If naltrexone therapy is chosen, it is preferable to start intramuscular naltrexone; when compared to placebo or no medication treatment, oral naltrexone was not found to be more effective reducing illicit opioid use or treatment retention. Starting with oral tablets may be appropriate in some cases such as highly motivated patients or in controlled settings to see if liver enzymes are affected or side effects emerge prior to committing to a longer course of treatment. 187,194 Intramuscular injections of naltrexone are given at a dose of 380mg into the gluteal muscle every 4 weeks, though some patients, such as those who metabolize naltrexone rapidly, may benefit from increasing the frequency to every 3 weeks. Naltrexone is contraindicated in patients in acute opioid withdrawal, and should be used with caution in patients who have hepatic disease, are pregnant or breastfeeding, and those with psychiatric disorders. 187 Adverse reactions seen with intramuscular naltrexone include nausea, fatigue, decreased appetite, and injection site reactions ranging from injection site pain to cellulitis and abscesses. Patients should be encouraged to report injection site reactions to their provider to prevent development into more serious skin conditions. 187,194 If oral naltrexone is chosen, it is typically started at 50mg per day, though some studies have used up to 100mg per day, or started with 25mg per day for a few days and increased to 50mg once the lower dose is tolerated well. Side effects with oral naltrexone include headache, dizziness, and nausea; these tend to subside with regular use. 187,194 . Liver enzymes should be monitored within several weeks of starting either oral or injectable naltrexone, and monitored every 6 months during continued treatment due to the risk of increase with naltrexone. Naltrexone is not recommended for use in patients taking opioids, since naltrexone will decrease the effectiveness of opioids. Patients with hepatic failure or acute hepatitis should also avoid using naltrexone (ASAM, 2020b; Bruneau et al, 2018). An important counseling point for naltrexone therapy is that patients who relapse are at an increased risked of overdose. Because they have withdrawn from opioids, they have reduced tolerance and an opioid dose they previously used could be fatal. Patients should also be counseled on the importance of adherence. Naltrexone therapy should be administered in combination with psychosocial treatment; there is no recommended length of treatment. 187,194 Methadone Methadone can also be used for medication assisted treatment, but federal regulations require this medication to be dispensed only from approved treatment centers, and require drug testing and diversion control, which can limit its use. In these programs, patients are seen daily for supervised dosing at the beginning of their treatment.
After they are stabilized, they may qualify for take home doses of methadone to reduce their frequency of clinic visits if they meet specified requirements determined by the clinic’s medical director. These can include absence of illicit drug use, participation in recovery-based activities, and productive social or occupational functioning. Stable patients may be seen less frequently per federal regulations: once weekly after six months of treatment, or once every two weeks after a year in treatment. 187 There is not a recommended time limit for treatment with methadone. Providers should avoid using pre-determined durations of treatment due to the individualized rates of progress toward remission of opioid use disorder. Long term treatment with methadone is generally associated with better outcomes. Treatment for less than 90 days is thought to have limited effectiveness, and guidelines recommend a minimum of 12 months of treatment with methadone, though some patients may require many years of methadone treatment. 187 Selection of Treatment and Treatment Barriers Access to treatment is still a major issue for opioid use disorder. In a study by Yarborough, Stumbo, McCarty, Mertens, Weisner and Green 195 , patients reported they were not given information on the various options for medication-assisted treatment. Others had reservations regarding using methadone because of the stigma associated with methadone clinics, and they believed methadone was extremely addictive. Based on these findings, clinicians should individualize treatment plans and fully discuss treatment alternatives with patients, along with the risks and benefits of each treatment. 195 According to Bisaga et al. 185 , although evidence supports the effectiveness of these medications, there is inadequate head-to- head data from randomized, controlled trials to support recommending one medication over another. Treatment decisions should be based on availability, insurance coverage, or patient factors or preference. Clinicians should consider the risks/benefits of treatment, side effects or drug Naloxone hydrochloride (Narcan) is a rapid acting competitive opioid antagonist that reverses the effects of agonistic opioids. It is able to displace opioid agonists from the mu-opioid receptor, quickly reversing the effects of opioids, including respiratory depression, sedation, and pain relief. It can be administered to patients experiencing opioid overdose via intranasal spray or by intramuscular, subcutaneous, or intravenous injection, and can be safely administered to children and pregnant patients. If the patient does not respond within two to three minutes after administration, a second dose should be administered. The duration of action of naloxone depends on the dose, route of administration, and drug overdose type. Patients who have overdosed on long-acting opioids (OxyContin, MS Contin, Kadian) typically require multiple doses or a continuous infusion of naloxone, interactions, and logistical issues. 185,187 Overdose Management with Naloxone
since the opioid duration of action may be longer than naloxone’s duration of action. The goal of naloxone therapy should be to restore adequate spontaneous breathing, not necessarily complete arousal. 196,197 Naloxone is a proven safe medication. When given to patients who are not opioid intoxicated or dependent, there are no clinical effects. Even though naloxone produces a rapid withdrawal in opioid-tolerant patients, it is generally not life threatening. These symptoms are unpleasant, and some patients may become agitated and combative and require medication (e.g., benzodiazepine) to remain calm. Withdrawal symptoms include the following: 197 • Body aches • Diarrhea
• Tachycardia • Runny nose • Sneezing • Piloerection
• Nausea • Vomiting • Restlessness • Agitation • Abdominal cramps • Increased blood pressure
The FDA has approved injectable naloxone, intranasal naloxone (Narcan nasal spray), and a naloxone autoinjector (Evzio) for the treatment of opioid overdose. Injectable naloxone can be administered intravenously, intramuscularly, or subcutaneously in healthcare settings at doses of 0.4 mg to 2 mg every two to three minutes until respiration is restored. The Narcan nasal spray is a prefilled, needle-free device that requires no assembly. It can deliver a single 4-mg dose of naloxone into one nostril. The Evzio autoinjector is injected into the anterolateral aspect of the thigh to deliver naloxone 2 mg / 0.4 mL in a prefilled autoinjector injected either intramuscularly or subcutaneously. Once Evzio is turned on, the device provides verbal and visual guidance to the user describing how to deliver the medication, similar to automated defibrillators, in a safe, confident manner. Both Narcan nasal spray and Evzio are packaged in a carton containing two doses to allow for repeat dosing if needed. Caregivers should be advised to repeat doses in two to three minutes if no response is seen or until emergency responders arrive. 182,197,198 Counseling Patients on Opioid Overdose Risk and Response Evidence has shown that laypersons can learn to recognize the signs of an opiate overdose. They also can learn how to safely administer the antidote, naloxone. Naloxone kits are safe, cost effective, and reduce overdose deaths. Multiple health organizations recommend providing naloxone kits to laypersons who may witness an opioid overdose, to patients in substance abuse treatment programs, to people with substance use disorders who are leaving prison or jail, and as a component of responsible opioid prescribing. 182
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