Review
The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities?

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Pregabalin is a specific ligand of the alpha2-delta (α2-δ) auxiliary subunit of voltage-gated calcium channels. A growing body of evidence from studies of anxiety and pain indicate that the observed responses with pregabalin may result from activity at the α2-δ auxiliary protein expressed presynaptically, in several different circuits of the central nervous system (CNS). The disorders that appear to be effectively treated with pregabalin are thematically linked by neuronal dysregulation or hyperexcitation within the CNS. This review proposes how binding to the α2-δ protein target in different regions of the CNS may contribute to the observed clinical activity of pregabalin, as well as to the adverse event profile of the compound. Whether this compound regulates synaptic function via α2-δ in additional conditions is yet to be discovered. The potential of pregabalin to regulate neuronal hyperactivity involving other CNS circuits will require further exploration.

Section snippets

Pregabalin

Pregabalin and gabapentin are specific ligands of the α2-δ auxiliary subunit of voltage-gated calcium channels that is expressed at presynaptic endings of neurons in the brain and spinal cord. Chemical structure/activity relationship studies with animal models [1] and experiments in transgenic mouse models show that binding of pregabalin at α2-δ subtype 1 (α2-δ-1) is necessary and likely to be sufficient to modulate nociception, anxiolytic-like action, and anticonvulsant action 1, 2, 3. They

Molecular and anatomical sites of action

Pregabalin and gabapentin are chemically and pharmacologically related amino acid drugs that are both used to prevent partial seizures of epilepsy and are also used to treat some kinds of neuropathic pain and other disorders. Despite chemical similarity to gamma-aminobutyric acid (GABA), pregabalin and gabapentin do not mimic GABA or act specifically at GABA receptors or GABA synapses [1]. Currently, no evidence indicates that relevant actions of pregabalin or gabapentin result from molecular

Action of pregabalin to treat epilepsy

Epileptic seizures entail abnormally synchronized neuronal activity that prevents normal function. Partial epilepsy is the most common type, affecting a small part of the brain, often in the neocortex or limbic system. Partial seizures may propagate and spread as they progress. By contrast, absence seizures are generalized from the start, affecting the neocortex and thalamus simultaneously. Seizures begin with hyperexcitability in both animal models [19] and human patients [20]. Pregabalin and

Action of pregabalin to reduce hyperalgesia, central sensitization, and chronic pain

Injuries to nerves often result in neuropathic pain, probably as a consequence of increased discharge to the CNS. Enhanced inputs can strengthen synapses and amplify nociceptive processing, a process termed ‘central sensitization’. This manifests in patients as pain along with sensory gain, which is reflected clinically in touch- or cold-induced ‘allodynia’ [28]. Sensitization of rat dorsal horn neurons is observed after peripheral nerve injury [29]. Injury-induced sensitization is mediated, in

Action of pregabalin to reduce anxiety

Anxiety disorders are characterized by the common symptoms of fear and worry, which are hypothetically linked to abnormal activation of the amygdala and its connections [45]. Preclinical data have linked the anxiolytic effects of pregabalin to required activity at the α2-δ-1 subunit using models of anxiety in mice [46]. In normal human volunteers, pregabalin reduces the activation of the amygdala and insula during anticipatory or emotional processing [47], analogous to the action of other

Action of pregabalin to reduce RLS

RLS is a relatively common sensory–motor neurological disorder characterized by the abnormal involuntary urge to move limbs, particularly the legs. Symptoms appear at rest and can worsen markedly at night. The paresthesias may be extremely discomforting and result in impaired sleep. Randomized and placebo-controlled clinical studies have documented the potential therapeutic benefit of pregabalin in patient populations expressing the primary symptoms of RLS [8]. However, it is not approved for

Action of pregabalin to enhance slow-wave sleep

Healthy sleep involves repeated sequences of different sleep stages [wakefulness, non-rapid eye movement (non-REM) sleep (stages 1, 2, 3, and 4), and REM sleep] [55]. Each is characterized by different firing patterns in the neocortex. Electroencephalography (EEG) studies distinguish between ‘fast’ delta waves that predominate during waking and REM sleep and ‘slow’ delta waves that predominate in slow-wave sleep (stages 3 and 4) [55]. Noradrenergic neurons (REM-off cells) originating from the

Pregabalin dose-related AEs

The two most common side effects of pregabalin, regardless of indication or use, are dizziness (or vertigo) and somnolence (or drowsiness) (http://labeling.pfizer.com/ShowLabeling.aspx?id=561). These AEs are usually dose related, are mild to moderate in intensity, occur soon after starting therapy, and often resolve over time. In some patients, dizziness and somnolence persist. In some trials, multiple doses of pregabalin were associated with occasional reports of peripheral edema, lazy eye,

Discussion

From increasing preclinical and clinical evidence, we suggest that the observed clinical effects of pregabalin may all result from drug action at the α2-δ protein in various circuits within the CNS. Several lines of evidence point to this conclusion, but as yet only one high-affinity molecular site of action has been identified. AEs associated with pregabalin also are likely to be caused by this molecular interaction.

The ability of pregabalin to subtly reduce the release of excitatory

Concluding remarks

In conclusion, we suggest that pregabalin does not target various diseases or anatomical areas per se. Instead, we suggest that several disorders (anxiety, epilepsy, pain, fibromyalgia, RLS, sleep interference) may share neuronal hyperactivity in various brain circuits that may be somewhat normalized by pregabalin acting at α2-δ protein targets.

Further study of drug actions at the α2-δ protein and the impact on the release of associated neurotransmitters and on network activity in several

Disclaimer statement

S.M.S. has served as a Consultant for Acadia, Astra Zeneca, Avanir, Biomarin, BristolMyers Squibb, Cenerex, Dey, Eli Lilly, Forest, GenoMind, GlaxoSmithKline, J&J, Jazz, Lundbeck, Merck, Neuronetics, Novartis, Noven, ONO, Orexigen, Otsuka, PamLabs, Pfizer, RCT Logic, Rexahn, Roche, Servier, Shire, Solvay, Sunovion, Trius, and Valeant. He has served on speakers’ bureaus for Arbor Scientia, Astra Zeneca, Eli Lilly, Forest, J&J, Merck, Neuroscience Education Institute, Pfizer, Servier, and

Acknowledgments

Medical writing support for the development of this manuscript was provided by Brenda Meyer of UBC Scientific Solutions and was funded by Pfizer Inc.

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