Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00029
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: April 2005
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Bibliographic ID: UF00087345
Volume ID: VID00029
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Tanja Lepir, Pharm.D. Candidate

Nervous system dysfunction leading to neu-
ropathic pain can occur from many causes: infec-
tion, trauma, metabolic abnormalities, chemother-
apy, surgery, irradiation, neurotoxins, inherited
neurodegeneration, nerve compression, inflamma-
tion, tumor infiltration, and spinal cord injuries.
Diabetic peripheral neuropathy (DPN) and posther-
petic neuralgia (PHN) are two manifestations of
nervous system dysfunction that result in neuro-
pathic pain. Early treatment of underlying causes is
the key to successful therapy.1
Neuropathic pain is usually described as tin-
gling, burning, lancinating, or shooting; however,
many patients with neuropathic pain also complain
of sharp, aching, or throbbing pain.1 Current op-
tions for treating neuropathic pain include gabapen-
tin, tricyclic antidepressants (TCAs), opioid analge-
sics (i.e. codeine, oxycodone, morphine sulfate),
tramadol, and topical therapies (i.e., capsaicin, li-
docaine). '2 More recently, duloxetine (Cymbalta)
was the first FDA-approved treatment for pain
caused by diabetic peripheral neuropathy.12
About three million people, or 20-24% of
the US diabetic population, are affected by DPN.
Symptoms in the lower limbs and feet can persist
for many years and reduce health-related quality of

life. Important risk factors for the development of
this condition are duration of diabetes mellitus and
glycemic control.
'Shingles' or herpes zoster infection is as-
sociated with a vesicular dermatomal rash that is
typically accompanied by pain. About one million
people in the US are affected by this condition,
which is commonly associated with allodynia.
About 50% of individuals over the age of 70 years
have pain that persists for 12 months even after
Gabapentin was the first oral medication ap-
proved for the treatment of PHN and is widely used
off label for DPN. It is believed to act as an analge-
sic primarily via calcium channel blockade. In ad-
dition, gabapentin enhances gamma-aminobutyric
acid (GABA) turnover in the CNS, attenuating glu-
tamate-mediated excitotoxic neurotransmission.
Due to fewer side effects (compared to TCAs) and
few drug interactions, gabapentin is extensively
used to treat neuropathic pain. However, gabapen-
tin shows nonlinear bioavailability and requires ti-
tration to the higher doses, which makes it cumber-
some to use in clinical practice. A few disadvan-
tages of other available agents used for treatment of
neuropathic pain include: a slow onset of analgesic
action (e.g., TCAs, capsaicin), adverse effects (e.g.,



1 1 F4 I

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Table 1. Clinical Trial Experience of Pregabalin in Diabetic Peripheral Neuropathy (DPN).

Study Demographics
Rosenstock et Symmetrical painful
al.4 symptoms in distal ex-
tremities for 1-5 years.
Mean duration of diabetes
was 9.3 years
Sharma et Painful DPN of 1-5 years
al.5'6 duration

lacobellis et

DPN of 1-5 years

8-week random-
ized, DB, PC, FD

randomized, DB,
PC, parallel
group study
randomized, DB,
PC study

Number of


Response (%)


Pregabalin 300 mg

Pregabalin 150 mg/d
Pregabalin 600 mg/d

Pregabalin 75mg/d
Pregabalin 300 mg/d
Pregabalin 600 mg/d

* all doses administered in three divided doses. DB-double-blind; PC-placebo-controlled; FD-fixed dose; d day; NR-not reported; NS- not significant

TCAs and opiates), potential opioid-related de-
pendency, and need for combination therapy. 2
Pregabalin (Lyrica) was developed by
Pfizer as a follow-up compound to gabapentin.
It has been approved by the FDA for neuropathic
pain associated with DPN and PHN and is expected
to be released in 2005. In addition, pregabalin has
demonstrated efficacy in epilepsy and generalized
anxiety disorder (GAD). 2,3 Pregabalin will be clas-
sified as a controlled substance, class IV or V, due
to low abuse characterized by euphoria in a minor-
ity of patients (Personal Communication with
Pfizer Inc. 01/26/05). This article will examine the
safety, efficacy, and tolerability of pregabalin for
the management of pain that results from shingles
or diabetes-related nerve damage.

Pharmacology and Pharmacokinetics
Pregabalin is the pharmacologically active
S-enantiomer of 3-aminomethyl-5-methyl-hexanoic
acid.2 It has a similar pharmacological profile to
that of gabapentin. The mechanism of action of pre-
gabalin may involve reduction of excitatory neuro-
transmitter release by binding to the t2-6 protein
subunit of voltage-gated calcium channels.
After oral administration in 86 healthy vol-
unteers, pregabalin was rapidly absorbed and dis-
played linear pharmacokinetics. Time to peak
plasma concentration is 1.3 hours. The oral
bioavailability of pregabalin is 90%. Absorption of
pregabalin is delayed with food; however, the ex-
tent of absorption is not affected. Pregabalin under-

goes negligible hepatic metabolism and does not
bind to plasma proteins. It is 98% really elimi-
nated, so dosage adjustment is necessary in really
impaired patients. The elimination half-life is 6
hours (4.6-6.8 hours following a single 300 mg
dose). Clearance of pregabalin is directly propor-
tional to creatinine clearance (CrC1).

Clinical Trials
Rosenstock et al 4 evaluated the efficacy
and safety of pregabalin in a two-phase trial: a one-
week baseline phase and an eight-week, fixed dose,
double-blind treatment phase. The study was a ran-
domized, double-blind, placebo-controlled trial
(Table 1). Patients were randomized to pregabalin
300 mg/day (administered in three divided doses)
or placebo. Mean pain score was the primary effi-
cacy parameter. Secondary efficacy parameters in-
cluded the Short-Form McGill Pain Questionnaire
(SF-MPQ), sleep score, Patient and Clinical Global
Impressions of Change (PGIC,CGIC), SF-36
Health Survey (SF-36), and Profile of Mood States
(POMs). This study showed a statistically signifi-
cant decrease in mean pain score for pregabalin
compared to placebo (-2.5 vs. -0.8, p=0.0001). By
week one, the pregabalin arm showed a 2.2 mean
pain score decrease compared to 0.4 in the placebo
group (p=0.0001), significant improvement in
weekly mean sleep interference scores (p<0.001),
and improvements on the SF-MPQ (p<0.05), PGIC
(p=0.001), CGIC (p=0.004), SF-36 (p<0.03), and
POMs subscales (p<0.03). The most common ad-

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Table 2. Clinical Trial Experience of Pregabalin in Postherpetic Neuralgia (PHN).

Dworkin et al 8

Van Seventer et

Sabatowski et

Pain persisting >3
months following
herpes zoster skin
rash. Mean age 71.5
years. Mean duration
of PHN, 33.8 months

PHN > 3 months du-
ration. Mean age
70.7 years

PHN of >6 months.
Mean age of 71.3

8-week randomized,
DB, PC, parallel
group, multicenter

13-week random-
ized, DB, PC, multi-
center study

8-week randomized,
DB, PC, multicenter

Dose (mg/d)*
Pregabalin 600 "

Number of

Pregabalin 150 I
Pregabalin 300 I
Pregabalin 300/600 I
Placebo I

Pregabalin 150
Pregabalin 300

Response (%)


*Doses administered in three divided doses unless otherwise noted. a Patients
Administered in two divided doses. DB double-blind; PC-placebo-controlled.

verse effects reported were dizziness (27%), som-
nolence (15%), infection (11%), and peripheral
edema (8%). This study showed that pregabalin is
effective and well tolerated in decreasing the pain,
mood disturbances, and sleep disruption associated
with DPN.
Sharma et al 5,6 compared the safety and ef-
ficacy of pregabalin 150 mg/day, pregabalin 600
mg/day, and placebo, administered in three divided
doses, in a six-week study. This was a randomized,
double-blind, placebo-controlled, parallel-group
trial (Table 1). Mean pain score was the primary
efficacy parameter. Pregabalin 600 mg/day was sig-
nificantly better than placebo (p=0.0002). When
comparing the secondary efficacy measures, pre-
gabalin was significantly better than placebo in
daily sleep interference score (p=0.0004), SF-MPQ,
CGIC, PGIC, and SF-36. The most common ad-
verse events included: dizziness and somnolence.
The authors concluded that pregabalin 600 mg/day
was safe and effective in reducing DPN-associated
lacobellis et al 7 conducted a 5-week ran-
domized, double-blind, placebo-controlled study
(Table 1). The study compared the safety and effi-
cacy of pregabalin 75 mg/day, 300 mg/day, 600
mg/day, or placebo, administered in three divided
doses. The primary efficacy parameter was mean

with a CrCl 30-60 ml/min received pregabalin 100 mg three times a day.

pain score. Secondary efficacy parameters included
SF-MPQ, sleep interference score, CGIC, PGIC,
and the proportion of patients who responded to
treatment. Significant improvements in mean pain
score were seen in patients receiving pregabalin
300 and 600 mg/day (p=0.0001) compared to pla-
cebo. The number of responders to pregabalin was
significantly better than placebo: 45.7% of patients
responded to pregabalin 300 mg/day, 48.1% to pre-
gabalin 600 mg/day, and 17.5% responded to pla-
cebo; (p=0.001). Patients who received 75 mg/day
of pregabalin reported similar pain scores as pa-
tients receiving placebo. The most common adverse
events included dizziness and somnolence. Pre-
gabalin 300 and 600 mg/day was safe and effective
in reducing DPN associated pain and reducing
sleep interference.
Dworkin et al 8 carried out an eight-week,
multicenter trial to evaluate the efficacy and safety
of pregabalin in patients with PHN. This was a ran-
domized, double-blind, placebo-controlled, paral-
lel-group study. (Table 2) Patients were dosed
based on renal function such that patients with a
CrCl >60 ml/min received pregabalin 200 mg three
times a day and patients with a CrCl between 30
and 60 ml/min received 100 mg three times a day.
The primary efficacy measure was the difference
between pregabalin and placebo in the mean pain

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Table 3. Most common adverse effects (%) in treatment of DPN.4
Pregabalin Placebo
Adverse Event n=89 (%) n=84 (%)
Dizziness 25(28.1) 10(11.9)
Time median to onset (days) 2 to 3
The median duration (days) 33 3
Somnolence 22(24.7) 6(7.1)
Time median to onset (days) 2 to 3
The median duration (days) 53 17
Peripheral edema 17 (19.1) 2(2.4)
The median time to onset (days) 24
The median duration (days) 31
Amblyopia 10(11.2) 1(1.2)
Dry mouth 10(11.2) 2(2.4)

ratings (average of last 7 days was tabulated) at 8
weeks. Secondary endpoints included additional
pain ratings, sleep interference, quality of life,
mood, and patient and clinician ratings of global
improvement. Patients treated with pregabalin had
greater decreases in pain compared to placebo
(endpoint mean scores 3.60 vs. 5.29, p = 0.0001).
The proportion of patients with >30% and > 50%
decreases in mean pain scores were 63% and 50%
in the pregabalin arm, respectively vs. 25% and
20% in the placebo arm, respectively (p=0.001).
Compared to placebo, sleep also improved in pa-
tients treated with pregabalin (p = 0.0001). Pre-
gabalin treatment was associated with greater
global improvement than treatment with placebo
(p=0.001). The authors concluded that treatment of
PHN with pregabalin is safe and effective for re-
lieving pain and sleep interference and has accept-
able tolerability compared to placebo.
Van Seventer et al 9 compared twice-daily
pregabalin to placebo in a 13-week study. This was
a randomized, double-blind, placebo-controlled,
multicenter study (Table 2). The trial compared the
safety and efficacy of pregabalin 150 mg/day, 300
mg/day, 300/600 mg/day (patients with a CrC1 be-
tween 30 and 60 ml/min received pregabalin 300
mg/day and those with CLcr >60 ml/min received
600 mg/day), or placebo. The mean pain score was
improved for all pregabalin groups compared with
placebo (for pregabalin 150 mg/day, p=0.005, for
pregabalin 300 mg/day, p=0.0002, and for pre-
gabalin 300/600 mg/day, p=0.0002). The most
common adverse events were dizziness, somno-

lence, and peripheral edema.
Sabatowski et al 10 conducted an 8-week,
randomized, double-blind, placebo-controlled,
multicenter study (Table 2). Patients received pre-
gabalin 150 mg/day administered in three divided
doses, pregabalin 300 mg/day administered in three
divided doses, or placebo. The primary efficacy
measure was the mean pain score. The secondary
efficacy measures were the mean sleep interference
score, PGIC, CGIC, SF-36, Zung Self-Rating De-
pression Scale, and VAS of the SF-MPQ. The mean
pain scores at end of follow-up (intention-to-treat,
ITT population) were 5.14 (p=0.0002), 4.76
(p=0.0001), and 6.33 for pregabalin 150 mg/day,
pregabalin 300 mg/day, and placebo, respectively.
Pain relief was evident during the first week of
treatment and was maintained for the duration of
the study. Mean sleep interference scores (ITT
population) were 3.13 (p=0.0003) for pregabalin
150 mg/day, 2.81 (p=0.0001) for pregabalin 300
mg/day, and 4.24 for placebo. The most frequently
reported adverse events (> 10%) were dizziness,
somnolence, peripheral edema, headache, and dry

Toxicity and Safety
The most commonly reported adverse
events reported in clinical trials with pregabalin are
dizziness, somnolence, peripheral edema, headache,
blurred vision, constipation, dry mouth, and diar-
rhea. 2,3 The adverse effect profile for pregabalin in
patients with DPN and PHN is listed in Tables 3

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Table 4. Most common adverse effects (%) in the treatment of PHN.8
Pregabalin Placebo
Adverse Event n=76 (%) n=70 (%)
Dizziness 27(35.5) 8(11.4)
Somnolence 15 (19.7) 2 (2.9)
Infection 11(14.5) 4(5.7)
Peripheral edema 8 (10.5) 1(1.4)
Euphoria 4 (5.3) 0 (0)
Days Days
Time to onset
Dizziness < 1 day <1 day
Somnolence < 1 day <1 day
Peripheral edema 31 days 4 days (1 patient)

Dizziness 10.5 10.5 days 3.5 days
Somnolence 30.0 30 days 4 days
Peripheral edema 18 days 53 days (1 patient)

and 4, respectively.

Dosing and Administration
Formal dosing recommendations await
FDA approval of the final labeling. Based on clini-
cal trial data and approved doses in Europe, the
dosage range for the treatment of neuropathic pain
(DPN and PHN) is expected to be 150-600 mg/day
administered in two or three divided doses (with or
without food). An initial dose of 150 mg/day may
be increased to 300 mg/day after 3-7 days and to
600 mg/day after an additional 7 days. 23 Pre-
gabalin will be available as 25, 50, 75, 100, 150,
200, 225 and 300 mg capsules.

Pregabalin is contraindicated in patients
with a known hypersensitivity to this agent. More-
over, it seems prudent to avoid pregabalin in pa-
tients with gabapentin hypersensitivity given the
structural similarities between these two agents.
Central nervous system (CNS) depression may oc-
cur in patients treated with pregabalin, thus, coun-
seling should include warnings about performing
tasks that mandate mental acuity. Pregabalin
should not be acutely discontinued; instead, a grad-
ual tapering of 1 week is recommended. Physical

and psychological dependence may occur in pre-
gabalin-treated patients; it should be avoided in pa-
tients with a history of substance abuse. Pregabalin
will accumulate in patients with renal insufficiency,
so cautious dosage adjustment is necessary. Fi-
nally, experience with pregabalin is limited in preg-
nant and lactating women, adolescents, and infants.

The cost for Lyrica (pregabalin) has not
been established. Table 5 lists average retail costs
from 3 pharmacies in Gainesville, FL.

Even though diabetic neuropathic pain af-
fects over 3.7 million individuals in the US, until
2004, no treatment had been FDA approved for this
indication. Gabapentin is frequently used off-label
for neuropathic pain. Based on the clinical trial
data, FDA has approved pregabalin for three indi-
cations: neuropathic pain associated with DPN,
PHN, and as adjunctive therapy in the treatment of
partial seizures in adults. Pregabalin has also been
evaluated for treatment of GAD.
Pregabalin has a rapid onset of analgesic
effect. In contrast to gabapentin pregabalin exhib-
its linear pharmacokinetics and does not require po-

PharmaNote Volume 20, Issue 7, April 2005


Volume 20, Issue 7, April 2005

Table 5. The average retail cost of frequently used agents for the treatment of neuropathic pain.

Drug Dose One-month of therapy (dollars)
Duloxetine (Cymbalta) 60 mg/d 111.98

Lidocaine patch (Lidoderm) one 5% patch daily 277.8

257.68 (brand)
Gabapentin (Neurontin) 1800 mg/day 195.18 (eneri)
S( 195.18 (generic)
Amitriptyline (Elavil) 100mg/day 10.41 (generic)

tentially lengthy or complicated dose titration. Pre-
gabalin may be titrated to the effective target dose
of 300 to 600 mg/day over one week. Multiple
clinical studies have shown that pregabalin, at dos-
ages of 150 to 600 mg/day, demonstrates signifi-
cant efficacy for improving pain and pain-related
sleep interference as early as one week after start-
ing treatment. Pregabalin appears to be well toler-
ated; the most common adverse effects are dizzi-
ness and somnolence. Pregabalin offers clinicians
another agent with which to treat neuropathic pain
syndromes and may prove to be particularly useful
in patients who have not responded to or did not
tolerate other treatments.

1. Staats P, Argoff C, Brewer R et al. Neuropathic Pain:
Incorporating New Consensus Guidelines Into The
reality Of Clinical Practice. Adv Stud Med 2004;4:
2. Frampton J, Scott L. Pregabalin In the Treatment of
Painful Diabetic Peripheral Neuropathy. Drugs 2004;
3. Frampton J, Foster R. Pregabalin In the Treatment of
Postherpetic Neuralgia. Drugs 2005:65:111-118.
4. Rosenstock J, Touhman, LaMoreaux L, et al. Pre-
gabalin for the treatment of painful diabetic periph-
eral neuropathy: a double-blind, placebo-controlled
trial. Pain 2004;110:628-38.
5. Sharma U, Allen R, Glessner C, et al. Pregabalin ef-
fectively relieves pain in patients with diabetic pe-
ripheral neuropathy: study 1008-014 (abstract). Dia-
betes 2000;49 Suppl 1:A167.
6. Sharma U, Iacobellis D, Glessner C, et al. Pregabalin
reduces pain interference with sleep in patients with
painful diabetic peripheral neuropathy (poster). Pre-
sented at the American Psychiatric Association An-
nual Meeting; May, 17, 200, Chicago, Illinois.
7. Iacobellis D, Allen R, Lamoreaux L, et al. A double-
blind, placebo-controlled trial of pregabalin for the
treatment of painful diabetic peripheral neuropathy
(abstract). Neurology 2000;54 Suppl 3:A177.
8. Dworkin RH, Corbin AE, Young JP Jr, et al. Pre-

gabalin for the treatment of postherpetic neuralgia: a
randomized, placebo-controlled trial. Neurology
9. Van SeventerR, Bladin C, Hoggart B, et al. Pre-
gabalin dosed twice a day (BID) efficaciously and
safely treats neuropathic pain associated with
postherpetic neuralgia (poster). Presented at the
European Federation of IASP Charters Congress;
September 2-6, 2003; Prague, Czech Republic.
10. Sabatowski R, Galvaz R, Cherry DA, et al. Pre-
gabalin reduces pain and improves sleep and mood
disturbances in patients with post-herpetic neuralgia:
results of a randomized, placebo-controlled clinical
trial. Pain 2004;109:26-35.
11. Lyrica (Pregabalin)-New Gabapentinoid With Wide
Clinical Application. Available at http://www.
pregabalin/. Accessed on January 20, 2005.
12. FDA Approves Antidepressant Cymbalta for Treat-
ment of Pain Caused by Diabetic Peripheral Neu-
ropathy, Which Affects Up to 5 Million Americans.
Available at http://newsroom.lilly.com/
ReleaseDetail.cfm?ReleaseID=148686. Accessed on
January 23, 2005.

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor

PharmaNote Volume 20, Issue 7, April 2005


Volume 20, Issue 7, April 2005

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