Overview of the Program Medication Assisted (Supported) Treatment Michael Delman MD, FACP, FASCG, FASAM Assistant Professor of Medicine Hofstra North Shore-LIJ School of Medicine Stephen A. Wyatt, D.O. Dept. of Psychiatry Middlesex Hospital Middletown, CT Edwin A. Salsitz, M.D., FASAM Mount Sinai Beth Israel Credits

Volkow ND et al. N Engl J Med 2016;374: Stages of the Addiction Cycle.

Disulfiram It is most effective in people who have already gone through detoxification or are in the initial stage of abstinence. This drug is offered in a tablet form and is taken once a day. Disulfiram should never be taken while intoxicated and it should not be taken for at least 12 hours after drinking alcohol. Unpleasant side effects (nausea, headache, vomiting, chest pains, difficulty breathing) can occur as soon as ten minutes after drinking even a small amount of alcohol and can last for an hour or more. Acamprosate Acamprosate is a medication for people in recovery who have already stopped drinking alcohol and want to avoid drinking. It works to prevent people from drinking alcohol, but it does not prevent withdrawal symptoms after people drink alcohol. The use of acamprosate typically begins on the fifth day of abstinence, reaching full effectiveness in five to eight days. It is offered in tablet form and taken three times a day, preferably at the same time every day. The medication’s side effects may include diarrhea, upset stomach, appetite loss, anxiety, dizziness, and difficulty sleeping. Naltrexone When used as a treatment for alcohol dependency, naltrexone blocks the euphoric effects and feelings of intoxication. This allows people with alcohol addiction to reduce their drinking behaviors enough to remain motivated to stay in treatment, avoid relapses, and take medications. Medications Approved for Alcohol Addiction

Objectives Review the development, science and prescribing policies of the currently available medications for the treatment of opiate dependence. Understand the factors important in the decision of which treatment would be indicated. Understand the factors associated with the initiation of a treatment for opiate dependence.

Medically assisted withdrawal and abstinence. Methadone maintenance Naltrexone: oral and injectable Buprenorphine/naloxone Current Treatments

Historical Review The 1914 Harrison Act was a commerce act restricting the sales of narcotics, it excluded physicians treating patients In 1919 when the Harrison Act was ratified by the Supreme Court it excluded the treatment of opiate dependence: not considered a disease. ‐ No longer was it legal for physicians to prescribe opiates for maintaining opiate dependence or for the treatment of the disease. ‐ Medically assisted withdrawal of opiates and abstinence was the only legal treatment. The historical records identify the relapsing nature of this disease.

Historical Review  As the death rate from heroin injectors continued to rise in the late 1950’s and early 1960’s, with a concurrent rise in associated crime, there was growing support for the establishment of opiate maintenance programs.  There was an increase in federal funding for research into treating these patients.  In 1962 Vincent Dole, MD received a grant to study the feasibility of opiate maintenance treatment. In 1964 Marie Nyswander, MD, a psychiatrist with experience in treating addicted patients joined the research team.  Methadone was eventually selected as the most efficacious opiate for maintenance treatment.

Neurobiology: Methadone Blocks the euphoric and sedating effects of other opiates Reduces the craving for other opioids Relieves symptoms associated with withdrawal from opiates With stable dosing tolerance develops and does not cause euphoria or intoxication, thus allowing a person to participate in normal daily activities including employment and family responsibilities Has a long half-life and is excreted slowly, allowing for once daily dosing. Neurobiology: Methadone

Methadone Maintenance Treatment: A treatment program in which addicted individuals receive daily doses of methadone Multi-component treatment program Encourages abstinence from other drugs of abuse including alcohol Resocialization – Sober supports Vocational training Coordination of healthcare HIV Hepatitis C Pregnancy

Methadone Treatment ‐ reduced risk of overdose ‐reduced or stopped use of injection drugs; ‐reduced mortality – the median death rate of opiate-dependent individuals in MMT is 30 percent of the rate of those not in MMT; ‐reduced risk of acquiring or transmitting diseases such as HIV, hepatitis B or C, bacterial infections, endocarditis, soft tissue infections, thrombophlebitis, tuberculosis, and STDs; ‐reduced criminal activity; ‐possible reduction in sexual risk taking ‐ Improved employment potential; ‐ improved family stability ‐ improved pregnancy outcomes Identified Benefits of MMT

Methadone Treatment Drawbacks  ‐ Physical dependence, possibly strengthening neurobiological adaptation to opiate dependence.  ‐ Daily administration at a licensed methadone treatment center is required in initial phase of treatment  ‐ Early mild to moderate opiate like effects; e.g. sedation, reduction in cognitive awareness  ‐ Long term maintenance effects on hormonal adaptations; reductions in testosterone, menstruation, calcium metabolism  ‐ Drug/drug interactions  ‐ Neonatal abstinence syndrome in babies born to methadone-maintained mothers

Historical Review The next approved medication for opiate dependence was naltrexone approved in As an opiate antagonist it blocks the opiate receptor significantly changing the response to the administration of an opiate. ‐ The lack of compliance and less reduction in craving are thought to be the prominent problems associated with poor efficacy of the oral product. A sustained release form was determined to have an adequate safety profile and to be effective by the FDA in 2010.

Neurobiology: Naltrexone Binds to the opiate receptor without activation Available as both oral and injectable formulations. ‐ Oral typically daily administration, however may be given on a three times per week schedule (Monday: 100 mg – Wednesday: 100 mg – Friday: 150 mg) Injectable form is given once monthly. Evidence of reduction in opiate craving through a combination of; ‐ Reduced opiate receptor activation due to partial endorphins blockade ‐ Total blockade reducing initial consideration of opiate use. Injectable product resulting more positive results

Naltrexone Treatment Drawbacks Blockade of opiate receptors interferes with opiate analgesia Opiate dependent patients must be detoxified from opiates before naltrexone can be started Compliance is the major drawback to the oral product. Injectable requires continued patient compliance after detoxification until administration.

Historical Review With the establishment of DATA 2000 another treatment option was made available. ‐ This act of Congress established that any schedule III, IV, V controlled substance with FDA approval for treatment of opioid dependence could be prescribed by a “qualified” physician. This opened the door to buprenorphine products which are placed on schedule III. This resulted in availability of office based opiate dependent treatment with an agonist medication. This further broadened the availability of maintenance treatment.

Neurobiology: Buprenorphine Opioid Partial agonist  ‐ High affinity for mu opioid receptor  ‐ Slow dissociation from receptor  ‐ Displaces other opioids from mu receptor including Heroin  ‐ Improved safety profile due to reduction in potential respiratory depression

Buprenorphine Treatment Approved for office based treatment ‐ Allows for normalization of treatment in the primary care or behavioral health care settings. ‐ Allows for wider availability of agonist treatment for opioid dependence Opioid partial agonist properties reduce potential for overdose Once a day administration Fewer drug interactions described than for methadone currently Relative blocking of other opiates Significant reduction in craving Improved reentry into normal socialization Helps to shift from drug abusing behavior to normal life activities

Buprenorphine Treatment Drawbacks  ‐ Physical dependence, possible strengthening of the opiate dependence  ‐ Potential diversion for abuse  ‐ Reduces the patients drive to put in place relapse prevention behaviors due to the pharmacologic reduction in the drive to use other opiates.  ‐ There is evidence of both hormonal adaptation.  - Neonatal abstinence syndrome can occur in babies born to mothers maintained on buprenorphine though less than that seen in the methadone treated patient.

Treatment Selection Logistical considerations  Lack of access to a methadone treatment center has been a major limitation to this form of treatment  Buprenorphine has limitations in access due to a lack of waivered physician availability though office based treatment has improved treatment access in rural areas in particular.  Does a physician prescribing buprenorphine/naloxone have access to assistance with drug counseling in their community?  Need for detoxification from opiates prior to the administration of naltrexone. Can be a challenge due to relapse potential in the period following last dose of opioid and time necessary for opioid to be eliminated and physical dependence to resolve.

Treatment Selection There is significant overlap in the indications of one form of therapy over another. Patients may have a strong bias to one form of treatment over another. Honoring this when possible may improve compliance and effectiveness. Physician knowledge and level of comfort will also be a consideration. Patients with co-occurring medical or psychiatric illness need special consideration. Poly substance abuse may need the daily oversight provided by MMT The opportunity for the pregnant patient to be treated in an established methadone maintenance pregnancy program should be strongly considered if available. Buprenorphine has been shown to reduce both days of hospitalization for NAS and morphine dose need for treatment of NAS following del ivery.

Cost Comparison of medication assisted treatment vs. no medication for inpatient, outpatient, and pharmacy costs ‐ 29% lower for patients who received a medication for opioid dependence versus patients treated without medication. Injectable sustained release naltrexone had fewer opioid- related and non–opioid-related hospitalizations than patients receiving oral medication. Total healthcare costs were not significantly different between oral or injectable naltrexone and buprenorphine/ naltrexone and were 49% lower than those for methadone. ‐ This in part was a reflection on the increased co- morbidities in the methadone population. Baser, AJ of Managed Care, 2011

Medically Assisted Opioid Treatment Abstinence remains an option particularly in the young person or those with a low level of dependence. However: ‐ There is strong evidence of improved outcomes with medication assisted maintenance treatment ‐ Patients should be made aware of their options ‐ Treatment providers should be aware of these medications to better educate patients and make appropriate treatment recommendations.