Product Beschrijving

Clinical Monograph: Tramadol 200 mg (Extended-Release)

1. Classification and Chemical Overview
Tramadol hydrochloride is a centrally acting synthetic aminocyclohexanol analog of codeine. Chemically designated as (±)-cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride, it functions as a racemic mixture of two enantiomers. Under the Anatomical Therapeutic Chemical (ATC) system, tramadol is indexed under N02AX02.
The 200 mg strength is typically formulated as an extended-release (ER) oral tablet designed to provide sustained 24-hour plasma concentrations. Internationally, tramadol is classified as a Controlled Substance (Schedule IV in the US; Class A / Controlled Drug in the UK) and is strictly regulated as a Prescription Only Medicine (POM) due to risks of physical dependence, tolerance, and misuse.

2. Mechanism of Action and Pharmacodynamics
Tramadol provides analgesia through a synergistic, dual-action mechanism:
μ-Opioid Receptor Activation: The (+)-enantiomer and its primary active metabolite (O-desmethyltramadol or M1) bind to central μ-opioid receptors, suppressing ascending pain transmission in the dorsal horn.
Monoaminergic Reuptake Inhibition: Both enantiomers inhibit the neuronal reuptake of serotonin (5-HT) and norepinephrine (NE) in descending spinal inhibitory pathways, enhancing spinal gating of nociceptive signals.
3. Approved Clinical Indications and Dosing Scope
Licensing for Tramadol 200 mg ER includes:
Moderate to Severe Chronic Pain: Management of moderate to moderately severe chronic pain in adults requiring continuous, around-the-clock opioid therapy for an extended period.
Dosing & Administration Regimen:
Extended-Release Schedule: Taken once daily, approximately every 24 hours, at the same time each day.
High Unit Strength Caution: The 200 mg tablet is a high-strength maintenance dose. It is never used as an initial starting dose; patients must be titrated up gradually from lower strengths (e.g., 100 mg/day).
Administration Integrity: Tablets must be swallowed whole with liquid. Do not cut, crush, chew, or dissolve extended-release tablets, as doing so destroys the polymer matrix, causing rapid drug dumping and fatal overdose.
4. Pharmacokinetic Profile and Metabolic Fate
Absorption: Formulated with a prolonged-release matrix that extends absorption over 24 hours, flattening peak plasma fluctuations compared to immediate-release formulations.
Distribution: Plasma protein binding is low (~20%). Readily crosses the blood-brain barrier and placenta.
Biotransformation: Extensively metabolized in the liver via Cytochrome P450 enzymes:
CYP2D6 Pathway: O-demethylation converts tramadol into the potent active metabolite M1 (O-desmethyltramadol).
CYP3A4 Pathway: N-demethylation converts tramadol into inactive metabolites.
Elimination: Excreted primarily via the kidneys in urine as unchanged drug and polar metabolites. The effective elimination half-life (t1/2
​) of extended-release tramadol is approximately 6 to 7 hours for the parent drug and roughly 7 to 9 hours for M1.
5. Physiological Effects and Adverse Event Spectrum
Extended-release tramadol alters central nervous system neurotransmission, lowers seizure thresholds, and depresses respiratory drive over prolonged periods.

Adverse Drug Reaction Spectrum
Very Common (≥1/10): Dizziness, nausea, constipation, somnolence, headache, dry mouth.
Common (≥1/100 to <1/10): Vomiting, sweating, fatigue, vertigo, dyspepsia, diarrhea, abdominal pain, asthenia, anxiety, confusion.
Uncommon (≥1/1,000 to <1/100): Palpitations, tachycardia, orthostatic hypotension, flushing, pruritus, rash, urticaria, visual disturbances.
Rare / Severe (<1/1,000): Generalized tonic-clonic seizures (dose-dependent risk), serotonin syndrome, life-threatening respiratory depression, anaphylaxis, severe hypoglycemia, hallucinations, and physical dependence.
6. Contraindications, Drug Interactions, and Clinical Precautions
Contra-indicaties
Known hypersensitivity to tramadol or other opioids.
Acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids, or psychotropic medications.
Concomitant use with Monoamine Oxidase Inhibitors (MAOIs) or within 14 days of their discontinuation.
Patients with severe epilepsy, a history of seizures, or uncontrolled seizure disorders.
Severe respiratory depression or acute bronchial asthma.
Key Drug Interactions
Monoamine Oxidase Inhibitors (MAOIs) & Serotonergic Agents (SSRIs, SNRIs, Triptans): Co-administration triggers severe, potentially fatal serotonin syndrome (hyperthermia, clonus, autonomic instability, and mental status changes).
CYP2D6 Inhibitors (e.g., Fluoxetine, Paroxetine, Quinidine): Inhibit the formation of the active M1 metabolite, altering analgesic efficacy.
CYP3A4 Inhibitors/Inducers (e.g., Ketoconazole, Erythromycin, Carbamazepine): Alter parent drug clearance and systemic exposure.
CNS Depressants & Alcohol: Additive central nervous system depression leading to profound sedation, respiratory arrest, coma, and death.
Clinical Precautions and Monitoring
Seizure Threshold Lowering: Tramadol lowers the seizure threshold in a dose-dependent manner. High doses like 200 mg ER elevate this risk, particularly in patients with a history of seizures, head trauma, or concurrent use of medications that lower the seizure threshold.
Dependence & Withdrawal: Prolonged administration establishes physical and psychological dependence. Abrupt cessation triggers a severe withdrawal syndrome (anxiety, sweating, insomnia, rigors, nausea, and hallucinations). Gradual tapering under medical supervision is mandatory.