Part of the book: Severe Sepsis and Septic Shock
In the past two decades, many preclinical works have been carried out assisting in our understanding of the underlying pathophysiological mechanisms that cause chronic pain. Chronic pain involves multiple pathophysiological mechanisms with peripheral and central components. This research in basic and clinical research has greatly expanded the options for analgesic pharmacotherapy. This chapter gives information regarding the major classes of medication used to assist in the management of chronic pain, including nonopioids analgesics such as NSAIDs and acetaminophen, opioids analgesics, antidepressants and anticonvulsants and an emerging area as the field of cannabinoids is. Importantly, chronic pain treatment encompasses multiple agents to take advantage of synergistic mechanism of actions, but drug‐drug interactions have to be taken into account in order to avoid lack of efficacy or toxicity.
Part of the book: Pain Relief
Methadone acts as a μ opioid agonist, a serotonin and norepinephrine reuptake inhibitor, and a noncompetitive N-methyl-D-aspartate receptor antagonist. These actions altogether are responsible for its efficacy in the management of chronic pain. It is available as a racemic mixture of (R)- and (S)-methadone, both being stereoisomers responsible for its analgesic effect. Methadone elimination occurs mainly through metabolism in the liver by CYP3A4, CYP2B6, and CY2C19 and to a lesser extent by CYP2D6 and in the intestine by CYP3A4. The relative intestinal content of CYP2B6 and CY2C19 is unknown but it seems that CYP2B6 is not present at the intestine. CYP3A4, CYP2B6, and CYP2C19 convert methadone mainly into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine(EDDP). CYP2B6 and CYP2C19 are stereoselective to S- and R-enantiomer, respectively. The pharmacokinetic study carried out in healthy volunteers by our research group confirmed that MTD undergoes recirculation via gastric secretion and intestinal reabsorption and revealed that the drug is extensively metabolized in the liver but intestinal metabolism is not only relevant but also stereoselective. Polymorphisms of the CYP2B6 and CYP2C19 isoenzymes and their relationship with the pharmacokinetics of MTD were also assessed.
Part of the book: Drug Discovery and Development