(1) Evaluation of the Local and Systemic Effects of Oral Submucosal Ketamine

Abstract: Few therapeutic alternatives exist for patients with allergies to amide and ester local anesthetics. While diphenhydramine’s efficacy has been verified experimentally, its use is associated with significantly decreased duration of pulpal anesthesia and increased subjective pain scores during exodontia procedures as compared to prilocaine 1. Additionally, complications such as confusion, diplopia, and skin necrosis have been reported. Several investigators have examined ketamine’s use as a post-operative analgesic adjunct when combined with commonly used amide anesthetics during oral surgery procedures 2. However, its effect as a sole anesthetic agent on oral hard and soft tissue has not been elucidated. The objective of this study was to observe the effect of submucosally administered ketamine on pulpal sensitivity. The primary outcome measure was the presence of pulpal anesthesia, as defined by three consecutively negative electric pulp tests or consecutive negative cold tests. Secondary outcome measures included anesthetic duration, sedation level using the Richmond Agitation Sedation Scale (RASS), and vital sign changes.

A non-randomized, single-blinded study with split-mouth design was implemented. American Society of Anesthesiologists physical status I and II participants underwent baseline vital sign monitoring (non-invasive blood pressure, 3-lead electrocardiogram, and pulse oximetry) followed by baseline pulp sensitivity assessment with a standard digital electric pulp tester and ethyl chloride application. Subjects then received a buccal submucosal injection of 1.7mL (51mg) mepivacaine at one vital maxillary premolar site and a similar injection of 1mL of ketamine (50mg/mL) at the contralateral site. Pulp sensitivity testing was repeated every five minutes at each site for sixty minutes. Pulse oximetry and heart rate were monitored continuously. Blood pressure and sedation level were recorded every five minutes. Univariate analysis was conducted with Pearson's chi-square test to determine the presence of a statistically significant association between the medication used and the achievement of pulpal anesthesia. Unpaired t-test was used to determine statistical significance of pulpal anesthesia duration between the two drugs. Significance was defined as p < 0.05.

Nine subjects completed the study; one withdrew due to restlessness prior to completion, so the data were excluded in that case. Seven (77.8%) sites achieved pulpal anesthesia with 50mg of locally administered ketamine compared to 8 (88.9%) with 51mg mepivacaine (p=0.53). Mean duration of pulpal anesthesia was 23.3 (+/-19.8) minutes for ketamine and 25.6 (+/-18.6) minutes for mepivacaine (p=0.81). Mean heart rate increase was 32.2 (+/-18)% above baseline with normalization within 11 minutes. Mean arterial pressure (MAP) increase was 22.4 (+/-10)% above baseline with normalization within 12.4 minutes. The average time spent in RASS sedation of –1 and –2 was 39.4 (+/-14.6) and 7.2 (+/-7.7) minutes, respectively. All subjects who completed the trial remained within 0 to –2 RASS throughout. No desaturation events occurred.

Results of the pilot study demonstrated no statistically significant differences in anesthetic efficacy or duration between ketamine and mepivacaine. Transoral ketamine may have utility as a local anesthetic alternative for select patients with allergies or intolerances to amide and ester anesthetics or antihistamines. However, double-blinded placebo-controlled trials are necessary to further elucidate its effects. Further, vital sign perturbations, drowsiness, light sedation, and restlessness were observed with submucosal administration, highlighting the need for vigilant patient monitoring even with low-dose administration.


References:
1. Uckan S, Guler N, Sumer M, Ungor M. Local anesthetic efficacy for oral surgery: Comparison of diphenhydramine and prilocaine. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998 Jul;86(1):26-30.
2. Satilmiş T, Garip H, Arpaci E, Sener C, Göker K. Assessment of combined local anesthesia and ketamine for pain, swelling, and trismus after surgical extraction of third molars. J Oral Maxillofac Surg. 2009 Jun;67(6):1206-10.