Comparison of the cardio-respiratory effects of methadone and morphine in conscious dogs††
Presented in part at the 2007 AVA/ECVAA Autumn Meeting, Leipzig, Germany.
Abstract
The effects of methadone and morphine were compared in conscious dogs. Six animals received morphine sulfate (1 mg/kg) or methadone hydrochloride (0.5 mg/kg [MET0.5] or 1.0 mg/kg [MET1.0]) intravenously (i.v.) in a randomized complete block design. Cardiopulmonary variables were recorded before (baseline), and for 120 min after drug administration. One outlier was not included in the statistical analysis for hemodynamic data. Morphine decreased heart rate (HR) compared to baseline from 30 to 120 min (−15% to −26%), while cardiac index (CI) was reduced only at 120 min (−19%). Greater and more prolonged reductions in HR (−32% to −46%) and in CI (−24% to −52%) were observed after MET1.0, while intermediate reductions were recorded after MET0.5 (−19 to −28% for HR and −17% to −27% for CI). The systemic vascular resistance index (SVRI) was increased after methadone; MET1.0 produced higher SVRI values than MET0.5 (maximum increases: 57% and 165% for MET0.5 and MET1.0, respectively). Compared to morphine, oxygen partial pressure (PaO2) was lower (−12% to −13%) at 5 min of methadone (0.5 and 1.0 mg/kg), while carbon dioxide partial pressure (PaCO2) did not change significantly. It was concluded that methadone induces cardiovascular changes that are dose-related and is a more potent cardiovascular depressant agent than morphine in conscious dogs.
Introduction
Opioids are widely used as part of balanced anesthetic techniques and for treating pain in animals. Sedation and analgesia are among the main therapeutic effects provided by these drugs in canine species (Lascelles, 2000; Pascoe, 2000). The use of methadone in animal species has become popular in several countries, yet there is scant information on the safety and analgesic effectiveness of this drug in veterinary medicine. Methadone is a competitive μ opioid agonist that is considered to have the same analgesic potency of morphine in humans (Coda, 2001). Based on dose-response studies, the analgesic potency of methadone in dogs was estimated to be 1.75 greater than analgesic potency of morphine (Vaupel & Jasinski, 1997). The analgesic effects induced by this opioid have also been attributed to a noncompetitive antagonism of N-methyl-d-aspartate receptors located in the central nervous system (CNS) (Ebert et al., 1995). Although the pharmacokinetic profile of methadone is highly variable among individuals, in human patients, this opioid has a longer elimination half-life (22 h) than morphine (2.9 h) (Stanski et al., 1978; Eap et al., 2002). Because of its prolonged elimination half-life, methadone produces postoperative analgesia that lasts longer than morphine in humans (Gourlay et al., 1982; Chui & Gin, 1992). Canine species differs from humans because methadone and morphine are rapidly eliminated from the body because of a high clearance. In dogs, the elimination half lives ranged from 1.53 to 4.3 h and from 0.87 to 1.28 h for i.v. methadone and morphine, respectively (Schmidt et al., 1994; Kukanich et al., 2005a,b,c; KuKanich and Borum, 2008a,b). As methadone and morphine are more rapidly eliminated in dogs than in humans, one may expect that this opioid will require shorter administration intervals in canine species.
In most instances, therapeutic doses of opioids produce cardiovascular stability even in hemodynamically compromised patients. Hypotension arising out of a histamine release from mast cells into the circulation is one of the main cardiovascular side effects induced by some opioids such as morphine. However, clinically relevant increases in histamine plasma levels in dogs are more likely to occur when high doses of morphine (1–2 mg/kg) are administered intravenously (Robinson et al., 1988; Guedes et al., 2007). I.v. methadone was also reported to induce histamine release in a small percentage of human subjects (Bowdle et al., 2004). Increases in histamine plasma levels were recorded in 8.7% of the individuals from a population that received 20 mg (total dose) of methadone intravenously; in spite of this effect, methadone did not cause signs of cardiovascular impairment (e.g. hypotension) (Bowdle et al., 2004). Methadone also appears to produce little cardiovascular changes in canine species (Stanley et al., 1980). Administration of cumulative doses of methadone (0.3–5.3 mg/kg) to dogs anesthetized with pentobarbital did not induce substantial hemodynamic changes; the highest cumulative dose (5.3 mg/kg) caused mild to moderate decreases in cardiac output (CO) (21% decrease from baseline) (Stanley et al., 1980). In another study, methadone administration to conscious dogs (0.5–1.0 mg/kg) induced negative chronotropic effects and caused mild increases in arterial blood pressure and in carbon dioxide partial pressure (PaCO2) (Hellebrekers et al., 1989). The study reported here aimed to compare the cardio-respiratory actions of two doses of methadone (0.5 or 1.0 mg/kg, intravenously) with the effects produced by a high-dose of morphine (1.0 mg/kg, intravenously) in conscious dogs.
Materials and methods
Animals and study design
The guidelines of the Brazilian College of Animal Experimentation were followed and the study obtained previous approval by the Institutional Animal Care and Use Committee under the protocol number 128/2006.
A total of six healthy adult mongrel dogs, four spayed females and two castrated males, weighing 16.4 ± 2.8 kg (mean ± SD) were used. Health status was assessed by physical examination and laboratory screening (complete blood cell count and serum biochemistry). All laboratory values were within reference ranges. Prior to the start of the study, animals were acclimated to the experimentation room and conditioned to remain undisturbed, while restrained in lateral and/or in sternal recumbency.
Animals received three treatments administered intravenously (1 mg/kg of morphine sulfate or two doses of methadone hydrochloride (0.5 or 1.0 mg/kg) in a randomized complete block design. A minimum washout period of 1-week was allowed among treatments.
Instrumentation and parameters evaluated
Dogs were fasted for 12 h with free access to water until just prior to the beginning of each experiment. Instrumentation was accomplished with animals anesthetized with isoflurane (Isoforine; Cristália, Itapira, Brazil). Initially, the inhalant anesthetic was administered via face mask connected to a circle breathing circuit with the vaporizer adjusted to deliver 5% of isoflurane (Linea C, Intermed, São Paulo, Brazil). After orotracheal intubation was performed, vaporizer settings were adjusted to maintain moderate depth of anesthesia on the basis of clinical assessment. Pressure controlled ventilation (peak inspiratory pressure 9–15 mmHg, inspiration to expiration ratio: 1/2, and respiratory rate 8–16 breaths/min) was instituted to maintain end tidal carbon dioxide (A/S3 Monitor; Datex-Ëngstrom, Helsinki, Finland) between 35 and 45 mmHg, while an electric heated pad was used to maintain esophageal temperature (A/S3 Monitor) above 37.0 °C throughout anesthesia.
Adhesive electrodes (Lead II) were placed to record the electrocardiography (ECG) using a data acquisition interface (TEB 2.17 version; Tecnologia Eletrônica Brasileira, São Paulo, Brazil). For each data sampling time, the ECG tracing was downloaded to a computer for later analysis of changes in HR.
Twenty Gauge catheters (Insyte®; Becton Dickinson, São Paulo, Brazil) were aseptically placed into a cephalic vein and into a dorsal pedal artery. After surgical preparation of the skin over the neck, a six French catheter introducer (Intro-Flex; Edwards Critical Care Division, Irvine, CA, USA) was placed into the jugular vein according to a Seldinger technique. Via the introducer, a five French pulmonary artery catheter (Swan-Ganz Catheter Model 132F5; Edwards Critical Care Division) connected to a multiparametric monitor (A/S3 Monitor) was advanced into the jugular vein until its distal lumen was positioned in the pulmonary artery. Correct location of the pulmonary artery catheter was based on the observation of characteristic pressure waveforms. The pressure sensing lumens of the pulmonary artery catheter, and the catheters placed in the cephalic vein and in the dorsal pedal artery were filled 0.9% NaCl solution containing heparin (4 IU/mL) and temporarily occluded until the start of baseline data collection after the animals were recovered from isoflurane anesthesia.
After 60 min of induction of anesthesia, when the instrumentation phase was completed, isoflurane administration was discontinued and the orotracheal tube was removed upon the return of the swallowing reflex. After discontinuation of isoflurane administration, conversation and movement of the individuals involved in the study was kept to a minimum necessary to reduce environmental stimulation that could interfere with the awareness level and with the cardio-respiratory variables.
After animals were fully recovered from anesthesia, as indicated by ambulation without ataxia and normal responsiveness to environmental stimuli, they were placed on a padded table using minimal physical restraint for reattaching the data interface. ECG leads to the skin electrodes and the multiparametric monitor to catheters placed in the pulmonary artery and in the dorsal pedal artery, via fluid-filled pressure transducers. The proximal lumen of the pulmonary artery catheter was used for recording the central venous pressure (CVP) and for injection of 5% dextrose during CO determinations; the distal lumen of this catheter recorded mean pulmonary arterial pressure (MPAP) and pulmonary arterial occlusion pressure (PAOP). The PAOP was obtained by temporary inflation of the balloon located at the tip of the pulmonary artery catheter with 0.7 mL of air. The pressure transducer connected to the catheter placed in the dorsal pedal artery was used for monitoring mean arterial pressure (MAP). The reference pressures (0 mmHg) were set at the level of the olecranon in case the animal was positioned in sternal recumbency or at the level of the manubrium in case the animal was positioned in lateral recumbency. Accuracy of these transducers was confirmed with a mercury column prior to each experiment.
The thermistor located at the tip of the pulmonary artery catheter was used for recording changes in blood temperature during thermodilution CO measurements and for recording body temperature (BT). Five milliliter boluses of cold 5% dextrose solution (10–18 °C) were administered into the central venous port of the pulmonary artery catheter for CO measurements. For each data sampling time, dextrose boluses were administered until a series of 3 CO values within 10% from each other were obtained or until a maximum of five boluses (totaling 25 mL of 5% dextrose) were injected. The CO value representative of each data sampling time was calculated as the arithmetic mean of the three values that were closer to each other.
Arterial blood samples were collected in heparinized syringes and immediately analyzed by an automated blood gas system (Model 348 Blood Gas Analyzer; Chiron Diagnostics, Halstead, UK) for recording pH, carbon dioxide and oxygen partial pressures (PaCO2 and PaO2, respectively), bicarbonate (HCO3−), and hematocrit (Ht). Displayed blood gas values were corrected on the basis of BT.
Variables obtained by calculation (Shoemaker & Parsa, 2000) included: body surface area (BSA = weight [grams] 2/3 × 10.1 × 10−4), cardiac index (CI = CO × BSA−1), stroke index (SI = CI × HR−1), systemic vascular resistance index [SVRI = (MAP−CVP) × CI−1 × 79.9], and pulmonary vascular resistance index [PVRI = (PAP−PAOP) × CI−1 × 79.9].
Sedation level was assessed after treatment drug administration using a modification of a quantitative sedation scoring system reported in the literature (Vainio et al., 1989). On the basis of this scoring system, the minimum score (0) represents a fully conscious and alert individual, while the maximum score (22) indicates a deep level of sedation or hypnosis (Appendix). The same individual blinded to the treatment administered was responsible for scoring the sedation and for recording the possible occurrence of drug reactions, such as vomiting, defecation, dysphoria (characterized by opisthotonus, whimpering, and repetitive head movements), and vocalization throughout the study.
Study protocol
Baseline data sampling was accomplished after at least 60 min of stopping isoflurane administration by using minimal physical restraint (animals remained in lateral or sternal recumbency), and following baseline measurements each dog randomly received 1 mg/kg of morphine sulfate (Dimorf®; Cristália) or methadone hydrochloride (Metadon®; Cristália) (0.5 mg/kg [MET0.5] or 1.0 mg/kg [MET1.0]). Treatment drugs were diluted in 5 mL of 0.9% NaCl and injected intravenously over 1-min through the catheter placed in the cephalic vein. Physiologic variables were recorded after 5, 15, 30, 60 and 120 min of treatment administration. Sedation scores were recorded at the same time after drug injection, with the exception of the 5 min data sampling time. After completion of the last data sampling, catheters were removed and a single dose of meloxicam (Meloxicam; Eurofarma, São Paulo, Brazil) (0.2 mg/kg, subcutaneous [s.c.]) was administered for analgesia.
Statistical analysis
Normal distribution of data was verified by using the Kolgomorov–Smirnov test and a Grubb’s test for detecting outliers. Parametric variables are presented as mean (±SD), while nonparametric variables (sedation scores) are presented as medians, percentiles 25 and 75, and upper/lower ranges (boxplots). Using a computer software program (sas for Windows v. 8.02; SAS Institute Inc, Cary, NC, USA), a split-plot design was used for the analysis of the effects of treatments on the parametric variables, with time as plot and treatment as subplot. The F-value of the anova table was used for analyzing the effect of time, treatment and treatment × time interaction, followed by a multiple comparison test for comparing the effects of drugs and time on the continuous variables. A Kruskal–Wallis followed by a Dunn’s test was used for comparison of sedation scores among treatments. The null hypothesis was rejected when P < 0.05.
Results
Cardiovascular variables
One animal presented some hemodynamic variables that were significantly (P < 0.05) different from variables recorded in the remaining population on the basis of the outlier detection test. The hemodynamic data for this animal are presented, but were not included in the statistical analysis.
Baseline physiologic variables did not differ among treatments. Compared to baseline, morphine reduced HR values from 30 until 120 min (mean HR values were 15–26% lower than mean HR values recorded at baseline) (Fig. 1). Both doses of methadone (0.5 and 1 mg/kg) reduced HR throughout the observational period (19–28% and 32–46% reduction from baseline in the MET0.5 and MET1.0 treatment groups, respectively). Comparisons among treatment groups showed that HR was significantly lower in dogs that received 1 mg/kg of methadone than in dogs that received the same dose of morphine during 90 min after opioid administration. The MET0.5 treatment resulted in intermediate changes in HR, with values significantly lower than values observed in the morphine treatment, but significantly larger than values observed with the highest dose of methadone (1 mg/kg) for 30 min after drug injection.
Cardiovascular variables recorded in five dogs (mean ± SD) at baseline (BL) and for 120 min after intravenous dose of 1.0 mg of morphine or two doses of methadone (0.5 mg/kg or 1.0 mg/kg). HR, heart rate; CI, cardiac index; MAP, mean arterial pressure; SVRI, systemic vascular resistance index; CVP, central venous pressure; PAOP, pulmonary artery occlusion pressure. Within each treatment group: Brackets that follow the symbol (*) indicate the time points that are significantly different from BL (P < 0.05). Among treatment groups: Means followed by different superscript letters are significantly different from each other (P < 0.05; A > B > C).
Morphine significantly reduced the CI from baseline only at the last data sampling time (19% reduction at 120 min). Methadone induced greater and more prolonged reductions in CI than morphine. While the 0.5 mg/kg dose of methadone reduced CI from baseline for 60 min after injection (17–27% reduction in mean CI values), the highest dose of this drug reduced the CI throughout the observational period (24–52% de reduction in mean CI values). Comparison among treatments showed that methadone (0.5 and 1.0 mg/kg) resulted in CI values that were significantly lower than morphine for 60 min after opioid administration. A significant difference in CI between the two doses of methadone was detected at 30 min after drug injection (MET1.0 treatment resulted in lower CI than the MET0.5 treatment).
Mean arterial pressure was increased from baseline (16%) after 5 min of morphine administration. Methadone increased MAP from baseline for up to 60 min after drug injection; maximum increases (23% and 35% above baseline) were recorded 5 min after the 0.5 and the 1.0 mg/kg doses of methadone, respectively. Compared to morphine, MAP values remained higher for the 1.0 mg/kg dose of methadone for 60 min after opioid injection; for the 0.5 mg/kg dose of methadone, MAP values were higher than in the morphine treatment only at 15 and 60 min after opioid injection.
The use of morphine did not cause significant changes in SVRI. Dose of 1.0 mg/kg of methadone increased SVRI from baseline for 90 min after treatment drug administration, while 0.5 mg/kg of methadone increased SVRI above baseline at 5, 15 and 60 min. In animals that received the 1.0 mg/kg dose of methadone, maximum increases in SVRI (165% increase in from baseline) were recorded after 5 min of opioid injection. With the 0.5 mg/kg dose of methadone, maximum increases in SVRI from baseline (57%) were recorded at 15 min. The high dose of methadone resulted in significantly higher SVRI values than in the morphine treatment for 60 min after drug injection. The SVRI values in the MET0.5 treatment were lower than values in the MET1.0 treatment (from 5 to 30 min) and higher than values observed in the morphine treatment (5, 15 and 60 min).
The CVP and PAOP values increased from baseline in all treatment groups. Morphine caused increases in CVP (50% from baseline at 5 and 120 min) and in PAOP (71% from baseline at 5 min) from baseline that were of shorter duration and of smaller magnitude than the increases in these variables induced by methadone. For both doses of methadone, CVP was increased from baseline for 120 min after opioid injection (233% and 333% above baseline at 5 min in the MET0.5 and in the MET1.0 treatment groups, respectively). PAOP was also increased from baseline for 90 and 120 min after 0.5 and 1.0 mg/kg of methadone (129% and 143% above baseline 5 min after 0.5 and 1.0 mg/kg of methadone, respectively). When compared to the morphine treatment, CVP was increased after administration of both doses of methadone for 60 min after drug injection. Dose of 0.5 mg/kg of methadone resulted in lower CVP values than the 1.0 mg/kg dose of methadone at 5, 15 and 60 min. The PAOP was significantly higher for both doses of methadone in comparison with morphine during 30 min after drug injection. At 60 min, only the MET1.0 treatment resulted in higher PAOP values in comparison with the morphine treatment.
While morphine increased MPAP from baseline only at 5 min after drug injection (25% increase), this variable remained increased from baseline for 60 min after 0.5 and 1.0 mg/kg of methadone (maximum increases of 44% and 56% at 5 min in the MET0.5 and in the MET1.0 treatment groups, respectively) (Table 1). Compared with morphine, the MET0.5 and the MET1.0 treatment groups resulted in higher MPAP values at some time points (5 and 15 min for MET0.5, and 5 and 30 min for MET1.0).
| Variable | Treatment | BL | Time after opioid administration (min) | |||||
|---|---|---|---|---|---|---|---|---|
| 5 | 15 | 30 | 60 | 90 | 120 | |||
| SI (mL/beat/m2) | MORPH | 46 ± 9 | 54 ± 8 | 53 ± 8 | 51 ± 9 | 57 ± 8 | 55 ± 11 | 51 ± 7 |
| MET0.5 | 47 ± 7 | 45 ± 8 | 47 ± 4 | 50 ± 7 | 49 ± 10 | 48 ± 6 | 53 ± 13 | |
| MET1.0 | 55 ± 22 | 47 ± 16 | 49 ± 19 | 50 ± 21 | 54 ± 17 | 60 ± 24 | 58 ± 17 | |
| MPAP (mmHg) | MORPH | 16 ± 3 | 20 ± 2*B | 19 ± 2B | 17 ± 1B | 18 ± 1 | 19 ± 2 | 19 ± 1 |
| MET0.5 | 16 ± 2 | 23 ± 3*A | 22 ± 4*A | 20 ± 1*AB | 20 ± 3* | 18 ± 2 | 17 ± 2 | |
| MET1.0 | 16 ± 2 | 25 ± 2*A | 21 ± 2*AB | 21 ± 2*A | 20 ± 1* | 17 ± 2 | 17 ± 2 | |
| PVRI (dyne/s/cm5/m2) | MORPH | 146 ± 42 | 117 ± 56B | 143 ± 33 | 146 ± 30 | 138 ± 34 | 171 ± 22 | 206 ± 53A |
| MET0.5 | 136 ± 23 | 160 ± 49AB | 202 ± 108 | 146 ± 36 | 176 ± 16 | 134 ± 47 | 150 ± 20AB | |
| MET1.0 | 122 ± 40 | 213 ± 99*A | 178 ± 110 | 152 ± 58 | 142 ± 63 | 112 ± 35 | 126 ± 43B | |
- SI, stroke index; MPAP, mean pulmonary artery pressure; PVRI, pulmonary vascular resistance index; BL, baseline; MORPH, morphine. Lines: Values followed by the symbol (*) are significantly different from baseline values (BL) at a 5% probability level. Columns: Values followed by different superscript letters are significantly different from each other at a 5% probability level (A > B).
Pulmonary vascular resistance index was increased from baseline (75%) at 5 min after 1.0 mg/kg of methadone. At this time, PVRI in the MET1.0 treatment was also higher in comparison with the morphine treatment.
Cardiovascular parameters recorded in the outlier are reported in Table 2. While the hemodynamic changes induced by morphine in the population (n = 5) was characterized by moderate decreases in HR and CI (maximum decreases from baseline of 26% and 19%, respectively) without significant changes SVRI, the outlier presented greater reductions in HR and in CI (54% and 69% decreases from baseline at 5 min, respectively) that were paralleled by substantial increases in SVRI (352% above baseline) and in CVP (550% above baseline). HR values in this animal remained lower than the values that encompass 95.4% of the population in a Gaussian distribution (mean ± 2 × SD) from 5 to 60 min; while CI remained below this interval for 90 min after morphine injection. Because of the substantial increase in SVRI after morphine, this variable was an outlier from 5 to 60 min after opioid was injected (P < 0.05); SVRI values were above the 95.4% intervals for a Gaussian distribution from 5 until 90 min. During baseline conditions, MAP values were below 95.4% intervals, increasing above this interval at 15 min after morphine.
| Variable | Treatment | BL | Time after opioid administration (min) | |||||
|---|---|---|---|---|---|---|---|---|
| 5 | 15 | 30 | 60 | 90 | 120 | |||
| HR (beats/min) | MORPH | 103 | 44* | 61* | 57* | 64* | 75 | 84 |
| MET0.5 | 129 | 130† | 127† | 112† | 108† | 101 | 108† | |
| MET1.0 | 111 | 73 | 67 | 67 | 74 | 68 | 83 | |
| CI (L/min/m2) | MORPH | 5.62 | 1.75* | 2.17* | 2.26* | 3.10* | 3.22* | 3.68 |
| MET0.5 | 7.01 | 7.04† | 6.37† | 5.96† | 6.45† | 5.68 | 6.21† | |
| MET1.0 | 5.36 | 3.03 | 3.00 | 3.48 | 3.62 | 3.97 | 4.39 | |
| SI (L/beat/m2) | MORPH | 55 | 40 | 36* | 40 | 48 | 43 | 44 |
| MET0.5 | 54 | 54 | 50 | 53 | 60 | 56 | 58 | |
| MET1.0 | 48 | 42 | 45 | 52 | 49 | 58 | 53 | |
| MAP (mmHg) | MORPH | 76* | 117 | 125† | 111 | 105 | 93 | 86 |
| MET0.5 | 93 | 88* | 82* | 88 | 82 | 83 | 91 | |
| MET1.0 | 81 | 85*‡ | 89*‡ | 88* | 94 | 95 | 95 | |
| CVP (mmHg) | MORPH | 2 | 13† | 8† | 8† | 6 | 4 | 5 |
| MET0.5 | 2 | 3* | 4 | 5 | 4 | 3 | 5 | |
| MET1.0 | 2 | 1* | 0* | 1* | 1* | 6 | 5 | |
| SVRI (dyne/s/cm5/m2) | MORPH | 1052 | 4758†‡ | 4303†‡ | 3644†‡ | 2553†‡ | 2206† | 1757 |
| MET0.5 | 1037* | 965* | 979 | 1113* | 966* | 1126 | 1107 | |
| MET1.0 | 1179 | 2216 | 2374 | 2001 | 2055 | 1791 | 1638 | |
| PAOP (mmHg) | MORPH | 4 | 15 | 13† | 12† | 10 | 10 | 9 |
| MET0.5 | 5 | 8* | 9 | 9 | 9 | 9 | 10 | |
| MET1.0 | 2* | 1*‡ | 1* | 4* | 4* | 5 | 6 | |
| MPAP (mmHg) | MORPH | 12 | 19 | 18 | 16 | 17 | 17 | 17 |
| MET0.5 | 17 | 20 | 19 | 22 | 19 | 19 | 21 | |
| MET1.0 | 17 | 10*‡ | 10*‡ | 11* | 15* | 15 | 16 | |
| PVRI (dyne/s/cm5/m2) | MORPH | 114 | 183 | 184 | 142 | 181 | 174 | 174 |
| MET0.5 | 137 | 136 | 126 | 174 | 124 | 141 | 142 | |
| MET1.0 | 224 | 237 | 240 | 161 | 243 | 201 | 182 | |
- *Value below the mean ± 2 × SD intervals generated for the studied population (n = 5). †Value above the mean ± 2 × SD intervals generated for the studied population (n = 5). ‡Outlier according to the Grubb’s outlier detection test (P < 0.05).
Overall, MAP, PAOP, and CVP were lower after methadone in the animal excluded from statistical analysis than in the remaining of the population (values below the 95.4% intervals). When this animal was treated with methadone, MAP values were outliers at 5 and 15 min after 1.0 mg/kg of methadone, while PAOP and MPAP were also detected as outliers at some time points (Table 2).
Arterial blood gases, temperature and hematocrit
Baseline arterial blood gas variables (pH, PaCO2, PaO2 and HCO3−), Ht and BT did not differ among treatment groups (Table 3). Panting (defined as respiratory rate above 120 movements/minute) was observed in five of six animals that received morphine and in three of six animals that received methadone, regardless of the dose.
| Variable | Treatment | BL | Time after opioid administration (min) | |||||
|---|---|---|---|---|---|---|---|---|
| 5 | 15 | 30 | 60 | 90 | 120 | |||
| pH | MORPH | 7.38 ± 0.03 | 7.39 ± 0.04A | 7.36 ± 0.03 | 7.35 ± 0.04 | 7.33 ± 0.03* | 7.35 ± 0.03* | 7.36 ± 0.03 |
| MET0.5 | 7.38 ± 0.02 | 7.36 ± 0.03AB | 7.33 ± 0.03* | 7.31 ± 0.03* | 7.32 ± 0.03* | 7.34 ± 0.03* | 7.35 ± 0.02 | |
| MET1.0 | 7.39 ± 0.02A | 7.35 ± 0.01B | 7.33 ± 0.06* | 7.32 ± 0.02* | 7.31 ± 0.02* | 7.31 ± 0.04* | 7.32 ± 0.03* | |
| PaCO2 (mmHg) | MORPH | 40 ± 4 | 40 ± 6 | 42 ± 4 | 44 ± 5A | 44 ± 3 | 44 ± 3 | 43 ± 4 |
| MET0.5 | 36 ± 4 | 39 ± 4 | 41 ± 4 | 39 ± 16B | 41 ± 5 | 41 ± 4 | 40 ± 3 | |
| MET1.0 | 38 ± 4 | 41 ± 5 | 41 ± 9 | 40 ± 6AB | 43 ± 5 | 45 ± 5* | 43 ± 5 | |
| PaO2 (mmHg) | MORPH | 87 ± 9 | 92 ± 9A | 83 ± 9 | 81 ± 15 | 82 ± 7 | 85 ± 6 | 84 ± 10 |
| MET0.5 | 88 ± 9 | 81 ± 14B | 81 ± 10 | 83 ± 8 | 85 ± 6 | 88 ± 6 | 85 ± 5 | |
| MET1.0 | 89 ± 8 | 80 ± 17B | 87 ± 19 | 90 ± 8 | 87 ± 8 | 85 ± 7 | 87 ± 6 | |
| HCO3−(mmol/L) | MORPH | 22.8 ± 2.8 | 21.2 ± 3.6 | 22.5 ± 3.8 | 23.3 ± 3.7A | 23.5 ± 3.4 | 24.4 ± 3.8A | 25.2 ± 3.8A |
| MET0.5 | 20.5 ± 2.7 | 21.2 ± 1.5 | 20.9 ± 1.5 | 21.5 ± 2.5AB | 20.8 ± 1.5 | 21.4 ± 1.2B | 21.9 ± 1.2B | |
| MET1.0 | 22.1 ± 2.0 | 21.7 ± 2.4 | 20.7 ± 2.3 | 20.0 ± 2.8B | 21.0 ± 2.4 | 22.1 ± 2.4AB | 22.0 ± 3.0B | |
| Ht (%) | MORPH | 40 ± 4 | 41 ± 4B | 44 ± 3*B | 44 ± 2*B | 43 ± 2*B | 44 ± 3*B | 43 ± 3* |
| MET0.5 | 41 ± 4 | 42 ± 4B | 45 ± 5*B | 49 ± 4*A | 49 ± 3*A | 48 ± 2*A | 46 ± 2* | |
| MET1.0 | 39 ± 3 | 46 ± 4*A | 50 ± 2*A | 50 ± 3*A | 50 ± 3*A | 47 ± 3*AB | 45 ± 2* | |
| BT (oC) | MORPH | 38.4 ± 0.4 | 38.1 ± 0.4A | 37.6 ± 0.4* | 37.4 ± 0.3* | 37.1 ± 0.5*A | 36.7 ± 0.4*A | 36.7 ± 0.4*A |
| MET0.5 | 38.1 ± 0.2 | 37.6 ± 0.3*B | 37.3 ± 0.3* | 37.3 ± 0.4* | 36.5 ± 0.3*B | 36.3 ± 0.4*B | 36.3 ± 0.3*B | |
| MET1.0 | 38.1 ± 0.2 | 37.8 ± 0.1AB | 37.6 ± 0.2* | 37.3 ± 0.3* | 36.9 ± 0.5*A | 36.6 ± 0.5*AB | 36.5 ± 0.5*AB | |
- PaCO2, carbon dioxide partial pressure, PaO2, oxygen partial pressure; HCO3−, bicarbonate; Ht, hematocrit; BT, body temperature; BL, baseline; MORPH, morphine. Lines: Values followed by the symbol (*) are significantly different from baseline values (BL) at a 5% probability level. Columns: Values followed by different superscript letters are significantly different from each other at a 5% probability level (A > B).
A statistically significant decrease in pH was observed after opioid administration in all treatment groups. However, such decrease was of small magnitude with maximum differences in mean arterial pH from baseline ranging from 0.05 to 0.08 units. There were no significant changes in PaCO2 and HCO3− within treatment groups. Mean HCO3− values remained within reference ranges (20–25 mmol/L) in all treatment groups. However, compared to morphine, HCO3− was significantly lower at 30 and 90 min after dose of 1.0 mg/kg of methadone and at 90 and 120 min after 0.5 mg/kg of methadone. Five minutes after opioid administration, PaO2 values were significantly lower with the use of 0.5 and 1.0 mg/kg of methadone (81 ± 14 and 80 ± 17 mmHg, respectively) in comparison with the morphine treatment (92 ± 9 mmHg). Hypoxemia (defined as PaO2< 60 mmHg) was not detected in the morphine treatment; the lowest PaO2 value (59 mmHg) was recorded in one animal 5 min after the dose of 1.0 mg/kg of methadone.
Compared to baseline, the Ht increased from 15 min until 120 min in the morphine (7.5–10% above baseline) and in the MET0.5 (10–19% above baseline) treatment groups; dose of 1.0 mg/kg of methadone increased the Ht from baseline (15–28% above baseline) throughout the observational period. The 1 mg/kg dose of methadone significantly increased the PCV compared to the morphine treatment group from 5 until 60 min of opioid administration; the 0.5 mg/kg dose of methadone increased Ht compared to morphine from 30 to 90 min after drug injection.
Body temperature decreased from baseline in all treatment groups. The MET0.5 treatment group resulted in lower BT values compared with morphine at some time points (5, 60, 90 and 120 min), but absolute differences in mean values was small (maximum difference of 0.6 °C).
Sedative effects
There was no difference in the sedation scores among treatments (Fig. 2) and the sedation level ranged from discrete to moderate. All treatments caused the dogs to remain spontaneously in lateral recumbency without the use of physical restraint during most time points of the observational period. Regardless of the treatment, the palpebral reflexes remained active, but with methadone, the eyeball was semi-rotated during the early observational period. It was evident that the high dose of methadone induced substantial relaxation of the mandible. The tongue could be manually exposed in all animals receiving the 1.0 mg/kg dose of methadone.
Boxplots of the sedation scores recorded in six dogs that received intravenous dose of morphine (1.0 mg/kg) or methadone (0.5 or 1.0 mg/kg) in a randomized crossover design. The median scores are represented by the line within each box. The boxes (percentiles 25 and 75) contain 50% of the scores and the bars show the upper and lower ranges of scores.
Maximum intensity of sedative effects was observed at 15–30 min after opioid administration, followed by a progressive waning of the sedation until 120 min. After the last data sampling time, all catheters were removed and all dogs were able to ambulate without ataxia.
Dysphoric behavior was observed in one of six animals that were treated with methadone (0.5 and 1.0 mg/kg). Dysphoria was characterized by opisthotonus, whimpering, and repetitive head movements. Episodes of vocalization (whimpering), salivation, defecation were observed in all treatments (Table 4).
| Incidence (number of animals) | |||
|---|---|---|---|
| MORPH | MET0.5 | MET1.0 | |
| Dysphoria | 0/6 | 1/6 | 1/6 |
| Vocalization | 5/6 | 3/6 | 4/6 |
| Salivation | 3/6 | 2/6 | 3/6 |
| Defecation | 1/6 | 1/6 | 3/6 |
Discussion
The results of this study provide evidence that methadone is a more potent cardiovascular depressant on a mg/kg basis than morphine in dogs. Contrasting with the mild hemodynamic changes induced by a high-end dose of morphine (1.0 mg/kg), the same dose of methadone had a greater impact on cardiovascular function. The hemodynamic effects of methadone were characterized by substantial decreases in HR and in CI that were accompanied consistent and sustained increases in SVRI. These cardiovascular changes are qualitatively similar to those reported after the administration of alpha-2 adrenergic agonists in dogs (Sinclair et al., 2002). Of particular interest are the actions of methadone on the vascular resistance, as these effects were previously unrecognized.
Vasodilation caused by histamine release into the systemic circulation mast cells has been implicated as one of the causes of cardiovascular instability after the use of i.v. morphine at doses above 1 mg/kg (Robinson et al., 1988). As histamine is rapidly metabolized in the plasma by the enzyme histamine-methyl-transferase, its hemodynamic effects are short lived; in humans, a significant decrease in arterial blood pressure and in systemic vascular resistance was observed only at 10 min after administration of a high-dose morphine (1 mg/kg administered intravenously over 10 min) (Rosow et al., 1982). In dogs, i.v. morphine administration caused dose-related increases in plasma histamine levels: while a 0.5 mg/kg dose of morphine did not cause significant increases in plasma histamine levels, a dose two times higher (1 mg/kg) of this opioid increased plasma histamine levels for only 2 min after drug injection, with a wide variation in plasma histamine concentrations reported among individual dogs after morphine administration (Guedes et al., 2007). In spite of the substantial release of histamine observed in individual dogs (440 and 589 ng /mL for 0.5 and 1.0 mg/kg of morphine, respectively), these changes have not been correlated with hypotension in most of the animals (Guedes et al., 2007). Even though plasma histamine levels were not measured in this study, one may hypothesize that the i.v. dose of morphine (1 mg/kg) used in this study might have caused an increase in plasma histamine levels. As it was not possible to detect decreases in SVRI or arterial blood pressure after morphine administration, it is evident that the hypothetical histamine release that might have been caused by morphine was not enough to induce cardiovascular instability in healthy animals. However, care should be taken with the use of this opioid at high i.v. doses in sick dogs, as this animal population may be more sensitive to the cardiovascular instability that might be promoted by histamine release.
In the studied population, the use of a high dose of morphine (1 mg/kg, intravenously) did not cause substantial negative chronotropic effects (15–26% reductions in HR from 30–120 min after opioid administration) and the decrease in CI caused by this opioid was also relatively small (19% decrease in CI at 120 min). Data from the study reported here confirm other previous reports in humans (Lowenstein et al., 1969) and in dogs (Priano & Vatner, 1981) showing that morphine results in hemodynamic stability, even when administered at high doses intravenously (1 mg/kg). In conscious dogs, dose of 1 mg/kg of morphine did not cause substantial changes in arterial pressure, systemic vascular resistance, HR, and CO (Priano & Vatner, 1981).
The two doses of methadone caused dose-dependent reductions in HR (19–28% and 32–46% decreases from baseline after the use of 0.5 and 1.0 mg/kg of methadone, respectively) that were of greater magnitude than the reductions in HR observed after morphine. Similar to other opioids, the negative chronotropic effects of methadone can be attributed to centrally mediated increases in vagal tone (Stanley et al., 1980). Methadone was also associated with more intense and prolonged reductions in CI when compared with morphine. The decreases in CI observed after methadone in this study (−17% to −27% and −24% to −52% after dose of 0.5 and 1.0 mg/kg of methadone, respectively) were substantially greater than the changes in CO observed after the administration of methadone to pentobarbital anesthetized dogs (Stanley et al., 1980). In that study, cumulative doses of methadone (0.3–5.3 mg/kg) caused only mild to moderate cardiovascular changes; after the maximum cumulative dose was administered (5.3 mg/kg), CO was decreased by 21% (Stanley et al., 1980).
Concomitantly to the reductions in HR and in CI, methadone induced significant increases in SVRI. The increase in SVRI was of greater magnitude and lasted longer after the use of the 1 mg/kg dose of methadone (maximum increases in SVRI of 57% and 165% after the use of 0.5 and 1.0 mg/kg of methadone, respectively). MAP did not increase to the same extent as SVRI after methadone treatment (23% and 35% increases in MAP after the use of 0.5 and 1.0 mg/kg of methadone, respectively) because of a compensatory decrease in CI. Although the negative chronotropic effects of opioids are attributed to centrally mediated increases in vagal activity (Coda, 2001), the increase in SVRI and MAP observed after the use of methadone in the study reported here suggests that a peripheral mechanism, mediated by increased baroreceptor activity secondary to increased vascular resistance, could have contributed to opioid induced bradycardia (Hellebrekers et al., 1989).
Cardiovascular stimulation caused by the CNS excitatory effects of opioids is commonly observed after the use of high doses of opioids in healthy cats and in horses (Gaumann et al., 1988; Carregaro et al., 2006). Systemic vasoconstriction leading to increased arterial blood pressure may be caused by increased sympathetic tone secondary to the CNS stimulatory action of opioids. An increase in circulating catecholamine levels that is coincident with increased arterial pressure is reported to occur in cats treated with opioids such as sufentanil (Gaumann et al., 1988). In human, opioids such as morphine may eventually cause a hyperdynamic circulatory response (Thomson et al., 1986; Mildh et al., 2000). However, in human subjects, it is not evident that the cardiovascular stimulation reported after the use of opioids is caused by increased sympathetic efferent activity (Thomson et al., 1986; Mildh et al., 2000). In one report, increases in HR and arterial blood pressure following the use of morphine (0.07–0.14 mg/kg, i.v.) were not associated with the increases in epinephrine or norepinephrine circulating levels (Mildh et al., 2000).
In canine species, arginin vasopressin plasma levels were reported to increase after the use of the same doses of methadone than those used in the study reported here, and increases in this hormone may explain the increases in SVRI and MAP recorded after the use of methadone (Hellebrekers et al., 1987, 1989). Vasopressin may cause vasoconstriction by stimulating V1 receptors located in the smooth muscle of peripheral blood vessels, while its antidiuretic effects are mediated via V2 receptors located in the collecting ducts of the kidneys (Jackson, 1996). A dose of 0.5 mg/kg of methadone did not cause significant increases in plasma arginin vasopressin levels in dogs, while a dose two times larger (1 mg/kg) caused prolonged increases in this hormone (above 2 h), with plasma concentrations increasing up to 40-fold above baseline (predrug) levels (Hellebrekers et al., 1989). In that study, increases in plasma arginin vasopressin were coincident with increased arterial blood pressure and with decreased HR, and authors suggested that a baroreceptor mediated mechanism induced could have been involved in methadone induced bradycardia (Hellebrekers et al., 1989).
While morphine caused minor and transient increases in CVP and in PAOP (50% increase in CVP and 71% increase in PAOP), methadone caused more intense and prolonged increases in these variables. The increases in CVP and in PAOP induced by methadone could be attributed to the greater decreases in HR caused by this opioid and/or to a venoconstricting effect caused by arginin vasopressin resulting in centralization of the circulating blood volume. The significant increase in Ht recorded after methadone in this study corroborates with the hypothesis of vasoconstriction causing increased circulating volume. The increase in Ht after the use of methadone was previously reported and could be attributed to arginin vasopressin mediated contraction of blood vessels located in the spleen causing the release of red blood cells into the systemic circulation (Hellebrekers et al., 1989).
Increased SVRI coupled with marked increases in PAOP (above 15 mmHg) were observed after the use of 1 mg/kg of methadone. Although these effects are tolerated in healthy dogs, substantial increases in SVRI and PAOP have the potential of causing cardiovascular compromise in dogs presenting with heart failure or in animals with reduced cardiovascular reserve. The increase in afterload because of vasoconstriction (increased SVRI) may result in greater depression of indices of systolic function in animals with heart disease, as the failing heart could be more sensitive to the effects of increased afterload on myocardial performance (Schwinn & Reves, 1989; Lawson & Johnson, 2001). In this study, mean PAOP values were increased above 15 mmHg for 5 and 30 min after administration of the low and high doses of methadone, respectively. Pulmonary artery occlusion pressure is considered a good indicator of left ventricular preload, and abnormally high PAOP values (above 15 mmHg) maybe associated with worsening of signs of congestion/edema in patients with congestive heart failure (Binanay et al., 2005).
One animal was considered an outlier because of changes in SVRI induced after morphine and because of MAP and PAOP changes after the dose of 1.0 mg/kg of methadone. Contrasting to the other animals, where morphine caused mild-to-moderate cardiovascular changes, in the animal not included in the statistical analysis, morphine administration induced marked increases in SVRI (352% increase from baseline) that were paralleled by substantial decreases in HR and in CI (−54% and −69% reduction in HR and in CI at 5 min, respectively). It was not possible to identify the cause for this contrasting cardiovascular response that approached the cardiovascular changes induced by the high dose of methadone (1 mg/kg). Although such dose regimen is associated with hemodynamic stability in most individuals, it appears that a high-end dose of morphine (1 mg/kg) may eventually induce idiosyncratic drug reactions that require further investigation.
Although panting was observed in animals receiving either morphine or methadone, the increase in respiratory rate did not result in increased alveolar ventilation (PaCO2 < 35 mmHg). Panting caused by opioids has been attributed to a resetting of the hypothalamic thermoregulatory center, recognizing the BT as falsely elevated, thus resulting in an increase in respiratory rate as a part of a compensatory thermoregulatory response (Lascelles, 2000; Pascoe, 2000).
In this study, morphine and methadone did not cause significant decreases in alveolar ventilation, as mean PaCO2 values remained within reference ranges (35–45 mmHg). Respiratory depression is an adverse side effect induced by opioids and is likely to become evident when these drugs are co-administered with potent respiratory depressant agents, such as general anesthetics. I.v. administration of morphine (1 mg/kg) to halothane or isoflurane caused respiratory depression (hypercapnia) that was of similar magnitude for both inhalant anesthetics (Steffey et al., 1993). In isoflurane anesthetized dogs, epidural administration of methadone (0.3 mg/kg) did not produce substantial respiratory changes, but 50% of the dogs that received i.v. methadone (0.3 mg/kg) during anesthesia received artificial ventilatory support (Leibetseder et al., 2006).
Although mean PaO2 values were maintained within reference ranges (80–100 mmHg) in all treatment groups, hypoxemia (PaO2 < 60 mmHg) was recorded in one animal at 5 min after receiving 1.0 mg/kg of methadone (59 mmHg). However, decreased alveolar ventilation was not the likely cause for the hypoxemia in this dog as PaCO2 was not increased at that moment (40 mmHg); suggesting that the oxygenation impairment recorded in this animal was likely caused by ventilation-to-perfusion inequalities.
In the study reported here, all treatments produced mild-to-moderate sedation, without statistically significant differences in the level of sedation among treatments. Intermittent vocalization and dysphoric behavior were observed in all treatments and are common side effects caused by opioids when administered to pain free animals (Lascelles, 2000; Pascoe, 2000). In dogs, methadone was reported to produce less sedation and nausea than morphine (Lascelles, 2000). Further studies are necessary to investigate the analgesic effects of methadone in animals.
In summary, both morphine and methadone provided adequate chemical restraint in dogs. However, methadone induced dose related cardiovascular changes and was a more potent cardiovascular depressant agent than morphine. Due to the marked cardiovascular changes induced by the 1 mg/kg dose of methadone (decreased HR and CI; increased SVRI, CVP and PAOP), this dose may not be recommended for routine clinical use. Idiosyncratic reactions to opioids and the role of arginin vasopressin on the cardiovascular changes induced by methadone (e.g. increases in SVRI) deserve further investigation.
Acknowledgment
This work was partially funded by “FAPESP (Fundação de Apoio à Pesquisa de São Paulo)”.
Appendix
Criteria for evaluating the level of sedation by means of cumulative score (Modified from Vainio et al., 1989).
| Posture (0–4) | 0: Standing position, normal proprioception (animal ambulates without ataxia) |
| 1: Animal remains in external or lateral position but is able to stand when verbally stimulated | |
| 2: Remains in external recumbency | |
| 3: Lateral recumbency, eventually moves or lifts the head | |
| 4: Lateral recumbency, if not verbally stimulated does not move or lifts the head | |
| Eyelid reflex (0–3) | 0: Strong lateral and medial eyelid reflexes* |
| 1: Lateral and medial eyelid reflexes present but reduced | |
| 2: Lateral eyelid reflex absent and medial eyelid reflex present | |
| 3: Lateral and medial eyelid reflexes absent | |
| Eye globe position (0–2) | 0: Eye centrally positioned |
| 1: Partial rotation of the eye globe | |
| 2: Full rotation of the eye globe | |
| Relaxation of the tongue and mandible (0–4) | 0: Normal tone of the mandible and tongue |
| 1: Reduced tone of the mandible and tongue allowing opening of the mandible with little difficulty. Tongue can be exposed with some difficulty and is readily retracted after released | |
| 2: Reduced tone of the mandible, tongue can be easily exposed but is readily retracted after being released | |
| 3: Mouth can be easily opened with jaw tone markedly reduced, tongue can be easily exposed, but animal retracts the tongue a few seconds after being released | |
| 4: Mandible and tongue fully relaxed, tongue can be exposed and it is not retracted after being released | |
| Response to sound (clapping) (0–2) | 0: Alert attitude, readily reacts (looks, lifts the head) to the stimulus |
| 1: Reduced reaction (discrete movement, lifting of the head). However the animal appears sedated | |
| 2: No reaction/movement | |
| Resistance to physically restraining in lateral recumbency (0–3) | 0: Animal resists. Readily returns to standing position or external recumbency after being released |
| 1: Offers little resistance, however readily returns to standing positon or external recumbency after being released | |
| 2: Does not offer resistance. However eventually moves or lifts the head and returns to external recumbency | |
| 3: Remains in lateral recumbency, does not offer resistance | |
| General appearance (0–4) | 0: Alert, normal consciousness |
| 1: Animal lightly sedated, promptly reacts/moves in response to environmental stimulation | |
| 2: Animal moderately sedated, eventually reacts to environmental stimulation | |
| 3: Animal appears to be moderately to deeply sedated, reduced reaction to environmental stimulation | |
| 4: Animal appears to be deeply sedated, does not react to environmental stimulation |
- *Lateral eyelid reflex represents the contraction of the eyelids in response to touching the lateral cantus of the eyelids (reflex lost during light hypnosis/anesthesia). Medial eyelid reflex represents the contraction of the eyelids in response to touching the medial cantus of the eyelids (reflex lost during moderate to deep hypnosis/anesthesia).
