Awareness is rising of the use of donkeys as pack and draft animals in developing countries and as companion animals or for leisure activities in developed countries. Veterinary interest is also increasing with respect to the welfare of these animals, including pain assessment and management.1 In recent years, donkey-related research has increased in volume, and results have suggested that the distinctive physiologic and pharmacological features of donkeys warrant their consideration as distinct species.2
The α2-adrenoceptor agonists are commonly used in equine practice for procedures requiring sedation and analgesia. In the United Kingdom, detomidine is the most commonly used α2-adrenoceptor agonist and the third most popular drug used by veterinarians to provide analgesia for donkeys.3 This drug is available as an injectable solution and as an oromucosal gel. The sedative and analgesic effects of detomidine after IV administration of the injectable solution to donkeys have been reported.4–10 However, the authors are unaware of any reports on use of the oromucosal gel in this species.
The purpose of the study reported here was to assess and compare the sedative and mechanical hypoalgesic effects in donkeys of sublingual administration of 2 doses of detomidine hydrochloride gel. It was hypothesized that, similar to results achieved with IV administration of detomidine solution,10 sublingual administration of detomidine gel would induce sedation and hypoalgesia in donkeys, but only the hypoalgesic effect would be dose dependent.
Materials and Methods
Animals
Six 5- to 7-year-old castrated male standard donkeys owned by the Ross University School of Veterinary Medicine were used in the study. Donkeys were assessed as healthy on the basis of unremarkable results of physical examination, CBC, and serum biochemical analysis. Donkeys were kept in an open paddock and fed Guinea grass twice daily; free access to water was provided throughout the study. All donkeys were weighed weekly. The study protocol was approved by the Institutional Animal Care and Use Committee of the Ross University School of Veterinary Medicine and complied with national11 and international12 guidelines for humane animal treatment.
Treatments
In a crossover, Latin-square design, donkeys received each of the following 3 sublingual treatments separated by a 1-week washout period: molassesa (1 mL; placebo) or detomidine hydrochloride gelb at 20 μg/kg (9 (μg/lb) or 40 μg/kg (18 μg/lb). All treatments were drawn into 1-mL syringesc to achieve accurate doses and were administered beneath the tongue by the same investigator (FC-A), in accordance with the manufacturer's instructions for detomidine gel administration. Treatment orders were randomized by use of an online list randomizer.d
On days on which treatments were to be administered, 2 donkeys at a time were haltered and brought into a stall where they were loosely tied approximately 1.5 m apart from each other to prevent roaming and allow for accurate observation during testing. Donkeys were allowed approximately 15 minutes to acclimatize to the stall environment before any assessment was performed. Sedation score, HHAG, and MNT were always assessed in this order by different investigators (KMV, LSR, and IL, respectively), who were blinded to treatment received. Assessments were made 5 times at 2- to 3-minute intervals before treatment administration and then at 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, and 180 minutes after administration.
Assessments of SS and HHAG
Quality of sedation was assessed by use of a 4-point simple descriptive scale10,13 as follows: 0 = no sedation (alert with typical posture), 1 = mild sedation (low head carriage, ears pointing out, and pendulous upper lip), 2 = moderate sedation (head lowered toward ground and wide stance of forelimbs), and 3 = marked sedation (swaying of hind limbs with or without attempts to become recumbent).
Additionally, with the ventral aspect of the nostrils as reference, HHAG was measured. For this measurement, 3 wooden sticks to which 140-cm measuring tapes were attached were mounted approximately 1.5 m apart from each other on the stall wall to which donkeys were tied. This placement allowed for full visibility of the measuring tapes during testing. To account for variations in donkey heights, mean baseline (pretreatment) values were considered as 100% HHAG for each trial, and actual HHAG values after treatment administration were converted to percentages of the 100% HHAG value.10,13 During SS assignment, actual position of the head above the ground was not measured, whereas actual position was measured during HHAG assignment.
Assessment of MNT
Mechanical nociceptive devices were attached with a hook-and-loop fastening strap to the proximodorsal aspect of the left metacarpal bone.7,10,13,14 Devices consisted of a 2-mm blunt-ended pin housed in the plunger of a 5-mL loss-of-resistance syringe, which was connected, via a 3-way tap and plastic tubing, to a pressure gauge and a 50-mL air-filled syringe. By pressurizing the syringe, the blunt-ended pin was pressed against the limb until the donkey lifted it (ie, nociceptive threshold). The pressure (in kilopascals) needed to elicit this response was recorded, and the applied pressure was immediately discontinued.
Prior to testing, devices were calibrated by clamping the actuator over an electronic scale (maximum capacity, 3,000 g; resolution, 1 g) and measuring the weight exerted at various pressures; 100 g was equated to 1 N. Measurements were repeated 10 times at each Newton interval for up to 20 N, and statistical regression of pressure on force yielded linear results (R = 0.996). Therefore, the recorded pressure was translated into and reported as force. To prevent tissue damage, the force applied to the donkey's limb was incrementally increased (approx 0.5 N/s) up to a cutoff force of 20 N, and this value was recorded if there was no reaction. To avoid flies acting as possible triggers of limb withdrawal, fly spraye was applied onto each donkey's skin before nociceptive testing took place and as needed thereafter.
Statistical analysis
The trapezoidal method was used to calculate AUCs for posttreatment periods 0 to 30, 30 to 60, 60 to 120, and 120 to 180 minutes (with the pretreatment [baseline] value subtracted) for SS (SS-AUCs), HHAG (HHAG-AUCs), and MNT (MNT-AUCs). Data were evaluated for normality of distribution by use of the Kolmogorov-Smirnov test. Normally distributed data are reported as mean ± SD, and nonnormally distributed data are reported as median (range).
Differences in AUC values for SS among treatments were examined by use of the Friedman test followed by the Dunn multiple comparison test, and those for HHAG and MNT were examined by means of repeated-measures 1-way ANOVA followed by the Tukey test. The lowest HHAG value and its time of occurrence were determined for each treatment, and differences among treatments were examined through 1-way ANOVA followed by the Bonferroni test and Kruskal-Wallis test, respectively. Baseline MNT values were grouped for each treatment and analyzed by means of 1-way ANOVA. All analyses were performed with the aid of statistical software.f Values of P < 0.05 were considered significant.
Results
Animals
Each of the 3 treatments (placebo or detomidine gel at 20 or 40 μg/kg) was administered sublingually to all 6 donkeys without difficulty. All donkeys successfully completed the study. Mean ± SD body weight during the study period was 164.08 ± 12.46 kg (360.98 ± 27.41 lb). Effects of detomidine administration other than those systematically assessed included snorting, penis prolapse, and micturition.
Assessments of SS and HHAG
No clinical signs of sedation were observed at any point following placebo administration (SS = 0). Both detomidine doses consistently resulted in clinical signs of sedation, but the onset and quality of sedation varied among individual donkeys. At 20 minutes after receiving the 20 μg/kg dose of detomidine gel, all donkeys had an SS of 0, except for 1 donkey, which had an SS of 1 (mild sedation). Gradual onset of sedation was identified for the other 5 donkeys until 50 minutes after treatment, by which point all 6 donkeys had an SS ≥ 1. Only 1 donkey had an SS of 2 at 50 and 60 minutes after treatment. Another donkey had an SS of 0 at most assessment points, except from 50 to 70 minutes after treatment, when it had an SS of 1. The SS returned to 0 for the donkeys after treatment with 20 μg/kg of detomidine gel at different points: 80 minutes for 1 donkey, 120 minutes for 1 donkey, 150 minutes for 3 donkeys, and 180 minutes for the final donkey. These values remained at 0 for the duration of the assessment period for the 20 μg/kg dose of detomidine gel (Figure 1).
Median and range SSs for 6 healthy donkeys before (prior to 0 minutes) and at various points after sublingual administration of a placebo (squares) or detomidine hydrochloride gel at 20 μg/kg (9 μg/lb; upright triangles) or 40 μg/kg (18 μg/lb; inverted triangles). Donkeys received each of the 3 treatments (at 0 minutes) 1 week apart in a crossover, Latin-square design. An SS of 0 indicates no sedation, and an SS of 3 indicates marked sedation.
Citation: Journal of the American Veterinary Medical Association 249, 1; 10.2460/javma.249.1.83
For assessments of the 40 μg/kg dose of detomidine gel, SSs began at 0 for all donkeys. At 20 minutes after treatment, 2 donkeys had an SS of 1. Gradual onset of sedation for the other donkeys was observed until 40 minutes after treatment, by which point all 6 donkeys had an SS ≥ 1. Three donkeys had an SS of 2 at different points between 40 and 90 minutes after treatment. Two donkeys still had an SS of 1 at 180 minutes after treatment, and SSs for the other donkeys returned to 0 at 150 (n = 2) and 180 (2) minutes after treatment. Compared with corresponding placebo values, SS-AUCs for between 60 and 120 minutes after treatment with detomidine gel at 20 and 40 μg/kg were significantly (P < 0.01) larger. No significant differences in SS-AUCs were identified among treatments for any other period (Table 1).
Median (range) AUCs for SSs for various periods after sublingual administration of a placebo or detomidine hydrochloride gel at 20 or 40 μg/kg (9 or 18 μg/lb) to 6 healthy donkeys.
| Period after administration (min) | ||||
|---|---|---|---|---|
| Treatment | 0–30 | 30–60 | 60–120 | 120–180 |
| Placebo | 0 (0–0) | 0 (0–0) | 0 (0–0)* | 0 (0–0) |
| Detomidine at 20 μg/kg | 0 (0–2) | 3 (2–6) | 7 (3–8) | 1 (0–2) |
| Detomidine at 40 μg/kg | 1 (0–2) | 4.5 (3–7) | 7.5 (7–11) | 2 (1–3) |
Value differs significantly (P < 0.01) from the corresponding values for detomidine at 20 and 40 μg/kg.
Donkeys received each of the 3 treatments 1 week apart in a crossover, Latin-square design.
Sublingual administration of detomidine gel at 20 and 40 μg/kg but not of the placebo was followed by a consistent decrease in HHAG (Figure 2). Similar to findings for SSs, 30 to 60 minutes elapsed between drug administration and an approximately 50% decrease in HHAG; the depth of sedation also varied among donkeys. Significantly (P < 0.01) higher HHAG-AUCs for all periods assessed between 30 and 180 minutes after treatment were obtained for the placebo versus both doses of detomidine gel. The HHAG-AUCs for 60 to 120 minutes after treatment were also significantly (P < 0.001) higher for detomidine gel at 20 versus 40 μg/kg. No significant differences in HHAG-AUC were identified among treatments for the period 0 to 30 minutes. The lowest mean percentage change in HHAG values from baseline (before treatment) for detomidine gel at 20 and 40 μg/kg was approximately 28% and 14%, respectively, and these changes were significantly (P < 0.01) lower than that for the placebo (approx 90%). No significant (P = 0.41) differences were identified in periods during which the lowest HHAG values were recorded (Table 2).
Mean ± SD percentage changes in HHAG from pretreatment (prior to 0 minutes) values and at various points after treatment for the 6 healthy donkeys in Figure 1. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 249, 1; 10.2460/javma.249.1.83
Mean ± SD AUCs for HHAG (percentage change in minutes) for various periods and lowest percentage change in HHAG as well as median (range) time of lowest percentage change in HHAG after treatment for the 6 healthy donkeys in Table 1.
| Period after administration (min) | ||||||
|---|---|---|---|---|---|---|
| Treatment | 0–30 | 30–60 | 60–120 | 120–180 | Lowest percentage change in HHAG | Time of lowest percentage change in HHAG (min) |
| Placebo | 124.83 ± 84.64 | 128.67 ± 158.21* | 259.00 ± 379.12† | 309.67 ± 544.55‡ | 89.38 ± 8.50* | 30 (10–110) |
| Detomidine at 20 μg/kg | −155.33 ± 198.24 | −1,225.83 ± 366.38 | −2,884.00 ± 726.01† | −1,500.67 ±813.71 | 27.96 ± 8.72 | 70 (60–100) |
| Detomidine at 40 μg/kg | −281.83 ± 288.22 | −2,013.88 ±477.07 | −4,382.33 ± 420.32† | −2,415. 00 ± 1,321.44 | 13.93 ± 6.51 | 65 (40–120) |
Value differs significantly from corresponding values for detomidine at 20 (P < 0.01) and 40 (P < 0.001) μg/kg.
Value differs significantly (P < 0.001) from corresponding values for all other treatments.
Value differs significantly (P < 0.001) from corresponding values for detomidine at 20 and 40 μg/kg.
See Table 1 for remainder of key.
Assessment of MNT
Mean ± SD baseline MNTs were 5.47 ± 0.88 N for the placebo, 5.36 ± 1.18 N for detomidine gel at 20 μg/kg, and 5.02 ± 1.01 N for detomidine gel at 40 μg/kg. These values did not differ significantly (P = 0.22). Administration of detomidine gel at both doses but not of the placebo resulted in an increase in MNT (Figure 3). Similar to findings for SS and HHAG, approximately 30 to 60 minutes elapsed between treatment administration and increases in MNT. Great variability among donkeys in MNT was also observed after treatment with either dose of detomidine gel. Compared with corresponding placebo values, the MNT-AUCs for all periods assessed between 30 and 180 minutes after treatment were significantly greater for the 40 μg/kg dose of detomidine gel (P < 0.01) and for the period 60 to 120 minutes for the 20 μg/kg dose (P < 0.001). No significant differences were identified among treatments for MNT-AUCs representing the period 0 to 30 minutes (Table 3).
Mean ± SD MNTs (N) from pretreatment (prior to 0 minutes) values and at various points after treatment for the 6 healthy donkeys in Figure 1. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 249, 1; 10.2460/javma.249.1.83
Mean ± SD AUCs for MNTs (N min) for various periods after treatment for the 6 healthy donkeys in Table 1.
| Period after administration (min) | ||||
|---|---|---|---|---|
| Treatment | 0–30 | 30–60 | 60–120 | 120–180 |
| Placebo | −3.99 ± 15.87 | 7.88 ± 33.27* | −20.12 ± 32.69† | −32.83 ± 49.94‡ |
| Detomidine at 20 μg/kg | 18.04 ±35.08 | 207.02 ± 145.81 | 404.08 ± 322.19 | 50.65 ± 80.80 |
| Detomidine at 40 μg/kg | 57.17 ± 30.05 | 324.65 ± 94.51 | 706.52 ± 220.74 | 312.30 ± 235.88 |
Value differs significantly (P < 0.001) from corresponding values for detomidine at 40 μg/kg.
Value differs significantly (P < 0.001) from corresponding values for detomidine at 20 and 40 μg/kg.
Value differs significantly (P < 0.01) from corresponding values for detomidine at 40 μg/kg.
See Table 1 for remainder of key.
Discussion
The study reported here revealed sedative and mechanical hypoalgesic effects of sublingual administration of detomidine hydrochloride gel at 2 doses (20 and 40 μg/kg). The sedative and analgesic effects induced in donkeys by IV administration of detomidine injectable solution have been reported.4–10 However, to the authors' knowledge, this is the first report of sublingual administration of the gel form to donkeys. Such administration (> 1 mL/donkey) was easily accomplished by 1 investigator, requiring minimal restraint of the donkeys, and appeared to be well accepted by the recipients. Compared with IV administration, sublingual administration may provide for no pain and less distress for donkeys, a lesser degree of restraint required, and fewer technical skills for treatment delivery.
The large surface area and extensive blood supply of the oromucosal cavity allow drugs to be readily absorbed into the systemic circulation.15 The integrity of the oral cavity of donkeys was not systematically assessed throughout the present study, but results of oral examination at the end of the study led us to believe that the donkeys tolerated the gel formulation of detomidine well. Only 1 report16 exists of barely perceptible, diffuse, transient (< 4 hours' duration) erythema of oral mucous membranes in 2 of 9 horses that received detomidine gel sublingually.
In the present study, SS and HHAG were used to assess quality and depth of sedation, respectively. Donkeys developed obvious clinical signs of sedation after detomidine administration at both doses. Although onset of sedation occurred at 20 minutes after administration for a few donkeys, 40 to 50 minutes was required for all donkeys to have an SS ≥ 1 (at least mild sedation). The SS returned to baseline values by 180 minutes after treatment administration for most donkeys. Similar results were obtained for horses that received detomidine gel sublingually at 40 μg/kg: onset of sedation was noticed 20 minutes after treatment, maximum sedation was achieved 60 minutes after treatment, and sedative effects were maintained to 180 minutes after treatment.17 In the present study, the quality of sedation did not differ between detomidine doses for the 60- to 120-minute posttreatment period. Sedation of comparable quality was also identified in donkeys to which 4 doses (10 to 20 μg/kg [4.5 to 9 μg/lb]) of detomidine solution were administered IV in another study.10 The quality of sedation induced by various doses of detomidine is similar in donkeys.
Donkeys were assessed in pairs in the study reported here, and although the same 2 donkeys were always assessed together, some degree of comparison might have inadvertently occurred between the 2, potentially impacting SS assignment. A more complete picture of sedation quality could have been achieved by also scoring the response of donkeys to auditory stimuli and touch. However, the interventions required to assess such responses might have conditioned the donkeys to expect MNT testing to take place after the auditory and tactile stimulation test. If so, MNT readings would have been lower than the ones actually obtained. Assessments of SS and HHAG were purely observational and did not involve any type of interaction that may have affected MNT test results. Likewise, had MNT testing taken place before SS assessment, this would have affected the SS results by altering the posture and alertness of donkeys. Alternatively, sedation and hypoalgesia could have been assessed separately in different treatment trials.
Depth of sedation, assessed by HHAG, differed significantly in the present study between placebo and both doses of detomidine during the 30- to 180-minute posttreatment periods. Detomidine at 40 μg/kg induced deeper sedation than detomidine at the lower dose during the 60- to 120-minute posttreatment period, suggesting a dose-dependent effect. This was in contrast to the longer duration of sedation rather than the deeper sedation achieved with IV administration of increasing doses of detomidine solution to donkeys and horses.4,5,10,18 A decrease in HHAG was evident 30 minutes after detomidine administration at both doses, and the mean lowest HHAG values of 28% and 14% were recorded 70 and 65 minutes after administration of the 20 and 40 μg/kg doses, respectively. The HHAG values returned to baseline values by the end of the follow-up period (180 minutes after treatment) for detomidine gel at 20 μg/kg but not 40 μg/kg. In donkeys, IV administration of detomidine solution (10 to 20 μg/kg) results in similar mean lowest HHAG values (15% to 25%), but such values are achieved faster (median time after administration, 7.5 to 17.5 minutes).10 At a dose of 40 μg/kg, sublingual administration of detomidine gel to horses results in effects similar to those obtained in the present study. Onset of sedation occurs 20 to 30 minutes after administration; lowest HHAG values are attained 60 minutes after administration, and those results are variable (between approx 80% and 50%); and sedation persists to 180 minutes after administration.16,17,19
Sublingual administration of detomidine gel induces adequate sedation to facilitate the completion of common husbandry and veterinary procedures for which horses are commonly sedated.20 This type of treatment is also used prior to infiltration of local anesthetic and disbudding in calves21 and to provide sedation and anxiolysis to dogs to facilitate their handling.22 Although the study reported here revealed that sublingual administration of detomidine gel provided sedation for donkeys, the usefulness of these sedative effects needs to be assessed in clinical situations.
Mechanical nociceptive threshold testing is a robust technique to assess pain sensation and the hypoalgesic effects of drugs in equids, including donkeys.23,24 Although MNT testing is able to discriminate between sedation and hypoalgesia,14,25 this ability has been recently questioned, and additional studies are required to clarify this function.10 Mean baseline MNT values for donkeys of the present study were comparable to those for donkeys in other studies7,10,13,14 in which similar mechanical nociceptive testing devices and rates of application of force (approx 0.5 N/s) were used.
Sublingual administration of detomidine gel in the present study resulted in an increase in MNT, which is indicative of hypoalgesia. An overall increase in MNT was detected from 60 to 120 minutes and from 30 through 180 minutes after administration of detomidine gel at 20 and 40 μg/kg, respectively. However, no dose-dependent effect on MNT was identified with the 2 doses used. In contrast, IV administration of detomidine solution (10 to 20 μg/kg) to donkeys has a fast onset and induces dose-dependent mechanical hypoalgesia.10 In another study17 involving horses, when pressure algometry on the dorsal apex of the L6 spinous process and the medial gluteal muscles was used to assess MNT, sublingual administration of detomidine gel (40 μg/kg) resulted in an increase in MNT from 40 to 140 minutes after treatment.17 The results of studies involving healthy, pain-free equids suggest that sublingual administration of detomidine gel has the potential to induce analgesia. However, clinical trials involving donkeys and other equids in need of analgesics are required to evaluate the usefulness of detomidine gel for the pharmacological management of pain.
A high degree of variability among donkeys in SS, HHAG, and MNT values was identified in the present study. Every effort was made to ensure that the entire treatment dose was delivered and remained underneath the tongue. Although no loss of drug via expulsion from the mouth was observed, some of the dose may have been swallowed and undergone first-pass metabolism before reaching the systemic circulation.26 Sublingual administration of higher volumes of detomidine gel than were used in the present study might have increased the likelihood of swallowing. Although the donkeys received small volumes of detomidine gel (< 1 mL/treatment session), they received twice the volume when given the 40 (vs 20) μg/kg dose. This might have affected drug absorption, and dilution of the 20 μg/kg dose in the same vehicle as in the original gel formulation might have helped to overcome any bias related to the volume administered.
Interestingly, a great degree of variability in maximum plasma drug concentration and time to maximum plasma drug concentration has been reported for horses after sublingual administration of detomidine gel.27 The authors of that report suggested that differences among horses in pH of the oral cavity may also have contributed to this effect. Possible individual pharmacokinetic variations after sublingual administration of detomidine gel may have contributed to the variability in clinical effects among donkeys in the study reported here. However, the lack of available pharmacokinetic data for detomidine in donkeys precludes the drawing of conclusions. Additional studies are required to determine the pharmacokinetics in donkeys of various administration routes and formulations of detomidine to allow establishment of species-specific doses and administration intervals.
Snorting, prolapse of the penis, and micturition were noticed after sublingual administration of detomidine gel to donkeys in the present study. These effects have also been reported for horses that received detomidine gel sublingually8,19 and donkeys that received detomidine solution IV.7,10 The effects were transient and should not otherwise adversely affect healthy equids.
Bradycardia and atrioventricular blocks have also been reported for horses after sublingual administration of detomidine gel. These effects, correlated with maximum plasma detomidine concentration, were less pronounced than with IV or IM administration of detomidine solution and were partially reversed with administration of α2-adrenoceptor antagonists.16,17,19,27 Cardiovascular depression has also been reported for donkeys that receive detomidine solution IV and can also be partially reversed with α2-adrenoceptor antagonists.4,5,9 Although the cardiovascular effects of detomidine gel were not assessed in the present study, they should be considered when administering any detomidine formulation to donkeys.
The present study revealed that the sublingual administration of detomidine gel was easily performed by the authors, well tolerated by the donkeys, and effective at inducing sedation and mechanical hypoalgesia. Onset of sedation and hypoalgesia was observed approximately 40 minutes after treatment administration for most donkeys. Contrary to IV administration of detomidine solution,10 sublingual administration of detomidine gel induced sedation, but not mechanical hypoalgesia, in a dose-dependent manner in donkeys. Clinical studies are needed to assess the usefulness of the sedative and hypoalgesic effects achieved with detomidine gel after sublingual administration to donkeys.
Acknowledgments
Supported by an intramural grant from the Ross University School of Veterinary Medicine.
The authors declare that there were no conflicts of interest.
Presented in abstract form at the 47th European Veterinary Conference Voorjaarsdagen, Amsterdam, The Netherlands, April 2014.
ABBREVIATIONS
| AUC | Area under the effect change-versus-time curve |
| HHAG | Head height above the ground |
| MNT | Mechanical nociceptive threshold |
| SS | Sedation score |
Footnotes
Brer Rabbit, B&G Foods Inc, Parsippany, NJ.
Dormosedan Gel, Orion Corp, Turku, Finland.
Terumo 1-mL syringe, Terumo (Philippines) Corp, Biñan, Philippines.
Random.org list randomizer, Randomness and Integrity Services Ltd, Dublin, Ireland. Available at: www.random.org/lists. Accessed Oct 3, 2013.
Equine fly & mosquito spray, Manna Pro Corp, St Louis, Mo.
GraphPad Prism, version 4.0b for Macintosh, GraphPad Software, La Jolla, Calif.
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