_________________________________________________________________________ Opioid Use Disorder
OPIOID ANTAGONISTS Opioid antagonists have obvious therapeutic value in the treatment of opioid overdose. Relatively minor changes in the structure of an opioid can convert an agonist drug into one with antagonistic actions at one or more opioid receptor types. Opioid antagonists include naloxone, naltrexone, and nalmefene. Nalmefene is not approved in the United States [55]. Interestingly, naloxone also appears to block the analgesic effects of placebo medications and acupuncture. Naltrexone and naloxone have little or no potential for abuse [9].
In 2014, the FDA approved a buccal film containing both buprenorphine and naloxone [71]. This combination therapy is applied once daily to suppress signs and symptoms of opioid withdrawal [55]. In 2016, the FDA approved the first buprenor- phine implant (Probuphine) for opioid dependence [72]. The implant provides a constant, low-level dose of buprenorphine for six months. It is designed for use in patients who are already stable on a low dose of other forms of buprenorphine, as part of a complete treatment program. Because Probuphine must be inserted and removed surgically, healthcare providers are required to complete training and certification through the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program [72]. In 2017, the FDA approved a once-monthly sub- cutaneous injection (Sublocade) for opioid use disorder [73]. Sublocade is intended for use in adult patients with moderate- to-severe opioid use disorder who have been on a stable dose of buprenorphine treatment for a minimum of seven days. The drug must be administered in a healthcare setting to avoid inadvertent IV administration that could result in death [73]. In 2023, the FDA approved buprenorphine extended-release (Brixadi) for subcutaneous injection [74]. Brixadi is approved in both weekly and monthly subcutaneous injectable formu- lations at varying doses, including lower doses that may be appropriate for those who do not tolerate higher doses of extended-release buprenorphine that are currently available. The weekly doses are 8, 16, 24, and 32 mg; the monthly doses are 64, 96, and 128 mg [74]. Buprenorphine use is contraindi- cated for patients with alcohol intoxication, delirium tremens, and treatment with monoamine oxidase inhibitors. Cases of lethal buprenorphine intoxication almost always involve polyintoxication [69]. Buprenorphine contains a black box warning regarding the potential for serious, life-threatening, or fatal respiratory depression, especially during initiation or dose escalation [55]. Upon discontinuation, a withdrawal syn- drome develops, with a delayed emergence in two days to two weeks. Signs and symptoms of buprenorphine withdrawal are typical of a milder morphine-type withdrawal and last roughly one to two weeks [9]. The more benign withdrawal syndrome is due to its partial agonist property at the mu receptor and weak antagonist property at the kappa receptor [56]. Section 1262 of the Consolidated Appropriations Act of 2023 removes the federal requirement for practitioners to apply for a special waiver prior to prescribing buprenorphine for the treatment of OUD. It also removes other federal requirements association with the waiver, such as patient limits. Separately, section 1263 of the Act requires new or renewing DEA registrants to meet one of three requirements (i.e., training, certification, or educa- tion). This section became effective June 27, 2023. Additional information is available on the SAMHSA website at https:// www.samhsa.gov/medications-substance-use-disorders/waiver- elimination-mat-act [75; 76].
NATURAL HISTORY OF OPIOID DEPENDENCE
Although the time from initiation to daily use and serious physiologic and psychologic dependence is highly variable, the different stages of opioid dependence are clearly delineated [8]. These stages include initiation, continuation, withdrawal, and relapse. Each stage is characterized by specific neurotransmitter action, involvement of specific brain structures, and activation of specific neural circuits. An understanding of these differ- ent processes is crucial to develop an understanding of the therapeutic strategies [77]. INITIATION During the initiation phase, acute reinforcement of the initial drug effect is mediated by mu-opioid receptors and dopamine that inhabit the ventral tegmental area and nucleus accumbens. This results in conditioned responses and drug craving [77]. CONTINUATION The second phase of continued drug use is characterized by diverse neurotransmitter involvement, including dopamine in the nucleus accumbens, corticotrophin-releasing hormone in the amygdala, and glutamate in the frontal-cingulate circuit. As tolerance develops, the dose and route of administration often change, with progression to IV use a frequent outcome [8]. DETOXIFICATION AND WITHDRAWAL During detoxification and withdrawal from opioids and other central nervous system depressants, glutamate and norepineph- rine in the locus coeruleus are primarily involved in causing the associated symptoms [77]. RELAPSE FOLLOWING SUSTAINED ABSENCE Brain regions implicated in relapse to opioid use include the orbitofrontal cortex, anterior cingulate gyrus, and amygdala. Norepinephrine and corticotrophin-releasing hormones are involved in stress-induced relapse. Gamma-aminobutyric acid (GABA) and glutamate mediate brain systems that are involved in compulsive and habitual behavior and mediate cue-induced relapse [77].
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MDRI2026
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