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Anesth Analg 2004;98:371-376 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000099716.02783.C4
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Abstract |
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In this randomized, double-blinded, placebo-controlled, crossover trial of 42 human subjects, we examined the speed of onset of cutaneous anesthesia by eutectic mixture of local anesthetics (EMLA) cream after brief (approximately 10-s) pretreatment of the underlying skin with low-frequency (55 kHz) ultrasound. Four treatments were compared: ultrasound pretreatment followed by application of 1 g EMLA or placebo cream for 5 min, 10 min, 15 min, and 60 min without ultrasound pretreatment as positive control. Pain was tested by pricks with a 20 g needle. Pain scores and patient preference for EMLA or placebo cream were measured at each time point. Based on both pain scores and patient preference, cutaneous anesthesia was achieved in the EMLA groups as compared with placebo at all time points. After ultrasound pretreatment and then 5, 10, or 15 min after EMLA cream application, pain scores and overall preference were statistically indistinguishable from EMLA cream application for 60 min (without ultrasound pretreatment). There were no significant adverse effects. Low-frequency ultrasound pretreatment appears to be safe and effective in producing rapid onset of EMLA cream in this model, with results as early as 5 min.
IMPLICATIONS: A prospective, randomized, double-blinded, placebo-controlled clinical trial demonstrated rapid onset of cutaneous anesthesia by pretreatment of the skin with ultrasound before application of EMLA cream.
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Introduction |
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Rapid anesthesia of the skin has long been sought as a means of preventing pain associated with common procedures such as venipuncture, IV cannulation, and skin biopsy. Eutectic mixture of local anesthetics (EMLA) cream, a eutectic mixture of the two amide local anesthetics lidocaine and prilocaine, is indicated for use on normal intact skin to induce local analgesia approximately 60 min after application (1). In many clinical situations this waiting period is impractical. Thus, it is likely that EMLA cream and similar topical anesthetics are under-used and that topical anesthesia would be more widely used if the onset to analgesia was more rapid.
Iontophoresis, the use of electric current to enhance drug transport, has been proposed to accelerate transdermal delivery of the EMLA cream constituent lidocaine. Iontophoresis of lidocaine has been effective, but has not been widely adopted, perhaps because it is cumbersome and too slow (2–6). Similarly, sonophoresis—the use of sound energy to enhance drug transport—has been suggested for anesthetic delivery, but no successful controlled studies have been reported. A device has been developed (SonoPrep device; Sontra Medical, Cambridge, MA) to deliver safely low-intensity ultrasound to the skin in a manner that increases the permeability of the skin, allowing rapid delivery of medications across the epidermis. We conducted a double-blinded, placebo-controlled proof-of-principle trial of a prototype device in volunteers to determine whether ultrasound pretreatment with this device facilitated the rapid onset of cutaneous anesthesia with EMLA cream.
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Methods |
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The study was a randomized, double-blinded, placebo-controlled, crossover trial comparing the onset and efficacy of cutaneous anesthesia using ultrasound pretreatment or no pretreatment followed by transdermal application of EMLA cream (AstraZeneca LP, Wilmington, DE) or placebo cream (Lubriderm Skin Therapy Moisturizing Lotion, Fragrance-Free; Warner-Lambert Consumer Healthcare, Morris Plains, NJ). The comparison was made on various sites on the ventral forearms of 42 healthy human subjects who gave written informed consent to participate in the study. The study protocol was approved by the Human Research Committee of Brigham & Women’s Hospital. Subjects were compensated for participation.
The study was open to healthy volunteers aged 18–65 yr old with intact skin in the area of treatment. Subjects who were pregnant, had significant medical illnesses, or potential difficulty complying with the protocol were excluded. Before the study procedures, subjects were interviewed for medical history and demographics. A physical examination was performed, vital signs were recorded, and subjects were asked to rate their skin types with respect to oiliness and tanning.
Four treatment regimens were studied:
- Ultrasound pretreatment followed by application of 1 g EMLA compared to placebo cream, tested after 5 min of cream application;
- Ultrasound pretreatment followed by application of 1 g EMLA compared to placebo cream, tested after 10 min of cream application;
- Ultrasound pretreatment followed by application of 1 g EMLA compared to placebo cream, tested after 15 min of cream application; and
- Application of 1 g EMLA versus placebo cream tested after 60 min cream application, without ultrasound pretreatment.
Within-subject variations in pain sensitivity occur across various body surfaces, as well as at different time points (7). To control for any potential right-left or proximal-distal differences in forearm sensitivity and to maintain double-blinding throughout, each subject had 2 circular sites of approximately 0.8 cm2 outlined with surgical marker on each ventral forearm, for a total of 4 treatment sites per subject, a proximal pair and a distal pair (Fig. 1). The proximal sites were placed 5 cm from the elbow crease and the distal sites were placed 10 cm from the elbow crease, avoiding hair-bearing skin.
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Subjects were randomized into two groups. Subjects in Group 1 had all sites pretreated with ultrasound. The proximal and the distal pairs of sites were then treated with EMLA cream on one side and placebo cream on the opposite side in a double-blinded manner. Then, by random assignment, the proximal pair was tested at 5 min after application of cream and the distal pair at 15 min or vice versa. Group 2 subjects had either the two distal or the two proximal sites pretreated with ultrasound, treated with EMLA cream on one side and placebo cream on the other, and the ultrasounded pair of sites tested at 10 min after cream application. The remaining pair of sites that had not received ultrasound but was treated with EMLA cream on one side and placebo cream on the other was tested at 60 min after cream was applied to serve as a positive control. Sham ultrasound was not used.
Sites were covered with Tegaderm dressings (3M, St. Paul, MN). Immediately before pain evaluation the dressings were removed and the cream was wiped from the site. Neither the subject nor any of the individuals performing the study knew which sites received EMLA cream and which sites received placebo cream during the study. Before the study began, investigators were unable to distinguish between EMLA and placebo creams by visual appearance, touch, or smell.
Immediately after the study procedures were completed, vital signs were again recorded and the arms were observed for any adverse events and any notable effect on skin appearance. Subjects returned 24–48 h after the study procedures for assessment of any adverse events or effect on skin appearance. Cutaneous changes were classified into pallor, redness, piloerection, or other cutaneous change and rated as mild, moderate, or severe.
All skin sites randomized to receive ultrasound were treated with a device designed and built by Sontra Medical. This device, shown schematically in Figure 2, contained a cylindrical titanium horn inside a titanium housing. A coupling buffer was introduced into the airspace of the annular region between the horn, the housing, and the skin. The coupling buffer was a suspension of 0.5% (w/v) Tamsil silica particles (Unimin Specialty Minerals, Tamms, IL) in phosphate-buffered saline solution and 1% (w/v) sodium dodecyl sulfate (both Sigma, St. Louis, MO, USA). A pair of transepidermal nerve stimulator electrodes (Uni-Patch Medical Supplies, Wabasha, MN) was placed above the elbow on the same arm as the site to be treated and was used to complete a very-low-current circuit through the coupling buffer so that the degree of permeability of the skin to ions could be assessed. The horn was driven at a maximum power of 12 W RMS and a frequency of 55 kHz. Ultrasound was applied to each skin site for 9.0 ± 4.53 s (mean ± SD, n = 128). The ultrasound treated a circular area of skin of 0.8 cm2 at each site.
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Two separate systems were used to assess cutaneous anesthesia/analgesia in this initial feasibility population: pain score and patient preference. The pain scoring that was selected was chosen based on modifications of others’ previously successful efforts (6,8–10). The subject was pricked once using a 20-gauge hypodermic needle in a section of the ventral forearm that was near the treatment sites but not near enough to have received ultrasound pretreatment or exposure to EMLA or placebo cream. The subject was told to consider the pain caused by this prick as a reference. The subject was then pricked 5 times at various places in each treated skin site and asked after each prick to rate the pain of that prick as "sharp" (scored as 1.0 and considered as sharp or painful as the control prick), "less sharp" (scored as 0.5 and considered less sharp or painful than the control prick), or "dull" (scored as 0.0 and considered painless). The pain score for each skin site was defined as the mean of the 5 individual pain ratings. After each time point was completed, the subject was asked to rate whether the left or right arm was preferred (i.e., had less pain) or whether sensation in both arms was equivalent.
All statistical analysis was performed using SAS Version 8 software (SAS Institute, Cary, NC). All P values were 2-sided, with statistical significance defined as P < 0.05. The target sample size of 40 subjects was chosen to give 90% statistical power to detect a within-subject difference of 
2 painful pinpricks of 5 with a 2-sided 0.05-level test, assuming the standard deviation of the within-subject difference would be at most 2.47 based on a previous study (9).
As this was a crossover trial in which each subject received both EMLA and placebo cream for a given treatment time, all efficacy analyses were based on pairwise within-subject differences between EMLA and placebo cream. Because the treatment allocation was randomized and balanced between left and right arm and between distal and proximal location, all efficacy analyses were adjusted for a possible effect of arm or location. Both parametric methods that assume a normal distribution (analysis of variance, ANOVA) and nonparametric rank-based methods that do not assume a normal distribution (Van Elteren test) were used to calculate P values for efficacy based on pain scores. Simultaneous 95% confidence intervals for the difference in pain score for each treatment time were calculated using the Bonferroni procedure, which adjusts for the multiple comparisons.
The difference in efficacy of EMLA cream with or without ultrasound pretreatment was assessed using both of the study’s outcome measurements: pain score and arm preference. The efficacy difference for pain scores was computed by pairwise comparison of the differences between EMLA versus placebo creams at 5, 10, and 15 min with the positive control at 60 min. Dunnett’s procedure for multiple comparisons with a control was used to calculate P values and simultaneous 95% confidence intervals for the 3 pairwise differences in pain scores. The efficacy difference for arm preference was assessed using all three categories (prefer EMLA cream arm, prefer placebo cream arm, no preference). ANOVA analyses were conducted to assess whether mean efficacy differed according to arm or forearm location. Univariate and multivariate ANOVA analyses were conducted to assess whether mean efficacy differed according to the following covariates: race, skin type (tanning, oiliness), and gender. Because there was only one Hispanic subject, Asian and Hispanic subjects were combined for these analyses. Baseline characteristics of Groups 1 and 2 were compared using Wilcoxon’s rank-sum test, 
2 testing, or Fisher’s exact test. Skin safety assessments between EMLA and placebo cream at each time (5, 10, 15, and 60 min) were compared using McNemar’s test when only none or mild changes were observed or Bowker’s test when moderate changes were also observed. Vital signs pre- and posttreatment were compared using Wilcoxon’s signed-rank test.
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Results |
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Baseline characteristics of subjects are shown in Table 1. The median age was 26.6 yr, 45% of the subjects were male, and 83% were Caucasian. There were no statistically significant differences in characteristics between subjects enrolled in Group 1 and Group 2. All patients acknowledged the reference needle pricks as painful.
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Pain scores were significantly non-normally distributed (Tables 2 and 3 ). EMLA cream was significantly better than placebo cream at each time for both pain score and arm preference. EMLA with ultrasound at all time points (5, 10, and 15 min) performed at least as well as EMLA without ultrasound (60 min) according to both outcome measures (pain scores and preference).
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The efficacy of EMLA cream with ultrasound at all time points was compared to EMLA cream without ultrasound at 60 min. The estimates of difference in treatment effect favored the ultrasound-treated sites over EMLA cream at 60 min in all comparisons, but the differences did not reach statistical significance. Similarly, the number of subjects who preferred the EMLA to the placebo arm was larger for each of the ultrasound-treated sites compared with EMLA cream without ultrasound after 60 min, but this difference also did not reach statistical significance. This finding was true regardless of whether arm preference was analyzed using all 3 of its categories or with the no-preference and preferred-placebo-cream categories combined.
No clear relationship was found between efficacy and arm or between efficacy and distal versus proximal location.
In a within-subject analysis comparing 10-min versus 60-min data, fairer skin and female gender were statistically significantly associated with greater efficacy in univariate and multivariate analyses. In a between-subject analysis comparing 5-min versus 60-min data, gender was the only statistically significant covariate in univariate and multivariate analysis. Ultrasound alone (as distinct from EMLA cream) was not a statistically significant covariate or effect-modifier, which suggests that apparent relationships between efficacy and subject characteristics are not attributable to, or altered by, ultrasound pretreatment. No severe cutaneous changes were observed. A few cases of moderate pallor or moderate needle marks and several cases of mild pallor, redness, piloerection, and needle marks were noted. All resolved without treatment. The only cutaneous change that differed significantly between EMLA and placebo cream was mild or moderate pallor, a known effect of EMLA cream, which was more common with EMLA cream than with placebo cream at all 4 observation times. No side effects were specifically associated with ultrasound treatment. There were no clinically significant changes in vital signs compared before and after the procedure.
At the 24–48 h follow-up visit, the most common cutaneous changes observed were mild needle marks. Almost all observations of pallor noted immediately after treatment had resolved at the follow-up visit. No changes were statistically different between sites treated with EMLA or placebo cream.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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As part of the continued quest for rapid cutaneous analgesia, we performed a study to determine whether the onset of cutaneous analgesia with EMLA cream, generally considered to be around 60 minutes, could be made more rapid by ultrasound pretreatment, assessed at 5, 10, and 15 minutes. Ultrasound pretreatment was safe and effective in this regard. After only 5 minutes (subsequent to ultrasound pretreatment), EMLA cream provided a level of analgesia that was not significantly different from that of EMLA cream applied to untreated skin for 60 minutes, as confirmed against a placebo comparator. This effect was also seen after 10 and 15 minutes of application to pretreated skin and was observed whether pain was scored by individual needle pricks or by subject preference. The estimates of difference in analgesia favored all ultrasound-pretreated time points over EMLA cream without ultrasound.
Trends were noted for improved analgesia for female subjects and improved analgesia for subjects with lighter skin. These trends were apparent for treatment with EMLA cream without ultrasound; therefore, if these numerical differences represent a reproducible phenomenon, they are likely attributable to EMLA cream and not to ultrasound. However, a separate, adequately powered study will be needed to resolve these questions.
Several aspects of our methodology deserve mention for future efforts in this area. Our randomization scheme considered potential differences in sensitivity between left and right and between proximal and distal forearm. However, no such differences were noted in multivariate analyses. All of our treatments were performed on nonglabrous skin (but avoiding areas with hair) to avoid mixing glabrous and non-glabrous skin, which may have different sensory properties (11). As might be anticipated, pallor was associated with application of the EMLA cream, potentially confounding the blinding of the investigator. However, most pallor scores were "none" or "mild," only the 60-minute application sites resulted in any scores of "moderate" pallor, and no sites were judged as demonstrating "severe" pallor. This factor needs to be better blinded in future prospective, comparative, controlled studies of this and similar drugs.
Previous reports describe attempts to accelerate local analgesia with clinically available therapeutic ultrasound instruments, but no controlled studies have been reported, technical details are sparse, and results are negative or unclear (12–17). Applying sonophoresis at low frequency (below 100 kHz) has been more successful; lidocaine was delivered to hairless mice using sonophoresis at 48 kHz (18). Sonophoresis is thought to be more effective at low frequencies because the physical phenomenon of cavitation, more easily created at low frequencies, effectively modifies the stratum corneum and renders the skin temporarily more permeable (19). Thus, unlike iontophoresis, ultrasound energy does not need to be continuous for drug delivery. Instead, skin can be briefly pretreated with ultrasound, and the drug can be applied thereafter (20,21).
Our study has several limitations. Ideally, we would have compared all four treatment regimens in the same subjects during the same session. Unfortunately, our pilot efforts suggested that this would be impractical because of limitations in arm size and subject compliance. Therefore, our results combine two groups of subjects with two different treatment regimens. We also did not investigate any times earlier than 5 minutes and cannot determine the precise onset of anesthesia of EMLA cream with ultrasound. We did not attempt to measure the effect of EMLA without ultrasound pretreatment within 5, 10, or 15 minutes of application, as it has been well established in the literature that this drug requires a dwell time of 60 minutes for efficacy (1,22,23). With regard to our outcome measures, we observed that after a pinprick many subjects were able to distinguish between painless touch (i.e., "dull") and no touch, which in our schema would have been lumped together as a zero score. In the future we would separate these categories to preserve this information. We are aware of the growing acceptance of 0–10 cm visual analog scales as pain measures, but deliberately chose to avoid these scales because the only previous study of cutaneous anesthesia using these measures failed (24). It seemed most sensible to adapt previously successful outcome measures from similar studies. Another issue is that, ideally, to address the question of whether EMLA with ultrasound is faster than EMLA without ultrasound, we could have directly compared EMLA with ultrasound to EMLA with sham ultrasound at multiple time points. Unfortunately, at this stage there is no appropriate sham ultrasound because the device makes noise and may create a tingling sensation during treatment. Furthermore, comparing two active treatments without a contemporaneous placebo control creates interpretation problems that have been well described (25). However, comparison with sham ultrasound should be pursued once technology permits.
A question remains regarding the clinical relevance of our findings to common procedures, such as venipuncture, as we studied only superficial analgesia in this study. Although passage of local anesthetic through the stratum corneum has been considered the major obstacle to establishing rapid cutaneous anesthesia, future studies are planned to determine the onset time of deeper, more clinically relevant anesthesia.
This study confirms the hypothesis that onset of at least superficial cutaneous analgesia with EMLA cream can be achieved as fast as 5 min after a brief pretreatment with low energy ultrasound. Our results suggest the potential for rapid analgesia for painful cutaneous procedures. Future studies are needed to determine the optimal drug and protocol needed to achieve rapid, clinically relevant analgesia of deeper cutaneous structures.
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Acknowledgments |
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Supported by Sontra Medical, Franklin, Massachusetts.
We thank My-Quyen Trieu and Amy Gaspar for study execution and database auditing, and Donald Blood, Jr., RPh, of the Brigham & Women’s Hospital Pharmacy Investigational Drug Service for choosing the placebo cream and for preparing and randomizing the placebo and drug samples.
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Footnotes |
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Joseph Kost and Linda M. Custer have an equity interest in Sontra Medical.
EMLA is a registered trademark of AstraZeneca LP. SonoPrep is a trademark of Sontra Medical, Inc.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- EMLA cream and EMLA anesthetic disc prescribing information. Wilmington, DE: AstraZeneca LP, 2001.
- Gangarosa LP Sr. Defining a practical solution for iontophoretic local anesthesia of skin. Methods Find Exp Clin Pharmacol 1981; 3: 83–94.[Web of Science][Medline]
- Bezzant JL, Stephen RL, Petelenz TJ, Jacobsen SC. Painless cauterization of spider veins with the use of iontophoretic local anesthesia. J Am Acad Dermatol 1988; 19: 869–75.[Web of Science][Medline]
- Zeltzer L, Regalado M, Nichter LS, et al. Iontophoresis versus subcutaneous injection: a comparison of two methods of local anesthesia delivery in children. Pain 1991; 44: 73–8.[Web of Science][Medline]
- Irsfeld S, Klement W, Lipfert P. Dermal anaesthesia: comparison of EMLA cream with iontophoretic local anaesthesia. Br J Anaesth 1993; 71: 375–8.
[Abstract/Free Full Text] - Greenbaum SS, Bernstein EF. Comparison of iontophoresis of lidocaine with a eutectic mixture of lidocaine and prilocaine (EMLA) for topically administered local anesthesia. J Dermatol Surg Oncol 1994; 20: 579–83.[Web of Science][Medline]
- Meh D, Denislic M. Quantitative assessment of thermal and pain sensitivity. J Neurol Sci 1994; 127: 164–9.[Web of Science][Medline]
- Woolfson AD, McCafferty DF, McClelland KH, Boston V. Concentration-response analysis of percutaneous local anaesthetic formulations. Br J Anaesth 1988; 61: 589–92.
[Abstract/Free Full Text] - Juhlin L, Evers H. EMLA: a new topical anesthetic. Adv Dermatol 1990; 5: 75–91.[Medline]
- Sakamoto M, Kano T, Sadanaga M, et al. Dermal patch anaesthesia: comparison of 10% lignocaine gel with absorption promoter and EMLA cream. Anaesthesia 1993; 48: 390–2.[Web of Science][Medline]
- Harrison JL, Davis KD. Cold-evoked pain varies with skin type and cooling rate: a psychophysical study in humans. Pain 1999; 83: 123–35.[Web of Science][Medline]
- Cameroy BM. Ultra sound enhanced local anesthesia. Am J Orthop 1966; 8: 47.
- Novak EJ. Experimental transmission of lidocaine through intact skin by ultrasound. Arch Phys Med Rehabil 1964; 45: 231–2.[Medline]
- Quillin WS. Ultrasonic phonophoresis. Phys Sportsmed 1982; 10: 211.
- Moll MJ. A new approach to pain: lidocaine and decadron with ultrasound. USAF Med Serv Dig 1979; 30: 8–11.
- Williams AR. Phonophoresis: an in vivo evaluation using three topical anaesthetic preparations. Ultrasonics 1990; 28: 137–41.[Web of Science][Medline]
- McElnay JC, Matthews MP, Harland R, McCafferty DF. The effect of ultrasound on the percutaneous absorption of lignocaine. Br J Clin Pharmacol 1985; 20: 421–4.[Web of Science][Medline]
- Tachibana K, Tachibana S. Use of ultrasound to enhance the local anesthetic effect of topically applied aqueous lidocaine. Anesthesiology 1993; 78: 1091–6.[Web of Science][Medline]
- Mitragotri S, Edwards DA, Blankschtein D, Langer R. A mechanistic study of ultrasonically-enhanced transdermal drug delivery. J Pharm Sci 1995; 84: 697–706.[Web of Science][Medline]
- Kost J, Mitragotri S, Gabbay RA, et al. Transdermal monitoring of glucose and other analytes using ultrasound. Nat Med 2000; 6: 347–50.[Medline]
- Mitragotri S, Kost J. Low-frequency sonophoresis: a noninvasive method of drug delivery and diagnostics. Biotechnol Prog 2000; 16: 488–92.[Medline]
- Lawson RA, Smart NG, Gudgeon AC, Morton NS. Evaluation of an amethocaine gel preparation for percutaneous analgesia before venous cannulation in children. Br J Anaesth 1995; 75: 282–5.
[Abstract/Free Full Text] - Friedman PM, Mafong EA, Friedman ES, Geronemus RG. Topical anesthetics update: EMLA and beyond. Dermatol Surg 2001; 27: 1019–26.[Web of Science][Medline]
- Maddi R, Horrow JC, Mark JB, et al. Evaluation of a new cutaneous topical anesthesia preparation. Reg Anesth 1990; 15: 109–12.[Web of Science][Medline]
- Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part I: Ethical and scientific issues. Arch Int Med 2000; 133: 455–63.
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