"In the 12 months after a nonfatal overdose, 2040 persons (11%) enrolled in MMT for a median of 5 months (interquartile range, 2 to 9 months), 3022 persons (17%) received buprenorphine for a median of 4 months (interquartile range, 2 to 8 months), and 1099 persons (6%) received naltrexone for a median of 1 month (interquartile range, 1 to 2 months). Among the entire cohort, all-cause mortality was 4.7 deaths (95% CI, 4.4 to 5.0 deaths) per 100 person-years and opioid-related mortality was 2.1 deaths (CI, 1.9 to 2.4 deaths) per 100 person-years. Compared with no MOUD, MMT was associated with decreased all-cause mortality (adjusted hazard ratio [AHR], 0.47 [CI, 0.32 to 0.71]) and opioid-related mortality (AHR, 0.41 [CI, 0.24 to 0.70]). Buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 [CI, 0.46 to 0.87]) and opioid-related mortality (AHR, 0.62 [CI, 0.41 to 0.92]). No associations between naltrexone and all-cause mortality (AHR, 1.44 [CI, 0.84 to 2.46]) or opioid-related mortality (AHR, 1.42 [CI, 0.73 to 2.79]) were identified."

"However, one problem markedly reduces naltrexone’s efficacy and has limited its use for treating heroin and other forms of opioid dependence worldwide: patients often do not like it and do not take it on a daily basis. The dropout rate with oral naltrexone has been better in the limited number of patients in whom there is substantial external motivation to remain abstinent, such as physicians who are in monitoring programs and could lose their license if they relapse, those involved in the criminal justice system who could go to prison if they relapse, and those facing loss of employment [1•, 2–4].

"A few US studies have shown positive effects with psychosocial or behavioral therapies. In two, contingency management combined with naltrexone was helpful [5, 6]. In another, naltrexone combined with individual [7] and group [2] psychotherapy yielded positive effects. A third tested a behavioral therapy that used rewards for negative urine tests [8]; however, it had a relatively limited effect and was identified by Nunes et al. [9] as one of several examples indicating that there appears to be a ceiling effect on the degree to which behavioral interventions can be used to improve naltrexone treatment outcomes."

"Precipitation of Opioid Withdrawal

"The symptoms of spontaneous opioid withdrawal (which are associated with the discontinuation of opioid in a dependent individual) are uncomfortable, but they are not generally believed to be severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly by the administration of an opioid antagonist to an opioid-dependent patient, the resulting withdrawal syndrome can be severe enough to require hospitalization. Review of postmarketing cases of precipitated opioid withdrawal in association with naltrexone treatment has identified cases with symptoms of withdrawal severe enough to require hospital admission, and in some cases, management in the intensive care unit.

"To prevent occurrence of precipitated withdrawal in patients dependent on opioids, or exacerbation of a pre-existing subclinical withdrawal syndrome, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting VIVITROL treatment. An opioid-free interval of a minimum of 7–10 days is recommended for patients previously dependent on short-acting opioids. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as two weeks.

"If a more rapid transition from agonist to antagonist therapy is deemed necessary and appropriate by the healthcare provider, monitor the patient closely in an appropriate medical setting where precipitated withdrawal can be managed.

"In every case, healthcare providers should always be prepared to manage withdrawal symptomatically with non-opioid medications because there is no completely reliable method for determining whether a patient has had an adequate opioid free period. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Patients should be made aware of the risks associated with precipitated withdrawal and encouraged to give an accurate account of last opioid use. Patients treated for alcohol dependence with VIVITROL should also be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with VIVITROL. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids."

"Findings from a 24-week randomized controlled trial comparing extended-release injectable naltrexone (Vivitrol, Alkermes) to placebo in individuals with current opioid dependence have been considered in the recent indication for extended-release injectable naltrexone for the treatment of opioid dependence. In this trial, subjects having completed 30-day detoxification were recruited from 13 sites in Russia received either 380 mg intramuscular injections of extended-release naltrexone (n = 126) or placebo injection (n = 124) every 4 weeks for 24 weeks. Primary outcome data of opioid abstinence, measured by urine and self-report as well as secondary data including opioid craving, dependence relapse and study ­retention were measured. Opioid-free weeks from week 5 to 24 were significantly different between treatment groups (P, 0.0002), with a median of 90% percent of opioid-free urines in the extended-release ­ naltrexone group and 35% in the placebo group. Total ­abstinence measured as 100% opioid-free weeks in weeks 5 through 24 was 35.7% in the extended-release ­naltrexone group versus 22.6% in the placebo group. With extended-release naltrexone, subjects reported a 50% mean reduction in ­subjective craving compared with no change in craving for subjects receiving placebo, and retention in the extended-release naltrexone group was significantly longer compared to the placebo group (168 days vs. 96 days, P = 0.0042).⁴³"

"VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema, bruising, or pruritus; however, in some cases injection site reactions may be very severe. In the clinical trials, one patient developed an area of induration that continued to enlarge after 4 weeks, with subsequent development of necrotic tissue that required surgical excision. In the postmarketing period, additional cases of injection site reaction with features including induration, cellulitis, hematoma, abscess, sterile abscess, and necrosis, have been reported. Some cases required surgical intervention, including debridement of necrotic tissue. Some cases resulted in significant scarring. The reported cases occurred primarily in female patients.

"VIVITROL is administered as an intramuscular gluteal injection, and inadvertent subcutaneous injection of VIVITROL may increase the likelihood of severe injection site reactions. The needles provided in the carton are customized needles. VIVITROL must not be injected using any other needle. The needle lengths (either 1 1/2 inches or 2 inches) may not be adequate in every patient because of body habitus. Body habitus should be assessed prior to each injection for each patient to assure that the proper needle is selected and that the needle length is adequate for intramuscular administration. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1 1/2 -inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. Healthcare providers should ensure that the VIVITROL injection is given correctly, and should consider alternate treatment for those patients whose body habitus precludes an intramuscular gluteal injection with one of the provided needles.

"Patients should be informed that any concerning injection site reactions should be brought to the attention of the healthcare provider [see Patient Counseling Information (17)]. Patients exhibiting signs of abscess, cellulitis, necrosis, or extensive swelling should be evaluated by a physician to determine if referral to a surgeon is warranted."

"There are currently no specific clinical guidelines for transitioning patients with opioid use disorder to Vivitrol while minimizing the risk of precipitating withdrawal and relapse.²⁵ However, a number of opioid detoxification and induction strategies are being investigated to assist patients transitioning to Vivitrol.^90,91 The US prescribing recommendation that individuals abstain from opioids for seven to 10 days, combined with conventional methods of opioid-agonist tapering over several days, represents a delay of at least two weeks before Vivitrol can be started.^23,90 In addition, guidance is needed for transitioning patients from oral naltrexone, buprenorphine/naloxone, or methadone to Vivitrol or re-initiating treatment with Vivitrol following discontinuation.²³ Because of the time required for detoxification, current guidelines recommend residential or intensive outpatient settings for initiating treatment with Vivitrol.²

"Pain management is a concern in patients receiving treatment with Vivitrol.^25,92 Patients undergoing emergency or elective surgery will not respond to normal therapeutic doses of opioid analgesics because of the opioid-receptor antagonist mechanism of action of Vivitrol. In addition, re-initiating Vivitrol soon after opioid use may precipitate withdrawal. Therefore, it is recommended that pain be treated with regional or local anesthetic techniques, and non-opioid pharmacologic therapies (including ketorolac and gabapentin).⁹² If non-opioid modalities prove ineffective or are contraindicated, the effects of opioid titration would need to be closely monitored by professionals trained in the management of the effects of high-dose opioids, including assisted ventilation and cardiopulmonary rescucitation.⁹²

"There are currently no recommendations for the duration of treatment with Vivitrol.²⁵ An ongoing trial is assessing the effect of Vivitrol compared with placebo when given for 48 weeks versus 24 weeks in 130 patients addicted to opioids who have completed in-patient treatment.⁹³ Outcome measures include proportion with urine tests positive for opiates and HIV risk behaviours at 12 months.

"Following Vivitrol treatment, opioid tolerance is reduced from the pre-treatment baseline, and patients are vulnerable to potentially fatal overdose, particularly if they take large amounts of opioids in an attempt to overcome the blockade effect of Vivitrol.²³ None of the published phase III trials or studies in real-world settings have investigated the long-term risk of relapse, opioid overdose, and death among those participants who choose not to continue therapy with Vivitrol for longer than 78 months.
Research comparing Vivitrol with oral naltrexone and with opioid agonists (such as methadone or buprenorphine/naloxone) is needed to improve our understanding of its place in therapy for opioid use disorder. One ongoing, randomized, open-label trial is assessing the comparative effectiveness of Vivitrol versus buprenorphine/naloxone in 600 adults with opioid use disorder in the US.⁹⁴ The primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) during the 24-week treatment phase. Secondary outcomes include retention in treatment, opioid abstinence, HIV risk behaviours, quality of life, genetic moderators, and cost-effectiveness. A smaller randomized, open-label trial is also studying Vivitrol versus buprenorphine/naloxone in 180 patients with opioid use disorder in Norway.95 Primary outcomes are abstinence from illicit opioids, as well as retention in treatment. Following the 12-week randomized period, there will be a 36-week period during which participants will continue to receive Vivitrol in order to investigate long-term outcomes. A third trial is investigating whether Vivitrol has greater efficacy and is more cost-effective than oral naltrexone, with or without behavioural therapy and HIV risk reduction counselling, in 320 opiate-dependent patients in Russia.⁹⁶ Primary outcome measures include reductions in HIV risk behaviours, reductions in illicit opiate use, and treatment retention during the six-month treatment phase and the six-month follow-up.

"There has been interest in using Vivitrol in various subpopulations, as agonist therapy with buprenorphine/naloxone or methadone may be less suitable for some patients. Several ongoing phase III and IV trials are evaluating the effect of Vivitrol in people within the criminal justice system, in those living with HIV, and in young adults and adolescents with opioid use disorder. Results from these and future studies will be needed to determine the clinical impact and value of Vivitrol in a broad and diverse population of patients with opioid use disorder."

"Depression and Suicidality

"Alcohol- and opioid-dependent patients, including those taking VIVITROL, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with VIVITROL should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider.

"Alcohol Dependence
"In controlled clinical trials of VIVITROL administered to adults with alcohol dependence, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in patients treated with VIVITROL than in patients treated with placebo (1% vs 0). In some cases, the suicidal thoughts or behavior occurred after study discontinuation, but were in the context of an episode of depression that began while the patient was on study drug. Two completed suicides occurred, both involving patients treated with VIVITROL.

"Depression-related events associated with premature discontinuation of study drug were also more common in patients treated with VIVITROL (~1%) than in placebo-treated patients (0).

"In the 24-week, placebo-controlled pivotal trial in 624 alcohol-dependent patients, adverse events involving depressed mood were reported by 10% of patients treated with VIVITROL 380 mg, as compared to 5% of patients treated with placebo injections.

"Opioid Dependence
"In an open-label, long-term safety study conducted in the US, adverse events of a suicidal nature (depressed mood, suicidal ideation, suicide attempt) were reported by 5% of opioid-dependent patients treated with VIVITROL 380 mg (n=101) and 10% of opioid-dependent patients treated with oral naltrexone (n=20). In the 24-week, placebo-controlled pivotal trial that was conducted in Russia in 250 opioid-dependent patients, adverse events involving depressed mood or suicidal thinking were not reported by any patient in either treatment group (VIVITROL 380 mg or placebo)."