African pygmy hedgehogs (Atelerix albiventris) are commonly kept as pets owing to their inquisitive, often convivial nature. Despite this popularity and their regular presentation for veterinary care, however, there is little information regarding analgesia in hedgehogs. Information on efficacious analgesic drugs is desperately needed for this species, as hedgehogs are frequently examined because of painful conditions, including neoplastic, urogenital, dental, and ocular disease.1,2 Suggested dosages of analgesic medications (eg, opioids and NSAIDs) for hedgehogs3–6 are routinely extrapolated from dosages determined to be efficacious in markedly different species, such as rodents, ferrets, and cats. This can lead to a multitude of problems, including poor efficacy and adverse effects. Poor analgesia during painful conditions has the potential to lead to deleterious physiologic consequences, especially in small exotic mammals with high metabolic rates and a low tolerance for stress.7,8
Buprenorphine is a potent, partial μ-opioid receptor agonist that is widely used in veterinary medicine.9 It has a relatively longer onset and duration of action than other opioids, is considered nonsedating, and has few adverse effects.10 Because of these characteristics, it is frequently used for pain management in animals. Buprenorphine is readily commercially available in an injectable form, is one of the most commonly used analgesic drugs in small exotic mammals, and is often recommended for use specifically in hedgehogs.2,3,9,11,12 However, its efficacy and potential for adverse effects in this species are unknown. Currently recommended dosages for buprenorphine in hedgehogs range from 0.01 to 0.5 mg/kg (0.0045 to 0.23 mg/lb) with a recommended dosing frequency of 6 to 12 hours.1,3,4,11 Buprenorphine has a high therapeutic index in rodents.13 Reported adverse effects in rats include ingestion of wood-based bedding material or pica14; however, these adverse effects were not reported in studies15,16 with chinchillas and guinea pigs.
The goal of the study reported here was to determine the antinociceptive efficacy and safety of SC buprenorphine administration in hedgehogs. Our hypothesis was that buprenorphine would provide antinociception for up to 12 hours and mild sedation in hedgehogs when used at currently recommended dosages.
Materials and Methods
Animals
The study protocol was approved by the University of Wisconsin-Madison School of Veterinary Medicine Institutional Animal Care and Use Committee (protocol V005874). Twelve captive-bred African pygmy hedgehogs (7 males and 5 females) that were 7 to 8 months old and had a mean ± SD weight of 430 ± 100 g (0.95 ± 0.22 lb) were used in the study. Animals were housed in a climate-controlled room with a photoperiod of 12 hours of light and 12 hours of darkness and a room temperature of 27°C (80°F). Hedgehogs were housed individually in ventilated enclosures measuring 84 × 51 × 36 cm (33 × 20 × 14 inches). Each enclosure was lined with a cardboard substrate and contained a hide box and exercise wheel; shredded paper was provided for burrowing. Hedgehogs were offered fresh water ad libitum in a bowl and maintained on a commercial hedgehog diet. All hedgehogs were acclimated to the housing conditions for several weeks prior to the study and were deemed healthy on the basis of results of a routine CBC and serum biochemical panel, serial physical examinations, and long-term monitoring of food intake and body weight. Food was not withheld prior to the trials. Trials occurred in a separate climate-controlled room maintained within 3°C (5°F) of the temperature for the housing room.
Drug administration
Buprenorphinea or an equivalent volume of sterile saline (0.9% NaCl) solution was administered SC with an insulin syringeb under the dorsal-spined skin (ie, mantle) at a depth of 1.3 cm (0.5 inches) in an area over the right scapula.
Antinociceptive evaluation
Analgesimetry was performed with a Hargreaves apparatusc as described for other species.17 Briefly, animals were placed in ventilated measurement chambers (22 × 17 × 13.5 cm [8.6 × 6.7 × 5.3 inches]) positioned on a heated glass surface maintained at 29°C (84°F). The animals were unable to visualize the observer because the walls of the chambers were opaque. A noxious infrared radiant heat stimulus (50% maximum intensity) was applied to the metatarsal pad of a hind limb, and the latency of limb withdrawal was recorded in seconds. The same hind limb metatarsal pad was used for all treatments. If hedgehogs adopted a rolled-up defensive posture such that the pad could not be reliably accessed for analgesimetry, the hedgehog was gently removed from the chamber and then replaced. Following repositioning, the hedgehog was allowed to acclimate to the chamber for a minimum of 1 minute before measurement was reattempted. The skin of the metatarsal pad used for thermal testing was examined for gross abnormalities (eg, erythema, swelling, erosions, or ulcerations) prior to each measurement. The thermal stimulus was immediately terminated when the hedgehog moved the limb to which the stimulus was applied. To prevent tissue damage, the stimulus was turned off after 20 seconds if no withdrawal response had occurred prior to this time. Thermal withdrawal latency measurements for each time point, including baseline measurements, were performed in duplicate 5 minutes apart. If these 2 measurements varied by > 20%, a third measurement was performed, and the 3 latencies were averaged. Hedgehogs were placed in the Hargreaves chamber 5 minutes prior to measurement and were removed from the chamber immediately after each measurement. A single observer (GAD) who was blinded to the treatment administered all injections and performed all measurements.
Sedation scoring
At the time of each thermal withdrawal latency measurement, hedgehogs were evaluated while being moved into the Hargreaves chamber for evidence of sedation with a scoring system based on behavioral responses to handling and auditory stimuli (Appendix). A baseline sedation score was assigned prior to injection of buprenorphine. Potential sedation scores ranged from 0 to 2.
Experimental protocol
Three experimental trials were performed to assess the antinociceptive efficacy and safety of SC buprenorphine administration.
Low-dose buprenorphine trial—In a randomized, blinded, complete crossover design, the 12 hedgehogs each received a single SC injection of buprenorphine at a dose of 0.01 mg/kg (0.0045 mg/lb), buprenorphine at a dose of 0.03 mg/kg (0.014 mg/lb), or sterile saline solution at a dose of 0.16 mL/kg (0.073 mL/lb); treatments were administered in random order with a minimum 7-day washout period between treatments. Baseline thermal withdrawal latency was measured, and sedation was scored in each hedgehog 5 minutes prior to each injection. Additional assessments were performed 0.5, 4, 12, 24, 36, 48, and 72 hours after each injection.
High-dose buprenorphine trial—Because no overt adverse effects were noted when hedgehogs were given buprenorphine at a dose of 0.01 or 0.03 mg/kg, treatment with a higher dose was tested to determine whether a higher dose would result in greater antinociceptive effects and a longer duration of action. Six hedgehogs (3 males and 3 females) were given single SC injections of buprenorphine at a dose of 0.05 mg/kg (0.023 mg/lb) or sterile saline solution at a dose of 0.16 mL/kg, with treatments administered in random order and a minimum 7-day washout period between treatments. Baseline thermal withdrawal latency was measured and sedation was scored in each hedgehog 5 minutes prior to each injection. Additional assessments were performed 0.5, 4, 12, 24, 36, 48, 72, and 96 hours after each injection.
Multidose buprenorphine trial—In 10 hedgehogs (5 males and 5 females), the effects of 3 doses of buprenorphine (0.05 mg/kg, SC, q 24 h) were compared with the effects of 3 doses of saline solution (0.16 mL/kg, SC, q 24 h). Food intake and body weight were measured every 24 hours, during the same 1-hour window each morning; sedation was scored once daily during handling for weighing. Baseline values were obtained for 48 hours prior to each treatment, and assessments were continued for 6 days after the third dose was given. A single individual (GAD) blinded to treatment performed all measurements.
Statistical analysis
For each experimental trial, treatment sequences were randomized with free online softwared; standard commercial softwaree was used for all data analyses. Data were evaluated for a normal distribution with the Shapiro-Wilk test (data were transformed if necessary) and for equality of group variances with the Brown-Forsythe test. Data were analyzed for effects of drug and time by use of repeated-measures 2-way ANOVA with the Holm-Sidak method used for post hoc analyses. Values of P < 0.05 were considered significant. Data are reported as mean ± SD unless otherwise indicated.
Results
In the first trial, the change in hind limb thermal withdrawal latency was significantly higher 4 and 36 hours after injection when hedgehogs were given buprenorphine at a dose of 0.01 mg/kg and 4, 36, and 48 hours after injection when hedgehogs were given buprenorphine at a dose of 0.03 mg/kg, compared with the change in latency when hedgehogs were given saline solution (Figure 1). In the second trial, hind limb thermal withdrawal latency was significantly (P ≤ 0.01) higher from 0.5 to 48 hours after injection of buprenorphine at a dose of 0.05 mg/kg, compared with latency after hedgehogs were given saline solution (Figure 2). The magnitude of hind limb thermal withdrawal latencies was greater following administration of buprenorphine at a dose of 0.05 mg/kg than after administration of buprenorphine at a dose of 0.01 or 0.03 mg/kg.
Mean ± SEM change in hind limb thermal withdrawal latency for 12 African pygmy hedgehogs (Atelerix albiventris) administered buprenorphine SC at a dose of 0.01 mg/kg (0.0045 mg/lb; gray circles), buprenorphine SC at a dose of 0.03 mg/kg (0.014 mg/lb; black circles), or saline (0.9% NaCl) solution SC at a dose of 0.16 mL/kg (0.073 mL/lb [control]; white circles) in a randomized, blinded, complete crossover experiment. *Significantly (P < 0.05) different from the value for the control treatment. †Significant (P < 0.05) effect of treatment in the overall model.
Citation: Journal of the American Veterinary Medical Association 257, 6; 10.2460/javma.257.6.618
Mean ± SEM change in hind limb thermal withdrawal latency for 12 African pygmy hedgehogs (Atelerix albiventris) administered buprenorphine SC at a dose of 0.01 mg/kg (0.0045 mg/lb; gray circles), buprenorphine SC at a dose of 0.03 mg/kg (0.014 mg/lb; black circles), or saline (0.9% NaCl) solution SC at a dose of 0.16 mL/kg (0.073 mL/lb [control]; white circles) in a randomized, blinded, complete crossover experiment. *Significantly (P < 0.05) different from the value for the control treatment. †Significant (P < 0.05) effect of treatment in the overall model.
Citation: Journal of the American Veterinary Medical Association 257, 6; 10.2460/javma.257.6.618
Mean ± SEM change in hind limb thermal withdrawal latency for 12 African pygmy hedgehogs (Atelerix albiventris) administered buprenorphine SC at a dose of 0.01 mg/kg (0.0045 mg/lb; gray circles), buprenorphine SC at a dose of 0.03 mg/kg (0.014 mg/lb; black circles), or saline (0.9% NaCl) solution SC at a dose of 0.16 mL/kg (0.073 mL/lb [control]; white circles) in a randomized, blinded, complete crossover experiment. *Significantly (P < 0.05) different from the value for the control treatment. †Significant (P < 0.05) effect of treatment in the overall model.
Citation: Journal of the American Veterinary Medical Association 257, 6; 10.2460/javma.257.6.618
Mean ± SEM hind limb thermal withdrawal latency for 6 African pygmy hedgehogs administered buprenorphine SC at a dose of 0.05 mg/kg (0.023 mg/lb; black circles) or sterile saline solution SC at a dose of 0.16 mL/kg (control; white circles) in a randomized, blinded, complete crossover experiment. *Values differed significantly (P < 0.05) between treatments.
Citation: Journal of the American Veterinary Medical Association 257, 6; 10.2460/javma.257.6.618
Mean ± SEM hind limb thermal withdrawal latency for 6 African pygmy hedgehogs administered buprenorphine SC at a dose of 0.05 mg/kg (0.023 mg/lb; black circles) or sterile saline solution SC at a dose of 0.16 mL/kg (control; white circles) in a randomized, blinded, complete crossover experiment. *Values differed significantly (P < 0.05) between treatments.
Citation: Journal of the American Veterinary Medical Association 257, 6; 10.2460/javma.257.6.618
Mean ± SEM hind limb thermal withdrawal latency for 6 African pygmy hedgehogs administered buprenorphine SC at a dose of 0.05 mg/kg (0.023 mg/lb; black circles) or sterile saline solution SC at a dose of 0.16 mL/kg (control; white circles) in a randomized, blinded, complete crossover experiment. *Values differed significantly (P < 0.05) between treatments.
Citation: Journal of the American Veterinary Medical Association 257, 6; 10.2460/javma.257.6.618
For all 3 experimental trials, the sedation score was 0 for all hedgehogs at all assessment times. One of the 12 hedgehogs had increased, nonataxic locomotor activity when placed in the testing chamber 4 hours after administration of a single 0.03-mg/kg dose of buprenorphine; increased locomotor activity was not observed in this hedgehog following administration of saline solution. Two of the 6 hedgehogs had increased locomotor activity when placed in the testing chamber after administration of a single 0.05-mg/kg dose of buprenorphine. This period of hyperactivity consisted of an abnormally long initial period of ambulation after being placed in the testing chamber, in contrast to the typical response of assuming a balled-up body position. No ataxia was noted. Increased locomotor activity was seen in the 2 hedgehogs 0.5 hours after the injection and again in 1 of these hedgehogs 4 hours after the injection. Increased locomotor activity was not seen in either of these hedgehogs following administration of saline solution.
In the multidose trial involving administration of 3 doses of buprenorphine (0.5 mg/kg, SC, q 24 h) or saline solution, there were no significant differences in food intake or body weight either within or between treatments.
Discussion
Results of the present study indicated that in African pygmy hedgehogs, SC administration of buprenorphine at doses ranging from 0.01 to 0.05 mg/kg resulted in long-lasting antinociception and did not produce sedation. Additionally, administration of buprenorphine at a dosage of 0.05 mg/kg every 24 hours for 3 days had no significant effect on food intake or body weight.
Buprenorphine is considered a long-lasting opioid, with reported analgesic duration varying depending on dose administered and species. Recommended dosing intervals typically range from 4 to 12 hours for small exotic mammals.18 In the present study, SC administration of single 0.01-, 0.03-, and 0.05-mg/kg doses of buprenorphine resulted in a significant increase in thermal withdrawal latencies in hedgehogs that lasted from 36 to 48 hours, depending on the dose administered. This duration of antinociceptive effect was substantially longer than durations previously reported for other mammals and was comparable to durations reported following administration of sustained-release and depot formulations of buprenorphine to cats and small exotic mammals.15,19
There are several possible factors that could explain the prolonged effects observed in the present study. Numerous aspects, including properties of the drug itself or drug vehicle, activity of the drug at the injection site, blood supply at the injection site, volume of injection, injection technique, and even individual patient variation, can have an effect on the pharmacokinetics of injected drugs.20 Both the injection route and properties of buprenorphine likely played a major role in the prolonged antinociceptive duration we observed. Owing to the large adipose tissue layer in the mantle of hedgehogs, SC injections administered in this area can easily result in intra-adipose drug deposition, and it has been suggested that injections in the mantle of hedgehogs may result in delayed absorption owing to poor vascularization.1 Given the depth of injection used in the present study, intra-adipose administration of buprenorphine likely occurred, prolonging absorption. In pigs, absorption of lipophilic drugs administered in adipose tissue was markedly prolonged when compared with absorption of the same compounds administered IM.21 Further research investigating the pharmacokinetics of buprenorphine in hedgehogs following injection by various routes would help determine what factors may have led to the prolonged antinociceptive effect seen in the present study.
In the present study, the magnitude of antinociceptive effect was higher following administration of buprenorphine at a dose of 0.05 mg/kg than was observed following administration at the 2 lower doses. Similar dose-dependent antinociceptive effects have been reported with buprenorphine in cats22 and may be relevant when determining buprenorphine dosing in hedgehogs. Given the results of our study, 0.05 mg/kg may be a more suitable dose of buprenorphine when treating more severe pain in hedgehogs, whereas doses of 0.01 and 0.03 mg/kg could be more appropriate for less painful conditions. However, because the efficacy of opioids can vary depending on the nociceptive test used,9 further research on the use of buprenorphine in hedgehogs is needed. Studies investigating clinical pain in hedgehogs through development of surgical nociception models and validated pain-scoring systems would assist in validating the findings of the thermal nociception model and help establish accurate analgesic protocols for various painful conditions in this species.
The time to onset of antinociceptive effects was noticeably faster following administration of buprenorphine at a dose of 0.05 mg/kg, when compared with the onset of effects following administration at the 2 lower doses. This finding suggested that in hedgehogs, buprenorphine would ideally be administered 30 minutes to several hours prior to a painful stimulus, depending on the dose used. However, further research evaluating the use of buprenorphine in hedgehogs is needed before definitive recommendations regarding dosing timing can be made.
Increased locomotor activity was seen in several hedgehogs in the present study following administration of buprenorphine at a dose of 0.03 or 0.05 mg/kg. This adverse effect of buprenorphine has been reported in mice, albeit at higher doses (0.1 to 2.0 mg/kg [0.045 to 0.91 mg/lb], SC) than the ones evaluated in our study.13,23 Buprenorphine appears to have variable effects on activity in rats. Subcutaneous administration of buprenorphine at doses of 0.01 and 0.05 mg/kg in rats resulted in a significant increase in activity.24 However, in another study,25 SC administration of buprenorphine at a dose of 0.05 mg/kg decreased voluntary running wheel activity in rats. The increased locomotor activity seen in the hedgehogs of the present study was noted to occur for up to 4 hours after buprenorphine administration. This was comparable to findings for mice, in which a single dose of buprenorphine resulted in increased locomotor activity for approximately 4 hours.23 The increased locomotor activity noted with the hedgehogs in the present study is likely to have little clinical relevance, considering its short duration and lack of accompanying ataxia.
Repeated doses of buprenorphine did not have a clinically relevant effect on food intake or body weight in hedgehogs of the present study. This minimal effect on food intake was in contrast to findings in rats, in which buprenorphine resulted in a significant decrease in food intake.24,26 Similar to findings of the present study, however, buprenorphine had little effect on body weight in chinchillas.16
A limitation of our study was that efficacy and safety of buprenorphine were evaluated in healthy hedgehogs, whereas this drug is most likely to be used in debilitated patients. Although the effects of buprenorphine on food intake and body weight in the present study were minimal, this may not be true in ill patients. Veterinarians should exercise caution when extrapolating the results of our study for the treatment of ill hedgehogs. Hedgehogs in our study were not monitored for alterations in food intake or body weight following single doses of buprenorphine. However, because administration of multiple 0.05-mg/kg doses had no clinically relevant effect on these variables, it was anticipated that SC administration of single 0.01-, 0.03-, and 0.05-mg/kg doses of buprenorphine would have similar results.
In rodents, repeated thermal nociceptive testing can result in a facilitation phenomenon, whereby high stimulus intensities and frequent measurements can result in increased nociceptive receptor activity.27 To minimize this possibility in the present study, a minimum of 300 seconds elapsed between individual measurements, and the Hargreaves apparatus thermal stimulus intensity was set to a maximum of 50% to allow the paw used for measurement to return as close to baseline temperature as possible.
In conclusion, SC administration of buprenorphine at single doses of 0.01, 0.03, and 0.05 mg/kg provided safe, long-lasting antinociception in African pygmy hedgehogs without apparent sedative effects. Administration of multiple 0.05-mg/kg doses of buprenorphine at 24-hour intervals did not have clinically relevant effects on food intake or body weight. Increased locomotor activity was noted in some hedgehogs following buprenorphine administration. Further research in this species is needed to help determine the best approach to providing analgesia for painful conditions.
Acknowledgments
Supported by a grant from the Association of Exotic Mammal Veterinarians. The funding source 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.
Footnotes
Buprenex (0.3 mg/mL), Hospira, Lake Forest, Ill.
U-100 insulin syringe (29 gauge, 0.3 mL), UltiCare VetRx, Excelsior, Minn.
Plantar Analgesia Meter, ITTC Life Science, Woodland Hills, Calif.
Research Randomizer, version 4.0, Urbaniak GC, Plous S, Middletown, Conn. Available at: www.randomizer.org. Accessed Sep 17, 2018.
SigmaPlot, version 13, Systat Software, San Jose, Calif.
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Appendix
System used to score sedation after SC administration of sterile saline (0.9% NaCl) solution or buprenorphine hydrochloride in African pygmy hedgehogs (Atelerix albiventris).
| Score | Description |
|---|---|
| 2 | Lethargic; hedgehog does not roll up despite stimulation and does not resist handling; hedgehog can be easily grabbed by the scruff of the neck without resistance. |
| 1 | Inactive; hedgehog rarely rolls into ball despite stimulation and mildly resists handling; hedgehog can be grabbed by the scruff of the neck with difficulty. |
| 0 | Active; hedgehog quickly rolls into a ball when stimulated and greatly resists handling; hedgehog cannot be grabbed by the scruff of the neck. |
