Naltrexone: (Vivitrol )

Transcription

1 Naltrexone: Injectable Formulation (Vivitrol ) 1

2 Opioid Receptors and Alcohol Dependence 4 1. 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 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 Dermis Vivitrol it must not be administered i d Adipose intravenously Muscle 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) 6 2

3 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 7 3

4 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 4

5 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 Withdrawal Increased glutamatergic activity Effect: Acute: dysphoria, hallucinations Post acute: sleep/mood NMDA = N-methyl-D-aspartate. disturbances Source: Littleton J. Alcohol Health Res World. 1998;22: Adaptation # and/or function of NMDA receptors on neurons Balances acute alcohol effect Effect: tolerance, dependence Removal of Alcohol Pathophysiology of Potential Relapse Ca 2+ Glutamate NMDA Receptor mglur5 5

6 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 6

7 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 ~ $

8 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 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 8

9 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 lreward and craving for alcohol l 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 9

10 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 aents 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. 10

11 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 tedetoxification) may be used for treatment of the protracted withdrawal syndrome beyond the initial withdrawal phase. Campral (acamprosate) theoretically should have efficacy for sedative hypnotic dependence due to it s effect on the GABA and glutamate receptor systems (similar to its effects for alcohol dependence). Break Time 11

12 Opiate Use Disorders 12

13 Progression of Opioid Abuse and Addiction Dopamine System and Drug Misuse Early Phase (Use) LIKE Pleasure circuit Middle Phase (Abuse) WANT Desire and urge circuit Late Phase (Addiction) NEED Pathologic desire and demand circuit Opioid Withdrawal Patients worst nightmare a major barrier to beginning treatment It doesn t kill, you, just makes you wish you were dead Objective, subjective, acute and protracted withdrawal symptoms 13

14 Opioid Withdrawal Syndrome Acute and protracted phases Can occur after even two weeks of opioid use Duration of acute withdrawal is dependent upon the half lifeofthe drug used: Peak of withdrawal occurs 36 to 72 hours after last dose Acute symptoms subside over 3 to 10 days Protracted symptoms may linger for weeks or months Opioid Withdrawal Acute symptoms (generally last 3 10 days) Autonomic symptoms (Physiologic) Rebound increased norepinephrine activity from the locus coeruleus Increase blood pressure and heart rate, peristalsis (intestinal cramps and diarrhea), diaphoresis (sweating), irritability, anxiety, etc. Affective symptoms (Subjective) Suppressed in the dopaminergic reward pathways Depression, anxiety, anhedonia, craving, anergia Protracted Opioid Withdrawal Can persist for 3 6 months Anergia Anhedonia Sleep disturbance, poor appetite Emotional lability/dysphoria Stress over sensitivity Drug cravings and obsessive thoughts of drugs Deep muscle aches and pains Reduced libido, impotence, anorgasmia 14

15 Comprehensive Treatment of Opiate Addiction 15