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© 2001 International Anesthesia Research Society
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Abstract |
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Sixty volunteers, divided into four groups of 15 each, received IV regional anesthesia of the upper limb with 40 mL tramadol 0.25%, sodium chloride 0.9%, lidocaine 0.5%, or 100 mg tramadol-containing lidocaine 0.5%. By using a double-blinded method, we tested the onset and recovery of sensory block at six sites of the forearm and hand as well as onset of complete motor block. The symptoms after deflation of the tourniquet were recorded. The onset and recovery of sensory block and the onset of motor block were similar in the tramadol and saline groups. However, in the Tramadol-Lidocaine Group, the speed of onset of sensory block was faster than in the Lidocaine Group. In the Tramadol and the Tramadol-Lidocaine Groups, the incidence of skin rash and painful or burning sensation at the injection site was increased. We conclude that tramadol 0.25% does not have a local anesthetic effect when used as a sole drug for IV regional anesthesia, but might modify the action of local anesthetic, providing a shorter onset time of sensory block.
Implications: Tramadol, a centrally acting analgesic, might have local anesthetic properties, as do some opioid drugs. We demonstrated that 0.25% tramadol solution containing 100 mg tramadol is not effective as a sole drug, but may improve the action of 0.5% lidocaine for intravenous regional anesthesia. The increased incidence of side effects may limit the clinical use of tramadol.
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Introduction |
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Because opioids such as meperidine and fentanyl have local anesthetic properties in vitro (1), several authors have investigated the addition of various opioids to local anesthetic solutions for IV regional anesthesia (IVRA). Although morphine (2) and fentanyl (3) proved to be of limited benefit, the addition of meperidine to lidocaine significantly improved the onset and duration of IVRA (4) and was also efficient when it was administered as a sole drug (5).
Tramadol is a weak opioid, selective for the mu receptors (6). Recent studies suggest that tramadol may have specific local anesthetic properties on peripheral nerves when used alone (7,8). A dose of 100 mg tramadol added to 40 mL 1% mepivacaine improved the quality of the brachial plexus blockade in patients scheduled for surgery of the forearm and hand (9).
On the basis of these results, we hypothesized that the same dose of 100 mg tramadol would be efficient for IVRA. The present study was designed to evaluate the quality, onset and duration of IVRA with tramadol, alone, or added to 0.5% lidocaine.
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Methods |
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Sixty ASA physical status I volunteers (medical students), aged 21–37 yrs, were the subjects in this study. The study protocol was approved by the Ethics Committee of the hospital, and all volunteers gave informed consent. None of them had experienced allergy to tramadol or local anesthetics. Each subject had IVRA on only one occasion. To compare 0.25% tramadol with control (isolated ischemia), 30 of the 60 volunteers were allocated to the first study group and received IVRA in a double-blinded fashion with 40 mL of either 0.9% saline (Group S, n = 15) or 0.25% tramadol (Group T, n = 15). The 0.25% tramadol solution consisted of 100 mg tramadol (Tramal®, Grunenthal, Stolberg, Germany) in 0.9% saline. To evaluate the adjuvant effect of tramadol added to a local anesthetic, the other 30 volunteers were allocated to the second study group and received IVRA in a double-blinded fashion with 40 mL of either 0.5% lidocaine (Group L, n = 15) or a mixture of 0.5% lidocaine and 0.25% tramadol (Group TL, n = 15). The lidocaine-tramadol solution consisted of 100 mg tramadol (100 mg Tramal®) in 0.5% lidocaine.
Before establishing the anesthetic block, two cannulae were inserted, one in a vein on the dorsum of the selected hand (the same site in all volunteers) and the other in the opposite hand, to assure an IV route in case of any incidents. The arm was exsanguinated by using an Esmarch bandage, and then a pneumatic tourniquet, placed around the upper arm, was inflated to 250 mm Hg (at least 100 mm Hg higher than the systolic blood pressure for all subjects). After the bandage was removed, the 40 mL of solution was injected over 60 s. The solutions were administered as mentioned above, in a double-blinded, randomized fashion by using an envelope system. At 90-s intervals after administration (considered as time zero), the sensory block was assessed by using a 22-gauge, short-beveled needle. The subject reported verbally the sensation as pinprick, touch, or absent. Cold sensation was assessed by using a cube of ice. Six areas supplied by the ulnar, radial, and median nerves (Figure 1) were tested in a random sequence with the subject unable to observe the testing. The performance of testing required approximately the same duration of time in all cases. At the same time the motor function was assessed by asking the subject to flex and extend his wrist and fingers and complete motor block was noted when no voluntary movement was possible. The tourniquet was deflated after a 22.5-min, necessary for 15 measurements, and the sensory assessment continued at similar time intervals until full recovery had occurred at all six sites. The subjects reported any systemic sensation experienced after cuff release.
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The respiratory rate and systemic blood pressure were recorded 5 min before time zero and at 5,10, and 15 min after cuff release. The rate of onset and the extent of loss of pinprick, touch and cold sensation were compared with each of the four groups by calculating the area under the curve (AUC). For each subject, separate graphs were drawn of the number of sites that had lost the sensation against the time for the period between injection and tourniquet deflation. The AUC was calculated from each graph (GraphPad Prism, version 2.01; GraphPad, San Diego, CA) to give a measure of the rate of onset and the extent of the block. Comparison between the groups was made with Student’s unpaired t-test. Recovery of sensation was also compared by calculating the AUC, the curves in this case being drawn for the period from tourniquet deflation to the moment when full recovery had occurred. To analyze the demographic data and the onset of complete motor block, Student’s t-tests was used. The comparative incidence of side effects was determined by the
2 test. A P value of <0.05 was considered statistically significant. |
Results |
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Study Group One: IVRA with Tramadol Only
There were no significant differences with regard to age, sex distribution, and weight of the patients between the 0.25% tramadol group (Group T) and the 0.9% saline group (Group S) (P > 0.05). The speed of onset and the overall degree of blockade to pinprick, touch, and cold were comparable between the two groups (P > 0.05, P < 0.1).
Within the 22.5-min period when the tourniquet was inflated, the pinprick sensation was lost at all six sites in two subjects from the Group S and in three subjects from the group T; there were subjects in both groups, 1 in Group S and 2 in Group T, in whom the pinprick sensation did not disappear within 22.5 min at any of the six sites tested. The touch sensation was lost at all six sites in two subjects from Group T and in none of the subjects of the Group S. All 15 subjects from the Group T and 11 subjects from group S lost cold sensation at all six sites within 22.5 min. The speed of total recovery of the sensory block (pinprick, touch, and cold) was also similar between the two groups (P > 0.05, P < 0.1). In both groups, the cold sensation decreased faster than the pinprick sensation whereas the touch sensation was most resistant to blockade. Recovery of sensation occurred in reverse order; touch returned first and cold last.
Within 22.5 min a complete motor block developed in 10 subjects from Group T (19.0 ± 1.7 min) and in 11 subjects from Group S (19.2 ± 1.4 min); no significant difference was recorded between groups (P > 0.05). The difference between groups remained nonsignificant when the subjects who did not develop a complete motor block were included. In these cases, an interval of 30 min was considered when a complete motor block would be installed as a result of ischemia.
Side effects were noted in both groups, with a significantly increased incidence in Group T. Ten patients in Group T versus one patient in Group S complained of painful or burning sensations at the injection site, and six patients in Group T versus none in Group S developed a skin rash below the tourniquet level (P < 0.001). There were no changes in the respiratory rate in either group after the tourniquet release, and the variations of blood pressure did not exceed 20% of basal values.
Study Group Two: IVRA with Tramadol Added to Lidocaine
There were no significant differences with regard to age, gender distribution, and weight of the patients between the 0.5% lidocaine-0.25% tramadol group (Group TL) and the 0.5% lidocaine group (Group L) (P > 0.05).
Within the 22.5-min period when the tourniquet was inflated, the pinprick, touch, and cold sensations were lost at all six sites in all subjects from both Groups L and TL (Figure 2, 3, 4). Comparison of AUC demonstrated statistically significant differences between the two groups for the onset of each type of sensory block (Table 1). The speed of onset and the overall degree of blockade to pinprick, touch and cold were more in the Group TL than in the Group L (P < 0.05, P < 0.001), suggesting a possible adjuvant effect of tramadol added to the local anesthetic. Comparison of AUC for the return of sensation (Table 2) demonstrated that the speed of total recovery of the sensory block was similar between the two groups when considering the pinprick and cold sensations (P > 0.05). With regard to the touch sensation, the speed of total recovery was faster in Group L than in Group TL (P < 0.05). In each group, the cold sensation decreased faster than the pinprick sensation whereas the touch sensation was most resistant to blockade. Recovery of sensation occurred in reverse order; touch returned first and cold last.
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= 200 mg lidocaine.
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All subjects from Groups L and TL developed a complete motor block within 22.5 min: at 14.5 ± 2.5 min in Group L and at 11.8 ± 3.9 min in group TL; no significant difference was recorded between groups (P > 0.05). In both groups, the subjects developed the motor block concomitantly with or after the sensory block and there were minor time differences between the onset of the motor block and the onset of the touch sensation block.
Side effects were noted in both groups with a significantly increased incidence of skin rash below the tourniquet level in Group TL (9 patients) when compared with Group L (0 patient) (P < 0.01). Five patients in Group TL versus one patient in Group L complained of painful or burning sensation at the injection site (P > 0.05). All complaints subsided spontaneously during a 1 h follow-up period. There were no changes in the respiratory rate in either group after the tourniquet release, and the variations of blood pressure did not exceed 20% of basal values.
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Discussion |
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Recent studies have shown a local anesthetic action of tramadol. Pang et al. (7) were able to induce a sensory block to pinprick, touch and cold at the intradermic injection site of 5% tramadol similar to that of 1% lidocaine. The suggested site of action of tramadol was the nerve endings and a possible associated central effect of tramadol was excluded because of the small doses used (25 mg). The same authors demonstrated that IV retention of 3 mL of 1.66% tramadol for 3 minutes significantly reduced the local pain associated with injection of propofol by the same route (8). As the study used a modified IVRA technique (venous occlusion by a tourniquet), a local action of tramadol on the endovenous sensory endings was suggested.
By using IVRA, the present study eliminates any central effect of tramadol that may interfere with its peripheral action. However, in our study 0.25% tramadol did not develop an anesthetic effect on the isolated arm. The onset and recovery of the sensory block was similar in Groups S and T, as was the onset of the complete motor block. The lack of local anesthetic effect can be explained by the small concentration of tramadol solution. The existing data suggest an effect on peripheral nerve endings when larger concentrations are used. The use of large concentrations of tramadol for IVRA, without exceeding the safe dose, is limited by the small volume of solution that could be injected. Use of 40 mL 1.66% solution for instance, results in the IV administration of 664 mg tramadol, a dose that is exceedingly large.
However, the 0.25% tramadol was effective for prolongation of axillary brachial plexus blockade when 100 mg tramadol was mixed with 40 mL 1% mepivacaine (9). The duration of both sensory block to pinprick and motor block was significantly longer when tramadol was added to mepivacaine.
In our study, the addition of 100 mg tramadol to 0.5% lidocaine for IVRA was also effective. The speed of onset of sensory block was faster in Group TL than in Group L and the recovery of touch sensation was prolonged in the TL group. The lack of effect on motor block could be explained by the small concentration of tramadol solution.
A study regarding the site of action of IVRA using lidocaine showed that in small concentrations, lidocaine acts on the sensory nerve endings and small nerves, whereas a larger concentration of lidocaine was needed for the nerve trunks (10). Accordingly, 0.25% tramadol solution could be inadequate to modify the blockage of the motor fibers responsible for flexion and extension of the wrist and fingers. However, Kapral et al. (9) obtained a prolongation of the motor blockade of the brachial plexus with the same concentration of tramadol added to mepivacaine.
It is difficult to reconcile the contradictory results obtained with 0.25% tramadol in IVRA and in brachial plexus block. The differences could reflect failure of tramadol to reach an effective concentration in the nerve trunks during IVRA. The discrepancy could be explained by the different mechanisms of blockade of the brachial plexus and of the peripheral nerves during IVRA. While at the brachial plexus, the whole anesthetic solution penetrates the large mixed nerves; in IVRA, the initial effect is a direct block of nerve endings near the injection site, followed later by a profound block of main nerve trunks (11). The nonuniform anatomy of the peripheral nervous system also provides a basis for differential sensory and motor blockade. Different types of fibers have a varying susceptibility to blockade in vivo.
Although contradictory, the findings of both studies suggest that 0.25% tramadol may improve the local anesthetic blockade of peripheral nerves.
The present study confirms the time course of differential sensory blockade during IVRA with cold sensation decreasing faster than the pinprick and the touch sensation being the most resistant to blockade.
The addition of tramadol to lidocaine intensified the differential effect, mainly for touch sensation. In comparison with the effect on pinprick and cold sensation, addition of tramadol produced a more pronounced increase in the speed of onset of touch blockade and only the touch blockade was prolonged during recovery.
This is the first study to document that the addition of an opioid (tramadol) to a local anesthetic (lidocaine) may influence the extent of differential blockade during IVRA. The difference in the speed of onset appears mainly for touch sensation, which is also the only sensation significantly prolonged during recovery. That represents an interesting fact, as this test is correlated with the deepest stage of anesthesia.
The precise mechanism by which tramadol exerts its anesthetic effect is unknown. Tramadol is structurally related to codeine (12), and is selective for the mu-receptors (6). However, a possible interaction of tramadol with the peripheral opioid receptors is less probable, as this cannot explain the modified motor blockade of the brachial plexus after addition of tramadol to mepivacaine (9). Moreover, an action on peripheral opioid receptors was not observed in our first study group, in which there were no differences between the sensory blocks induced by tramadol and isolated ischemia. The lack of effect after the addition of fentanyl to local anesthetic for IVRA (13) represents another argument for the absence of peripheral opioid-mediated mechanism in such circumstances.
Besides its opioid action, tramadol is also acting on the monoaminergic system. Unlike the traditional morphine-like analgesics, tramadol has a dual mechanism of action, also blocking the reuptake of the norepinephrine and 5-hydroxy-tryptamine at the 
2 adrenergic receptors level (14). The pretreatment with -adrenoreceptor antagonists yohimbine and idazoxan resulted in a significant reduction of tramadol’s antinociceptive effect (15,16). The result is that tramadol has a profile of action similar to that of clonidine, which inhibits the release of norepinephrine from prejunctional 2 adrenoceptors in the periphery (17). Therefore, we can hypothesize that added to local anesthetics for peripheral nerve block, tramadol may act in a similar way as clonidine.
Clonidine has depressant properties on the C-fiber action potential and produces tonic and phasic inhibition of nerve conduction in vitro (18). As an adjunct, clonidine showed an enhancing effect on lidocaine-induced inhibition of C-fiber action potential (19). Added to mepivacaine for brachial plexus blockade, clonidine prolonged the duration of sensory and motor block whereas onset characteristics were not influenced (20). Similar results were obtained by Kapral et al. (9) by using 0.25% tramadol in mepivacaine solution for brachial plexus blockade.
Addition of clonidine to local anesthetics for IVRA produced contradictory results. Kleinschmidt et al. (21) did not find any significant improvement in block characteristics or postoperative analgesia, whereas Reuben et al. (22) demonstrated improved postoperative analgesia. In our study, by addition of 100 mg tramadol to lidocaine for IVRA, only the onset of sensory block was increased.
A major disadvantage for the use of tramadol as a local anesthetic is the increased frequency of side effects. Fifteen patients from both the T and TL groups exhibited a skin rash distal to the tourniquet, suggesting histamine release. Although one of the proposed sites of action of tramadol is the nerve endings along the veins (8), the incidence of pain/burning at the injection site was significantly greater in Group T versus Group S. The incidence of painful or burning sensation was nonsignificant when an admixture of tramadol and lidocaine was injected (five patients in Group TL versus one patient in Group L). An increased incidence of pain/burning at the injection site was also noted when meperidine was compared with lidocaine for IVRA (5). Both tramadol and meperidine have a local irritating effect, which overrides the anesthetic effect on the endovenous sensory endings.
In conclusion, tramadol 0.25% does not have a local anesthetic effect when used as a sole drug for IVRA. A local anesthetic effect using a larger concentration cannot be excluded, but possible secondary effects of toxic doses may limit its use in clinical practice. However, the present study suggests that tramadol may modify the action of a local anesthetic, providing a shorter onset time of sensory block in IVRA.
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References |
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