Efficacy of oral transmucosal and intravenous administration of buprenorphine before surgery for postoperative analgesia in dogs undergoing ovariohysterectomy

Jeff C. Ko Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Lynetta J. Freeman Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Michele Barletta Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Ann B. Weil Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Mark E. Payton Department of Statistics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK 74078.

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Brenda M. Johnson Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Tomohito Inoue Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Abstract

Objective—To compare the efficacy of preoperative administration of buprenorphine (via oral transmucosal [OTM] and IV routes) for postoperative analgesia in dogs undergoing ovariohysterectomy.

Design—Prospective, randomized, blinded study.

Animals—18 dogs undergoing routine ovariohysterectomy.

Procedures—Dogs were allocated to 3 groups (6 dogs/group) and were assigned to receive buprenorphine (20 μg/kg [9.09 μg/lb], IV; a low dose [20 μg/kg] via OTM administration [LOTM]; or a high dose [120 μg/kg [54.54 μg/lb] via OTM administration [HOTM]) immediately before anesthetic induction with propofol and maintenance with isoflurane for ovariohysterectomy. Postoperative pain was assessed by use of a dynamic interactive pain scale. Dogs were provided rescue analgesia when postoperative pain exceeded a predetermined threshold. Blood samples were collected, and liquid chromatography-electrospray ionization-tandem mass spectrometry was used to determine plasma concentrations of buprenorphine and its metabolites. Data were analyzed with an ANOVA.

Results—Body weight, surgical duration, propofol dose, isoflurane concentration, and cardiorespiratory variables did not differ significantly among treatment groups. Number of dogs requiring rescue analgesia did not differ significantly for the HOTM (1/6), IV (3/6), and LOTM (5/6) treatments. Similarly, mean ± SEM duration of analgesia did not differ significantly for the HOTM (20.3 ± 3.7 hours), IV (16.0 ± 3.8 hours), and LOTM (7.3 ± 3.3 hours) treatments. Plasma buprenorphine concentration was ≤ 0.60 ng/mL in 7 of 9 dogs requiring rescue analgesia.

Conclusions and Clinical Relevance—Buprenorphine (HOTM) given immediately before anesthetic induction can be an alternative for postoperative pain management in dogs undergoing ovariohysterectomy.

Abstract

Objective—To compare the efficacy of preoperative administration of buprenorphine (via oral transmucosal [OTM] and IV routes) for postoperative analgesia in dogs undergoing ovariohysterectomy.

Design—Prospective, randomized, blinded study.

Animals—18 dogs undergoing routine ovariohysterectomy.

Procedures—Dogs were allocated to 3 groups (6 dogs/group) and were assigned to receive buprenorphine (20 μg/kg [9.09 μg/lb], IV; a low dose [20 μg/kg] via OTM administration [LOTM]; or a high dose [120 μg/kg [54.54 μg/lb] via OTM administration [HOTM]) immediately before anesthetic induction with propofol and maintenance with isoflurane for ovariohysterectomy. Postoperative pain was assessed by use of a dynamic interactive pain scale. Dogs were provided rescue analgesia when postoperative pain exceeded a predetermined threshold. Blood samples were collected, and liquid chromatography-electrospray ionization-tandem mass spectrometry was used to determine plasma concentrations of buprenorphine and its metabolites. Data were analyzed with an ANOVA.

Results—Body weight, surgical duration, propofol dose, isoflurane concentration, and cardiorespiratory variables did not differ significantly among treatment groups. Number of dogs requiring rescue analgesia did not differ significantly for the HOTM (1/6), IV (3/6), and LOTM (5/6) treatments. Similarly, mean ± SEM duration of analgesia did not differ significantly for the HOTM (20.3 ± 3.7 hours), IV (16.0 ± 3.8 hours), and LOTM (7.3 ± 3.3 hours) treatments. Plasma buprenorphine concentration was ≤ 0.60 ng/mL in 7 of 9 dogs requiring rescue analgesia.

Conclusions and Clinical Relevance—Buprenorphine (HOTM) given immediately before anesthetic induction can be an alternative for postoperative pain management in dogs undergoing ovariohysterectomy.

Buprenorphine is an opioid partial μ-receptor agonist that has been used extensively for both preoperative and postoperative pain management in dogs via routes of delivery other than OTM administration.1–7 When used in a clinical setting, buprenorphine doses in dogs commonly range from 5 to 20 μg/kg (2.27 to 9.09 μg/lb), IV or IM.1–7 Administration of buprenorphine via the OTM route is a novel concept for providing postoperative analgesia in dogs and may be useful in a multimodal approach to pain management. Oral administration of opioids can result in poor bioavailability, presumably because of extensive hepatic and extrahepatic first-pass extraction of the drugs, and most of the literature discourages this route of administration in dogs.8–10 Extended release and traditional tablet formulations of morphine have a bioavailability of 5% to 17% in dogs.8,9 Similarly, the bioavailability of orally administered buprenorphine is only 3% to 6% in dogs because of the first-pass gastrointestinal-hepatic clearance of this drug.10,11 In humans, bioavailability after oral administration of buprenorphine is 15%,12 with higher bioavailability (27.8% to 55%) when administered via the OTM route.13–15

Administration of opioids via the OTM route provides several potential advantages over parenteral administration.16 First, it allows the drug to bypass the gastrointestial-hepatic portal first-pass metabolism, which increases the bioavailability over orally administered medications.16 The OTM route eliminates pain associated with parenteral injection, and it is relatively convenient and easy to use, with minimal training required.16 The oral cavity provides a large mucosal surface area, including the areas of the tongue, cheeks, and soft and hard palate, which can enable drugs to be absorbed rapidly into the systemic circulation.17 Factors influencing drug absorption after OTM administration are size of drug molecule, lipophilicity, protein affinity, pKa, and pH of the vehicle and saliva.16,17 The OTM route of administration for buprenorphine is commonly used in cats,18 but this route has not been used extensively in dogs because of a lack of pharmacodynamic data supporting such use.

To determine the dose and efficacy for OTM administration of buprenorphine in dogs, pharmacokinetic studies11,19–21 were performed to compare the bioavailability, dosage, and dosing interval for administration via the IV and OTM routes. In those studies, bioavailability of buprenorphine administered via the OTM route at doses of 20 or 120 μg/kg (9.09 or 54.54 μg/lb) was reported to be approximately 47%,21 but the clinical importance of this value for the management of postoperative pain in dogs is unknown. Plasma concentrations increased rapidly following OTM administration and could be detected within minutes, reaching a peak within 30 to 40 minutes after administration in conscious dogs.11,21 Given that the OTM route is an acceptable route of administration, we wanted to evaluate the efficacy of buprenorphine administered via the OTM route and determine the duration of effective postoperative analgesia in dogs undergoing routine ovariohysterectomy. This preoperative buprenorphine administration via the OTM route could potentially be beneficial to animals when multimodal pain management techniques or frequent administration of analgesics during the postoperative period is not possible. In addition, we wanted to know whether preopearative administration of either dose (20 or 120 μg/kg) alone would provide a sparing effect on subsequent anesthetic agents. Finally, on the basis of an objective scoring system for postoperative pain, we wanted to determine the plasma concentrations of buprenorphine administered via the IV and OTM routes that were associated with the need for rescue analgesia. We hypothesized that the higher dose of buprenorphine administered via the OTM route would be more effective in providing postoperative analgesia in dogs than would the lower dose administered via the OTM or IV routes.

Recognizing that multimodal approaches to analgesia are recommended, the objectives of the study reported here were to isolate, evaluate, and compare the efficacy and analgesic duration of burprenorphine administered IV (20 μg/kg) or via the OTM route (20 or 120 μg/kg) immediately before induction of anesthesia as the sole agent for postoperative pain management in dogs undergoing routine ovariohysterectomy, to determine the sparing effect on other anesthetic drugs used during the surgical procedure, and to measure the plasma concentrations of buprenorphine and its metabolites that were associated with the need for rescue analgesia.

Materials and Methods

Animals—Eighteen healthy female client-owned dogs that were scheduled for an ovariohysterectomy were enrolled in the study. They ranged from 8 months to 4 years of age and weighed between 9 and 23 kg. Dogs were assessed as healthy on the basis of results of physical examinations and hematologic and biochemical analyses to evaluate PCV and total protein, BUN, and blood glucose concentrations. Informed consent for inclusion of dogs in the study was obtained from each owner. Approval for the conduct of the study was granted by the Purdue University Animal Care and Use Committee.

Treatments—To assess the efficacy and duration of the drug, a single dose of buprenorphine as the only premedication was evaluated for its analgesic efficacy and duration during the postoperative period. The dogs were randomly assigned to treatment groups (n = 6 dogs/group), and only the principal investigator was aware of the treatments being given to each dog.

Baseline physiologic measurements were recorded, and a catheter was placed in a cephalic vein of each dog. The dogs were administered buprenorphinea on the basis of their respective treatment group (20 μg/kg, IV; 20 μg/kg via OTM administration [LOTM]; or 120 μg/kg via OTM administration [HOTM]) immediately before anesthetic induction. For OTM administration, the syringe was placed in the cheek pouch of each dog, and buprenorphine was slowly administered over a period of 1 to 3 minutes to ensure the drug did not drip out of the dog's mouth or that the dog did not swallow it. For the IV treatment, buprenorphine was administered as a single bolus over a period of 1 minute. Time of completion of buprenorphine administration was designated as time 0.

Immediately after buprenorphine administration, anesthesia was induced by administration of propofolb (8 mg/kg [3.6 mg/lb], IV, titrated to effect) to enable endotracheal intubation. Isofluranec in oxygen then was administered via a circle system to maintain anesthesia. Each dog was clipped, prepared for aseptic surgery, and moved to the operating room. Balanced electrolyte fluidsd were administered at a rate of 10 mL/kg/h (4.5 mg/lb/h).

Surgical procedure—All surgeries were performed by the same surgeon (LJF). Ovariohysterectomy was accomplished via an abdominal midline incision and a 3-clamp method for pedicle ligation, with 2 sutures placed on each pedicle and the uterine body. The incision was closed in 3 layers. Attempts were made to standardize the durations of the surgery and anesthesia.

Monitoring—All monitoring was performed by 2 trained observers (MB and BMJ) who were unaware of the treatment assignments for the dogs. Evaluations were recorded on videotape for future reference. Both observers scored the dogs throughout the day, and 1 observer scored the dogs after midnight. Heart rate, respiratory rate, and noninvasive blood pressures were measured and recorded immediately before buprenorphine administration (baseline values) and 3 minutes after anesthetic induction. Heart rate, ECG,e respiratory rate, end-tidal CO2, hemoglobin saturation,e non-invasive blood pressure,e and rectal temperaturee were monitored and recorded at 5-minute intervals during surgery. Isoflurane concentration was adjusted to maintain an appropriate surgical plane of anesthesia for the ovariohysterectomy. The end-tidal isoflurane concentration was recordedf at 3-minute intervals during the surgery, and the results were analyzed to detect differences among treatment groups. Rectal temperature of the dogs was maintained with forced hot air and a warm water circulating heating blanket during the surgery.

After surgery, dogs were kept on a circulating water heating pad and monitored until extubation. Rectal temperature, heart rate, and respiratory rate were recorded for each dog, and the dogs were monitored for evidence of postoperative pain at 1, 2, 3, 4, 6, 8, 12, 14, 16, 18, 20, and 24 hours after buprenorphine administration. Postoperative pain was evaluated by use of a DIVAS and palpometer assessment of the incision site.

The DIVAS was used in another study,1 and the technique was slightly modified for the study reported here to specifically detect pain associated with the abdomen and incision following ovariohysterectomy. Briefly, the DIVAS consisted of 3 phases of assessments. In phase 1, the dogs were undisturbed and assessed by an investigator located outside the cage or run. In phase 2, the dogs were approached, spoken to, and gently encouraged to walk and move around. During phase 3, the dog's abdomen was palpated firmly by the evaluator, with a hand on each side of the abdomen moving in a cranial to caudal direction from the last rib to the hip area. Responses to abdominal palpation, including turning of the head, vocalization, avoidance, or biting behavior, were recorded and included in determining the DIVAS score for phase 3. For each phase, assessments were scored on a scale of 0 to 100 mm, with 0 indicating no pain and 100 indicating the worst pain possible.

In addition to palpation of the abdomen in phase 3 of the DIVAS, a palpometerg was used to provide data on pain in the abdomen after ovariohysterectomy. The palpometer has been successfully used in cats22 for assessing pain after onychectomy and in ferrets23 for assessing pain after abdominal hernia repair. The palpometer is a medical device that controls the pressure of manual palpation by measuring the pressure of the evaluator's finger. This pressure-controlled palpation provides the evaluator with objective information on how firmly to press on the tissues, thereby standardizing the pressure stimulus of conventional manual palpation. Beeping noises from the palpometer indicate increases in pressure applied to a testing site. Palpometer pressure-controlled palpation assessments were designated as light (first beep, 250 gf/cm2), moderate (second beep, 700 gf/cm2), and high (third beep, 1,000 gf/cm2) amounts of pressure applied to the incision site. Pressure was applied to the cranial, middle, and caudal portions of the incision. Palpometer assessments were also made on the right tibia to validate palpometer function as well as to detect hypersensitivity of a nonsurgical site. If a dog responded to light pressure at both sites, it was assumed that the dog had hypersensitivity.

Postoperative sedation scores were determined for each dog by assessment of posture and response to noise. Posture was scored on a scale of 0 to 3 (0, typical standing posture; 1, mild sedation but standing; 2, laterally recumbent but able to attain sternal recumbency; and 3, laterally recumbent and unable to attain sternal recumbency). Response to noise (a hand clap near the dog's head) was scored on a scale of 0 to 3 (0, typical reaction; 1, weakened reaction; 2, very delayed and weak reaction; and 3, no reaction).

Rescue analgesia—On the basis of the authors' experiences with using the DIVAS scoring system, dogs with a pain score of ≥ 70 mm for 1 or more phases of the DIVAS or that had a response during palpation of the incision via the palpometer at the lightest pressure (250 gf/cm2) were considered to have evidence of pain, and rescue analgesics were administered immediately after collection of a blood sample. In those dogs, supplemental buprenorphine (0.02 mg/kg [0.009 mg/lb]) was administered IV every 6 hours or as needed, and the dogs were continually monitored for evidence of pain until the end of the study; any data collected after provision of rescue analgesia were not used in the statistical analysis. The time at which rescue analgesia was provided and the amount of supplemental buprenorphine administered were recorded, and the dog was considered to have completed the study at the time of rescue analgesia.

All dogs received carprofenh (4.4 mg/kg [2.0 mg/lb], SC) 24 hours after surgery for additional pain management.

Collection of blood samples and buprenorphine analysis—Blood samples (3 mL) were obtained from a cephalic vein via the preplaced catheter. After collection of each blood sample, 9 mL of balanced electrolyte fluidsd was injected as a replacement volume. Blood samples were collected immediately before buprenorphine administration (baseline value) and 0.25, 0.5, 1, 3, 6, 8, 12, 18, and 24 hours after administration of buprenorphine. When a dog was considered to have evidence of pain, a blood sample was collected immediately before administration of the rescue analgesia. Once a dog received rescue analgesia, no additional blood samples were collected.

The methods for measuring buprenorphine and its metabolites (norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide) in blood via liquid chromatography-electrospray ionization-tandem mass spectrometry were established and described in another study21 conducted by our research group. Briefly, the lower limit of quantitation for all 4 analytes was 0.1 ng/mL. Prior to analyzing study samples, intra-assay accuracy and precision in the dog plasma matrix were validated via analysis of 3 concentrations of quality-control samples (n = 8 samples/concentration) prepared in pooled dog plasma and the lower limit of quantitation (1 for each of 6 sources of matrix) in a single analytic batch. Dog plasma used for this experiment and other calibrators and quality-control samples were from a commercial source. Calibrators were also prepared in dog plasma. For the intrarun precision and accuracy experiment, lower limit-of-quantitation samples had mean results within 18.0% of the target concentration and a coefficient of variation within 13.6%. Results for other quality-control samples were within 8.0% of the target concentration, with coefficients of variation within 6.7%. Dog plasma calibrators and dog plasma quality-control samples were used for all analyses; 24 quality-control samples were assayed, and mean results were within 10.6% of the target concentration, with coefficients of variation within 10.6%. The assay was performed in accordance with previously published methods21 by personnel at the Center for Human Toxicology at the University of Utah.

Statistical analysis—A statistical programi was used for all analyses. An AVOVA for fixed effects was used to determine significant differences attributable to treatments. When results for the ANOVA were significant, pairwise t tests were performed. Data were reported as mean ± SEM. Significance was set at P < 0.05. A Kaplan-Meier survival test was used to test for differences in the number of dogs receiving rescue analgesia during the postoperative period.

Results

Intraoperative findings—Treatment groups did not differ significantly with regard to body weights of the dogs, surgical duration, anesthesia duration, dose of pro-pofol for induction, and maintenance end-tidal isoflurane concentrations for the area under the curve versus time (Table 1). Mean ± SEM duration of ovariohysterectomy (from initial skin incision until closure of the incision) was 29 ± 4.8 minutes. There were no significant differences among treatment groups with regard to mean ± SEM intraoperative heart rate (range, 87.6 ± 4.3 beats/min to 142.2 ± 11.2 beats/min), respiratory rate (range, 13.3 ± 2.6 breaths/min to 40.0 ± 8.6 breaths/min), systolic arterial blood pressure (range, 96.0 ± 9.9 mm Hg to 151.5 ± 6.9 mm Hg), diastolic arterial blood pressure, (range, 39.4 ± 4.2 mm Hg to 88.5 ± 13.8 mm Hg), mean arterial blood pressure (range, 65.8 ± 5.8 mm Hg to 101.6 ± 23.6 mm Hg), end-tidal CO2 (range, 36.6 ± 5.9 mm Hg to 46.7 ± 3.8 mm Hg), hemoglobin saturation for oxygen (range, 96.1% to 98.1%), and rectal temperature (37.4° to 38.9°C [99.3° to 102.0°F]); all of these values were within the respective reference ranges for anesthetized dogs. Mean ± SEM end-tidal isoflurane concentrations during the surgery ranged from 1.2 ±0.1 volume % to 1.6 ± 0.32 volume %.

Table 1

Mean ± SEM results of variables for groups of dogs (n = 6 dogs/group) that received buprenorphine (20 μg/kg [9.09 μg/lb], IV; 20 μg/kg via OTM administration [LOTM]; or 120 μg/kg [54.54 μg/lb] via OTM administration [HOTM]) immediately before anesthetic induction for an ovariohysterectomy.

Treatment groupIVLOTMHOTMP value*
Body weight (kg)16.7 ± 1.3716.0 ± 0.9016.3 ± 1.870.200
Surgery duration (min)29.7 ± 1.2829.2 ± 2.6429.8 ± 1.760.971
Anesthesia duration (min)48.7 ± 2.046.5 ± 2.853.0 ± 3.50.258
Dose of propofol for induction (mg/kg)5.65 ± 0.326.95 ± 0.535.31 ± 0.400.200
Isoflurane concentration for the area under the time curve (%/min)35.2 ± 3.4633.1 ± 1.7535.6 ± 2.830.794

Values were considered significant at P < 0.05.

Value reported is the area under the time curve.

Postoperative analgesia—All of the dogs recovered from surgery and anesthesia smoothly and without complications in the immediate postoperative period. There was no evidence of dysphoria or delirium during recovery in any of the dogs. Postoperative heart and respiratory rates did not differ significantly among treatment groups (Figure 1).

Figure 1—
Figure 1—

Mean ± SEM postoperative heart rate (A) and respiratory rate (B) in dogs (n = 6 dogs/group) that received buprenorphine (20 μg/kg [9.09 μg/lb], IV [squares]; 20 μg/kg via OTM administration [LOTM; triangles]; or 120 μg/kg [54.54 μg/lb] via OTM administration [HOTM; circles]) immediately before anesthetic induction for an ovar-iohysterectomy. Buprenorphine was administered over a period of 1 to 3 minutes for the HOTM and LOTM groups and over a period of 1 minute for the IV group; time of completion of buprenorphine administration was designated as time 0. Values did not differ significantly (P ≥ 0.05) among treatment groups.

Citation: Journal of the American Veterinary Medical Association 238, 3; 10.2460/javma.238.3.318

Rescue analgesia—Kaplan-Meier survival analysis was used to determine the duration of postoperative analgesia on the basis of the time of administration of supplemental buprenorphine and number of dogs that required rescue analgesia (Figure 2). Of the 18 dogs in the study, 9 required rescue analgesia. Of these 9 dogs, 5 had plasma buprenorphine concentrations ≤ 0.16 ng/mL at the time of rescue analgesia, 2 had plasma buprenorphine concentrations of 0.56 and 0.60 ng/mL, respectively, at the time of rescue analgesia, and 2 had plasma buprenorphine concentrations of 1.56 and 5.41 ng/mL, respectively, at the time of rescue analgesia. The videotapes for pain assessment of the 2 dogs with the highest plasma buprenorphine concentrations at the time of rescue analgesia were reviewed by the other investigators (who were not apprised of the treatments and plasma buprenorphine concentrations), and it was universally agreed that these 2 dogs indeed had evidence of pain and required rescue analgesia at the time of assessment.

Figure 2—
Figure 2—

Kaplan-Meier survival analysis for dogs administered buprenorphine before anesthetic induction for an ovariohysterectomy that required rescue analgesia during the postoperative period. Dogs (n = 6 dogs/group) received buprenorphine via the OTM route of administration (HOTM [solid line] and LOTM [dotted line]) or IV (dashed-and-dotted line). See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 238, 3; 10.2460/javma.238.3.318

The number of dogs that required rescue analgesia did not differ significantly (P = 0.057) among groups. Only 1 dog in the HOTM group required rescue analgesia (1 hour after the administration of buprenorphine; plasma buprenorphine concentration, 5.41 ng/mL). Three dogs in the IV group required rescue analgesia (2, 8, and 13 hours after the administration of buprenorphine, respectively, with plasma buprenorphine concentrations of 1.56, < 0.10, and 0.14 ng/mL, respectively). Five dogs in the LOTM group required rescue analgesia after the administration of buprenorphine; time of rescue analgesia was 2, 3.3, 3.5, 4, and 6 hours, respectively, with plasma concentrations of 0.60, 0.56, 0.11, 0.16, and 0.13 ng/mL, respectively.

Duration of postoperative analgesia did not differ significantly (P = 0.066) among treatment groups. Mean ± SEM duration was 20.3 ± 3.7 hours for the HOTM group, 16.0 ± 3.8 hours for the IV group, and 7.3 ± 3.3 hours for the LOTM group.

Palpometer assessment—Palpation pressures applied to the surgical site and nonsurgical site (ie, right tibia) of the dogs were assessed by use of a palpometer (Figure 3). The palpometer values for the nonsurgical site were significantly lower for the LOTM group than those for the HOTM and IV groups, which indicated that these dogs may have had hypersensitivity.

Figure 3—
Figure 3—

Mean ± SEM scores assessed with a palpometer at the surgical site (A) and a nonsurgical site (right tibia; B) in dogs (n = 6 dogs/group) administered buprenorphine (IV group [squares], LOTM group [triangles], or HOTM group [circles]) before anesthetic induction for an ovariohysterectomy. Higher palpation pressures indicated less sensitivity to the palpation pressure and therefore a stronger degree of analgesia. *Within a time point, values differs significantly (P < 0.05) from the values for the other 2 treatment groups. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 238, 3; 10.2460/javma.238.3.318

Plasma concentrations of buprenorphine and metabolites—Plasma buprenorphine and norbuprenorphine concentrations were determined for each treatment group over time (Table 2). Concentrations of buprenorphine were highest at 0.25 hours and decreased rapidly during the first 3 hours after administration. The HOTM group had significantly higher mean ± SEM concentrations at 0.25 hours (9.2 ± 1.3 ng/mL), compared with plasma concentrations for the LOTM (1.4 ± 0.2 ng/mL) and IV (5.0 ± 0.3 ng/mL) groups. By 3 hours after buprenorphine administration, mean plasma concentration of buprenorphine was 2.5 ± 0.70 ng/mL, 0.32 ± 0.08 ng/mL, and 0.70 ± 0.22 ng/mL, for the HOTM, LOTM, and IV treatment groups, respectively. By 8 hours after administration, mean buprenorphine concentrations were 0.38 ± 0.06 ng/mL for the HOTM group and 0.18 ± 0.04 ng/mL for the IV group, but they were undetectable for the LOTM group. By 24 hours after administration, only the HOTM group had a detectable plasma concentration of buprenorphine (0.11 ± 0.01 ng/mL). The same pattern was evident for norbuprenorphine concentrations throughout the study.

Table 2

Mean ± SEM plasma buprenorphine and norbuprenorphine concentrations in dogs that received buprenorphine immediately before anesthetic induction for an ovariohysterectomy.

Time (h)*Treatment groupNo. of dogsPlasma buprenorphine concentration (ng/mL)Plasma norbuprenorphine concentration (ng/mL)
BaselineHOTM6< 0.10< 0.10
 IV6< 0.10< 0.10
 LOTM6< 0.10< 0.10
0.25HOTM69.20 ± 1.3a0.79 ± 0.10a
 IV65.00 ± 0.33b0.19 ± 0.04b
 LOTM61.40 ± 0.20b0.02 ± 0.02b
0.5HOTM67.30 ± 0.32a0.90 ± 0.11a
 IV63.40 ± 0.26b0.16 ± 0.02b
 LOTM61.20 ± 0.15c0.04 ± 0.04b
1HOTM65.70 ± 0.62a0.80 ± 0.11a
 IV63.00 ± 0.23a0.12 ± 0.03b
 LOTM61.20 ± 0.41b0.07 ± 0.05b
3HOTM62.50 ± 0.68a0.32 ± 0.10
 IV50.70 ± 0.22b< 0.10
 LOTM50.32 ± 0.083b≤ 0.10
6HOTM50.72 ± 0.190.07 ± 0.05
 IV50.32 ± 0.14< 0.10
 LOTM20.12 ±0.03 
8HOTM50.38 ± 0.06< 0.10
 IV40.18 ± 0.04< 0.10
 LOTM   
12HOTM50.21 ± 0.02< 0.10
 IV30.12 ±0.04< 0.10
 LOTM
18HOTM50.11 ±0.01< 0.10
 IV1< 0.10< 0.10
 LOTM
24HOTM50.11 ±0.01< 0.10
 IV1< 0.10< 0.10
 LOTM

The baseline concentration was determined from a sample collected immediately before buprenorphine administration. Buprenorphine was administered over a period of 1 to 3 minutes for the HOTM and LOTM groups and over a period of 1 minute for the IV group; time of completion of buprenorphine administration was designated as time 0.

The number of dogs varied because some dogs received rescue analgesia and were removed from the study at that point.

— = Not determined.

Within a time point for each analyte, values with different superscript letters differ significantly (P < 0.05).

See Table 1 for remainder of key.

Concentrations of buprenorphine metabolites, including norbuprenorphine, buprenorphine-3-G, and norbuprenorphine-3-G, were extremely low throughout the study. Most of the samples had concentrations < 0.10 ng/mL (data not shown); therefore, there was a minimal likelihood that these metabolites played any role in sedation or analgesia in these dogs.

Postoperative sedation—On the basis of the authors' experience that buprenorphine-sedated dogs have a reduction in their response to auditory stimuli, postoperative sedation was assessed via body posture and response to an auditory stimulus (ie, a hand clap). There were no significant differences in response to a hand clap among the treatment groups at any time point (Table 3). There was mild to moderate sedation during the first 3 hours after buprenorphine administration, but the dogs could be aroused by a clapping noise and would interact with the observers when their names were spoken. Differences in posture were most profound at 3 hours. Dogs in the HOTM group had a significantly higher posture score, compared with the posture score for the LOTM group, at 3 hours after buprenorphine administration. There were no other significant differences in posture score among the treatment groups at any other time points. None of the dogs had signs of sedation by 8 hours after buprenorphine administration.

Table 3

Mean ± SEM postoperative sedation scores in dogs that received buprenorphine immediately before anesthetic induction for an ovariohysterectomy.

  Time after buprenorphine administration (h)*
VariableTreatment group12346812–24
PostureIV20 ± 0420 ± 031.6 ± 0.2a,b10 ± 0408 ± 0502 ± 020
 LOTM2.3 ± 0.31.4 ±0.20.8 ± 0.4a0.7 ± 0.70.0 ± 0.000
 HOTM1.7 ± 0.41.6 ±0.52.2 ± 0.2b1.2 ±0.40.6 ± 0.20.4 ± 0.40
Response to noiseIV2.0 ± 0.51.2 ±0.21.0 ±0.30.6 ± 0.40.2 ± 0.20.2 ± 0.20
 LOTM1.7 ± 0.40.8 ± 0.20.6 ± 0.20.3 ± 0.30.5 ± 0.500
 HOTM1.7 ± 0.31.4 ±0.21.0 ±0.01.0 ±0.30.6 ± 0.20.2 ± 0.20

Posture was scored on a scale of 0 to 3 (0, typical standing posture; 1, mild sedation but standing; 2, laterally recumbent but able to attain sternal recumbency; and 3, laterally recumbent and unable to attain sternal recumbency). Response to noise (a hand clap near the dog's head) was scored on a scale of 0 to 3 (0, typical reaction; 1, weakened reaction; 2, very delayed and weak reaction; and 3, no reaction).

Time of completion of buprenorphine administration was designated as time 0.

Each treatment group initially consisted of 6 dogs; however, the number of dogs at each time point > 3 hours varied because some dogs received rescue analgesia and were removed from the study at that point.

Represents result for only 1 dog.

Within a time point, values with different superscript letters differ significantly (P < 0.05).

See Table 1 for remainder of key.

Discussion

The study reported here was a follow-up to a pharmacokinetic study21 conducted by our research group in which we found that bioavailability of 38% to 47% could be achieved following OTM administration of 20 and 120 μg of buprenorphine/kg to dogs. Recognizing the limitations of individual variations in pain sensitivity and response to buprenorphine, the study reported here was used to evaluate OTM administration of buprenorphine for use in multimodal pain management of dogs undergoing ovariohysterectomy. The results of the present study indicated that OTM administration of buprenorphine can be used as an alternative method for pain management in dogs and strongly supported the hypothesis that postoperative pain could be managed with preoperative administration of 120 μg of buprenorphine/kg via the OTM route in dogs undergoing ovariohysterectomy when multimodal analgesic combinations or frequent administration of analgesics is not possible. Furthermore, results of the study supported our hypothesis that a higher dose (120 μg/kg) of buprenorphine induced a longer and more consistent duration of analgesia and provided higher plasma concentrations than did a lower dose (20 μg/kg) of buprenorphine after OTM or IV administration.

One of the most interesting results of the present study was the consistent and long analgesic duration for the HOTM treatment in dogs undergoing ovariohysterectomy. Five of 6 dogs in the HOTM group had analgesia for 24 hours with this treatment. These dogs appeared to be comfortable and did not react to palpation of the surgical site or nonsurgical site. In contrast, the LOTM group had only 1 dog and the IV group had only 3 dogs that had a 24-hour duration of analgesia. Furthermore, although all of these dogs did not require rescue analgesia on the basis of the study criteria, they did have signs of less tolerance to palpation of the surgical and nonsurgical sites. Collectively, these results indicated that 120 μg of buprenorphine/kg administered via the OTM route was capable of minimizing individual variation in response to pain and inducing a more consistent analgesia than for the other 2 treatments. We believe this is because HOTM acted as a preemptive analgesic in that high plasma concentrations of buprenorphine were achieved early, thus supressing pain induced by ovariohysterectomy and preventing further wind-up pain.

In dogs, pharmacokinetics and related pharmaco-dynamics of clinically relevant analgesic doses of buprenorphine administered via the IV or OTM route have not been clearly established. In the study reported here, we attempted to determine the threshold of the plasma concentrations of buprenorphine at the time of rescue analgesia in dogs following ovariohysterectomy. To do so, we examined all of the dogs that received rescue analgesia in this study (9/18 dogs), regardless of treatment group. We then grouped the dogs that received rescue analgesia on the basis of the plasma concentrations of buprenorphine at the time of rescue analgesia. We found that 5 of 9 dogs had a plasma concentration between < 0.10 and 0.16 ng/mL and that 2 of 9 dogs had a plasma concentration between 0.50 and 0.60 ng/mL; the remaining 2 dogs had relatively high plasma concentrations of buprenorphine (1.46 and 5.41 ng/mL, respectively). We suspect that these latter 2 dogs had a higher sensitivity to pain, compared with the sensitivity for the general population, and that these 2 dogs may have responded better to a multimodal analgesic approach rather than to administration of a single opioid for effective treatment of pain, which greatly emphasizes the importance of a multimodal pain management approach. Removing these 2 dogs with high plasma buprenorphine concentrations from consideration, it was possible to determine a reasonable pain plasma concentration threshold for buprenorphine in dogs undergoing ovariohysterectomy. We found that 7 of 9 dogs had a plasma buprenorphine concentration of < 0.60 ng/mL at the time of rescue analgesia.

In the previous pharmacokinetic study21 conducted by our research group, we reported that 120 μg of buprenorphine/kg administered via the OTM route resulted in a Cmax (mean ± SD, 19.5 ± 9.6 ng/mL) similar to that for 20 μg of buprenorphine/kg administered IV (19.0 ± 4.9 ng/mL), whereas administration of 20 μg of buprenorphine/kg via the OTM route resulted in a Cmax of 2.2 ± 0.3 ng/mL. Therefore, in the present study, the choice of 120 μg/kg as a dose for OTM administration in these dogs undergoing ovariohysterectomy was appropriate and should not be considered as an excessively high dose. Although the HOTM and IV treatments resulted in a similar Cmax of buprenorphine, the major advantage in terms of the pharmacokinetic profile for buprenorphine administered via the OTM route at a dose of 120 μg/kg over buprenorphine administered IV at a dose of 20 μg/kg is that a higher plasma concentration can be sustained for a longer period with the HOTM treatment than with a single bolus administered IV. The buprenorphine plasma concentrations in the study reported here closely mimicked the pharmacokinetic profile in our previous study,21 and it was significantly higher for the HOTM treatment than for the IV or LOTM treatments throughout the first 3 hours after administration. The HOTM treatment continued to sustain higher plasma concentrations than did the IV and LOTM treatments throughout the 24-hour study period. On the basis of this result, we hypothesize that sustained high buprenorphine concentrations over time as a result of the HOTM treatment played a key role in reducing individual variation and maintaining a long duration of analgesia in these dogs. In contrast to the HOTM treatment, the LOTM treatment appeared to be inadequate for providing analgesia following ovariohysterectomy because there was more variation in response and 5 of 6 dogs required rescue analgesia. The IV treatment resulted in an analgesic duration with individual variations that was between the durations for the LOTM and HOTM treatments, with 3 of 6 dogs in the IV treatment group requiring rescue analgesia.

Buprenorphine has a high affinity for opioid μ-receptors and a slow dissociation from such receptors, which accounts for its long duration of action.24 A mechanism-based pharmacokinetic-pharmacodynamic model has been successfully applied to characterize the time course of the antinociceptive effect of buprenorphine in rats25 and healthy humans.26 The model could be used to separate buprenorphine biophase equilibration and receptor association-dissociation properties.25,26 The rate of onset and offset of the antinociceptive effect of buprenorphine is predominantly determined by distribution of these drugs to the effect site-brain tissues (ie, the biophase).25,26 The biophase equilibration determines the buprenorphine disposition characteristic at the effect site and influences the intensity of the biological effect and the duration of the antinociceptive effect.25,26 On the basis of pharmacokinetic-pharmacodynamic analysis, it is suggested that the elimination of buprenorphine from the brain is slower than it is from plasma; therefore, the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association-dissociation.25,26 The results of those 2 studies25,26 revealed that, contrary to common belief, the slow onset and offset of the buprenorphine-induced antinociceptive effect is determined by slow biophase equilibration kinetics, rather than slow receptor association-dissociation kinetics. This theory may be a reasonable explanation for the analgesic effect detected in the present study when the buprenorphine concentrations decreased to < 0.60 ng/mL during the latter part of the study and some of the treated dogs (especially dogs in the HOTM treatment group) still appeared to have analgesia and did not require rescue analgesia. Future studies are needed to evaluate the association of biophase distribution with the pharmacokinetic and pharmacodynamic responses in dogs.

In the study reported here, concentrations of buprenorphine and its metabolites, including norbuprenorphine, buprenorphine-3-G, and norbuprenorphine-3-G, were measured in all samples. However, plasma concentrations of all the buprenorphine metabolites, including norbuprenorphine and its glucuronide metabolites, were much less than the plasma buprenorphine concentrations. The low concentrations of buprenorphine metabolites were consistent with results in our previous pharmacokinetic study21 in conscious dogs. The role of norbuprenorphine in clinical analgesia in humans is controversial. Some authors27,28 have considered norbuprenorphine to contribute to the analgesic effect following buprenorphine administration. Other authors29,30 have discounted the contribution of norbuprenorphine to clinical analgesia because of its low plasma concentrations and the premise that glucuronide metabolites are inactive. Because of the extremely low concentrations of buprenorphine metabolites detected in the present study, it was reasonable to assume that the contribution of all the buprenorphine metabolites to the overall analgesic effect in the treated dogs was minimal.

Oral transmucosal administration is a convenient route for providing buprenorphine for pain management in hospital and home settings. In contrast to the efficacy for OTM administration of buprenorphine in cats,18 efficacy of OTM administration in dogs has not been reported previously. In that study18 in cats, investigators detected bioavailability of 116.3% for OTM administration of buprenorphine, and the high pH (approx 9) of saliva in cats contributes to the high bioavailability after OTM administration in this species. In our previous study21 in dogs, we determined that the pH of the saliva of dogs was between 9 and 10 and is similar to that of cats. Many factors affect buprenorphine absorption through oral mucosa and the bioavailability, including pH of the saliva, drug volume, mucosal permeability, drug formulation, metabolism, and physico-chemical reactions pertaining to oral retention.11,16,17,21 Because buprenorphine is a weak base with a pKa of 8.24,11 buprenorphine in the alkaline saliva environment of these dogs would primarily have been nonionized, thus enhancing its lipophilic nature and facilitating the absorption of buprenorphine molecules across the oral-cheek-lingual mucosa membrane lipid bilayers.21 Entry into the bloodstream would be rapid.11,21

In the study reported here, the highest plasma buprenorphine and norbuprenorphine concentrations in these dogs anesthetized with propofol followed by isoflurane were achieved 0.25 hours after 20 and 120 μg of buprenorphine/kg were administered via the OTM route. This was the first blood sample collected after buprenorphine administration in these dogs. We do not know whether the plasma buprenorphine concentrations peaked earlier. However, the highest mean ± SEM plasma concentration of buprenorphine at 0.25 hours was 1.4 ± 0.2 ng/mL and 9.2 ± 1.3 ng/mL for the LOTM and HOTM treatments, respectively. These results were slightly different from those in our pharmacokinetic study21 in which we used the same doses of buprenorphine administered via the OTM route in conscious dogs. In that study,21 plasma buprenorphine concentrations were detectable 3 minutes after OTM administration and peaked between 30 and 40 minutes, with the highest mean ± SD plasma concentrations of 2.2 ± 0.3 ng/mL and 19.5 ± 9.6 ng/mL for 20 and 120 μg of buprenorphine/kg, respectively. The precise reasons for this earlier peak and lower Cmax of buprenorphine in the anesthetized dogs of the present study, versus the conscious dogs in the other study,21 are unknown. However, results of 1 study31 revealed pharmacokinetic changes between anesthetized and conscious horses that received lidocaine; anesthetized horses had a smaller volume of distribution, lower clearance, and a shorter half-life for lidocaine. Differences in buprenorphine pharmacokinetics and pharmacodynamics in conscious and anesthetized dogs warrant further investigation.

Another issue is whether there is a difference in oral pH in anesthetized and conscious dogs, which could result in differences in the rate of buprenorphine absorption. The pH of the mouth, as well as pH of the saliva, can influence buccal absorption of fentanyl in humans32 and dogs,16 with faster absorption and increased permeability when the pH of the oral environment becomes more basic (alkalotic).16 In our pharmacokinetic study21 in which we evaluated OTM administration of buprenorphine in dogs, pH of the saliva did not change during the first hour after buprenorphine administration and remained basic in the conscious dogs. Because we did not measure oral or saliva pH in the present study, it is unknown whether pH of the saliva or mouth changed during anesthesia with propofol-isoflurane and therefore whether they may have played a role in altering the buccal absorption rate. Nevertheless, the difference in peak time and Cmax of buprenorphine administered via the OTM route between anesthetized and conscious dogs should be mentioned and warrants further investigations.

Analysis of plasma concentrations in the present study revealed that the Cmax was detected during maintenance of anesthesia with isoflurane while the dogs were undergoing ovariohysterectomy. This study was not designed to evaluate the minimum alveolar concentrations of isoflurane in dogs; however, we were interested in isoflurane maintenance requirements for the various treatment groups. We did not appreciate any differences in end-tidal isoflurane concentrations for maintenance of anesthesia in the dogs undergoing ovariohysterectomy for the 3 treatment groups, despite significant differences in plasma buprenorphine concentrations during the surgery. There are several plausible explanations for this lack of apparent difference in the concentration of isoflurane needed for maintenance despite the significant difference in plasma buprenorphine concentrations. One explanation is that buprenorphine is not a potent isoflurane-sparing opioid in dogs, regardless of dose (and therefore the plasma concentration). However, a study33 in humans revealed that IV administration of buprenorphine reduces the minimum alveolar concentration of halothane in a dose-dependent manner. A second possible explanation is that buprenorphine has a ceiling effect. This ceiling effect could have resulted in similar isoflurane-sparing effects between high and low plasma concentrations for the 3 treatment groups. Investigators in a clinical study3 reported that doubling the dose of buprenorphine does not significantly affect the maintenance requirement of isoflurane in dogs undergoing castration. Observations in the study reported here were consistent with those for the dog castration study,3 with minimal difference in isoflurane concentrations needed for maintenance of anesthesia.

As expected, we did not detect a significant difference in the dose of propofol needed for induction among treatment groups. This lack of a propofol-sparing effect was attributable mainly to a slower onset of buprenorphine action because propofol administration commenced immediately after buprenorphine administration. The action of buprenorphine was unlikely to have a sparing effect even when buprenorphine was administered IV to dogs in the IV treatment group.

In the present study, there were no significant differences among the treatment groups in heart rate, respiratory rate, arterial blood pressures, and hemoglobin saturation for oxygen. All variables were within the respective reference ranges for anesthetized dogs. In another study,34 healthy dogs received 16 μg of buprenorphine/kg IV while anesthetized with isoflurane, which resulted in a reasonable decrease in heart rate, blood pressure, and cardiac output, and these decreases were considered to be of minimum clinical relevance. Furthermore, buprenorphine (100 and 1,000 μg/kg, IV) has a minimal effect on hemodynamic variables in open-chest cats anesthetized and maintained with chloralose.35 We are not aware of studies conducted to compare the cardiorespiratory effects of OTM with those of IV administration of buprenorphine in dogs anesthetized with propofol-isoflurane, but on the basis of the cardiorespiratory results of the study reported here, we considered that buprenorphine administered via IV and OTM routes in this study was relatively safe in healthy dogs undergoing ovariohysterectomy.

One limitation for the use of 120 μg of buprenorphine/kg in a clinical setting is that currently available commercial formulations of buprenorphine are designed for human patients and are available only at concentrations of 300 μg/mL. As a result, the administration volume for a 120 μg/kg dose of a dog weighing 25 kg (55 lb) can be up to 10 mL. However, the 120 μg/kg dose administered via the OTM route remains attractive for smaller dogs. Administration of OTM in the cheek pouch was relatively simple to perform, and the rapid increase in plasma concentrations indicated the efficacy for the OTM administration of buprenorphine. The advantages of consistent and long-duration analgesia offset the large volume and the cost of buprenorphine for OTM administration to large dogs and do not cause problems for OTM administration in smaller dogs.

In the present study, the degree of sedation induced by buprenorphine varied among treatment groups, although the only significant differences among treatment groups were at 3 hours after buprenorphine administration. Sedation induced by buprenorphine is unique and differs from that induced by other sedatives. The dogs in the present study could be aroused by a clapping noise and could interact with the evaluators during the pain assessment. Therefore, we do not consider buprenorphine-induced sedation to be a serious adverse effect when buprenorphine is administered for managing postoperative pain.

Although we were able to determine the clinical analgesic efficacy for the HOTM-treated dogs, there was a limitation to this study. The number of dogs used in each group was insufficient to detect significant differences among treatment groups in the duration of analgesia and the number of dogs requiring rescue analgesia. Future studies that involve the use of more dogs in each treatment group would likely detect significant differences for these variables.

We concluded that 120 μg of buprenorphine/kg administered via the OTM route before ovariohysterectomy was an effective analgesic with minimal intra-operative and postoperative adverse effects. The higher dose of buprenorphine administered via the OTM route resulted in a unique pharmacokinetic profile that minimized individual pain sensation and provided long-lasting analgesia in dogs. Finally, we determined the efficacy for a high dose of buprenorphine administered via the OTM route, a delivery method that has not been examined in dogs to our knowledge. This delivery method for a high dose of buprenorphine will aid in multimodal pain management for providing a longer duration of analgesia. When considering all dog populations with highly variable individual sensitivities to pain and responses to analgesics, it is wise to use a multimodal pain management approach that includes > 1 class of analgesic or > 1 dose of the same opioid when treating pain of any nature, including surgical pain. A single high dose of buprenorphine administered via the OTM route before surgery may be particularly beneficial for achieving reasonable postoperative analgesia when the situation does not allow the use of multimodal pain management techniques or frequent administration of pain medications.

ABBREVIATIONS

Cmax

Maximum plasma concentration

DIVAS

Dynamic interactive visual analogue scale

gf/cm2

Gram-force per square centimeter

HOTM

High dose given via oral transmucosal administration

LOTM

Low dose given via oral transmucosal administration

OTM

Oral transmucosal

pKa

Negative logarithm of the ionization constant of an acid

a.

Hospira Inc, Lake Forest, Ill.

b.

Propoflo, Abbott Animal Health, Abbott Park, Ill.

c.

IsoFlo, Abbott Animal Health, Abbott Park, Ill.

d.

Normosol, Hospira Inc, Lake Forest, Ill.

e.

PC-VetGuard Plus, VMed Technology Inc, Mill Creek, Wash.

f.

Max Multigas Analyzer, PhaseIN Medical Technologies, Danderyd, Sweden.

g.

Palpometer Systems Inc, Victoria, BC, Canada.

h.

Rimadyl, Pfizer Animal Health, New York, NY.

i.

SAS, version 9.1, SAS Institute Inc, Cary, NC.

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