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

Topical 2% Amitriptyline and 1% Ketamine in NeuropathicPain SyndromesA Randomized, Double-blind, Placebo-controlled TrialMary 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-controlled3-week study evaluated the efficacy of topical 2% amitriptyline,1% ketamine, and a combination of both in treating patientswith neuropathic pain.Methods: Ninety-two patients with diabetic neuropathy, pos-

therpetic neuralgia, or postsurgical/posttraumatic neuropathicpain with allodynia, hyperalgesia, or pinprick hypesthesiawere randomly assigned to receive one of four creams (placebo,2% amitriptyline, 1% ketamine, or 2% amitriptyline1% ket-amine combined). The primary outcome measure was changein average daily pain intensity (baseline week vs. final week)using an 11-point numerical pain rating scale. Secondary out-comes included the McGill Pain Questionnaire, measures ofallodynia 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 betweengroups. Blood concentrations revealed no significant systemicabsorption. Minimal side effects were encountered.Conclusion: This randomized, placebo-controlled trial exam-

ining topical 2% amitriptyline, 1% ketamine, and a combinationin the treatment of neuropathic pain revealed no differencebetween groups. Optimization of doses may be required, be-cause another study has revealed that higher concentrations ofthese agents combined do produce significant analgesia.

NEUROPATHIC pain is now understood to involve neu-ral responses in which both peripheral and centralmechanisms contribute to the generation of spontane-ous pain and evoked aspects of pain, including allodyniaand hyperalgesia.14 The involvement of peripheralmechanisms suggests the use of topical approaches inthe treatment of neuropathic pain. Both capsaicin5,6 andlocal anesthetics79 can be useful in the relief of neuro-pathic pain when administered locally to peripheral sitesas a cream or a patch, respectively.

Additional novel drug classes may also be effective inalleviating 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 neuropathicpain1114 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 ofperipheral origin.17 Local injections of ketamine, whichblocks N-methyl-D-aspartate receptors, produce antinoci-ception in a preclinical model of ongoing pain18 and leadto antihyperalgesic and some analgesic actions in humanexperimental models of inflammatory pain.19,20 Therealso are case reports of pain relief after topical adminis-tration of ketamine in sympathetically maintainedpain21,22 and cancer pain,23 but there are no publishedcontrolled trials demonstrating such efficacy.24

In a previous pilot trial, we examined the potentialanalgesic effects of a topical formulation of a creamcontaining 1% amitriptyline and 0.5% ketamine.25 Al-though there was no acute treatment effect during the2-day placebo-controlled part of the trial, in 11 patientswho took part in the 7-day open phase of the trial, therewas a significant analgesic effect by day 3 of treatment,which continued to increase to day 7. The results of theopen phase trial suggested that a longer treatment pe-riod was necessary to observe a beneficial effect. Instudies using topical doxepin for neuropathic pain ofmixed etiology, pain relief was observed primarily1028 days after drug application.15,16 The purpose ofthe current study was to examine the efficacy of topicalpreparations of 2% amitriptyline, 1% ketamine, and acombination of amitriptyline with ketamine for the treat-ment of neuropathic pain over a 3-week treatment pe-riod in a randomized placebo-controlled trial. Patientswith mixed neuropathic pain were chosen for studybecause they reflect the reality of clinic populations, andprevious studies have demonstrated that patients withneuropathic pain from different diagnostic categoriesexhibit a response to peripheral doxepin (another tricy-clic antidepressant)15,16 and peripheral ketamine.21,22

Materials and Methods

SubjectsStudy subjects were recruited from three hospital out-

patient pain management units in eastern Canada. Thestudy took place from September 2001 to December2002. 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 HealthSciences Centre, Halifax, Nova Scotia, Canada. Associate Professor, Departmentof 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, DalhousieUniversity, 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 meetingof 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 theJournal Web site, www.anesthesiology.org.

Anesthesiology, V 103, No 1, Jul 2005 140

using prestudy oral analgesics including nonsteroidalantiinflammatory drugs, opioids, antidepressants (includ-ing amitriptyline and other tricyclics), and anticonvul-sants.

Study subjects were examined by physician specialistsin pain management who confirmed the diagnostic sub-category of neuropathic pain and completed the sensoryexamination. It was also ascertained that subjects did nothave any other medical condition that would affect theirability to safely take part in the study. All those who metthe criteria listed in table 1 and provided written in-formed consent were included. The study was approvedby 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).

InterventionsStudy 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 wereidentical in consistency, color, and volume.

ProcedureSubjects were instructed to clean the area and then

apply 4 ml cream to the site of maximum pain (size ofthe area of pain varied) three times per day for 3 weeks.Subjects returned to the study site 2 and 3 weeks afterinitiation of treatment, at which time pain levels weredocumented using measures described below (Out-comes section), and blood samples were taken for assayof amitriptyline and ketamine concentrations. The usedtubes of cream were collected, weighed, and recordedto assess compliance with treatment.

ObjectivesThe primary objective of the study was to determine

whether topical creams containing amitriptyline, ket-amine, or a combination exhibited analgesic efficacy fortreatment of neuropathic pain. Secondary study objec-tives included identifying patient satisfaction with thecream and determination of whether systemic absorp-tion occurred.

OutcomesSpontaneous Pain. The primary outcome measure

consisted of an 11-point numerical rating scale for painintensity (NRS-PI) with the anchors no pain and se-vere pain. The short-form McGill Pain Questionnairewas included as an additional measure of spontaneouspain; this generates subscales that assess sensory andaffective dimensions of pain experience. These mea-sures have been developed and validated as measures ofclinical pain.26,27 The baseline level of pain consisted ofthe average of NRS-PI scores taken daily over the 5 daysbefore the start of treatment, and subsequent scoreswere completed daily during treatment. Subjects com-pleted the McGill Pain Questionnaire at the first visitbefore the initiation of treatment and again at the end of3 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-widefoam brushes,28 whereby strokes of 35 cm in lengthand 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 eachextreme stated not unpleasant and extremely unpleas-ant. Pinprick hyperalgesia was tested using an auto-claved standardized safety pin applied over the painfulsite, and subjects were asked to grade the magnitude ofhyperalgesia on a visual analog scale by comparing theevoked sensation caused by the pin in the area of theirpain with that experienced in a corresponding normalsite (usually contralateral). Pinprick hypesthesia wastested using the same pin over the entire affected limb orbody 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 painas severe as the pain understudy

Established diagnosis ofpostherpetic neuralgia,*diabetic neuropathy, orpostsurgical/posttraumaticneuropathic pain

Evidence of another type ofneuropathic pain not includedin this study

Moderate to severe pain all ormost of the time persistingdespite other treatmentmodalities

Major depression requiringtreatment

Pain has persisted for 3months or longer

Allergy to amitriptyline orketamine

Presence of dynamic tactileallodynia or pinprickhyperalgesia in the area ofpain

Ongoing use of a monoamineoxidase inhibitor

Normal cognitive andcommunicative ability asjudged by clinicalassessment and ability tocomplete self-reportquestionnaires

* Postherpetic neuralgia: chronic pain precipitated by an episode of acute herpeszoster which persists after the vesicles have healed. Diabetic neuropathy:symptoms and signs of diffuse, painful, predominantly sensory neuropathy orsingle or multiple mononeuropathy related to diabetes. Postsurgical/post-traumatic neuropathic pain: symptoms of spontaneous pain for 3 months orlonger after a surgical procedure or trauma.

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was done on the first visit prior to treatment, and againafter 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 on11-point scales with the endpoints 0 (no disability) and10 (total disability). The Pain Disability Index has beenshown to be internally reliable and significantly corre-lated with objective indices of disability.30 The PainDisability 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 completionof week 3. Subjects were asked to rate their satisfactionwith the treatment. Verbal anchors included not at allor completely satisfied.

Measurement of Plasma ConcentrationsAmitriptyline was measured by reverse-phase high-per-

formance liquid chromatography with ultraviolet detec-tion.31 The lower limit of detection was 15.7 ng/mlor 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 of55,000 ng/ml for ketamine and 2.52,500 ng/ml fornorketamine.# Blood was collected for drug concentra-tions after 2 and 3 weeks of treatment. For patientsalready taking oral amitriptyline, pretreatment plasmaamitriptyline concentrations were also measured beforeinitiation of treatment.

RandomizationSubjects were randomly assigned to one of four treat-

ment groups using a computer-generated randomizationlist. The randomization list was used at the manufactur-ing site to assign a study number to each allotment ofcream. The study medication containers were numberedsequentially. The manufacturing site (Pharmaform LLC,Austin, TX) was separate from the study site. At the studysite, successfully screened patients were entered intothe 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 HealthSciences Centre laboratory, Halifax, Nova Scotia, Canada, and 20 ng/ml at ACMLabs, Rochester, New York.

# The ketamine analysis is an internally validated method at ACM Labs,Rochester, New York, and was performed under Good Laboratory Practiceconditions.

Fig. 1. Summary of study design and conduct.

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saw only the sequential numbers on the containers ofcream, thus achieving double-blind randomization.

Data AnalysisThe study was estimated to have 83% power to detect

a difference of 1.0 on the pain diary scale as statisticallysignificant (P 0.05, two sided), based on an estimatedSD of 1.1 and a sample size of 20 evaluable patients pergroup. The study recruited 92 subjects with a SD of 1.4,giving 80% power to detect the specified difference.

Statistical analyses on the primary outcome measure(NRS-PI) consisted of intent-to-treat analysis conductedon all subjects initially randomly assigned to treatmentcondition, with the last pain rating carried forward. Painseverity ratings were transformed to change-from-base-line scores. Change scores were analyzed as a two-waymixed factorial analysis of variance (ANOVA) with treat-ment (placebo, amitriptyline, ketamine, amitriptylineketamine) as the between-groups factor and time (week1, week 2, week 3) as the within-groups factor.

Two-way (treatment time) ANOVAs were con-ducted separately for McGill Pain Questionnaire sensoryand 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 conductedseparately for evoked pain measures allodynia and pin-prick hyperalgesia. One-way ANOVAs were performedon patient ratings of perceived disability on the PainDisability Index and patient satisfaction at the end oftreatment.

Results

Subject ProfileThe study design and conduct is summarized in figure

1. Ninety-two subjects were randomized, and 80 sub-jects completed the protocol. Adverse events promptedfive 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 studysample were diabetic neuropathy (n 20), postherpeticneuralgia (n 14), and postsurgical/posttraumatic pain(n 58). The mean age of patients included in the studywas 54 yr for men (range, 2684 yr) and 50 yr forwomen (range, 2482 yr); age did not vary significantlyas a function of sex. Sex distribution, duration of pain,pain severity at baseline, and number of concurrentanalgesics did not vary significantly as a function ofdiagnostic classification or treatment condition. How-ever, there was a significant difference in age acrossdifferent diagnostic classifications in that patients withpostherpetic neuralgia were older than patients withdiabetic neuropathy, who in turn were older than pa-tients with postsurgical/posttraumatic neuropathy(F2,89 27.8, P 0.001).

Spontaneous pain duration ranged from 3 months to22 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 acombination of allodynia, hyperalgesia, and hypesthesiaat the affected area.

Pain SeverityIntent-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 atwo-way (treatment time) repeated-measures ANOVAon NRS-PI scores revealed only a significant main effectfor time (F3,264 27.2, P 0.001). There was nosignificant effect for treatment (F3,88 1.3, P 0.27)and no significant interaction (F9,264 0.25, P 0.95).These results are presented in figure 2.

Analyses conducted on the individuals who completedthe study protocol again revealed a significant 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 23Men, % 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 7Median 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 31 8 3 5 82 5 5 6 83 3 5 6 0 3 1 1 1 1Total 22 19 19 20

* F3,88 1.16; P 0.19 (no significant difference). In the 80 subjects who completed the trial.

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over the course of the study (F3,228 28.4, P 0.001).No other effects emerged.

For the McGill Pain Questionnaire sensory subscale,the analysis revealed a significant main effect for time(F1,76 26.2, P 0.001). The main effect for treatment(F3,76 1.9, not significant [NS]**) and the two-wayinteraction (F3,76 0.21, NS) were not significant. Col-lapsed across treatments, there was a 29% reduction insensory pain ratings. A similar pattern of findings wasobtained for the McGill Pain Questionnaire affective sub-scale. A two-way ANOVA yielded a significant main ef-fect for time (F1,76 13.6, P 0.01), whereas the maineffect for treatment (F3,76 1.4, NS) and the interaction(F3,76 0.82, NS) were not significant. Collapsed acrosstreatments, there was a 27% reduction in affective painratings.

Secondary MeasuresDynamic tactile allodynia and hyperalgesia were as-

sessed before treatment and at the end of the second andthird weeks of treatment. The pattern of means showsno discernible pattern associated with treatment. Fromthe first to the third assessment, all conditions showedan overall decline in allodynia (F2,102 6.7, P 0.01). Asimilar pattern of findings was observed for ratings ofhyperalgesia. Again, there was a significant main effectfor time (F2,128 18.9, P 0.001).

There were no significant differences in perceiveddisability. All treatment conditions were associated witha moderate level of patient satisfaction.

Responder RateThe 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% forplacebo (chi-square (3) 1.1, P 0.76).

Adverse EventsAdverse events were reported by 30% of the entire

sample of the 92 patients randomized. Reporting ofadverse events was evenly distributed across treatments(amitriptyline, 26%; ketamine, 30%; ketamineamitripty-line, 35%; placebo, 27%) (chi-square (3) 0.43, NS). Themost commonly reported adverse events were minorand 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 theplacebo cream. Five patients reported sedation (3 onamitriptyline, 2 on combination cream) with discontin-uation of the cream in one patient (on amitriptylinecream). Miscellaneous adverse events reported included;tinnitus (1 subject on amitriptyline cream), mint or men-thol taste (1 subject on combination cream), peeling skinat site of cream application (1 subject on ketaminecream), facial acne (1 subject applying combinationcream to trunk), burning feet (1 subject on combinationcream), and swollen feet (1 subject on ketamine cream).Patients using the placebo cream reported sensitivity tolight (1 subject), pleasant tingling (1 subject), poor sleepand restless hands (1 subject), and a burning sensation (1subject).

Plasma Drug ConcentrationsPlasma drug concentrations for subjects who were

taking oral amitriptyline concurrently are presented intable 4. Three subjects who were not taking oral ami-triptyline exhibited detectable amitriptyline concentra-tions (table 5); two of these values were false positivesonly, because there was no amitriptyline present in theassigned treatment cream. Three subjects exhibited de-tectable ketamine concentrations (20, 22, and 33 ng/ml),** Nonsignificant effects indicate P 0.05.

Table 3. Demographic Characteristics and Baseline PainScores of Subjects in the Different Diagnostic Categories

DiabeticNeuropathy

PostherpeticNeuralgia

Postsurgical/Posttraumatic

n 20 14 58Men 16 5 26Women 4 9 16Median age (range),

yr54* (3875) 71 (4684) 48 (2470)

Baseline painseverity, mean (SD)

7.20 (1.23) 7.21 (1.65) 6.8 (1.08)

* Subjects in different diagnostic categories exhibited significantly differentages (F2,89 27.8, P 0.001). Pairs of values with different symbols differ atP 0.05.

Fig. 2. Change in pain intensity as recorded by the numericalpain rating scale for pain intensity for all treatment groups.Ami amitriptyline; Ket ketamine.

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none of whom reported any systemic side effects. In theremaining subjects, there was no detectable amitripty-line or ketamine.

Concurrent Analgesics and Treatment ResponseThe numbers of concurrent analgesics according to

treatment group are presented in table 2. All subjectswere stabilized on their concurrent analgesics for 30days before the study but continued to report pain ofsufficient intensity to meet the inclusion criteria. Themajority of patients (80%) were using at least one con-current analgesic, and 53% were using two or moreconcurrent analgesics. Correlational analysis was con-ducted to address whether the number of concurrentanalgesics was associated with lack of response to treat-ment. The analysis revealed that the greater number ofconcurrent analgesics was associated with a significantlyattenuated response to treatment during the first (r 0.25, P 0.05) and third weeks (r0.24, P 0.05)but not the second (r 0.19, P 0.08) week oftreatment. The number of concurrent analgesics did notdiffer significantly as a function of treatment (F3,76 1.0,P 0.30). With specific reference to oral amitriptyline,there was no significant difference in treatment response

between patients taking oral amitriptyline and thosewho were not. The mean dosage of oral amitriptyline inall 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 ofneuropathic pain. The study involved a 3-week, double-blind, placebo-controlled trial. Pain levels at the end ofthe study revealed no significant differences in changesin pain scores between treatment groups.

The dose of amitriptyline (2%) was selected on thebasis of a previous trial,25 efficacy of topical doxepin inhuman trials (3.35%),15,16 (amitriptyline and doxepinshow 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 previoustrial,25 but higher concentrations have been used in casestudies.21,23 In preclinical studies using the formalin test(a model involving inflammation and ongoing pain),both amitriptyline and a combination of amitriptylinewith ketamine produced antinociception of a similarmagnitude.32 However, there is no preclinical data ex-amining effects of this combination of drugs in a modelof neuropathic pain where the neurobiology of pain isknown to be altered from the uninjured state.14 There-fore, there is scope for optimization of doses of bothagents.

Plasma concentrations of amitriptyline and ketamineindicated no or minimal detectable concentrations ofeither active agent or metabolite, indicating a lack ofsystemic effect. Only three subjects exhibited any evi-dence of plasma ketamine, and the concentrations weregenerally less than 30 ng/ml (20, 22, 30 ng/ml). The lackof 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 89/21006 (A) ND 25/ND 25/ND015 (AK) 50/16 64/18 28/ND016 (P) 150/37 119/47 50/24018 (AK) 22/ND 17/ND019 (A) ND 19/ND023 (P) 17/21 ND ND024 (A) 19/ND 29/ND ND038 (A) 19/13 31/21 ND039 (P) 86/34 105/50 108/47041 (K) 28/47 19/45 19/40043 (AK) 19/ND 22/ND 22/ND048 (A) 58/45 61/63 50/58050 (A) ND/92 ND/90 ND/65053 (P) 17/16 19/16073 (P) ND/29 ND ND088 (AK) 56/34 53/30 51/31089 (P) 64/21 57/ND 40/ND094 (AK) ND/20 35/33 41/35116 (K) ND ND ND117 (A) 28/ND 42/20 31/22

The only side effects reported in this group were local irritation in subject 94and tinnitus in subject 117. Missing values are due to unavailable bloodplasma concentrations.

* Nortriptyline is an active metabolite of amitriptyline. The lower limit ofdetection was 20 ng/ml at ACM Labs, Rochester, New York, and 15.7 ng/mlat the Queen Elizabeth II Health Sciences Centre laboratory, Halifax, NovaScotia, 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/NortriptylineConcentrations (ng/ml) Exhibited in Three Subjects NotTaking Oral Amitriptyline

Subject No.(Treatment Group) Week 2 Week 3

027 (K)* 111/416 144/540102 (P) 24/ND ND104 (A) 73/ND 92/24

* The lower limit of detection was 20 ng/ml at ACM Labs, Rochester, NewYork, and 15.7 ng/ml at the Queen Elizabeth II Health Sciences Centrelaboratory, Halifax, Nova Scotia, Canada; the asterisk designates valuesobtained at the Queen Elizabeth II Health Sciences Centre laboratory. Subject 027 was not taking oral amitriptyline or any other tricyclic or similarmedication; he reported no side effects that would be unusual at this plasmaconcentration. The concentration detected therefore reflects a false positivevalue. Subject 102 was using placebo cream; the concentration detectedtherefore reflects a false positive value. Subject 104 reported no sideeffects.

A amitriptyline; K ketamine; ND not detectable; P placebo.

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centrations is supported by a recent study that demon-strated that plasma concentrations of ketamine in therange of 126362 ng/ml were required to increase painthresholds in patients with neuropathic pain; lower con-centrations of ketamine exhibited no significant 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 enrollmentdesign.34 That study identified a 52% responder rate in250 subjects with postherpetic neuralgia after 1 week ofopen treatment with the drug combination; 118 subjectswere then randomly assigned to receive 4% amitripty-line2% ketamine, 2% amitriptyline1% ketamine, or pla-cebo for 2 weeks.34 Mean average daily pain intensityusing the NRS-PI went from 6.4 at baseline to 3.28 forthe higher-dose cream, 4.08 for the lower-dose cream,and 4.34 for placebo, with the higher-dose cream effectbeing statistically significant. The number of subjectsattaining a 30% reduction in pain intensity was 46% forthe higher-dose cream, 26% for the lower-dose cream,and 19% for the placebo; again, the higher-concentrationcream effect was statistically significant. Plasma concen-trations of either drug were minimal.34 These resultsindicate that the higher-concentration cream leads to agreater responder rate than was observed with the low-er-concentration cream, without significantly increasingthe risk of systemic absorption in the majority of subjects.

Conclusion

In conclusion, this randomized, placebo-controlledtrial 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 anotherstudy has revealed that higher concentrations of theseagents combined do produce significant 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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