Drug Review

Brand Name: Lyrica™

Generic Name: Pregabalin

Manufacturer: Pfizer, Inc.

Drug Class: Antiepileptic

Uses:¹

Labeled Uses

· Pregabalin is used for neuropathic pain that is associated with diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN).

Unlabeled Uses

§ Pregabalin has also been used to treat generalized anxiety disorder, social anxiety disorder, and as adjunct therapy in the treatment of partial seizures.

Mechanism of Action:^{2, 3}

Pregabalin is a lipophylic analogue of GABA that can diffuse over the blood brain barrier; however, it is not pharmacologically active at GABA receptors. It exerts it actions at the alpha-2-delta binding site that is located on voltage gated calcium channels in the central nervous system (CNS). Binding at calcium channels causes a decreased depolarization-induced calcium influx resulting in a reduction in the release of excitatory neurotransmitters.

Pharmacokinetics:

The pharmacokinetics of pregabalin has been investigated in many separate clinical pharmacology studies that have included a total of 472 patients. Data from all of the trials have indicated that pregabalin exhibits predictable and linear pharmacokinetics with very little inter-subject variability. No major differences have been seen with pharmacokinetic data when pregabalin is compared based on race or gender.²

Table 1: Pharmacokinetic Characteristics of Pregabalin Following Oral Administration in Various Degrees of Renal Function.⁴

	CrCl > 60 mL/min	CrCl 30-60 mL/min	CrCl 15-29 mL/min	CrCl < 15 mL/min	Hemodialysis
C_max(ug/mL)	1.86	1.53	1.90	1.69	1.24
t_max (h)	1.00	1.29	1.93	1.00	3.18
AUC_0-infinity (ug ^.h/mL)	15.6	28.2	52.3	101	94.6
t_1/2 (h)	9.11	16.7	25.0	48.7	54.7
Cl_oral (mL/min)	56.5	30.6	16.7	8.30	11.8
Cl_I (mL/min)	44.9	15.4	9.23	4.30	0.453
Vd_oral (l)	42.1	42.4	35.7	34.9	-
Percent excreted (Ae%)	75.4	48.5	56.3	52.0	2.23

- = not calculated

· Absorption: Pregabalin is rapidly absorbed after oral administration in a fasting state. Food or fatty meals do not seem to alter pregabalin’s absorption characteristics. Maximum plasma concentrations occur ~ 1 hour following single or multiple doses. Steady state is achieved in roughly 24-48 hours following repeated administration. Oral bioavailability is excellent at ≥ 90% which is independent of the dose administered.²

· Distribution: Pregabalin is a substrate of the L transporter which is responsible for the transportation of large amino acids across the brain and gut.²

· Metabolism: Less than 2% of the drug is metabolized and most of the drug is excreted unchanged. Pregabalin does not undergo any metabolism via the liver and does not induce or inhibit any liver enzymes; therefore, pregabalin should not create any pharmacokinetic drug-drug interactions.²

· Elimination: Pregabalin is eliminated exclusively via the kidneys. Subsequently, the mean elimination half-life and area under the curve increases with decreased renal function. Decreases in doses should be considered if a patients creatinine clearance is < 60 mL/min.²

Efficacy:

For use in DPN:⁵

Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004 Aug;110(3):628-38.

A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8 week clinical trial was carried out to test the effectiveness of pregabalin in decreasing the amount of pain associated with DPN. One hundred forty-six patients were enrolled in the study. Seventy patients received placebo, and 76 patients received pregabalin 300 mg/day. Patients could use acetaminophen, aspirin, and selective serotonin reuptake inhibitors throughout the study, but not medications that could treat DPN such as benzodiazepines, anticonvulants, and tricyclic antidepressants. The primary endpoint of the study was change in mean pain scores recorded via daily patient diaries. Mean pain scores, from a numerical eleven-point pain rating scale, in the pregabalin group showed a statistically significant decrease of -1.47 (CI=95%, -2.19 - -0.75)(P=0.0001) when compared to placebo. It was determined that pregabalin “was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.”⁵ This study was carried out by the help of Pfizer, Inc. and compared no other drug to pregabalin when treating DPN. Although results showed favorable clinical outcomes and statistical significance, larger, randomized trials are needed comparing pregabalin to existing pharmacological agents utilized to treat DPN.

For use in PHN:⁶

Dworkin RH, Corbin AE, Young JP Jr, Sharma U, LaMoreaux L, Bockbrader H, etal. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2003 Apr 22;60(8):1274-83.

A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8 week clinical trial was carried out to test the effectiveness of pregabalin in decreasing the amount of pain associated with PHN. One hundred seventy three patients participated in the study. Eighty-four patients received placebo, and 89 patients received pregabalin (600 mg/day, or 300 mg/day if renally impaired). Sixty-eight percent of the patients enrolled were already taking pain medications to treat PHN. The most common medications being taken were acetaminophen and aspirin. The primary endpoint for the study was to evaluate the mean score of the last seven daily pain ratings of patients who had PHN. Patients used an 11-point, numerical pain rating scale to assess the efficacy of the medication. It was found, when pregabalin was compared to placebo, there was a clinically significant (P=0.0001) decrease in mean pain scores of -1.69 (CI=95%, -2.33 - -1.05). It was determined that pregabalin was “safe [and] efficacious in relieving pain and sleep interference, and associated with greater global improvement than treatment with placebo.”⁶ This study was funded by Pfizer, Inc. and compared no other drug to pregabalin when treating PHN. Additionally, improvements in mood and quality of life were not seen because the scales used to measure these parameters may have been general and not disease specific. Although results showed favorable clinical outcomes and statistical significance, larger, randomized trials are needed comparing pregabalin to existing pharmacological agents utilized to treat PHN. Further studies should also be conducted to assess the efficacy of pregabalin in treating PHN in the absence of all other pain medications that could be used to treat PHN.

Adverse Effects:^5,6 (As identified through available clinical studies.)

The most common adverse effects noticed during clinical trials when pregabalin was used for the treatment of DPN and PHN in ≥ 10% of patients included:

Pregabalin has a low potential to potentiate any significant drug-drug interactions. The medication is not bound nor metabolized by plasma proteins. In addition, pregabalin does not affect the P450 enzyme system at therapeutic doses, and the medication does not affect other drugs that are metabolized by this route. Furthermore, the co-administration of pregabalin with other anti-epileptic drug (such as valproate, phenytoin, lamotrigine, carbamazepine, phenobarbital, and topiramate) has yielded no significant changes in those drugs pharmacokinetic profiles as well as that of pregabalin. Pregabalin also appears to not affect the pharmacokinetics of oral contraceptives, oral hypoglycemics, diuretics, and insulin. Pregabalin does appear to contribute additive effects of cognitive and motor function impairment when it is administered with oxycodone, and pregabalin may increase the sedative effects of ethanol and lorazepam.

· Renal Insufficiency – Patients who are renally compromised (creatinine clearance < 60 mL/min) require a 50% reduction in dose compared to those who have a creatinine clearance > 60 mL/min. Dosage should be reduced 50% for each 50% decrease in creatinine clearance below 60 mL/min.

· Co-administration of alcohol or CNS depressants along with pregabalin – Concurrent administration of alcohol or CNS depressants with pregabalin can compound sedative properties leading to further sedation.

· Stopping Therapy – Pregabalin dosages should be gradually decreased for at least one week before the medication is discontinued.

· Sedation – Because pregabalin can induce sedation, caution should be exerted when the medication is first employed. Patients should avoid driving or operating heavy machinery until the medications full effects are realized.

· Hepatic Effects – Elevated liver enzymes have been seen with high doses of pregabalin.

Information not available from the manufacturer pending release of package insert.

For DPN: Administer orally 300 to 600 mg daily in divided doses (usually three times daily)

For PHN: Administer orally up to 600 mg daily in divided doses three times daily.

In Renal Impairment: Patients who are renally compromised (creatinine clearance < 60 mL/min) require a 50% reduction in dose compared to those who have a creatinine clearance > 60 mL/min. Dosage should be reduced 50% for each 50% decrease in creatinine clearance below 60 mL/min.

Information not available from the manufacturer pending release of package insert.

Pregabalin appears to be a superior choice when compared to placebo when it is used for DPN or PHN; however, it has not yet defined itself as a definite therapeutic choice for treating these conditions since it has not been compared to drugs such as gabapentin, benzodiazepines, tricyclic antidepressants, opiods, or other agents currently used to treat DPN or PHN. Nonetheless, pregabalin has advantages since it possess’ excellent oral bioavailability and causes virtually no drug-drug interactions when administered with other medications. Further testing is needed to see if pregabalin truly offers more relief to the population it intends to treat when compared to other therapeutic options within that population.

1.) FDA approves Pfizer’s Lyrica for the treatment of the two most common forms of neuropathic (nerve) pain. Pfizer, Inc. 31 Dec 2004. http://www.pfizer.com/are/ investors_releases/2004pr/mn_2004_1231.cfm. [Accessed 22 Jan 2005].

2.) Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45 Suppl 6:13-8.

4.) Pfizer, Inc. Pharmacokinetics of pregabalin. Obtained via manufacturer on 20 Jan 2005.

5.) Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004 Aug;110(3):628-38.

6.) Dworkin RH, Corbin AE, Young JP Jr, Sharma U, LaMoreaux L, Bockbrader H, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2003 Apr 22;60(8):1274-83.

7.) Randinitis EJ, Posvar EL, Alvey CW, Sedman AJ, Cook JA, Bockbrader HN. Pharmacokinetics of pregabalin in subjects with various degrees of renal
function. J Clin Pharmacol. 2003 Mar;43(3):277-83.