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The Canadian Veterinary Journal logoLink to The Canadian Veterinary Journal
. 2014 Sep;55(9):875–885.

Effects of acepromazine or methadone on midazolam-induced behavioral reactions in dogs

Bradley T Simon 1,✉, Elizabeth M Scallan 1, Carlo Siracusa 1, Amy Henderson 1, Meg M Sleeper 1, M Paula Larenza Menzies 1
PMCID: PMC4137930  PMID: 25183896

Abstract

This study evaluated whether acepromazine or methadone reduced behavioral parameters, overall excitement, and activity associated with midazolam administration to healthy dogs. Dogs received midazolam (M) alone [M: 0.25 mg/kg body weight (BW)] or with methadone (MM) (MM: 0.75 mg/kg BW) or acepromazine (MA) (MA: 0.03 mg/kg BW) or saline (S) solution alone, all intramuscularly. Two blinded observers evaluated behavioral parameters using video recordings 30 min before and after injection of drugs. Accelerometery was used to evaluate “total activity counts” (TAC) at baseline and post-treatment. Post-treatment excitement scores were significantly higher in M and MA compared to baseline, M and MM compared to S, and M compared to MA. Behavioral parameters showed significantly higher proportions of “pacing” post-treatment in all groups receiving midazolam, and “restlessness,” “chewing/licking,” and “sniffing” in M. No significant differences were found for TAC at baseline and post-treatment. Midazolam-induced paradoxical behavioral changes (excitation, panting, pacing, restlessness, licking/chewing, and vocalization) were not prevented by acepromazine or methadone in healthy dogs.

Introduction

Midazolam, a benzodiazepine, is commonly used as a pre-anesthetic agent to provide sedation and muscle relaxation in dogs (1,2). Some anesthetists prefer the use of this agent with an opioid or other pre-medication agent because it does not cause significant cardiorespiratory changes, prevents seizure activity, and is well-absorbed after intramuscular injection (3,4). Despite its attractive features, veterinary anesthesia textbooks and reviews suggest that the clinical use of midazolam as a sedative agent in dogs should be restricted to the very young, the old, the debilitated, and the emergent patient (3–7). These restrictions are recommended because there is a risk of eliciting paradoxical behavioral reactions when midazolam is administered to healthy young adult or mature adult dogs (8,9–11). These paradoxical behavioral reactions include: agitation, excitation, hyper-responsiveness to noise, restlessness, change in handling behavior, aggression, ataxia, increased appetite, drooling, licking, chewing, vocalization, and nosing (9,11,12). It has been suggested that the paradoxical behavioral reactions may be associated with “disinhibitory” effects of benzodiazepines on suppressed behavior or an excitement phase due to muscle weakness ataxia (9,13).

Dogs that develop excitement during the premedication period may not cooperate with handling and catheterization and may require higher doses of injectable anesthetics to induce anesthesia (10). However, it has been proposed that association of benzodiazepines with other agents that have sedative properties may decrease the incidence of such undesired behaviors (11). For this reason midazolam is rarely administered alone as premedication and in the authors’ clinical experience, the administration of midazolam occurs mostly in combination with other premedications, such as opioids. No studies have evaluated how the paradoxical reactions created by benzodiazpines can be affected by combining other classes of sedatives such as opioids or phenothiazines. Therefore the aim of the present study was to assess whether the co-administration of an opioid (methadone) or phenothiazine (acepromazine) would attenuate the incidence of excitement associated with a clinically used dose of midazolam administered to healthy, young adult dogs.

Materials and methods

Study design and animals

The study was designed as a prospective, randomized, controlled, crossover, blinded trial and was approved by the University of Pennsylvania Animal Care and Use Committee. Dogs were raised under National Institutes of Health and US Department of Agriculture guidelines for the care and use of animals in research.

Five 1- to 3-year-old research-bred female retriever cross dogs, weighing between 21 and 25 kg were recruited. Animals were considered healthy on the basis of physical examination and complete blood (cell) count (CBC) and chemistry values. All dogs remained on their normal feeding schedule and were fed once daily post-treatment. Room temperature and humidity were maintained between 22°C to 23°C and 16% to 17%, respectively. All experimental procedures took place in the month of February, during the hours of 13:00 to 15:00.

Experimental procedure

During the experimental evaluation all subjects were placed in a quiet confined kennel located within the same facilities and similar to the one in which the subjects were normally housed. A retractable dog gate was used to separate the kennel into 2 areas: the dogs were placed in the larger area (2.3 m2) and the video recording equipment was kept in the smaller area during the experiments (Figure 1). The video camera (JVC Everio Camcorder; JVC USA, Wayne, New Jersey, USA) was placed on a tripod outside the reach of the subjects to record their behavior during the experiment.

Figure 1.

Figure 1

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A — Schematic drawing depicting the study kennel (1 — entrance; 2 — individual; 3 — barricade; 4 — video camera) used to evaluate behavioral parameters of the dogs in the study. B — Photograph of the view obtained from the video recording of a dog during the acclimation period prior to the recording of behavioral parameters.

An accelerometer (Actical Activity Monitor; Philips Respironics, Bend, Oregon, USA) (14–16) was placed on all subjects’ ventral neck with a collar. The accelerometer contains a piezoelectric device that is sensitive to omnidirectional movements and continuously measures movement frequency, intensity, and duration. With a change in velocity per unit time, the piezoelectric sensor generates a voltage that is converted to a numerical value. This value during movement is compared with a steady baseline value. The difference between this movement value and baseline value is used to create a raw activity value (RAV). The RAV per measurement period is defined as an epoch. The epoch in this case was set to 15-second increments and the RAV was then converted by computer software and reported as an “activity count” every 15 s during the evaluation.

Before each experiment, dogs were allowed a 15-minute acclimation period to their new environment and to the accelerometer. The acclimation period was based on a pilot study performed with 4 dogs to determine length of time to return to normal behavior and respiratory rates as examined in their usual habitat. This acclimation period was not analyzed for the experiment. To obtain behavioral parameters, each subject was left unattended without disruption within the confinement of the kennel for 30 min before treatment (baseline evaluation period) under video surveillance. This baseline evaluation segment was then sectioned and divided into two 2-minute segments corresponding to the 10 to 12 and 20 to 22 minutes baseline evaluation period (pre10 and pre20, respectively). These 2 clips were the only segments evaluated for behavioral analysis.

For each dog, the total activity count (TAC) was obtained using the accelerometer as previously described for the 30-minute period before drug administration. For every 30-minute evaluation period 120 epoch values were calculated. These 120 values were summed to determine the TAC for each period. The final TACs were analyzed for comparison.

After this sequence, dogs were allocated to receive 1 of the 4 treatments in a randomized manner using an Internet-based random number generator (Research Randomizer, http://www.randomizer.org/) with a 1-week washout period between treatments. Each subject was designated to receive 1 treatment/week totaling all 4 treatment groups over 4 wk. Treatments consisted of midazolam HCl (M) (Midazolam Hydrochloride 5 mg/mL; Hospira, Lake Forest, Illinois, USA), 0.25 mg/kg body weight (BW), IM; midazolam and methadone (MM) (Methadone Hydrochloride 10 mg/mL; Bioniche Pharm, Lake Forest, Illinois, USA), 0.25 mg/kg BW, IM, and 0.75 mg/kg BW, IM, respectively; midazolam and acepromazine maleate (MA) (Acepromazine Maleate 10 mg/mL; Phoenix Pharmaceuticals, St. Joseph, Missouri, USA), 0.25 mg/kg BW, IM, and 0.03 mg/kg BW, IM, respectively; physiologic saline (S) (Sodium Chloride 0.9%; Abbott, Abbott Park, Illinois, USA) solution, 0.125 mL/kg BW, IM. All drug dosages were determined based on the authors’ clinical experience in a university setting. In order to create an equal volume amongst all the treatment groups, physiologic saline solution was added to the syringes containing M, MM, and MA to a final volume of 0.125 mL/kg BW, IM. The goal was to avoid potential bias associated with discomfort in the dogs due to different intramuscular volumes. The 4 treatments were prepared immediately prior to injection and all syringes were visually inspected for signs of cloudiness or precipitation. All injections were administered into the lumbar epaxial muscles with a 22-gauge 1.5-inch needle.

Each subject was again left unattended without disruption in the same kennel for 32 min (post-treatment evaluation period). Three 2-minute segments corresponding to the 10 to 12, 20 to 22, and 30 to 32 min post-injection (pst10, pst20, and pst30, respectively) were additionally considered for behavioral analysis.

As described previously, the TAC was obtained for the 30-minute period after drug administration. These 120 values were summed to determine the TAC and analyzed for comparison.

Behavioral analysis

Video segments from all the subjects and treatments were assigned a random sequence number to preserve the blinding of the study. The evaluated video segments did not contain human interaction.

Two blinded observers (ES and MPLM), unaware of the time-period and treatment allocation, assessed each video using behavioral parameters associated with the administration of benzodiazepines and other anesthesia premedicant agents to dogs (9,17–19). Parameters analyzed, restlessness (inability to rest or remain still), pacing (walking back and forth and/or around the kennel), vocalization (barking, growling, howling, whining, and/or whimpering), chewing/licking (masticating or licking an object), panting (breathing rapidly in short gasps) and sniffing (inhaling a short, audible breath through the nose), were evaluated for each 2-minute segment as “yes” (presence of parameter) or “no” (absence of parameter) categories. If a subject expressed one of the above-mentioned parameters during the 2-minute segment it received a “yes,” regardless of frequency. After evaluating the single behavioral parameters, the observers were asked to rate the overall magnitude of the excitatory phenomena for each 2-minute segment using a 4-point numerical rating scale (0 — no excitation, 1 — slight excitation, 2 — moderate excitation, and 3 — severe excitation). This scale was a subjective assessment and the format of the numerical rating scale was adapted from individualized numerical rating scales used to assess pain in non-verbal children and dogs (20–21).

Statistical analysis

Data obtained from both observers were included in the analysis. Excitement scores obtained at the evaluated time points were compared among and within treatment groups using Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks, corrected for ties. Bonferroni multiple comparison tests were used to establish significance between post-treatment and baseline scores and among post-treatment scores at each evaluated time point. Chi-squared tests were used to compare post-treatment behavioral parameters with baseline values within each group, baseline behavioral categories among groups and post treatment behavioral categories of M, MM, and MA with S. Inter-rater agreement was evaluated with kappa coefficients. Kruskal-Wallis one-way ANOVA on ranks, corrected for ties were used to compare baseline and post-treatment TAC values among groups. Wilcoxon tests were used to analyze the baseline and post-treatment TAC values within groups using each dog as its own match. Statistical significance was set at P < 0.05. Numerical data are presented as median and (range) or inter-quantile ranges. Categorical data are presented as proportions (percentage). Commercial software packages were used for all analyses (NCSS 2007; Kaysville, Utah, USA; MedCalc Software, Mariakerke, Belgium).

Results

All dogs recovered well from the procedures and were returned to their kennels after completion of the experiments. Visual inspection of the syringes prior to injection did not show signs of cloudiness or precipitation. Video recordings of 2 subjects at time point Post30 given the MM and MA treatment were not evaluated due to technical problems (dogs not in video frame). Video recordings of 1 subject receiving treatment M were not evaluated due to deviations from the study protocol (change in stage of estrus). Therefore, a total of 93, 2-minute long videos were available for behavioral analysis. Median kappa coefficient showed very good agreement [0.87 (0.71–0.91)] between the 2 observers (22).

Baseline behavioral categories were not significantly different among groups (Figures 2–7; “restlessness,” P = 0.12; “pacing,” P = 0.61; “vocalization,” P = 0.59; “chewing/licking,” P = 0.78; “sniffing,” P = 0.11; “panting,” P = 0.62). Evaluation of behavioral parameters showed a significantly higher proportion of “restlessness,” “pacing,” “chewing/licking,” and “sniffing” events after test drug administration compared with baseline values and group S in dogs allocated to M (Figures 2, 3, 5, 6, respectively). Compared with baseline values and group S, dogs allocated to MM showed increased “pacing” and “vocalization” episodes after treatment (Figures 3 and 4, respectively). Group MM also showed increased “sniffing” episodes compared with baseline values after treatment (Figure 6). “Panting” episodes were increased after treatment in groups M and MM compared with group S (Figure 7). Dogs allocated to MA showed increased “pacing” episodes when compared to baseline values and group S after treatment (Figure 3).

Figure 2.

Figure 2

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Proportion of restlessness manifestations (in percentage) that were present (black bars) or absent (white bars), observed by 2 blinded investigators from the evaluation of 2-minute long videos of dogs receiving midazolam (A; group M; n = 4), midazolam and methadone (B; group MM; n = 5), midazolam and acepromazine (C; group MA; n = 5), and saline (D; group S; n = 5), all IM, obtained 20 and 10 min prior (Pre10 and Pre20, respectively) and 10, 20, and 30 min after (Pst10, Pst20, and Pst30, respectively) drug administration. a, b, and * — significantly different (i.e., P < 0.05) from values obtained at Pre10 and Pre20 within treatment group and with group S at the evaluated time point, respectively, by means of Chi-squared tests.

Figure 7.

Figure 7

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Proportion of panting events (in percentage) that were present (black bars) or absent (white bars) observed by 2 blinded investigators from the evaluation of 2-minute long videos of dogs receiving midazolam (A; Group M; n = 4), midazolam and methadone (B; Group MM; n = 5), midazolam and acepromazine (C; Group MA; n = 5) and saline (D; Group S n = 5), all IM, obtained 20 and 10 min prior (Pre10 and Pre20, respectively) and 10, 20, and 30 min after (Pst10, Pst20, and Pst30, respectively) drug administration. * — significantly different (i.e., P < 0.05) from values obtained in group S at the evaluated time point by means of Chi-squared tests.

Figure 3.

Figure 3

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Proportion of pacing manifestations (in percentage) that were present (black bars) or absent (white bars), observed by 2 blinded investigators from the evaluation of 2-minute long videos of dogs receiving midazolam (A; group M; n = 4), midazolam and methadone (B; group MM; n = 5), midazolam and acepromazine (C; group MA; n = 5) and saline (D; group S; n = 5), all IM, obtained 20 and 10 min prior (Pre10 and Pre20, respectively) and 10, 20, and 30 min after (Pst10, Pst20, and Pst30, respectively) drug administration. a, b, and * — significantly different (i.e., P < 0.05) from values obtained at Pre10 and Pre20 within treatment group and with group S at the evaluated time point, respectively, by means of Chi-squared tests.

Figure 5.

Figure 5

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Proportion of chewing/licking events (in percentage) that were present (black bars) or absent (white bars) observed by 2 blinded investigators from the evaluation of 2-minute long videos of dogs receiving midazolam (A; group M; n = 4), midazolam and methadone (B; group MM; n = 5), midazolam and acepromazine (C; group MA; n = 5) and saline (D; group S; n = 5), all IM, obtained 20 and 10 min prior (Pre10 and Pre20, respectively) and 10, 20, and 30 min after (Pst10, Pst20, and Pst30, respectively) drug administration. a, b, and * — significantly different (i.e., P < 0.05) from values obtained at Pre10 and Pre20 within treatment group and with group S at the evaluated time point, respectively, by means of Chi-squared tests.

Figure 6.

Figure 6

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Proportion of sniffing manifestations (in percentage) that were present (black bars) or absent (white bars) observed by 2 blinded investigators from the evaluation of 2-minute long videos of dogs receiving midazolam (A; group M; n = 4), midazolam and methadone (B; group MM; n = 5), midazolam and acepromazine (C; group MA; n = 5) and saline (D; group S; n = 5), all IM, obtained 20 and 10 min prior (Pre10 and Pre20, respectively) and 10, 20, and 30 min after (Pst10, Pst20, and Pst30, respectively) drug administration. a, b, and * — significantly different (i.e., P < 0.05) from values obtained at Pre10 and Pre20 within treatment group and with group S at the evaluated time point, respectively, by means of Chi-squared tests.

Figure 4.

Figure 4

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Proportion of vocalization events (in percentage) that were present (black bars) or absent (white bars) observed by 2 blinded investigators from the evaluation of 2-minute long videos of dogs receiving midazolam (A; group M; n = 4), midazolam and methadone (B; group MM; n = 5), midazolam and acepromazine (C; group MA; n = 5) and saline (D; group S; n = 5), all IM, obtained 20 and 10 min prior (Pre10 and Pre20, respectively) and 10, 20, and 30 min after (Pst10, Pst20, and Pst30, respectively) drug administration. b and * — significantly different (i.e., P < 0.05) from values obtained at Pre20 within the same group and with group S at the evaluated time point, respectively, by means of Chi-squared tests.

Baseline excitement scores were not statistically different among groups (P = 0.14); however, post-injection scores were different among groups (P < 0.01). Figure 8 displays the excitement scores over time. Post-injection excitement scores were statistically different from pre-injection scores for groups M, MA and S (P = 0.03, P = 0.04, and P = 0.01, respectively) but not for group MM (P = 0.18). Excitement scores were increased after treatment for groups M and MM when compared to group S. Group M excitement scores were also increased after treatment when compared to group MA at similar time points.

Figure 8.

Figure 8

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Box-plots displaying the median or 50th percentile, the 25th percentile (lower box), the 75th percentile (upper box), the interquartile ranges (whiskers) and outliers (circles) of excitation scores (0 — no excitement to 3 — severe excitement) over time (Pre10 and Pre20, 10 and 20 min after commencing experiments, respectively; Pst10, Pst20, and Pst30, 10, 20, and 30 min after treatment, respectively) of dogs (n = 5) receiving midazolam 0.25 mg/kg (A — group M), midazolam 0.25 mg/kg BW together with methadone 0.75 mg/kg BW (B — group MM), midazolam 0.25 mg/kg BW together with acepromazine 0.03 mg/kg BW (C — group MA) and saline 0.125 mL/kg BW (D — group S); all IM. * — significantly different (i.e., P < 0.025) from values obtained at Pre10 and Pre20 (a and b, respectively) within the same group and from values obtained in groups MA and S (# and *, respectively) at the evaluated time point, by means of Kruskal-Wallis one-way ANOVA on ranks tests and Bonferroni corrections.

No significant differences were found for baseline and post-treatment TAC among groups (P = 0.45 and 0.28, respectively) and within groups (Table 1).

Table 1.

Total activity count (TAC) obtained from female dogs before (baseline) and after (post-treatment) intramuscular administration of midazolam, either alone (M) or associated with acepromazine (MA) or, methadone (MM), and saline (S). P-values obtained by means of Wilcoxon tests

TAC
Group n Baseline Post-treatment P
M 4 1492 (278–2695) 10435 (1604–29 558) 0.14
MA 5 1079 (489–2183) 6086 (772–15 605) 0.08
MM 5 758 (31–2186) 4775 (1191–11 712) 0.08
S 5 3494 (412–6886) 1175 (580–8404) 0.89
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Discussion

Similar to previous reports (9–11), the findings herein indicate that the intramuscular administration of clinically used doses of midazolam (i.e., 0.25 mg/kg BW) is associated with excitement in dogs. Excitement was attenuated by the co-administration of acepromazine; however, acepromazine and methadone failed to reduce TAC. Specific behaviors associated with paradoxical reactions were still observed in all groups receiving midazolam.

Dogs receiving midazolam alone exhibited a significantly higher proportion of restlessness and pacing compared with pre-treatment and group S values, which probably contributed to the higher excitation scores observed 30 min after drug administration. This is in line with previous reports that both intramuscular and intravenous administration of 0.5 mg/kg BW of midazolam to healthy dogs resulted in agitation and hyper-responsiveness within 5 min after injection and lasted for 5 to 20 min (9). Excitation, excessive restlessness, enhanced alertness, anxiousness, and disruption of sleeping patterns have also been reported after the administration of other benzodiazepines (e.g., diazepam, oxazepam, flunitrazepam) to healthy dogs (12–13). Excitation was observed as well after the administration of mid-azolam to cats, humans, and horses (17,23,24). Interestingly, dogs in Group S had a significant decrease in excitation 30 min after injection compared with baseline values. At that time, some of the dogs were observed to lie down and rest. This is most likely due to the dog’s comfort level in the testing environment and to the lack of drugs inducing paradoxical behaviors.

In order to minimize excitation and enhance tranquilization, midazolam is often administered with sedatives or opioids in dogs (11,25,26), but in the present study acepromazine along with midazolam did not prevent the occurrence of pacing episodes and increases in excitement scores 20 min post-injection. However, there was a significant decrease in overall excitement 30 min after injection of the drug combination suggesting a delayed action of the tranquilizing effects of acepromazine. Nevertheless, dogs still had significantly more post-treatment pacing episodes compared with baseline and group S data.

Administration of midazolam with methadone did not result in significant changes to the excitement scores compared with pre-treatment values but the scores were significantly higher compared with group S 30 min after injection. Increases in pacing and vocalization were observed during the post-treatment period in the group receiving methadone. Methadone has also been associated with signs of excitement (i.e., anxiety and crying) in dogs (18).

All drug combinations were administered in the lumbar epaxial muscles to simulate a clinical premedication setting. Monteiro et al (18) showed that both acepromazine and methadone, at a dose of 0.1 mg/kg BW or 0.5 mg/kg BW, respectively, exhibited sedentary behavioral changes at 15 min after IM administration. A separate study showed 0.11 mg/kg BW acepromazine to have peak behavioral effects 15 to 20 min after IM injection (27). Similarly, midazolam appears to be rapidly and almost completely absorbed after IM administration to dogs, reaching peak plasma concentrations within 15 min that correlate with peak behavioral changes observed 18 to 20 min after its administration (9). Therefore, the potential tranquilizing effects of these 2 agents when combined with midazolam should have become apparent during our evaluation period.

Dogs in M also had a higher proportion of chewing/licking behaviors compared with baseline and group S values. Dogs in MM had more panting and sniffing events when compared to group S and baseline values, respectively. Benzodiazepines have been reported to increase appetite; however, there may be additional confounding factors which resulted in the increased chewing/licking after test drug administration (28). For example, nausea, altered salivary production, or a reaction to a noxious taste within the oral cavity may have been factors. Interestingly, mu-agonist opioids have also been reported to increase appetite and could have the potential for increasing food-seeking behaviors (29). Although phenothiazines (i.e., promazine) are also reported to increase appetite, midazolam in conjunction with acepromazine did not increase chewing or licking behaviors in rats (30). The authors can only speculate that these behaviors exhibited during the M and MM treatments were associated with changes in appetite.

Group S exhibited fewer panting events compared with groups M and MM, probably because dogs allocated to group S tended to rest during the post-injection period. On the other hand, panting may have been increased in M and MM as a consequence of the respiratory effects of methadone, and/or the excitation induced by midazolam (31). Group MA displayed no significant changes in panting. Acepromazine has been reported to reduce the incidence of panting (18).

In previous studies, the evaluation of the activity of dogs via accelerometry using an activity-count collar was reported to correlate with the movements evaluated by observing videographic recordings (15). However, in the current study the post-treatment data obtained from the evaluation of the dogs’ TAC via accelerometry was not significantly different from baseline values, despite the incidence of excitement or pacing observed in some groups. The low P values (i.e., P = 0.08 to 0.14) obtained after the comparison of baseline and post-treatment TAC values in all groups receiving midazolam suggest that a type II error may have occurred and a larger number of dogs (i.e., n = 10 to 15; power — 0.8, alpha — 0.05) would have been required to demonstrate a statistical significance in this parameter. Yam et al (32) reported that prolongation of the evaluation period improved accelerometer TAC reliability. On the other hand, the signs of excitement may not be equivalent to increases in TAC. Since the accelerometer was placed on the ventral neck attached to a collar, normal head movements may have acted as confounders. To alleviate these confounding factors the accelerometer could have been placed on the forearm, sternum, or lateral portion of the thorax. However, a study by Hansen et al (33) that evaluated 5 accelerometer locations in dogs wearing a custom housing vest showed agreement or only minor differences (2% to 4%) within every possible paired comparison between the 5 locations.

The dosage of midazolam may also correlate with unfavorable reactions. Doses of 0.5 mg/kg BW of midazolam have been associated with transient agitation followed by a period of quiescence in dogs (9). In the present study, a dose of 0.25 mg/kg BW was chosen, as it is commonly used in the clinical setting. Despite using a smaller dose, some behavioral changes were still observed. Similarly, the tested doses of acepromazine or methadone reflected the clinically used doses of these agents to premedicate dogs undergoing general anesthesia. It remains to be determined whether higher doses of each individual agent would provide more significant synergistic effects.

The health status and the age of the patient have also been associated with the incidence of paradoxical reactions in dogs after the administration of benzodiazepines. Although research trials are scarce, the use of benzodiazepines as sedative agents has been advocated in pediatric, geriatric, and systemically ill dogs, as the incidence of behavioral reactions seems to be diminished in these patients (5,6,34). For instance, a high dose of midazolam (i.e., 10 mg/kg BW) caused agitation in normovolemic dogs but induced unconsciousness or sleepiness in acutely hypovolemic dogs (35). Potentially, age and health status could also affect the synergistic effects of methadone or acepromazine. In the present study, only young adult healthy female dogs were included. Hence the results may not reflect the effects of midazolam and its association with acepromazine or methadone in geriatric or pediatric patients and/or in dogs with disease.

It is unclear whether the combination of midazolam with acepromazine or methadone in the same syringe affected the physicochemical property and effects of the drug. Combining all these agents in a syringe was adopted to emulate common daily practice. Likewise, other researchers have also combined midazolam with a variety of sedatives and opioids in the same syringe for IM injection in dogs (11,25–26). Visual inspection of the syringes and previous observations suggested that midazolam maintained its physicochemical stability after mixing with other water-soluble agents (e.g., morphine, haloperidol) in the same syringe (36).

A limitation of the study was that sedation could not be evaluated. Adequate evaluation of sedation implies interaction with the patient to assess the degree of unresponsiveness of the subject (11). Interaction with the dogs was disregarded in this study to avoid introducing additional confounding factors. A second potential limitation of the study was that during the experiment each subject was evaluated individually. Normally the dogs participating in this study were housed with a companion and this could potentially lead to stereotypical behavior not normally seen in their normal living quarters. However, dogs were typically separated from their kennel’s companion for short periods of time and, from the data obtained in the S group, it can be deduced that the observed behavioral changes were the result of the treatment-drug administration rather than a stereotypical behavior. The third limitation may include the subjects themselves. The dogs entering this study were research animals and different responses may be expected from client-owned dogs. As previously mentioned one of the theories for observed paradoxical behavioral reactions is that benzodiazepines are associated with “disinhibitory” effects on suppressed behavior (9). The research subjects in this study had limited exposure to human training; therefore, little suppressed behavior is available to disinhibit. As a result a lack of dramatic change is seen from their normal behavior to paradoxical behavior. In the clinical situation, client-owned animals are commonly trained and undergo behavior modifications for a domestic lifestyle. This can result in a larger change from normal behavior to paradoxical behavior with standard premedication dosages.

The lack of validated methods to evaluate specific behaviors in dogs can be challenging when designing studies to analyze drug-induced excitatory phenomena in dogs. In the present study, the observers subjectively allocated a numerical-rating-scale score to the overall excitement phenomenon observed for the evaluated 2-minute long video segment. Thus, the allocation was performed after the evaluation of the single behavioral parameters (i.e., restlessness, pacing, vocalization, chewing-licking, sniffing, and panting) and represents the subjective (i.e., observer-dependent) integration of that information. Although it was subjective, the scores provided by both observers were not statistically different, indicating a good inter-observer agreement. Numerical rating scales are commonly used to subjectively assess other parameters that are difficult to quantify such as pain in children and dogs (20–21).

Among other goals, an appropriate anesthesia pre-medication should aim to minimize excitement before induction of anesthesia in order to facilitate the handling of the patient and allow for a smooth induction (37). Based on the current findings, the use of midazolam as an anesthetic pre-medicant agent in healthy adult dogs seems disadvantageous because it was linked to an increase in excitation, pacing, restlessness, chewing, and licking behaviors. The addition of acepromazine or methadone to midazolam at doses reported here did not prevent some of these behavioral patterns nor reduce the TAC in the post-treatment period. Therefore, it seems that the use of midazolam, midazolam-acepromazine, or midazolam-methadone as anesthetic pre-medicant agents provides little clinical benefit in healthy adult dogs. Further studies are required to establish the clinical advantage of associating these agents in regards to their effects on patient handling for diagnostic procedures, catheter placement, and anesthesia induction.

Acknowledgments

The authors thank Drs. Margret Casal, Daniel Boruta, and Joaquin Araos. CVJ

Footnotes

Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office (hbroughton@cvma-acmv.org) for additional copies or permission to use this material elsewhere.

The dogs used in this study were supported by the National Institutes of Health (NIH; RR02512). Other support came from a Departmental Research Grant, provided by the University of Pennsylvania, Department of Clinical Studies — Philadelphia.

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