Opioid Use Disorder __________________________________________________________________________
that of morphine. In equianalgesic doses, meperidine produces comparable sedation, respiratory depression, and euphoria as morphine. Some patients may experience dysphoria. Meperi- dine can cause central nervous system excitation, character- ized by tremors, muscle twitches, and seizures, primarily due to accumulation of the metabolite normeperidine [1]. Large doses repeated at short intervals by addicts who have developed a tolerance to the sedative effects can produce an excitatory syndrome characterized by hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions [9]. Meperidine is primarily abused by healthcare profession- als [9]. Diphenoxylate and Loperamide Diphenoxylate (in combination with atropine as Lomotil) and loperamide (Imodium) are meperidine congeners that are approved by the U.S. Food and Drug Administration (FDA) for the treatment of diarrhea [55]. These drugs slow gastro- intestinal motility by affecting the circular and longitudinal muscles of the intestine, presumably through interaction with opioid receptors in the intestine [9]. Fentanyl and Congeners Fentanyl is a synthetic opioid related to the phenylpiperidines. The actions of fentanyl and its congeners (sufentanil, remifen- tanil, and alfentanil) are similar to those of other mu-receptor agonists. Fentanyl is a popular drug in anesthesia practice because of its relatively short time to peak analgesic effect, rapid termination of effect after small bolus doses, and relative cardiovascular stability. Fentanyl is approximately 100 times more potent than morphine, and sufentanil is approximately 10 times more potent than fentanyl. These drugs are usually administered intravenously and are substantially more lipo- philic than morphine. Time to peak analgesia is rapid, usually within five minutes. Respiratory depression potential is similar to other mu-receptor agonists with a more rapid onset. Fentanyl and sufentanil treatment of chronic pain has become more widespread, and transdermal patches that provide sustained release for 48 hours or more are available [9]. Fentanyl is delivered via the transdermal route for up to 72 hours, with patches containing 2.5, 5, 7.5, or 10 mg of fen- tanyl. Abuse of both the injectable formulation of fentanyl (Sublimaze) and the transdermal patch is primarily, but not exclusively, a problem among healthcare professionals due to availability and proximity. Fentanyl may be extracted from the patch and injected, or the patch contents may be chewed, ingested, or inhaled. Even a patch that has been used for three days contains sufficient fentanyl to be abused [1]. Methadone Methadone was first synthesized as an analgesic in Germany during World War II as a response to the difficulty in obtain- ing raw opium [56]. Methadone is a long-acting mu-receptor agonist with pharmacologic properties quantitatively similar to those of morphine [9]. Methadone is well-absorbed from the gastrointestinal tract and can be detected in plasma within
30 minutes of oral ingestion. Peak concentrations occur in the brain within one or two hours of subcutaneous or intra- muscular administration [9]. Oral bioavailability approaches 100% [55; 56]. In contrast to heroin, the activity of methadone is due almost exclusively to the parent drug rather than its metabolites. The drug is characterized by a long, but highly variable, half-life. One of the primary elimination pathways of methadone is N -demethylation, with cytochrome P450 3A4 (CYP 3A4) the major enzyme involved [55]. Inhibition of CYP 3A4 with drugs such as ketoconazole and erythromycin may enhance and pro- long the effect of methadone. Its induction with drugs such as rifampin, carbamazepine, and phenytoin will have the opposite effect [51; 55]. Liver disease can increase the half-life of metha- done, but renal failure will not [56]. Additionally, CYP 2D6 may be involved in the metabolism of the active enantiomer of methadone; less than 7% of white persons and more than 25% of Ethiopian persons are ultrarapid metabolizers at CYP 2D6. Individuals with this polymorphism may be more likely to experience methadone overdose [51; 57]. Following absorption, methadone is distributed to the brain, liver, kidneys, muscles, and lungs. Tissue binding predominates over binding to plasma proteins, and accumulation of the drug occurs in these tissues with repeated dosing. Plasma concentra- tions are maintained by this peripheral reservoir. Methadone reabsorption from the tissues may continue for weeks after administration has ceased. It has an elimination half-life of about 22 hours, but metabolism varies in each person [58]. One of the most significant advantages of methadone is that it alleviates cravings for opioids (a primary reason for relapse) and blocks many of the pleasurable effects of heroin, which helps reinforce abstinence [56]. Some of the characteristic properties of methadone are its analgesic activity, its efficacy by the oral route, its extended duration of action in suppress- ing withdrawal symptoms in physically dependent individuals, and its ability to demonstrate persistent effects with repeated administration [9]. Accidental overdose fatalities can occur when pain patients re-administer methadone when the analgesia wears off and pain returns, potentially elevating plasma concentrations to life-threatening levels. These same pharmacologic properties also imperil those who use it illicitly. Opioid abusers often co-administer benzodiazepines, which greatly elevates lethality risk with methadone. Concurrent use of alcohol poses the same risk [47]. In methadone clinics, methadone is usually dispensed in prepared individual doses mixed with fruit juice to discourage IV use. Methadone is also prescribed for pain. Until recently, there had been little evidence that diversion of methadone from pain management was occurring on any substantial scale. The majority of diverted methadone is used by heroin addicts to self-medicate symptoms of opioid withdrawal. To date, there is no evidence that diversion of methadone from methadone clinics has resulted in significant numbers of new opioid addicts [59].
24
MDRI2026
Powered by FlippingBook