Postoperative pain control in cats: clinical trials with pre-emptive lidocaine epidural co-administered with morphine or methadone

Abstract

Objectives

The aim of the study was to evaluate the effectiveness of epidural lidocaine in combination with either methadone or morphine for postoperative analgesia in cats undergoing ovariohysterectomy.

Methods

Under general anesthesia, 24 cats that underwent ovariohysterectomy were randomly allocated into three treatment groups of eight each. Treatment 1 included 2% lidocaine (4.0 mg/kg); treatment 2 included lidocaine and methadone (4.0 mg/kg and 0.3 mg/kg, respectively); and treatment 3 included lidocaine and morphine (4.0 mg/kg and 0.1 mg/kg, respectively). All drugs were injected in a total volume of 0.25 ml/kg via the lumbosacral route in all cats. During the anesthetic and surgical periods, the physiologic variables (respiratory and heart rate, arterial blood pressure and rectal temperature) were measured at intervals of time zero, 10 mins, 20 mins, 30 mins, 60 mins and 120 mins. After cats had recovered from anesthesia, a multidimensional composite pain scale was used to assess postoperative analgesia 2, 4, 8, 12, 18 and 24 h after epidural.

Results

The time to first rescue analgesic was significantly (P <0.05) prolonged in cats that received both lidocaine and methadone or lidocaine and morphine treatments compared with those that received lidocaine treatment alone. All cats that received lidocaine treatment alone required rescue analgesic within 2 h of epidural injections. All treatments produced significant cardiovascular and respiratory changes but they were within an acceptable range for healthy animals during the surgical period.

Conclusions and relevance

The two combinations administered via epidural allowed ovariohysterectomy with sufficient analgesia in cats, and both induced prolonged postoperative analgesia.

Introduction

For many years there was doubt regarding the use of opioids in cats because of possible adverse effects (excitation, nausea, vomiting and euphoria), but these can be avoided with the use of clinically appropriate dosages. The route of administration of opioids may determine the occurrence of some of these adverse effects; for example, subcutaneous hydromorphone in this species results in a higher incidence of vomiting than does intravenous hydromorphone. ¹ However, currently there are several studies recommending its use.^1–4 Lumbosacral epidural blocks are commonly used as a regional analgesic technique in small animals prior to abdominal or hindlimb surgeries.^1,5

Several opioid drugs, such as morphine, fentanyl, pethidine and methadone, combined or not with local anesthetics, administered via the epidural route have been successfully used in cats.^6–9 Morphine is probably the most commonly used opioid drug for this purpose because of its long duration of analgesic action and few adverse effects by this route.^1,3,4,10 Methadone is an intermediately lipophilic opioid that readily transfers from the epidural space into the spinal cord, but it is also taken up systemically via the epidural space and spinal blood supply.^9,11 Opioids like methadone have been used as an adjunct for epidural administration in combination with local anesthetic to achieve a prolonged duration of analgesia in dogs.^12,13 Few studies have evaluated epidural methadone in cats.^1,9 Clinical and experimental studies have shown that methadone is systemically effective for analgesia, inducing a dose-dependent period of analgesia without significant adverse effects in cats.^14–16 However, no recent studies have evaluated the use of methadone via the epidural route in cats.

The aim of this randomized, blinded study was to compare the duration of postoperative analgesia, sedation and the incidence of selected adverse events of single-dose lumbar epidural lidocaine, or methadone vs morphine in combination with lidocaine in cats undergoing ovariohysterectomy (OHE).

Materials and methods

Twenty-four healthy female domestic cats, aged 6–18 months and weighing 1.8–5.3 kg, admitted for elective OHE to the clinic of our faculty were used in this study in accordance with the Good Clinical Practice guidelines. Owners’ written consent and ethical approval from the Federal University of Mato Grosso do Sul were obtained. Inclusion criteria were age >6 months (after the first estrus), American Society of Anesthesiologists physical status 1 or 2 after clinical examination, weight >1.5 kg, docile, easy to handle, no contraindications to epidural administration (previous pelvic fractures, obesity, dermatitis at the insertion of the epidural needle) and absence of known systemic diseases. Cats were admitted to the clinic of the veterinary hospital 1 day before surgical procedures and were maintained in cages in the small animal laboratory room to adapt to the environment and the investigators. All animals were fasted overnight but had free access to water up to 1 h before the time of premedication. All anesthetic procedures and epidural injections were performed by the same anesthetist. The OHE was performed by the same surgeon using a routine method via a midline approach and 3-hemostat technique, and did not take longer than 30 mins.

Cats undergoing OHE were randomly allocated to three treatment groups (n = 8 in each group). On the day of experiments, all cats were premedicated with an intramuscular injection of 0.05 mg/kg acepromazine (Acepran 0.2%; Univet SA). After premedication, the animals were kept in a quiet environment for 10 mins. Then, a 22 G intravenous catheter was placed in a cephalic vein. Total intravenous anesthesia (TIVA) was induced with propofol using an intermittent bolus technique (4–5 mg/kg) with the required dose for the loss of protective reflexes. The depth of anesthesia was clinically assessed using jaw tone, eye position, coughing reflex and ocular–palpebral reflex, and the dose of propofol was altered accordingly. If anesthesia was considered inadequate (increase in arterial blood pressure, heart rate [HR] or respiratory rate [RR] of >15%, and somatic responses such as voluntary gross movements of the forelimbs and head or swallowing), then a propofol bolus of 1 mg/kg was administered as needed. During the TIVA, epidural injections and surgical procedures, the HR, RR, arterial blood pressure and rectal temperature (RT) were evaluated. Arterial pressure was measured with a multivariable analyzer (Dixtal DX 2021; Dixtal Biomédica Ind e Com) by using a non-invasive oscillometric device, with the cuff (width 2.5–4.0 cm) placed over the ulnar artery on the forearm. HR was measured using electrocardiography, RR was determined as the number of chest movements per min and RT was obtained with a digital thermometer at baseline (T₀) before premedication, 10 mins after premedication (T₁₀), after TIVA (T₂₀), after epidural injections (T₃₀) and after the end of surgeries (T₆₀ and T₁₂₀).

After induction, all cats were placed on a surgical bed in sternal recumbency with the hindlimbs pulled forward. The lumbosacral (L7–S1) area was cleaned with antiseptic, and a 22 G Tuohy needle was inserted. Correct positioning of the needle was confirmed by the hanging-drop method and loss of resistance by injected air (0.5 ml) into the epidural space. If cerebrospinal fluid or blood outflow was detected when the needle was aspirated, then the cat was removed from the study. Each animal was randomly assigned to one of three pain management treatments. Cats in the control treatment group received an epidural injection of 2% lidocaine without epinephrine (4.0 mg/kg Xylestesin 2%; Cristália Chemical and Pharmaceutical Products). The other two groups received a combination of lidocaine and methadone hydrochloride (LDMT; 4.0 mg/kg and 0.3 mg/kg, respectively, Mytedom; Cristália Chemical and Pharmaceutical Products) or a combination of lidocaine and morphine sulfate (LDMO; 4.0 mg/kg and 0.1 mg/kg, respectively, Dimorf 10 mg/ml; Cristália Chemical and Pharmaceutical Products). In all treatment groups, the total volume administered into the epidural space (0.25 ml/kg) was achieved by the addition of saline solution. All drugs were administered over 30 s; cats were maintained in sternal recumbency for at least 10 mins to facilitate the uniform spread of the drugs. After surgery, the cats were taken to a postoperative ward with individual cages for total anesthetic recovery and analysis of the treatments described.

We considered the final motor effect of the local anesthetic lidocaine when spontaneous movements and pedal reflex returned. This was measured by stimulating the cats to walk or placing them in a standing position, or by pedal withdrawal after a brief clamping stimulus. Evaluation of postoperative analgesia and sedation was conducted using a score composed of physiologic and behavioral parameters (Table 1). ¹⁷ The scoring values ranged from 0–18, with 0 representing a total lack of physiologic/behavior indicative of pain and 18 representing the worse pain possible. The assessments were performed at 2, 4, 8, 12, 18 and 24 h after the end of the local anesthetic effect and always by the same person blinded to the treatment. The first rescue analgesics during the postoperative period were an intramuscular administration of morphine (0.5 mg/kg) and ketoprofen (2 mg/kg) if the evaluation score exceeded 6. When the score remained more than 6 during the first 20 mins after administration of the first rescue analgesic, the cat was removed from the experiment and subsequent injections were administered   until the pain signals ended. If the score was lower than 6 after analgesic treatment, assessments were still performed at pre-established times. Other variables evaluated were salivation, vomiting and attention to surgical site.

Table 1.

Multidimensional composite pain scale applied to cats after ovariohysterectomy

Observation	Score	Criteria
Response to stimuli	0	No response, cat does not react when the surgical wound is touched or pressed
	1	Mild response, tense muscles and cat moves slowly when the surgical wound is touched
	2	Moderate response, tense muscles, cat turns head and licks after touch or pressure on the surgical wound
	3	Severe response, cat is restless, quick to react and tries to attack the evaluator when the wound is touched or pressed
Movement	0	Normal posture, stance considered normal for the species, cat moves spontaneously inside and outside the cage
	1	Cat in sternal recumbency or continuous position changes; when in recumbency cat holds the hindlimbs extended or contracted
	2	Cat does not move after being stimulated, inside or outside the cage
Vocalization	0	Quiet; cat keeps silent, purrs when stimulated
	1	Cat purrs spontaneously and interacts with the evaluator
	2	Cat growls or hisses when stimulated by the evaluator
	3	Cat purrs or growls spontaneously, without being manipulated
Behavior	0	Cat is alert and interested in the environment, cleaning up and playing, and is friendly when stimulated by the evaluator
	1	Slow reaction, depressed; cat is not interested in the environment and does not interact with the evaluator
	2	Aggressive; cat tries to bite or scratch when handled or when stimulated by the evaluator
Return of appetite	0	Cat eats normally during the postoperative period
	1	Cat eats less during the postoperative period
	2	Cat is not interested in food during the postoperative period
Heart rate	0	Normal (140–170 beats/min)
	1	⩾20% above values in preoperative period
	2	⩾30% above values in preoperative period
Respiratory rate	0	Normal (20–40 breaths/min)
	1	⩾25% above values in preoperative period
	2	⩾50% above values in preoperative period
Mydriasis	0	No
	1	Yes

The maximum possible score (greatest pain) was 18. Score 0 indicates no pain, scores of 1–6 indicate mild pain, scores of ⩾7–12 indicate moderate pain, scores ⩾13–18 indicate severe pain. Additional analgesics were given to cats with a score of 6 or more

Statistical analysis

Statistical analysis was performed with the SAS 9.2 (SAS Institute). Continuous variables were assessed for normality of residuals by the UNIVARIATE procedure and submitted to the Bartlett test to analyze the homogeneity of variances. Only data for RR were not normal; therefore, they were transformed to inverse square root. Data were grouped and summarized as mean ± SD of the mean or median and confidence interval. Data for HR, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), RR and RT were analyzed by Proc GLIMMIX for repeated measures, with treatment and time as independent variables. When a significant difference or interaction was obtained, least-squares means test or planned comparison was performed as appropriate. For the analgesia variable, the non-parametric Friedman’s test was used, followed by multiple comparisons for ranked data using Dunnett’s test, with T₀ as the baseline. In each analysis, differences were considered significant if P <0.05.

Results

Twenty-four female cats undergoing OHE that met the pre-established inclusion criteria were enrolled in this study. Mean time from premedication to induction of general anesthesia was 8 ± 4 mins in all three treatment groups, whereas the administration of epidural injections occurred approximately 10 mins after the induction of anesthesia. The duration of the surgical procedures in these female cats was similar between lidocaine (26 ± 10 mins), LDMO (22 ± 7 mins) and LDMT (25 ± 9 mins) treatment groups (P >0.05). There were no statistically significant differences between groups for any of the timings assessed (time from premedication to induction, time from induction to epidural injections, surgery duration and time from the end of the local anesthetic effect of lidocaine). Only two cats in the lidocaine treatment group and one in the LDMT treatment group required a second dose of propofol during the perioperative period. All cats showed normal behavior (eg, quiet, attentive to surroundings) and regained movement in the hindlimbs through the duration of pain scoring. None of the cats exhibited salivation or vomiting during the experimental period in any of the treatments. The surgical wounds healed normally in all animals.

After premedication, anesthetic induction and epidural administration, all three treatments caused significant changes in HR, SAP, DAP, MAP, RR and RT compared with baseline during the evaluation period (Table 2). HR and RR showed significant decreases at 20, 30 and 60 mins (P <0.05) compared with data obtained before premedication in the three treatments. The same effect was observed with MAP (SAP and DAP), which decreased significantly at 20 and 30 mins compared with data obtained before premedication in the three treatment groups. All three treatment groups showed a significant decrease in the RT at 20, 30 and 60 mins compared with the basal values. All the variables recorded had returned to within the reference interval after mean of 120 mins in the three treatment groups.

Table 2.

Heart (HR) and respiratory rates (RR), and rectal temperature (RT) in cats undergoing ovariohysterectomy (n = 8/treatment) receiving lidocaine (LD), lidocaine plus morphine (LDMO) or lidocaine plus methadone (LDMT)

	Treatments	Time (mins)
		T0	T10	T20	T30	T60	T120
HR (beats/min)	LD	168 ± 12	170 ± 9	152 ± 8*	149 ± 8*	148 ± 9*	157 ± 11
	LDMO	199 ± 9	204 ± 9	166 ± 6*	160 ± 8*	164 ± 11*	182 ± 13
	LDMT	180 ± 8	178 ± 12	149 ± 7*	144 ± 9*	153 ± 10*	166 ± 9
RR (breaths/min)	LD	59 ± 3	51 ± 4	42 ± 5*	38 ± 4*	36 ± 3*	47 ± 6
	LDMO	47 ± 5	48 ± 5	35 ± 4*	28 ± 3*	28 ± 3*	40 ± 5
	LDMT	56 ± 5	49 ± 5	26 ± 3*	26 ± 4*	26 ± 3*	43 ± 13
SAP (mmHg)	LD	121 ± 4	113 ± 3	97 ± 3*	105 ± 6*	113 ± 5	107 ± 11
	LDMO	110 ± 3	102 ± 4	92 ± 5*	95 ± 4*	111 ± 7	107 ± 4
	LDMT	107 ± 3	96 ± 5	87 ± 5*	86 ± 7*	99 ± 3	101 ± 5
DAP (mmHg)	LD	87 ± 5	80 ± 6	57 ± 5*	70 ± 7*	80 ± 7	96 ± 7
	LDMO	81 ± 4	72 ± 8	50 ± 4*	61 ± 5*	75 ± 6	78 ± 9
	LDMT	79 ± 4	76 ± 4	52 ± 4*	57 ± 6*	70 ± 5	73 ± 10
MAP (mmHg)	LD	99 ± 5	93 ± 4	73 ± 4*	85 ± 6*	96 ± 6	97 ± 5
	LDMO	93 ± 3	85 ± 5	67 ± 4*	79 ± 4*	91 ± 7	94 ± 6
	LDMT	89 ± 2	79 ± 5	70 ± 4*	68 ± 6*	80 ± 5	81 ± 4
RT (°C)	LD	39.0 ± 0.1	39.0 ± 0.1	38.5 ± 0.1*	37.7 ± 0.2*	37.0 ± 0.2*	38.9 ± 0.2
	LDMO	38.9 ± 0.1	38.8 ± 0.1	38.4 ± 0.1*	37.4 ± 0.2*	36.4 ± 0.2*	38.6 ± 0.2
	LDMT	38.9 ± 0.2	38.9 ± 0.2	38.1 ± 0.3*	37.5 ± 0.4*	36.8 ± 0.2*	38.5 ± 0.3

Data are mean ± SD

^*Significantly different (P <0.05) from baseline

T₀ = before premedication; T₁₀ = 10 mins after premedication; T₂₀ = 20 mins after total intravenous anesthesia; T₃₀ = 30 mins after epidural injections; T₆₀ = 60 mins after epidural injections; T₁₂₀ = 120 mins after epidural injections; SAP = systolic arterial pressure; DAP = diastolic arterial pressure; MAP = mean arterial pressure

During the postoperative period evaluation, both treatments with epidural opioids (methadone and morphine) combined with lidocaine had similar pain scores; in almost all cats, these treatments produced low pain scores according to the scale used in this study. There were no significant differences (P >0.05) at the time of the first rescue analgesia between the LDMT and LDMO treatments. Based on the pain assessment scoring, with a maximum score of 18, the first rescue analgesic for the LDMT treatment occurred at 18 ± 2 h (highest score 6) and occurred at 22 ± 3 h (highest score 6) for the LDMO treatment (Figure 1). Thus, there was no need for rescue analgesia during the period before these times after surgical procedure in these two treatment groups. All cats in the lidocaine treatment group required the first rescue analgesic within the 2 h. The score exceeded 6 in cats in the lidocaine treatment group at 4, 8, 12, 18 and 24 h, and the scores at these times were statistically different from those of the LDMT and LDMO treatment groups (P <0.05). In these animals, the rescue analgesia with morphine and ketoprofen decreased the pain scores after intramuscular administration, and none of them required further analgesia during the experimental period.

Figure 1.

Median postoperative analgesia score in cats that underwent ovariohysterectomy with epidural administration of lidocaine (LD), lidocaine plus morphine (LDMO) or lidocaine plus methadone (LDMT) during a 24 h period. Time of the first rescue analgesia with LD (¤), LDMO (‡) or LDMT (¥) treatment. In all treatments the analgesia score was still measured at pre-established intervals after the first rescue analgesic. Error bars represent the third quartile at each given time period. *Differed significantly (P <0.05) from the respective baseline (time 0) values

Discussion

Local anesthetic lidocaine is the drug most commonly used for epidural administration for surgical procedures in the hindlimbs, orthopedic procedures, tail injuries, caudal abdominal procedures, intrathoracic procedures and even forelimb procedures in cats.^1,3,5,18,19 Lidocaine is a low-risk, low-cost drug that can provide epidural anesthesia with fast onset but short duration. ³ This short-term effect increases postoperative pain scores and increases the requirement of analgesics. The duration of analgesia can be prolonged by the addition of various adjuvants, especially opioids.^8,12,13 Opioid receptors (µ, κ and δ) are present in high concentrations in the spinal cord, mainly in the dorsal horn. Activation of these receptors by opioids inhibits release of substance P from C nociceptive fibers; however, opioids are not effective for A-δ inhibition. ²⁰ The A-δ fibers are responsible for peracute (surgical) pain, which are activated throughout a surgical procedure owing to persistence of stimulus. ³ Local anesthetics are effective at these fibers producing anesthesia. The combination of a local anesthetic with opioids has advantages because it reduces the doses of both drugs in the epidural space and can probably confer synergism in preventing surgical pain transmission. ²¹ Because of the long duration of analgesic action and few adverse effects, morphine is probably the most appropriate opioid for epidural administration in cats.

The advantages of the combination of local anesthetics and opioids in small animals include an increase in the duration of postoperative analgesia, thus reducing the doses of each drug, allowing fewer adverse effects, decreasing the dose of intravenous anesthetics required to maintain surgical anesthesia and reducing inhalant requirements.^{5,8,12,13,22,23} Methadone is an opioid with intermediate lipophilicity; it has a dual analgesic effect when administered epidurally, a direct effect through a spinal mechanism and a central effect after its systemic absorption. ²⁴ Hydrophilic opioids like morphine administered epidurally are expected to cause analgesia of slow onset (30–60 mins) and prolonged duration (6–24 h) at doses lower than systemic doses. ³ In our study, the duration of analgesia did not differ between LDMT and LDMO (approximately 19 and 23 h, respectively). Our results were similar to those of a study that used a combination of epidural morphine and bupivacaine that provided analgesia of longer duration (19.6 h) in dogs and cats undergoing surgery. ⁸ However, the duration obtained in our study after epidural administration of methadone in cats was longer than that in other studies after epidural methadone in dogs undergoing orthopedic surgery.^18,25 A comparison between epidural morphine and tramadol in cats after noxious skin stimuli indicated that both drugs provided similar analgesic effects for the first 6 h, with epidural morphine resulting in longer-lasting analgesia when compared with tramadol. ⁴ These differences may be related to the type of noxious stimuli (visceral vs orthopedic), amount of fat in the epidural space, speed of vascular absorption causing supraspinal effects and anatomy of the epidural space in cats.

It is expected that opioids administered via the epidural route do not interfere with ambulation and do not cause central nervous system depression as the analgesic effect is through the opiate receptor in the dorsal horn of the spinal cord. Opioids with µ-agonism have the potential to affect motor function from hyperpolarizing motor neurons, but motor weakness is rarely seen.^3,20 Based on the scale used, we did not observe any significant change in ambulation or hindlimb weakness after the first 2 h of the epidural injections in any of the treatments studied. Despite the misconception that cats change their behavior with excitement after opioid administration, when administered in therapeutic doses the behavior effects usually include euphoria with purring, rolling and kneading with their front paws. ¹ In our study, cats receiving epidural methadone or morphine were alert and interested in the environment during the entire experimental period. In the treatment group in which cats received lidocaine, the first rescue analgesia occurred within 2 h of the epidural injections for ethical reasons. We were careful not to allow confusion between pain assessment and the occurrence of sedation. It is difficult to recognize and measure pain in animals because each individual animal may react differently to painful stimuli (experimental or surgical) and may vary with regard to its ability to communicate.

Regarding systemic administration, the dose of epidural opioids can influence changes in cardiorespiratory functions. These effects are more likely with lipophilic opioids because the highest doses are required for these opioids. ³ An epidural of high-dose fentanyl (4 µg/kg) in isoflurane-anaesthetized cats decreased blood pressure and HR for at least 2 h. ²⁶ Bradycardia and respiratory depression have been reported in dogs after epidural morphine. ⁸ In our study, lidocaine alone and its combination with methadone and morphine decreased HR, RR, SAP, DAP, MAP and RT in these healthy cats, but they were still within clinically acceptable ranges. These effects were possibly induced by the vasodilation (B-fibers) caused by local anesthetic lidocaine. We detected a decrease in RR in all of the treatments; however, because we did not measure PaCO₂, hypoventilation could not be quantified.

Conclusions

Lumbosacral epidural administration of methadone and morphine with lidocaine provided a longer duration of postoperative analgesia when compared with lidocaine alone in cats undergoing OHE. Methadone and morphine did not differ in terms of their adverse effects. The two combinations with opioids used in this study, lidocaine plus methadone and lidocaine plus morphine, induced a longer period of effective analgesia and time to first rescue analgesia after OHE in cats. For these reasons, these combinations should be considered analgesic techniques for the relief of postoperative pain with this type of surgery.