Articles: analgesics.
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Opioids were available in clinical practice since before the birth of modern anaesthesia--Setürner isolated morphine in 1806. They have a record of safety which is reflected in their high therapeutic ratios, especially the synthetic opioids introduced recently (table III). The most serious immediate adverse effect, respiratory depression, is a predictable effect related closely to analgesia. It is fortunate for anaesthetists who use opioids regularly, that recognition and treatment of respiratory problems are an integral part of their craft and that opioid antagonists are effective in reversing respiratory depression.
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Pharmacol. Biochem. Behav. · Jan 1987
Determination of cross tolerance in rat spinal cord using intrathecal infusion via sequential mini-osmotic pumps.
Continuous intrathecal (IT) infusion via ALZET mini-osmotic pumps was used to induced spinal tolerance to morphine in the rat. Naloxone (1 mg/kg IP), injected on day 3 of continuous IT morphine (10 micrograms/hr), produced mild withdrawal symptoms in all morphine-treated animals. In rats pretreated with continuous IT morphine (10 micrograms/hr) or saline, systemic morphine (2, 4, 8, 10 and 15 mg/kg IP) produced equivalent, dose-dependent antinociception using the tail-flick and paw pressure tests. ⋯ A sequential, double mini-osmotic pump technique for cross tolerance studies in rat spinal cord is described. In rats pretreated with continuous IT norepinephrine for 4 days, the antinociceptive actions of continuous IT morphine were reduced but not significantly different from saline-pretreated animals. These data suggest that morphine, injected into the spinal cord, does not produce behavioural analgesia by activation of local adrenergic systems.
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Concomitant administration of flupirtine maleate at a single low dose (15 mg/kg, mice; 35 mg/kg, rats) with a wide range of doses of each of the peripherally acting analgesics enhanced the antinociceptive activity of paracetamol, acetylsalicyclic acid and ibuprofen in the acetic acid writhing test, acetylsalicylic acid in the hot plate test and paracetamol, acetylsalicyclic acid and ibuprofen in the Randall-Selitto test. The concomitant administration of a single low dose of the peripherally acting analgesics (at about 1/2 ED50) with a wide range of doses of flupirtine maleate resulted in enhancement of flupirtine maleate analgesic activity by paracetamol (in the hot plate and Randall-Selitto tests), acetylsalicyclic acid (in the acetic acid writhing test), ibuprofen (in the Randall-Selitto test) and indomethacin (in the acetic acid and Randall-Selitto tests). Thus flupirtine maleate enhanced the analgesic activity of paracetamol, acetylsalicyclic acid and ibuprofen in mice and rats. Each of the peripherally acting analgesics enhanced the analgesic activity of flupirtine maleate in one or more of the analgesic tests used.
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In order to investigate the efficacy and safety of long-term treatment with flupirtine in patients with chronic pain, in particular arthrosis and arthritis, a study was planned which, when completed, will encompass the treatment of 200 patients over a 12-month period. The present paper is a preliminary report of this ongoing study. The report deals with 104 patients: 55 of whom completed the 12-month treatment period and a 2-week follow-up phase, during which flupirtine was replaced by placebo in order to be able to detect drug-withdrawal effects. ⋯ If the withdrawal phenomena had corresponded to the flupirtine's terminal half-life, then the symptoms ought to have been present mainly in the first few days. There was a slight trend for lowering systolic blood pressure but no changes in diastolic blood pressure or heart rate, nor changes in the ECG or laboratory analysis that could be related to flupirtine. These preliminary data suggest that flupirtine is safe when given for a period of one year.
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Flupirtine maleate is a centrally acting analgesic with a novel chemical structure and pharmacological profile. Because of its central mechanism(s) of action, flupirtine maleate was studied for physical dependence liability and abuse potential using the following four laboratory animal models: (1) mouse jumping test--jumping behaviour after narcotic antagonist challenge; (2) Hosoya test in rats--body weight reduction after drug withdrawal or narcotic antagonist challenge; (3) tolerance in mice--reduced analgesic activity after repeated dosing; and (4) self-administration in addicted Rhesus monkeys. Unlike the narcotic analgesic agents morphine and codeine, flupirtine maleate did not display evidence of physical dependence liability or abuse potential as measured by jumping behaviour in mice or body weight reduction in rats following repeated oral administration. ⋯ No tolerance developed to the analgesic activity of flupirtine maleate in mice or rats dosed for up to 19 consecutive days. Finally, in morphine-dependent Rhesus monkeys, there was no difference in the rate of self-administration of flupirtine maleate when compared to the saline vehicle. Therefore, these results clearly show that flupirtine maleate, in animals, is without abuse potential and physical dependence liability.