Potentiation of epidural lidocaine by co-administering tramadol by either intramuscular or epidural route in cats

Abstract

This study investigated the analgesic and systemic effects of intramuscular (IM) versus epidural (EP) administration of tramadol as an adjunct to EP injection of lidocaine in cats. Six healthy, domestic, shorthair female cats underwent general anesthesia. A prospective, randomized, crossover trial was then conducted with each cat receiving the following 3 treatments: EP injection of 2% lidocaine [LEP; 3.0 mg/kg body weight (BW)]; EP injection of a combination of lidocaine and 5% tramadol (LTEP; 3.0 and 2.0 mg/kg BW, respectively); or EP injection of lidocaine and IM injection of tramadol (LEPTIM; 3.0 and 2.0 mg/kg BW, respectively). Systemic effects, spread and duration of analgesia, behavior, and motor blockade were determined before treatment and at predetermined intervals afterwards. The duration of analgesia was 120 ± 31 min for LTEP, 71 ± 17 min for LEPTIM, and 53 ± 6 min for LEP (P < 0.05; mean ± SD). The cranial spread of analgesia obtained with LTEP was similar to that with LEP or LEPTIM, extending to dermatomic region T13–L1. Complete motor blockade was similar for the 3 treatments. It was concluded that tramadol produces similar side effects in cats after either EP or IM administration. Our findings indicate that EP and IM tramadol (2 mg/kg BW) with EP lidocaine produce satisfactory analgesia in cats. As an adjunct to lidocaine, EP tramadol provides a longer duration of analgesia than IM administration. The adverse effects produced by EP and IM administration of tramadol were not different. Further studies are needed to determine whether EP administration of tramadol could play a role in managing postoperative pain in cats when co-administered with lidocaine after painful surgical procedures.

Introduction

Studies suggest that epidural (EP) analgesics are an effective means of managing postoperative pain in humans and other animals (1–4). Due to proximity to the receptor sites, the therapeutic efficacy of spinal/EP opioid application lasts longer and reduces systemic side effects (5). However, some cats are unable to tolerate EP morphine and suffer side effects, including decreased heart rate and hypotension (6,7), respiratory depression (8), pruritus, and chronic urinary and bowel dysfunction (9). Tramadol, which is a synthetic codeine analogue that is a weak μ-opioid receptor agonist (10), is a racemic mixture of 2 enantiomers: (+)-tramadol and (−)-tramadol. (+)-Tramadol has a moderate affinity for the opioid receptor and greater than that of (−)-tramadol (11). (+)-Tramadol inhibits serotonin uptake and increases its extracellular release and (−)-tramadol is a potent noradrenalin inhibitor. Their combination results in a synergistic antinociceptive interaction (11). Tramadol promotes analgesia by binding (+)-tramadol to μ-opioid receptors and the analgesic properties of the main active metabolite, O-desmethyl-tramadol (11,12). This metabolite binds to μ-opioid receptors with a much greater affinity than tramadol and appears to contribute significantly to the analgesic effect (12,13). After oral administration of tramadol in cats, the plasma concentration-time profile of O-desmethyl-tramadol closely followed that of tramadol, which suggests that it is one of the main metabolites produced (14).

Another aspect of alleviating pain in cats is the recognition of pain and the lack of communication between owners, animals, and their attendants. Similar studies in cats have found that simple descriptive and visual analogue scales for assessing levels of pain in the postoperative period are useful clinical tools (15–17). Besides assessing analgesic drugs for duration of action, we should evaluate which route of administration leads to the most favorable outcome. Postoperative pain has been managed effectively with neuraxial administration (subarachnoid and EP) of analgesics, whether combined with local anesthetics or not (8,16,18).

In this study, tramadol was administered to cats by either the intramuscular (IM) or EP route to determine analgesic effects during the first 3 h and to identify which route produces the maximum duration of analgesia with minimal adverse effects in cats.

Materials and methods

Six healthy, adult domestic, shorthair female cats (mean weight ± SD, 3.0 ± 0.7 kg) were used in this study. They were acquired from an animal protection society and were selected if docile and able to accept the manipulation. After the study, the animals were spayed and placed for adoption. According to the regulations of the institution of animal care, both parts were in agreement and the final owner was informed of the study. All cats were maintained in cages in the small animal laboratory room and had free access to food and water during the experimental period. The study was approved by the Institutional Animal Care and Use Committee.

On the day of experiments, the cats were premedicated with an IM injection of 0.05 mg/kg body weight (BW) of acepromazine (Acepran 0.2%; Univet SA, São Paulo, Brazil) at 15 min before induction of anesthesia. A 20-gauge IV catheter was placed in the cephalic vein and anesthesia was induced with 0.2% etomidate IV (Etomidato; Cristália Chemical and Pharmacological Products, Itapira, Brazil) (mean dose ± SD, 1.6 ± 0.4 mL) (19). At 2 to 3 min after induction, the animal was placed in sternal recumbency with the hind limbs pulled forward. The lumbosacral (L7–S1) area was cleaned with antiseptic and a 22-gauge 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 EP space. If cerebrospinal fluid or blood outflow was detected when the needle was aspirated, the experiment was stopped and the procedure was repeated after a week. The drugs were injected through the epidural needle with the cats under general anesthesia with etomidate. Full recovery occurred when tactile sensation could be discerned and cats freely moved the forepaws. Animals were fully conscious and breathing spontaneously when assessments began in each treatment.

Cats received the following 3 treatments administered in random order, allowing a 7-d washout interval between each study: LEP, an EP injection of 2% lidocaine (3.0 mg/kg BW) without adrenaline (Cloridrato de Lidocaína; Teuto Brasileiro, Anápolis, Brazil); LTEP, an EP injection of a combination of lidocaine (3.0 mg/kg BW) and 5% tramadol chlorhydrate (2.0 mg/kg BW) (Tramadon; Cristália Chemical and Pharmacological Products); or LEPTIM, an EP injection of lidocaine (3.0 mg/kg BW), and an IM injection of 2.0 mg/kg BW of tramadol in 1.0 mL of saline solution. All EP treatments were diluted with saline to a volume of 0.25 mL/kg BW administered over 30 s.

After administration of the drugs, a blinded evaluator measured each cat’s response to painful mechanical stimuli by applying pressure from hemostatic forceps (Halstead) closed to the first ratchet, with each stimulus applied for 2 s. Attempts were made to standardize these stimuli among treatments. The painful stimuli were applied to the skin of the tail, both lateral aspects of the hind limbs, perineum, and upper and lower abdominal wall. The analgesic score was assessed and recorded at time 0 min (baseline), at 10 min (recovery time of induction), and every 15 min for 1 h after EP or IM injection and then every 30 min for 3 h. Satisfactory analgesia was considered to be achieved when the cat did not respond to clamping in any tested area. We observed cats closely for evidence of segmental spread of analgesia using a short, bevelled, blunt needle. The cats were evaluated for behavioral or motor blockade at 15-min intervals until 60 min and at 30-min intervals thereafter until the end of the experiment. We observed characteristic behaviors of the species, e.g., purring, playful, kneading, when in an unfamiliar environment and in contact with the researchers. The cats were evaluated for motor blockade or presence of ataxia by being walked outside the cage. Analgesia, behavioral, and motor blockade traits were evaluated with a numerical pain-scoring system (Table I).

Table I.

Numerical pain-scoring system applied to cats after mechanical painful stimulus

Observation	Score	Criteria
Analgesia	1	Strong reaction when standard painful stimulus is applied in the surveyed regions
	2	Mild analgesia; depressed reaction when standard painful stimulus is applied in the surveyed regions
	3	Moderate analgesia; cats are alert but do not react when standard painful stimulus is applied in the surveyed regions
	4	Complete analgesia; cats calm and indifferent when standard painful stimulus is applied in the surveyed regions
Behavioral	0	Normal reaction, but cat tries to bite or scratch when handled or painfully stimulated by the evaluator
	1	Slow reaction, depressed; cat not interested in the environment and does not interact with the evaluator during painful stimulus
	2	Cat is alert and interested in the environment, playing and friendly when painfully stimulated by the evaluator
Motor blockade	0	Normal motor function, standing position
	1	Mild motor incoordination; cat has difficulty maintaining a standing position
	2	Moderate motor block; cat is recumbent, with movement of hind limbs
	3	Complete motor block; cat is in sternal recumbency, without movement of hind limbs

Heart rate (HR), arterial pressure (systolic, SAP; diastolic, DAP; mean, MAP), and respiratory rate (RR) were evaluated before administration (basal; time 0) and at 10, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min after drug injections. Arterial pressure was measured through a multivariable analyzer (DX 2021; Dixtal Biomédica Ind e Com, Manaus, Brazil) by using a noninvasive oscillometric device, with the cuff (width, 2.5 to 4.0 cm) placed over the ulnar artery on the forearm. Heart rate was measured using electrocardiography, RR was determined as the number of chest movements per minute, and rectal temperature (RT) was obtained with a digital thermometer. All cardiovascular variables and RR were recorded before painful stimulation so as not to interfere with the values obtained.

Statistical analysis

All data were analyzed using a general linear model with the SAS software package (SAS Institute, Cary, North Carolina, USA). Data were grouped and summarized as mean ± SD. Data for HR, SAP, DAP, MAP, RR, and RT were grouped and analyzed using 2-way repeated measures analysis of variance (ANOVA), with treatment and time as independent variables. When a significant difference or interaction was obtained, Dunnett’s test or planned comparison was carried out as appropriate. For analgesia, behavioral, and motor blockade variables, the nonparametric Friedman’s test was used, followed by multiple comparisons for ranked data using Dunnett’s test, with time 0 as the baseline. In each analysis, differences were considered significant if P ± 0.05.

Results

After recovery from etomidate anesthesia (approximately 5 min) and after IM or EP administrations, cats showed normal behavior throughout the experimental period, e.g., quiet, attentive to surroundings. One cat was excluded from the experiment and replaced with another because myoclonus occurred during induction and recovery from anesthesia. Two cats in the LEP treatment had outflow of blood in the EP needle and the procedure was repeated after a week. Two cats in the LTEP treatment showed agitation and another vomited during recovery from etomidate-induced anesthesia. No adverse effect was observed after tramadol was administered by either IM or EP routes.

There was no significant difference in general anesthesia induction time among treatments: 1.0 ± 0.6 min for LEP, LTEP, and LEPTIM (P > 0.05). Onset of complete analgesia was rapid in all treatments (1.9 ± 1.3 min) after EP or IM administration of the drugs (mean ± SD). LTEP produced a longer duration of analgesia (120 ± 31 min, P < 0.05) than did LEPTIM (71 ± 17 min) or LEP (53 ± 6 min) (Figure 1). The cranial spread of analgesia obtained with LTEP was similar to that of LEP or LEPTIM, extending to dermatomic region T13–L1. In LEPTIM, 1 animal presented a depressed response to painful stimuli across the whole body. The behavioral scores were not modified by treatments (P > 0.05). There was no significant difference (P > 0.05) among treatments in terms of motor blockade (LEP, 53 ± 6 min; LTEP, 56 ± 9 min; LEPTIM, 53 ± 15 min). For LTEP, the motor blockade period was approximately half as long as the analgesic period.

Figure 1.

Median analgesia score in response to a standard noxious stimulus at tail, both lateral aspects of the hind limbs, perineum, and upper and lower abdominal wall after LEP, LTEP, or LEPTIM treatments in 6 cats. Error bars represent the 3rd quartile at each given time period.

* Significantly (P < 0.05) different from the baseline value (time 0).

After premedication, anesthetic induction and EP and IM administrations, none of the 3 treatments caused significant changes in HR, SAP, or RR compared with baseline throughout the experimental period (Table II). However, there was a significant decrease (P < 0.05) in DAP and MAP in the 3 treatments: LEP induced a significant decrease in DAP and MAP immediately after anesthetic induction until 45 min; DAP and MAP decreased significantly in the LEPTIM treatment from 5 to 75 min and 30 to 75 min, respectively; and LTEP induced a significant decrease in DAP and MAP from 5 to 90 min. Only the LEP treatment caused a significant change in RT, which decreased from 30 to 75 min.

Table II.

Mean ± SD values for cardiovascular variables and respiratory rate in 6 cats receiving epidural injection of 2% lidocaine (LEP; 3.0 mg/kg BW) and a combination of lidocaine and 5% tramadol (LTEP; 3.0 and 2.0 mg/kg BW, respectively) or epidural injection of lidocaine and intramuscular injection of tramadol (LEPTIM; 3.0 and 2.0 mg/kg BW, respectively)

		Time (min)
	Treatments	Basal	EPI	10	15	30	45	60	75	90	120	150	180	210
HR	LEP	166 ± 21	140 ± 32	137 ± 24	141 ± 26	141 ± 30	138 ± 38	136 ± 30	146 ± 37	149 ± 26	ND	ND	ND	ND
	LTEP	157 ± 9	135 ± 28	134 ± 26	142 ± 28	144 ± 27	146 ± 21	149 ± 17	146 ± 22	147 ± 18	148 ± 24	137 ± 14	144 ± 10	141 ± 14
	LEPTIM	158 ± 17	137 ± 26	140 ± 28	139 ± 25	135 ± 19	136 ± 18	141 ± 18	139 ± 17	139 ± 23	139 ± 21	ND	ND	ND
SAP	LEP	134 ± 19	123 ± 18	138 ± 23	120 ± 27	134 ± 18	119 ± 19	120 ± 18	139 ± 17	125 ± 13	ND	ND	ND	ND
	LTEP	128 ± 18	117 ± 12	117 ± 21	120 ± 7	121 ± 8	119 ± 8	115 ± 19	114 ± 12	126 ± 6	129 ± 11	126 ± 11	118 ± 11	121 ± 10
	LEPTIM	131 ± 15	138 ± 24	135 ± 11	135 ± 19	125 ± 27	134 ± 22	133 ± 12	125 ± 12	124 ± 20	124 ± 12	ND	ND	ND
DAP	LEP	102 ± 20	70 ± 4*	88 ± 8*	78 ± 23*	83 ± 14*	68 ± 15*	84 ± 23	98 ± 21	88 ± 16	ND	ND	ND	ND
	LTEP	100 ± 19	67 ± 17*	63 ± 12*	65 ± 14*	68 ± 13*	77 ± 10*	69 ± 10*	75 ± 9*	77 ± 14*	89 ± 16	93 ± 17	91 ± 8	92 ± 6
	LEPTIM	105 ± 14	76 ± 14*	80 ± 9*	72 ± 17*	72 ± 28*	82 ± 14*	82 ± 12*	77 ± 21*	90 ± 15	89 ± 10	ND	ND	ND
MAP	LEP	109 ± 20	83 ± 5*	95 ± 6*	89 ± 17*	90 ± 7*	80 ± 12*	95 ± 20	112 ± 18	100 ± 15	ND	ND	ND	ND
	LTEP	111 ± 19	86 ± 16*	86 ± 11*	85 ± 8*	89 ± 10*	87 ± 8*	86 ± 13*	87 ± 7*	95 ± 9*	104 ± 7	104 ± 11	102 ± 6	101 ± 2
	LEPTIM	112 ± 14	97 ± 13	101 ± 8	104 ± 17	90 ± 22*	89 ± 15*	91 ± 13*	92 ± 13*	100 ± 16	101 ± 8	ND	ND	ND
RR	LEP	45 ± 12	43 ± 8	39 ± 13	38 ± 14	39 ± 8	41 ± 10	40 ± 8	41 ± 7	35 ± 6	ND	ND	ND	ND
	LTEP	52 ± 18	38 ± 11	34 ± 9	34 ± 9	41 ± 19	30 ± 22	30 ± 19	48 ± 20	50 ± 21	44 ± 18	46 ± 21	44 ± 19	38 ± 11
	LEPTIM	49 ± 18	32 ± 12	33 ± 15	35 ± 19	36 ± 14	43 ± 13	47 ± 18	42 ± 17	42 ± 21	40 ± 16	ND	ND	ND

EPI — epidural injection; HR — heart rate (beats/min); SAP — systolic arterial pressure (mmHg); DAP — diastolic arterial pressure (mmHg); MAP — mean arterial pressure (mmHg); RR — respiratory rate (breaths/min); ND — not determined.

^*In a within-treatment comparison, the value differed significantly (P < 0.05) from the respective baseline (time 0) value.

Discussion

According to previous studies, when injected into the EP space, tramadol produces useful analgesia of relatively long duration in several animal species (2–4) and humans (1,18). Tramadol has a selective spinal action similar to that of other opioids (20), as revealed by the much lower serum concentrations of tramadol after EP injection than after IV injection (1,21). In cats, EP administration of morphine or tramadol provided satisfactory analgesia to a noxious stimulus, but the effect of morphine was longer lasting than that of tramadol (2). In the current study, either EP or IM administration of tramadol induced a rapid onset of analgesia in cats, probably because the drug was combined with EP injection of local anesthetic lidocaine. Similar doses of tramadol administered by EP or IV routes have resulted in similar mean serum concentrations in dogs (3). These facts tend to support the view that systemic absorption of EPtramadol may be necessary for its action (1,22,23). In our study, the addition of tramadol to EPlidocaine to cats induced a longer duration of analgesic action than those of LEP or LEPTIM treatments. In a study comparing EP and IM tramadol in dogs, although EP administration of tramadol was shown to be safe, it did not improve analgesic effects compared with IM administration (24), as was found when comparing EP with IV administration (3).

After systemic (oral or IV) tramadol administration, O-desmethyltramadol had a longer terminal half-life in cats than in dogs (25). In humans, the demethylation reaction producing O-desmethyl-tramadol is catalyzed by isoenzyme cytochrome P-450 2D6 (26). Pypendop and Ilkiw (14) noted that this might be related to the poor ability of cats to eliminate glucuronidate compounds, as elimination of O-desmethyl-tramadol has been reported to require glucuronidation in humans (27).

Results are conflicting regarding the duration of postoperative analgesia in humans after EP tramadol administration. Epidural administration of tramadol alone (2 mg/kg BW) provided better and longer lasting postoperative analgesia than IV administration of tramadol (2 mg/kg BW) (28). A study comparing 3 doses of tramadol with bupivacaine found a prolonged dose-dependent duration of postoperative analgesia in children who underwent inguinal herniotomy (18). Prosser et al (1) concluded that EP tramadol had a slow onset of action and that adding tramadol to EP bupivacaine did not significantly prolong the duration of action of bupivacaine. In our study of cats, we found a longer duration when tramadol was added to EP lidocaine compared to IM tramadol.

After EP or IM administration of tramadol (2 mg/kg BW) to conduct ovariohysterectomy in bitches, serum cortisol levels and nor-adrenaline increased significantly in the early postoperative period (120 min) compared with the intraoperative period (24). Although we did not conduct surgical procedures in our study, we obtained a similar duration of analgesia in cats with the addition of tramadol to lidocaine at the same doses, with EP administration of both drugs (120 ± 31 min).

The hypotension produced by the sympathetic blockade occurs because of the EP injection of local anesthetic. Previous studies of tramadol administered by various routes (IV, IM, or EP) did not find significant changes in the cardiovascular system in humans (1,18) or other animals (3,24). In the current study, all treatments induced a significant decrease in DAP and MAP. These effects were probably induced because the EP block with local anesthetic lidocaine was carried out in all treatments. Tramadol is an opioid without a respiratory depressant effect, despite having an analgesic potency approximately equal to that of pethidine (29,30). Although we did not analyze blood gas, no change was observed in RR in any of the treatments. Nausea is a possible side effect when tramadol is administered by EP, although its incidence is low in humans (1,18). In our study, only 1 animal vomited in all 3 treatments, which we believe was due to the recovery from etomidate anesthesia.

Because of the difficulty of EP puncture in conscious cats, this procedure is typically done after induction of anesthesia (31) or heavy sedation (32). Etomidate was used as an anesthetic agent to minimize the stress and anxiety associated with EP injections. It has a short duration of action, its hemodynamic effects are minimal, and the recovery of cats after etomidate induction is smooth (19,33,34).

This study has certain limitations. We did not have a control treatment with tramadol alone. Others studies on cats or dogs, however, indicated that this drug caused few side effects after EP administration (2,3). Another limiting factor was the technique used to assess analgesia: the duration of analgesic action was taken as the time from EP or IM injection to first reaction to painful stimuli. However, there was only a single blinded observer in order to eliminate interob-server variability. In the current study, we found that analgesia was more profound and longer lasting after a combined epidural administration of lidocaine and tramadol rather than an epidural administration of lidocaine and intramuscular administration of tramadol. The occurrence of analgesia and similar side effects after tramadol administered by both EP and IM routes suggests that they may have similar actions sites. We evaluated the analgesic effect for a limited time (3 h) until the appearance of the first painful reactions, although it is possible that useful analgesia may have continued longer. Although we used a numerical scoring system to assess pain, we also evaluated the behavior and physiological changes such as heart and respiratory rates, which can be measured without causing discomfort to the animal.

In conclusion, our findings indicate that EP and IM administration of tramadol (2 mg/kg BW) with EP lidocaine produces satisfactory analgesia in cats. As an adjunct to lidocaine, EP administration of tramadol provides a longer duration of analgesia than IM administration. There was no difference in adverse side effects when tramadol was administered by either the EP or IM route. Additional studies are needed to determine whether tramadol could play a role in managing postoperative pain in cats when co-administered with lidocaine after painful surgical procedures.