Absorption, Distribution and Excretion
Oral Administration Tramadol is administered in racemic form, and both [-] and [+] forms of tramadol and its metabolite M1 are detectable in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability is attributable to 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and its major metabolite M1 occur at 2 and 3 hours, respectively, after administration. Following a single oral dose of 100 mg tramadol, its Cmax is approximately 300 μg/L, and Tmax is 1.6-1.9 hours; while the Cmax of metabolite M1 is 55 μg/L, and Tmax is 3 hours. Steady-state plasma concentrations of both tramadol and M1 are reached within two days after administration. There is no evidence of self-induction. Following multiple oral administrations, the peak plasma concentration (Cmax) was 16% higher and the area under the curve (AUC) was 36% higher than after a single administration, suggesting that saturated first-pass hepatic metabolism may play a role in improving bioavailability. Intramuscular Administration Tramadol was rapidly and almost completely absorbed after intramuscular injection. After an injection of 50 mg tramadol, the peak plasma concentration (Cmax) was 166 μg/L, and the time to peak concentration (Tmax) was 0.75 hours. Rectal Administration After rectal administration using a suppository containing 100 mg tramadol, the peak plasma concentration (Cmax) was 294 μg/L, and the time to peak concentration (Tmax) was 3.3 hours. The study found that the absolute bioavailability of rectal administration was higher than that of oral administration (77% vs 75%), which may be due to reduced first-pass metabolism compared to oral administration. Tramadol is primarily eliminated through hepatic metabolism, with its metabolites mainly excreted via the kidneys (90% of total excretion) and the remaining 10% via feces. Approximately 30% of the dose is excreted unchanged in the urine, while 60% is excreted as metabolites. The mean terminal plasma elimination half-lives for racemic tramadol and racemic M1 are 6.3 ± 1.4 hours and 7.4 ± 1.4 hours, respectively. After repeated administration, the plasma elimination half-life of racemic tramadol increases from approximately 6 hours to 7 hours. Tramadol has been reported to have a volume of distribution ranging from 2.6 to 2.9 L/kg. Tramadol exhibits high tissue affinity; the total volume of distribution after oral administration is 306 L, and after parenteral administration, it is 203 L. Tramadol can cross the blood-brain barrier, reaching peak brain concentration 10 minutes after oral administration. It can also cross the placental barrier, with umbilical cord blood concentrations approximately 80% of maternal blood concentrations. In clinical trials, tramadol clearance was 3.73 mL/min/kg in patients with renal impairment and 8.50 mL/min/kg in healthy adults. This study aimed to determine the pharmacokinetics of two oral doses (5 mg/kg and 10 mg/kg) of tramadol and its major metabolite (O-desmethyltramadol) (M1) in loggerhead turtles (Caretta caretta). Following oral administration, the half-lives of tramadol at 5 mg/kg and 10 mg/kg were 20.35 h and 22.67 h, respectively, while the half-lives of M1 were 10.23 h and 11.26 h, respectively. Following oral administration, the maximum plasma concentrations (Cmax) of tramadol at 5 mg/kg and 10 mg/kg were 373 ng/mL and 719 ng/mL, respectively, while the maximum plasma concentrations of M1 were 655 ng/mL and 1376 ng/mL, respectively. In loggerhead turtles, after oral administration of both doses of tramadol, plasma concentrations of both tramadol and O-desmethyltramadol remained measurable for several days without adverse reactions. When tramadol was administered at a dose of 10 mg/kg, plasma concentrations of both tramadol and O-desmethyltramadol remained ≥100 ng/mL for at least 48 and 72 hours, respectively. The mean absolute bioavailability of the 100 mg oral dose was approximately 75%. In healthy adults, the mean peak plasma concentrations of racemic tramadol and M1 occurred at 2 hours and 3 hours after administration, respectively. Typically, the time course of tramadol and its two enantiomers in vivo is similar after single and multiple administrations, although there are slight differences in the absolute content of each enantiomer (approximately 10%). Tramadol is primarily eliminated through hepatic metabolism, and its metabolites are primarily eliminated through the kidneys. This study aimed to investigate the bioavailability of tramadol hydrochloride after oral administration of 50 mg tramadol capsules manufactured by Synteza Pharmaceuticals, Poznan. The tramadol reference formulation, Tramal (50 mg capsules, Grundenthal, Germany), was used as the standard. A randomized, two-way crossover design was employed in 20 healthy volunteers under fasting conditions to study the two formulations. Blood samples were collected at pre-defined time points within 24 hours after administration to determine plasma tramadol concentrations. A one-week elution period was observed between two administration cycles. Plasma tramadol concentrations were determined using a validated high-performance liquid chromatography (HPLC, fluorescence detector, verapamil as internal standard). The AUC(0-∞) values of tramadol and Tramal were 1226.4 ng/hr/ml and 1397.01 ng/hr/ml, respectively, indicating that the drug absorption of the two formulations was almost identical. The maximum plasma concentrations (Cmax) of tramadol and the reference formulation were 217.81 ng/ml and 246.0 ng/ml, respectively, and the time to reach maximum plasma concentration (Tmax) were 2.14 hours and 2.31 hours, respectively, with no significant difference between the two. …The bioavailability of tramadol hydrochloride after administration was the same as after administration of tramadol (Tramal), the latter's clinical efficacy of which has been validated in previous studies. For more complete data on the absorption, distribution, and excretion of tramadol (20 items in total), please visit the HSDB record page.
Metabolism/Metabolites
Tramadol undergoes extensive first-pass metabolism in the liver, including N- and O-demethylation and conjugation reactions. Extensive metabolism has identified at least 23 metabolites. Tramadol is primarily metabolized via two pathways: O-demethylation catalyzed by CYP2D6 to produce O-demethyltramadol (M1); and N-demethylation catalyzed by CYP3A4 and CYP2B6 to produce N-demethyltramadol (M2). Significant differences in pharmacokinetic characteristics among patients are partly attributed to polymorphisms in the CYP2D6 gene, which determine its enzymatic activity. CYP2D61 is considered the wild-type allele, associated with normal enzyme activity and a "fast metabolizer" phenotype; 90-95% of Caucasians are considered "fast metabolizers" (normal CYP2D6 function), while the remaining 5-10% are considered "slow metabolizers" with reduced or absent enzyme activity. Alleles associated with CYP2D6 enzyme nonfunction include 3, 4, 5, and 6, while alleles associated with reduced enzyme activity include 9, 10, 17, and 41. Individuals with poor metabolic capacity have reduced CYP2D6 enzyme activity, resulting in decreased production of tramadol metabolites M1 and M2, ultimately leading to reduced analgesic effects, as tramadol primarily interacts with μ-opioid receptors via M1. The frequencies of these alleles also differ significantly among different ethnic groups: for example, 3, 4, 5, 6, and 41 are more common in Caucasians, while 17 is more common in Africans. Compared to 5–10% of Caucasians, only about 1% of Asians are considered to have poor metabolic capacity. However, the frequency of the CYP2D6 10 allele is much higher in Asian populations (51%), an allele relatively rare in Caucasians, leading to higher tramadol exposure in Asian populations. Some individuals are considered "ultra-fast metabolizers," such as those carrying a duplicate or doubled CYP2D6 gene (CYP2D6DUP). Due to their higher concentrations of the active metabolite (M1), these individuals are at risk of tramadol poisoning or enhanced drug effects. This phenotype occurs in approximately 1% to 2% of East Asians (Chinese, Japanese, Koreans), 1% to 10% of Caucasians, 3% to 4% of African Americans, and may exceed 10% in certain racial/ethnic groups (e.g., Oceanians, North Africans, Middle Easterners, Afro-Jews, Puerto Ricans). The U.S. Food and Drug Administration (FDA) recommends avoiding tramadol use in these populations. After oral administration, tramadol is primarily metabolized through multiple pathways, including CYP2D6 and CYP3A4, as well as the binding of the parent drug to metabolites. Approximately 30% of the dose is excreted unchanged in the urine, and 60% is excreted as metabolites. The remainder is excreted as unidentified or unextractable metabolites. The primary metabolic pathway appears to be N- and O-demethylation and glucuronidation or sulfation in the liver. One of the metabolites (O-demethyltramadol, denoted as M1) is pharmacologically active in animal models. M1 production is dependent on CYP2D6 and is therefore susceptible to inhibition, which may affect treatment response. Tramadol has up to 11 metabolites. One of these metabolites (O-demethyltramadol, also known as M1) may have a stronger opioid effect than the parent drug (e.g., an opioid effect 200-300 times stronger than tramadol), but still weaker than morphine. In animals that produce sufficient amounts of this metabolite, some analgesic effects may be attributed to the opioid action mediated by this active metabolite. Other metabolites have not yet shown analgesic activity. Tramadol is primarily metabolized via multiple pathways, including CYP2D6 and CYP3A4, as well as conjugation to the parent metabolite. One of these metabolites, M1, is pharmacologically active in animal models. M1 production depends on cytochrome P-450 (2D6), therefore its metabolism is both induced and inhibited, which may affect treatment response. /Unspecified salt/
Tramadol is a synthetic opioid widely used for postoperative pain and chronic pain. Fatal overdose caused solely by tramadol is uncommon; poisoning is usually due to the combination of tramadol with other substances. A case of suicide due to tramadol poisoning has been reported. Tramadol and its metabolites O-demethyltramadol (M1), N-demethyltramadol (M2), N,N-didemethyltramadol (M3), and N,O-didemethyltramadol (M5) were detected in biological fluids (femoral vein blood, bile, urine, gastric contents) and visceral organs (brain, lungs, liver, kidneys) by gas chromatography-mass spectrometry (GC/MS). The concentration of tramadol in femoral venous blood was 61.83 μg/mL, approximately 30 times the lethal concentration. According to other authors, preferential formation of M1 relative to M2 (M1/M2 ratio > 1) suggests acute death, while an M1/M2 ratio < 1 suggests death occurring a longer time after tramadol ingestion. Known metabolites of tramadol include O-demethyltramadol and N-demethyltramadol. The main metabolic pathways appear to be N- and O-demethylation in the liver, followed by glucuronidation or sulfation. One metabolite (O-demethyltramadol, denoted as M1) exhibits pharmacological activity in animal models. CYP3A4 and CYP2B6 promote the bioconversion of tramadol to N-demethyltramadol. CYP2D6 promotes the bioconversion of tramadol to O-demethyltramadol. After oral administration, racemic tramadol is rapidly and almost completely absorbed. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. In healthy adults, the mean peak plasma concentrations of racemic tramadol and M1 occurred at 2 and 3 hours post-administration, respectively. Tramadol is metabolized in the liver by the cytochrome P450 isoenzyme CYP2D6, resulting in five distinct metabolites via O- and N-demethylation. M1 (O-demethyltramadol) is the most important, as it has a 200-fold greater affinity for (+)-tramadol and an elimination half-life of 9 hours, compared to tramadol's own 6-hour elimination half-life. Therefore, the analgesic effect may be slightly reduced in the 6% of individuals with slower CYP2D6 activity. Phase II hepatic metabolism makes the metabolites water-soluble and facilitates renal excretion. Therefore, the dose may be reduced in cases of impaired renal and hepatic function (A308, L1160). Elimination pathway: Tramadol is primarily eliminated through hepatic metabolism, and its metabolites are mainly excreted through the kidneys. Approximately 30% of the dose is excreted unchanged in the urine, while 60% is excreted as metabolites. Half-life: Tramadol and its metabolites are primarily excreted in the urine. The observed plasma half-lives for tramadol and M1 are 6.3 hours and 7.4 hours, respectively. Biological half-life: Tramadol has been reported to have a half-life of 5–6 hours, while the half-life of the M1 metabolite is 8 hours. Plasma tramadol concentrations and elimination half-lives in healthy elderly individuals aged 65–75 years were comparable to those in healthy subjects under 65 years of age. Compared to subjects aged 65–75 years, subjects over 75 years of age had higher peak serum concentrations (208 ng/mL vs. 162 ng/mL) and prolonged elimination half-lives (7 hours vs. 6 hours).
In patients with advanced cirrhosis, the metabolism of tramadol and M1 is slowed, leading to prolonged elimination half-lives for both (13 hours for tramadol and 19 hours for M1).
The mean terminal plasma elimination half-lives for racemic tramadol and racemic M1 were 6.3 ± 1.4 hours and 7.4 ± 1.4 hours, respectively. Following multiple administrations, the plasma elimination half-life of racemic tramadol increased from approximately 6 hours to 7 hours.
This study aimed to determine the pharmacokinetics of two oral doses (5 and 10 mg/kg) of tramadol and its major metabolite (O-desmethyltramadol) (M1) in loggerhead turtles (Caretta caretta). Following oral administration, the half-lives of tramadol at 5 mg/kg and 10 mg/kg doses were 20.35 hours and 22.67 hours, respectively, while the half-lives of M1 were 10.23 hours and 11.26 hours, respectively. ...
For more complete data on the biological half-life of tramadol (9 species), please visit the HSDB record page.

Toxicity Summary
Identification and Uses: Tramadol is a white, odorless, bitter-tasting crystalline powder. Tramadol is an opioid analgesic used to treat moderate to moderate-to-severe pain in adults. In veterinary medicine, it can be used to treat postoperative pain, chronic pain, or cough. Human Exposure and Toxicity: Overdose symptoms are similar to other opioid agonists, including respiratory depression, drowsiness, skeletal muscle relaxation, coma, seizures, bradycardia, hypotension, cardiac arrest, miosis, vomiting, cold and clammy skin, heart failure, and death. Severe and rare fatal anaphylactic reactions have been reported. Other reported hypersensitivity reactions include pruritus, urticaria, angioedema, bronchospasm, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Tramadol use can lead to life-threatening serotonin syndrome, especially when taken concurrently with other serotonergic drugs, drugs that affect serotonin metabolism (such as monoamine oxidase inhibitors), or drugs that affect tramadol metabolism (such as cytochrome P-450 [CYP] isoenzyme 2D6 and 3A4 inhibitors). Tramadol use is associated with an increased risk of hyponatremia, which may require hospitalization. One study suggests that tramadol may have moderate teratogenic effects. There is a serious risk of neonatal withdrawal syndrome when tramadol is used during pregnancy. Animal studies: Between 2009 and 2013, the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center received 910 reports of single-drug tramadol poisoning. Of these, 749 dogs were poisoned, and 142 showed symptoms. Symptoms included sedation/drowsiness, vomiting, tachycardia, vocalizations or ataxia, and agitation or tremors. Of the 157 cats poisoned, 96 exhibited symptoms including dilated pupils, excessive salivation, lethargy, ataxia or tachycardia, and vomiting. Rats with decreased serotonin levels were more susceptible to tramadol-induced seizures, and serotonin concentration was negatively correlated with the seizure threshold. At maternally toxic doses, tramadol showed embryotoxicity and fetal toxicity in mice, rats, and rabbits, but no teratogenicity was observed at these dose levels. Tramadol did not show mutagenicity in the following tests: Ames Salmonella microsomal activation assay, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), mouse dominant lethal mutation assay, Chinese hamster chromosomal aberration assay, and mouse and Chinese hamster bone marrow micronucleus assay. In the presence of metabolic activation, weak mutagenicity was observed in the mouse lymphoma assay and rat micronucleus assay. In mice, no carcinogenic effects of tramadol were observed at oral doses up to approximately twice the MDHD (based on body surface area) of a 60 kg adult (400 mg daily) for 26 weeks. In rats, no carcinogenic effects of tramadol were also observed at oral doses up to approximately twice the MDHD for two years. In mice, a slight, statistically significant, increase in the incidence of two common mouse tumors (lung and liver cancer) was observed at oral doses up to 0.36 times the MDHD for approximately two years. Tramadol and its O-demethyl metabolite (M1) are selective, weak OP3 receptor agonists. Opioid receptors are coupled to G proteins and act as positive and negative regulators of synaptic transmission by activating G proteins of effector proteins. Since the effector system consists of adenylate cyclase and cAMP located on the inner side of the plasma membrane, opioids reduce intracellular cAMP levels by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and norepinephrine is inhibited. Tramadol's analgesic effect can be attributed to its blocking of the reuptake of norepinephrine and serotonin in the central nervous system, thereby inhibiting pain signal transmission in the spinal cord. The (+) enantiomer has a higher affinity for OP3 receptors, preferentially inhibiting serotonin uptake and enhancing serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by stimulating α(2)-adrenergic receptors.

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Toxicity Data
LD50: 300-350 mg/kg (oral, rat) (A2833)Interactions
To investigate the potential analgesic effect of serotonin receptor subtype 3 (5-HT(3)), we evaluated the combined use of the 5-HT(3) selective antagonist ondansetron and tramadol, a centrally acting analgesic that relies on enhancing serotonergic transmission. Fifty-nine patients undergoing otolaryngological surgery received patient-controlled analgesia with tramadol for 24 hours postoperatively (single dose 30 mg, lockout time 10 min). Patients were randomly assigned to two groups: one group received continuous ondansetron infusion (1 mg/mL/hr) to relieve postoperative nausea and vomiting (Group O), and the other group served as a control group receiving saline infusion (Group T). Pain and vomiting scores, as well as tramadol dosage, were assessed at 4, 8, 12, and 24 hours postoperatively. Pain scores in both groups did not exceed 4 points (using a 0-10 numerical rating scale). Patients in group O required significantly higher doses of tramadol at 4 hours (213 mg vs 71 mg, P<0.001), 8 hours (285 mg vs 128 mg, P<0.002), and 12 hours postoperatively (406 mg vs 190 mg, P<0.002). Vomiting scores in group O were also higher than in other groups at 4 hours (P<0.05) and 8 hours (P=0.05). We conclude that ondansetron reduces the overall analgesic effect of tramadol, possibly due to its blocking of spinal 5-HT(3) receptors. …Serotonin is an important neurotransmitter in the descending pathway and can downregulate spinal nociceptive sensation. In postoperative pain, the selective 5-HT(3) receptor antagonist ondansetron increases the analgesic dose of tramadol. We believe that due to the site-dependent effects of 5-HT(3) receptors, their antagonism for antiemetic purposes may actually promote nociceptive sensation. The primary objective of this study was to evaluate the analgesic effect and adverse reactions of a single oral tramadol combined with acetaminophen for acute postoperative pain, and to use a meta-analysis to demonstrate the efficacy of this combination therapy compared to the use of either drug alone. The RW Johnson Pharmaceutical Research Institute in Laritan, New Jersey, provided individual patient data from seven randomized, double-blind, placebo-controlled trials of tramadol combined with acetaminophen for analysis. All trials used the same methodology to evaluate the efficacy of a single oral tramadol (75 mg or 112.5 mg) combined with acetaminophen (650 mg or 975 mg) in adult patients with moderate to severe postoperative pain. Pain intensity and analgesic relief data were extracted at 6 and 8 hours, as well as overall treatment efficacy at 8 hours. The number of patients (NNT) required to achieve at least 50% analgesia in one patient was calculated. The NNT calculated based on analgesic relief data was compared with the NNT calculated based on pain intensity data and overall assessment. Adverse reaction information was collected. The NNT of the combination analgesics (tramadol combined with acetaminophen) was significantly lower than (better than) that of either component alone, and the efficacy was comparable to 400 mg ibuprofen. These findings apply to dental pain but not to postoperative pain, as dental pain affects a larger number of patients. Adverse reactions were similar for combination drugs and opioids alone. Common adverse reactions included dizziness, drowsiness, nausea, vomiting, and headache. In conclusion, this meta-analysis demonstrates that combination drugs are superior to their single-component counterparts in analgesia without increasing toxicity.
This article reports a case of a 34-year-old white male patient who was found dead at home by his roommate. At the time of his death, he was taking tramadol/acetaminophen, methadone, oxycodone, and amitriptyline. The deceased's mother stated that he had been taking increasing amounts of painkillers to help him sleep at night. The autopsy revealed no obvious abnormalities; however, toxicological results supported the cause and manner of death as suicide due to combined tramadol and amitriptyline poisoning. This case report describes the distribution of acute fatal ingestion of tramadol, amitriptyline, and their metabolites in tissues and body fluids, aiming to record the concentrations of these analytes in 12 matrices and their interactions to assist toxicologists in interpreting complex cases. Tramadol has weak opioid properties, and its analgesic effect is mainly achieved by inhibiting the reuptake of norepinephrine and serotonin (5-HT) and promoting the release of 5-HT in the spinal cord (1,2). Since 5-HT3 receptors play a key role in pain transmission at the spinal cord level (3), the 5-HT3 receptor antagonist ondansetron may reduce the efficacy of tramadol… In a previous study, subjects received a low dose (1 mg/kg) of tramadol in combination with ondansetron (0.1 mg/kg) or placebo 15 minutes before anesthesia induction. Significant differences were observed in early postoperative pain scores among the experimental groups. Therefore, we tested the hypothesis that the required tramadol dose for patient-controlled analgesia (PCA) may increase when ondansetron is used for antiemetic prophylaxis.
For more complete data on tramadol interactions (24 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice: 270 mg/kg /tramadol hydrochloride/
Subcutaneous LD50 in mice: 200 mg/kg /tramadol hydrochloride/
Intravenous LD50 in mice: 60.45 mg/kg /tramadol hydrochloride/
Oral LD50 in rats: 228 mg/kg /tramadol hydrochloride/
For more complete data on tramadol interactions (6 in total), please visit the HSDB record page.

Therapeutic Uses

Analgesics, opioids; narcotics
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Tramadol is listed in the database.
Tramadol hydrochloride tablets (USP) are indicated for the treatment of moderate to moderate-to-severe pain in adults. /US Product Label Includes/
Tramadol Hydrochloride Extended-Release Tablets are indicated for the treatment of moderate to moderately severe chronic pain in adults requiring long-term, 24-hour analgesia.
Veterinary Drug: Tramadol can be used as an effective alternative or adjunctive treatment for postoperative or chronic pain or cough in dogs, cats, and other animals. It may be particularly effective for chronic pain when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics such as amantadine, gabapentin, and alpha-2 receptor agonists.
Drug Warnings

The US Food and Drug Administration (FDA) warns of several safety concerns across the entire opioid analgesic class. These safety risks include potential harmful interactions with many other medications, adrenal problems, and decreased sex hormone levels. We require all opioid labels to be changed to highlight these risks. Opioids may interact with antidepressants and migraine medications, leading to a serious central nervous system reaction called serotonin syndrome, in which levels of the brain chemical serotonin rise and can cause toxicity. Taking opioids can lead to a rare but serious condition where the adrenal glands cannot produce enough cortisol, the hormone that helps the body cope with stress. Long-term opioid use may be associated with decreased sex hormone levels and symptoms such as decreased libido, erectile dysfunction, or infertility. To continue educating prescribing physicians and patients about the potential risks associated with opioid use, the U.S. Food and Drug Administration (FDA) announced today that it is requiring a category-wide safety label change for all immediate-release (IR) opioid painkillers. Among these changes, the FDA requires the addition of a new black-box warning to drug packaging highlighting the serious risks of misuse, abuse, addiction, overdose, and death. Today’s move is part of a recently announced FDA initiative to reassess its approach to regulating opioids. This initiative focuses on developing policies aimed at reversing the opioid abuse crisis while ensuring that pain sufferers receive effective relief. The FDA is investigating the use of tramadol in children aged 17 and under because of the rare but serious risk of slowed or difficult breathing associated with the drug. This risk may be increased in children who use tramadol for pain relief after tonsillectomy and/or adenoidectomy. The FDA is evaluating all available information and will release final conclusions and recommendations to the public upon completion of its review. Tramadol is not FDA-approved for use in children; however, data indicate off-label use of the drug in the pediatric population. Healthcare professionals should be aware of this and consider prescribing alternative FDA-approved pain relievers for children. Tramadol is generally well tolerated at recommended doses. Adverse reactions are usually mild and occur at rates similar to those of active control drugs (e.g., acetaminophen 300 mg combined with codeine phosphate 30 mg, and aspirin 325 mg combined with codeine phosphate 30 mg). The frequency of some adverse reactions may be dose- and route of administration-related. In controlled clinical trials and open-label extensions involving patients with chronic non-malignant pain, the most common adverse reactions to tramadol were neurological reactions (e.g., dizziness) and gastrointestinal disturbances. For more complete data on drug warnings for tramadol (40 total), please visit the HSDB records page.

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Pharmacodynamics
Tramadol modulates the descending pain pathway in the central nervous system by binding to μ-opioid receptors through its parent drug and M1 metabolite, and weakly inhibiting the reuptake of norepinephrine and serotonin. In addition to its analgesic effects, tramadol may produce a range of symptoms similar to other opioids, including dizziness, drowsiness, nausea, constipation, sweating, and itching. Central Nervous System Unlike 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 indexes. Orthostatic hypotension has been observed. Tramadol produces respiratory depression by acting directly on the brainstem respiratory center. This respiratory depression manifests as a decrease in the brainstem center's responsiveness to increased carbon dioxide partial pressure and electrical stimulation. Tramadol inhibits the cough reflex by acting directly on the medullary cough center. Tramadol can produce an antitussive effect at doses lower than those typically required for analgesia. Tramadol can cause pupillary constriction even in complete darkness. Pinpoint pupils are a sign of opioid overdose, but are not specific (for example, similar symptoms can occur in hemorrhagic or ischemic pontine lesions). In cases of oxycodone overdose, significant pupillary dilation rather than constriction may occur during hypoxia. Seizures have been reported in patients taking tramadol within the recommended dose range. Post-marketing spontaneous reports indicate that tramadol doses exceeding the recommended range increase the risk of seizures. The risk of seizures may also be increased in patients with epilepsy, a history of epilepsy, patients with known seizure risk (e.g., head trauma, metabolic disorders, alcohol and drug withdrawal, central nervous system infections), and patients taking other medications known to lower the seizure threshold. Concomitant use of tramadol with serotonergic drugs (e.g., antidepressants, migraine medications) may lead to a rare but potentially life-threatening complication. If the following symptoms occur (characterized by a symptom cluster including high fever, rigidity, myoclonus, autonomic dysfunction with rapid fluctuations in vital signs, and altered mental status (including confusion, irritability, extreme agitation, and potential progression to delirium and coma), serotonergic drugs should be discontinued and symptomatic supportive treatment initiated. Tramadol should not be used concomitantly with monoamine oxidase inhibitors or serotonin precursors (such as tryptophan and oxithtriptan), and caution should be exercised when using it in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, and St. John's wort) due to the risk of serotonin syndrome. Gastrointestinal Tract and Other Smooth Muscles Tramadol can increase the tone of the smooth muscle in the gastric antrum and duodenum, thereby reducing gastrointestinal motility. Food digestion in the small intestine is delayed, and propulsive contractions are weakened. Colonic propulsive peristaltic waves are weakened, while tone may increase to the point of spasm, leading to constipation. Other opioid side effects may include decreased gastric, bile, and pancreatic juice secretion, sphincter of Oddi spasm, and transient elevation of serum amylase. Endocrine System Opioids can affect the hypothalamic-pituitary-adrenal axis or the hypothalamic-pituitary-gonadal axis. Some visible changes include elevated serum prolactin and decreased plasma cortisol and testosterone. These hormonal changes can cause clinical signs and symptoms. Hyponatremia is rarely reported with tramadol, and usually occurs in patients with predisposing risk factors, such as elderly patients and/or patients taking medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics). In some case reports, hyponatremia appears to be caused by syndrome of dysregulation of antidiuretic hormone secretion (SIADH), which resolves upon discontinuation of tramadol and appropriate treatment (e.g., fluid restriction). For patients with predisposing risk factors, monitoring for signs and symptoms of hyponatremia during tramadol treatment is recommended. Cardiovascular System Tramadol may cause severe hypotension in patients whose blood pressure maintenance is impaired due to decreased blood volume or concomitant use of phenothiazines and other sedatives, hypnotics, tricyclic antidepressants, or general anesthetics. These patients should be monitored for signs of hypotension after initiating tramadol or after dose adjustment. QTc Interval Prolongation After placebo adjustment, the maximum mean change in QTcF interval from baseline was 5.5 ms in the 400 mg/day treatment group and 6.5 ms in the 600 mg/day treatment group, both occurring at the 8-hour time point. QT interval prolongation was within the 10 ms threshold range in both treatment groups. Post-marketing experience with tramadol-containing products includes a few reports of QT interval prolongation following overdose. Tramadol should be used with extreme caution in patients suspected of having an increased risk of torsades de pointes during QTc prolongation therapy. Abuse and Misuse Like all opioids, tramadol carries the risk of 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 opioid receptors to prolonged exposure to opioids and are distinct from abuse and addiction. Tolerance and physical dependence can both develop after repeated use of opioids, but they are not in themselves evidence of addiction or abuse. Patients on long-term treatment should gradually reduce their dosage if they no longer need the medication to control pain. Withdrawal symptoms may occur after abrupt discontinuation of the medication or the use of an opioid antagonist. Some symptoms that may occur after abrupt discontinuation of opioid analgesics include: body aches, diarrhea, goosebumps, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shaking, stomach cramps, tachycardia, difficulty sleeping, abnormally increased sweating, palpitations, unexplained fever, weakness, and yawning.

C16H25NO2

263.37

263.188

27203-92-5

33741

Typically exists as solid at room temperature

178-181 °C
180 - 181 °C

2.6

1

3

4

19

282

2

CN(C)C[C@H]1CCCC[C@@]1(C2=CC(=CC=C2)OC)O

TVYLLZQTGLZFBW-ZBFHGGJFSA-N

InChI=1S/C16H25NO2/c1-17(2)12-14-7-4-5-10-16(14,18)13-8-6-9-15(11-13)19-3/h6,8-9,11,14,18H,4-5,7,10,12H2,1-3H3/t14-,16+/m1/s1

(1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)