_________________________________________________________________________ Opioid Use Disorder
More frequent adverse effects associated with methadone use include sweating, decreased libido, weight gain, constipation, and irregular menstrual periods, all occurring primarily during the initial stabilization process. Uncommon side effects include facial flushing, pruritus, euphoria or dysphoria, insomnia, urinary retention, and bradycardia [55]. Rarely observed side effects include biliary spasm, urticaria, syncope, overdose death, and torsades de pointes [56]. These effects are more common at higher doses and when methadone is combined with certain other drugs [60]. Risk of QTc prolongation and arrhythmia led to a 2006 black box warning [55]. Tolerance to the opioid properties of methadone develops within four weeks. The minimal effective dose is regarded as 40 mg, but some patients require much greater doses [55; 56]. Subcutaneous administration of 10-20 mg methadone to for- mer opioid addicts unambiguously produces euphoria similar in duration and magnitude to that of morphine. Methadone’s overall abuse potential is comparable to that of morphine [9]. Hydrocodone Hydrocodone is a semi-synthetic codeine derivative first used clinically as an antitussive and analgesic in the 1920s. Follow- ing a 10-mg oral dose, maximum serum level is observed in 1.3 hours [61]. Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-a- and 6-b-hydroxyme- tabolites. The 2D6 enzyme demethylates hydrocodone at the 3-carbon position into hydromorphone, which has much stronger mu binding than hydrocodone. Similar to codeine, it has been proposed that hydrocodone is a prodrug. Its analgesic properties are generally considered equipotent to codeine [62]. Oxycodone Oxycodone is similar in structure to hydrocodone, with the addition of a hydroxyl group at the 14-carbon. Oxycodone, as a hydrochloride salt, is a pure agonist opioid that has been in clinical use since 1917. Unlike codeine and hydrocodone, oxycodone is a potent analgesic in its own right and not a pro- drug, although 2D6 activity creates the active opioid analgesic metabolite oxymorphone (synthesized and marketed as the analgesic Opana). Oxycodone is suitable for oral administra- tion due to high bioavailability (60%) but may also be taken intramuscularly, intravenously, subcutaneously, or rectally; however, oxycodone is only commercially available in oral preparations [55]. In terms of analgesic potency and lipophi- licity, oxycodone is comparable to morphine, and both drugs possess similar abuse potential. With the exception of hallu- cinations, which occur more rarely with oxycodone than with morphine, the side effects of these drugs are highly similar [63]. Oxycodone is metabolized by demethylation to noroxycodone and oxymorphone followed by glucuronidation [55]. A urine screen may reveal oxycodone alone, oxycodone and oxymor- phone, or oxymorphone alone [64]. Since 1995, oxycodone has been marketed in the United States as OxyContin, a Schedule II controlled-release oral tablet formulation. Oxycodone is also available in immediate-release
tablets in combination with aspirin or acetaminophen under various trade names, including Percodan and Percocet, which contain 2.5–10 mg of oxycodone [55]. The oxycodone content of OxyContin ranges from 10 mg to 80 mg. When taken orally, OxyContin tablets release oxycodone over a 12-hour period. However, when the controlled-release mechanism is destroyed by crushing the tablet, the oxycodone can be snorted, ingested, or injected. It is this delivery of a large amount of the active drug in a relatively brief time period (compared to the intact tablet and the low-dose immediate-release form) that underlies addicts’ interest in OxyContin [1]. In 2014, the FDA approved an extended-release version of oxycodone that is formulated to include naloxone in order to deter misuse [65]. If crushed and snorted or crushed, dis- solved, and injected, the naloxone will block the euphoric effects of oxycodone, potentially deterring this type of abuse. This combination drug is intended for patients for whom alternative treatment options for chronic pain are ineffective or not tolerated [65]. The drug is no longer available in the United States [55]. Hydromorphone Hydromorphone is a semi-synthetic hydrogenated ketone of morphine and shares the pharmacologic properties typical of mu-opioid agonists. Hydromorphone is a more potent analge- sic than morphine; on a milligram basis, hydromorphone is 5 times as potent orally and 8.5 times as potent intravenously. Hydromorphone can be administered by infusion, intramus- cularly, orally, or rectally [66]. Following oral administration of conventional-release hydro- morphone, the drug is rapidly absorbed and undergoes hepatic first-pass elimination of approximately 50%. The terminal elimination half-life after IV administration is 2.5 to 3 hours. The primary mode of elimination is by urinary excretion as hydromorphone-3-glucuronide, the primary metabolite. Some metabolites may have greater analgesic activity than hydromor- phone itself but are unlikely to contribute to the pharmacologic activity. Side effects are comparable to morphine [66]. In 2023, the FDA issued a drug safety communication to update the prescribing information for immediate-release (IR) and extended-release (ER)/long-acting (LA) opioid analgesics. The safety communication includes updates to boxed warnings, indications and usage, dosage and administration, warnings and precautions, and the medication guide [67]. Revised labels must state that [67]: • The risk of overdose increases as the dosage increases for all opioid pain medicines. • IR opioids should not be used for an extended period of time unless a patient’s pain remains severe enough to require them and alternative treatment options con- tinue to be inadequate. • Many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
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MDRI2026
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