A Phase I Pharmacokinetic and Bioavailability Studyof a Sublingual Fentanyl Wafer in Healthy VolunteersChin Beng Stephen Lim, PhD,*† Stephan A. Schug, MD,‡§ Vivian Bruce Sunderland, PhD,†Michael James Paech, DM,‡� and Yandi Liu, PhD†

BACKGROUND: The sublingual administration of opioids is a simple and noninvasive methodthat provides rapid analgesia. In this phase I study we investigated the pharmacokinetics andbioavailability of a fentanyl wafer in healthy volunteers. The principal study objective was toinvestigate the pharmacokinetic profile of a new sublingual fentanyl wafer and to establish itsabsolute bioavailability.METHODS: Twenty-four healthy volunteers, mean age 23 years, were randomly assigned toreceive the equivalent of fentanyl 100 �g by both the sublingual and IV routes. Blood sampleswere collected in sterile polypropylene tubes for 24 hours after each fentanyl administration. Thepharmacokinetic parameters were determined by model-independent pharmacokinetic analysesof the plasma fentanyl concentration–time profiles.RESULTS: The mean absolute bioavailability of the sublingual fentanyl wafer was 78.9% (90%confidence interval [CI] 51.1% to 121.7%). The first detectable plasma fentanyl concentrationtime ranged from 2 to 10 minutes in all volunteers, and the mean (�SD) time to peak plasmaconcentration at 0.91 (�0.73) hours after administration.CONCLUSION: Sublingual administration of fentanyl as a wafer product resulted in rapidlydetectable plasma fentanyl concentrations. The absolute bioavailability of 78.9% indicated ahigh systemic availability of fentanyl and suggests that further development of this wafer isjustified. (Anesth Analg 2012;115:554–9)

Breakthrough pain is a transient exacerbation of painthat is commonly experienced by cancer patientsdespite treatment with otherwise adequate doses of

opioids. The prevalence of breakthrough pain in cancerpatients ranges from 40% to 93%, and these patients sufferan average of 4 episodes of breakthrough pain per day.1–2

Each episode of breakthrough pain is unpredictable, has arapid onset, and can last up to 35 minutes.

For the successful treatment of transient breakthroughpain, the analgesic (rescue medication) used must be fast-acting and provide immediate pain relief before the “natu-ral” disappearance of the pain.

Rescue medications most commonly used are oralmorphine, oxycodone, and hydromorphone. The reportedaverage time to meaningful pain relief after the adminis-tration of these medications is 31 minutes (range, 5 to 75minutes) with no difference among morphine, oxy-codone, or hydromorphone.2 These opioids are theoreti-cally far from ideal for breakthrough pain treatment,

because, although they may be deemed effective, theironset is such that the breakthrough pain may haveresolved spontaneously.2

Fentanyl is a rapidly acting lipophilic opioid that haspeak analgesic effects within a few minutes of IV adminis-tration and a duration of action, after small to moderatedoses, of 30 to 60 minutes.3 Unfortunately, parenteraladministration of fentanyl is usually unsuitable or inconve-nient for the patient for the self-management of breakthroughpain, especially in the home environment. Fentanyl has there-fore been formulated for administration by a number ofalternative routes including transdermal,4 pulmonary,5,6

oral,7–9 oral transmucosal,10–13 and intranasal (IN).14–17

Sublingual (SL) administration is noninvasive, and thetransmucosal absorption of lipophilic drugs is rapid.18,19 SLfentanyl appears to be clinically useful. It causes minimalmucosal irritation,13 is devoid of the bitter taste of otheropioids,20–23 and avoids presystemic metabolism and thehepatic first-pass effect.24–28

We evaluated a new SL wafer, which was prepared byfreeze-drying an aqueous dispersion of fentanyl citrate(equivalent to 100 �g fentanyl base) containing sodiumcarboxymethylcellulose and amylopectin as matrix form-ers. The fentanyl wafer dissolves rapidly with no residuewhen placed under the tongue.29

The lipophilicity of a drug influences its rate of absorp-tion through biological membranes. Fentanyl has a pKa

value of 8.4; hence at a pH of 7.0, almost 40% of fentanylcitrate should be present as the nonionized base. The waferincludes sodium bicarbonate to adjust the pH of the releasemicroenvironment to approximately 7.0. The pH of salivalies between 5.5 and 7.0.28 It was postulated that thenonionized (lipophilic) form of fentanyl would penetratethe SL mucosal membrane rapidly and that the absolutebioavailability of this wafer would exceed 70%.

From the *Pharmacy Department, Armadale Health Service, Armadale,Western Australia, Australia; †School of Pharmacy, Curtin Health Innova-tion Research Institute, Curtin University, Perth, Western Australia, Austra-lia; ‡School of Medicine and Pharmacology, University of Western Australia,Western Australia, Australia; §Department of Anaesthesia and Pain Medi-cine, Royal Perth Hospital, Perth, Western Australia, Australia; �Departmentof Anaesthesia and Pain Medicine, King Edward Memorial Hospital forWomen, Subiaco, Western Australia, Australia.

Accepted for publication March 16, 2012.

Funding: This study was supported by iX BioPharma Pty. Ltd., Singapore(research grant).

Conflicts of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Chin Beng Stephen Lim, PhD, School of Phar-macy, Curtin University, Perth, WA 6854, Australia, or Pharmacy Depart-ment, Armadale Health Service, 3056, Albany Highway, Armadale, WesternAustralia 6112, Australia. Address e-mail to stephen.lim@health.wa.gov.au.

Copyright © 2012 International Anesthesia Research SocietyDOI: 10.1213/ANE.0b013e3182575cbf

554 www.anesthesia-analgesia.org September 2012 • Volume 115 • Number 3

The primary aim of this open-label phase I study was toinvestigate the pharmacokinetic profile of a new fentanylcitrate wafer and to establish its absolute bioavailability viathe SL route.

METHODSAfter receiving Ethics Committee approval, the trial wasregistered with the Australian Therapeutic Goods Admin-istration under the Clinical Trial Notification scheme andwith the Australian and New Zealand Clinical Trials Reg-istry (number 2010/0606).

This study was performed at Linear Clinical ResearchLtd., Perth, Western Australia, in accordance with theprinciples of the Declaration of Helsinki1a and Good Clini-cal Practice Guidelines.2b

Study SubjectsHealthy volunteers gave written informed consent on anapproved subject consent form, before undergoing trialprocedures. Subjects between 19 and 32 years of age whohad a body mass index between 18 and 30 kg/m2, had nohistory or evidence of drug or alcohol dependence orabuse, had normal findings after a clinical history andlaboratory testing, were free of SL or buccal ulceration ordisease, and had negative findings for human immunode-ficiency virus, hepatitis B, and hepatitis C viral testing wereincluded in the study.

Twenty-four volunteers who met the study inclusionand exclusion criteria were enrolled in this study. On thebasis of an SD of the area under the curve (AUC), values of35% and a 20% difference being significant gives a power of84% (� � 0.05).

Study DesignThis was a single-center (Linear Clinical Research Ltd.,Perth, Australia), randomized, open-label, single-dose,2-treatment, 2-period, 2-way crossover study. According tothe randomization plan, subjects were divided into 2groups, in a 1:1 ratio using a computer-generated table ofrandom numbers. The volunteers were given either IVfentanyl citrate or an SL fentanyl citrate wafer (equivalentto 100 �g of fentanyl). Each volunteer subsequently re-ceived the alternative route after a 7-day washout period.The wafer was administered by placing it under the tongue.The volunteer was requested to avoid swallowing for aslong as possible, at least for 10 minutes.

A naltrexone tablet (50 mg) was administered orallyevery 12 hours from before day 1 to the evening of day 2 (12hours after the last fentanyl dose), so as to block anysystemic effects of fentanyl.

Before commencement of the study, a dedicated IVcannula was placed in the forearm for subsequent venous

blood sampling. Blood samples (7 mL) were taken predosebefore the commencement of wafer administration andthen at 2, 5, 10, 15, 20, 30, 45, 60, 120, 180, 360, 460, 600, 720,960, and 1440 minutes after administration commencement.For IV infusion, blood samples were taken at predose, at 2and 3 minutes after commencement, and at 5 minutes (endinfusion), then at 7, 10, 15, 20, 25, 30, 45, 60, 120, 180, 360,460, 600, 720, 840, 960, and 1440 minutes from infusioncommencement.

After collection, the blood samples were immediatelycentrifuged at 4°C, 2000 to 2500 g for 15 minutes and theplasma extracted and placed into polypropylene storagetubes. The plasma was stored at �80°C � 10°C untiltransfer to the bioanalytical laboratory. Sample extractswere analyzed on an API 4000 LC-MS/MS system (AppliedBiosystems, Foster City, CA), preceded by a ShimadzuProminence high-performance liquid chromatography sys-tem with d5-fentanyl as the internal standard. The assayhad a limit of detection of 10 pg/mL. Precision wasdetermined by duplicate analyses of plasma containing 10,40, and 400 pg/mL fentanyl. The results were precise towithin �6.2%, �3.3%, and �1.7% of the mean measuredconcentration values of 10, 40, and 400 pg/mL, respec-tively, and accurate to within 102%, 99.9%, and 101.4% ofthe nominal concentrations of 10, 40, and 400 pg/mL,respectively. At each concentration the number of repli-cates was 6.

PharmacokineticsThe pharmacokinetic parameters were determined usingPhoenix WinNonlin version 6.1 (Pharsight, A Certara™Company, St. Louis, MO). The pharmacokinetic data wereCmax, tmax, AUC0 to 12, AUC0�t, AUC0��, kel, and t1/2. Firstdetectable fentanyl plasma concentration after SL adminis-tration (Cfirst) and the time to Cfirst (tfirst) were read directlyfrom the plasma fentanyl concentration–time curves.

The terminal elimination rate constant (kel) was deter-mined as the slope of the regression line of best fit to theapproximately log-linear terminal elimination phase. Allfitting was performed with unity weighting of the data. Theterminal elimination half-life (t1/2) was obtained from kel

and equaled ln 2/kel. The AUC0 to 12 and AUC0�t valueswere obtained using the trapezoidal rule. The extrapolationto AUC0�� was calculated from AUC0�t � Ct/kel.

Safety and TolerabilitySafety and tolerability were assessed by monitoring vitalsigns (arterial blood pressure and heart rate) after fentanyladministration. A full physical examination was performedbefore and 48 hours after drug administration. Laboratorytests and a 12-lead electrocardiogram were performed atbaseline and completion of the study. Adverse events wereassessed using direct observation, spontaneous reporting,and nonspecific questioning.

Statistical AnalysisSummary statistics were computed by treatment of eachpharmacokinetic parameter. Bioavailability of SL fentanylwas determined separately for each subject as the ratio ofCmax, AUC0 to 12, AUC0�t, and AUC0�� for SL administra-tion in comparison with IV administration. Overall bio-availability was estimated as the back-transform of the

a World Medical Association (WMA) Declaration of Helsinki. Ethical Prin-ciples for Medical Research Involving Human Subjects. Adopted by the 18thWMA General Assembly, Helsinki, Finland, June 1964, and amended by the52nd WMA General Assembly, Edinburgh, Scotland, October 7, 2000.Available at: http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed September 20, 2007.b European Agency for the Evaluation of Medicinal Products (EMEA).International Conference on Harmonisation—World Health Organization.Guideline for Good Clinical Practice. ICH topic E 6 (R1). Available at:http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf. AccessedDecember 1, 2009.

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difference between treatments for log-transformed Cmax,AUC0 to 12, AUC0�t, and AUC0�� values using a linearmodel with terms for treatment, period, sequence, andsubject within sequence. The 90% confidence interval (CI)was also calculated, and P values �0.05 were consideredstatistically significant. All analyses were conducted usingSAS version 9.2 (SAS Institute Inc., 2008). Differences informulations were evaluated using Student t tests.

RESULTSTwenty-four patients were randomized, 12 to the SL:IVsequence and 12 to the IV:SL sequence. Two volunteers didnot complete the SL or the IV administration arm of thestudy and were eliminated from all analyses. The volunteercharacteristics are reported in Table 1.

Pharmacokinetic ResultsMean plasma (�SEM) fentanyl concentration versus timecurves for the IV and SL routes are shown in Fig. 1.Individual subject plasma concentration profiles are shownfor the SL route in Figure 2. The mean values (�1 SD) for the

plasma pharmacokinetic parameters Cmax, tmax, AUC0 to 12,AUC0�t, and AUC0�� for fentanyl are shown in Table 2.

The first detectable plasma fentanyl concentration(Cfirst), after SL administration, was observed between 2and 10 minutes after administration. The cumulative per-centage of the 22 volunteers with tfirst at 2, 5, and 10minutes and their mean plasma fentanyl concentration(Cfirst) were 12.5% (32.4 pg/mL), 62.5% (30.7 pg/mL), and100.0% (49.0 pg/mL), respectively.

The mean time to peak plasma concentrations (tmax)after commencing IV and SL administration was 0.12 hourand 0.92 hour, respectively (P � 0.0001) (Table 2).

The mean (�SD) terminal half-life (t1/2) for IV and SLadministration was 13.07 � 3.00 hours and 12.49 � 5.24hours, respectively (P � 0.889).

The mean (�SD) terminal elimination rate constant (kel)for IV and SL administration was 0.055 � 0.012 h�1 and0.064 � 0.025 h�1, respectively (P � 0.317).

Bioavailability was assessed by the percentage ratios ofSL/IV for AUC0 to 12, AUC0�t, and AUC0�� values. The meanbioavailability of SL fentanyl was estimated to be 72.1% (CI,65.3% to 79.6%) from AUC0 to 12, and 73.2% (CI, 66.3% to80.9%) from AUC0�t. Absolute bioavailability was 78.9% (CI,51.1% to 121.7%) on the basis of the AUC0�� values.

The Cmax of SL fentanyl was 18.8% (CI, 14.4% to 24.6%)of the IV administration value, with the average time tomaximum concentration being 0.9 hour. For IV administra-tion, Cmax generally occurred at the end of the infusion,with a rapid reduction over the half hour immediatelypostdose. From approximately 2 hours postdose, the mean

Figure 1. Mean (�SEM) plasma concentration (pg/mL) over time profiles for sublingual fentanyl wafer and IV fentanyl. Inset figure is anexpanded profile for the initial 2-hour period.

Table 1. Demographic Characteristics of theStudy VolunteersNumber 24Mean age years (range) 23.2 (19–32)Sex 14 female; 10 maleMean weight in kg (range) 67.1 (51.4–100.7)Study dose of fentanyl (�g) 100

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concentration–time profiles were similar for the 2 modes ofadministration.

TolerabilityAll reported adverse events were mild to moderate. Themean (�sd) time for the wafer to dissolve in the SL pouchwas 73 � 76 seconds.

There was only 1 (4%) of 24 volunteers who reportednausea, commencing 5 minutes after administration of thewafer and increasing in severity to a maximum rating of 2 (of10) at 30 to 60 minutes after administration. This volunteernevertheless rated the wafer as acceptable. Three volunteersreported sedation in the first 5 minutes after administration,the reported number increasing to 4 at 10 and 15 minutes, and5 at 30 minutes, then reducing to 1 volunteer only at 60minutes. One (4%) volunteer experienced a burning (tingling)sensation within 5 minutes of administration, which then

resolved. All � receptor effects would have been moderatedby concomitant naltrexone administration.

DISCUSSIONThis study was designed as a phase I study to determinethe basic pharmacokinetic parameters of a recently devel-oped rapidly dissolving fentanyl wafer. It also collectedsome data on subject acceptance of the product.

It was found that the Cmax and tmax values for the SLfentanyl (100 �g) wafer were comparable (Table 3) to datareported from a previously studied SL fentanyl (100 �g)tablet.30 The Cmax and tmax values provide an indication ofthe rate of absorption of drugs. The wafer has similar Cmax,tmax, and AUC values, in comparison with the SL tablet(P � 0.573, 0.331, and 0.103, respectively); no absolutebioavailability data were available for the SL tablet. It was

Figure 2. Plasma concentration data (pg/mL) over time profiles for sublingual fentanyl wafer for each volunteer (n � 22).

Table 2. Mean Values (�1 SD) of Fentanyl Plasma Pharmacokinetic Parametersa

TreatmentTmax

(hours)Cmax

(pg/mL)AUC0�12

(h*pg/mL)AUC0�t

(h*pg/mL)AUC0��

(h*pg/mL)IV fentanylb (100 �g) (n � 22) 0.12 (�0.05) 1451.0 (�970.1) 1404.8 (�285.5) 1703.7 (�375.9) 1952.9 (�378.8)Sublingual fentanyl wafer (100 �g) (n � 22) 0.91 (�0.73) 219.3 (�70.5) 1046.1 (�388.4) 1299.8 (�517.1) 1739.9 (�815.2)

AUC � area under curve.a Two volunteers were excluded. They did not complete IV administration.b Given as a 5-minute infusion.

Table 3. Comparative Literature Pharmacokinetic Data (Mean � 1 SD) for Buccal and Sublingual (SL)Fentanyl Dosage Formsa

Data Buccal soluble film8 Buccal tablet9 SL tablet32 SL wafer (this study)Dose (�g) 800 400 100 100Study period (hours) 48 72 10 24AUC0��, h/ng/mL 13.03 � 3.45 6.48 � 2.98 1.24 � 0.52 1.74 � 0.82t1/2, hours 19.03 � 8.31 11.6 � 7.8 6.1 � 2.0 12.5 � 5.2Cmax, ng/mL 1.33 � 0.31 1.02 � 0.42 0.24 � 0.14 0.22 � 0.07tmax, hours (range) 1.5 (0.75–4.00) 0.78 (0.33–4.0) 0.66 � 0.29 0.91 � 0.73Bioavailability (%) 71 65 Not available 78.9

AUC � area under curve; Cmax � peak plasma concentration; tmax � time to peak plasma concentration.a The t1/2 terminal elimination half-life.

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noted that the SL tablet was evaluated in cancer patientsover a 10-hour collection period, which causes different t1/2

values of 6.1 and 12.5 hours for the tablet and wafer,respectively (P � 0.0013).

After SL administration, rapid absorption of fentanylwas evidenced by detectable plasma concentrations within2 to 10 minutes (tfirst), occurring in most cases within 5minutes. The wafer formulation had a Cfirst similar to thatof the SL tablet.30 This reflects fentanyl’s high permeabilityinto the rich bloodflow (and good venous outflow) of theSL mucosa,16,27 which bypasses the hepatic “first-pass”effect. The SL mucosa (100 to 200 �m) is thicker than thenasal mucosa (40 to 80 �m); hence a slower absorption ratewas expected in comparison with that reported after INadministration (tmax for IN fentanyl 4.2 to 11.4 minutesversus 54.6 minutes for SL fentanyl in this study).15,27

Furthermore, IN fentanyl is delivered in solution, allowingimmediate absorption, whereas the SL wafer is in a soliddosage form that needs saliva for dissolution, thus creatinga lag period before absorption. On the other hand, thethicker SL mucosa may provide a “reservoir” effect,whereby the lipophilic fentanyl molecules are sequesteredand then released into the circulation.

The buccal mucosa is thicker (500 to 800 �m) than the SLmucosa (100 to 200 �m), which may also explain moreprolonged absorption after buccal administration.11a Thethicker buccal layer, plus underlying smooth muscle inthe buccal area of the oral cavity, may provide a moreretentive system,12,25 possibly also accounting for theslower drug absorption rate. It is notable that the plasma SLfentanyl concentrations were indistinguishable from the IVdata 2 hours after administration, indicating likely similartherapeutic effects. The initial high peak of the IV profilecould potentially produce more side effects.

The bioavailability of this SL fentanyl wafer was 78.9%,which was similar to the bioavailability of IN fentanyl71%15 and fentanyl buccal soluble film (71%).8

The high bioavailability of fentanyl from the wafersuggests that wafer fentanyl is reliably absorbed sublin-gually and less likely to be partially swallowed, henceavoiding first-pass metabolism. No attempt was made toapportion bioavailability to these routes of absorption inthis study. The analgesic efficacy of the wafer formulationappears satisfactory, on the basis of an earlier pilot studyconducted among postoperative surgical patients.29

CONCLUSIONThis SL fentanyl wafer resulted in rapidly detectableplasma fentanyl concentrations in healthy volunteers,within 10 minutes of administration, indicating potentialfor the treatment of breakthrough pain. The bioavailabilitywas 78.9% in relation to IV administration.

DISCLOSURESName: Chin Beng Stephen Lim, PhD.Contribution: This author helped design the study and pre-pare the manuscript.Conflict of Interest: Funding from iX BioPharma, Pty. Ltd.,Singapore, for this phase 1 study.

Name: Stephan A. Schug, MD.Contribution: This author helped design the study, conductthe study, and prepare the manuscript.Conflict of Interest: Funding from iX BioPharma, Pty Ltd.,Singapore, for this phase 1 study.Name: Vivian Bruce Sunderland, PhD.Contribution: This author helped design the study and pre-pare the manuscript.Conflict of Interest: The author has no conflict of interest todeclare.Name: Michael James Paech, DM.Contribution: This author helped prepare the manuscript.Conflict of Interest: The author has no conflict of interest todeclare.Name: Yandi Liu, PhD.Contribution: This author helped design the study and pre-pare the manuscript.Conflict of Interest: The author has no conflict of interest todeclare.This manuscript was handled by: Tony Gin, FANZCA, FRCA, MD.

REFERENCES1. Hagen N, Stiles C, Nekolaichuk C, Biondo P, Carlson L, Fisher

K, Fainsinger R. The Alberta Breakthrough Pain AssessmentTool for cancer patients: a validation study using a delphiprocess and patient think-aloud interviews. J Pain SymptomManage 2008;35:136–52

2. Zeppetella G. Opioids for cancer breakthrough pain: a pilotstudy reporting patient assessment of time to meaningful painrelief. J Pain Symptom Manage 2008;35:563–7

3. Allan L, Hays H, Jensen NH, de Waroux BL, Bolt M, Donald R,Kalso E. Randomised crossover trial of transdermal fentanyland sustained release oral morphine for treating chronic non-cancer pain. BMJ 2001;322:1154–8

4. Gourlay GK, Treatment of cancer pain with transdermal fen-tanyl. Lancet Oncol 2001;2:165–72

5. Mather LE, Woodhouse A, Ward ME, Stephen J, Farr JS,Rubsamen AR, Lorne G, Eltherington LG. Pulmonary admin-istration of aerosolised fentanyl: pharmacokinetic analysis ofsystemic delivery. Br J Clin Pharmacol 1998;46:37–43

6. Coyne PJ, Viswanathan R, Smith TJ. Nebulized fentanyl citrateimproves patients’ perception of breathing, respiratory rate,and oxygen saturation in dyspnea. J Pain Symptom Manage2002;23:157–60

7. Blick SKA, Wagstaff AJ. Fentanyl buccal tablets in break-through pain in opioid-tolerant patients with cancer. Drugs2006;66:2387–93

8. Vasisht N, Gever LN, Tagarro I, Finn AL. Single-dose pharma-cokinetics of fentanyl buccal soluble film. Pain Med2010;11:1017–23

9. Darwish M, Kirby M, Robertson P, Tracewell W, Jiang JG.Absolute and relative bioavailability of fentanyl buccal tabletand oral transmucosal fentanyl citrate. J Clin Pharmacol2007;47:343–50

10. Stanley TH, Hague B, Mock DL, Streisand JB, Bubbers S,Dzelzkalns RR, Bailey PL, Pace NL, East KA, Ashburn MA.Oral transmucosal fentanyl citrate (lollipop) premedication inhuman volunteers. Anesth Analg 1989;69:21–7

11. Christie J, Simmonds M, Patt R, Coluzzi P, Busch MA, Nord-brock E, Portenoy RK. Dose-titration multicenter study oftransmucosal fentanyl citrate for the treatment of break-through pain in cancer patients using transdermal fentanyl forpersistent pain. J Clin Oncol 1998;16:3238–45

12. Streisand JB, Varvel JR, Stanski DR, Le Maire L, Ashburn MA,Hague BI, Tarver SD, Stanley TH. Absorption and bioavailability oforal transmucosal fentanyl citrate. Anesthesiology 1991;75,223–9

13. Portenoy RK, Payne R, Coluzzi P, Raschko JW, Lyss A, BuschMA, Frigerio V, Inghan J, Loseth B, Nordbrock E, Rhiner M.Oral transmucosal fentanyl citrate (OTFC) for the treatment ofbreakthrough pain in cancer patients: a controlled dose titra-tion study. Pain 1999;79:303–12

Phase I Pharmacokinetic Study of Sublingual Fentanyl Wafer

558 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

14. Striebel HW, Kramer J, Luhman I, Rohierse-Hohler I, Rieger A.Pharmacokinetics of intranasal fentanyl (in German). Schmerz1993;7:122–5

15. Lim SCB, Paech M, Sunderland VB, Roberts M, Banks S,Rucklidge M. Pharmacokinetics of nasal fentanyl. J Pharm PracRes 2003;33:59–63

16. Mercadante S, Radbruck L, Davies A, Poulain P, Sitte T,Perkins P, Colberg T, Camba MA. A comparison of intranasalfentanyl spray with oral transmucosal fentanyl citrate for thetreatment of breakthrough cancer pain: an open-label, random-ized, crossover trial. Curr Med Res Opin 2009;25:2805–15

17. Kaasa S, Moksnes K, Nolte T, Lefebvre-Kuntz D, Popper L,Kress HG. Pharmacokinetics of intranasal fentanyl spray inpatients with cancer and breakthrough pain. J Opioid Manage2010;6:17–26

18. Bredenberg S, Duberg M, Lennernas B, Lennernas H, Pet-tersson A, Westerberg M, Nystrom C. In vitro and in vivoevaluation of a new sublingual tablet system for rapid oromu-cosal absorption using fentanyl citrate as the active substance.Euro J Pharm Sci 2003;20:327–34

19. Lennernas B, Frank-Lissbrant I, Lennernas H, Kalkner KM,Derrick R, Howell J. Sublingual administration of fentanyl tocancer patients is an effective treatment for breakthrough pain:results from a randomized phase II study. Palliat Med2010;24:286–93

20. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized,placebo-controlled study of fentanyl buccal tablet for break-through pain in opioid-treated patients with cancer. Clin J Pain2006;22:805–11

21. Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet forrelief of breakthrough pain in opioid-tolerant patients withcancer-related chronic pain. J Support Oncol 2007;5:327–34

22. Simpson DM, Messina J, Xie F, Hale M. Fentanyl buccal tabletfor the relief of breakthrough pain in opioid-tolerant adultpatients with chronic neuropathic pain: a multicenter, random-ized, double-blind, placebo-controlled study. Clin Ther2007;29:588–601

23. Gardner-Nix J. Oral transmucosal fentanyl and sufentanil forincident pain. J Pain Symptom Manage 2001;22:627–30

24. Rathbone MJ, Hadgraft J. Absorption of drugs from the humanoral cavity. Int J Pharm 1991;74:9–24

25. Aronoff G, Brennan M, Pritchard D, Ginsberg B. Evidence-based oral transmucosal fentanyl citrate (OTFC) dosing guidelines. Pain Med 2005;6:305–14

26. Zhang H, Zhang J, Streisand J. Oral mucosal drug deliveryclinical pharmacokinetics and therapeutic applications. ClinPharmacokinet 2002;41:661–80

27. Ghosh TK, Pfister WR. Drug delivery to the oral cavity. BocaRaton: CRC Press, 2005

28. Shojaei A. Buccal mucosa as a route for systemic drug delivery.J Pharm Pharm Sci 1998;1:15–30

29. Lim CB, Paech MJ, Sunderland VB, Liu Y. A pilot pharmaco-kinetic study of a sublingual fentanyl wafer in adult post-operative patients. (In press)

30. Lennernas B, Hedner T, Holmberg M, Bredenberg S, NystromC, Lennernas H. Pharmacokinetics and tolerability of differentdoses of fentanyl following sublingual administration of arapidly dissolving tablet to cancer patients: a new approach totreatment of incident pain. Br J Clin Pharmacol 2004;59:249–53

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