In the report “Analgesic effects of tramadol hydrochloride administered via caudal epidural injection in healthy adult cattle” (Am J Vet Res 2010;71:720–725), methods used for the statistical analyses were incorrect. The correct versions of the statistical analysis section, Results section, and Discussion are printed here. In addition to these changes, the legend for Figure 1 should read as follows:
Figure 1—Mean total analgesia scores for 5 standing adult cows that were administered tramadol hydrochloride via caudal epidural injection at a dose of 1 (black circles), 2 (black squares), or 3 (black triangles) mg/kg at 1-week intervals (3 treatments/cow). Injections were administered in the first intercoccygeal (Co1–2) space. Analgesia was evaluated by the responses to superficial and deep pinprick tests at 5-minute intervals after injection and was scored as follows: 0, no analgesia detected (vigorous response); 1, mild analgesia (slow or less vigorous response to stimulus); 2, moderate analgesia (substantially diminished response); and 3, complete analgesia (no response). Scores for 9 areas (tail, anus, perineum, vulva, medial thigh region, lateral thigh region, caudal udder attachment region, caudal glands of the udder, and midgluteal region) were determined and added together for each cow (maximum total score, 27). Data for each dose of tramadol were then averaged to determine mean total analgesia score. Mean total analgesia scores were significantly higher 5, 15, 20, 25, and 35 minutes after injection and from 5 to 80 minutes after injection when cows received 2 and 3 mg of tramadol/kg respectively, compared with scores when cows received 1 mg of tramadol/kg. Mean total analgesia scores were also significantly higher 30 minutes and 40 to 80 minutes after injection when cows received 3 mg of tramadol/kg, compared with scores when cows received 2 mg of tramadol/kg.
In addition, in the footnote to Table 1, the explanation for the double cross should be changed to “‡Values were significantly (P < 0.05) different between doses,” and the footnote to Table 2 (“*Rumen motility was decreased significantly (P < 0.05) 15 minutes after injection, compared with rumen motility at baseline”) should be deleted.
Statistical analysis—Mean analgesia, sedation, and ataxia scores were determined for the 5 cows after administration of each dose of tramadol (1, 2, or 3 mg/kg). The mean total analgesia score for each treatment was determined by adding the scores (determined from analgesia scores for all 9 tested regions) for the 5 cows and averaging the results for the data set. The Friedman test was used for analysis of total mean analgesia, sedation, and ataxia scores and for analysis of duration of complete analgesia.
Data for heart rate, respiratory rate, and rectal temperature at the various study times were determined to be normally distributed on the basis of results of the Shapiro-Wilk test. Therefore, repeated-measures 1-way and 2-way ANOVA with a Bonferroni adjustment for type 1 error was used for analysis of these data. The univariate or multivariate approach was selected on the basis of results of the Mauchly test. For heart rate and rectal temperature, a univariate approach was used, whereas a multivariate approach was used for analysis of respiratory rate data. Data for ruminal motility were not found to be normally distributed with the Shapiro-Wilk test. Therefore, the Friedman test was used for analysis of these data. Values for heart rate, respiratory rate, rectal temperature, and rumen motility were compared with baseline values (ie, measurements obtained prior to tramadol administration) and among the 3 doses of tramadol and are reported as mean ± SD.
All statistical analyses were performed with commercially available software.c Differences were considered significant at a value of P < 0.05.
Results
No adverse affects were associated with tramadol administration. Onset of motor nerve blockade of the tail (mean time to onset was < 156 seconds for each of the 3 doses of tramadol) afforded reliable evidence that the caudal epidural injection had been administered correctly. Mean duration of motor nerve blockade of the tail increased as the dose of tramadol increased (25, 74, and 91 minutes for doses of 1, 2, and 3 mg/kg, respectively). The duration of this effect when cows received tramadol at a dose of 2 or 3 mg/kg was significantly increased, compared with the duration of motor nerve blockade of the tail when cows received the 1 mg/kg dose. Similarly, there were significant dose-dependent changes in mean duration of anal relaxation (11, 68, and 86 minutes for doses of 1, 2, and 3 mg/kg, respectively).
An analgesia score of 3 (considered complete analgesia that was suitable for surgery) was not achieved when some cows received tramadol at a dose of 1 mg/kg, but complete analgesia was achieved in the tail, anus, perineum, vulva, and medial aspect of the thigh in all cows when doses of 2 or 3 mg/kg were administered (Table 1). Mean times to onset of complete analgesia were 5 to 12 minutes for the tail, anus, perineum, and vulva and 5 to 30 minutes for the lateral thigh region, medial thigh region, and caudal udder attachment region. Complete analgesia was not obtained in the caudal udder attachment region following administration of a dose of 1 mg/kg and was not obtained in the gluteal region following administration of any dose of tramadol. Mean duration of complete analgesia increased as the dose of tramadol increased, and mean duration was significantly different when cows received 3 mg of tramadol/kg, compared with mean duration when cows received 1 mg of tramadol/kg.
Mean total analgesia score for all 9 regions tested increased as the dose of tramadol increased. Mean total analgesia scores were significantly higher 5, 15, 20, 25, and 35 minutes after injection and from 5 to 80 minutes after injection when cows received 2 and 3 mg of tramadol/kg respectively, compared with scores when cows received 1 mg of tramadol/kg. Mean total analgesia scores were also significantly higher 30 minutes and 40 to 80 minutes after injection when cows received 3 mg of tramadol/kg, compared with scores when cows received 2 mg of tramadol/kg (Figure 1).
A slight sedative effect was detected in cows following administration of each of the 3 doses of tramadol. Ataxia was observed with higher doses (slight for the 2 mg/kg dose and moderate for the 3 mg/kg dose). Ataxia scores were significantly different when cows received 3 mg of tramadol/kg than when cows received 1 or 2 mg of tramadol/kg from 40 to 50 minutes after injection. No cows became recumbent following administration of any dose of tramadol.
Mean heart rate, respiratory rate, rectal temperature, and ruminal motility were similar 5 minutes prior to injection of each of the 3 doses of tramadol (Table 2). Values did not differ significantly from baseline values following administration of any dose of tramadol, and values recorded following administration of each of the 3 tramadol doses did not differ from each other.
Discussion
In the present study, 3 doses of tramadol (1,2, and 3 mg/kg) administered via caudal epidural injection were selected for use in adult cows. The lowest dose was the dose determined for use in horses13; use of this dose was based on results of a pilot study conducted at our facility, which indicated that doses of tramadol < 1 mg/kg may be less effective in cattle. The protocols for scoring analgesia, sedation, and ataxia were based on protocols used in studies14,15 by other investigators.
Following tramadol injection, analgesic effects were determined by the responses to superficial and deep pinprick tests, which were scored from 0 to 3 (0, no analgesia detected; 1, mild analgesia [diminished response]; 2, moderate analgesia [substantially diminished response]; and 3, complete analgesia [no response; considered suitable for surgical procedures]). The first signs of analgesic effects (motor nerve blockade of the tail) were seen < 3 minutes after injection, but onset of complete analgesia in the anus and perineum occurred in all 5 cows at 7 to 10 minutes after administration of 2 or 3 mg of tramadol/kg. Complete analgesia of these regions was not induced in all cows following administration of 1 mg of tramadol/kg. The reported onset of most other epidurally administered drugs in cattle is similar to the mean onset determined for tramadol in the present study: 5 to 6.5 minutes for ketamine hydrochloride,6,16 10 to 20 minutes for detomidine,17 5 to 20 minutes for lidocaine,18 and 5 to 10 minutes for medetomidine.18 Other investigators8 determined that the onset of analgesia in horses after epidural administration of tramadol was more rapid than the onset of analgesia after epidural administration of morphine because of its higher tissue affinity (which would decrease transit time across the dura mater); however, tramadol was substantially less potent than morphine. Similarly, tramadol was found to be less potent than morphine when administered epidurally in humans.10
Results of the study reported here indicated that the extent and duration of analgesia in cows after tramadol administration were dose dependent, similar to the effects described for tramadol in horses.14 The duration of complete analgesia of the perineum was 18, 60, and 92 minutes following administration of doses of 1, 2, and 3 mg of tramadol/kg, respectively. A lesser degree of analgesia was observed thereafter, regardless of dose. The duration of analgesia provided by epidural administration of a dose of 2 or 3 mg/kg may be considered sufficient for most minor surgical procedures of the perineum. Other investigators7 reported that analgesia of the perineal region (anus, perineum, and vulva) induced by epidural administration of lidocaine (0.2 mg/kg) combined with xylazine (0.02 mg/kg) was detectable for up to 150 minutes in calves. Ketamine administered epidurally at a dose of 2 mg/kg induced analgesia for 45 to 60 minutes, whereas a dose of 3 mg/kg provided analgesia for 55 to 70 minutes in cattle.16 Results of the present study indicated that the duration of analgesia after tramadol administration was shorter than that reported after administration of the combination of lidocaine and xylazine but was similar to the duration of analgesia reported after ketamine administration in cattle.
It has been proposed that tramadol affects sensory and motor nerve conduction by a mechanism similar to that of lidocaine, which acts on voltage-dependent Na+ channels and results in axonal blockage.19 However, tramadol might establish conduction blocks by a mechanism different from that of lidocaine; increased Ca2+ concentrations in the external medium increased tramadol activity but decreased lidocaine activity in an in vitro study of sciatic nerve tissue bundles obtained from frogs.20 Several factors may influence both the degree of analgesia and the area affected by epidurally administered drugs. In particular, intrinsic anatomic factors (eg, size of the epidural space, abundance of epidural fat, fibrosis of epidural tissue, and differences in negative epidural pressure) may play an important role in determining epidural distribution and extent of anatomic effects of administered drugs. The induction of caudal analgesia also depends on the total mass (volume × concentration) of the anesthetic administered.6,21 The authors did not find a recommended volume range for epidurally administered analgesics in standing cattle, but the volumes of tramadol administered in this study appeared to be tolerated well.
In horses, the duration of analgesia induced by the use of epidurally administered opioids was increased in regions proximal to the injection site, compared with the duration in distal regions. The duration of effect of opioids given via this route may also be influenced by the number of molecules retained in the CSF and spinal tissues and by the dissociation kinetics of the administered drug.8
In the study reported here, slight sedation and moderate ataxia were evident following administration of the highest dose of tramadol (3 mg/kg); results of a similar study13 in horses indicated that lowering of the head was observed in the first hour after administration and persisted for 3 hours, but no change in behavioral response or locomotor activity was observed. The minor sedative effect of tramadol could be explained by the fact that although tramadol is an agonist for μ-opioid receptors, it also increases synaptic release of the neurotransmitter 5-hydroxytryptamine (also called serotonin) and inhibits serotonin reuptake presynaptically, which could be related to awareness and insufficient sedation. In the study13 of tramadol in horses, it was speculated that tramadol induced a shorter duration of sedation, compared with the m-opioid receptor agonist morphine and the pure m-opioid receptor agonist U50488H because it causes activation of monoaminergic pathways in the CNS, likely increasing concentrations of serotonin and resulting in awareness. Tramadol-induced inhibition of norepinephrine reuptake is similar to inhibition by α2-adrenoceptor agonists22; it may be speculated that ataxia following epidural administration of tramadol could result from the contribution of a similar mechanism (ie, the possibility that inhibition of norepinephrine reuptake causes a reduction of sympathetic outflow, leading to enhanced muscle relaxation). Ataxia is also an adverse effect of epidural administration of drugs such as ketamine,6 xylazine-lidocaine combination,7 and detomidine17 in cattle.
Epidural injection of tramadol at any dose had no significant effects on heart rate, respiratory rate, or rectal temperature in cattle in the present study; these findings were in agreement with the results of studies performed in humans,23 horses,13 donkeys,24 and dogs.12 In the cattle in the present study, ruminal motility also did not change significantly.
After IV or IM administration in camels, tramadol and its main metabolite O-desmethyltramadol were detected in enzymatically hydrolyzed urine samples for 24 and 48 hours, respectively. Tramadol also had a short half-life and fast clearance in that species.25 However, withdrawal information for tramadol in food-producing animals has not been established; thus, taking a cautious approach to meat and milk withdrawal times is advised when administering tramadol, regardless of the route of administration. Further studies are needed to determine other possible undesirable effects of epidural administration of tramadol in cattle.
