Tramadol

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Bruno Megarbane - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms of Tramadol related neurotoxicity in the rat does diazepam Tramadol combination play a worsening role in overdose
    Toxicology and Applied Pharmacology, 2016
    Co-Authors: Camille Lagard, Lucie Chevillard, Isabelle Malissin, Patricia Risede, Jacques Callebert, Laurence Labat, Jeanmarie Launay, J L Laplanche, Bruno Megarbane
    Abstract:

    Poisoning with opioid analgesics including Tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate Tramadol-related neurotoxicity, consequences of diazepam/Tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of Tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of Tramadol and diazepam/Tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/Tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to Tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to Tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/Tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced Tramadol-induced seizures. Our study shows that diazepam/Tramadol combination does not worsen Tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.

  • Mechanisms of Tramadol-related neurotoxicity in the rat: Does diazepam/Tramadol combination play a worsening role in overdose?
    Toxicology and Applied Pharmacology, 2016
    Co-Authors: Camille Lagard, Lucie Chevillard, Isabelle Malissin, Patricia Risede, Jacques Callebert, Laurence Labat, Jeanmarie Launay, J L Laplanche, Bruno Megarbane
    Abstract:

    Poisoning with opioid analgesics including Tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate Tramadol-related neurotoxicity, consequences of diazepam/Tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of Tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of Tramadol and diazepam/Tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/Tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to Tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to Tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/Tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced Tramadol-induced seizures. Our study shows that diazepam/Tramadol combination does not worsen Tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.

Norman Rosenthal - One of the best experts on this subject based on the ideXlab platform.

  • randomized study of Tramadol acetaminophen versus placebo in painful diabetic peripheral neuropathy
    Current Medical Research and Opinion, 2007
    Co-Authors: Roy Freeman, David J. Hewitt, Donna Jordan, Philip Raskin, G Vorsanger, Jim Xiang, Norman Rosenthal
    Abstract:

    OBJECTIVE: To examine the efficacy and safety of Tramadol/acetaminophen (APAP) for the management of painful diabetic peripheral neuropathy (DPN). METHODS: Adults with painful DPN involving the lower extremities received 37.5 mg Tramadol/325 mg APAP or placebo, up to 1-2 tablets four times daily, for 66 days. Subjects rated average daily pain and sleep interference from 0 ('none') to 10 ('pain as bad as you can imagine' or 'complete interference') every night. Baseline values were recorded for 7 days before starting study medication. The primary endpoint was change in mean of average daily pain scores from baseline to final week. Secondary efficacy outcomes included pain intensity, sleep interference, quality of life, mood, and global impression of change. Potential study limitations included permission to use serotonin reuptake inhibitors concomitantly (except venlafaxine or duloxetine) and the lack of a Tramadol-alone or APAP-alone control group. RESULTS: A total of 160 subjects received Tramadol/APAP and 153 received placebo. Tramadol/APAP reduced average daily pain significantly compared to placebo from baseline to the final week (-2.71 vs. -1.83, p = 0.001). Tramadol/APAP was associated with significantly greater improvement than placebo (p 10% of subjects in either the Tramadol/APAP or placebo group was nausea (11.9% and 3.3%, respectively). Adverse events resulted in early study discontinuation for 8.1% and 6.5% of subjects in the Tramadol/APAP and placebo groups, respectively. CONCLUSION: Tramadol/APAP was more effective than placebo and was well tolerated in the management of painful DPN.

  • analgesic efficacy and safety of Tramadol acetaminophen combination tablets ultracet in treatment of chronic low back pain a multicenter outpatient randomized double blind placebo controlled trial
    The Journal of Rheumatology, 2004
    Co-Authors: Paul M Peloso, Luc Fortin, Andre Beaulieu, Marc Kamin, Norman Rosenthal
    Abstract:

    OBJECTIVE: To evaluate the analgesic efficacy and safety of Tramadol 37.5 mg/acetaminophen 325 mg (Tramadol/APAP) combination tablets for treatment of chronic low back pain (LBP). METHODS: This 91 day, multicenter, outpatient, randomized, double blind, placebo controlled study enrolled 338 patients with chronic LBP requiring daily medication for > or = 3 months. Patients with at least moderate pain [pain visual analog scale (VAS) with scores > or = 40/100 mm] after washout were randomized to Tramadol/APAP or placebo. After a 10 day titration, patients received 1 or 2 tablets QID. Primary outcome measure was final pain VAS score. Secondary measures included pain relief, quality of life and physical functioning, efficacy failure, and overall medication assessments. RESULTS: In total, 336 intent-to-treat patients received Tramadol/APAP (n = 167) or placebo (n = 169). Mean baseline pain VAS score was 67.8. Intent-to-treat analysis showed significantly better mean final pain VAS scores (47.4 vs 62.9; p < 0.001) and mean final pain relief scores (1.8 vs 0.7; p < 0.001) for Tramadol/APAP than for placebo. Roland Disability Questionnaire scores and physical-related subcategories of the McGill Pain Questionnaire and the Medical Outcome Study Short Form-36 Health Survey were significantly better for Tramadol/APAP patients. More patients rated Tramadol/APAP as "very good" or "good" than placebo (63.6 vs 25.2%; p < 0.001). Kaplan-Meier estimates of cumulative discontinuation rates due to efficacy failures were 22.9% (Tramadol/APAP) vs 54.7% (placebo; p < 0.001). The most common treatment related adverse events with Tramadol/APAP were nausea (12.0%), dizziness (10.8%), and constipation (10.2%). Average daily dose of Tramadol/APAP was 4.2 tablets (Tramadol 158 mg/APAP 1369 mg). CONCLUSION: Tramadol 37.5 mg/APAP 325 mg combination tablets show efficacy in pain reduction, in measures of physical functioning and quality of life, and in overall medication assessments, with a tolerability profile comparable with other opioids used for the treatment of chronic LBP.

  • A double-blind placebo-controlled comparison of Tramadol/acetaminophen and Tramadol in patients with postoperative dental pain.
    Pain, 2004
    Co-Authors: James R. Fricke, David J. Hewitt, Donna Jordan, Alan C. Fisher, Norman Rosenthal
    Abstract:

    Abstract The objective of this study was to compare the analgesic efficacy of Tramadol/acetaminophen (APAP) (total dose 75 mg/650 mg) and Tramadol (total dose 100 mg) for the control of pain after oral surgery. A total of 456 patients with moderate-to-severe pain within 5 h after extraction of two or more third molars were randomized to receive two identical encapsulated tablets containing Tramadol/APAP 37.5 mg/325 mg, Tramadol 50 mg, or placebo. Tramadol/APAP was superior to Tramadol (P

Camille Lagard - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms of Tramadol related neurotoxicity in the rat does diazepam Tramadol combination play a worsening role in overdose
    Toxicology and Applied Pharmacology, 2016
    Co-Authors: Camille Lagard, Lucie Chevillard, Isabelle Malissin, Patricia Risede, Jacques Callebert, Laurence Labat, Jeanmarie Launay, J L Laplanche, Bruno Megarbane
    Abstract:

    Poisoning with opioid analgesics including Tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate Tramadol-related neurotoxicity, consequences of diazepam/Tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of Tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of Tramadol and diazepam/Tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/Tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to Tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to Tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/Tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced Tramadol-induced seizures. Our study shows that diazepam/Tramadol combination does not worsen Tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.

  • Mechanisms of Tramadol-related neurotoxicity in the rat: Does diazepam/Tramadol combination play a worsening role in overdose?
    Toxicology and Applied Pharmacology, 2016
    Co-Authors: Camille Lagard, Lucie Chevillard, Isabelle Malissin, Patricia Risede, Jacques Callebert, Laurence Labat, Jeanmarie Launay, J L Laplanche, Bruno Megarbane
    Abstract:

    Poisoning with opioid analgesics including Tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate Tramadol-related neurotoxicity, consequences of diazepam/Tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of Tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of Tramadol and diazepam/Tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/Tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to Tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to Tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/Tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced Tramadol-induced seizures. Our study shows that diazepam/Tramadol combination does not worsen Tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.

Laurence Labat - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms of Tramadol related neurotoxicity in the rat does diazepam Tramadol combination play a worsening role in overdose
    Toxicology and Applied Pharmacology, 2016
    Co-Authors: Camille Lagard, Lucie Chevillard, Isabelle Malissin, Patricia Risede, Jacques Callebert, Laurence Labat, Jeanmarie Launay, J L Laplanche, Bruno Megarbane
    Abstract:

    Poisoning with opioid analgesics including Tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate Tramadol-related neurotoxicity, consequences of diazepam/Tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of Tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of Tramadol and diazepam/Tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/Tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to Tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to Tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/Tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced Tramadol-induced seizures. Our study shows that diazepam/Tramadol combination does not worsen Tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.

  • Mechanisms of Tramadol-related neurotoxicity in the rat: Does diazepam/Tramadol combination play a worsening role in overdose?
    Toxicology and Applied Pharmacology, 2016
    Co-Authors: Camille Lagard, Lucie Chevillard, Isabelle Malissin, Patricia Risede, Jacques Callebert, Laurence Labat, Jeanmarie Launay, J L Laplanche, Bruno Megarbane
    Abstract:

    Poisoning with opioid analgesics including Tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate Tramadol-related neurotoxicity, consequences of diazepam/Tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of Tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of Tramadol and diazepam/Tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/Tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to Tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to Tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/Tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced Tramadol-induced seizures. Our study shows that diazepam/Tramadol combination does not worsen Tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.

J L Laplanche - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms of Tramadol related neurotoxicity in the rat does diazepam Tramadol combination play a worsening role in overdose
    Toxicology and Applied Pharmacology, 2016
    Co-Authors: Camille Lagard, Lucie Chevillard, Isabelle Malissin, Patricia Risede, Jacques Callebert, Laurence Labat, Jeanmarie Launay, J L Laplanche, Bruno Megarbane
    Abstract:

    Poisoning with opioid analgesics including Tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate Tramadol-related neurotoxicity, consequences of diazepam/Tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of Tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of Tramadol and diazepam/Tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/Tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to Tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to Tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/Tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced Tramadol-induced seizures. Our study shows that diazepam/Tramadol combination does not worsen Tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.

  • Mechanisms of Tramadol-related neurotoxicity in the rat: Does diazepam/Tramadol combination play a worsening role in overdose?
    Toxicology and Applied Pharmacology, 2016
    Co-Authors: Camille Lagard, Lucie Chevillard, Isabelle Malissin, Patricia Risede, Jacques Callebert, Laurence Labat, Jeanmarie Launay, J L Laplanche, Bruno Megarbane
    Abstract:

    Poisoning with opioid analgesics including Tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate Tramadol-related neurotoxicity, consequences of diazepam/Tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of Tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of Tramadol and diazepam/Tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/Tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to Tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to Tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/Tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced Tramadol-induced seizures. Our study shows that diazepam/Tramadol combination does not worsen Tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin.