BACKGROUND AND OBJECTIVES Patient-controlled epidural analgesia (PCEA) with bupivacaine and hydromorphone provides high quality analgesia after orthopedic surgery but is associated with a frequent incidence of opioid-related side effects (15%-30%). Epidural clonidine has a different side effect profile, but there are no large surveys documenting its use. We performed this prospective survey to evaluate analgesia and the side effect profile in total hip replacement patients before and after a systematic change from PCEA with bupivacaine/hydromorphone to bupivacaine/clonidine. METHODS Five hundred consecutive patients received PCEA with 0.06% bupivacaine and hydromorphone (10 mcg/mL) as a previously described prechange control group. The standard analgesic regimen was then systematically changed to 0.06% bupivacaine and clonidine (1 mcg/mL) without changing the PCEA settings or other aspects of perioperative care, and 500 consecutive patients were included as a postchange group. All data were prospectively entered and then abstracted from the electronic medical record. Data collection included daily verbal pain scores (VPS), pruritus, nausea, hypotension, need for IV fluid boluses, sedation, and respiratory depression. An online survey to measure staff satisfaction with the changeover was sent to all participating surgeons, anesthesiologists, physical therapists, and physician's assistants. RESULTS Patient characteristics were similar between groups. Most patients received central neuraxial anesthesia (99%). The clonidine group had lower VPS at rest (2.3 vs 3.7, P<0.001 with 95% confidence interval [CI] of difference of 1.4 [1.1, 1.7]) on POD0. The incidence of nausea was 10%-11% for clonidine and 13%-15% for hydromorphone. The incidence of pruritus was less with clonidine (1 vs 10%, P<0.01 with 95% CI of difference of 9%[6, 12]). However, the incidence of hypotension (20 vs 11%, P<0.001 with 95% CI of differences 9%[5, 14]) and IV fluid boluses was more frequent with clonidine (36 vs 19%, P<0.001 with 95% CI of differences of 16 [11, 12]). Sixty-five percent of staff completed the online survey, and 70% considered clonidine worse than hydromorphone. CONCLUSION The systematic changeover from epidural hydromorphone to clonidine produced mixed results without obvious superiority. The VPS at rest was reduced only on postoperative day 0; pruritus was reduced, but hypotension was increased. On the basis of medical staff preference, we discontinued the systematic change and returned to our previous standard solution of bupivacaine and hydromorphone for PCEA after total hip replacement.

In a double-blind, placebo-controlled, cross-over trial, clonidine eliminated objective signs and subjective symptoms of opiate withdrawal for 240--360 min in eleven addicts in a hospital setting. In an open pilot study of the effects of clonidine on longer-term opiate abstinence and symptoms, the same patients did well while taking clonidine for one week. There was only one documented instance of heroin use, in a patient who did not take clonidine after hospital discharge. 6 weeks or more after the study, four patients were back on reduced doses of methadone, one was on tricyclic antidepressants, and seven were off of all opiates. All eleven patients were doing well. These data suggest that opiate withdrawal is due to increased neuronal activity in areas such as the locus coeruleus which are regulated by both alpha-2 adrenergic and opiate receptors.

The effects of inhibition of locus coeruleus neuronal discharge activity on cortical and hippocampal electroencephalographic activity were examined in halothane-anesthetized rats. A combined recording/infusion probe was used to place 35-150-nl infusions of the alpha 2-noradrenergic agonist, clonidine (1 ng/nl) which inhibits locus coeruleus neuronal discharge activity, immediately adjacent to the locus coeruleus. The recording electrode allowed verification and quantification of the electrophysiological effects of these infusions. Simultaneously, electroencephalographic activity was recorded from sites in frontal neocortex and dorsal hippocampus and subjected to power spectrum analyses. Neither cortical nor hippocampal electroencephalographic activity was substantially affected following unilateral locus coeruleus inactivation. In contrast, bilateral clonidine infusions that completely suppressed locus coeruleus neuronal discharge activity in both hemispheres altered cortical and hippocampal electroencephalographic status. The cortical response to bilateral LC inhibition was characterized by a shift from low-amplitude, high-frequency to large-amplitude, slow-wave activity. Additionally, theta-dominated activity in the hippocampus was replaced with mixed frequency activity. The onset of these changes in forebrain electroencephalographic activity was coincident with the complete bilateral inhibition of locus coeruleus neuronal discharge activity. The resumption of pre-infusion electroencephalographic patterns closely followed recovery of locus coeruleus neuronal activity or could be induced with systemic administration of the alpha 2-noradrenergic antagonist, idazoxan. Clonidine infusions placed 800-1200 microns from the locus coeruleus were less effective at inducing a complete suppression of locus coeruleus activity. These infusions either did not completely inhibit locus coeruleus discharge (35 nl infusions), or did so with a longer latency to complete locus coeruleus inhibition and a shorter duration of inhibition (150 nl infusions). Changes in forebrain electroencephalographic activity occurred only following the complete bilateral suppression of locus coeruleus neuronal discharge activity. These electroencephalographic responses closely followed or coincided with the onset of complete bilateral locus coeruleus inhibition and persisted throughout the period during which bilateral LC neuronal discharge activity was completely absent (60-240 min). Recovery of electroencephalographic patterns was coincident with the reappearance of locus coeruleus discharge activity. These results suggest that the clonidine-induced changes in forebrain electroencephalographic activity were dependent on the complete bilateral suppression of locus coeruleus discharge activity, and that under the present experimental conditions the locus coeruleus/noradrenergic system exerts a potent and tonic activating influence on forebrain electroencephalographic state. These results support the hypothesis that this system may be an important modulator of behavioral state and/or state-dependent processes.

BACKGROUND: Spinal cholinergic receptors have been shown to have a potent antinociceptive action, an effect that can be mimicked by spinal cholinesterase inhibitors. We (1) characterized the cholinergic receptor system through which intrathecally applied cholinesterase inhibitors produce their antinociceptive effect and (2) examined their interaction with spinal mu opioid and alpha 2-adrenergic receptors. METHODS: Rats were prepared with chronic intrathecal catheters and the nociceptive threshold was assessed by the use of the radiant heat-evoked hind paw withdrawal. RESULTS: Spinal administration of neostigmine, edrophonium, carbachol, clonidine, and morphine produced a dose-dependent increase on the thermally evoked hind paw withdrawal latency. The order of potency (dose producing a 50% effect, in nanomoles) was morphine (1.1)= neostigmine (1.2)> clonidine (4.4)> carbachol (15)>> edrophonium (112). Spinal pretreatment with atropine (35 nmol) attenuated the antinociceptive effect of intrathecal carbachol (55 nmol), neostigmine (15 nmol), and edrophonium (500 nmol) but did not affect the potency of intrathecal morphine (15 nmol) or clonidine (435 nmol). In addition, intrathecal pretreatment with naloxone (31 nmol) and yohimbine (28 nmol) attenuated the effects of intrathecally administered morphine and clonidine, respectively, but did not significantly affect the potency of carbachol, neostigmine, or edrophonium. The nicotinic receptor antagonist mecamylamine (60 nmol) did not affect thermal nociception. Isobolographic analysis revealed a synergistic interaction after the coadministration of neostigmine-clonidine (P < 0.001), edrophonium-clonidine (P < 0.0001), and edrophonium-morphine (P < 0.01) mixtures. Neostigmine-morphine exhibited simple additivity. CONCLUSIONS: These data indicate that analgesia after spinal cholinesterase inhibition is mediated through muscarinic, but not nicotinic cholinergic, opioid, or alpha 2-adrenergic receptor systems, and that these spinal effects of cholinesterase inhibition interact synergistically with the antinociceptive effects of intrathecal mu and alpha 2 agonists.

We examined plasma levels of the sympathetic neurotransmitter norepinephrine (NE) and its deaminated metabolite dihydroxyphenylglycol (DHPG) during supine rest in healthy human subjects and in sympathectomized patients, during physiological (tilt) or pharmacological (yohimbine, clonidine) manipulations known to affect sympathetically mediated NE release, during blockade of neuronal uptake of NE (uptake-1) using desipramine, and during intravenous infusion of NE. Healthy subjects had a mean arteriovenous increment in plasma DHPG in the arm (10%, P less than 0.05), whereas sympathectomized patients had a mean arteriovenous decrement in DHPG in the affected limb (mean decrease 21%, P less than 0.05 compared with healthy subjects). Tilt and yohimbine, which stimulate, and clonidine, which inhibits, release of endogenous NE, produced highly correlated changes in plasma NE and DHPG (r = 0.94). Pretreatment with desipramine abolished DHPG responses to yohimbine while enhancing NE responses. To attain a given increase in plasma DHPG, about a tenfold larger increment in arterial NE was required during NE infusion than during release of endogenous NE. When plasma NE was markedly suppressed after administration of clonidine, plasma DHPG decreased to a plateau level of 700-800 pg/ml. The results indicate that (i) plasma DHPG in humans is derived mainly from sympathetic nerves;(ii) increments in plasma DHPG during stimulation of NE release result from uptake of NE into sympathetic nerve endings and subsequent intraneuronal conversion to DHPG;(iii) plasma DHPG under basal conditions probably is determined mainly by net leakage of NE into the axonal cytoplasm from storage vesicles; and (iv) increments in NE concentrations at neuronal uptake sites can be estimated by simultaneous measurements of DHPG and NE during NE infusion and NE release. Measurement of NE and DHPG provides unique clinical information about sympathetic function.

PURPOSE: To investigate the effects of alpha(2)-adrenergic agonists on perioperative mortality and cardiovascular complications in adults undergoing surgery. METHODS: MEDLINE (1966 to May 2002), EMBASE (1980 to May 2002), the Cochrane Clinical Trials Register, the Science Citation Index, and bibliographies of included articles were searched without language restriction. Randomized trials comparing preoperative, intraoperative, or postoperative (first 48 hours) administration of clonidine, dexmedetomidine, or mivazerol with controls were included. Studies had to report any of the following outcomes: mortality, myocardial infarction, ischemia, or supraventricular tachyarrhythmia. Treatment effects were calculated using the fixed-effects model. Heterogeneity was assessed using the Q test. RESULTS: Twenty-three trials comprising 3395 patients were included. Overall, alpha(2)-adrenergic agonists reduced mortality (relative risk [RR]= 0.64; 95% confidence interval [CI]: 0.42 to 0.99; P = 0.05) and ischemia (RR = 0.76; 95% CI: 0.63 to 0.91; P = 0.003) significantly. They also reduced mortality (RR = 0.47; 95% CI: 0.25 to 0.90; P = 0.02) and myocardial infarction (RR = 0.66; 95% CI: 0.46 to 0.94; P = 0.02) during vascular surgery. During cardiac surgery, alpha(2)-adrenergic agonists reduced ischemia (RR = 0.71; 95% CI: 0.54 to 0.92; P = 0.01) and were associated with trends toward lower mortality (RR = 0.49; 95% CI: 0.12 to 1.98; P = 0.3) and a reduced risk of myocardial infarction (RR = 0.83; 95% CI: 0.35 to 1.96; P = 0.7). CONCLUSION: Alpha-2 adrenergic agonists reduce mortality and myocardial infarction following vascular surgery. During cardiac surgery, they reduce ischemia and may also have effects on mortality and myocardial infarction. Large randomized trials are needed to evaluate these agents during cardiac and vascular surgery.

BACKGROUND: Hot flashes are the most frequently reported side effect of tamoxifen treatment. Although hormones are an effective treatment, their safety is questionable in women with breast cancer. It is therefore important to evaluate nonhormonal treatments for hot flashes. OBJECTIVE: To evaluate the effectiveness of oral clonidine for control of hot flashes associated with tamoxifen therapy in postmenopausal women with breast cancer. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: University of Rochester Cancer Center Community Clinical Oncology Program. PATIENTS: 194 postmenopausal women with breast cancer who were receiving adjuvant tamoxifen therapy. INTERVENTION: Oral clonidine hydrochloride, 0.1 mg/d, or placebo for 8 weeks. MEASUREMENTS: In a daily diary, patients recorded number, duration, and severity of hot flashes and overall quality-of-life score (on a 10-point scale) during a 1-week baseline period and during the 4th, 8th, and 12th weeks of the study. RESULTS: Patients in the placebo and treatment groups were similar in age, duration of tamoxifen use, reported frequency and duration of hot flashes at baseline, and dropout rates. One hundred forty-nine patients completed 12 weeks of follow-up. The mean decrease in hot flash frequency was greater in the clonidine group than in the placebo group after 4 weeks of treatment (37% compared with 20%[95% CI for difference, 7% to 27%]) and 8 weeks of treatment (38% compared with 24%[CI for difference, 3% to 27%]). Patients receiving clonidine were more likely than patients receiving placebo to report difficulty sleeping (41% compared with 21%; P = 0.02). A significant difference was seen in the mean change in quality-of-life scores (0.3 points in the clonidine group compared with -0.2 points in the placebo group; P = 0.02) at 8 weeks, although the median difference was 0 in both groups. CONCLUSION: Oral clonidine, 0.1 mg/d, is effective against tamoxifen-induced hot flashes in postmenopausal women with breast cancer.

PURPOSE: To determine the efficacy of transdermal clonidine for alleviating tamoxifen-induced hot flashes in women with a history of breast cancer. PATIENTS AND METHODS: A randomized, double-blind, crossover design was used in this prospective study. Women with a history of breast cancer who were receiving tamoxifen and suffering from hot flashes were potentially eligible for this protocol study. RESULTS: Clonidine did reduce hot-flash frequency to a degree that was statistically impressive (P <.0001), but clinically moderate (20% reduction from baseline). It also decreased hot-flash severity (P =.02, 10% reduction from baseline). Clonidine was related to increased mouth dryness (P <.001), constipation (P <.02), itchiness under the patch (P <.01), and drowsiness (P <.05). CONCLUSION: Better means are needed to alleviate hot flashes among patients in whom estrogen therapy is contraindicated.

BACKGROUND & AIMS: Disturbed gastric accommodation and sensation contribute to postprandial symptoms in dyspepsia, but the controlling mechanisms are unclear. Nitrergic and alpha2-adrenergic modulation of gastric sensory and motor function were assessed in this study. METHODS: Using a factorial design, we assessed drug effects on gastric sensation during isobaric distentions and fasting and postprandial gastric motor function in 32 healthy volunteers. Each participant received one treatment: placebo; 0.3 or 0.5 microgram. kg-1. min-1 intravenous nitroglycerin; 0.0125, 0.025, or 0.1 mg clonidine orally; or combined nitroglycerin plus clonidine. In 16 other healthy subjects, the effects of clonidine and placebo on gastric emptying of solids were evaluated using the 13C-octanoic acid breath test. RESULTS: Clonidine and nitroglycerin increased gastric compliance, but normal postprandial accommodation was still observed despite the induced relaxation. Clonidine but not nitroglycerin reduced aggregate and pain perception averaged over four distention levels. There were no significant drug interactions. No dose effect of clonidine was observed on gastric emptying. CONCLUSIONS: Clonidine relaxes the stomach and reduces gastric sensation without inhibiting accommodation or emptying. Nitroglycerin relaxes the stomach without altering perception. Studies of the effects of clonidine on these gastric functions and symptoms in disease are warranted.

1 The central alpha-adrenoceptors responsible for mediating clonidine-induced sedation in rats have been characterized according to their sensitivity to alpha-adrenoceptor agonists and antagonists.2 Clonidine, injected intraperitoneally or intracerebroventricularly, caused dose-dependent sedation, both in terms of a reduction in the time that rats could remain on an accelerating rotarod and in terms of overt sedation assessed visually. Following intracerebroventricular injection, xylazine, naphazoline and methoxamine, but not phenylephrine, produced similar effects.3 The sedation caused by intraperitoneal injection of clonidine was antagonized by intracerebroventricularly injected phentolamine, yohimbine, piperoxan and tolazoline but not by labetalol, thymoxamine or prazosin.4 The relative potencies of the agonists in causing sedation and of the antagonists in inhibiting the sedative effect of clonidine clearly demonstrated that the central alpha-adrenoceptors mediating clonidine-induced sedation are the same as the peripheral presynaptic alpha(2)-adrenoceptors.5 All the alpha-adrenoceptor agonists caused hypothermia after intracerebroventricular injection, but their order of potency was different from that in producing sedation. The hypothermic effect of intraperitoneally injected clonidine was little affected by any of the antagonists administered intracerebroventricularly. No conclusions could be drawn concerning the type of receptor responsible for mediating hypothermia.

The kinetics of the disposition of intravenous and oral clonidine in five normotensive subjects have been determined. It is proposed that a two-compartment model adequately describes the disposition of the drug. The drug is rapidly distributed (t1/2alpha = 10.8 +/- 4.7 min) but slowly elimainated (t1/2beta = 8.5 +/- 0.9 hr). The bioavailability of oral clonidine in the tablets tested averaged 75.2% and 40 to 50% of the bioavailable dose is excreted unchanged in urine. Renal clearance of the drug showed considerable intersubject variation (1.82 +/- 0.34 ml/min/kg) and exceed the calculated glomerular filtration rate in some subjects. Oral and intravenous clonidine induced significant falls in blood pressure (greater than 20/15 mm Hg) in our normotensive subjects and consistently caused marked sedation and dryness of the mouth. Sedation and salivary flow correlated with plasma clonidine concentration over the range 0 to 4 ng/ml. Falls in blood pressure were related to plasma concentration to 1.5 to 2 ng/ml but at higher concentrations the hypotensive effect was attenuated.