indication

For the relief of mild to moderate pain

pharmacology

Propoxyphene, a synthetic opiate agonist, is structurally similar to methadone. Its general pharmacologic properties are those of the opiates as a group. The analgesic effect of propoxyphene is due to the d-isomer, dextropropoxyphene. It binds to the opiate receptors and leads to a decrease of the perception of pain stimuli. Propoxyphene possesses little to no antitussive activity and no antipyretic action.

mechanism of action

Propoxyphene acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Propoxyphene primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. Opioids such as propoxyphene also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

toxicity

Coma, respiratory depression, circulatory collapse, and pulmonary edema. Seizures occur more frequently in patients with propoxyphene intoxication than in those with opiate intoxication. LD₅₀=230mg/kg (orally in rat, Emerson)

biotransformation

Hepatic

half life

6-12 hours

route of elimination

The major route of metabolism is cytochrome CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the kidneys. In 48 hours, approximately 20% to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene.

drug interactions

Acenocoumarol: Propoxyphene may increase the anticoagulant effect of acenocoumarol.

Anisindione: Propoxyphene may increase the anticoagulant effect of anisindione.

Atomoxetine: The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine

Carbamazepine: Propoxyphene increases the effect of carbamazepine

Cimetidine: Cimetidine, a moderate CYP3A4 inhibitor, may decrease the metabolism of propoxyphene. Monitor for changes in the therapeutic and adverse effects of propoxyphene if cimetidine is intitiated, discontinued or dose changed.

Dicumarol: Propoxyphene may increase the anticoagulant effect of dicumarol.

Ritonavir: Ritonavir increases the levels of analgesic

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant use should be avoided.

Triprolidine: The CNS depressants, Triprolidine and Propoxyphene, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Warfarin: Propoxyphene may increase the anticoagulant effect of warfarin.