Does body possibly have mechanisms for blocking drugs at higher doses and making them less effective?
Drugs may have different actions at different concentrations.
So, for instance:
Buprenorphine is 25 to 100 times more potent than morphine.18 Buprenorphine exhibits partial agonist behavior at the mu-receptor and exhibits antagonist behavior at the kappa-receptor. Buprenorphine has a strong affinity for the mu-receptor causing tight binding and therefore competition at the receptor, displacing other opioids, such as methadone and morphine. Also, there is incomplete dissociation from the mu-receptor, causing prolonged activity at the receptor.18 Affinity is quantified using Ki values, and the smaller the Ki value, the stronger the binding affinity to the receptor. The mu binding affinity of buprenorphine compared with other opioids can be found in Table 5. Of note, buprenorphine has a higher binding affinity compared with naloxone and therefore at higher doses where buprenorphine is most likely to be abused, not readily reversed by naloxone. It is only at lower doses where there is some competitive binding, and only then should we reasonably expect some reversal by high doses of continuous infusion naloxone.