Pharmacology

The chemical name of pregabalin is: CI-1008 or (S)-3-isobutyl GABA, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid. It is an alpha2delta-ligand that has been found effective in a variety of animal models of neuropathic and nociceptive pain.

Pharmacodynamics. The mode of action of pregabalin is like that of gabapentin. Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma aminobutyric acid (GABA), it does not bind directly to GABA and has no effects on GABA uptake or degradation. Pregabalin selectively binds to the alpha2delta-subunit protein of voltage-gated calcium channels in various regions of brain and in the superficial dorsal horn of the spinal cord (20). It acts as a presynaptic inhibitor of the release of excitatory neurotransmitters in stimulated neurons. It reduces influx of calcium into isolated synaptic endings. Findings of a brain imaging study suggest that the mode of action of pregabalin is partly by reduction of insular glutamatergic activity, which reduces the increased functional connectivity between brain regions in chronic pain states (14).

Pharmacokinetics. Pregabalin oral bioavailability is approximately 90% and it is well absorbed after oral administration. Peak plasma concentrations are reached within 1.5 hours. Following repeated administration, steady state is achieved within 24 to 48 hours. Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter, which is responsible for the transport of large amino acids across the blood brain barrier. Pregabalin has been shown to cross the blood brain barrier in experimental animals.

Pregabalin undergoes negligible metabolism in humans. Approximately 90% of the administered dose can be recovered in the urine as unchanged pregabalin. Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of approximately 6 hours in subjects with normal renal function. Overall, pregabalin demonstrates highly predictable and linear pharmacokinetics, which makes it easy to use in clinical practice.

Formulations. The approved formulation of pregabalin is immediate release (IR) given twice or 3 times a day. A pharmacokinetic study in healthy adult volunteers has shown that total daily exposure with controlled-release (CR) multiple-dose pregabalin is equivalent to the corresponding pregabalin immediate release dose (07). Results of the only controlled trial of pregabalin CR for epilepsy were disappointing, but because it has some pharmacokinetic advantages, it should be further evaluated in specific populations of patients, especially fragile subjects with several comorbidities (26).

Pharmacogenetics. Studies in experimental animals indicate that effectiveness of gabapentin and pregabalin may correlate with genotype variation. No clinical studies have explored this idea.

Next generation pregabalin. Mirogabalin besylate (Tarlige®) has shown greater sustained analgesia than pregabalin due to a high affinity to, and slow dissociation from, the α2δ-1 subunits in the dorsal root ganglion and less central nervous system-specific adverse drug reactions (19). The equianalgesic daily dose for 30 mg of mirogabalin is 600 mg of pregabalin. The initial adult dose starts at 5 mg, given orally twice a day, and is gradually increased by 5 mg at an interval of at least a week, to 15 mg. In conclusion, mirogabalin is anticipated to be a novel and safe gabapentinoid anticonvulsant with a greater therapeutic effect for neuropathic pain.

Clinical trials

Clinical trials have been conducted in painful diabetic neuropathy, postherpetic neuralgia as well as epilepsy. A selection of those conducted during the past decade is shown in Table 1.

Table 1. Clinical Trials of Pregabalin

A systematic review of randomized controlled clinical trials showed that pregabalin, when used as an add-on drug for treatment-resistant partial epilepsy, is more effective than placebo at achieving a 50% or greater seizure reduction, with increasing efficacy of doses from 150 to 600 mg/day and increasing efficacy at 600 mg doses, but issues with tolerability were noted at higher doses (28).

A systematic review of randomized controlled trials showed efficacy of pregabalin in postherpetic neuralgia, painful diabetic neuralgia, and mixed or unclassified posttraumatic neuropathic pain (08). There is no efficacy in HIV neuropathy, and evidence of efficacy in central neuropathic pain is inadequate.

A prospective observational study has shown that pregabalin has a better safety profile and tolerability compared to duloxetine, but the latter is more effective in treating diabetic peripheral neuropathic pain (16).

Indications

Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and as adjunctive therapy for adults with partial onset seizures.

Off-label uses

Contraindications

Pregabalin is contraindicated in patients with known hypersensitivity to pregabalin or any of its components.

Goals and duration of treatment

In open-label trials, the efficacy of pregabalin was maintained suggesting no obvious tolerance developing over 2 years and treatment was well tolerated. The goal in long-term management is control of pain with minimum possible dose. For partial seizures, seizure-free rates were 8.9% and 5.8% for the last 6 months and 1 year of pregabalin treatment respectively (31).

A real-world study shows that both pregabalin and gabapentin are not used effectively to treat postherpetic neuralgia, as suboptimal dosing and discontinuation may be associated with supplementary use of other analgesics, particularly opioids (17).

Pregabalin can be effective as the first-line treatment for neuropathic pain, but it is not effective for low back pain, sciatica, spinal stenosis, or episodic migraine, and its off-label use for these conditions is not recommended (24).

Dosing

In patients with neuropathic pain associated with diabetic peripheral neuropathy, the maximum recommended dose of pregabalin is 100 mg 3 times a day (300 mg/day).

In patients with neuropathic pain associated with diabetic peripheral neuropathy, the maximum recommended dose of pregabalin is 100 mg 3 times a day (300 mg/day). In those with insufficient pain relief following 2 to 4 weeks of treatment and who can tolerate pregabalin, may be treated with up to 300 mg 2 times a day, or 200 mg 3 times a day (600 mg/day).

Doses of 150 to 600 mg/day have been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. The total daily dose should be divided and given either 2 or 3 times daily.

Special considerations

Pediatric. The safety and efficacy of pregabalin in pediatric patients have not been established.

Geriatric. No overall differences in safety and efficacy were observed between elderly patients and younger patients in clinical trials. Because pregabalin is eliminated primarily by renal excretion, the dose should be adjusted for elderly patients with renal impairment.

Pregnancy. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity have been observed in pregnant experimental animals. Findings of a cohort study nested in the United States Medicaid Analytic eXtract did not confirm the suggested teratogenic effects of exposure to pregabalin during the first trimester, although the possibility of a small effect was not ruled out (29). There are no adequate and well-controlled studies in pregnant women. Pregabalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

A nursing mother with Raynaud phenomenon of the nipple, which did not respond to other treatments, was given pregabalin 75 mg twice daily with resolution of the pain, and her infant was exclusively breastfed for 3 months without adverse effects (12).

Anesthesia. No interactions with anesthetic agents or contraindication for patients on pregabalin therapy for anesthesia are known.

Interactions

Pregabalin has no activity at GABA, or benzodiazepine receptors, and there are no known pharmacokinetic drugdrug interactions with pregabalin. Pregabalin does not inhibit human cytochrome P450 enzyme system.

Adverse effects

The most common adverse events occurring during all controlled clinical trials for patients taking pregabalin versus those taking a placebo were dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration or attention). Idiosyncratic hepatotoxicity has been reported with pregabalin use (34). For a detailed listing of adverse events see the Physicians Desk Reference.

Myoclonus has been reported in patients with epilepsy treated by use of pregabalin. Parkinsonism has been reported in a patient with diabetic neuropathy following treatment with pregabalin (30). Encephalopathy with focal cerebral edema can occur following sudden withdrawal of pregabalin in patients with neuropathic pain without any seizures. Management should include treatment of focal cerebral edema.

Pregabalin has a potential for abuse, but physical and psychological dependence is less than that associated with benzodiazepines.