30% decrease in pain
3/12
not much different to
ORIGINAL ARTICLE
control
NGX-4010, a Capsaicin 8% Dermal Patch,
Administered Alone or in Combination With
Systemic Neuropathic Pain Medications, Reduces
Pain in Patients With Postherpetic Neuralgia
Gordon A. Irving, MD,* Miroslav Backonja, MD,w Richard Rauck, MD,z Lynn R. Webster, MD,y
Jeffrey K. Tobias, MD,8 and Geertrui F. Vanhove, MD, PhD8
Objectives: Analyses of integrated data from 4 controlled
postherpetic neuralgia studies evaluated the effect of NGX-4010,
a capsaicin 8% patch, administered alone or together with systemic
neuropathic pain medications.
Methods: Patients recorded their “average pain for the past 24 hours”
daily for 12 weeks using an 11-point Numeric Pain Rating Scale
(NPRS). Efficacy assessment included the percentage NPRS score
reduction from baseline during weeks 2 to 8 and 2 to 12, the
proportion of patients responding during weeks 2 to 8 and 2 to 12 and
the Patient Global Impression of Change (PGIC) at weeks 8 and 12.
Results: During the studies, 302 NGX-4010 and 250 control
(capsaicin, 0.04% wt/wt) patients were using at least 1 systemic
neuropathic pain medication; 295 NGX-4010 and 280 control
patients were not. During weeks 2 to 8, NGX-4010 patients reported
greater reductions in NPRS scores compared with control both in
patients using systemic neuropathic pain medications ( 26.1% vs.
 18.1%, P = 0.0011) and in patients not using these medications
( 36.5% vs.  26.2%, P = 0.0002). Patients not using systemic
neuropathic pain medications reported a greater reduction in pain
compared with patients using these medications in both, NGX-4010
and control groups, resulting in comparable treatment differences
between NGX-4010 and control regardless of systemic neuropathic
pain medication use. Similar results were seen during weeks 2 to 12,
for the responder and PGIC analyses. Transient, capsaicin-related
application site reactions were the most common adverse events and
not affected by systemic neuropathic pain medication use.
Conclusion: A single 60-minute NGX-4010 treatment reduces PHN
for up to 12 weeks regardless of concomitant systemic neuropathic
pain medication use.
Key Words: postherpetic neuralgia, capsaicin patch, systemic
neuropathic pain medication
(Clin J Pain 2012;28:101–107)
Received for publication November 4, 2010; revised May 16, 2011;
accepted June 1, 2011.
From the *Swedish Pain Center, Seattle, WA; wUniversity of Wisconsin-
Madison, Madison, WI; zThe Center for Clinical Research,
Winston-Salem, NC; yLifetree Clinical Research and Pain Clinic,
Salt Lake City, UT; and 8NeurogesX, Inc., San Mateo, CA.
Funding for these studies was provided by NeurogesX. Drs Irving,
Backonja, Rauck, and Webster are consultants for NeurogesX and
Astellas. Dr Irving is part of the speaker’s bureau for NeurogesX
and Astellas. Drs Tobias and Vanhove are NeurogesX employees
and own NeurogesX stock.
Reprints: Geertrui F. Vanhove, MD, PhD, NeurogesX, 2215 Bridge-
pointe Parkway, Suite 200, San Mateo, CA 94404 (e-mail:
tvanhove@neurogesx.com).
Copyright r 2012 by Lippincott Williams & Wilkins
Clin J Pain  Volume 28, Number 2, February 2012
N europathic pain is pain that arises as a direct
consequence of a lesion or disease affecting the
somatosensory system1 and can originate in the peripheral
or the central nervous system. Peripheral neuropathic pain
refers to conditions with a predominant abnormality of the
sensory afferent fibers. Clinical features may include
disabling symptoms such as burning, stinging, shooting
pain or electrical sensations, paresthesis, dysesthesia, and
sensitivity to light touch over the area (allodynia and
hyperalgesia). Postherpetic neuralgia (PHN) is a peripheral
neuropathic pain condition consisting of chronic pain after
healing of herpes zoster, a disorder that results from
reactivation of latent varicella zoster virus.2 Estimates of
the incidence of PHN are variable and depend on the
definition used but generally range from approximately 8%
to 19.5% of all patients with herpes zoster; the likelihood of
developing PHN after herpes zoster increases with age.3–5
A large number of randomized clinical trials have made
possible evidence-based recommendations for the treatment
of neuropathic pain.6–9 The most commonly used classes of
drugs recommended include anticonvulsants such as prega-
balin and gabapentin, tricyclic antidepressants, selective
serotonine norepinephrine reuptake inhibitor antidepres-
sants, topical lidocaine, and opioids. However, poor toler-
ability, the need for titration, and administration of multiple
daily doses limit the usefulness of many of these systemic
treatments. In addition, many patients continue to experi-
ence significant pain while taking these treatments.8,10,11
Improved understanding of the pathophysiologic me-
chanisms of neuropathic pain allows a more specific pain
mechanism-based approach in managing PHN. For exam-
ple, sensitization of peripheral nociceptors that express
transient receptor potential vanilloid 1 receptor (TRPV1) is
evident in many patients with PHN.12 Therefore, targeting of
TRPV1 seems a logical approach to pain management.
Exposure of TRPV1 receptors to high concentrations of
capsaicin initially causes depolarization, action potential
initiation, and burning pain. This is followed by a reversible
defunctionalization and reduction of these nerve fibers in the
epidermis resulting in inhibition of pain transmission.13–15
The use of low-concentration capsaicin creams
(0.025% and 0.075%) has been limited by the requirement
for multiple daily applications, burning sensation at the
application site for several weeks, and a lack of adherence
despite demonstrated efficacy in the treatment of PHN.16–19
NGX-4010 is a capsaicin 8% dermal patch developed to
quickly deliver a therapeutic dose of capsaicin locally into
the skin.20 A single 60-minute application has been shown to
reduce pain for up to 12 weeks in patients with PHN.21–25
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Irving et al
The topical application of NGX-4010 is associated with
minimal systemic capsaicin exposure,26 has a low risk of
systemic adverse effects and is unlikely to have drug–
drug interactions making it an ideal candidate for multi-
modal therapy. However, in previous studies, the effect of
concomitant use of systemic neuropathic pain medication
such as anticonvulsants, non-selective serotonin reuptake
inhibitor (SSRI) antidepressants or opioids, on NGX-4010
efficacy was inconsistent. Although in all studies, patients
treated with NGX-4010 had better pain relief than patients
treated with control regardless of concomitant use of
systemic neuropathic pain medication, in 2 studies,23,24 the
treatment difference between NGX-4010treated patients
and control patients was larger in patients already taking
systemic neuropathic pain medication whereas in 2 stu-
dies,22,25 the treatment difference between NGX-4010
treated patients and control patients was larger in patients
not taking any systemic neuropathic pain medication.
Therefore, integrated analyses of four 12-week, double-
blind, randomized controlled studies in PHN patients were
undertaken to further investigate the efficacy and safety of
NGX-4010 either alone or in addition to the systemic
neuropathic pain medications patients were taking.
METHODS
Patients
Data from 4 double-blind controlled PHN studies
were integrated and analyzed.22–25 In all studies, partici-
pants were recruited directly by the study centers from their
existing patient data base, or through written advertising,
radio, and television ads. Individuals 18 to 90 years old with
a diagnosis of PHN and an average Numeric Pain Rating
Scale (NPRS)27 score of 3 to 9 (inclusive) were eligible if at
least 6 months had elapsed since herpes zoster vesicle
crusting (3 mo in 1 study). Patients taking chronic pain
medications, such as anticonvulsants, non-SSRI antide-
pressants, opioids, nonsteroidal anti-inflammatory drugs,
salicylates, or acetaminophen, had to be on a stable dose of
those medications for at least 21 days before the day of
study patch application and remain on a stable dose
throughout the study period. Women of childbearing age
were required to have a negative pregnancy test and be
willing to use an effective method of contraception for 30
days after exposure to study medication.
Exclusion criteria were as follows: use of any topically
applied pain medication on the painful area within 21 days
before the day of application of the study patch; current use
of any investigational drug or class I antiarrhythmic drug;
uncontrolled diabetes mellitus or uncontrolled hyperten-
sion; significant pain of an etiology other than PHN;
painful PHN areas located only on the face, above the scalp
hairline, or near mucous membranes; and hypersensitivity
to capsaicin, local anesthetics, oxycodone hydrochloride,
hydrocodone, or adhesives. As earlier use of high-dose
opioids could limit the responsiveness to the optional oral
opioid analgesics for treatment-associated discomfort used
during the treatment procedure, patients were excluded if
they were using concomitant opioid medication that was
not orally or transdermally administered or exceeded a total
dose of 60 mg/d morphine equivalent.
The study was approved by Institutional Review
Boards/Independent Ethics Committees at all participating
sites, and conducted in accordance with the ethical
principles of the Declaration of Helsinki, Good Clinical
102 | www.clinicalpain.com
Clin J Pain  Volume 28, Number 2, February 2012
Practice guidelines, and applicable regulatory requirements.
Written informed consent was obtained from all participat-
ing patients before initiating study-related procedures.
Procedures
The double-blind studies included a Z7-day to 14-day
baseline screening period followed by a treatment day (day
0), and a 12-week posttreatment assessment period with
clinic visits at weeks 4, 8, and 12. Eligible patients were
randomized to receive NGX-4010 (capsaicin 640 mg/cm2
8%; NeurogesX Inc, San Mateo, CA) or a control patch
that was identically formulated but contained a lower
concentration of capsaicin (3.2 mg/cm2 0.04%). The low-
concentration capsaicin control patches were used in place
of placebo patches to provide effective blinding in the study
as topical capsaicin can produce local erythema and a
burning sensation.
The actual treatment assigned to individual patients
was determined by a randomization scheme prepared by
Fisher Clinical Services (Allentown, PA) or Cardinal
Health (Morrisville, NC). Numbers were assigned only
once, and no participant was randomized into the study
more than once. The NGX-4010 and control patches were
identical in appearance, as were the blinded study drug
kits. Each kit was designated by a unique kit number,
which was printed on the investigational drug label affixed
to the outer bag enclosure and on each individual patch
envelope.
All patients were pretreated for 60 minutes with a
topical local anesthetic cream (ELA-Max or LMX4,
lidocaine 4%; Ferndale Laboratories, Inc, Ferndale, MI)
before application of the NGX-4010 patch(es) for 60 min-
utes or control patch(es) for 30, 60, or 90 minutes directly to
the painful area(s) (up to 1120 cm2). After patch removal,
the area was cleansed with a proprietary cleansing gel
(NeurogesX, San Mateo, CA) formulated to remove
residual capsaicin. Patients were monitored for 2 hours
after patch removal. Local cooling as well as oxycodone
hydrochloride oral solution (1 mg/mL) or equivalent could
be administered at the onset of treatment-associated
discomfort and as needed. Patients could take short-acting
opioid medication (hydrocodone bitartrate/acetaminophen
5 mg/500 mg) for up to 3 to 5 days (depending on the study)
after patch application for treatment-associated discomfort
as needed. Topical pain medications were not permitted
during the 12-week study period. Patients were allowed to
take acetaminophen up to 2 to 3 g/d (depending on the
study) as needed for aches and pains.
MEASURES AND DATA ANALYSIS
Efficacy
Efficacy was evaluated with daily NPRS scores
captured at 9 pm every evening in a paper diary throughout
the 12-week study period. The NPRS is an 11-point scale
(0 to 10) with 0 indicating no pain and 10 indicating the
worst possible pain.27 These NPRS assessments were for
“average pain for the past 24 hours.” Subgroup analyses by
concomitant systemic neuropathic pain medication use
were performed for primary and secondary end points. The
primary efficacy end point was the percentage change in
NPRS scores from baseline to weeks 2 through 8. Baseline
NPRS scores were recorded from day 14 to day 1. To
avoid the potential confounding effect of allowed opioid
r 2012 Lippincott Williams & Wilkins
Clin J Pain  Volume 28, Number 2, February 2012
medications for treatment-associated discomfort during
days 0 to 5, week 1 NPRS scores were not included in the
primary analysis. Secondary efficacy end points included:
percentage change in NPRS scores from baseline to weeks 2
to 12, the proportion of responders (mean percentage
decrease in NPRS score ofZ30%), the proportion of
patients with a Z50% or Z2-point reduction in NPRS
score from baseline to weeks 2 through 8 and weeks 2
through 12 and Patient Global Impression of Change
(PGIC; patients reported how they felt after treatment as
compared with before treatment on a scale of  3 indicating
“very much worse” to +3 indicating “very much im-
proved” with 0 being “no change”) at weeks 8 and 12. A
patient was defined as using systemic neuropathic pain
medication if he/she was on non-SSRI antidepressants,
anticonvulsants, or opioids on day 1 and was taking these
for at least 7 consecutive days.
Efficacy analyses were based on the intent-to-treat
population that consisted of all patients who received any
study treatment and had at least 3 days of available NPRS
scores during the baseline period. Mean percentage changes
and mean numeric changes in NPRS scores from baseline
to weeks 2 through 8 and 2 through 12 were analyzed using
a gender-stratified analysis of covariance (ANCOVA)
model with baseline pain score as the only covariate. For
each participant, the mean NPRS score for weeks 2 to n,
where n is any number greater than 2, was computed as the
average of the NPRS scores from day 8 to day 7*n. Missing
posttreatment NPRS scores were imputed using a modified
last-observation-carried-forward approach. If the NPRS
score was missing on any of days 0 to 8 or missing on day 8
and 1 or more consecutive days, then the baseline score was
imputed for those days. If the NPRS score was missing for
any day past day 8, then the missing score was imputed by
the latest available nonmissing score collected before that
day. If all posttreatment NPRS scores were missing
(including day 0), all scores were imputed using the baseline
score. The percentage of responders (Z30% reduction) and
the percentage of patients achieving a Z50% or Z2-point
reduction in NPRS score were compared between groups
using logistic regression analyses, with baseline pain score
and gender as covariates. For the calculation of NPRS
baseline scores, all available screening scores that were not
biased by pain medication changes were used in 2 studies.
For changes in non-SSRI antidepressant or anticonvulsant
medications, pain scores up to 14 days after the medication
change were considered biased. For changes in other pain
medications, pain scores up to the day of medication
change were considered biased. Changes in minor over-the-
counter analgesics (acetaminophen, aspirin) were ignored.
For the other 2 studies, the mean of all available screening
NPRS scores from day 14 to day 1 were used. The
percentage of patients reporting PGIC score improvement
(much, or very much improved) was compared between
treatment groups using Fisher’s exact test.
Safety
AEs were coded using the Medical Dictionary for
Regulatory Activities. One patient was randomized to
receive NGX-4010, but received control. This patient was
analyzed as randomized for the efficacy analyses and as
treated for the safety analyses. Subgroup analyses of AE by
systemic pain medication use were performed.
r 2012 Lippincott Williams & Wilkins
Capsaicin 8% Patch for Postherpetic Neuralgia
RESULTS
Patients
A total of 1127 patients were randomized and received
treatment: 597 were randomized to NGX-4010 and 530
were randomized to control (a 0.04% capsaicin patch) in
these four 12-week studies (Fig. 1). One patient was
randomized to receive NGX-4010 but mistakenly received
control. Similar proportions of NGX-4010 treated pa-
tients and control patients prematurely discontinued the
studies (9%). Two patients died. One patient, an 81-year-
old female who was treated with NGX-4010, died on day 31
owing to diverticulitis and 1 patient, a 91-year-old male,
who received control died of multi-organ failure on day
108. Neither event was considered related to study drug. An
AE was responsible for premature termination in less than
1% of NGX-4010 and control patients.
There were no meaningful differences in baseline pain
characteristics between the NGX-4010 treated patients
and control patients (Table 1). The mean age of patients
was 71 in both treatment groups. There were a slightly more
females than males and a large proportion of whites in both
treatment groups (92%). The mean baseline pain score was
5.7 for both treatment groups and the mean duration of
PHN pain was comparable between NGX-4010 and control
groups (3.4 and 3.5 years, respectively). In addition, for
both treatment groups, there were no meaningful differ-
ences in baseline pain characteristics between patients using
and not using systemic neuropathic pain medication. About
50% of patients were taking concomitant systemic neuro-
pathic pain medications (opioids, non-selective serotonin
reuptake inhibitor antidepressants and/or anticonvulsant
medications) in the NGX-4010 (51%) and control (47%)
groups at baseline. Of those taking systemic neuropathic
pain medications, the majority was taking only 1 medica-
tion (mostly anticonvulsants), about one third was taking
two medications and only 5 to 6% were taking 3 systemic
neuropathic pain medications.
Efficacy
A single 60-minute NGX-4010 application signifi-
cantly reduced NPRS scores versus control regardless of
concomitant systemic neuropathic pain medication use
(Table 2). NGX-4010 patients not using systemic neuro-
pathic pain medication reported a greater reduction in
mean percentage change from baseline ( 36.5%) com-
pared with NGX-4010 patients who were using systemic
neuropathic pain medications ( 26.1%). A similar trend in
the control group ( 26.2% for control patients not using
versus 18.1% for control patients using systemic neuro-
pathic pain medications) resulted in comparable treatment
differences between NGX-4010 and control regardless of
concomitant systemic neuropathic pain medication use.
Similar results were observed during weeks 2 to 12.
Patients responded to NGX-4010 treatment regardless
of systemic neuropathic pain medication use (Table 2).
More NGX-4010 patients not using systemic neuropathic
pain medications experienced a 30% or greater reduction in
pain from baseline compared with NGX-4010 patients who
were using concomitant systemic neuropathic pain medica-
tions during weeks 2 to 8 (52% vs. 36%, respectively). A
similar trend was observed in the control group (39% for
patients not using systemic neuropathic pain medications
vs. 28% for patients using systemic neuropathic pain
medications). Similar results were observed during weeks
www.clinicalpain.com | 103
Irving et al Clin J Pain  Volume 28, Number 2, February 2012

pain medication use (Table 2). More NGX-4010 patients

not using systemic neuropathic pain medications felt much
or very much improved compared with NGX-4010 patients
who were using systemic neuropathic pain medications at
week 8 (45% vs. 29%, respectively) and week 12 (43% vs.
30%, respectively). A similar trend was observed in the
control group (29% for patients not using systemic
neuropathic pain medications vs. 19% for patients using
systemic neuropathic pain medications at week 8 and 27%
for patients not using systemic neuropathic pain medica-
tions vs. 20% for patients using systemic neuropathic pain
medications at week 12).

Safety and Tolerability

Fig. 1. Patient randomization and disposition.
2 to 12 and for patients who experienced a Z2-point
reduction and a Z50% reduction in pain from baseline.
Analyses of PGIC demonstrated that significantly
more NGX-4010 patients felt much or very much improved
compared with controls regardless of systemic neuropathic
The overall incidence of AEs was higher among NGX-
4010–treated patients compared with controls. The propor-
tion of patients with at least 1 treatment-emergent AE was
90% in the NGX-4010 group and 80% in the control group
(Table 3). The higher incidence of treatment-emergent AEs
in the NGX-4010 group was primarily owing to expected,
capsaicin-related application site events reported by 77% of
NGX-4010 and 63% of control patients. Expected capsai-
cin-related application site reactions, including erythema
and pain were the most common AEs. These AEs were
transient, self-limited, and mostly mild-to-moderate in
severity. There was no difference in AEs between those
patients taking and not taking concomitant systemic
neuropathic pain medication except for a slightly higher
incidence of nausea in those taking concomitant systemic
neuropathic pain medication.

TABLE 1. Demographic and Baseline Characteristics

NGX-4010 Control
Not Using Not Using
Using Systemic Systemic Pain Using Systemic Systemic Pain
Total Pain Meds Meds Total Pain Meds Meds
Characteristic n = 597 n = 302 n = 295 n = 530 n = 250 n = 280
Age, mean (SD), years 71 (12) 71 (11) 70 (12) 71 (12) 72 (12) 70 (12)
Male, n (%) 286 (48) 148 (49) 138 (47) 251 (47) 112 (45) 139 (50)
Race, n (%)
Asian 9 (2) 5 (2) 4 (1) 6 (1) 3 (1) 3 (1)
Black 20 (3) 8 (3) 12 (4) 18 (3) 7 (3) 11 (4)
White 549 (92) 275 (91) 264 (89) 485 (92) 234 (94) 246 (88)
Other 19 (3) 14 (5) 15 (5) 21 (4) 6 (2) 20 (7)
Duration of pain, mean (SD), years 3.4 (3.9) 3.2 (3.9) 3.7 (3.8) 3.5 (4.3) 3.5 (4.5) 3.6 (3.8)
Baseline NPRS score, mean (SD)* 5.7 (1.6) 5.9 (1.6) 5.5 (1.6) 5.7 (1.6) 5.8 (1.6) 5.6 (1.6)
On concomitant neuropathic pain 302 (51) 302 (100) — 250 (47) 250 (100) —
medication, n (%)
Opioids only 48 (8) 48 (16) — 40 (8) 40 (16) —
Anticonvulsants only 112 (19) 112 (37) — 105 (20) 105 (42) —
Antidepressants (non-SSRI) 32 (5) 32 (11) — 33 (6) 33 (13) —
only
Opioids and anticonvulsants 52 (9) 52 (17) — 34 (6) 34 (14) —
Opioids and antidepressants 7 (1) 7 (2) — 7 (1) 7 (3) —
(non-SSRI)
Anticonvulsants and 32 (5) 32 (11) — 19 (4) 19 (8) —
antidepressants (non-SSRI)
All three 19 (3) 19 (6) — 12 (2) 12 (5) —
*Baseline NPRS scores for “average pain for the past 24 hours” were recorded in the evening (at 9:00 pm), beginning on the day of the Screening Visit
(usually day  14) through day 1, before study drug treatment.
NPRS indicates numeric pain rating scale; SD, standard deviation; SSRI, selective serotonin reuptake inhibitor.

104 | www.clinicalpain.com r 2012 Lippincott Williams & Wilkins

Clin J Pain  Volume 28, Number 2, February 2012 Capsaicin 8% Patch for Postherpetic Neuralgia

TABLE 2. Efficacy of NGX-4010

NGX-4010 Control
Using Not Using Using Not Using
Systemic Systemic Systemic Systemic
Total Pain Meds Pain Meds Total Pain Meds Pain Meds
n = 597 n = 302 n = 295 n = 530 n = 250 n = 280
Baseline Mean (SE) 5.7 (0.1) 5.9 (0.1) 5.5 (0.1) 5.7 (0.1) 5.8 (0.1) 5.6 (0.1)
Weeks 2-8
Percentage change LS mean (SE) 31.2 (1.3) 26.1 (1.6)  36.5 (1.9) 22.3 (1.4) 18.1 (1.8) 26.2 (2.0)
P* <0.0001 0.0011 0.0002
Treatment difference  8.9  8.0  10.3
Z30% response, n (%) 260 (44) 108 (36) 152 (52) 178 (34) 69 (28) 109 (39)
P** 0.0004 0.0187 0.0037
Z 50% response, n (%) 169 (28) 70 (23) 99 (34) 106 (20) 40 (16) 66 (24)
P** 0.0009 0.0204 0.0117
Z 2 unit decrease, n (%) 234 (39) 100 (33) 134 (45) 141 (27) 50 (20) 91 (33)
P** <0.0001 0.0004 0.0018
PGIC (week 8) n = 542 n = 268 n = 274 n = 488 n = 226 n = 262
Very much/much improved, n (%) 202 (37) 78 (29) 124 (45) 121 (25) 44 (19) 77 (29)
P*** <0.0001 0.0159 0.0002
Weeks 2-12
Percentage change LS mean (SE) 31.3 (1.3) 25.8 (1.7)  36.9 (2.0) 22.6 (1.4) 18.3 (1.8) 26.5 (2.0)
P* <0.0001 0.0030 0.0002
Treatment difference  8.7  7.5  10.4
Z30% response, n (%) 268 (45) 110 (36) 158 (54) 187 (35) 70 (28) 117 (42)
P* 0.0006 0.0159 0.0070
Z 50% response, n (%) 176 (29) 69 (23) 107 (36) 111 (21) 42 (17) 69 (25)
P** 0.0008 0.0477 0.0037
Z 2 unit decrease, n (%) 241 (40) 102 (34) 139 (47) 150 (28) 54 (22) 96 (34)
P* <0.0001 0.0010 0.0020
PGIC (week 12) n = 564 n = 282 n = 282 n = 498 n = 234 n = 264
Very much/much improved, n (%) 206 (37) 85 (30) 121 (43) 118 (24) 46 (20) 72 (27)
P*** <0.0001 0.0081 0.0002
*P values were computed using a gender-stratified ANCOVA model with baseline pain score as the covariate.
**P values were computed using logistic regression to test for differences between NGX-4010 and control groups with gender and baseline pain as
covariates.
***P values were computed using Fisher’s exact test.
LS indicates least squares; SE, standard error.

DISCUSSION control patients, significantly more patients treated with

These integrated analyses demonstrate that a single 60-
minute application of NGX-4010 can provide pain relief
that is maintained for up to 12 weeks in patients with PHN.
Pain scores began declining as early as day 1 after treatment
and were significantly lower than control by day 3 after
patch application (data not shown). This reduction
continued over the 12-week trial period. Compared with
the NGX-4010 patch had a clinically meaningful reduction
in pain (Z 30% reduction in NPRS score)27 or felt much or
very much improved. NGX-4010 and control patients not
using systemic neuropathic pain medication reported a
greater reduction in mean percentage change from baseline
compared with patients who were using systemic neuro-
pathic pain medications. This might suggest that patients

TABLE 3. Treatment-emergent Adverse Events That Occurred in Z5% of Total Patients and at an Incidence Greater Than Control
NGX-4010 Control
Using Systemic Not using Systemic Using Systemic Not using Systemic
System Organ Class, Total Pain Meds Pain Meds Total Pain Meds Pain Meds
Preferred Term, n (%) n = 596 n = 302 n = 294 n = 531 n = 250 n = 281
No. patients reporting 1 or more 534 (90) 275 (91) 259 (88) 425 (80) 204 (82) 221 (79)
treatment-emergent AEs
Gastrointestinal disorders 67 (11) 32 (11) 35 (12) 52 (10) 26 (10) 26 (9)
Nausea 29 (5) 20 (7) 9 (3) 15 (3) 9 (4) 6 (2)
General disorders and 458 (77) 229 (76) 229 (78) 333 (63) 159 (64) 174 (62)
administration site conditions
Application site erythema 391 (66) 204 (68) 187 (64) 270 (51) 126 (50) 144 (51)
Application site pain 260 (44) 135 (45) 125 (43) 104 (20) 57 (23) 47 (17)
Application site papules 40 (7) 20 (7) 20 (7) 15 (3) 7 (3) 8 (3)
Application site pruritus 37 (6) 11 (4) 26 (9) 25 (5) 9 (4) 16 (6)

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Irving et al
already taking systemic neuropathic pain medications have
more treatment resistant pain or that each additional pain
medication has an additive but smaller effect than the
preceding medication. Two previous studies, one studying
the combination of nortriptyline and gabapentin28 and the
other studying the combination of morphine and gabapen-
tin29 also showed that though there was additional benefit
obtained with the add-on drug, the additional benefit was
not as large as the benefit obtained with each drug by itself.
As such, it seems that even medications that work on
different mechanistic pathways do not have a pure additive
effect, possibly because some of the pathophysiologic
mechanisms implicated in the generation and maintenance
of neuropathic pain overlap or converge onto a common
pathway. Interestingly, the baseline pain score and the
duration of PHN pain were similar for patients using and
not using systemic neuropathic pain medication in both the
NGX-4010 and control group. Despite the difference in
response between patients using or not using systemic
neuropathic pain medications, treatment differences (be-
tween the active and control groups) were comparable. This
finding supports the conclusion that NGX-4010, a locally
acting therapy that produces pain relief through a distinctly
different mechanism than systemically administered medi-
cations used for the treatment of peripheral neuropathic
pain, can provide benefit to patients taken alone or as part
of a multimodal treatment regimen. In these studies,
patients taking concomitant systemic neuropathic pain
medications were required to remain on a stable dose
throughout the study period. As a result, no information
is available whether patients were able to reduce the dose
of or stop concomitant systemic neuropathic pain medi-
cations.
Although treatment differences (between the active
and control groups) were modest, it is important to point
out that in all studies, NGX-4010 was compared with a
low-dose control patch and not with an inert placebo patch
to maintain blinding. The low-dose control patch was able
to deliver an amount of capsaicin that, like NGX-4010, was
capable of producing local application site reactions. The
use of a low-dose control patch may have led to an
underestimation of the efficacy of NGX-4010 either because
of an analgesic effect of the low-concentration capsaicin
control patch or because of an enhanced placebo response
associated with the control patch owing to the mechanical
manipulation related to the treatment procedure and the
application site reactions resulting from the capsaicin in the
control patch.
Capsaicin-related local application site reactions were
the most common AEs and were transient, mostly mild to
moderate, and self-limited. Application site pain could be
adequately managed by local cooling or, if needed, by
short-acting oral opioid analgesics. There was no effect on
the AE profile when NGX-4010 was used alone or in
combination with systemic neuropathic pain medications
indicating that NGX-4010 can be used safely along with
these medications. Indeed, NGX-4010 is applied locally on
the areas of pain and associated with low (<5 ng/mL)
transient systemic exposure to capsaicin26 in only a
minority of patients reducing the risk for drug-drug
interactions and additional systemic side effects. The
slightly higher incidence of nausea in patients taking
concomitant systemic neuropathic pain medication may
be explained by the fact that a slightly larger proportion of
patients in this subgroup used medication for treatment-
106 | www.clinicalpain.com
Clin J Pain  Volume 28, Number 2, February 2012
related discomfort in both, the NGX-4010 and control
groups (data not shown).
In summary, treatment with a single 60-minute
topical application of NGX-4010 provided a significant
reduction in pain that was maintained for up to 3 months
in patients with PHN when used alone or concomitantly
with systemic neuropathic pain medications. NGX-4010
was generally well tolerated with local, transient applica-
tion site reactions as the most common AEs which were
not altered by the use of concomitant systemic neuropathic
pain medications.
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