Anesthesiology 2005; 103:1406 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Topical 2% Amitriptyline and 1% Ketamine in Neuropathic

Pain Syndromes
A Randomized, Double-blind, Placebo-controlled Trial
Mary E. Lynch, M.D., F.R.C.P.C.,* Alexander J. Clark, M.D., F.R.C.P.C., Jana Sawynok, Ph.D.,
Michael J. L. Sullivan, Ph.D.
Background: A double-blind, randomized, placebo-controlled
3-week study evaluated the efcacy of topical 2% amitriptyline,
1% ketamine, and a combination of both in treating patients
with neuropathic pain.
Methods: Ninety-two patients with diabetic neuropathy, pos-
therpetic neuralgia, or postsurgical/posttraumatic neuropathic
pain with allodynia, hyperalgesia, or pinprick hypesthesia
were randomly assigned to receive one of four creams (placebo,
2% amitriptyline, 1% ketamine, or 2% amitriptyline1% ket-
amine combined). The primary outcome measure was change
in average daily pain intensity (baseline week vs. nal week)
using an 11-point numerical pain rating scale. Secondary out-
comes included the McGill Pain Questionnaire, measures of
allodynia and hyperalgesia, and patient satisfaction.
Results: A reduction in pain scores of 1.11.5 units was ob-
served in all groups, and there was no difference between
groups. Blood concentrations revealed no signicant systemic
absorption. Minimal side effects were encountered.
Conclusion: This randomized, placebo-controlled trial exam-
ining topical 2%amitriptyline, 1%ketamine, and a combination
in the treatment of neuropathic pain revealed no difference
between groups. Optimization of doses may be required, be-
cause another study has revealed that higher concentrations of
these agents combined do produce signicant analgesia.
NEUROPATHIC pain is now understood to involve neu-
ral responses in which both peripheral and central
mechanisms contribute to the generation of spontane-
ous pain and evoked aspects of pain, including allodynia
and hyperalgesia.
14
The involvement of peripheral
mechanisms suggests the use of topical approaches in
the treatment of neuropathic pain. Both capsaicin
5,6
and
local anesthetics
79
can be useful in the relief of neuro-
pathic pain when administered locally to peripheral sites
as a cream or a patch, respectively.
Additional novel drug classes may also be effective in
alleviating neuropathic pain after topical administra-
tion.
10
Therefore, tricyclic antidepressants have been
shown to produce a peripherally mediated antinocicep-
tion in preclinical models of ongoing and neuropathic
pain
1114
and to produce analgesia in humans in placebo-
controlled studies involving patients with mixed neuro-
pathic pain.
15,16
Peripheral excitatory amino acid recep-
tor antagonists also might be useful in reducing pain of
peripheral origin.
17
Local injections of ketamine, which
blocks N-methyl-D-aspartate receptors, produce antinoci-
ception in a preclinical model of ongoing pain
18
and lead
to antihyperalgesic and some analgesic actions in human
experimental models of inammatory pain.
19,20
There
also are case reports of pain relief after topical adminis-
tration of ketamine in sympathetically maintained
pain
21,22
and cancer pain,
23
but there are no published
controlled trials demonstrating such efcacy.
24
In a previous pilot trial, we examined the potential
analgesic effects of a topical formulation of a cream
containing 1% amitriptyline and 0.5% ketamine.
25
Al-
though there was no acute treatment effect during the
2-day placebo-controlled part of the trial, in 11 patients
who took part in the 7-day open phase of the trial, there
was a signicant analgesic effect by day 3 of treatment,
which continued to increase to day 7. The results of the
open phase trial suggested that a longer treatment pe-
riod was necessary to observe a benecial effect. In
studies using topical doxepin for neuropathic pain of
mixed etiology, pain relief was observed primarily
1028 days after drug application.
15,16
The purpose of
the current study was to examine the efcacy of topical
preparations of 2% amitriptyline, 1% ketamine, and a
combination of amitriptyline with ketamine for the treat-
ment of neuropathic pain over a 3-week treatment pe-
riod in a randomized placebo-controlled trial. Patients
with mixed neuropathic pain were chosen for study
because they reect the reality of clinic populations, and
previous studies have demonstrated that patients with
neuropathic pain from different diagnostic categories
exhibit a response to peripheral doxepin (another tricy-
clic antidepressant)
15,16
and peripheral ketamine.
21,22
Materials and Methods
Subjects
Study subjects were recruited from three hospital out-
patient pain management units in eastern Canada. The
study took place from September 2001 to December
2002. Inclusion criteria and exclusion criteria are pre-
sented in table 1. Subjects were permitted to continue
* Director of Research, Pain Management Unit, Queen Elizabeth II Health
Sciences Centre, Halifax, Nova Scotia, Canada. Associate Professor, Department
of Psychiatry, Dalhousie University. Director, Calgary Chronic Pain Centre,
Professor, University of Calgary, Calgary, Alberta, Canada. Professor, Depart-
ment of Pharmacology, Dalhousie University. Professor, Department of Psy-
chology, University of Montreal, Montreal, Quebec, Canada.
Received from the Departments of Psychiatry and Anesthesiology, Dalhousie
University, Halifax, Nova Scotia, Canada. Submitted for publication October 6,
2004. Accepted for publication March 15, 2005. Supported by Epicept Corpora-
tion, Englewood Cliffs, New Jersey. Presented in a workshop at the joint meeting
of the Canadian and American Pain Societies in Vancouver, British Columbia,
Canada, May 8, 2004. Dr. Sawynok holds a patent for topical antidepressants
(other than amitriptyline) as analgesics (US patent No. 6,211,171).
Address reprint requests to Dr. Lynch: Pain Management Unit, Queen Eliza-
beth II Health Sciences Centre, Fourth Floor, Dickson Centre, Room 4086,
Halifax, Nova Scotia, B3H 1V7, Canada. Address electronic mail to:
mary.lynch@dal.ca. Individual article reprints may be purchased through the
Journal Web site, www.anesthesiology.org.
Anesthesiology, V 103, No 1, Jul 2005 140
using prestudy oral analgesics including nonsteroidal
antiinammatory drugs, opioids, antidepressants (includ-
ing amitriptyline and other tricyclics), and anticonvul-
sants.
Study subjects were examined by physician specialists
in pain management who conrmed the diagnostic sub-
category of neuropathic pain and completed the sensory
examination. It was also ascertained that subjects did not
have any other medical condition that would affect their
ability to safely take part in the study. All those who met
the criteria listed in table 1 and provided written in-
formed consent were included. The study was approved
by the research ethics committees of the study hospitals
(Queen Elizabeth II Health Sciences Centre, Halifax,
Nova Scotia, Canada; Ottawa General Hospital, Ottawa,
Ontario, Canada; St. Josephs Hospital, Hamilton, On-
tario, Canada).
Interventions
Study treatments consisted of four topical creams, con-
taining (1) placebo (vehicle only), (2) 2% amitriptyline,
(3) 1% ketamine, or (4) a combination of 2% amitripty-
line and 1% ketamine. The vehicle consisted of a mois-
turizing cream-like base. All topical formulations were
identical in consistency, color, and volume.
Procedure
Subjects were instructed to clean the area and then
apply 4 ml cream to the site of maximum pain (size of
the area of pain varied) three times per day for 3 weeks.
Subjects returned to the study site 2 and 3 weeks after
initiation of treatment, at which time pain levels were
documented using measures described below (Out-
comes section), and blood samples were taken for assay
of amitriptyline and ketamine concentrations. The used
tubes of cream were collected, weighed, and recorded
to assess compliance with treatment.
Objectives
The primary objective of the study was to determine
whether topical creams containing amitriptyline, ket-
amine, or a combination exhibited analgesic efcacy for
treatment of neuropathic pain. Secondary study objec-
tives included identifying patient satisfaction with the
cream and determination of whether systemic absorp-
tion occurred.
Outcomes
Spontaneous Pain. The primary outcome measure
consisted of an 11-point numerical rating scale for pain
intensity (NRS-PI) with the anchors no pain and se-
vere pain. The short-form McGill Pain Questionnaire
was included as an additional measure of spontaneous
pain; this generates subscales that assess sensory and
affective dimensions of pain experience. These mea-
sures have been developed and validated as measures of
clinical pain.
26,27
The baseline level of pain consisted of
the average of NRS-PI scores taken daily over the 5 days
before the start of treatment, and subsequent scores
were completed daily during treatment. Subjects com-
pleted the McGill Pain Questionnaire at the rst visit
before the initiation of treatment and again at the end of
3 weeks of treatment.
Evoked Pain. All subjects had a sensory examination
completed by study physicians at the time of screening.
Dynamic tactile allodynia was tested using 1-in-wide
foam brushes,
28
whereby strokes of 35 cm in length
and of 1 s in duration were applied over the site of pain,
and patients were asked to grade the magnitude of un-
pleasantness using a visual analog scale. Anchors at each
extreme stated not unpleasant and extremely unpleas-
ant. Pinprick hyperalgesia was tested using an auto-
claved standardized safety pin applied over the painful
site, and subjects were asked to grade the magnitude of
hyperalgesia on a visual analog scale by comparing the
evoked sensation caused by the pin in the area of their
pain with that experienced in a corresponding normal
site (usually contralateral). Pinprick hypesthesia was
tested using the same pin over the entire affected limb or
body region near the pain, and hypesthesia was docu-
mented as present or absent. Testing for evoked pain
Table 1. Inclusion and Exclusion Criteria
Inclusion Criteria Exclusion Criteria
Nonpregnant adult Evidence of another type of pain
as severe as the pain under
study
Established diagnosis of
postherpetic neuralgia,*
diabetic neuropathy, or
postsurgical/posttraumatic
neuropathic pain
Evidence of another type of
neuropathic pain not included
in this study
Moderate to severe pain all or
most of the time persisting
despite other treatment
modalities
Major depression requiring
treatment
Pain has persisted for 3
months or longer
Allergy to amitriptyline or
ketamine
Presence of dynamic tactile
allodynia or pinprick
hyperalgesia in the area of
pain
Ongoing use of a monoamine
oxidase inhibitor
Normal cognitive and
communicative ability as
judged by clinical
assessment and ability to
complete self-report
questionnaires
* Postherpetic neuralgia: chronic pain precipitated by an episode of acute herpes
zoster which persists after the vesicles have healed. Diabetic neuropathy:
symptoms and signs of diffuse, painful, predominantly sensory neuropathy or
single or multiple mononeuropathy related to diabetes. Postsurgical/post-
traumatic neuropathic pain: symptoms of spontaneous pain for 3 months or
longer after a surgical procedure or trauma.
141 TOPICAL AMITRIPTYLINE AND KETAMINE IN NEUROPATHIC PAIN
Anesthesiology, V 103, No 1, Jul 2005
was done on the rst visit prior to treatment, and again
after 2 and 3 weeks of treatment.
Perceived Disability. The Pain Disability Index as-
sesses the degree to which respondents perceive them-
selves to be disabled in 7 different areas of daily living
(home, social, recreational, occupational, sexual, self-
care, and life support).
29
For each life domain, respon-
dents are asked to provide perceived disability ratings on
11-point scales with the endpoints 0 (no disability) and
10 (total disability). The Pain Disability Index has been
shown to be internally reliable and signicantly corre-
lated with objective indices of disability.
30
The Pain
Disability Index was included to examine treatment ef-
fects on pain-related disability.
Patient Satisfaction. An 11-point numerical rating
scale for patient satisfaction was given at the completion
of week 3. Subjects were asked to rate their satisfaction
with the treatment. Verbal anchors included not at all
or completely satised.
Measurement of Plasma Concentrations
Amitriptyline was measured by reverse-phase high-per-
formance liquid chromatography with ultraviolet detec-
tion.
31
The lower limit of detection was 15.7 ng/ml
or 20 ng/ml for amitriptyline and nortriptyline. Ket-
amine and norketamine concentrations were deter-
mined by liquid chromatographymass spectrometry;
this method was validated in human serum for a range of
55,000 ng/ml for ketamine and 2.52,500 ng/ml for
norketamine.# Blood was collected for drug concentra-
tions after 2 and 3 weeks of treatment. For patients
already taking oral amitriptyline, pretreatment plasma
amitriptyline concentrations were also measured before
initiation of treatment.
Randomization
Subjects were randomly assigned to one of four treat-
ment groups using a computer-generated randomization
list. The randomization list was used at the manufactur-
ing site to assign a study number to each allotment of
cream. The study medication containers were numbered
sequentially. The manufacturing site (Pharmaform LLC,
Austin, TX) was separate from the study site. At the study
site, successfully screened patients were entered into
the trial and were provided the next allotment of medi-
cation according to the sequential numbers. Study staff
Two different laboratories were used for the amitriptyline concentrations.
The lower limit of detection was 15.7 ng/ml at the Queen Elizabeth II Health
Sciences Centre laboratory, Halifax, Nova Scotia, Canada, and 20 ng/ml at ACM
Labs, Rochester, New York.
# The ketamine analysis is an internally validated method at ACM Labs,
Rochester, New York, and was performed under Good Laboratory Practice
conditions.
Fig. 1. Summary of study design and conduct.
142 LYNCH ET AL.
Anesthesiology, V 103, No 1, Jul 2005
saw only the sequential numbers on the containers of
cream, thus achieving double-blind randomization.
Data Analysis
The study was estimated to have 83% power to detect
a difference of 1.0 on the pain diary scale as statistically
signicant (P 0.05, two sided), based on an estimated
SD of 1.1 and a sample size of 20 evaluable patients per
group. The study recruited 92 subjects with a SD of 1.4,
giving 80% power to detect the specied difference.
Statistical analyses on the primary outcome measure
(NRS-PI) consisted of intent-to-treat analysis conducted
on all subjects initially randomly assigned to treatment
condition, with the last pain rating carried forward. Pain
severity ratings were transformed to change-from-base-
line scores. Change scores were analyzed as a two-way
mixed factorial analysis of variance (ANOVA) with treat-
ment (placebo, amitriptyline, ketamine, amitriptyline
ketamine) as the between-groups factor and time (week
1, week 2, week 3) as the within-groups factor.
Two-way (treatment time) ANOVAs were con-
ducted separately for McGill Pain Questionnaire sensory
and affective subscales. Because the McGill Pain Ques-
tionnaire was administered only before and after treat-
ment, the time factor was reduced to two levels. Two-
way (treatment time) ANOVAs were conducted
separately for evoked pain measures allodynia and pin-
prick hyperalgesia. One-way ANOVAs were performed
on patient ratings of perceived disability on the Pain
Disability Index and patient satisfaction at the end of
treatment.
Results
Subject Prole
The study design and conduct is summarized in gure
1. Ninety-two subjects were randomized, and 80 sub-
jects completed the protocol. Adverse events prompted
ve withdrawals: two in the placebo group, two in the
ketamine group, and one in the amitriptyline group.
Patient characteristics at baseline are summarized in ta-
bles 2 and 3.
Neuropathic pain conditions represented in the study
sample were diabetic neuropathy (n 20), postherpetic
neuralgia (n 14), and postsurgical/posttraumatic pain
(n 58). The mean age of patients included in the study
was 54 yr for men (range, 2684 yr) and 50 yr for
women (range, 2482 yr); age did not vary signicantly
as a function of sex. Sex distribution, duration of pain,
pain severity at baseline, and number of concurrent
analgesics did not vary signicantly as a function of
diagnostic classication or treatment condition. How-
ever, there was a signicant difference in age across
different diagnostic classications in that patients with
postherpetic neuralgia were older than patients with
diabetic neuropathy, who in turn were older than pa-
tients with postsurgical/posttraumatic neuropathy
(F
2,89
27.8, P 0.001).
Spontaneous pain duration ranged from 3 months to
22 yr, with a mean duration of pain of 69.6 months
(SD 68.5). All subjects exhibited dynamic tactile allo-
dynia, pinprick hyperalgesia, pinprick hypesthesia, or a
combination of allodynia, hyperalgesia, and hypesthesia
at the affected area.
Pain Severity
Intent-to-treat analysis was conducted including all pa-
tients initially randomly assigned to treatment condition,
with the last pain rating carried forward. The results of a
two-way (treatment time) repeated-measures ANOVA
on NRS-PI scores revealed only a signicant main effect
for time (F
3,264
27.2, P 0.001). There was no
signicant effect for treatment (F
3,88
1.3, P 0.27)
and no signicant interaction (F
9,264
0.25, P 0.95).
These results are presented in gure 2.
Analyses conducted on the individuals who completed
the study protocol again revealed a signicant main ef-
fect of time where all groups showed decreased pain
Table 2. Patient Characteristics before Initiation of Topical Drug Treatments
Placebo Ketamine Amitriptyline Amitriptyline and Ketamine
n 25 22 22 23
Men, % 15 (60) 9 (41) 11 (50) 12 (52)
Women, % 10 (40) 13 (59) 11 (50) 11 (48)
Median age (range), yr 52 (3484) 51 (2476) 51 (3078) 52 (2582)
Patients taking oral amitriptyline 6 3 7 7
Median duration of pain (range), months 36 (3264) 36 (9240) 59 (3216) 65 (3240)
Baseline pain severity,* mean (SD) 7.16 (1.22) 7.38 (1.23) 6.85 (1.11) 6.66 (1.22)
Number of concurrent analgesics
0 5 5 1 3
1 8 3 5 8
2 5 5 6 8
3 3 5 6 0
3 1 1 1 1
Total 22 19 19 20
* F
3,88
1.16; P 0.19 (no signicant difference). In the 80 subjects who completed the trial.
143 TOPICAL AMITRIPTYLINE AND KETAMINE IN NEUROPATHIC PAIN
Anesthesiology, V 103, No 1, Jul 2005
over the course of the study (F
3,228
28.4, P 0.001).
No other effects emerged.
For the McGill Pain Questionnaire sensory subscale,
the analysis revealed a signicant main effect for time
(F
1,76
26.2, P 0.001). The main effect for treatment
(F
3,76
1.9, not signicant [NS]**) and the two-way
interaction (F
3,76
0.21, NS) were not signicant. Col-
lapsed across treatments, there was a 29% reduction in
sensory pain ratings. A similar pattern of ndings was
obtained for the McGill Pain Questionnaire affective sub-
scale. A two-way ANOVA yielded a signicant main ef-
fect for time (F
1,76
13.6, P 0.01), whereas the main
effect for treatment (F
3,76
1.4, NS) and the interaction
(F
3,76
0.82, NS) were not signicant. Collapsed across
treatments, there was a 27% reduction in affective pain
ratings.
Secondary Measures
Dynamic tactile allodynia and hyperalgesia were as-
sessed before treatment and at the end of the second and
third weeks of treatment. The pattern of means shows
no discernible pattern associated with treatment. From
the rst to the third assessment, all conditions showed
an overall decline in allodynia (F
2,102
6.7, P 0.01). A
similar pattern of ndings was observed for ratings of
hyperalgesia. Again, there was a signicant main effect
for time (F
2,128
18.9, P 0.001).
There were no signicant differences in perceived
disability. All treatment conditions were associated with
a moderate level of patient satisfaction.
Responder Rate
The number of subjects exhibiting a 30% reduction in
pain scores or greater according to the NRS-PI was 26%
for amitriptyline, 16% for ketamine, 40% for the combi-
nation, and 27% for placebo (chi-square (3) 2.8, P
0.40). The number of subjects exhibiting a 50% reduc-
tion in pain scores or greater was 10% for amitriptyline,
10% for ketamine, 20% for the combination, and 18% for
placebo (chi-square (3) 1.1, P 0.76).
Adverse Events
Adverse events were reported by 30% of the entire
sample of the 92 patients randomized. Reporting of
adverse events was evenly distributed across treatments
(amitriptyline, 26%; ketamine, 30%; ketamineamitripty-
line, 35%; placebo, 27%) (chi-square (3) 0.43, NS). The
most commonly reported adverse events were minor
and temporary skin irritation at the site of application
(n 7: 1 on amitriptyline, 1 on ketamine, 1 on combi-
nation cream, and 4 on placebo); this led to discontinu-
ation of the cream in one patient who was using the
placebo cream. Five patients reported sedation (3 on
amitriptyline, 2 on combination cream) with discontin-
uation of the cream in one patient (on amitriptyline
cream). Miscellaneous adverse events reported included;
tinnitus (1 subject on amitriptyline cream), mint or men-
thol taste (1 subject on combination cream), peeling skin
at site of cream application (1 subject on ketamine
cream), facial acne (1 subject applying combination
cream to trunk), burning feet (1 subject on combination
cream), and swollen feet (1 subject on ketamine cream).
Patients using the placebo cream reported sensitivity to
light (1 subject), pleasant tingling (1 subject), poor sleep
and restless hands (1 subject), and a burning sensation (1
subject).
Plasma Drug Concentrations
Plasma drug concentrations for subjects who were
taking oral amitriptyline concurrently are presented in
table 4. Three subjects who were not taking oral ami-
triptyline exhibited detectable amitriptyline concentra-
tions (table 5); two of these values were false positives
only, because there was no amitriptyline present in the
assigned treatment cream. Three subjects exhibited de-
tectable ketamine concentrations (20, 22, and 33 ng/ml), ** Nonsignicant effects indicate P 0.05.
Table 3. Demographic Characteristics and Baseline Pain
Scores of Subjects in the Different Diagnostic Categories
Diabetic
Neuropathy
Postherpetic
Neuralgia
Postsurgical/
Posttraumatic
n 20 14 58
Men 16 5 26
Women 4 9 16
Median age (range),
yr
54* (3875) 71 (4684) 48 (2470)
Baseline pain
severity, mean (SD)
7.20 (1.23) 7.21 (1.65) 6.8 (1.08)
* Subjects in different diagnostic categories exhibited signicantly different
ages (F
2,89
27.8, P 0.001). Pairs of values with different symbols differ at
P 0.05.
Fig. 2. Change in pain intensity as recorded by the numerical
pain rating scale for pain intensity for all treatment groups.
Ami amitriptyline; Ket ketamine.
144 LYNCH ET AL.
Anesthesiology, V 103, No 1, Jul 2005
none of whom reported any systemic side effects. In the
remaining subjects, there was no detectable amitripty-
line or ketamine.
Concurrent Analgesics and Treatment Response
The numbers of concurrent analgesics according to
treatment group are presented in table 2. All subjects
were stabilized on their concurrent analgesics for 30
days before the study but continued to report pain of
sufcient intensity to meet the inclusion criteria. The
majority of patients (80%) were using at least one con-
current analgesic, and 53% were using two or more
concurrent analgesics. Correlational analysis was con-
ducted to address whether the number of concurrent
analgesics was associated with lack of response to treat-
ment. The analysis revealed that the greater number of
concurrent analgesics was associated with a signicantly
attenuated response to treatment during the rst (r
0.25, P 0.05) and third weeks (r 0.24, P 0.05)
but not the second (r 0.19, P 0.08) week of
treatment. The number of concurrent analgesics did not
differ signicantly as a function of treatment (F
3,76
1.0,
P 0.30). With specic reference to oral amitriptyline,
there was no signicant difference in treatment response
between patients taking oral amitriptyline and those
who were not. The mean dosage of oral amitriptyline in
all groups was 53 mg/day.
Discussion
This study examined topical formulations of novel pe-
ripheral analgesics containing 2% amitriptyline, 1% ket-
amine, and a combination of both in the treatment of
neuropathic pain. The study involved a 3-week, double-
blind, placebo-controlled trial. Pain levels at the end of
the study revealed no signicant differences in changes
in pain scores between treatment groups.
The dose of amitriptyline (2%) was selected on the
basis of a previous trial,
25
efcacy of topical doxepin in
human trials (3.35%),
15,16
(amitriptyline and doxepin
show a similar potency in preclinical trials),
13
and pa-
tient tolerability. The dose of ketamine (1%) was se-
lected on the basis of the drug ratio in the previous
trial,
25
but higher concentrations have been used in case
studies.
21,23
In preclinical studies using the formalin test
(a model involving inammation and ongoing pain),
both amitriptyline and a combination of amitriptyline
with ketamine produced antinociception of a similar
magnitude.
32
However, there is no preclinical data ex-
amining effects of this combination of drugs in a model
of neuropathic pain where the neurobiology of pain is
known to be altered from the uninjured state.
14
There-
fore, there is scope for optimization of doses of both
agents.
Plasma concentrations of amitriptyline and ketamine
indicated no or minimal detectable concentrations of
either active agent or metabolite, indicating a lack of
systemic effect. Only three subjects exhibited any evi-
dence of plasma ketamine, and the concentrations were
generally less than 30 ng/ml (20, 22, 30 ng/ml). The lack
of a systemic effect with topical ketamine at these con-
Table 4. Plasma Amitriptyline/Nortriptyline* Concentrations
(ng/ml) in Patients Taking Oral Amitriptyline Concurrently
Subject No.
(Treatment
Group) Pretreatment Week 2 Week 3
003 (AK) 19/61 72/16 89/21
006 (A) ND 25/ND 25/ND
015 (AK) 50/16 64/18 28/ND
016 (P) 150/37 119/47 50/24
018 (AK) 22/ND 17/ND
019 (A) ND 19/ND
023 (P) 17/21 ND ND
024 (A) 19/ND 29/ND ND
038 (A) 19/13 31/21 ND
039 (P) 86/34 105/50 108/47
041 (K) 28/47 19/45 19/40
043 (AK) 19/ND 22/ND 22/ND
048 (A) 58/45 61/63 50/58
050 (A) ND/92 ND/90 ND/65
053 (P) 17/16 19/16
073 (P) ND/29 ND ND
088 (AK) 56/34 53/30 51/31
089 (P) 64/21 57/ND 40/ND
094 (AK) ND/20 35/33 41/35
116 (K) ND ND ND
117 (A) 28/ND 42/20 31/22
The only side effects reported in this group were local irritation in subject 94
and tinnitus in subject 117. Missing values are due to unavailable blood
plasma concentrations.
* Nortriptyline is an active metabolite of amitriptyline. The lower limit of
detection was 20 ng/ml at ACM Labs, Rochester, New York, and 15.7 ng/ml
at the Queen Elizabeth II Health Sciences Centre laboratory, Halifax, Nova
Scotia, Canada; the dagger designates values obtained at the Queen Eliza-
beth II Health Sciences Centre laboratory.
A amitriptyline; AK amitriptylineketamine combination; K ketamine;
ND not detectable; P placebo.
Table 5. Detectable Amitriptyline/Nortriptyline
Concentrations (ng/ml) Exhibited in Three Subjects Not
Taking Oral Amitriptyline
Subject No.
(Treatment Group) Week 2 Week 3
027 (K)* 111/416 144/540
102 (P) 24/ND ND
104 (A) 73/ND 92/24
* The lower limit of detection was 20 ng/ml at ACM Labs, Rochester, New
York, and 15.7 ng/ml at the Queen Elizabeth II Health Sciences Centre
laboratory, Halifax, Nova Scotia, Canada; the asterisk designates values
obtained at the Queen Elizabeth II Health Sciences Centre laboratory.
Subject 027 was not taking oral amitriptyline or any other tricyclic or similar
medication; he reported no side effects that would be unusual at this plasma
concentration. The concentration detected therefore reects a false positive
value. Subject 102 was using placebo cream; the concentration detected
therefore reects a false positive value. Subject 104 reported no side
effects.
A amitriptyline; K ketamine; ND not detectable; P placebo.
145 TOPICAL AMITRIPTYLINE AND KETAMINE IN NEUROPATHIC PAIN
Anesthesiology, V 103, No 1, Jul 2005
centrations is supported by a recent study that demon-
strated that plasma concentrations of ketamine in the
range of 126362 ng/ml were required to increase pain
thresholds in patients with neuropathic pain; lower con-
centrations of ketamine exhibited no signicant effect.
33
A recent randomized placebo-controlled trial exam-
ined a higher dose of topical amitriptyline and ketamine
(4% and 2%, respectively) using an enriched enrollment
design.
34
That study identied a 52% responder rate in
250 subjects with postherpetic neuralgia after 1 week of
open treatment with the drug combination; 118 subjects
were then randomly assigned to receive 4% amitripty-
line2% ketamine, 2% amitriptyline1% ketamine, or pla-
cebo for 2 weeks.
34
Mean average daily pain intensity
using the NRS-PI went from 6.4 at baseline to 3.28 for
the higher-dose cream, 4.08 for the lower-dose cream,
and 4.34 for placebo, with the higher-dose cream effect
being statistically signicant. The number of subjects
attaining a 30% reduction in pain intensity was 46% for
the higher-dose cream, 26% for the lower-dose cream,
and 19% for the placebo; again, the higher-concentration
cream effect was statistically signicant. Plasma concen-
trations of either drug were minimal.
34
These results
indicate that the higher-concentration cream leads to a
greater responder rate than was observed with the low-
er-concentration cream, without signicantly increasing
the risk of systemic absorption in the majority of subjects.
Conclusion
In conclusion, this randomized, placebo-controlled
trial examining topical 2% amitriptyline, 1% ketamine,
and a combination of both in the treatment of neuro-
pathic pain revealed no differences between groups.
Optimization of doses may be required, because another
study has revealed that higher concentrations of these
agents combined do produce signicant analgesia.
The authors thank James McChesney, M.D., F.R.C.P.C. (Department of Anes-
thesiology, St. Josephs Hospital, Hamilton, Ontario, Canada), Ellen Thompson,
M.D., F.R.C.P.C. (Department of Anesthesiology, Ottawa Pain Clinic, Ottawa,
Ontario, Canada), and Michael Moore, M.D., F.R.C.P.C. (Department of Anesthe-
siology, Oakville-Trafalger Memorial Hospital, Oakville, Ontario, Canada).
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