Pregabalin: An Antiepileptic Agent Useful for Neuropathic Pain

Matthew L. Blommel; Amy L. Blommel

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

Pharmacology

Pregabalin has demonstrated anticonvulsant, analgesic, and anxiolytic properties in preclinical models.^[7] The drug's exact mechanism of action is unclear, but it may reduce excitatory neurotransmitter release by binding to the α₂-δ protein subunit of voltage-gated calcium channels (Figure 2).^[8] Pregabalin is a structural analogue of GABA, like gabapentin, but does not interact with GABA A or B receptors or influence GABA uptake.^[9,10] In animal studies, pregabalin has been shown to be effective against seizures in a wide range of experimental models, exhibiting potent activity against seizures induced by maximal electroshock, pentylenetetrazol, bicuculline, and picrotoxin.^[11] Recent structure-activity studies using a mutant mouse model of neuropathic pain have found that binding to α₂-δ protein is a prerequisite for the analgesic actions of pregabalin.^[12]

(Enlarge Image)

Figure 2.

Proposed mechanism of action of pregabalin. Pregabalin binds to the α2-δ subunit of voltage-gated calcium channels in the central nervous system. Illustration by Marie Dauenheimer, CMI.

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Cite this: Pregabalin: An Antiepileptic Agent Useful for Neuropathic Pain - Medscape - Jul 01, 2007.

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

Pharmacology

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