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  • 21. Morgan D, Cook CD, Smith MA, et al. An examination of the interactions between the antinociceptive effects of morphine and various μ-opioids: the role of intrinsic efficacy and stimulus intensity. Anesth Analg 1999; 88: 407413.

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Antinociceptive effects of intravenous administration of hydromorphone hydrochloride alone or followed by buprenorphine hydrochloride or butorphanol tartrate to healthy conscious cats

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  • 1 Department of Clinical Sciences, School of Veterinary Medicine, Ross University, St Kitts, West Indies.
  • | 2 Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, QC J2S 8H5, Canada.
  • | 3 Department of Biomedical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, QC J2S 8H5, Canada.
  • | 4 Department of Biomedical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, QC J2S 8H5, Canada.
  • | 5 Department of Biomedical Sciences, School of Veterinary Medicine, Ross University, St Kitts, West Indies.

Abstract

OBJECTIVE To evaluate antinociceptive effects of IV administration of hydromorphone alone or followed by buprenorphine or butorphanol to cats.

ANIMALS 6 healthy adult cats.

PROCEDURES In a randomized, blinded crossover design, cats received each of 4 treatments in which 2 IV injections were given 30 minutes apart: 2 of saline (0.9% NaCl) solution (Sal-Sal) or 1 each of hydromorphone HCl and saline solution (H-Sal), hydromorphone and buprenorphine HCl (H-Bupre), or hydromorphone and butorphanol tartrate (H-Butor). Skin temperature and thermal threshold were recorded before (baseline) and for 12 hours after the first injection. Percentage of maximum possible effect (%MPE) and thermal excursion (TE) were compared among treatments and measurement points.

RESULTS Compared with baseline values, skin temperature was higher from 0.75 to 2 hours after the first injection for H-Sal; at 0.5, 1, 3, and 4 hours for H-Bupre; from 0.5 to 3 hours for H-Butor; and from 0.5 to 1 hours for Sal-Sal. Thermal excursion was higher than at baseline from 0.25 to 2 hours for H-Sal and H-Bupre and 0.25 to 0.75 hours for H-Butor; %MPE increased from 0.25 to 2 hours for H-Sal, 0.25 to 3 hours for H-Bupre, and 0.25 to 0.75 hours for H-Butor. Results were similar for comparisons with Sal-Sal, except TE was greater for H-Sal versus Sal-Sal and TE and %MPE were greater for H-Bupre versus Sal-Sal from 0.25 to 1 hours after the first injection.

CONCLUSIONS AND CLINICAL RELEVANCE Butorphanol administration decreased the duration of antinociception achieved with hydromorphone administration in cats. This opioid interaction and its impact on pain management require additional investigation.

Abstract

OBJECTIVE To evaluate antinociceptive effects of IV administration of hydromorphone alone or followed by buprenorphine or butorphanol to cats.

ANIMALS 6 healthy adult cats.

PROCEDURES In a randomized, blinded crossover design, cats received each of 4 treatments in which 2 IV injections were given 30 minutes apart: 2 of saline (0.9% NaCl) solution (Sal-Sal) or 1 each of hydromorphone HCl and saline solution (H-Sal), hydromorphone and buprenorphine HCl (H-Bupre), or hydromorphone and butorphanol tartrate (H-Butor). Skin temperature and thermal threshold were recorded before (baseline) and for 12 hours after the first injection. Percentage of maximum possible effect (%MPE) and thermal excursion (TE) were compared among treatments and measurement points.

RESULTS Compared with baseline values, skin temperature was higher from 0.75 to 2 hours after the first injection for H-Sal; at 0.5, 1, 3, and 4 hours for H-Bupre; from 0.5 to 3 hours for H-Butor; and from 0.5 to 1 hours for Sal-Sal. Thermal excursion was higher than at baseline from 0.25 to 2 hours for H-Sal and H-Bupre and 0.25 to 0.75 hours for H-Butor; %MPE increased from 0.25 to 2 hours for H-Sal, 0.25 to 3 hours for H-Bupre, and 0.25 to 0.75 hours for H-Butor. Results were similar for comparisons with Sal-Sal, except TE was greater for H-Sal versus Sal-Sal and TE and %MPE were greater for H-Bupre versus Sal-Sal from 0.25 to 1 hours after the first injection.

CONCLUSIONS AND CLINICAL RELEVANCE Butorphanol administration decreased the duration of antinociception achieved with hydromorphone administration in cats. This opioid interaction and its impact on pain management require additional investigation.

Opioid administration may provide analgesia and antinociception in cats.1–3 Hydromorphone is a synthetic full agonist of μ-opioid receptors that is commonly administered to treat moderate to severe pain in cats and dogs.3–6 Butorphanol is an agonist of κ-opioid receptors and antagonist of μ-opioid receptors, with a short duration of antinociception, compared with that of morphine and buprenorphine.6–9 That drug is suitable for treatment of mild to moderate pain.6,10 Buprenorphine is generally considered a partial agonist of μ-opioid receptors, although some classification systems include this drug as an antagonist of κ-opioid receptors or of μ-opioid receptors at high doses; the drug provides a varying range of analgesia in cats.2,6,11,12

Antinociceptive or analgesic effects of administration of a combination of different classes of opioids to cats have been reported.8,9,13 However, the associated studies8,9,13 did not include evaluation of antinociceptive effects when a full agonist of μ-opioid receptors was administered alone and a different class of opioid was administered sequentially. In clinical practice, cats may receive morphine or hydromorphone as part of the premedication protocol for routine ovariohysterectomy. Then, at the end of surgery, buprenorphine may be administered to provide postoperative analgesia.14 In that situation, whether buprenorphine decreases the magnitude of analgesia or whether the drug may actually extend the duration of analgesia induced by hydromorphone is unclear.

Thermal threshold testing is an important tool for predicting clinical efficacy of opioid analgesics in cats.5,10,15,16 The purpose of the study reported here was to evaluate thermal antinociception induced by IV administration of hydromorphone alone or with buprenorphine or butorphanol given sequentially to healthy conscious cats. The hypothesis was that administration of hydromorphone followed by buprenorphine or butorphanol would decrease the degree of thermal antinociception relative to that provided with hydromorphone alone.

Materials and Methods

Animals

Six healthy research-bred adult domestic shorthair cats (5 castrated males and 1 spayed female) with a mean ± SD body weight of 5.14 ± 0.6 kg were included in the study. Mean age was 3.9 ± 0.8 years. Cats were deemed healthy on the basis of their clinical history and results of physical examination, CBC, and serum biochemical analysis. Before the study began, cats received deworming medication and were vaccinated against Chlamydia psittaci and panleukopenia, calicivirus, and feline rhinotracheitis viruses. Results of PCR assays to detect FIV and FeLV infection were negative.

Cats remained in a facility with a controlled light cycle that alternated between 12 hours of light and 12 hours of dark and controlled temperature and humidity. Cats were housed together as a free-ranging colony at all times except during the acclimatization phase and testing period, in which they were housed individually in adjacent cages. Such housing was in accordance with Canadian Animal Care Council guidelines. Cats had been well handled and acclimated to the testing procedure, thermal threshold device, facilities, and observers for 28 days before the study began. Behavioral reactions associated with thermal stimulation were documented for each cat. Food was not withheld from cats prior to study drug administration. Water was available at all times, and food was offered twice daily. The study protocol was approved by the local animal care committee of the Faculty of Veterinary Medicine, University of Montreal.

Thermal nociceptive threshold testing

Antinociception was evaluated by means of a thermal threshold system that involved an infrared wireless remote control.a Briefly, a probe containing a heating element and temperature sensor was held against the shaved skin of the lateral aspect of the thorax by an elasticized band,17 and skin temperature was recorded. For thermal threshold testing, a ramped heat stimulus (rate of increase, 0.6°C/s) was then applied via a handheld remote unit and stopped when a withdrawal behavioral response (ie, jumping, flinching, vocalization, or turning toward the probe) was observed; the recorded temperature was considered the thermal threshold. A safety cutoff of 55°C was used to prevent burns if no reaction was observed, and this value was considered the thermal threshold in those situations. The probe was calibrated before the study in accordance with the manufacturer's instructions.

Prior to treatment administration, 3 recordings were performed at 15-minute intervals and their mean value calculated to indicate the baseline thermal threshold. Treatments were then administered, and thermal threshold was measured 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, and 12 hours after the first injection. Results of previous studies5,7,9 involving use of the thermal threshold method in cats have suggested that onset, magnitude, and duration of antinociception can be observed after opioid administration when these measurement points are used. The device was removed for 1 hour between the 2-hour testing intervals to give cats an opportunity to rest. Adverse effects were monitored and recorded. One observer (BTS) performed thermal threshold testing and was blinded to treatment administration.

Treatments

Prior to measurement of thermal threshold, the cranial aspect distal to 1 elbow joint was shaved. An eutectic mixture of local anestheticb was applied to the area over the cephalic vein and covered with plastic wrap and a light bandage.c After baseline thermal threshold was measured, the bandage was removed and a 22-gauge, 2.54-cm catheterd was inserted into the cephalic vein.

In a randomized, blinded, placebo-controlled crossover design, cats were randomly assigned to the order in which they would receive each of the 4 following treatments in which 2 IV injections were given 30 minutes apart: 2 injections of saline (0.9% NaCl) solutione (0.5 mL/injection; Sal-Sal) or 1 injection each of hydromorphone HClf (0.1 mg/kg) and saline solution (0.5 mL; H-Sal), hydromorphone HCl (0.1 mg/kg) and buprenorphine HClg (0.02 mg/kg; H-Bupre), or hydromorphone HCl (0.1 mg/kg) and butorphanol tartrateh (0.2 mg/kg; H-Butor). Treatments were administered IV to minimize variability in drug absorption and were based on doses used in other feline studies5,9 involving the thermal threshold device. Timing of administration was based on clinical experience whereby cats would receive hydromorphone as part of the premedication protocol before undergoing ovariohysterectomy and potentially a second and different class of opioid at endotracheal extubation approximately 30 minutes later.

The first IV injection was given soon after catheter placement, and the second IV injection was administered immediately after the 0.5-hour thermal threshold reading; the catheter was then removed. Each IV injection was performed over a 15-second period, and the catheter was subsequently flushed with 2 mL of saline solution. Catheter placement and treatment administration were performed by 2 veterinarians (BPM and PVS) in a room separate from that in which thermal threshold testing was performed; these individuals were not involved with thermal threshold testing. A 7-day washout period was allowed between testing sessions, and side of the thorax used for testing alternated between sessions.

Statistical analysis

Statistical analysis was performed by use of statistical software.i Normal distribution of data was confirmed by use of the Shapiro-Wilk test. Thermal excursion and %MPE were analyzed for changes over time from baseline values (0 hours) and from posthydromorphone values (0.5 hours after hydromorphone administration) with 1-way repeated-measures ANOVA, followed by the Dunnett test when appropriate. Thermal excursion was calculated as the difference between thermal threshold temperature and skin temperature prior to application of the thermal stimulus.16 Percentage of maximum possible effect was determined on the basis of the following equation:

article image

This value (%MPE) takes into account the cutoff temperature (55°C) of the thermal threshold device used to avoid thermal burns, interanimal differences, and intra-animal variability in baseline thresholds between treatments. The %MPE has been used as another method to evaluate changes in thermal threshold after analgesic treatment.18,19 Temporal changes in skin temperature from baseline were also evaluated with 1-way repeated-measures ANOVA, followed by the Dunnett test when appropriate.

Treatment results were compared by means of 2-way ANOVA, followed by the Bonferroni test, with time and treatment dealt with as categorical data. Before the study had begun, a power analysis was conducted, revealing that 6 cats would be sufficient to detect a significant difference, with a thermal threshold difference of > 2.5°C between treatments (α = 0.05; β = 0.20). Summary data are reported as mean ± SD. Values of P < 0.05 were considered significant for all analyses.

Results

Animals

No adverse effects were observed in cats after IV administration of the placebo treatment (Sal-Sal). Overall, signs of euphoria (ie, rolling, kneading with forepaws, vocalizing, and purring)8 were evident after all opioid treatments for all 6 cats. These effects were identified for up to 6 hours after the first IV injection for each opioid treatment combination (H-Sal, H-Butor, and H-Bupre). Two cats vomited (1 after receiving H-Sal and the other after receiving H-Butor) 10 hours and 6 hours after the first drug administration, respectively. Another cat had signs of lip licking and hypersalivation during H-Sal administration. Dysphoria and excitement were not observed for any cat at any point.

Mean ± SD baseline skin temperature for all treatments (n = 24) was 37 ± 0.5°C. Compared with baseline values, skin temperature was significantly greater for cats 0.25 to 1 hour after the first IV injection for Sal-Sal; 0.75 to 2 hours after the first injection for H-Sal; 0.5, 1, 3, and 4 hours after the first injection for H-Bupre; and 0.5 to 3 hours after the first injection for H-Butor (Table 1). Maximum skin temperatures for placebo, H-Sal, H-Bupre, and H-Butor administration were 38.1°, 38.6°, 38.4°, and 38.5°C, respectively. Mean baseline thermal threshold for all treatments (n = 24) was 45.1 ± 2.8°C and did not differ significantly among treatments or from baseline values at any point (Table 2).

Table 1—

Mean ± SD skin temperature (°C) immediately before (0 hours; baseline) and at various points after sequential (30 minutes apart) IV administration of 2 doses of saline (0.9% NaCl) solution, hydromorphone HCl (0.1 mg/kg) followed by saline solution (H-Sal), hydromorphone HCl (0.1 mg/kg) followed by buprenorphine HCl (0.02 mg/kg; H-Bupre), or hydromorphone HCl (0.1 mg/kg) followed by butorphanol tartrate (0.2 mg/kg; H-Butor) to each of 6 cats.

 Time (h)
Treatment00.250.50.751234681012
Sal-Sal36.8 ± 0.437.2 ± 0.6*37.4 ± 0.6*37.5 ± 0.6*37.5 ± 0.6*36.9 ± 0.637.0 ± 0.336.7 ± 0.736.5 ± 0.536.8 ± 0.436.6 ± 0.436.9 ± 0.5
H-Sal37.0 ± 0.537.3 ± 0.437.5 ± 0.537.7 ± 0.5*37.7 ± 0.4*37.9 ± 0.5*37.8 ± 0.337.5 ± 0.336.9 ± 0.236.9 ± 0.436.8 ± 0.437.1 ± 0.7
H-Bupre36.9 ± 0.737.3 ± 0.737.7 ± 0.5*37.5 ± 0.437.7 ± 0.4*37.5 ± 0.438.0 ± 0.3*37.8 ± 0.4*37.1 ± 0.237.2 ± 0.236.8 ± 0.337.0 ± 0.3
H-Butor37.0 ± 0.337.3 ± 0.537.6 ± 0.3*37.9 ± 0.5*37.9 ± 0.4*37.8 ± 0.4*37.6 ± 0.6*37.7 ± 0.637.1 ± 0.337.4 ± 0.337.1 ± 0.637.2 ± 0.6

Value differs significantly (P < 0.05) from the baseline value for the same treatment.

Value differs significantly (P < 0.05) from the value for Sal-Sal at the same measurement point.

A crossover study design was used, with all cats receiving all 4 treatments, and each treatment separated from the next by a 7-day washout period. The 0.5-hour measurement point represents the point at which the second injection was administered (ie, 30 minutes after the first injection).

Table 2—

Mean ± SD thermal threshold (°C) before (0 hours; baseline) and at various points after sequential (30 minutes apart) IV administration of 4 treatments to the cats in Table 1.

 Time (h)
Treatment00.250.50.751234681012
Sal-Sal44.3 ± 1.344.6 ± 1.744.5 ± 1.644.5 ± 2.043.8 ± 1.745.1 ± 3.245.2 ± 2.744.8 ± 3.544.4 ± 2.045.0 ± 2.343.6 ± 2.144.9 ± 1.9
H-Sal45.2 ± 2.352.0 ± 3.751.3 ± 3.250.5 ± 2.250.5 ± 3.550.9 ± 2.448.5 ± 4.348.3 ± 3.745.0 ± 2.145.4 ± 2.544.6 ± 2.544.6 ± 2.3
H-Bupre44.5 ± 2.253.5 ± 2.552.0 ± 3.951.8 ± 4.049.9 ± 4.149.5 ± 3.649.2 ± 3.748.3 ± 3.648.0 ± 3.647.0 ± 2.545.5 ± 2.146.2 ± 2.5
H-Butor46.0 ± 2.252.1 ± 4.353.2 ± 2.550.6 ± 3.947.9 ± 1.849.6 ± 3.047.2 ± 3.147.3 ± 3.547.1 ± 3.446.5 ± 1.947.7 ± 4.245.7 ± 3.2

See Table 1 for key.

Thermal excursion was significantly higher than at baseline from 0.25 to 2 hours after the first injection for H-Sal, from 0.25 to 2 hours after the first injection for H-Bupre, and from 0.25 to 0.75 hours after the first injection for H-Butor (Table 3). Percentage of maximum possible effect was higher than at baseline from 0.25 to 2 hours after the first injection for H-Sal, from 0.25 to 3 hours after the first injection for H-Bupre, and from 0.25 to 0.75 hours after the first injection for H-Butor. No significant differences from baseline values in thermal excursion and %MPE were detected for Sal-Sal.

Table 3—

Mean ± SD thermal excursion (°C) and %MPE before (0 hours; baseline) and at various points after sequential (30 minutes apart) IV administration of 4 treatments to the cats in Table 1.

 Time (h)
Treatment00.250.50.751234681012
Thermal excursion
 Sal-Sal7.5 ± 1.17.4 ± 1.77.0 ± 1.67.0 ± 1.86.3 ± l.38.2 ± 2.78.2 ± 2.78.1 ± 1.88.0 ± 2.08.2 ± 2.27.1 ± 2.28.0 ± l.5
 H-Sal8.2 ± 2.114.8 ± 3.4*13.8 ± 3.0*12.7 ± 2.3*12.8 ± 3.6*13.0 ± 2.3*10.7 ± 4.610.8 ± 3.98.2 ± 1.98.6 ± 2.47.8 ± 2.47.4 ± 1.8
 H-Bupre7.6 ± 2.116.2 ± 2.7*14.3 ± 3.6*14.3 ± 3.9*12.2 ± 4.1*12.0 ± 3.7*11.3 ± 3.710.5 ± 3.310.8 ± 3.89.8 ± 2.88.7 ± 2.19.2 ± 2.4
 H-Butor9.0 ± 2.014.8 ± 4.2*15.7 ± 2.3*12.7 ± 3.8*10.0 ± 1.611.8 ± 2.79.6 ± 2.89.7 ± 3.210.1 ± 3.19.2 ± 1.810.6 ± 3.98.5 ± 2.9
%MPE
 Sal-Sal0.0 ± 02.2 ± 17.11.4 ± 9.71.3 ± 15.6−5.3 ± 11.68.8 ± 24.98.9 ± 19.64.7 ± 31.91.6 ± 10.86.2 ± 17.9−6.38 ± 15.955.7 ± 10.0
 H-Sal0.0 ± 071.9 ± 33.6*63.7 ± 3l.6*48.9 ± 28.6*52.3 ± 40.5*f55.9 ± 23.3*f31.8 ± 39.428.8 ± 34.8−4.8 ± 25.11.6 ± 15.9−7.4 ± 12.9−11.2 ± 30.26
 H-Bupre0.0 ± 085.4 ± 22.8*73.9 ± 34.8*72.4 ± 34.2*55.3 ± 34.6*f51.2 ± 28.7*44.1 ± 30.9*40.4 ± 31.736.5 ± 35.521.1 ± 24.36.4 ± 20.313.4 ± 24.0
 H-Butor0.0 ± 069.9 ± 39.9*82.3 ± 22.6*52.0 ± 43.5*17.8 ± 21.142.1 ± 25.113.9 ± 23.213.1 ± 35.511.9 ± 30.73.3 ± 22.818.9 ± 44.7−3.7 ± 30.8

Value differs significantly (P < 0.05) from value at 0.5 hours for the same treatment.

See Table 1 for remainder of key.

Compared with respective values at 0.5 hours after the first injection (hydromorphone), thermal excursion was significantly lower from 6 to 12 hours after the first injection for H-Sal, from 8 to 12 hours after the first injection for H-Bupre, and from 1 to 12 hours after the first injection for H-Butor. Also compared with respective values at 0.5 hours after the first injection, %MPE was significantly lower from 6 to 12 hours after the first injection for H-Sal, from 8 to 12 hours after the first injection for H-Bupre, and at 1 hour and from 3 to 12 hours after the first injection for H-Butor. No significant differences in %MPE or thermal excursion were detected for comparisons between the 0.5-hour and subsequent measurement points for Sal-Sal.

Compared with values for Sal-Sal, skin temperature was significantly greater at 2 hours after the first IV injection for H-Sal, 3 and 4 hours after the first injection for H-Bupre, and 2 and 4 hours after the first injection for H-Butor. Also compared with values for Sal-Sal, thermal excursion was significantly greater from 0.25 to 1 hours after the first injection for H-Sal, from 0.25 to 1 hours after the first injection for H-Bupre, and from 0.25 to 0.75 hours after the first injection for H-Butor and %MPE was significantly greater from 0.25 to 2 hours for H-Sal, from 0.25 to 1 hours for H-Bupre, and from 0.25 to 0.75 hours for H-Butor. No significant differences were identified in thermal excursion and %MPE among opioid treatment combinations.

Discussion

The present study was designed to mimic the perioperative clinical scenario in which a full agonist of μ-opioid receptors is administered to cats as part of the premedication protocol and a different class of opioid is administered soon afterward (ie, 30 minutes later) to provide postoperative analgesia.14 Opioid doses used in the study were chosen on the basis of the authors’ clinical experiences and doses reported to provide antinociception in cats.20 Findings indicated that buprenorphine and butorphanol administered IV 30 minutes after hydromorphone may have induced changes in the thermal antinociceptive effects of hydromorphone. Overall, those findings suggested that administration of butorphanol after hydromorphone resulted in a briefer duration of the thermal antinociceptive effects provided by hydromorphone.

Butorphanol (agonist of κ-opioid receptors and antagonist of μ-opioid receptors) reportedly has an antinociceptive effect for a duration of 90 minutes in cats.7 It may antagonize the duration and magnitude of thermal antinociception of hydromorphone (full agonist of μ-opioid receptors),21 although thermal excursion and %MPE did not differ significantly between H-Sal and H-Butor treatments in the present study. These results were in contrast with those of previous studies in which different classes of opioids were administered simultaneously. For example, simultaneous IM administration of butorphanol (0.4 mg/kg) and hydromorphone (0.1 mg/kg) results in a longer duration but reduced magnitude of thermal antinociception, compared with the effects of IM administration of hydromorphone alone.8 In addition, the combination of oxymorphone (full agonist of μ-opioid receptors) and butorphanol increases the magnitude of visceral antinociception, compared with the effects of oxymorphone alone.13 Moreover, low doses of butorphanol have been used to antagonize the respiratory depression and sedation that occur in dogs with administration of μ-opioid receptor agonists.22

It is possible that butorphanol, when administered IV to cats after hydromorphone, may decrease the analgesic effects of IV administration of hydromorphone in clinical practice, as was observed with the antinociception findings in the present study. When %MPE for H-Butor after the first injection was compared with the value at 0.5 hours (immediately prior to the second injection), there was a short period in which the extent of thermal antinociception increased (ie, at 2 hours after the first injection). This increase might have been associated with the transient effect of butorphanol on antinociception, compared with that of hydromorphone.7 Therefore, the decreasing effect of butorphanol on hydromorphone-induced antinociception may be short-lived in cats.

Thermal antinociception, as indicated by thermal excursion and %MPE in the present study, was evident for up to 2 and 3 hours, respectively, after the first injection for H-Bupre, as identified through comparison with baseline values. The %MPE for H-Bupre was significantly longer than was identified for the comparison of postadministration H-Sal values with respective baseline values. Compared with thermal excursion and %MPE at 0.5 hours, H-Bupre also provided greater antinociception of a longer duration than was achieved with H-Sal. In contrast, thermal excursion and %MPE were greater for H-Bupre than for Sal-Sal for up to 1 hour after the first injection. Percentage of maximum possible effect for H-Bupre reflected a shorter duration of antinociception than that for H-Sal. No significant differences in thermal excursion or %MPE were detected among opioid treatment combinations. Given these findings, additional investigation into the effects of buprenorphine on the antinociceptive effects of hydromorphone is warranted.

The effects of buprenorphine administered alone were not evaluated in the present study, but thermal antinociceptive effects of buprenorphine can be identified in cats from 35 minutes to 12 hours after IM administration.9,15 The small sample size used (6 cats) in the present study may have limited the ability to detect differences among treatment combinations, and we could not eliminate the possibility that IV administration of buprenorphine following hydromorphone does indeed reduce the duration of thermal antinociception provided by hydromorphone alone but that insufficient power existed to identify such an effect.

The present study represented the first in which the antinociceptive effects of buprenorphine and hydromorphone administered sequentially were evaluated in cats, so the clinical implications of our findings are unclear. However, a clinical trial23 involving humans undergoing abdominal exploratory surgery revealed that the combination of buprenorphine and morphine provides similar and effective analgesia with respect to visceral pain when compared with the effects of morphine alone. In a study24 involving mice in which a tail-flick test was used, IV administration of morphine or hydromorphone before or after buprenorphine resulted in additive or synergistic analgesic effects, compared with the effects of either drug alone. Conversely, the antinociceptive effects of buprenorphine in combination with a full μ-opioid receptor agonist were unclear in other studies21,25 involving mice and rats. On the basis of results of the present study, buprenorphine appeared to somehow affect the antinociceptive effects of hydromorphone in cats; however, the extent and clinical relevance of that effect remain unclear.

The antinociceptive effects of hydromorphone in the study reported here were briefer (1 to 2 hours) than those identified in other studies5,8 involving cats in which the thermal threshold device was used (approx 3 to 6 hours). Higher mean baseline thermal threshold readings in the present study (45.1°C) than in the other studies5,8 (40° to 41°C) may have precluded detection of significant differences among the various measurement points.5,7,8,16,26 In addition, thermal threshold values for H-Sal in the present study were similar to those of another study8 in which the same dose of hydromorphone (0.1 mg/kg, IV) was administered to cats.8 However, duration of action for hydromorphone was as long as 345 minutes in the other study and could be explained by a lower baseline thermal threshold than was achieved in the present study, which would have improved the ability to detect significant temporal differences.

Skin temperature increased significantly from baseline for all 4 treatments in the present study but did not differ significantly among treatments. Increases in skin temperature were prolonged by administration of hydromorphone alone (H-Sal) and prolonged even further when butorphanol or buprenorphine was added. Opioids reportedly act at the level of the hypothalamus, thereby essentially resetting the threshold point for thermoregulation.27 In cats, SC administration of hydromorphone (0.1 mg/kg) results in a significant increase in skin temperature.28 Increases in skin temperature have been also identified in cats after administration of buprenorphine and butorphanol.29 An increase in skin temperature was detected between 0.5 and 1 hour after the first IV injection of saline solution when cats received Sal-Sal in the present study. This increase might have been associated with an increase in frequencies of cat handling and thermal threshold testing during the initial period (15-minute intervals) after the first injection, given that all treatments resulted in skin temperature changes during the first hour after the first injection. When cats received treatments that included opioids, agitation, rolling, and increases in other physical activity were observed. These behavioral changes may have also contributed to the increase in skin temperature to some extent. In addition, opioid administration can result in excitement, hypersalivation, vomiting, and dysphoria in cats.30 In the study reported here, 2 cats had opioid-induced vomiting and hypersalivation after receiving H-Sal or H-Butor.

The present study had some limitations. Large SDs caused by high interindividual variability in measurements obtained after opioid administration may have reduced the power of the study to detect differences that truly existed, particularly among opioid treatment combinations for which differences were not detected. Furthermore, the study was designed to evaluate thermal antinociceptive effects when buprenorphine or butorphanol was administered IV 30 minutes after hydromorphone, so the effects of other orders or timings of treatment administration remained unknown. On the basis of findings from previous studies,17,31 it appears that outcomes associated with administration of a full μ-opioid receptor agonist alone or with another class of opioid are influenced by drug dose, timing, and route of administration; type of opioid; individual and observer variability; pharmacokinetics and pharmacodynamics; number of cats used; and method and cutoff used to detect antinociceptive effects. These factors would explain the wide range in values and outcomes reported in the scientific literature on this controversial subject. The present study was designed to address some of those potential effects in that calculation of %MPE allowed treatment comparisons by accounting for the measurement limit of the thermal threshold device.18

At the doses and regimens used in the present study, buprenorphine influenced the thermal antinociceptive effects of hydromorphone when administered IV to cats; however, whether duration and magnitude of antinociception decreased or increased could not be determined. Compared with saline solution, butorphanol decreased the duration of thermal antinociception provided by hydromorphone; however, compared with the effects of hydromorphone alone, IV administration of butorphanol 30 minutes after hydromorphone provided a similar duration of thermal antinociception. The interaction between these opioids and their impact on analgesia and pain management for cats require further investigation.

Acknowledgments

This manuscript represents a part of a thesis that will be submitted by Dr. Simon to the Ross University Department of Clinical Sciences as partial fulfillment of the requirements for a Master of Science degree.

Supported by the Ross University School of Veterinary Medicine.

Presented in abstract form at the American College of Veterinary Anesthesia and Analgesia meeting, Indianapolis, Ind, September 2014.

ABBREVIATIONS

%MPE

Percentage of maximum possible effect

Footnotes

a.

Topcat Metrology Ltd, Ely, Cambridgeshire, England.

b.

EMLA cream, Astra Zeneca, Mississauga, ON, Canada.

c.

3M Vetrap Bandaging Tape, Animal Care Products, Saint Paul, Minn.

d.

BD Insyte, Sandy, Utah.

e.

Hospira, Montreal, QC, Canada.

f.

Hydromorphone 2 mg/mL, Summit Veterinary Pharmacy, Aurora, ON, Canada.

g.

Vetergesic 0.3 mg/mL, Champion Alstoe, Whitby, ON, Canada.

h.

Torbugesic 10 mg/mL, Wyeth Animal Health, Guelph, ON, Canada.

i.

GraphPad Prism, version 4, GraphPad Software Inc, La Jolla, Calif.

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Contributor Notes

Address correspondence to Dr. Simon (bsimondacvaa@gmail.com).