Disposition of nasal, intravenous, and oral methadone in healthy volunteers

Objective: Nasal administration of many opioids demonstrates rapid uptake and fast onset of action. Nasal administration may be an alternative to intravenous and oral administration of methadone and was therefore studied in human volunteers. Methods: The study was approved by the Institutional Review Board of the University of Washington, Seattle. Eight healthy volunteers (6 men and 2 women) aged 19 to 33 years were enrolled after informed written consent was obtained. Subjects received 10 mg methadone hydrochloride nasally, orally, or intravenously on 3 separate occasions in a crossover design. Nasal methadone (50 mg/mL in aqueous solution) was given as a 100- L spray in each nostril (Pfeiffer BiDose sprayer). Blood samples for liquid chromatography-mass spectrometry analyses of methadone and the metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium were drawn for up to 96 hours. The methadone effect was measured by noninvasive infrared pupilometry coincident with blood sampling. Results: Nasal uptake of methadone was rapid, with maximum plasma concentrations occurring within 7 minutes. The maximum effects of intravenous, nasal, and oral methadone, on the basis of dark-adapted pupil diameter, were reached in about 15 minutes, 30 minutes, and 2 hours, respectively. The respective durations were 24, 10, and 8 hours. Both nasal and oral bioavailabilities were 0.85. Subjects reported that nasal methadone caused a burning sensation. Conclusions: Nasal administration of methadone results in rapid absorption and onset of effect and high bioavailability, which was greater than that reported for other nasal opioids, with a similar duration of effect. Nasal administration may be an alternative route of methadone administration; however, improved formulations are desirable to reduce nasal irritation. (Clin Pharmacol Ther 2002;72:536-45.)

Ola Dale, MD, PhD, Christine Hoffer, AS, Pamela Sheffels, BS, and Evan D. Kharasch, MD, PhD Seattle, Wash, and Trondheim, Norway

Oral opioids are the mainstay of long-term therapy for cancer pain in conjunction with radiotherapy and
From the Department of Anesthesiology, University of Washington, Seattle; and Department of Anesthesia and Medical Imaging, Norwegian University of Science and Technology, and Department of Anesthesia and Intensive Care, St Olavs University Hospital, Trondheim. Supported in part by Norwegian Research Council grant 136286/300 (O.D.), National Institutes of Health grants K24 DA00417 and R01DA 14211, a Merit Award from the Veterans Affairs Medical Research Bureau (E.D.K.), and National Institutes of Health grant M01-RR-00037 to the University of Washington General Clinical Research Center. Received for publication May 13, 2002; accepted July 2, 2002. Reprint requests: Ola Dale, MD, PhD, Department of Anesthesia and Medical Imaging, Norwegian University of Science and Technology, 7489 Trondheim, Norway. E-mail: ola.dale@medisin.ntnu.no Copyright 2002 by the American Society for Clinical Pharmacology & Therapeutics. 0009-9236/2002/$35.00 0 13/1/128386 doi:10.1067/mcp.2002.128386

chemotherapy.1,2 For the last decade, controlled-release oral morphine has been a principal therapy because it reasonably maintains analgesic concentrations within the desired therapeutic range. However, breakthrough pain with a rapid onset and brief duration is common,1,3 often occurring at the end of the regular opioid dosing interval.3 Thus current opioids for treatment of baseline pain frequently have an insufcient duration of action. Methadone has attracted renewed interest in palliative care.4-13 It differs from morphine pharmacologically by its antagonist action on the N-methyl-Daspartate receptor, its lack of active metabolites, its high oral bioavailability, its relative independence from renal excretion, and, nally, its long terminal halflife.11,14-23 The long terminal half-life may theoretically lead to accumulation and toxicity in patients4; however, a recent study demonstrated its safe use in outpatients.13 The usefulness of methadone for patients who are not properly treated with morphine, because of either adverse effects or inadequate pain relief, has

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been documented in several reports, underlining the pharmacologic differences between the two opioids.24,25 Methadone is an inexpensive alternative to other opioids.8,26 Most patients with moderate to severe pain from cancer can be treated with oral opioids, but 50% to 70% will require alternative routes of administration.27 For methadone, only oral and intravenous commercial formulations are available, because subcutaneous infusion has been abandoned.28 Nasal administration is an alternative route that may achieve rapid opioid onset of effect. The nasal mucosa has characteristics that favor rapid drug uptake.29,30 Pharmacokinetic studies with various opioids have shown bioavailabilities of 50% to 70%, which are generally higher than for oral or rectal administration. Maximum serum concentrations have been reached 10 to 50 minutes after administration.30-35 Studies in postoperative patients with nasal opioids have demonstrated mean times of onset of pain relief from 12 to 16 minutes.30,36-38 The use of nasal fentanyl in patients with cancer pain has also been reported.39 The slow elimination and long duration of the methadone effect, allowing for relatively infrequent dosing, make it an attractive candidate for nasal administration in selected patients. The disposition of nasally administered methadone has not been previously studied. To use drugs by various routes safely, it is important to provide comparative pharmacokinetic data. Comparative time-course data on opioid effectsfor instance, noninvasive pupilometry40,41may show outcome differences after pharmacologic interventions.42-44 Thus the goal of this study was to compare the disposition and pharmacodynamics of orally, nasally, and intravenously administered methadone in young healthy volunteers. METHODS Ethics This study was conducted according to the principles of the Declaration of Helsinki and was approved by the Institutional Review Board for Human Studies at the University of Washington Medical Center, Seattle, Wash. Informed written consent was obtained from subjects before inclusion. Inclusion and exclusion criteria Healthy male and female volunteers, aged 18 to 40 years, were eligible. Subjects with a history of liver disease, those who were taking any medications metabolized by or affecting cytochrome P450 (CYP) 3A, and those who had any local nasal disease, any history of drug allergies, or a history of drug abuse or professional

access to drugs of abuse were excluded from the study. Pregnant women were also excluded. Eight subjects (6 men and 2 women), aged 19 to 33 years, were studied. The weight and height (given as median with range in parentheses) of the men were 73.5 kg (59-99 kg) and 177 cm (167-182 cm), respectively, and those of the women were 59 kg (57-61 kg) and 151 cm (150-152 cm). Setting and design The setting for this study was the General Clinical Research Center facilities at the University of Washington Medical Center. Subjects received 10 mg methadone hydrochloride intravenously, orally, or nasally. Although the original design was a randomized 3-way crossover study, subjects were randomized to receive oral or intravenous methadone, followed by nasal methadone, because of a delay in obtaining the nasal formulation. Each study session consisted of a 13-hour stay in the clinical research center, followed by daily visits for 4 additional days. The sessions were separated by at least 1 week. Drug doses and administration Ten milligrams of methadone hydrochloride (corresponding to 8.94 mg free base) (Roxane Laboratories, Inc, Columbus, Ohio) was administered at each session. Commercial preparations were used for intravenous (10 mg/mL) and oral (2 mg/mL) administration. Nasal methadone was prepared by the hospital pharmacy by dissolving methadone (dry substance) in sterile water to a concentration of 50 mg/mL. The pH of the solution (5.4) was not adjusted. The nasal dose was given with a Pfeiffer BiDose sprayer (Ing. Erich Pfeiffer GmbH, Radolfzell, Germany); one actuation delivered 100 L in each nostril. Procedures Because certain foods may affect drug kinetics, volunteers were asked not to ingest alcohol, grapefruit, grapefruit juice, caffeine, or medications for 12 hours before and during each study period (6 days). Subjects were asked to abstain from food and liquids after midnight the day before methadone administration. For each methadone administration, one or two peripheral intravenous catheters were inserted in a hand or arm vein for drug administration and blood sampling. Subjects were monitored for 2 hours (blood pressure and oxygen saturation). Oxygen was administered if oxygen saturation decreased below 94%. Venous blood samples (5 mL) were drawn at 0, 2, 5, 10, 15, 30, 45, and 60 minutes and 1.5, 2, 3, 4, 5, 6, 7,

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Fig 1. The time course (0-96 hours) of plasma concentrations of methadone (mean and standard deviation [SD]) in 8 healthy volunteers after intravenous (IV), oral, and nasal administration of methadone hydrochloride (HCl) (10 mg). Pharmacokinetic calculations are shown in Table I.

Fig 2. The time course (0-2 hours) of plasma concentrations of methadone (mean and SD) in 8 healthy volunteers after IV, oral, and nasal administration of methadone HCl (10 mg). Note the linear scale on the ordinate. Pharmacokinetic calculations are shown in Table I. 8, 10, and 12 hours after drug administration on the rst day. Subjects were given a standard breakfast 2 hours after methadone administration and had free access to food thereafter. Subjects were admonished not to drive, operate machinery, or engage in any other dangerous activity for the remainder of the day. Subjects returned once daily for additional blood sampling at 24, 48, 72, and 96 hours after drug administration. Dark-adapted pupil diameter was assessed by noninvasive infrared pupilometry (Pupilscan, model 6; Fairville Medical Op-

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tics, Inc, United Kingdom) at every methadone determination, except at 12 hours.40-42 In addition, pupilometry was performed at 3, 5, and 7 hours. Analysis Plasma concentrations of methadone and its metabolites 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP) were determined by HPLC-positive electrospray mass spectrometry (Agilent 1100 MSD; Agilent Technologies, Palo Alto, Calif). The internal standard (7-dimethylamino-5,5-diphenyl-4-octanone, 2.5 ng) was added to plasma (0.5 mL), which was acidied, and then processed by solid phase extraction (Oasis MCX cartridges; Waters Corp, Milford, Mass) according to the manufacturers instructions. Eluents were evaporated to dryness under nitrogen and reconstituted in 50 L of 30% methanol, and 12 L was injected onto the HPLC. Compounds were eluted from a Zorbax Eclipse XDB-C18 column (2.1 50 mm, 5 m, with guard column) (Agilent Technologies) by an isocratic mobile phase of methanol, 55%, in 0.05% triuoroacetic acid (pH 3.6), at 0.25 mL/min and detected by single-ion monitoring (methadone mass to charge ratio [m/z], 310.1; EDDP m/z, 278.1; EMDP m/z, 264.1; and internal standard m/z, 324.1). Standard curves were prepared with the use of blank plasma and were linear over 0.5 to 200 ng/mL for methadone and 0.5 to 10 ng/mL for metabolites. The lower limit of quantication was dened by the lowest calibration sample. Interday coefcients of variation were 12%, 12%, and 9% for 1, 15, and 100 ng/mL methadone and 18% (1 and 5 ng/mL) for EDDP. Plasma concentration data were analyzed by noncompartmental techniques. Methadone clearance, volume of distribution, elimination rate, maximum concentration (Cmax), time to maximum methadone plasma concentration (tmax), and area under the curve (AUC) (linear trapezoidal rule) were calculated by computerized curve tting with WinNonlin Standard 3.0 (Pharsight Corporation, Mountain View, Calif). The following equations were used: Systemic clearance (CL) Dose/AUCiv. Observed oral clearance (CLoral) Dose/ AUCoral. Observed nasal clearance (CLn) Dose/ AUCn. Bioavailability (Fx) (AUCx/Dosey)/(AUCy/ Dosex). Primary and secondary outcome measures The primary outcome measure was bioavailability. The secondary outcome measures were as follows: methadone intravenous, oral, and nasal half-life, clearance, and volume of distribution; AUC of plasma meth-

adone concentration versus time; AUC of plasma methadone metabolite concentrations (EDDP) versus time; pupil diameter; and AUC of pupil diameter versus time. Sample size determination Sample size was not calculated for this exploratory pilot study. Statistics Data are reported as mean and 95% condence interval (CI), mean and standard deviation (SD), or median and range when appropriate. ANOVA or t tests were used for group comparisons when appropriate. Kinetic and dynamic measures were compared by repeated-measures ANOVA. Post hoc testing was performed with the Student-Newman-Keuls method. RESULTS Pharmacokinetics The time course (mean and SD) for the plasma concentrations of methadone are displayed in Figs 1 and 2. The pharmacokinetic data (mean and 95% CI) are shown in Table I. Fig 1 shows the plasma concentration for the whole study period, whereas Fig 2 displays the rst 2 hours (in which it should be observed that the ordinate is linear). Interindividual variation in plasma concentrations after intravenous and nasal administration was considerable for the rst 15 minutes. The tmax values were 0.03 (rst sample), 0.12, and 2.1 hours for intravenous, oral, and nasal methadone, respectively (Table I). The corresponding Cmax values were 135, 43, and 114 ng/mL. Oral tmax and Cmax values were statistically different from the nasal and intravenous values. Mean terminal half-lives of 33 to 37 hours and clearances of 4300 to 6100 mL/h were observed for the 3 sessions (no statistically signicant difference). Oral and nasal absolute bioavailabilities were 0.85 (95% CI, 0.79-0.92) and 0.85 (95% CI, 0.7-1.10), respectively. Plasma concentrations of EDDP, the major metabolite of methadone, showed signicant interindividual variation and were much lower than those of methadone (Fig 3). The tmax value was statistically signicantly shorter after oral administration (2.1 hours) compared with intravenous administration (20.8 hours) (Table II). The mean apparent terminal half-lives observed for EDDP were 39 to 44 hours (no statistically signicant difference). EDDP AUCs and the AUC ratios (AUCEDDP/AUCmethadone) for the different administrations did not differ statistically. No EMDP was

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Table I. Pharmacokinetic variables after intravenous, oral, and nasal administration of methadone hydrochloride (10 mg) in 8 human volunteers studied in a crossover fashion
Route Intravenous Oral Nasal tmax (h) 0.03 2.1* (1.5-2.8) 0.12 (0.07-0.177) Cmax (ng/mL) 135 (90-179) 43* (32-54) 114 (76-153) t1/2 (h) 34.0 (26.7-41.3) 33.9 (27.2-40.4) 37.1 (29.1-45.2)

Data are presented as mean and 95% condence interval. tmax, Time to maximum methadone plasma concentration; Cmax, maximum concentration; t1/2, half-life; AUClast, area under the curve from time 0 to last sampling point; AUCinf, area under the curve from time 0 to innity; VZ (obs), observed volume of distribution in the terminal phase; CL (obs), observed clearance. *Statistically signicantly different (P .05) from intravenous and nasal administration.

Table II. Pharmacokinetic variables for 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP) after intravenous, oral, and nasal administration of methadone hydrochloride (10 mg) in 8 human volunteers studied in a crossover fashion
Route Intravenous Oral Nasal tmax (h) 20.8 (12.4-28.4) 2.1* (1.3-2.8) 10.8 (3.1-18.4) Cmax (ng/mL) 3.5 (2.1-4.9) 4.5 (2.9-6.1) 3.0 (2.3-3.8) t1/2 (h) 45.3 (31.2-59.0) 39.8 (31.0-48.7) 48.0 (36.2-59.9) AUClast (h ng/mL) 195 (141-251) 198 (113-285) 171 (129-214) Ratio AUClast (EDDP/methadone) 0.13 (0.1-0.16) 0.15 (0.11-0.20) 0.14 (0.11-0.17)

Data are presented as mean and 95% condence interval. *Statistically signicantly different (P .05) from intravenous administration.

detected in any plasma sample above the lower limit of quantication. Pupilometry The time course (mean and SD) of dark-adapted pupil diameter after intravenous, oral, and nasal administration for the rst 24 hours is shown in Fig 4. No statistically signicant difference in the AUCs between the administrations was observed. After intravenous administration, dark-adapted pupil diameters were statistically signicantly different (2-way repeatedmeasures ANOVA, P .01) from the prestudy diameter from 0.033 to 24 hours. The same was true for oral and nasal administration from 2 to 10 hours and from 0.167 to 8 hours, respectively. Minimum pupil diameter occurred at 0.25 hour, 2 hours, and 0.5 hour after intravenous, oral, and nasal administration, respectively. Safety All subjects completed the 3 sessions. No severe adverse events occurred. No subject required supplemental oxygen. All subjects, however, reported stinging and burning in the nose after drug administration. All but one reported that symptoms dissipated within 3 to 5 minutes. One subject complained of pain persisting for almost 1 hour.

DISCUSSION This is the rst study of the pharmacokinetics and pharmacodynamics of nasal methadone. In addition, it is also the rst study reporting plasma concentrations of the methadone metabolites EDDP and EMDP in volunteers. The major ndings are that nasal methadone administration achieves rapid absorption, with a resulting rapid onset of action, closely resembling that of intravenous administration; that oral and nasal methadone bioavailabilities were equal and high; and that the duration of effect of a single 10-mg methadone dose (at least 8-24 hours, on the basis of pupil diameter) is similar to that reported for oral and intravenous methadone in chronic pain and postoperative clinical studies.6,45 However, an unmodied aqueous methadone formulation is associated with too much local irritation for clinical use. Local irritation has been reported with subcutaneously administered methadone and prohibited its use in patients with cancer pain, although this has recently been questioned.28,46 Nasal irritation or unpleasant taste has been reported for other nasal opioids,30 for instance, meperidine (INN, pethidine).37 However, such problems have not been seen with fentanyl.30 The nasal mucosa has features that may allow for very rapid uptake of xenobiotics.29,30 Previous pharmacokinetic studies on nasal administration of opioids

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AUClast (h ng/mL) 1513 (1219-1807) 1258 (940-1546) 1258 (940-1576)

AUCinf (h ng/mL) 1774 (1340-2208) 1514 (1044-1986) 1499 (1070-1927)

VZ (obs) (mL) 253,406 (212,855-293,957) 304,290 (253,703-354,877) 343,789 (242,108-445,469)

CL (obs) (mL/h) 5400 (4197-6603) 6615 (4731-8500) 6614 (4730-8499)

such as alfentanil, fentanyl, sufentanil, oxycodone, buprenorphine, and butorphanol have shown that mean maximum serum concentrations were achieved between 5 and 49 minutes, although signicant interindividual variation was observed.30-35,47 It should be noted that in several of these studies the sampling was performed too infrequently to accurately determine tmax. Our data, with a mean tmax of 7 minutes, conrm that nasal absorption is ultrarapid for methadone, and as a consequence, rapid onset of effect may be expected. Methadone nasal bioavailability was 0.85, equivalent to oral bioavailability, although a larger interindividual variation was observed, as compared with oral bioavailability. Previous reported mean bioavailabilities for nasal opioids were 0.46 to 0.78. Several factors may reduce apparent nasal bioavailability. First, the nasal cavity generally cannot accommodate volumes greater than 150 to 200 L. Larger nasal volumes may pass directly into the oropharynx, may be swallowed, and therefore may be subject to gut and liver presystemic metabolism. For the majority of the above-mentioned studies, this may explain the rather low bioavailabilities reported. Conversely, in our study, adequate (ie, smaller) volumes were used. Second, the nasal mucosa contains drug-metabolizing enzymes, including CYP3A, which is responsible for methadone metabolism.30,48-50 Thus there is a potential for presystemic methadone metabolism in the nasal mucosa. However, EDDP formation did not differ between the routes of administration; thus we found no evidence for presystemic metabolism of methadone. The validity of this conclusion is limited by a large interindividual variation in a small number of subjects. Although the major focus of this study was nasal administration, we conrm the previously reported methadone oral bioavailability of 0.79 in 5 healthy volunteers.19 In that study individual bioavailability ranged from 0.41 to 0.99, whereas our subjects apparently had less variation (0.74 to 0.95). However, data from 9 cancer patients demonstrated a mean oral bioavailability of 0.79 (range, 0.60-0.95).20 Methadone

clearance, volume of distribution, and terminal half-life did not differ between groups and were similar to previously published data on methadone kinetics.19,20,45,51,52 The methadone dose used in our volunteers is less than what might be used clinically in opioid-tolerant patients with chronic pain; care should be taken if extrapolations are made. Additional studies are required to determine the disposition of larger nasal methadone doses, preferably with a nasal methadone formulation that is less locally irritating. To the best of our knowledge, the time course of methadone metabolite plasma concentrations after single-dose administration has not been previously published. Because we used a sensitive and specic liquid chromatography-mass spectrometry method, we have been able to provide these data. EDDP is not pharmacologically active, and concentration measurements permit determination of presystemic elimination. Presystemic elimination was not a prominent feature in nasal methadone pharmacokinetics in healthy volunteers, consistent with the bioavailability observed. In addition, the observation in patients with cancer that methadone is a low-extraction drug ts our observations.52 Methadone is usually given as a racemic mixture. Studies in patients with chronic pain have demonstrated that the analgesically active R-enantiomer has a significantly longer elimination half-life, a more rapid clearance, and a larger volume of distribution. However, oral lag times and bioavailabilities did not differ.53 In contrast, total clearance and AUC did not differ between the stereoisomers, whereas oral tmax was slower for R-methadone compared with S-methadone in opioid replacement patients receiving methadone.54 This means that our data on racemic bioavailability, our primary outcome measure, probably reect those of the respective enantiomers. However, any pharmacokinetic-pharmacodynamic modeling would require knowledge of active R-enantiomer concentrations rather than racemic concentration and is beyond the scope of this investigation. Thus future studies on

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Fig 3. The time course (0-8 hours) of plasma concentrations of the methadone metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP) (mean and SD) in 8 healthy volunteers after IV, oral, and nasal administration of methadone HCl (10 mg). Note the linear scale on the ordinate. Pharmacokinetic calculations are shown in Table II.

Fig 4. The time course (0-24 hours) of resting pupil diameter (mean and SD) in 8 healthy volunteers after intravenous (iv), oral, and nasal administration of methadone HCl (10 mg). For the intravenous administration, resting pupil diameters were statistically signicantly different (2-way repeatedmeasures ANOVA, P .01) from prestudy diameter in the period 0.033 to 24 hours. The same was true for oral administration between 2 and 10 hours and between 0.167 and 8 hours for the nasal study. The time points for the smallest mean pupil diameter rst observed were 0.25 hour, 2 hours, and 0.5 hour for intravenous, oral, and nasal administration, respectively.

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nasal methadone aiming at establishing a relationship between serum concentrations and clinical effect should include stereoselective analysis. Pupil size was used to assess the effects of methadone. Pupil size is a highly signicant indicator of experimental pain intensity,55 as well the central effects of opioids.42-44 Pupilometry has been extensively validated.40,41,56,57 In this study we utilized dark-adapted resting pupil diameter, rather than dynamic pupil measurements, as used previously.42 Our pupilometry data thus demonstrate that rapid absorption of nasal methadone results in a rapid onset of action (10 minutes, with a maximum effect at about 30 minutes), only slightly slower than for intravenous administration but much faster than for oral administration (2 hours). The intravenous and nasal pupilometry data compare well with clinical data on pain management demonstrating median onset times of 12 to 21 minutes and median times to maximum effect from 26 to 106 minutes.30,36-38,58 In conclusion, we have shown that nasal methadone displays rapid uptake and onset of effect, a long duration of effect, and a high bioavailability similar to that of the oral formulation. No signicant presystemic metabolism was seen. Nasal administration may be an advantageous route of methadone dosing. However, the unmodied aqueous formulation of methadone is not optimal for clinical use because of local irritation.
We thank Mikkel Juul, Dansk Glaskontor, Denmark, for supplying the Pfeiffer BiDose nasal sprayers. We also appreciate the contribution of the staff of the General Clinical Research Center, as well as Sheree Miller and her colleagues at the Hospital Pharmacy.

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