Epidural administration of analgesic drugs has gained in popularity over the past decade. Local anesthetic drugs can be administered to provide regional anesthesia both during and after procedures performed on the pelvic limbs. The duration of anesthesia varies according to the local anesthetic agent used. Lidocaine, mepivacaine, and bupivacaine have a reported duration of effect of 1 to 1.5 h, 1.5 to 2 h, and 3 to 4 h, respectively (2), although provision of analgesia may extend beyond these time frames.

Epidural administration of opioids limits the side effects of sedation, bradycardia, respiratory depression, and vomiting commonly associated with systemic administration, while providing a relatively long duration of segmental spinal analgesia with maintained motor function (3). The time to peak activity, the duration of activity, and the mechanism of action of epidurally administered opioids is incompletely understood. The mechanism of action is thought to involve diffusion of the drug across the meninges and into the spinal cord, with subsequent binding to opioid receptors in the dorsal horn (4). Transfer of opioids across the meningeal tissues is dependent upon lipophilicity of the drug. Relatively hydrophilic agents, such as morphine, have slow transfer rates with peak cerebrospinal fluid concentrations achieved approximately 3 h after epidural injection (5). The analgesia that results from epidural morphine is related to the cerebrospinal fluid concentration that interacts with spinal opioid receptors (6,7). Although the time to peak activity of epidural morphine is not well documented in dogs, onset of activity is reported as approximately 45 to 60 min, with a duration of activity of 16 to 24 h (2,4).

The mechanism of action of NSAIDs is thought to be dependent upon inhibition of the enzyme cyclooxygenase, limiting the production of prostaglandins from arachidonic acid (8). Recently, 2 distinct isoforms of the cyclooxygenase enzyme have been described. The COX-1 enzyme is constitutive and is associated with physiological functions of prostaglandins. The COX-2 enzyme is inducible and is associated with inflammatory responses. Since many of the adverse side effects of NSAIDs are due to inhibition of the normal physiological role of prostaglandins, there has been an effort to develop COX-2 specific agents. Meloxicam is a COX-2 preferential NSAID with established efficacy and safety (9,10,11).

It is generally accepted that NSAIDs lack the potency required for analgesia in the early postoperative period following major orthopedic surgery, when administered as single agents. However, when used in combination with opioids, NSAIDs can provide an additive effect due to their disparate mechanisms of action.

Prior to premedication all dogs were assessed to determine a baseline pain score, visual analog score (VAS) and analgesiometer reading. Pain scores were based on a numerical scale from 1 to 10, as previously described by Mathews (Table 1) (12). Visual analog scores (VAS) were subjectively determined by marking a 10-cm line at a point corresponding to the severity of pain, as assessed by a trained observer, with 0 cm indicating no pain and 10 cm indicating extreme pain. The analgesiometer consisted of a pressure sensitive transducer that was applied to the skin overlying the medial aspect of the tibia adjacent to the incision. Pressure was applied until an observable avoidance response from the patient was noted, and the maximum pressure reading was recorded. A single observer (KI), who was blinded to treatment group, performed all pain assessments in all dogs.

A total of 20 dogs were randomly entered into 1 of 2 treatment groups. Ten dogs in group I (meloxicam group) were premedicated with acepromazine maleate (Atravet; Ayerst, Montreal, Quebec), 0.05 mg/kg body weight (BW), IM; hydromorphone hydrochloride (Sabex, Boucherville, Quebec), 0.1 mg/kg BW, IM; and meloxicam (Metacam; Boehringer Ingelheim, Burlington, Ontario), 0.2 mg/kg BW, SC. Ten dogs in group II (control group) were premedicated with acepromazine and hydromorphone only, at the same doses used for group I dogs. Anesthesia was induced with approximately 10 mg/kg BW thiopental sodium (Pentothal; Abbott Laboratories, Montreal, Quebec), administered to effect, and was maintained on isoflurane (Isoflo; Abbott Laboratories, Saint-Laurent, Quebec) and oxygen. Fol lowing induction of general anesthesia, the lumbosacral region was clipped and surgically scrubbed. Dogs in both groups received epidural 2% mepivacaine hydrochloride (Carbocaine; Upjohn Animal Health, Orangeville, Ontario), 1 mL/6 kg BW, combined with morphine sulfate (10 mg/mL) (Sabex, Boucherville, Quebec), 0.1 mg/kg BW. The total volume of combined epidural morphine/mepivacaine was 1.06 mL/6 kg BW in all dogs. Epidural placement was confirmed by establishing loss of resistance to a small volume of injected air prior to epidural injection. Efficacy of epidural anesthesia was documented in all dogs by reducing the required levels of volatile gas anesthetic to less than 1 minimal anesthetic concentration (MAC) based on vaporizer setting during surgical manipulations, without an associated increase in heart rate, indirect blood pressure measurement, or respiratory rate. The time of epidural administration was considered as time zero for the purpose of subsequent pain assessments.

All surgical procedures were performed by an experienced surgeon (DF). The surgical technique was standardized and consisted of a limited arthrotomy; debridement of the medial meniscus, as necessitated by meniscal pathology; release of the medial meniscus; and tibial plateau leveling.

Pain score, VAS, and analgesiometer readings were obtained at 0, 6, 8, 12, 16, and 24 h after epidural injection. The 6-hour time point was the earliest time point at which all dogs were recovered sufficiently from anesthesia to allow evaluation. Analgesiometer readings were obtained after determination of pain and VAS to avoid the influence of provocative subject interference. Analgesiometer readings were subtracted from baseline readings to determine a difference between baseline and postoperative pain thresholds for each time point. In order to standardize analgesiometer scores and account for differences in baseline values, the percentage change was determined and expressed as the analgesiometer score. Animals with lower pain thresholds would be expected to have a greater percentage difference between baseline and postoperative analgesiometer readings.

The primary goal of the numerical pain scores was to determine the need for postoperative rescue analgesia. All dogs with a pain score of 4 or higher received hydromorphone, 0.1 mg/kg BW, IM.

The association between treatment status (meloxicam or control), sample time, and pain score were analyzed by using a generalized estimating equations (GEE) method to account for over dispersion within the data resulting from the repeated measures design. Data were analyzed by using a statistical computer software program (13). Model specification included a normal distribution, identity link function, repeated statement with subject equal to dog identification, and an unstructured correlation structure. Only the variables remaining in the final mutivariable model at P < 0.05, based on the robust empirical standard errors produced by the GEE analysis, are reported here. This statistical technique does not allow for missing data. Therefore, for dogs that required rescue analgesia, the last pain observation prior to drug administration was carried forward through the analysis. By carrying forward the last observation prior to rescue analgesia, the treatment is penalized for failure.

Three dogs in the control group (30%) required rescue analgesia, while no dogs in the meloxicam group required rescue analgesia. This difference was not statistically significant. Two dogs required rescue analgesia at 6 h after epidural injection, and 1 dog required rescue analgesia at 6 and 12 h after epidural injection.

Analgesiometry, as performed in this study, assesses cutaneous hypersensitivity to pressure through the use of a pressure sensitive transducer. Analgesiometry readings varied widely over time within both groups in this study. Similar findings were reported in a previous study comparing the efficacy of carprofen, ketoprofen, meloxicam, and tolfenamic acid for postoperative analgesia in cats (11). Cutaneous wound hyperalgesia is reported to occur after ovariohysterectomy in dogs with or without opioid or NSAIDs analgesia (18,19). It is likely that the analgesia provided in this study, although effective systemically, had less effect on cutaneous mechanical nociceptive thresholds.

All dogs in this study received epidural analgesia with a combination of morphine and mepivacaine. A placebo treated group was not incorporated into this study design due to the anticipated severity of postoperative pain. The need for rescue analgesia in a potential placebo treated group was anticipated to approach 100%, making interpretation of repeated measures pain scores and VAS difficult or impossible.

Mepivacaine was selected as a local anesthetic agent due to its intermediate duration of effect, lasting 1.5 to 2 h (2,4). This provided regional anesthesia during the period of surgical manipulation, allowing a reduction of volatile gas anesthetic to less than 1 MAC. Regional anesthetic effects from the administration of mepivacaine, however, were expected to be minimal at the 1st postoperative assessment, 6 h following epidural administration.

Morphine has a reported onset of action between 45 to 60 min after administration and a duration of effect lasting between 16 to 24 h (2,4). The time to peak activity is not well documented in dogs. The maximum plasma concentration following parenteral administration of meloxicam in humans is reached within 1.5 h of administration, and 90% of the C_max is reached within 30 to 90 min (20). The elimination half-life in humans is 15 to 20 h (20,21). The pharmacokinetics of meloxicam in dogs is reported to be similar to its pharmacokinetics in humans (22).

Dogs receiving meloxicam plus epidural analgesia had significantly lower visual analog scores, as compared with dogs receiving epidural analgesia only, at 6 and 8 h after epidural administration. Differences between the groups failed to reach significance at subsequent time periods. Differences seen at 6 and 8 h could be explained if the time to peak analgesic activity of epidural morphine occurred after the 8-hour evaluation period and a subsidence of analgesia provided by mepivacaine occurred prior to the 6-hour evaluation period. The analgesic effect of meloxicam, in this event, would be more apparent due to the diminished efficacy of the epidural morphine and mepivacaine at these time points. However, this seems unlikely, since peak activity of epidural morphine, according to previous reports, occurs prior to 6 h after administration (5).

Alternatively, the difference between meloxicam treated and control groups at the 6- and 8-hour time intervals could be explained if the analgesic effect of meloxicam administered SC was at its peak at this time, followed by a gradual waning. It is possible that plasma concentrations were adequate to provide a significant additive analgesic effect at the 6- and 8-hour time intervals, but that plasma concentrations of meloxicam decreased below a required threshold level by the 12-hour time interval.

The requirement for rescue analgesia in 3 of 10 dogs receiving epidural analgesia only versus 0 of 10 dogs receiving epidural analgesia plus meloxicam is clinically relevant. A larger number of dogs would be necessary to determine the statistical significance of this finding.

This study was not designed to assess postoperative renal function. Renal prostaglandins are physiologically important in the regulation of renal blood flow, as well as of sodium and water balance, and inhibition of renal prostaglandin production through the use of NSAIDs has been reported to have detrimental effects on renal function in a number of species (9,23,24). The COX-2 isoform of the cyclooxygenase enzyme is constititutively expressed in the kidney, and the potential renal toxicity of COX-2 preferential NSAIDs has not been thoroughly examined (9,24). Although renal impairment in healthy dogs receiving NSAIDs has not been well documented (25), the preemptive administration of even COX-2 preferential NSAIDs in dogs with preexisting renal disease or at high risk for either hypotension or hemorrhage during operative procedures should be used with caution.

Meloxicam, as a COX-2 preferential NSAID, has little purported potential for adverse effects on platelet function. Platelet function was spared in healthy human volunteers receiving meloxicam at a dose of 15 mg daily (26). Bleeding times were not assessed in this study, but they were not affected by the preemptive administration of meloxicam in a previous study (27). Subjectively, no difference in intraoperative hemorrhage was noted between dogs receiving meloxicam and dogs not receiving meloxicam in this study.

Based on this study, meloxicam administered preoperatively at a dose of 0.2 mg/kg BW, SC, in combination with epidural morphine and mepivacaine provides analgesia that is superior to that obtained with the use of epidural morphine and mepivacaine alone. Mepivicaine, a local anesthetic of intermediate duration, was chosen in this study to shorten the time frame during which potential differences between groups would become apparent. Bupivacaine and ropivacaine have a longer duration of anesthesia than does mepivacaine. It is unknown whether the use of one of these agents, as opposed to mepivacaine, would have dampened the difference between groups seen at 6 and 8 h.