Opioids can be grouped according to their intrinsic activity as full agonists, partial agonists, agonists or mixed agonist-antagonists. Full agonists include morphine, fentanyl, hydromorphone, codeine, methadone, tramadol and meperidine. Relative efficacy can be stated in terms of number needed to treat (NNT). Codeine is a weak opioid with a combined NNT of 16.7 at 30 mg. By comparison, strong opioids such as morphine (NNT 2.9) at 10 mg for postoperative pain and oxycodone (NNT 2.9) have a much greater potency.1
Mu-opioid receptor agonists appear to have differential capacities to promote receptor internalization. The differential ability of various mu-opioid receptor agonists to induce rapid receptor desensitization and endocytosis of mu-opioid receptors could arise simply from differences in their efficacy to activate G proteins or, alternatively, be due to differential capacity for activation of other signaling processes.2
One study using relative efficacies determined for G protein coupling were DAMGO (H-Tyr-D-Ala-Gly-N-MePhe-Gly-OH) (1); ≥ methadone (0.98); > morphine (0.58); > pentazocine (0.15). The same rank order of efficacies for rapid desensitization of was observed, but greater concentrations of agonist were required than for G protein activation.3
These results indicate that the efficacy of opioids to produce activation of G proteins and rapid desensitization is distinct from their capacity to internalize mu-opioid receptors but that, contrary to some previous reports, morphine can produce rapid, homologous desensitization of MOP.4
Tolerance to the analgesic and other effects of opioid drugs, such as morphine, undermines their use in long-term treatment. Mu-opioid receptors are similar to many other G protein-coupled receptors (GPCR) in that they undergo desensitization within several minutes of stimulation by agonists, and continued agonist exposure results in removal of receptors from the cell surface.5
An important question is whether a loss of analgesic efficacy after recurring application of agonists develops at peripheral opioid receptors. Peripheral tolerance has been observed in animal models using repeated opioid pretreatment in the absence of persistent inflammation.6
However, because the number, affinity and coupling efficacy of opioid receptors are enhanced under inflammatory conditions, these studies do not permit conclusions regarding tolerance in pathological situations. In other models, peripheral opioid analgesia is resistant to the development of tolerance and clinical studies suggest a lack of cross-tolerance between peripheral exogenous and endogenous opioids in synovial inflammation.7
From the clinician’s viewpoint, the induction of tolerance by opioid pretreatment in the absence of painful tissue injury is not illustrative because patients usually do not consume opioids when they are not in pain (except in the case of opioid abuse).8
