Tramadol API Manufacturers & Suppliers
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Tramadol | CAS No: 27203-92-5 | GMP-certified suppliers
A medication that provides reliable management of moderate to severe pain in adults and is also used in some settings for premature ejaculation.
Therapeutic categories
Primary indications
- Tramadol is approved for the management of moderate to severe pain in adults
- Tramadol is also used off-label in the treatment of premature ejaculation
Product Snapshot
- Tramadol is a small‑molecule analgesic available in multiple oral, injectable, and topical formulations
- It is used for moderate to severe pain in adults, with additional off‑label use in premature ejaculation
- It is approved in the US and Canada, with some investigational listings for other potential uses
Clinical Overview
Tramadol exerts analgesic effects through a dual mechanism. The parent compound and its active metabolite O‑desmethyl‑tramadol (M1) act as μ‑opioid receptor agonists, while the racemic mixture also weakly inhibits serotonin and norepinephrine reuptake. The (+)‑enantiomer contributes primarily to μ‑agonism and serotonin reuptake inhibition, whereas the (–)‑enantiomer predominantly inhibits norepinephrine reuptake. M1 demonstrates higher μ‑receptor affinity than tramadol and is a key contributor to analgesic potency. Additional interactions with adrenergic, muscarinic, NMDA, TRPV1, and other neuronal targets, as well as modulation of inflammatory mediators, further influence its pharmacological profile.
Tramadol is absorbed orally with extensive metabolism via CYP2D6 and CYP3A pathways, forming both active and inactive metabolites. It is eliminated primarily by the kidneys, and exposure can increase in renal impairment. Its pharmacodynamic complexity leads to opioid-like effects along with SNRI‑related properties.
Safety considerations include dose‑related respiratory depression, risk of serotonin syndrome when co-administered with serotonergic drugs, and increased seizure risk, particularly at high doses or in patients with predispositions. Opioid-related effects such as miosis, constipation, orthostatic hypotension, and endocrine alterations may occur. Rare hyponatremia associated with SIADH has been reported. Tramadol has abuse potential, and dependence or withdrawal can develop with prolonged use.
Tramadol is marketed globally in immediate‑ and extended‑release formulations under multiple brand names, often as single-agent or combination analgesics.
For API procurement, manufacturers should verify enantiomeric composition, impurity profiles, and compliance with relevant pharmacopeial monographs. Control of residual solvents, stereochemical integrity, and consistency of polymorphic form are essential for formulation robustness and regulatory acceptance.
Identification & chemistry
| Generic name | Tramadol |
|---|---|
| Molecule type | Small molecule |
| CAS | 27203-92-5 |
| UNII | 39J1LGJ30J |
| DrugBank ID | DB00193 |
Pharmacology
| Summary | Tramadol is a centrally acting analgesic that combines weak μ‑opioid receptor agonism with inhibition of serotonin and norepinephrine reuptake, producing modulation of descending pain pathways. Its active metabolite, O‑desmethyltramadol, provides stronger μ‑opioid receptor activity, while additional interactions with receptors and ion channels involved in nociception contribute to its overall pharmacologic profile. The drug’s multimodal actions support its use in managing moderate to severe pain. |
|---|---|
| Mechanism of action | 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. |
| Pharmacodynamics | 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. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Mu-type opioid receptor | Humans | agonist |
| Sodium-dependent noradrenaline transporter | Humans | inhibitor |
| Sodium-dependent serotonin transporter | Humans | inhibitor |
ADME / PK
| Absorption | **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. |
|---|---|
| Half-life | Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours. |
| Protein binding | About 20% of the administered dose is found to bind to plasma proteins. Protein binding appears to be independent of concentrations up to 10μg/mL. Saturation only occurs at concentrations outside of the clinical range. |
| Metabolism | 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. |
| Route of elimination | 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. |
| Volume of distribution | 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. |
| Clearance | 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. |
Formulation & handling
- Suitable for oral solid and liquid dosage forms as well as parenteral solutions, with ER formulations relying on controlled‑release matrices rather than intrinsic API properties.
- Moderate lipophilicity and low aqueous solubility may require solubilizers or pH adjustment for concentrated injectable solutions.
- Food has minimal impact on absorption, but formulations must avoid co‑administration with alcohol due to enhanced CNS effects.
Regulatory status
| Lifecycle | Most key U.S. patents expired between 2013 and 2020, with remaining Canadian protection ending in 2023, indicating the product has moved into a mature post‑patent phase. With commercialization in the United States and Canada, the market is now characterized by full generic entry and established competition. |
|---|
| Markets | Canada, US |
|---|
Supply Chain
| Supply chain summary | Tramadol’s supply landscape includes multiple originator entities, but the market is now dominated by a large number of generic manufacturers and repackagers, reflecting mature commoditization of the API. Branded products have broad presence in the US and Canada, with long‑expired US patents and recently expired Canadian protection indicating established and ongoing generic competition. This has resulted in a widely distributed manufacturing and packaging base across North American markets. |
|---|
Safety
| Toxicity | The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg. In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity. |
|---|
- Oral LD50 in mice is ~350 mg/kg, indicating moderate acute toxicity
- Appropriate controls for exposure and containment are required
- Non‑mutagenic in standard assays, though murine tumor findings are not considered predictive for humans
Certificate of Suitability
CEP (also known as COS) is a certificate that proves that qualifies to the relevant monograph of the European Pharmacopoeia. It links the monograph in the Ph.Eur. to the API itself. A CEP is submitted by the manufacturer as part of the market authorization process, and they will become the CEP holder of the document. Being a European certificate, the CEP is granted by the EDQM but is recognized by other countries or institutes such as the FDA in the US. Furthermore, just like the DMF, the data as submitted in the CEP is handled strictly confidential and provides a centralized system recognized by many countries.
Tramadol is a type of Opioid analgesics
Opioid analgesics are a subcategory of pharmaceutical Active Pharmaceutical Ingredients (APIs) that are commonly used for pain management. These potent substances interact with specific receptors in the central nervous system, producing analgesic effects and reducing the perception of pain. Opioid analgesics are derived from opium alkaloids or synthetic compounds that mimic their effects. They are classified based on their strength, with some being classified as strong opioids (e.g., morphine, fentanyl) and others as weak opioids (e.g., codeine, tramadol). These APIs work by binding to opioid receptors, primarily located in the brain, spinal cord, and gastrointestinal tract. By activating these receptors, opioid analgesics modulate pain signals, resulting in pain relief. Additionally, they can induce feelings of euphoria, sedation, and respiratory depression, which can be both beneficial and potentially harmful.
Due to their potency and potential for abuse, opioid analgesics are tightly regulated substances. They are primarily prescribed for acute and chronic pain management, such as post-surgical pain, cancer pain, and severe injuries. However, their misuse and addiction potential have led to a public health crisis in many countries.
In conclusion, opioid analgesics are a subcategory of pharmaceutical APIs that play a crucial role in pain management. While they provide effective pain relief, their use requires careful monitoring and adherence to prescribing guidelines to mitigate the risks associated with their potential for abuse and addiction.
Tramadol (Opioid analgesics), classified under Analgesics
Analgesics are a category of pharmaceutical Active Pharmaceutical Ingredients (APIs) that are commonly used to relieve pain. They are designed to alleviate discomfort by targeting the body's pain receptors or by reducing inflammation. Analgesics are widely utilized in the medical field to manage various types of pain, ranging from mild to severe.
One of the primary classes of analgesics is nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs work by inhibiting the production of prostaglandins, substances that contribute to pain and inflammation. This class includes well-known drugs like ibuprofen and naproxen. Another class of analgesics is opioids, which are derived from opium or synthetic compounds that mimic the effects of opium. Opioids act on the central nervous system to reduce pain perception and provide potent pain relief. Examples of opioids include morphine, codeine, and oxycodone.
Analgesics are available in various forms, such as tablets, capsules, creams, and injections, allowing for different routes of administration based on the patient's needs. They are commonly used to manage pain associated with conditions like arthritis, headaches, dental procedures, and post-operative recovery.
It is important to note that analgesics should be used under medical supervision, as improper use or overuse can lead to adverse effects, including gastrointestinal complications, addiction, and respiratory depression in the case of opioids. Therefore, it is crucial for healthcare professionals to assess each patient's individual needs and prescribe the appropriate analgesic and dosage.
In summary, analgesics are a vital category of pharmaceutical APIs used to alleviate pain by targeting pain receptors or reducing inflammation. With various classes and forms available, they provide valuable options for pain management when used responsibly and under medical guidance.
Tramadol API manufacturers & distributors
Compare qualified Tramadol API suppliers worldwide. We currently have 22 companies offering Tramadol API, with manufacturing taking place in 7 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Apollo Healthcare Resourc... | Distributor | Singapore | Singapore | BSE/TSE, CEP, CoA, EDMF/ASMF, FDA, GMP, ISO9001, JDMF, KDMF, MSDS, USDMF, WC | 200 products |
| Arevipharma | Producer | Germany | Unknown | CEP, CoA, FDA | 25 products |
| AXXO GmbH | Distributor | Germany | World | CEP, CoA, GMP, GDP, MSDS, USDMF | 243 products |
| Boehringer Ingelheim | Producer | Germany | Unknown | CEP, CoA, FDA, GMP | 35 products |
| Chemizo Enterprise | Distributor | India | India | CoA | 19 products |
| Chr. Olesen Group | Distributor | Denmark | India | CEP, CoA, GMP, MSDS, USDMF | 252 products |
| CSPC Ouyi Pharma | Producer | China | China | CEP, CoA, FDA, USDMF | 3 products |
| Duchefa Farma B.V. | Distributor | Netherlands | India | CoA, GMP, ISO9001, MSDS | 170 products |
| Emmennar Pharma | Producer | India | India | CEP, CoA, FDA | 3 products |
| Global Pharma Tek | Distributor | India | India | BSE/TSE, CoA, FDA, GMP, ISO9001, MSDS | 484 products |
| GVK Biosciences Pvt Ltd | Producer | India | India | CEP, CoA, FDA, GMP, KDMF, WC | 10 products |
| Ipca Labs. | Producer | India | Unknown | CEP, CoA, FDA, GMP, USDMF | 69 products |
| Jubilant Pharmova | Producer | India | India | BSE/TSE, CoA, GMP, ISO9001, JDMF, MSDS, USDMF | 52 products |
| Pen Tsao Chemical Industr... | Producer | Germany | China | CoA | 18 products |
| Piramal Healthcare | Producer | United Kingdom | India | CoA, GMP, WC | 31 products |
| Piramal Pharma Solutions | Producer | India | India | CoA, USDMF, WC | 44 products |
| Raks Pharma | Producer | India | India | CEP, CoA, FDA, KDMF, USDMF | 58 products |
| Sun Pharma | Producer | India | India | CEP, CoA, JDMF, KDMF, USDMF, WC | 219 products |
| Temad Co. | Producer | Iran | Iran | CoA, GMP, ISO9001, MSDS, USDMF, WC | 24 products |
| Tresinde Biotech | Producer | India | India | CoA, GMP | 50 products |
| Vonage Pharma (Former Plu... | Producer | Turkey | Turkey | CoA, GMP, MSDS, USDMF, WC | 28 products |
| Wanbury | Producer | India | India | CEP, CoA, FDA, GMP, KDMF, USDMF, WC | 15 products |
When sending a request, specify which Tramadol API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
Use the list above to find high-quality Tramadol API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
