(Actos cuja publicação é uma condição da sua aplicabilidade) REGULAMENTO (CE) N.o 2006/2004 DO PARLAMENTO EUROPEU E DO CONSELHO de 27 de Outubro de 2004 relativo à cooperação entre as autoridades nacionais responsáveis pela aplicação da legislação de defesa do consumidor («regulamento relativo à cooperação no domínio da defesa do consumidor») (Texto relevante para
Doi:10.1016/j.jpain.2005.04.008Topical 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
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.
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
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
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
POSSIBLE TREATMENT RELATED ADVERSE EVENT 15/0/14/0/0/15/0
Occasional sensation of increased heart rate (45/31/28/39/30/60/67)
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- and postsurgical/posttraumatic pain.
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