_________________________________________________________________________ Opioid Use Disorder
between 1997 and 2007 shows an increase of 1,293% [45; 46]. This rising use of methadone occurred simultaneously with concerns over the abuse potential of other opioids and the search for a relatively inexpensive long-acting opioid analgesic alternative [47]. Since the mid-2000s, methadone has become disproportion- ately represented in cases of opioid analgesic fatality. Based on data showing that 70% of fatalities among those prescribed methadone occurred in the first seven days of treatment, the FDA changed the methadone labeling in 2006 to lengthen dosing intervals from every 3 to 4 hours to every 8 to 12 hours; the initial recommended dose of 2.5–10 mg was unchanged [48]. In 2008, use of the highest oral dose (40 mg) preparations was prohibited from use in pain treatment and restricted to addiction therapy [49]. In addition to the general risk factors for opioid overdose, spe- cific factors that contribute to methadone fatality include [49]: • Payer policies that encourage or mandate methadone as first-line therapy • Methadone prescribing in opioid-naïve patients • Lack of prescriber knowledge of methadone pharmacol- ogy CLASSIFICATION Opioid broadly refers to all compounds related to opium. The term opium is derived from opos , the Greek word for “juice,” as the drug is derived from the latex sap of the opium poppy Papaver somniferum . Drugs derived from opium, including the natural products morphine, codeine, and thebaine, may be referred to as opiates [9]. However, for the purposes of simplification, all compounds will be referred to as opioids throughout this course. The narcotic analgesics can be categorized into three groups. The first group includes the natural opium derivatives (heroin, morphine, and codeine) and the semisynthetic derivatives from this group, including hydromorphone, oxymorphone, hydro- codone, oxycodone, dihydrocodeine, and buprenorphine. The two other groups are synthetic chemicals: the phenylpiperi- dines, including meperidine and fentanyl, and the pseudo- piperidines, including methadone and propoxyphene [50]. OPIOID SYNTHESIS As noted, opium is obtained from the unripe seed capsules of the poppy plant P. somniferum . The sides of the unripe seed pod are slit, and the milky sap that emerges is dried to make powdered opium. Although raw opium contains numerous alkaloids, only a few, such as morphine, codeine, thebaine, and papaverine, have clinical utility. Because morphine synthesis is difficult, the drug is still primarily obtained from opium or extracted from poppy straw [9].
Heroin, or diacetylmorphine, is synthesized by collecting and converting powdered opium to heroin hydrochloride in clandestine laboratories [8]. Impurities in the processing, par- ticularly in heroin from Mexico, result in some street heroin being brown in color. This type of heroin, often referred to as “black tar,” is the predominant type available in the western United States. The purity of Colombian and Mexican heroin powder averages 40% to 60% [8]. From the point of entry in the United States to the consumer, heroin hydrochloride is adulterated by the addition of quinine, lactose, mannitol, dextrose, or talc at each level of distribution, to the point that bags costing $10 (“dime bags”) may contain only 6% heroin hydrochloride [8]. The numerous synthetic derivatives of morphine and thebaine are made by relatively simple modifications of the molecule. Examples of this include the transformation of morphine to diacetylmorphine by acetylation at the 3 and 6 positions. The main goals of opioid structural modification are to increase the affinity for various species of opioid receptors, alter the activity of the drug from agonist to antagonist, change the lipid solubility, and alter the resistance to metabolic breakdown [9]. PHARMACOLOGY Opioids have been the mainstay of pain treatment for thou- sands of years, exerting their effects by mimicking naturally occurring endogenous opioid peptides or endorphins [9]. Although many new opioids have been developed with phar- macologic properties similar to morphine, morphine remains the standard against which new analgesics are measured [9]. ENDOGENOUS OPIOID PEPTIDES The endogenous opioid system is complex and subtle, with diverse functions. The system plays a sensory role, which is prominent in inhibiting response to painful stimuli; a modula- tory role in gastrointestinal, endocrine, and autonomic func- tions; an emotional role evidenced by the powerful rewarding and addicting properties of opioids; and a cognitive role involving modulation of learning and memory [9]. There are three distinct families of classical opioid peptides: enkephalins, endorphins, and dynorphins. Each of these families is derived from a distinct precursor protein and has a characteristic anatomical distribution. The precursor proteins, preproenkephalin, prepro-opiomelanocortin (POMC), and preprodynorphin are encoded by three corresponding genes. The primary opioid peptide derived from POMC is beta- endorphin. The POMC precursor is also processed into the non-opioid peptides adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (alpha-MSH), and beta- lipotropin (beta-LPH), suggesting a common precursor for the stress hormone ACTH and the opioid peptide beta-endorphin. This association indicates a shared physiologic linkage between the stress axis and opioid systems, which has been validated by the observation of stress-induced analgesia [9].
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MDRI2026
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