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Randomized Study of Phentolamine Mesylate for Reversal of Local Anesthesia
1 Northwest Kinetics, Tacoma, WA, USA; Correspondence: * corresponding author, jyagiela{at}dentistry.ucla.edu
Local anesthetic solutions frequently contain vasoconstrictors to increase the depth and/or duration of anesthesia. Generally, the duration of soft-tissue anesthesia exceeds that of pulpal anesthesia. Negative consequences of soft-tissue anesthesia include accidental lip and tongue biting as well as difficulty in eating, drinking, speaking, and smiling. A double-blind, randomized, multicenter, Phase 2 study tested the hypothesis that local injection of the vasodilator phentolamine mesylate would shorten the duration of soft-tissue anesthesia following routine dental procedures. Participants (122) received one or two cartridges of local anesthetic/vasoconstrictor prior to dental treatment. Immediately after treatment, 1.8 mL of study drug (containing 0.4 mg phentolamine mesylate or placebo) was injected per cartridge of local anesthetic used. The phentolamine was well-tolerated and reduced the median duration of soft-tissue anesthesia in the lip from 155 to 70 min (p < 0.0001).
Key Words: phentolamine • local anesthesia • reversal • dentistry
Local anesthetics in dentistry are typically administered in combination with  -adrenergic agonists such as epinephrine to provide vasoconstriction of the injected tissues. The resulting slower systemic absorption of the local anesthetic provides more profound and longer-lasting pulpal anesthesia for most dental procedures (Abel and Piascik, 2004). However, vasoconstriction also results in soft-tissue anesthesia that lasts several hours beyond the time needed for the completion of treatment (Malamed, 2004). The prolonged anesthesia is frequently associated with a diminished ability to perform normal activities such as speaking, eating, drinking, and smiling. Accidental biting of the lips or tongue—causing soft-tissue injury—is a particular concern in children (Malamed, 2004). Reducing the post-operative duration of soft-tissue anesthesia would diminish these adverse consequences.
The non-specific Proof-of-principle and dose-ranging safety studies in healthy individuals (unpublished data, Novalar Pharmaceuticals, Inc.) informed this prospectively randomized, double-blind, Phase 2 study to evaluate the safety and efficacy of NV-101, a new formulation of phentolamine mesylate, in persons undergoing restorative or periodontal dental procedures.
Healthy individuals (from 10 to 65 yrs old) scheduled to receive a local anesthetic/vasoconstrictor for routine periodontal maintenance, restorative procedures, or single crowns were enrolled at six study centers in the United States (identified in the Appendix). The study design complied with requirements of the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol used in this study was approved for each center by an independent institutional review board. All participants (and parents of minor children) provided written informed consent. Specific inclusion and exclusion criteria are listed in the Appendix. Participants were randomized (1:1), in a double-blind manner, to phentolamine mesylate or placebo, based on a randomization scheme derived by Novalar from a table of random numbers. The randomization scheme was blocked in groups of 10 for each of the following local anesthetics: 2% lidocaine with 1:100,000 epinephrine, 4% articaine with 1:100,000 epinephrine, 2% mepivacaine with 1:20,000 levonordefrin, and 4% prilocaine with 1:200,000 epinephrine. Persons meeting all inclusion/exclusion criteria were assigned a 3-digit number and given active phentolamine or placebo control according to the predetermined random order for their center (see Appendix for details). Before the procedure, each person received one or two injections of anesthetic/vasoconstrictor. A single local anesthetic was used at five of the six centers; participant enrollment was controlled to generate approximately equal exposures to each local anesthetic in the study. Local anesthetic was administered to the maxilla by supraperiosteal infiltration or by middle or anterior superior alveolar nerve injection. Local anesthetic was administered to the mandible by an inferior alveolar/lingual nerve block. Phentolamine (1.8 mL containing 0.4 mg phentolamine mesylate) or placebo (1.8 mL) was injected at the same site(s) as the local anesthetic, 20 min to 70 min following the last local anesthetic injection. Participants self-evaluated the return of normal sensation in the upper lip (maxillary procedures) or in the lower lip, chin, and tongue (mandibular procedures) at five-minute intervals, beginning 1 min before study drug injection and continuing for at least 3 hrs or until normal sensation returned. Sensation was determined by: (1) tapping, for lips; (2) tapping the lateral edge, for the tongue; and (3) pressing with the forefinger, for the chin. Responses were recorded separately for each tissue and categorized as (1) numb (no feeling), (2) feeling of pins and needles (tingling), or (3) normal sensation. Safety was assessed by pre-operative investigations (12-lead electrocardiogram, complete blood count with platelets and differential, blood chemistries, and urinalysis), intra-operative Holter monitoring, periodic vital signs (blood pressure and heart rate) determinations, pain ratings (Heft-Parker visual analog scale), physical examinations (including intra-oral examinations), and adverse events. All analyses used the intent-to-treat study population (defined as all participants randomized to a treatment group who received a study drug). No interim or per-protocol analyses were performed. The primary efficacy endpoint was time to recovery of normal sensation in the lip. Secondary endpoints were the times to recovery of normal sensation in the tongue and chin. A sample size of 15 persons for each of the eight treatment groups was based on a desired study power of at least 0.9 for comparisons of the effect of phentolamine on the primary endpoint for each of the four local anesthetics. A subsequent decision to use non-parametric statistics precluded these individual comparisons (see Appendix). We used the Kaplan-Meier method to estimate the median time for return of normal sensation, as well as the 25% and 75% quartile times. The 95% confidence intervals for median recovery times were calculated according to the method of Collett (1994). Statistical significance of recovery time differences after phentolamine treatment compared with placebo was determined by the log-rank test, as was the influence on recovery of each of the following covariates: participant age, gender, dental procedure, number of injections of study drug, and time between injection of local anesthetic and study drug. Safety data (adverse events, vital signs, and pain reports) were analyzed with descriptive statistics. Pain reports (taken hourly from 0 to 8 hrs after study drug injection and then on the mornings of the next two days) were also analyzed by repeated-measures analysis of variance after square-root transformation of the data to temper the effect of skewness. SAS software was used for the statistical tests reported herein.
Participants Recruitment of participants began on February 28, 2003, and last contact occurred on June 8, 2003. Among 139 persons screened for participation, 122 were randomized to placebo or phentolamine; 16 persons were not randomized because they failed to meet eligibility requirements, withdrew consent, or were unnecessary to meet enrollment goals. Additionally, one person did not develop adequate pulpal numbness and was discontinued prior to randomization. All 122 participants completed the study. Protocol deviations occurred with 17 participants. Minor deviations in the timing of study drug injections occurred in five participants, one person received a second local anesthetic injection 29 min after the first injection, and 11 had taken oral analgesics within 24 hrs before to 48 hrs after receiving study medication. Of these, six took medication solely for pain unrelated to the dental treatment. Four persons receiving phentolamine in the maxilla after articaine/epinephrine and three receiving phentolamine in the maxilla after prilocaine/epinephrine had deviations; two deviations each were recorded in the mepivacaine/levonordefrin groups receiving placebo. None of the deviations is believed to have affected study results.
Participant characteristics at baseline were similar for the randomized treatment groups (Table 1
Most participants (103; 84%) received one injection of study drug (phentolamine, 50; placebo, 53), and the remainder (19; 16%) received two injections (phentolamine, 11; placebo, 8). The interval between administration of anesthetic and study drug was comparable for the two treatment groups: phentolamine, 44 ± 15 min; placebo, 43 ± 13 min (mean ± SD).
Efficacy
No significant effects of age, sex, time interval between anesthetic and study drug injections, number of injections of study drug, or type of dental procedure on the time to return to normal sensation in the lips were uncovered by log-rank tests (data not shown).
Secondary Endpoints
Safety Phentolamine was well-tolerated, with no serious adverse events (defined as death; a reaction that is life-threatening, permanently disabling, or requiring hospitalization; a persistent or significant disability/incapacity; or a congenital anomaly/birth defect) or withdrawals from the study because of adverse events. One or more non-serious adverse events (related or unrelated to treatment) were recorded for 76 (62%) participants. The overall number of treatment-related adverse events in the phentolamine group (57) was similar to that in the placebo group (50) in a total of 70 persons judged to have experienced treatment-related adverse events. Most of these events were mild in severity; the only severe event (an event that is incapacitating, with inability to work or perform normal daily activity) was an injection site reaction in a control individual. The most frequent adverse event deemed related to study drugs was tachycardia, occurring at similar rates in both the phentolamine (22 events in 22 persons) and control groups (25 events in 25 persons). All tachycardia episodes were mild and brief, typically occurring within 10 min after study drug injection. Although the episodes were deemed by individual investigators to be related to the study drugs, complete examination of the data for the entire study population revealed that the majority of tachycardia episodes (33/47) occurred in persons who were required to walk to another location shortly after study drug injection. Other drug-related adverse events included injection site conditions (12 events in eight persons treated with phentolamine; eight events in six persons treated with placebo), extrasystole (two events in two persons treated with phentolamine; one treated with placebo), bradycardia (four events in four persons treated with phentolamine; two events in two persons treated with placebo), and headache (six persons in each treatment group, one event each). Other drug-related adverse events that involved the oral cavity were one mild case of aphthous stomatitis and one mild tongue disorder in two persons treated with phentolamine. There were no apparent adverse effects of phentolamine on vital signs or electrocardiogram readings. Participants treated with phentolamine reported weak pain in the maxilla and mandibular injection site, and weak mandible soreness during the first 8 hrs after study drug administration. By comparison, those treated with placebo reported faint pain or soreness in these areas. These differences were statistically significant (p < 0.001 for the maxilla, p = 0.03 for mandibular injection site, and p = 0.04 for mandible soreness) only at 1 hr after study drug administration, when their respective median (and interquartile range) scores on the 170-mm Heft-Parker scale were 30 (52) vs. 4 (23) mm, 32.5 (60) vs. 2 (23) mm, and 23.5 (43) vs. 1 (21) mm. These differences were not considered clinically meaningful. It should be noted, however, that four persons treated with phentolamine and three treated with placebo used a pain reliever within 24 hrs of study drug administration, which may have affected pain ratings.
This multicenter, randomized, double-blind, placebo-controlled study investigated the ability of phentolamine to reverse soft-tissue anesthesia in persons undergoing restorative and periodontal maintenance procedures requiring local anesthesia combined with a vasoconstrictor. Results showed that phentolamine significantly accelerated recovery of normal sensation in the lips, with recovery times for phentolamine-treated individuals reduced by approximately 1 hr compared with placebo-treated persons. Phentolamine treatment also shifted the distribution curve of recovery times in the lips such that, relative to placebo-treated controls, the percentage of persons treated with phentolamine who experienced normal sensation within 1 hr after study drug administration was increased 14-fold (43% vs. 3%), and the percentage requiring more than 3 hrs to recover was reduced by a factor of 10 (3% vs. 31%). The effect of phentolamine on recovery in the lips was more pronounced for persons undergoing procedures involving the maxilla than for the mandible, but it was not significantly influenced by the age or sex of the person, the type of dental procedure performed, the interval between anesthetic and study drug injections, or whether one or two injections of study drug were given. Recovery times in the chin and tongue also were significantly reduced for phentolamine treated individuals compared with placebo-treated persons. The safety results demonstrated that one or two injections of 0.4 mg phentolamine were well-tolerated. The adverse events profile was similar for persons treated with phentolamine and for those treated with placebo, with no serious adverse events or withdrawals because of adverse events. There were no clinically significant arrhythmias or noticeable effects on blood pressure or heart rate within 30 min after the administration of the study drug. A mild and apparently exercise-induced tachycardia was frequently reported in the subset of phentolamine and placebo participants who were required to walk to another location after the dental procedure. Other frequent adverse events (bradycardia, injection site conditions, headache) were equally likely to be related to placebo or phentolamine. Pain ratings at the mandibular injection site, mandibular jaw, and maxillary procedure/injection sites were increased 1 hr after study drug administration in phentolamine persons relative to control persons, which may reflect injection or treatment site pain that was unmasked by early reversal of the anesthetic. However, since pain was rated weak for phentolamine-treated persons and faint for placebo-treated persons, the result was not considered clinically significant. Moreover, the mandibular pulpal pain ratings were low throughout the 8-hour reporting period following study drug administration and were not different for the two treatment groups, suggesting that the dental procedures conducted in this study did not result in residual tooth pain after the procedure and recovery from anesthesia had been completed. In summary, the results of this Phase 2 trial indicate that doses of phentolamine up to 0.8 mg are safe and effective for reducing the duration of soft-tissue anesthesia in the lips, chin, and tongue of healthy individuals receiving local anesthetics with vasoconstrictors for routine dental procedures. Thus, phentolamine may provide a new treatment option for persons receiving dental treatment.
This investigation was supported by contracts from Novalar Pharmaceuticals, Inc., San Diego, CA, USA. R. Bruce Rutherford is currently an employee of Novalar Pharmaceuticals.
A supplemental appendix to this article is published electronically only at http://jdr.iadrjournals.org/cgi/content/full/87/7/635/DC1. Received for publication November 21, 2006. Revision received February 29, 2008. Accepted for publication March 10, 2008.
Journal of Dental Research, Vol. 87, No. 7,
635-639 (2008) This article has been cited by other articles:
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