Acepromazine is a commonly used sedative in dogs.1 It is a phenothiazine sedative with α1-receptor antagonist properties that can cause hypotension.2 Nonetheless, the reliable sedation, inexpensive cost, and long duration of action of acepromazine make it an effective and valuable medication for use prior to anesthesia in dogs.1 Hydromorphone is an opioid approximately 8 times as potent as morphine that is used as an analgesic in dogs.1 Hydromorphone has minimal adverse effects, is relatively inexpensive, and has a duration of action that makes it clinically useful.1 The combination of acepromazine and opioids such as hydromorphone can result in superior sedation, compared with that achieved by administration of either drug alone.3
The sedative effects of acepromazine and hydromorphone have been investigated in a variety of ways.
In 1 study3 hydromorphone alone and the combination of acepromazine and hydromorphone were evaluated, but acepromazine alone was not evaluated and there was not a negative control group. In another sedation study4 acepromazine was used as a positive control treatment but was not combined with an opioid. In a recent study5 acepromazine, methadone, and the acepromazine-methadone combination were evaluated and a negative control treatment was included. However, that study did not reveal a significant sedative effect of acepromazine or methadone alone, which is in contrast with the authors' clinical experience and with results reported in other studies.3,4 The lack of sedation in that study5 may have been attributable to the low sample size or to the scoring technique, which involved use of a categorical system (grades 0 to 3). A scoring technique that involves use of a continuous measurement may be superior to a categorical system, which would allow detection of more subtle degrees of sedation. An evaluation of the effects of each drug alone and in combination is important to detect synergistic effects of sedation for the 2 drugs. Furthermore, inclusion of a negative control treatment is needed to rule out a maturation internal validity threat, which can result with sedation scoring.4,6,7 A prospective power analysis is necessary to ensure that the likelihood of committing a type II error is minimized.
Therefore, the purpose of the study reported here was to determine the sedative effects of acepromazine, hydromorphone, and the combination of acepromazine-hydromorphone in experiments that included a negative control treatment and appropriate sample size. A secondary objective was to compare a descriptive and a simple sedation scoring technique. The hypotheses were that administration of the acepromazine-hydromorphone combination would induce greater sedation than would be achieved by administration of either drug alone and that there would be no difference between the 2 scoring techniques.
Materials and Methods
Animals—Forty-six random-source female dogs that were being anesthetized for a surgical exercises laboratory for third-year veterinary students were used in the study Animal husbandry was provided in accordance with established institutional guidelines, and the protocol for the study reported here was approved by the University of Georgia Animal Care and Use Committee.
Any dog deemed unhealthy on the basis of results of physical examination or with an abnormal PCV (< 34% or > 55%) or total protein concentration (< 6.2 g/dL or > 7.8 g/dL) was excluded. Body condition score was assessed by use of a method described elsewhere.8 Body weight and sex were also recorded. Age was not recorded because a definitive age could not be established on most dogs; however, all dogs were estimated to be < 4 years of age. Food was not withheld and was available to the dogs throughout the day.
Treatments—Dogs were randomly assigned by lottery to 1 of 4 treatment groups. Dogs received acepromazinea (0.5 mg/kg [0.23 mg/lb]), hydromorphoneb (0.1 mg/kg [0.045 mg/lb]), acepromazine-hydromorphone (0.5 mg/kg and 0.1 mg/kg, respectively), or saline (0.9% NaCl) solution (0.05 mL/kg [0.023 mg/lb]). All treatments were administered IM in the caudal epaxial muscles by a trained person; the person administering the treatments did not perform sedation scoring. All dogs were administered premedications between 5 pm and 7 pm. Time of medication administration was recorded and designated as time 0. Any adverse reactions were recorded. The study was conducted over a 30-day period.
Sedation scoring—Dogs were acclimated to the presence of the observer for approximately 20 minutes before treatments were administered. Dogs were housed separately for at least 12 hours before initiation of the study and also during sedation scoring. During data collection, dogs were allowed to roam freely in their cages.
Sedation scores were obtained at 0, 15, 30, 45, and 60 minutes. One investigator (EHH), who was not aware of the treatment administered to each dog, performed all sedation scoring. A simple NRS (scale of 0 to 10, with 0 = no sedation and 10 = maximum possible sedation), with the observer able to make marks at each whole number, was obtained by visual examination. This was a subjective technique that used an ordinal, rather than an interval, scaling method such that any whole number (including 0 and 10) could be chosen. The NRS was recorded prior to sedation scoring by use of the SSS.
Sedation scores were assigned by use of an SSS technique described elsewhere,3,4 with slight modifications (Appendix). For sedation scoring by use of the SSS, each dog was initially visually examined from outside its cage. The investigator then entered the cage to allow interactive behaviors and restraint to be evaluated. The response to noise was then evaluated while the observer was still in the cage with the dog. The scoring procedure was performed in the exact same order for all dogs and required approximately the same amount of time for each dog.
Statistical analysis—A power calculation conducted on the basis of information reported elsewhere3 revealed that 11 dogs were required (α of 0.05 and β of 0.20) to detect a 3-point difference in sedation score among treatments. An additional dog was recruited for the acepromazine and acepromazine-hydromorphone groups to increase power for comparisons involving those treatments. Therefore, there were 12 dogs in the acepromazine and acepromazine-hydromorphone groups and 11 dogs in the hydromorphone and saline solution groups.
Normality was determined by use of the Kolmogorov-Smirnov test. For data that were normally distributed, a 1-way ANOVA was performed to compare groups at each time point and a repeated-measures ANOVA was used to evaluate within-treatment changes over time. Post hoc analysis was performed by use of the Tukey multiple comparison test. For nonparametric data, a Kruskal-Wallis test was used. To test the relationship between SSS and NRS, linear regression analysis was performed. Significance was set at values of P < 0.05. The person performing the statistical analysis remained unaware of treatment group assignment for all dogs until all analyses were completed.
Results
Mean ± SD body weight was 17.6 ± 7.6 kg (38.72 ± 16.72 lb), and dogs in the saline solution group weighed significantly more than did dogs in the hydromorphone group. However, body condition score did not differ significantly among the treatment groups. In addition, time of premedication administration did not differ significantly among the treatment groups.
The SSS and NRS scores were summarized (Figures 1 and 2). Comparison of SSS and NRS scores for all time points and all treatment groups revealed a significant correlation (r2 = 0.72; P < 0.001). There was a poor correlation at time 0 (r2 = 0.21), but there was a good correlation at all other time points (15 minutes, r2 = 0.73; 30 minutes, r2 = 0.68; 45 minutes, r2 = 0.74; and 60 minutes, r2 = 0.62).
Mean ± SD score for an SSS in 12 dogs given acepromazine (0.5 mg/kg [0.23 mg/lb]; Ace), 11 dogs given hydromorphone (0.1 mg/kg [0.045 mg/lb]; Hydro), 12 dogs given acepromazine-hydromorphone (0.5 mg/kg and 0.1 mg/kg, respectively; Ace-Hydro), or 11 dogs given saline (0.9% NaCI) solution (0.05 mL/kg [0.023 mL/lb]; Sal) via IM injection. Sedation was scored at 0 (time of administration [diagonal-striped bars]), 15 (white bars), 30 (gray bars), 45 (black bars), and 60 (horizontal-striped bars) minutes. *Within a treatment group, value differs significantly (P < 0.05) from the value for time 0. † Within a time point, value differs significantly (P < 0.05) from the value for the saline solution group. ‡ Within a time point, value differs significantly (P < 0.05) from the value for the hydromorphone group.
Citation: Journal of the American Veterinary Medical Association 237, 10; 10.2460/javma.237.10.1155
Mean ± SD score for an SSS in 12 dogs given acepromazine (0.5 mg/kg [0.23 mg/lb]; Ace), 11 dogs given hydromorphone (0.1 mg/kg [0.045 mg/lb]; Hydro), 12 dogs given acepromazine-hydromorphone (0.5 mg/kg and 0.1 mg/kg, respectively; Ace-Hydro), or 11 dogs given saline (0.9% NaCI) solution (0.05 mL/kg [0.023 mL/lb]; Sal) via IM injection. Sedation was scored at 0 (time of administration [diagonal-striped bars]), 15 (white bars), 30 (gray bars), 45 (black bars), and 60 (horizontal-striped bars) minutes. *Within a treatment group, value differs significantly (P < 0.05) from the value for time 0. † Within a time point, value differs significantly (P < 0.05) from the value for the saline solution group. ‡ Within a time point, value differs significantly (P < 0.05) from the value for the hydromorphone group.
Citation: Journal of the American Veterinary Medical Association 237, 10; 10.2460/javma.237.10.1155
Mean ± SD score for an SSS in 12 dogs given acepromazine (0.5 mg/kg [0.23 mg/lb]; Ace), 11 dogs given hydromorphone (0.1 mg/kg [0.045 mg/lb]; Hydro), 12 dogs given acepromazine-hydromorphone (0.5 mg/kg and 0.1 mg/kg, respectively; Ace-Hydro), or 11 dogs given saline (0.9% NaCI) solution (0.05 mL/kg [0.023 mL/lb]; Sal) via IM injection. Sedation was scored at 0 (time of administration [diagonal-striped bars]), 15 (white bars), 30 (gray bars), 45 (black bars), and 60 (horizontal-striped bars) minutes. *Within a treatment group, value differs significantly (P < 0.05) from the value for time 0. † Within a time point, value differs significantly (P < 0.05) from the value for the saline solution group. ‡ Within a time point, value differs significantly (P < 0.05) from the value for the hydromorphone group.
Citation: Journal of the American Veterinary Medical Association 237, 10; 10.2460/javma.237.10.1155
Mean ± SD score for an NRS in 12 dogs given acepromazine, 11 dogs given hydromorphone, 12 dogs given acepromazine-hydromorphone, or 11 dogs given saline solution via IM injection. § Within a treatment, value differs significantly (P < 0.05) from the value for 15 minutes. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 237, 10; 10.2460/javma.237.10.1155
Mean ± SD score for an NRS in 12 dogs given acepromazine, 11 dogs given hydromorphone, 12 dogs given acepromazine-hydromorphone, or 11 dogs given saline solution via IM injection. § Within a treatment, value differs significantly (P < 0.05) from the value for 15 minutes. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 237, 10; 10.2460/javma.237.10.1155
Mean ± SD score for an NRS in 12 dogs given acepromazine, 11 dogs given hydromorphone, 12 dogs given acepromazine-hydromorphone, or 11 dogs given saline solution via IM injection. § Within a treatment, value differs significantly (P < 0.05) from the value for 15 minutes. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 237, 10; 10.2460/javma.237.10.1155
In the hydromorphone group, 1 dog vomited, 1 dog defecated, and 2 dogs both vomited and defecated. In the acepromazine-hydromorphone group, 2 dogs vomited. Overall, 5 of 23 (22%) dogs receiving hydromorphone (alone or in combination with acepromazine) vomited. There were no adverse reactions detected in the acepromazine or saline solution groups.
Discussion
As expected, dogs in the acepromazine and acepromazine-hydromorphone groups had significantly higher SSS scores at all time points, compared with SSS scores for the saline solution group. Sedation scores obtained by use of the NRS were less predictable because dogs in the acepromazine group had NRS scores that were not significantly different from those of dogs in the saline solution group at 15 and 45 minutes, although NRS scores differed significantly between acepromazine and saline solution groups at 30 and 60 minutes. At 30, 45, and 60 minutes, use of the NRS revealed a significant difference between the acepromazine-hydromorphone and hydromorphone groups, which was only detected by use of the SSS at 30 minutes. However, dogs in the hydromorphone group did not have sedation scores that differed significantly from those of dogs in the saline solution group (as assessed by use of either technique), which suggested that hydromorphone does not induce any sedation detectable with the NRS or SSS.
Acepromazine alone can cause sedation at 10 minutes after administration in dogs,4 which is consistent with the score obtained by use of the SSS. The mechanism of action for sedation with acepromazine is suspected to be attributable to modulation of dopamine within the CNS.2 The sedation induced by acepromazine is maintained for 4 to 6 hours after injection.2 When combined with an opioid, acepromazine causes sedation in < 5 minutes.3 Neuroleptanalgesia, induced by the combination of acepromazine and an opioid, supposedly results in greater sedation than does acepromazine alone,1 although evidence for this finding is lacking. In the study reported here, the combination of acepromazine and hydromorphone did not result in significantly greater sedation than did acepromazine alone, which suggested that at the doses used, the synergistic effects of acepromazine and hydromorphone were not evident.
Hydromorphone causes sedation as a result of agonist activity at μ-opioid receptors. Sedation can be evident within 5.4 minutes3 and lasts at least 120 minutes.9 However, the results from the present study indicated that the sedative effects of hydromorphone were not significantly different from those for saline solution. In the study3 in which investigators detected sedation after administration of hydromorphone, the dose was more than twice the dose we used in the study reported here. Also, the technique for scoring used in that study3 included a value for analgesia (which was not included in the present study) because of the fact that 2 of the groups in that study did not receive any analgesics and therefore subjecting them to painful conditions would have been unacceptable. This additional value for analgesia or the higher dose used in that previous study3 may explain the difference detected between hydromorphone and acepromazine-hydromorphone in the present study in which the combination of acepromazine-hydromorphone resulted in significantly greater sedation than did hydromorphone alone. Our results concur with the findings for that study3 which indicates that effects for the combination of acepromazine-hydromorphone are superior to the effects for hydromorphone alone but not to the effects for acepromazine alone.
As expected on the basis of results from other reports,4,6,7 there were significant increases in the SSS and NRS over time in all groups, including the saline solution group. This suggests that there is acclimation to the observer and procedures over time. This is similar to a maturation internal threat in which the observed subject changes over time despite any effect of the experiment. Investigators can control for a maturation threat by including a control group, and it is therefore recommended that any sedation scoring experiment include such a group.
Although there were differences in results obtained by use of the SSS and the NRS, there was good correlation between the 2 techniques at all time points, except at time 0. This lack of correlation at time 0 most likely represented the fact that the SSS accounted for excited animals, whereas the lowest value on the NRS was simply a score of 0 for no sedation. An NRS ranging from −10 (maximum possible excitement) to 10 (maximum possible sedation) may eliminate this difference between the 2 techniques. However, despite this lack of correlation at time 0, both techniques did not detect significant differences among treatment groups at time 0. Use of the SSS yielded more consistent results, but use of the NRS enabled investigators to detect a difference between the acepromazine-hydromorphone and hydromorphone groups at later time points than were detected by use of the SSS. The inability for use of the NRS to detect a difference between the acepromazine and saline solution groups at 15 and 45 minutes represented a potentially major shortcoming for this method. A sedation scoring method should be able, at the minimum, to delineate between negative and positive control treatments.
Five of 23 (22%) dogs receiving hydromorphone vomited, whereas 23 dogs that did not receive hydromorphone did not vomit. Opioids can cause emesis in dogs as a result of stimulation of the chemoreceptor trigger zone.10 The proportion of dogs that vomited in the present study is less than that reported in another study10 which may have been attributable to different patient populations (random-source dogs vs client-owned dogs). Two dogs receiving hydromorphone defecated, which can be attributed to duodenal contraction induced by stimulation of μ-opioid receptors.11 Dysphoria or other adverse effects were not detected, which indicated that these are infrequent adverse effects for these protocols in dogs.
Acepromazine and acepromazine-hydromorphone, but not hydromorphone alone, induced significantly greater sedation than did saline solution. The SSS yielded consistent, reliable measures of sedation in this sample of dogs. The NRS yielded less-reliable measures of sedation. All dogs had significantly greater SSS and NRS scores over time, which indicated that a control group should be included in any study of sedation scoring.
ABBREVIATIONS
| NRS | Numeric rating scale |
| SSS | Subjective scoring system |
References
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Appendix
Description of an SSS used to determine the effects after IM administration of acepromazine, hydromorphone, or acepromazine-hydromorphone in dogs.
| Observation | Score | Description |
|---|---|---|
| Vocalization | 0 | Quiet |
| −1 | Whining softly but quiets with soothing touch | |
| −2 | Whining continuously | |
| −3 | Barking continuously | |
| Posture | 3 | Lateral recumbency |
| 2 | Sternal recumbency | |
| 1 | Sitting or ataxic while standing | |
| 0 | Standing | |
| −1 | Moving continuously | |
| Appearance | 3 | Eyes sunken, glazed, or unfocused; ventromedial rotation |
| 2 | Eyes glazed but follow movement | |
| 1 | Protrusion of nictitating membrane; normal visual responses | |
| 0 | Normal appearance | |
| −1 | Pupils dilated; abnormal facial expression | |
| Interactive behavior | 3 | Recumbent; no response to voice or touch |
| 2 | Recumbent; lifts head in response to voice or touch | |
| 1 | Recumbent but stands in response to voice or touch | |
| 0 | Standing or sitting up; normal response to voice or touch | |
| −1 | Moves away from voice or touch; appears anxious | |
| −2 | Growls or hisses when approached or touched | |
| −3 | Bites or swats when approached | |
| Restraint | 2 | Lies on floor with minimal restraint needed |
| 1 | Lies on floor with light restraint of head or neck | |
| 0 | Sits up on floor; attempts to jump despite restraint | |
| −1 | Struggles continuously against restraint | |
| −2 | Cannot be restrained for > 20 seconds | |
| Response to noise | 3 | No response to a hand clap near the head |
| 2 | Minimal response to a hand clap nearthe head | |
| 1 | Slow or moderate response to a hand clap near the head | |
| 0 | Brisk response to a hand clap near the head; raises head with eyes open |
