Clinical efficacy of hydrocodone-acetaminophen and tramadol for control of postoperative pain in dogs following tibial plateau leveling osteotomy

Marian E. Benitez Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.

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James K. Roush Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Rose McMurphy Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Butch KuKanich Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Claire Legallet Department of Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Abstract

OBJECTIVE To evaluate clinical efficacy of hydrocodone-acetaminophen and tramadol for treatment of postoperative pain in dogs undergoing tibial plateau leveling osteotomy (TPLO).

ANIMALS 50 client-owned dogs.

PROCEDURES Standardized anesthetic and surgical protocols were followed. Each patient was randomly assigned to receive either tramadol hydrochloride (5 to 7 mg/kg, PO, q 8 h; tramadol group) or hydrocodone bitartrate–acetaminophen (0.5 to 0.6 mg of hydrocodone/kg, PO, q 8 h; hydrocodone group) for analgesia after surgery. The modified Glasgow composite measure pain scale was used to assess signs of postoperative pain at predetermined intervals by an investigator who was blinded to treatment group. Scoring commenced with the second dose of the assigned study analgesic. Pain scores and rates of treatment failure (ie, dogs requiring rescue analgesia according to a predetermined protocol) were compared statistically between groups.

RESULTS 12 of 42 (29%; 5/19 in the hydrocodone-acetaminophen group and 7/23 in the tramadol group) dogs required rescue analgesic treatment on the basis of pain scores. Median pain score for the hydrocodone group was significantly lower than that of the tramadol group 2 hours after the second dose of study analgesic. The 2 groups had similar pain scores at all other time points.

CONCLUSIONS AND CLINICAL RELEVANCE Overall, differences in pain scores between dogs that received hydrocodone-acetaminophen or tramadol were minor. The percentage of dogs with treatment failure in both groups was considered unacceptable.

Abstract

OBJECTIVE To evaluate clinical efficacy of hydrocodone-acetaminophen and tramadol for treatment of postoperative pain in dogs undergoing tibial plateau leveling osteotomy (TPLO).

ANIMALS 50 client-owned dogs.

PROCEDURES Standardized anesthetic and surgical protocols were followed. Each patient was randomly assigned to receive either tramadol hydrochloride (5 to 7 mg/kg, PO, q 8 h; tramadol group) or hydrocodone bitartrate–acetaminophen (0.5 to 0.6 mg of hydrocodone/kg, PO, q 8 h; hydrocodone group) for analgesia after surgery. The modified Glasgow composite measure pain scale was used to assess signs of postoperative pain at predetermined intervals by an investigator who was blinded to treatment group. Scoring commenced with the second dose of the assigned study analgesic. Pain scores and rates of treatment failure (ie, dogs requiring rescue analgesia according to a predetermined protocol) were compared statistically between groups.

RESULTS 12 of 42 (29%; 5/19 in the hydrocodone-acetaminophen group and 7/23 in the tramadol group) dogs required rescue analgesic treatment on the basis of pain scores. Median pain score for the hydrocodone group was significantly lower than that of the tramadol group 2 hours after the second dose of study analgesic. The 2 groups had similar pain scores at all other time points.

CONCLUSIONS AND CLINICAL RELEVANCE Overall, differences in pain scores between dogs that received hydrocodone-acetaminophen or tramadol were minor. The percentage of dogs with treatment failure in both groups was considered unacceptable.

Pain relief following surgery is most often provided through opioid analgesic treatment with or without the addition of NSAIDs. Tramadol hydrochloride is a synthetic opioid that is commonly used for analgesia in dogs, and it is currently classified by the US Drug Enforcement Agency as a schedule IV drug. Tramadol is reported to have weak μ-opioid receptor affinity as a parent compound, but its metabolites are reported to be more potent.1 In humans, 1 active metabolite (O-desmethyltramadol or M1) exerts most of its pharmacological effects as a high-affinity μ-opioid receptor agonist and is highly correlated with analgesic activity.1,2 Another metabolite (N-desmethyltramadol or M2) is present in dogs but is considered to be inactive on the basis of results in humans and laboratory animal species.3 Unlike findings in human studies, the inactive metabolite M2 was found to be a major metabolite in dogs, with circulating concentrations exceeding those of tramadol and M1.4–6 In addition to its opioid receptor activity, tramadol can act as a serotonin and norepinephrine reuptake inhibitor. Only a few studies have been conducted to evaluate the pharmacokinetics of tramadol following oral administration in dogs. There are large divergences in reported bioavailability of tramadol following oral administration, with values ranging from 10%5 to 65%.7 Given the apparent discrepancies in its bioavailability, many veterinarians anecdotally question clinical efficacy of the drug, despite the frequent clinical administration of tramadol tablets.

Hydrocodone bitartrate is a schedule II opioid analgesic and is a semisynthetic derivative of codeine. Hydrocodone is variably metabolized to hydromorphone in many species including humans, rats, rabbits, pigs, guinea pigs, and dogs and is approximately equipotent to morphine in producing opiate effects.8 Historically, it has been infrequently used as an oral opioid analgesic in veterinary medicine, but it is more commonly used as a potent antitussive agent in both human and veterinary patients. To our knowledge, there are no clinical reports of studies to evaluate efficacy of orally administered hydrocodone-acetaminophen for treatment of postoperative pain in dogs.

It is widely accepted that advances in animal welfare and adequate patient care should include effective postoperative pain management. Identification of signs of postoperative pain and administration of adequate analgesics is a necessary skill for any veterinarian practicing surgery. Unfortunately, pain assessment in animals is difficult. Attempts to improve pain assessment in veterinary patients include use of pain assessment rating systems such as the simple descriptive scale, the numeric rating scale, and the visual analogue scale.9–12 At present, the only validated method for evaluating signs of postoperative pain in dogs is the GCMPS.13,14 Reid et al15 have modified the GCMPS for clinical use in postoperative settings.

The purpose of the study reported here was to evaluate the pharmacodynamics of hydrocodone-acetaminophen and tramadol with multiple-dose administration in a hospital setting and to compare, by use of a composite pain scale, the analgesic effects of these drugs in dogs undergoing TPLO. We hypothesized that orally administered hydrocodone-acetaminophen would provide better postoperative analgesia (as determined by pain score analysis and frequency of rescue analgesic treatment) for dogs undergoing this treatment, compared with that after orally administered tramadol, when each drug was given at 8-hour dosing intervals.

Materials and Methods

Animals

We designed a prospective, randomized, blinded clinical study to compare the pharmacodynamics of hydrocodone bitartrate–acetaminophen and tramadol hydrochloride in dogs. Fifty client-owned dogs admitted to Kansas State University Veterinary Health Center for TPLO to treat unilateral cranial cruciate ligament rupture were initially included in this study. Written informed consent was obtained from owners prior to enrollment of dogs. The study was performed with approval from the Kansas State University IACUC and in accordance with applicable local animal use regulations.

For all dogs enrolled, routine physical and orthopedic examinations were performed and results were recorded. To be included in the study, dogs were required to weigh ≥ 10 kg, to have confirmed cranial cruciate ligament rupture as determined by physical examination and diagnostic imaging, and to have TPLO selected as treatment. Each study animal was considered an adequate candidate for anesthesia. Only dogs with an American Society of Anesthesiologists score of 1 or 2 (indicating mild to no systemic disease present) were included in the study.16 Dogs deemed to have chronic painful conditions or concurrent metabolic or systemic disorders were also excluded from the study. Dogs that were receiving hydrocodone-acetaminophen or tramadol prior to evaluation for TPLO were not included in the study, but dogs receiving NSAIDs were included following discontinuation of the drug ≥ 24 hours prior to preoperative pain assessment and surgery. Dogs were hospitalized and acclimated to a quiet location in the hospital so that accurate behavioral assessment could be made. Preoperative CBC, serum biochemical analysis, and urinalysis were performed for all dogs.

Dogs were assigned by means of random lottery distribution to receive either tramadola (tramadol group) or hydrocodone-acetaminophenb (hydrocodone group) at predetermined intervals after surgery. Variability in response to treatment was unknown prior to the start of this study. On the basis of the investigators’ clinical experience, a target enrollment of ≥ 25 dogs in each treatment group was considered sufficient to detect a clinical difference between results.

Anesthesia and surgery protocol

American Society of Anesthesiologists scores were recorded for each patient. All dogs were treated with a similar anesthetic protocol of morphine (0.3 to 0.5 mg/kg, SC) in conjunction with acepromazine (0.01 to 0.06 mg/kg, SC) or midazolam (0.2 mg/kg, SC) as premedication. Anesthesia was induced with propofol (2 to 7 mg/kg, IV) to effect. Dogs were intubated, and anesthesia was maintained with isoflurane delivered with 30 mL of oxygen/kg/min into a circle breathing circuit. Perioperative decisions requiring a change to the anesthetic or surgical protocol, or both, were made according to the clinical judgment of the veterinarian responsible for the case and were solely determined in consideration of the patient's best interest. These dogs were removed from the study prior to pain scoring and analysis.

The TPLO procedures were performed as described by Slocum and Slocum17 by a Diplomate of the American College of Veterinary Surgeons or by a surgical resident with supervision. All dogs were given an intra-articular injection of 0.5% bupivicaine (0.5 to 1.5 mg/kg) administered in the affected joint prior to the end of the surgery for additional perioperative analgesia. Variations in surgical procedures including arthrotomy, meniscectomy, or meniscal release were recorded. In addition, the duration of surgery and surgeon identification were recorded.

Analgesic administration protocol

The timing of the initial postoperative administration of drugs varied according to clinically assessed needs of the individual patient; however, all dogs were given 1 dose of morphine (0.25 to 0.5 mg/kg, SC) immediately following surgery or up to 4 hours after extubation following the surgical procedure, depending on the progression of their recovery from the procedure and anesthesia.

Oral administration of the assigned test analgesic medication began after recovery from anesthesia and postoperative morphine injection when patients were awake, alert, and able to swallow and stand without difficulty. Dogs received either tramadola (5 to 7 mg/kg) or hydrocodone-acetaminophenb (0.5 to 0.6 mg of hydrocodone/kg) orally every 8 hours throughout their hospital stay and were discharged to their owners with instructions for oral analgesic drug administration as determined by the primary care clinician. The acetaminophen dose was limited by the content in tablets formulated with hydrocodone and ranged from 13 to 18 mg/kg. The postoperative morphine treatment did not influence the timing of oral drug administration; however, oral drug administration did not precede the (maximal) 4-hour time period for injectable morphine administration.

Heart rate, respiratory rate, and temperature were recorded for each patient 1 hour prior to surgery, immediately after surgery, and then every 8 hours until discharge from hospital.

Assessment for signs of pain and pharmacodynamic analysis

Each patient was evaluated by an assessor (MEB) who was thoroughly trained in the use of the modified short form GCMPS15 and was blinded to patient treatment group. All patients were monitored for signs of pain after surgery at frequent intervals as a part of routine standard of care for surgery patients. Any patient that required additional medication prior to the second scheduled dose of the orally administered analgesic was excluded from pain score analysis. Pain score assessments were initiated following the second oral dose of each study drug to assess efficacy of this dose. The study assessment protocol began at the second dose of oral pain medication to take into consideration multiple-dose pharmacokinetics18 as well as to ensure minimal to negligible lingering effects of sedative and anesthetic drugs in the postoperative assessment period. The IACUC protocol permitted 5 assessment times for manipulation of each dog to minimize patient stress and handling. The pain assessment time points assigned to each patient were arbitrarily staggered across the patient population so that analysis of several patients could be performed at 0, 15, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the second dose of the assigned analgesic. The possible range of cumulative pain scores (from least to most evidence of pain) for an individual dog at a given time point ranged from 0 to 24 when dogs were mobile and 0 to 20 when dogs were not mobile. A score ≥ 6 of 24 or ≥ 5 of 20 was defined as treatment failure, at which point rescue analgesia (morphine [0.25 to 0.5 mg/kg, SC, q 4 h or as needed]) was administered. Patients that received this treatment were excluded from further pharmacodynamic analysis. Venous blood samples (2 to 3 mL) were obtained at these same examination times, including the time of treatment failure, for analysis of drug concentrations in a study18 conducted simultaneously by our group.

Patient-related, surgical, and drug-related factors that could affect postoperative pain scores were compared between drug treatment groups, and a success-versus-failure model was used to determine the clinical efficacy of each tested drug formulation. Pain scores were used to determine the overall efficacy of oral drug formulations.

All dogs were observed for adverse reactions following oral administration of analgesics. Adverse reactions were characterized as minor if they were self-limiting and did not require additional treatment. Minor adverse reactions included sedation; excessive drooling; dysphoria; inappetence; constipation without the need for laxatives, fecal softeners, or manual evacuation; and limited episodes of regurgitation or vomiting. Major adverse reactions were those that required medical intervention and included continued vomiting or regurgitation (> 2 times in a 12-hour period); diarrhea; dysphoria requiring sedative administration; constipation requiring treatment with laxatives, fecal softeners, or manual evacuation; and seizures.

Statistical analysis

Nonparametric modified GCMPS scores were compared between treatment groups at each time period by means of the Mann-Whitney U test. Body weight and age were compared between treatment groups by means of an independent group t test. The number of dogs requiring rescue analgesic administration was compared between treatment groups by χ2 analysis. The prevalence of adverse effects, surgery on left versus right hind limb, procedures performed by an American College of Veterinary Surgeons board-certified surgeon or resident, and dogs that did or did not undergo arthrotomy were compared between groups by χ2 analysis. The number of dogs requiring rescue analgesia was compared between arthrotomy and nonarthrotomy categories by χ2 analysis. Values of P ≤ 0.05 were considered significant. Treatment variability within this study design was unknown prior to the start of the study. A power analysis was performed after results from the study were obtained.

Results

Of the 50 client-owned dogs initially enrolled in the study, 2 (1 from each drug treatment group) were removed from the study and eliminated from all data analysis. One dog in the hydrocodone group was disqualified because of a breach in the standard anesthetic protocol. One dog in the tramadol group was not amenable to handling in the postoperative period despite having pain scores that did not indicate additional analgesic treatment was needed. Breeds of the remaining 48 dogs included mixed (n = 16), Labrador Retriever (11), Golden Retriever (4), Boxer (2), German Shepherd Dog (2), and Rottweiler (2), with 11 other breeds represented by 1 dog each. There was no significant (P = 0.421) difference in mean body weight between the hydrocodone (34.4 ± 7.85 kg) and tramadol (37.53 ± 11.79 kg) groups. The mean age of dogs enrolled was 5.1 ± 2.4 years. There was no significant (P = 0.433) difference in age between drug treatment groups.

The mean ± SD dose of hydrocodone bitartrate–acetaminophen administered was 0.51 ± 0.04 mg of hydrocodone/kg and 16.6 ± 1.41 mg of acetaminophen/kg. The mean ± SD dose of tramadol hydrochloride administered was 5.85 ± 0.61 mg/kg.

Of the surgical and patient factors evaluated, the only significant difference found between drug treatment groups was the affected hind limb. Eight of 24 (33%) dogs in the hydrocodone group underwent TPLO of the left hind limb, whereas 18 of 24 (75%) dogs in the tramadol group underwent TPLO of the left hind limb (P = 0.004). Thirteen of 24 (54%) dogs in the hydrocodone group and 10 of 24 (42%) dogs in the tramadol group had surgery performed by a board-certified surgeon (P = 0.386). On the basis of surgeon preference, an arthrotomy was performed in 17 of 24 (71%) dogs in the hydrocodone group and 11 of 24 (46%) dogs in the tramadol group (P = 0.234). There was no significant (P = 0.282) difference in the need for rescue analgesic treatment between dogs that did or did not undergo arthrotomy.

Both drugs were well tolerated throughout the study period. Adverse events occurred in 3 of 24 (13%) dogs in the hydrocodone group versus 6 of 24 (25%) dogs in the tramadol group. This difference was nonsignificant (P = 0.464). Adverse events included self-limiting regurgitation (3 in the hydrocodone group and 5 in the tramadol group), excessive drooling (1 in the hydrocodone group), and regurgitation requiring medical treatment (1 in the tramadol group).

Of the 48 dogs enrolled, 6 (5 and 1 from the hydrocodone and tramadol groups, respectively) were removed from the pharmacodynamic study because of perceived postoperative pain prior to the second dose of the assigned study drug (the starting point for comparison of pain scores and treatment failures between groups). Overall, 12 of 42 (29%) dogs required rescue analgesia on the basis of pain scores of ≥ 6 of 24 (when mobile) or ≥ 5 of 20 (when immobile) after second oral drug dose administration. This included 5 dogs in the hydrocodone group and 7 dogs in the tramadol group (P = 0.505). For all dogs, the median time to first rescue analgesic administration on the basis of pain scores was 37.5 minutes after the second dose of the orally administered drug, with a range from 0 to 4 hours after the second administration of the study drug. Median pain scores of the 2 drug groups at each evaluation time were recorded (Table 1). During the evaluation period, both drug groups had similar median pain scores at most time points. The hydrocodone group had a significantly (P = 0.044) lower median pain score than did the tramadol group 2 hours after drug administration. At other time points, post hoc power analysis revealed that 64 to 465 dogs would have been needed to detect significant differences in pain scores between treatments at α = 0.05.

Table 1—

Median modified GCMPS scores of 48 client-owned dogs that underwent unilateral TPLO for treatment of cranial cruciate ligament rupture and were randomly assigned to receive hydrocodone-acetaminophen (0.5 to 0.6 mg of hydrocodone/kg) or tramadol (5 to 7 mg/kg) orally every 8 hours for postoperative analgesia.

 No. of dogs remaining in studyNo. of dogs assessedMedian pain score 
Time pointHydrocodoneTramadolHydrocodoneTramadolHydrocodoneTramadolP value
Before surgery24242424110.477
0 min19211018330.885
15 min1620157431.000
30 min16208152.530.383
45 min162013633.50.405
1 h1419815330.420
2 h141813634.50.044
4 h14166152.530.436
6 h1416134330.865
8 h14161718331.000

All dogs received 1 dose of morphine (0.25 to 0.5 mg/kg, SC) immediately following surgery or ≤ 4 hours after extubation, depending on anesthetic recovery progress. Administration of the test medication began after recovery from anesthesia and morphine administration, when patients were alert and able to stand and swallow without difficulty.

Dogs were removed from the analysis before pain scoring commenced if they required additional analgesic administration for signs of pain before the second dose of the assigned study drug was administered (n = 5 in the hydrocodone group and 1 in the tramadol group). Scores were assigned by 1 observer who was blinded to treatment group of the dogs and trained in pain assessment and use of the modified GCMPS. To limit patient stress and handling, not all dogs were evaluated at every time point but assessment was arbitrarily staggered across the patient population so that analysis could be performed at depicted time points. Rescue analgesia was provided for dogs with pain scores ≥ 6 of 24 (when mobile) or ≥ 5 of 20 (when immobile) after the second oral drug dose administration (time 0); these were considered treatment failures and removed from the remaining analysis. Values of P ≤ 0.05 were considered significant.

Discussion

In this study, we compared the effects of hydrocodone bitartrate–acetaminophen and tramadol hydrochloride administered after surgery as analgesics for dogs undergoing unilateral TPLO. Analgesic effects were assessed for study purposes beginning with the second dose of the orally administered study medication; 6 dogs were removed from the study prior to this time because of clinical signs that warranted additional analgesic treatment.

We found no significant difference in clinical analgesic effects of hydrocodone-acetaminophen or tramadol at the dosages administered in this study with the exception of 1 time point 2 hours after administration of the second dose of study drugs. Otherwise, modified GCMPS scores throughout the study period were similar between groups. Twelve of 42 (29%) dogs were categorized as having analgesic treatment failure after the second oral dose of hydrocodone-acetaminophen (n = 5) or tramadol (7) and received rescue analgesia on the basis of pain scores. This was an unacceptably large number; however, recommendations in the current literature for analgesic administration in dogs have been made on the basis of modified GCMPS scores, with the proportions of dogs in those studies19–21 requiring rescue analgesia ranging from 2 of 16 (12.5%) to 4 of 10 (40%) in study populations with similar patient numbers. The percentage of dogs that required rescue analgesia in the present study may have reflected inconsistencies or poor sensitivity in pain assessment with the scoring system or the use of low cutoffs for the decision to provide rescue analgesia. It may also have represented ineffectiveness of either drug to produce an acceptable degree of analgesia in the postoperative period in this study.

Hydrocodone is a semisynthetic derivative of codeine that has been used as an oral opioid analgesic as well as a potent antitussive agent in human and veterinary patients. Following oral administration to dogs, hydrocodone is more bioavailable at 39%,22 compared with codeine (4% to 6.5%),23,24 and its bioavailability is less variable than that of tramadol (10% to 65%).5,7 Hydromorphone is a predictable metabolite present in clinically relevant concentrations in several species, including dogs, after oral administration of hydrocodone.8,22,23 Drug concentrations of hydromorphone following hydrocodone administration were found to be 11 to 20 times as great as the concentration of morphine after oral administration of codeine to dogs on the basis of previous studies.23 KuKanich and Spade22 evaluated the pharmacokinetics of hydrocodone-acetaminophen and the active hydromorphone metabolite following administration of a single dose of the combined drug (calculated to deliver 0.5 mg of hydrocodone/kg) to 6 healthy Greyhounds. Findings of that study22 indicated that both hydrocodone and its hydromorphone metabolite were present in plasma at high concentrations (with hydromorphone concentrations ≥ 2 ng/mL), and dosing every 6 to 8 hours was recommended. Results of previous studies25,26 in dogs that received hydromorphone IV suggested antinociceptive effects with circulating concentrations of hydromorphone near 1.6 ng/mL up to 4 hours after drug administration. On the basis of those results and results from the study by KuKanich and Spade,22 plasma concentrations of hydromorphone following oral hydrocodone administration are expected to exceed the previously published concentration of 1.6 ng/mL throughout a treatment period with an 8-hour dosing interval.

Hydrocodone is currently classified as a schedule II controlled substance by the US Drug Enforcement Agency. In general, schedule II substances have abuse potential. Hydrocodone with acetaminophen is a frequently prescribed formulation in human medicine. This combination drug is a formulation used to limit abuse potential. The mechanism of action of acetaminophen remains to be elucidated, but it is thought to act by cyclooxygenase pathway inhibition as well as to have some involvement with the serotonergic pathways.27 At high doses (near 100 mg/kg), acetaminophen is known to have hepatotoxic effects in dogs.28 On the basis of mean body weights and drug dosages in the present study, dosages of acetaminophen did not exceed 18 mg/kg at any dose of hydrocodone administered. Acetaminophen is rapidly absorbed after oral administration in dogs with peak blood concentrations reached within 60 minutes.24,28 Although acetaminophen may have contributed to the analgesic effects of hydrocodone, the drug's half-life is short, ranging from 0.5 to 3 hours following oral administration in dogs,24,28 and it was not likely to contribute to analgesia throughout the entire study period.

Tramadol is a synthetic opioid analgesic that is widely used in human and veterinary medicine. It has a complex mode of action involving opioid receptors and inhibition of serotonin and norepinephrine transporters through its metabolism and available metabolite, O-desmethyltramadol (also called M1).2,29 There are several other metabolites of tramadol; however, the pharmacological effects have only been confirmed for M1 after routine tramadol administration in humans. The M1 metabolite acts as a high-affinity μ-opioid receptor agonist (> 200 times as potent as tramadol) and can also inhibit serotonin and norepinephrine reuptake.1,29

In humans, the pharmacological effects attributed to the M1 metabolite are highly related to metabolism of tramadol via CYP enzymes, in particular CYP2D6. This isoenzyme is responsible for metabolism of tramadol; however, it has extensive genetic polymorphism in humans, leading to the belief that there are different genotypes for the isoenzyme.30 Phenotypes include ultra, extensive, and poor metabolizers of tramadol (to M1) on the basis of circulating M1 concentrations following oral administration of tramadol. Previous drug failure rates among humans labeled as poor metabolizers of the drug are reported to be as high as 14 of 30 (47%).2 It is possible that genetic polymorphisms or differences in expression of CYP enzymes exist in dogs and that an inability to adequately metabolize tramadol contributes to treatment failure rates with this drug in some animals. To the authors’ knowledge, the CYP enzymes responsible for metabolism of tramadol in dogs have not been fully elucidated. Further investigations would be needed to determine this.

Several other studies4–6,31 involving dogs have found very low circulating M1 concentrations throughout an 8-hour period following oral administration of tramadol. These were exceptionally low concentrations of the drug metabolite and not considered likely to contribute to analgesic effects. In the study by KuKanich and Spade,22 dogs that received approximately 10 mg of tramadol/kg had minimal, if any, change in plasma concentrations of the M1 metabolite. However, concentrations of the parent tramadol compound climbed very high (> 200 ng/mL). In that same study,22 use of a von Frey pressure threshold device revealed antinociceptive effects were present at 5 to 6 hours after drug administration. The M1 metabolite concentrations during that same time period were < 1 ng/mL and not believed to be contributing to analgesic effects.6 Thus, it is likely that dogs, unlike humans, must rely on the activity of other potential metabolites or the parent tramadol compound for analgesic effects, and tramadol may potentially be a less effective analgesic in dogs than in people. If the antinociceptive effects in dogs are attributable to tramadol alone, its effects may be independent of opioid receptor activity all together. Although the parent compound tramadol acts as a low-affinity μ-opioid receptor agonist, it can also act as a serotonin and norepinephrine reuptake inhibitor because of complementary action of its 2 enantiomers, and those actions may have a substantial role in inhibition of pain transmission. Additionally, previous reports5,7 indicating a large range of bioavailability suggest that clinical efficacy of tramadol in dogs is variable; however, it should be noted that investigators in those studies5,7 used different methods of metabolite analysis.

In the present study, pain scoring was performed by use of a modified GCMPS.15,32 Accurate pain assessment in veterinary patients is challenging. The modified GCMPS relies on assessment of an animal's behavior in 6 categories to detect signs of pain. Use of these 6 categories allows for multiple aspects of postoperative pain to be evaluated through rating of spontaneous and evoked behaviors, interactions with people, and clinical observations. The modified GCMPS provides a degree of consistency that allows for the adequate evaluation because each behavior category assessed has specific definitions of behavior descriptors to reduce bias. This scoring system also allows for assignment of a number to a behavioral category. Numeric scores allow for tabulation of a cumulative score. Scores have been shown to provide a descriptive and repeatable assessment of pain.15 The modified GCMPS has been used successfully in other studies19–21,32 of animals to differentiate among degrees of pain and to monitor changes in pain intensity over time.

One individual experienced in pain assessment and use of the modified GCMPS was assigned to evaluate dogs at the designated time points in an effort to reduce the variability in pain assessment scoring. This investigator was blinded to treatment group of the dogs. Dogs received rescue analgesic treatment if they scored ≥ 6 of 25 or 5 of 20 on the modified GCMPS scoring system (or if an assessor determined that medical intervention was needed for signs of discomfort in a given patient independent of scoring times). The scores used for intervention were based on cutoffs by a previous study15 in which the same intervention decision point was applied in use of the modified GCMPS scoring system.

Although the modified GCMPS scoring system was developed to decrease variability in pain assessments, like other pain scales, it still relies on subjective evaluations to measure treatment outcomes. With the exception of the 2-hour time point after the second dose of study drugs, our inability to detect a difference in pain scores between the tramadol and hydrocodone treatment groups at all other time points may have been because the scoring system was not sufficiently sensitive to detect differing degrees of pain in some dogs. Differences in how dogs interacted with the assessor, how the assessor interpreted the scoring criteria, and the threshold at which dogs showed signs of pain could also have contributed to this result. The use of other markers or methods for evaluation of pain (eg, pressure threshold devices, vital signs, serum biochemical markers, or force plate gait analysis) could have been attempted; however, data regarding the efficacy and use of those markers for recognition of pain in veterinary patients are inconsistent.12,33–35 Other limitations of our study included the small number of dogs (50) and enrollment of dogs of various breeds leading to small numbers of dogs per breed and inability to evaluate breed differences between the drug groups. Despite this limitation, it accurately represented the population of dogs undergoing TPLO for treatment of cranial cruciate ligament rupture at our hospital. A recent study in dogs by Coleman et al36 evaluated surgical site sensitivity to a mechanical stimulus as a measure of postoperative pain. The authors concluded that learning occurred over repeated time points, with dogs anticipating the stimulus and reacting at lower thresholds.36 Because of that report36 and our IACUC protocol, the number of assessments per dog was limited to avoid the effects of anticipation in patients undergoing pain assessment. This decreased the total number of dogs assessed at each predetermined time point after surgery and drug administration. In addition, lingering effects of anesthesia or dysphoria are a concern for many studies evaluating signs of postoperative pain. The pain assessments in the present study were performed following the second dose of orally administered analgesic. This resulted in pain assessments taking place at various times from 8 to 12 hours after surgery, including a period in which the effects of anesthesia and injectable medication were expected to be negligible. However, individual differences in the pharmacokinetics and effects of sedative and anesthetic drugs could have resulted in effects persisting in some dogs in the assessment period.

Opioid drugs such as morphine decrease gastrointestinal motility and may decrease transit of orally administered drugs to the intestinal tract, where they are absorbed. However, specific studies have not documented this interaction with hydrocodone-acetaminophen or tramadol in dogs. Further studies assessing the effects of morphine and other opioids on the pharmacokinetics of orally administered analgesics are needed. Likewise, the amount of water ingested can also affect the pharmacokinetics of orally administered drugs. Considering that water ingestion may differ among dogs in the perioperative period, further studies assessing the effects of this variable on the pharmacokinetics of orally administered drugs in dogs are needed.

Assessment of effective pain management relies on comparisons to treatments that may or may not have been definitively demonstrated to relieve pain. Because of animal welfare concerns, a negative control group was not included in the study. A gold standard analgesic that could be used as a positive control has not yet been demonstrated; also, the use of a positive control group would not address whether the pain assessment method was sensitive enough to distinguish truly effective analgesia versus stoicism in some dogs. The lack of control groups makes it difficult to conclude that either treatment provided better analgesia in dogs that underwent TPLO.

Ideally, studies assessing the pharmacokinetics and their relationship to the pharmacodynamics of analgesic drugs would be helpful in assessing the clinical potential of analgesics. Although direct extrapolation to clinical patients should be interpreted with caution, as the relationship of mechanical stimulus in a laboratory setting to postoperative pain in a clinical setting has not been developed, the integrated pharmacokinetic-pharmacodynamic model does allow for assessment of some targeted responses in relation to plasma concentrations of drugs or their metabolites. The pharmacokinetic-pharmacodynamic relationships of hydrocodone-acetaminophen or tramadol in dogs have not been reported but would be useful in interpretation of the results of studies such as this one.

On the basis of our study results, the hypothesis that hydrocodone-acetaminophen would be clinically superior to tramadol for postoperative analgesia in dogs (as determined by comparison of modified GCMPS scores and the proportions of patients requiring rescue analgesia) was rejected. Although pain scores were significantly lower in dogs of the hydrocodone group 2 hours after the second oral dose of analgesic, this was likely a spurious finding, considering that no significant differences were detected at other time points. Considerations of the need for analgesia, dosage and route requirements, and drug bioavailability should ultimately determine the best agent for analgesic therapy in a given patient.

Acknowledgments

This manuscript represents a portion of a thesis submitted by Dr. Benitez to the Kansas State University Department of Clinical Sciences as partial fulfillment of the requirements for a Master of Science degree. Supported in part by the MCAT CVM Intramural Grant Program and Doughman Professorship funds through Kansas State University.

The authors declare no conflict of interest.

ABBREVIATIONS

CYP

Cytochrome P450

GCMPS

Glasgow composite measure pain scale

IACUC

Institutional animal care and use committee

TPLO

Tibial plateau leveling osteotomy

Footnotes

a.

Tramadol hydrochloride (50 mg), Amneal Pharmaceuticals LLC, Paterson, NJ.

b.

Hydrocodone bitartrate (5 mg and 10 mg)–acetaminophen (325 mg), Qualitest Pharmaceuticals, Huntsville, Ala.

References

  • 1. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an “atypical” opioid analgesic. J Pharmacol Exp Ther 1992; 260: 275285.

    • Search Google Scholar
    • Export Citation
  • 2. Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype on postoperative analgesia. Pain 2003; 105: 231238.

  • 3. Gillen C, Haurand M, Kobelt DJ, et al. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 116121.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Giorgi M, Del Carlo S, Saccomanni G, et al. Pharmacokinetics and urine profile of tramadol and its major metabolites after oral immediate release capsule administration in the dog. Vet Res Commun 2009; 33: 875885.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Giorgi M, Saccomanni G, Lebkowska-Wieruszewska B, et al. Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog. Vet J 2009; 180: 253255.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. KuKanich B, Papich MG. Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds. Am J Vet Res 2011; 72: 256262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. KuKanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther 2004; 27: 239246.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Cone EJ, Darwin WD, Gorodetzky CW, et al. Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog. Drug Metab Dispos 1978; 6: 488493.

    • Search Google Scholar
    • Export Citation
  • 9. Sanford J, Ewbank R, Molony V, et al. Guidelines for the recognition and assessment of pain in animals. Vet Rec 1986; 118: 334338.

  • 10. Molony V, Kent JE. Assessment of acute pain in farm animals using behavioral and physiologic measurements. J Anim Sci 1997; 75: 266272.

  • 11. Stasiak KL, Maul D, French E, et al. Species-specific assessment of pain in laboratory animals. Contemp Top Lab Anim Sci 2003; 42: 1320.

    • Search Google Scholar
    • Export Citation
  • 12. Quinn MM, Keuler NS, Lu Y, et al. Evaluation of agreement between numerical rating scales, visual analogue scoring scales, and force plate gait analysis in dogs. Vet Surg 2007; 36: 360367.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Holton L, Reid J, Scott EM, et al. Development of a behavior-based scale to measure acute pain in dogs. Vet Rec 2001; 148: 525531.

  • 14. Morton CM, Reid J, Scott EM, et al. Application of a scaling model to establish and validate an interval level pain scale for assessment of acute pain in dogs. Am J Vet Res 2005; 66: 21542166.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Reid J, Nolan AM, Hughes JM, et al. Development of the short-form Glasgow composite measure of pain scale and derivation of an analgesic intervention score. Anim Welf 2007; 12: 97104.

    • Search Google Scholar
    • Export Citation
  • 16. Muir WW. Considerations for general anesthesia. In: Tranquilli WJ, Thurmon JC, Grimm KG, eds. Lumb and Jones' veterinary anesthesia and analgesia. 4th ed. Ames, Iowa: Blackwell, 2007;1730.

    • Search Google Scholar
    • Export Citation
  • 17. Slocum B, Slocum TD. Tibial plateau levelling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet Clin North Am Small Anim Pract 1993; 23: 777795.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Benitez ME, Roush JK, KuKanich B, et al. Pharmacokinetics of hydrocodone and tramadol administered for control of postoperative pain in dogs following tibial plateau leveling osteotomy. Am J Vet Res 2015; 76: 763770.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Bienhoff SE, Smith EA, Roycroft LM, et al. Efficacy and safety of deracoxib for control of postoperative pain and inflammation associated with soft tissue surgery in dogs. Vet Surg 2012; 41: 336344.

    • Search Google Scholar
    • Export Citation
  • 20. Davila D, Keeshen TP, Evans RB, et al. Comparison of the analgesic efficacy of perioperative firocoxib and tramadol administration in dogs undergoing tibial plateau leveling osteotomy. J Am Vet Med Assoc 2013; 243: 225231.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Perez TE, Grubb TL, Greene SA, et al. Effects of intratesticular injection of bupivacaine and epidural administration of morphine in dogs undergoing castration. J Am Vet Med Assoc 2013; 242: 631642.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. KuKanich B, Spade J. Pharmacokinetics of hydrocodone and hydromorphone after oral hydrocodone in healthy Greyhound dogs. Vet J 2013; 196: 266268.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Findlay JW, Jones EC, Welch RM. Radioimmunoassay determination of the absolute oral bioavailabilities and O-demethylation of codeine and hydrocodone in the dog. Drug Metab Dispos 1979; 7: 310314.

    • Search Google Scholar
    • Export Citation
  • 24. KuKanich B. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucoronide in healthy Greyhound dogs. J Vet Pharmacol Ther 2010; 33: 1521.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Wegner K, Horais KA, Tozier NA, et al. Development of a canine nociceptive thermal escape model. J Neurosci Methods 2008; 168: 8897.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. Guedes AG, Papich MG, Rude EP, et al. Pharmacokinetics and physiological effects of intravenous hydromorphone in conscious dogs. J Vet Pharmacol Ther 2008; 31: 334343.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Pickering G, Loroit M, Libert F, et al. Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther 2006; 79: 371378.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Boothe DM. Anti-inflammatory drugs. In: Small animal clinical pharmacology and therapeutics. 2nd ed. St Louis: Elsevier Saunders, 2012;281311.

    • Search Google Scholar
    • Export Citation
  • 29. Lee CR, McTavish D, Sorkin EM. Tramadol—a preliminary review of its pharmacodynamics and pharmacokinetic properties and therapeutic potential in acute and chronic pain states. Drugs 1993; 46: 313340.

    • Search Google Scholar
    • Export Citation
  • 30. Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 636644.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Wu WN, McKowen LA, Gauthier AD, et al. Metabolism of analgesic drug, tramadol hydrochloride, in rat and dog. Xenobiotica 2001; 31: 423441.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Murrell JC, Psatha EP, Scott EM, et al. Application of a modified form of the Glasgow pain scale in a veterinary teaching centre in the Netherlands. Vet Rec 2008; 162: 403408.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33. Holton LL, Scott EM, Nolan AM, et al. Relationship between physiological factors and clinical pain in dogs scored using a numerical rating scale. J Small Anim Pract 1998; 39: 469474.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Smith JD, Allen SW, Quandt JE, et al. Indicators of postoperative pain in cats and correlation with clinical criteria. Am J Vet Res 1996; 57: 16741678.

    • Search Google Scholar
    • Export Citation
  • 35. Cambridge AJ, Tobias KM, Newberry RC, et al. Subjective and objective measurement of postoperative pain in cats. J Am Vet Med Assoc 2000; 217: 685690.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Coleman KD, Schmeidt CW, Kirkby KA, et al. Learning confounds algometry assessment of mechanical thresholds in normal dogs. Vet Surg 2014; 43: 361367.

    • Crossref
    • Search Google Scholar
    • Export Citation

Contributor Notes

Address correspondence to Dr. Benitez (marian.benitez19@gmail.com).
  • 1. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an “atypical” opioid analgesic. J Pharmacol Exp Ther 1992; 260: 275285.

    • Search Google Scholar
    • Export Citation
  • 2. Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype on postoperative analgesia. Pain 2003; 105: 231238.

  • 3. Gillen C, Haurand M, Kobelt DJ, et al. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 116121.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Giorgi M, Del Carlo S, Saccomanni G, et al. Pharmacokinetics and urine profile of tramadol and its major metabolites after oral immediate release capsule administration in the dog. Vet Res Commun 2009; 33: 875885.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Giorgi M, Saccomanni G, Lebkowska-Wieruszewska B, et al. Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog. Vet J 2009; 180: 253255.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. KuKanich B, Papich MG. Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in Greyhounds. Am J Vet Res 2011; 72: 256262.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. KuKanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther 2004; 27: 239246.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Cone EJ, Darwin WD, Gorodetzky CW, et al. Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog. Drug Metab Dispos 1978; 6: 488493.

    • Search Google Scholar
    • Export Citation
  • 9. Sanford J, Ewbank R, Molony V, et al. Guidelines for the recognition and assessment of pain in animals. Vet Rec 1986; 118: 334338.

  • 10. Molony V, Kent JE. Assessment of acute pain in farm animals using behavioral and physiologic measurements. J Anim Sci 1997; 75: 266272.

  • 11. Stasiak KL, Maul D, French E, et al. Species-specific assessment of pain in laboratory animals. Contemp Top Lab Anim Sci 2003; 42: 1320.

    • Search Google Scholar
    • Export Citation
  • 12. Quinn MM, Keuler NS, Lu Y, et al. Evaluation of agreement between numerical rating scales, visual analogue scoring scales, and force plate gait analysis in dogs. Vet Surg 2007; 36: 360367.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Holton L, Reid J, Scott EM, et al. Development of a behavior-based scale to measure acute pain in dogs. Vet Rec 2001; 148: 525531.

  • 14. Morton CM, Reid J, Scott EM, et al. Application of a scaling model to establish and validate an interval level pain scale for assessment of acute pain in dogs. Am J Vet Res 2005; 66: 21542166.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Reid J, Nolan AM, Hughes JM, et al. Development of the short-form Glasgow composite measure of pain scale and derivation of an analgesic intervention score. Anim Welf 2007; 12: 97104.

    • Search Google Scholar
    • Export Citation
  • 16. Muir WW. Considerations for general anesthesia. In: Tranquilli WJ, Thurmon JC, Grimm KG, eds. Lumb and Jones' veterinary anesthesia and analgesia. 4th ed. Ames, Iowa: Blackwell, 2007;1730.

    • Search Google Scholar
    • Export Citation
  • 17. Slocum B, Slocum TD. Tibial plateau levelling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet Clin North Am Small Anim Pract 1993; 23: 777795.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Benitez ME, Roush JK, KuKanich B, et al. Pharmacokinetics of hydrocodone and tramadol administered for control of postoperative pain in dogs following tibial plateau leveling osteotomy. Am J Vet Res 2015; 76: 763770.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Bienhoff SE, Smith EA, Roycroft LM, et al. Efficacy and safety of deracoxib for control of postoperative pain and inflammation associated with soft tissue surgery in dogs. Vet Surg 2012; 41: 336344.

    • Search Google Scholar
    • Export Citation
  • 20. Davila D, Keeshen TP, Evans RB, et al. Comparison of the analgesic efficacy of perioperative firocoxib and tramadol administration in dogs undergoing tibial plateau leveling osteotomy. J Am Vet Med Assoc 2013; 243: 225231.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Perez TE, Grubb TL, Greene SA, et al. Effects of intratesticular injection of bupivacaine and epidural administration of morphine in dogs undergoing castration. J Am Vet Med Assoc 2013; 242: 631642.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. KuKanich B, Spade J. Pharmacokinetics of hydrocodone and hydromorphone after oral hydrocodone in healthy Greyhound dogs. Vet J 2013; 196: 266268.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Findlay JW, Jones EC, Welch RM. Radioimmunoassay determination of the absolute oral bioavailabilities and O-demethylation of codeine and hydrocodone in the dog. Drug Metab Dispos 1979; 7: 310314.

    • Search Google Scholar
    • Export Citation
  • 24. KuKanich B. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucoronide in healthy Greyhound dogs. J Vet Pharmacol Ther 2010; 33: 1521.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Wegner K, Horais KA, Tozier NA, et al. Development of a canine nociceptive thermal escape model. J Neurosci Methods 2008; 168: 8897.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. Guedes AG, Papich MG, Rude EP, et al. Pharmacokinetics and physiological effects of intravenous hydromorphone in conscious dogs. J Vet Pharmacol Ther 2008; 31: 334343.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Pickering G, Loroit M, Libert F, et al. Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther 2006; 79: 371378.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Boothe DM. Anti-inflammatory drugs. In: Small animal clinical pharmacology and therapeutics. 2nd ed. St Louis: Elsevier Saunders, 2012;281311.

    • Search Google Scholar
    • Export Citation
  • 29. Lee CR, McTavish D, Sorkin EM. Tramadol—a preliminary review of its pharmacodynamics and pharmacokinetic properties and therapeutic potential in acute and chronic pain states. Drugs 1993; 46: 313340.

    • Search Google Scholar
    • Export Citation
  • 30. Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 636644.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Wu WN, McKowen LA, Gauthier AD, et al. Metabolism of analgesic drug, tramadol hydrochloride, in rat and dog. Xenobiotica 2001; 31: 423441.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Murrell JC, Psatha EP, Scott EM, et al. Application of a modified form of the Glasgow pain scale in a veterinary teaching centre in the Netherlands. Vet Rec 2008; 162: 403408.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33. Holton LL, Scott EM, Nolan AM, et al. Relationship between physiological factors and clinical pain in dogs scored using a numerical rating scale. J Small Anim Pract 1998; 39: 469474.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Smith JD, Allen SW, Quandt JE, et al. Indicators of postoperative pain in cats and correlation with clinical criteria. Am J Vet Res 1996; 57: 16741678.

    • Search Google Scholar
    • Export Citation
  • 35. Cambridge AJ, Tobias KM, Newberry RC, et al. Subjective and objective measurement of postoperative pain in cats. J Am Vet Med Assoc 2000; 217: 685690.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Coleman KD, Schmeidt CW, Kirkby KA, et al. Learning confounds algometry assessment of mechanical thresholds in normal dogs. Vet Surg 2014; 43: 361367.

    • Crossref
    • Search Google Scholar
    • Export Citation

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