Opioids bind to specific receptors located throughout the central nervous system, gastrointestinal tract, and other tissues. Three major opioid receptor types were first identified: mu (μ, with subtypes μ1 and μ2), kappa (κ), and delta (δ). All opioid receptors couple to G proteins; the binding of an agonist to an opioid receptor typically causes membrane hyperpolarization. Acute opioid effects are mediated by inhibition of adenylate cyclase (reductions in intracellular cyclic adenosine monophosphate concentrations) and activation of phospholipase C.
The clinical actions of opioids depend on which receptor is bound (and in the case of spinal and epidural administration of opioids, where the receptor is located in the spinal cord) and the binding affinity of the drug. Agonist–antagonists (eg, nalbuphine, nalorphine, butorphanol, buprenorphine) have less efficacy than full agonists (eg, fentanyl, morphine), and under some circumstances, agonist–antagonists will antagonize the actions of full agonists.
Opioid receptor activation inhibits the presynaptic release and postsynaptic response to excitatory neurotransmitters (eg, acetylcholine, substance P) released by nociceptive neurons. Transmission of pain impulses can be selectively modified at the level of the dorsal horn of the spinal cord with intrathecal or epidural administration of opioids. Modulation through a descending inhibitory pathway from the periaqueductal gray matter to the dorsal horn of the spinal cord may also play a role in opioid analgesia. Certain opioid side effects (eg, constipation) are the result of opioid binding to receptors in peripheral tissues (eg, the gastrointestinal tract), and there are now selective antagonists for opioid actions outside the central nervous system (alvimopan and methylnaltrexone).
Rapid and complete absorption follows the intramuscular or subcutaneous injection of hydromorphone, morphine, or meperidine, with peak plasma levels usually reached after 20–60 min. Oral transmucosal fentanyl citrate absorption (fentanyl “lollipop”) provides rapid onset of analgesia and sedation in patients who are not good candidates for oral, intravenous, or intramuscular dosing of opioids. The low molecular weight and high lipid solubility of fentanyl also favor transdermal absorption (the transdermal fentanyl “patch”). The amount of fentanyl absorbed per unit of time depends on the surface area of skin covered by the patch and also on local skin conditions (eg, blood flow). Continued absorption from the dermal reservoir accounts for persisting fentanyl serum levels many hours after patch removal. Fentanyl is often administered in small doses (10–25 μg) intrathecally with local anesthetics for spinal anesthesia and adds to the analgesia when included with local anesthetics in epidural infusions. Morphine in doses between 0.1 mg and 0.5 mg and hydromorphone in doses between 0.05 mg and 0.2 mg provide 12–18 h of analgesia after intrathecal administration.
After intravenous administration, the distribution half-lives of the opioids are short (5–20 min). The low lipid solubility of ...