Cranial cruciate ligament rupture is one of the most common orthopedic injuries in dogs.1 Many surgical techniques have been proposed for stifle joint stabilization, including osteotomy techniques such as TTA and TPLO. As with many other orthopedic surgeries, patients can have moderate to severe pain following these procedures. Traditionally, in the immediate postoperative period, opioid medications are administered via oral, SC, IM, or IV routes. However, opioid-related adverse effects such as ileus, nausea, vomiting, constipation, bradycardia, hypotension, respiratory depression, sedation, and dysphoria can occur.2–5 These adverse effects can prolong patient recovery and hospitalization. Repeated dosing can also be labor-intensive, increase financial cost to the owner, and increase patient stress.
Epidural analgesia has been suggested as an alternative to overcome systemic opioid-related adverse effects. Disadvantages of epidural analgesia include technical difficulty, especially for overweight dogs in which the landmarks might be more difficult to localize; CSF or blood contamination; neurologic complications; urinary retention; pruritus; and slow hair regrowth at the injection site.4,6,7 Also, if the epidural injection is administered incorrectly, inadequate analgesia will result. In a series of 636 dogs receiving epidural pain management, it was reported that signs of pain persisted in 12% of the dogs treated.8
The intra-articular use of local anesthetic drugs has been shown to improve postoperative pain scores and reduce opioid administration and its related adverse effects.9
However, multiple studies have shown that several of the most commonly used local anesthetics, such as bupivacaine, lidocaine, and ropivacaine, are toxic to human and animal chondrocytes both in vitro and in vivo, which raises concerns about their inclusion in an ideal pain management protocol.10–13
Opioids have been administered intra-articularly in humans and dogs. In humans, an intra-articular injection of morphine has been reported to have a 24- to 48-hour duration of effect after knee arthroscopy.14,15 In comparison, intra-articular morphine administration in dogs has been reported to have a 6-hour duration of effect after lateral extracapsular stabilization of the stifle joint.16
A recent study17 on humans revealed that intra-articular administration of dexmedetomidine enhanced postoperative pain relief, decreased the need for postoperative rescue analgesia, and prolonged the time to the first rescue analgesic protocol after arthroscopic knee surgery. In humans, intra-articular administration of morphine and clonidine, an α2-adrenoceptor agonist, in combination resulted in longer postoperative pain relief, compared with each drug given alone.18 That clinical study18 revealed the potential peripheral analgesic effect of the combination of an opioid and α2-adrenoceptor agonist after intra-articular administration. A study19 on rats also supports a longer analgesic duration of action when coadministering these 2 drugs. In a canine study,20 a combination of medetomidine and morphine epidurally had a synergistic effect, producing a superior duration of effect than did either drug used alone.
To the authors' knowledge, intra-articular use of dexmedetomidine alone or in combination with morphine for postoperative pain management following TPLO or TTA in dogs has not been evaluated. The objective of the study reported here was to compare the analgesic effects of intra-articularly administered morphine, dexmedetomidine, and their combination versus saline (0.9% NaCl) solution (control). It was hypothesized that morphine and dexmedetomidine in combination would provide a longer duration of analgesia than morphine or dexmedetomidine alone. It was further hypothesized that morphine would produce a longer analgesic duration than dexmedetomidine.
Materials and Methods
Animals—Client-owned dogs with cranial cruciate ligament rupture that were admitted to the Purdue Veterinary Teaching Hospital from June 2012 to June 2013 for unilateral TTA or TPLO procedures were eligible for inclusion in the study. The type of surgery was determined by clinician and owner preference. Dogs that received NSAIDs within 72 hours prior to surgery or dogs that needed additional orthopedic procedures were excluded from the study. Informed consent was obtained from all owners for dogs included in the study. The study was approved by the Purdue Animal Care and Use Committee.
Experimental design—The study was conducted in a blinded, randomized manner. A randomized number table was used to assign dogs to 1 of 4 treatment groups for intra-articular administration of the following: saline solution (control group, 0.2 mL/kg [0.09 mL/lb]; 8 dogs), preservative-free morphinea (morphine group, 0.1 mg/kg [0.045 mg/lb]; 12 dogs), dexmedetomidineb (dexmedetomidine group, 2.5 μg/kg [1.14 μg/lb]; 12 dogs), or morphine and dexmedetomidine combined (morphine-dexmedetomidine group, 0.1 mg/kg and 2.5 μg/kg, respectively; 12 dogs). All treatments were of equal volume to that of the control group by diluting drugs in saline solution. The preservatives in dexmedetomidine were methylparaben (1.6 mg/mL) and propylparaben (0.2 mg/mL).
An a priori sample size calculation was used to determine that 12 dogs/treatment group would be necessary for 90% power to detect differences in the duration of analgesia of 5 to 9 hours, with an SD of 3 hours, at an α = 0.05. Because of ethical concerns, the number of dogs assigned to receive saline solution (control group) was less than that used for the other treatment groups.
Procedures—Prior to surgery, all dogs were pre-medicated with hydromorphonec (0.1 mg/kg, IM) and acepromazined (0.01 mg/kg [0.0045 mg/lb], IM), and anesthesia was induced with propofole (4 to 6 mg/kg [1.82 to 2.73 mg/lb], IV) and maintained with isofluranef (1% to 2.5% to effect) in oxygen. No additional analgesics were given during the anesthetic period. Heart rate and rhythm, respiratory rate, and body temperature measurements were obtained immediately after premedication but prior to anesthetic induction. Oscillometric blood pressure,g end-tidal Pco2, and oxygen saturation as determined by pulse oximetry were monitored every 5 minutes during anesthesia until extubation. When hypotension (mean arterial blood pressure < 60 mm Hg or systolic arterial blood pressure < 80 mm Hg) was identified, dogs were treated to effect with an inotrope (constant-rate infusion of dopamine) at the discretion of the anesthesiologist on duty.
Routine TTA or TPLO through a medial skin and arthrotomy approach was performed by a board-certified surgeon or a surgical resident experienced in these techniques. All dogs received antimicrobials during the perioperative period, and postoperative continuation of antimicrobial administration was determined at the surgeon's discretion. Carprofenh (4.4 mg/kg [2.0 mg/lb], SC) and all intra-articular injections were administered after completion of the corrective osteotomy procedure just prior to skin closure. Following intra-articular injection, the stifle joint was repeatedly flexed and extended to circulate the medications throughout the joint. Following skin closure, all dogs underwent radiography and received hydromorphone (0.05 mg/kg [0.023 mg/lb], IV) at extubation. Intervals between intra-articular injection, second hydromorphone injection, and first pain assessment were kept consistent for all patients. No bandages or ice was used on the hind limbs that had undergone surgery during the study.
All dogs were assessed for signs of pain on the basis of modified criteria adopted from 2 pain scoring systems: the DIVAS for soft tissue surgery21,22 and the MPS developed for stifle joint arthrotomy.16 Signs of pain were assessed in the following sequence: dogs were observed undisturbed, and signs of pain were assessed from outside of the cage or run; dogs were approached and spoken to, and behavior suggestive of pain was assessed; heart rate, respiratory rate, and blood pressure (measured with a Doppler ultrasound monitor) were assessed; and finally the stifle joint that had undergone surgery was palpated with a palpometer.22–24 The general impression of pain consisted of a mean behavioral pain score (undisturbed behaviors and interactive behaviors, including the palpometer use) and a mean objective pain score (increase in heart rate, respiratory rate and systolic arterial blood pressure; Appendix 1). All dogs were continuously monitored visually for the first 4 hours following extubation. The pain scoring assessments were conducted at 2, 4, 6, 8, 10, and 12 hours following the intra-articular injection by a single trained investigator (NS), who was blinded to treatment. If dogs were observed to have signs of pain during the first 4 hours, additional pain scoring assessments were performed.
The palpometer devicei indicates the pressure exerted by digital pressure and was used to provide consistent palpation pressure. This device has been used at the Purdue Veterinary Teaching Hospital as part of a pain assessment tool in dogs22 and ferrets24 and found to be effective in assessing signs of muscle and skin pain. A detailed description of its use has been reported elsewhere.22,24 Briefly, the palpometer was applied to the affected stifle joint on the lateral side of the patellar ligament. Digital pressure was increased gradually until a maximum of 1,000 gram-force/cm2 was reached or until the dog responded adversely to the stimulus, such as turning the head, vocalizing, or pulling the limb away. At that point, the pressure was recorded and integrated into the behavioral pain assessment (Appendix 2).
If either mean score (behavioral or objective scores) was ≥ 2.00, the dog was given hydromorphone (0.05 mg/kg, SC) as rescue analgesia. The time that hydromorphone was administered was recorded (as time to rescue analgesia), and the patient was removed from the study and returned to routine standard of care. For dogs that received rescue analgesia outside the scheduled assessment times, the time of administration was recorded as the next scheduled time point. Those dogs that did not develop signs of pain by 12 hours were assigned an arbitrary time to rescue analgesia of 14 hours and also resumed a standard postoperative pain management protocol.
Statistical analysis—Because of the ordinal nature of the time measurements (every 2 hours), nonparametric tests were used for comparisons. Descriptive data were presented as mean ± SD or median (range). The Kruskal-Wallis equality-of-populations rank test was used to compare time to rescue analgesia across all 4 treatment groups, and the Wilcoxon rank sum test was used to compare time to rescue analgesia between the treatment groups and between dogs that underwent TPLO versus TTA. Analyses were performed with statistical software,j and significance was set at P < 0.05.
Results
Forty-four client-owned dogs were enrolled in the study. The dogs were between 1.8 and 12 years of age (mean, 5.8 ± 2.26 years; median, 6.02 years). The body weight of dogs was between 15.3 and 65 kg (33.7 and 143 lb), with a mean of 37.9 ± 10.4 kg (83.4 ± 22.9 lb) and median of 37.6 kg (82.7 lb). No adverse surgical events or complications were encountered during any of the procedures performed. No leakage of intra-articular solution was observed, and all the volume was successfully administered within the joint. Only 1 dog (in the dexmedetomidine group) was reported to have hypotension; the condition occurred during the surgery period and was treated with dopamine.
Dogs were not randomly assigned to undergo TTA or TPLO. An equal number (n = 22) of dogs underwent TTA and TPLO. In the control group, 3 dogs underwent TPLO versus 5 that underwent TTA. In the morphine group, 7 dogs underwent TPLO versus 5 that underwent TTA. Equal numbers of dogs (n = 6) underwent TTA and TPLO in the dexmedetomidine group and morphine-dexmedetomidine group.
Box and whiskers plots depicting time to rescue analgesia (median and range) in 44 dogs receiving intra-articular administration of saline (0.9% NaCl) solution (0.2 mL/kg [0.09 mL/lb]; group S; 8 dogs) or an equal volume (diluted in saline solution) of morphine (0.1 mg/kg [0.045 mg/lb]; group M; 12 dogs), dexmedetomidine (2.5 μg/kg [1.14 μg/lb]; group D; 12 dogs), or the combination of morphine (0.1 mg/kg) and dexmedetomidine (2.5 μg/kg; group M + D; 12 dogs) immediately following TTA or TPLO for repair of cranial cruciate ligament rupture. Boxes represent the interquartile range, or 25th to 75th percentiles, except where the 25th percentile and lowest value are the same (group S [control]). Whiskers are extended to the highest or lowest values (range) except if such a value exceeds 1.5× the interquartile range, in which case the outlier value is shown as a dot (group M). *Median time to rescue analgesia of morphine-dexmedetomidine group differed significantly (P < 0.05) from that for all other treatment groups.
Citation: Journal of the American Veterinary Medical Association 244, 11; 10.2460/javma.244.11.1291
Box and whiskers plots depicting time to rescue analgesia (median and range) in 44 dogs receiving intra-articular administration of saline (0.9% NaCl) solution (0.2 mL/kg [0.09 mL/lb]; group S; 8 dogs) or an equal volume (diluted in saline solution) of morphine (0.1 mg/kg [0.045 mg/lb]; group M; 12 dogs), dexmedetomidine (2.5 μg/kg [1.14 μg/lb]; group D; 12 dogs), or the combination of morphine (0.1 mg/kg) and dexmedetomidine (2.5 μg/kg; group M + D; 12 dogs) immediately following TTA or TPLO for repair of cranial cruciate ligament rupture. Boxes represent the interquartile range, or 25th to 75th percentiles, except where the 25th percentile and lowest value are the same (group S [control]). Whiskers are extended to the highest or lowest values (range) except if such a value exceeds 1.5× the interquartile range, in which case the outlier value is shown as a dot (group M). *Median time to rescue analgesia of morphine-dexmedetomidine group differed significantly (P < 0.05) from that for all other treatment groups.
Citation: Journal of the American Veterinary Medical Association 244, 11; 10.2460/javma.244.11.1291
Box and whiskers plots depicting time to rescue analgesia (median and range) in 44 dogs receiving intra-articular administration of saline (0.9% NaCl) solution (0.2 mL/kg [0.09 mL/lb]; group S; 8 dogs) or an equal volume (diluted in saline solution) of morphine (0.1 mg/kg [0.045 mg/lb]; group M; 12 dogs), dexmedetomidine (2.5 μg/kg [1.14 μg/lb]; group D; 12 dogs), or the combination of morphine (0.1 mg/kg) and dexmedetomidine (2.5 μg/kg; group M + D; 12 dogs) immediately following TTA or TPLO for repair of cranial cruciate ligament rupture. Boxes represent the interquartile range, or 25th to 75th percentiles, except where the 25th percentile and lowest value are the same (group S [control]). Whiskers are extended to the highest or lowest values (range) except if such a value exceeds 1.5× the interquartile range, in which case the outlier value is shown as a dot (group M). *Median time to rescue analgesia of morphine-dexmedetomidine group differed significantly (P < 0.05) from that for all other treatment groups.
Citation: Journal of the American Veterinary Medical Association 244, 11; 10.2460/javma.244.11.1291
Median time from the intra-articular injection to extubation was 50.5 minutes (range, 43 to 91 minutes) for the control group, 67 minutes (range, 35 to 140 minutes) for the dexmedetomidine group, 53.5 minutes (range, 38 to 77 minutes) for the morphine group, and 60.5 minutes (range, 48 to 98 minutes) for the morphine-dexmedetomidine group. No significant (P = 0.219) difference in time from intra-articular injection to extubation was found among groups. The median time between extubation and the first scheduled scoring time (2 hours after the administration of the intra-articular injection) was 68 minutes (range, 23 to 75 minutes) for the control group, 51 minutes (range, 0 to 80 minutes) for the dexmedetomidine group, 62.5 minutes (range, 0 to 82 minutes) for the morphine group, and 60.5 minutes (range, 22 to 72 minutes) for the morphine-dexmedetomidine group. No significant (P = 0.108) difference in time between extubation and first scheduled scoring time was found among groups.
Kaplan-Meier curve depicting time to rescue analgesia for 44 dogs receiving intra-articular administration of saline solution, morphine, dexmedetomidine, or a morphine-dexmedetomidine combination immediately following TTA or TPLO for repair of cranial cruciate ligament rupture. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 244, 11; 10.2460/javma.244.11.1291
Kaplan-Meier curve depicting time to rescue analgesia for 44 dogs receiving intra-articular administration of saline solution, morphine, dexmedetomidine, or a morphine-dexmedetomidine combination immediately following TTA or TPLO for repair of cranial cruciate ligament rupture. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 244, 11; 10.2460/javma.244.11.1291
Kaplan-Meier curve depicting time to rescue analgesia for 44 dogs receiving intra-articular administration of saline solution, morphine, dexmedetomidine, or a morphine-dexmedetomidine combination immediately following TTA or TPLO for repair of cranial cruciate ligament rupture. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 244, 11; 10.2460/javma.244.11.1291
All dogs except 1 dog in the morphine-dexmedetomidine group required rescue analgesia before 12 hours following the intra-articular injection. Only 1 dog in the morphine group required rescue analgesia before the 2-hour assessment point (immediately after extubation). The median time to rescue analgesia was 5 hours (range, 4 to 10 hours) for the control group, 6 hours (range, 2 to 10 hours) for the dexmedetomidine group, 7 hours (range, 2 to 10 hours) for the morphine group, and 10 hours (range, 4 to 14 hours) for the morphine-dexmedetomidine group (Figures 1 and 2). Time to rescue analgesia significantly (P = 0.017) differed between the groups. Time to rescue analgesia did not significantly (P = 0.416) differ between the dexmedetomidine and morphine groups. Compared with time to rescue analgesia for the control group, time to rescue analgesia did not significantly differ for the dexmedetomidine (P = 0.749) and morphine (P = 0.382) groups. Time to rescue analgesia for the morphine-dexmedetomidine group was significantly longer than that for either the control group (P = 0.016), dexmedetomidine group (P = 0.007), or morphine group (P = 0.026). No significant (P = 0.914) difference in time to rescue analgesia was found between dogs undergoing the TTA (median, 8 hours; range, 2 to 14 hours) and TPLO (median, 7 hours; range, 2 to 12 hours) procedures.
Discussion
Recent studies have shown chondrotoxic effects following the use of local anesthetic agents such as bupivacaine in humans,10 rabbits,11 and dogs.25 These effects prompted the present study to look for alternative analgesic agents for intra-articular administration. In addition, repeated administration of analgesics is time-consuming and disruptive for the patient. There is a need for a safe and effective analgesic agent for intra-articular administration with a long duration of action.
To the authors' knowledge, this is the first reported use of the combination of morphine and dexmedetomidine for intra-articular injection in dogs. In the study reported here, intra-articular use of morphine and dexmedetomidine in combination produced a longer duration of analgesia than either morphine or dexmedetomidine alone, following TPLO or TTA surgery in dogs.
The duration of analgesia was not significantly different between the morphine (7 hours) and dexmedetomidine (6 hours) groups, which did not support the hypothesis that morphine would produce a significantly longer analgesic duration than dexmedetomidine. The dexmedetomidine dose was low, and a substantial analgesic effect was not anticipated. The doses used in the present study were similar to those used in a previous canine study20 examining the epidural administration of morphine (0.1 mg/kg), medetomidine (5 μg/kg [2.3 μg/lb]), and their combination. In that study,20 a dose of 5 μg of medetomidine/kg failed to produce sufficient analgesia at 2 and 4 hours after administration. This dose is equivalent to the 2.5 μg/kg dose of dexmedetomidine used in the present study (ie, dexmedetomidine is the active enantiomer of medetomidine, so the dose of dexmedetomidine should be half that of racemic medetomidine26). Nevertheless, the results in the present study for the dexmedetomidine group (median duration of analgesia, 6 hours) are comparable to those in a recent human study,17 in which the mean time of postoperative analgesia following intra-articular administration of dexmedetomidine after arthroscopic knee surgery was 5.2 hours.
Opioid receptors have been discovered in the peripheral nervous system and joints in several species, including dogs,27 cats,28 horses,29 and humans.30 The duration of action of intra-articularly administered morphine in humans has been reported to be 24 to 48 hours after knee arthroscopy.14,15 In a veterinary study,16 intra-articular administration of morphine provided an analgesic effect of 6 hours after exploratory stifle joint arthrotomy and extracapsular lateral suture stabilization. However, in that study,16 the analgesic effects were not assessed past 6 hours after the procedures were performed. Results of the present study are consistent with those of Day et al,16 in that the median duration of analgesia in the morphine group was 7 hours.
In the present study, the median duration of analgesic effect when coadministering dexmedetomidine and morphine intra-articularly was 10 hours. The additive or synergistic activity between morphine and dexmedetomidine observed with intra-articular administration is consistent with findings in a previous study,20 in which epidural morphine in combination with medetomidine produced a longer duration of analgesia than did either morphine or medetomidine alone.
It is hypothesized that the longer analgesic effect when simultaneously administering dexmedetomidine and morphine intra-articularly is the result of an indirect and a direct effect. The indirect effect of dexmedetomidine causes periarticular vasoconstriction, which reduces absorption and retains morphine in the injected joint longer. Dexmedetomidine is a sedative with analgesic properties when administered IV; therefore, it could have a local analgesic effect when administered into the joint. It has been previously suggested that dexmedetomidine, like clonidine (an α2-adrenoceptor agonist), acts at a peripheral site in the joint to produce analgesia.17,31
In the present study, the intra-articular administration of dexmedetomidine and morphine was intended to have a purely local synovial analgesic effect, but some systemic absorption cannot be excluded. This could have potentially caused systemic central adverse effects, such as nausea, respiratory depression, and dysphoria4,5 in the case of morphine and cardiovascular depression, bradycardia, hypotension, and respiratory depression32 for dexmedetomidine. In the study reported here, however, the doses administered in the morphine, dexmedetomidine, and morphine-dexmedetomidine groups were low, and any systemic effects in the patients would have been mild and transient and would not have impaired accurate assessment of pain responses.
For all dogs in the present study, drug contact time between intra-articular injection and extubation was a minimum of 30 minutes. This was considered to be of sufficient duration to produce synovial analgesia. The onset of analgesia following intra-articular administration of morphine in horses with lipopolysaccharide-induced synovitis is from 30 to 60 minutes.33 The onset of analgesia for intra-articularly administered dexmedetomidine in humans and animals is unknown, although the onset of action following IV administration of dexmedetomidine in dogs is rapid, within minutes.34 Studies addressing the onset of action of both drugs in canine joints are lacking.
No significant difference was found in the time to rescue analgesia among the control, morphine, and dexmedetomidine groups. The duration of analgesic effect of the control group (5 hours) can be explained by the fact that hydromorphone was administered at extubation, and the duration of action of IV administered hydromorphone is approximately 4 to 5 hours.35 Administering hydromorphone at extubation could have confounded the duration of action of morphine (7 hours) and dexmedetomidine (6 hours), whereas their median time to rescue analgesia differed by only 1 hour. Furthermore, the additional analgesia associated with carprofen, administered SC after completion of the surgery, may also have contributed to the similar analgesic duration in these 3 groups. None of the dogs required postoperative sedatives that could have affected the postoperative pain scores.
Veterinary and human studies36–38 have found bupivacaine to be one of the most effective drugs for local, intra-articular analgesia. In 1 study,36 the reported duration of action of bupivacaine when administered intra-articularly after cranial cruciate ligament repair was 24 hours. However, in that study,36 each dog was assessed every hour after surgery for a period of 6 hours and then again at 24 hours. Therefore, it is difficult to determine whether and when the dogs had signs of pain between 6 and 24 hours. The mean postoperative time to first rescue dose of analgesia following intra-articular administration of bupivacaine has been reported as 7.3 hours.37 Although bupivacaine could have a long-lasting analgesic effect, it has also been reported as cytotoxic to canine articular chondrocytes.25 In vitro studies39,40 confirming local anesthetic toxicity have shown that exposing chondrocytes to either bupivacaine, lidocaine, and ropivacaine caused a decrease in cellular viability and an increase in the induction of apoptosis.
Chondrotoxicity is a concern with the use of intra-articular drugs. Morphine does not cause chondrotoxicity in vitro,41 although no in vivo studies have been reported to date. To the authors' knowledge, chondrotoxicity of dexmedetomidine has not been determined. One study42 in healthy Sprague-Dawley rats demonstrated that a single intra-articular injection of dexmedetomidine caused mild synovial inflammation when the joints were assessed at 24 hours, 48 hours, and 7 days. However, there were no significant differences in inflammatory changes observed between the intra-articular dexmedetomidine groups and the control group (given saline solution). Therefore, it could not be concluded that dexmedetomidine was chondrotoxic because chondrocyte viability, necrosis, and apoptosis were not investigated in that study.42 The joint changes in rats may not be equivalent to those found in dogs. The preservative methylparaben has no reported effect on chondrocyte cultures,43 but to the authors' knowledge, the chondrotoxicity of propylparaben has not been determined. Given that the chondrotoxicity of intra-articularly administered dexmedetomidine in canine joints is still unknown, further studies should be performed.
Pain assessment is a difficult task and is a constant challenge in veterinary medicine because animals cannot communicate the intensity of their pain. In the study reported here, both behavioral (subjective) and objective scales were combined in an attempt to overcome this difficulty. The pain scoring system used was a modification and combination of the DIVAS21,22 for soft tissue surgeries and MPS system used in a stifle joint arthrotomy study.16 The DIVAS pain score is a modified visual analog score that includes dynamic and interactive assessments of a dog's behavior while undisturbed as well as how the dog responds to being approached and petted following surgery (developed for ovariohysterectomy).21,22 The DIVAS overcomes some of the deficiencies of a purely observational scoring system.21,22 A modified MPS system, which assesses objective data (heart rate, respiratory rate, and blood pressure) and was developed for stifle joint arthrotomy in dogs, 16 was also used.
The volume of solution administered intra-articularly (0.2 mL/kg) was determined by the collective experience of surgeons and anesthetists at the Purdue Veterinary Teaching Hospital, with the goal of limiting the total volume to decrease the risk of leakage from the joint capsule while providing adequate exposure to the whole synovial surface. The injection was given before skin closure so that needle placement was easier and the surgeon could confirm there was no leakage from the joint and confirm intra-articular placement by mild joint distension. This also allowed time for the analgesic medications to take effect before recovery from anesthesia.16
There are several limitations of the present study. The sample size was elected to permit identification of clinically useful differences between groups. It is probable that the number of cases were insufficient to detect significant differences between the morphine, dexmedetomidine, and control groups. Detecting significant differences was further hindered by variability within groups.
Multiple breeds of dogs were used in the present study, and different breeds have different temperaments and sensitivity to pain. These factors could have affected the study results. For example, dogs with separation anxiety could have been perceived to have signs of pain, or conversely, stoic dogs could have been perceived as having less signs of pain, even though they were experiencing pain. To eliminate anxiety and their reaction to a different, stressful environment, the dogs were admitted at least 12 hours prior to the surgery and were assigned to a specific cage for the duration of the hospitalization to allow them a period of acclimation. Baseline objective and subjective data such as heart rate, respiratory rate, blood pressure, and temperament of dogs could have been evaluated cage side the day prior to surgery, and those results could have been compared with the results obtained after surgery. In the present study, patients were monitored every 2 hours from the time of intra-articular injection to ensure minor changes could be noticed when assessing the patient for pain. Also, to increase consistency, a single trained observer, blinded to the type of treatment, performed all repeated examinations.
Different surgeons conducted the surgical procedures, and this could have affected the duration of surgical time, degree of tissue inflammation, and operative technique selected, which could all have influenced postoperative pain scores. However, all surgeons were experienced in the procedures they performed. Also, some dogs had medial meniscal damage requiring a partial meniscectomy. These factors could all affect the degree of postoperative pain in each dog.
Some dogs required a higher dose of isoflurane at times during surgical stimulation than the recommended dose (1.5% to 2.5%).44 The analgesic protocol used in the present study was designed to provide effective analgesia, yet to allow comparison between intra-articular treatments. Carprofen was administered at the end of the surgical procedure so as to not confound the pain assessment during the early recovery period. Healthy orthopedic patients should receive additional preoperative NSAID, epidurals, or additional doses of opioids systemically to obviate the need for high concentrations of inhalation anesthetic agents and their concomitant adverse cardiorespiratory effects.
Results of the study reported here reveal that there is a potential benefit of providing long-lasting analgesia when dexmedetomidine and morphine are given in combination intra-articularly. The combination may simplify postoperative management by reducing the frequency of repeated dosing of systemically administered analgesics. The reduction in repeated dosing of other systemic pain medication can potentially reduce the risk of CNS, gastrointestinal, respiratory, and cardiovascular adverse effects.
ABBREVIATION
| DIVAS | Dynamic interactive visual analog scale |
| MPS | Multifactorial pain score |
| TPLO | Tibial plateau leveling osteotomy |
| TTA | Tibial tuberosity advancement |
Morphine sulfate preservative-free (1 mg/mL), Hospira Inc, Lake Forest, Ill.
Dexdomitor (500 μg/mL), Zoetis Animal Health, New York, NY.
Hydromorphone (2 mg/mL), Baxter Health Care Corp, Deerfield, Ill.
PromAce (10 mg/mL), Aveco, Fort Dodge, Iowa.
PropoFlo (10 mg/mL), Abbott Laboratories, North Chicago, Ill.
Isoflo, Abbott Animal Health, Abbott Park, Ill.
BP-AccuGard, Oscillometric blood pressure monitor, Vmed Techenology Inc, Mill Creek, Wash.
Rimadyl (50 mg/mL), Pfizer Animal Health, Exton, Pa.
Model No. 188, Sonic Palpometer Systems Inc, Victoria, BC, Canada.
Stata SE, version 12.1, StataCorp, College Station, Tex.
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Appendix 1
Scoring systems (behavioral pain scores [undisturbed, followed by interaction] and objective pain scores [respiratory rate, heart rate, and Doppler ultrasound-measured systolic arterial blood pressure]*) used to obtain a general impression of postoperative pain severity in dogs undergoing TTA or TPLO for cranial cruciate ligament rupture.
| Variable | Description | Score |
|---|---|---|
| Behavioral pain score details | ||
| Undisturbed observation for signs of pain included vocalization and its frequency, body positions, and ability to move around | No signs of pain | 0 |
| Mild signs of pain | 1 | |
| Moderate signs of pain | 2 | |
| Severe signs of pain | 3 | |
| Interactions inside or outside of the cage and palpation of surgical limb with palpometer | No signs of pain | 0 |
| Mild signs of pain | 1 | |
| Moderate signs of pain | 2 | |
| Severe signs of plains | 3 | |
| Objective pain score details | ||
| Respiratory rate (URRL, 40 breaths/min) | Within RR | 0 |
| 50% above URRL | 1 | |
| Panting | 2 | |
| Heart rate (URRL, 100 beats/min) | Within RR | 0 |
| 25% to 50% above URRL | 1 | |
| > 50% above URRL | 2 | |
| Indirect systolic arterial blood pressure (URRL, 140 mm Hg) | Within RR | 0 |
| < 20% above URRL | 1 | |
| 20% to 50% above URRL | 2 |
Appendix 2
Palpometer scale and associated pain score.
| Pressure level indicator (beeps) | Amount of pressure applied | Equivalent pressure unit (gram-force/cm2) | Pain score assigned |
|---|---|---|---|
| 5 | Marked | 1,000 | No signs of pain (0) |
| 4 | Firm | 700 | Mild signs of pain (1) |
| 3 | Moderate | 425 | Moderate signs of pain (2) |
| 2 | Mild | 250 | Moderate signs of pain (2) |
| 1 | Slight | 100 | Severe signs of pain (3) |
