Dexmedetomidine, an α2-adrenoceptor agonist commonly administered to dogs, is the active dextrorotatory isomer of the racemate medetomidine.1 Dexmedetomidine is highly selective for α2-adrenoceptors (ratio, 1,621:1 for the α2-adrenoceptor to the α1-adrenoceptor) and has more potent sedative and analgesic effects than the racemate, but it can cause dose-dependent cardiopulmonary depression in a manner similar to that for other α2-adrenoceptor agonists.2
The administration of opioids to provide analgesia is relatively common in veterinary medicine. In addition to their sedative effects, opioids form the basis for pain management in dogs.3 The analgesic efficacy of morphine, methadone, meperidine, and butorphanol in dogs has been established, but information on efficacy of nalbuphine and tramadol has been less well evaluated.4–6
Opioids and α2-adrenoceptor agonists are often combined and administered to veterinary patients to provide sedation and analgesia for a variety of procedures and as premedication prior to induction of anesthesia. Combinations of α2-adrenoceptor agonists and opioids can lead to supra-additive or synergistic antinociceptive and sedative effects.7–9 In dogs, the combination of dexmedetomidine and meperidine or dexmedetomidine and butorphanol results in better sedation scores than use of any of the drugs alone.10,11 In another study,12 investigators analyzed the effects of dexmedetomidine combined with methadone, morphine, or tramadol in dogs and reported that the combinations caused potentiation of sedation.
The objective of the study reported here was to compare the cardiopulmonary, sedative, and antinociceptive effects and determine differences in blood gas values and acid-base status when dexmedetomidine was administered alone or in combination with butorphanol, meperidine, methadone, morphine, nalbuphine, or tramadol to conscious healthy Beagles. We hypothesized that dexmedetomidine in combination with any of the opioids would result in superior antinociception and sedation but would cause similar cardiopulmonary depression, compared with results for administration of dexmedetomidine alone.
Materials and Methods
Animals
Eight healthy (as determined on the basis of results of clinical examination, a CBC, renal and hepatic function tests, fecal parasitological examination, and ECG) laboratory Beagles were used in the study. All dogs (3 males and 5 females) were 24 months old; mean ± SD body weight was 15.4 ± 2.9 kg. A sample size of 8 dogs was selected on the basis of initial data obtained from a preliminary experiment and power calculations performed by the use of results obtained in that experiment for heart rate and blood pressure values.
The dogs were allowed to acclimate to the experimental environment and research team for 30 days prior to commencement of the study. Food and water were withheld for 6 hours prior to start of the experiment. The study was approved by the Ethics Committee on Animal Use of the University of Franca (No. 053/12). All procedures were conducted in accordance with ethical principles for animal experimentation.
Study design and treatments
Hair in the area over the right cephalic vein and dorsal pedal arteries was clipped from each dog, and a catheter (22 gauge) was introduced into the right cephalic vein for the administration of supportive treatments, if necessary. Dogs were randomly assigned (by drawing of lots) to receive each of 7 treatments in a crossover study with a minimum interval of 7 days between treatments. Treatments consisted of dexmedetomidinea (0.01 mg/kg; Dex treatment) and the same dose of dexmedetomidine combined with butorphanolb (0.15 mg/kg; Dex-But treatment), meperidinec (5 mg/kg; Dex-Mep treatment), methadoned (0.5 mg/kg; Dex-Meth treatment), morphinee (0.5 mg/kg; Dex-Mor treatment), nalbuphinef (0.5 mg/kg; Dex-Nal treatment), and tramadolg (5 mg/kg; Dex-Tram treatment). Drugs were combined in the same syringe and injected IM into a semitendinosus muscle. Final volume was adjusted to 2 mL by the addition of saline (0.9% NaCl) solutionh to ensure investigators were not aware of the treatment administered to each dog. Variables were measured before drug administration (time 0; baseline) and every 15 minutes after drug administration for 120 minutes.
Cardiopulmonary, blood gas, and electrolyte variables
Heart rate was determined by measuring the interval between R waves for 1 minute during intermittent ECGi; cardiac rhythm was also assessed at that time. Subcutaneous tissues over a dorsal pedal artery were infiltrated with 2% lidocaine,j and the artery was percutaneously catheterized with a 22-gauge catheterk by use of aseptic techniques. That catheter was used to measure MAP. Blood pressure was measured intermittently by use of an aneroid manometer,l which was calibrated against a mercury column before use. The system was calibrated to zero by use of the air–saline solution junction at the point of the shoulder in standing and sternally recumbent dogs and the xiphoid process in laterally recumbent dogs as reference points. Respiratory rate was assessed by counting the number of chest movements. Arterial blood samples were collected from the catheter inserted in the dorsal pedal artery into heparinized (50 U) syringes and immediately analyzed to measure arterial blood pH, Paco2, Pao2, arterial oxygen saturation, base excess, and electrolyte (Na, K, Cl, and HCO3−) concentrations. Values were corrected by the analyzer on the basis of each dog's body temperature. Accuracy and precision of the blood gas analyzerm were assessed by use of quality control solutions.
Sedative effects
For evaluation of sedation, dogs were placed in a quiet room to which they had been acclimated. Dogs were videotaped after IM injections, and sedation was subsequently evaluated separately by 3 examiners (LTN, JS, and BHBV); examiners were not aware of the treatment administered to each dog. Evaluations were performed on the same day as the experiment. Dogs were positioned on a rubber-coated examination table. Changes in posture, the palpebral reflex, position of the ocular globe, mandibular and tongue relaxation, response to hand clapping, resistance to positioning in lateral recumbency, and overall appearance were used to score sedation, which could range from 0 to 20 points, as described elsewhere13 (Appendix). The mean was calculated by use of values recorded by each of the 3 examiners.
Antinociceptive effects
Antinociception was evaluated by use of the withdrawal reflex to heat stimulation, whereby a metallic proben with a controlled temperature of 60°C was inserted into the interdigital space of a hind limb for a maximum of 5 seconds, as described elsewhere.14 Withdrawal of the paw was considered a positive response, and absence of the withdrawal reflex was considered a negative response.
Statistical analysis
Results were analyzed with statistical software.o,p Data were subjected to the Shapiro-Wilk test of normality and reported as mean ± SD. An ANOVA for repeated measures and complementary Dunnett test were used for cardiorespiratory and blood gas variables within the same treatment. A Tukey test was used for comparisons among treatments. Sedation scores were subjected to a κ test to evaluate examiner reliability, sedative effects were analyzed by use of the Kruskal-Wallis test with a Dunn correction, and antinociceptive effects were analyzed by use of the Cochran Q test. Arrhythmias were compared by use of the Fisher exact test. Values of P < 0.05 were considered significant.
Results
Cardiorespiratory variables
A significant decrease in heart rate was detected at all time points after injection, compared with the baseline value, for the treatments Dex-But (P = 0.01), Dex-Mep (P < 0.05), Dex-Meth (P = 0.01), and Dex-Mor (P = 0.01; Table 1). A significant decrease in heart rate was also detected for treatments Dex at 15, 30, and 60 to 120 minutes (P = 0.01); Dex-Nal from 30 to 60 minutes (P < 0.05) and 75 to 105 minutes (P = 0.01); and Dex-Tram at 30, 60, and 105 minutes (P < 0.05), compared with the baseline value. However, no significant (P = 0.470) differences were detected among treatments.
Mean ± SD values for cardiorespiratory variables of 8 healthy Beagles before (time 0) and after IM injection of dexmedetomidine alone or in combination with an opioid.
| Time (min) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Variable | Treatment | 0 | 15 | 30 | 45 | 60 | 75 | 90 | 105 | 120 |
| Heart rate | Dex | 119 ± 20 | 90 ± 20* | 93 ± 15* | 102 ± 16 | 90 ± 12* | 91 ± 17* | 87 ± 15* | 87 ± 7* | 87 ± 17* |
| (beats/min) | Dex-But | 118 ± 21 | 90 ± 20* | 90 ± 20* | 82 ± 18* | 86 ± 20* | 83 ± 17* | 85 ± 16* | 89 ± 16* | 84 ± 17* |
| Dex-Mep | 107 ± 10 | 86 ± 12* | 92 ± 16† | 87 ± 19* | 81 ± 16* | 85 ± 9* | 88 ± 10* | 92 ± 10† | 84 ± 15* | |
| Dex-Meth | 11 ± 16 | 86 ± 27* | 87 ± 21* | 80 ± 17* | 85 ± 7* | 78 ± 13* | 78 ± 17* | 80 ± 19* | 83 ± 22* | |
| Dex-Mor | 116 ± 17 | 91 ± 9* | 96 ± 19† | 86 ± 13* | 93 ± 18† | 84 ± 11* | 85 ± 18* | 80 ± 6* | 82 ± 10* | |
| Dex-Nal | 111 ± 9 | 95 ± 21 | 91 ± 11† | 90 ± 15† | 89 ± 8† | 82 ± 16* | 81 ± 18* | 88 ± 28* | 95 ± 26 | |
| Dex-Tram | 105 ± 15 | 95 ± 11 | 89 ± 20† | 91 ± 16 | 89 ± 8† | 91 ± 9 | 91 ± 8 | 89 ± 14† | 95 ± 12 | |
| MAP (mm Hg) | Dex | 119 ± 10 | 109 ± 7 | 104 ± 8† | 107 ± 17 | 99 ± 18* | 98 ± 24* | 98 ± 15* | 96 ± 17* | 93 ± 12* |
| Dex-But | 117 ± 12 | 102 ± 11† | 95 ± 13* | 95 ± 11* | 94 ± 5* | 96 ± 12* | 97 ± 8* | 97 ± 13* | 99 ± 10* | |
| Dex-Mep | 120 ± 10 | 108 ± 9† | 99 ± 10* | 95 ± 11* | 96 ± 7* | 96 ± 9* | 95 ± 7* | 102 ± 8* | 108 ± 10* | |
| Dex-Meth | 119 ± 13 | 111 ± 9 | 101 ± 10* | 91 ± 10* | 90 ± 11* | 91 ± 14* | 95 ± 14* | 95 ± 8* | 98 ± 12* | |
| Dex-Mor | 127 ± 10 | 111 ± 16* | 100 ± 9* | 99 ± 8* | 96 ± 8* | 93 ± 11* | 94 ± 12* | 94 ± 11* | 98 ± 9* | |
| Dex-Nal | 124 ± 14 | 109 ± 10 | 104 ± 10 | 99 ± 8† | 97 ± 10* | 106 ± 38 | 94 ± 10* | 100 ± 15† | 99 ± 17† | |
| Dex-Tram | 119 ± 10 | 107 ± 9 | 94 ± 17* | 97 ± 9* | 99 ± 9* | 99 ± 11* | 101 ± 8* | 100 ± 10* | 104 ± 15† | |
| Respiratory rate | Dex | 56 ± 27 | 31 ± 17* | 24 ± 8* | 19 ± 6* | 20 ± 5* | 22 ± 13* | 22 ± 8* | 20 ± 12* | 18 ± 8* |
| (breaths/min) | Dex-But | 42 ± 15 | 30 ± 11* | 19 ± 6* | 17 ± 5* | 16 ± 3* | 17 ± 5* | 20 ± 5* | 18 ± 5* | 18 ± 4* |
| Dex-Mep | 40 ± 22 | 29 ± 22 | 17 ± 5* | 17 ± 3* | 18 ± 4* | 28 ± 15 | 19 ± 4* | 18 ± 4* | 18 ± 3* | |
| Dex-Meth | 35 ± 9 | 21 ± 7* | 17 ± 6* | 15 ± 4* | 22 ± 16* | 21 ± 14* | 18 ± 4* | 17 ± 5* | 18 ± 6* | |
| Dex-Mor | 45 ± 20 | 29 ± 16 | 25 ± 17 | 29 ± 28 | 24 ± 14 | 27 ± 18 | 27 ± 22 | 26 ± 21 | 25 ± 21 | |
| Dex-Nal | 36 ± 18 | 28 ± 12 | 18 ± 5* | 19 ± 5* | 15 ± 4* | 19 ± 8* | 16 ± 3* | 19 ± 7* | 19 ± 4* | |
| Dex-Tram | 33 ± 9 | 20 ± 6* | 19 ± 5* | 21 ± 5* | 21 ± 4* | 18 ± 2* | 19 ± 7* | 19 ± 7* | 22 ± 7* | |
Treatments consisted of IM injection of dexmedetomidine (0.01 mg/kg; Dex) and the same dose of dexmedetomidine plus butorphanol (0.15 mg/kg; Dex-But), meperidine (5 mg/kg; Dex-Mep), methadone (0.5 mg/kg; Dex-Meth), morphine (0.5 mg/kg; Dex-Mor), nalbuphine (0.5 mg/kg; Dex-Nal), or tramadol (5 mg/kg; Dex-Tram).
Within a treatment, value differs significantly (P = 0.01) from the value at time 0.
Within a treatment, value differs significantly (P < 0.05) from the value at time 0.
Alterations in cardiac rhythm were sinus arrest (37/56 [66.0%] dogs) and first- and second-degree atrioventricular block (14/56 [25.0%] and 6/56 [10.7%] dogs, respectively) and were detected for all treatments during the entire period of evaluation. There were no significant differences in the frequency of events among treatments.
There was a significant decrease in MAP at all time points, compared with the baseline value, for treatment groups Dex-But (P < 0.05), Dex-Mep (P < 0.05), and Dex-Mor (P = 0.01). A significant decrease in MAP was also detected for treatments Dex at 30 (P < 0.05) and 60 to 120 (P = 0.01) minutes; Dex-Meth at 30 to 120 minutes (P = 0.01); Dex-Nal at 45 (P < 0.05), 60 (P = 0.01), 90 (P = 0.01), and 105 to 120 (P < 0.05) minutes; and Dex-Tram at 30 to 105 (P = 0.01) and 120 (P < 0.05) minutes. No significant (P = 0.565) differences were detected among the treatments.
There was a significant (P = 0.01) reduction in respiratory rate at all time points, compared with the baseline value, for treatments Dex, Dex-But, Dex-Meth, and Dex-Tram. A significant (P = 0.01) decrease in respiratory rate was also detected for treatment Dex-Mep at 30 to 60 minutes and 90 to 120 minutes and for treatment Dex-Nal at 30 to 120 minutes. No significant (P = 0.430) differences were detected among the treatments.
Blood gas and electrolyte variables
Arterial blood pH decreased significantly (P = 0.01) for all treatments at all time points, compared with the baseline value (Table 2). Comparisons among treatments revealed that values were significantly lower, compared with values for the other groups, for Dex-Mep at 15 minutes (P = 0.01) and for Dex-Mor at 60 to 120 minutes (P < 0.05). There was a significant increase in Paco2 at all time points, compared with the baseline value, for treatments Dex-Mep (P = 0.01), Dex-Meth (P = 0.01), Dex-Mor (P < 0.05), and Dex-Nal (P = 0.01). A significant increase in Paco2, compared with the baseline value, was detected for Dex-But at 15 to 45 (P = 0.01), 75 (P = 0.01), 105 (P < 0.05), and 120 (P = 0.01) minutes and for Dex-Tram at 30, 45, and 75 to 105 minutes. Comparisons among treatments revealed that Paco2 was significantly lower for treatments Dex at 15 (P < 0.05), 30 (P = 0.01), 45 (P < 0.05), 75 (P < 0.05), and 120 (P < 0.05) minutes and for Dex-Tram at 120 minutes; there was an increase in Paco2 for treatment Dex-Meth at 60 (P = 0.01) and 90 (P < 0.05) minutes and for treatment Dex-Mor at 105 minutes (P = 0.01).
Mean ± SD values for blood gas variables of 8 healthy Beagles before (time 0) and after IM injection of dexmedetomidine alone or in combination with an opioid.
| Time (min) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Variable | Treatment | 0 | 15 | 30 | 45 | 60 | 75 | 90 | 105 | 120 |
| pHa | Dex | 7.44 ± 0.03 | 7.40 ± 0.02* | 7.30 ± 0.01*† | 7.40 ± 0.03*† | 7.39 ± 0.02* | 7.39 ± 0.02* | 7.38 ± 0.01* | 7.39 ± 0.02* | 7.39 ± 0.02* |
| Dex-But | 7.40 ± 0.04 | 7.38 ± 0.04* | 7.37 ± 0.03* | 7.37 ± 0.03* | 7.37 ± 0.03* | 7.37 ± 0.03* | 7.39 ± 0.03* | 7.38 ± 0.03* | 7.38 ± 0.03* | |
| Dex-Mep | 7.40 ± 0.02 | 7.36 ± 0.03*‡ | 7.34 ± 0.02* | 7.35 ± 0.02* | 7.36 ± 0.02* | 7.37 ± 0.02* | 7.37 ± 0.01* | 7.38 ± 0.01* | 7.38 ± 0.01* | |
| Dex-Meth | 7.44 ± 0.00 | 7.37 ± 0.05* | 7.35 ± 0.04* | 7.35 ± 0.05* | 7.35 ± 0.04* | 7.36 ± 0.04* | 7.37 ± 0.04* | 7.38 ± 0.04* | 7.38 ± 0.04* | |
| Dex-Mor | 7.42 ± 0.02 | 7.37 ± 0.03* | 7.35 ± 0.02* | 7.34 ± 0.02* | 7.34 ± 0.02*‡ | 7.34 ± 0.01*‡ | 7.34 ± 0.01*‡ | 7.34 ± 0.02*† | 7.34 ± 0.02*† | |
| Dex-Nal | 7.42 ± 0.04 | 7.37 ± 0.02* | 7.37 ± 0.02* | 7.36 ± 0.02* | 7.36 ± 0.02* | 7.36 ± 0.01* | 7.36 ± 0.01* | 7.37 ± 0.03* | 7.37 ± 0.02* | |
| Dex-Tram | 7.42 ± 0.01 | 7.38 ± 0.02* | 7.37 ± 0.02* | 7.37 ± 0.02* | 7.37 ± 0.01* | 7.38 ± 0.02* | 7.38 ± 0.01* | 7.39 ± 0.02* | 7.39 ± 0.02* | |
| Paco2 (mm Hg) | Dex | 28 ± 2 | 29 ± 2† | 29 ± 5‡ | 29 ± 6† | 30 ± 2 | 28 ± 4† | 31 ± 3 | 31 ± 2 | 31 ± 3† |
| Dex-But | 30 ± 2 | 34 ± 3* | 34 ± 3* | 34 ± 3* | 33 ± 3 | 35 ± 3* | 32 ± 4 | 33 ± 4§ | 35 ±3* | |
| Dex-Mep | 30 ± 2 | 34 ± 3* | 36 ± 3* | 37 ± 2* | 35 ± 2* | 35 ± 2* | 35 ± 1* | 33 ± 3* | 33 ± 2* | |
| Dex-Meth | 29 ± 2 | 35 ± 4* | 36 ± 4* | 36 ± 5* | 37 ± 4*‡ | 37 ± 3* | 36 ± 4*† | 36 ± 3* | 36 ± 3* | |
| Dex-Mor | 28 ± 2 | 32 ± 3§ | 34 ± 3* | 36 ± 4* | 35 ± 3* | 36 ± 2* | 36 ± 3* | 37 ± 3*‡ | 37 ± 4* | |
| Dex-Nal | 28 ± 2 | 33 ± 2* | 32 ± 2* | 33 ± 2* | 33 ± 2* | 32 ± 2* | 34 ± 2* | 33 ± 4* | 34 ± 3* | |
| Dex-Tram | 29 ± 2 | 31 ± 2 | 32 ± 2§ | 32 ± 3§ | 31 ± 3 | 32 ± 4§ | 32 ± 2§ | 31 ± 3§ | 31 ± 3† | |
| Pao2 (mm Hg) | Dex | 81 ± 5 | 79 ± 5 | 79 ± 4‡ | 79 ± 6 | 82 ± 6 | 82 ± 5 | 83 ± 5 | 86 ± 6* | 82 ± 8 |
| Dex-But | 82 ± 6 | 74 ± 4§ | 76 ± 7 | 79 ± 7 | 81 ± 4 | 82 ± 5 | 84 ± 4 | 84 ± 5 | 82 ± 4 | |
| Dex-Mep | 78 ± 3 | 65 ± 4*† | 69 ± 4* | 73 ± 3* | 80 ± 3* | 82 ± 4* | 85 ± 5* | 86 ± 7* | 86 ± 5* | |
| Dex-Meth | 80 ± 2 | 66 ± 8* | 69 ± 9* | 73 ± 11 | 77 ± 13 | 83 ± 8 | 86 ± 10 | 87 ± 12§ | 85 ± 11 | |
| Dex-Mor | 81 ± 7 | 74 ± 7 | 72 ± 8§ | 74 ± 9 | 77 ± 7 | 79 ± 6 | 82 ± 7 | 83 ± 5 | 85 ± 5 | |
| Dex-Nal | 82 ± 3 | 73 ± 5* | 76 ± 4 | 78 ± 4 | 82 ± 4 | 86 ± 3 | 85 ± 5 | 89 ± 7* | 86 ± 4 | |
| Dex-Tram | 79 ± 5 | 73 ± 3 | 75 ± 4 | 78 ± 4 | 80 ± 3 | 84 ± 6 | 84 ± 3 | 89 ± 14* | 86 ± 3 | |
| Sao2 (%) | Dex | 96 ± 1 | 95 ± 1 | 95 ± 0† | 95 ± 1 | 95 ± 1 | 96 ± 1 | 96 ± 1 | 96 ± 1 | 95 ± 1 |
| Dex-But | 96 ± 1 | 94 ± 2* | 94 ± 2* | 95 ± 2§ | 95 ± 1 | 95 ± 1 | 96 ± 0 | 96 ± 1 | 96 ± 1 | |
| Dex-Mep | 96 ± 1 | 91 ± 2* | 92 ± 2* | 93 ± 1 | 95 ± 1 | 95 ± 1 | 96 ± 1 | 96 ± 1 | 96 ± 0 | |
| Dex-Meth | 96 ± 1 | 89 ± 6*† | 92 ± 3* | 93 ± 3§ | 94 ± 2 | 95 ± 1 | 96 ± 1 | 96 ± 1 | 96 ± 1 | |
| Dex-Mor | 96 ± 1 | 94 ± 2§ | 93 ± 2* | 93 ± 3* | 94 ± 2 | 94 ± 1† | 95 ± 1 | 95 ± 1 | 95 ± 1 | |
| Dex-Nal | 96 ± 1 | 94 ± 2* | 94 ± 1* | 94 ± 1* | 95 ± 1 | 96 ± 1 | 96 ± 1 | 96 ± 1 | 96 ± 0 | |
| Dex-Tram | 96 ± 1 | 94 ± 1* | 94 ± 1* | 95 ± 1 | 95 ± 1 | 96 ± 1 | 96 ± 1 | 96 ± 1 | 96 ± 1 | |
| BE (mmol/L) | Dex | −4 ± 1 | −5 ± 1§ | −6 ± 3§ | −6 ± 2§ | −6 ± 1§ | −7 ± 2§ | −5 ± 1* | −5 ± 2* | −6 ± 2 |
| Dex-But | −3 ± 1 | −4 ± 1 | −5 ± 1* | −5 ± 1* | −6 ± 1* | −5 ± 1* | −5 ± 2* | −5 ± 1* | −4 ± 1 | |
| Dex-Mep | −4 ± 1 | −6 ± 1* | −6 ± 1* | −5 ± 1* | −5 ± 1* | −5 ± 1* | −5 ± 1* | −5 ± 1* | −5 ± 1* | |
| Dex-Meth | −3 ± 2 | −4 ± 1* | −5 ± 1* | −5 ± 2* | −5 ± 1* | −4 ± 1*† | −4 ± 2 | −4 ± 2 | −4 ± 2 | |
| Dex-Mor | −5 ± 1 | −6 ± 1* | −6 ± 2* | −6 ± 1* | −6 ± 1* | −6 ± 1* | −6 ± 1* | −5 ± 1* | −5 ± 1* | |
| Dex-Nal | −4 ± 1 | −5 ± 1* | −6 ± 1* | −6 ± 1* | −6 ± 1* | −6 ± 1* | −6 ± 1* | −5 ± 1* | −5 ± 1* | |
| Dex-Tram | −4 ± 1 | −6 ± 1§ | −6 ± 1§ | −6 ± 1§ | −6 ± 1§ | −6 ± 1§ | −5 ± 1§ | −5 ± 1* | −5 ± 1§ | |
Within a treatment, value differs significantly (P < 0.05) from the value at time 0.
Within a time point, value differs significantly (P < 0.05) from the values for all other treatments.
Within a time point, value differs significantly (P < 0.01) from the values for all other treatments.
Within a treatment, value differs significantly (P = 0.01) from the value at time 0.
BE = Base excess. pHa = Arterial blood pH. Sao2 = Arterial oxygen saturation.
See Table 1 for remainder of key.
A significant reduction in Pao2, compared with the baseline value, was detected for treatments Dex-But (P < 0.05) and Dex-Nal (P = 0.01) at 15 minutes, Dex-Mor (P < 0.05) at 30 minutes, Dex-Mep (P = 0.01) at 15 to 45 minutes, and Dex-Meth (P = 0.01) at 15 and 30 minutes. Comparisons among treatments revealed that Pao2 was significantly (P < 0.05) lower for treatment Dex-Mep at 15 minutes.
Base-excess values were significantly lower, compared with the baseline value, at all time points for treatments Dex-Mep, Dex-Mor, Dex-Nal, and Dex-Tram and for Dex-But at 30 to 90 minutes. Base-excess values were significantly lower, compared with the baseline value, for treatment Dex at 15 to 75 (P = 0.01), 90, and 105 (P < 0.05) minutes and for Dex-Meth at 15 to 75 minutes (P < 0.05). Comparisons among treatments revealed that Dex-Meth had significantly lower base-excess values than the other groups at 75 minutes.
No significant differences in Na, K, Cl, and HCO3−concentrations were detected (data not shown).
Sedative effects
A κ test was used to evaluate examiner reliability; a moderate score (κ = 0.412) was found. Higher sedation scores were detected in dogs treated with Dex-But, Dex-Mep, and Dex-Meth, and the effect remained evident for at least 60 minutes after administration.
Significant differences from the baseline value were detected for treatments Dex at 15 to 120 minutes (P < 0.05), Dex-But at 30 to 75 minutes (P < 0.05), Dex-Mep at 15 to 60 minutes (P = 0.01), Dex-Meth at 15 to 75 minutes (P < 0.05), Dex-Mor at 30 to 90 minutes (P < 0.05), Dex-Nal at 15 to 75 minutes (P = 0.01), and Dex-Tram at 15 to 75 minutes (P = 0.01; Figure 1).
Sedation scores for 8 healthy Beagles determined before (time 0; baseline) and after IM injection of dexmedetomidine (0.01 mg/kg; A) and the same dose of dexmedetomidine combined with butorphanol (0.15 mg/kg; B), meperidine (5 mg/kg; C), methadone (0.5 mg/kg; D), morphine (0.5 mg/kg; E), nalbuphine (0.5 mg/kg; F), and tramadol (5 mg/kg; G). Sedation was scored on a scale of 0 to 20. Each circle represents results for 1 Beagle, and each horizontal bar represents the median. *†Within a treatment, value differs significantly (*P < 0.05; †P < 0.001) from the baseline value. ‡§Within a time point, value differs significantly (‡P < 0.001; §P < 0.05) from the value for the treatment of dexmedetomidine alone.
Citation: American Journal of Veterinary Research 79, 3; 10.2460/ajvr.79.3.267
Compared with results for treatment Dex, significantly higher sedation scores were detected for treatment Dex-Mep at 15 to 60 minutes (P < 0.001) and for treatment Dex-Meth at 15 to 75 minutes (P < 0.05).
Antinociceptive effects
A significant (P < 0.001) negative response (ie, absence of withdrawal reflex was detected for treatments Dex-But, Dex-Meth, Dex-Mor, and Dex-Nal at all time points. A significant negative response also was detected for treatment Dex-Mep at 15 to 75 and 105 minutes (P < 0.001); Dex-Tram at 15, 45, 75, and 90 minutes (P < 0.001); and Dex at 15, 45, 105, and 20 minutes (P = 0.01). Comparisons among treatments revealed a significant (P = 0.027) negative response for treatments Dex-Meth, Dex-Mor, and Dex-Nal at 120 minutes.
Discussion
Results for the study reported here indicated that the sedative effects of dexmedetomidine were more pronounced when it was combined with a variety of opioids, particularly with butorphanol, meperidine, and methadone, compared with the sedative effects when dexmedetomidine was administered alone to healthy dogs. Clinical doses of dexmedetomidine differ among reports and depending on whether the drug is administered alone or in combination with opioids. The dose of 0.01 mg/kg was chosen for the present study to reflect the dose administered in other studies,10,15,16 and it also reflected that dexmedetomidine was to be administered in conjunction with a variety of opioids. Similarly, the doses of opioids administered were selected on the basis of equipotent analgesic doses used in other studies.4,17
It is widely accepted that dexmedetomidine administration leads to a reduction in heart rate, changes in heart rhythm, or both.18 This decrease in heart rate is a baroreceptor-mediated response to peripheral vasoconstriction and hypertension, and blood pressure then returns to values equal to or lower than those recorded before treatment.1 Combining dexmedetomidine with buprenorphine, methadone, morphine, or tramadol causes a reduction in arterial blood pressure without causing hypotension in dogs.12,15 Opioids may also induce vagally mediated bradycardia,19 and studies20,21 of dogs have revealed further reductions in heart rate when an opioid is administered in combination with an α2-adrenoceptor agonist, compared with the results when the α2-adrenoceptor agonist is administered alone. These cardiovascular effects are suggestive of a combined or potentiated effect when drugs of the 2 classes are administered in combination. However, we did not detect this effect in the dogs of the present study because there were no differences in heart rate or MAP among treatments. This may have been a reflection of the dose of dexmedetomidine that was administered, which was higher than doses administered in those aforementioned studies, and the fact that the cardiovascular effects of medetomidine are dose dependent.1 There is evidence to suggest that dexmedetomidine has antiarrhythmic properties through enhancement of vagal activity.22,23 Continuous rate infusion of dexmedetomidine to anesthetized dogs did not induce important arrhythmias.22,24 In studies10,12 that involved the combined administration of dexmedetomidine and meperidine, methadone, morphine, or tramadol, arrhythmias were not reported, which suggested that they were not observed. Seemingly in contrast to the aforementioned studies, some cardiac arrhythmias were detected following the administration of all treatments in the present study, but they did not appear to be clinically relevant. Furthermore, there were no differences among treatments; thus, we concluded that opioids did not potentiate this effect when the drugs were administered at the doses used in this study.
The α2-adrenoceptor agonists cause respiratory depression through their effects on the respiratory center,25,26 which is worse if they are combined with other respiratory depressant drugs such as anesthetics.25 Opioids may depress the ventilatory response to hypercapnia (ie, alter chemoreceptor sensitivity to CO2),27 but clinically important respiratory depression is rare when these drugs are used alone at clinical doses in healthy conscious animals.26 In studies5,13,17,27–29 conducted to examine the effects of dexmedetomidine, morphine, methadone, meperidine, butorphanol, and tramadol in dogs, there was little effect on ventilation. In the study reported here, respiratory rate was significantly reduced following all opioid treatments, and Paco2 was higher, except for treatment Dex-Mor. However, Paco2 remained within physiologic reference limits, and the changes were not clinically relevant. Use of a combination of dexmedetomidine and opioids may enhance the total respiratory depressant effect of each drug; however, there was no difference among treatments in the present study. Changes in Paco2 were reflected in arterial blood pH (ie, an increase in Paco2 was concomitant with a decrease in arterial blood pH); however, this also was not clinically relevant, and arterial blood pH remained within the physiologic reference limits.
Administration (IM or continuous rate infusion) of dexmedetomidine does not lower Pao2 in conscious16,20 or isoflurane-anesthetized30 dogs. Effects of opioids on oxygenation in dogs differ among reports.3,13,28,31 High doses of methadone (1.0 mg/kg) administered IV to conscious dogs can cause hypoxemia (defined as Pao2 < 60 mm Hg).17 The authors of that study17 concluded that this was not a result of reduced alveolar ventilation but was more likely a result of ventilation-perfusion impairment. In the present study, we detected significant reductions in Pao2, particularly when dogs received the Dex-Meth or Dex-Mep treatments. Similar to the results of the aforementioned study,17 we believe that impaired alveolar ventilation was unlikely the sole cause of the changes for the study reported here. Recumbency that affected ventilation-perfusion matching was a possible alternative explanation for this finding. The effect appeared to be transient, lasting for approximately 45 minutes, and hypoxemia was not evident. However, we recommend pulse oximetry be used to measure oxygen saturation and that clinicians have access to supplemental oxygen when these combinations are used in clinical settings.
Sedation resulting from the administration of dexmedetomidine and opioid binding to receptors in the CNS has been described.1,19 The combination of α2-adrenoceptor agonists (eg, dexmedetomidine) and opioids is often used in veterinary practice to enhance each individual drug's sedative and analgesic effects, and there is a complex molecular interaction when ligands bind to both α2-adrenergic and μ-opioid receptors.9 Administration of a combination of dexmedetomidine and methadone or morphine to conscious dogs results in improved sedation, compared with results when dexmedetomidine is given alone or combined with tramadol.12 Similarly, sedation improves when a combination of dexmedetomidine and meperidine is administered, compared with effects when dexmedetomidine is administered alone to conscious dogs.10 Adding butorphanol (0.2 mg/kg) to medetomidine also improves sedation in dogs.32 Sedation was observed for all treatments for up to 60 minutes after injection, with superior sedation occurring in dogs for the Dex-Mep or Dex-Meth treatments. Duration of sedation after administration of some treatments likely was a result of the pharmacokinetic profile of individual opioids in dogs. Furthermore, in the present study, equipotent doses of opioids were used, and therefore, the dose of butorphanol was slightly lower than the dose used clinically, which may have limited the sedative effects of the Dex-But treatment. Another possible limitation was that there was only moderate agreement among examiners for the scores assigned, but this likely was attributable to the subjective nature of the evaluation.
Assessment of antinociception in sedated animals can be affected if sedation is profound because the distinction between antinociception and sedation is problematic.32 Furthermore, thermal cutaneous threshold testing is not the same as clinical pain, which is often more diffuse and severe.33 However, to be able to assess the antinociceptive efficacy of drug combinations, this limitation is difficult to resolve. A thermal test that has a positive or negative response is a compromise for the assessment of nociception in sedated animals. By use of this method, nociceptive responses differed, lasting up to 2 hours when dogs received Dex-But, Dex-Meth, Dex-Mor, and Dex-Nal. It is difficult to determine that the other combinations did not have similar effects because sedation also played a role and the number of dogs included in the study was small. In a similar study,12 higher analgesia scores were detected in dogs that received dexmedetomidine combined with methadone, morphine (up to 75 minutes), or tramadol (up to 60 minutes). However, the noxious insult differed from that used in the present study in that those authors assessed pedal withdrawal in response to mechanical pinching of a toe; therefore, direct comparisons between that study and the present study cannot be made.
In the present study, combining dexmedetomidine with butorphanol, meperidine, methadone, morphine, nalbuphine, or tramadol resulted in similar cardiorespiratory depression. Monitoring of ventilation and oxygenation is recommended, particularly when a combination of dexmedetomidine and meperidine or methadone is used. Superior sedation was achieved when dexmedetomidine was combined with meperidine or methadone. Antinociceptive effects were difficult to interpret because of sedation, but they appeared to be better when dexmedetomidine was combined with butorphanol, methadone, morphine, or nalbuphine.
Acknowledgments
Support for Dr. Nishimura was provided by a scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
The authors thank Ana Márcia Zago for assistance with creating the figure and Professor Daniel Kan Honsho for use of the experimental area.
ABBREVIATIONS
| MAP | Mean arterial blood pressure |
Footnotes
Dexdomitor, Zoetis, Parsippany, NJ.
Torbugesic, Zoetis, Parsippany, NJ.
Dolosal, Cristália Produtos Químicos e Farmacěuticos Ltda, Itapira, Brazil.
Mytadon, Cristália Produtos Químicos e Farmacěuticos Ltda, Itapira, Brazil.
Dimorf, Cristália Produtos Químicos e Farmacěuticos Ltda, Itapira, Brazil.
Nubain, Cristália Produtos Químicos e Farmacěuticos Ltda, Itapira, Brazil.
Tramadon, Cristália Produtos Químicos e Farmacěuticos Ltda, Itapira, Brazil.
Isofarma Indústria Farmacěutica Ltda, Eusébio, Brazil.
TEB, version 1.1, Tecnologia Eletrônica Brasileira Ltda, São Paulo, Brazil.
Xylestesin, Cristália Produtos Químicos e Farmacěuticos Ltda, Itapira, Brazil.
Safelet, Nipro Medical Ltda, São Paulo, Brazil.
Indústria Bic de Aparelhos Médicos Ltda, Itupeva, Brazil.
Cobas b 121, Roche, Basel, Switzerland.
IOPE, Instrumentos de Precisão Ltda, São Paulo, Brazil.
GraphPad PRISM, version 5, GraphPad Software Inc, La Jolla, Calif.
MedCalc, version 14.12.0, MedCalc Software bvba, Ostend, Belgium.
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Appendix
Scale used to score sedation of 8 healthy Beagles after IM injection of dexmedetomidine alone or in combination with an opioid.
| Variable | Score | Description |
|---|---|---|
| Posture | 0 | Normal; standing |
| 1 | Sternal recumbency | |
| 2 | Alternating standing and sternal and lateral recumbencies | |
| 3 | Lateral recumbency | |
| Palpebral reflex | 0 | Normal |
| 1 | Slightly reduced | |
| 2 | Moderately reduced | |
| 3 | Very slow or absent | |
| Position of the eye | 0 | Centered |
| 1 | Slightly rotated | |
| 2 | Rotated | |
| Relaxation of the jaws and tongue | 0 | No relaxation |
| 1 | Slight relaxation of the jaw; tongue remains in mouth | |
| 2 | Moderate relaxation of the jaw; tongue easily protracted | |
| 3 | Profound relaxation of the jaw; tongue remains outside the mouth spontaneously or when protracted | |
| Response to sound (hand clap) | 0 | Attention to or alarmed by clap |
| 1 | Attention to but not alarmed by clap | |
| 2 | Reduced attention to but not alarmed by clap | |
| 3 | No attention to clap | |
| Resistance to lateral recumbency | 0 | Refuses to be positioned in recumbency |
| 1 | Moderate resistance | |
| 2 | Mild resistance | |
| 3 | No resistance or spontaneous lateral recumbency | |
| General appearance | 0 | Complete interaction with environment and researchers |
| 1 | Moderate interaction with environment and researchers | |
| 2 | Poor interaction with environment and researchers | |
| 3 | No interaction with environment and researchers |
(Adapted from Kuusela E, Raekallio M, Antilla M, et al. Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs. J Vet Pharmacol Ther 2000;23:15–20. Reprinted with permission.)
