Ropinirole has similar efficacy to apomorphine for induction of emesis and removal of foreign and toxic gastric material in dogs

Natalie A. Rosenstein Ocean State Veterinary Specialists, East Greenwich, RI

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Justine A. Johnson Ocean State Veterinary Specialists, East Greenwich, RI

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Kevin S. Kirchofer Ocean State Veterinary Specialists, East Greenwich, RI

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Abstract

OBJECTIVE

Assess efficacy of ropinirole versus apomorphine in inducing vomiting in dogs.

ANIMALS

279 client-owned dogs with known or suspected ingestion of a foreign material (n = 129) or toxin (150) between August 2021 and February 2022.

PROCEDURES

In this non-randomized non-controlled clinical trial, ropinirole topical ophthalmic solution was applied to dogs’ eyes, with a target dose of 3.75 mg/m2. A second dose was administered after 15 minutes based on clinician discretion. Reversal with metoclopramide was provided based on clinician discretion. Results of ropinirole’s efficacy were compared to previous literature assessing the efficacy of apomorphine.

RESULTS

Of 279 dogs, 255 (91.4%) vomited after ropinirole administration, including 116 of the 129 dogs (89.9%) dogs that ingested foreign material and 139 of the 150 dogs (92.7%) that ingested toxins. Success of emesis did not differ between groups. With a single dose of ropinirole, 78.9% produced vomit. Fifty-nine dogs received 2 doses of ropinirole, resulting in 79.7% that produced vomit. Overall, 74.2% of the dogs vomited all the expected ingested material. Average time to emesis was 11.0 minutes with 50% of dogs vomiting within 7 to 18 minutes. Adverse effects were observed for 17.0% of dog and were self-limiting. Ropinirole was less effective than apomorphine in inducing vomiting (91.4% ropinirole, 95.6% apomorphine [P < .0001]) and equally effective at evacuating all ingested material (74.2% ropinirole, 75.6% apomorphine [P = .245]).

CLINICAL RELEVANCE

Ropinirole ophthalmic solution is a safe and effective emetic for use in dogs. It has a small but statistically significant decrease in efficacy compared to IV apomorphine.

Abstract

OBJECTIVE

Assess efficacy of ropinirole versus apomorphine in inducing vomiting in dogs.

ANIMALS

279 client-owned dogs with known or suspected ingestion of a foreign material (n = 129) or toxin (150) between August 2021 and February 2022.

PROCEDURES

In this non-randomized non-controlled clinical trial, ropinirole topical ophthalmic solution was applied to dogs’ eyes, with a target dose of 3.75 mg/m2. A second dose was administered after 15 minutes based on clinician discretion. Reversal with metoclopramide was provided based on clinician discretion. Results of ropinirole’s efficacy were compared to previous literature assessing the efficacy of apomorphine.

RESULTS

Of 279 dogs, 255 (91.4%) vomited after ropinirole administration, including 116 of the 129 dogs (89.9%) dogs that ingested foreign material and 139 of the 150 dogs (92.7%) that ingested toxins. Success of emesis did not differ between groups. With a single dose of ropinirole, 78.9% produced vomit. Fifty-nine dogs received 2 doses of ropinirole, resulting in 79.7% that produced vomit. Overall, 74.2% of the dogs vomited all the expected ingested material. Average time to emesis was 11.0 minutes with 50% of dogs vomiting within 7 to 18 minutes. Adverse effects were observed for 17.0% of dog and were self-limiting. Ropinirole was less effective than apomorphine in inducing vomiting (91.4% ropinirole, 95.6% apomorphine [P < .0001]) and equally effective at evacuating all ingested material (74.2% ropinirole, 75.6% apomorphine [P = .245]).

CLINICAL RELEVANCE

Ropinirole ophthalmic solution is a safe and effective emetic for use in dogs. It has a small but statistically significant decrease in efficacy compared to IV apomorphine.

Introduction

One of the most common emergencies observed in veterinary medicine is ingestion of a foreign object or toxin. The first line of treatment is often to induce emesis. Vomiting is initiated by the emetic center in the brain stem. This area contains serotonergic (5HT1) receptors, adrenergic (α2) receptors and neurokinergic (NK1) receptors which may be stimulated to achieve emesis.1 These receptors are activated either directly or via neural pathways from the gastrointestinal tract, cerebral cortex, or vestibular system.

The emetic center may also be indirectly activated via the humoral pathways by way of the chemoreceptor trigger zone (CRTZ), which is located within the dorsal surface of the medulla oblongata, on the floor of the fourth ventricle of the brain.2 The CRTZ lacks a blood-brain barrier allowing it to receive stimulation from endogenous and exogenous stimuli circulating in the bloodstream. It contains the following receptors: dopaminergic (D2), histaminergic (H1), adrenergic (α2), Serotonergic (5HT3), Cholinergic (M1), Enkephalinergic (ENKµγ), and Neurokinergic (NK1). There are also opioid receptors present which is why opioid administration can lead to nausea or vomiting.1,3

There are multiple drugs used in veterinary medicine to activate many of these receptors and each come with their own efficacy and side effects. Apomorphine is one of the most common emetics used. It is a nonselective dopamine receptor agonist4 which stimulates receptors in the CRTZ.5 Apomorphine also crosses the blood-brain-barrier where it interacts with μ-receptors acting as an agonist leading to antiemetic activity but also potential sedation.6 Apomorphine is not licensed for animal use in the United States and is licensed only for parenteral administration in Europe.7

In 2020, the US Food and Drug Administration’s Center for Veterinary Medicine approved Clevor (ropinirole ophthalmic solution) for inducing emesis in dogs.8 Ropinirole is a full dopamine receptor agonist with high selectivity for the dopamine D2-like receptor family (D2, D3, D4) without dopamine (D1) receptor activity9 and without opioid receptor activity. Metoclopramide is the recommended antidote10 as it antagonizes D2 receptor sites which are the primary receptors in the CRTZ associated with emesis. Metoclopramide also has central antiemetic mechanisms as a weak inhibitor of serotonin 5-HT3 receptors and an agonist for serotonin 5-HT4 receptors.

Ropinirole is an ophthalmic solution contained in a single use ampule. The package contains a chart11 to determine the number of drops needed to obtain a target dose of 3.75mg/m2, with an acceptable dose range being 2.7 to 5.4 mg/m2. In a randomized, double-blind, clinical field study performed by Suokko et al,10 ropinirole was administered to induce vomiting in healthy, client-owned dogs that had recently ingested a meal. The study confirmed 95% efficacy in inducing vomiting within 30 minutes. It is described to have a rapid onset of action with short duration.

Advantages of ropinirole not only include it being the first emetic drug licensed for use in dogs, but it is also an ophthalmic drop. An ophthalmic drop is less technically challenging to administer which may make it a better product for traveling veterinarians or clinics with limited staff as minimal restraint is required. It can also be administered by a client in dogs that are aggressive with veterinary staff but manageable with the client.

To the authors’ knowledge there are no other studies for this drug on animals that have ingested toxins or foreign material, and no other studies which compare ropinirole to other common emetics. The purpose of this study was to determine ropinirole’s effectiveness in inducing emesis of toxins and foreign material. A second objective of this study was to compare the effectiveness of ropinirole to that of apomorphine using a previous study performed by Kirchofer et al12 as a historical comparison.

Materials and Methods

This was a nonrandomized, noncontrolled clinical trial utilizing client-owned dogs that presented to a 24-hour emergency and referral veterinary hospital after known or suspected ingestion of foreign material or toxin. Consent to induce emesis was obtained from all clients prior to the administration of ropinirole ophthalmic drops. Only animals that were clinically normal without overtly obvious abnormal clinical signs were included in the study. Dosing was administered based on weight to deliver a target dose of 3.75 mg/m2 using the manufacturer’s dosing chart.11 Dogs were then monitored for vomiting and development of clinical signs with specific instructions to monitor for ocular changes, sedation, and continued vomiting. If no emesis occurred or the ingested substance was not produced within 15 to 20 minutes, a second dose was administered per the primary clinician’s discretion. Waiting 20 minutes to give the second dose is the labeled instruction. Some clinicians chose to readminister a dose after only 15 minutes during a busy emergency shift, but this was considered acceptable based on personal communication with the manufacturer.

A form was completed by the technician and/or clinician which included patient name, weight, dose, which eye or eyes were treated, and how many drops were administered. The form also documented the type of material ingested, time of ingestion, time from ropinirole administration to first emesis, whether a second dose was given, the time from the second dose to second emesis, a description of the vomited material, whether all the material was thought to be vomited, as well as any observed side effects. Adverse effects were documented before administration of any further medications. Administration of metoclopramide (reversal agent) 0.5 mg/kg IV or SC was also documented and was given per doctor discretion or if continual vomiting was noted. Dogs were excluded if the form was not completed, and the incomplete information could not be retrieved from the medical record.

Induction of emesis was considered successful if dogs expelled stomach contents such as liquid, foam, food, foreign material, or toxin. Satisfactory or successful removal of foreign material from the stomach was defined as vomitus containing the type and amount ingested by the dog as described by the owner or confirmed with radiographic evidence. Successful emesis of a toxin was considered as visible evidence of the toxin if the toxin was expected to be obvious (such as chocolate or rodenticides), or just successful emesis for other toxins that are unlikely to be visible (dissolved tablets, liquids), as any reduction in quantity was considered as successfully decreasing the toxic dose and part of decontamination. If dogs were treated with ropinirole for multiple ingestions during the study period, each event was considered as a separate case, and all cases that met the inclusion criteria were included in the study.

Patient outcome was also evaluated with follow-up telephone communications with owners. Information of interest included whether continued emesis occurred after the pet’s visit, whether side effects were noted, and whether further intervention was required.

The results from this study were then compared to the data set from the 2019 study performed by Kirchofer et al12 which assessed the efficacy of apomorphine administration for removal of gastric foreign material in dogs. The overall efficacy of inducing vomit and success of evacuation of all of the expected ingested material after 1 or 2 doses was compared using all of the dogs in both studies. The efficacy was then compared using just the foreign body patients in the ropinirole study, as the apomorphine study did not include dogs with toxin ingestion.

Statistical analysis

Data distributions of continuous variables (weight, ropinirole dose, and time to vomit) were tested for normality by use of the Shapiro-Wilk test and visual examination of normal probability plots. Results were reported as the mean ± SD or median with the interquartile (25th to 75th percentile) range (IQR) for the continuous variables that were and were not normally distributed, respectively. Descriptive statistics were calculated. Comparisons of continuous variables were by means of the Wilcoxon rank sum test or Kruskal Wallis test, as appropriate. Categorical variables were compared by means of χ2 and Fisher exact testing as appropriate. Frequencies with 95% confidence limits were calculated. To compare the efficacy of ropinirole in this study with the efficacy of apomorphine in the study by Kirchofer et al,12 the variables compared included success of vomiting, success of producing the intended material, success of the first dose producing vomit and/or the intended substance, and whether a second dose was administered and if it was successful in producing vomit and/or the intended substance. The frequencies of these categorical variables were computed and compared by means of χ2 and Fisher exact tests. All analyses were performed by use of a commercial statistical software program (NCSS 2019), and values of P < .05 were considered significant.

Results

During the study period of August 2021 through February 2022, 312 dogs were treated with ophthalmic ropinirole solution, applied topically to one or both eyes, with the dose based on body weight per the manufacturer’s recommendation. Of these, 33 dogs were excluded from the study due to incomplete data sets. Of the 279 dogs remaining, 97 (34.8%) were neutered males, 50 (17.9%) were sexually intact males, 90 (32.2%) were spayed females, 41 (14.7%) were sexually intact females, and 1 (0.4%) did not have a documented sex in the medical record. There were 133 (47.7%) mixed-breed dogs and 146 (52.3%) purebred dogs representing 53 breeds. The most common breeds represented in the study included Labrador Retrievers (29 [10.3%]), Golden Retriever (10 [3.6%]), Australian Shepherds (8 [2.9%]), and German Shepherd Dogs (6 [2.1%]).

Weights for the dogs ranged from 2.4 kg to 94.0 kg. The overall median (25th, 75th quartiles) weight was 17.4kg (8.8 kg, 29.0 kg), for the dogs with foreign body ingestions was 17.8 kg (10.5 kg, 28.1 kg) and for the dogs with toxin ingestion was 17.0 kg (8.3 kg, 30.0 kg). This difference was not significant (P = .69). The time elapsed between ropinirole administration and emesis ranged from 2 minutes to 75 minutes. The overall median (25th, 75th quartiles) time to emesis was 11.0 minutes (8.0 minutes, 16.0 minutes), for dogs with foreign body ingestion was 11.5 minutes (7.0 minutes, 18.0 minutes) and for dogs with toxin ingestion was 11.0 minutes (9.0 minutes, 15.0 minutes). This difference was not significant (P = .79). These variables were not normally distributed, based on histogram, normal probability plot, and Shapiro-Wilk test of normality.

Depending on body weight, 1 to 6 drops were administered to each dog. Doses received by the dogs ranged from 1.1 to 7.4 mg/m2. As each drop contains 810 µg of ropinirole, this resulted in an average dose of ropinirole of 3.88 mg/m2 (SD, 0.84 mg/m2). Results for this variable were normally distributed, based on histogram and normal probability plot. Of the 279 dogs, 129 ingested foreign bodies and 150 ingested toxins. Two dogs presented twice for separate, independent ingestions and these events were counted as separate dogs. Dogs were presented due to known or suspected ingestion of a foreign object or toxin and not due to clinical signs. The time elapsed from ingestion of foreign material to administration of ropinirole ranged from less than 5 minutes to several days. The time elapsed from ingestion of toxin to administration of ropinirole ranged from 8 minutes to 14 hours.

Ropinirole efficacy

Ropinirole administration was successful in inducing emesis in 255 of 279 (91.4%) dogs and failed to induce emesis in 24 of 279 dogs (8.6%). Of the 129 dogs that ingested foreign bodies, 116 (89.9%) produced vomit. Of the 150 dogs that ingested toxins, 139 (92.7%) produced vomit. There was no significant difference in the success of inducing emesis between the foreign body and toxin groups (P = .415). The average dose for dogs that vomited after a single dose of ropinirole was 3.85mg/m2 (SD, 0.80mg/m2) and the average dose for dogs that did not produce vomit after a single dose was 3.99 mg/m2 (SD, 0.98 mg/m2). The difference was not statistically significant (P = .30). Among the 279 dogs, the first dose of ropinirole was successful in producing vomit in 78.9% of all dogs (95% CI, 73.7% to 83.2%), including 98 (75.9%; 95% CI, 67.9% to 82.5%) of the foreign body dogs and 122 (81.3%; 95% CI, 74.3% to 86.8%) of the toxin dogs. There was no statistical difference between the success of the first dose in inducing emesis between the foreign body and toxin groups (P = .274). Fifty-nine dogs received a second dose of ropinirole, of which 47 (79.7%; 95% CI, 67.7% to 87.9%) produced vomit. Twenty-five (73.5%; 95% CI, 56.9% to 85.4%) of the foreign body cases that received a second dose successfully produced vomit, and 22 (88.0%; 95% CI, 70.0% to 95.8%) of the toxin cases that received a second dose successfully produced vomit. There was no significant difference between the 2 groups (P = .172). Of the 255 dogs that successfully vomited with ropinirole administration, 35 (13.7%) required a second dose to do so. Of the 59 dogs that did not vomit after 1 dose of ropinirole, 21 dogs did not receive a second dose of ropinirole. Eight dogs received no second emetic agent, and 13 dogs were administered apomorphine.

In 47 dogs, a second dose of ropinirole was given because the first dose did not result in emesis, but in 12 dogs the second dose was given due to incomplete removal of the ingested substance. Seven of those dogs ingested a foreign body and of those, only 2 produced the expected foreign body after the second dose. Five of the foreign body dogs successfully vomited with both doses but the emesis did not contain the expected foreign material. One vomited a candy wrapper and stick when the client reported ingestion of a sock. Another dog had linear opaque unknown material on a radiograph but only vomited leaves after both doses. Radiography confirmed the presence of remaining foreign material (coins and a battery) in 2 of the dogs that failed to produce the expected emesis. The dog that ingested coins had them removed via endoscopy and the owner of the dog that ingested a battery declined further intervention and was lost to follow-up. Five dogs that ingested toxins were given a second dose after vomiting from the initial dose. Four of the 5 dogs did not produce any of the expected toxin after the first dose and 1 of the dogs was administered a second dose because a large volume of intoxicant was ingested, and further decontamination was warranted.

Overall, of the combined foreign body and toxin cases, 207 (74.2%; 95% CI, 68.8% to 78.9%) produced all of the expected material. Of the foreign body cases, 91 (70.5%; 95% CI, 62.2% to 77.7%) vomited all of the expected ingested foreign material. Five of the foreign body cases required endoscopy for full resolution and 1 dog had a negative endoscopy suggesting the dog never ingested the reported foreign material. No dog required surgical intervention based on the provided medical records and follow-up communication. Of the toxin cases, 116 (77.3%; 95% CI, 70.0% to 83.3%) produced the expected material. There was no significant difference between the 2 groups (P = .196).

Side effects

Of the 279 dogs, 276 were observed for side effects. One dog from the foreign body group and 2 dogs from the toxin group did not have the side effects questions completed on their questionnaire. Among the 276 dogs, 47 (17.0%; 95% CI, 13.1% to 21.9%) experienced side effects while being observed in the hospital. Side effects were noted after administration of ropinirole but before any other medications were considered or given. Of the foreign body cases, 25 (19.5%; 95% CI, 13.6% to 27.2%) experienced side effects. Of the toxin cases, 22 (14.9%; 95% CI, 10.0% to 21.5%) experienced side effects. No significant difference was noted between the 2 groups (P = .304). Side effects included protracted vomiting (2 dogs, [0.7%]), conjunctival hyperemia (34 dogs, [12.3%]), protrusion of the third eyelids (16 dogs, [5.8%]), ocular discharge (6 dogs, [2.2%]), and sedation (2 dogs, [0.7%]). Among the 47 dogs that experienced side effects, 12 (4.4%) experienced more than 2 side effects at a time. Thirty-four dogs of the 279 dogs (12.2%) experienced side effects with 1 dose alone whereas 13 dogs of the 59 dogs receiving a second dose (22.0%) experienced side effects. Side effects were significantly more likely after a second dose (P = .047), although 45 of the 59 dogs (76.2%) experienced no side effects despite receiving 2 doses. One dog that received 2 doses of ropinirole did not have side effects documented and their owner did not return calls for follow-up. All side effects were self-limiting and required no further treatment or intervention.

Long-term follow-up information was obtained from telephone communication with the owner for 104 of the 279 (37.2%) dogs. Of the 104 respondents, 10 (9.6%) reported persistent side effects including conjunctival hyperemia, rubbing eyes, ocular discharge, and self-limiting sedation which resolved within hours of the visit. One client reported frequent ocular discharge, and another reported the dog appeared “cross eyed” but this was self-limiting after a few hours. One owner reported decreased appetite which improved with a bland diet. Three owners (2.9%) reported continued vomiting after discharge with 2 of those vomiting post metoclopramide administration. One dog did require further treatment with dialysis for acute kidney injury following ingestion of a toxic dose of carprofen and was subsequently transferred to a different referral hospital.

Anti-emetic medication

A total of 165 (59.4%; 95% CI, 53.5% to 64.9%) dogs were administered metoclopramide after administration of ropinirole. Among the foreign body dogs, 77 (59.7%; 95% CI, 51.1% to 67.8%) received metoclopramide and of the toxin dogs, 88 (59.1%; 95% CI, 51.0% to 66.6%) received metoclopramide. During a portion of the study period, metoclopramide was on back-order so other antiemetic medications were administered. Forty dogs received other antiemetics including ondansetron (n = 22) or maropitant (18) at the primary clinician’s discretion. Ten dogs received both metoclopramide and an additional ant-emetic. Eighty-three dogs (29.7%) received no anti-emetic medication. There was no significant difference between the foreign body and toxin groups as to whether they received anti-emetics (P = .915).

Comparison to apomorphine

In Kirchofer et al,12 the efficacy of apomorphine for inducing vomiting was assessed in 495 dogs with confirmed gastric foreign material. The results of the current study were compared first for overall efficacy of vomiting after a single dose of ropinirole or apomorphine, and then for efficacy in successful elimination of foreign material only (toxin cases removed). When comparing the 2 medications for producing vomit, the findings were similar with 95.6% of dogs given apomorphine producing vomit and 91.4% of dogs given ropinirole producing vomit. This difference was statistically significant, (P < .0001). When comparing for only foreign material ingestion, apomorphine-induced vomiting in 95.6% of dogs and ropinirole induced vomiting in 89.9% of dogs. This difference was statistically significant (P = .013). For all cases (toxin and foreign body), the first dose of medication was successful in 92.3% of dogs given apomorphine and 78.9% of dogs administered ropinirole. This difference was statistically significant, (P < .0001). For only foreign body cases, after a single dose of ropinirole, 75.9% vomited. The difference compared with apomorphine was statistically significant, (P < .0001).

Of the 495 dogs in the apomorphine study, 374 (75.6%) successfully vomited the intended foreign material. When comparing all dogs in this study (foreign material and toxin ingestion), the intended material was successfully produced in 74.0% (95% CI, 68.8% to 78.9%) of dogs administered ropinirole. This was not statistically significant (P = .634). Of the dogs that ingested foreign material in this study, 91 (70.5%; 95% CI, 62.2% to 77.7%) successfully vomited the intended substance. This compared with apomorphine was not statistically significant (P = .245).

Of the 473 dogs that vomited in the apomorphine study, 16 (3.4%) required a second dose to do so. Of the 255 dogs that vomited with ropinirole, 35 (13.7%) required a second dose to do so. This was statistically significant, (P < .0001). Following a second dose of drug, 80% of dogs vomited with apomorphine and 79.7% vomited with ropinirole. When evaluating the foreign body group only, 73.5% vomited after a second dose of ropinirole. There was no significant difference in the efficacy of a second dose at inducing emesis whether comparing all dogs (P = .974) or just foreign body dogs (P = 0.591) given ropinirole to those given apomorphine.

Discussion

To our knowledge, the present study is the first to evaluate the efficacy of ropinirole to induce emesis in dogs that ingested foreign material or toxic substances and then to compare its use to apomorphine. The results of this study demonstrate that ropinirole is effective at inducing emesis in dogs with foreign material or toxic substance ingestion. There was a small but significant difference in the efficacy of ropinirole compared to apomorphine in inducing emesis with apomorphine being more effective, although this difference is likely not clinically relevant.

One explanation for the difference in efficacy may be the route of administration. Apomorphine may be more effective as it was administered intravenously compared to ropinirole’s ocular administration. Ropinirole may have had a decreased dose if it was not fully absorbed due to inadequate administration or possible increased tear production. There is also the possibility that immediate serum levels of the apomorphine given IV affected the CRTZ more effectively than the ropinirole, which reaches peak serum levels after 10 to 20 minutes if administered in an eye drop.11

Ropinirole is dosed in multiples of drops, each containing 810 mcg, with the target dose being 3.75mg/m2 and the accepted dose range being 2.7 to 5.4 mg/m2 which limits the ability to administer a consistent dose to every dog. The dose received by the dogs in this study ranged from 1.1 to 7.4 mg/m2 (mean 3.88 mg/m2, SD 0.84). This dose variability did not explain the decreased efficacy of ropinirole compared to apomorphine, as failure to vomit was not correlated with receiving a lower dose of ropinirole. There was some dose variability in the apomorphine study as well, due to being a retrospective study. Further prospective studies should be considered with standardized dosing of both drugs to truly assess their comparative efficacy.

The median time to emesis following ropinirole administration in this study was 11 minutes. In Cote et al,6 median time to emesis using an intravenous administration of apomorphine was 1 minute.6 Studies utilizing the ocular insert of apomorphine report a time to emesis ranging from 6 minutes6 to 18.6 minutes13 which is similar to our findings with ropinirole. In a study comparing subcutaneous to intravenous administration of apomorphine, the subcutaneous route had a slower time to emesis (median 13.5 minutes)14 which is similar to the ocular administration reports.

Administration of a second dose appears to be beneficial, as the efficacy of ropinirole increased from 78.9% if just 1 dose was administered to 91.4% when a second dose was administered to dogs that did not vomit or did not vomit all of the expected material. Although, it is possible the vomiting that occurred was a delayed response from the first dose, it is more likely that a second dose provided a higher peak concentration leading to productive emesis. While the 91.4% is still lower than the reported efficacy of intravenous apomorphine, the difference may not be clinically relevant. Despite the difference in efficacy at inducing emesis, there was no significant difference in the ability of the 2 drugs to result in effective removal of the expected ingested substance (75.6% for apomorphine,11 74.2% for ropinirole in this study).

Of the 59 dogs that did not vomit after the first dose of ropinirole, 21 dogs (13 dogs that ingested foreign material and 8 dogs that ingested toxins) were not given a second dose of ropinirole. It is unclear whether these dogs would have vomited after a second dose of ropinirole, and this might have affected the reported efficacy of a second dose in this paper. Four of the dogs that ingested toxins and 9 of the dogs that ingested foreign material were administered apomorphine after the ropinirole was not successful due to clinician discretion. It is unclear why apomorphine was chosen over a second dose of ropinirole. It could be due to the clinician’s familiarity with apomorphine and lack of experience with ropinirole. The administration of apomorphine after ropinirole would be considered extra-label dosing. Three of the 4 dogs that ingested toxins vomited, and 1 dog did not vomit despite 2 doses of apomorphine. Of the 9 dogs that ingested foreign material that vomited post-apomorphine, 2 did not have complete records so it is unclear if they successfully produced the foreign material. Only 2 dogs successfully vomited the foreign material (a sock and a stick respectively) and 2 dogs required endoscopy for full resolution. One dog had received maropitant the day prior which may be why both emetics were unsuccessful. While it appears safe to administer apomorphine and ropinirole during the same visit, it is unclear how many dogs would benefit from this compared to multiple doses of the same agent. Further studies are warranted.

Side effects of ropinirole were uncommon and included continued vomiting, conjunctival hyperemia, protrusion of the third eyelids, ocular discharge, and sedation. Three dogs were reported to have vomited 1 to 5 times following discharge from the hospital. The vomiting was considered to be an adverse effect of the ropinirole, and not due to the ingested substance because dogs were only included if they did not show abnormal clinical signs prior to the ropinirole administration. The vomiting resolved without treatment. Only 2 dogs (0.7%) experienced sedation as an adverse effect. One of these dogs also received maropitant, but the sedation was noted prior to the maropitant administration. Despite being a centrally acting non-selective dopamine agonist, apomorphine is also a synthetic derivative of morphine and well known to cause sedation as an adverse effect.4 In Cote et al,6 sedation was reported in 11.1% of dogs given the ocular insert formulation of apomorphine, and 43.8% of dogs administered intravenous apomorphine.6 Ropinirole is highly selective for D2 receptors and has no opioid receptor activity which makes it more likely to induce vomiting with less CNS depression and sedation than apomorphine. As a selective dopamine agonist, it has a reversal agent which can lead to full resolution of side effects which is not possible with apomorphine. The sedation and central nervous system depression associated with apomorphine can be reversed with naloxone,15 but doing so may lead to protracted vomiting.16 Most of the side effects of ropinirole reported in this study were signs of ocular irritation that resolved without further intervention. No serious adverse drug events were noted in this study.

After ropinirole was administered and side effects were monitored for, anti-emetics were administered if deemed warranted by the supervising clinician. One hundred and sixty-five dogs were administered metoclopramide. During a portion of the study period, metoclopramide was on back-order so other antiemetic medications were administered including ondansetron and maropitant. It is likely more dogs would have received metoclopramide if it were more readily available. Some clinicians at the study hospital were likely to give anti-nausea medication even if no further vomiting was noted and reversal was not warranted due to concern for unperceived nausea. Based on the client follow-up, no refractory vomiting was noted in either the dogs that did receive reversal with metoclopramide or the dogs that did not. While this suggests that metoclopramide may not be required in most dogs, it is reasonable to consider giving it if there is evidence of nausea or to lessen the chance of vomiting after the patient is discharged.

In Kirchofer et al,12 it was suggested that some medications, such as opioids, sedatives, and antiemetics, can impair the efficacy of apomorphine. In our study, 1 dog vomited with ropinirole despite receiving maropitant 18 hours prior. A different dog received maropitant the day before and did not vomit after receiving both ropinirole and apomorphine. Three dogs vomited after receiving premedications including dexmedetomidine, butorphanol, and/or hydromorphone. Due to the small number of dogs that received premedications, no conclusion could be drawn from the current study regarding the effect of premedications on the efficacy of ropinirole. Often sedation is required for radiography to confirm the presence of foreign material and if ropinirole’s efficacy is not reduced by sedation drugs, it may be more suited in these situations compared to apomorphine. Further investigation is warranted.

The present study had limitations. Although follow-up information was obtained for many dogs, some patients that required additional interventions may have gone unidentified or required further treatment with their primary care veterinarian. As the study was designed to have the clinicians and support staff fill out a questionnaire, due to caseload and variable compliance, this was not always completed with all requested information. Although clinicians were given specific guidelines on how to administer ropinirole and metoclopramide, they were not specifically instructed to avoid giving alternative medications. If the desired outcome was not achieved, a few elected to give apomorphine or different anti-emetic medications if they felt it was best for their patient. The combination of ropinirole followed by apomorphine would be considered extra-label use of both drugs, although no negative effects were appreciated when the 2 drugs were used together. It is unfortunate that these dogs were not given a second dose of ropinirole as they could not contribute to our assessment of efficacy of a second dose. When reviewing medical records to complete the data, some entries were not noted such as time of vomit, complete description of vomitus, and if further diagnostics such as radiography was completed. There is also an inherent limitation to using historical data for comparison. We compared data acquired prospectively on ropinirole to that acquired in a retrospective study on apomorphine. Ideally the 2 drugs would be compared in a side-by-side, blinded prospective study.

Ropinirole may be advantageous as compared to apomorphine as it is less technically challenging to administer and can be considered in clinics which may have limited staffing making restraint more difficult. It may also be easily administered by a client in a dog that is aggressive with veterinary staff but manageable with the client. Other advantages include not being a controlled substance like apomorphine and being the only FDA-approved emetic medication for use in dogs. Hydrogen peroxide is used off-label to induce emesis and is sometimes suggested for use by clients at home when dogs ingest dangerous material. Hydrogen peroxide can lead to adverse effects including hematemesis, foaming at the mouth which can lead to respiratory obstruction or aspiration, painful gastric distension, tissue ulceration and oropharyngeal burns, irritation of respiratory tissues if aspirated, confusion, coma, convulsions, apnea, and death.17 Due to the ease of administration and lack of clinically significant risks or side effects, ropinirole could be dispensed for home use for dogs with a history of repeated foreign material ingestion.

Results of the present study demonstrated that administration of ropinirole was safe and effective for induction of emesis in dogs that ingested foreign material or intoxicants. If successful removal of the foreign body or toxin is not achieved after 1 dose of ropinirole, administration of a second dose should be considered.

Acknowledgments

No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.

The authors thank Hecmar Delgado for assistance with data acquisition and Joe Hauptman, DVM, MS, DACVS for assistance with statistical analyses.

References

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    Smith HS, Smith JM, Seidner P. Opioid-induced nausea and vomiting. Ann Palliat Med. 2012;1(2):121129. doi:10.3978/j.issn.2224-5820.2012.07.08

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    Suokko M, Saloranta L, Lamminen T, Laine T, Elliott J. Ropinirole eye drops induce vomiting effectively in dogs: a randomised, double-blind, placebo-controlled clinical study. Vet Rec. 2020;186(9):283283. doi:10.1136/vr.104953

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    CLEVOR-Ropinirole Hydrochloride Solution [US Produce Label for Dogs]. Vetoquinol USA, Inc; 2020.

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    Kirchofer KS, Block G, Johnson JA. Efficacy of intravenous administration of apomorphine for removal of gastric foreign material in dogs: 495 cases (2010-2015). J Am Vet Med Assoc. 2019;255(4):459465. doi:10.2460/javma.255.4.459

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    Khan SA, Mclean MK, Slater M, et al. Effectiveness and adverse effects of the use of apomorphine and 3% hydrogen peroxide solution to induce emesis in dogs. J Am Vet Med Assoc. 2012;241:11791184.

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    Fischer C, Drobatz KJ, Thawley VJ. Evaluation of subcutaneous versus intravenous administration of apomorphine for induction of emesis in dogs. J Am Vet Med Assoc. 2021;259(3):283287. doi:10.2460/javma.259.3.283

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    Scherkl R, Hashem A, Frey HH. Apomorphine-induced emesis in the dog—routes of administration, efficacy and synergism by naloxone. J Vet Pharmacol Ther. 1990;13:154158.

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    Montastruc JL, Lapeyre-Mestre M, Llau ME, Senard JM, Rascol O, Montastruc P. Naloxone does not prevent apomorphine-induced emesis or hypotension in dogs. Clin Auton Res. 1994;4(6):303305. doi:10.1007/BF01821529

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Contributor Notes

Corresponding author: Dr. Rosenstein (nrosenstein@osvs.net)
  • 1.

    Gallagher A. Vomiting and regurgitation. In: Ettinger SJ, ed. Textbook of Veterinary Internal Medicine. 8th ed. WB Saunders Co; 2016:610618.

    • Search Google Scholar
    • Export Citation
  • 2.

    Miller AD, Leslie RA. The area postrema and vomiting. Front Neuroendocrinol. 1994;15(4):301320. doi:10.1006/frne.1994.1012

  • 3.

    Smith HS, Smith JM, Seidner P. Opioid-induced nausea and vomiting. Ann Palliat Med. 2012;1(2):121129. doi:10.3978/j.issn.2224-5820.2012.07.08

    • Search Google Scholar
    • Export Citation
  • 4.

    Ribarič S. The pharmacological properties and therapeutic use of apomorphine. Molecules. 2012;17(5):52895309. doi:10.3390/molecules17055289

    • Search Google Scholar
    • Export Citation
  • 5.

    Harding RK, Hugenholtz H, Kucharczyk J, Lemoine J. Central mechanisms for apomorphine induced emesis in the dog. Eur J Pharmacol. 1987;144(1):6165. doi:10.1016/0014-2999(87)90009-4

    • Search Google Scholar
    • Export Citation
  • 6.

    Cote DD, Collins DM, Burczynski FJ. Safety and efficacy of an ocular insert for apomorphine-induced emesis in dogs. Am J Vet Res. 2008;69:13601365.

    • Search Google Scholar
    • Export Citation
  • 7.

    Plumb DC. Plumb’s Veterinary Drug Handbook. 9th ed. Wiley-Blackwell; 2018:6769.

  • 8.

    Schafer JH. Freedom of Information Summary. Original New Animal Drug Application. Clevor. Ropinirole Ophthalmic Solution. FDA. Accessed December 4, 2021. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/9248

    • Search Google Scholar
    • Export Citation
  • 9.

    Reavill C, Boyfield I, Coldwell M, Nelson P. Comparative pharmacological study of ropinirole (SKF-101468) and its metabolites in rats. J Pharm Pharmacol. 2000;52(9):11291135. doi:10.1211/0022357001774895

    • Search Google Scholar
    • Export Citation
  • 10.

    Suokko M, Saloranta L, Lamminen T, Laine T, Elliott J. Ropinirole eye drops induce vomiting effectively in dogs: a randomised, double-blind, placebo-controlled clinical study. Vet Rec. 2020;186(9):283283. doi:10.1136/vr.104953

    • Search Google Scholar
    • Export Citation
  • 11.

    CLEVOR-Ropinirole Hydrochloride Solution [US Produce Label for Dogs]. Vetoquinol USA, Inc; 2020.

  • 12.

    Kirchofer KS, Block G, Johnson JA. Efficacy of intravenous administration of apomorphine for removal of gastric foreign material in dogs: 495 cases (2010-2015). J Am Vet Med Assoc. 2019;255(4):459465. doi:10.2460/javma.255.4.459

    • Search Google Scholar
    • Export Citation
  • 13.

    Khan SA, Mclean MK, Slater M, et al. Effectiveness and adverse effects of the use of apomorphine and 3% hydrogen peroxide solution to induce emesis in dogs. J Am Vet Med Assoc. 2012;241:11791184.

    • Search Google Scholar
    • Export Citation
  • 14.

    Fischer C, Drobatz KJ, Thawley VJ. Evaluation of subcutaneous versus intravenous administration of apomorphine for induction of emesis in dogs. J Am Vet Med Assoc. 2021;259(3):283287. doi:10.2460/javma.259.3.283

    • Search Google Scholar
    • Export Citation
  • 15.

    Scherkl R, Hashem A, Frey HH. Apomorphine-induced emesis in the dog—routes of administration, efficacy and synergism by naloxone. J Vet Pharmacol Ther. 1990;13:154158.

    • Search Google Scholar
    • Export Citation
  • 16.

    Montastruc JL, Lapeyre-Mestre M, Llau ME, Senard JM, Rascol O, Montastruc P. Naloxone does not prevent apomorphine-induced emesis or hypotension in dogs. Clin Auton Res. 1994;4(6):303305. doi:10.1007/BF01821529

    • Search Google Scholar
    • Export Citation
  • 17.

    Watt BE, Proudfoot AT, Vale JA. Hydrogen peroxide poisoning. Toxicol Rev. 2004;23(1):5157. doi:10.2165/00139709-200423010-00006

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