Pregabalin: An Antiepileptic Agent Useful for Neuropathic Pain

Matthew L. Blommel; Amy L. Blommel

Am J Health Syst Pharm. 2007;64(14):1475-1482.

Adverse Effects

Pregabalin has demonstrated similar adverse effects in clinical trials for its various indications. Pregabalin was generally well tolerated in clinical trials, with most treatment-related adverse effects being dose dependent. Adverse effects tended to be mild or moderate in intensity and generally self-limiting. The most commonly reported adverse effects were related to the central nervous system. The rate of adverse effects seen in clinical trials varied by pregabalin dosage and dosing regimen (fixed or flexible) used. Common adverse effects reported include dizziness (8-43%),^{[4,13,17,18,19,20,21,22,23,24,25]} somnolence (6-30%),^{[4,13,17,18,19,20,21,22,23,24,25]} weight gain (5-20%),^{[4,13,17,20,23,24,25]} ataxia, (highest rates reported in seizure trials) (2-21%),^{[4,13,19,21,23,24,25]} peripheral edema (3-19%),^{[13,17,18,19,20,21,22]} amblyopia (1-17%),^{[4,13,17,18,19,21,23,24,25]} abnormal thinking (1-10%),^[13,24] and diplopia (2-13%).^{[13,23,24,25]} Other adverse effects seen in clinical trials include asthenia, euphoria, dry mouth, headache, constipation, vertigo, tremor, confusion, and nausea.^{[4,13,17,18,19,20,21,22,23,24,25]}

The adverse effects that most frequently led to discontinuation in the clinical trials were dizziness and somnolence. Overall, discontinuation rates due to adverse events support a tolerability advantage of flexible-dosage adjustment, with the highest rate of drug discontinuation being observed in the pregabalin fixed-dosage groups (25-33%), followed by the flexible-dosage (12-17%) and placebo groups (7-8%).^[20,23]

Drug Interactions

The lack of hepatic metabolism and interaction with CYP isoenzymes explain the absence of drug interactions with pregabalin. Administration of pregabalin with lorazepam, oxycodone, ethanol, and oral contraceptives had no effect on the steady-state pharmacokinetics of pregabalin.^[13] However, when pregabalin was coadministered with oxycodone, lorazepam, or ethanol, additive effects on cognitive and gross motor functioning were observed. In addition, potential pharmacokinetic interactions were assessed with other antiepileptic medications. Pregabalin in combination with monotherapy regimens of valproate, phenytoin, lamotrigine, and carbamazepine had no effect on trough steady-state concentrations of any of these individual agents.^[26] This supports the use of multiple-therapy regimens in hard-to-treat refractory seizure patients. Concomitant administration of pregabalin and gabapentin was investigated after single- and multiple-dose administration, and neither medication's extent of absorption was affected.^[13] Due to the lack of binding to plasma proteins, it is unlikely that pregabalin will displace medications with higher protein-binding properties.

Potential for Abuse

Pregabalin has been designated as a Schedule V controlled substance because of its potential for abuse and dependence. The Drug Enforcement Administration has stated pregabalin is likely to be abused for its positive psychological effects because it produces some pharmacologic effects that are similar to those of diazepam and alprazolam.^[27] However, some of the positive psychological effects produced by pregabalin are limited and not sustained over time for continued drug use. The data obtained from clinical trials suggest that the drug could be abused periodically for reward but not for reinforcement.^[27] Euphoria has been reported by 4% of patients in controlled clinical studies enrolling more than 5500 patients, with a range of 1-12% in some patient populations.^[13] Symptoms suggestive of physical dependence (e.g., insomnia, nausea, headache, diarrhea) have been observed in some patients in clinical studies after the abrupt discontinuation of pregabalin. Patients should be evaluated for a history of drug abuse. Physicians should monitor patients for signs of pregabalin abuse, including dosage escalation, tolerance, and drug-seeking behavior.

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Table 1. Dosage Adjustments for Patients with Renal Dysfunction ^[13]
Creatinine Clearance (mL/min)	Total Pregabalin Dose (mg/day)^a			Administration Regimen
30-60	75	150	300	Twice or thrice daily
15-30	25-50^b	75^c	150	Once or twice daily
<15	25^d	25-50^b	75^c	Once daily

^aThe three most commonly used maintenance doses are depicted.
^bPatients taking 25-50 mg once daily should take one supplemental pregabalin dose of 50 or 75 mg after hemodialysis.
^cPatients taking 75 mg once daily should take one supplemental pregabalin dose of 100 or 150 mg after hemodialysis.
^dPatients taking 25 mg daily should take one supplemental pregabalin dose of 25 or 50 mg after hemodialysis.

Table 2. Selected Multicenter, Randomized, Double-Blind Trials of Pregabalin for All Approved Indications
Ref.	Duration of Study	Primary endpoint(s)^a	Treatment Regimen(s)	Results^b	Adverse Effects^c
Diabetic peripheral neuropathy
17 (n = 246)	6 wk	Mean pain score	150 mg/day 600 mg/day Placebo	4.9 (NS) 4.3 (p= 0.0002) 5.8	Dizziness, somnolence, peripheral edema, headache, asthenia, weight gain, amblyopia
18 (n= 146)	8 wk	Mean pain score	300 mg/day Placebo	4.0 (p= 0.0001) 5.3	Dizziness, somnolence, peripheral edema, amblyopia, euphoria
19 (n= 338)	5 wk	Mean pain score	75 mg/day 300 mg/day 600 mg/day Placebo	4.91 (NS) 3.8 (p= 0.0001) 3.6 (p= 0.0001) 5.06	Dizziness, somnolence, peripheral edema, amblyopia, ataxia, confusion, asthenia, euphoria
Neuropathic pain
20 (n= 338)	12 wk	No. pts with ≥ 30% decrease in mean pain score	300 mg/day, increased after 1 wk to 600 mg/day 150, 300, 450, and 600 mg/day^d Placebo	66.4 (p< 0.001) 59 (p= 0.003) 37.1	Dizziness, peripheral edema, weight gain, somnolence, nausea, asthenia
20 (n= 338)	12 wk	No. pts with ≥ 50% decrease in mean pain score	300 mg/day, increased after 1 wk to 600 mg/day 150, 300, 450, and 600 mg/day^d Placebo	52.3 (p< 0.001) 48.2 (p<0.001) 24.2
Postherpetic neuralgia
21 (n= 173)	8 wk	No. pts with ≥ 30% decrease in mean pain score	600 or 300 mg/day, based on CL_cr Placebo	63 (p= 0.001) 25	Dizziness, somnolence, peripheral edema, amblyopia, dry mouth, ataxia, confusion
21 (n= 173)	8 wk	No. pts with ≥ 50% decrease in mean pain score	600 or 300 mg/day, based on CL_cr Placebo	50 (p= 0.001) 20
22 (n= 238)	8 wk	No. pts with ≥ 50% decrease in mean pain score	150 mg/day 300 mg/day Placebo	26 (p= 0.006) 28 (p= 0.003) 10	Dizziness, somnolence, peripheral edema, headache, dry mouth, asthenia
Partial-onset seizures
4 (n = 453)	12 wk	% pts with significantly reduced seizure frequency	50 mg/day b.i.d. 150 mg/day b.i.d. 300 mg/day b.i.d. 600 mg/day b.i.d. Placebo	12% (NS) 34% (p ≤ 0.0001) 44% (p ≤ 0.0001) 54% (p ≤ 0.0001) 7%	Dizziness, somnolence, ataxia, asthenia, amblyopia, tremor, weight gain
23 (n= 312)	12 wk	% pts with significantly reduced seizure frequency	600 mg/day b.i.d.	49.3% (p= 0.0001)	Dizziness, ataxia, weight gain, asthenia, somnolence
23 (n= 312)	12 wk	% pts with significantly reduced seizure frequency	150 and 300 mg/day for 2 wk each, 450 and 600 mg/day for 4 wk each, all given b.i.d. Placebo	35.4% (p= 0.0091) 10.6%	All adverse events occurred more frequently in pts receiving fixed dosage
24 (n= 312)	12 wk	% pts with significantly reduced seizure frequency	600 mg/day b.i.d. 600 mg/day t.i.d. Placebo	44% (p ≤ 0.0001) 53% (p ≤ 0.0001) 1% increase	Dizziness, somnolence, ataxia, weight gain, asthenia, diplopia, abnormal thinking
25 (n= 287)	12 wk	% pts with significantly reduced seizure frequency	150 mg/day t.i.d. 600 mg/day t.i.d. Placebo	20.6% (p= 0.0007) 47.8% (p ≤ 0.0001) 1.8% increase	Somnolence, dizziness, ataxia, asthenia, diplopia, weight gain, tremor, amblyopia

^aMean pain score on a numeric scale of 0 (no pain) to 10 (worst possible pain).
^bCompared with placebo. NS = not significant, CL_cr = creatinine clearance.
^cShowed dose-related increases.
^dWith weekly dose escalations based on patient response and tolerability.

Table 2. Selected Multicenter, Randomized, Double-Blind Trials of Pregabalin for All Approved Indications
Ref.	Duration of Study	Primary endpoint(s)^a	Treatment Regimen(s)	Results^b	Adverse Effects^c
Diabetic peripheral neuropathy
17 (n = 246)	6 wk	Mean pain score	150 mg/day 600 mg/day Placebo	4.9 (NS) 4.3 (p= 0.0002) 5.8	Dizziness, somnolence, peripheral edema, headache, asthenia, weight gain, amblyopia
18 (n= 146)	8 wk	Mean pain score	300 mg/day Placebo	4.0 (p= 0.0001) 5.3	Dizziness, somnolence, peripheral edema, amblyopia, euphoria
19 (n= 338)	5 wk	Mean pain score	75 mg/day 300 mg/day 600 mg/day Placebo	4.91 (NS) 3.8 (p= 0.0001) 3.6 (p= 0.0001) 5.06	Dizziness, somnolence, peripheral edema, amblyopia, ataxia, confusion, asthenia, euphoria
Neuropathic pain
20 (n= 338)	12 wk	No. pts with ≥ 30% decrease in mean pain score	300 mg/day, increased after 1 wk to 600 mg/day 150, 300, 450, and 600 mg/day^d Placebo	66.4 (p< 0.001) 59 (p= 0.003) 37.1	Dizziness, peripheral edema, weight gain, somnolence, nausea, asthenia
20 (n= 338)	12 wk	No. pts with ≥ 50% decrease in mean pain score	300 mg/day, increased after 1 wk to 600 mg/day 150, 300, 450, and 600 mg/day^d Placebo	52.3 (p< 0.001) 48.2 (p<0.001) 24.2
Postherpetic neuralgia
21 (n= 173)	8 wk	No. pts with ≥ 30% decrease in mean pain score	600 or 300 mg/day, based on CL_cr Placebo	63 (p= 0.001) 25	Dizziness, somnolence, peripheral edema, amblyopia, dry mouth, ataxia, confusion
21 (n= 173)	8 wk	No. pts with ≥ 50% decrease in mean pain score	600 or 300 mg/day, based on CL_cr Placebo	50 (p= 0.001) 20
22 (n= 238)	8 wk	No. pts with ≥ 50% decrease in mean pain score	150 mg/day 300 mg/day Placebo	26 (p= 0.006) 28 (p= 0.003) 10	Dizziness, somnolence, peripheral edema, headache, dry mouth, asthenia
Partial-onset seizures
4 (n = 453)	12 wk	% pts with significantly reduced seizure frequency	50 mg/day b.i.d. 150 mg/day b.i.d. 300 mg/day b.i.d. 600 mg/day b.i.d. Placebo	12% (NS) 34% (p ≤ 0.0001) 44% (p ≤ 0.0001) 54% (p ≤ 0.0001) 7%	Dizziness, somnolence, ataxia, asthenia, amblyopia, tremor, weight gain
23 (n= 312)	12 wk	% pts with significantly reduced seizure frequency	600 mg/day b.i.d.	49.3% (p= 0.0001)	Dizziness, ataxia, weight gain, asthenia, somnolence
23 (n= 312)	12 wk	% pts with significantly reduced seizure frequency	150 and 300 mg/day for 2 wk each, 450 and 600 mg/day for 4 wk each, all given b.i.d. Placebo	35.4% (p= 0.0091) 10.6%	All adverse events occurred more frequently in pts receiving fixed dosage
24 (n= 312)	12 wk	% pts with significantly reduced seizure frequency	600 mg/day b.i.d. 600 mg/day t.i.d. Placebo	44% (p ≤ 0.0001) 53% (p ≤ 0.0001) 1% increase	Dizziness, somnolence, ataxia, weight gain, asthenia, diplopia, abnormal thinking
25 (n= 287)	12 wk	% pts with significantly reduced seizure frequency	150 mg/day t.i.d. 600 mg/day t.i.d. Placebo	20.6% (p= 0.0007) 47.8% (p ≤ 0.0001) 1.8% increase	Somnolence, dizziness, ataxia, asthenia, diplopia, weight gain, tremor, amblyopia

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Pregabalin: An Antiepileptic Agent Useful for Neuropathic Pain

Adverse Effects

Drug Interactions

Potential for Abuse

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