Abstract
This study evaluated the effects of 3 morphine doses combined with acepromazine, on sedation and physiological parameters in 5 clinically healthy dogs. Four treatments were administered intramuscularly in a randomized, blinded, crossover design: acepromazine, 0.05 mg/kg, alone (ACP) and acepromazine plus morphine at doses of 0.25, 0.5, and 1.0 mg/kg body weight (BW) (AM0.25, AM0.5, and AM1.0, respectively). Sedation scores and cardiorespiratory variables were evaluated for 120 min after drug administration. The sedation scores were significantly higher with the AM0.25 and AM1.0 treatments than with the ACP treatment. At 30 min the scores were 36% to 66% higher with AM1.0 than with AM0.25 and AM0.5, respectively, but these differences were not significant. The physiological variables remained acceptable for dogs. The results of this study do not support the use of AM0.5 over AM0.25 to improve sedation in dogs, but they do indicate that sedation may be greater with AM1.0 than with AM0.25 and AM0.5. Studies with a greater number of samples are warranted to confirm this statement.
Résumé
Cette étude visait à évaluer les effets de trois doses de morphine combinées à de l’acépromazine, sur la sédation et des paramètres physiologiques chez cinq chiens cliniquement en santé. Quatre traitements furent administrés par voie intramusculaire dans un design croisé randomisé à l’aveugle : acépromazine, 0,05 mg/kg seule (ACP) et acépromazine plus morphine à des doses de 0,25, 0,5, et 1,0 mg/kg de poids corporel (AM0,25, AM0,5, et AM1,0, respectivement). Les pointages de sédation et des variables cardiorespiratoires furent évalués pour 120 min après l’administration des drogues. Les pointages de sédation étaient significativement plus élevés avec les traitements AM0,25 et AM1,0 qu’avec le traitement ACP. À 30 min, les pointages étaient 36 % et 66 % plus élevés avec AM1,0 qu’avec AM0,25 et AM0,5, respectivement, mais ces différences n’étaient pas significatives. Les variables physiologiques sont demeurées acceptables pour les chiens. Les résultats de cette étude ne militent pas en faveur de l’utilisation d’AM0,5 par rapport à AM0,25 pour améliorer la sédation chez les chiens, mais ils indiquent que la sédation peut être plus grande avec AM1,0 qu’avec AM0,25 et AM0,5. Des études avec un plus grand nombre d’échantillons sont requises pour confirmer cet énoncé.
(Traduit par Docteur Serge Messier)
Morphine is one of the opioids most often used for relief of acute pain, including surgical pain, in dogs. When administered alone to this species, morphine induced mild to moderate sedation (1). Opioids are also administered in combination with tranquilizers, such as acepromazine, to induce neuroleptoanalgesia (2). Acepromazine is a phenothiazine derivative that causes mild to moderate sedation in dogs (3,4). More pronounced sedation was observed in dogs when acepromazine was combined with opioid analgesics compared with administration of each drug alone (3). Reported side effects of such combinations in dogs were decreased arterial blood pressure and heart rate; however, the magnitude of these effects was not greater than when each drug was administered alone (3,4).
The degree of sedation induced by acepromazine–opioid combinations has been shown to be influenced by the choice of opioid. In a previous study in dogs (4), sedation scores were compared after administration of acepromazine [0.05 mg/kg body weight (BW)] combined with methadone (0.5 mg/kg BW), morphine (0.5 mg/kg BW), butorphanol (0.2 mg/kg BW), or tramadol (2 mg/kg BW). Sedation was greatest when acepromazine was combined with methadone, lowest when it was combined with tramadol, and intermediate when it was combined with either morphine or butorphanol. In a recent study in dogs (5), methadone at doses of 0.25, 0.5, and 0.75 mg/kg BW improved the sedation induced by acepromazine, the highest dose providing a longer duration of effect. Conversely, another study (6) showed that tramadol at doses of 3 and 5 mg/kg BW failed to improve acepromazine-induced sedation in dogs.
Despite the widespread use of acepromazine–morphine (AM) combinations in dogs, to the authors’ knowledge no study has compared the influence on sedation level in dogs of different morphine doses in combination with acepromazine. The present study aimed to do that and to study the effects on some physiological parameters. The hypothesis was that sedation and physiological changes would be greater with higher morphine doses.
This study was approved by the institutional Animal Research Ethical Committee (protocol 336/2014). Six adult crossbreed dogs (3 males and 3 females) were used. The dogs were considered clinically healthy according to the results of physical examination, a complete blood (cell) count, and serum biochemistry analyses. Each dog underwent 4 treatments, on different occasions, with 1-week washout intervals, in a randomized, blinded, crossover design. All treatments were administered intramuscularly. For treatment with acepromazine alone (ACP), Acepran 0.2% (Vetnil; Louveira, São Paulo, Brazil) was administered at a dose of 0.05 mg/kg BW. For combination treatments, designated AM0.25, AM0.5, and AM1.0, acepromazine (same dose) was mixed in the same syringe with morphine [Dimorf (Cristália, Itapira, São Paulo, Brazil)] at doses of 0.25, 0.5, and 1.0 mg/kg BW, respectively. On all occasions the final volume of the injection was 0.125 mL/kg BW, obtained by adding physiologic saline as appropriate. A person not involved in other phases of the study prepared the solutions.
Food, but not water, was withheld for 12 h before treatment. A 20-gauge catheter was percutaneously introduced into a dorsal pedal artery after local infiltration of lidocaine. The catheter was connected to a noncompliant tubing system and a pressure transducer (TruWave; Edwards Lifesciences, Draper, Utah, USA) filled with heparinized saline. The transducer was connected to a multiparameter monitor (Lifewindow 6000Vet; Digicare Animal Health, Boynton Beach, Florida, USA), zeroed at the level of the manubrium of the sternum, to allow measurement of systolic, mean, and diastolic arterial pressures (SAP, MAP, and DAP). Thereafter, the dogs were left undisturbed for 30 min before baseline variables were recorded. Heart rate and respiratory rate were counted by auscultation with a stethoscope and by observation of chest wall movements, respectively. Rectal temperature was measured with a digital thermometer. Blood samples from the arterial catheter were collected for measurement of arterial pH, oxygen partial pressure (PaO2), carbon dioxide partial pressure (PaCO2), and bicarbonate (HCO3−) concentration with a portable analyzer (i-STAT 1; Abbott Point of Care, Princeton, New Jersey, USA). On all occasions blood gas analysis was done immediately after sampling.
Sedation was evaluated with the use of 2 scoring systems: a visual analogue scale (VAS) and a numeric descriptive scale (NDS). The VAS consisted of a 10-cm line on which the left end, 0, represented no sedation and the right end, 10, represented the most sedation possible. On each occasion the distance between the left end and the mark assigned by the observer provided the VAS score for that occasion. The NDS ranged from 1 to 6 as follows: 1 — alert: no motor deficits, equivalent to the state before anesthesia; 2 — faint sedation: stands, walks, some ataxia and disorientation; 3 — slight sedation: stands but ataxic, can remain sternal; 4 — mild sedation: can stay sternal, cannot stand, may struggle; 5 — moderate sedation: can raise head, usually laterally recumbent; and 6 — heavy sedation: nonresponsive, cannot raise head (7). Data collection was standardized. Between assessments the dogs were left on the floor. At each time point the dog was first observed undisturbed and lying on the floor. Then the dog was gently positioned in lateral recumbency on a table, and the physiological parameters were measured. The dog was then returned to the floor and encouraged to stand and walk. Finally, the observer recorded the VAS and NDS scores. A single observer, unaware of the assigned treatment, evaluated sedation on all occasions. This person was familiar with the dogs’ behavior and the scoring systems.
For all variables a baseline value was recorded before treatment. Values for SAP, MAP, heart rate, and respiratory rate, as well as sedation scores, were reassessed at 15, 30, 45, 60, 90, and 120 min after drug administration. Rectal temperature was recorded at 30, 60, 90, and 120 min, and a 2nd sample for blood gas analysis was collected 45 min after drug administration.
Sample size was calculated by means of G*Power statistical software for Windows (Version 3.1.6; Universität Kiel, Kiel, Germany). Six dogs per group were considered necessary to detect a 3.0-cm difference in VAS sedation scores with an α error of 0.05 and a power of 80%. The assumption of normality of data was examined by a Kolmogorov–Smirnov test. For cardiorespiratory and temperature data a 1-way repeated-measures analysis of variance (ANOVA) followed by Dunnett’s test was used to compare differences between each time point (15 to 120 min) and baseline. For blood gas variables a paired t-test was used to compare data at 45 min with baseline values. Differences among treatments were identified by means of a 2-way repeated-measures ANOVA. When a difference was significant, the Bonferroni correction was used to identify the time point at which the difference existed. For subjective data (VAS and NDS scores) Friedman and Dunn’s tests were done to compare differences over time and between treatments. For all analyses, differences were considered significant at a P-value < 0.05.
Signs of disease developed in 1 male dog just before the beginning of the study, and the animal was excluded. Therefore, only 5 dogs completed the study. Mean ± standard deviation weight of dogs was 15.6 ± 3.2 kg. As Table I shows, with ACP treatment the heart rate was increased above baseline at all time points, but significant differences were detected only at 60 and 90 min (P = 0.03). With AM0.25, AM0.5, and AM1.0 treatments there was a trend toward a decrease in heart rate over time, but a significant difference was observed only with AM0.5 treatment at 90 min (P = 0.04). With ACP treatment the SAP was decreased below baseline at 15 (P = 0.04), 30 (P = 0.03), and 90 (P = 0.04) min and the MAP was decreased at 15 (P = 0.03) and 30 (P = 0.02) min. With AM0.25 treatment the SAP was decreased at 30 (P = 0.0009), 45 (P < 0.0001), 60 (P < 0.0001), 90 (P < 0.0001), and 120 (P = 0.004) min, the MAP was decreased at 30 (P = 0.006), 45 (P = 0.0001), 60 (P = 0.0003), and 90 (P = 0.002) min, and the DAP was decreased at 45 (P = 0.005) and 60 (P = 0.004) min. With AM0.5 treatment the SAP was decreased at 45 (P = 0.04) min, the MAP was decreased at 15 (P = 0.03), 30 (P = 0.0004), 45 (P = 0.0003), and 60 (P = 0.0005) min, and the DAP was decreased at 45 (P = 0.04) and 60 (P = 0.02) min. With AM1.0 treatment the SAP was decreased from 15 to 120 min (P-values: 0.005 at 15 min, < 0.0001 from 30 to 60 min, 0.0011 at 90 min, and 0.005 at 120 min), and the MAP was decreased at 30 (P = 0.002), 45 (P = 0.0006), 60 (P = 0.01), and 90 (P = 0.02) min.
Table I.
Mean values [± standard deviation (SD)] for heart rate (HR), systolic, mean, and diastolic arterial pressures (SAP, MAP, and DAP), respiratory rate (RR), and rectal temperature (Temp.) in 5 clinically healthy dogs before (Baseline) and after intramuscular administration of 0.05 mg/kg body weight (BW) of acepromazine alone (ACP) or in combination with morphine, 0.25 mg/kg BW (AM0.25), 0.5 mg/kg BW (AM0.5), or 1.0 mg/kg BW (AM1.0).
| Parameter and treatment | Baseline | Time (min) after drug administration | |||||
|---|---|---|---|---|---|---|---|
|
| |||||||
| 15 | 30 | 45 | 60 | 90 | 120 | ||
| HR (beats/min) | |||||||
| ACP | 73 ± 13 | 86 ± 23 | 84 ± 24 | 85 ± 25 | 89 ± 22a | 88 ± 25a | 84 ± 23 |
| AM0.25 | 73 ± 18 | 80 ± 16 | 72 ± 16 | 70 ± 19 | 67 ± 21 | 63 ± 16 | 67 ± 19 |
| AM0.5 | 79 ± 9 | 82 ± 12 | 73 ± 10 | 72 ± 14 | 69 ± 16 | 67 ± 13a | 74 ± 20 |
| AM1.0 | 76 ± 10 | 88 ± 17 | 75 ± 12 | 72 ± 13 | 69 ± 11 | 69 ± 16 | 69 ± 14 |
| SAP (mmHg) | |||||||
| ACP | 142 ± 22 | 127 ± 24a | 126 ± 31a | 130 ± 35 | 129 ± 28 | 127 ± 24a | 134 ± 22 |
| AM0.25 | 149 ± 10 | 140 ± 19 | 133 ± 17a | 127 ± 17a | 129 ± 16a | 129 ± 20a | 135 ± 17a |
| AM0.5 | 150 ± 14 | 131 ± 18 | 126 ± 17 | 124 ± 15a | 127 ± 13 | 141 ± 6 | 139 ± 14 |
| AM1.0 | 147 ± 12 | 132 ± 17a | 125 ± 13a | 120 ± 11a | 122 ± 16a | 129 ± 16a | 131 ± 17a |
| MAP (mmHg) | |||||||
| ACP | 85 ± 5 | 75 ± 6a | 74 ± 11a | 78 ± 13 | 78 ± 11 | 78 ± 10 | 82 ± 8 |
| AM0.25 | 87 ± 2 | 84 ± 8 | 78 ± 6a | 74 ± 7a | 75 ± 6a | 77 ± 7a | 82 ± 6 |
| AM0.5 | 86 ± 7 | 76 ± 7a | 70 ± 6a | 70 ± 8a | 71 ± 5a | 79 ± 9 | 83 ± 10 |
| AM1.0 | 86 ± 5 | 80 ± 7 | 72 ± 5a | 71 ± 4a | 75 ± 12a | 76 ± 9a | 78 ± 11 |
| DAP (mmHg) | |||||||
| ACP | 61 ± 6 | 55 ± 4 | 54 ± 5 | 58 ± 9 | 58 ± 9 | 57 ± 6 | 61 ± 7 |
| AM0.25 | 64 ± 5 | 62 ± 6 | 58 ± 3 | 55 ± 4a | 55 ± 2a | 58 ± 4 | 61 ± 2 |
| AM0.5 | 60 ± 6 | 55 ± 7 | 51 ± 4 | 51 ± 6a | 50 ± 4a | 57 ± 6 | 60 ± 12 |
| AM1.0 | 61 ± 4 | 59 ± 5 | 54 ± 3 | 53 ± 5 | 54 ± 6 | 57 ± 8 | 60 ± 14 |
| RR (breaths/min) | |||||||
| ACP | 21 ± 2 | 18 ± 3 | 18 ± 3 | 16 ± 3a | 15 ± 2a | 16 ± 3a | 16 ± 3a |
| AM0.25 | 22 ± 10 | 21 ± 7 | 18 ± 5 | 17 ± 5 | 17 ± 3 | 17 ± 4 | 18 ± 5 |
| AM0.5 | 30 ± 20 | 20 ± 8 | 18 ± 5 | 16 ± 5a | 18 ± 6 | 18 ± 6 | 15 ± 5a |
| AM1.0 | 27 ± 12 | 23 ± 3 | 24 ± 2 | 22 ± 2 | 22 ± 5 | 21 ± 6 | 18 ± 4a |
| Temp. (°C) | |||||||
| ACP | 38.3 ± 0.4 | — | 38.0 ± 0.3 | — | 38.0 ± 0.4 | 38.0 ± 0.7 | 38.1 ± 0.7 |
| AM0.25 | 38.3 ± 0.5 | — | 38.0 ± 0.4 | — | 37.7 ± 0.3a | 37.4 ± 0.3a | 37.3 ± 0.2a,b |
| AM0.5 | 38.6 ± 0.3 | — | 38.0 ± 0.4a | — | 37.5 ± 0.5a | 37.2 ± 0.7a,b | 37.0 ± 0.8a,b |
| AM1.0 | 38.4 ± 0.3 | — | 38.0 ± 0.4 | — | 37.5 ± 0.3a | 36.9 ± 0.6a,b | 36.7 ± 0.8a,b |
Significantly different from baseline.
Significantly different from the value with ACP treatment (P < 0.05).
The respiratory rate (Table I) decreased significantly below baseline with ACP treatment, from 45 to 120 min (P-values at 45, 60, 90, and 120 min: 0.02, 0.002, 0.007, and 0.02, respectively). With AM0.5 and AM1.0 treatments the respiratory rate was significantly decreased at 45 (P = 0.03) and 120 (P = 0.02) min and at 120 (P = 0.04) min, respectively. Significant decreases from baseline in pH and increases in PaCO2 concentration (Table II) were observed at 45 min with AM0.5 treatment (P = 0.008 and P = 0.005, respectively) and with AM1.0 treatment (P = 0.009 and P = 0.02, respectively). Compared with ACP treatment the treatments with AM0.5 and AM1.0 resulted in a lower pH (P = 0.008 and P = 0.0003, respectively) at 45 min, and treatment with AM1.0 resulted in a higher PaCO2 (P = 0.02) at 45 min. The HCO3− concentration was increased from baseline with AM0.5 treatment at 45 min (P = 0.04) but did not differ significantly from the values with the other treatments (Table II). The mean PaO2 values (Table II) were > 80 mmHg with all the treatments at baseline and at 45 min, but with AM0.5 treatment the value was below baseline at 45 min (P = 0.046).
Table II.
Mean values (± SD) for arterial pH, carbon dioxide partial pressure (PaCO2), oxygen partial pressure (PaO2), and bicarbonate concentration (HCO3−) in the 5 dogs before (Baseline) and 45 min after drug administration.
| Parameter and treatment | Baseline | 45 min after drug administration |
|---|---|---|
| pH | ||
| ACP | 7.39 ± 0.02 | 7.39 ± 0.02 |
| AM0.25 | 7.37 ± 0.03 | 7.36 ± 0.03 |
| AM0.5 | 7.38 ± 0.03 | 7.35 ± 0.03a,b |
| AM1.0 | 7.39 ± 0.02 | 7.33 ± 0.02a,b |
| PaCO2 (mmHg) | ||
| ACP | 34 ± 4 | 34 ± 2 |
| AM0.25 | 34 ± 4 | 36 ± 2 |
| AM0.5 | 34 ± 2 | 39 ± 2a |
| AM1.0 | 33 ± 3 | 40 ± 3a,b |
| PaO2 (mmHg) | ||
| ACP | 91 ± 3 | 91 ± 6 |
| AM0.25 | 84 ± 8 | 89 ± 4 |
| AM0.5 | 89 ± 2 | 86 ± 1a |
| AM1.0 | 88 ± 4 | 86 ± 5 |
| HCO3− (mEq/L) | ||
| ACP | 20.9 ± 2.2 | 20.5 ± 1.8 |
| AM0.25 | 19.9 ± 1.8 | 20.3 ± 1.6 |
| AM0.5 | 20.3 ± 1.4 | 21.3 ± 1.4a |
| AM1.0 | 20.0 ± 1.0 | 21.1 ± 0.8 |
Significantly different from baseline.
Significantly different from the value with ACP treatment (P < 0.05).
Rectal temperature (Table I) was decreased significantly below baseline with AM0.5 at 30 min (P = 0.03) and from 60 to 120 min (P = 0.0001 at 60 min and P < 0.0001 at 90 and 120 min). It was also decreased significantly below baseline from 60 to 120 min with AM0.25 (P = 0.002 at 60 min and P < 0.0001 at 90 and 120 min) and with AM1.0 treatment (P = 0.004 at 60 min and P < 0.0001 at 90 and 120 min). Compared with ACP treatment the combination treatments resulted in significantly lower temperatures, at 90 min with AM0.5 (P = 0.004) and AM1.0 (P = 0.0001) and at 120 min with AM0.25 (P = 0.0073), AM0.5 (P = 0.0001), and AM1.0 (P < 0.0001). No significant difference in temperature was detected among the combination treatments. The maximum decreases in mean temperature were 0.2°C, 1.0°C, 1.6°C, and 1.7°C with ACP, AM0.25, AM0.5, and AM1.0, respectively.
Administration of all treatments increased the sedation scores above the baseline values (Table III). With ACP treatment the increases were observed only with the VAS (P = 0.006). Compared with the baseline values the VAS scores with AM0.25 treatment were higher at 30 (P = 0.008), 45 (P = 0.006), and 60 (P = 0.008) min, and the NDS scores were higher at 15 (P = 0.016), 30 (P = 0.016), and 45 (P = 0.016) min. With AM0.5 treatment the scores were higher than at baseline at 30 min (P = 0.0009 and P = 0.0046 for VAS and NDS, respectively) and 45 min (P = 0.0015 and P = 0.0046 for VAS and NDS, respectively). With AM1.0 treatment the scores were higher than at baseline at 30, 45, and 60 min (P = 0.0407, P = 0.0099, and P = 0.0060 for VAS and P = 0.0206, P = 0.0206, and P = 0.0206 for NDS, respectively). Compared with ACP treatment the AM0.25 (P = 0.042) and AM1.0 (P = 0.009) treatments, but not the AM0.5 treatment, resulted in higher VAS scores. However, the NDS scores were significantly higher only for AM1.0 treatment (P = 0.020) in comparison with ACP treatment. There was no significant difference in sedation scores among the AM0.25, AM0.5, and AM1.0 treatments at any time point during the observation period.
Table III.
Median (and interquartile range) of sedation scores measured on 2 scales in the 5 dogs before and after drug administration.
| Score and treatment | Baseline | Time (min) after drug administration | |||||
|---|---|---|---|---|---|---|---|
|
| |||||||
| 15 | 30 | 45 | 60 | 90 | 120 | ||
| VAS (cm) | |||||||
| ACP | 0 | 1.3 (0.8–3.0) | 2.5 (1.0–3.0)a | 2.0 (1.0–3.1)a | 2.0 (1.0–3.4)a | 2.1 (0.6–3.0) | 1.2 (0.3–2.8) |
| AM0.25 | 0 | 5.8 (4.4–7.7)b | 5.8 (4.6–8.3)a | 5.1 (4.3–7.8)a | 4.9 (4.3–8.4)a,b | 5.0 (3.3–7.8) | 3.8 (2.5–7.6) |
| AM0.5 | 0 | 5.0 (4.4–6.0) | 5.7 (4.8–8.1)a | 5.7 (4.9–7.7)a | 4.7 (3.7–7.1) | 4.8 (3.7–7.2) | 4.7 (3.2–6.9) |
| AM1.0 | 0 | 6.0 (5.7–8.1)b | 7.9 (6.9–8.4)a,b | 7.3 (5.8–9.4)a,b | 7.7 (4.8–9.5)a,b | 7.5 (4.5–9.4)b | 6.5 (4.0–9.1)b |
| NDS | |||||||
| ACP | 1.0 (1.0–1.0) | 2.0 (2.0–2.0) | 2.0 (2.0–2.0) | 2.0 (2.0–2.0) | 2.0 (2.0–2.0) | 2.0 (2.0–2.0) | 2.0 (1.5–2.0) |
| AM0.25 | 1.0 (1.0–1.0) | 3.0 (3.0–5.0)a | 3.0 (3.0–5.0)a | 3.0 (3.0–5.0)a | 3.0 (2.5–5.0) | 3.0 (2.0–5.0) | 2.0 (2.0–5.0) |
| AM0.5 | 1.0 (1.0–1.0) | 3.0 (3.0–4.0) | 3.0 (3.0–5.5)a | 3.0 (3.0–5.5)a | 3.0 (2.5–4.5) | 3.0 (2.5–4.0) | 3.0 (2.0–4.0) |
| AM1.0 | 1.0 (1.0–1.0) | 3.0 (3.0–5.0)b | 5.0 (3.5–5.5)a,b | 4.0 (3.0–6.0)a,b | 4.0 (3.0–6.0)a,b | 3.0 (3.0–6.0)b | 3.0 (2.5–6.0) |
Significantly different from baseline.
Significantly different from the value with ACP treatment (P < 0.05).
VAS — Visual analogue scale (range: 0 to 10 cm); NDS — Numeric descriptive scale (range: 0 to 6).
In the present study AM0.25 and AM1.0 treatment improved the sedation induced by acepromazine in dogs. Although no significant difference was observed in sedation among the 3 morphine doses, the sedation scores were 36% to 66% higher with AM1.0 treatment than with AM0.25 and AM0.5 treatment at 30 min.
The overall results of this study agree with previous reports that combinations of acepromazine with opioid analgesics result in greater sedation than acepromazine alone in dogs (3–5,8). However, the present study did not identify a dose–response relationship between morphine dose and degree of sedation induced by the combination. Similarly, in a recent study (5) the combination of acepromazine (0.05 mg/kg BW administered intramuscularly) and incremental doses of methadone (0.25, 0.50, and 0.75 mg/kg BW) was not associated with significant improvement in sedation. Nevertheless, in this previous study the higher methadone doses resulted in prolonged sedation compared with the lower doses, which is different from the results in our study, in which the sedation scores were significantly higher than at baseline until 45 to 60 min for the AM0.25, AM0.5, and AM1.0 treatments. At 120 min the dogs still presented some degree of sedation with all the treatments, but no significant difference in sedation scores compared with baseline or among the combination groups was detected.
These results must be interpreted with caution considering a major limitation. According to the preliminary sample size calculation, 6 dogs per group would be necessary to detect a 3.0-cm difference in VAS scores with adequate statistical power. At peak sedation (30 min) the maximum difference in VAS scores between the AM1.0, AM0.5, and AM0.25 treatments was 2.1 cm. At 60 min the scores with the AM1.0 and AM0.5 treatments were 7.7 and 4.7 cm, respectively. Besides a 3.0-cm difference in VAS score, no significant difference was detected, which might indicate that the study was underpowered because the sample size was only 5 dogs. Another point to consider is that the VAS and NDS scores were significantly higher with the AM1.0 treatment than with the ACP treatment at several time points, but most of the time such differences were not detected between the ACP treatment and the AM0.25 and AM0.5 treatments. These results may indicate that sedation was greater with the AM1.0 treatment and that differences from the AM0.25 and AM0.5 treatments were not detected because of the small sample size. Therefore, a study with a larger sample may yield different results. Although this study might lack the power to support the absence of a significant difference in sedation between the highest morphine dose and the 2 other doses of the opioid, our results provide evidence that increasing the dose of morphine from 0.25 to 0.50 mg/kg BW in the combination does not improved sedation: the scores determined with both sedation scales were nearly the same with AM0.25 and AM0.50 treatment throughout the observation period.
The cardiovascular effects observed in this study are typical of combinations of acepromazine with opioids in dogs (3–5,8). The heart rate decreased by 15% and the SAP and MAP by 15% to 19%, respectively, compared with baseline values but were still within the clinically acceptable range for dogs. The decrease in arterial blood pressure resulted from acepromazine-induced blockage of α-adrenergic receptors in the vascular beds, as reported in a previous study in dogs (9). However, decreases in myocardial contractility and cardiac output have also been reported as a cause of the decrease in arterial pressure in dogs administered 0.1 mg/kg BW of acepromazine intravenously (8). The decrease in heart rate with the AM0.25, AM0.5, and AM1.0 treatments is likely associated with a centrally mediated effect induced by the opioid that results in an increase in vagal tone (10). The reduction in heart rate was not influenced by the morphine dose, as was the case in another study in dogs administered acepromazine–methadone combinations (5). However, our dogs were well-conditioned to the laboratory environment and had low baseline heart rates. In stressed dogs with a high heart rate, one might expect decreases in the rate greater than the 15% reduction observed herein.
In this study, arterial samples were collected for blood gas analysis 45 min after administration of the drugs. The moment for blood sampling was chosen in order to evaluate blood gases at the peak sedative effect. According to previous studies the peak sedative effect after intramuscular administration of acepromazine–opioid combinations occurs within 30 to 45 min after injection (3,5). Compared with baseline values, the respiratory rate decreased with all treatments except AM0.25. The reduction might be attributable to a calming effect of the acepromazine. Another reason could be respiratory depression induced by morphine. Opioid agonists at μ-receptors can decrease minute volume and increase PaCO2 (11). Despite the significant decreases in respiratory rate found in this study, the influence on blood gases was minimal and not of clinical relevance.
A reduction in body temperature among dogs given acepromazine was reported in 1 study (3) but not observed in another (5). In the present study, body temperature was not decreased in the dogs given acepromazine alone during the 120-minute observation period. Conversely, administration of morphine and methadone alone resulted in temperature decreases in unanesthetized dogs (1). Moreover, the decrease was similar in dogs given methadone alone (0.5 mg/kg BW) or in combination with acepromazine (0.05 mg/kg BW) (3). These findings indicate that the opioid is responsible for the drop in body temperature in dogs given an acepromazine–opioid combination.
In conclusion, this study has provided evidence that increasing the morphine dose in a combination with acepromazine from 0.25 to 0.5 mg/kg BW does not improve sedation, but increasing the dose to 1.0 mg/kg BW might result in greater sedation than with the lower doses of the opioid. Studies with a greater number of samples are warranted to confirm this statement.
References
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