The use of naltrexone was first approved for the treatment of opiate dependence in 1984 and for alcohol dependence in 1994. In 2006, Vivitrol, a new formulation of this medication was approved for alcohol and in 2010 Vivitrol was approved for the prevention of relapse to opiate dependence. Naltrexone does not cause an antabuse-like aversion reaction. Naltrexone is an opiate receptor antagonist that blocks the pleasurable effects of alcohol and reduces cravings. “Craving” is defined as an intense desire and perceived need for some object/experience. Neurochemical alterations caused by chronic exposure to addictive agents form the biological basis of drug/alcohol cravings.
Oral naltrexone is effective in the treatment of alcohol and opiate dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. The solution; a biodegradable, long-acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for one month (Vivitrol).
Vivitrol (naltrexone for extended-release) is a formulation that uses microspheres that can be administered by intramuscular injection. It has received FDA approval for the treatment of alcohol dependence and opiate dependence. The dose of 380 mg is designed to be injected once every four weeks. Vivitrol is metabolized in the liver and is eliminated in the urine.
Vivitrol is a non-addictive and safe medication which uses pharmacologic means to improve the likelihood of successful treatment for alcohol and opiate dependence. Acknowledging that alcohol and opiate dependence are medical diseases with powerful physiological components points to an objective use of a medication to aid in the treatment of these diseases. While this medication may not be suitable for every patient suffering from alcohol and/or opiate dependence, it will aid the treatment provider in offering yet another alternative to complement ongoing support and treatment.
Several clinical studies have looked at the efficacy of Vivitrol:
Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. Garbutt JC; Kranzler HR; O’Malley SS; Gastfriend DR; Pettinati HM; Silverman BL; Loewy JW; Ehrich EW; JAMA. 2005; 293(13):1617-25
OBJECTIVE: To determine efficacy and tolerability of a long-acting intramuscular formulation of naltrexone for treatment of alcohol-dependent patients.
DESIGN, SETTING, AND PARTICIPANTS: A 6-month, randomized, double-blind, placebo-controlled trial conducted between February 2002 and September 2003 at 24 US public hospitals, private and Veterans Administration clinics, and tertiary care medical centers. Of the 899 individuals screened, 627 who were diagnosed as being actively drinking alcohol-dependent adults were randomized to receive treatment and 624 received at least 1 injection.
INTERVENTION: An intramuscular injection of 380 mg of long-acting naltrexone (n = 205) or 190 mg of long-acting naltrexone (n = 210) or a matching volume of placebo (n = 209) each administered monthly and combined with 12 sessions of low-intensity psychosocial intervention.
RESULTS: Compared with placebo, 380 mg of long-acting naltrexone resulted in a 25 percent decrease in the event rate of heavy drinking days (P = .02) [corrected] and 190 mg of naltrexone resulted in a 17 percent decrease (P = .07). Sex and pretreatment abstinence each showed significant interaction with the medication group on treatment outcome, with men and those with lead-in abstinence both exhibiting greater treatment effects. Discontinuation due to adverse events occurred in 14.1 percent in the 380-mg and 6.7 percent in the 190-mg group and 6.7 percent in the placebo group. Overall, rate and time to treatment discontinuation were similar among treatment groups.
CONCLUSIONS: Long-acting naltrexone was well tolerated and resulted in reductions in heavy drinking among treatment-seeking alcohol-dependent patients during six months of therapy. These data indicate that long-acting naltrexone can be of benefit in the treatment of alcohol dependence.
In another study that can be found in Lancet (2011 Apr 30; 377(9776):1506-13). Krupitsky and his co-authors used Vivitrol in a double-blind, placebo-controlled, multicenter randomized trial. Their premise was that opioid dependence is associated with low rates of treatment-seeking, poor adherence to treatment, frequent relapse, and major societal consequences.
DESIGN, SETTING, AND PARTICIPANTS: They used a double-blind, placebo controlled, randomized, 24-week trial of patients with opioid dependence disorder. Patients aged 18 years or over who had 30 days or less of inpatient detoxification and seven days or more off all opioids were enrolled at 13 clinical sites in Russia. The patients were randomly assigned to either 380 mg XR-NTX (extended-release injectable naltrexone) or placebo. Participants also received 12 biweekly counseling sessions. Participants, investigators, staff, and the sponsor were masked to treatment allocation. The primary endpoint was the response profile for confirmed abstinence during weeks 5 – 24, assessed by urine drug tests and self report of non-use. Secondary endpoints were self-reported opioid-free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence.
RESULTS: Between July 3, 2008, and Oct 5, 2009, 250 patients were randomly assigned to XR-NTX (n=126) or placebo (n=124). The median proportion of weeks of confirmed abstinence was 90.0 percent in the XR-NTX group compared with 35.0 percent in the placebo group. Patients in the XR-NTX group self-reported a median of 99.2 percent (range 89.1-99.4) opioid-free days compared with 60.4 percent (46.2-94.0) for the placebo group (p=0.0004). The mean change in craving was -10.1 (95 percent CI -12.3 to -7.8) in the XR-NTX group compared with 0.7 (-3.1 to 4.4) in the placebo group (p<0.0001). Median retention was over 168 days in the XR-NTX group compared with 96 days (95 percent CI 63-165) in the placebo group(p=0.0042). Naloxone challenge confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group (p<0*0001). XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events.
CONCLUSIONS: XR-NTX represents a new treatment option that is distinct from opioid agonist maintenance treatment. XR-NTX in conjunction with psychosocial treatment might improve acceptance of opioid dependence pharmacotherapy and provide a useful treatment option for many patients.
There was a comment on this article in the Lancet by Wolfe et al which did bring up some important points:
The Lancet study does not make clear what follow-up was done to evaluate post-treatment opioid overdose in the participants in the Russian trial.
The FDA’s Adverse Event Reporting System includes 51 reports of deaths associated with depot naltrexone between 2006 and 2010 (US Food and Drug Administration. Quarterly data from FDA Adverse Event Reporting System, 2006-10).
The FDA’s Adverse Event Reporting System includes 51 reports of deaths associated with depot naltrexone between 2006 and 2010 (US Food and Drug Administration – Quarterly Data from FDA Adverse Event Reporting System, 2006-10). Of these 51 reports, 19 were unique cases; only 1 was attributed by the reporting physician as “possibly related” to Vivitrol. During the time period of the FDA’s evaluation, approximately 45,000 patients were treated with Vivitrol. The FDA reviewed two studies of Vivitrol in opioid dependent patients in addition to the trial reported by Krupitsky et al. Since then, a retrospective, health-economic analysis addressed sample differences using instrumental variable analysis on demographic, clinical, utilization and provider characteristics (Baser et al. 2011). Results primarily showed comparable or lower total healthcare costs for patients treated with XR-NTX (N=156) vs. agonists, apparently because mean days of refill persistence did not differ significantly among patients treated with antagonists vs. agonists (XR-NTX 61.49 days; buprenorphine 68.92 days; methadone 62.8 days – and XR-NTX patients experienced fewer hospitalizations: XR-NTX patients had 93 opioid-related hospitalizations per 1000 patients over 6 months, vs. 249 for buprenorphine (p=0.007) and 198 for methadone (p=0.025). Importantly, these differences were measured during a period that included, on average, several months after the pharmacotherapy treatment ended. (Baser O, Chalk M, Fiellin DA, Gastfriend DR. Cost and utilization outcomes of opioid-dependence treatments. Am J Manag Care. 2011; 17(8):S235-S248.)
Experience with oral naltrexone highlights the importance of adequate investigation of overdose risk following treatment with depot naltrexone. Risk of overdose for detoxified heroin-dependent patients receiving oral naltrexone treatment is well documented. A review of 13 trials of Pharmacotherapies for opioid dependence in Australia showed that the heroin overdose rates were more than trebled (at 6.8 per 100 person-years) for patients on oral naltrexone treatment compared with those receiving opioid agonist treatment (1.9 per 100 person-years) (Digiusto E, Shakeshaft A, Ritter A, O’Brien S, Mattick RP. Serious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD). Addiction 2004; 99:450-60.)
What patients cannot take Vivitrol?
- Taking opioid medications (must be off all opioids for a minimum of 7 – 10 days)
- In opioid withdrawal or dependent on opioids
- Any individual who is allergic to naltrexone, carboxymethycellulose, polysorbate or polylactide-co-glycolide (PLG)
- Have acute or severe liver or kidney disease
- Have a positive urine drug screen for opiates
- Fail a Naloxone challenge test (see Physician’s Desk Reference)
- Pregnant women or nursing mothers.
- This medication has not been studied in the geriatric or pediatric population.
- This medication has not been studied in those younger than 18 years of age.
What are the possible side effects when using Vivitrol?
- Difficulty sleeping
- Abdominal cramps
- Joint and muscle pains
- Injection site pain, nodules, and severe injection site reactions
Mild nausea is the most common side effect following an initial Vivitrol dose. It is usually not associated with anorexia or vomiting, and is typically limited to two to three days post-injection. It tends to occur following the first injection, when blood levels of naltrexone rise quickly, but tends not to re-occur upon subsequent injections, when naltrexone is already at a steady-state. Rates of nausea and GI symptoms are lower when using Vivitrol compared to oral naltrexone.
Soreness at the injection site is common and can be managed with massage, NSAIDS, or ice packs. This is a similar side effect to other IM buttocks injections, such as antibiotics, and is not related to naltrexone itself. Non-painful nodules lasting several weeks post-injection are common, self-limited, and not concerning; they resolve steadily over four to six weeks.
Severe injection site reactions have been reported in several cases since Vivitrol’s alcohol approval in 2006 and likely stem from misinjection into subcutaneous adipose tissue rather than muscle. Obese persons and those with increased hip and buttock adipose tissue are likely at greater risk. Providers should use their judgment and only inject Vivitrol when they are confident an IM injection can be delivered successfully. Severe injection site reactions are similar to sterile abscesses and should be treated with a prompt referral to an appropriate medical provider such as a general surgeon. While severe injection site reactions are rare, this risk prompted several FDA alerts from December, 2009 to early 2010.
Fishman reported a case of precipitated withdrawal in a 17-year-old adolescent female receiving Vivitrol for opioid dependence, following her third serial monthly dose of the medication, several days after using Oxycodone with mild intoxication. The author’s conclusion was that, in some circumstances, the opioid blockade may be overcome when naltrexone levels drop towards the end of the dosing interval, producing vulnerability to subsequent naltrexone-induced withdrawal. This may provide cautionary guidance for clinical management and dosing strategies. (Fishman, M. Addiction, 103, 1399-1401)
All patients considering Vivitrol treatment should be counseled regarding these potential side effects.
In younger opioid dependent patients (N=133), also in a community setting, Fishman et al (2011) reported retention and relapse in a chart review study. Patients who received treatment without anti-relapse pharmacotherapy had mean cumulative retention of 10.3 weeks vs. 16.3 weeks with XR-NTX (p=0.0001) and 15.9 weeks with buprenorphine (p=0.0008). Mean cumulative time without opioid use (combining self-report and urine testing) was 7.0 weeks for those on no medication vs. 13.7 weeks with XR-NTX (p<0.0001) and 10.6 weeks with buprenorphine (p=0.009).(Fishman M, Curran E, Shah S, Perry-Parrish C. Treatment outcomes with relapse prevention medications for opioid dependence in youth. Presented at the 73rd Annual Meeting of the College on Problems of Drug Dependence, Hollywood FL, June 22, 2011).
In the emergency pain management situation, it is suggested that the patient who had been receiving Vivitrol be managed with regional analgesia, conscious sedation, non-opioid pain medications or general anesthesia.
The patients should be monitored for the development of depression or suicidal thoughts. In the patient who is drinking, Vivitrol will not decrease the withdrawal symptoms.
The opiate dependent patient who stops Vivitrol should be monitored and educated about the risk of opiate overdose.
Who is a candidate for Vivitrol?
A patient with an alcohol-dependence and/or opioid dependence diagnosis, who wants to use this medication as part of a comprehensive treatment plan and understands that this medication does not take the place of treatment. The patient must be opioid-free and not have signs of significant liver or kidney disease.
Vivitrol is appropriate for any opioid-dependent client who can achieve abstinence long enough for naltrexone induction. Abstinence in the opioid-dependent person is best achieved with a detoxification protocol that allows for the complete elimination of opioids from the patient’s system over a prescribed number of days (depending on the half-life of the opiate/opioid.) Non-opioid-based detox protocol, such as one using clonidine, is currently the most efficient way of achieving this. See Ockert et al., Journal of Addiction Medicine, Volume 5, Number 2, June 2011.
Counseling of the opioid-dependent patient should begin from the first contact, well before the detoxification begins, through the entire post-detoxification/Vivitrol initiation and stabilization periods. This is an opportunity to explore with the patient any issues or concerns they may have with utilizing a medication to support their recovery and to develop the understanding that their ongoing work in counseling can help them resolve the challenges ahead. It is also the opportunity to strengthen a therapeutic alliance and explore with them how you are prepared to respond to critical events they may face.
At the initial counseling, Vivitrol must be thoroughly explained:
- The nature of the opioid antagonist
- How it differs from agonist treatments
- The benefits of using the antagonist approach, including the rapid up-regulation of the mu-ligand receptor system with Vivitrol: the concept of neuro-biological recovery.
- Naltrexone/Vivitrol eliminates some of the most severe protracted-abstinence symptoms, especially lack of energy and depression
- Faster restoring of endorphin activity
- Unlike agonist therapy, Vivitrol is unlikely to reduce sexual drive.
- The convenience of monthly administration.
- Reduced cravings and protection from impulsive relapse.
- Greater ease of establishing non-drug-related life patterns: less contact with drug-involved persons.
- If naltrexone is taken with opioids/opiates remaining in the nervous system it will cause precipitated withdrawal.
- Vulnerability to overdose following discontinuation of opioid antagonists (Vivitrol, Naltrexone) can increase due to lack of tolerance.
Follow-up visits should encourage the patient to express not only their physical response to the medication, but also the emotional adjustments they may have made in accepting this form of treatment. It’s possible patients may see themselves as cured and ready to move on, or tethered to a “crutch” due to some perceived inadequacy on their part; either of which might lead to a precipitous discontinuation of treatment. It is important that the patient perceive that the practitioner is interested and understanding of their perceptions and prepared to help work them through.
Following discontinuation of Vivitrol, patients should be given the option to continue on oral naltrexone.