Patients treated with long-term spinal infusion of high doses of morphine develop a granuloma at the location of the catheter tip. Diagnosis is based on a steady increase in intrathecal morphine dosage after a relatively prolonged period of stability, on the gradual development of neurologic signs and symptoms suggesting radicular or spinal cord compression, and on magnetic resonance images. We describe a man with central neuropathic pain after removal of a tumor. The presence of all 3 of the aforementioned diagnostic criteria led to suspicion of a spinal granuloma.

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 & 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.

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: 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.

BACKGROUND: alpha 2-Adrenergic agonists such as clonidine produce behavioral analgesia and cardiovascular depression in animals, but clonidine's site of action in clinical analgesia and cerebrospinal fluid (CSF) pharmacokinetics have not been defined. METHODS: Clonidine was administered in the lumbar epidural space to nine volunteers while monitoring blood pressure, heart rate, finger and toe blood flow, and response to cold pain testing, and while sampling CSF and arterial plasma for clonidine analysis. Effects were correlated to plasma and CSF clonidine concentrations. Ten other volunteers received stepped intravenous infusions of the opioid alfentanil with similar testing. RESULTS: Clonidine decreased pain report in the foot but not the hand, and this effect correlated stronger with CSF than with plasma clonidine, suggesting a spinal site for analgesia. Extrapolation of CSF clonidine pharmacokinetics suggests the minimum effective CSF clonidine concentration for postoperative pain relief is 76 +/- 15 ng/ml. Clonidine increased finger and toe blood flow, decreased blood pressure and heart rate, produced sedation, and mildly increased arterial PCO2, in most cases correlating better with plasma than CSF clonidine concentrations, suggesting actions at central sites. In 10 other volunteers, intravenous infusion of the opioid alfentanil produced analgesia of similar intensity to clonidine but was accompanied by significant respiratory depression. CONCLUSIONS: These data support previous studies in animals and provide the scientific rationale for this novel analgesic therapy. In comparison to the potent opioid alfentanil, epidural clonidine produces a similar degree of analgesia but less respiratory depression.

In an attempt to maintain stable levels of an alpha 2-adrenergic agonist throughout the perioperative period, two different oral-transdermal clonidine dosage regimens were administered according to a randomized, double-blind, placebo-controlled study in patients undergoing abdominal surgery. We determined the clinical efficacy of a high- and a low-dose clonidine regimen on sedation, hemodynamic parameters, anesthesia, and analgesia. The low-dose clonidine group of patients (n = 14) received a 7-cm2 clonidine transdermal patch (Catapres-TTS #2), which was supplemented with oral doses of clonidine approximately 3 micrograms.kg-1 on the evening prior to surgery and on the morning of surgery. The high-dose clonidine group (n = 14) received a 10.5-cm2 clonidine transdermal patch (Catapres-TTS #3) with oral clonidine approximately 4.5 micrograms.kg-1 at bedtime and 6.0 micrograms.kg-1 on the morning of surgery. Placebo-treated (control) patients received the same occlusive patch without active ingredient and oral placebo tablets at bedtime and on the morning of surgery. Preanesthetic medication included midazolam 50 micrograms.kg-1 intramuscularly (im). Anesthesia was induced with alfentanil 30 micrograms.kg-1 intravenously (iv), thiopental 3 mg.kg-1 iv, and vecuronium 0.1 mg.kg-1 iv, and was maintained with 70% nitrous oxide in oxygen and a continuous infusion of alfentanil 0.5 microgram.kg-1.min-1. Isoflurane was added when the blood pressure exceeded 110% of the patient's prestudy value. For pain relief postoperatively, the patients received morphine, 1-2-mg iv boluses, via a patient-controlled analgesia pump. The low-dose clonidine patient group had mean plasma clonidine concentrations that varied from 1.47 ng.ml-1 (preoperative) to 1.32 ng.ml-1 (postoperative day 2).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE: To investigate the serum levels of insulin-like growth factor-I (IGF-I) in patients with fibromyalgia (FM) compared to healthy controls and patients with other rheumatic diseases, and to explore possible etiologic mechanisms of low IGF-I levels in patients with FM. METHODS: Five hundred patients with FM and 152 controls (74 healthy blood donors, 26 myofascial pain patients and 52 patients with other rheumatic diseases) were studied. All had measurements of acid extracted serum IGF-I. A subset of 90 patients with FM were evaluated for clinical features that might explain low IGF-I levels. Twenty-five patients with FM underwent growth hormone (GH) provocation testing with l-dopa and clonidine. RESULTS: The mean serum IGF-I level in patients with FM was 138 +/- 56 ng/ml and in controls 215 +/- 86 ng/ml (p = 0.00000000001). Low levels of IGF-I were not due to depression, tricyclic medications, nonsteroidal antiinflammatory drugs, poor aerobic conditioning, obesity, or pain level. Patients with focal myofascial pain syndromes had normal IGF-I levels (236 +/- 68), as did most patients with other rheumatic disorders, unless they had concomitant FM. Patients with FM with initially normal levels often had a rapid decline of IGF-I over 1 to 2 years. Most patients with FM with low IGF-I levels failed to secrete GH after stimulation with clonidine and l-dopa. CONCLUSION: Many, but not all, patients with FM have low levels of IGF-I that cannot be explained by clinical associations. These results suggest that low IGF-I levels in patients with FM are a secondary phenomenon due to hypothalamic-pituitary-GH axis dysfunction.

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.