Pharmacokinetic differences of tramadol in several animal species and human beings (original) (raw)
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.
Novel approaches in the development of new analgesics
Neurophysiologie Clinique/Clinical Neurophysiology, 1990
A recently developed series of highly selective and systemically active g-agonists such as Tyr-X~Gly-Pfie~Letl~Thr(OtBu), with X = D.Ser (OtBu) in BUBU and X = D.Cys(StBu) in BUBUC~ and complete ifihibitors of enkeptmlin metabolism (Kelatorphan, RB 38 A, PC 12) have enabled the major role played by/z-opioid receptors in supraspinal analgesia to be demonstrated• This is in agreement With the~results of in vivo ~t-receptor.~occupancy measured by taking into account the cross-reactivity of the ~-lig~md~. for ~,-sites,.In contrast(# and 3 binding sites seem to act independently to control pain at th~ spinal level. S~rong.anai'gesic effects, especially in arthritic rats, can also be obtained by complete protection of toni-cally~or tplra~gmall~¢ released endogenous enkephalins with mixed inhibitors such as RB38A. Chronic icv • ¢ , administration of tll~t agomst,DAGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the g agonist, DSTBULET or with RB 38 A. Moi-eo~vev;rmi~d.,inhibi'tors did not induce any significant respiratory depression• All these data emphasize the iriterest ink'de-vel6pping~--agonis,l~s,and mixed inhibitors with appropriate biovailability for clinical evaldati0m analgesics / pain R~suml~-'---D~veloppement r~cent d'une nouvelle s~rie d'agonistes opioides, ,Le ddveloppement r~cent d'une nouvellb s~rie d'agonistes opioi'des ~ hautement sdlectifs et actifs par voie ayst~mique te'ts tlue Tyr-X-Gly-Phe-Leu= Thr(OtB~):avec X = D. Ser(OtBu) B UB U et x = D. Cys(StBu) B UBUC,/ainsi que d " une nou velle. sd/ie d'fiihibiteurs complets du mdtabolisme des enkdphdines (k~latorphan, RB 38A., PC 12) a permis de'dd}nontrer l'implication majoritaire des rdcepteurs tz clans l'analgdsie supraspinale. Ceci est e~ ae¢ord avec les expdriences,in vivo d'occupation des sites tz, lorsque l'on prend en compte la:rdaetivit~ eroisde des,ligands~ pou~les sites ~z. Inversement les sites de liaison tt et ~ semblek~t modulds ind~pendamment lg contr~le'de;douleur au niveau spinal. De plus, l'utilisation d'inhibiteurs tel tlRe le RB 384, qui protbgent compldtement~:les enkdphtffines endog~nes libdrdes de fa~on tonique,et'plrasique de la ddgradation enzymatique, conduit d des eff~ts analgdsiques intenses, en particulier chez le rat arthitique.: Une administration chronique~par voie icy de DAGO, un agoniste ~z sdlectif,-suivie;d'une administrationde naldxone; induit un sysdrome de, manctu, e sdvbre, analogue d celui induit par la morphine, alors qu'un effet de ddpendclnce fait~esrob,~ervd avec le DSTBULET ou le RB 38A. Par ailleurs, les inhibiteurs mixtes n'induisent pfts de ddpression respiratoire. Toutes ces donndes ddmontrent l'int~r~t "de d~velopper des agonistes ~et des inhibiteurs mixles prdsentant la biodisponibilitd ndcessaire pour une ~valuation clinique. analgdsique ,/ douleur
Journal of Pharmacology and Experimental Therapeutics, 2003
In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (ϩ)-tramadol [(ϩ)-T] has been explored in rats. Male Wistar rats were infused with (ϩ)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (ϩ)-T, and (ϩ)-O-demethyltramadol [(ϩ)-M1], and measuring antinociception. Pharmacokinetics of (ϩ)-M1, but not (ϩ)-T, was affected by Q pretreatment: early after the start of (ϩ)-T infusion, levels of (ϩ)-M1 were significantly lower (P Ͻ 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (ϩ)-M1. In fact, results from another experiment where (ϩ)-M1 was given in the presence and in absence of Q showed that (ϩ)-M1 elimination clearance (CL ME0 ) was significantly lower (P Ͻ 0.05) in animals receiving Q. Inhibition of both (ϩ)-M1 formation clearance (CL M10 ) and CL ME0 were modeled by an inhibitory E MAX model, and the estimates (relative standard error) of the maximum degree of inhibition (E MAX ) and IC 50 , plasma concentration of Q eliciting half of E MAX for CL M10 and CL ME0 , were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (ϩ)-T was negligible and (ϩ)-M1 was responsible for the observed effects, which depend linearly on (ϩ)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (ϩ)-T administration. Tramadol (T) is a safe and effective analgesic used during the last two decades in the treatment of several types of pain . Despite its long-term use, the understanding and prediction of the time course of its pharmacological effects are still hampered by the presence of active metabolites and the coexistence of opioid and nonopioid mechanisms. In fact, T is administered as a racemic mixture of two enantiomers, (ϩ)-T and (Ϫ)-T, which are metabolized in the liver forming, among others, the two main active metabolites (ϩ)-O-demethyltramadol [(ϩ)-M1] and (Ϫ)-O-demethyltramadol [(Ϫ)-M1], respectively. Data from literature suggest that (ϩ)-enantiomers show opioid properties, while (Ϫ)-enantiomers are able to inhibit the uptake of norepinephrine. This duality of action makes T an atypical opioid . Recently the antinociceptive properties of the two active metabolites of T, (ϩ)-M1 and (Ϫ)-M1, have been evaluated in the pharmacokinetic/pharmacodynamic (pk/pd) perspective in the rat. The results showed that (ϩ)-M1, in accord with its -opioid receptor agonist properties , was able to produce maximum antinociception in the tail-flick test; however, when (Ϫ)-M1, a monoamine re-uptake inhibitor , was given alone, no significant effects were found . However, showed that in the presence of (ϩ)-M1, (Ϫ)-M1 significantly contributed to the antinociception elicited by the opioid, and this contribution could be well described by a mechanismbased pk/pd model incorporating the known pharmacological properties of the two metabolite enantiomers. The relative role of the enantiomers of T and M1 in anal-This work was supported by Gru ¨nenthal GmbH (Aachen, Germany). Article, publication date, and citation information can be found at .
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.
IJBCP International Journal of Basic & Clinical Pharmacology
Background: Adjuvant analgesics are added to pain management regimen to reduce opioid consumption and minimise their side effect. Newer ones like dexmedetomidine and pregabalin have not been thoroughly researched. Objectives of the study to study the opioid sparing effect of dexmedetomidine and pregabalin using tail flick and hot plate method in male wistar rats. Methods: Forty two rats were grouped into seven groups with six in each group. Analgesic activity was tested using tail flick, where in the reaction time to flick its tail on a heated surface was noted. In the hot plate method, the reaction time to withdraw or lick the paws when placed on heated surface was noted. Results: The reaction time to flick its tail was prolonged with dexmedetomidine and pregabalin when combined with opioids even in sub therapeutic doses. Conclusion: Adjuncts like dexmedetomidine and pregabalin can be very useful in mutimodal pain management and also to reduce the opioid consumption.
OPIOID Pharmacology : A Review
Pain is an unpleasant sensation that originates from ongoing or impending tissue damage. Management of different types of pain (acute, postoperative, inflammatory, neuropathicor cancer) is challenging and yet the most frequent issue encountered by clinicians. Pharmacological therapy is the first line of approach for the treatment of pain and opioid drugs are prescribed for acute and chronic pain of moderate/severe intensity arising from malignant and non-malignant diseases. The opium poppy was cultivated as early as 3400BC in Mesopotamia. The term opium refers to a mixture of alkaloids from the poppy seed. Opiates are naturally occurring alkaloids such as morphine or codeine and opioid is the term used broadly to describe all compounds that work at the opioid receptors. The physiologic modulation of noxious stimuli involves a highly complex system that integrates the actions of multiple opioid receptors and endogenous opioid peptides. Opioids produce their actions at a cellular level by activating opioid receptors. These receptors are distributed throughout the central nervous system (CNS) with high concentrations in the nuclei of tractus solitarius, peri-aqueductal grey area (PAG), cerebral cortex, thalamus and substantia gelatinosa (SG) of the spinal cord. They have also been found on peripheral afferent nerve terminals and many other organs. The efficacy of centrally applied opioids is well recognized, but when applied peripherally, for example in post-traumatic and inflammatory states, their actions are less reliable. Although they are associated with addiction, dependence, tolerance and abuse liability even then their place in pain management remains undebatable and unchallenged.
British Journal of Pharmacology, 1993
1 Tramadol is a centrally acting analgesic with low opioid receptor affinity and, therefore, presumably additional mechanisms of analgesic action. Tramadol and its main metabolite 0-desmethyltramadol were tested on rat central noradrenergic neurones of the nucleus locus coeruleus (LC), which are involved in the modulation of nociceptive afferent stimuli. 2 In pontine slices of the rat brain the spontaneous discharge of action potentials of LC cells was recorded extracellularly. (-)-Tramadol (0.1-100JM), (+)-tramadol (0.1-100tJM), (-)-O-desmethyltramadol (0.1-100 JM) and (+)-O-desmethyltramadol (0.01-1 JM) inhibited the firing rate in a concentration-dependent manner. (+)-O-desmethyltramadol had the highest potency, while all other agonists were active at a similar range of concentrations.
A role for heterodimerization of µ and opiate receptors in enhancing morphine analgesia
Proceedings of The National Academy of Sciences, 2004
Opiates such as morphine are the choice analgesic in the treatment of chronic pain. However their long-term use is limited because of the development of tolerance and dependence. Due to its importance in therapy, different strategies have been considered for making opiates such as morphine more effective, while curbing its liability to be abused. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, ␦ opioid receptor ligands have been useful in enhancing morphine's potency. The underlying molecular basis for these observations is not understood. We propose the modulation of receptor function by physical association between and ␦ opioid receptors as a potential mechanism. In support of this hypothesis, we show that -␦ interacting complexes exist in live cells and native membranes and that the occupancy of ␦ receptors (by antagonists) is sufficient to enhance opioid receptor binding and signaling activity. Furthermore, ␦ receptor antagonists enhance morphine-mediated intrathecal analgesia. Thus, heterodimeric associations between -␦ opioid receptors can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies.
European Journal of Pharmaceutical Sciences, 2016
Tramadol hydrochloride is a centrally acting analgesic used for the treatment of moderate-to-severe pain. It has three main metabolites: O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5). Because of the frequent use of tramadol by patients and drug abusers, the ability to determine the parent drug and its metabolites in plasma and cerebrospinal fluid is of great importance. In the present study, a pharmacokinetic approach was applied using two groups of five male Wistar rats administered a 20 mg/kg dose of tramadol via intravenous (i.v.) or intraperitoneal (i.p.) routes. Plasma and CSF samples were collected at 5-360 min following tramadol administration. Our results demonstrate that the plasma values of C max (C 0 in i.v. group) and area under the curve (AUC) 0-t for tramadol were 23,314.40 ± 6944.85 vs. 3187.39 ± 760.25 ng/mL (C max) and 871.15 ± 165.98 vs. 414.04 ± 149.25 μg•min/mL in the i.v. and i.p. groups, respectively (p b 0.05). However, there were no significant differences between i.v. and i.p. plasma values for tramadol metabolites (p N 0.05). Tramadol rapidly penetrated the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) (5.00 ± 0.00 vs. 10.00 ± 5.77 min in i.v. and i.p. groups, respectively). Tramadol and its metabolites (M1 and M2) were present to a lesser extent in the cerebrospinal fluid (CSF) than in the plasma. M5 hardly penetrated the CSF, owing to its high polarity. There was no significant difference between the AUC 0-t of tramadol in plasma (414.04 ± 149.25 μg•min/mL) and CSF (221.81 ± 83.02 μg•min/mL) in the i.p. group. In addition, the amounts of metabolites (M1 and M2) in the CSF showed no significant differences following both routes of administration. There were also no significant differences among the K p,uu,CSF(0-360) (0.51 ± 0.12 vs. 0.63 ± 0.04) and K p,uu,CSF(0-∞) (0.61 ± 0.10 vs. 0.62 ± 0.02) for i.v. and i.p. pathways, respectively (p N 0.05). Drug targeting efficiency (DTE) values of tramadol after i.p. injection were more than unity for all scheduled time points. Considering the main analgesic effect of M1, it is hypothesized that both routes of administration may produce the same amount of analgesia.