory neurotransmitter release, including glutamate, norepinephrine, serotonin, dopamine, and substance P 3, 4, 6, 7.
- Pregabalin does not demonstrate effects on GABAergic mechanisms 3.
- The reduction in neurotransmitter release is thought to contribute to the observed clinical activity of pregabalin, including its antiepileptic, analgesic, and anxiolytic effects 5, 6.
Pharmacokinetics of Pregabalin
- Pregabalin demonstrates highly predictable and linear pharmacokinetics, with extensive, rapid, and proportional absorption to dose 3.
- The time to maximal plasma concentration is approximately 1 hour, and steady state is achieved within 24-48 hours 3.
- Pregabalin has high bioavailability, a mean elimination half-life of 6.3 hours, and dose-proportional maximal plasma concentrations and total exposures 3.
- Pregabalin is excreted virtually unchanged by the kidneys, with less than 2% metabolism, and is not subject to hepatic metabolism or induction/inhibition of liver enzymes 3.