Opiate analgesics, tolerance

Chronic opiate treatment results in complex adaptations in opioid receptor signaling. Much has been learned from studies on mechanisms of tolerance to the analgesic effects of opiates. This is a major clinical problem, as it means that ever-escalating doses are required for the treatment of chronic pain. The classic view was that tolerance reflects a decrease in functional opioid receptors via desensitization and internalization. Desensitization occurs when receptors are uncoupled from G proteins as a result of phosphorylation by G-protein-coupled receptor... 

Since morphine releases histamine from central stores [292] and chronic administration of histamine alters brain catecholamine levels [300], it has also been proposed that opiate-induced changes in central concentrations or tissue levels of other biogenic amines may be initiated by decreases in brain histamine [295], Whilst a role for brain histamine has yet to be determined in the antinociceptive effects of the narcotic analgesics, this amine may interact with one or more other amines to subserve the antinociceptive, tolerance and physical dependence effects of morphine-like agents. 

As an oral drug, codeine is much less effective as an analgesic due to its large first-pass hepatic metabolism compared to morphine, hydrocodone and oxycodone. The plasma half-life of codeine is also shorter than many other orally available opiates such as morphine, hydromorphone, and oxymorphone. Like all opioids, continued use of codeine may result in tolerance development and physical dependence. However, when compared to potent mu agonists, codeine is less addictive and is associated with mild withdrawal symptoms. 

Hydromorphone 0.2 mg/mL intravenously is used extensively for patient-controlled analgesia (PCA) in the treatment of acute pain. A typical bolus dose is 0.2 mg with a lock-out period of 6 minutes. When used on an as-needed basis hydromorphone is given at a dose of 1-2 mg every 4-6 hours. A lower initial dose should be used in opiate-naive patients. Doses can be escalated in refractory pain. Again, a decrease in the duration of pain-free periods suggests the development of tolerance to the analgesic effects of hydromorphone. Intravenous administration of hydromorphone should be slow over 2-3 minutes. 

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