Table 7. FDA-approved medications for OUD 147
“Buprenorphine treatment provides one of the rare opportunities in primary care to see dramatic clinical improvement: it’s hard to imagine a more satisfying clinical experience than helping a patient escape the cycle of active addiction.”
Buprenorphine •
Buprenorphine/naloxone buccal film (Bunavail)
• Buprenorphine/naloxone sublingual film (Suboxone, generics) • Buprenorphine/naloxone sublingual tablets (Zubsolv, generics) • Buprenorphine sublingual tablets (generics) • Buprenorphine subdermal implant (Probuphine) • Buprenorphine extended-release subcutaneous injection (Sublocade) Methadone
--Wakeman et al. NEJM 2018;379(1):1-4
It may, however, take days to weeks to achieve a therapeutic dose, which requires individualized monitoring in order to minimize cravings and reduce the risk of relapse. As a full agonist, methadone sustains opioid tolerance and physical dependence, thus missing doses may precipitate opioid withdrawal. Overdose risk is highest in the first two weeks of methadone treatment, 149 after which risk is significantly lower compared to people who are not in treatment. 150,151 Common side effects of methadone are constipation, vomiting, sweating, dizziness, and sedation. Although respiratory depression can be induced by methadone, the FDA advises that methadone not be withheld from patients taking benzodiazepines or other central nervous system depressants because the risk of overdose is even higher among patients not on methadone for OUD. 152 The other potential harms of methadone include hypogonadism, which is a potential side effect of chronic use of any opioid, and QTc segment prolongation. Buprenorphine Buprenorphine is a high-affinity partial opioid agonist at the mu-opioid receptor as well as an antagonist of the kappa opioid receptor. 153 Like methadone, buprenorphine can relieve opioid withdrawal symptoms, and, because of its partial agonist effect, it can reduce the rewarding effect of other opioids used simultaneous with buprenorphine. Buprenorphine’s partial agonist status also translates into a lower risk of respiratory depression compared to methadone and other opioids, 148 and a therapeutic dose may be achieved within a few days. 155 Buprenorphine is available as sublingual tablets, sublingual/buccal films, subdermal implants, or extended-release subcutaneous injection (Table 10). Some film and tablet formulations are combined with the opioid antagonist naloxone to discourage misuse by crushing and injecting the medication. (A buprenorphine-only patch [Butrans] is only FDA- approved as an analgesic.) • Tablets (Dolophine, MethaDose, generics) • Oral concentrate (MethaDose, generics) Naltrexone extended-release injection (Vivitrol)
Extended-release naltrexone Naltrexone is not an opioid. It is a full antagonist of the mu-opioid receptor, which blocks both the euphoric and analgesic effects of all opioids, including endogenous opioids (i.e., endorphins) and also reduces cravings for opioids. 153 Naltrexone does not cause physical dependence, nor does it produce any of the rewarding effects of opioids. Patients may try to use opioids while on extended- release naltrexone, but it is unlikely that they will experience any rewarding effects from such use, unless the binding affinity of naltrexone is overcome. 147 The most common side effects of extended-release naltrexone are injection site pain, nasopharyngitis, insomnia, and toothache. Treatment initiation requires a 7-10 day period during which the patient is free from all opioids, including methadone and buprenorphine. This is usually achieved with medicallysupervised withdrawal followed by at least 4 to 7 days without any opioids (including methadone and buprenorphine). This process is a very significant barrier to naltrexone use. 147 Naltrexone is currently available both as a once- daily oral tablet and in a once monthly, extended- release depot injection. The oral formulation, however, was found to be no better than placebo in a 2011 Cochrane review of 13 trials with 1,158 participants, 159 and only the extended-release formulation has been approved for OUD by the FDA. Patients may have an increased risk of overdose when they approach the end of the 28-day period of the extended-release formulation. 160 Naloxone vs. Naltrexone: What’s the difference? Naloxone (Narcan) is an opioid antagonist given by injection or nasal spray to reverse overdoses. It acts within minutes and lasts for only about an hour due to rapid metabolism. Naltrexone has a very similar chemical structure to Naloxone and is also an opioid antagonist, but it acts more slowly and lasts longer. Extended- release naltrexone is used clinically to block cravings for opioids and other drugs.
Some forms of buprenorphine can be self- administered by patients after filling their prescription at regular pharmacies. In order to prescribe buprenorphine, physicians in the United States must complete an 8-hour training and apply for a waiver (informally called an X-waiver) from the Drug Enforcement Administration (for details see “Obtaining an X-waiver” section below). The Comprehensive Addiction and Recovery Act of 2016 authorized nurse practitioners and physician assistants to be eligible to apply for training and X-waivers, although the associated required training is 24 hours. 156 As with methadone, buprenorphine sustains opioid tolerance and physical dependence in patients, so discontinuation can lead to withdrawal—although buprenorphine’s withdrawal syndrome may be less severe. The most common side effects are constipation, vomiting, headache, sweating, insomnia, and blurred vision. One risk of buprenorphine (as well as naltrexone) is the risk of precipitating opioid withdrawal at first dose if the patient has recently used either prescription or illicit drugs, due to buprenorphine’s partial- agonist properties high binding affinity for the opioid receptor. 141 Thus, a patient must be in mild to moderate withdrawal prior to initiation to avoid precipitating withdrawal. The risk of opioid overdose declines immediately when patients with OUD initiate buprenorphine treatment. 145 The risk of hypogonadism is lower with buprenorphine compared to methadone, and buprenorphine is not associated with QTc prolongation or cardiac arrhythmias. 157 The various non-oral routes of buprenorphine avoid the significant hepatic metabolism inherent with oral administration, and appear to be largely equivalent in their efficacy for maintaining abstinence and reducing risk of overdose. For example, a randomized trial comparing buprenorphine implant to sublingual buprenorphine found higher levels of negative urine screens and abstinence with the implant, but the differences did not reach statistical significance. 158 (Note that use of implantable agents require stabilization on sublingual doses first.)
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