Pain Study to Assess Local Anesthetic Efficacy and Safety of CTY-5339 on Gingival Mucosal Tissue in Normal Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to determine if the topical application to gingival tissue of the combination of benzocaine and tetracaine has a longer duration of local anesthetic activity than benzocaine alone.

Detailed Description
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In a blinded study, either benzocaine alone or the combination of benzocaine and tetracaine will be sprayed onto the gingival mucosal tissue. Onset and duration of local anesthesia will be evaluated over a one hour period using pin prick and quantitative sensory testing of heat (QST-heat) stimulation. Subjects will receive both treatments in a cross-over design with each session separated by 4-14 days. A total of 50 subjects (normal volunteers) will be evaluated.

Official Title
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A Double-blind, Cross-over, Incomplete Factorial Study to Assess the Local Anesthetic Efficacy and Safety of CTY-5339 Anesthetic Spray (CTY-5339A) When Applied to the Gingival Mucosal Tissue in Normal Volunteers

Conditions
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No Disease State or Condition

Intervention / Treatment
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* Combination Product: One spray CTY-5339-A
* Device: One spray CTY-5339-CB
* Device: One spray CTY-5339-P


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between 18-75 years of age with a Body Mass Index (BMI) ≤32; Subjects are category I or II on the American Society of Anesthesiologists physical status classification system (ASA category I or II) and are in normal physical health as judged by physical and laboratory examinations; Subjects have normal appearance of the oral mucosal tissues; At screening and at Baseline during Stage 1 and Sessions 1 and 2, of Stage 2 subjects with Pin-Prick-Test (PPT) scores of at least 3 (on a 10 point numerical rating scale [NRS]) on the 2 readings, 1 of which must be a score of at least 4; Subjects have mean quantitative sensory test of heat (QST-Heat) pain sensation temperature assessments on the gingival mucosa of 46.5 °C or less based on the average of the 2 readings at screening and at the Baseline Study Sessions for Stages 1 and 2; Subjects must agree to refrain from ingesting any systemic or topical analgesic medication for 3 days or 5 half-lives of the drug prior to and during the study period and alcohol for 1 day prior to and during the study period; Subjects must agree to refrain from using mouth rinses, cough drops or throat lozenges on the day of each test session; Female subjects must be physically incapable of childbearing potential (postmenopausal for more than 1 year or surgically sterile) or practicing an acceptable method of contraception (hormonal, barrier with spermicide, intrauterine device, vasectomized or same sex partner, or abstinence). Subjects using hormonal birth control must have been on a stable dose of treatment for at least 30 days and received at least 1 cycle of treatment prior to randomization. At Screening and at Baseline of both sessions, all females of childbearing potential must have a negative urine pregnancy test and not be breastfeeding; Negative urine drug screen for drugs of abuse at Screening and at Baseline for each Study Session. A positive drug screen result may be permitted if the subject has been on a stable dose of an allowed medication for >30 days; Subjects must be capable of reading, comprehending, and signing the informed consent form. Exclusion Criteria: Subjects with a history of any significant hepatic, renal, endocrine, cardiac, neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic disorders, including glaucoma, diabetes, emphysema, and chronic bronchitis; Subjects with a history of any type of cancer other than skin related cancers; Subjects with conditions that affect the absorption, metabolism, or passage of drugs out of the body, (e.g., sprue, celiac disease, Crohn's disease, colitis, or liver, kidney, or thyroid conditions); Subjects with any history of alcohol or substance abuse (including a positive drug screen test); Subjects that currently have or have a history of uncontrolled hypertension; Subjects with a known hypersensitivity to any local anesthetic drug; Subjects with a hematocrit level significantly below the normal range on the screening laboratory examination (as judged by the PI); Subjects with any clinically significant abnormal lab result (as judged by the PI); Subjects with any condition or history felt by the Investigator to place the subject at increased risk; Subjects who have smoked or chewed tobacco-containing substances within 6 months prior to the start of the study; Subjects judged by the Investigator to be unable or unwilling to comply with the requirements of the protocol; Subjects who have used an investigational drug within 30 days prior to entering the study; Subjects who have donated blood within 3 months prior to the start of the study; Subjects who have previously participated in the trial; Subjects who are members of the study site staff directly involved with the study or a relative of the Sponsor or other personnel involved with the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage II: One spray CTY-5339-A, then one spray CTY-5339-CB<br>A single spray of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) tested over a 60 minute session. Used in Stage II of the study only. | Combination Product: One spray CTY-5339-A<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 28 mg) and 2.0% Tetracaine Hydrochloride (USP = 4 mg). Administered in a single anesthetic spray.<br>* Other names: benzocaine and tetracaine;Device: One spray CTY-5339-CB<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredient: 14.0% Benzocaine (USP = 28 mg). Administered in a single anesthetic spray.<br>* Other names: 14.0% benzocaine;|
| Active Comparator: Stage II: One spray of CTY-5339-CB, then one spray CTY-5339-A<br>A single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a single spray of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session. Used in Stage II of the study only. | Combination Product: One spray CTY-5339-A<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 28 mg) and 2.0% Tetracaine Hydrochloride (USP = 4 mg). Administered in a single anesthetic spray.<br>* Other names: benzocaine and tetracaine;Device: One spray CTY-5339-CB<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredient: 14.0% Benzocaine (USP = 28 mg). Administered in a single anesthetic spray.<br>* Other names: 14.0% benzocaine;|
| Experimental: Stage I: One spray CTY-5339-A<br>Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 28 mg) and 2.0% Tetracaine Hydrochloride (USP = 4 mg). Administered in a single anesthetic spray. Tested over a 60 minute session. Used in Stage I of the study only. | Combination Product: One spray CTY-5339-A<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 28 mg) and 2.0% Tetracaine Hydrochloride (USP = 4 mg). Administered in a single anesthetic spray.<br>* Other names: benzocaine and tetracaine;|
| Active Comparator: Stage I: One spray CTY-5339-CB<br>Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredient: 14.0% Benzocaine (USP = 28 mg). Administered in a single anesthetic spray. Tested over a 60 minute session. Used in Stage I of the study only. | Device: One spray CTY-5339-CB<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredient: 14.0% Benzocaine (USP = 28 mg). Administered in a single anesthetic spray.<br>* Other names: 14.0% benzocaine;|
| Placebo Comparator: Stage I: One spray CTY-5339-P<br>Metered spray bottle with ≈200 uL total spray volume. Contains no active ingredient (placebo: vehicle control). Administered in a single anesthetic spray. Tested over a 60 minute session. Used in Stage I of the study only. | Device: One spray CTY-5339-P<br>* Placebo. Metered spray bottle with ≈200 uL total spray volume. Contains no active ingredient (vehicle control).<br>* Other names: vehicle control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage II: Duration of Anesthesia as Measured by Pin Prick Test (PPT) for One Spray CTY-5339-A Compared to One Spray CTY-5339-CB | The duration of effect, was defined as the length of time in minutes from onset of anesthesia to the absence of anesthesia.Onset was the time point at which the PPT average pain score was less than the Baseline PPT average score by any amount. Also, in 10 minutes or less, the subject must have had a lower PPT average pain score of ≥ 1 unit than Baseline. Absence of anesthesia was defined as follows: After Onset had been established, absence was the first of two time points with consecutive occurrences of regression of absence of analgesia. Reports of less pain by ≥1 unit than Baseline indicated analgesia; while a report of similar (< 1 unit) or more pain than Baseline indicated regression or absence of analgesia. The minimum onset time was 1 minute. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage II outcome. | Up to one hour post-application | 
| Stage II: Duration of Anesthesia as Measured by Heat Sensation Threshold (QST Heat) for One Spray CTY-5339-A Compared to One Spray CTY-5339-CB | The duration of effect, was defined as the time from onset to treatment failure, as measured by QST Heat score. QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. The QST Heat-based Duration of effect was calculated by the length of time in minutes from onset of anesthesia to the absence of anesthesia where Onset of anesthesia was defined by PPT unless specific QST thresholds were not met. After Onset had been established, absence of analgesia or offset was the first of two time points with consecutive occurrences of regression or absence of analgesia. Reports of QST heat pain temperature by ≥ 3 °C of the Baseline QST indicated analgesia; while a report of similar (<3 °C) than Baseline indicated regression or absence of analgesia. Stage | Up to one hour post-application | 
| Stage I: Duration of Anesthesia as Measured by Pin Prick Test (PPT) for One Spray CTY-5339-A Compared to One Spray CTY-5339-CB Compared to One Spray CTY-5339-P (Placebo: Vehicle Control) | The duration of effect, was defined as the length of time in minutes from onset of anesthesia to the absence of anesthesia.Onset was the time point at which the PPT average pain score was less than the Baseline PPT average score by any amount. Also, in 10 minutes or less, the subject must have had a lower PPT average pain score of ≥ 1 unit than Baseline. Absence of anesthesia was defined as follows: After Onset had been established, absence was the first of two time points with consecutive occurrences of regression of absence of analgesia. Reports of less pain by ≥1 unit than Baseline indicated analgesia; while a report of similar (< 1 unit) or more pain than Baseline indicated regression or absence of analgesia. The minimum onset time was 1 minute. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage I outcome. | Up to one hour post-application | 
| Stage I: Duration of Anesthesia as Measured by Heat Sensation Threshold (QST Heat) for One Spray CTY-5339-A Compared to One Spray CTY-5339-CB Compared to One Spray CTY-5339-P (Placebo: Vehicle Control) | The duration of effect, was defined as the time from onset to treatment failure, as measured by QST Heat score. QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. The QST Heat-based Duration of effect was calculated by the length of time in minutes from onset of anesthesia to the absence of anesthesia where Onset of anesthesia was defined by PPT unless specific QST thresholds were not met. After Onset had been established, absence of analgesia or offset was the first of two time points with consecutive occurrences of regression or absence of analgesia. Reports of QST heat pain temperature by ≥ 3 °C of the Baseline QST indicated analgesia; while a report of similar (<3 °C) than Baseline indicated regression or absence of analgesia. Stage I outcome. | Up to one hour post-application | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage II: Onset of Anesthesia for Pin Prick Test (PPT) | Onset of anesthesia was the time point at which the PPT average pain score was less than the Baseline PPT average score by any amount. Also, in 10 minutes or less, the subject must have had a lower PPT average pain score of ≥ 1 unit than the Baseline PPT. Onset was expected to be between 1 and 5 minutes. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage II outcome. | Up to one hour post-application | 
| Stage II: Onset of Anesthesia for Heat Sensation Threshold (QST Heat) | Onset of anesthesia was defined by Pin Prick Test (PPT) unless specific QST thresholds were not met. If the PPT Onset was 5 minutes or less, then QST must have been greater than the Baseline QST temperature at 5 minutes by any amount and QST must have been ≥ 3 °C of the Baseline QST at 5 or 10 minutes. If the PPT Onset was 10 minutes, then QST must have been ≥ 3 °C of the Baseline QST temperature at 10 minutes. If PPT did not achieve Onset, then QST alone could have achieved onset at either 5 or 10 minutes if QST was greater than the Baseline QST temperature at 5 or 10 minutes by any amount and the QST was ≥ 3 °C of the Baseline QST at 5 or 10 minutes. QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage II outcome. | Up to one hour post-application | 
| Stage II: Percentage of Responders for Pin Prick Test (PPT) at Each Time Point | Response at at time point is defined as when the PPT average pain score was less than the Baseline PPT average score by any amount. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage II outcome. | Up to one hour post-application | 
| Stage II: Percentage of Responders for Heat Sensation Threshold (QST Heat) at Each Time Point | Response at a time point is defined as an increase of QST heat pain temperature by ≥ 3 degrees C compared to the Baseline QST. QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage II outcome. | Up to one hour post-application | 
| Stage II: Percentage of Subjects Reaching Minimal Pain on Pin Prick Test (PPT) (≤2 on Numerical Rating Scale Pain Scale) | Response is defined as a subject having a PPT average pain score of ≤2 recorded at any single time point where PPT was performed. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage II outcome. | Any time within one hour post-application | 
| Stage II: Duration of Minimal Pain for Pin Prick Test (PPT) (≤2 on Numerical Rating Scale Pain Scale) | Response at a time point is defined as having the PPT average pain score of ≤2. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage II outcome. | Up to one hour post-application | 
| Stage II: Percentage of Subjects Reaching Maximum Heat for Heat Sensation Threshold (QST Heat) | QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Reaching maximum heat for QST Heat was defined as subjects reaching the maximum temperature without reporting pain at one or more time points. Stage II outcome. | Any time within one hour post-application | 
| Stage II: Sum of Pain Intensity Differences (SPID) for Pin Prick Test (PPT) (Post-hoc) | SPID was calculated as a sum of the delta PPT scores at each time point until the designated time point. The delta PPT score is defined as the change in PPT score from baseline. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. The total possible scale range was from -100 (best) to +100 (worst) for SPID at the 30 minute time point, and from -160 (best) to +160 (worst) for SPID at the 60 minute time point Lower scores signify a better outcome (less sensitive to pain than at baseline = less pain with therapy = therapy was more effective). Stage II outcome. | Up to one hour post-application | 
| Stage II: Sum of Temperature Differences (STID) for Heat Sensation Threshold (QST Heat) (Post-hoc) | STID was calculated as a sum of the delta QST Heat scores at each time point until the designated time point. The delta QST Heat score is defined as the change in QST Heat score from baseline. QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. The total possible scale range was from -155 ºC (best) to +155 ºC (worst) for STID at the 30 minute time point, and from -248 ºC (best) to +248 ºC (worst) for SPID at the 60 minute time point Lower scores signify a better outcome (less sensitive to pain than at baseline = less pain with therapy = therapy was more effective). Stage II outcome. | Up to one hour post-application | 
| Stage I: Percentage of Responders for Pin Prick Test (PPT) at Each Time Point | Response at at time point is defined as when the PPT average pain score was less than the Baseline PPT average score by any amount. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage I outcome. | Time of application up to one hour post-application | 
| Stage I: Percentage of Responders for Heat Sensation Threshold (QST Heat) at Each Time Point | Response at a time point is defined as an increase of QST heat pain temperature by ≥ 3 degrees C compared to the Baseline QST. QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage I outcome. | Time of application up to one hour post-application | 
| Stage I: Duration of Minimal Pain for Pin Prick Test (PPT) (≤2 on Numerical Rating Scale Pain Scale) | Response at a time point is defined as having the PPT average pain score of ≤2. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage I outcome. | Up to one hour post-application | 
| Stage I: Percentage of Subjects Reaching Maximum Heat for Heat Sensation Threshold (QST Heat) | QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Reaching maximum heat for QST Heat was defined as subjects reaching the maximum temperature without reporting pain at one or more time points. Stage I outcome. | Any time within one hour post-application | 
| Stage I: Onset of Anesthesia for Pin Prick Test (PPT) | Onset of anesthesia was the time point at which the PPT average pain score was less than the Baseline PPT average score by any amount. Also, in 10 minutes or less, the subject must have had a lower PPT average pain score of ≥ 1 unit than the Baseline PPT. Onset was expected to be between 1 and 5 minutes. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage I outcome. | Up to one hour post-application | 
| Stage I: Onset of Anesthesia for Heat Sensation Threshold (QST Heat) | Onset of anesthesia was defined by Pin Prick Test (PPT) unless specific QST thresholds were not met. If the PPT Onset was 5 minutes or less, then QST must have been greater than the Baseline QST temperature at 5 minutes by any amount and QST must have been ≥ 3 °C of the Baseline QST at 5 or 10 minutes. If the PPT Onset was 10 minutes, then QST must have been ≥ 3 °C of the Baseline QST temperature at 10 minutes. If PPT did not achieve Onset, then QST alone could have achieved onset at either 5 or 10 minutes if QST was greater than the Baseline QST temperature at 5 or 10 minutes by any amount and the QST was ≥ 3 °C of the Baseline QST at 5 or 10 minutes. QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage I outcome. | Up to one hour post-application | 
| Stage I: Percentage of Subjects Reaching Minimal Pain on Pin Prick Test (PPT) (≤2 on Numerical Rating Scale Pain Scale) | Response is defined as a subject having a PPT average pain score of ≤2 recorded at any single time point where PPT was performed. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. Stage I outcome. | Any time within one hour post-application | 
| Stage I: Sum of Pain Intensity Differences (SPID) for Pin Prick Test (PPT) (Post-hoc) | SPID was calculated as a sum of the delta PPT scores at each time point until the designated time point. The delta PPT score is defined as the change in PPT score from baseline. PPT scores were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. The total possible scale range was from -100 (best) to +100 (worst) for SPID at the 30 minute time point, and from -160 (best) to +160 (worst) for SPID at the 60 minute time point Lower scores signify a better outcome (less sensitive to pain than at baseline = less pain with therapy = therapy was more effective). Stage I outcome. | Up to one hour post-application | 
| Stage I: Sum of Temperature Differences (STID) for Heat Sensation Threshold (QST Heat) (Post-hoc) | STID was calculated as a sum of the delta QST Heat scores at each time point until the designated time point. The delta QST Heat score is defined as the change in QST Heat score from baseline. QST Heat scores were the temperature where the sensation of a heat stimuli was felt: ranging from 35 ºC to a maximum of 50.5 ºC with intervals of 0.5 ºC, at a frequency of every 1 minute for the first 5 minutes and then every 5 minutes thereafter until the final 60 minute time point. The total possible scale range was from -155 ºC (best) to +155 ºC (worst) for STID at the 30 minute time point, and from -248 ºC (best) to +248 ºC (worst) for SPID at the 60 minute time point Lower scores signify a better outcome (less sensitive to pain than at baseline = less pain with therapy = therapy was more effective). Stage I outcome. | Up to one hour post-application | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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local anesthesia, pain tolerance, experimental pain