Topical Amitriptyline and Ketamine in Neuropathic Pain
Mary Elizabeth Lynch,* Alexander John Clark,† Jana Sawynok,‡ and Michael J. Sullivan§
Abstract: Twenty eight subjects with refractory, moderate to severe peripheral neuropathic pain participated in an open label prospective trial examining perceived analgesic effect, patient satisfac- tion, and safety of topical amitriptyline 2%/ketamine 1% cream. Outcome measures included an 11-point numerical rating scale for pain intensity (NRS-PI), a 5-point satisfaction scale, blood chemistry screen, drug and metabolite levels, urinalyses, electrocardiogram (ECG), and physical examination. Adverse events were monitored. Twenty-one subjects completed the trial. At 6 months, subjects reported an average long-term reduction in pain of 34% (standard deviation [SD] ؍ 37%); 5 subjects (25%) achieved 50% or greater reduction in pain and 1 subject (5%) achieved 100% reduction in pain. At 12 months, the average reduction in pain was 37% (SD ؍ 40%); 7 subjects (40%) achieved 50% or greater pain reduction. At the end of the study, 89% of subjects rated their satisfaction as 3/5 or greater and 2 subjects (10%) were pain free. Minimal adverse events were reported and there were no serious medication related adverse events. Blood levels revealed minimal systemic absorption. In conclusion, topical 2% amitriptyline/ 1% ketamine cream was associated with long-term reduction (6-12 months) in perceived pain, moderate to complete satisfaction, and was well tolerated in treatment of neuropathic pain. There was no significant systemic absorption of amitriptyline or ketamine. Perspective: This study demonstrates that topical 2% amitriptyline/1% ketamine, given over 6-12 months, is associated with long-term perceived analgesic effectiveness in treatment of neuropathic pain. Antidepressants and ketamine both produce multiple pharmacologic effects that may contribute to peripheral analgesia; such actions include block of peripheral N-methyl-D-aspartate receptors, local anesthetic properties, and interactions with adenosine systems.
2005 by the American Pain Society Key words: Neuropathic pain, topical amitriptyline and ketamine, clinical trial.
Theinvolvementofperipheralmechanismsinthe trial, in 11 patients who took part in the 7-day open
generation of neuropathic pain suggests that the
phase of the trial, there was a significant analgesic effect
use of topical approaches may be a useful treat-
from day 3 to day 7 of treatment. The goal of this open-
ment Controlled clinical trials have demon-
label prospective study was to assess perceived effec-
strated efficacy for topical local anaesthet-
tiveness, patient satisfaction, and tolerability of a
higher-dose combination cream (2% amitriptyline/1%
pain. In a previous pilot trial, we examined the analgesic
ketamine) over a longer period of time (6-12 months)
effects of a topical cream containing 1% amitriptyline/
in a mixed group of patients with neuropathic pain due
0.5% Although there was no acute treatment
to diabetic neuropathy, postherpetic neuralgia, or post-surgical/post-traumatic pain. A mixed group was chosen
effect during the 2-day placebo controlled part of the
for study because this group most closely resembles thepopulation we see in the pain clinic. In addition, this is
Received December 22, 2004; Revised April 27, 2005; Accepted April 29,
the same group used in previous trials examining topical
From the *Pain Management Unit, Queen Elizabeth II Health SciencesCentre and Department Psychiatry, Dalhousie University, Halifax, NovaScotia, Canada; †Chronic Pain Centre, Calgary Health Region and Depart-ment of Anesthesia, University of Calgary, Calgary, Alberta, Canada; ‡De-
Materials and Methods
partment of Pharmacology, Dalhousie University, Halifax, Nova Scotia,Canada; and the §Department of Psychology, University of Montreal,Montreal, Quebec, Canada. Participants
Supported by Epicept Corporation, Englewood Cliffs, NJ.
Study subjects were recruited from a tertiary care pain
Address reprint requests to Mary Lynch, MD, FRCPC, Director of Research,
clinic (Pain Management Unit, Queen Elizabeth II Health
Pain Management Unit, Queen Elizabeth II Health Sciences Centre, 4thFloor Dickson Centre, Room 4086, Halifax, Nova Scotia, B3H 1V7. E-mail:
Sciences Center, Halifax, Nova Scotia). Subjects had pre-
viously completed a randomized controlled trial with the
same topical Subjects from that trial who were
2005 by the American Pain Societydoi:10.1016/j.jpain.2005.04.008
interested in participating in the current trial and who
The Journal of Pain, Vol 6, No 10 (October), 2005: pp 644-649
had not experienced an adverse event were eligible for
Subject Satisfaction
the current trial. Inclusion criteria were: 1) nonpregnant
A 5-point numerical rating scale for satisfaction with
adults with a neuropathic pain diagnosis of postherpetic
the treatment was used to assess how satisfied subjects
neuralgia, diabetic neuropathy, or postsurgical/post-
were with the cream. Subjects were asked by the study
traumatic neuropathic pain; 2) presence of moderate to
nurse to rate their satisfaction with the topical cream
severe pain all or most of the time despite other treat-
since the last visit on a 1 to 5 point scale: (1 ϭ poor, 2 ϭ
ment modalities; 3) pain that has persisted for 3 months
fair, 3 ϭ good, 4 ϭ very good, 5 ϭ excellent).
or longer; 4) presence of dynamic tactile allodynia orpinprick hyperalgesia in the area of pain; and 5) normal
Laboratory Measures and Physical
cognitive and communicative ability as judged by clinical
Assessment
assessment and completion of self-report question-
Routine blood screens for hematology (complete
naires. Exclusion criteria were: 1) evidence of another
blood count [CBC] and differential) and blood chemistry
type of pain as severe as the pain under study; 2) evi-
(hepatic and renal function, glucose, electrolytes) were
dence of another type of neuropathic pain not included
done at the start and end of the study and every 2
in this study; 3) a major depression requiring treatment;
months during the study, along with vital signs and a
4) an allergy to ketamine or amitriptyline; or 5) concom-
urinalysis. A full physical examination and electrocardio-
itant use of a monoamine oxidase inhibitor. Subjects
gram (ECG) were performed at the start and finish of the
were permitted to continue using previous oral analge-
sics including nonsteroidal antiinflammatory drugs, opi-oids, antidepressants (including amitriptyline and other
Measurement of Serum Levels
Study subjects were examined by physician specialists
Amitriptyline was measured by reverse phase high-per-
in pain management who confirmed the diagnostic sub-
formance liquid chromatography with ultraviolet (UV)
category of neuropathic pain and completed the physical
The lower limit of detection was 15.7 ng/mL
and sensory examination. It was also ascertained that
for amitriptyline and nortriptyline. Ketamine and nor-
subjects did not have any other medical condition that
ketamine levels were determined by liquid chromatog-
would affect their ability to safely take part in the study.
raphy/mass spectrometry; this method was validated in
All those who met the criteria listed above, and who
human serum for a range of 5 to 5000 ng/mL for ket-
provided written informed consent, were included. The
amine and 2.5 to 2500 ng/mL for norketamine. (The ket-
study was approved by the research ethics review com-
amine analysis is an internally validated method at PPD
mittee at the Queen Elizabeth II Health Sciences Centre,
Pharmaco Labs and was performed under GLP condi-
tions.) Blood was collected for drug levels every 2 monthsduring treatment and at the end of treatment. For sub-
Procedure
jects taking oral amitriptyline, pretreatment serum ami-
The study treatment consisted of a topical cream con-
triptyline levels were performed prior to initiation of
taining a combination of 2% amitriptyline/1% ketamine.
The vehicle consisted of a moisturizing creamlike base,
Adverse Events
consisting of an oil water emulsion system containingstandard compendial emollients. The cream base used to
Adverse events were monitored, recorded, and re-
formulate the topical delivery formulation is proprietary
ported according to ICH-GCP guidelines.
and in development, and was formulated to enhancedelivery of compounds. Subjects were instructed to clean
the area and then apply 4 mL of cream to the site of
Twenty-eight subjects participated in the study. During
maximum pain (size of the area of pain varied) 3 times
the study, 7 subjects withdrew. Reasons for withdrawal
per day. Subjects returned to the study site every 2
included: adverse events (4), lack of efficacy (2), and pro-
months subsequent to initiation of treatment, at which
tocol violation (1). In total, 21 subjects completed the
time pain levels and satisfaction were documented using
study (18 of whom used the cream for 12 months, 3 for 6
the measures described below, vital signs were recorded,
months). (The reason for the shorter duration in the last
and blood and urine samples were done. A full physical
3 patients is that the manufacturer stopped supplying
examination was completed pretreatment and at the
this concentration of cream.) The characteristics of the
study population are presented in Details re-
Outcomes
garding the 7 subjects who did not complete the studyare presented in
Spontaneous Pain
The measure of spontaneous pain consisted of an 11-
Perceived Effectiveness and Patient
point numerical rating scale for pain intensity (NRS-PI)
Satisfaction With Treatment
with the anchors “no pain” and “severe pain.” Patients
At the end of 6 months, subjects reported average
were asked by the nurse to grade the severity of their
long-term reduction in pain of 34% (SD ϭ 37%); 5 sub-
jects (25%) achieved 50% or greater reduction in pain,
Topical Amitriptyline Ketamine in Neuropathic Pain
and 1 subject (5%) achieved 100% reduction in pain
Table 1. Demographic Characteristics and
At the end of 12 months the average pain reduc-
Baseline Pain Scores of Subjects in the
tion was 37% (SD ϭ 40%); 7 subjects (40%) achieved 50%
Different Diagnostic Categories Who
or greater reduction in pain and 2 (11%) achieved 100%
Completed the Trial
reduction in pain, which they attributed to the cream,
and were pain free by the end of the study. The majority
of subjects (89%) rated their satisfaction as 3/5 or greater(good – excellent) Five subjects (24%) were
able to decrease or discontinue oral analgesics (including
opioids) due to the decreased pain they attributed to the
Dose of Cream
Subjects were instructed to use the cream at a dose of
4 mL 3 times per day (tid); however, there was flexibility
in that they were permitted to use less. The details of
doses used were as follows: 6 subjects continued to use
the cream 3 times a day throughout the study, 5 used 3
*There was no significant difference between groups in baseline pain.
mL tid, 2 used 2.5 mL tid, 6 used 2 mL tid, 2 used 1.5 mLtid, 3 used 1 mL tid, and 1 used less than 1 mL tid; 2patients changed their dose during the study, 1 from 4
Table 2. Data Regarding the 7 subjects Who Did Not Complete the Trial, Reasons for Noncompletion and Bloodwork (NORTRIPTYLINE) PRETREATMENT/ (NORKETAMINE) PRETREATMENT/ 24/17/45/11/0/0 0/0/0/0/360/0
(20/0/41/0/0/0) 0/23/13/17/0 0/33/0/26/0
(0/0/0/0/0)
(0/0/0/0/0) 16/15/19
(11/14/15)
NOTE: 0 ϭ none detected. *Patients on oral amitriptyline concurrently.
†Patient not on oral amitriptyline, appears to be a false positive value. Table 3. NRS-PI and Satisfaction Scores for Subjects Who Completed the Study
Abbreviation: NRS-PI, numerical pain rating scale-pain intensity.
NOTE: Satisfaction scale; 1 ϭ poor, 2 ϭ fair, 3 ϭ good, 4 ϭ very good, 5 ϭ excellent. Table 4. Subject Characteristics and Case Comments Regarding All Subjects Who Entered the Trial
Reported decreased pain at first, but by 8 mos lost effect and
Pain, stamina, activity all improved, able to wear dress shoes, able to
get back to work part time, allodynia resolved
Excellent pain relief, able to do physical activities had not been able
Overall benefit, able to discontinue muscle relaxant
Pain improved with the cream, patient was able to return to work
Pain improved, able to walk and stand for longer, able to
discontinue Tylenol #3, decrease in severity of allodynia
Improvement in surface pain and sensitivity, able to shave again,
Decrease in pain and decrease in severity of allodynia
Pain improved, able to pursue outdoor activities with greater ease,
states “I don’t know what I will do without it” (the cream), ableto decrease hydromorphone
Pain improved with cream but patient had to be withdrawn from
study due to alcoholic relapse with elevated liver enzymesresolving rash as well.
Pain much improved, down to 2/10, hyperalgesia also improved,
able to do more without worrying about feet, able to discontinueNSAID and Tylenol #3, decreased Tylenol #1 and Tylenol
Patient withdrew at 18 weeks due to lack of effectiveness
Dramatic decrease in pain 9/10 down to 2/10, resolution of
Much improved, able to discontinue gabapentin
Patient never ended up using the cream, said inconvenient with
Pain decreased “a lot,” allodynia and hyperalgesia also decreased,
now able to wear flip-flops, unable to tolerate these before cream
Patient reports pain as much better, especially appreciates no side
Pain and allodynia resolved, patient reported no pain
Surface pain and sensitivity improved, clothing more tolerable
Patient reported cream helped, also had DCSI inserted during the
trial which brought significant benefit, but wanted to continuecream, returned to work, discontinued hydromorphone
Cream most helpful with surface pain and sensitivity, able to shave
Patient reported fatigue and decided to withdraw from the study at
3 weeks, no amitriptyline, ketamine, or metabolites detected onbloodwork
Patient noted significant decrease in dysesthetic pruritic foot pain (a
part of her pain) that gave her an overall feeling of better paincontrol
Patient reports cream helps with his facial pain
Cream helped with sensitivity at first but then noted fatigue, dry
mouth, and weight gain so withdrew at 16 weeks, noamitriptyline or ketamine detected on bloodwork
Abbreviations: A, allodynia; H, hyperalgesia; O, hypoesthesia.
NOTE: NC indicates noncompleter for reasons indicated in
*Concurrent medications included oral antidepressants, anticonvulsants, nonsteroidal anti- inflammatories and opioids.
Topical Amitriptyline Ketamine in Neuropathic Pain
Table 5. Drug Levels in 7 Completers with Detectable Amitriptyline or Nortriptyline levels PRETREATMENT/SUBSEQUENT LEVELS POSSIBLE TREATMENT RELATED ADVERSE EVENT15/0/14/0/0/15/0
(0/0/0/0/0/0/0) 0/13*/0/0/0/0/0
(0/0/0/0/0/0/0) 0/0/0/0/0/0/0
(29/64/57/70/97/56/130) 26/19/22/28/15/39/35
Occasional sensation of increased heart rate
(45/31/28/39/30/60/67) 22/40/58/56/27/0
(19/32/47/34/18/0) 0/12/11/0/23/14/13*
(0/0/0/0/0/0/0) 63/120/98/0
(18/38/45/0)
mL tid to 6 mL twice daily (bid) at 17 weeks, the other
Discussion
from 3 mL tid to 3 mL tid at 30 weeks.
Randomized controlled trials have demonstrated that
topical doxepin produces analgesia in a mixed group of
Adverse Events
patients with neuropathic and that topical ami-
Of 21 subjects who completed the study, 3 experienced
triptyline 4% in combination with ketamine 2% exhibits
adverse events judged to be possibly related to the study
a significant analgesic effect in patients with posther-
drug. One subject reported intermittent drowsiness and
petic A lower-dose cream containing 2% am-
dry mouth but wanted to continue on the cream (blood
itriptyline and 1% ketamine did not exhibit a statistically
levels revealed detectable amitriptyline 30 ng/mL at visit
significant analgesic effect in a randomized controlled
2, but none was detectable at other visits), 1 further
trial of patients with mixed diagnoses of neuropathic
subject reported intermittent sensations of rapid heart
however, post hoc analyses identified that the
rate, and another reported intermittent palpitations
lower dose amitriptyline/ketamine cream may be anal-
(both of these patients were also taking oral amitripty-
gesic in a subgroup of subjects with mixed neuropathic
line and blood levels taken throughout the study re-
There are also case reports that topical ketamine
vealed minimal changes) There were no clini-
provides analgesia in certain instances of neuropathic
cally significant abnormalities on patient ECG or vital
signs. Physical examination at the exit visit revealed no
The present open-label study extends previous litera-
medication-related adverse events. Two subjects exhib-
ture by demonstrating that the long-term use (ie, up to
ited abnormalities on laboratory studies; 1 exhibited
12 months) of topical 2% amitriptyline/1% ketamine is
transient elevation in total bilirubin and lactate dehy-
associated with long-term perceived analgesic effective-
drogenase (LDH) at visit 4 that resolved and did not re-
ness and satisfaction for treatment of a mixed group of
cur, and 1 exhibited a low blood sugar on 2 occasions.
patients with neuropathic pain, with no significant sys-
None of these events was judged to be related to the
temic absorption and minimal adverse events. Prior to
study drug. It should be noted, however, that only sub-
treatment, subjects reported moderate to severe pain
jects who had not developed adverse events in a previous
that persisted in spite of previous or ongoing use of an-
randomized controlled trial were included in the current
algesics and were thus refractory to other treatments.
trial and there were still 4 withdrawals due to adverse
The lack of significant systemic absorption supports a
topical rather than a systemic effect. This study also indi-cates that topical delivery is associated with minimal side
Serum Drug Levels
In the 21 subjects who completed the trial, there was
The mechanisms involved in peripheral analgesia in in-
no detectable ketamine or norketamine. In 14 subjects,
stances of neuropathic pain are unclear. Although the
there was no amitriptyline or nortriptyline detected. Five
neurobiology of pain is altered in neuropathic pain con-
of the 7 subjects exhibiting detectable blood amitripty-
ditions (and this leads to an altered systemic pharmacol-
line or nortriptyline were taking oral amitriptyline con-
ogy), topical approaches have been shown to be of use in
currently; details appear in Overall, there was no
neuropathic Antidepressants and ketamine both
significant systemic absorption of amitriptyline or ket-
exhibit peripheral analgesic properties in various preclin-
ical models of pain, and produce multiple pharmacolog-
ical effects that may contribute to peripheral analgesia;
Conclusions
such actions include block of peripheral N-methyl-D-as-partate receptors, local anesthetic properties, and inter-
Topical 2% amitriptyline/ 1% ketamine cream was as-
sociated with long-term patient satisfaction and waswell tolerated with minimal side effects in the treatment
As with all open-label studies, the results of this study
of chronic moderate to severe neuropathic pain in a
should be interpreted cautiously. While further random-
group of 21 subjects in an open-label trial. Future con-
ized controlled trials are necessary to clearly identify an-
trolled trials should be performed to further evaluate
algesic efficacy of the low-dose amitriptyline/ketamine
the role of topical amitriptyline and ketamine in the
cream, the current trial along with the randomized pla-
cebo controlled trial regarding the higher-dose amitrip-tyline/ketamine support the notion that topical
Acknowledgments
amitriptyline/ketamine cream appears to be a reason-able treatment option in the treatment of neuropathic
The authors thank Ms. Paulette Nauss for her assis-
pain due to diabetic neuropathy, postherpetic neuralgia,
tance with data collection and Ms. Myrna Yazer for ad-
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