Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD.

OBJECTIVE: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. BACKGROUND: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. METHODS: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. RESULTS: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off" total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 microg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 microg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. CONCLUSIONS: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues--putamen and substantia nigra.

Internal globus pallidotomy in dystonia secondary to Huntington's disease.

INTRODUCTION AND METHOD: The prototypic motor feature of Huntington's disease (HD) is chorea, but parkinsonism and involuntary movements such as dystonia and myoclonus can also be present. Pallidotomy has been shown to be an effective treatment for medically refractory Parkinson's disease (PD). We performed bilateral microelectrode guided-stereotactic pallidotomies targeted at globus pallidum internus (GPi) to treat a 13-year-old patient diagnosed with Westphal variant of HD with intractable generalized dystonia and parkinsonism. RESULTS: Intraoperative microelectrode recordings of GPi cells showed a relatively low firing rate, 29 +/- 14 Hz, with most neurons showing pauses. Acutely, after surgery, limb dystonia mildly improved but trunk dystonia persisted. Postoperative follow up 3 months later showed minimal clinical improvement in dystonic features with marked worsening of spasticity. CONCLUSION: In our case, bilateral pallidotomy produced modest palliative functional improvement in dystonic features. Cellular firing patterns were markedly different than in PD and were similar to those found in dystonia.

Long-term testing of an intracranial pressure monitoring device.

OBJECT: Long-term monitoring of intracranial pressure (ICP) is limited by the lack of an implantable sensor with low drift. The goal of this study was to demonstrate that a new capacitive transducer system will produce accurate and stable ICP records over extended periods. METHODS: Intracranial pressure sensors were implanted into the frontal white matter of four dogs. In addition, a fluid-filled catheter was placed in the cisterna magna (CM) to measure cerebrospinal fluid (CSF) pressure. The animals were tested using standard physiological maneuvers such as jugular vein compression, head elevation, and CSF withdrawal from and saline injection into the CM to verify that the ICP sensor precisely matched CSF pressure changes. The mean ICP pressure and CM pressure were compared for months to demonstrate that the transducer system produced minimal drift over time. The change in the ICP sensor record closely duplicated that of the CSF waveform in the CM in response to well-known physiological stimuli. More important, mean ICP pressure remained within 3 mm Hg of CM pressure for months, with a mean difference of less than 0.3 mm Hg. Histological examination of the dog brains revealed only minimal tissue reaction to the presence of the sensor. CONCLUSIONS: The authors demonstrate a new implantable solid-state sensor that reliably measures ICP for months, with minimal drift. The clinical application of this sensor and its telemetry is for long-term monitoring of patients with head injury, mass lesions, and hydrocephalus.

Impaired frontostriatal cognitive functioning following posteroventral pallidotomy in advanced Parkinson's disease.

We investigated the long-term effects of posteroventral pallidotomy on tests sensitive to the functional integrity of frontostriatal neural systems in a sample of 11 patients with advanced Parkinson's disease (PD). Patients were assessed within 1 month prior to surgery and at 12 months following pallidotomy. Changes in outcome measures were compared to a control sample of equally performing PD patients receiving nonsurgical medical management assessed over a 12-month period. Measures of cognitive abilities sensitive to frontostriatal functional integrity tested psychomotor processing speed, executive components of working memory, and reasoning. Additional tests of general mental status and semantic memory ability were utilized to assess the specificity of the effect of pallidotomy on cognitive function. Significant declines in performance on all measures sensitive to frontostriatal integrity were found for the surgery group but not the PD control group. No significant changes in performance were found on the measures of general mental status or semantic memory for either the surgery or PD control samples. These results suggest that the posteroventral pallidotomy selectively impairs performance on tests of frontostriatal cognitive abilities.

Adverse effects associated with the intrathecal administration of ziconotide.

The omega-conopeptide, ziconotide, is an N-type calcium-channel blocker that has been shown to produce antinociception in animals using formalin and hot-plate tests. Initial reports of intrathecal administration of ziconotide in cancer and AIDS patients whose pain was unrelieved with opioids demonstrated analgesic efficacy. Although adverse effects were reported, these appeared to be easily managed through dose reduction or symptomatic treatment. This clinical report describes the experiences of three patients with serious adverse effects associated with intrathecal ziconotide.

Chronic intrathecal administration of dexamethasone sodium phosphate: pharmacokinetics and neurotoxicity in an animal model.

OBJECTIVE: Although corticosteroids have been used intraspinally for many years, long-term intrathecal administration has not been examined. We have assessed the stability, bioavailability, and safety of continuously delivering the prodrug dexamethasone sodium phosphate into the lumbar subarachnoid space. METHODS: High-performance liquid chromatography studies were performed to determine whether dexamethasone sodium phosphate is degraded either in vials or in an infusion pump at 37 degrees C during a period of weeks. Rats then received implants with a combined intrathecal delivery and microdialysis sampling catheter to determine whether the prodrug is converted to free dexamethasone. A neurotoxicity study was performed in which rats received implants with an intrathecal catheter and were continuously infused with the corticosteroid during a 2-week period. RESULTS: Dexamethasone sodium phosphate, diluted in saline, is stable at body temperature in vials and implantable infusion pumps for at least 2 weeks. When delivered into the cerebrospinal fluid as a bolus, virtually all of the prodrug is converted to free dexamethasone within 40 minutes. When administered continuously, most of the corticosteroid is in its active form at steady state. Low doses of corticosteroid (< or =12.5 ng/h) produced no side effects or neuropathology in the rats, but a higher dose (125 ng/h) was associated with inflammation in the lumbar subarachnoid space. CONCLUSION: Dexamethasone sodium phosphate is a stable prodrug that is efficiently converted to free dexamethasone when delivered intrathecally. Low continuous intrathecal doses seem safe, but higher doses may lead to increased inflammation.

A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis.

BACKGROUND: Brain derived neurotrophic factor (BDNF) is a potent survival factor for motoneurons. This study investigated the safety and tolerability of recombinant methionyl human BDNF (r-metHuBDNF) infused intrathecally by means of an implanted pump in patients with ALS. METHODS: Twenty-five patients with probable or definite ALS were treated with either r-metHuBDNF (25, 60, 150, 400 or 1000 microg/day) or placebo in a 12-week, randomized, double-blinded, sequential, dose-escalation study. Test treatment was interrupted by a washout period from days 11 to 25 to allow the evaluation of laboratory safety measures. In each dose cohort four patients received r-metHuBDNF and one received placebo. On completion of the double-blind period of the study all patients continued to receive r-metHuBDNF in an open-label extension for up to 60 weeks. Lumbar cerebrospinal fluid (CSF) samples were taken periodically from all patients for the measurement of r-metHuBDNF levels and in a minority of patients these were supplemented by cistemal samples. RESULTS: Within days after the initiation of infusion the majority of patients receiving r-metHuBDNF reported mild sensory symptoms, including paraesthesias or a sense of warmth, which were usually confined to the lower limbs and were frequently exacerbated by neck flexion. In most instances these symptoms decreased or even disappeared over several weeks. Sleep disturbance, dry mouth, agitation and other behavioural effects were encountered at higher doses (>150 microg/day) and necessitated dose reductions. The spinal CSF levels of r-metHuBDNF were directly related to dose, with a lumbar to cervical ratio of approximately 4:1. CONCLUSIONS: The intrathecal delivery of r-metHuBDNF in doses of up to 150 microg/day was well tolerated and appears feasible. The reversible CNS effects with higher dose indicate that BDNF can be delivered cranially against CSF flow. The small number of patients and the design of the study did not permit conclusions to be drawn about the efficacy of the treatment.

Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report.

The authors present a case of Hallervorden-Spatz disease (HSD) in a 10-year-old boy treated with stereotactic pallidotomy for control of severe dystonia. Hallervorden-Spatz disease is a rare type of neuraxonal dystrophy that can be familial or sporadic. This is the first case of HSD reported in the literature in which a pallidotomy was performed. The patient had progressively worsening dystonias and spasms that prevented useful function of his entire right side and eventually threatened his respiratory ability. Pre- and postoperative magnetic resonance images are presented along with electrophysiological recordings made in the globus pallidus at the time of surgery. Functional improvement in the use of the patient's limbs and relief from the painful dystonia were observed. Stereotactic pallidotomy should be considered as a potential treatment in the management of HSD.

Pallidotomy and bradykinesia: implications for basal ganglia function.

BACKGROUND AND OBJECTIVE: The scientific rationale for pallidotomy as a treatment for PD is that the lesion will reduce excessive tonic inhibition of the thalamus, thereby allowing movement to proceed more normally. If true, then PD patients who move slowly while on medication should increase movement speed following pallidotomy. To test this we used a simple motor task to determine if pallidotomy leads to an improvement in "on" motor performance when those movements are impaired before surgery. METHODS: Nine patients with PD performed elbow flexion movements "as fast as possible" while they were "on" before and 1 month after pallidotomy. Patients with mild PD and healthy control subjects were also tested. RESULTS: The clinical effects of pallidotomy were typical of those found in other studies. "Off" Unified Parkinson's Disease Rating Scale scores improved and dyskinesias were reduced. Although before surgery the patients were far slower while they were "on" than the groups of mild PD patients and healthy control subjects, there was no change in mean peak velocity while they were "on" after pallidotomy. There was no change in other mean "on" motor performance measures such as peak acceleration, peak deceleration, initiation time, and symmetry. There was a decrease in the variability of peak acceleration, symmetry, and initiation time. CONCLUSION: Despite the clinical efficacy of pallidotomy while patients were "off," bradykinesia of elbow flexion movements while patients were "on" is not affected by pallidotomy. Therefore, we conclude that the bradykinesia observed in this experiment is due to a mechanism other than excessive tonic inhibition of the motor thalamus. Our results are consistent with the idea that pallidotomy reduces the noise from the abnormally functioning basal ganglia.

Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats.

UNLABELLED: N-methyl-D-aspartate (NMDA) antagonists, such as MK801, delay the development of morphine tolerance. Magnesium, a noncompetitive NMDA antagonist, reduces postoperative morphine requirements. The present study was designed to evaluate the effects of intrathecal co-administration of magnesium sulfate with morphine on antinociceptive potentiation, tolerance, and naloxone-induced withdrawal signs. Magnesium sulfate (40-60 microg/h) co-administration for 7 days, similar to MK801 (10 nmol/h), prevented the decline in antinociceptive response compared with morphine (20 nmol/h). Magnesium sulfate (60 microg/h) produced no antinociception, but co-infused with morphine (1 nmol/h), it resulted in potentiated antinociception compared with morphine throughout the 7-day period. Probe morphine doses after 7-day infusions demonstrated a significantly greater 50% effective dose value for morphine 1 nmol/h (109.7 nmol) compared with saline (10.9 nmol), magnesium sulfate 60 microg/h (10.9 nmol), and magnesium sulfate 60 microg/h plus morphine 1 nmol/h (11.2 nmol), which indicates that magnesium had delayed morphine tolerance. Morphine withdrawal signs after naloxone administration were not altered by the co-infusion of magnesium sulfate. Cerebrospinal fluid magnesium levels after intrathecal magnesium sulfate (60 microg/h) for 2 days increased from 17.0 +/- 1.0 microg/mL to 41.4 +/- 23.6 microg/mL, although serum levels were unchanged. This study demonstrates antinociceptive potentiation and delay in the development of morphine tolerance by the intrathecal coinfusion of magnesium sulfate and morphine in the rat. IMPLICATIONS: The addition of magnesium sulfate, an N-methyl-D-aspartate antagonist, to morphine in an intrathecal infusion provided better analgesia than morphine alone in normal rats. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.

Stereotactic pallidotomy for the treatment of Parkinson's disease. Efficacy and adverse effects at 6 months in 26 patients.

We evaluated the safety and efficacy of microelectrode-guided stereotactic pallidotomy in patients with advanced Parkinson's disease (PD). Using diagnostic criteria and evaluations outlined in the Core Assessment Programme in Transplantation (CAPIT) protocol, we studied unilateral pallidotomy in 26 patients with advanced idiophatic PD, motor fluctuations, and peak dose dyskinesias. All underwent unilateral stereotactic pallidotomy. Assessments conducted in the "practically defined off" and "best on" states at baseline and at 1 and 6 months postoperatively included Unified Parkinson's Disease Rating Scale (UPDRS) parts II, III, and IV and timed motor testing as outlined in CAPIT. Motor UPDRS in the "off" state improved at 1 and 6 months after surgery (p = 0.002, p = 0.008) Likewise, the sum of individual "off" contralateral motor UPDRS items improved (p = 0.0002, p = 0.0005). The duration (p = 0.0001 at 1 and p = 0.001 at 6 months) and severity (p = 0.003 at 1 and p = 0.0005 at 6 months) of dyskinesia improved, but other aspects of the "on" function were unchanged. Serious adverse effects occurred in eight patients and included one fatal deep and three nonfatal frontal lobe hemorrhages with resultant language or behavioral deficits. Nonhemorrhagic complications included one hemiparesis and three frontal lobe syndromes. Pallidotomy improves PD motor disability in the "off" state. Peak dose dyskinesias are reduced, although other aspects of "on" motor function are unchanged. Although morbidity may limit its use, pallidotomy is effective in targeting particular symptoms such as unremitting dyskinesia and severe "off" motor disability in advanced PD.

Effect of stereotaxic intrastriatal cografts of autologous adrenal medulla and peripheral nerve in Parkinson's disease: two-year follow-up study.

Studies in nonhuman primates with experimental parkinsonism have shown that intrastriatal cografts of autologous adrenal medulla and peripheral nerve yield greater behavioral improvement and graft survival than do adrenal medulla grafts alone. To test these observations, five patients with advanced Parkinson's disease were selected to receive unilateral intrastriatal adrenal medulla-intercostal nerve cografts. They were evaluated using the Core Assessment Program for Intracerebral Transplantation (CAPIT) protocol. Three of these patients also underwent quantitative motor testing for the measurement of upper limb bradykinesia (movement time; MT). Following right flank adrenalectomy, cografts consisting of small fragments of adrenal medullary tissue and minced intercostal nerve were stereotaxically implanted into three targets in the right striatum using computerized tomography guidance. Surgery was uneventful and postoperative magnetic resonance imaging revealed accurate placement of the grafts. No morbidity was encountered. Results of 24 months of clinical and quantitative motor assessments postoperatively are reported. Total UPDRS motor scores in the "off" state improved from a mean preoperative score of 39.5 to 32.1 at 3, 29.7 at 6, 27.6 at 9, 28.5 at 12, 31.4 at 18, and 26.5 at 24 months after surgery. Total timed motor test scores during the "off" state improved 17.9% at 6, 23.3% at 9, 18.2% at 12, 38.2% at 18, and 34.9% at 24 months postoperatively compared to baseline. Movement time showed statistically significant improvement (repeated measures ANOVA, P < 0.05) in the left arm (contralateral to surgery) in all three patients tested. These results indicate that stereotaxic intrastriatal implantation of autologous adrenal medulla-peripheral nerve cografts can be performed safely and clinical improvement from this procedure is sustained for a period of 24 months. The clinical improvement was paralleled by improvement in objective, quantitative motor testing.

Multidimensional assessment of motor function in a child with cerebral palsy following intrathecal administration of baclofen.

This case report describes an 11-year-old boy with spastic diplegia whose reflex status, range of motion (ROM), strength, and motor performance were measured before and after implantation of an indwelling system for delivery of intrathecally administered baclofen. Before baclofen use, the subject experienced clonus that interfered with walking, needed assistance with transfers, and was unable to independently put on underwear and socks. Measures of spasticity, kinematics and electromyographic activity during voluntary movements, ROM, Gross Motor Function Measure (GMFM) scores, and self-reports of change were obtained at baseline, before and after bolus baclofen injection, during a double-blind placebo-controlled clinical trial of baclofen administration via an indwelling pump, and after 1 and 2 years of baclofen therapy. Spasticity, Babinski reflexes, clonus, strength, and coactivation of antagonist muscles during voluntary movement were decreased shortly after baclofen administration began. Hip and ankle ROM increased, upper-extremity movement speed increased, independence in dressing and transfers improved, and orthoses were discarded. After 1 and 2 years, GMFM scores were 7.8% and 6.4% above baseline, respectively; the subject won a fitness award. After 2 years, ROM was worse than at baseline and concerns regarding hip subluxation arose. Single-joint movement control and independence improved and spasticity decreased during baclofen administration.

Effects of intrathecal nonnarcotic analgesics on chronic tactile allodynia in rats: alpha 2-agonists versus somatostatin analog.

The effects of the intrathecal alpha 2-agonists tizanidine and clonidine and the somatostatin analog octreotide on an experimental rat model of tactile allodynia were investigated to determine the therapeutic potential for treating chronic neuropathic pain. Allodynia was induced by ligating the rat sciatic nerve. The mechanical threshold for paw withdrawal was assessed by applying von Frey hairs to quantify analgesic actions. Mean 50% paw withdrawal thresholds were converted to the percentage of maximum possible effect (%MPE) where %MPE = (postdrug threshold-predrug threshold) divided by (15 g-predrug threshold) x 100. Dose-response curves were plotted for suppression of paw withdrawal 30 minutes after intrathecal injection of various doses of tizanidine, clonidine, and octreotide. Thresholds on the non-lesioned side were greater than 15 g. The lesioned side had baseline thresholds of less than 4.5 g. Dose-response curves were established for the antiallodynia effects of each drug. Tizanidine and clonidine at a 25-micrograms dose increased the threshold to greater than 97% of the MPE, but caused transient hindpaw weakness or sedation. No side effect was observed at a 10-micrograms dose, at which the threshold was 88-96% of MPE. Intrathecal octreotide modestly increased the threshold to only 49-67% of MPE, showing a lesser analgesic effect, although no side effect was observed at a 4-micrograms dose. The antiallodynic effects of intrathecal tizanidine and clonidine were more potent than that of octreotide.

Intrathecal ciliary neurotrophic factor delivery for treatment of amyotrophic lateral sclerosis (phase I trial).

OBJECTIVE: This Phase I trial of ciliary neurotrophic factor (CNTF) delivered intrathecally for the treatment of patients with amyotrophic lateral sclerosis was designed to determine the safety of this new mode of administration as well as the pharmacokinetics and drug distribution. METHODS: CNTF was administered using a drug pump implanted into the lumbar subarachnoid space in each of four patients with amyotrophic lateral sclerosis. Escalating doses (0.4, 0.8, 1.6, 4, and 8 micrograms/h) were infused for 48 hours per week in 2-week cycles until the highest tolerated dose was achieved. Patients were observed for side effects, and standardized muscle and respiratory function tests were performed. Cerebrospinal fluid (CSF) levels of CNTF were determined using simultaneous lumbar and cervical taps. Plasma and CSF levels of antibodies, CSF cells and protein, and routine blood chemistries were monitored, as were weight and vital signs. RESULTS: Pharmacokinetic studies of four patients demonstrated that the distribution and clearance of recombinant human (rH)CNTF are similar to those of many small, water-soluble agents (morphine, baclofen, clonidine) and that the steady-state concentration of rHCNTF at the cervical level was 18 to 36% of that at the lumbar level. Lumbar CSF levels were in the range of 44 to 1230 ng/ml. Intrathecally administered rHCNTF had different adverse effects than the systemically delivered drug. With intrathecal administration, no asthenia, fever, chills, nausea, weight loss, increased cough, or sputum production was found. All patients who received rHCNTF intrathecally experienced dose-related CSF pleocytosis (primarily lymphocytic) and rises in protein levels. No clinical signs of meningeal irritation, such as stiff neck, photophobias, or nausea, were seen. However, one patient who had lumbar spinal stenosis developed severe burning and cramping leg pain. A second patient developed a severe headache and leg and back cramping. No abnormal clinical chemistry or hematological findings were encountered. Plasma levels of rHCNTF were below detection. Antibodies to rHCNTF were found in the systemic circulation of only one patient. The gradual decline in motor strength and performance of standard skills did not improve or worsen. CONCLUSIONS: In this first trial of a recombinant neurotrophic factor to be administered intrathecally by drug pump, the CNTF was well distributed along the spinal canal. Pain syndromes (headache, radicular pain) that were dose-related occurred in two patients, but systemic side effects, which had been observed with subcutaneous rHCNTF, did not occur. Intrathecal drug pump delivery of neurotrophic factors may be the most appropriate way in which to test the efficacy of these high-molecular weight proteins, because high CSF levels can be achieved without significant systemic side effects.

Effect of stimulation in the ventral intermediate nucleus of the thalamus on limb control in Parkinson's disease: a case study.

This study focuses on upper extremity strength and movement control in a patient with Parkinson's disease who had stimulating electrodes surgically implanted in the ventral intermediate nucleus (VIM) of the left thalamus. We examined torque generation and control of movement distance in single degree-of-freedom elbow movements under three different stimulation conditions: (a) no stimulation, (b) high stimulation, in which tremor was minimized but there was also tingling and perceived weakness, and (c) moderate stimulation, in which tremor was partially reduced, but there was also a subjective sense of increased strength compared with the high-stimulation condition. The patient's ability to generate both steady torque and rapid movements was poorest with no stimulation. The patient generated the largest torques with moderate stimulation and performed the fastest movements with high stimulation. However, even with tremor minimized, the patient's electromyogram (EMG) burst patterns were not typical of those of neurologically healthy subjects, although the movements were clearly improved.

Deep brain stimulation for essential tremor.

We examined the effects and safety of deep brain stimulation (DBS) as a treatment for essential tremor (ET). Ten ET patients with disabling medication-refractory tremor underwent stereotactic implantation of a DBS lead in the left Vim thalamic nucleus and completed a 6-month follow-up. The Clinical Tremor Rating Scale and disability assessments were performed at baseline, 1-, 3-, and 6-month follow-up. There were significant improvements in dressing, drinking, eating, bathing, and handwriting as reported by the subjects. Tremor severity, writing, pouring, and spiral and line drawing were significantly improved as rated by the examiner. Improvements persisted through the 6-month follow-up period. Although global disability significantly lessened in the group as a whole, one subject with hand-finger tremor accentuated by writing had no change in disability status. In this 6-month open-label study, DBS was effective and safe in reducing tremor and functional disability in ET.

Intrathecal clonidine and tizanidine in conscious dogs: comparison of analgesic and hemodynamic effects.

Intrathecal delivery of alpha(2)-adrenergic agonists produces an analgesic effect. However, hemodynamic side effects limit their clinical usage. To more fully characterize the effects on heart rate and arterial blood pressure of alpha(2)-adrenergic agonists, clonidine and tizanidine were injected intrathecally in conscious dogs. Both compounds produced a potent inhibition of thermal foot-withdrawal latencies at 1000 micrograms, which was blocked by the alpha(2)-adrenergic antagonist yohimbine. Tizanidine (250-500 micrograms) did not change heart rate. Clonidine (500 -2000 micrograms) and tizanidine (1000-2000 micrograms) decreased heart rate. The tizanidine effect was inhibited by yohimbine and the alpha(2)/imidazoline antagonist idazoxan, as well as the parasympathetic blocker glycopyrrolate. No drug completely inhibited the clonidine-induced bradycardia. Clonidine had a biphasic effect on arterial blood pressure, a decrease at 500 micrograms and an increase at 2000 micrograms. Tizanidine decreased arterial blood pressure at all doses. The results indicate that, while the analgesic effects of both drugs are similar, the hemodynamic responses differ. While the decrease in heart rate with tizanidine is consistent with alpha(2)-adrenergic binding and vagal action, the bradycardia induced by clonidine is more complex. In addition, the increased arterial blood pressure with high doses of clonidine, which is suggestive of a peripheral vasoconstrictive effect, does not occur with tizanidine.