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Tramadol induces antidepressant-type effects in mice
by
Rojas-Corrales MO, Gibert-Rahola J, Mico JA
Department of Neuroscience,
Faculty of Medicine,
University of Cadiz, Spain.
Life Sci 1998; 63(12):PL175-80

ABSTRACT
Tramadol is a clinically-effective, centrally-acting analgesic. This drug is a racemic mixture of two enantiomers, each one displaying different mechanisms: (+)tramadol displays opioid agonist properties and inhibits serotonin reuptake while (-)tramadol inhibits preferentially noradrenaline reuptake. The action of tramadol on the monoaminergic reuptake is similar to that of antidepressant drugs. Therefore, we have examined the effects of (+/-)tramadol, (+)tramadol and (-)tramadol in a test predictive of antidepressant activity, the forced swimming test in mice. Both (+/-)tramadol and its (-) enantiomer displayed a dose-dependent reduction on immobility; while the effect induced by the (+) enantiomer was not significant. Inhibition of noradrenaline synthesis, but not of serotonin synthesis, was capable of blocking the effect of (+/-)tramadol. The alpha-adrenoceptor antagonist phentolamine, as well as the alpha2-adrenergic antagonist yohimbine, and the beta-adrenoceptor blocker propranolol countered the immobility-reducing action of (+/-)tramadol. Moreover, neither the serotoninergic blocker methysergide nor the opioid antagonist naloxone antagonized the effect of (+/-)tramadol. Our results show that (+/-)tramadol and (-)tramadol have antidepressant-like effect in mice, probably mediated by the noradrenergic system rather than the serotoninergic or opioidergic ones.

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Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro
by
Driessen B, Reimann W, Giertz H
Grunenthal GmbH,
Abteilung Pharmakologie,
Aachen,
Germany.
Br J Pharmacol 1993 Mar; 108(3):806-11

ABSTRACT
1. The centrally acting analgesic, tramadol, has low affinity for opioid receptors and therefore presumably other mechanisms of analgesic action. Neurotransmitter release and uptake experiments were used to characterize the effects of tramadol on the central noradrenergic and dopaminergic systems. 2. Tramadol inhibited the uptake of [3H]-noradrenaline into purified rat hypothalamic synaptosomes with an IC50 of 2.8 microM; the (-)-enantiomer was about ten times more potent than the (+)-enantiomer. Results with the principal metabolite O-desmethyltramadol were very similar. Inhibition of dopamine uptake into purified rabbit caudate nucleus synaptosomes was very weak with 62% inhibition of 100 microM. 3. Rat occipital cortex slices were preincubated with [3H]-noradrenaline and rabbit caudate nucleus slices with [3H]-dopamine, then superfused and stimulated electrically. Tramadol, 1 and 10 microM, enhanced the stimulation-evoked [3H]-noradrenaline overflow by 25 and 69%, respectively; the (-)-enantiomer was more potent than the racemate or the (+)-enantiomer. Tramadol, 10 microM, had no effect on dopamine release. 4. The effects of tramadol on the stimulation-evoked [3H]-noradrenaline release were abolished when uptake sites were already blocked by a high concentration of cocaine. 5. The metabolite O-desmethyltramadol showed a slight facilitation of the stimulation-evoked noradrenaline release; the effect was more pronounced in the presence of a high concentration of naloxone. In the presence of cocaine, inhibition of the release was observed similar to the effect of morphine but less potent. 6. The results show that tramadol blocks noradrenaline uptake with selectivity as compared to dopamine uptake. The interaction with the noradrenaline transporter is stereoselective.

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In vivo microdialysis and conditioned place preference studies in rats are consistent with abuse potential of tramadol
by
Sprague JE, Leifheit M, Selken J,
Milks MM, Kinder DH, Nichols DE.
The Department of Pharmaceutical & Biomedical Sciences,
The Raabe College of Pharmacy,
Ohio Northern University, Ada, Ohio 45810.
Synapse 2002 Feb;43(2):118-21

ABSTRACT
The abuse potential of tramadol was investigated using both in vivo microdialysis measures of dopamine (DA) release within the nucleus accumbens (NAc) shell and the conditioned place preference (CPP) paradigm in rats. Tramadol (75 mg/kg, i.p.) induced a statistically significant increase (starting 80 min posttreatment) in DA release within the NAc shell, which was maintained for at least 120 min posttreatment. Tramadol (18.75, 37.5, and 75 mg/kg i.p.) produced a statistically significant CPP, with the effects of the two highest doses comparable to those induced by morphine (5 mg/kg, s.c.). The release of DA within the NAc shell may be responsible for the rewarding properties of tramadol and, together with the CPP results, provide evidence that tramadol may possess greater abuse potential than originally believed.

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Affinity, potency and efficacy of tramadol
and its metabolites at the cloned human mu-opioid receptor
by
Gillen C, Haurand M, Kobelt DJ, Wnendt S
Department of Molecular Pharmacology,
Grunenthal GmbH,
Aachen, Germany.
Naunyn Schmiedebergs Arch Pharmacol 2000 Aug; 362(2):116-21

ABSTRACT
The present study was conducted to characterise the centrally active analgesic drug tramadol hydrochloride [(1RS,2RS)-2-[(dimethyl-amino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride] and its metabolites M1, M2, M3, M4 and M5 at the cloned human mu-opioid receptor. Membranes from stably transfected Chinese hamster ovary (CHO) cells were used to determine the four parameters of the ligand-receptor interaction: the affinity of (+/-)-tramadol and its metabolites was determined by competitive inhibition of [3H]naloxone binding under high and low salt conditions. The agonist-induced stimulation of [35S]GTPgammaS binding permits the measurement of potency (EC50), efficacy (Emax = maximal stimulation) and relative intrinsic efficacy (effect as a function of receptor occupation). The metabolite (+)-M1 showed the highest affinity (Ki=3.4 nM) to the human mu-opioid receptor, followed by (+/-)-M5 (Ki=100 nM), (-)-M1 (Ki=240 nM) and (+/-)-tramadol (Ki=2.4 microM). The [35S]GTPgammaS binding assay revealed an agonistic activity for the metabolites (+)-M1, (-)-M1 and (+/-)-M5 with the following rank order of intrinsic efficacy: (+)-M1>(+/-)-M5>(-)-M1. The metabolites (+/-)-M2, (+/-)-M3 and (+/-)-M4 displayed only weak affinity (Ki> 10 microM) and had no stimulatory effect on GTPgammaS binding. These data indicate that the metabolite (+)-M1 is responsible for the mu-opioid-derived analgesic effect.

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The opioid tramadol demonstrates excitatory properties of non-opioid character - a preclinical study using alfentanil as a comparison
by
Freye E, Latasch L, Von Bredow G, Neruda B.
Abteilung fur Gefasschirurgie und Nierentransplantation,
Operatives Zentrum,
Heinrich-Heine-Universitat Dusseldorf.
Schmerz. 1998 Feb 28;12(1):19-24

ABSTRACT
ramadol, an analgesic with mean potency one tenth that of morphine is used regularely for the treatment of chronic and postoperative pain. Previous reports have indicated that tramadol may induce seizure activity when given together with a selective serotonine reuptake inhibitor (SSRI). Therefore, its major mode of action may be questioned which purportedly is due to binding with the opioid receptor and partly due to the inhibition of monoamine reuptake.We therefore set out to study its potential in inducing seizure activity and to quantify its effect on EEG-power spectra and on the central modulation of sensory afferents in awake and trained dogs (n=7). In order to demonstrate if opioid receptors mediated these effects, incremental doses of tramadol were given which was followed by naloxone for possible reversal. After a wash-out period the same animals were exposed to graded doses of alfentanil, a pure &mgr;-receptor agonist. Again this was followed by the opioid antagonist naloxone for reversal.The electroencephalogram (EEG) and the event-related evoked potentials (SEP) were used to demonstrate possible excitatory effects. In order to derive the SEP the front paw was stimulated electrically (Digi Stim II trade mark ) while the evoked potentials were picked up contralaterally from the somatosensory cortex using stick-on elektrodes. 256 sweeps were averaged (Lifescan trade mark ) and the peak-to-peak amplitude was measured to demonstrate CNS excitation compared to control (%). Additionally, the raw electroencephalogram was viewed for epileptogenic changes and its power computed into the various power bands alpha, beta, delta und theta using FFT over a time epoch of 60 s. Following control, graded doses of either tramadol (2-5-10 mg/kg i.v.) or alfentanil (10-30-60 &mgr;g/kg i.v.) were given every 15 min while the EEG and the SEP were recorded. Thereafter naloxone (20 &mgr;g/kg i.v.) was injected for reversal.Tramadol did not suppress the amplitude of the SEP at any dose. High doses (>5 mg/kg i.v.) resulted in an increase (+100%) of the amplitude of the evoked potential. This was accompanied by short-term muscle fibrillations, and a short-term spike-and-wave activity in the EEG followed by a long-lasting theta-dominance. These effects could not be reversed by naloxone. In contrast to tramadol, alfentanil induced a dose-related depression of amplitude in the SEP with a maximum of 82% suggesting a depressive effect of modulation of afferents in the sensory cortex. This effect was fully naloxone reversible and was followed by a rebound in amplitude of the SEP together with an increase in fast beta-waves in the EEG.Tramadol very little mediates its central action via the &mgr;-opioid receptor as the present effects were not naloxone reversible. Consistent with the results is the very low affinity of tramadol to the opioid receptor which is several thousand times less than that of morphine. Most likely, inhibition of central norepinephrine and serotonine reuptake as well as the reduction in 5-HT-turnover may contribute to the effects of tramadol. Due to the monoamine reuptake inhibition an increase in transmission may result, triggering off excitatory phenomena with spike-and-wave activity in the CNS. Such excitatory effects, however, may only be seen when tramadol is used in doses exceeding the therapeutic range.

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Pharmacology of tramadol
by
Dayer P, Desmeules J, Collart L
Service de Pharmacologie Clinique
et Consultation de la Douleur,
Hopital Cantonal Universitaire, Geneve, Suisse.
Drugs 1997; 53 Suppl 2:18-24

ABSTRACT
(+/-)-Tramadol is a synthetic analogue of codeine. It is a central analgesic with a low affinity for opioid receptors. Its selectivity for mu receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.

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Drug dependence and
abuse potential of tramadol
by
Liu ZM, Zhou WH, Lian Z,
Mu Y, Ren ZH, Cao JQ, Cai ZJ
National Institute on Drug Dependence,
Beijing,
China.

Chung Kuo Yao Li Hsueh Pao 1999 Jan;20(1):52-4

ABSTRACT
AIM: To assess the drug dependence and abuse liability of tramadol. METHODS: Subjects of opiate addicts with history of tramadol abuse were 219. Physical dependence of tramadol was assessed using opiate withdrawal scale (OWS), psychic dependence was assessed by association test of Addiction Research Center Inventory-Chinese Version (ARCI-CV); the degrees of craving experienced for tramadol was self-reported on visual analogue scale (VAS). RESULTS: The scores of OWS of tramadol were 0.05-1.07; 3 scores on scales in particular being used the identify euphoric effects--MBG, sedative effects--PCAG, and psychotomimetic effects--LSD of ARCI were 7.3, 6.1, and 3.4, respectively (F = 38.1, P

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The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds
by
Gray AM, Spencer PS, Sewell RD
Division of Pharmacology,
The Welsh School of Pharmacy, UWC, Cardiff, Wales.
Br J Pharmacol 1998 Jun; 124(4):669-74

ABSTRACT
1. Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception. 2. All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. 3. Opioid antagonists, naloxone (0.5 mg kg(-1), s.c.) and naltrindole (1 mg kg(-1), s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. 4. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg(-1) (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception. 6. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs. 7. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without affecting morphine antinociception, implicates the delta-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.

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Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis
by
Wilder-Smith CH, Hill L, Osler W, O'Keefe S
Gastrointestinal Clinic,
Groote Schuur Hospital,
University of Cape Town,
South Africa.
Dig Dis Sci 1999 Jun; 44(6):1107-16

ABSTRACT
Tramadol and morphine were compared for treatment of severe chronic pancreatitis pain and their interaction with gut motor function. Oral tramadol or morphine doses were titrated double-blinded and randomized for five days in 25 patients and pain, side effects, bowel function, orocecal and colonic transit, anal resting pressure, and rectal distension thresholds were measured. Pain intensities (mean+/-SD, 0 = none, 100 = unbearable) before treatment and on day 4 were 75+/-19 and 8+/-13 with tramadol (P

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Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, enhances the analgesic effect of tramadol
by
Rojas-Corrales MO, Ortega-Alvaro A,
Gibert-Rahola J, Roca-Vinardell A, Mico JA
Department of Neuroscience,
Neuropsycopharmacology Unit,
University of Cadiz, Plz. Fragela 9,
11003, Cadiz, Spain
Pain 2000 Nov 1; 88(2):119-124

ABSTRACT
The ability of pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, to enhance the clinical antidepressant response to selective serotonin re-uptake inhibitors is generally attributed to a blocking of the feedback that inhibits the serotoninergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to enhance the analgesic effect of tramadol, an atypical centrally-acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the re-uptake of 5-HT in the raphe nuclei. Racemic pindolol (2 mg/kg, s.c.), rendered analgesic a non-effective acute dose of tramadol (10-40 mg/kg, i.p.) in two nociceptive tests: a hot plate test in mice and a plantar test in rats. Moreover, (+/-)8-OH-DPAT (0.125-1 mg/kg, s.c.), a selective 5-HT(1A) agonist, reduces the analgesic effect of tramadol in the same tests. These results suggest an implication of the somatodendritic 5-HT(1A) receptors in the analgesic effect of tramadol and open a new adjuvant analgesic strategy for the use of this compound.

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Comparison of respiratory effects
of tramadol and oxycodone
by
Tarkkila P, Tuominen M, Lindgren L
Department of Anaesthesia,
Helsinki University Central Hospital,
Finland.
J Clin Anesth 1997 Nov; 9(7):582-5

ABSTRACT
STUDY OBJECTIVE: To compare the respiratory effects of tramadol and oxycodone. DESIGN: Placebo-controlled, double-blind randomized study. SETTING: IV Department of Surgery, Helsinki University Central Hospital. PATIENTS: 36 ASA physical status I and II patients undergoing minor surgery with general anesthesia. INTERVENTIONS: The respiratory effects of intravenous (i.v.) tramadol 0.6 mg/kg and oxycodone 0.04 mg/kg were compared after induction of anesthesia with propofol and succinylcholine-facilitated endotracheal intubation. Patients spontaneously breathed halothane in 70% nitrous oxide and oxygen via a nonrebreathing valve. The trial drugs or placebo were given after recovery from neuromuscular block. MEASUREMENTS AND MAIN RESULTS: Inspiratory and expiratory oxygen and end-tidal carbon dioxide concentrations (ETCO2), tidal volume (VT) minute volume of ventilation (VE), and respiratory rate (RR) were recorded by side-stream spirometry with end-tidal halothane of 0.3% for 30 minutes before surgery. Oxycodone caused a significant respiratory depression seen as an increase in the inspiratory-expiratory oxygen difference and ETCO2 and as a decrease in VE and RR. On the contrary, the effect of tramadol were similar to those of placebo. VT was not affected by any study drug. CONCLUSION: Tramadol was not associated with respiratory depression in the present setting.

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