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OVERVIEW

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Opioids are among the oldest documented medications used by humans. All opioids are derivatives of pharmacologically active alkaloids from the milky exudate of the opium poppy. These drugs act by binding at opioid receptors found in the CNS, the colon, and to a lesser extent, the periphery. Mu and kappa opioid receptors have clinical utility and delta opioid receptors offer promise, but no delta agonist has been found acceptable for human use to date. However, new work with biased legends offers promise of a possible future delta opioid agonist analgesic. Most clinically useful opioids are mu agonists that also have varying agonist activity at kappa receptors. The mu-1 aspect of the receptor is responsible primarily for analgesia and the mu-2 for other, largely adverse, opioid effects. Numerous subtypes of the mu-1 receptors have been isolated and cloned, clearly indicating genetic polymorphism. Recent work on opioid agonist G protein coupled receptors, and specifically beta arrestin, has elucidated our understanding of biased ligands that helps explain the mechanisms by which opioids cause some adverse effects. This offers promise of new agents which offer full analgesia with fewer adverse effects.1, 2, 3, 4, and 5

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The majority of opioid agents are indicated and FDA-approved for management of acute and chronic pain. However, some have indications other than pain (e.g., naloxone for opioid overdose reversal, naltrexone for abuse mitigation, naloxegol for opioid-induced constipation (OIC), buprenorphine for maintenance therapy in patients with a history of substance abuse, dextromethorphan and codeine for cough, diphenoxylate, codeine, and loperamide for diarrhea). In order to better understand and differentiate the therapeutic differences among natural, semisynthetic, and synthetic opioids, one must first appreciate the physiology and pharmacology associated with the class. This chapter will focus on those medications used specifically for analgesia but will include buprenorphine, as it too is indicated for pain.

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These medications fall generally into four chemical classes: phenanthrenes, benzomorphans, phenylpiperidines, and diphenylheptanes. A fifth hybrid class of synthetics has some chemical similarities to several of these four groups. These dimethylamino compounds include tramadol and tapentadol and are seen in Figure 13-1. The chemical class of an opioid has little effect on its clinical utility. Note that Figure 13-1 lists cross-sensitivities as probable, possible, or low risk for each class from left to right. Although a true allergic reaction to any opioid is rare, pruritis is quite common. Pruritic reactions are a result of histamine release from mast cells. Such a reaction to one chemical class subjects a patient to histamine reactions to opioids within the same class. The fentanyl family has minimal histamine reactivity compared to all other opioids.6

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Synthetic and semisynthetic opioids exhibit the same pharmacological properties as naturally occurring opium alkaloids and derivatives. Synthetic opioids do not contain the ...

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