Clinical Pharmacology of Methadone in Dogs.
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Transcript of Clinical Pharmacology of Methadone in Dogs.
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7/27/2019 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.
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
48
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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.
Methadone in dogs C Ingvast-Larsson et al.
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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.
Methadone in dogs C Ingvast-Larsson et al.
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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.
Methadone in dogs C Ingvast-Larsson et al.
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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
Methadone in dogs C Ingvast-Larsson et al.
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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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