Long-term dosing, safety, and tolerability of fentanyl buccal tablet in the management of noncancer-related breakthrough pain in opioid-tolerant patients.

OBJECTIVE: To evaluate the long-term dosing, safety, and tolerability of fentanyl buccal tablet (FBT) in a large cohort of opioid-tolerant patients with chronic noncancer pain and breakthrough pain (BTP). DESIGN: Combined analysis of three double-blind, placebo-controlled, and two open-label studies. RESULTS: Of 1160 patients who received ≥1 dose of FBT, 83% achieved a successful dose, ranging from 100 to 800 µg, mostly at 600 or 800 µg. Not all of the patients included in this analysis were enrolled in long-term studies and 156 (13%) patients were still receiving ongoing treatment when their study site closed. Median treatment duration was 106.0 days. The mean FBT dose in the post-titration population (n = 946) increased from 2108 to 3132 µg/day, with ≥1 FBT dose increase in 27% of patients; most dose increases occurred during the first 6 months. The FBT daily dose as a proportion of the daily opioid dose remained fairly stable (59-65%) throughout the treatment period. Overall, 925 (80%) enrolled patients had ≥1 adverse event (AE). The most frequent AEs were nausea (21% of patients), vomiting (11%), dizziness (10%), and headache (10%). Common AEs generally occurred within 7 days of starting treatment and lasted for ≤2 days. Serious AEs occurred in 136 (12%) patients and included six deaths (none related to FBT) and 11 instances of opioid overdose (all with satisfactory resolution). AE-related discontinuations occurred in 163 (14%) patients and were similar to the common AEs. CONCLUSIONS: Despite the limitations, including the controlled clinical setting, this pooled analysis of several clinical studies provides valuable information for the long-term management of BTP with FBT. Patients require regular evaluation and, when necessary, adjustment of opioid medications to maintain adequate pain control. FBT was generally safe and well tolerated in this setting.

Regulation of carboxypeptidase E. Effect of Ca2+ on enzyme activity and stability.

Carboxypeptidase E (CPE), an enzyme that functions in the post-translational processing of bioactive peptides, is a member of the metallocarboxypeptidase gene family. A 12-residue region of CPE has 70% amino acid identity with the bacterial enzyme carboxypeptidase T (CPT); in CPT, this region has been identified previously as the Ca(2+)-binding region (Teplyakov, A., Polyakov, K., Obmolova, G., Strokopytov, B., Kuranova, I., Osterman, A., Grishin, N., Smulevitch, S., Zagnitko, O., Galperina, O., Matz, M., and Stepanov, V. (1992) Eur. J. Biochem. 208, 281-288). Using 45Ca2+ binding, we determined that CPE binds Ca2+. To investigate the potential function for the interaction of CPE with Ca2+, we investigated the effect of Ca2+ on aggregation, thermostability, and enzyme activity of CPE. CPE does not aggregate under a variety of Ca2+ concentrations at either pH 5.5 or 7.5, and with protein concentrations ranging from 10 to 100 micrograms/ml. Whereas Ca2+ generally stabilizes proteins to thermal denaturation, CPE was destabilized by Ca2+ and stabilized by low concentrations of EGTA. The Ca(2+)-induced destabilization of CPE was more pronounced at pH 8 than at lower pH values. At pH 8, CPE was unstable even at 37 degrees C, with approximately 40% loss of activity upon incubation for 30 min in the absence of added Ca2+ and 70% loss of activity upon incubation in the presence of 10 mM CaCl2. Enzyme activity was not influenced by added Ca2+, but was stimulated by micromolar concentrations of EGTA; kinetic analysis showed this stimulation to be due to a change in Vmax, and not Km. Taken together, these data suggest that Ca2+ plays a role in the regulation of CPE activity.