Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h  pg/ml, CV% = 32.86), followed by intravenous (672 h  pg/ml, CV% = 32.18) and intranasal administration (515 h  pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option

Quo Vadis PCA? A Review on Current Concepts, Economic Considerations, Patient-Related Aspects, and Future Development with respect to Patient-Controlled Analgesia

This review assesses four interrelating aspects of patient-controlled analgesia (PCA), a long-standing and still widely used concept for postoperative pain management. Over the years, anaesthesiologists and patients have appreciated the benefits of PCA alike. The market has seen new technologies leveraging noninvasive routes of administration and, thus, further increasing patient and staff satisfaction as well as promoting safety aspects. Pharmaceutical research focuses on the reduction or avoidance of opioids, side effects, and adverse events although influence of these aspects appears to be minor. The importance of education is still eminent, and new educational formats are tested to train healthcare professionals and patients likewise. New PCA technology can support the implementation of efficient processes to reduce workload and human errors; however, these new products come with a cost, which is not necessarily reflected through beneficial budget impact or significant improvements in patient outcome. Although first steps have been taken to better recognize the importance of postoperative pain management through the introduction of value-based reimbursement, in most western countries, PCA is not specifically compensated. PCA is still an effective and valued technique for postoperative pain management. Although there is identifiable potential for future developments in various aspects, this potential has not materialized in new products