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To Five-Year-Old Dental Patients Elliot V PEDIATRIC DENTISTRY V 39 / NO 1 JAN / FEB 17 O RANDOMIZED CONTROL TRIAL Phase Four, Randomized, Double-Blinded, Controlled Trial of Phentolamine Mesylate in Two- to Five-year-old Dental Patients Elliot V. Hersh, DMD, MS, PhD1 • Rochelle Lindemeyer, DMD2 • Joel H. Berg, DDS, MS3 • Paul S. Casamassimo, DDS, MS4 • Judith Chin, DDS, MS5 • Adam Marberger, DDS6 • Brent P. Lin, DMD7 • Matthew C. Hutcheson, MS8 • Paul A. Moore, DMD, PhD, MPH9 • Pediatric Soft Tissue Anesthesia Recovery Group10 Abstract: Purpose: The purpose of this study was to evaluate, using a randomized, double-blind methodology: (1) the safety of phentolamine mesylate (Oraverse) in accelerating the recovery of soft tissue anesthesia following the injection of two percent lidocaine plus 1:100,000 epine- phrine in two- to five-year-olds; and (2) efficacy in four- to five-year-olds only. Methods: One hundred fifty pediatric dental patients underwent routine dental restorative procedures with two percent lidocaine plus 1:100,000 epinephrine with doses based on body weight. Phentolamine mesylate or a sham injection (two to one ratio) was then administered. Subjects were monitored for safety and, in four- to five-year-olds, for efficacy during the two-hour evaluation period. Results: There were no significant differences in adverse events between the phentolamine and sham injections. Compared to sham, phentolamine was not associated with nerve injury, increased analgesic use, or abnormalities of the oral cavity. Phentolamine was associated with transient decreased blood pressure in some children. In four- and five-year-olds, phentolamine induced more rapid recovery of lip anesthesia by 48 minutes (P<0.0001). Conclusions: Phentolamine was well tolerated and safe in three- to five-year-olds; in four- to five-year-olds, a statistically significant more rapid recovery of lip sensation compared to sham injections was deter- mined. (Pediatr Dent 2017;39(1):39-45) Received May 7, 2016 | Last Revision October 17, 2016 | Accepted October 19, 2016 KEYWORDS: PHENTOLAMINE MESYLATE, RANDOMIZED CONTROLLED CLINICAL TRIAL, LIDOCAINE, LOCAL ANESTHESIA Providing pain control by administering local anesthetic agents The results of a prospective study of 320 children showed containing a vasoconstrictor (epinephrine or levonordefrin) is a that 16 percent of four- to seven-year-olds and 13 percent of routine part of outpatient dentistry.1 One of the shortcomings eight- to 11-year-olds reported having postoperative soft tissue of dental local anesthetic agents, especially when employed trauma after mandibular block injections that profoundly for routine restorative and scaling procedures that are usually numbed the lower lips and tongue.5 The swelling and tissue completed in an hour or less, is that the duration of soft tissue injury associated with this type of trauma has even led to at anesthesia (numbness to the lip and tongue) typically lasts for least one reported hospital emergency room visit and the unnec- three to five hours.2 These types of dental procedures produce essary administration of antibiotic therapy, because the tissue significantly less (P<0.05) postprocedural pain than stainless appearance resembled that of a postprocedural infection.6 steel crowns and pulpotomies,3 although 25 to 30 percent of Phentolamine mesylate is a nonselective alpha-adrenergic children report pain following restorative dentistry procedures.3,4 blocking agent that has been in the United States marketplace Approximately 15 percent of children also complain about since 1952. It lacks intrinsic activity but possesses higher affi- numbness after dental treatment.3 The persistent anesthesia nity than norepinephrine and epinephrine for postsynaptic beyond the procedure is also associated with difficulty in eat- alpha-adrenergic receptors; thus, it antagonizes (reverses) their ing, drinking, speaking, drooling, and inadvertent biting of the vasoconstrictive action. It was originally developed to treat hy- lips, tongue, and cheek. pertension.7 An intraoral submucosal injectable formulation of phentol- amine mesylate was developed by Novalar Pharmaceuticals (San 1 Dr. Hersh is a professor of pharmacology and division director of pharmacology and Diego, Calif., USA) to help terminate the numbing action of therapeutics, Department of Oral Surgery and Pharmacology, and 2Dr. Lindemeyer is an local anesthesia when it is no longer desired. This product con- associate professor of pediatric dentistry, Department of Preventive and Restorative Sci- tains 0.4 mg phentolamine mesylate packaged in a 1.7-mL ences, both in the School of Dental Medicine, University of Pennsylvania, Philadelphia, dental cartridge. Based on the results of two phase two and two Pa., USA. 3Dr. Berg is a professor of pediatric dentistry, Lloyd and Kay Chapman Chair phase three randomized placebo- or sham-controlled clinical for Oral Health, and dean, University of Washington School of Dentistry, Seattle, Wash., 7-9 USA. 4Dr Casamassimo is a professor of pediatric dentistry, Division of Pediatric Denti- trials (see Table 1 for description of FDA clinical trial phases), stry, School of Dentistry, The Ohio State University, Columbus, Ohio, USA. 5Dr. Chin is a phentolamine mesylate, under the proprietary name OraVerse professor of pediatric dentistry, Department of Pediatric Dentistry, College of Dental (Septodont Inc., Lancaster, Pa., USA) was granted FDA ap- Medicine, Nova Southeastern University, Fort Lauderdale, Fla., USA. 6Dr. Marberger is a proval in 2008 for accelerating the return of sensation and clinical director for dental research, Jean Brown Research; and is in private practice, function following nonsurgical dental procedures requiring local 7 Salt Lake City, Utah, USA. Dr. Lin is a clinical professor of pediatric dentistry and di- anesthetic plus epinephrine or levonordefrin in adult and pedi- rector of predoctoral pediatric dentistry, University of California School of Dentistry, 10 San Francisco, Calif., USA. 8Mr. Hutcheson is founder and a partner, Tegra Analytics, atric dental patients as young as six years old. Doylestown, Pa., USA. 9Dr. Moore is a professor of pharmacology, dental anesthesiol- The first published placebo-controlled phase two study ogy, and dental public health, School of Dental Medicine, University of Pittsburgh, Pitts- reported that, in 10- to 58-year-old dental patients, an injec- burgh, Pa., USA. 1 0 Pediatric Soft Tissue Anesthesia Recovery Group - see acknowledgment tion of phentolamine, at a one-to-one volume ratio at the site section. of the previous local anesthetic injection, accelerated median Correspondence with Dr. Hersh at [email protected] PHENTOLAMINE IN PEDIATRIC DENTAL PATIENTS 39 PEDIATRIC DENTISTRY V 39 / NO 1 JAN / FEB 17 Table 1. DESCRIPTION OF FDA CLINICAL TRIAL PHASES Phase 1 A small group (10-30) of normal volunteers, usually without the disease condition, is evaluated to assess dose, pharmacokinetics, and safety. Phase 2 A larger group of subjects with the disease condition (in this case, those with lip and tongue numbness after local anesthetic injections) are evaluated. This involves efficacy, establishing a dose-response, safety, and pharmacokinetic studies. Up to a few hundred individuals are typically studied. Phase 3 An even larger group of patients with the disease condition are studied. Efficacy and safety are again evaluated; dosing schedules are firmly established. Five hundred to 1,000 subjects are typically evaluated. After the completion of Phase 3, the pharmaceutical manufacturer submits a new drug application to the FDA. The FDA may approve, deny approval, or request that additional research be performed on the drug. Phase 4 This occurs following FDA drug approval. Additional studies may be performed to support marketing claims or broaden the label (in this case, that phentolamine mesylate is effective and safe in children younger than six years old). Another part of Phase 4 is post-marketing drug surveillance. As the drug is used by or administered to many thousands of patients, rare side effects that were not seen in Phase 1 to 3 clinical trials may become apparent to clinicians and reported to the FDA through the Medwatch System. This may result in additional side effects being added to the drug’s package insert or even removal of the drug from the market. recovery time to normal sensation of the upper and lower lips was by 56 percent or 75 minutes (P<0.0001).8 These children by 55 percent or 85 minutes.8 There was no difference in the were also not able to discriminate any pain experienced from incidence or severity of adverse events between the phentola- the phentolamine injections versus the sham injections based mine and the placebo vehicle group. on their responses to the Wong-Baker Faces Pain-Rating Scale Two large pivotal phase three studies employed a sham in- (W-B PRS).11,12 jection instead of a placebo injection because the FDA advised Since the release of phentolamine in dentistry, several that the injection of a placebo vehicle added unnecessary risk. additional clinical trials have been published confirming these In these two studies, the median recovery time to normal lip initial findings.13-15 A recent meta-analysis has reviewed the sensation was accelerated by 55 percent or 85 minutes in the literature and found seven eligible clinical trials that validate the mandibular arch (P<0.0001) and 62 percent or 82.5 minutes efficacy of phentolamine for soft-tissue reversal of anesthesia in the maxillary arch (P<0.0001) compared to sham injections.7 and
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