Strive-Phentolamine Mesylate

February, 2011 edition  

Phentolamine Mesylate
By Lisa Wu, RDH

Introduction

Most individuals take everyday orofacial functions for granted. The ability to smile, speak and drink in a normal fashion is often not appreciated until those functions become impaired. Most clients leaving the dental office with residual soft-tissue anesthesia will have a crooked smile, drool without knowing it, and possibly be unable to drink because they are not able to completely close their lips. This lack of sensation and awareness caused by the residual soft-tissue anesthesia serves as a concern for the clinician due to the risk of possible posttreatment adverse effects, especially in the case of pediatric clients who may accidentally cause lip or soft tissue trauma. The ability to reverse soft-tissue local anesthesia before the end of a dental appointment not only serves as a preventive measure for potential oral trauma but also alleviates self-image concerns the client may have. Phentolamine mesylate is a drug designed to reverse residual soft-tissue local anesthesia. 

History of Local Anesthesia

Local anesthesia has increased in duration and efficacy since the time of its first use in 1884. The development of the first amino-ester anesthetic, procaine (Novocain®) in 1905, provided short-duration anesthesia. As dental procedures began to require longer appointments, longer-acting local anesthesia was in high demand. Development of an amino-amide local anesthesia in 1943 called lidocaine (Xylocaine®) with a vasoconstricting agent, epinephrine, soon followed suit. The availability of lidocaine with epinephrine provided clinicians with approximately one hour of pulpal anesthesia and three to five hours of soft-tissue anesthesia in which to work.[1] With some surgical dental procedures, like implant placements, third molar extractions and gum grafts, longer-duration of soft-tissue anesthesia provided client comfort for two to four hours post surgery, which served as a benefit to the client in comfort, as well as to the clinician in client compliance. However, with typical nonsurgical outpatient dental procedures, such as root debridement or direct restorations, which usually last less than one hour, the pulpal anesthesia was sufficient but the soft-tissue anesthesia was excessive.[1,2] 

Concerns with Residual Soft-Tissue Anesthesia

Soft-tissue anesthesia that last two to four hours after nonsurgical dental appointments serves as a source of concern rather than a benefit to both the clinician and client.[1] Without the constant supervision by the clinician, clients—especially pediatric clients—who leave the dental office without sensation in their lips, tongue or gingival tissue could accidentally bite or puncture soft-tissue, possibly causing significant traumatic injury. Although mainly a concern for pediatric clients, residual soft-tissue anesthesia is also a concern in the adult population.

The main concerns that arise with residual soft-tissue anesthesia in the adult clients involve three main areas: perceptual, sensory and functional. The altered perception of anesthetized oral structures; the lack of sensation; and the inability to speak, drink or smile properly can become an inconvenience, interfering with normal daily activities.[1]

In addition to physical trauma and self-image concerns, clinicians may also worry about clients with systemic diseases that require scheduled intervals of food consumption, such as clients with diabetes mellitus, in which food consumption at proper intervals is critical to avoid hypoglycemia. Clinicians are typically taught to advise their clients to avoid eating until the anesthesia has completely gone away to avoid possible self-induced trauma to their soft tissue. Hence, diabetic clients who have residual soft-tissue anesthesia following their dental appointment are at an increased risk either for soft-tissue trauma due to their need to eat at appropriate intervals, or for the potential effects of postponing their food ingestion beyond the recommended interval. Trauma may result from temperature burns, accidental biting of the lips, and/or gingival punctures from hard food substances. Therefore, clinicians are advised to schedule clients with diabetes appropriately to account for the clients’ ability to maintain a proper meal schedule, or suggest alternatives that require less mastication and are at cold or neutral temperatures.

Phentolamine Mesylate Discovery

The types of client-clinician scenarios and concerns mentioned above spawned the development of phentolamine mesylate. During a dental appointment, Howard Katz, DDS, suggested to his client the development of a substance to reverse dental local anesthesia. His client, Eckard Weber, MD, was a partner at a venture capital firm as well as a medical doctor. Katz knew epinephrine was a common ingredient in some local anesthetics that prolonged the duration of action through vasoconstriction of blood vessels at an injection site. Additionally, Weber knew that phentolamine had been used since the 1950s in the medical field to reverse the effects of epinephrine to treat allergy attacks and cardiac problems.[3] The combination of Katz’s and Weber’s knowledge led to the development of phentolamine mesylate to counter the effects of the vasoconstrictor epinephrine.[4]

Pharmacokinetics

Phentolamine mesylate, chemical formula C17H19N3O·CH4SO3, is a non-selective alpha-adrenergic antagonist.[5] It acts as a competitive inhibitor, blocking the effects of epinephrine, an active ingredient in some local anesthetics that causes vasoconstriction.[3,6] As an alpha-adrenergic blocking agent, phentolamine’s main effect is vasodilation of the blood vessels. Phentolamine will reverse alpha-adrenergic receptors and cause smooth muscle relaxation. This relaxation will lead to greater blood flow, resulting in a more rapid systemic absorption of the local anesthetic. Thus, phentolamine mesylate, marketed as OraVerse(TM), is not an antagonist of the local anesthetic itself but of the epinephrine. Therefore, phentolamine mesylate has not been tested for efficacy following use of local anesthetic without added vasoconstrictors.[6]

The delivery method of phentolamine mesylate is similar to that of local anesthesia; it comes in a cartridge like that of regular local anesthetics. Each cartridge contains 0.4mg/1.7mL of solution. The amount of phentolamine mesylate delivered equals the amount of vasoconstrictor containing local anesthesia delivered during the appointment. In addition, the location for the delivery is the same as that used for the original local anesthesia. For example, delivery of three-fourths of a cartridge of lidocaine as an inferior alveolar block injection would require three-fourths of a cartridge of phentolamine mesylate to be delivered at the same inferior alveolar block injection site.

The main challenge to the clinician using phentolamine mesylate is the timing of the injection. Since there is a delayed onset, the clinician needs to plan ahead to ensure that the client will regain sensation of soft tissue by the end of the dental appointment. Unlike local anesthesia, there are no known contraindications for phentolamine mesylate delivery. The only documented adverse reaction is injection-site discomfort.[7]

Studies

Multiple double-blind studies have been conducted involving subjects between 4 and 65 years of age and older. Subjects for the studies were pooled from clients who required local anesthesia for dental treatment, regardless if treatment was to be rendered on the maxilla or mandible. Since phentolamine mesylate diminishes residual local anesthesia, subjects were required to need dental treatments that lasted approximately 60 minutes while still having soft-tissue anesthesia after the appointment.

One study, sponsored by Novalar Pharmaceuticals and conducted by Hersh, et al., showed subjects between the ages of 12 and 65 years and older having a 54 percent reduction in time for return of normal sensation in the mandible and 63 percent reduction in time for return of normal sensation in the maxilla with less effectiveness in subjects between the ages of 12 to 17 years.[8]

A second study, also sponsored by Novalar Pharmaceuticals and conducted by Tavares et al., showed subjects between the ages of 4 and 11 years having a 55.6 percent reduction in time for return of normal lip sensation and a 60 percent reduction in time in the return of normal tongue sensation.[9]

A third study supported by Novalar Pharmaceuticals and conducted by Laviola et al. showed subjects between the ages of 10 to 65 years having a 62 percent reduction in time in the return of normal sensation in the maxilla and a 31.6 percent reduction in time in the return of normal sensation in the mandible.[10]

The aforementioned studies used lidocaine with epinephrine. Additionally, all three studies found no significant postoperative adverse effects of phentolamine mesylate.

Feedback and Testimonials

In addition to the studies and data required for a drug to be approved, the success of a drug also depends on the demand by its consumers. The consumers of phentolamine mesylate include clients of dental offices as well as dental team members who will be recommending the product to their clients. Allan Melnick, DDS, a former faculty member of the University of California, Los Angeles, stated in a press interview that “OraVerse would be especially helpful for children, the elderly and special needs patients, who are more prone to bite their lip or tongue during the time their mouth is numb.”[11] Pediatric dentist David Chin, DDS (electronic communication with the author, April 2010), who has been compensated by Novalar Pharmaceuticals to host continuing education courses regarding OraVerse(TM), said, “Most of the parents of patients are appreciative of the action of Oraverse(TM) when I ask at the next appointment.” On the other hand, Magnus Yang, DDS, speaking as a dental client (oral communication with the author, March 2010), said that he had experienced postoperative soreness at the site of the injection that was different than injections he had received during previous dental visits without phentolamine mesylate. Yang also stated that he would not request the use of phentolamine mesylate unless he had a function to attend soon afterwards.

Conclusion

Phentolamine mesylate (marketed as OraVerse[TM]) is an injectable drug that reverses the effects of the vasoconstricting agent found in some local anesthesia. The goal of the drug is to reverse residual soft-tissue anesthesia after the client has completed a dental appointment. Phentolamine mesylate functions as a vasoconstricting agent antagonist, therefore is not shown to act on local anesthetics that do not contain vasoconstrictors. Benefits include preventing lip or soft-tissue trauma in elderly or pediatric clients, or those with special needs, and regaining everyday function of the oral cavity with the adult clients. Disadvantages were injection site discomfort after residual anesthesia was removed and clinician skill to correctly time the delivery of phentolamine mesylate during the appointment due to the delayed onset. Phentolamine mesylate has been tested only in clients ranging between ages of 4 and 65 years and older. The lack of studies conducted on clients under the age of 4 years or below 33 lbs (15kg) in weight suggests clinicians not recommend phentolamine mesylate for use in this group. However, for clients between the ages of 4 and 65 years and older, studies showed a significant decrease in the time needed to reverse anesthesia effects in clients with the drug than those without.

References

1.  Malamed S. Phentolamine mesylate for the reversal of residual soft-tissue anesthesia. The Academy of Dental Therapeutics and Stomatology. 2008. Available at www.ineedce.com/courses/1597/PDF/Phentolaminerev.pdf.

2.  Malamed S. Reversing local anesthesia. Inside Dentistry. 2008; July/August: 100-2.

3.  Moore PA, Hersh EV, Papas AS et al. Pharmacokinetics of lidocaine with epinephrine following local anesthesia reversal with phentolamine mesylate. Anesth Prog. 2008; 55: 40-8. 

4.  Somers T. Dental anesthesia reversal drug ok’d. The San Diego Union-Tribune. May 10, 2008; A1.

5.  Material safety data sheet: phentolamine mesylate. 2008. Available at www.sciencelab.com.

6.  Wynn RL. (2009).  Phentolamine mesylate – an old medical drug becomes a new dental drug. Gen Dent. 2009; 57: 200-2.

7.  OraVerse. (2009, January). Novalar product insert.

8.  Hersh EV, Moore PA, Papas AS, et al. (2008). Reversal of soft-tissue local anesthesia with phentolamine mesylate in adolescents and adults. J Am Dent Assoc. 2008; 139: 1080-93.

9.  Tavares M, Goodson JM, Studen-Pavlovich D et al.  Reversal of soft-tissue local anesthesia with phentolamine mesylate in pediatric patients. J Am Dent Assoc. 2008; 139: 1095-1104.

10.  Laviola M, McGavin SK, Freer GA, et al. (2008). Randomized study of phentolamine mesylate for reversal of local anesthesia. J Dent Research.  2008; 87: 635-639.

11.  Breakthrough dental anesthesia reversal drug introduced. PRWeb; May 5, 2009. Available at www.prweb.com/releases/2009/05/prweb2379094.htm.

Lisa Wu, RDH, is a graduate of the class of 2010 dental hygiene program at the University of the Pacific in Stockton, Calif. She currently practices in Southern California and volunteers one day a month at a free medical clinic in Stanton, Calif. offering her dental hygiene services.

The faculty mentor for this edition of Strive was Deborah J. Horlak, RDH.