Articles: analgesics.
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J. Pharmacol. Exp. Ther. · Oct 1989
Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine.
The effects on nociception, blood pressure and heart rate of clonidine administered intrathecally to the lumbar level were determined in conscious rats and in rats anesthetized lightly with pentobarbital. In anesthetized rats, intrathecal (i.t.) clonidine (3.2-32.0 micrograms) inhibited the nociceptive tail-flick reflex and had biphasic effects on blood pressure; lesser doses (1.0-10.0 micrograms) produced depressor effects, whereas a greater dose (32.0 micrograms) produced a marked pressor response. Clonidine also produced biphasic effects on blood pressure in conscious rats, with the dose-response function shifted upward and to the left of that observed in anesthetized rats. ⋯ After i.t. injection of 32.0 micrograms of [3H]clonidine, peak levels of radioactivity in the blood were observed at 2 min and corresponded to a blood concentration of 38.8 ng/ml. Injection of an i.v. bolus dose (2.5 micrograms/kg) sufficient to produce these blood levels resulted in a transient pressor response. These results suggest that after i.t. administration of greater doses of clonidine, sufficient amounts of the drug are rapidly redistributed systemically to produce pressor effects by stimulation of vascular alpha adrenoceptors.
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Forty patients with cancer pain receiving intermittent narcotics were admitted to a prospective study designed to assess the cognitive effects of narcotics. Twenty patients had undergone no change in narcotic dose or type greater than or equal to 7 days (stable dose, SD, group), and 20 patients had undergone an increase of greater than or equal to 30% in dose less than or equal to 3 days before (increased dose, ID, group). Age, primary tumor, type, dose and route of narcotic were not different between the SD and ID group. ⋯ Mean percentual change in FT 10 sec, FT 30 sec, A, RM, and VM after the narcotic dose were 97 +/- 9%, 100 +/- 14%, 100 +/- 13%, 100 +/- 15%, 98 +/- 19%, in the SD group, vs. 77 +/- 14% (P less than 0.001), 83 +/- 13% (P less than 0.001), 124 +/- 21% (P less than 0.001), 60 +/- 21% (P less than 0.001) and 68 +/- 21% (P less than 0.001) in the ID group, respectively. Our results suggest that patients who undergo a significant increase in the dose of intermittent narcotics experience significant cognitive impairment, that disappears after 1 week of the increase. More research is needed to better characterize the cognitive toxicity of intermittent narcotics, and to determine the cognitive effects of long acting narcotics, continuous infusions, or of the addition of amphetamines.
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Comprehensive therapy · Oct 1989
Review Case ReportsThe pharmacologic management of pain in children.
We have attempted to dispel many of the myths and misconceptions surrounding the use of narcotic analgesics in the treatment of childhood pain. Our hope is that an improved understanding and application of effective and safe therapies will minimize the suffering of the child with acute or chronic pain.
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J. Pharmacol. Exp. Ther. · Oct 1989
Kappa-opioid receptor-mediated antinociception in the rat. II. Supraspinal in addition to spinal sites of action.
This study examines whether there is a supraspinal, in addition to spinal, component to the antinociceptive actions against heat and pressure stimuli of kappa-opioid receptor agonists (U-69,593, U50,488H, bremazocine and tifluadom) as compared to mu-opioid receptor agonists (Tyr-D-Ala-Gly-NMe-Gly-ol, fentanyl and morphine) in the rat. The antinociception induced by kappa- and mu-opioids (applied s.c.) was unaffected by systemic quaternary naltrexone (50 mg/kg) revealing that it is mediated in the central nervous system. All kappa- and mu-opioids produced dose-dependent antinociception upon intrathecal application, in each case reversible by naloxone (5 mg/kg s.c.). ⋯ Naltrexone was 10-fold more potent in blocking morphine as compared to U50,488H whereas nor-binaltorphimine, a preferential kappa-antagonist, was 6-fold more potent against U50,488H than morphine. Indeed, whereas a dose of 0.2 mg/kg of naltrexone reversed mu-agonist actions, this dose was inactive against all kappa-agonists: the actions of these could be antagonized only by 2.0 mg/kg. These data indicate that in addition to kappa-receptors in the spinal cord, kappa-receptors in the brain can mediate antinociception against noxious heat and pressure.
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1. The relative spinal effectiveness of mu- and kappa-opioids has been assessed by their intravenous potencies on nociceptive responses (heat and/or pinch) of single motoneurones recorded in alpha-chloralose anaesthetized, spinalized rats. 2. The depressant actions of both mu- and kappa-opioids were reversed by low intravenous doses of naloxone (10 to 100 micrograms kg-1). ⋯ The agonist potency values obtained in this study contrast with those reported for local spinal administration. By this route, the potency of lipophilic opioids (e.g. fentanyl, U-50,488 and tifluadom) relative to hydrophilic opioids (e.g. morphine) is much reduced, implying that activity of intrathecally administered opioids is more dependent on the physico-chemical properties of the agonists used than on the relative abundance in the spinal cord of functional opioid receptors of the mu- and kappa-subtypes. This conclusion indicates that the results with locally applied opioids should not be used to assess spinal opioid receptor function.