<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03279757</url>
  </required_header>
  <id_info>
    <org_study_id>NL53766.018.15b</org_study_id>
    <nct_id>NCT03279757</nct_id>
  </id_info>
  <brief_title>Fractional Laser Assisted Delivery of Anesthetics IIIb</brief_title>
  <official_title>Parameters in Fractional Laser Assisted Delivery of Topical Anesthetics: Role of Anesthetic and Application Time</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Netherlands Institute for Pigment Disorders</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Netherlands Institute for Pigment Disorders</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study are to compare the efficacy of two different commercially available&#xD;
      local anesthetics on AFXL pretreated skin and to assess the role of the application time in&#xD;
      this technique.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale: In dermatology anesthetics are frequently injected or topically applied to achieve&#xD;
      local anesthesia. Injectable anesthetics are effective but uncomfortable during&#xD;
      administration, especially for people who are needle phobic. Application of topical&#xD;
      anesthesia is painless but time consuming and often only partial aesthesia is achieved due to&#xD;
      the barrier function of the stratum corneum. (Manuskiatti, Triwongwaranat et al. 2010)&#xD;
      Penetration of local anesthetics could be enhanced by pretreatment of the skin with ablative&#xD;
      fractional lasers (AFXL) which locally disrupts the stratum corneum by creating an array of&#xD;
      microscopic ablation channels. (Sklar, Burnett et al. 2014) In a previous pilot study,&#xD;
      conducted at our institute, we demonstrated that effective anesthesia could be achieved&#xD;
      within ten minutes after application of a topical anesthetic on skin pretreated with AFXL at&#xD;
      painless settings. (Meesters, Bakker et al. 2015) However, little is still known about the&#xD;
      role of the type of anesthetic the type of anesthetic and the application time on the&#xD;
      efficacy of the anesthesia.&#xD;
&#xD;
      Objective: The objective of this study is to compare the efficacy of two different&#xD;
      commercially available local anesthetics on AFXL pretreated skin, a low concentration&#xD;
      articaine solution and a high concentration lidocaine/tetracaine cream. We also aim to&#xD;
      compare the efficacy of AFXL assisted topical anesthesia after various different application&#xD;
      times.&#xD;
&#xD;
      Study design: Prospective, single blinded, randomized, controlled, within subject, pilot&#xD;
      study.&#xD;
&#xD;
      Study population: 15 healthy volunteers ≥18 years, who give written informed consent&#xD;
&#xD;
      Intervention: In each subject, six test regions on subject's back of 1x1 cm will be&#xD;
      pretreated with the fractional carbon dioxide (CO2) laser at 2.5 mJ and 15% density and will&#xD;
      be randomly allocated to application of (I) articaine hydrochloride 40 mg/ml + epinephrine 10&#xD;
      μg/ml 30 solution (AHES) (5 minutes application time), (II) AHES (15 minutes application&#xD;
      time), (III) AHES (25 minutes application time), (IV) lidocaine 70 mg/g + tetracaine 70 mg/g&#xD;
      cream (LTC) (5 minutes application time, (V) LTC (15 minutes application time), (VI) LTC (25&#xD;
      minutes application time). After 15 minutes a pain stimulus, consisting of a pass with the&#xD;
      fractional CO2 laser at 50 mJ and 5% density (scanned area 6x6 mm), will be given at each&#xD;
      test region. In addition, a reference pain stimulus with the CO2 laser at the same settings&#xD;
      will be given at unanesthetized skin. Subjects will be asked to indicate pain on a visual&#xD;
      analogue scale (VAS) from 0-10 (0: no pain; 10: worst imaginable pain) directly after each&#xD;
      pain stimulus&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2016</start_date>
  <completion_date type="Actual">December 1, 2016</completion_date>
  <primary_completion_date type="Actual">December 1, 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pain score</measure>
    <time_frame>After 5 minutes application time of the anesthetics</time_frame>
    <description>The main study parameter is pain, as scored on a VAS from 0-10 (0: no pain; 10: worst imaginable pain).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pain score</measure>
    <time_frame>After 15 minutes application time of the anesthetics</time_frame>
    <description>The main study parameter is pain, as scored on a VAS from 0-10 (0: no pain; 10: worst imaginable pain).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pain score</measure>
    <time_frame>After 25 minutes application time of the anesthetics</time_frame>
    <description>The main study parameter is pain, as scored on a VAS from 0-10 (0: no pain; 10: worst imaginable pain).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pain score</measure>
    <time_frame>Directly after pretreatment.</time_frame>
    <description>The secondary study parameter is pain, as scored on a VAS from 0-10 (0: no pain; 10: worst imaginable pain) directly after pretreatment</description>
  </secondary_outcome>
  <number_of_arms>7</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Local Anesthesia of the Skin</condition>
  <arm_group>
    <arm_group_label>AHES 5 minutes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml solution (AHES) will be applied at this test region. 5 minutes after AHES application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AHES 15 minutes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml solution (AHES) will be applied at this test region. 15 minutes after AHES application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AHES 25 minutes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml solution (AHES) will be applied at this test region. 25 minutes after AHES application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>LTC 5 minutes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment lidocaine 70 mg/g + tetracaine 70 mg/g cream (LTC) will be applied at this test region. 5 minutes after LTC application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>LTC 15 minutes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment lidocaine 70 mg/g + tetracaine 70 mg/g cream (LTC) will be applied at this test region. 15 minutes after LTC application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>LTC 25 minutes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment lidocaine 70 mg/g + tetracaine 70 mg/g cream (LTC) will be applied at this test region. 25 minutes after LTC application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Unanesthetized skin</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>A pain stimulus will be given at unanesthetized skin with the fractional CO2 laser, 50 mJ, 5% density</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AHES 5 minutes</intervention_name>
    <description>Topical application of AHES with 5 minutes application time After 5 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density</description>
    <arm_group_label>AHES 5 minutes</arm_group_label>
    <other_name>Ultracain D-S forte</other_name>
    <other_name>Articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AHES 15 minutes</intervention_name>
    <description>Topical application of AHES with 15 minutes application time After 15 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density</description>
    <arm_group_label>AHES 15 minutes</arm_group_label>
    <other_name>Ultracain D-S forte</other_name>
    <other_name>Articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AHES 25 minutes</intervention_name>
    <description>Topical application of AHES with 25 minutes application time After 25 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density</description>
    <arm_group_label>AHES 25 minutes</arm_group_label>
    <other_name>Ultracain D-S forte</other_name>
    <other_name>Articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LTC 5 minutes</intervention_name>
    <description>Topical application of LTC with 5 minutes application time After 5 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density</description>
    <arm_group_label>LTC 5 minutes</arm_group_label>
    <other_name>Pliaglis cream</other_name>
    <other_name>Lidocaine 70 mg/g + tetracaine 70 mg/g cream</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LTC 15 minutes</intervention_name>
    <description>Topical application of LTC with 15 minutes application time After 15 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density</description>
    <arm_group_label>LTC 15 minutes</arm_group_label>
    <other_name>Pliaglis cream</other_name>
    <other_name>Lidocaine 70 mg/g + tetracaine 70 mg/g cream</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LTC 25 minutes</intervention_name>
    <description>Topical application of LTC with 25 minutes application time After 25 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density</description>
    <arm_group_label>LTC 25 minutes</arm_group_label>
    <other_name>Pliaglis cream</other_name>
    <other_name>Lidocaine 70 mg/g + tetracaine 70 mg/g cream</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>fractional CO2 laser, 50 mJ, 5% density</intervention_name>
    <description>Pain stimulus with the fractional CO2 laser, 50 mJ, 5% density</description>
    <arm_group_label>AHES 15 minutes</arm_group_label>
    <arm_group_label>AHES 25 minutes</arm_group_label>
    <arm_group_label>AHES 5 minutes</arm_group_label>
    <arm_group_label>LTC 15 minutes</arm_group_label>
    <arm_group_label>LTC 25 minutes</arm_group_label>
    <arm_group_label>LTC 5 minutes</arm_group_label>
    <arm_group_label>Unanesthetized skin</arm_group_label>
    <other_name>Fractional carbon dioxide laser</other_name>
    <other_name>UltraPulse®, DeepFx handpiece; Lumenis Inc.</other_name>
    <other_name>Ablative fractional laser</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Fitzpatrick skin type I or II&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Patient is willing and able to give written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of keloid or hypertrophic scar formation or complicated wound healing&#xD;
&#xD;
          -  Presence of any active skin disease&#xD;
&#xD;
          -  Known allergy to local anesthesia&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Incompetency to understand what the procedure involves&#xD;
&#xD;
          -  Current complaints of chronic pain or other alterations in pain sensation (e.g. due to&#xD;
             diabetes mellitus or lepra)&#xD;
&#xD;
          -  Current treatment with systemic analgesics or other medication that can influence pain&#xD;
             sensation&#xD;
&#xD;
          -  Current treatment with anticoagulants&#xD;
&#xD;
          -  Fitzpatrick skin type III-VI&#xD;
&#xD;
          -  Excessive sun tan&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Albert Wolkerstorfer, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Netherlands Institute for Pigment Disorders, Department of Dermatology, Academic Medical Center, University of Amsterdam</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Menno A De Rie, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Department of Dermatology, Academic Medical Center, University of Amsterdam</affiliation>
  </overall_official>
  <reference>
    <citation>Meesters AA, Bakker MM, de Rie MA, Wolkerstorfer A. Fractional CO2 laser assisted delivery of topical anesthetics: A randomized controlled pilot study. Lasers Surg Med. 2016 Feb;48(2):208-11. doi: 10.1002/lsm.22376. Epub 2015 May 29.</citation>
    <PMID>26032635</PMID>
  </reference>
  <reference>
    <citation>Sklar LR, Burnett CT, Waibel JS, Moy RL, Ozog DM. Laser assisted drug delivery: a review of an evolving technology. Lasers Surg Med. 2014 Apr;46(4):249-62. doi: 10.1002/lsm.22227. Epub 2014 Mar 24.</citation>
    <PMID>24664987</PMID>
  </reference>
  <reference>
    <citation>Oni G, Brown SA, Kenkel JM. Can fractional lasers enhance transdermal absorption of topical lidocaine in an in vivo animal model? Lasers Surg Med. 2012 Feb;44(2):168-74. doi: 10.1002/lsm.21130. Epub 2012 Feb 2.</citation>
    <PMID>22302761</PMID>
  </reference>
  <reference>
    <citation>Oni G, Rasko Y, Kenkel J. Topical lidocaine enhanced by laser pretreatment: a safe and effective method of analgesia for facial rejuvenation. Aesthet Surg J. 2013 Aug 1;33(6):854-61. doi: 10.1177/1090820X13496248.</citation>
    <PMID>23908302</PMID>
  </reference>
  <reference>
    <citation>Ong MW, Bashir SJ. Fractional laser resurfacing for acne scars: a review. Br J Dermatol. 2012 Jun;166(6):1160-9. doi: 10.1111/j.1365-2133.2012.10870.x. Epub 2012 May 8.</citation>
    <PMID>22296284</PMID>
  </reference>
  <reference>
    <citation>Manuskiatti W, Triwongwaranat D, Varothai S, Eimpunth S, Wanitphakdeedecha R. Efficacy and safety of a carbon-dioxide ablative fractional resurfacing device for treatment of atrophic acne scars in Asians. J Am Acad Dermatol. 2010 Aug;63(2):274-83. doi: 10.1016/j.jaad.2009.08.051.</citation>
    <PMID>20633798</PMID>
  </reference>
  <reference>
    <citation>Wolfe JW, Butterworth JF. Local anesthetic systemic toxicity: update on mechanisms and treatment. Curr Opin Anaesthesiol. 2011 Oct;24(5):561-6. doi: 10.1097/ACO.0b013e32834a9394.</citation>
    <PMID>21841477</PMID>
  </reference>
  <reference>
    <citation>Hahn IH, Hoffman RS, Nelson LS. EMLA-induced methemoglobinemia and systemic topical anesthetic toxicity. J Emerg Med. 2004 Jan;26(1):85-8. doi: 10.1016/j.jemermed.2003.03.003.</citation>
    <PMID>14751483</PMID>
  </reference>
  <reference>
    <citation>Haedersdal M, Sakamoto FH, Farinelli WA, Doukas AG, Tam J, Anderson RR. Fractional CO(2) laser-assisted drug delivery. Lasers Surg Med. 2010 Feb;42(2):113-22. doi: 10.1002/lsm.20860.</citation>
    <PMID>20166154</PMID>
  </reference>
  <reference>
    <citation>Bachhav YG, Heinrich A, Kalia YN. Controlled intra- and transdermal protein delivery using a minimally invasive Erbium:YAG fractional laser ablation technology. Eur J Pharm Biopharm. 2013 Jun;84(2):355-64. doi: 10.1016/j.ejpb.2012.11.018. Epub 2012 Nov 30.</citation>
    <PMID>23207321</PMID>
  </reference>
  <reference>
    <citation>Haak CS, Farinelli WA, Tam J, Doukas AG, Anderson RR, Haedersdal M. Fractional laser-assisted delivery of methyl aminolevulinate: Impact of laser channel depth and incubation time. Lasers Surg Med. 2012 Dec;44(10):787-95. doi: 10.1002/lsm.22102. Epub 2012 Dec 4. Erratum In: Lasers Surg Med. 2013 Nov;45(9):617.</citation>
    <PMID>23212624</PMID>
  </reference>
  <reference>
    <citation>Haak CS, Bhayana B, Farinelli WA, Anderson RR, Haedersdal M. The impact of treatment density and molecular weight for fractional laser-assisted drug delivery. J Control Release. 2012 Nov 10;163(3):335-41. doi: 10.1016/j.jconrel.2012.09.008. Epub 2012 Sep 21.</citation>
    <PMID>23000695</PMID>
  </reference>
  <reference>
    <citation>Tierney EP, Hanke CW. Fractionated carbon dioxide laser treatment of photoaging: prospective study in 45 patients and review of the literature. Dermatol Surg. 2011 Sep;37(9):1279-90. doi: 10.1111/j.1524-4725.2011.02082.x.</citation>
    <PMID>22988990</PMID>
  </reference>
  <reference>
    <citation>Paasch U, Haedersdal M. Laser systems for ablative fractional resurfacing. Expert Rev Med Devices. 2011 Jan;8(1):67-83. doi: 10.1586/erd.10.74.</citation>
    <PMID>21158542</PMID>
  </reference>
  <reference>
    <citation>Farkas JP, Richardson JA, Burrus CF, Hoopman JE, Brown SA, Kenkel JM. In vivo histopathologic comparison of the acute injury following treatment with five fractional ablative laser devices. Aesthet Surg J. 2010 May-Jun;30(3):457-64. doi: 10.1177/1090820X10373060.</citation>
    <PMID>20601578</PMID>
  </reference>
  <reference>
    <citation>Hantash BM, Bedi VP, Chan KF, Zachary CB. Ex vivo histological characterization of a novel ablative fractional resurfacing device. Lasers Surg Med. 2007 Feb;39(2):87-95. doi: 10.1002/lsm.20405.</citation>
    <PMID>17115384</PMID>
  </reference>
  <reference>
    <citation>Taudorf EH, Haak CS, Erlendsson AM, Philipsen PA, Anderson RR, Paasch U, Haedersdal M. Fractional ablative erbium YAG laser: histological characterization of relationships between laser settings and micropore dimensions. Lasers Surg Med. 2014 Apr;46(4):281-9. doi: 10.1002/lsm.22228. Epub 2014 Feb 5.</citation>
    <PMID>24500855</PMID>
  </reference>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>September 3, 2017</study_first_submitted>
  <study_first_submitted_qc>September 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>September 10, 2017</last_update_submitted>
  <last_update_submitted_qc>September 10, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 12, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Fractional laser</keyword>
  <keyword>Topical anesthesia</keyword>
  <keyword>Drug delivery</keyword>
  <keyword>CO2 laser</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lidocaine</mesh_term>
    <mesh_term>Epinephrine</mesh_term>
    <mesh_term>Racepinephrine</mesh_term>
    <mesh_term>Tetracaine</mesh_term>
    <mesh_term>Carticaine</mesh_term>
    <mesh_term>Epinephryl borate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03279757
org study id: NL53766.018.15b
nct id: NCT03279757
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
The purpose of this study are to compare the efficacy of two different commercially available
      local anesthetics on AFXL pretreated skin and to assess the role of the application time in
      this technique.
Rationale: In dermatology anesthetics are frequently injected or topically applied to achieve
      local anesthesia. Injectable anesthetics are effective but uncomfortable during
      administration, especially for people who are needle phobic. Application of topical
      anesthesia is painless but time consuming and often only partial aesthesia is achieved due to
      the barrier function of the stratum corneum. (Manuskiatti, Triwongwaranat et al. 2010)
      Penetration of local anesthetics could be enhanced by pretreatment of the skin with ablative
      fractional lasers (AFXL) which locally disrupts the stratum corneum by creating an array of
      microscopic ablation channels. (Sklar, Burnett et al. 2014) In a previous pilot study,
      conducted at our institute, we demonstrated that effective anesthesia could be achieved
      within ten minutes after application of a topical anesthetic on skin pretreated with AFXL at
      painless settings. (Meesters, Bakker et al. 2015) However, little is still known about the
      role of the type of anesthetic the type of anesthetic and the application time on the
      efficacy of the anesthesia.

      Objective: The objective of this study is to compare the efficacy of two different
      commercially available local anesthetics on AFXL pretreated skin, a low concentration
      articaine solution and a high concentration lidocaine/tetracaine cream. We also aim to
      compare the efficacy of AFXL assisted topical anesthesia after various different application
      times.

      Study design: Prospective, single blinded, randomized, controlled, within subject, pilot
      study.

      Study population: 15 healthy volunteers ≥18 years, who give written informed consent

      Intervention: In each subject, six test regions on subject's back of 1x1 cm will be
      pretreated with the fractional carbon dioxide (CO2) laser at 2.5 mJ and 15% density and will
      be randomly allocated to application of (I) articaine hydrochloride 40 mg/ml + epinephrine 10
      μg/ml 30 solution (AHES) (5 minutes application time), (II) AHES (15 minutes application
      time), (III) AHES (25 minutes application time), (IV) lidocaine 70 mg/g + tetracaine 70 mg/g
      cream (LTC) (5 minutes application time, (V) LTC (15 minutes application time), (VI) LTC (25
      minutes application time). After 15 minutes a pain stimulus, consisting of a pass with the
      fractional CO2 laser at 50 mJ and 5% density (scanned area 6x6 mm), will be given at each
      test region. In addition, a reference pain stimulus with the CO2 laser at the same settings
      will be given at unanesthetized skin. Subjects will be asked to indicate pain on a visual
      analogue scale (VAS) from 0-10 (0: no pain; 10: worst imaginable pain) directly after each
      pain stimulus
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Pain score
time frame: After 5 minutes application time of the anesthetics
description: The main study parameter is pain, as scored on a VAS from 0-10 (0: no pain; 10: worst imaginable pain).
measure: Pain score
time frame: After 15 minutes application time of the anesthetics
description: The main study parameter is pain, as scored on a VAS from 0-10 (0: no pain; 10: worst imaginable pain).
measure: Pain score
time frame: After 25 minutes application time of the anesthetics
description: The main study parameter is pain, as scored on a VAS from 0-10 (0: no pain; 10: worst imaginable pain).
measure: Pain score
time frame: Directly after pretreatment.
description: The secondary study parameter is pain, as scored on a VAS from 0-10 (0: no pain; 10: worst imaginable pain) directly after pretreatment
arm group label: AHES 5 minutes
arm group type: Experimental
description: This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml solution (AHES) will be applied at this test region. 5 minutes after AHES application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.
arm group label: AHES 15 minutes
arm group type: Experimental
description: This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml solution (AHES) will be applied at this test region. 15 minutes after AHES application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.
arm group label: AHES 25 minutes
arm group type: Experimental
description: This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml solution (AHES) will be applied at this test region. 25 minutes after AHES application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.
arm group label: LTC 5 minutes
arm group type: Experimental
description: This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment lidocaine 70 mg/g + tetracaine 70 mg/g cream (LTC) will be applied at this test region. 5 minutes after LTC application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.
arm group label: LTC 15 minutes
arm group type: Experimental
description: This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment lidocaine 70 mg/g + tetracaine 70 mg/g cream (LTC) will be applied at this test region. 15 minutes after LTC application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.
arm group label: LTC 25 minutes
arm group type: Experimental
description: This test region will be pretreated with a fractional carbon dioxide laser with a 120 μm spot at 15% density and a pulse energy of 2.5 mJ/microbeam (Fractional CO2 laser, 2.5 mJ, 15% density) in a subject blinded fashion. After pretreatment lidocaine 70 mg/g + tetracaine 70 mg/g cream (LTC) will be applied at this test region. 25 minutes after LTC application (under occlusion), a pain stimulus will be given at the test region with the fractional CO2 laser, 50 mJ, 5% density.
arm group label: Unanesthetized skin
arm group type: Other
description: A pain stimulus will be given at unanesthetized skin with the fractional CO2 laser, 50 mJ, 5% density
intervention type: Drug
intervention name: AHES 5 minutes
description: Topical application of AHES with 5 minutes application time After 5 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density
arm group label: AHES 5 minutes
other name: Ultracain D-S forte
other name: Articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml
intervention type: Drug
intervention name: AHES 15 minutes
description: Topical application of AHES with 15 minutes application time After 15 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density
arm group label: AHES 15 minutes
other name: Ultracain D-S forte
other name: Articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml
intervention type: Drug
intervention name: AHES 25 minutes
description: Topical application of AHES with 25 minutes application time After 25 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density
arm group label: AHES 25 minutes
other name: Ultracain D-S forte
other name: Articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml
intervention type: Drug
intervention name: LTC 5 minutes
description: Topical application of LTC with 5 minutes application time After 5 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density
arm group label: LTC 5 minutes
other name: Pliaglis cream
other name: Lidocaine 70 mg/g + tetracaine 70 mg/g cream
intervention type: Drug
intervention name: LTC 15 minutes
description: Topical application of LTC with 15 minutes application time After 15 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density
arm group label: LTC 15 minutes
other name: Pliaglis cream
other name: Lidocaine 70 mg/g + tetracaine 70 mg/g cream
intervention type: Drug
intervention name: LTC 25 minutes
description: Topical application of LTC with 25 minutes application time After 25 minutes: pain stimulus with the fractional CO2 laser, 50 mJ, 5% density
arm group label: LTC 25 minutes
other name: Pliaglis cream
other name: Lidocaine 70 mg/g + tetracaine 70 mg/g cream
intervention type: Device
intervention name: fractional CO2 laser, 50 mJ, 5% density
description: Pain stimulus with the fractional CO2 laser, 50 mJ, 5% density
arm group label: AHES 15 minutes
arm group label: AHES 25 minutes
arm group label: AHES 5 minutes
arm group label: LTC 15 minutes
arm group label: LTC 25 minutes
arm group label: LTC 5 minutes
arm group label: Unanesthetized skin
other name: Fractional carbon dioxide laser
other name: UltraPulse®, DeepFx handpiece; Lumenis Inc.
other name: Ablative fractional laser
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Albert Wolkerstorfer, MD, PhD
role: Principal Investigator
affiliation: Netherlands Institute for Pigment Disorders, Department of Dermatology, Academic Medical Center, University of Amsterdam
last name: Menno A De Rie, MD, PhD
role: Study Director
affiliation: Department of Dermatology, Academic Medical Center, University of Amsterdam
citation: Meesters AA, Bakker MM, de Rie MA, Wolkerstorfer A. Fractional CO2 laser assisted delivery of topical anesthetics: A randomized controlled pilot study. Lasers Surg Med. 2016 Feb;48(2):208-11. doi: 10.1002/lsm.22376. Epub 2015 May 29.
PMID: 26032635
citation: Sklar LR, Burnett CT, Waibel JS, Moy RL, Ozog DM. Laser assisted drug delivery: a review of an evolving technology. Lasers Surg Med. 2014 Apr;46(4):249-62. doi: 10.1002/lsm.22227. Epub 2014 Mar 24.
PMID: 24664987
citation: Oni G, Brown SA, Kenkel JM. Can fractional lasers enhance transdermal absorption of topical lidocaine in an in vivo animal model? Lasers Surg Med. 2012 Feb;44(2):168-74. doi: 10.1002/lsm.21130. Epub 2012 Feb 2.
PMID: 22302761
citation: Oni G, Rasko Y, Kenkel J. Topical lidocaine enhanced by laser pretreatment: a safe and effective method of analgesia for facial rejuvenation. Aesthet Surg J. 2013 Aug 1;33(6):854-61. doi: 10.1177/1090820X13496248.
PMID: 23908302
citation: Ong MW, Bashir SJ. Fractional laser resurfacing for acne scars: a review. Br J Dermatol. 2012 Jun;166(6):1160-9. doi: 10.1111/j.1365-2133.2012.10870.x. Epub 2012 May 8.
PMID: 22296284
citation: Manuskiatti W, Triwongwaranat D, Varothai S, Eimpunth S, Wanitphakdeedecha R. Efficacy and safety of a carbon-dioxide ablative fractional resurfacing device for treatment of atrophic acne scars in Asians. J Am Acad Dermatol. 2010 Aug;63(2):274-83. doi: 10.1016/j.jaad.2009.08.051.
PMID: 20633798
citation: Wolfe JW, Butterworth JF. Local anesthetic systemic toxicity: update on mechanisms and treatment. Curr Opin Anaesthesiol. 2011 Oct;24(5):561-6. doi: 10.1097/ACO.0b013e32834a9394.
PMID: 21841477
citation: Hahn IH, Hoffman RS, Nelson LS. EMLA-induced methemoglobinemia and systemic topical anesthetic toxicity. J Emerg Med. 2004 Jan;26(1):85-8. doi: 10.1016/j.jemermed.2003.03.003.
PMID: 14751483
citation: Haedersdal M, Sakamoto FH, Farinelli WA, Doukas AG, Tam J, Anderson RR. Fractional CO(2) laser-assisted drug delivery. Lasers Surg Med. 2010 Feb;42(2):113-22. doi: 10.1002/lsm.20860.
PMID: 20166154
citation: Bachhav YG, Heinrich A, Kalia YN. Controlled intra- and transdermal protein delivery using a minimally invasive Erbium:YAG fractional laser ablation technology. Eur J Pharm Biopharm. 2013 Jun;84(2):355-64. doi: 10.1016/j.ejpb.2012.11.018. Epub 2012 Nov 30.
PMID: 23207321
citation: Haak CS, Farinelli WA, Tam J, Doukas AG, Anderson RR, Haedersdal M. Fractional laser-assisted delivery of methyl aminolevulinate: Impact of laser channel depth and incubation time. Lasers Surg Med. 2012 Dec;44(10):787-95. doi: 10.1002/lsm.22102. Epub 2012 Dec 4. Erratum In: Lasers Surg Med. 2013 Nov;45(9):617.
PMID: 23212624
citation: Haak CS, Bhayana B, Farinelli WA, Anderson RR, Haedersdal M. The impact of treatment density and molecular weight for fractional laser-assisted drug delivery. J Control Release. 2012 Nov 10;163(3):335-41. doi: 10.1016/j.jconrel.2012.09.008. Epub 2012 Sep 21.
PMID: 23000695
citation: Tierney EP, Hanke CW. Fractionated carbon dioxide laser treatment of photoaging: prospective study in 45 patients and review of the literature. Dermatol Surg. 2011 Sep;37(9):1279-90. doi: 10.1111/j.1524-4725.2011.02082.x.
PMID: 22988990
citation: Paasch U, Haedersdal M. Laser systems for ablative fractional resurfacing. Expert Rev Med Devices. 2011 Jan;8(1):67-83. doi: 10.1586/erd.10.74.
PMID: 21158542
citation: Farkas JP, Richardson JA, Burrus CF, Hoopman JE, Brown SA, Kenkel JM. In vivo histopathologic comparison of the acute injury following treatment with five fractional ablative laser devices. Aesthet Surg J. 2010 May-Jun;30(3):457-64. doi: 10.1177/1090820X10373060.
PMID: 20601578
citation: Hantash BM, Bedi VP, Chan KF, Zachary CB. Ex vivo histological characterization of a novel ablative fractional resurfacing device. Lasers Surg Med. 2007 Feb;39(2):87-95. doi: 10.1002/lsm.20405.
PMID: 17115384
citation: Taudorf EH, Haak CS, Erlendsson AM, Philipsen PA, Anderson RR, Paasch U, Haedersdal M. Fractional ablative erbium YAG laser: histological characterization of relationships between laser settings and micropore dimensions. Lasers Surg Med. 2014 Apr;46(4):281-9. doi: 10.1002/lsm.22228. Epub 2014 Feb 5.
PMID: 24500855
responsible party type: Sponsor
mesh term: Lidocaine
mesh term: Epinephrine
mesh term: Racepinephrine
mesh term: Tetracaine
mesh term: Carticaine
mesh term: Epinephryl borate