(+)-トラマドール

DEA NFLIS-Drug Category -> Narcotic Analgesics

Pharmaceuticals -> Analgesics

Pharmaceuticals -> Listed in ZINC15

Pharmaceutical

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Soluble

7.50e-01 g/L

>39.5 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Analgesics, Opioid; Narcotics

Pharmaceuticals

178-181 °C

180 - 181 °C

9.41

pKa1 = 9.23 (tertiarary amine); pKa2= 13.08 (alcohol)

Danger

H300 (28.6%): Fatal if swallowed [Danger Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P316, P317, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 7 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

Status: Active Update: 29-05-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/24188

Tramadol: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tramadol hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tramadol hydrochloride/

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. (b) Narcotic drugs. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation containing any of the following narcotic drugs, or their salts calculated as the free anhydrous base or alkaloid, in limited quantities as set forth below. 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, its salts, optical and geometric isomers and salts of these isomers (including tramadol) is included on this list.

CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016; This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death.[Dowell D et al; Morbidity and Mortality Weekly Report (MMWR) 65 (1):1-49 (2016); Available from, as of March 22, 2016: http://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm]

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Tramadol hydrochloride/

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Tramadol hydrochloride/

Store at 25 °C (77 °F); excursions permitted to 15 - 30 °C (59 -86 °F).

Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place. /Tramadol hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Tramadol hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /Tramadol hydrochloride/

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /Tramadol hydrochloride/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Tramadol hydrochloride/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Tramadol hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Tramadol hydrochloride/

Skin protection: Handle with gloves. /Tramadol hydrochloride/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Tramadol hydrochloride/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Tramadol hydrochloride/

In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all, symptoms caused by overdosage with ULTRAM, the risk of seizures is also increased with naloxone administration. (L1712)

To investigate a possible antinociceptive role of serotonin receptor subtype 3 (5-HT(3)), we evaluated the effects of a coadmin 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-hr 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/hr) for postoperative nausea and vomiting (Group O) or to a control group receiving saline (Group T). Pain & vomiting scores & tramadol consumption were evaluated at 4, 8, 12, and 24 hr. 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 hr (213 vs 71 mg, P<0.001), 8 hr (285 vs 128 mg, P<0.002), and 12 hr (406 vs 190 mg, P<0.002). Vomiting scores were higher in Group O at 4 hr (P<0.05) and 8 hr (P=0.05). We conclude that ondansetron reduced the overall analgesic effect of tramadol, probably blocking spinal 5-HT(3) receptors. ... 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.

The primary aims of this study were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen in acute postoperative pain and to use meta-analysis to demonstrate the efficacy of the combination drug compared with its components. Individual patient data from 7 randomized, double blind, placebo controlled trials of tramadol plus acetaminophen were supplied for analysis by the R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, USA. All trials used identical methods and assessed single-dose oral tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) in adult patients with moderate or severe postoperative pain. Summed pain intensity and pain relief data over 6 and 8 hr and global evaluations of treatment effect after 8 hrs were extracted. Number-needed-to-treat (NNT) for one patient to obtain at least 50% pain relief was calculated. NNTs derived from pain relief data were compared with those derived from pain intensity data and global evaluations. Information on adverse effects was collected. Combination analgesics (tramadol plus acetaminophen) had significantly lower (better) NNTs than the components alone, and comparable efficacy to ibuprofen 400 mg. This could be shown for dental but not postsurgical pain, because more patients were available for the former. Adverse effects were similar for the combination drugs and the opioid component alone. Common adverse effects were dizziness, drowsiness, nausea, vomiting, and headache. In sum, this meta-analysis demonstrated analgesic superiority of the combination drug over its components, without additional toxicity.

A case report involving a 34-year-old white male who was found dead at home by his roommate is presented. At the time of his death, he was being treated with tramadol/acetaminophen, metaxalone, oxycodone, and amitriptyline. The decedent's mother stated that he had been taking increasing amounts of pain medication in order to sleep at night. There were no significant findings at autopsy; however, toxicology results supported a cause and manner of death resulting from suicidal mixed tramadol and amitriptyline toxicity. This case reports the tissue and fluid distribution of tramadol, amitriptyline, and their metabolites in an acutely fatal ingestion in an effort to document concentrations of these analytes in 12 matrices with respect to one another to assist toxicologists in difficult interpretations.

Tramadol has weak opioid properties, and an analgesic effect that is mediated mainly by inhibition of the reuptake of norepinephrine & serotonin (5-hydroxytryptamine [5-HT]) and facilitation of 5-HT release (1,2) at the spinal cord. Because 5-HT3 receptors play a key role in pain transmission at the spinal level (3), the 5-HT3 antagonist ondansetron may decr the efficacy of tramadol ... . In /a previous/ study, a small dose of 1 mg/kg tramadol was administered along with ondansetron 0.1 mg/kg or placebo, 15 min before the induction of anesthesia. Early postoperative pain scored differed significantly between the test groups. We therefore tested the hypothesis that the tramadol requirement by patient-controlled analgesia (PCA) may be increased when ondansetron is administered for antiemetic prophylaxis.

For more Interactions (Complete) data for TRAMADOL (24 total), please visit the HSDB record page.

Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. The respiratory depressant effects include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients (RxList, A308). Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.

Serum aminotransferase levels can be elevated in a small proportion of patients receiving tramadol, particularly with high doses. Intentional and accidental overdoses of tramadol can cause respiratory arrest as well as acute liver failure, several fatal instances of which have been reported. In these cases, however, the liver injury may have been caused by shock, hypoxia or ischemia secondary to the respiratory arrest. Liver injury attributed to tramadol overdose has also been associated with hyperammonemia, lactic acidosis and hepatic steatosis, suggestive of direct mitochondrial injury. In some situations, acute liver failure after tramadol overdose may be related to acetaminophen taken separately or in combination with tramadol. Clinically apparent idiosyncratic liver injury with recommended doses of tramadol has not been reported.

TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 616(2) indicates that tramadol is expected to have low mobility in soil(SRC). The estimated pKa of tramadol is 9.23(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Tramadol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Tramadol is classified as not readily biodegradable in water(6) suggesting that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), a Koc value of 616(2) indicates that tramadol is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.23(3) indicates tramadol will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 25(SRC), from an estimated log Kow of 3.01(5) and a regression-derived equation(5), suggests the potential for bioconcentration in aquatic organisms is low(SRC). A photodegradation half-life of 3.7 days in water under natural sunlight conditions was reported(6). Tramadol is classified as not readily biodegradable in water(6) indicating that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tramadol, which has an estimated vapor pressure of 4.6X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase tramadol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1 hour(SRC), calculated from its rate constant of 1.5X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase tramadol may be removed from the air by wet and dry deposition(SRC). A photodegradation half-life of 3.7 days in water under natural sunlight conditions(4) suggests that tramadol may be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

The most common adverse drug reactions with tramadol are nausea, dizziness, pruritus, constipation, vomiting, somnolence, and headache. They tend to occur during the initial treatment rather than the maintenance phase. Tramadol-induced mania has been reported in a patient with no history of bipolar disorder.

Inhalation. Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults.

IDENTIFICATION AND USE: Tramadol is white, odorless crystalline powder with a bitter taste. Tramadol is an opioid analgesic which is indicated for the management of moderate to moderately severe pain in adults. In veterinary care, it may be used for the treatment of post-operative or chronic pain or cough. HUMAN EXPOSURE AND TOXICITY: Manifestations of overdosage are similar to those of other opiate agonists and include respiratory depression, lethargy, skeletal muscle flaccidity, coma, seizure, bradycardia, hypotension, cardiac arrest, miosis, vomiting, cold and clammy skin, cardiac collapse, and death. Serious and rarely fatal anaphylactoid reactions have been reported. Other reported hypersensitivity reactions include pruritus, urticaria, angioedema, bronchospasm, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Potentially life-threatening serotonin syndrome may occur with tramadol, particularly with concurrent use of other serotonergic drugs, drugs that impair the metabolism of serotonin (e.g., MAO inhibitors), or drugs that impair the metabolism of tramadol (e.g., inhibitors of cytochrome P-450 [CYP] isoenzymes 2D6 and 3A4). The use of tramadol has been associated with an increased risk of hyponatremia requiring hospitalization. One study suggests a moderately increased risk of a teratogenic effect of tramadol. When tramadol is used during pregnancy, there is a serious risk for neonatal abstinence syndrome. ANIMAL STUDIES: There were 910 single agent exposures to tramadol reported to the ASPCA Animal Poison Control Center during 2009-2013. Of the 749 dogs, 142 were symptomatic. Symptoms included being sedated/lethargic, vomiting, tachycardic, vocalizing or ataxic, and agitated or tremoring. Of the 157 cats, 96 were symptomatic with symptoms such as having mydriasis, hypersalivating, lethargic, ataxic or tachycardic, and vomiting. Serotonin-reduced rats were predisposed to tramadol-induced seizures, and serotonin concentrations were negatively associated with seizure thresholds. Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats, and rabbits at maternally toxic doses, but was not teratogenic at these dose levels. Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. No carcinogenic effect of tramadol was observed in mice at oral doses up to approximately twice the MDHD of 400 mg/day for a 60 kg adult based on body surface conversion, for 26 weeks and in rats at oral doses up to approximately twice the MDHD for two years. A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in mice dosed orally up to 0.36 times the MDHD for approximately two years.

Signs and Symptoms of Overdose

Tramadol and its O-desmethyl metabolite (M1) are selective, weak OP3-receptor agonists. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. The analgesic properties of Tramadol can be attributed to norepinephrine and serotonin reuptake blockade in the CNS, which inhibits pain transmission in the spinal cord. The (+) enantiomer has higher affinity for the OP3 receptor and preferentially inhibits serotonin uptake and enhances serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by stimulating alpha(2)-adrenergic receptors.

Tramadol was present at a maximum of 1,129 ng/L in untreated wastewater near Hesse, Germany sampled between January and September, 2010(1). The compound was reported in unspecified influent at a range of 733-48,999 ng/L and in the final effluent 739-59,046 ng/L, with <50% removal (secondary treatment). The primary breakdown product is desmethyltramadol(2). The compound was detected at an average concentration of 256 ng/L (1166 ng/L max) in 100% of eflluents sampled from 90 wastewater treatment plants in the European Union sampled in 2010; detection limit = 0.5 ng/L(3).

The presence of the anesthetic lidocaine (LDC), the analgesic tramadol (TRA), the antidepressant venlafaxine (VEN) and the metabolites O-desmethyltramadol (ODT) and O-desmethylvenlafaxine (ODV) was investigated in wastewater treatment plant (WWTP) effluents, in surface waters and in groundwater. The analytes were detected in all effluent samples and in only 64% of the surface water samples. The mean concentrations of the analytes in effluent samples from WWTPs with wastewater from only households and hospitals were 107 (LDC), 757 (TRA), 122 (ODT), 160 (VEN) and 637 ng L(-1) (ODV), while the mean concentrations in effluents from WWTPs treating additionally wastewater from pharmaceutical industries as indirect dischargers were for some pharmaceuticals clearly higher. WWTP effluents were identified as important sources of the analyzed pharmaceuticals and their metabolites in surface waters. The concentrations of the compounds found in surface waters ranged from <LOQ to 176 (LDC), 381 (TRA), 261 (ODT), 122 (VEN) and 743 ng L(-1) (ODV) and were dependent on the concentrations of the compounds in the WWTP effluents, the proportion of wastewater in the recipient water, the mean flow rate of the surface water, and the proximity of the sampling point to the WWTP discharge point. The dependence of the concentrations of the target compounds in the surface water on the distance between the sampling points and the points of WWTP discharge into the recipient rivers and streams indicates possible degradation of the compounds in the surface waters. Infiltration of the target analytes into groundwater was not observed.

A log Koc of 2.79 (Koc 616) Kd value of 22 L/kg was reported using an agricultural soil (pH 6.3) from Corrstown, Co Dublin, Ireland(1). According to a classification scheme(2), this Koc value suggests that tramadol is expected to have low mobility in soil. The estimated pKa1 of tramadol is 9.23(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Sorption isotherms (Kd, L/kg) of 1.1X10+2 and 1.9X10+2 have been reported using primary and secondary sludge, respectively, from the Klagshamn waste water treatment plant in Malmo City, Sweden(5).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tramadol hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tramadol hydrochloride/

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. (b) Narcotic drugs. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation containing any of the following narcotic drugs, or their salts calculated as the free anhydrous base or alkaloid, in limited quantities as set forth below. 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, its salts, optical and geometric isomers and salts of these isomers (including tramadol) is included on this list.

N02AX02

N02AX02

N - Nervous system

QN - Nervous system

Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin. Apart from analgesia, tramadol may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. **Central Nervous System** In contrast to [morphine], tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation. Tramadol depresses the cough reflex by a direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose. Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections), or with concomitant use of other drugs known to reduce the seizure threshold. Tramadol can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g., anti-depressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Tramadol should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, St. John’s Wort) due to the risk of serotonin syndrome. **Gastrointestinal Tract and Other Smooth Muscle** Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. **Endocrine System** Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes. Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics). In some reports, hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of tramadol and appropriate treatment (e.g., fluid restriction). During tramadol treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors. **Cardiovascular** Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquillizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of tramadol. **QTc-Interval Prolongation** The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms in the 400 mg/day treatment arm and 6.5 ms in the 600 mg/day mg treatment arm, both occurring at the 8h time point. Both treatment groups were within the 10 ms threshold for QT prolongation. Post-marketing experience with the use of tramadol containing products included rare reports of QT prolongation reported with an overdose. Particular care should be exercised when administering tramadol to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug. **Abuse and Misuse** Like all opioids, tramadol has the potential for abuse and misuse, which can lead to overdose and death. Therefore, tramadol should be prescribed and handled with caution. **Dependence/Tolerance** Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.

Tramadol is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to [codeine] and [morphine]. Tramadol binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine. Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor), muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor), Adenosine A1 receptors, and nicotinic acetylcholine receptor. In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages.

Tramadol is a racemic mixture (R & S) that has a complicated mechanism of action. It has some mu-opioid receptor action, but this effect is 10 times lower than codeine and 6000 timex lower than morphine. Tramadol also inhibits the reuptake of norepinephrine (NE) and serotonin (5 HT) and produces secondary effects on alpha-2 adrenergic receptors in pain pathways. One isomer has greater effect on 5 HT reuptake and greater affinity for mu-opiate receptors. The other isomer is more potent for NE reuptake and less active for inhibiting 5 HT reuptake. Taken together, the effects of of tramadol may be explained through inhibition of 5 HT reuptake, action on alpha2 receptors, and mild activity on opiate mu-receptors.

The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to mu-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively. We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording. Tramadol and M1 (0.01-10 uM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 uM) and M1 (1-10 uM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 uM) decreased the inward currents induced by AITC. These data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds.

Tramadol is an effective analgesic substance widely used in medical practice. Its therapeutic action have been mainly attributed to the activation of mu-opioid receptors as well as to the inhibition of neurotransmitter reuptake mechanisms and various voltage- and ligand-gated ion channels of the nociceptive system. As transient receptor potential vanilloid-1 (TRPV1, "the capsaicin receptor") has been shown to function as a central integrator molecule of pain sensation, our aim in the current study was to define the involvement of TRPV1 in the complex mechanism of action of tramadol. To achieve these goals, we used single-cell Ca-imaging as well as fluorescent image plate reader assays on Chinese hamster ovary (CHO) cells heterologously over-expressing TRPV1. We found that (1) tramadol, similar to the well-known TRPV1 agonist, capsaicin, significantly increased [Ca(2+)](i) of TRPV1-CHO cells in a concentration-dependent fashion; (2) its effect was reversibly prevented by the TRPV1 antagonist capsazepine; (3) repeated application of tramadol resulted in marked tachyphylaxis; and (4) tramadol did not modify [Ca(2+)](i) in control (empty vector expressing) CHO cells. Collectively, these findings strongly support the intriguing and novel concept that tramadol acts as an agonist of TRPV1. Considering that activation of TRPV1 on sensory neurons is followed by a local release of vasoactive neuropeptides and a marked desensitization of the afferent fibers (hence termination of pain sensation), our findings may equally explain both the desired analgesic as well as the often-seen, yet "unexpected," local side effects (e.g., initiation of burning pain and erythema) of tramadol.

Tramadol has a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O:-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher affinity for mu receptors and may thus contribute to the effects of the parent compound. Furthermore, the pharmacological effects of tramadol appear to be related to the different, but complementary and interactive pharmacologies of its enantiomers.

Tramadol has been used as an analgesic for several decades. mu-Opioid receptors (muORs) are the major receptors that mediate the analgesic effects of opioids. Although muORs have been thought to be one of the sites of action of tramadol, there has been no report that directly proves whether tramadol is an agonist of muOR or not. In this study, we examined the effects of tramadol and its main active metabolite O-desmethyltramadol (M1), on the function of muORs using Xenopus oocytes expressing cloned human muORs. The effects of tramadol and M1 were evaluated using the Ca(2+)-activated Cl(-) current assay method for G(i/o)-protein-coupled receptors by using a muOR fused to G(qi5) (muOR-G(qi5)) in Xenopus oocytes. DAMGO [(D-Ala(2), N-MePhe(4), Gly(5)-ol)-enkephalin] evoked Cl(-) currents in oocytes expressing muOR-G(qi5) in a concentration-dependent manner. Tramadol and M1 also evoked Cl(-) currents in the oocytes expressing muOR-G(qi5); however, relatively higher concentrations (compared to DMAGO) were necessary to induce such currents. Tramadol and M1 had a direct effect on muORs expressed in Xenopus oocytes. Although the monoamine uptake system and several types of ligand-gated ion channels are thought to be one of the targets for tramadol, tramadol-induced antinociception may be mediated at least in part, by the direct activation of muORs.

Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours.

Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age.

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in ... longer tramadol and M1 elimination half-lives (13 hr for tramadol and 19 hr for M1).

The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 +/- 1.4 and 7.4 +/- 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

The objective of this study was to determine the pharmacokinetics of two orally administered doses of tramadol (5 and 10 mg/kg) and its major metabolite (O-desmethyltramadol) (M1) in loggerhead sea turtles (Caretta caretta). After oral administration, the half-life of tramadol administered at 5 and 10 mg/kg was 20.35 and 22.67 hr, whereas the half-life of M1 was 10.23 and 11.26 hr, respectively. ...

For more Biological Half-Life (Complete) data for TRAMADOL (9 total), please visit the HSDB record page.

Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6. The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity. CYP2D6\*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme. CYP2D6 alleles associated with non-functioning enzyme include *3, *4, *5, and *6 while alleles associated with reduced activity include *9, *10, *17, and *41. Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the μ-opioid receptor primarily via M1. There are also large differences in the frequency of these alleles between different ethnicities: \*3, \*4, \*5, \*6, and \*41 are more common among Caucasians while \*17 is more common in Africans for example. Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6\*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol. Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications. These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1). The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). The FDA label recommends avoiding the use of tramadol in these individuals.

Tramadol is extensively metabolized after oral administration by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response

Tramadol has as many as 11 metabolites. One metabolite (o-desmethyl tramadol, also called M1) may have greater opiate effects than the parent drug (for example, 200-300 times greater opiate effect than tramadol) but still lower than morphine. In animals that produce this metabolite in sufficient amounts, some analgesic action may be attributed to opiate-mediated effects from the active metabolite. The other metabolites have not been shown to have active analgesic activity.

Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent metabolites. One metabolite, M1, is pharmacology active in animal models. The formation of M1 is dependent upon Cytochrome P-450(2D6) and as such is subject to both metabolic induction and inhibition which may affect the therapeutic response. /Salt not specified/

Tramadol is a synthetic opioid, widely used for post-surgical and chronic pain. Lethal overdose due only to tramadol is not common; more often the poisoning is due to tramadol in combination with other substances. Reported is a suicidal case of lethal tramadol poisoning in a 48-year-old woman. Tramadol and its metabolites O-desmethyltramadol (M1), N-desmethyltramadol (M2), N,N-didesmethyltramadol (M3), N,O-didesmethyltramadol (M5) were detected by GC/MS in biological fluids (femoral blood, bile, urine, gastric content) and viscera (brain, lung, liver and kidney). The tramadol concentration in femoral blood was 61.83 ug/mL which is approximately 30 times higher than that believed to be lethal. According with other Authors, a preferential formation of M1 over M2 (M1/M2 ratio >1) is indicative of acute death, while M1/M2 ratio <1 suggests that death occurred after a longer time lapse from ingestion.

Tramadol has known human metabolites that include N-desmethyltramadol and O-desmethyl-tramadol.

39J1LGJ30J

TRAMADOL

Mechanisms of Action [MoA] - Full Opioid Agonists

Established Pharmacologic Class [EPC] - Opioid Agonist

Tramadol is an Opioid Agonist. The mechanism of action of tramadol is as a Full Opioid Agonist.

Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.

Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS.

**Oral Administration** Tramadol is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction. Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability. **Intramuscular Administration** Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours. **Rectal Administration** Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration.

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations.

In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults.

The objective of this study was to determine the pharmacokinetics of two orally administered doses of tramadol (5 and 10 mg/kg) and its major metabolite (O-desmethyltramadol) (M1) in loggerhead sea turtles (Caretta caretta). After oral administration, the half-life of tramadol administered at 5 and 10 mg/kg was 20.35 and 22.67 hr, whereas the half-life of M1 was 10.23 and 11.26 hr, respectively. The maximum concentration (Cmax) for tramadol after oral administration at 5 mg/kg and 10 mg/kg was 373 and 719 ng/mL, whereas that of M1 was 655 and 1,376 ng/mL, respectively. Tramadol administered orally to loggerhead sea turtles at both dosages provided measurable plasma concentrations of tramadol and O-desmethyltramadol for several days with no adverse effects. Plasma concentrations of tramadol and O-desmethyltramadol remained >/= 100 ng/mL for at least 48 and 72 hr when tramadol was administered at 10 mg/kg.

The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (approximately 10%) exist in the absolute amount of each enantiomer present.

2-[(Ddimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, its salts, optical and geometric isomers and salts of these isomers (including tramadol) is a Schedule IV controlled substance.

Schedule IV Controlled Substance: (A) The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule III. (B) The drug or other substance has a currently accepted medical use in treatment in the United States. (C) Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III.

Analgesics, Opioid; Narcotics

MEDICATION (VET)

MEDICATION

Use (kg) in Switzerland (2009): >1000

Grignard reaction of 2-(dimethylaminomethyl)cyclohexanone (obtained by Mannich reaction of cyclohexanone, formaldehyde, and dimethylamine hydrochloride) and the Grignard reagent of 3-bromoanisole yields tramadol as a cis/trans mixture (cis:trans = 85:15). Tramadol (cis isomer) is separated from the reaction mixture by crystallization of the hydrochloride salt. ... The trans isomer can be epimerized to the cis isomer by strong acids

Oral: Tablets: 100 mg, 200 mg, 300 mg, Ralivia

Amadol; Contramal; Tradonal; Tramal; Ultram; Zamudol; Zydol. /Tramadol hydrochloride/

Table: Tramadol Hydrochloride Preparations [Table#6671]

Table: Tramadol Hydrochloride Combinations Preparations [Table#6672]

Pharmaceuticals

Pharmaceuticals -> Nervous System -> Analgesics -> Opioids