Author's Reply

AUTHORS' REPLY: Grassin-Delyle and colleagues correctly point out the presence of 2 marketed formulations of intranasal fentanyl and further suggest that the review of intranasal fentanyl in the October issue of The Annals is potentially misleading, as a distinction between formulations was not clearly stated. We thank Grassin-Delyle and colleagues for highlighting the differences in pharmacokinetics of the 2 formulations. However, our intent was not to mislead the readers but instead to summarize the available evidence for intranasal fentanyl for breakthrough cancer pain (BTCP) independent of the formulation.

As noted, one intranasal formulation is a simple solution, while the other is a pectin-based gel that adheres to the nasal mucosa. Differences in the formulations lead to minor differences in the pharmacokinetic profiles. As noted in our review, the onset of analgesia for the pectin-based formulation is approximately 10 minutes, whereas the simple solution has an onset of approximately 5 minutes. Although the onset of analgesia may appear different there have been no head-to-head studies comparing the 2 formulations to determine whether the pharmacokinetic differences translate into a clinically significant difference. Additionally, as the pain of a typical BTCP episode peaks at approximately 3 minutes and lasts a median of 45 minutes, ¹ both formulations appear to be well suited, based on their pharmacokinetic profile, to provide analgesia with a rapid onset to effectively combat the quick onset and resolution of a BTCP episode, regardless of whether the onset of analgesia is 5 minutes or 10 minutes.

We agree that differences in pharmacokinetics exist between the 2 intranasal fentanyl formulations and commend Grassin-Delyle and colleagues for clarifying these differences. However, both formulations provide analgesia to a much more rapid extent than traditional oral therapies such as morphine, which has an onset of analgesia of 30–60 minutes. ² Compared to current therapies for BTCP, the benefit of a quicker onset of analgesia provided by intranasal fentanyl, regardless of the specific formulation, remains clinically important. In the absence of head-to-head clinical trials between the 2 formulations, differences in clinical efficacy cannot be extrapolated from the current data. It is our opinion that both formulations are clinically efficacious, and although not directly interchangeable, they provide the same advantages over current analgesics for the treatment of BTCP.

We appreciate the letter by Perelman and Leake. In their table, the authors correctly relate differences in the pharmacokinetics of the 2 intranasal formulations. Indeed, a pharmacokinetic difference exists between the formulations as highlighted, but the clinical relevance of these differences is unknown. The pharmacokinetic profile may play an important role in the clinical efficacy of a drug but making clinical comparisons based solely on pharmacokinetic profiles should likely be avoided. Any conclusions of clinical differences between the formulations based on the C_max and AUC values cannot be supported in the absence of head-to-head comparisons, as the authors suggest.

Interestingly, Perelman and Leake directly compare the results of 2 clinical studies, each of which used a different formulation of intranasal fentanyl. They highlight the need for many Instanyl users to use an additional dose of fentanyl to adequately treat their initial and subsequent BTCP episodes, ³ whereas no Lazanda users required a subsequent dose and instead continued to experience increasing efficacy at 60 minutes. ⁴ We question whether this information is being included to highlight an undocumented perceived benefit of Lazanda over Instanyl. To date there have been no head-to-head studies comparing the 2 formulations, and comparative conclusions based on the results of 2 distinct independent trials should be considered speculative.

Lastly, we trust that Perelman and Leake were motivated in their letter by an evidence-based belief that clinical differences exist between the products. The fact that both are employees of the company responsible for the marketing of the pectin-based gel formulation and multiple references to the brand name in their letter does, however, raise suspicions. Perhaps the employer of Perelman and Leake should fund a head-to-head trial in an effort to document any clinical differences between the 2 formulations, should they exist. In the absence of such a trial we do not believe there is sufficient evidence to conclude that one formulation of intranasal fentanyl is clinically superior.