Evaluation of subcutaneous versus intravenous administration of apomorphine for induction of emesis in dogs

Christiana Fischer From the Department of Clinical Studies and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Kenneth J. Drobatz From the Department of Clinical Studies and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Vincent J. Thawley From the Department of Clinical Studies and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Abstract

OBJECTIVE

To prospectively compare the effectiveness and any adverse effects of apo-morphine administered SC or IV for induction of emesis in dogs.

ANIMALS

42 client-owned dogs.

PROCEDURES

Dogs for which emesis induction was deemed appropriate by the attending clinician were prospectively randomized to receive apomorphine (0.03 mg/kg [0.01 mg/lb]) either SC (n = 20) or IV (22). Data collected included whether emesis was successfully induced, time from drug administration to emesis, number of emetic events, and adverse events (eg, sedation, protracted vomiting, or other).

RESULTS

Of the 20 dogs given apomorphine SC, 16 (80%) vomited. Of the 22 dogs given apomorphine IV, 18 (82%) vomited. With regard to route of administration, the number of dogs in which emesis was induced did not differ significantly. Median time to the first emetic event was 13.5 minutes (range, 3 to 32 minutes) in the SC treatment group and 2 minutes (range, 1 to 5 minutes) in the IV treatment group; the difference was significant. There was no significant difference in the number of emetic events or frequency of adverse events between the 2 groups.

CONCLUSIONS AND CLINICAL RELEVANCE

Apomorphine administered SC or IV reliably induced emesis in dogs. Compared with SC administration of apomorphine, the time from drug administration to emesis associated with IV administration was significantly shorter, a finding that has clinical importance. (J Am Vet Med Assoc 2021;259:283–287)

Abstract

OBJECTIVE

To prospectively compare the effectiveness and any adverse effects of apo-morphine administered SC or IV for induction of emesis in dogs.

ANIMALS

42 client-owned dogs.

PROCEDURES

Dogs for which emesis induction was deemed appropriate by the attending clinician were prospectively randomized to receive apomorphine (0.03 mg/kg [0.01 mg/lb]) either SC (n = 20) or IV (22). Data collected included whether emesis was successfully induced, time from drug administration to emesis, number of emetic events, and adverse events (eg, sedation, protracted vomiting, or other).

RESULTS

Of the 20 dogs given apomorphine SC, 16 (80%) vomited. Of the 22 dogs given apomorphine IV, 18 (82%) vomited. With regard to route of administration, the number of dogs in which emesis was induced did not differ significantly. Median time to the first emetic event was 13.5 minutes (range, 3 to 32 minutes) in the SC treatment group and 2 minutes (range, 1 to 5 minutes) in the IV treatment group; the difference was significant. There was no significant difference in the number of emetic events or frequency of adverse events between the 2 groups.

CONCLUSIONS AND CLINICAL RELEVANCE

Apomorphine administered SC or IV reliably induced emesis in dogs. Compared with SC administration of apomorphine, the time from drug administration to emesis associated with IV administration was significantly shorter, a finding that has clinical importance. (J Am Vet Med Assoc 2021;259:283–287)

Introduction

A pomorphine is an opioid derivative used to induce emesis in dogs. The emetic effect of apo-morphine is a result of agonism of the dopaminergic receptors within the chemoreceptor trigger zone in the area postrema of the medulla, which triggers the vomiting reflex.1,2 Clinically, apomorphine is commonly used to induce emesis in dogs that have ingested toxicants or other foreign material.3,4 Adverse effects of apomorphine are uncommon but can include protracted vomiting, sedation, respiratory depression, hypotension, and tachyarrhythmias.2

Apomorphine can be administered by several routes (eg, IV, IM, and SC). Additionally, apomorphine tablets may be crushed and inserted into the conjunctival sac.2 The route of apomorphine administration selected may depend on clinician preference, availability of the injectable formulation or tablets, and patient demeanor (IV injection of the drug may be technically more challenging than other routes in fractious dogs or when limited staff is available for patient restraint). However, the route chosen may impact the effectiveness of emesis induction.1

Although IV administration of apomorphine rapidly and reliably induces emesis in dogs,3,5 the authors have observed that SC administration often results in successful induction of emesis. There is some experimental data regarding the effect of apomorphine administered by different routes,1 but to the authors' knowledge this has not been investigated in clinical patients. Thus, the purpose of the prospective study reported here was to evaluate the effectiveness and adverse effects of apomorphine administered either IV or SC for emesis induction in dogs for which induction of emesis was warranted. We hypothesized that apomorphine administration SC would be as effective as IV for induction of emesis. We also hypothesized that there would be no differences in the frequency and types of adverse events between routes of administration.

Materials and Methods

Dogs that were presented to the emergency service of the University of Pennsylvania's veterinary teaching hospital between December 2018 and March 2019 and for which emesis induction was deemed appropriate by the attending clinician were included in the study. Owner consent was not required because administration of apomorphine by an IV or SC route is a standard treatment.2 Dogs were excluded if emesis induction had been attempted elsewhere or if they had already vomited prior to enrollment in the study. The study protocol was approved by the university's animal care and use committee.

Dogs were randomly assigned to receive apomorphinea (0.03 mg/kg [0.01 mg/lb]) either IV or SC. This dose was within a range previously used in dogs.1,2,5 Randomization was performed in blocks of 10 by use of an online randomization plan.b Induction of emesis was defined as successful when a treated dog vomited at least once after apomorphine administration. If induction of emesis was not successful, a second dose of apomorphine could be administered. For repeated administrations, the dose and route of administration were determined by the attending clinician.

For each dog, data collected included signalment, type of material ingested, route of apomorphine administration, whether emesis occurred (success rate), time to first emetic event (minutes), frequency of repeated dose administration, and number of emetic events. For any dog that did not vomit after initial apomorphine administration and that was subsequently retreated, emesis was considered to have failed, and time to emesis was not included in the data analysis. Frequency and type of adverse events (including sedation and protracted vomiting [defined as > 3 emetic events over a > 10-minute period]) were recorded. Use of an antiemetic was at the discretion of the attending clinician. All data were recorded in an electronic spreadsheet program.c

Statistical analysis

A Shapiro-Wilk test was used to assess for normality of the continuous variables (age, time between drug administration and first emetic event, and number of emetic events). All these variables were not normally distributed; hence, those variables are reported as median (range). A rank sum test was used to compare these variables between treatment groups, and Spearman correlation was used to assess for correlations. A Fisher exact test was used to compare categorical variables. A commercially available statistical software program was used for analysis.d A value of P < 0.05 was considered significant.

Results

Forty-three dogs were initially enrolled in the study. One dog that was randomized to the IV treatment group was excluded from the data analysis because of a missing data sheet; data for 42 dogs were analyzed. Twenty dogs were allocated to the SC treatment group, and 22 dogs were allocated to the IV treatment group. Sixteen breeds were represented, including mixed-breed dog (20/42 [48%]), Dachshund (3/42 [7%]), Greyhound (3/42 [7%]), Shetland Sheepdog (2/42 [5%]), pit bull–type dog (2/42 [5%]), and 1 each of 12 other breeds. There were no signifi-cant differences between dogs that received apomorphine SC or IV with regard to breed (P = 0.19), sex (P = 0.38), or age (P = 0.57; Table 1).

Table 1

Summary of data for 20 dogs that were administered apomorphine (0.03 mg/kg) SC and 22 dogs that were administered the same dose of apomorphine IV to induce emesis.

Variable Route of administration P value
SC IV
No. of dogs Median (range) No. of dogs Median (range)
Age (y) 20 4.87 (0.4–10.6) 22 2.66 (0.25–10.25) 0.57
Age (y) 20 4.87 (0.4–10.6) 22 2.66 (0.25–10.25) 0.57
Time from drug administration to induction of emesis (min) 18 13.5 (3–32) 20 2.0 (1–5) < 0.001
No. of emetic events 18 2.0 (0–9) 20 3.0 (0–6) 0.91

Forty-three dogs were initially enrolled in the study. Data for 1 dog that was allocated to the IV treatment group were excluded from the data analysis because of a missing data sheet; data for 42 dogs were analyzed. Among the dogs in the SC treatment group, there were 9 males (of which 2 were sexually intact) and 11 females (of which 3 were sexually intact). Among the dogs in the IV treatment group, there were 11 males (of which 3 were sexually intact) and 11 females (of which none were sexually intact).

For each dog requiring apomorphine administration, the type of material ingested was determined and categorized into 1 of 3 groups: toxicant, fabric or clothing, or other. The most common reason for induction of emesis was toxicant ingestion (30/42 [71.4%]). Among the 42 dogs, 5 (11.9%) had ingested clothing or fabric and 6 (14.3%) had ingested something other than a toxicant, fabric, or clothing. The ingested item for 1 dog was not recorded. The category of item ingested (toxicant, fabric or clothing, or other) was not significantly different between the 2 treatment groups (P = 0.46).

Induction of emesis was successful in 16 of 20 (80%) dogs in the SC treatment group and 18 of 22 (82%) dogs in the IV treatment group. Overall, 8 (19%) dogs failed to vomit after apomorphine was administered either SC or IV. Those 8 dogs included the 1 dog for which the type of material ingested was not recorded; that dog received apomorphine IV and did not vomit. With regard to induction of emesis, the success rate did not differ significantly (P = 1.00) between the 2 treatment groups.

The time from drug administration to the first emetic event differed significantly (P < 0.001) between routes of administration. Dogs that received apomorphine SC took longer to vomit than dogs that received apomorphine IV (median time, 13.5 minutes [range, 3 to 32 minutes] and 2 minutes [range, 1 to 5 minutes], respectively). There was no difference in the number of emetic events following SC or IV administration of apomorphine (Table 1).

For dogs in both treatment groups, data were collected regarding attempts at repeated dose administration. Four dogs (2/20 [10%] dogs in the SC treatment group and 2/22 [9%] dogs in the IV treatment group) were given a second dose of apomorphine because they did not vomit following the initial dose. Three of those dogs had ingested toxicants, and 1 dog had ingested foreign material. Time to emesis was not recorded for these dogs because emesis was considered failed for the purposes of this study. Three of those 4 dogs received 0.03 mg of apomorphine/kg, IV; 1 dog received 0.02 mg of apomorphine/kg (0.009 mg/lb), IV. Two dogs that were initially administered apomorphine SC were treated a second time, one at 25 minutes and the other at 30 minutes after the initial drug administration. Two dogs that were initially administered apomorphine IV were treated a second time, one at 19 minutes and the other at 75 minutes after the initial drug administration. All 4 (100%) dogs vomited following a second dose of apomorphine.

The number and type of adverse events in dogs that received apomorphine SC or IV were evaluated (Table 2). There were no significant differences between the number of dogs in each treatment group with regard to sedation (P = 0.89), prolonged vomiting (P = 0.48), and other adverse events (P = 0.22). The 2 dogs with other adverse events were both allocated to the SC treatment group. After apomorphine administration, one dog developed trembling and the other had a suspected cutaneous hypersensitivity reaction; the latter was treated with an IM injection of diphenhydramine and recovered. No dogs had more than 1 adverse event.

Table 2

Summary of adverse events for dogs in Table 1 that received SC or IV administration of apomorphine for induction of emesis.

Adverse event Route of administration P value
SC (n = 20) IV (n = 22)
Sedation 7 6 0.89
Prolonged emesis 5 3 0.48
Other 2 0 0.22

No dogs had > 1 adverse event. Adverse events in the category of other were trembling and a suspected cutaneous hypersensitivity reaction.

Nine dogs in the SC treatment group and 12 dogs in the IV treatment group were administered an antiemetic after vomiting. Between the 2 treatment groups, use of an antiemetic did not differ significantly (P = 0.603). Of the 21 dogs that received an anti-emetic, 2 (9.5%) were administered metoclopramide and 19 (90.5%) were administered maropitant. Dosages and routes of administration of the antiemetics were not recorded. No dogs required administration of a sedation reversal agent.

Discussion

The results of the present study supported the hypothesis that SC administration of apomorphine would be as effective as IV administration of the drug for induction of emesis in dogs. However, compared with the response following IV administration, the time between drug administration and induction of emesis was longer for dogs that received apomorphine SC.

Among the 20 dogs that were administered apo-morphine SC, 16 (80%) vomited, whereas among the 22 dogs that were administered apomorphine IV, 18 (82%) vomited. The success rates were lower than those previously determined in studies3,6 that investigated the effectiveness of apomorphine. In 1 study,3 20 of 22 (91%) dogs vomited when apomorphine was administered into the conjunctival sac and 26 of 26 (100%) dogs vomited when apomorphine was administered IV.3 The mean dose of IV apomorphine administered in that study3 was 0.035 mg/kg (0.016 mg/lb [range, 0.026 to 0.054 mg/kg {0.01 to 0.02 mg/ lb}]). Although that mean dose of apomorphine was similar to the dose administered in the present study, it is possible that the higher dose range could have resulted in the comparatively higher success rates. Another study6 evaluated the use of apomorphine to induce emesis in dogs with gastric foreign bodies; among 495 dogs, 473 (95.6%) dogs vomited when they were administered 1 or 2 doses of apomorphine. In fact, most dogs in that study (457/495 dogs) vomited following a single IV dose of apomorphine (mean dose, 0.03 mg/kg).6 Zersen et al7 evaluated the use of 0.03 mg of apomorphine/kg (range, 0.02 to 0.05 mg/kg [0.009 to 0.023 mg/lb]) administered IV as a treatment for gastric foreign bodies in dogs. Induction of emesis was successful in 59 of 61 (97%) dogs, and 89% of the dogs in that study received 0.03 mg of apomorphine/kg, IV.7 In a pharmacokinetic study,1 all dogs that received apomorphine IV and SC vomited, whereas only 8 of 10 dogs vomited when the drug was administered IM. The reason for the difference in treatment effectiveness between the present study and the previously reported investigations is unclear but could be related to differences in patient population size and demographics, doses of apomorphine, material ingested,3 and the interval between ingestion and attempted induction of emesis.6

In the present study, the median time to emesis following apomorphine administration in the SC treatment group was 13.5 minutes, compared with a median time of 2 minutes in the IV treatment group. Other studies3,8 have found similar intervals between IV apomorphine administration and induction of emesis. After IV injection of apomorphine in 1 study,8 29 of 32 dogs vomited with a median elapsed time of 1 minute. Conversely, in another study,3 apomorphine was administered to dogs either IV or within the conjunctival sac, and the mean time from drug administration to onset of emesis was 18.6 minutes. Although that study3 failed to provide data about time to emesis for IV versus conjunctival administration of apomorphine, the mean interval to onset of emesis is longer than that achieved for either route of administration in the present study. After SC injection in dogs, peak plasma concentration of apomorphine is reached in approximately 25 minutes; after IV injection, mean peak plasma concentration of apomorphine is twice that achieved following SC administration of apomorphine.2 In the present study, the difference in time from drug administration to induction of emesis between the SC and IV treatment groups may be related to differences in the rate of drug absorption between the 2 routes of administration. In a pharmacokinetic study1 involving dogs, apomorphine administered SC had a bioavailability of 86%, whereas the assumed bioavailability when the drug was administered IV at the same dose was 100%. Results of that study also indicated that at a dose of 0.1 mg of apomorphine/ kg (0.045 mg/lb) IV or SC, the maximum plasma concentration of apomorphine was 60 and 30 ng/mL, respectively.1 In the present study, the same dose of apomorphine was administered by both routes of administration. It is possible that a higher dose of apo-morphine administered SC might have induced emesis more rapidly.

Four dogs in the present study were given a second dose of apomorphine following failure of the first dose to induce emesis. Three of those dogs had ingested toxicants, and 1 dog had ingested foreign material. The decision regarding administration of repeated doses of apomorphine was made by the attending clinician. That decision may have been influenced by apomorphine's mechanism of action or the object or material ingested. In cases wherein the likelihood of toxicosis or exposure to a toxicant was low, it was possible that the potential adverse effects associated with repeated doses of apomorphine outweighed the risks of unsuccessful decontamination. All of the 4 dogs that were treated twice with apomorphine (administered IV the second time) vomited. The use of repeated doses of apomorphine for induction of emesis is somewhat controversial. Apomorphine causes vomiting through agonism of the dopaminergic receptors in the chemoreceptor trigger zone, which is located outside of the blood-brain barrier; however, with repeated doses or after prolonged exposure, the drug can directly depress the medullary emetic center through stimulation of µ-opioid receptors.2 Results of 1 study3 indicate an increased risk of adverse events with repeated doses of apomorphine. For this reason, administration of repeated doses to dogs may not result in vomiting but could cause CNS depression or other adverse effects, such as lethargy, respiratory depression, and hypotension.2

In the present study, the success rate for induction of emesis was not significantly different between the 2 treatment groups when data were evaluated on the basis of the category of the ingested material. The most common materials ingested by the 42 dogs were toxicants, including chocolate (n = 8), grapes or raisins (7), rodenticide (6), and xylitol-containing products (2). Many of these toxicants have the potential to cause life-threatening complications, and rapid and successful decontamination is prudent. Data obtained during the present study indicated that apomorphine administered by either route reliably causes emesis; however, if the time from administration to vomiting is clinically important (ie, in cases of toxicant ingestion), the authors advise to administer the drug by the IV route, if possible. A previous study3 included only dogs that were exposed to toxicants, but data regarding the type of toxicant were not provided; thus, it is difficult to compare findings of that study with those of the present investigation. In the present study, dogs were enrolled from December 2018 through March 2019, which coincided with the holiday season as well as colder months in the greater Philadelphia area. This may explain why ingestion of toxicants such as chocolate, grapes or raisins, and rodenticides was the top reason for induction of emesis among the study dogs. The authors believe that seasonality may have had a role in the distribution of type of toxicants ingested by the study dogs. Reports of other studies6,7 evaluating the use of apomorphine for gastric foreign body recovery did include foreign body type. Five of the 42 (11.9%) dogs in the present study ingested fabric or clothing; that percentage of dogs was lower than the percentage of dogs that ingested fabric or clothing (137/495 [27.6%]) reported by Kirchofer et al.6 This difference was likely due to the sizes of the patient populations in the 2 studies. The present study also included dogs that ingested bathroom waste, popsicle sticks, duct tape, and dog toys, which have been successfully recovered by induction of emesis in previous investigations.6,7 To the authors' knowledge, the effectiveness of SC administration of apomorphine for induction of emesis in dogs, regardless of the type of item ingested, has not been previously evaluated; results of this evaluation have highlighted the usefulness of apomorphine administration when induction of emesis is warranted.

There was no difference in frequency or type of apomorphine-related adverse events between the 2 treatment groups. Although sedation was the most common adverse effect recorded (13/42 [30%] dogs), none of the dogs required sedation reversal. Naloxone may be used to reverse apomorphine-induced CNS or respiratory depression, but it is unlikely to reverse the emetic effects of apomorphine.1 Naloxone may in fact prolong or worsen the emetic effects through µ-opioid receptor inhibition.1 In the present study, 8 dogs were reported to have protracted vomiting following apomorphine administration. Each of these dogs, as well as 13 others, received an antiemetic (either maropitant or metoclopramide) selected by the attending clinician. Although these 2 drugs have different mechanisms of action, their effectiveness at preventing apomorphine-induced emesis is similar.9

Among the dogs that required an antiemetic in the present study, 90.5% were given maropitant and 9.5% were given metoclopramide. We did not limit the use or dosage of antiemetics in this study, but it is plausible that these drugs were routinely used because of their safety, ease of administration, and effectiveness at preventing emesis in addition to clinician preference. A similar finding was reported by Kirchofer et al7; in their study, 96 of 495 (19.4%) dogs were administered an antiemetic after apomorphine-induced emesis, and maropitant was the most frequently administered antiemetic (64/96 [66.7%] cases).

The present study had a few notable limitations. The patient population was small, which might have caused a type II error in the assessment that there was no difference in effectiveness of apomorphine given IV versus SC. However, given the significant difference in time from drug administration to the first emetic event between the 2 treatment groups noted at the time of interim data analysis, we elected to discontinue enrollment in the study. For any study dog, data regarding the time elapsed since the dog's last meal were not collected, and radiography to determine the amount of ingesta within the stomach was not routinely performed. These factors could have affected the time from drug administration to the first emetic event or even successful induction of emesis, especially if there was a small amount of food in the stomach or if the interval since the dog last ate was long. According to the Animal Poison Control Center of the American Society for the Prevention of Cruelty to Animals, it is typically recommended that dogs be offered a small meal prior to induction of emesis unless they have eaten in the preceding 2-hour period because induction of emesis is more likely to be successful when there is food present in the stomach.3 Also, information regarding the dogs' current medications was not obtained. In the study6 performed by Kirchofer et al, 11 of the 22 dogs that did not vomit after IV administration of apomorphine had received medications prior to an attempt at induction of emesis. In the present study, it was possible that dogs that received antiemetics as part of a routine medication plan at home may have failed to vomit with apomorphine administration. Another limitation of the study was that dogs were enrolled over a 4-month period during the winter season in an urban area, which may have had an effect on the types of toxicant exposure. It could be speculated that, had the study period been longer, there would have been more variability in the types of toxicants to which the dogs were exposed.

The results of the present study indicated that SC administration of 0.03 mg of apomorphine/kg is as effective at inducing emesis as IV administration of the same dose in dogs. The time from drug administration to induction of emesis was significantly longer when apomorphine was given SC, but there is no difference in frequency or type of adverse effects. On the basis of the study findings, an SC route of apomorphine administration could be considered when IV administration is not possible. However, an IV route of administration is recommended following ingestion of toxicants associated with rapid gastrointestinal absorption. Further investigation of different doses of apomorphine or comparison of SC and IV administration with IM administration of the drug for induction of emesis in dogs is warranted.

Acknowledgments

No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. Funding sources did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript. The authors declare that there were no conflicts of interest.

Presented in abstract form at the 25th International Veterinary Emergency and Critical Care Symposium, Washington, DC, 2019.

Footnotes

a.

Apomorphine HCl, purchased and compounded from Wedge-wood Pharmacy, Swedesboro, NJ.

b.

Randomization generator. Available at: www.randomization.com. Accessed Dec 11, 2018.

c.

Excel, Microsoft Corp, Redmond, Wash.

d.

Stata 14.0 for Mac, StataCorp, College Station, Tex.

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