µ-Opioid receptor in the CA1 involves in tramadol and morphine cross state-dependent memory.

In the present study, the effect of tramadol - an opioid painkiller drug with abuse potential- on amnesia and state-dependent memory and its interaction with the opioidergic system was investigated in male Wistar rats. Intra CA-1 administration of tramadol (0.5, 1, and 2 µg/rat) before training, dose-dependently decreased the learning ability in passive avoidance task. Amnesia induced by pre-train tramadol administration was significantly reversed by pre-test administration of tramadol (1 µg/rat). Pre-test administration of naltrexone (a µ-opioid receptor (MOR) antagonist) inhibited the effect of tramadol on memory retrieval. In addition, the pre-test administration of morphine (1 µg/rat, intra-CA1) also reversed memory impairment induced by pre-train tramadol administration. Although, pre-train morphine administration (1 µg/rat, intra-CA1), induced memory impairment reversed by pre-test tramadol administration (1 µg/rat, intra-CA1). In addition, the level of MOR in the hippocampus decreased in animals with memory impairment due to using tramadol in the training day. However, state-dependent retrieval using tramadol or cross state-dependent retrieval using morphine enhanced the MOR level in the hippocampus. The results of the study suggested that intra-CA1 tramadol administration induced memory impairment, improved by pre-test administration of either tramadol or morphine (MOR agonist). It could be concluded that tramadol is capable to induced state-dependent memory and also, it has a cross state-dependent memory with morphine in the hippocampus, done possibly through MOR.

The effect of tramadol on sneeze-induced urethral continence reflex through µ-opioid receptors in the spinal cord in rats.

AIMS: We examined the efficacy of tramadol on the urethral reflex during sneezing, as well as the role of µ-opioid receptors in the spinal cord, in rats. METHODS: Forty-one female Sprague-Dawley rats were used. The rats were divided into normal female rats and rats with vaginal distension (VD), which mimics stress urinary incontinence (SUI) in humans. Under urethane anesthesia, the sneeze-induced amplitude of urethral responses (AUR) and baseline pressure (BP) were examined after intravenous injection of tramadol using a microtransducer-tipped catheter in both rat groups. The effect of intrathecal cyprodime, a selective µ-opioid receptor antagonist, following intravenous tramadol injection was examined in normal rats. The tilt leak point pressure (tilt LPP) after intravenous tramadol injection was also evaluated in both groups. RESULTS: In normal rats, tramadol enhanced the AUR and BP by 33.2% and 19.5%, respectively. Tramadol also increased BP by 13.9% in rats with VD, but it did not change AUR. Intrathecal cyprodime alone did not change AUR, but it decreased BP. However, tramadol-provoked increments in AUR were blocked by intrathecal cyprodime, while BP was recovered to the level that it was before administration of cyprodime. Tramadol was associated with a significant elevation in tilt LPP: 24.8% and 19.5% in normal and VD rats, respectively. CONCLUSIONS: These findings suggest that tramadol effectively enhances the AUR at the spinal level and BP peripherally. Therefore, stimulation of the spinal µ-opioid receptors may be useful for the treatment of SUI.

Nalbuphine could decrease the rewarding effect induced by tramadol in mice while enhancing its antinociceptive activity.

Nalbuphine, a kappa-opioid agonist and mu-opioid partial agonist, has been used as an analgesic or an adjuvant with morphine to attenuate the development of morphine dependence and rewarding effect. In this study, we investigated the effect of nalbuphine on tramadol rewarding effect and antinociception. Using the conditioned place preference (CPP) paradigm in mice, we demonstrated that co-administration of nalbuphine (7mg/kg, s.c.) with tramadol (70mg/kg, s.c.) during conditioning completely blocked the CPP induced by tramadol. Co-administration of nalbuphine blocked the increase in dopamine level in the nucleus accumbens induced by tramadol. These actions were accompanied by an increase rather than attenuation of the antinociceptive effect of tramadol. These results suggest that nalbuphine could have a great potential as a pharmacotherapy for tramadol abuse.

Involvement of nitric oxide and ATP-sensitive potassium channels in the peripheral antinoceptive action of a tramadol-dexketoprofen combination in the formalin test.

Systemic coadministration of tramadol and dexketoprofen can produce antinociceptive synergism in animals. There has been only limited evaluation of this drug combination in the peripheral nervous system in terms of the antinociceptive interaction and its mechanisms. The aim of the present study was to evaluate the peripheral antinociceptive interaction between tramadol and dexketoprofen in the formalin test and the involvement of the nitric oxide (NO)-cyclic guanosine monophosphate pathway and ATP-sensitive K(+) channels. Different doses of tramadol or dexketoprofen were administered locally to the formalin-injured mouse paw and the antinociceptive effect evaluated. ED50 values were calculated for both drugs alone and in combination. Coadministration of tramadol and dexketoprofen produced an antinociceptive synergistic interaction during the second phase of the formalin test. Pretreatment with NO antagonists, including l-NG-nitroarginine methyl ester and 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, or the ATP-sensitive K(+) channel antagonist glibenclamide reversed the antinociceptive synergistic effect of the tramadol-dexketoprofen combination, suggesting that NO and ATP-sensitive K(+) channels were involved.

Tramadol antinociception is potentiated by clonidine through α2-adrenergic and I2-imidazoline but not by endothelin ET(A) receptors in mice.

Tramadol is a centrally acting analgesic that acts via µ-opioid agonism and by blocking the neuronal uptake of norepinephrine and serotonin. Clonidine potentiates the antinociceptive effects of tramadol; however the receptors involved in this potentiation have not been studied. Endothelin ET(A) receptor antagonists potentiate antinociceptive effects of morphine and oxycodone; however the effects of endothelin ET(A) receptor antagonists on tramadol antinociception have not been evaluated. This study was conducted to determine the effect of clonidine on tramadol antinociception; the role of opioid, α2-adrenergic and I2-imidazoline receptors in clonidine potentiation of tramadol antinociception; and the effect of endothelin ET(A) receptor antagonists in modulating tramadol antinociception. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with tramadol; clonidine plus tramadol; or antagonists plus tramadol. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α2-adrenoceptor antagonist), idazoxan (α2-adrenoceptor/I2-imidazoline antagonist), BMS182874 or BQ123 (endothelin ET(A) receptor antagonists) to study the involvement of these receptors. Tramadol produced a dose dependent increase in antinociceptive latencies. Tramadol antinociception was partially blocked by naloxone but not by yohimbine or idazoxan. Clonidine potentiated tramadol antinociception; potentiation was blocked by naloxone, yohimbine and idazoxan. Idazoxan produced a more pronounced blockade of potentiation than yohimbine. BMS182874 or BQ123 had no effect on tramadol antinociception, indicating that endothelin ET(A) receptors are not involved in tramadol antinociception in mice. Results demonstrate the involvement of opioid but not α2-adrenergic/I2-imidazoline receptors in tramadol antinociception and that opioid, α2-adrenergic and I2-imidazoline receptors are involved in clonidine potentiation of tramadol antinociception.

Antagonistic effect of atipamezole, flumazenil and naloxone following anaesthesia with xylazine, tramadol and tiletamine/zolazepam combinations in pigs.

OBJECTIVE: To evaluate the antagonistic effects of atipamezole (ATI), flumazenil (FLU) and naloxone (NAL) alone and in various combinations following administration of tiletamine-zolazepam-xylazine-tramadol. STUDY DESIGN: Prospective, experimental, randomized cross-over study. ANIMALS: Eight Chinese miniature pigs (three females and five males) mean age 8 (range 7-10) months and bodyweight 57.5 (52.4-62.1) kg. METHODS: All animals were anaesthetized with tiletamine/zolazepam (3.0 mg kg(-1)), xylazine (1.2 mg kg(-1)) and tramadol (1.6 mg kg(-1)) given intramuscularly (IM). Thirty minutes later, one of eight treatments was administered IM: saline control, ATI (0.12 mg kg(-1)), FLU (0.1 mg kg(-1)), NAL (0.03 mg kg(-1)), ATI-FLU, FLU-NAL, ATI-NAL or ATI-FLU-NAL. After injection of antagonists the following times were recorded: to recovery of the palpebral, pedal and tail clamp reflexes, to head movement, sternal recumbency, standing and walking. Posture, sedation, analgesia, jaw relaxation and auditory response were scored at set times until 120 minutes after injection of antagonists. Heart rates, respiratory rates and rectal temperature were measured at those times. Data were analyzed by anova for repeated measures, followed by the Tukey's test to compare differences between means, or by Kruskal-Wallis test as appropriate. RESULTS: FLU, NAL alone, or FLU-NAL did not effectively antagonize anaesthesia induced by tiletamine/zolazepam-xylazine-tramadol. ATI, ATI-FLU, ATI-NAL and ATI-FLU-NAL produced an immediate and effective recovery from anaesthesia. The combination of ATI-FLU-NAL was the most effective combination in antagonizing the anaesthetic effect. Adverse effects such as tachycardia, tachypnoea, excitement and muscle tremors were not observed during this study. CONCLUSION AND CLINICAL RELEVANCE: ATI-FLU-NAL is the most effective combination for antagonizing tiletamine/zolazepam-xylazine-tramadol anaesthesia in pigs. However, ATI alone or in various combinations also provides effective antagonism.

Laser-evoked potentials as a tool for assessing the efficacy of antinociceptive drugs.

Laser-evoked potentials (LEPs) are brain responses to laser radiant heat pulses and reflect the activation of Adelta nociceptors. LEPs are to date the reference standard technique for studying nociceptive pathway function in patients with neuropathic pain. To find out whether LEPs also provide a useful neurophysiological tool for assessing antinociceptive drug efficacy, in this double-blind placebo-controlled study we measured changes induced by the analgesic tramadol on LEPs in 12 healthy subjects. We found that tramadol decreased the amplitude of LEPs, whereas placebo left LEPs unchanged. The opioid antagonist naloxone partially reversed the tramadol-induced LEP amplitude decrease. We conclude that LEPs may be reliably used in clinical practice and research for assessing the efficacy of antinociceptive drugs.

Efectividad de la morfina por vía subaracnoidea versus tramadol más ketorolaco por vía intravenoso en el control del dolor postquirúrgico en cirugías ortopédicas de miembros inferiores / Effects of morphine by more subarachnoid tramadol versus intravenous ketorolac in controlling postoperative pain in orthopedic surgery of the lower limbs

Se realizó un ensayo clínico, ciego simple, aleatorizado, con intención a tratar. EL objetivo fue valorar la efectividad analgésica postquirúrgica de cirugias de miembros inferiores y los efectos secundarios del sulfato de morfina administrado por vía subaracnoidea versus el tramadol más Ketorolaco por vía intravenosa. La muestra fue de 122 sujetos, divididos en dos grupo A (n=60) a quienes se les administró 500 microgramos de morfina más bupivacaína hiperbárica vía subaracnoidea y al grupo B (n=60) a los que se les administro tramadol 100 mg más ketorolaco 60 mg vía intravenosa, los resultados fueron que la morfina más bupivacaina fue más efectiva que el tramadol más ketorolaco para el control del dolor postquirúrgico. Con un efecto análgesico de 23 horas versus 12 horas del grupo B valor de p menor 0.005. Las reacciones adversas más frecuentes fueron: prurito, náuseas y retención urinaria...

Altered antinociceptive efficacy of tramadol over time in rats with painful peripheral neuropathy.

Pain due to peripheral nerve injury or disease is a dynamic process, such that the mechanism that underlies it alters over time. Tramadol has been reported to be analgesic in clinical neuropathic pain, with varying levels of efficacy due to a patient population that has had neuropathic pain for a wide range of time. In order to address and examine the issue, the antinociceptive efficacy of tramadol over time was tested in rats with a chronic constriction injury (CCI) of the left sciatic nerve. Rats developed a robust hind paw hypersensitivity to innocuous mechanical stimulation ipsilateral to CCI surgery. Subcutaneous injection of tramadol in rats two weeks after CCI surgery dose-dependently attenuated mechanical hypersensitivity, which was abolished with the mu-opioid receptor antagonist naloxone but not the alpha(2)-adrenoceptor antagonist yohimbine. Systemic tramadol also attenuated mechanical hypersensitivity four weeks after CCI surgery, but the efficacy significantly diminished at this time point. In addition, the effect of tramadol at this later time point could be reduced with yohimbine as well as naloxone. These data demonstrate that the efficacy of tramadol depends in part on the duration of nerve injury-evoked nociception, and that its antinociceptive mechanism changes over time. Alteration in antinociceptive mechanism over time may explain the inconsistency in efficacy of this and other analgesic drugs in chronic pain patients.

Interaction between tramadol and two anti-emetics on nociception and gastrointestinal transit in mice.

BACKGROUND: Clinical studies suggest that tramadol-induced analgesia is partially antagonized by ondansetron. AIMS: To investigate the type of interaction between tramadol and two anti-emetics on antinociception and gastrointestinal transit in mice. METHODS: We assessed the antinociceptive (acetic acid writhing test, plantar test) and antitransit (charcoal meal) effects of tramadol individually, and combined with ondansetron or droperidol in female Swiss CD-1 mice. Isobolograms and analysis of variance were used to determine the type of interaction. RESULTS: In the writhing test, tramadol, ondansetron and droperidol, each induced dose-related inhibition of nociception. The ED(50)'s were: tramadol 4.2+/-0.33 mg kg(-1); ondansetron 1.03+/-0.05 mg kg(-1), and droperidol 1.00+/-0.14 mg kg(-1). Dose-response curves were also obtained with tramadol combined with ondansetron or droperidol at 1:1 fixed ratios. The isobolographic analysis demonstrated antagonism for both combinations. In the plantar test, the ED(50) for tramadol was 51.4+/-2.3 mg kg(-1), but no dose-response curves could be obtained with ondansetron or droperidol individually. The interaction was assessed from dose-response curves to tramadol in the presence of a fixed dose of ondansetron (0.1 mg kg(-1)) or droperidol (0.05 mg kg(-1)). The results show antagonism between tramadol-ondansetron (p<0.05) and no interaction for the tramadol-droperidol combination. Both anti-emetics antagonized the antitransit effects of tramadol. CONCLUSIONS: The interaction of tramadol with ondansetron or droperidol on antinociception can be antagonistic or additive, depending on the type of stimuli. Both anti-emetics antagonize the anti-transit effects of tramadol. The results demonstrate antagonism between tramadol and the two anti-emetics for analgesia and inhibition of gastrointestinal transit, supporting previous clinical studies.

Isobolographic analysis of interaction between cyclooxygenase inhibitors and tramadol in acetic acid-induced writhing in mice.

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. Combined use of NSAIDs and opioids has been indicated for achieving better analgesia with reduced side effects. The present study was aimed at evaluating the combination of different NSAIDs, which inhibit cyclooxygenase (COX) enzymes and tramadol against acetic acid-induced writhing in mice. The expected beneficial effect of combination regimen was analyzed by isobolographic analysis. The oral and intrathecally administered tramadol, a mu-opioid and naproxen, a nonselective COX inhibitor produced dose-dependent antinociception, however, rofecoxib, a selective COX-2 inhibitor lacked analgesic efficacy in writhing test. Isobolographic analysis showed synergistic or supra-additive interactions for the combinations of naproxen and tramadol after oral and intrathecal administration. However, similar interaction was not observed when tramadol was combined with rofecoxib. Pretreatment with naloxone partially reversed the antinociceptive effect of tramadol per se and its combination with naproxen without modifying the per se effect of NSAID. The results demonstrated marked synergistic interaction between naproxen and tramadol and such interaction involved opioid as well as non-opioid mechanisms of tramadol and inhibition of COX-1 but not COX-2 by naproxen.

Evidence of self-synergism in the antinociceptive effect of tramadol in rats.

Tramadol is an atypical opioid with a complex mechanism of action including the synergistic interaction between the parent drug and an active metabolite. However, the local action of the parent drug is poorly documented. This study was designed to evaluate the site-site interaction of the antinociception produced by tramadol given by two different routes. The effects of individual and fixed-ratio combinations of locally (subcutaneous) and systemically (intraperitoneal) dosed tramadol were evaluated using the formalin test in rats. Isobolographic analysis was employed to identify the synergy produced by combinations. In the second phase of the formalin test, tramadol was active not only by the systemic (ED50 7.15+/-0.46 mg/kg i.p.) but also by the local route (ED50 134.6+/-25.1 microg/paw). The isobolographic analysis evidenced a "self-synergism" in the antinociceptive effect between the two routes of administration since the experimental ED50 (30.8+/-0.1 "dose units") of the combination was significantly lower than the theoretical ED50 (70.9+/-12.6 "dose units"). The mechanism underlying this self-synergism appears to be partially opioid since naloxone reversed the potentiation. The observed site-site interaction in the antinociceptive action of tramadol provides insights for alternatives in the management of pain.

Non-steroidal anti-inflammatory drugs antagonise the constipating effects of tramadol.

We report an antagonistic interaction between tramadol and non-steroidal anti-inflammatory drugs (NSAIDs), on gastrointestinal transit in rats. Transit was evaluated with charcoal and results are expressed as %inhibition. Tramadol and morphine had ED(50)s of 120.70+/-9.54 and 3.20+/-0.26 mg/kg, respectively, while metamizol (85 mg/kg), paracetamol (100 mg/kg) or ibuprofen (50 mg/kg) had no effect. All combinations of tramadol plus an NSAID, resulted in a rightward, non-parallel shift of the curves, which showed (two-way analysis of variance, ANOVA) significant differences from tramadol alone for the dose (P<0.0001), the drug (P<0.0001) and their interaction (P<0.0001), demonstrating antagonism. No interaction was present for morphine plus NSAIDs. The results demonstrate that NSAIDs antagonise the constipating effects of tramadol in rats, a fact that could have clinical relevance when combinations of these drugs are used in pain management in humans.

Actions of tramadol on micturition in awake, freely moving rats.

1 (+/-)-Tramadol, a widely used analgesic, is a racemate stimulating opioid receptors and inhibiting reuptake of noradrenaline and serotonin, that is, pharmacological principles previously shown to influence rat micturition. 2 We studied both (+/-)-tramadol and its enantiomers in conscious Sprague-Dawley rats undergoing continuous cystometry. The effects of these agents were compared to those of morphine ( micro -opioid receptor agonist) and tested after pretreatment with naloxone ( micro -opioid receptor antagonist). Cystometries were evaluated before and after intravenous (i.v.), intraperitoneal (i.p.) and intrathecal (i.t.) drug administrations. 3 The most conspicuous effects of i.v. (+/-)-tramadol (0.1-10 mg kg(-1)) was an increase in threshold pressure and an increase in micturition volume. 4 These effects were mimicked by (+)-tramadol (0.1-5 mg kg(-1) i.v.), whereas (-)-tramadol (5 mg kg(-1) i.v.) did not influence threshold pressure and micturition volume. 5 The effects of (+/-)-tramadol 5 mg kg(-1) on micturition volume were blocked by pretreatment with naloxone 0.3 mg kg(-1). Morphine (0.3-10 mg kg(-1) i.p.) increased threshold pressure but did not significantly increase micturition volume in doses not resulting in overflow incontinence. 6 (+/-)-Tramadol 10 mg kg(-1) increased urine production, an effect blocked by desmopressin 25 ng kg(-1). 7 (+/-)-Tramadol effectively inhibits micturition in conscious rats by stimulating micro -opioid receptors. A synergy between opioid receptor stimulation and monoamine reuptake inhibition may contribute to the micturition effects.

Respiratory depression by tramadol in the cat: involvement of opioid receptors.

BACKGROUND: Tramadol hydrochloride (tramadol) is a synthetic opioid analgesic with a relatively weak affinity at opioid receptors. At analgesic doses, tramadol seems to cause little or no respiratory depression in humans, although there are some conflicting data. The aim of this study was to examine whether tramadol causes dose-dependent inhibitory effects on the ventilatory carbon dioxide response curve and whether these are reversible or can be prevented by naloxone. METHODS: Experiments were performed in cats under alpha-chloralose-urethane anesthesia. The effects of tramadol and naloxone were studied by applying square-wave changes in end-tidal pressure of carbon dioxide (Petco2; 7.5-11 mmHg) and by analyzing the dynamic ventilatory responses using a two-compartment model with a fast peripheral and a slow central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and a single offset (apneic threshold). RESULTS: In five animals 1, 2, and 4 mg/kg tramadol (intravenous) increased the apneic threshold (control: 28.3 +/- 4.8 mmHg [mean +/- SD]; after 4 mg/kg: 36.7 +/- 7.1 mmHg; P < 0.05) and decreased the total carbon dioxide sensitivity (control: 109.3 +/- 41.3 ml x min(-1) x mmHg(-1) ) by 31, 59, and 68%, respectively, caused by proportional equal reductions in sensitivities of the peripheral and central chemoreflex loops. Naloxone (0.1 mg/kg, intravenous) completely reversed these effects. In five other cats, 4 mg/kg tramadol caused an approximately 70% ventilatory depression at a fixed Pet co2 of 45 mmHg that was already achieved after 15 min. A third group of five animals received the same dose of tramadol after pretreatment with naloxone. At a fixed Petco of 45 mmHg, naloxone prevented more than 50% of the expected ventilatory depression in these animals. CONCLUSIONS: Because naloxone completely reversed the inhibiting effects of tramadol on ventilatory control and it prevented more than 50% of the respiratory depression after a single dose of tramadol, the authors conclude that this analgesic causes respiratory depression that is mainly mediated by opioid receptors.

The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors.

UNLABELLED: Tramadol is a widely used analgesic, but its mechanism of action is not completely understood. Muscarinic receptors are involved in neuronal function in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets of analgesic drugs in the central nervous system. In this study, we investigated the effects of tramadol on type-3 muscarinic (M(3)) receptors using the Xenopus oocyte expression system. Tramadol (10 nM-100 micro M) inhibited acetylcholine-induced currents in oocytes expressing M(3) receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. Moreover, tramadol inhibited the specific binding sites of [(3)H]quinuclidinyl benzilate. These findings suggest that tramadol at clinically relevant concentrations inhibits M(3) function via quinuclidinyl benzilate-binding sites. This may explain the modulation of neuronal function and the anticholinergic effects of tramadol. IMPLICATIONS: Muscarinic receptors are involved in neuronal function and are targets of analgesic drugs. We here report that tramadol inhibits type-3 muscarinic receptors function via quinuclidinyl benzilate-binding sites at clinically relevant concentrations. These findings may explain the modulation of neuronal function and the anticholinergic effects of tramadol.

Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans.

UNLABELLED: To investigate a possible antinociceptive role of serotonin receptor subtype 3 (5-HT(3)), we evaluated the effects of a coadministration of ondansetron, a 5-HT(3) selective antagonist, and tramadol, a central analgesic dependent on enhanced serotonergic transmission. Fifty-nine patients undergoing ear, throat, and nose surgery, using tramadol for 24-h postoperative patient-controlled analgesia (bolus = 30 mg; lockout interval = 10 min) were randomly allocated either to a group receiving ondansetron continuous infusion (1 mg. mL(-1). h(-1)) for postoperative nausea and vomiting (Group O) or to a control group receiving saline (Group T). Pain and vomiting scores and tramadol consumption were evaluated at 4, 8, 12, and 24 h. Pain scores were never >4, according to a 0-10 numerical rating scale, in both groups. Group O required significantly larger doses of tramadol at 4 h (213 versus 71 mg, P < 0.001), 8 h (285 versus 128 mg, P < 0.002), and 12 h (406 versus 190 mg, P < 0.002). Vomiting scores were higher in Group O at 4 h (P < 0.05) and 8 h (P = 0.05). We conclude that ondansetron reduced the overall analgesic effect of tramadol, probably blocking spinal 5-HT(3) receptors. IMPLICATIONS: Serotonin is an important neurotransmitter of the descending pathways that down-modulate spinal nociception. In postoperative pain, ondansetron, a selective 5-HT(3) receptor antagonist, increased the analgesic dose of tramadol. We suggest that, when antagonized for antiemetic purpose, 5-HT(3) receptors foster nociception, because of their site-dependent action.

Prospective multicenter evaluation of tramadol exposure.

BACKGROUND: Tramadol is a novel analgesic possessing both opiate and noradrenergic effects. Its low potential for abuse suggests increasing use, but there are limited data on the toxicity in overdose. METHODS: Multicenter prospective case series. All exposures from October 1995 through August 1996 reported to seven Poison Centers were evaluated. RESULTS: There were 126 cases of which 87 were tramadol alone. Of the tramadol alone cases, 51 were female (59%). Age ranged from 1 to 86 y with a mean and median of 26.8 y (SD 17.2) and 25 y, respectively. There were 15 cases of children less than 6 years old. Symptoms reported with overdose were: lethargy 26 (30%), nausea 12 (14%), tachycardia 11 (13%), agitation 9 (10%), seizures 7 (8%), 4 each (5%) of coma and hypertension, and respiratory depression 2 (2%). All seizures were brief. Naloxone reversed sedation and apnea in 4 of 8 patients. One patient experienced a seizure immediately after administration of naloxone. Other treatments were: diazepam (3 patients), and phenytoin, lorazepam and nifedipine (1 patient each). Tramadol 500 mg was the lowest dose associated with seizure, tachycardia, hypertension or agitation while 800 mg was the lowest dose associated with coma and respiratory depression. Urine drug screens performed on 19 patients were negative for opiates. All symptomatic cases exhibited effects within 4 h of ingestion. Mean hospital stay was 15.2 h (range 2-96 h, SD 15.8). Nineteen patients were admitted to an intensive care unit with a mean stay of 25 h (SD 20). DISCUSSION: Much of the toxicity in tramadol overdose appears to be attributable to the monoamine uptake inhibition rather than its opioid effects. Agitation, tachycardia, confusion and hypertension suggest a possible mild serotonin syndrome. No arrhythmias beyond tachycardia were seen. CONCLUSION: This study suggests significant neurologic toxicity from tramadol overdose. Serious cardiovascular toxicity was not seen.

Muscle rigidity induced by the opioid analgesic tramadol, but not by the non-opioid flupirtine.

The influence of high doses of two analgesic drugs, tramadol and flupirtine on the electromyographic activity in the gastrocnemius soleus muscles was examined. Tramadol (100-200 mg/kg po) dose-dependently induced a tonic electromyographic activity, which is generally accepted as a model of the opiate-induced muscle rigidity. That effect was antagonized by intraperitoneal injection of naloxone (0.8 mg/kg ip). On the other hand, flupirtine even in the high doses (100-200 mg/kg po) did not induce any tonic electromyographic activity. The obtained results confirm an opiate-like action of tramadol, but not that of flupirtine, on the muscle tension.

[Duality of the analgesic effect of tramadol in humans]. / Dualité de l'effet analgésique du tramadol chez l'homme.

Tramadol is a central analgesic with low affinity for opioid receptors. A major active metabolite (O-desmethyl-tramadol) shows a higher affinity for opioid receptors than tramadol. The influence of naloxone and quinidine (a selective P450DB1 or CAP2D6 inhibitor) on tramadol effect was investigated crossover and double-blind vs placebo in healthy subjects. They received tramadol (100 mg p.o.), tramadol+naloxone (0.8 mg i.v.) and tramadol+quinidine (50 mg p.o.). Analgesia was assessed, after transcutaneous electrical stimulation, by a categorical numerical scale and by measurement of the antinociceptive effect at spinal level by R-III reflex. Analgesia peaked at 3 hours and lasted about 6 hours. The mean decrease in peak tramadol analgesia by naloxone was only 31%. Quinidine had no effect on the extent of tramadol analgesia, but inhibited tramadol induced myosis. We therefore conclude that tramadol analgesia is only partially mediated by a mu opioid agonist effect. Tramadol analgesia thus results from an action on opioid receptors other than the mu subtype and/or from nonopioid effects (monoaminergic system). Quinidine blockade of tramadol myosis suggests that the mu agonist component of tramadol effect results from its O-demethylation by the polymorphic P450DB1 enzyme.