Lyrica Mechanism of Action

Pharmacotherapeutic group: Antiepileptics. ATC code: N03A (proposed).
Pharmacology: Pharmacodynamics: The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3-(aminomethyl)-5-methylhexanoic acid).
Mechanism of action: Pregabalin binds to an auxiliary subunit (α₂-δ protein) of voltage-gated calcium channels in the central nervous system.
Evidence from animal models with nerve damage has shown that pregabalin reduces calcium dependent release of pronociceptive neurotransmitters in the spinal cord possibly by disrupting calcium trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage suggest the antinociceptive activities of pregabalin may also be mediated through interactions with the descending noradrenergic and serotonergic pathways.
Clinical experience: Neuropathic pain: Efficacy has been shown in studies in diabetic neuropathy and post-herpetic neuralgia. Efficacy has not been studied in other models of neuropathic pain.
Pregabalin has been studied in 9 controlled clinical studies of up to 13 weeks with twice a day dosing and up to 8 weeks with three times a day dosing. Overall, the safety and efficacy profiles for twice a day and three times a day dosing regimens were similar.
In clinical trials up to 13 weeks, a reduction in pain was seen by Week 1 and was maintained throughout the treatment period.
In controlled clinical trials 35% of the pregabalin-treated patients and 18% of the patients on placebo had a 50% improvement in pain score. For patients not experiencing somnolence, such an improvement was observed in 33% of patients treated with pregabalin and 18% of patients on placebo. For patients who experienced somnolence the responder rates were 48% on pregabalin and 16% on placebo.
Fibromyalgia: Pregabalin as monotherapy has been studied in 5 placebo-controlled studies, three of 12 weeks fixed-dose duration, one of 7 weeks fixed-dose duration, and a 6-month study demonstrating long-term efficacy. Pregabalin treatment in all fixed-dose studies produced a significant reduction in pain associated with fibromyalgia at doses from 300 to 600 mg/day (BID).
In the three 12-week fixed-dose studies, 40% of pregabalin-treated patients experienced a 30% or more improvement in pain score versus 28% of the patients on placebo; 23% of treated patients experienced a 50% or more improvement in pain score versus 15% of the patients on placebo.
Pregabalin produced significantly superior global assessment scores via the Patient Global Impression of Change (PGIC) in the three 12-week fixed-dose studies as compared to placebo treatment (41% patients feeling very much or much improved on pregabalin versus 29% on placebo). As measured by Fibromyalgia Impact Questionnaire (FIQ), pregabalin produced a statistically significant improvement in function versus placebo treatment in 2 out of the 3 fixed-dose studies in which it was evaluated.
Pregabalin treatment produced significant improvements in patient-reported sleep outcomes in the 4 fixed-dose studies as measured by Medical Outcomes Study Sleep Scale (MOS-SS) Sleep disturbance subscale, MOS-SS overall sleep problem index, and the daily sleep quality diary.
In the 6-month study, improvement in pain, global assessment (PGIC), function (FIQ total score) and sleep (MOS-SS Sleep disturbance subscale) were maintained for pregabalin-treated patients for a significantly longer period compared to placebo.
Pregabalin 600 mg/day showed an additional improvement in patient-reported sleep outcomes as compared to 300 and 450 mg/day; mean effects on pain, global assessment, and FIQ were similar at 450 and 600 mg/day, although the 600 mg per day dose was less well tolerated.
A 15-week, placebo-controlled trial was conducted with 107 pediatric patients with fibromyalgia, ages 12 through 17 years, at pregabalin total daily doses of 75-450 mg per day. The primary efficacy endpoint of change from baseline to Week 15 in mean pain intensity (derived from an 11 point numeric rating scale) showed numerically greater improvement for the pregabalin-treated patients compared to placebo-treated patients, but did not reach statistical significance. The most frequently observed adverse reactions in the clinical trial included dizziness, nausea, headache, weight increased, and fatigue. The overall safety profile in adolescents was similar to that observed in adults with fibromyalgia.
Epilepsy: Pregabalin has been studied in 3 controlled clinical studies of 12-week duration with either twice a day dosing or three times a day dosing. Overall, the safety and efficacy profiles for twice a day and three times a day dosing regimens were similar.
A reduction in seizure frequency was observed by Week 1.
Generalised anxiety disorder: Pregabalin has been studied in 6 controlled studies of 4 to 6 weeks duration, an elderly study of 8 weeks duration and a long-term relapse prevention study with a double-blind relapse prevention phase of 6 months duration.
Relief of the symptoms of GAD as reflected by the Hamilton Anxiety Rating Scale (HAM-A) was observed by Week 1.
In controlled clinical trials (4-8 weeks duration) 52% of the pregabalin-treated patients and 38% of the patients on placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.
Pharmacokinetics: Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy receiving anti-epileptic drugs, and patients with chronic pain.
Absorption: Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1 hour following both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥90% and is independent of dose. Following repeated administration, steady-state is achieved within 24 to 48 hours. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in C_max by approximately 25-30% and a delay in t_max to approximately 2.5 hours. However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin absorption.
Distribution: In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the apparent volume of distribution of pregabalin following oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins.
Metabolism: Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, there was no indication of racemisation of pregabalin S-enantiomer to the R-enantiomer.
Elimination: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance (see Pharmacokinetics in special patient groups: Renal impairment as follows).
Dosage adjustment in patients with reduced renal function or undergoing hemodialysis is necessary (see Table 1 under Dosage & Administration).
Linearity/Non-linearity: Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.
Pharmacokinetics in special patient groups: Gender: Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of pregabalin.
Renal impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (following a 4-hour hemodialysis treatment plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dosage reduction in patients with renal impairment and dosage supplementation following hemodialysis is necessary (see Table 1 under Dosage & Administration).
Hepatic impairment: No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.
Elderly (over 65 years of age): Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age related compromised renal function (see Table 1 under Dosage & Administration).
Breast-feeding mothers: The pharmacokinetics of 150 mg pregabalin given every 12 hours (300 mg daily dose) was evaluated in 10 lactating women who were at least 12 weeks postpartum. Lactation had little to no influence on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk with average steady-state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose.
Toxicology: Preclinical safety data: In conventional safety pharmacology studies in animals, pregabalin was well-tolerated at clinically relevant doses. In repeated-dose toxicity studies in rats and monkeys CNS effects were observed, including hypoactivity, hyperactivity and ataxia. An increased incidence of retinal atrophy commonly observed in aged albino rats was seen after long-term exposure to pregabalin at exposures ≥5 times the mean human exposure at the maximum recommended clinical dose.
Teratogenicity: Pregabalin was not teratogenic in mice, rats or rabbits. Foetal toxicity in rats and rabbits occurred only at exposures sufficiently above human exposure. In pre-natal/post-natal toxicity studies, pregabalin induced offspring developmental toxicity in rats at exposures >2 times the maximum recommended human exposure.
Mutagenicity: Pregabalin is not genotoxic based on results of a battery of in vitro and in vivo tests.
Carcinogenicity: Two-year carcinogenicity studies with pregabalin were conducted in rats and mice. No tumours were observed in rats at exposures up to 24 times the mean human exposure at the maximum recommended clinical dose of 600 mg/day. In mice, no increased incidence of tumours was found at exposures similar to the mean human exposure, but an increased incidence of haemangiosarcoma was observed at higher exposures. The non-genotoxic mechanism of pregabalin-induced tumour formation in mice involves platelet changes and associated endothelial cell proliferation. These platelet changes were not present in rats or in humans based on short-term and limited long-term clinical data. There is no evidence to suggest an associated risk to humans.
In juvenile rats the types of toxicity do not differ qualitatively from those observed in adult rats. However, juvenile rats are more sensitive. At therapeutic exposures, there was evidence of CNS clinical signs of hyperactivity and bruxism and some changes in growth (transient body weight gain suppression). Effects on the estrus cycle were observed at 5-fold the human therapeutic exposure. Neurobehavioral/cognitive effects were observed in juvenile rats 1-2 weeks after exposure >2 times (acoustic startle response) or >5 times (learning/memory) the human therapeutic exposure. Reduced acoustic startle response was observed in juvenile rats 1-2 weeks after exposure at >2 times the human therapeutic exposure. Nine weeks after exposure, this effect was no longer observable.