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      Journal of Pain Research (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on reporting of high-quality laboratory and clinical findings in all fields of pain research and the prevention and management of pain. Sign up for email alerts here.

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      Considerations in selecting rapid-onset opioids for the management of breakthrough pain

      Journal of Pain Research
      Dove Medical Press

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          Abstract

          Dear editor We read with great interest the recent publication by Smith.1 This article provides a valuable perspective on the selection of an agent to manage breakthrough pain. Smith recognizes the importance of a fast onset-of-action and the identification by Farrar et al2 of a 33% (often ≥2 point) change in the pain intensity difference as a measure of a ‘clinically important improvement’. For these reasons, Smith focuses on the various transmucosal fentanyl formulations that offer a rapid onset and he provides a nice summary of the key features of each of the available products. Smith1 also provides some ‘advantages and disadvantages’ of different routes of administration which can be used to select an appropriate formulation for an individual patient. We agree with much of the commentary presented but feel that the grouping of dissimilar formulations based on route of administration is potentially too simple. For example, Smith1 includes two different products in the intranasal route discussion, despite earlier recognition of key formulation differences, and in doing so allocates weaknesses of one formulation to the other. We would like to inform readers of three important points regarding one intranasal fentanyl formulation: First, fentanyl pectin nasal spray (Lazanda®/PecFent® Archimedes Development Ltd Nottingham, UK) includes the unique PecSys® technology that forms a bioadhesive gel on the nasal mucosa, which significantly reduces run-off/drip compared with a simple solution.3,4 This means that the fentanyl is retained in the nasal cavity and that variable absorption associated with nasal drip or swallowing is not an issue for fentanyl pectin nasal spray. Other formulations (nasal and oral) explicitly acknowledge in their prescribing information, the potential for variable absorption.5,6 Secondly, the absorption of fentanyl from fentanyl pectin nasal spray has been specifically studied in patients with rhinitis;7 in that setting the absorption of fentanyl was not affected by nasal inflammation (area under the curve from time 0 to time of last quantifiable plasma concentration, area under the curve from time 0 to 1 hour after administration, maximum plasma concentration, and time to maximum plasma concentration) – which by implication suggests that patients with colds or illnesses that result in changes to the nasal mucosa are suitable candidates for fentanyl pectin nasal spray. Finally, data from fentanyl pectin nasal spray Phase III trials8–10 show that patients did not have difficulty using the spray device; in fact the vast majority reported a high degree of satisfaction. We agree with Smith’s conclusions1 that treatment selections should be based on patient needs, but we felt it important to offer an added perspective on the criteria being used to make such a selection.

          Most cited references9

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          PecSys: in situ gelling system for optimised nasal drug delivery.

          PecSys (PS) is a proprietary pectin-based drug delivery system designed to gel when applied to mucosal surfaces and with potential areas of application for drugs used in local and systemic disease therapy. The current area of focus is intranasal drug delivery where PS is being used to optimise absorption of lipophilic drugs into the systemic circulation. Pectin is described as GRAS (generally regarded as safe) with an excellent regulatory position through its long history of pharmaceutical and food usage. Tests to measure the functional gelling properties of pectin raw material and PS have been devised and validated. The PS-based products at the most advanced stages of development are intranasal formulations containing opioid analgesics intended to provide rapid pain relief with simple and convenient dosing and minimal side effects. The profile of such drugs may not be optimal through current routes of delivery and the ability of PS to modulate their pharmacokinetic profiles, such as attenuation of the peak plasma concentration (Cmax), has been demonstrated in clinical testing. The lead product using PS is a fentanyl nasal spray formulation (NasalFent), which has successfully met the primary objective in a pivotal Phase III clinical study and is scheduled for regulatory filings in the first half of 2009.
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            Consistency of efficacy, patient acceptability, and nasal tolerability of fentanyl pectin nasal spray compared with immediate-release morphine sulfate in breakthrough cancer pain.

            We recently reported that fentanyl pectin nasal spray (FPNS) provides superior pain relief from breakthrough cancer pain (BTCP) compared with immediate-release morphine sulfate (IRMS), with significant effects by five minutes and clinically meaningful pain relief from 10 minutes postdose. To report the consistency of efficacy, tolerability, and patient acceptability of FPNS vs. IRMS. Patients (n=110) experiencing one to four BTCP episodes/day while taking ≥60 mg/day oral morphine (or equivalent) for background pain entered a double-blind, double-dummy (DB/DD), multiple-crossover study. Those who completed an open-label titration phase (n=84) continued to a DB/DD phase; 10 episodes were randomly treated with FPNS and overencapsulated placebo or IRMS and nasal spray placebo (five episodes each). Pain intensity (PI) and pain relief scores were assessed. Patient acceptability scores were assessed at 30 and 60 minutes. Safety and tolerability were assessed by adverse events (AEs) and nasal assessments. Per-episode analysis revealed that FPNS consistently provided relief from pain more rapidly than IRMS; by 10 minutes, there were significant differences in PI difference scores and in the percentages of episodes showing clinically meaningful pain relief (P<0.05). Overall acceptability scores were significantly greater for FPNS than for IRMS at 30 (P<0.01) and 60 (P<0.05) minutes. Patients were "satisfied/very satisfied" with the convenience (79.8%) and ease of use (77.2%) of FPNS. Only 4.7% of patients withdrew from titration because of AEs; no significant nasal effects were reported. This study demonstrates that FPNS is efficacious, well accepted, and well tolerated by patients with BTCP. Copyright © 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
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              Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology, to reduce nasal run-off and drip

              Many of the increasing number of intranasal products available for either local or systemic action can be considered sub-optimal, most notably where nasal drip or run-off give rise to discomfort/tolerability issues or reduced/variable efficacy. PecSys, an in situ gelling technology, contains low methoxy (LM) pectin which gels due to interaction with calcium ions present in nasal fluid. PecSys is designed to spray readily, only forming a gel on contact with the mucosal surface. The present study employed two in vitro models to confirm that gelling translates into a reduced potential for drip/run-off: (i) Using an inclined TLC plate treated with a simulated nasal electrolyte solution (SNES), mean drip length [±SD, n = 10] was consistently much shorter for PecSys (1.5 ± 0.4 cm) than non-gelling control (5.8 ± 1.6 cm); (ii) When PecSys was sprayed into a human nasal cavity cast model coated with a substrate containing a physiologically relevant concentration of calcium, PecSys solution was retained at the site of initial deposition with minimal redistribution, and no evidence of run-off/drip anteriorly or down the throat. In contrast, non-gelling control was significantly more mobile and consistently redistributed with run-off towards the throat. Conclusion In both models PecSys significantly reduced the potential for run-off/drip ensuring that more solution remained at the deposition site. In vivo, this enhancement of retention will provide optimum patient acceptability, modulate drug absorption and maximize the ability of drugs to be absorbed across the nasal mucosa and thus reduce variability in drug delivery.
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                Author and article information

                Journal
                23785243
                3682851
                10.2147/JPR.S45774
                https://creativecommons.org/licenses/by-nc/3.0/

                Anesthesiology & Pain management
                Anesthesiology & Pain management

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