Tramadol is a fully-synthetic opioid pro-drug with SSNRI activity. Upon ingestion, the digestive cytochrome enzymes - the cytochrome P450 family specifically - metabolize Tramadol into five distinct compounds. O-Desmethyltramadol, one of the five, has a markedly high affinity for the µ-opioid receptor, far more so than Tramadol itself. The same enzymes that convert Tramadol to its 5 metabolites, cytochrome P450, ionize these metabolites for water-soluble excretion. Therefore, the metabolism of Tramadol revolves entirely around the metabolic activity of cytochrome P450 in the liver.
Cimetidine (Tagamet) is a potent inhibitor of the cytochrome P450 enzyme, in addition to acting as a pH neutralizer. Therefore, if one were to ingest cimetidine prior to ingestion of Tramadol, one would likely experience a reduction of effects. However, if one were to wait until ingested Tramadol had time to be converted to its metabolites (30-180 mins), the ionization of the metabolites of Tramadol should be inhibited. This would be expected to enhance and prolong the effects of Tramadol at the µ-opioid receptor considerably. In sum, in order to potentiate the effects of Tramadol with cimetidine, timing and sequence is key.
In addition, subsequent to regular administration of recommended doses of cimetidine, the liver will up-regulate the expression of the enzymes responsible for converting Tramadol to its more potent metabolites. In other words, after ingesting cimetidine for a regular interval of time, one will become more sensitive to the effects of Tramadol. It should be noted, however, that this dynamic would render an individual less sensitive to other non-synthetic and semi-synthetic opiates over time.
This method should produce no anticipated ill-effects, as the magnitude of effects will never exceed the SSNRI activity inherent to the initial dose ingested. So long as one takes care not to initially ingest too-high a dose, this method of potentiation will not enhance SSNRI activity – rather, it should selectively enhance µ-opioid activity because it's the metabolites, not Tramadol, that are being enhanced.
