Update and Review of Medication Assisted Treatments for Opiate and

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1 Update and Review of Medication Assisted Treatments for Opiate and Alcohol Use Disorders Richard N. Whitney, MD Medical Director Addiction Services Shepherd Hill Newark, Ohio Medication Assisted Treatment of Addiction Which patients? Which diagnoses? Which medication? How long? Fit in with program philosophy? Affordability? Prescribers in area? Proven efficacy? OK with 12-Step groups? How do I refer patients? Why is this Still a Controversial Subject in 2015??? This topic elicits strong negative reactions from many persons in recovery as well as treatment professionals with an anti-medication bias. Many in the addiction treatment field as well as other medical fields suggest that using medications in the treatment of addictive disease is replacing one drug addiction with another. 1

2 Why is this Still a Controversial Subject in 2015??? How do we reconcile the incompatibility between the scientific literature which clearly documents the benefits of medication assisted therapies and the widespread resistance against appropriate pharmacotherapy among treatment professionals? Scientific evidence clearly demonstrates the short and, most importantly, the long-term efficacy of medications used in the treatment of addictive disease, especially alcohol and opiate use disorders. Why is this Still a Controversial Subject in 2015??? Even in the face of increasingly serious national epidemics of opioid and alcohol use disorders, medication-assisted therapies are underutilized. Studies have found that only about 30% of licensed addiction treatment programs offer any of the medications approved for opioid addiction, and only about 50% of potentially eligible patients within these program receive any of these medications. 18 Why is this Still a Controversial Subject in 2015??? Should we not strongly promote therapies which produce both favorable outcomes (abstinence, treatment compliance and retention, decreased medical and physical complications) as well as indirect benefits (reduced criminal behavior and legal involvement, family reunification, increased employment, improved physical health and overall quality of life)? 2

3 Addiction is a Brain-Based Disease 3

4 Depression is a Brain-Based Disease Anxiety is a Brain-Based Disease 4

5 Schizophrenia is a Brain-Based Disease Normal Brain Schizophrenic Brain 5

6 Abstinence Based Treatment Only? Would we recommend only non-medication therapy for other serious brain-based, life-disruptive, potentially fatal illnesses like depression, severe anxiety and/or panic disorder, or schizophrenia? If so, would we do so in what we believe is the patient s best interests, or in our own best interest or because that is how we ourselves were treated? Would that recommendation change depending upon the longevity and severity of the patient s disease, or if our current treatment plan was not successful in alleviating the patient s symptoms? Opposition to Medication Assisted Therapy Implies rejection of disease model itself Substitution of one drug for another Drug-free state is only valid treatment goal Substantial amounts of research have shown that this drug-free state is neither achieved nor sustained by many heroin addicts, 4 and numerous studies support the efficacy of FDA approved medications in patients with alcohol use disorders. Substance Use Disorders Addiction to alcohol as well as to pharmaceutical opiates, heroin, and other opioid drugs, are nationally prominent problems producing significant suffering, substantial tragic and expanding levels of morbidity and mortality, as well as significant costs to society, especially in law enforcement and healthcare. 6

7 Substance Use Disorders Effective medications are available to treat alcohol and opiate addiction, but they are substantially underutilized. We in the addiction field need to evaluate the safety effectiveness of these medications, and recommend them appropriately to our patients with addictive disease. Medication Assisted Therapy for Alcohol Addiction Medications for Alcohol Addiction Antabuse (disulfiram) Naltrexone - ReVia Vivitrol Campral (acamprosate) Anticonvulsants Other agents 7

8 Antabuse (disulfiram) FDA-Approved Pharmacotherapies for Alcohol Dependence: Older Options Drug Class Disulfiram (Antabuse ) Naltrexone (ReVia ) Mini-Profile Inhibits aldehyde dehydrogenase When taken with alcohol, [acetaldehyde] leads to nausea, dizziness, headache, flushing Decreases desire to drink Poor tolerability profile Black box warning, safety issues Opioid antagonist Binds to opioid receptors, thus blocking alcohol reward pathways Black box warning, safety issues 8

9 Disulfiram: Indications and Usage Patients with an alcohol use disorder who manifest significant problems in initiating or sustaining abstinence Those persons with addiction to alcohol who need a really good reason not to drink Persons who manifest alcohol abuse who really need to not drink (e.g.: hazardous occupations) Disulfiram: Indications and Usage Persons without alcohol use disorders but who wish to avoid high-risk drinking Patients without a diagnosed alcohol use disorder for whom alcohol use in any amount serves as a trigger for relapse to their drug of choice Persons with co-occurring cocaine dependence (??) Disulfiram: Mechanism of Action Inhibition of aldehyde dehydrogenase enzyme Alcohol then cannot proceed on its normal metabolic path to acetate Aldehyde builds up in a 1:1 response to the dose of ethanol presented Dose-response phenomenon, so a trivial dose of EtOH (e.g.: inhaled fumes) results in a minor buildup of acetaldehyde, and minor symptoms only 9

10 Disulfiram: Mechanism of Action A behavioral therapy more than a pharmacological therapy Effective but not always efficacious a patient has to swallow it for the medication to work Double-blind studies show it s no better than placebo unless medication administration is monitored Disulfiram: Dosing 250 mg daily is most common dose Usually started 125 mg nightly for 4 8 nights Can give 500 mg three times weekly Monitoring of dosing is key! Aqueous suspension (250 mg/5 ml) can improve adherence (i.e., pill cannot be cheeked ) 10

11 Disulfiram: Adverse Effects Hepatotoxicity with long-term treatment need to check liver function tests after initiating treatment May cause sedation, increase in depression or psychosis, cognitive impairment, i or worsening of dementia Metallic or garlic-like taste or breath often reported Sensory neuropathy with long-term therapy Disulfiram: Alcohol Reaction Hypotension, flushing, tachycardia, diaphoresis and dyspnea (shortness of breath) Severe headache, nausea, vomiting, abdominal pain, sulfur or garlic odor on breath Agitation, dysarthria (difficulty in speaking), chorea (abnormal involuntary movements) and lethargy Disulfiram: Therapeutic Approach May be used short-term or long-term May be used episodically, as for high risk circumstances (e.g., business trips, vacations) Optimal duration of use unclear Does not need to be tapered 11

12 Naltrexone: Oral Formulations (ReVia ) FDA-Approved Pharmacotherapies for Alcohol Dependence: Other Options Drug Class Disulfiram (Antabuse ) Naltrexone (ReVia ) Mini-Profile Inhibits aldehyde dehydrogenase When taken with alcohol, [acetaldehyde] leads to nausea, dizziness, headache, flushing Decreases desire to drink Poor tolerability profile Black box warning, safety issues Opioid antagonist Binds to opioid receptors, thus blocking alcohol reward pathways Black box warning, safety issues Naltrexone: Patient Selection Diagnosis of alcohol use disorder Strongly positive family history of AUD Strong subjective cravings for alcohol Strong subjective reward from alcohol An expressed desire to be in recovery and a willingness to engage in and complete treatment 12

13 Naltrexone: Contraindications Acute hepatitis or liver failure Persons on methadone maintenance therapy or buprenorphine maintenance therapy (due to opiate receptor blockade) Current or proximate need to be on opioid analgesic therapy (e.g.: upcoming major surgery) History of significant adverse effects or history of allergy to naltrexone Naltrexone: Purported Mechanism Competitive antagonist at mu opioid receptor Blocks endogenous opioid-mediated release of dopamine in the nucleus accumbens in response to EtOH, thus blocking EtOH-induced d euphoria Blunts rewarding effects of alcohol in humans Reduces subjective cravings and reduces return to heavy drinking 13

14 Naltrexone: Injectable Formulation (Vivitrol ) 14

15 Opioid Receptors and Alcohol Dependence Gianoulakis C. Alcohol Health Res World. 1998;22: Woodward JJ. Principles of Addiction Medicine. 3rd ed. 2003: Opioid Receptors and Alcohol Dependence The mechanism by which VIVITROL exerts its effects in alcohol dependent patients is not entirely understood VIVITROL [full prescribing information]. Cambridge, MA: Alkermes, Inc; May Oswald LM et al. Physiol Behav. 2004;81: Kenna GA et al. Am J Health Syst Pharm. 2004;61: Gianoulakis C. Alcohol Health Res World. 1998;22: Dosage and Administration Epidermis Dermis Adipose Muscle Vivitrol is given as an intramuscular (IM) gluteal injection every 4 weeks or once a month Vivitrol should not be given subcutaneously or in the adipose layer Vivitrol itrol must not be administered intravenously Vivitrol should be administered by a healthcare professional, into alternating buttocks each month Vivitrol should be injected into the upper outer quadrant of the buttock, deep into the muscle-not the adipose tissue (fat) 45 15

16 Vivitrol Pharmacokinetics: Alcohol Dependence and the Liver Vivitrol is given as an intramuscular injection Reduces first-pass hepatic metabolism compared to oral naltrexone Delivers ¼ the total monthly dose of oral naltrexone (380 mg vs.1500 mg) Naltrexone s boxed warning came from the use of oral naltrexone given in excessive doses Patients in study received greater than 5 times the recommended dose Vivitrol does not appear to be a hepatotoxin at the recommended dose Available only in 1 dose (380 mg) Dispensed in single-dose cartons Administered by a healthcare professional Patients who experience symptoms and/or signs of acute hepatitis should seek medical attention and discontinue use of Vivitrol 46 16

17 Campral (acamprosate) Campral: Patient Selection Diagnosis of alcohol use disorder Anxiety/insomnia during periods of abstinence which, by the patient s history, leads to relapse Patients who report relief of negative emotional states when they drink alcohol Patients who desire to be in recovery, are willing to engage in treatment, and endorse the goal of total abstinence 17

18 Pharmacokinetics (cont.) Special Populations No pharmacokinetic differences due to gender No pharmacokinetic differences in alcohol dependent subjects No dose adjustment necessary with mild to moderate hepatic (liver) impairment or mild renal (kidney) disease Dose adjustment is necessary in moderate renal disease (i.e., creatinine clearance, ml/min) Contraindicated in severe renal disease (i.e., creatinine clearance, 30 ml/min) Effects of Alcohol on Neural Circuits Glutamate System Administration of Alcohol Acute Alcohol Effect Inhibits NMDA receptors Effect: anxiety, sedation Chronic Alcohol Use Alcohol Free CNS Equilibrium Adaptation # and/or function of NMDA receptors on neurons Balances acute alcohol effect Effect: tolerance, dependence Withdrawal Increased glutamatergic activity Effect: Acute: dysphoria, Removal of hallucinations Alcohol Post-acute: sleep/mood NMDA = N-methyl-D-aspartate. disturbances Source: Littleton J. Alcohol Health Res World. 1998;22: Pathophysiology of Potential Relapse Ca 2+ Glutamate NMDA Receptor mglur5 18

19 Balancing Pathophysiology Campral (acamprosate calcium) C Reduction in glutamate release C Reduction in postsynaptic effects Glutamate C Campral C C NMDA Receptor C mglur5 Neuroadaptation: Potential for Relapse Normal Acute Alcohol Intake Tolerance Alcohol Alcohol Adaptation Inhibition (GABA) Excitation (Glutamate) Acute Withdrawal Adaptation Post-Acute Withdrawal and Cue-Induced Responses C Campral (acamprosate calcium) may balance glutamate over-activity, thus reducing the potential for relapse Acamprosate 48- and 52-Week Clinical Trials: % Days Abstinent of Days ent Percentage Abstine % P<.001* 74% 48-Week Study 67% P<.001* 85% 52-Week Study n=136 n=136 n=177 n=173 (1332/1998 mg/d) (1998 mg/d) ACAMP Placebo 19

20 Acamprosate Common Spontaneously Reported Adverse Events in Placebo- Controlled Trials Event Diarrhea Asthenia Nausea Pruritus Flatulence Acamprosate (n=2019) 16% 6% 4% 4% 3% Placebo (n=1706) 10% 5% 3% 3% 2% Dosage and Administration Initiate as soon as possible after alcohol withdrawal when patient achieves abstinence Maintain treatment if patient relapses Recommended dose: two 333 mg tablets taken 3 times a day Patients with moderate renal impairment should have a starting dose of 1 x 333 mg 3 times daily Patients with severe renal impairment should not be given Campral (acamprosate) Can be taken with or without meals Monthly Cost of Medications Antabuse ~ $100 Oral naltrexone ~ $ Vivitrol ~ $750 1,500 Campral ~ $

21 Anticonvulsants Anticonvulsants Topamax (topiramate), Tegretol (carbamazepine), and Depakote (divalproex) have increasingly been of interest, with one study confirming topiramate as being beneficial. These medications act as GABA agonists and glutamate antagonists (similar il to acamprosate). Preliminary studies show superiority to placebo in reductions in drinks/day, drinks/drinking day, drinking days, and GGTP reduction levels. Topiramate shows the greatest amount of research support, and should be initiated in a slowly increasing dosage (maximum 300 mg/day). Topiramate: Patient Selection Diagnosis of alcohol use disorder Patents with co-occurring bipolar disorder Persons with high reward from alcohol or who use it to relieve negative emotional states 21

22 Topiramate: Mechanism of Action GABA-ergic agent (facilitates GABA functioning via action on a non-benzodiazepine site on the GABA-A receptor) Also inhibits dopamine release in the limbic system, thus attenuating alcohol reward and craving for alcohol May decrease obsessional thoughts and compulsions about drinking Topiramate: Dosing Morning Dose Evening Dose Week 1 25 mg 25 mg Week 2 50 mg 50 mg Week 3 75 mg 75 mg Week mg 100 mg Week mg 150 mg Topiramate: Adverse Effects Sedation/somnolence, fatigue Dizziness Tingling of arms and legs Cognitive clouding Decreased appetite and weight loss Funny tastes, nausea Decreased sweating, increased body temperature 22

23 Topiramate: Adverse Effects Acute secondary-angle glaucoma (acute eye pain and myopia) Metabolic acidosis via decreased serum bicarbonate (symptoms of hyperventilation, tiredness, loss of appetite, irregular heartbeat, decreased alertness) Kidney stone formation Must warn about pregnancy complications or increase in suicidal thinking Other Agents Other Agents Lioresal (baclofen) antispasmodic with GABA-B agonist activity. However, there is evidence of misuse, overdose, delirium sufficient to recommend more research prior to use in alcoholism. SSRI agents inconsistent findings with no likely benefit in alcohol dependent patients without co-morbid depression. Zofran (ondansetron) serotonin receptor (5-HT3) antagonist selectively reduced drinking among some patients with early onset of problem drinking, but more studies are needed before differentiating treatment by alcohol dependence subtypes. 23

24 Medication Assisted Therapy for Sedative-Hypnotic Addiction Agents for Sedative-Hypnotic Dependence No medications have been approved or found to be effective specifically for sedative-hypnotic dependence (usually benzodiazepines taken for anxiety or imidazopyridines [e.g.: Ambien] for sleep). Phenobarbital (used for acute detoxification) may be used 24