Proof of systemic safety of a lidocaine ointment in the treatment of patients with anorectal pain.

OBJECTIVE

The aim of the study was to demonstrate that repeated anorectal administration of a 5% lidocaine ointment (CAS 137-58-6; LidoPosterine Salbe, Posterisan akut Rektalsalbe) in the treatment of patients with acute anorectal pain does not result in systemically efficacious plasma concentrations of lidocaine.

PATIENTS AND METHODS

In an open single-center study 24 male or female patients with anorectal pain due to hemorrhoids, anal fissures, fistulas or proctitis administered lidocaine ointment as a single anorectal dose (2.5 g ointment corresponding to 125 mg lidocaine) followed by repeated administration (2.5 g ointment t.i.d.) for 4 days. Safety evaluation was performed with respect to plasma concentrations of lidocaine, vital signs, electrocardiogram (ECG), physical findings and adverse events. Blood samples were drawn prior to the first single administration and at 13 time points over the first 24 h in order to create a pharmacokinetic profile. Blood samples were also drawn prior to administration of the last dose on day 5 and thereafter using the identical time points for blood sampling as on day 1. Vital signs and ECG were recorded immediately before and 1 and 4 h after the first and last administration, respectively. Adverse events and skin tolerability were also recorded at predefined times during the study period.

RESULTS

After a single dose of 125 mg lidocaine the average extent of exposure in terms of the AUC(tau,sd) during a 6 h dosage interval amounted to 397.7 ng/ml x h (geometric mean). C(max,sd) reached a mean value of 131.8 ng/ml (geometric mean). Only a minor accumulation of the lidocaine plasma concentrations was observed after multiple dose application. The geometric mean of the AUC(tau,md) (503.8 ng/ml x h, tau = 6 h) and the geometric mean of C(max,md) (145.9 ng/ml) were slightly higher than the corresponding single dose values. The AUC accumulation ratio was calculated as 127% (90% CI: 108-148%) and the C(max) accumulation ratio reached 120% (90% CI: 101-139%). Plasma peak concentrations of lidocaine in all subjects remained with a sufficient safety margin below the minimal effective therapeutic plasma concentration (1.5 microg/ml) as well as by an order of magnitude below toxic concentrations (5 microg/ml). There were neither unexpected, serious nor severe adverse events. There were no clinically relevant findings with respect to vital signs and ECG.

CONCLUSIONS

Repeated anorectal administration of a 5% lidocaine ointment proved to be safe with respect to systemic plasma concentrations of lidocaine and vital signs.