Sublingual Sufentanil for the Management of Acute Pain

Forrest Ringold, MD¹, Harold Minkowitz, MD², Tong-Joo Gan, MD³, Yu-kun Chiang, PhD⁴, Karen DiDonato, RN, MSN⁵, Pamela Palmer, MD, PhD⁵. ¹Mobile Infirmary Medical Center, ²Memorial Hermann Memorial City Medical Center, ³Stony Brook University Hospital, ⁴Essence Sciences, Inc., ⁵AcelRx Pharmaceuticals

Description of Technology: The sufentanil sublingual tablet system (Zalviso™) is a non-invasive, patient-controlled analgesia (PCA) drug/device product currently under review by the U.S. FDA and European Medicines Agency for treatment of moderate to severe acute pain in a hospital setting. A second sublingual sufentanil product (30mcg tablet), dispensed using a single-dose applicator, is also in development for treatment of acute pain in a medically-supervised setting, such as Ambulatory Surgery Centers. Sufentanil appears well-suited for acute pain management when delivered sublingually as a result of its high lipid solubility, favorable therapeutic index (as suggested in animal models) and lack of active metabolites.

Objective: The primary objective of this analysis was to examine the repeat-dose safety and efficacy of sublingual sufentanil tablets (SST) when used for post-operative pain management in both a Phase 2 ambulatory surgery population (20 mcg and 30 mcg tablets) and a Phase 3 major abdominal surgery population (15 mcg tablets). Both trials were randomized and placebo-controlled with primary efficacy measures that included the time-weighted sum of pain intensity differences (SPID) to baseline over the 12 and 48-hour study periods. Safety assessments consisted of adverse events (AE), vital signs and early termination.

Results: 101 and 178 patients were randomized in the phase 2 (P2) and phase 3 (P3) studies, respectively. SST 30 mcg was superior to placebo (PBO) for SPID12 (p=0.003) in the P2 study and SST 15mcg was superior to PBO for SPID48 (p=0.001) in the P3 study. Analysis of pain relief by evaluation time point yielded statistically significant differences in favor of SST as early as 30 minutes(p<0.001) following first dose in P2 and 45 minutes (p=0.027) following first dose in P3. AE’s in general were mild to moderate in severity and similar across all treatment assignments. The most common treatment-related AEs for patients receiving SST were nausea, vomiting, dizziness and somnolence.

Conclusions: Sufentanil tablets dispensed sublingually with a handheld PCA device or by a healthcare professional using a single-dose applicator, are in development for treatment of patients with moderate-to-severe acute pain. When administered sublingually, sufentanil’s fast onset of analgesia, non-invasive route of delivery and patient satisfaction/tolerability make it a useful alternative to IM or IV dosing.