Pharmacokinetic differences of tramadol in several animal species and human beings (original) (raw)
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Role of active metabolites in the use of opioids
European Journal of Clinical Pharmacology, 2009
The opioid class of drugs, a large group, is mainly used for the treatment of acute and chronic persistent pain. All are eliminated from the body via metabolism involving principally CYP3A4 and the highly polymorphic CYP2D6, which markedly affects the drug's function, and by conjugation reactions mainly by UGT2B7. In many cases, the resultant metabolites have the same pharmacological activity as the parent opioid; however in many cases, plasma metabolite concentrations are too low to make a meaningful contribution to the overall clinical effects of the parent drug. These metabolites are invariably more water soluble and require renal clearance as an important overall elimination pathway. Such metabolites have the potential to accumulate in the elderly and in those with declining renal function with resultant accumulation to a much greater extent than the parent opioid. The best known example is the accumulation of morphine-6-glucuronide from morphine. Some opioids have active metabolites but at different target sites. These are norpethidine, a neurotoxic agent, and nordextropropoxyphene, a cardiotoxic agent. Clinicians need to be aware that many opioids have active metabolites that will become therapeutically important, for example in cases of altered pathology, drug interactions and genetic polymorphisms of drug-metabolizing enzymes. Thus, dose individualisation and the avoidance of adverse effects of opioids due to the accumulation of active metabolites or lack of formation of active metabolites are important considerations when opioids are used.
European Journal of Pharmacology, 2007
In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED 50 = 1.9 (0.7 -5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED 80 of (-)-NIH 11082 in the PPQ test [AD 50 = 0.75 (0.26 -2.20) mg/kg, s.c]. beta-Funaltrexamine and norbinaltorphimine, selective mu-and kappa-receptor antagonists, respectively, were inactive versus the ED 80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.
Behavioural Brain Research, 1998
Like psychomotor stimulants, a weak amphetamine-like agent, such as phenylpropanolamine, enhances the analgesic effects of morphine (MOR). Thus, it is possible that full psychomotor stimulant potency is not required to increase the analgesic action of opiates. The validity of this assumption is here tested by studying the ability of (-)-norpseudoephedrine (NPE), an enantiomer of phenylpropanolamine and a metabolite of cathinone, to influence both the analgesic effects of MOR and its discriminative stimulus properties. In mice NPE (5.6-10.0-17.0 mg/kg i.p.) did not prolong the latency to lick or to remove paws from a plate warmed at 54 degrees C. However, it significantly potentiated the analgesic effect of 3.2 mg/kg of MOR. These results were replicated in rats by use of the formalin test, which measures the numbers of hind paw flinches produced by injecting 50 microl of formalin into the dorsal surface of the paw. The higher dose of NPE (17 mg/kg) increased the effect of sub-analgesic doses of MOR (0.56 and 1.0 mg/kg). In rats trained to discriminate between 0.5 mg/kg of amphetamine and solvent in a two-lever operant behavior reinforced by water access. NPE induced a dose-dependent increment of drug lever responding from 0% at 1.0 mg/kg to 100% at 32.0 mg/kg. In contrast, NPE did not generalize for the MOR cue up to the dose of 56.0 mg/kg, which produced a substantial reduction of the response rate. However, when given in combination, NPE attenuated the discriminative effects of MOR and potentiated its inhibitory action on the response rate. These results exclude a direct action of NPE on the mu opiate system. In conclusion, NPE preserves amphetamine-like properties and these properties are probably responsible for the interaction of the drug with the analgesic and discriminative effects of MOR. Therefore, this study contradicts the assumption that the analgesic effects of MOR can be enhanced by a sympathomimetic drug that lacks significant psychostimulant actions.
Chemical Methodologies
One of the most significant medication families of drugs utilized for intensive treatment, and acute or chronic pain are morphine, opium, and opium-like drugs. The chemical synapse is the place of the effect of drugs and neurotransmitters. Opioids exert their analgesic properties through biochemical changes at chemical synapses by stimulating opioid receptors. Opioids prevent the transmission of pain messages to higher nerve centers by releasing the inhibitory transmitters in the synapse. The problem of using these substances is addiction and severe dependence on them due to the feeling of euphoria, relaxation, and painlessness caused by the use of these substances. Many aspects of the clinical action of opiates are still unknown. Therefore, research on the novel features of these compounds is ongoing in biochemistry and pharmaceutical sciences to synthesize drugs with fewer side effects and more effectiveness. On the other hand, the gate theory is one of the most important theories in controlling pain signals and analgesic drugs. Therefore, comprehensive knowledge and study of analgesic compounds are necessary to achieve the primary goal. Aromatic NH such as in tetrazole and mitragynine, and NH resonance next to the carbonyl functional group like that in carbamates has a high potential to create opioid properties due to the potential of creating tautomeric structures.
The pharmacology of chronic pain management
Seminars in Anesthesia, Perioperative Medicine and Pain, 1997
M " ORPHINE, THE active alkaloid in opium,. was discovered in 1803 after many of the world's cultures had already acknowledged the euphoric and analgesic effects of opium for centuries. 1 Since then, there has been growing knowledge of the neuropharmacology of opioid analgesia. Opioids are a class of drugs that are derived from the opium of the poppy flower. They are distinctive in that, as opposed to other analgesics, there is no ceiling dose, z which allows for increased analgesia with increased doses. These increases are essentially only limited by observed side effects. The mechanism of action is through activation of opioid receptors throughout the nervous system. The agonist group of opioids that are used for chronic pain management achieve analgesia primarily through a subset of these receptors called the/z~-opioid receptors. There are several other subsets that when activated are responsible for the side effects seen with opioids (eg, respiratory depression, constipation, sedation). 1 This system of pain modulation is extensive and includes peripheral nerve endings (primary afferent nociceptors), dorsal horn of the spinal cord, midbrain, brain stem, thalamus, limbic system, and cortex. L3 The opioids are metabolized by the liver, and they should be used with caution in patients with hepatic impairment. The metabolites are at least partially excreted in the urine. Therefore, in drugs that have an active metabolite (such as morphine) or toxic metabolite (such as meperidine, whose metabolite normeperidine may lead to seizures with accumulation), renal dysfunction may also significantly affect the dose, schedule, and choice of opioid. The long-term use of opioids in the treatment
Effect of 12-monoketocholic acid on modulation of analgesic action of morphine and tramadol
European Journal of Drug Metabolism and Pharmacokinetics, 2009
This work is concerned with the potential promotive action of l2-monoketocholic acid (12-MKC) on the analgesic effect of morphine and tramado!. The investigation was carried out on laboratory Wistar rats divided into five test groups, each treated with either morphine (2 mg/kg), tramadol (9.6 mg/kg), I2-MKC (2 mg/kg), morphine + I2-MKC, or tramadol + l2-MKC, the control group receiving physiological solution (2 mg/kg). The effect of 12-MKC on the analgesic action of morphine and tramadol was determined by radiation heat method. Morphine and tramadol, given in equimolar doses, did not show significant difference in the degree of analgesia. In combination with morphine, l2-MKC increased significantly the analgesic effect compared with the group treated with morphine alone. However, 12-MKC caused no change in the action of tramado!. The 5-day intravenous application of l2-MKC in combination with the two analgesics caused no changes in the biochemical parameters nor pathohistological changes in the liver parenchyma of tested animals.
The role of metabolites in morphine analgesic effects
Palliative Medicine in Practice
Morphine is metabolized into two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide. Morphine-6-glucuronide is a potent analgesic that is responsible for up to 97% of the analgesic effect. Morphine-3-glucuronide does not bind to opioid receptors and is devoid of any analgesic effect. However, it activates the Toll-like 4 receptors initiating neurogenic inflammation in the central nervous system. This, in turn, is responsible for anti-analgesic and hyperalgesic effects. There are a number of strategies on how to inhibit this pronociceptive effect and finally improve morphine analgesia.