Learning Goals
- Understand the potential adverse reactions and common side effects associated with Phentolamine mesylate administration.
- Familiarize yourself with the average duration of residual soft tissue anesthesia after common dental treatments.
- Examine the proposed mechanism through which OraVerse™ (Phentolamine mesylate) reverses local anesthesia effects.
- Analyze clinical trial results from multiple studies regarding the safety and effectiveness of OraVerse™.
- Explore the prescribing guidelines for OraVerse™ tailored to various patient demographics, including pediatric, adult, and geriatric groups.
- Gain awareness of the possible detrimental side effects and consequences linked to residual local anesthesia post-surgery.
- Be informed about the current pricing, CDT coding status, and reimbursement opportunities from third-party payers for OraVerse™.
Residual Anesthesia
Local anesthetics are among the most commonly used medications in dentistry, with an estimated annual total exceeding 500 million dental injections in the United States. These agents offer reliable and deep anesthesia for various dental office procedures and have a proven safety and efficacy record. Despite their general acceptance and tolerance during surgical interventions, there exists a significant side effect that is often unwelcome: residual soft tissue anesthesia in areas adjacent to the injection site. Unfortunately, the anesthetic effect on nearby soft tissues often lasts much longer than the profound pulpal anesthesia needed for most dental or periodontal operations.
One frequently asked question from patients is, “How long will my lip remain numb?” This concern is one of the most commonly heard in dental practices. While many individuals tolerate the initial injection and procedure, complaints often arise at follow-up visits, with remarks like, “I couldn’t feel my tongue for five hours after I left your office, and I drooled all afternoon!” This reflects the personal and often frustrating deficits associated with local anesthetic administration, which include:
- Loss of motor control
- Perception of swollen tissues
- Inability to control drooling
- Altered facial expression
- Impaired ability to eat, drink, and speak
- Loss of sensation
These side effects can be not only inconvenient and embarrassing but also potentially harmful. The absence of sensation may lead patients to accidentally bite their lip, cheek, or tongue, resulting in significant soft tissue injuries. Such traumatic events involving the lip, tongue, and cheek can be painful and may lead to complications like swelling, ulceration, and secondary infections. Limiting these injuries and their consequences would offer considerable advantages to patients receiving local anesthetic injections. The sole exception is for those who specifically receive longer-acting local anesthetics, such as bupivacaine, which can provide pain relief for up to 12 hours.
Certain groups, including disabled individuals, mentally-challenged adults, the elderly, and children, face a higher risk of post-operative soft tissue trauma. Research indicates that 13% of pediatric patients who received a mandibular block experienced accidental biting of the lower lip as a negative outcome. The likelihood of post-operative lip biting tends to increase with decreasing patient age, with younger children being the most susceptible:
- Under 4 years old: 18%
- Ages 4-7: 16%
- Ages 8-11: 13%
- Ages 12 and older: 7%
Most routine dental and periodontal procedures typically last between 30 to 60 minutes. The most commonly used local anesthetic, 2% lidocaine with epinephrine 1:100,000, usually provides pulpal anesthesia for about one hour, while the soft tissue anesthesia associated with it generally lasts from two to five hours. The duration and extent of residual soft tissue anesthesia are influenced by several factors, including:
- Type of injection (infiltration, block, intraosseous, PDL, etc.)
- Patient anatomy
- Local anesthetic agent utilized
- Amount of anesthetic solution used
- Condition of tissue (normal, infected, lowered pH, etc.)
- Operator technique
- Location of injection (maxillary arch vs. mandibular arch)
- Presence of vasoconstrictor in anesthetic formulation
- Patient metabolism and sensitivity
Research Findings on OraVerse™
The FDA has recommended OraVerse™ for use in patients who are at least 6 years old and weigh a minimum of 33 pounds (15 kg). Clinical trials involving multiple centers were conducted across 18 research sites, with participants aged between 4 and 92. These trials aimed to assess the safety and efficacy of OraVerse™ in reversing soft tissue anesthesia in both the maxillary and mandibular regions. To monitor physiologic responses, researchers utilized a soft tissue anesthesia recovery (STAR) questionnaire, alongside a functional assessment battery (FAB) to evaluate the return of normal behaviors such as speech, drinking, and smiling.
Patients, as well as research assistants, received training to assess residual anesthesia in the lip, tongue, and cheek, using palpation and tapping techniques to rate the level of sensation. Ratings compared the injected side, which received local anesthetic with a vasoconstrictor, to the non-injected contralateral side. Each adult participant received a conventional local anesthetic through infiltration, block, or both methods prior to necessary dental procedures. The following four randomized local anesthetics were used:
- 2% lidocaine (“Xylocaine™”) with epinephrine 1:100,000
- 4% articaine (“Septocaine™”) with epinephrine 1:100,000
- 2% mepivacaine (“Carbocaine™”) with levonordefrin 1:20,000
- 4% prilocaine (“Citanest™”) with epinephrine 1:200,000
In terms of administration, these anesthetics were distributed in a 6:1:1:1 ratio, reflecting the current usage of these agents in the United States (66% of patients received lidocaine, while 11% each received mepivacaine, articaine, and prilocaine). After their dental treatment, patients were assigned to one of two groups. The first group received an injection of 0.4mg to 0.8mg of OraVerse™ at the same site where the original anesthetic had been administered, utilizing the same injection technique. The control group, on the other hand, received a feigned injection with a capped needle and without tissue penetration.
Follow-up for adult patients occurred over a span of up to 5 hours post-OraVerse™ administration. In trials focusing on the maxillary region, the median recovery time for normal upper lip sensation was:
- OraVerse™ group: 50 minutes
- Control group: 133 minutes
This indicates a significant reduction of 1 hour and 23 minutes in maxillary lip anesthesia duration.
In the mandibular trials, the median time to recover lower lip sensation was as follows:
- OraVerse™ group: 70 minutes
- Control group: 155 minutes
This signifies a reduction of 1 hour and 25 minutes in mandibular anesthesia duration.
To further analyze the data, one can track the percentage of patients reporting full sensation recovery in 30-minute increments. In the maxillary trial, the percentages reporting a return of normal sensation were:
- After 30 minutes: 27% in the OraVerse™ group, 2% in the feigned injection group
- After 60 minutes: 59% in the OraVerse™ group, 12% in the feigned injection group
- After 90 minutes: 75% in the OraVerse™ group, 25% in the feigned injection group
Similarly, for the mandibular trial, the percentages were:
- After 30 minutes: 17% in the OraVerse™ group, 1% in the feigned injection group
- After 60 minutes: 41% in the OraVerse™ group, 7% in the feigned injection group
- After 90 minutes: 71% in the OraVerse™ group, 13% in the feigned injection group
The efficacy of OraVerse™ was confirmed based on the data collected. Safety was also evaluated by monitoring vital signs before and after injection, including blood pressure, pulse rate, respiration rate, and body temperature, at regular intervals during the trial. Adverse reactions were recorded, showing similar types and frequencies in both maxillary and mandibular studies. Notably, no serious or severe adverse reactions were reported, with only 5% of patients experiencing moderate oral pain related to the administered dental injections. Importantly, there was no significant increase in the frequency or severity of adverse events, changes in vital signs, pain levels, or adverse tissue reactions within the OraVerse™ groups. Aside from age and weight restrictions, there are no specific contraindications for administering phentolamine in dental patients.
As with all alpha-adrenergic blocking agents, there is a possibility of tachycardia and cardiac arrhythmias following injection. Reports of hypotension and dizziness have also been noted, along with facial flushing. Since no specific antidote for phentolamine exists, treatment for adverse reactions is limited to supportive care and patient monitoring.
Overdoses of phentolamine can lead to symptoms such as headache, visual disturbances, nausea, vomiting, and diarrhea; however, there have been no reported fatalities due to phentolamine overdose. Studies examining the safety of phentolamine injection during pregnancy are lacking, and its excretion in human milk has not been determined, which warrants caution for nursing patients to avoid potential exposure to phentolamine.
Pediatric trials included patients aged 4 to 11, all of whom received injections of 2% lidocaine with epinephrine 1:100,000. Children weighing between 15 to 30 kg received half a dental carpule, while those over 30 kg received a full dental carpule. The average time for children to regain normal lip sensation following OraVerse™ administration was 60 minutes in both the maxillary and mandibular trials. In contrast, the feigned injection groups reported a return to normal lip sensation in an average of 135 minutes.
Administration Protocol for OraVerse™
OraVerse™ is available in standard 1.8 ml dental carpules, each containing 0.4 mg of phentolamine mesylate. The maximum recommended dose for adult patients is two carpules. For administration, it is advised to inject an amount of OraVerse™ equal in volume to the original anesthetic injection, following the same method and at the same site of the initial injection, using a 1:1 ratio.
The most frequently reported adverse reaction associated with phentolamine injection is pain at the injection site, with 5% of patients experiencing this compared to 4% of those receiving a feigned injection. This underscores the need for a cost-benefit analysis for each patient. Practitioners should consider the fragility of a patient’s tissues or their tendency for post-injection soreness or bleeding when weighing the benefits of reducing residual soft tissue anesthesia against the risks of potential tissue injury from a second injection. With block anesthesia, the risks of hematoma, trismus, or nerve trauma due to a second injection should also be evaluated, although clinical trials did not show an increased risk of injection site complications.
The integration of OraVerse™ into standard dental treatment practices is straightforward. It can be dispensed and administered without the necessity for new dental equipment or special training for practitioners. The time required for administration is comparable to that of a local anesthetic injection, and there is no need for topical anesthetic application since the injection site is already anesthetized.
According to the Novalar Pharmaceuticals price list, the current cost of OraVerse™ is $13.00 per carpule ($650.00 for a box of 50 carpules). This could result in an additional charge of $26.00 for a dental procedure if the maximum dosage is utilized. At present, there is no Current Dental Terminology (CDT) code for billing insurance for the use of a soft tissue anesthesia reversal agent. Novalar is actively working to establish a CDT code for this innovative agent and procedure.
Quiz For Oraverse Anesthesia Reversal Agent
