Clinical Pharmacology of Methadone in Dogs.

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R E S E A R C H P A P E R

Clinical pharmacology of methadone in dogs

Carina Ingvast-Larsson*, Anja Holgersson*, Ulf Bondesson, Anne-Sofie Lagerstedt & Kerstin Olsson

*Division of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health,

Swedish University of Agricultural Sciences, Uppsala, Sweden

Division of Analytical Pharmaceutical Chemistry, Biomedical Center, Uppsala University, Uppsala and Department of

Chemistry, National Veterinary Institute, Uppsala, Sweden

Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden

Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden

Correspondence: Carina Ingvast-Larsson, Division of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and

Veterinary Public Health, Swedish University of Agricultural Sciences, P.O. Box 7028, SE-750 07 Uppsala, Sweden. E-mail: carina.

[email protected]

Abstract

ObjectiveTo investigate the pharmacokinetics and

effects of methadone on behaviour and plasma

concentrations of cortisol and vasopressin in

healthy dogs.

Study design Randomized, cross-over, experimentaltrial.

Animals Nine adult dogs (beagle and beagle cross

breeds), four males and five females.

MethodsMethadone hydrochloride, 0.4 mg kg)1,

was administered intravenously (IV) and subcuta-

neously (SC) with a crossover design. Drug and

hormone analyses in plasma were performed using

Liquid ChromatographyElectrospray Ionization

Tandem Mass Spectrometry and radioimmunoassay

respectively. Behavioural data were collected using

a standardized protocol.

Results After IV administration, the plasma con-

centration of methadone at 10 minutes was

82.1 9.2 ng mL)1 (mean SD), the terminal

half-life was 3.9 1.0 hours, the volume of distri-

bution 9.2 3.3 L kg)1 and plasma clearance

27.9 7.6 mL minute)1 kg)1. After SC adminis-

tration, time to maximal plasma concentration was

1.26 1.04 hours and maximal plasma concen-

tration of methadone was 23.9 14.4 ng mL)1,

the terminal half-life was 10.7 4.3 hours and

bioavailability was 79 22%. Concentrations of

both cortisol and vasopressin were increased for an

hour following IV methadone. The observed

behavioural effects of methadone were decreased

licking and swallowing and an increase in whiningafter SC administration. The latter finding is notable

as it can be misinterpreted as pain when methadone

is used as an analgesic.

Conclusion and clinical relevance When methadone

was administered by the SC route, the half-life was

longer, but the individual variation in plasma

concentrations was greater compared with IV admin-

istration. Increased frequency of whining occurred

after administration of methadoneand maybe a drug

effect and not a sign of pain. Cortisol and vasopressin

concentrations in plasma may not be suitable for

evaluating analgesia after methadone treatment.

Keywords behaviour, cortisol, dog, methadone,

pharmacokinetics, vasopressin.

Introduction

Methadone is an opioidl-receptor agonist, which is

frequently used both in companion animals as well

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as humans for the relief of pain. The use in animals

is off-label as the drug is only approved for use in

humans. Methadone is of higher relative intrinsic

efficacy at the l-receptor than morphine (Selley

et al. 2001). In human medicine, there are several

reports of methadone effectiveness when treatingpain resistant to other opioids like morphine and

hydromorphone and it has a high oral bioavail-

ability and a long terminal half-life compared with

many other opioids (Dale et al. 2002, 2004). In

dogs, however, the oral bioavailability is low and

terminal half-lives range from 1.754 hours and

212 hours following intravenous (IV) and subcu-

taneous (SC) administration, respectively (Schlitt

et al. 1978; Garrett et al. 1985; Schmidt et al. 1994;

Kukanich et al. 2005; Kukanich & Borum 2008).

The effect of opioids on the release of cortisol

seems to be highly species-dependent (Pfeiffer &

Herz 1984; Pechnick 1993). An increase in

plasma cortisol after single administration of mor-

phine and butorphanol was reported in cats

(Borrell et al. 1975) and dogs (Fox et al. 1998)

respectively, but in cows (Nanda et al. 1992)

and in humans, opioids usually decreased the

concentrations of cortisol in plasma. Nevertheless,

increases of cortisol concentrations in blood are

often used as an indicator of distress and pain and

also to evaluate analgesia in animals (Minton

1994; Molony & Kent 1997; Devitt et al. 2005;

Sibanda et al. 2006; Vinuela-Fernandez et al.

2007). Hellebrekers et al. (1989) reported anincrease in concentrations of vasopressin in plasma

after administration of methadone in dogs. There

are also indications that both plasma cortisol and

vasopressin become increased in dogs subjected to

stress (Hydbring-Sandberg et al. 2004).

The aim of the study was to describe the

pharmacokinetic profile of methadone after IV and

SC administration in dogs as well as to assess the

effects on behaviour, cortisol and vasopressin

plasma concentrations.

Material and methods

Animals and experimental procedure

Ten clinically healthy Beagle and Beagle cross-bred

dogs, AJ, five males and five females weighing

17.0 3.1 kg (mean SD) and 5.6 3.0 years-

old were used. They were born and housed at the

Department of Clinical Sciences, Swedish University

of Agricultural Sciences, Uppsala, Sweden. Nor-

mally they lived in groups and were allowed out-

door exercise every day.

On the experimental days, the dogs were fed at

0800 and were let out in the outdoor kennel pen

according to the normal routines. At 0900, the dogs

were weighed and prepared for the experiment. Thedogs front legs (dorsal area above carpus) were

shaved and cleaned and one or two (when the dogs

received intravenous drugs) catheters were inserted

into the cephalic veins. One catheter was used for

the IV administration and the other for blood

sampling. A large funnel was placed around their

neck and they were put into individual cages during

the day. The Local Ethical Committee in Uppsala,

Sweden approved the care of the animals and the

experimental design.

Drugs, study design and blood sampling

Methadone hydrochloride (Metadon Recip, solution

for injection 10 mg mL)1, RecipAB, Sweden) was

used both for IV and SC administration at a dose of

0.4 mg kg)1. In the control study, physiological

saline solution (Natriumklorid Fresenius Kabi,

solution for injection, 9 mg mL)1, Fresenius Kabi

AB, Sweden) was administered IV. Methadone was

administered IV in the cephalic vein via the catheter

and was also administered SC in the neck region

in a crossover design (Table 1). The order of the

first drug administration was randomized. The wash

out period between the different routes of adminis-tration was at least two weeks. Blood samples

were collected before and 10, 30 and 60 minutes

and 3, 6, 12, 22, 31 and 47 hours after adminis-

tration of methadone. The venous catheter was used

for blood samples up to and including 6 hours.

The remaining blood samples were taken by direct

cephalic vein puncture. In the control study, the

same protocol for blood sampling as in the metha-

done experiments was used. However, to avoid too

much blood loss, sampling was only performed at

10 and 60 minutes and 6 hours, while sampling at

other time points was simulated. After 6 hours, the

dogs returned to normal routines together with the

other dogs.

Blood samples, 3 mL, were collected into ice-

chilled tubes containing EDTA (ethylenediamine-

tetraacetic acid) as an anticoagulant. The blood was

centrifuged at 1500 g for 20 minutes at 4 C. The

plasma, 1.2 mL was stored at )20 C until drug

analyses and the rest was stored at )80 C until

hormone analyses.

Methadone in dogs C Ingvast-Larsson et al.

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Methadone assay

To 0.5 mL plasma was added 100 lL internal

standard solution [2H3]-methadone (14 ng

100 lL)1 MeOH), 0.5 mL of MilliQ-water, 5.0 mL

hexane/2-butanol (97:3) and 0.1 mL of sodium

hydroxide. The mixture was extracted for 20 min-

utes. After centrifugation, the organic phase was

transferred to a glass tube and evaporated to dry-

ness in a stream of nitrogen at 50 C. The residue in

each vial was reconstituted in 60 lL of 0.1% formic

acid in water. The reconstituted samples were

quantified with liquid chromatographyelectrosprayionizationtandem mass spectroscopy (LCESIMS/

MS). LC/MS/MS analyses were performed using a

Surveyor LC system interfaced to a Finnigan TSQ

Quantum Ultra (Thermo Electron Corporation, CA,

USA) mass spectrometer. The separation was per-

formed in a Zorbex Eclipse XAD-18 (2.1 50 mm,

5 lM; Aglient Technologies, Sweden). The mobile

phases were 0.2% formic acid in MilliQ-water (A)

and methanol (B). The gradient program was: 0 to

2.0 minutes, 15% B; 2.0 to 5.0 minutes, 15 to 85%

B; 5.2 to 8.0 minutes, 15% B. The mobile phase was

delivered at a flow rate of 200 lL minute)1. The

mass spectrometer was run in selected reaction

monitoring mode (SRM). The ionization technique

was electrospray (ESI) in positive mode. The ESI

source voltage was set at 3.5 kV and sheath gas

flow-rate and auxiliary gas were 50 and 2 arbitrary

units, respectively. When running collision-induced

dissociation (CID), argon was used as the collision

gas at a pressure of 1.5 mTorr. For SRM mode, the

following transitions were recorded: methadone

[M+H] m/z 310 fi 265 and [2H3]-methadone

[M+H]+ m/z 313 fi 268 using collision energy

20 V. The limit of quantification was 0.6 ng meth-

adone mL)1 plasma. The standard curve was linear

in the range 0.3 to 976 ng mL)1. The coefficients of

variance for methadone at the 1 ng mL)1 level were

6% (n = 6).

Pharmacokinetic analyses

The plasma concentrations versus time profile for

methadone in each individual were analyzed using

noncompartmental methods based on statisticalmoment theory (Gibaldi & Perrier 1982). A com-

mercially available software program was used (Win

Nonlin 5.0.1; Pharsight Corporation, CA, USA). The

area under the curve (AUCinf) was calculated using

the linear trapezoidal approximation. To extrapolate

the area under the curve from time zero to infinity,

the terminal rate constant (k) was used. The terminal

half-lives were determined from t = ln2/k. The SC

bioavailability (F) was calculated from the AUCsinfusing the equation:

F% 100AUCinf;sc=AUCinf;iv

The observed time (Tmax) to maximal plasma

concentration (Cmax) and the Cmax were read from

the plotted concentration-time curve for each indi-

vidual animal after SC administration.

Hormone assays

Dilutions of plasma were parallel to the standard

curve in the radioimmunoassays used. Plasma

Table 1 Study design

Day 1 Day 2 Day 3 Day 4 Day 5

Dog Treatment Dog Treatment Dog Treatment Dog Treatment Dog Treatment

First week

A Saline D Saline G SC A IV C IV

B* Saline E Saline H SC B SC D IV

C Saline J SC I SC F IV E IV

Second week

F Saline I Saline B* IV E SC H IV

G Saline J Saline C SC F SC I IV

H Saline A SC D SC G IV J IV

SC, methadone subcutaneously; IV, methadone intravenously; saline control days, saline administered IV.

*Accidentally, dog B received another SC injection and all data were excluded.

Wash-out period was 2 weeks between the two experimental weeks.


50 2010 The Authors. Journal compilation 2010 Association of Veterinary Anaesthetists, 37, 4856


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cortisol was measured using the Coat-a-Count RIA

(Diagnostic Products Corporation, CA, USA). The

lower detection limit was 1.90 nmol L)1. The

intra-assay coefficient of variance was


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Plasma cortisol and vasopressin concentrations

Before IV and SC administration of methadone,

the cortisol plasma concentrations were 86

27 nmol L)1 and 72 25 nmol L)1 respectively

(Fig. 2). After IV administration, the cortisol con-

centration increased and was higher compared with

control days at time 1 hour (p < 0.05). After SC

administration, however, the cortisol concentration

decreased and it was lower than the value before the

administration at times 0.5, 1, 6 and 31 hours

(p < 0.05), but there was no difference compared

with the control values.

The vasopressin concentration was 0.82 0.43pmol L)1 and 0.75 0.31 pmol L)1 before the IV

and SC administration respectively (Fig. 3). Also the

vasopressin concentration was higher after IV

administration compared with the saline adminis-

trations at times 10 minutes and 1 hour (p < 0.01).

Behaviour

The dogs were calm for most of the time during the

study. In total, 13 different kinds of behaviours were

recorded. Results are shown where the noticed

behaviour was repeated more than three times

during the day. The average of 90 observations

between 1040 and 1540 hours was used in the

statistical analyses.

The dogs were lying down at 74 21 and

73 27 times of the 90 observation occasions after

IV and SC administration respectively. The corre-

sponding value after saline administration was

69 23 [NS (not significant)] versus either admin-

istration. While they were lying down, they were

noticed to sleep at 32 34, 33 28 and 31 25

times after IV and SC administration and the control

day respectively (NS).

The dogs sat 14 20, 14 23 and 16 23times after IV and SC administration and on the

Table 2 Pharmacokinetic parameters in plasma

(mean SD) after intravenous and subcutaneous admin-

istration of methadone (0.4 mg kg)1) to dogs (n = 9)

Parameter

Intravenous

administration

Subcutaneous

administration

AUC (ng hour mL)1)* 257 77.8 195 57.2

Cl (mL kg)1 minute)1) 27.9 7.6 NA

Vd(ss) (L kg)1) 9.2 3.3 NA

T1/2,k (hour) 3.9 1.0 10.7 4.5

T1/2,k (hour) 3.6 1.3 9.2 5.2

Cmax(ng mL)1) NA 19.4 10.7

Tmax(hour) NA 1.2 1.1

F(%) NA 79 22

AUC, area under the concentration-time curve from time 0 to

infinity; Cl, total body clearance; Vd(ss), volume of distribution at

steady state; T1/2,k, terminal half-life; Cmax, maximal plasma

concentration after intramuscular administration; Tmax, theobserved time to Cmax. F, SC bioavailability; NA, not applicable.

*Significant difference (Students paired t-test,p< 0.02).

Significant difference (Students paired t-test,p< 0.001).

Harmonic mean pseudo SD.

0 1 20

50

100

150

200

2 8 14 20 26 32 38 44 50

IV

SC

C

**

#

**

Time (hours)

Cortisolconcentration(nmolL

1)

Figure 2 Plasma cortisol concentration (mean SD) after

intravenous (IV) and subcutaneous (SC) administration of

methadone (0.4 mg kg)1) in dogs (n = 9). Control = cor-

tisol concentration in samples taken at time 10 minutes, 1

and 6 hours after IV administration of isotonic saline (C).

*p < 0.05 versus the value before the SC administration

#p < 0.05 IV versus C.

0 1 20

1

2

3

4

2 8 14 20 26 32 38 44 50

IV

SC

C

#

#

Time (hours)

Vasopressinconcentration(pmolL

1)

Figure 3 Plasma vasopressin concentration (mean SD)

after intravenous (IV) and subcutaneous (SC) administra-

tion of methadone (0.4 mg kg)1) in dogs (n = 9). Con-

trol = vasopressin concentration in samples taken at time

10 minutes, 1 and 6 hours after IV administration of

isotonic saline (C). #p < 0.05 or less IV versus C.




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control day (NS). The corresponding numbers for

eye contact were 6 11, 7 9 and 8 9 times

(NS).

Methadone administered SC resulted in frequent

whining compared with control days (Fig. 4).

Licking and swallowing were decreased aftermethadone compared with after saline administra-

tion (Fig. 4).

Discussion

The pharmacokinetic parameters after IV adminis-

tration in this study were comparable with those

previously reported in dogs. The methadone plasma

clearance was in accordance with previous reportedvalues (Kukanich et al. 2005; Kukanich & Borum

2008). The clearance value is of clinical importance

because it can be used for calculating the mainte-

nance dose. Methadone in dogs is mainly extracted

by the liver (Garrett et al. 1985) and the high

clearance value corresponds to 89% of the hepatic

blood flow in dogs (Davies & Morris 1993), which

implies that oral bioavailability would be poor. This

suggestion is further supported by the findings that

after oral administration of methadone (2 mg kg)1)

in dogs the drug could not be detected in plasma

(Kukanich et al. 2005). In humans, methadone is a

low-clearance drug and the oral bioavailability is

high (Meresaar et al. 1981).

The volume of distribution (Vd(ss)), calculated in

the present study, was large and was of the same

magnitude as shown in both humans and

dogs (Meresaar et al. 1981; Kukanich et al. 2005;

Kukanich & Borum 2008). This parameter is

required to calculate an appropriate loading dose.

Terminal half-life post-IV administration has

previously been reported to be between 24 hours

when measuring methadone plasma concentration

until 8 hours after administration (Garrett et al.

1985; Kukanich et al. 2005; Kukanich & Borum2008) and approximately 4 hours, measuring the

methadone plasma concentrations up to 15 hours

(Schmidt et al. 1994). The longer the plasma

concentrations are measured the less is the possi-

bility that the half-life is underestimated. In the

present study, we measured the concentrations of

methadone in plasma up to between 24 and

30 hours and the terminal half-life was 3.9 hours

after IV administration. As the terminal half-life

after IV administration is dependent both on volume

of distribution and clearance the half-life in humans

is considerably longer than in dogs. The published

kinetic studies on methadone in humans indicated a

terminal half-life of between 1555 hours (Meres-

aar et al. 1981; Wolff et al. 1993, 1997). The

terminal half-life is of clinical importance when

choosing the dose interval.

The half-life increased significantly after SC

administration but also the individual variation

compared with IV administration. The longer half-

life is probably because of absorption rate-limited

IV SC C0

200

400

600

800

1000

1200*

Whining

(no/30min)

IV SC C

0

10

20

30

40

**

Licking(no/30min)

IV SC C

0

2

4

6

8

*

*

Swallowing(no/30min)

(a)

(b)

(c)

Figure 4 Whining, licking and swallowing frequencies

during 30 minutes (mean SD of 90 observations in

six 5-minute sessions) recorded after intravenous (IV) and

subcutaneous (SC) administration of methadone

(0.4 mg kg)1) in dogs (n = 9) and during days when

saline was administered (C). *p < 0.05 versus C.




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elimination (flip-flop phenomenon). The variability

in absorption kinetics is dependent on the site of

administration and also of massaging of the admin-

istration site (Rowland & Tozer 1995). The

increased half-life is an advantage if the drug will

be used for a longer period as the dose interval canbe longer. With a half-life of 11 hours once to twice

daily dosing will be adequate. The SC bioavailability

was high, but the Cmaxwas low compared with the

initial methadone plasma concentrations received

after IV administration. SC administration will

produce less plasma fluctuations but also a need

for a loading dose as a steady state will not occur

until about approximately 2 days (4 half-lives). The

most suitable approach if immediate analgesia is

required is to begin with IV administration of the

drug and after approximately 3 hours start the SC

dosage regimen.

After IV administration of methadone, the plasma

concentrations of both cortisol and vasopressin

increased. These effects correlated with the drug

plasma concentrations, were short-lasting and the

hormone concentrations were back to control

values within 3 hours post-drug administration.

Increased cortisol plasma concentration after acute

administration of opioids has been reported in many

other species including rat (Guaza et al. 1979),

mouse, guinea pig, (Pechnick 1993), cat (Borrell

et al. 1975; Guaza et al. 1979) and goat (Ingvast-

Larsson et al. 2007). Vasopressin concentrations

after opioid administration have been reported toincrease in the dog (Hellebrekers et al. 1989) and in

the goat (Ingvast-Larsson et al. 2007), but the

majority of studies have suggested an inhibition of

vasopressin release of opioids in vivo(Pfeiffer & Herz

1984). Increased cortisol plasma concentrations are

often used as a marker of pain and stress in animals

and increased vasopressin concentrations in con-

nection with stress and pain have also been

suggested (Hydbring et al. 1999; Hydbring-Sand-

berg et al. 2004). After SC administration, no

increases of hormone concentrations were observed;

most likely because of the low plasma concentra-

tions of methadone. Instead, the plasma concentra-

tions of cortisol were lower when compared to the

concentrations before drug administration probably

reflecting the dogs becoming stressed by the han-

dling before the drug was administered. The results

show that increased hormone concentrations are

not useful parameters when assessing analgesic

efficacy of methadone in dogs as the drug per se

induced changes in hormone concentrations in

plasma. The plasma concentrations of methadone

were unlikely to have exceeded clinically relevant

concentrations as the dose used was in the lower

range of the dose interval that often is recom-

mended in dogs (Plumb 2005). In humans, meth-

adone plasma concentrations eliciting 50% ofmaximal pain relief are reported to be between

53604 ng mL)1 (Inturrisi et al.1990; Garrido &

Troconiz 2000). The individual variation in hu-

mans is dependent on previous exposure to opioids

(cross-tolerance) and degree of pain. A mean

estimate for methadone plasma concentrations

eliciting 50% of maximal pain relief in nontolerant

subjects was 60 ng mL)1 (Gourlay et al.1984). In

this study, the dogs at the plasma concentrations of

between 5282 ng methadone mL)1 were calm and

the hormone concentrations were increased, but the

plasma concentration able to provide analgesia in

dogs is not yet established.

The individual variations in plasma vasopressin

concentration were large and thus the values were

high in some dogs. This vasopressin concentration

will cause a maximal antidiuretic effect in the

kidney, which should be taken into account in the

evaluation of fluid therapy if methadone is admin-

istered.

We observed drug-induced effects on behaviour.

For technical reasons, the same person had to be

responsible for both blood sampling and the obser-

vations of behaviour and hence the administration

order could not be blinded. This was unfortunate,but not considered as a major obstacle to perform

the study, since the observations were done using

standardized scoring. Methadone increased the

whining and this phenomenon was most obvious

after SC administration. It is important to appreciate

that methadone may cause whining and this should

not be misinterpreted as the dog being in pain. A

similar result has been observed with butorphanol

where dogs vocalized both after butorphanol alone

and after surgery and butorphanol (Fox et al.

2000). Behaviours such as licking and swallowing

known to be typical for dogs experiencing discom-

fort (Beerda et al. 1997, 1998) decreased after

methadone administration indicating whining was

not because of discomfort. None of the dogs vomited

and no signs of agitation and excitement were

noticed in any dog. Morphine, another opioid acting

on the l-receptor, has been shown to induce

vomiting in dogs (Kukanich et al. 2005).

In conclusion, when methadone was adminis-

tered by the SC route of administration the half-life




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was longer, but the inter-individual variation in

plasma concentrations was greater compared with

IV administration. Increased frequency of whining

occurred after administration of methadone and

may be a drug effect and not a sign of pain. Cortisol

and vasopressin concentrations in plasma are notsuitable for evaluating analgesia after IV methadone

treatment. Future studies are required to establish

the methadone plasma concentration needed for

analgesia in the dog.

Acknowledgements

This study was supported by the Swedish Animal

Welfare Agency and by the Swedish Research

Council Medicine. We thank Gunilla Drugge,

Department of Anatomy, Physiology and Biochem-

istry and Emma Hornebro, Department of Clinical

Sciences, Swedish University of Agricultural Sci-

ences, Uppsala, Sweden for excellent assistance.

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Received 8 July 2008; accepted 22 September 2008.




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Clinical Pharmacology of Methadone in Dogs.

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