Tramadol hydrochloride

Chemical Properties

White Cyrstalline Solid

Originator

Tramadol,Gruenenthal,W. Germany,1977

Uses

An Analgesic

Definition

ChEBI: (R,R)-tramadol hydrochloride is a hydrochloride resulting from the reaction of (R,R)-tramadol with 1 molar equivalent of hydrogen chloride; the (R,R)-enantiomer of the racemic opioid analgesic tramadol hydrochloride, it exhibits ten-fold higher analgesic potency than the (S,S)-enantiomer. It has a role as a delta-opioid receptor agonist, a kappa-opioid receptor agonist, a mu-opioid receptor agonist, an adrenergic uptake inhibitor, an antitussive, a capsaicin receptor antagonist, a muscarinic antagonist, a nicotinic antagonist, a NMDA receptor antagonist, an opioid analgesic, a serotonergic antagonist and a serotonin uptake inhibitor. It contains a (R,R)-tramadol(1+). It is an enantiomer of a (S,S)-tramadol hydrochloride.

Manufacturing Process

5 g of magnesium turnings are treated while stirring with a mixture of 37.4 g of m-bromoanisole and 160 ml of absolute tetrahydrofuran at such a rate that the reaction mixture boils gently because of the heat produced by the immediately starting reaction. Thereafter, the reaction mixture is boiled under reflux while stirring until all the magnesium dissolves. The reaction mixture is cooled to 0°C to -10°C and then a mixture of 23.25 g of 2- dimethylaminomethylcyclohexanone and 45 ml of absolute tetrahydrofuran is added dropwise.
The resulting mixture is stirred for 4 hours at room temperature and then poured, while stirring slowly, into a mixture of 25 g of ammonium chloride, 50 ml of water and 50 g of ice. The layers are separated and the aqueous layer is extracted twice with 50 ml portions of ether. The organic layers are combined, dried with sodium sulfate and evaporated. The residue is distilled, and 1-(m_x0002_methoxyphenyl)-2-dimethylaminomethyl-cyclohexanol-(1), boiling point at 0.6 mm Hg 138°C to 140°C, is obtained in a yield of 78.6% of theoretical. The hydrochloride obtained from the product, e.g., by dissolving in ether and treating with dry hydrogen chloride, melts at 168°C to 175°C. By recrystallization from moist dioxan this hydrochloride is separated into isomers melting at 162°C to 163°C and 175°C to 177°C, respectively.

Therapeutic Function

Analgesic

Clinical Use

Analgesic

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: possible opioid withdrawal with buprenorphine and pentazocine.
Anticoagulants: enhances effect of coumarins.
Antidepressants: possibly increased serotonergic effects with duloxetine, mirtazapine or venlafaxine; possible CNS excitation or depression with MAOIs and moclobemide - avoid with MAOIs as increased risk of serotonergic effects and convulsions; increased risk of CNS toxicity with SSRIs or tricyclics.
Antiepileptics: effect reduced by carbamazepine.
Antihistamines: increased sedative effects with sedating antihistamines.
Antipsychotics: enhanced hypotensive and sedative effects; increased risk of convulsions.
Atomoxetine: increased risk of convulsions.
Dapoxetine: possible increased risk of serotonergic effects - avoid.
Dopaminergics: avoid with selegiline.
Nalmefene: avoid concomitant use.
Sodium oxybate: enhanced effect of sodium oxybate - avoid concomitant use.

Metabolism

Tramadol is metabolised by N- and O-demethylation via the cytochrome P450 isoenzymes CYP3A4 and CYP2D6 and glucuronidation or sulfation in the liver. Only O-desmethyl-tramadol is pharmacologically active. Tramadol and its metabolites are almost completely excreted renally.