• View in gallery
    Figure 1—

    Mean ± SD blood glucose concentration measured before surgery (ie, baseline) and at 1, 3, 5, and 24 hours after analgesic administration performed 30 minutes before the end of maxillectomy or mandibulectomy to remove oral neoplasms from client-owned dogs. Eight dogs received tramadolh (2 mg/kg, q 8 h for 24 hours [diagonal-striped bars]), 9 dogs received codeine (2 mg/kg, q 8 h for 24 hours [black bars]), 9 dogs received ketoprofenj (2 mg/kg, q 24 h [gray bars]), 8 dogs received tramadol + ketoprofen (2 mg of tramadol/kg, q 8 h for 24 hours, and 2 mg of ketoprofen/kg, q 24 h [white bars]), and 8 dogs received codeine + ketoprofen (2 mg of codeine/kg, q 8 h for 24 hours, and 2 mg of ketoprofen/kg, q 24 h [horizontal-striped bars]). *Within a treatment group, value differs significantly (P < 0.05) from the baseline value.

  • View in gallery
    Figure 2—

    Mean ± SD NRS score measured before surgery (ie, baseline) and at 1, 2, 3, 4, 5, and 24 hours after analgesic administration performed 30 minutes before the end of maxillectomy or mandibulectomy to remove oral neoplasms from client-owned dogs. The NRS ranged from 0 (lack of pain) to 10 (excruciating pain). *Within a treatment group, value differs significantly (P < 0.05) from the baseline value. See Figure 1 for remainder of key.

  • View in gallery
    Figure 3—

    Mean ± SD sedation score measured before surgery (ie, baseline) and at 1, 2, 3, 4, 5, and 24 hours after analgesic administration performed 30 minutes before the end of maxillectomy or mandibulectomy to remove oral neoplasms from client-owned dogs. The sedation scale ranged from 0 to 3 (0 = no sedation, no sensory or motor deficits; 1 = mild sedation, slight sensory or motor deficits evident as ataxia or disorientation; 2 = moderate sedation, sternal recumbency and slight protrusion of the third eyelid; and 3 = strong sedation, right or left recumbency and accentuated protrusion of the third eyelid). *Within a treatment group, value differs significantly (P < 0.05) from the baseline value. See Figure 1 for remainder of key.

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Comparison of the effects of tramadol, codeine, and ketoprofen alone or in combination on postoperative pain and on concentrations of blood glucose, serum cortisol, and serum interleukin-6 in dogs undergoing maxillectomy or mandibulectomy

Teresinha L. MartinsPostgraduate Program of Anesthesiology of Faculdade de Medicina, Universidade de São Paulo, São Paulo, CEP 05403-900, Brazil

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Márcia A. P. KahvegianPostgraduate Program of Anesthesiology of Faculdade de Medicina, Universidade de São Paulo, São Paulo, CEP 05403-900, Brazil

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Jessica Noel-MorganPostgraduate Program of Anesthesiology of Faculdade de Medicina, Universidade de São Paulo, São Paulo, CEP 05403-900, Brazil

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Marco A. Leon-RománDepartment of Surgery, Faculdade de Medicina Veterinaria e Zootecnia, Universidade de São Paulo, São Paulo, CEP 05463-900, Brazil

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Denise A. OtsukiLaboratory of Medical Investigation, LIM08/Anestesiologia of Faculdade de Medicina, Universidade de São Paulo, São Paulo, CEP 01246-903, Brazil

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Denise T. FantoniDepartment of Surgery, Faculdade de Medicina Veterinaria e Zootecnia, Universidade de São Paulo, São Paulo, CEP 05463-900, Brazil

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Abstract

Objective—To compare analgesic effects of tramadol, codeine, and ketoprofen administered alone and in combination and their effects on concentrations of blood glucose, serum cortisol, and serum interleukin (IL)-6 in dogs undergoing maxillectomy or mandibulectomy.

Animals—42 dogs with oral neoplasms.

Procedures—30 minutes before the end of surgery, dogs received SC injections of tramadol (2 mg/kg), codeine (2 mg/kg), ketoprofen (2 mg/kg), tramadol + ketoprofen, or codeine + ketoprofen (at the aforementioned dosages). Physiologic variables, analgesia, and sedation were measured before (baseline) and 1, 2, 3, 4, 5, and 24 hours after surgery. Blood glucose, serum cortisol, and serum IL-6 concentrations were measured 1, 3, 5, and 24 hours after administration of analgesics.

Results—All treatments provided adequate postoperative analgesia. Significant increases in mean ± SD blood glucose concentrations were detected in dogs receiving tramadol (96 ± 14 mg/dL), codeine (120 ± 66 mg/dL and 96 ± 21 mg/dL), ketoprofen (105 ± 22 mg/dL), and codeine + ketoprofen (104 ± 16 mg/dL) at 5, 1 and 3, 5, and 3 hours after analgesic administration, respectively, compared with preoperative (baseline) values. There were no significant changes in physiologic variables, serum IL-6 concentrations, or serum cortisol concentrations. Dogs administered codeine + ketoprofen had light but significant sedation at 4, 5, and 24 hours.

Conclusions and Clinical Relevance—Opioids alone or in combination with an NSAID promoted analgesia without adverse effects during the 24-hour postoperative period in dogs undergoing maxillectomy or mandibulectomy for removal of oral neoplasms. (Am J Vet Res 2010;71:1019–1026)

Abstract

Objective—To compare analgesic effects of tramadol, codeine, and ketoprofen administered alone and in combination and their effects on concentrations of blood glucose, serum cortisol, and serum interleukin (IL)-6 in dogs undergoing maxillectomy or mandibulectomy.

Animals—42 dogs with oral neoplasms.

Procedures—30 minutes before the end of surgery, dogs received SC injections of tramadol (2 mg/kg), codeine (2 mg/kg), ketoprofen (2 mg/kg), tramadol + ketoprofen, or codeine + ketoprofen (at the aforementioned dosages). Physiologic variables, analgesia, and sedation were measured before (baseline) and 1, 2, 3, 4, 5, and 24 hours after surgery. Blood glucose, serum cortisol, and serum IL-6 concentrations were measured 1, 3, 5, and 24 hours after administration of analgesics.

Results—All treatments provided adequate postoperative analgesia. Significant increases in mean ± SD blood glucose concentrations were detected in dogs receiving tramadol (96 ± 14 mg/dL), codeine (120 ± 66 mg/dL and 96 ± 21 mg/dL), ketoprofen (105 ± 22 mg/dL), and codeine + ketoprofen (104 ± 16 mg/dL) at 5, 1 and 3, 5, and 3 hours after analgesic administration, respectively, compared with preoperative (baseline) values. There were no significant changes in physiologic variables, serum IL-6 concentrations, or serum cortisol concentrations. Dogs administered codeine + ketoprofen had light but significant sedation at 4, 5, and 24 hours.

Conclusions and Clinical Relevance—Opioids alone or in combination with an NSAID promoted analgesia without adverse effects during the 24-hour postoperative period in dogs undergoing maxillectomy or mandibulectomy for removal of oral neoplasms. (Am J Vet Res 2010;71:1019–1026)

Pain currently is considered to be the fifth vital sign, and as such, it should be regularly assessed and properly managed.1 Improper treatment of acute pain, including postoperative pain, is a risk factor for the development of chronic pain.2–5 Although subjective in essence, pain has been extensively studied over the years, both experimentally and clinically, in domestic animals and humans. Scales used for the clinical assessment of pain have been derived from these studies.6–9

Postoperative pain is the result of tissue damage that incites nociception and inflammation, surgical manipulation, and other stimuli, such as anesthesia and stress.4,10 Changes in blood glucose, plasma cortisol, and catecholamine concentrations have been evaluated in studies11,12 that involved pain recognition in small animals and have yielded important information regarding attenuation of the neuroendocrine response to pain. During surgery, various mediators, including prostaglandins, bradykinins, substance P, calcitonin-G-related protein, and cytokines, are released and interact to mediate and modulate pain.4,13,14 Inflammation and stress are associated with an increase in tumor necrosis factor-α and proinflammatory, pain-generating cytokines such as IL-1β and IL-6.10,15 Such cytokines may also have anti-inflammatory properties.4,16,17 Interleukin-6 is the primary chemical mediator involved in bone inflammation and bone pain.10

Several drugs may be used for the treatment of pain. General guidelines have been offered by the World Health Organization.18 Those guidelines state that mild pain should be treated with a nonopioid drug (with or without an adjuvant). As pain increases from moderate to severe, mild to strong opioids should be added to the protocol. Ketoprofen is an NSAID commonly used in veterinary medicine.11,19–21 As an anti-inflammatory drug, ketoprofen may be used as a nonopioid agent for the management of mild pain.18,22,23 Tramadol and codeine are opioids used, either alone or in association with other drugs, in veterinary medicine for the control of mild to moderate pain.12,14,24,25 Tramadol may be as effective as morphine for postoperative analgesia of bitches undergoing ovariohysterectomy.12 Metamizole has analgesic, antipyretic, and spasmolytic properties,26 and prolonged use of this drug does not cause adverse effects in the digestive tract.27 Metamizole affects the CNS,28 and metabolites of metamizole act in the peripheral nervous system to inhibit synthesis of prostaglandins.29

Although numerous clinical studies have been conducted to evaluate analgesics and pain control in dogs, few have been performed in animals with cancer pain that underwent surgical resection of bone and soft tissues. The study reported here was performed with the purpose of evaluating the use of various drugs or drug combinations for the management of pain in dogs undergoing orthopedic or oncological surgery of the mandible or maxilla. Pain and analgesia were clinically assessed through the measurement of physiologic variables, use of pain scales, and clinical observations. Alterations in blood glucose, serum cortisol, and serum IL-6 concentrations were also evaluated.

Materials and Methods

Animals—Client-owned dogs (n = 42) of various breeds, body weights, and ages and both sexes were used in the study. Dogs eligible for inclusion were those evaluated at the Veterinary Hospital of the Faculdade de Medicina Veterinária e Zootecnia of the Universidade de São Paulo and classified with invasive or malignant oral neoplasia that was treatable by maxillectomy or mandibulectomy with removal of margins that included resection of osseous and soft tissues. Medical history was obtained, and complete physical examination, CBC, and biochemical analysis were performed for all dogs 48 hours before surgery to exclude those with neurologic, renal, hepatic, or endocrine disease as well as any condition that would contraindicate the use of NSAIDs or opioids. Dogs that had received any analgesic or NSAID 48 hours prior to the study were excluded. Client consent was obtained before entry of any dog into the study. This study was approved by the Bioethics Committee of the College of Veterinary Medicine, Faculdade de Medicina Veterinária e Zootecnia of the Universidade de Sào Paulo and by the Ethics Committee for Research Project Analysis of the College of Medicine, Faculdade de Medicina of the Universidade de São Paulo.

Surgical preparation and surgery—Food was withheld for 12 hours and water was withheld for 8 hours before surgery. On the day of surgery, a complete physical examination, including assessment of pain, was performed on each dog, and a blood sample was collected before surgery (baseline) for measurement of glucose, cortisol, and IL-6 concentrations. Dogs then were premedicated by IM administration of acepromazine maleatea (0.05 mg/kg) and pethidine hydrochlorideb (2 mg/kg). One of the cephalic veins was then cannulated with a catheter of appropriate size (18 to 22 gauge) for infusion of drugs and fluids. Thirty minutes after premedications were administered, anesthesia was induced by IV administration of propofolc (2.3 to 6.5 mg/kg, to effect) to enable intubation with an endotracheal tube of appropriate size. Anesthesia was maintained by administration of isofluraned in 100% oxygen delivered through a rebreathing system.e An adapter was inserted between the orotracheal tube and the rebreathing system for continuous measurement of end-tidal concentrations of anesthetic gases (ie, isoflurane) and carbon dioxide by use of an anesthetic gas analyzer and capnographf that was calibrated before each experiment. Settings for the isoflurane vaporizer were adjusted to maintain surgical depth of anesthesia, as determined on the basis of clinical signs, whereas the positive-pressure ventilation rate was adjusted to maintain the end-tidal concentration of carbon dioxide between 35 and 45 mm Hg. Lactated Ringer's solution was administered IV at a rate of 10 mL/kg/h. Rectal temperature, which was recorded by the monitor via a rectal temperature probe, was maintained at > 37°C by means of a forced-air warming blanketg and electric heating pad. Heart rate and rhythm, oxygen saturation measured by use of pulse oximetry, and oscillometric NIBP were monitored with a monitor.h

All surgeries were performed by the same surgeon (MALR). The same resection pattern and suture material were used for each surgery.

Analgesic treatments—Thirty minutes before the end of surgery, analgesics were administered SC to each dog. Dogs were assigned to 1 of 5 treatment groups. Eight dogs received tramadori (2 mg/kg, q 8 h for 24 hours), 9 dogs received codeinej (2 mg/kg, q 8 h for 24 hours), 9 dogs received ketoprofenk (2 mg/kg, q 24 h once), 8 dogs received tramadol + ketoprofen (2 mg of tramadol/kg, q 8 h for 24 hours, and 2 mg of ketoprofen/kg, q 24 h once), and 8 dogs received codeine + ketoprofen (2 mg of codeine/kg, q 8 h for 24 hours, and 2 mg of ketoprofen/kg, q 24 h once). Drugs were administered by a researcher (TLM) who was responsible for anesthesia and assessment of pain and who was not aware of the treatment administered to each dog. Tramadol dosage was based on results of previous studies12,30,31 for control of acute pain in dogs. Codeine dosage was based on data obtained from reference books13,32–34 because of the lack of clinical studies with this drug in dogs. Additional treatments (ie, antimicrobials) not related to control of pain were administered as prescribed by the surgeon.

The endotracheal tube was removed when laryngeal reflexes were restored. Rectal temperature was monitored, and appropriate action was taken (use of blankets and of warm airg) when necessary to maintain a rectal temperature between 37.5° and 38°C.

Postoperative evaluation—Dogs were visually assessed to determine respiratory rate, and heart rate was evaluated via thoracic auscultation with a stethoscope. The NIBP was measured 3 times with the same monitor used during anesthesia. Blood samples (4 mL/sample) were collected via the catheter in the cephalic vein at 1, 3, 5, and 24 hours after administration of the analgesics and used for measurement of blood glucose, serum cortisol, and serum IL-6 concentrations.

Blood glucose concentrations were measured by use of a portable biamperometric glycemia measuring devicel immediately after sample collection. Three measurements were obtained, and the minimum and maximum values were discarded. Limit of detection of the assay was 10 to 600 mg/dL, as established by the manufacturer. Serum cortisol concentrations were determined by use of a competitive radioimmunoassay.m After clotting, blood samples were centrifuged (2,500 × g for 10 minutes at 4°C), and serum was harvested and stored at −80°C. Samples were analyzed in duplicate, and a mean value was calculated. Serum IL-6 concentrations were measured by use of an ELISA that used specific monoclonal antibodies.n A trained professional performed the ELISA in accordance with the manufacturer's instructions. The samples analyzed were aliquots processed as described for the serum cortisol samples. Samples were analyzed in duplicate, and a mean value was calculated.

Pain was assessed via an NRS and a descriptive scale described elsewhere35 at 1, 2, 3, 4, 5, and 24 hours after administration of analgesics. At time points when a blood sample was collected, pain was assessed immediately after collection of the blood sample. The assessment was always performed by the same researcher (TLM), who was unaware of the treatment administered to each dog and who had extensive experience with use of the NRS and descriptive scale to score pain in animals. Briefly, the NRS ranged from 0 (lack of pain) to 10 (excruciating pain). The descriptive scale ranged from 0 to 3 (0 = complete analgesia, no overt signs of discomfort and no reaction to the application of firm pressure; 1 = good analgesia, no overt signs of discomfort but with a reaction to the application of firm pressure; 2 = moderate analgesia, some overt signs of persistent discomfort that was made worse by the application of firm pressure; and 3 = no analgesia, obvious signs or persistent discomfort that was made worse by the application of firm pressure). Both methods were assessed by use of manual application of pressure to the surgical site.

Sedation also was visually assessed at 1, 2, 3, 4, 5, and 24 hours after administration of analgesics. Sedation was graded by use of a scale that ranged from 0 to 38,36 (0 = no sedation, no sensory or motor deficits; 1 = mild sedation, slight sensory or motor deficits evident as ataxia or disorientation; 2 = moderate sedation, sternal recumbency and slight protrusion of the third eyelid; and 3 = strong sedation, in right or left lateral recumbency and accentuated protrusion of the third eyelid).

Dogs judged to have moderate to severe pain (NRS ≥ 4 or descriptive scale = 3) were given metamizoleo (25 mg/kg, IV, administered slowly),37 and the dogs were reassessed 60 minutes later. If a similar degree of pain still persisted at that time, the dogs were medicated with morphinep (0.1 mg/kg, IV, administered slowly). Additional doses of morphine (0.1 mg/kg, IV) were administered when necessary.

All dogs were offered water ad libitum after recovery from anesthesia. Soft or liquefied food (prepared from their typical diet they received at home) was offered during the period from 5 to 12 hours after surgery. Adverse effects (vomiting and diarrhea) were evaluated throughout the 24-hour observation period.

At the end of the 24-hour observation period, all dogs were medicated with tramadol (2 mg/kg, PO, q 8 h) and ketoprofen (1 mg/kg, PO, q 24 h) for 4 days.

Data analysis—Data were analyzed for a normal distribution by use of the Kolmogorov-Smirnov test, and nonparametric tests were used to analyze data that did not conform to a Gaussian distribution. Heart rate, respiratory rate, NIBP, and glucose, cortisol, and IL-6 concentrations were analyzed by use of a 2-way ANOVA (group and time effect). Pain and sedation scores were compared within each group by use of the Friedman test followed by the Dunn test and between groups by use of the Kruskal-Wallis test followed by the Dunn post hoc test. Surgery and extubation times were compared by use of a 1-way ANOVA. A χ2 test was used to compare rescue analgesia requirements. Data were analyzed by use of statistical software packages.q,r Values of P < 0.05 were considered significant.

Results

Of the 42 dogs included in the study, 19 underwent maxillectomy and 23 underwent mandibulectomy. Despite the overall similar numbers for the 2 procedures, there was a significant difference in the number for each procedure among the 5 treatment groups (Table 1). Surgical procedures ranged from small resections of rostral bones to total removal of the mandible on 1 side.

Table 1—

Comparison of demographic characteristics, pain scores, and concentrations of blood glucose, serum cortisol, and serum IL-6 during the 24-hour observation period after maxillectomy or mandibulectomy among dogs in 5 analgesic treatment groups.*

VariableTramadolCodeineKetoprofenTramadol + ketoprofenCodeine + ketoprofen
No. of dogs89988
   Female33345
   Male56643
Age (y)6.18 ± 3.209.00 ± 3.428.66 ± 4.24§10.50 ± 4.3110.62 ± 2.92
Body weight (kg)21.5 ± 10.913.7 ± 8.424.7 ± 15.518.2 ± 11.925 ± 14.6
Surgery     
   Maxillectomy53616
   Mandibulectomy36372
Duration of surgery (min)72 ± 3768 ± 2981 ± 2884 ± 36111 ± 53
Time until extubation (min)7.5 ± 2.47.3 ± 1.67.1 ± 2.07.5 ± 3.37.6 ± 2.2
Rescue analgesia23522
   (No. of dogs)     
NRS1.16 ± 0.981.77 ± 1.000.95 ± 0.911.00 ± 0.921.22 ± 1.00
Descriptive scale0.74 ± 0.490.72 ± 0.450.59 ± 0.500.59 ± 0.490.46 ± 0.50
Sedation score#0.51 ± 0.790.47 ± 0.770.69 ± 0.860.40 ± 0.790.58 ± 0.76
Blood glucose (mg/dL)86 ± 2093 ± 3796 ± 2487 ± 1894 ± 27
Serum cortisol (μ/dL)4.04 ± 2.194.80 ± 2.914.36 ± 2.744.37 ± 2.224.02 ± 2.50
Serum IL- 6 (pg/mL)95.26 ± 87.1264.36 ± 55.89106.64 ± 82.396.5 ± 62.3963.56 ± 56.62

Dogs received analgesics via SC injection 30 minutes before the end of the surgical procedure as follows: tramadol (2 mg/kg, q 8 h for 24 hours), codeine (2 mg/kg, q 8 h for 24 hours), ketoprofen (2 mg/kg, q 24 h), tramadol + ketoprofen (2 mg of tramadol/kg, q 8 h for 24 hours, and 2 mg of ketoprofen/kg, q 24 h), and codeine + ketoprofen (2 mg of codeine/kg, q 8 h for 24 hours, and 2 mg of ketoprofen/kg, q 24 h).

Value reported is mean ± SD.

Value differs significantly (P < 0.05) from the value for codeine.

The NRS scale ranged from 0 (lack of pain) to 10 (excruciating pain).

The descriptive scale ranged from 0 to 3 (0 = complete analgesia, no overt signs of discomfort and no reaction to the application of firm pressure; 1 = good analgesia, no overt signs of discomfort but with a reaction to the application of firm pressure; 2 = moderate analgesia, some overt signs of persistent discomfort that was made worse by the application of firm pressure; and 3 = no analgesia, obvious signs or persistent discomfort that was made worse by the application of firm pressure).

The sedation scale ranged from 0 to 3 (0 = no sedation, no sensory or motor deficits; 1 = mild sedation, slight sensory or motor deficits evident as ataxia or disorientation; 2 = moderate sedation, sternal recumbency and slight protrusion of the third eyelid; and 3 = strong sedation, right or left recumbency and accentuated protrusion of the third eyelid).

n = Number of dogs.

Treatment groups did not differ significantly with regard to body weight, sex, duration of surgery, and extubation time (Table 1). Body weight ranged from 3.0 to 45.3 kg, and surgical time ranged from 30 to 180 minutes. Interval between the end of anesthesia and extubation ranged from 5 to 15 minutes. Dogs ranged from 2 to 19 years of age, which differed significantly among groups. Heart rate, respiratory rate, and NIBP did not differ significantly among groups or time points.

Blood glucose concentrations were significantly increased, compared with baseline values, in all groups, except for tramadol + ketoprofen (Figure 1). The blood glucose concentration was significantly increased in dogs receiving codeine at 1 and 3 hours, dogs receiving codeine + ketoprofen at 3 hours, and dogs receiving tramadol + ketoprofen at 5 hours.

Figure 1—
Figure 1—

Mean ± SD blood glucose concentration measured before surgery (ie, baseline) and at 1, 3, 5, and 24 hours after analgesic administration performed 30 minutes before the end of maxillectomy or mandibulectomy to remove oral neoplasms from client-owned dogs. Eight dogs received tramadolh (2 mg/kg, q 8 h for 24 hours [diagonal-striped bars]), 9 dogs received codeine (2 mg/kg, q 8 h for 24 hours [black bars]), 9 dogs received ketoprofenj (2 mg/kg, q 24 h [gray bars]), 8 dogs received tramadol + ketoprofen (2 mg of tramadol/kg, q 8 h for 24 hours, and 2 mg of ketoprofen/kg, q 24 h [white bars]), and 8 dogs received codeine + ketoprofen (2 mg of codeine/kg, q 8 h for 24 hours, and 2 mg of ketoprofen/kg, q 24 h [horizontal-striped bars]). *Within a treatment group, value differs significantly (P < 0.05) from the baseline value.

Citation: American Journal of Veterinary Research 71, 9; 10.2460/ajvr.71.9.1019

Baseline serum cortisol concentrations were near the upper limit of 6 µg/dL.38 No significant differences were detected among treatment groups or times.

Baseline serum IL-6 concentrations were similar among all groups, with a global mean value of 100.32 pg/mL. No significant changes in serum IL-6 concentrations were detected among treatment groups or times.

Visual evaluation of dogs did not reveal signs of pain at any time point. However, palpation of the surgical site (ie, application of firm pressure) elicited differences in signs of pain (Figure 2). All dogs had a mean baseline NRS score ≤ 1, and most dogs had a baseline NRS score of 0. There was a significant increase in pain score at 2 hours after analgesic administration, compared with the baseline value, for dogs receiving tramadol. Dogs receiving codeine had the greatest mean increase in NRS, although it was not significantly different from the baseline value or from values for the other treatment groups. At 24 hours after analgesic administration, the NRS scores for all treatment groups were similar (range, 1.3 to 1.9).

Figure 2—
Figure 2—

Mean ± SD NRS score measured before surgery (ie, baseline) and at 1, 2, 3, 4, 5, and 24 hours after analgesic administration performed 30 minutes before the end of maxillectomy or mandibulectomy to remove oral neoplasms from client-owned dogs. The NRS ranged from 0 (lack of pain) to 10 (excruciating pain). *Within a treatment group, value differs significantly (P < 0.05) from the baseline value. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 71, 9; 10.2460/ajvr.71.9.1019

Fourteen dogs required rescue medication. Of these, 13 dogs (2 receiving tramadol, 2 receiving tramadol + ketoprofen, 2 receiving codeine + ketoprofen, 3 receiving codeine, and 4 receiving ketoprofen) required 1 dose of metamizole and 1 dog (receiving ketoprofen) required 2 doses of rescue medication (metamizole followed 1 hour later by morphine). No significant differences were detected among treatment groups.

Sedation was detected at 1 hour after analgesic administration in all treatment groups (Figure 3). The sedation score was lowest in dogs receiving tramadol (1.0) and was successively higher in dogs receiving codeine (1.1), ketoprofen (1.4), tramadol + ketoprofen (1.5), and codeine + ketoprofen (1.8). Significant decreases in sedation scores, compared with scores at 1 hour after analgesic administration, were detected for dogs receiving ketoprofen (24 hours), tramadol + ketoprofen (5 and 24 hours), and codeine + ketoprofen (4, 5, and 24 hours). Dogs receiving ketoprofen were the first treatment group in which sedation totally subsided (sedation score of 0), which was detected 5 hours after analgesic administration.

Figure 3—
Figure 3—

Mean ± SD sedation score measured before surgery (ie, baseline) and at 1, 2, 3, 4, 5, and 24 hours after analgesic administration performed 30 minutes before the end of maxillectomy or mandibulectomy to remove oral neoplasms from client-owned dogs. The sedation scale ranged from 0 to 3 (0 = no sedation, no sensory or motor deficits; 1 = mild sedation, slight sensory or motor deficits evident as ataxia or disorientation; 2 = moderate sedation, sternal recumbency and slight protrusion of the third eyelid; and 3 = strong sedation, right or left recumbency and accentuated protrusion of the third eyelid). *Within a treatment group, value differs significantly (P < 0.05) from the baseline value. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 71, 9; 10.2460/ajvr.71.9.1019

Discussion

Studies that involve clinical assessment of pain are particularly troublesome to perform, given the subjective nature of such evaluation.39,40 In this regard, clinical trials have contributed greatly to the study of pain and to the use of analgesics in dogs. Unfortunately, there is a paucity of prospective clinical studies in which investigators evaluated postoperative pain in dogs with cancer.

In the study reported here, administration of analgesics in accordance with each of the proposed protocols ultimately resulted in analgesia in dogs undergoing maxillectomy or mandibulectomy. One of the purposes of this study was to determine the drugs or drug combinations that would result in adequate pain management with minimal detrimental repercussions. In this regard, the chosen methods suited this purpose well.

Oral neoplasia is common in dogs and cats, and the oral cavity ranks as the fourth most common site for neoplasms in these species (incidence of 6% and 3%, respectively41). The most frequently diagnosed malignant oral neoplasms are melanoma, fibrosarcoma, and squamous cell carcinoma.41,42 Surgeries for the removal of oral neoplasms reportedly are associated with high pain scores,43 which make maxillectomy and mandibulectomy good methods for use in investigating druginduced analgesia. Although there are protocols for use in postoperative analgesia of oral cavity–related surgeries,41,44–46 few blinded, prospective veterinary studies have been published on this topic.

In the present study, invasive and malignant tumors of the oral cavity were excised via maxillectomy or mandibulectomy, with removal of a safety margin that included resection of osseous and soft tissues. As stated in the results, surgical time was similar for all dogs.

Randomization of dogs among treatments resulted in groups that were not completely homogeneous. Thus, there was a difference with regard to age and type of surgery among groups. Nevertheless, the authors believe that these differences did not compromise the study because differences in age were relatively small and the degree of pain resulting from the type of surgery was estimated to be similar for the 2 procedures. One fact that emphasizes this belief is that the value for preoperative evaluation of pain was similar in all dogs. An observation period of 24 hours after surgery was chosen because this is the most critical time during the postoperative period.47 Pain assessment by use of the NRS and scores of the response to palpation of the surgical site by a single observer has been described in other studies.12,20,21,48–52

In the study reported here, all dogs originally had a preoperative (ie, baseline) mean NRS score ≤ 1. In fact, most dogs had a score of 0, and nearly all of them reportedly were eating normally. This is an interesting finding when compared with results for human studies53–55 in which mild to moderate pain is not uncommon. A speculative reason for this lack of oncological pain could have been a possible adaptation of the dogs to their condition. As expected, an increase in postoperative pain was observed for all treatment groups (mean score ranged from 1 to 3 after analgesic administration). The small difference in analgesia detected at 24 hours was likely attributable to the duration of action of each drug because the action of ketoprofen lasts from 12 to 24 hours19 and that of tramadol lasts for 8 hours.14,34 Thus, tramadol was administered at 8-hour intervals during the 24-hour observation period.

Only dogs receiving tramadol had a significant increase in NRS score (at 2 hours after analgesic administration). However, this does not mean that the administration of tramadol alone was inefficient in pain control because the NRS score was only 2. This observation is in agreement with that in a study12 in which investigators compared preemptive administration of tramadol (used at the same dosage as for the study reported here), with an equipotent dose of morphine in the evaluation of postoperative (ie, ovariohysterectomy) pain in bitches. The authors of that study12 concluded that both drugs had similar efficiency in pain control. Dogs treated with codeine also had a similar increase in NRS score, although it was not significant.

Mean pain scores for the descriptive scale were < 1.1 at all times, which indicated that this scale also provided evidence of adequate pain control. No significant difference was detected in mean pain scores for the descriptive scale among treatment groups.

Rescue analgesia was necessary for some dogs in every treatment group, and the greater need for rescue analgesia for dogs receiving ketoprofen (4/8 dogs) was not significantly different from that for other treatment groups. However, 1 aspect that is clinically important is that the perception of pain may have differed among individual dogs. Therefore, regardless of the regimen chosen for use in pain control, pain must always be continually assessed in every animal.

The sedation observed at 1 hour after analgesic administration could have been attributed, at least in part, to residual effects of the anesthetic regimen used.56 However, moderate sedation at 1 hour was most evident in dogs receiving codeine + ketoprofen, compared with that for dogs receiving tramadol, with a mean difference in sedation score of 0.8. Indeed, dogs receiving codeine + ketoprofen had a significant decrease in sedation at 4, 5, and 24 hours, compared with the sedation score at 1 hour after analgesic administration.

No significant difference among groups was detected regarding the evaluated physiologic variables. No important change was detected relative to baseline values, which indicated that these medications are safe for use as postoperative analgesics for this specific population.

As a stress factor, pain may be associated with increases in cortisol and glucose concentrations,11,12 and changes in these concentrations may provide an accurate means of determining analgesic efficacy.2,57,58 In the study reported here, tramadol + ketoprofen was the only treatment that prevented an increase in blood glucose concentration in relationship to the baseline concentration. When dogs were medicated with only tramadol or only ketoprofen, a significant increase in mean glucose concentrations was detected for each analgesic at 5 hours. Similarly, analgesia provided by codeine + ketoprofen was superior to that of codeine alone because glucose concentration in dogs administered codeine alone increased significantly at 2 time points. However, administration of codeine + ketoprofen was not superior to the use of ketoprofen alone. It should be mentioned that despite these significant increases in glucose concentration, the blood glucose concentration remained within the upper portion of the reference interval. For suppression of pain- or stress-associated hyperglycemia, tramadol + ketoprofen was best, whereas codeine alone had a minimal effect.

Mean serum cortisol concentrations did not exceed 6 mg/mL, which meant that they were high but within the physiologic reference interval,38 and no significant differences among groups or times were detected, which suggested satisfactory analgesia. Increases in cortisol concentrations were detected for individual dogs, which could empirically be associated with increases in blood glucose concentrations. However, most of these concentrations were only slightly higher than the physiologic reference interval and were detected at 1 hour after analgesic administration, which indicated that stress could have derived from additional factors other than pain (eg, recovery from anesthesia).

Interleukin-6 is a proinflammatory, pain-generating cytokine that has active roles in immunologic responses, neoplasia, osteoclastogenesis, and osteoclast activity, among other processes.10,15,59,60 There are conflicting results among studies involving proinflammatory ILs and neoplasia that may be explained by differences in methods of measurement, study populations, pathological conditions, and cytokines evaluated. Investigators in a study61 of humans with squamous cell carcinoma of the oral cavity and oropharyngeal region found a mean IL-6 serum concentration of 87 pg/mL. Unfortunately, few studies have related the physiologic range for this cytokine in dogs, especially dogs with oncological disease. A study62 in which investigators compared healthy dogs with dogs naturally infected with visceral leishmaniasis revealed mean plasma concentrations of 7.4 ± 3.8 pg/ mL and 16.2 ± 6.6 pg/mL, respectively, as determined by use of a human IL-6 ELISA. The study reported here, in which we used a canine IL-6 ELISA, revealed higher concentrations of this cytokine at baseline, which corroborated the general belief that this IL is strongly associated with bone inflammation and bone pain.10 This is an interesting finding because measurement of IL-6 could be used to indentify populations with injurious diseases that involve inflammation.

An increase in serum IL-6 concentrations should be expected in animals with excessive stress, signs of pain, surgical stimulus, or substantial injury. In a local intervention, only a small increase in plasma IL-6 concentrations is expected, as opposed to the much larger increase in IL-6 concentrations at the surgical site.63 Conversely, anesthesia and opioid use have been related to diminished serum cytokine concentrations and other inhibition of the immune response.63–66 In the present study, serum IL-6 concentrations remained relatively unchanged, with no significant difference among times (including baseline) or treatment groups, independent of whether an opioid was used as part of the analgesic regimens. Such a finding could indicate satisfactory pain control in all treatment groups, which was confirmed by direct evaluation of signs of pain and of a lack of increase in cortisol concentrations, as previously discussed. This could be evaluated in future studies by analysis of other proinflammatory ILs (eg, IL-1ß) as well as tumor necrosis factor and C-reactive protein.

Although all animals in the study were of the same species and selected in accordance with specific criteria (ie, species, type of disease, and treatment), the clinical nature of this study posed some limitations on the data obtained, particularly data referring to breeds, which in turn, reflected on variability in size, body weight, and sex. The number of dogs was also limited, given the criteria and need for owner consent. Because this was a clinical trial involving procedures that were known to cause pain, it was believed that a group of dogs that did not receive analgesia would be of no benefit because rescue analgesia would have to be promptly provided and no further values for subsequent time points would be available for comparison. The clinical nature of this study reflected the advantage of working with real clinical situations that are encountered daily.

Administration of analgesics in accordance with all of the protocols appeared to provide adequate analgesia. Although minor differences could be detected among the analgesic regimens, we suggest that an opioid-NSAID combination is the best alternative for this population of dogs. Furthermore, if the use of an NSAID is contraindicated, then administration of tramadol alone may be a good alternative.

ABBREVIATIONS

IL

Interleukin

NIBP

Noninvasive blood pressure

NRS

Numeric rating scale

a.

Acepran 0.2%, Vetnil, São Paulo, Brazil.

b.

Dolosal, Cristália, São Paulo, Brazil.

c.

Propofol 1% Profolen, Blausiegel, São Paulo, Brazil.

d.

Isoforine, Cristália, São Paulo, Brazil.

e.

Shogun Evolution Pró 2700, K. Takaoka, São Paulo, Brazil.

f.

Poet IQ, Criticare Systems Inc, Waukesha, Wis.

g.

Warm air hyperthermia system, Cincinnati Sub-Zero Products Inc, Cincinnati, Ohio

h.

M3 patient monitor, Agilent Technologies, Böblingen, Germany.

i.

Tramadon, Cristália, São Paulo, Brazil.

j.

Codeine, Cristália, São Paulo, Brazil.

k.

Ketofen 10%, Merial of Brazil, São Paulo, Brazil.

l.

Accu-chek Advantage II, Roche, Mannheim, Germany

m.

Diagnostic Products Corp, Los Angeles, Calif.

n.

Quantikine canine cytokine assay, R&D Systems, Minneapolis, Minn.

o.

Dipirona, Ibasa, São Paulo, Brazil.

p.

Dimorf, Cristália, São Paulo, Brazil.

q.

Instat, GraphPad, San Diego, Calif.

r.

SigmaStat 3.11, Systat Software Inc, Richmond, Calif.

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Contributor Notes

Supported by a grant from Fundaçao de Amparo à Pesquisa do Estado de São Paulo-FAPESP (05/59109-5). Dr. Martins was supported by a grant (Fellowship DS/PROAP) from Coordenaçao de Aperfeiçoamento de Pessoal de Nivel Superior-CAPES.

Address correspondence to Dr. Fantoni (pg.anestesiologia@incor.usp.br).