Tramadol (Contramal): FDA Approval, Licensing in Türkiye, and Reimbursement Status

• FDA Approval: Yes (first approval date: March 3, 1995)
• Trade Names: Ultram, Contramal (one of the best-known brands), and other trade names including Conzip and Ryzolt.
• Active Ingredient: Tramadol hydrochloride
• Administration: Oral tablets (immediate and extended release), oral capsules, oral drops/solution, and injection (intravenous or intramuscular)
• Class: Opioid analgesic (narcotic-like analgesic)
• Category: Pain reliever (analgesic)
• Manufacturer: Original manufacturer: Janssen Pharmaceuticals (part of Johnson & Johnson). It is now also manufactured by many generic companies.
• Availability in Türkiye: Medicines containing tramadol are sold under the green prescription system in Türkiye.
• Trade names: Available under brands including Contramal, Dolparin, Tramosel, and Tradoz.
• Cancers for Which It Is Approved: Tramadol is not approved as a direct cancer treatment. However, it is used as supportive (palliative) treatment to control moderate to severe cancer pain.

What Is Tramadol and How Does It Work?

Tramadol is an analgesic (pain reliever) that acts on the central nervous system. It is used to treat moderate to severe pain. Although chemically an opioid derivative, its effects are weaker than those of conventional opioids. Prescription tramadol is particularly used for postoperative pain, chronic musculoskeletal pain, and palliative treatment of cancer pain. Because of its low potential for dependence, some pain management protocols consider it an alternative to strong opioids such as morphine.

How Does It Work?

Tramadol reduces pain through two main mechanisms:

• Opioid receptor agonism: Tramadol binds to μ-opioid receptors (MOR) in specific areas of the brain and spinal cord, producing a partial agonist effect. This binding suppresses transmission of pain signals, reducing perceived pain. This effect of tramadol is weaker than that of full opioid agonists such as morphine.
• Monoamine reuptake inhibition: Tramadol also inhibits reuptake of the neurotransmitters serotonin and norepinephrine from the synaptic cleft. This helps downregulate pain signals, particularly at the spinal level. It therefore both reduces pain transmission and lowers central sensitivity to pain.

FDA (United States Food and Drug Administration) Approval History

• 1977: Tramadol was first marketed in Germany by Grünenthal GmbH. (It came into use in many countries outside the United States under the trade name “Tramal.”)
• 1993: Janssen Pharmaceuticals applied to the FDA for approval of tramadol in the United States.
• March 3, 1995: The FDA approved tramadol under the name Ultram®. (Indication: treatment of moderate to severe pain. It was not initially classified as a controlled substance.)
• August 10, 1998: The FDA required strengthened warnings about the risks of dependence and misuse with tramadol. (Additional warnings about its potential for dependence were added to the product label.)
• July 23, 2014: The United States Drug Enforcement Administration (DEA) formally classified tramadol as a Schedule IV controlled substance. (From this date, tramadol was included at the federal level in the category of controlled medicines with the potential to cause dependence.)
• After 2015: Prescription requirements and restrictions on use were expanded for all products containing tramadol. Additional safety warnings were introduced, particularly concerning use in young people and during pregnancy.
• September 2017: The FDA issued a warning placing substantial restrictions on tramadol use in children and adolescents. (In particular, it highlighted that tramadol after tonsil or adenoid surgery could cause life-threatening respiratory problems in children.)
• 2018-2023: The FDA identified tramadol as a medicine requiring careful monitoring as part of the opioid crisis and included it in general risk evaluation programs for opioid medicines.

Licensing in Türkiye

Tramadol is licensed in Türkiye under the following trade names and in the following formulations:

• Contramal (Abdi İbrahim): 50 mg capsules, 100 mg/2 ml solution for injection, and 100 mg controlled-release tablets (Contramal Retard)
• Tramosel (İstanbul Ecza Koop): 100 mg/2 ml ampoules (IV/IM/SC injection)
• Zaldiar (Abdi İbrahim): tramadol 37.5 mg + paracetamol 325 mg film-coated tablets (combination product)

All these products require a green prescription; sale without a prescription is prohibited.

Therapeutic Indications

• Treatment of moderate and severe pain: Used for conditions such as postoperative pain, pain caused by trauma, and musculoskeletal pain.
• Chronic pain syndromes: Used for chronic painful conditions such as osteoarthritis and herniated lumbar discs.
• Cancer pain: Used for pain control in patients with cancer as part of palliative treatment.
• Tramadol is an effective analgesic for treating both acute and chronic pain.

Is It Reimbursed?

It is reimbursed by SGK (Social Security Institution). The listed current prices are: 

• Contramal 50 mg, 20 capsules: 151.50 TL
• Contramal 100 mg/2 ml, 5 ampoules: 113.62 TL
• Contramal 100 mg/2 ml, 10 ampoules: 151.50 TL
• Contramal 100 mg controlled-release tablets (Retard), 30 tablets: 267.60 TL
• Tramturk, 100 mg/2 ml solution for injection, 5 ampoules: 92.01 TL
• Tramadolor 50 mg, 50 capsules: 151.50 TL
• Zaldiar, tramadol 37.5 mg + paracetamol 325 mg, 20 tablets: 151.50 TL

Mechanisms of Resistance

• Opioid receptor tolerance: Tramadol produces analgesia by binding to μ-opioid receptors. During prolonged use, these receptors may decrease in number (downregulation) or become less sensitive. As a result, higher doses are needed to achieve the same effect (tolerance develops).
• Variations in CYP2D6 metabolism: In the liver, the CYP2D6 enzyme converts tramadol into its active metabolite, O-desmethyltramadol. Some people are genetically poor metabolizers. They produce insufficient active metabolite, reducing the effect. Conversely, rapid breakdown in ultrarapid metabolizers may cause unstable plasma levels, creating a risk of ineffectiveness or adverse reactions.
• Neurotransmitter desensitization: Tramadol also inhibits reuptake of serotonin and norepinephrine. These neurotransmitter systems may adapt over time, reducing synaptic sensitivity. Tramadol's analgesic effect may therefore diminish over time.
• Neuronal adaptation and pain pathway plasticity: In patients with chronic pain, pain pathways may reorganize themselves (central sensitization). Tramadol may become ineffective against these neuroplastic changes, and pharmacological resistance may develop.

Absorption

Oral tramadol is rapidly absorbed. Absorption is high, and its bioavailability is approximately 70%. Controlled-release tablets spread this more evenly over time. Maximum plasma concentrations are usually reached 1.5–2 hours after oral administration.

Distribution

Tramadol is widely distributed throughout body fluids and tissues. Plasma protein binding is low, at approximately 20%. This low binding allows more of the drug to circulate in its active, unbound form. Its high volume of distribution enables it to readily reach effective concentrations in the central nervous system and brain.

Metabolism

• Tramadol is mainly metabolized in the liver. Its principal metabolic pathway involves CYP2D6 and CYP3A4 enzymes in the cytochrome P450 system.
• O-desmethyltramadol (the M1 metabolite), formed through CYP2D6, is largely responsible for tramadol's strong analgesic effect.
• Other inactive or weakly active metabolites are formed through CYP3A4.
• Metabolism can vary between individuals, particularly according to CYP2D6 enzyme activity (effects may be more pronounced in ultrarapid metabolizers).

Elimination

Tramadol and its metabolites are eliminated mainly through the kidneys. Both unchanged tramadol and its metabolites are present in urine. Its mean elimination half-life is approximately 6–7 hours. This may be longer with controlled-release formulations. Reduced kidney function slows elimination of tramadol and its metabolites, potentially increasing the risk of toxicity.

Dose Range

• Acute pain (such as postoperative pain): Oral: 50–100 mg, repeated every 4–6 hours as needed. Maximum daily dose: 400 mg.
• Chronic pain (such as osteoarthritis, lower back pain, or cancer pain): Controlled-release tablets (retard formulation): 100 mg once or twice daily. If necessary, the dose is adjusted in weekly increments of 100 mg. Maximum daily dose: 400 mg.
• Injection (intramuscular, intravenous, or subcutaneous): Initial dose: 50–100 mg, repeated every 4–6 hours as needed. Maximum daily dose: 400 mg.
• Older patients (≥ 75 years): Start with lower doses and extend administration intervals. Maximum daily dose: 300 mg.
• Patients with kidney or liver impairment: Extend dosing intervals (for example, to every 12 hours). Reduce the maximum daily dose (usually to 200 mg/day).
• Use in children: Under 12 years: contraindicated (prohibited). Ages 12–18: start at 1–2 mg/kg, which may be repeated every 4–6 hours. The maximum dose must not exceed adult limits.
• Controlled-release formulations require different dosing from immediate-release formulations.
• Lower doses should be preferred in patients at risk of serotonin syndrome or seizures.

Drug Interactions

• Central Nervous System Depressants (Sedatives): Tramadol depresses brain activity. Combining it with alcohol, benzodiazepines (such as diazepam or lorazepam), other opioids, or antipsychotics increases the risk of respiratory depression, excessive sedation, and confusion.
• Medicines That Increase Serotonin Levels: Tramadol inhibits serotonin reuptake. Combining it with SSRIs (such as sertraline or fluoxetine), SNRIs (such as venlafaxine or duloxetine), tricyclic antidepressants (such as amitriptyline), or MAO inhibitors (such as selegiline) may cause serotonin syndrome. This can be life-threatening and may present with agitation, muscle contractions, fever, and sweating.
• Antiepileptic Medicines (Anticonvulsants): Tramadol may increase seizure risk. This risk increases further when it is combined with medicines used in epilepsy (such as carbamazepine).
• CYP2D6 and CYP3A4 Enzyme Inhibitors or Inducers: Tramadol is metabolized in the liver by CYP2D6 and CYP3A4. CYP2D6 inhibitors (such as fluoxetine or paroxetine) reduce formation of tramadol's active metabolite and may weaken its effect. CYP3A4 inhibitors (such as ketoconazole or erythromycin) delay tramadol elimination and may increase adverse reactions. CYP3A4 inducers (such as rifampicin) may reduce tramadol's effectiveness.
• Anticoagulants (Blood Thinners): Combining tramadol with coumarin derivatives such as warfarin may increase bleeding risk. INR levels should be monitored closely.
• Migraine Medicines (Triptans): Combining tramadol with sumatriptan or other triptans may increase serotonin levels, raising the risk of serotonin syndrome.

Precautions

• Risk of Respiratory Depression: Tramadol may suppress the respiratory center, particularly at high doses or in combination with other central nervous system depressants. Respiratory depression risk is higher in older people, those with lung diseases such as COPD, and people with sleep apnea.
• Development of Dependence and Tolerance: Tramadol has a lower risk of dependence than conventional opioids, but prolonged use or high doses may lead to tolerance and psychological or physical dependence. Particular caution is required in patients with a history of substance misuse.
• Risk of Serotonin Syndrome: Because tramadol inhibits serotonin reuptake, potentially life-threatening serotonin syndrome may develop, particularly when combined with serotonergic medicines such as SSRIs, SNRIs, or triptans. Patients should therefore be monitored for symptoms including excessive sweating, agitation, muscle contractions, or high fever.
• Risk of Seizures: Tramadol may increase the risk of convulsions in patients with epilepsy or when combined with medicines that lower the seizure threshold. Patients with known epilepsy should receive it only when absolutely necessary and at low doses.
• Kidney and Liver Impairment: Tramadol is metabolized and eliminated through the liver and kidneys. Impairment of these organs increases the risk of accumulation and therefore toxicity. Dose adjustment and longer dosing intervals are needed in these situations.
• Older Patients: Drug elimination slows in older people, and adverse reactions occur more frequently. Risks of dizziness, falls, and respiratory depression are particularly increased. Treatment should therefore begin with low doses, with close monitoring.
• Pregnancy and Breastfeeding: Its pregnancy category is C. Although adverse effects have been observed in animal studies, adequate human studies are lacking. Use should be avoided particularly in the last trimester of pregnancy. During breastfeeding, tramadol passes into breast milk and is not recommended because it may cause respiratory depression in the infant.
• Use with Alcohol and Other Depressants: Combining tramadol with alcohol or other central nervous system depressants increases the risk of excessive sedation, respiratory depression, and coma. Patients should be firmly advised to avoid these combinations.
• Risk of Overdose with Combination Products: Some combination medicines contain tramadol together with other analgesics such as paracetamol (for example, Zaldiar). With these combinations, the dose limits of both tramadol and the accompanying medicine must not be exceeded.
• Poor and Ultrarapid Metabolizers: Genetic differences cause some individuals to metabolize tramadol very rapidly or very slowly. Ultrarapid metabolizers have a higher risk of adverse reactions, while poor metabolizers may have reduced analgesia. Dose adjustment or alternative treatment should be considered in these individuals.

Adverse Reactions

• Nausea: 25-30%
• Dizziness: 20-25%
• Constipation: 15-20%
• Headache: 15-18%
• Drowsiness (sedation): 15-20%
• Dry mouth: 10-15%
• Vomiting: 10-15%
• Increased sweating: 5-10%
• Fatigue: 5-10%
• Indigestion (dyspepsia): 5-10%
• Diarrhea: 5-8%
• Itching (pruritus): 5-8%
• Anxiety: approximately 5%
• Weakness: approximately 5%
• Shaking (tremor): 3-5%
• Palpitations (tachycardia): 2-4%
• Hypotension (low blood pressure): 2-4%
• Confusion: 2-3%
• Seizures (convulsions): <1%
• Serotonin syndrome: <1%
• Allergic reactions (rash, urticaria): <1%