How does the pharmacokinetics of the sufentanil sublingual tablet system differ from intravenous morphine?
The effector site of action for all opioids is in the CNS, requiring penetration and pharmacokinetics (PK) that match the needs of the patient. Most of the commonly used opioids have inconsistent CNS penetration due to differences in PK or mismatched pharmacokinetic/pharmacodynamics (PD) profiles. An important cause of the PK/PD mismatch is the inability of certain opioids to penetrate the blood-brain barrier into the CNS effector site, resulting in high plasma drug levels that do not represent PD effects. The transit time from plasma to CNS effector site is termed the plasma: CNS equilibration half-life (TT). The TT for lipophilic drugs such as fentanyl or sufentanil is very fast, within 6 minutes. The TT for hydrophobic drugs such as morphine or hydromophone is very long (about 2.8 hours for morphine), resulting in a PK/PD mismatch and delayed analgesic effect, as well as delayed side effects such as respiratory depression. In addition, there are other factors that increase morphine’s PK/PD mismatch, as it is a substrate for efflux transporters and has active metabolites with even longer TT (morphine-6-glucuronide). A sufentanil sublingual tablet system (SSTS; Zalviso; AcelRx Pharmaceuticals, Redwood City, California) has completed phase III trials. The SSTS allows for the self-administration of a 15-µg sublingual sufentanil tablet via a preprogrammed, handheld device. Like an intravenous patient-controlled analgesic device, the SSTS has a 20-minute lockout before the next dose can be administered. Due to the high lipid solubility, sufentanil is rapidly absorbed transmucosally, resulting in a rapid and reliable intravenous uptake. Compared to intravenous sufentail, the sublingual delivery results in a 10-fold lower C max and a greatly extended plasma half-time (time from C max to 50% C max = 2.61 hours vs. 0.18 hours). As sufentanil has a very short TT and no active metabolites, effector site activity is fast, reliable, and with fewer delayed side effects. A phase III study showed that SSTS was superior to IV PCA morphine in patient global assessment method of pain control.