Jou, I-Ming MD*; Chu, Koung-Shing MD†; Chen, Hsing-Hong MD‡; Chang, Pei-Jung MD†; Tsai, Yu-Chuan MD†
Tramadol, a centrally acting analgesic drug, is used mainly for treatment of moderate-to-severe pain (1). Tramadol is not a single-mechanism analgesic. In addition to a μ-opioid agonist effect, it exerts a modulatory effect on central monoaminergic pathways, inhibiting neuronal uptake of noradrenaline and serotonin (2–4). In a previous in vivo study using direct application of tramadol to the sciatic nerve, we proved that tramadol inhibits spinal somatosensory-evoked potentials (SSEPs) in rats, which indicates that tramadol exerts a local anesthetic-type effect on peripheral nerves (5). When administered epidurally, tramadol provides adequate and prolonged postoperative analgesia without serious side effects (6,7). The analgesic effects of epidural tramadol have been explained by receptor-mediated actions. However, it has been recognized that the spinal cord displays a high degree of organizational complexity in regulating a variety of processes including sensory, motor, and autonomic functions. Many functions of transmitter, receptor, channel, and intracellular messenger systems in nociceptive transmission can be demonstrated and manipulated at the spinal level. The mechanisms by which epidural and intrathecal tramadol produce analgesia or anesthesia in the central nervous system remain unclear. Direct effects of tramadol on spinal cord function have not been examined. We evaluated the effects of tramadol on sensory and motor neural conduction when administered intrathecally by observing spinal SSEPs and evoked compound muscle action potentials (CMAPs).
This study was approved by the Research Committee of National Cheng Kung University Hospital. All animals were treated in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Male Sprague-Dawley rats weighing 400–500 g were obtained from the Animal Center of the National Cheng Kung University (Tainan, Taiwan). Animals were housed at 21° ± 0.5°C in cages, with free access to food and water. The vivarium was maintained on a 12-h light/12-h dark cycle, with lights on at 07:00.
Each rat was implanted with a subarachnoid PE-10 catheter under intraperitoneal pentobarbital anesthesia. The technique was performed according to the method described previously by Yaksh and Rudy (8). A sterile incision was made along the occipital ridge, and the nuchal muscles were reflected. The atlanto-occipital membrane was identified. The catheter was inserted into the subarachnoid space through a midline incision and gently threaded caudally for 8.5 cm so as to position the tip at the L45 segment of the spinal cord. The proximal end of the catheter was then fixed percutaneously to the top of the head. The function and location of the catheter were verified by using an intrathecal injection of 10 μL of 2% lidocaine. Only animals with functioning catheters were used for this experiment. The rats were housed individually after surgery and allowed 7 days to recover before further study. Animals with any neurologic deficits (observing the walking tract) were excluded from the study.
Twenty rats were randomly allocated to three groups with four rats in the control and eight rats in each of the other two groups. Tramadol hydrochloride (not released for intrathecal use; Grünenthal GmbH, Stolberg, Germany) at 0, 1, or 2 mg, and diluted if needed with saline to a total volume of 40 μL, was administered through the intrathecal catheter. Then, a 10-μL saline flush was given via the chronic indwelling catheter. The dosage used was determined by preliminary studies, which showed that paw withdrawal latency to radiant heat increased to 170%–200% of predrug values when tramadol 2 mg was used. Evoked potentials were measured before (pretreatment baseline) and at 5, 15, and 30 min after treatment, and at 30- or 60-min intervals thereafter for another 4.5 h. Amplitudes of the major peaks in these recordings were expressed as a percentage of the pretreatment baseline. To detect the specific effects of the opioid receptor on spinal cord neural conduction, 5 separate rats were treated with 20 μg of naloxone intrathecally 20 min after intrathecal injection of 1 mg of tramadol, followed by the same neurophysiologic measurement procedure.
For neurophysiologic measurement, rats were anesthetized with intraperitoneal sodium pentobarbital (50 mg/kg). The SSEP response was recorded as previously described (5,9,10). Rats were included only when the following conditions were fulfilled: the SSEP and CMAP before intrathecal administration of tramadol (baseline) showed no significant difference between right and left extremities, and both the latency and amplitude values were in acceptable range when compared with those in our previous studies (5,10). Anesthetic depth was determined by noting the withdrawal reflex upon pinching the tail and supplemented with intraperitoneal doses of pentobarbital (usually 10 mg/kg per dose) as necessary. The right femoral artery was cannulated for monitoring heart rate and mean arterial blood pressure. Mean arterial blood pressure was maintained within 100–120 mm Hg by IV infusion of metaraminol as needed. Rectal temperature was maintained at approximately 37°C with a warm water mattress and a heating lamp. Radiographs were taken before setup of the electrophysiologic monitoring system with a metal marker to confirm the level for the recording of SSEP and CMAP. The rat was then placed in the prone position with the hips extended. A midline posterior longitudinal incision was made from the mid-thoracic to the mid-lumbar spine, the paravertebral muscles were retracted, and the thoracolumbar interspinous ligament was identified.
Two electrophysiologic surveillance systems for SSEP and CMAP were used. SSEPs were recorded by bipolar needle electrodes, with the cathode placed in the thoracolumbar interspinous ligament and the anode 3 mm proximal to it. Stimulation was delivered by the electrodes placed under the left sciatic nerve just proximal to the bifurcation of the peroneal branch, with the cathode 3 mm proximal to the anode on a 1.5-cm segment of the sciatic nerve. Access to the sciatic nerve was obtained by a dorsal approach and intermuscular incision of the plane between the biceps femoris and the vastus lateralis muscles in the left thigh. The stimulation was presented as a supramaximal intensity squared pulse at 5 impulses/s with a total of 20 repetitions that were 0.2 ms in duration. The recording was filtered for data within a range of 10–5000 Hz, and the recording time was 2 ms.
CMAPs were recorded from monopolar myographic needle electrodes placed in the belly of the left intrinsic muscles of the foot by the stimulation of the spinal cord at T12-13 using needle electrodes in the interspinous ligament. The acquisition variables were similar to those of the SSEPs, but the presentation rate of stimulation decreased to 1/s and the low and high linear values of the filter were between 1 and 2000 Hz. A ground electrode was placed subcutaneously between the stimulus and the recording site. At least three sequential runs of a single sweep were recorded with similar waveforms to check the consistency of the responses.
The electrophysiologic data were collected, stored, and analyzed on a Neuropack Z electrodiagnostic device (Nihon Koden, Tokyo, Japan). The amplitude and latency of the major peaks in these recording were expressed as a percentage of the values before intrathecal infusion (baseline). Data were presented as mean ± sem. A P value < 0.05 was considered statistically significant. Statistical analysis of the data on amplitudes and latencies of both SSEPs and CMAPs at every time point after drug injection was performed by using the Kruskal-Wallis test or one-way analysis of variance. Differences between the baseline and posttreatment physiologic values were compared by using the paired Student’s t-test.
Two rats (1 in the 1-mg and 1 in the 2-mg tramadol group) were excluded from the study because they died before completion of the electrophysiologic study. Hemodynamic responses to intrathecal injections of tramadol were stable during the experiment, and differences among the groups were insignificant.
The SSEPs recorded from thoracolumbar interspinous electrodes showed a consistent, reproducible, high negative peak wave preceded by a small positive wave. The CMAP composed of two- or three-phasic waves of very large amplitude was consistent and reproducible as well, despite the fact that there were variations in morphology and polarity in different animals. The baseline amplitude varied between 86–250 (160 ± 31) μV and 596–4519 (3297 ± 1209) μV for SSEPs and CMAPs, respectively. The values for latency were 1.22–1.90 (1.62 ± 0.13) ms and 3.12–5.50 (4.21 ± 0.28) ms for SSEPs and CMAPs, respectively (Fig. 1).
All animals demonstrated a significant deterioration of evoked potentials, with a more evident reduction of amplitude and a less evident elongation of latency. These changes occurred immediately after intrathecal tramadol injection. The amplitude decreased and latency was significantly delayed in a dose-dependent manner in all animals. However, reversal of the potentials was initiated approximately 30 min after drug injection. Compared with the preinjection amplitude, the relative percentages revealed significant differences between experimental and control groups for every time point within 2 h after treatment (Figs. 2 and 3).
There were no significant differences in SSEP and CMAP between the 1-mg tramadol group and the group treated with tramadol 1 mg combined with naloxone 20 μg.
The results of this study demonstrate that intrathecal tramadol produces dose-dependent inhibition of both spinal SSEPs and CMAPs, which nearly returned to baseline in the 1-mg group and approximately 80% of the pretreatment value in the 2-mg group by 120 minutes. Our results indicate that intrathecal tramadol exerts dose-related suppressive effects on both somatosensory and motor neural conduction in the spinal cord.
Direct application of opioids to the spinal cord induces pronounced limitations in spinal function, which was demonstrated by the inhibition of spinal reflexes and dorsal horn nociceptors (11,12). The effects of intrathecal opioids on SSEPs, the H-reflex, and the spinal motor reflex in humans and on dorsal root axons have been studied (13–16). It has been shown that the intrathecal administration of μ-opioid agonists such as morphine, sufentanil, or fentanyl do not induce significant depressing effects on SSEPs, the H-reflex, or the spinal motor reflex. These results suggest that opioid-activated spinal pathways do not interfere with transmission of afferent impulses resulting from electrical stimulation peripherally. However, the central nervous conduction blockade effects of meperidine have been demonstrated in both in vitro and in vivo studies (13,14). Conflicting results for the effects of opioids on central neural blockade may depend on the drugs themselves, the dosage, or methodology used.
Several clinical studies have shown that tramadol may have peripheral local anesthetic-type properties (17). Using direct tramadol application to sciatic nerves in rats, we have proven that tramadol exerts a local anesthetic-type effect (5). However, no study has described its central effects on neural conduction. In the present study, the reversible depressant effects of intrathecal tramadol on SSEPs and CMAPs indicate that nerve conduction is temporarily attenuated, which may mean that synaptic or axonal conduction may be impaired. This is similar to the effect produced by local anesthetics (13). Moreover, suppression of spinal SSEPs by intrathecal tramadol was not reversed by naloxone, suggesting that these effects are not related to the presence of opiate receptors in dorsal root axons or the dorsal horn (18) and are more likely mediated by a non-opioid receptor-dependent mechanism. We suggest that tramadol affects sensory and motor nerve conduction by a similar mechanism to that of lidocaine, which acts on voltage-dependent Na+ channels leading to axonal blockade (19), but that was not assessed in this study.
After intrathecal administration, tramadol acts locally on spinal opioid receptors, binds to supraspinal opioid receptors, and diffuses into the cerebral spinal fluid and rostrally to the brain. An action at supraspinal sites should be considered. Tramadol may have entered the brain over time, which may also have contributed to suppressive effects via inhibitory descending pathways. However, spinal SSEPs were obtained at the thoracolumbar interspinous ligament in the present study; we did not assess cortical or subcortical SSEP, which may have elucidated this point.
In a study by Carlsson and Jurna (20), the effects of tramadol on motor and sensory responses of the spinal nociceptive system were tested in the rat. They found differences between tramadol and morphine in their activities on ascending axons. Tramadol at 100 and 200 μg injected intrathecally depressed both the spontaneous activity in ascending axons and their activities because of stimulation of C fibers and activation from Aδ fibers in the sural nerve. Although activation from Aδ fibers is not affected by intrathecal morphine, intrathecal tramadol caused a marked reduction of activation from Aδ fibers of ascending axons, which was resistant to even a large dose of naloxone. A local anesthetic action of tramadol might have a role. Although those authors suggested that tramadol could act on impulse transmissions from nociceptive afferents by a mechanism not involving opiate receptors, the likelihood of a local anesthetic action of tramadol was excluded by the observation that 200 μg of intrathecal tramadol did not reduce the activity in axons activated by stimulation of Aβ fibers in the sural nerve. This may have resulted because an insufficient amount of intrathecal tramadol could not depress the activity of Aβ fibers, or because of the lower sensitivity of the methodology they used. In our study, relatively larger doses of 1 and 2 mg of tramadol were used to detect central neural conduction effects. This might indicate that intrathecal tramadol exerts a weak local anesthetic-type effect, which would be evident only at larger dosage.
Results of a study by Schubert et al. (15) indicate that cortical SSEPs by posterior tibial nerve stimulation remain unaffected despite the administration of a relatively large dose of intrathecal morphine sulfate (15 μg/kg). This implies that opioid-related neural effects at the spinal cord level do not affect neural transmission of afferent impulses resulting from electrical stimulation of a somatic nerve. Furthermore, morphine selectively suppresses spontaneous firing in neurons responding to noxious stimuli whereas leaving neurons that respond to proprioceptive input relatively unaffected (21). Although intrathecal fentanyl and tramadol suppress nociceptive spinal reflexes (12,20), electrically stimulated cutaneous-evoked potentials are carried by Aβ fibers, which do not carry major nociceptive inputs (22).
Tramadol produces analgesia through both opiate and adrenergic mechanisms; analgesia would be expected to be produced with intrathecal administration. Although intrathecal tramadol has been shown to produce analgesia in a tail flick model in rats (23), another study, using a noxious thermal stimulus to the rat hindpaw, showed little differences in the analgesic effect between systemic and intrathecal administration (24). No data are available on the clinical use of intrathecal tramadol. The toxicity of intrathecal tramadol should be further evaluated, despite there being no adverse side effects reported with epidural tramadol (6,7).
In conclusion, intrathecal tramadol caused dose-related effects on both sensory and motor neural blockades, which indicates that tramadol exerts dose-related central neural blockade effects.
The authors thank Miss Ya-Ting Tsai and Mr. Yao-Hung Hsieh for their excellent technical assistance.
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