Morphine is metabolized via UDP-glucuronosyltransferase-catalyzed conjugations to two active glucuronides: at the 6-hydroxyl position to morphine-6-glucuronide (M6G) and at the 3-hydroxyl position to morphine-3-glucuronide (M3G) ( 24). Opioid-induced depression of neurotransmitter release appears to be quite general, since it has been demonstrated for neurotransmitters of diverse chemical classes, such as the excitatory amino acid glutamate, the catecholamine norepinephrine, the ester acetylcholine, the indoleamine 5-HT (5-hydroxytryptamine, also known as serotonin) and the undecapeptide substance P ( 23). On postsynaptic neurons, they enhance K + efflux at inwardly rectifying K + channels, and thereby hyperpolarize the postsynaptic neuron, rendering it less responsive to stimulation by presynaptic neurotransmitter release on presynaptic neurons, they attenuate Ca 2+ influx (at ligand-gated Ca 2+ ion channels), and thereby reduce Ca 2+-dependent neurotransmitter release from vesicular stores ( 22). Agonist-induced activation of μ opioid receptors produces two well-established actions on neurons that express these receptors ( 21). Morphine (5α,6α-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol) is an agonist (determined by an increase in -GTPγS binding) at all three opioid receptors, having the highest affinity for the μ subtype ( 20). All of the currently identified opioid receptors are members of the 7-transmembrane G protein-coupled receptor family ( 19). Genes encoding three types of opioid receptors (named μ, δ, and κ) have been identified ( 17) and there is pharmacological evidence for subtypes of each type (μ 1, μ 2, δ 1, δ 2, and κ 1 through κ 3) ( 18), possibly arising from alternate splice variants of a common gene. Receptors for the endogenous opioid peptides (namely, the endorphins, enkephalins, dynorphins and endomorphins) are located at multiple levels of nociceptive pathways (mainly in the spinal cord and brain, but also the periphery, particularly during injury) ( 16). Herein, we review four oxycodone combinations for the treatment of chronic pain: oxycodone in combination with morphine, aspirin–nonsteroidal anti-inflammatory drugs (NSAIDs)–acetaminophen, pregabalin and gabapentin. Some oxycodone combination formulations are familiar to clinicians, and new combination products are being marketed. Oxycodone combination drugs can also be misused ( 15), and care should be taken on the part of healthcare providers to confirm and monitor appropriate use. In 1995, the Food and Drug Administration (FDA) approved a sustainedrelease formulation of oxycodone (Ox圜ontin®, Purdue Pharma) although the sustained-release formulation was designed to deter drug misuse, drug abusers could circumvent the design ( 13, 14). Oxycodone has been shown to be a safe and effective pain reliever with side effects comparable to those of other opioids. name) or paracetamol (international name) ( 12). To address the shortcomings of single-agent use, combination analgesics have long been prescribed for moderate to severe acute and chronic pain, and new drug formulations now offer the practicality of dual analgesic agents in a single tablet that may help address this unmet need.Īlthough oxycodone has been available as an analgesic agent for nearly a century, it is marketed in the United States, Canada and Australia primarily as part of a combination, such as oxycodone and aspirin or oxycodone and acetaminophen (U.S. Less frequently discussed is the fact that single agents, even when appropriately prescribed in an adherent patient, are not always sufficient to control pain or do so only at doses that produce excess adverse effects. Inadequate analgesia can occur for many well-documented reasons: failure to prescribe according to guidelines ( 4, 5), poor understanding of analgesia on the part of prescribers ( 6), challenging patient populations such as the elderly ( 7), lack of availability of proper medications ( 8), excessive legal restrictions on opioids ( 9), patient misconceptions about drugs or resistance to them ( 10, 11), and changes in the patient’s condition or comorbidities requiring drug adjustments that may not be followed. While numerous pharmacological advances have made more and better drugs available to manage pain, it often goes unrelieved ( 1– 3). The challenge in treating patients with acute or chronic pain has always been to find safe, effective and adequate analgesia.
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