Page last updated September 14, 2023 by Doug McVay, Editor.

1. X:BOT Study Seriously Flawed

"The X:BOT study is an influential randomised trial comparing safety and efficacy of buprenorphine and naltrexone to treat opioid dependence.The original publication reported no statistically significant difference in the safety endpoint of overdose.We reanalysed the trial using the public datasetand replicated most findings., However, we identified six additional overdose events that the original analysis missed. Five of these additional events were in the naltrexone group, and one was in the buprenorphine group.

"Assuming similar efficacy, inclusion of these originally misclassified cases fundamentally alters the clinical risk–benefit: 19 (7%) of 283 participants had overdoses in the naltrexone group compared with 9 (3%) of 287 in the buprenorphine group (appendix).In addition to correcting the misclassification, our reanalysisaccounted for timing of safety outcomes. The hazard ratio (HR) for overdose in the naltrexone group, relative to buprenorphine, becomes 2·40 (95% CI 1·09–5·30, p=0·03; appendix) with misclassification corrected. After we published our reanalysis,the presence of additional overdoses was confirmed by the original authors."

Dasgupta N, Ajazi EM, Schwartz TA, Marshall SW. Misclassification of overdose events in the X:BOT study. Lancet. 2023;402(10401):526-527. doi:10.1016/S0140-6736(23)00113-7

2. X:BOT Study Seriously Flawed

"The risk of overdose with naltrexone results when patients try to overcome μ-opioid receptor antagonism by taking increasingly high doses of unregulated drugs., Concerns about overdose misclassification in naltrexone trials have also been raised.Large epidemiological studies have found naltrexone to be less protective against overdose than buprenorphine, consistent with known pharmacology.Post-marketing data suggest waning protection with the monthly extended-release injectable naltrexone formulation used in X:BOT,although this is contested by the manufacturer.

"The original report found that induction failures affected the naltrexone group differentially: 28% for naltrexone versus 5·9% for buprenorphine. In a commentary from 2022, Lee and colleagues correctly acknowledge that the corresponding per-protocol analysis might, therefore, not represent a sample with treatment assigned at random.Statistical methods accounting for induction failures substantiate differential overdose risk., Lee and colleagues also suggest focusing on the maintenance period (ie, study days 22–168, after induction and before therapy discontinuation), when most overdoses (61%) occurred. Doing so, we found HR 3·77 (95% CI 1·23–11·57; Wald p=0·02; appendix) for intention-to-treat analysis, and 3·81 (95% CI 1·01–14·36; p=0·05) for per-protocol analysis. X:BOT shows increased risk of overdose with naltrexone than buprenorphine even during therapy.In X:BOT, Lee and colleaguesconcluded that “once initiated, both medications were equally safe”. We believe this statement is not supported by the public data. Although we think it is important to acknowledge that the number of participants experiencing an overdose in X:BOT could appear small from a statistical perspective (28 [5%] of 570), the other major trial comparing these two medications had only one overdose among 143 participants in Norway.

"Over the past decade drug overdoses in the USA have increased substantially. Given the demonstrated safety risk, naltrexone should not be presented as the only option for opioid dependence treatment, as is the case in many prisons and drug courts. With more than 100 000 overdose deaths annually, clinicians must make treatment decisions based on accurate information. We believe the original X:BOT reportshould be retracted or corrected quickly."

Dasgupta N, Ajazi EM, Schwartz TA, Marshall SW. Misclassification of overdose events in the X:BOT study. Lancet. 2023;402(10401):526-527. doi:10.1016/S0140-6736(23)00113-7

3. Product Guide: Vivitrol - Extended Release Injectable Naltrexone

"What is VIVITROL?

"VIVITROL is a prescription injectable medicine used to:
"• treat alcohol dependence. You should stop drinking before starting VIVITROL.
"• prevent relapse to opioid dependence, after opioid detoxification.

"This means that if you take opioids or opioid-containing medicines, you must stop taking them before you start receiving VIVITROL. See “What is the most important information I should know about VIVITROL?”

"To be effective, treatment with VIVITROL must be used with other alcohol or drug recovery programs such as counseling. VIVITROL may not work for everyone.

"It is not known if VIVITROL is safe and effective in children."

Medication Guide: Vivitrol (Naltrexone for Extended Release Injectable Suspension). Alkermes, Inc. Revised July 2013.


4. Number of Treatment Programs in the US and Types of Treatment Provided

"Facility Operation
"Table 2.2 and Figure 2. The operational structure of the substance abuse treatment system (i.e., the types of entities responsible for operating facilities) had some notable changes between 2010 and 2020.

"● Private non-profit organizations operated 58 percent of all facilities in 2010, decreasing to 50 percent in 2020 [Table 2.2 and Figure 2].

"● Private for-profit organizations operated 30 percent of facilities in 2010, increasing to 41 percent of facilities in 2020 [Table 2.2 and Figure 2].

"● Local, county, or community governments operated 6 percent of facilities in 2010, decreasing to 4 percent in 2020 [Table 2.2 and Figure 2].

"● State governments operated 3 percent of facilities in 2010, decreasing to 2 percent in 2020 [Table 2.2 and Figure 2].

"● The federal government operated 2 to 3 percent of facilities each year between 2010 and 2020 [Table 2.2 and Figure 2].5

"● Tribal governments operated 1 to 2 percent of facilities each year between 2010 and 2020 [Table 2.2 and Figure 2].

"Type of Care Offered6
"Table 2.3 and Figure 3. The proportions of facilities that offered outpatient, residential (non-hospital), and hospital inpatient care were stable between 2010 and 2020. OTPs, certified by SAMHSA, provide MAT with methadone, buprenorphine, and naltrexone. Facilities with OTPs can be associated with any type of care. Facilities with OTPs made up 8 to 11 percent of all facilities between 2010 and 2020 [Table 2.4].

"● Outpatient treatment was provided by 81 to 83 percent of facilities during this period [Table 2.3].

"● Residential (non-hospital) treatment was provided by 24 to 26 percent of facilities in this period [Table 2.3].

"● Hospital inpatient treatment was provided by 5 to 6 percent of facilities during this time period [Table 2.3].

"● Outpatient treatment was provided by 90 to 95 percent of facilities with OTPs between 2010 and 2020 [Table 2.3].

"● Residential (non-hospital) treatment was provided by 7 to 9 percent of facilities with OTPs between 2010 and 2020 [Table 2.3].

"● Hospital inpatient treatment was provided by 7 to 10 percent of facilities with OTPs between 2010 and 2020 [Table 2.3].

"Facilities That Use MAT
"Table 2.4. MAT includes the use of methadone or buprenorphine for the treatment of opioid use disorder (OUD) and the use of naltrexone for relapse prevention in OUD. Methadone for OUD is available only at the OTPs that are certified by SAMHSA’s Center for Substance Abuse Treatment.7 Buprenorphine may be prescribed by physicians or other authorized medical practitioners (physicians, physician assistants, and nurse practitioners) who have received Drug Addiction Treatment Act of 2000 (DATA 2000) specific training and received a waiver to prescribe the medication for treatment of OUD; some of these authorized medical practitioners are affiliated with facilities (either OTPs or other). All medical practitioners with prescribing privileges can prescribe injectable naltrexone.

"● The proportion of OTPs that provided methadone-only treatment decreased from 52 percent of all facilities with OTPs in 2010 to 17 percent of all facilities with OTPs in 2020 [Table 2.4].

"● The proportion of OTPs that provided only methadone and buprenorphine treatment decreased from 47 percent of all facilities with OTPs in 2010 to 42 percent in 2020. Between 2012 and 2020, the proportion of facilities with OTPs that offered methadone, buprenorphine, and injectable naltrexone increased from 12 percent in 2012 to 31 percent in 2020; over the same period, the proportion of facilities that offered only buprenorphine and injectable naltrexone increased from less than 1 percent to 6 percent [Table 2.4].8

"● The proportion of facilities (either OTP or non-OTP) that provided any buprenorphine services increased from 18 percent of all facilities in 2010 to 44 percent of all facilities in 2020 [Table 2.4].

"● The percentage of all facilities that provided any extended-release injectable naltrexone treatment increased from 10 percent in 2012 to 37 percent in 2020 [Table 2.4]."

Substance Abuse and Mental Health Services Administration, National Survey of Substance Abuse Treatment Services (N-SSATS): 2020. Data on Substance Abuse Treatment Facilities. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2021.


5. Treatment with Methadone or Buprenorphine Following Nonfatal Overdose Leads to Decreased Mortality

"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."

Larochelle MR, Bernson D, Land T, Stopka TJ, Wang N, Xuan Z, et al. Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study. Annals of Internal Medicine. Epub ahead of print 19 June 2018. doi: 10.7326/M17-3107.


6. Severe Opioid Withdrawal Precipitated by Vivitrol

"The risk of severe precipitated opioid withdrawal (POW) is amplified when precipitated by a long-acting opioid antagonist. IM [intramuscular] extended release naltrexone (XRNTX; Vivitrol®) is an FDA approved therapy to prevent relapse of opioid and alcohol abuse. Two cases of precipitated opioid withdrawal from XRNTX are presented that illustrate different patient reactions to POW. A 56-year-old woman developed a hypertensive emergency and required continuous intravenous vasodilator, clonidine, and intensive care monitoring after re-initiation of XRNTX following opioid relapse. A 25-year-old man developed agitation and altered mental status after receipt of XRNTX at the conclusion of a twelve-day detoxification program during which he continued surreptitious use of heroin. The patient received benzodiazepines and haloperidol without adequate affect, and required intubation with propofol, lorazepam, and dexmedetomidine infusions. Management of POW from XRNTX is a challenge to emergency providers and protocols to guide management do not exist. Recommended therapies include intravenous fluids, anti-emetics, clonidine, or benzodiazepines as well as therapy tailored to the organ system affected. To minimize risk of POW it is important for providers instituting XRNTX to adhere to the manufacturers warnings and clinic protocols including a naloxone challenge and ensure an adequate opioid free period prior to administration of XRNTX."

Wightman RS, Nelson LS, Lee JD, Fox LM, Smith SW. Severe opioid withdrawal precipitated by Vivitrol®. Am J Emerg Med. 2018 Mar 21. pii: S0735-6757(18)30244-4. doi: 10.1016/j.ajem.2018.03.052. [Epub ahead of print] PubMed PMID: 29605483.


7. Naltrexone

"Originally approved for use in the treatment of opioid dependence by the United States Food and Drug administration (FDA) in 1984, naltrexone is a competitive ?-opioid receptor antagonist with negligible agonist effects, blocking euphoric and physiological effects of opioid agonists.11,12 Naltrexone does not cause the development of dependence or tolerance over time, and dosing cessation does not result in withdrawal.13

"Orally dosed naltrexone is subject to first pass metabolism, where it is converted to active (6-? naltrexol) and inactive metabolites.14 ­First-pass metabolism of orally dosed naltrexone is high, evidenced by the peak dose of naltrexone and its ­metabolites 1 hour after oral dosing.15 Serum ­half-life for chronic oral administration is approximately 10 hours.15 The half-life, when compared to naloxone, another ?-opioid antagonist, is longer, and naltrexone is able to block the agonist effects of other opioids for 48 hours.16 Oral dosing is accomplished by either 50 mg daily dosing or three times weekly dosing with two 100 mg doses and one 150 mg dose."

Kjome, Kimberly L. and Moeller, F. Gerard, "Long-Acting Injectable Naltrexone for the Management of Patients with Opioid Dependence," Substance Abuse: Research and Treatment 2011:5 1–9, doi: 10.4137/SART.S5452.


8. Reduced Efficacy of Naltrexone (Vivitrol) Treatment

"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."

Krupitsky, Evgeny, Zvartau, Edwin, and Woody, George, "Use of Naltrexone to Treat Opioid Addiction in a Country in Which Methadone and Buprenorphine Are Not Available," Curr Psychiatry Rep. 2010 October; 12(5): 448–453. doi:10.1007/s11920-010-0135-5.


9. Vivitrol and Risk of Opioid Overdose According To The Manufacturer

"Vulnerability to Opioid Overdose

"After opioid detoxification, patients are likely to have reduced tolerance to opioids. VIVITROL blocks the effects of exogenous opioids for approximately 28 days after administration. However, as the blockade wanes and eventually dissipates completely, patients who have been treated with VIVITROL may respond to lower doses of opioids than previously used, just as they would have shortly after completing detoxification. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval, after missing a scheduled dose, or after discontinuing treatment.

"Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after VIVITROL treatment is discontinued, especially at the end of a dosing interval (i.e., near the end of the month that VIVITROL was administered), or after a dose of VIVITROL is missed. It is important that patients inform family members and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose [see Patient Counseling Information (17)].

"There is also the possibility that a patient who is treated with VIVITROL could overcome the opioid blockade effect of VIVITROL. Although VIVITROL is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids. Any attempt by a patient to overcome the antagonism by taking opioids is especially dangerous and may lead to life-threatening opioid intoxication or fatal overdose. Patients should be told of the serious consequences of trying to overcome the opioid blockade [see Patient Counseling Information (17)]."

Full Prescribing Information. Vivitrol (Naltrexone for Extended-Release Injectable Suspension). Alkermes. Revised December 2015.


10. Vivitrol and Sudden Opioid Withdrawal According To The Manufacturer

"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."

Full Prescribing Information. Vivitrol (Naltrexone for Extended-Release Injectable Suspension). Alkermes. Revised December 2015.


11. Efficacy of Extended-Release Injectable Naltrexone

"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"

Kjome, Kimberly L. and Moeller, F. Gerard, "Long-Acting Injectable Naltrexone for the Management of Patients with Opioid Dependence," Substance Abuse: Research and Treatment 2011:5 1–9, doi: 10.4137/SART.S5452.


12. Effect of Inappropriate Use of Vivitrol (Naltrexone)

"Naltrexone is a long acting opioid receptor antagonist used in drug rehabilitation programmes to maintain opioid abstinence. However, when consumed in conjunction with an opioid substance, prolonged opioid withdrawal will be precipitated resulting in unpredictable and life threatening medical consequences."

Boyce SH, Armstrong PAR, Stevenson J. Effect of innappropriate naltrexone use in a heroin misuser. Emergency Medicine Journal 2003;20:381-382.


13. Vivitrol and Hepatoxicity According To Manufacturer

"Hepatotoxicity

"Cases of hepatitis and clinically significant liver dysfunction were observed in association with VIVITROL exposure during the clinical development program and in the postmarketing period. Transient, asymptomatic hepatic transaminase elevations were also observed in the clinical trials and postmarketing period. Although patients with clinically significant liver disease were not systematically studied, clinical trials did include patients with asymptomatic viral hepatitis infections. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae including acute liver injury.

"Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of VIVITROL should be discontinued in the event of symptoms and/or signs of acute hepatitis."

Full Prescribing Information. Vivitrol (Naltrexone for Extended-Release Injectable Suspension). Alkermes. Revised December 2015.


14. Vivitrol and Injection Site Reactions According To The Manufacturer

"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."

Full Prescribing Information. Vivitrol (Naltrexone for Extended-Release Injectable Suspension). Alkermes. Revised December 2015.


15. Compliance Problems with Naltrexone (Vivitrol)

"Despite the ease of outpatient dosing and its ability to effectively block the euphoric effects of ?-opioid agonists, naltrexone has had limited success for relapse prevention when compared with maintenance t­herapy with methadone or buprenorphine. Studies have shown that fewer patients choose to start t­reatment with naltrexone,21 and few of those remain compliant with medications.22,23 Patients who have been treated previously with methadone are also less likely to sustain opioid abstinence with naltrexone compared with individuals who had only had naltrexone for treatment of opioid dependence.24–26 Poor compliance with naltrexone is also associated with higher dosages of heroin used daily.26 Of patients in treatment with naltrexone, many drop out quickly within the first few weeks, especially if they used opioids again after missing ­ naltrexone doses.27 The numbers of drop-outs from naltrexone treatment are very high, with over one quarter dropping out after a few days,28 and almost one-half dropping out in first few weeks.29"

Kjome, Kimberly L. and Moeller, F. Gerard, "Long-Acting Injectable Naltrexone for the Management of Patients with Opioid Dependence," Substance Abuse: Research and Treatment 2011:5 1–9, doi: 10.4137/SART.S5452

http://www.ncbi.nlm.nih.gov/p…

http://www.ncbi.nlm.nih.gov/p…


16. Clinical Challenges and Knowledge Gaps Regarding Treatment with Vivitrol

"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."

Ndegwa S, Pant S, Pohar S, et al. Injectable Extended-Release Naltrexone to Treat Opioid Use Disorder. 2017 Aug 1. In: CADTH Issues in Emerging Health Technologies. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016. 163.

https://www.ncbi.nlm.nih.gov/…


17. Depression, Suicidality, and Vivitrol

"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)."

Full Prescribing Information. Vivitrol (Naltrexone for Extended-Release Injectable Suspension). Revised December 2015.

https://www.vivitrol.com/cont…


18. Number and Characteristics of Patients Receiving Opioid Treatment Programs (OTPs) in the US

"Facilities were asked how many clients in treatment on March 31, 2016, received medication-assisted opioid therapy drugs for detoxification or maintenance purposes. MAT includes the use of methadone and buprenorphine for the treatment of opioid addiction or dependence, and the use of extended-release injectable naltrexone (Vivitrol®) for relapse prevention in opioid addiction. Methadone is available only at OTP facilities that are certified by SAMHSA’s Center for Substance Abuse Treatment. Buprenorphine may be prescribed by physicians who have received DATA 2000 specific training and received a waiver to prescribe the medication for treatment of opioid addiction; some of these physicians are affiliated with facilities (either OTPs or other).22 All physicians or approved medical personnel can prescribe extended-release injectable naltrexone (Vivitrol®).

"• Of the total 1,150,423 clients in treatment, 365,064 (32 percent) received MAT in OTP facilities.
"• There were 345,443 clients receiving methadone in OTP facilities.
" • Of the clients receiving methadone, 215,576 clients (62 percent) were provided treatment at private for-profit OTPs and 109,504 clients (32 percent) were provided treatment at private non-profit OTPs.
"• There were 18,716 clients receiving buprenorphine in OTP facilities and 42,770 clients receiving buprenorphine in non-OTP facilities.
" • Of the clients receiving buprenorphine in OTPs, 12,495 clients (67 percent) were provided treatment at private for-profit OTPs and 4,675 clients (25 percent) were provided treatment at private non-profit OTPs.
" • Of the clients receiving buprenorphine in non-OTP facilities, 19,309 clients (45 percent) were provided treatment at private for-profit non-OTPs and 18,117 clients (42 percent) were provided treatment at private non-profit non-OTPs.

"• There were 905 clients receiving extended-release injectable naltrexone (Vivitrol®) in OTP facilities and 9,223 clients receiving extended-release injectable naltrexone (Vivitrol®) in non-OTP facilities.
" • Of the clients receiving extended-release injectable naltrexone (Vivitrol®) in OTPs, 500 clients (55 percent) were provided treatment at private non-profit OTPs and 251 clients (28 percent) were provided treatment at private for-profit OTPs.
" • Of the clients receiving extended-release injectable naltrexone (Vivitrol®) in non-OTP facilities, 4,464 clients (48 percent) were provided treatment at private non-profit non-OTPs and 3,085 clients (33 percent) were provided treatment at private for-profit non-OTPs."

Substance Abuse and Mental Health Services Administration. National Survey of Substance Abuse Treatment Services (N-SSATS): 2016. Data on Substance Abuse Treatment Facilities. BHSIS Series S-93, HHS Publication No. (SMA) 17-5039. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2017.