Pregabalin

Pregabalin is an anticonvulsant used for the treatment of neuropathic pain conditions and fibromyalgia and for the treatment of partial seizures (epilepsy) in combination with other anticonvulsants.

Indications

Pregabalin is indicated for the treatment of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain associated with spinal cord injury, and as adjunctive therapy for the treatment of partial seizures in patients 1 month of age and older. Additionally, it can be used for generalized anxiety disorder and for epilepsy. Pregabalin is administered orally.

Pregabalin was discovered by U.S. chemist Richard Bruce Silverman. In 2004, pregabalin was approved in the U.S. and the EU.

Pharmacodynamics and mechanism of action

Pregabalin is structurally similar to endogenous gamma-aminobutyric acid (GABA)-an inhibitory neurotransmitter. Despite this similarity, it does not bind directly to GABA or benzodiazepine receptors, but to the α2δ-subunit of voltage-gated calcium channels. By presynaptically binding to this subunit of calcium channels in the central nervous system, pregabalin modulates the release of several excitatory neurotransmitters such as glutamate, substance-P, norepinephrine, and calcitonin gene-related peptides. The excessive release of these excitatory transmitters is thereby normalized.

Although pregabalin does not itself bind to the GABA receptor, a dose-dependent increase in the expression of L-glutamic acid decarboxylase (GAD) in the brain was noted. GAD is enzyme responsible for the synthesis of GABA. Pregabalin may therefore have indirect GABA-ergic effects by increasing GABA levels in the brain.

Pharmacokinetics

Following oral administration in the fasting state, absorption of pregabalin is rapid and extensive. The oral bioavailability of pregabalin is greater than 90%. Maximum plasma concentration is reached within 1.5 hours after single or multiple doses, and a steady plasma level is reached within 24-48 hours with repeated dosing. Food decreases the absorption rate of pregabalin and therefore decreases the maximum concentration by an estimated 25-30%. Pregabalin is not bound to plasma proteins. Less than 2% of pregabalin is metabolized and eliminated virtually unchanged. Excretion occurs almost exclusively in the urine. The elimination half-life of pregabalin is approximately 6.3 hours.

Drug Interactions

There are a number of drug interactions that have depressant effects on the CNS.

These agents include:

• Opioids
• Benzodiazepines
• Barbiturates
• Ethanol (alcohol)
• other drugs that depress the central nervous system.

ACE inhibitors may increase the harmful/toxic effects of pregabalin. Pregabalin may increase the fluid-retaining effect of certain antidiabetic drugs (thiazolidinediones).

Side effects

The most common adverse drug reactions of pregabalin include:

• Dizziness
• Drowsiness.
• Blurred vision
• Diplopia
• Increased appetite and subsequent weight gain
• Euphoria
• Confusion
• Vivid dreams
• Changes in libido (increase or decrease)
• Irritability
• Ataxia
• Changes in attention
• Intoxication
• Abnormal coordination
• Memory impairment
• Tremors
• Dysarthria
• Parasthesia
• Dizziness
• Dry mouth
• Constipation
• Vomiting
• Flatulence
• Erectile dysfunction
• Fatigue
• Peripheral edema
• Feeling the effects of drunkenness
• Abnormal walking
• Asthenia
• Nasopharyngitis
• Increased creatine kinase level

Although pregabalin is a sedative and an anticonvulsant, it can sometimes paradoxically cause seizures, especially in severe overdose.

Rare side effects include: Depression, lethargy, agitation, anorgasmia, hallucinations, myoclonus, hypoesthesia, hyperesthesia, tachycardia, excessive salivation, hypoglycemia, sweating, flushing, skin rash, muscle cramps, myalgia, Arthralgia, urinary incontinence, dysuria, thrombocytopenia, kidney stones, neutropenia, first-degree heart block, hypotension, hypertension, pancreatitis, dysphagia, oliguria, rhabdomyolysis, suicidal ideation or behavior.

Precautions

After abrupt or rapid discontinuation of pregabalin, there is a possibility of symptoms suggestive of physical dependence.

It is unclear whether it is safe for use in pregnancy. Therefore, use during this time is discouraged unless absolutely necessary.