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Anesth Analg 2003;96:776-782 © 2003 International Anesthesia Research Society
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Abstract |
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Alpha-2-adrenergic agonists, such as clonidine, produce antinociception in animal pain models after intrathecal administration. However, clinical usage is limited by cardiovascular side effects. To investigate alternative
2-adrenergic agonists as analgesics, we implanted six dogs with an intrathecal catheter and infusion pump. After baseline saline infusion, animals received clonidine or tizanidine (crossover study) each week at escalating doses of 125–750 µg/h. Analgesia, blood pressure, heart rate, respiratory rate, sedation, and coordination were evaluated. A 28-day safety study was performed with another nine dogs receiving intrathecal tizanidine (3 or 6 mg/d) or saline. Equal doses of clonidine and tizanidine produce the same antinociception in thermal withdrawal tests. Blood pressure was reduced with 125–500 µg/h of clonidine, but not with tizanidine at any dose. Clonidine 250 µg/h reduced heart rate by 45.8%, and five of six animals had bradyarrhythmias (marked bradycardia), whereas tizanidine decreased heart rate by 15.1% without arrhythmias, even at the largest dose. Respiratory rate decreased with 250 µg/h of clonidine and larger doses. Sedation or incoordination occurred only at the largest dose for either drug. The safety study indicated that 3 mg/d of tizanidine in dogs produced no side effects or histopathologic changes. Tizanidine may be a useful alternative in patients experiencing cardiovascular side effects with intrathecal infusion of clonidine. IMPLICATIONS: Clonidine is an effective spinal analgesic, but it is dose-limited by cardiovascular side effects. We compared the analgesic properties and side effects of clonidine with those of a similar drug, tizanidine. Continuous spinal infusion of tizanidine produced similar analgesia as clonidine, but with fewer adverse effects on blood pressure and heart rate.
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Introduction |
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An alternative to morphine for intrathecal infusion for pain control is needed because some types of chronic pain do not respond initially to opioids, tolerance to opioids can develop over time, and side effects occur. Alpha-2-adrenergic agonists are another option for chronic intrathecal drug infusion, both alone and in combination with other drugs (1). There is some clinical experience with continuous spinal delivery of clonidine for the treatment of pain (2–4). Unfortunately, when clonidine is used as a single drug, there are dose-limiting side effects, such as hypotension and bradycardia, that have restricted the use of clonidine to admixtures, such as with opioids (2,5,6).
Tizanidine, another 2-adrenergic agonist, produces antinociception in animal pain models by the intrathecal (7–9), epidural (10), and systemic (10–12) routes of administration. When it is given intrathecally, the analgesic potency of tizanidine seems to be similar to that of clonidine (7,8). However, after intrathecal administration in dogs, clonidine produced bradycardia at smaller doses than tizanidine (8). All of these previous animal studies involved bolus drug administration despite the greater relevance of continuous drug administration for the treatment of chronic pain.
Because tizanidine has not been given intrathecally in patients, little is known about side effects and potential toxicity after spinal administration. In a study in sheep, tizanidine was infused intrathecally over months at 4 mg/d without affecting behavior, coordination, or heart rate and without histological abnormalities at the spinal cord (13). Still, additional long-term safety data would be valuable before any clinical trials are considered.
In this cross-over study, we examined the dose response of clonidine and tizanidine on analgesia, blood pressure, heart rate, respiratory rate, sedation, and motor coordination in six dogs receiving continuous intrathecal infusion. In addition, in another group of nine animals, we assessed the safety of long-term intrathecal tizanidine administration.
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Methods |
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After Institutional Animal Care and Use Committee approval, experiments were performed on 15 mongrel dogs (20–32 kg) of either sex. Each animal was anesthetized with sodium thiopental 20 mg/kg IV and intubated. Anesthesia was maintained with 1.2% isoflurane and oxygen, and the animal was mechanically ventilated. A 10-cm midline incision was made over the L6 vertebra, and muscle was retracted to expose the spinal processes. The L6 spinal process was removed, and a 5-mm-diameter hole was drilled in the L6 vertebra. A small slit was made in the dura-arachnoid membrane, and a silicone rubber catheter (1.2-mm outer diameter) was inserted and advanced 6 cm cranially (8,14); the tip was placed at the L4 spinal segment. A purse-string suture was used to close the dura around the catheter. A subcutaneous pocket was opened on the right dorsolateral back, between the 13th rib and the iliac crest. The catheter was attached to a programmable Medtronic SynchroMed pump (Medtronic, Minneapolis, MN). The pump, with a Dacron mesh jacket, was inserted into the pocket, and the jacket was sutured to the underlying muscle and fascia. The muscle layers around the spinal column were sutured back together, and all skin incisions were closed. Animals received 0.15 mg of buprenorphine IM immediately after surgery and on the morning of the next day for postsurgical pain.
Clonidine/Tizanidine Crossover Study
In addition to the intrathecal catheter and pump implant, the six dogs in this study were also implanted with a chronic catheter and port to measure blood pressure (and heart rate). With the animal in the supine position, a 10-cm incision was made in the lower abdomen, and the tissue surrounding the tail arteries (just below iliac artery) was dissected away. One of the arteries was cannulated with a silicone rubber catheter (2.0-mm outer diameter) that was connected to a subcutaneous injection port.
Initially, all dogs received intrathecal saline at 20 µL/h for 1 wk. Three dogs then began receiving intrathecal clonidine (125 µg/h), whereas the other three received intrathecal tizanidine (125 µg/h). Clonidine HCl (Sigma Chemicals, St. Louis, MO) and tizanidine HCl (Novartis Pharmaceuticals, Whitby, Ontario, Canada) were dissolved in a 0.9% sodium chloride injection. All drug doses are expressed as salts. Doses were escalated weekly, up to 750 µg/h. After a 1-wk washout period with intrathecal saline infused at 20 µL/h (to control for carryover effects), each animal was crossed over to the other drug at 125 µg/h, with another series of dose escalations. At the end of the final drug infusion, each dog received an intrathecal saline infusion for 1 wk. The following variables were measured at saline baseline and at 2, 4, and 7 days after each test drug dose change: analgesia, blood pressure, heart rate, respiratory rate, sedation, and motor coordination.
Analgesia was evaluated with two different tests. In one test, withdrawal latency was recorded when the dog plantar hindpaw was placed on a slit above a high-intensity bulb (8). A 6-s cutoff time was used to avoid tissue damage. Overall latency was calculated as the average of four trials, two from each side. In the other test, a 60°C probe was applied to the shaved skin on the lower dorsolateral back, and latency to produce a contraction of the underlying muscles was recorded (15). The cutoff time was 10 s. The overall latency was the mean of two different locations. Latencies were converted (16) to the maximum possible effect of the heat withdrawal test (%MPE): equation
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Blood pressure was monitored by inserting a needle connected to a polyvinyl catheter into the subcutaneous arterial port. A calibrated pressure transducer was connected to a chart recorder to continuously monitor blood pressure and the derived heart rate.
Sedation was evaluated on a scale of 0–5, with 0 = normal alertness and 5 = nonarousable (8,15). Respiratory rate was measured by observing chest movement with the animal at rest. Motor coordination was assessed by the ability of the dog to walk forward and backward on its hindlimbs while the forepaws were elevated.
Sample size analysis determined that six animals were required to detect a large difference (large effect size: d = difference in means/SD = 1.0; effective d = d x 1.414 = 1.4) for a paired-samples two-tailed Student’s t-test, with = 0.05 and power = 0.6 (16). The large effect size assumption was based on our previous bolus study (8) in which all animals showed analgesia with intrathecal clonidine or tizanidine, and all animals receiving intrathecal clonidine had decreased heart rates at all doses (the difference in mean heart rate between clonidine, at any dose, and saline was greater than the SD). Data for analgesia (%MPE), blood pressure, heart rate, and respiratory rate were compared by using repeated-measures analysis of variance. Posthoc testing (P < 0.05) was performed with the Bonferroni-corrected paired-samples Student’s t-test. Sedation scores were compared by using Friedman’s test. Motor coordination and arrhythmias were analyzed with Fisher’s exact test.
Tizanidine Toxicity Study
Nine dogs were assigned to three intrathecal testing groups: tizanidine 6 mg/d, tizanidine 3 mg/d, and saline (n = 3 per group). Before that, all animals had received saline at 40 µL/h for 7 days. Pumps were refilled at 14 days, and the study ended at 28 days. The following variables were measured in the morning at saline baseline (the seventh day of saline infusion) and twice each week (at 3- to 4-day intervals): sedation, motor coordination, body weight, rectal body temperature, heart rate, and respiratory rate. Sedation, motor coordination, and respiratory rate were evaluated as in the crossover study. Heart rate was determined by palpation with the dog at rest.
After 28 days of drug infusion, each animal was anesthetized as in the implant surgery, and the spinal muscle was retracted to expose the L2 and L3 vertebrae. A small slit was made in the dura arachnoid membrane, and a fresh, short silicone rubber catheter was inserted 3 cm cranially. Cerebrospinal fluid (CSF) was aspirated (0.4 mL) and frozen for later high-performance liquid chromatography assay of drug level, to verify drug delivery to the spinal cord. Because of CSF leakage at this time, accurate pharmacokinetic assessment of tizanidine lumbar clearance was not possible. The animal was then perfused transcardially with phosphate-buffered saline followed by 10% buffered formalin. A 25-cm length of lumbar thoracic spinal column was removed and stored in formalin. The pump reservoir was emptied to allow high-performance liquid chromatography analysis of the reservoir tizanidine concentration. After storage in formalin, the spinal cord and roots were removed from the vertebral column with the intrathecal catheter in situ. The spinal cord and roots were cut transversely into blocks, embedded in paraffin, cut into 5-µm sections, and stained with hematoxylin and eosin and Luxol fast blue/cresyl violet. Slides were analyzed by a neuropathologist who was blinded to the animal groups.
Sample size analysis determined that three animals per group were required to detect a very large difference (large effect size: f = 0.85) for the F test with three groups: = 0.05 and power = 0.5 (16). The effect-size assumption was based on our previous bolus study in which all animals receiving intrathecal clonidine had decreased heart rates (8). If lesser changes occurred with tizanidine, then they could not be distinguished with this sample size. Data for heart rate, respiratory rate, body weight, and body temperature were compared by using analysis of variance for repeated mea-sures of dose and time period. Post hoc testing was performed (P < 0.05) with the Tukey B method. Sedation scores were compared by using Friedman’s test. Motor coordination was analyzed with Fisher’s exact test.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clonidine/Tizanidine Crossover Study
The increase in withdrawal latency (plantar foot or back skin thermal stimuli) with dose was not different for the two drugs (Fig. 1). At 500 µg/h, the %MPE was 41.3% for clonidine and 44.7% for tizanidine in the foot-withdrawal test and was 51.4% and 51.1%, respectively, in the back skin-twitch test. The baseline latencies (after 7 days of saline infusion) were no different at the start of the clonidine dose-escalation phase versus the tizanidine phase (foot, 2.33 ± 0.12 s [mean ± SEM] versus 2.30 ± 0.14 s; back, 1.10 ± 0.15 s versus 1.22 ± 0.16 s).
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The baseline blood pressure (after 7 days of saline infusion) at the start of the clonidine dose-escalation phase was 113.8 ± 3.8 mm Hg versus 110.3 ± 3.2 mm Hg at the start of the tizanidine phase (no difference). Blood pressure was decreased from baseline at doses of 125–500 µg/h of clonidine, but not tizanidine (Fig. 2). At 125 µg/h of clonidine, blood pressure decreased 21.2% from the saline infusion baseline versus 2.4% with tizanidine at the same dose. There was no overshoot hypertension on switching from either drug at the largest dose back to saline infusion (measured 2 days after the drug change); i.e., postdrug saline infusion blood pressure was not different from predrug saline infusion blood pressure.
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Heart rate differed between the clonidine and tizanidine phases of the study (Fig. 3). The baseline heart rate (after 7 days of saline infusion) at the start of the clonidine dose-escalation phase was 127.7 ± 2.3 bpm versus 132.2 ± 7.1 bpm at the start of the tizanidine phase (no difference). At doses of 250–750 µg/h, the decrease in heart rate was larger for clonidine than tizanidine. The heart rate was decreased at all doses (125–750 µg/h) of clonidine as compared with baseline. At 250 µg/h of clonidine, heart rate was decreased 45.8%, and five of six animals had bradyarrhythmias. When arrhythmias appeared, they persisted for the entire 7 days at that clonidine dose. With tizanidine, heart rate decreased at 250 µg/h (-15.1%) and larger doses, but there were no arrhythmias even at the largest dose. On switching from the largest dose of clonidine to saline, there was an overshoot tachycardia (heart rate on returning to saline was 44.0 ± 8.6 bpm above the starting saline baseline). This did not occur for tizanidine.
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from clonidine at the same dose.Respiratory rate decreased at 250 µg/h or larger with clonidine, but not tizanidine (Fig. 4). The baseline respiratory rate (after 7 days of saline infusion) at the start of the clonidine dose-escalation phase was 34.8 ± 2.3 breaths/min versus 33.8 ± 2.9 breaths/min at the start of the tizanidine phase (no difference). At 500 µg/h or less, there was no sedation with either drug. At 750 µg/h, three of six animals had sedation scores of 1 (quiet repose, eyes closed, but readily alerted and retaining head tone continuously) with clonidine, and none was sedated with tizanidine. There was no motor incoordination at 250 µg/h with either drug. At 500 µg/h, one of six animals showed motor side effects, and at 750 µg/h, three of six animals had incoordination with either drug. For each infusion dose period, with either clonidine or tizanidine, there was no difference in the data obtained on Day 4 versus Day 7 for withdrawal latency, blood pressure, heart rate, or respiratory rate.
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Tizanidine Toxicity Study
There was no sedation or motor incoordination in any of the animals at any time during the toxicity study. There was no difference in body weight over time with any of the groups or between groups. The body weight varied <1 kg after 28 days in all three groups (Table 1). Body temperature did not differ over time or between groups. The body temperature range varied <0.5°F after 28 days in all three groups. Respiratory rate did not differ over time in any group, nor was there a difference between groups. Change in respiratory rate was <2 breaths/min after 28 days in all three groups. Heart rate did not change over time or between groups. However, there was a large variability (SD) of heart rate within each group on some days.
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The spinal cord gray and white matter was within normal limits histologically in all nine animals. No necrosis or demyelination was observed, even though the catheters caused a slight deformation of the spinal cord along their track. At spinal levels nearest the catheter tip, the spinal roots and rootlets were normal. There was an occasional damaged root at the catheter dural insertion point, but this occurred equally in all three groups. All animals evidenced some chronic inflammatory activity in the subarachnoid space, with a fibrous capsule around the catheter itself. There was no difference in the degree of inflammation (mild) between the tizanidine 3 mg/d group and the saline group. In the 6 mg/d tizanidine group, two animals had mild inflammation, but a third animal had more lymphocytes and plasma cells in the subarachnoid space.
All of the dogs receiving the tizanidine infusion had measurable levels of the drug (>0.3 µg/mL) in the CSF at Day 28. The concentration of tizanidine in the pump reservoir at Day 28 was >97% of the original drug concentration prepared at the start of the study for all dogs receiving drug.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clonidine/Tizanidine Crossover Study
There appears to be no difference in the antinociception produced by equal continuous intrathecal doses of clonidine or tizanidine. This is similar to the results observed in a previous study in dogs with bolus intrathecal drug administration (8). Although an escalating-dose protocol is not the optimal method for evaluating drug tolerance, there is no obvious plateau in the Figure 1 dose-response curves that would suggest tolerance in analgesic efficacy for either compound with continuous intrathecal infusion over weeks. The most dramatic difference between the two drugs was with heart rate. Clonidine at 250 µg/h slowed the heart rate by almost half, whereas at the same dose of tizanidine, heart rate was reduced slightly. In addition, five of six animals had bradyarrhythmias at this and all larger clonidine doses. Overshoot tachycardia was pronounced when the animals were switched from the largest dose of clonidine back to saline. Clonidine also produced hypotension over the dose range of 125–500 µg/h. Respiratory rate decreased with clonidine at 250 µg/h or larger. The basic assumption of the crossover study—that the washout phase between the drugs is long enough to prevent carryover effects—was confirmed by the lack of difference in the saline baseline values of all of the variables before the start of either the clonidine or the tizanidine dose-escalation phase. There was no sedation for either drug at doses up to 500 µg/h, and motor incoordination occurred only occasionally (one of six animals) for either drug at this dose.
Delivery system patency was verified by two methods. The decrease in the pump reservoir volume was measured at each refill and at the end of the study, and in all instances these values matched the amount programmed for delivery, indicating no catheter blockage. In addition, all animals had a %MPE >50% in the heat-withdrawal test during the last drug-infusion week (either drug at 750 µg/h), indicating that the catheters were still located intrathecally. Our previous bolus delivery study showed that 1000 µg of tizanidine administered intrathecally yielded an 80% MPE in the heat-withdrawal test, whereas the same drug given IV had no effect (<10%) on %MPE (8).
The exact basis for the differential cardiovascular effect of intrathecal clonidine versus tizanidine is not known. In a previous bolus intrathecal study in dogs, 500 µg of clonidine decreased heart rate (37% below baseline), whereas tizanidine at the same dose did not produce this effect (8). Continuous intrathecal infusion resulted in a similar effect on heart rate as bolus administration. The bradyarrhythmias seen with clonidine in this study cannot be explained by vagal stimulation alone, because in the bolus study, both drugs also decreased heart rate by parasympathetic activation (8). Instead, the effect of clonidine may be due to direct inhibition of sympathetic control by central or peripheral mechanisms (17). The overshoot tachycardia after cessation of clonidine is similar to that observed in both normal and hypertensive rats after the discontinuation of daily systemic clonidine (18). Tachycardia has been documented in hypertensive patients after cessation of clonidine treatment (19). However, it is difficult to directly compare our results with those of clinical studies, because many involve patients with long-term hypertension and do not provide predrug baseline data for comparison.
Continuous intrathecal clonidine reduced blood pressure at all but the largest dose. This was also seen after bolus intrathecal clonidine administration in dogs (8), in which blood pressure reduction occurred at 500-µg doses, normotension at 1000-µg doses, and hypertension at 2000-µg doses. Although other side effects (sedation and motor incoordination) prevented evaluation of doses larger than 750 µg/h in this study, the trend in Figure 2 suggests that blood pressure would increase with larger doses, as occurred in the bolus studies. Presumably this effect is due to systemic reabsorption of the drug and direct action on peripheral -adrenergic receptors (17,20,21). Continuous intrathecal tizanidine did not produce hypotension, suggesting less sympathetic inhibition with this drug. However, cardiac output was not measured in the dogs, and so the role of peripheral vasoconstriction and decreased perfusion with intrathecal tizanidine needs to be assessed, especially in any clinical studies. The lack of overshoot hypertension in this study is consistent with studies of systemic clonidine administration in normotensive animals that have demonstrated overshoot tachycardia but no overshoot hypertension (22). It should be noted that blood pressure measurements were performed 2 days after the return to saline infusion, so some short-term overshoot effects may have been undetected.
Tizanidine Toxicity Study
Continuous intrathecal tizanidine up to 6 mg/d does not appear to have any adverse effect on body weight, body temperature, respiratory rate, heart rate, sedation, or motor coordination. However, with only n = 3 per group, the statistical tests have low power, and moderate group differences could be undetected. Overall systemic toxicity was not examined because oral tizanidine has been used since the late 1970s in spasticity patients at larger daily doses (23). Histologically, the spinal cord and roots appeared to be within normal limits in all six animals receiving tizanidine. All animals, drug groups and control, had mild chronic inflammatory activity in the subarachnoid space, presumably because of the surgery and the presence of the silicone rubber catheter. Tizanidine was stable in the pump reservoir, and all animals had detectable levels of tizanidine in the CSF, indicating that the delivery system remained patent throughout the study and assuring that the spinal cord and roots were exposed to the drug. However, there may be variability in the tizanidine clearance for each animal, so some animals may have had a larger effective drug exposure during the infusion period.
The intrathecal infusion of tizanidine in dogs at 3 mg/d (0.125 µg/h) for 28 days was not associated with neurotoxicity. This is consistent with a similar study in sheep evaluating doses up to 4 mg/d (13). Because the lumbar CSF clearance of a dog is only one tenth that of a human, the 3 mg/d dose in the dog is equivalent to 30 mg/d in a human (24). Although tizanidine has not been infused intrathecally in humans, clonidine at doses of up to 0.6 mg/d has been used in patients with refractory neurogenic and musculoskeletal pain (4). On the basis of this, it appears that it would be appropriate to evaluate the use of much larger intrathecal doses of tizanidine in clinical trials.
In conclusion, continuous intrathecal infusion of tizanidine in dogs produced similar analgesia as clonidine, but with significantly fewer adverse effects on blood pressure and heart rate. There was no evidence of any adverse histopathologic or physiologic effects after long-term intrathecal infusion of tizanidine.
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Acknowledgments |
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Support for the tizanidine safety section of the study was provided by Medtronic, Inc.
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