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Figure 1.
CONSORT Flow Diagram
CONSORT Flow Diagram
Figure 2.
Summary of Pain Assessment
Summary of Pain Assessment

A, Spring-loaded needle lancet pain stimuli were assessed in all participants using a visual analog scale (VAS) (0-100 mm) on the right and left volar forearms at 2, 5, 10, and 30 minutes after microneedle (MN) and sham pretreatment. B, Participants who were more sensitive to pain from the spring-loaded needle lancets (>20 mm on the VAS; range, 0-100 mm) were assessed for pain on the right and left volar forearms at 2, 5, 10, and 30 minutes. Results are shown as means; error bars represent SD.

aP < .05 compared with sham treatment.

1.
Duan  D, Moeckly  C, Gysbers  J,  et al.  Enhanced delivery of topically-applied formulations following skin pre-treatment with a hand-applied, plastic microneedle array.  Curr Drug Deliv. 2011;8(5):557-565.PubMedGoogle ScholarCrossref
2.
Nayak  A, Das  DB, Vladisavljević  GT.  Microneedle-assisted permeation of lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel.  Pharm Res. 2014;31(5):1170-1184.PubMedGoogle ScholarCrossref
3.
Spierings  EL, Brevard  JA, Katz  NP.  Two-minute skin anesthesia through ultrasound pretreatment and iontophoretic delivery of a topical anesthetic: a feasibility study.  Pain Med. 2008;9(1):55-59.PubMedGoogle ScholarCrossref
4.
Ito  Y, Ohta  J, Imada  K,  et al.  Dissolving microneedles to obtain rapid local anesthetic effect of lidocaine at skin tissue.  J Drug Target. 2013;21(8):770-775.PubMedGoogle ScholarCrossref
5.
Nayak  A, Das  DB, Chao  TC, Starov  VM.  Spreading of a lidocaine formulation on microneedle-treated skin [published online September 7, 2015].  J Pharm Sci.PubMedGoogle Scholar
6.
Zhang  Y, Brown  K, Siebenaler  K, Determan  A, Dohmeier  D, Hansen  K.  Development of lidocaine-coated microneedle product for rapid, safe, and prolonged local analgesic action.  Pharm Res. 2012;29(1):170-177.PubMedGoogle ScholarCrossref
7.
ClinicalTrials.gov. The Effect of Microneedle Pretreatment on Topical Anesthesia. NCT02596750. https://clinicaltrials.gov/ct2/show/NCT02596750. Accessed November 30, 2015.
Research Letter
April 2016

Effect of Microneedle Pretreatment on Topical Anesthesia: A Randomized Clinical Trial

Author Affiliations
  • 1Medical Student, School of Medicine, University of California, Davis, Sacramento
  • 2Department of Dermatology, University of California, Davis, Sacramento
JAMA Dermatol. 2016;152(4):476-477. doi:10.1001/jamadermatol.2015.5544

Microneedles are microscopic needles capable of creating microchannels through the stratum corneum to improve transdermal drug delivery.1-3 Microneedles have been shown1,2,4-6 to enhance the delivery of topical anesthetics with use of in vitro and animal models. In this split-body, randomized clinical trial, we investigated whether pretreatment with microneedles enhanced the anesthetic effect produced by topical lidocaine cream, 4%.

Methods

This study was approved by the institutional review board at the University of California, Davis. The participants provided written informed consent and received financial compensation. A summary of the study protocol is available in the Supplement and registered at clinicaltrials.gov (NCT02596750).7 Twenty-one men (mean [SD] age, 29 [1.9] years) were recruited from January 12 to May 1, 2015; there were no reported allergies to topical or injected anesthetics. Previous studies3 indicated that women have a higher pain tolerance than men, so only men were recruited to delineate pain improvement. In a binary design, participants were randomized by coordinators who did not perform the treatments, and the participants’ identity was revealed to the investigators on recruitment to receive pretreatment on each volar forearm with either an MR2 (0.2-mm) microneedle roller (Clinical Resolution Laboratories, Inc) or a sham microneedle roller containing no microneedles (Figure 1). Participants remained blinded throughout the study. Topical lidocaine cream, 4%, was applied to both arms. Each participant served as his own control, and pain was assessed using a spring-loaded needle lancet (LifeScan, Inc) at an identical site on both volar forearms at 2, 5, 10, and 30 minutes. A power analysis showed more than 90% power in discerning a 6-mm difference on the 100-mm pain visual analog scale at the 30-minute time point (primary end point) scale with significance set at P < .05. Differences at 2, 5, and 10 minutes were secondary end points. Participants graded pain after microneedle or sham treatment and pain stimulus using a 100-mm visual analog scale, which also served as a secondary end point. Statistical analyses were performed with 1-way analysis of variance. Data analysis was performed from June 16 to July 1, 2015.

Results

There were no dropouts and the intent-to-treat population was equivalent to the evaluable population in this study. All participants completed all study procedures. Needle lancet pain with microneedle pretreatment was significantly decreased at 30 minutes (microneedle: mean [SD], 4 [1.3] mm; sham: 14.4 [3.8] mm; P < .05) but not at earlier times (Figure 2A). When stratifying the data for participants who were more sensitive to pain (scores >20 mm on the visual analog scale), the pain level resulting from microneedle pretreatment followed by a spring-loaded needle lancet was significantly decreased at 10 and 30 minutes (P < .05) (Figure 2B).

Discussion

Results of this study indicate that pretreatment with microneedles improves the onset of lidocaine cream, 4%, anesthesia. These results are clinically significant since topical lidocaine cream, 4%, is typically used to produce anesthesia 60 minutes after application.4,6 Our results suggest that the use of microneedle pretreatment can reduce the incubation time to 30 minutes—perhaps even to 10 minutes in more pain-sensitive individuals—to achieve sufficient anesthesia for needle insertion.

Our study has several limitations. First, the pain stimulus was needle based and it is not known how laser- or scalpel-based pain would have been altered. Second, our study was limited to men; future studies should include women. Finally, this study evaluated pain on the volar forearms, but pain sensitivity can vary by anatomical site. Because the participants served as their own controls and the anatomical site at each pain assessment had a symmetrically placed control, the role of the site was minimized. The study should be repeated using other anatomical sites.

Randomized clinical trials should be conducted with laser- or scalpel-based stimuli to simulate other dermatologic procedures. In particular, studies in a pediatric population can help clarify the role of microneedle pretreatment in topical anesthesia before invasive procedures. Regardless, the findings of this study are promising, showing that microneedles offer a minimally painful method of enhancing the effects of topical anesthesia.

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Article Information

Corresponding Author: Raja K. Sivamani MD, MS, CAT, Department of Dermatology, University of California, Davis, 3301 C St, Ste 1400, Sacramento, CA 95816 (rksivamani@ucdavis.edu).

Accepted for Publication: November 11, 2015.

Published Online: January 13, 2016. doi:10.1001/jamadermatol.2015.5544.

Author Contributions: Ms Ornelas and Dr Sivamani had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Sivamani.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ornelas, Foolad, Sivamani.

Critical revision of the manuscript for important intellectual content: Shi, Burney.

Statistical analysis: Sivamani.

Administrative, technical, or material support: Ornelas, Foolad, Sivamani.

Study supervision: Foolad, Sivamani.

Conflict of Interest Disclosures: Dr Sivamani reported serving as a paid consultant for Valeant Pharmaceuticals; however, that consulting was not relevant to the material presented in this article. No other disclosures were reported.

Funding/Support: Ms Ornelas was supported in part by a T32 Predoctoral Clinical Research Fellowship from the University of California, Davis.

Role of the Funder/Sponsor: The University of California, Davis, had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Duan  D, Moeckly  C, Gysbers  J,  et al.  Enhanced delivery of topically-applied formulations following skin pre-treatment with a hand-applied, plastic microneedle array.  Curr Drug Deliv. 2011;8(5):557-565.PubMedGoogle ScholarCrossref
2.
Nayak  A, Das  DB, Vladisavljević  GT.  Microneedle-assisted permeation of lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel.  Pharm Res. 2014;31(5):1170-1184.PubMedGoogle ScholarCrossref
3.
Spierings  EL, Brevard  JA, Katz  NP.  Two-minute skin anesthesia through ultrasound pretreatment and iontophoretic delivery of a topical anesthetic: a feasibility study.  Pain Med. 2008;9(1):55-59.PubMedGoogle ScholarCrossref
4.
Ito  Y, Ohta  J, Imada  K,  et al.  Dissolving microneedles to obtain rapid local anesthetic effect of lidocaine at skin tissue.  J Drug Target. 2013;21(8):770-775.PubMedGoogle ScholarCrossref
5.
Nayak  A, Das  DB, Chao  TC, Starov  VM.  Spreading of a lidocaine formulation on microneedle-treated skin [published online September 7, 2015].  J Pharm Sci.PubMedGoogle Scholar
6.
Zhang  Y, Brown  K, Siebenaler  K, Determan  A, Dohmeier  D, Hansen  K.  Development of lidocaine-coated microneedle product for rapid, safe, and prolonged local analgesic action.  Pharm Res. 2012;29(1):170-177.PubMedGoogle ScholarCrossref
7.
ClinicalTrials.gov. The Effect of Microneedle Pretreatment on Topical Anesthesia. NCT02596750. https://clinicaltrials.gov/ct2/show/NCT02596750. Accessed November 30, 2015.
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