Summary

• Vivitrol is an extended-release injectable formulation of naltrexone, administered as an intramuscular injection once a month. Naltrexone is an opioid-receptor antagonist that blocks the euphoric effects of opioids. Unlike other treatments for opioid use disorder, including buprenorphine/naloxone and methadone, naltrexone is not associated with the development of tolerance and dependence, and lacks the potential for misuse and diversion. However, because the oral formulation requires a daily dosage, poor adherence to the medication has limited its efficacy for the prevention of relapse in patients with opioid use disorder. The extended-release injectable formulation of naltrexone was developed to improve treatment adherence and retention.
• Vivitrol has not received marketing approval in Canada and is available only for research purposes or through Health Canada’s Special Access Programme for the treatment of opioid use disorder or alcohol use disorder. In October 2010, the US FDA approved Vivitrol for the prevention of relapse to opioid dependence following opioid detoxification. Before starting Vivitrol, an opioid-free period of a minimum of seven to 10 days is recommended to avoid precipitating withdrawal, symptoms of which may be severe enough to require hospitalization. There are currently no recommendations to guide the duration of treatment with Vivitrol.
• Results from one phase III, randomized, placebo-controlled, double-blind trial in patients with opioid use disorder who had recently undergone detoxification showed Vivitrol to be superior to placebo for improving abstinence and treatment retention, as well as for reducing opioid cravings over a six-month treatment period. Approximately one-half of patients who received Vivitrol for an additional year in an open-label extension study remained abstinent from opioids.
• Preliminary evidence from phase III trials and studies in real-world clinical settings demonstrates that Vivitrol may be beneficial for preventing relapse in two subpopulations: people living within the corrections system and people living with HIV.
• None of the phase III trials reported deaths due to overdose in patients receiving Vivitrol. The majority of commonly reported adverse effects, including nasopharyngitis (cold symptoms), insomnia, hypertension, influenza, and injection-site pain, were mild or moderate. Abnormal liver function test results occurred primarily in patients with existing hepatitis C infection, but were transient and not clinically significant. Severe injection-site reactions were noted in some patients.
• There are several clinical challenges and knowledge gaps associated with the initiation, long-term use, and role of Vivitrol relative to other treatments for opioid use disorder. These will need to be addressed when considering adopting Vivitrol in clinical practice. They include the approach to transitioning patients from other treatments (including methadone or buprenorphine/naloxone) to treatment with Vivitrol, pain management, duration of treatment, long-term risk of relapse and opioid overdose, efficacy and cost compared with other therapies for opioid use disorder, and use in certain subpopulations. When considering adopting Vivitrol in clinical practice, the requirement for total abstinence from opioids for seven to 10 days before initiating treatment may present a challenge.
• A Risk Evaluation and Mitigation Strategy, consisting of directions for proper injection technique and patient counselling materials, is in place in the US to inform health care providers and patients about the potentially serious risks associated with the use of Vivitrol, including severe injection-site reactions, sudden opioid withdrawal during treatment initiation, vulnerability to opioid overdose, and hepatotoxicity (drug-induced liver damage).

Background

Opioid use disorder (also known as opioid dependence), defined as a problematic pattern of opioid use leading to clinically significant impairment or distress, is a growing public health concern in Canada associated with significant morbidity and mortality.^1–3 Individuals with opioid use disorder are at greater risk for incarceration, blood-borne infections, and fatal overdose.⁴ In addition, babies born to mothers who used opioids during pregnancy are at increased risk for neonatal abstinence syndrome, a condition that can be life-threatening if not promptly recognized and treated.⁵ While heroin has historically been the most commonly misused opioid, non-medical use of prescription opioid analgesics (such as morphine, oxycodone, hydromorphone, and fentanyl) is now the dominant form of opioid misuse.⁶ “Misuse” has been defined as “the intentional or unintentional use of a prescribed medication in a manner that is contrary to directions, regardless of whether a harmful outcome occurs.”⁷

Canada is the world’s second largest per-capita consumer of prescription opioids.⁸ A total of 3.8 million Canadians more than 15 years of age (representing 13% of the total population) reported using opioid pain relievers in the past year, according to a Statistics Canada survey conducted in 2015.⁹ Among users of opioid pain relievers, 2.0% (83,000 Canadians, representing 0.3% of the total population) reported misusing them. A joint report by the Canadian Institute for Health Information and the Canadian Centre on Substance Abuse found that, between 2007–2008 and 2014–2015, the rate of hospitalizations due to opioid poisoning in Canada increased by more than 30%.¹⁰ Results from the report showed that opioid poisoning results in more than 13 hospitalizations per day in Canada, with an average length of stay of eight days. The report also found that the rate of emergency department visits due to opioid poisoning increased by 53% in Alberta and by 22% in Ontario between 2010–2011 and 2014–2015. The number of people enrolled in methadone maintenance treatment programs in Ontario increased from approximately 7,800 in 2001 to more than 35,000 in 2011.¹¹ Available preliminary data from all the provinces and territories (excluding Quebec) from 2016 indicate that there were 2,458 apparent opioid-related deaths in Canada.¹² The significant burden of opioid misuse on the Canadian health care system has triggered multi-pronged efforts in various jurisdictions to identify key factors contributing to the epidemic, as well as to address the unmet treatment needs of patients with opioid use disorder.¹³

Current guidelines recommend maintenance therapy with buprenorphine/naloxone or methadone for the treatment of patients with opioid use disorder.² When taken as prescribed, these medications alleviate withdrawal symptoms and diminish cravings without the typical euphoric effects of opioids.² However, both medications are considered controlled substances that carry certain prescribing and dispensing restrictions, depending on the jurisdiction, which limits accessibility, particularly in remote settings.^1,2,14–16 Currently available formulations of both buprenorphine/naloxone and methadone require daily supervised administration early in treatment or daily self-administration once the patient is clinically stable.¹⁷ Thus, particularly in an office-based treatment setting where medication administration is unsupervised, effectiveness relies on long-term patient adherence to daily treatment, and there is a risk of diversion, misuse, and overdose.¹⁷ Furthermore, there is also a risk of accidental pediatric exposure. The US Centers for Disease Control and Prevention reported that, between 2010 and 2011, 9.5% of emergency hospitalizations for drug ingestion among children younger than six years of age were caused by buprenorphine/naloxone.¹⁸

Oral naltrexone (Revia or its generic equivalents) is available in Canada as an alternative to buprenorphine/naloxone or methadone for treatment of opioid use disorder.¹⁹ Naltrexone is an opioid-receptor antagonist that blocks the euphoric effects of opioids.²⁰ Potential benefits of naltrexone over buprenorphine/naloxone or methadone include few known drug–drug interactions; greater accessibility; lack of development of physical tolerance during long-term treatment; and lack of potential for dependence, misuse, and diversion.^2,21 However, because the oral formulation requires daily dosage, poor medication adherence has limited its efficacy for the prevention of relapse in patients with opioid use disorder.² An additional barrier to use is the requirement for total abstinence from opioids before starting treatment with naltrexone.

These limitations in currently available treatment options for opioid use disorder in Canada have spurred interest in alternative formulations.

The Technology

Vivitrol (Alkermes, Inc., Waltham, Massachusetts) is an extended-release injectable formulation of naltrexone.²² It is administered by a health care professional as an intramuscular injection into the gluteal muscle.²³ Naltrexone is encapsulated in microspheres made of a biodegradable polymer and continuously released over one month at a set dose of 380 mg per injection.²² In the US, the extended-release injectable formulation was first approved for patients with alcohol use disorder. It was later used to improve treatment adherence and retention in comparison with oral naltrexone in patients with opioid use disorder. Before initiating Vivitrol, an opioid-free period of at least seven to 10 days is recommended to avoid precipitating withdrawal, which may be severe enough to require hospitalization.²³ A Risk Evaluation and Mitigation Strategy, consisting of directions for proper injection technique and patient counselling materials, is in place in the US to inform health care providers and patients about the potentially serious risks associated with the use of Vivitrol, including severe injection-site reactions, sudden opioid withdrawal during treatment initiation, vulnerability to opioid overdose, and hepatotoxicity.²⁴ To prevent severe injection-site reactions, Vivitrol must not be given intravenously, subcutaneously, or into adipose (fat) tissue. Customized needles of two different lengths are provided with the medication. The proper needle, based on body build, should be selected. Vivitrol must not be injected with any other needle. It is also recommended that the medication be administered on alternating sides of the patient for each subsequent injection.²⁴ There are currently no recommendations to guide the duration of treatment with Vivitrol.²⁵

Regulatory Status

Vivitrol has not received marketing approval in Canada, and it is not known whether a submission to Health Canada is planned. Vivitrol is available in Canada only for research purposes or through Health Canada’s Special Access Programme for the treatment of opioid use disorder or alcohol use disorder.² In October 2010, the US FDA approved Vivitrol for the prevention of relapse to opioid dependence following opioid detoxification,²⁶ and the drug is indicated as part of a comprehensive management program that includes psychosocial support. The FDA has also approved Vivitrol for the treatment of alcohol use disorder in patients who can abstain from alcohol in an outpatient setting before starting treatment.²⁶

Patient Group

Although the true prevalence of opioid use disorder in Canada is unknown, there are an estimated 75,000 to 125,000 injection-drug users (the vast majority of whom inject opioids such as heroin) and 200,000 people with prescription opioid use disorder.^27,28 The misuse of opioids leads to tolerance to the euphoric effects of the opioid, cravings for the drug, and a physiological withdrawal state when use is tapered quickly or stopped.²⁹ Opioid use disorder is characterized by the compulsive, prolonged administration of opioid substances despite the treatment of acute withdrawal.³ As a result, individuals experience physical dependence, medical and psychological problems, and social dysfunction.⁶ Opioid use disorder increases the risk of death, local and systemic infections (including cellulitis, endocarditis, osteomyelitis, tuberculosis, and pneumonia), infection with a blood-borne pathogen (such as HIV, hepatitis B, and hepatitis C), and narcotic bowel syndrome (an increase in abdominal pain associated with continued or escalating dosages of opioids).⁴ Opioid users also have a higher rate of accident-related injuries compared with the general population.⁴

According to US prescribing information, the patient population approved by the FDA for Vivitrol is individuals who have undergone opioid detoxification and wish to prevent relapse.²³ Vivitrol may also be considered for those with concurrent opioid and alcohol abuse disorders, as this group is at even higher risk for opioid overdose.³⁰ There are currently no estimates of the number of patients who have received oral naltrexone following opioid detoxification in Canada. Data from Ontario Drug Benefit database records between April 2011 and March 2012 indicate that fewer than 1% of patients who were eligible for public coverage of naltrexone for alcohol use disorder received treatment, although it was not reported whether any of these patients had concomitant opioid use disorder.³¹

In the US, there has been interest in using Vivitrol in various subpopulations, since agonist therapy with buprenorphine/naloxone or methadone may be less suitable for certain patients, including young adults and adolescents; those with a brief history of opioid use disorder or who are new to treatment; those whose employment might prohibit opioid use (e.g., health care providers, pilots, police force, firefighters, and military personnel); and those who have achieved abstinence during in-patient or residential treatment or incarceration and are at risk of relapse after discharge.^25,32–35 There is some evidence from phase III clinical trials that Vivitrol may be beneficial in criminal justice settings and for those living with HIV (described in The Evidence section).^33,36,37

Several ongoing phase III and IV trials are evaluating the effect of Vivitrol in opioid-dependent incarcerated offenders who are returning to the community.^38–42 Outcomes include relapse, treatment adherence, re-incarceration, injection-drug use, and HIV risk behaviours. One of these trials is specifically evaluating the clinical efficacy of Vivitrol for controlling viral load and preventing relapse in people living with HIV who are opioid-dependent and are prisoners or jail detainees.⁴¹ One phase IV trial is assessing the feasibility of using Vivitrol in opioid-dependent individuals in drug-court settings that offer substance use treatment as a sentencing option in lieu of incarceration.⁴³ Outcome measures include the number of new arrests and incarcerations, and positive drug screens over a 12-month period. A phase IV ongoing, randomized, open-label trial is evaluating Vivitrol versus usual treatment with buprenorphine and psychosocial counselling in young adults and adolescents (aged 15 to 21 years) with opioid use disorder.⁴⁴ Outcomes include opioid use, treatment retention, and HIV risk behaviours at six months.

Current Practice

Opioid use disorder is a chronic, relapsing illness that requires long-term maintenance treatment.² Guidelines strongly recommend against withdrawal management alone (i.e., detoxification without transition to longer-term treatment), as this approach has been associated with elevated rates of relapse, transmission of infectious diseases, criminal activity, and an increased risk of death from overdose, following the loss of tolerance to the effects of opioids after complete discontinuation.^1,2,4 Maintenance treatment of opioid use disorder involves a comprehensive approach that combines approved pharmacological therapy with counselling, psychosocial rehabilitation, and other behavioural therapies to reduce opioid drug misuse by decreasing cravings, addressing withdrawal symptoms, and promoting functional recovery in everyday living.² Treatment goals focus on functional recovery rather than solely on abstinence outcomes. Long-term maintenance treatment for two years is recommended.^45–48 However, according to the clinical expert consulted for this bulletin, at least six months of complete abstinence from opioids should be achieved before any tapering of maintenance therapy is attempted (Dr. Peter Selby, Director, Medical Education, and Clinician Scientist, Addictions, Centre for Addiction and Mental Health, Toronto, ON: personal communication, 2017 Jun 26). The requirements for abstinence may vary in patients seeking transition to another pharmacotherapy for opioid use disorder.

Current guidelines recommend maintenance therapy with buprenorphine/naloxone as first-line treatment for opioid use disorder because of its potential advantages compared with methadone. These include a potentially improved safety profile, a lower risk of overdose or diversion, and the potential for more flexible at-home administration, or administration every second day.² Increasingly, provinces are removing the requirement for physicians to hold a methadone exemption before prescribing buprenorphine/naloxone.^15,16,49 Methadone may be considered first-line when there are contraindications to buprenorphine/naloxone or when a challenging induction is anticipated because of prior failures of buprenorphine/naloxone treatment, a history of severe withdrawal symptoms, or an anticipated need for high-dose maintenance treatment.² Because of its narrow therapeutic index in some patients, especially during the first few weeks of treatment, methadone can be prescribed only by physicians who hold a methadone exemption granted by Health Canada.^1,14 Depending on the jurisdiction, for the first two to six months of therapy, methadone is dispensed for daily witnessed ingestion at specialized drug treatment clinics or pharmacies. This has proved to be a barrier for patients, especially those in rural communities.^1,50 Alternative approaches for patients with opioid use disorder who respond poorly to other maintenance treatments include slow-release oral morphine and injectable diacetylmorphine (also known as heroin).² In September 2016, Health Canada amended regulations allowing doctors to prescribe diacetylmorphine under the Special Access Programme to individuals with severe opioid use disorder for whom other treatment approaches have repeatedly failed.⁵¹

Although naltrexone is not considered a controlled substance in Canada and has no special prescribing or dispensing requirements, the oral short-acting formulation is rarely used in clinical practice.² This is largely because patients are required to abstain completely from opioids for a minimum of seven to 10 days to avoid precipitating withdrawal and because poor adherence to the daily dosage results in a high rate of relapse.² Oral naltrexone may be considered for individuals who wish to avoid opioid-agonist treatment and who are highly motivated to stay abstinent, including individuals with occupations that may prohibit opioid-agonist treatment (including health care professionals, firefighters, and those who transport hazardous materials).² In this case, gradual opioid-agonist tapering (over more than one month) in a supervised outpatient or residential setting with transition to long-term addiction treatment is recommended over rapid (less than one week) opioid-agonist taper in an in-patient setting. For individuals with a successful and sustained response to opioid-agonist treatment, a slow tapering of therapy over 12 months, with transition to oral naltrexone upon cessation of opioids, may be considered.² Oral naltrexone should be prescribed only to patients who are engaged in ongoing addiction care and can be assessed regularly on follow-up for risk or signs of relapse to opioid use.

In the US, guidelines also recommend treatment with buprenorphine or methadone as first-line treatment options for opioid use disorder.^25,52 Vivitrol is considered when treatment with buprenorphine or methadone is contraindicated, unacceptable, unavailable, or discontinued, and when abstinence has been achieved for a sufficient period of time.⁵² The guidelines state that there is insufficient evidence for the efficacy of oral naltrexone and that it should be reserved for patients in whom adherence can be supervised and monitored.^25,52 Psychosocial treatment is recommended in conjunction with Vivitrol treatment.²⁵ There are no recommendations for the duration of treatment, which may instead be based on clinical judgment and on the patient’s individual circumstances.²⁵

Methods

A peer-reviewed literature search was conducted using the following bibliographic databases: MEDLINE, PubMed, Embase, and the Cochrane Library. Grey literature was identified by searching relevant sections of the Grey Matters checklist (https://www.cadth.ca/grey-matters). No methodological filters were applied. Where possible, retrieval was limited to the human population. The search was limited to English-language documents with no date limit applied. Regular alerts updated the search until project completion; only citations retrieved before May 25, 2017 were incorporated into the analysis. Conference abstracts were excluded from the search results. Published phase III randomized controlled trials reporting the clinical efficacy and safety of the FDA-approved formulation of extended-release injectable naltrexone (Vivitrol) for the treatment of opioid use disorder were selected for inclusion in The Evidence and Adverse Event sections of this bulletin. Studies reporting the effect of Vivitrol on patient outcomes in real-world clinical settings were also included in The Evidence section. An open-label extension study of one of the selected phase III trials evaluating the long-term safety of Vivitrol was also included in the Adverse Event section. Meta-analyses, case reports, editorials, letters, and narrative literature reviews were excluded.

The Evidence

Four phase III trials evaluated the efficacy of Vivitrol for the prevention of relapse in patients with opioid use disorder.^32,33,36,37 Details of these trials are summarized in Table 1. One of the trials served as a pivotal trial for regulatory approval in the US.³² An open-label extension study of the pivotal trial evaluated the safety and efficacy of Vivitrol over one year following completion of the pivotal trial.⁵³ In addition, three studies have reported the effect of Vivitrol on patient outcomes in real-world clinical settings.^54–56

Table 1

Summary of Vivitrol Phase III Efficacy Trials

Adverse Effects

Cost

The manufacturer’s price for Vivitrol in Canada is currently unavailable, as the drug has not been approved for marketing.

In the US, the drug cost of Vivitrol is more than that for Probuphine (buprenorphine implant for subdermal administration, Braeburn Pharmaceuticals, Inc.), the only other long-acting non-oral treatment approved for opioid use disorder in the US (wholesale acquisition cost of US$1,309 per month for Vivitrol versus US$825 per month for Probuphone).⁵⁸ At this wholesale acquisition cost, one month of treatment with Vivitrol costs more than maintenance treatment with generic buprenorphine sublingual tablets (US$278.63), Suboxone sublingual films (US$443.40), or generic buprenorphine/naloxone sublingual tablets (US$468.98).⁵⁹ Alkermes Inc. offers a co-pay savings program, which covers up to US$500 per month of co-pay or deductible expenses for eligible patients with a Vivitrol prescription.⁶⁰

Concurrent Developments

The following section briefly describes some of the other long-acting treatment options for opioid use disorder that are in development.

Implementation Issues

Opioid misuse poses a significant burden on patients, their families, communities, and the Canadian health care system. As a result, there are current intensified efforts to increase access to safe and effective treatment options for opioid use disorder by regulators, health care providers, and health advocates. In light of these trends, it is anticipated that, if the drug is approved, there might be significant interest in Vivitrol. A recent survey of a community-recruited cohort of individuals with opioid use disorder in Vancouver reported that 52.1% of participants were willing to try Vivitrol.²¹ Although Vivitrol has been available in the US for several years, the rate of its adoption in routine clinical practice settings has been limited.^88,89 Several barriers to the use of Vivitrol have been noted, including high wholesale acquisition cost compared with currently available daily medications (including buprenorphine and methadone) or with the long-acting buprenorphine implant, lack of familiarity with its use, and perception of low patient demand (due, in part, to its mechanism of action as a pure opioid antagonist). The requirement for total abstinence from opioids for seven to 10 days before initiating treatment may also be a barrier for many patients.

There are also several clinical challenges and knowledge gaps associated with the initiation, long-term use, and role of Vivitrol relative to other for treatments of opioid use disorder:

• 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.

Acknowledgments

CADTH thanks the external reviewers who kindly provided comments on an earlier draft of this bulletin.

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