`
`
`
`
`et al.
`
`British Journal of Clinical Pharmacology
`
`DOI:10.1111/j.1365-2125.2004.02116.x
`
`Bioavailabilities of rectal and oral methadone
`in healthy subjects
`
`Ola Dale,1,2 Pamela Sheffels1 & Evan D. Kharasch1
`1Department of Anaesthesiology, University of Washington, Seattle, Washington, USA 2Department of Circulation and Medical Imaging,
`Norwegian University of Science and Technology and Department of Anaesthesia and Acute Medicine, St. Olavs. University Hospital,
`Trondheim, Norway
`
`Correspondence
`Ola Dale,
`Department of Circulation
`and Medical Imaging, Norwegian
`University of Science and Technology,
`7489 Trondheim, Norway.
`Tel: +47 73598849
`Fax: +47 73869495
`E-mail: ola.dale@medisin.ntnu.no
`
`Keywords
`Methadone, metabolites,
`bioavailability, rectal, oral, intravenous,
`human, volunteers, pharmacokinetics,
`pupillometry
`
`Received
`1 September 2003
`Accepted
`26 January 2004
`
`Aims
`Rectal administration of methadone may be an alternative to intravenous and oral
`dosing in cancer pain, but the bioavailability of the rectal route is not known. The
`aim of this study was to compare the absolute rectal bioavailability of methadone
`with its oral bioavailability in healthy humans.
`
`Methods
`Seven healthy subjects (six males, one female, aged 20–39 years) received 10 mg
`d5-methadone-HCl rectally (5 ml in 20% glycofurol) together with either d0-
`methadone intravenously (5 mg) or orally (10 mg) on two separate occasions. Blood
`samples for the LC-MS analyses of methadone and it’s metabolite EDDP were drawn
`for up to 96 h. Noninvasive infrared pupillometry was peformed at the same time as
`blood sampling.
`
`Results
`The mean absolute rectal bioavalability of methadone was 0.76 (0.7, 0.81), compared
`to 0.86 (0.75, 0.97) for oral administration (mean (95% CI)). Rectal absorption of
`methadone was more rapid than after oral dosing with Tmax values of 1.4 (0.9, 1.8)
`vs. 2.8 (1.6, 4.0) h. The extent of formation of the metabolite EDDP did not differ
`between routes of administration. Single doses of methadone had a duration of action
`of at least 10 h and were well tolerated.
`
`Conclusions
`Rectal administration of methadone results in rapid absorption, a high bioavailability
`and long duration of action. No evidence of presystemic elimination was seen. Rectal
`methadone has characteristics that make it a potential alternative to intravenous and
`oral administration, particularly in cancer pain and palliative care.
`
`Introduction
`Oral opioids are the mainstay of chronic cancer pain
`therapy, and >50% of patients have severe pain requiring
`opioids classified as Step 3 [1]. Morphine is the WHO
`opioid of choice for Step 3 therapy [1]. However, meth-
`adone has attracted an increasing interest in palliative
`care [2–10]. The usefulness of the latter for patients that
`are not properly managed with morphine, either due to
`
`adverse effect or inadequate pain relief, is documented
`in several reports underlining the pharmacological dif-
`ferences between the two opioids [9–15].
`Most patients with moderate to severe cancer pain
`can be managed by oral opioids, but 50–70% will
`require alternative routes of administration during their
`clinical history, particularly during their last months of
`life [16]. In many countries only oral and intravenous
`
`Br J Clin Pharmacol
`
`58:2
`
`156–162
`
`156
`
`© 2004 Blackwell Publishing Ltd
`
`ALKERMES EXHIBIT 2031
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
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`formulations of methadone are available. Subcutaneous
`infusion has been discontinued due to local toxicity
`[17]. Nasal administration results in rapid absorption
`and high bioavailability, but also causes local irritation
`[18].
`Rectal administration of opioids may be an alternative
`to (a) the oral route in cancer pain patients with nausea
`and vomiting, or (b) to repeated parenteral injections in
`patients with immunological deficiencies and bleeding
`disorders, or (c) when infusion pumps may not be avail-
`able [19–22].
`Only a few studies have reported on the pharmacok-
`inetics and clinical effects of rectal methadone.
`Moolenaar
` [23, 24] compared aqueous solutions
`et al.
`and fatty suppositories for rectal and oral dosing of
`10 mg methadone in healthy subjects. The bioavailabil-
`ity and AUC of the rectal solution were lower than after
`oral dosing, and those of the suppositories were even
`lower. Ripamonti [2] studied the clinical effects and
`pharmacokinetics of rectal methadone in 6 opioid-naïve
`cancer patients with pain. Analgesia was significant at
`.
`30 min and lasted for at least 8 h
` Rectal methadone was
`shown to be an acceptable alternative to oral hydromor-
`phone or morphine in patients requiring high dose opi-
`oids [3, 4, 25, 26].
`Relatively little is known about the pharmacokinetics
`of rectal methadone, and its absolute rectal bioavailibil-
`ity has not been determined. The aim of this study was
`thus to compare the pharmacokinetics of oral, rectal and
`intravenous methadone in healthy subjects.
`
`Methods
`This study was conducted according to the guidelines of
`the Helsinki declaration and approved by the Institu-
`tional Review Board at the University of Washington.
`Informed, written consent was obtained from all sub-
`jects before inclusion.
`
`Subjects
`Subjects with a history of liver disease, those taking
`any medications metabolized by or affecting CYP3A,
`having local anal/rectal disease, with a history of drug
`allergies, or a history of drug abuse were excluded
`from the study, as were pregnant women. Nine sub-
`jects (8 male, 1 female; aged 20–39 years) entered the
`study. One subject withdrew after one session due to
`schedule constraints, and one subject received incor-
`rect drug doses. Seven subjects completed the study.
`.
`Safety data are reported for all subjects
` For the seven
`subjects who completed the study, weight and height
`(mean, min-max) of the males were 84 (70–93) kg
`and 177 (170–185) cm, respectively, and the corre-
`
`Rectal methadone
`
`sponding values for the female were 47 kg and
`167 cm.
`
`Setting and study design
`This randomised two-way crossover study was con-
`ducted at the General Clinical Research Center (GCRC)
`at the University of Washington Medical Center. Sub-
`jects received deuterated rac-(d
`) methadone rectally at
`5
`each session, together with rac-(d
`) intravenous or rac-
`0
`(d
`) oral methadone. Each phase separated by at least
`0
`one week, consisted of a 13 h stay followed by daily
`visits for 4 additional days.
`
`Drug doses and administration
`Ring-deuterated rac-d
`-methadone-HCl was synthe-
`5
`sized in our laboratory as described previously [27].
`) was obtained from Roxane
`Rac-methadone-HCl (d
`0
`Laboratories, INC (Columbus, Ohio). The rectal for-
`mulation was produced by the Hospital Pharmacy,
`whereas commercially obtained solutions were used
`for intravenous and oral administration. Methadone
`/d
` was dosed simultaneously either by the intrave-
`d
`0
`5
`nous and rectal routes (
`) or by the oral and
`IV-rectal
`rectal
`routes
`(
`). Rectal methadone-d
`oral-rectal
`5
`(10 mg) was given in an aqueous solution (5 ml) con-
`taining 20% glycofurol at a concentration of 2 mg
`-
`1
` delivered by a syringe with a rectal tip. Intrave-
`ml
`-methadone-HCl was given in a dose of 5 mg,
`nous d
`0
`while d
`-oral methadone was given as a 5-ml solution
`0
`containing 10 mg. Ten mg of methadone-HCl corre-
`sponds to 8.94 mg free base.
`
`Protocol
`Volunteers were asked to ingest no alcohol, grapefruit,
`grapefruit juice, caffeine or drug medication for 12 h
`prior to and during each study period (6 days).
`Subjects were asked to abstain from food and
`liquids after midnight prior to the day of methadone
`administration.
`Two 20 g peripheral intravenous catheters were
`inserted in a hand or arm vein for drug administration
`and blood sampling. The blood pressure and oxygen
`saturation of the subjects were monitored for 2 h.
`Oxygen was administered
`if oxygen saturation
`decreased below 94%.
`Venous blood samples (5 ml) were drawn at 0, 2, 5,
`15 and 30 min and 1, 1.5, 2, 4, 6, 8, 10, and 12 h after
`drug administration. Subjects were fed a standard break-
`fast 2 h after receiving methadone, and had free access
`to food thereafter. Subjects were advised not to drive,
`operate machinery or engage in other activities with
`similar risk for the remainder of the day. Subjects
`
`Br J Clin Pharmacol
`
`58
`
`:2
`
`157
`
`Page 2 of 7
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`Statistics
`Data are reported as mean or median with 95% CI, s.d.
`or range as appropriate. The nonparametric Mann–
`Whitney
`-test was used for the comparison or t
`, as
`U
`max
`normality could not be assumed. Ninety-three percent
`CIs were calculated for the median difference regarding
`Tmax (StatExact®, Cytel corp.), as 95% intervals were
`noninformative due to the low sample size. Dynamic
`.
`measures were compared by repeated measures
`ANOVA
`Post-hoc testing was performed using the Student-
`Newman-Keuls Method.
`
`Results
`The time course of the plasma concentrations of meth-
`adone are displayed in Figures 1 and 2 and the pharma-
`cokinetic measurements are shown in Table 1. Times to
`maximum plasma methadone concentration (Tmax)
`were 0.04 (estimated from the first sample), 2.8, 1.3 and
`1.4 hs for IV, oral, rectal (IV) and rectal (oral), respec-
`tively. The corresponding maximum concentrations
`(Cmax) were 93, 31, 32 and 26 ng/ml. Mean terminal
`half-lives of 31–35 hs and clearances (Cl or Cl/F) of
`8.3–11 l/h were observed for the four administrations.
`The absorption of rectally administered methadone was
`faster than after oral administration. Thus, a mean
`-
`1
` was reached
`plasma concentration of about 10 ng ml
`10–15 min after rectal administration, while this con-
`centration took 60 min to achieve after oral dosing. The
`lag time observed after oral methadone did not occur
`with rectal methadone. The best estimate of rectal
`t
`max
`was considered to be the mean value of the two mea-
`
`100
`
`10
`
`1
`
`Methadone (ng/ml)
`
`0.1
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Time (h)
`
`Figure 1
`The time course (0–96 h) of plasma concentrations of methadone (mean
`(s.d.)) in seven healthy subjects after IV-rectal, and oral-rectal
`administration of methadone-HCl (5 mg IV, 10 mg rectally (deuterated
`methadone) and orally). IV (
`); rectal (IV) (
`); oral (
`); rectal (oral) (
`䊉
`䉱
`䊏
`䉲
`
`)
`
`O. Dale et al.
`
`returned once daily for additional blood samples at 24,
`48, 72, and 96 h after drug administration. Dark-adapted
`pupil diameter was assessed by noninvasive infrared
`pupilometry (Pupilscan-model 2.1 (Fairville Medical
`Optics, Inc, UK), except at 12 h, under constant lighting
`intensity [18].
`
`Drug analysis
`Plasma concentrations of methadone and its metabo-
`lites 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium
`(EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline
`(EMDP) were determined by HPLC-positive electro-
`spray mass spectrometry (Agilent 1100 MSD). The
`internal standard (7- dimethylamino-5,5-diphenyl-4-
`octanone, 2.5 ng) was added to plasma (0.5 ml), which
`was acidified and processed by solid phase extraction
`(Oasis MCX cartridges, Waters Corp, Massachusetts
`USA) according to the manufacturers instructions.
`Eluants were evaporated to dryness under nitrogen,
`m
`m
`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
`¥
`m
`50 mm
` 5
`m, with guard column) using an isocratic
`mobile phase of 55% methanol
`in 0.05% TFA
`-
`1
`, and detected by selected ion
`(pH 3.6) at 0.25 ml min
`monitoring (methadone
` 310.1, EDDP
` 278.1,
`m/z
`m/z
`EMDP
` 264.1, and internal standard
` 324.1).
`m/z
`m/z
`Standard curves were prepared using blank plasma
`-
`1
` for
`and were linear over the range 0.5–200 ng ml
`-
`1
`methadone and 0.5–10 ng ml
` for metabolites. The
`lower limit of determination was defined by the lowest
`calibration sample. Interday coefficients of variation
`-
`1
` metha-
`were 12, 12 and 9% for 1, 15 and 100 ng ml
`-
`1
`done and 18% (1 and 5 ng ml
`) for EDDP. EMDP
`was not detected in plasma. Concentrations can be
`converted from ng/ml to nmol/l by multiplying by
` and methadone-d
`,
`3.12 and 3.08 for methadone-d
`0
`5
`respectively. The corresponding conversion factors
`are 3.62 and 3.54 for EDDP-d
` and EDDP-d
`,
`respectively.
`Plasma concentration data were analysed by noncom-
`partmental
`techniques. Pharmacokinetic parameters
`(Table 1) were calculated by computerized curve fitting
`using Win-Nonlin Standard 4.0.1 (Pharsight Corpora-
`tion, Mountain View, California). Bioavailabilities
`) = (AUC
`·dose
`)/(AUC
`·dose
`)
`were estimated from (
`F
`x
`x
`y
`y
`x
`where x denotes rectal or oral AUC and dose, and y
`denotes the corresponding parameters for intravenous
`administration. Results are reported for the four differ-
`ent datasets, namely
` (intravenous),
` (oral),
`IV
`oral
`rectal
`(
`) (rectal given with IV methadone) and
` (
`)
`IV
`rectal
`oral
`(rectal given with oral methadone).
`
`0
`
`5
`
`158
`
`58
`
`:2
`
`Br J Clin Pharmacol
`
`Page 3 of 7
`
`

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`Rectal methadone
`
`surements in each subject. The median difference
`between rectal and oral Tmax was 1,75 h (93% CI 0,5–
`4,25),
` = 0.0625 (Mann-Whitney). No statistically
`P
`significant differences were observed for the mean
`clearances and terminal half-lives between the three
`routes of administration. The mean rectal and oral bio-
`availability were 0.76 and 0.86 respectively (Table 2),
`-
`-
`(mean difference [95% CI] =
`0.1 [
`0.24; +0.04]). The
`mean relative rectal/oral bioavailabilites were 0.90 and
`0.88 for the two rectal studies.
`Plasma concentrations of EDDP showed significant
`inter individual variation, and were much lower than
`those of methadone (Figure 3). None of the pharmaco-
`kinetic parameters for EDDP, especially the AUC
`EDDP/AUC methadone ratios, differed between routes
`of administration (Table 3), although concentrations
`after oral methadone appeared somewhat higher.
`The time-course (mean and s.d.) of dark-adapted
`pupil diameter after IV-rectal and oral-rectal methadone
`administration for the first 24 h is shown in Figure 4.
`
`100
`
`10
`
`1
`
`Methadone (ng/ml)
`
`0.1
`
`0.0
`
`0.5
`
`1.0
`Time (h)
`
`1.5
`
`2.0
`
`Figure 2
`The time course (0–2 h) of plasma concentrations of methadone (mean
`(s.d.)) in seven healthy subjects after IV-rectal, and oral-rectal
`administration of methadone-HCl (5 mg IV, 10 mg rectally (deuterated
`methadone) and orally). IV (
`); rectal (IV) (
`); oral (
`); rectal (oral) (
`䊉
`䉱
`䊏
`䉲
`
`)
`
`Table 1
`Pharmacokinetic variables (mean, 95% CI) for methadone after IV (5 mg methadone-HCl) and oral and rectal (10 mg methadone
`HCI) in 7 human subjects
`
`Route
`
`Tmax (h)
`
`C
`
`max
`
` (ng/ml)
`
`T1/2 (h)
`
`AUClast (hr*ng/ml)
`
`AUCinf (h*ng/ml)
`
`Vz (obs)(l)
`
`Cl (obs) or Cl/F (l/h)
`
`IV
`
`Oral*
`
`Rectal
`(IV)
`Rectal
`(oral)
`
`0.04
`0.02, 0.06
`2.8
`1.3, 4.3
`1.3
`0.83, 1.9
`1.4
`0.83, 2.0
`
`93
`58 129
`30
`25, 36
`32
`20, 43
`26
`20, 31
`
`32
`27, 37
`31
`26, 35
`32
`27, 37
`35
`28, 41
`
`517
`356, 678
`866
`648, 1083
`793
`480, 1105
`737
`565, 909
`
`587
`388, 786
`980
`720, 1240
`901
`520, 1281
`861
`638, 1083
`
`375
`229, 470
`430
`398, 562
`502
`358, 648
`552
`380, 724
`
`8.3
`6.2, 10.5
`9.8
`7.2,12.3
`11.2
`8.0, 14.4
`11.2
`8.0, 14.4
`
`The estimated median difference between rectal (mean of rectal (IV) and rectal (oral))and oral T
`
`*
`max
`0.5–4.25), P = 0.0625 (Mann -Whitney)
`.
`
`was 1.75 h (93% CI
`
`Table 2
`Rectal, oral and relative rectal/oral bioavailabilities* (mean, 95% CI, and 90%CI #) for methadone after IV (5 mg methadone-
`HCl) and oral and rectal (10 mg methadone HCl) in 7 human subjects
`
`Rectal
`
`Oral
`
`Rectal (IV)/oral
`
`Rectal (oral)/oral
`
`0.76 (0.69, 0.82)
`(0.70, 0.81)#
`
`0.86 (0.72,0.99)
`(0.75,0.97)#
`
`0.90 (0.76–1.04)
`(0.78–1.01)#
`
`0.88 (0.83–0.93)
`(0.84–0.92)#
`
`*
`
`-
`-
`The mean (95%) CI for the difference between oral and rectal bioavailabilities was
`0.1 (
`0.24–0.04.) #, 90%CI
`.
`
`Br J Clin Pharmacol
`
`58
`
`:2
`
`159
`
`Page 4 of 7
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`

`

`O. Dale et al.
`
`
`
`Table 3
`Pharmacokinetic variables (mean, 95% CI) for EDDP after IV (5 mg) and oral and rectal (10 mg) administration of methadone
`in 7 human subjects
`
`Route
`
`Tmax (h)
`
`Cmax (ng/ml)
`
`T1/2 (h)
`
`AUClast (h*ng/ml)
`
`Ratio AUClast (EDDP/Methadone)
`
`IV
`
`Oral
`
`Rectal (IV)
`
`Rectal
`(Oral)
`
`5.6
`-0.2, 13.5
`2.1
`1.3, 2.9
`2.0
`1.1, 2.9
`1.5
`1.2, 1.8
`
`2.0
`1.5, 2.5
`6.7
`4.9, 8.6
`4.4
`2.4, 6.4
`5.2
`3.6, 6 .7
`
`46
`22, 69
`29
`23, 35
`38
`24, 51
`33
`23, 42
`
`86
`51, 121
`203
`139, 268
`129
`71, 187
`155
`104, 206
`
`0.18
`0.10, 0.27
`0.25
`0.15, 0.36
`0.18
`0.08, 0.28
`0.23
`0.12, 0.35
`
`8
`
`6
`
`4
`
`02
`
`Pupil diameter (mm)
`
`0
`
`2
`
`4
`
`6
`
`Time (h)
`
`8
`
`10
`
`24
`
`Figure 4
`The time course (0–24 h) of resting pupil diameter (mean (s.d.)) in
`seven healthy subjects after IV-rectal, and oral-rectal administration
`of methadone-HCl (5 mg IV, 10 mg rectally and orally)pp For the IV-
`rectal administration dark-adapted pupil diameters were statistically
`significant different (two-way, repeated measures ANOVA, P < 0.001)
`from prestudy diameter in the period 0.167–10 h. The same was true
`for the oral-rectal administration between 2 and 10 h. Oral-rectal (䊏);
`IV-rectal (䊉)
`
`oral-rectal phase. No severe adverse effects occurred.
`The one female subject was significantly sedated and
`nauseated (with emesis) during the oral-rectal phase,
`and was treated with droperidol. The episode resolved
`before discharge from the study unit. This subject expe-
`rienced no problems during the IV-rectal phase.
`
`Discussion
`The major findings of this study are that rectal absorp-
`tion of methadone is rapid and the bioavailability of the
`drug given by this route is 76%, only slightly lower than
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`EDDP (ng/ml)
`
`0
`
`2
`
`4
`Time (h)
`
`6
`
`8
`
`Figure 3
`The time course (0–8 h) of plasma concentrations of the methadone
`metabolite EDDP (mean (s.d.)) in seven healthy subjects after IV-rectal,
`and oral-rectal administration of methadone-HCl (5 mg IV, 10 mg
`rectally (deuterated methadone) and orally). Note the linear scale on
`the ordinate. IV (䊉); rectal (IV) (䉱); oral (䊏); rectal (oral) (䉲)
`
`There was considerable inter-individual variation in
`pupil diameters, but no differences in the areas under
`the curves were observed for the different routes. The
`oral-rectal combination had a slower onset of action
`than the IV-rectal route which, consistent with the lower
`initial plasma concentrations. However, the same maxi-
`mum effect as the IV-rectal combination was achieved
`at about 2 h. For the IV-rectal administration, dark-
`adapted pupil diameters were statistically different from
`the prestudy values over the period 0.2–10 h. The same
`was true for the oral-rectal administration between 2 and
`10 h.
`Nine subjects were enrolled in the study and received
`methadone at least once. One subject withdrew after the
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`reported by us for oral and nasal administration [18]. No
`evidence of presystemic metabolism was found. Pupil-
`lometry confirmed that the duration of action of a single
`dose of methadone given by this route was at least 10 h.
`There was no loss of drug after rectal dosing, indicating
`that bioavailability was accurately determined, and that
`the formulation and route were well tolerated.
`We employed a formulation described by Moolenaar
`et al. [23, 24], due to its favourable absorption pattern.
`Our findings confirm their claim that the difference in
`the oral and rectal bioavailability of methadone is small.
`It is a common view that rectal uptake is highly variable
`and erratic [21]. However, in our study rectal and oral
`variabilities with pharmacokinetics of methadone were
`low and essentially the same. These and earlier findings
`suggest that methadone can be rotated safely between
`the various routes of administration without substantial
`change in dose. However, the results should be con-
`firmed in patients.
`Methadone is usually given as a racemic mixture.
`Studies in chronic pain and opioid replacement patients
`have shown different pharmacokinetic characteristics of
`the enantiomers. However, the bioavailabilities and
`AUCs of the latter did not differ in any of these studies
`[28, 29]. Thus, our data on racemic bioavailability prob-
`ably reflects those of the respective enantiomers.
`Absorption of rectal methadone was significantly
`more rapid than oral methadone, for which there may
`be several reasons. First, rectal uptake takes place at the
`site of administration, whereas oral absorption requires
`gastric emptying into the intestine. Second, the absorp-
`tion of methadone across mucosal membranes is rapid,
`as demonstrated previously for nasal administration
`[18]. Third, the rectal mucosa provides a larger surface
`area for absorption compared to the nasal route [21, 30].
`Fourth, we used a volume that the rectum can easily
`accommodate [21], Fifth, we used a solution formulated
`with the absorption enhancer glycofurol [23]. Sixth, rec-
`tal contents are usually alkaline, favouring uptake of
`alkaline drugs such as methadone [21]. Last, there is
`minimal, presystemic elimination of rectal methadone.
`There are several reasons for employing rectal ad-
`ministration of opioids in palliative care [21, 22, 31].
`Alternatives to oral dosing, other than parenteral admin-
`istration, may be required in patients with altered mental
`status, neuromuscular dysfunction, nausea, vomiting,
`dysphagia, bowel obstruction or malabsorption. Rectal
`dosing may also be an alternative to repeated parenteral
`injections in patients with immunological deficiencies
`and bleeding disorders, or when infusions systems may
`not be available or in home health care settings [19, 20,
`20]. Rectal administration is efficacious, technically
`
`Rectal methadone
`
`easy for patients and caregivers to administer, and eco-
`nomical. It is considered safe, and adverse effects are
`usually reversible [21], but some patients may dislike
`the rectal route due to concerns of modesty [32].
`There is an increasing interest in the use of metha-
`done in palliative care, particularly in the context of
`opioid rotation [9, 10, 26]. Methadone has favourable
`characteristics, both with respect to pharmacodynamics
`(faster onset of effect, long duration of action, incom-
`plete cross tolerance towards morphine, and possible
`effects on NMDA receptors) and pharmacokinetics
`(faster absorption, long half-life, no active or toxic
`metabolites and little dependence on metabolite renal
`excretion) compared to morphine [9]. Methadone is
`therefore often preferred when morphine fails, either
`due to lack of adequate analgesia or intolerable side-
`effects. For patients converted to methadone or on meth-
`adone for other reasons, intravenous administration has
`been the only alternative to oral medication, since sub-
`cutaneous infusion is unfavourable due to local irrita-
`tion, and nasal methadone awaits the development of
`formulations that also do not cause local irritation [17,
`18]. Thus patients not able to take methadone orally may
`require prolonged hospitalization or more intensive
`home health care to enable intravenous dosing. Thus,
`rectal methadone would be a less invasive and less
`expensive, and an effective alternative to intravenous
`methadone [26].
`In conclusion, we have shown that methadone has
`good rectal bioavailability in healthy subjects, and only
`slightly lower than that of the oral route. Furthermore,
`the absorption of rectal methadone was significantly
`more rapid than that of oral drug. Pupillometry con-
`firmed the long duration of action of a single dose of
`rectal methadone.
`
`We thank Christine Hoffer, A.S., Troy Joseph, R.N, and
`Carole Jubert, Ph.D. for their technical assistance. We
`appreciate the contribution of the staff of the GCRC, and
`Sheree Miller, Pharm. D., and her colleagues at the
`Hospital Pharmacy. This work was partially supported
`by Norwegian Research Council grant 136286/300 –
`(OD), by National Institutes of Health grant K24
`DA00417, a Merit Award from the Veterans Affairs Med-
`ical Research Bureau, and NIH grant M01-RR-00037 to
`the UW General Clinical Research Center.
`
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