Jakovlev, V; Sofia, RD; Achterrath-Tuckermann, U; Von Schlichtegroll, A; Thiemer, K
The analgesic potency of ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl]carbamate (flupirtine, D 9998) in mice and rats in Haffner's test, electro-pain test and Randall-Selitto test (inflammation induced pain) lies between the more potent dextromoramide and methadone and the more weakly active pethidine, dextropropoxyphene, codeine, phenacetin and paracetamol. In comparison to codeine, flupirtine is up to 4 times more potent, up to 2 times more active than pethidine and 4 times more potent than dextropropoxyphene. With one exception of inflammation-induced pain, where flupirtine shows activity about 1 1/2 times that of phenacetin and paracetamol, both analgesics are about 10 to nearly 30 times less active than flupirtine. In the hot plate test, flupirtine is twice as active as codeine and approximately 10 times more active than phenacetin and paracetamol. The weakest analgesic activity of flupirtine is seen in the acetic acid test where it is about half as active as codeine and approximately as active as dextropropoxyphene. Nevertheless, flupirtine is up to 10 times more potent than phenacetin and paracetamol. The acetic acid test is claimed to be non-specific. Flupirtine is enterally absorbed to a higher degree than the other tested centrally acting analgesics. In regard to the results of various analgesic investigations in mice and rats flupirtine can be classified as a medium to strong acting analgesic. The duration of action of flupirtine is comparable to that of codeine. Experiments with flupirtine suggest that there are some convincing criteria for a pronounced central acting component of its analgesic activity. These criteria are the strong efficacy in the hot-plate and Haffner's test, in which only centrally acting analgesics show distinct effects, and the finding that flupirtine increases the pain threshold for vocalisation in rats and mice, excluding a pure reflex of the spinal cord. In current experiments cncerning the mode of action, flupirtine exhibits a distinct central analgesic component of action. Flupirtine does not show any other signs of opiate properties or those of other potent analgesics. Thus, flupirtine does not develop tolerance in mice and rats after 19 or 17 days of daily administration. Flupirtine does not trigger jumping behavior in the mouse jumping test and does not show any withdrawal symptoms after 5 weeks of daily administration after deprivation of flupirtine alone or after deprivation and additional administration of naloxone. Also, in self-administration experiments with rhesus monkeys flupirtine does not indicate any properties comparable to those of morphine. Flupirtine is devoid of respiratory depression in rabbits and its antagonism against the morphine-induced tail phenomenon in mice. Also, flupirtine does not show any antitussive action. Last but not least, flupirtine shows no affinity to the opiate receptor of rat brain, and does not affect the morphine receptors of guinea-pig ileum in vitro in a morphine-like way. As seen in rat paw edema and in adjuvant arthritis, flupirtine possesses a peripheral antiinflammatory component of action. These effects show a further important difference between flupirtine and opiates or other potent analgesics which develop dependence. Beause the antiinflammatory doses of flupirtine are obviously higher than the analgesically effective doses and, furthermore, the inhibition of prostaglandin biosynthesis by flupirtine is observed only in higher concentrations, its antiinflammatory activity observed in animals can hardly be expected in humans. Ulcerogenic effects, occurring often after stronger antiinflammatory agents, have not been found after flupirtine. In contrast to opiates and other strong acting analgesics, flupirtine shows an antipyretic activity in the yeast fever test in rats, which is comparable to that of phenacetin. This activity could not be observed in human studies up till now.
analgesic agent; codeine; dextromoramide; dextropropoxyphene; flupirtine; methadone; naloxone; paracetamol; pethidine; phenacetin; animal cell; animal experiment; drug interaction; mouse; nervous system; nonhuman; pharmacology; priority journal; rat; Aminopyridines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antitussive Agents; Drug Tolerance; Guinea Pigs; Kinetics; Lethal Dose 50; Levallorphan; Male; Mice; Muscle Contraction; Muscle, Smooth; Naloxone; Rats; Reaction Time; Receptors, Opioid; Species Specificity