Anesthesia drug ketamine may fight depression by muzzling ‘bursting’ brain cells

The anesthesia medication ketamine has shown promise in treating depression, but its exact effects on the brain are unclear. Now, researchers have discovered that the drug changes the firing patterns of cells in a pea-size structure hidden away in the center of the brain. This could explain why ketamine is able to relieve symptoms of depression so quickly—and may provide a fresh target for scientists developing new antidepressants.

“It’s a spectacular study,” says Roberto Malinow, a neuroscientist at the University of California, San Diego, who was not involved in the work. “It will make a lot of people think.”

In clinical trials, ketamine appears to act much faster than existing antidepressants, improving symptoms within hours rather than weeks. “People have tried really hard to figure out why it’s working so fast, because understanding this could perhaps lead us to the core mechanism of depression,” says Hailan Hu, a neuroscientist at Zhejiang University School of Medicine in Hangzhou, China, and a senior author on the new study.

Hu suspected the drug might target a tiny region in the middle of the brain called the lateral habenula, the so-called “anti–reward center.” This region inhibits nearby reward areas, which can be useful in learning; for example, if a monkey pulls a lever expecting a treat but never receives it, the lateral habenula will reduce the activity of reward areas, and the monkey will be less likely to pull the lever in the future. But research over the past decade has suggested that the area may be overactive in depression, dampening down those reward centers too much.

In a series of experiments using mouse and rat models of depression reported today in Nature, Hu and her colleagues found that ketamine did affect the lateral habenula—but it was the pattern of firing, rather than the overall amount of activity, that proved crucial. A small proportion of the neurons in the lateral habenula fire several times in quick bursts, rather than firing once at regular intervals; the team found that “depressed” rodents had a lot more of these quick burst cells. In brain slices from normal rats, only about 7% of cells were the bursting type, but in rats bred to display depressionlike behavior, the number was 23%.

Direct recordings from the neurons of live mice showed the same pattern: Animals that had gone through a stressful procedure had more bursting cells in the lateral habenula. And, importantly, this bursting behavior appeared to cause depressionlike states. When researchers used optogenetics—a technique that allows cells to be switched on and off with light—to increase the amount of bursting in the lateral habenula, mice behaved in a more “depressed” way, remaining motionless when forced to swim in a container of water, for example. This kind of despair is thought to be similar to the feelings of hopelessness experienced in depression.

When “depressed” mice and rats were given ketamine, the number of bursting cells was much lower, similar to the number in normal animals, Hu’s team found. And even when the researchers forced the neurons to fire in bursts, animals that had been given ketamine no longer showed depressionlike behaviors.

Hu says that neurons firing several times in quick succession produce a more powerful signal. This means that bursting cells may be sending particularly strong messages to dampen down activity in reward areas, which could lead to depression. “Bursting has a special kind of signaling power,” Malinow says. “You get more bang for your buck.”

The findings could also explain why ketamine acts so quickly. By immediately blocking bursts in the lateral habenula, the drug releases the reward areas from those strong signals. This suggests that other drugs that reduce burst firing could also alleviate depression, whether they act on the same receptors or different ones. “Anything that can block the bursting … should be a potential target based on our model,” Hu says. In an accompanying paper, her team reports that a protein found on astrocytes, another type of brain cell that interacts closely with neurons, could be one of these targets.

Panos Zanos, a neuropharmacologist at the University of Maryland in Baltimore, says the immediate effects of the drug in the lateral habenula were interesting. “I’m very excited … to see whether this [also] applies to the long-lasting antidepressant effects of ketamine,” he says. “This is a great study that adds to the literature on how ketamine might work.”

APA Releases New Practice Guideline on AUD Pharmacotherapy

APA Releases New Practice Guideline on AUD Pharmacotherapy

APA today released a new practice guideline for the pharmacological treatment of alcohol use disorder (AUD). Despite the high prevalence of AUD and its significant public health consequences, patients with this disorder remain undertreated.

“This new guideline is an important step in bringing effective, evidence-based treatments for alcohol use disorder to many more people and in helping address the public health burden of alcohol use,” APA President Anita Everett, M.D., said in a press release.

The guideline aims to increase physician and public knowledge on the effectiveness and risks of the five medications that may be used for the treatment of AUD: acamprosate, disulfiram, gabapentin, naltrexone, and topiramate.

Of these five, naltrexone and acamprosate have the best available evidence related to their benefits, and both have minimal side effects. As such, they should be considered the preferred pharmacological options for patients with moderate to severe AUD who want to reduce drinking or achieve abstinence. However, acamprosate should be avoided in patients with significant renal impairment, and naltrexone should be avoided in patients with acute hepatitis or liver failure, or in patients currently taking opioids or who may be expected to take opioids.
Disulfiram, gabapentin and topiramate are also options for treatment of AUD but should typically be considered after trying naltrexone and acamprosate, unless the patient has a strong preference for one of these medications. Disulfiram is a special case as it does cause a series of adverse reactions if alcohol is consumed within 12 to 24 hours of taking the medication; the reactions include elevated heart rate, flushed skin, headache, nausea, and vomiting. Therefore, disulfiram is suggested only to patients who wish to achieve abstinence from drinking. Patients taking topiramate are at an increased risk of cognitive dysfunction, dizziness, and loss of appetite, whereas patients taking gabapentin may experience fatigue, insomnia, and headache.

While the guideline focuses specifically on evidence-based pharmacological treatments for AUD, it also includes recommendations and suggestions related to psychiatric evaluation of patients with AUD and developing a person-centered treatment plan. Evidence-based psychotherapeutic treatments for alcohol use disorder also play a major role in treatment and peer support groups such as Alcoholics Anonymous, and other 12-step programs can be helpful for many patients. However, specific recommendations related to these treatments are outside the scope of this guideline.

PROBUPHINE IMPLANT FOR TREATMENT OF OPIOID DEPENDENCE

The U.S. Food and Drug Administration today approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for six months in patients who are already stable on low-to-moderate doses of other forms of buprenorphine, as part of a complete treatment program.

Until today, buprenorphine for the treatment of opioid dependence was only approved as a pill or a film placed under the tongue or on the inside of a person’s cheek until it dissolved. While effective, a pill or film may be lost, forgotten or stolen. However, as an implant, Probuphine provides a new treatment option for people in recovery who may value the unique benefits of a six-month implant compared to other forms of buprenorphine, such as the possibility of improved patient convenience from not needing to take medication on a daily basis. An independent FDA advisory committee supported the approval of Probuphine in a meeting held earlier this year.

“Opioid abuse and addiction have taken a devastating toll on American families. We must do everything we can to make new, innovative treatment options available that can help patients regain control over their lives,” said FDA Commissioner Robert M. Califf, M.D. “Today’s approval provides the first-ever implantable option to support patients’ efforts to maintain treatment as part of their overall recovery program.”

Expanding the use and availability of medication-assisted treatment (MAT) options like buprenorphine is an important component of the FDA’s opioid action plan and one of three top priorities for the U.S. Department of Health and Human Services’ Opioid Initiative aimed at reducing prescription opioid and heroin related overdose, death and dependence.

Opioid dependence is the diagnostic term used for the more common concept, “addiction,” in the Probuphine clinical trials. Addiction is defined as a cluster of behavioral, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use, persisting in drug use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, as well as the possibility of the development of tolerance or development of physical dependence. Physical dependence is not the same as addiction. Newer diagnostic terminology uses the term “opioid use disorder,” which includes both milder forms of problematic opioid use as well as addiction.

MAT is a comprehensive approach that combines approved medications (currently, methadone, buprenorphine or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use, without causing the cycle of highs and lows associated with opioid misuse or abuse. At sufficient doses, it also decreases the pleasurable effects of other opioids, making continued opioid abuse less attractive. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for their opioid use disorder cut their risk of death from all causes in half.

“Scientific evidence suggests that maintenance treatment with these medications in the context of behavioral treatment and recovery support are more effective in the treatment of opioid use disorder than short-term detoxification programs aimed at abstinence,” said Nora Volkow, M.D., director of the National Institute on Drug Abuse at the National Institutes of Health. “This product will expand the treatment alternatives available to people suffering from an opioid use disorder.”

Probuphine should be used as part of a complete treatment program that includes counseling and psychosocial support. Probuphine consists of four, one-inch-long rods that are implanted under the skin on the inside of the upper arm and provide treatment for six months. Administering Probuphine requires specific training because it must be surgically inserted and removed. Only a health care provider who has completed the training and become certified through a restricted program called the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program should insert and remove the implants. If further treatment is needed, new implants may be inserted in the opposite arm for one additional course of treatment. The FDA is requiring postmarketing studies to establish the safety and feasibility of placing the Probuphine implants for additional courses of treatment.

The safety and efficacy of Probuphine were demonstrated in a randomized clinical trial of adults who met the clinical criteria for opioid dependence and were considered stable after prior buprenorphine treatment. A response to MAT was measured by urine screening and self-reporting of illicit opioid use during the six month treatment period. Sixty-three percent of Probuphine-treated patients had no evidence of illicit opioid use throughout the six months of treatment – similar to the 64 percent of those who responded to sublingual (under the tongue) buprenorphine alone.

The most common side effects from treatment with Probuphine include implant-site pain, itching, and redness, as well as headache, depression, constipation, nausea, vomiting, back pain, toothache and oropharyngeal pain. The safety and efficacy of Probuphine have not been established in children or adolescents less than 16 years of age. Clinical studies of Probuphine did not include participants over the age of 65.

Probuphine has a boxed warning that provides important safety information for health care professionals, including a warning that insertion and removal of Probuphine are associated with the risk of implant migration, protrusion, expulsion and nerve damage resulting from the procedure. Probuphine must be prescribed and dispensed according to the Probuphine REMS program because of the risks of surgical complications and because of the risks of accidental overdose, misuse and abuse if an implant comes out or protrudes from the skin. As part of this program, Probuphine can only be prescribed and dispensed by health care providers who are certified with the REMS program and have completed live training, among other requirements.

Probuphine implants contain a significant amount of drug that can potentially be expelled or removed, resulting in the potential for accidental exposure or intentional misuse and abuse if the implant comes out of the skin. Patients should be seen during the first week after insertion and a visit schedule of no less than once-monthly is recommended for continued counseling and psychosocial support.

Probuphine is marketed by San Francisco-based Titan Pharmaceuticals Inc. and Braeburn Pharmaceuticals based in Princeton, New Jersey.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

FYI VIVITROL

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?

  • Nausea
  • Difficulty sleeping
  • Anxiety
  • Abdominal cramps
  • Diarrhea
  • Joint and muscle pains
  • Headaches
  • 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).

Special Populations

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

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.

For additional information see Vivitrol Billing for OASAS-certified Programs or Vivitrol Billing Information

9/2011

SUBLOCADE, A ONCE-MONTHLY BUPRENORPHINE INJECTION

The FDA has approved Sublocade (Indivior, Inc.), the first once-monthly buprenorphine injection for the treatment of moderate-to-severe opioid use disorder (OUD) in adults who have initiated treatment with a transmucosal buprenorphine-containing product. It is indicated for patients who have been on a stable dose of buprenorphine treatment for at least seven days.

Buprenorphine for OUD treatment is currently approved to administer as a tablet or film that dissolves in the mouth or as an implant.

Sublocade should be used as part of a complete treatment program that includes counseling and psychosocial support. It is a drug–device combination product that utilizes buprenorphine and the Atrigel delivery system in a prefilled syringe. It is injected subcutaneously by a health care professional as a solution and forms a solid deposit, or depot, containing buprenorphine. Buprenorphine is released by the biodegradation of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

The safety and efficacy of Sublocade were evaluated in two clinical trials of 848 adults with a diagnosis of moderate-to-severe OUD who began treatment with buprenorphine/naloxone sublingual film. Once the dose was determined stable, patients were given Sublocade by injection. Sublocade-treated patients had more weeks without positive urine tests or self-reports of opioid use, and a higher proportion of patients had no evidence of illicit opioid use throughout the treatment period, compared with the placebo group.

The FDA is requiring post-marketing studies to assess which patients would benefit from a higher dosing regimen, to determine whether Sublocade can be safely initiated without a dose stabilization period of sublingual buprenorphine, to assess the feasibility of administering Sublocade at a longer interdose interval than once monthly, and to determine a process for transitioning patients with long-term stability on a transmucosal buprenorphine dose to a monthly dose of Sublocade without the use of a higher dose for the first two months of treatment.

Sublocade has a boxed warning that includes the risks of intravenous self-administration. If the product is administered intravenously, the solid mass could cause occlusion, tissue damage, or embolus. Sublocade must be prescribed and dispensed under a risk evaluation and mitigation strategy.

Source: FDA, November 30, 2017

KETAMINE FOR THE TREATMENT OF ADDICTIONS

Ketamine for the treatment of addiction: Evidence and potential mechanisms.

Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine’s ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine’s efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed.
Ketamine for the treatment of addiction: Evidence and potential mechanisms.

Author information
Ivan Ezquerra-Romano I1, Lawn W2, Krupitsky E3, Morgan CJA4.

LINK TO ORIGINAL ARTICLE