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Section 34: Addiction Medications Richard A. Rawson, Ph.D., Professor Semel Institute for Neuroscience and Human Behavior David Geffen School of Medicine University of California at Los Angeles Opiate Agonist and Partial Agonist Therapy Methadone and Buprenorphine Global Abuse of Opiates Overview: Sixteen million (0.4%) of world’s population age 15-64 abuse opiates Heroin abusers make up about 71% of opiate abusers Opiates accounts for 2/3 of all treatment demands in Asia and 60% of treatment demand in Europe Regional Breakdown of Opiate Abusers Africa Oceania 6% 1% Americas 14% Asia 54% Europe 25% Sources: UNODC, Annual Reports Questionnaire Data, Govt. reports, reports of regional bodies, UNODC estimates. 3 Opioids Opiate (n) an unlocked door in the prison of identity. It leads to the jail yard. Ambrose, Bierce (1906) The Devil’s Dictionary 4 Opioid-related Problems Most prominent problems are associated with heroin dependence Not all users of heroin develop dependence. Between 1:4 to 1:3 regular users develop dependence Development of heroin dependence usually requires regular use over months (or longer where use is more irregular). 5 The Revolving Door Heroin dependence is a chronic relapsing disorder. It is a dependency which is very difficult to resolve Relapse is extremely common. It is part of the process of resolving the dependence – much like giving up tobacco A principal health care objective is to get the patient into treatment, help keep them in treatment and to return them to treatment when relapse occurs. 6 Classification of Opioids Pure Opioid Agonists opium papaverine morphine codeine heroin buprenorphine hydromorphone oxycodone Partial Agonists/Antagonists naltrexone buprenorphine LAAM Synthetic LAAM fentanyl meperidine hydrocodone methadone pentazocine pethidine 7 Opioids: Long-term Effects (1) Little evidence of long-term direct toxic effects on the CNS from opioid use Long-term health-related complications may result from: – – – – – dependence antisocial behaviour poor general self-care imprisonment drug impurities or contaminants, BBV. 8 Opioids: Considerations for assessment Pregnancy BBV Polydrug dependence Opioid related overdose Major or pre-existing medical conditions (e.g. liver, cardiac) Major psychiatric/mental health issues (e.g. psychosis, depression, suicide). 9 Opioid Withdrawal Signs Yawning Lacrimation, mydriasis Diaphoresis Rhinorrhoea, sneezing Tremor Piloerection Diarrhoea and vomiting. Symptoms Anorexia and nausea Abdominal pain or cramps Hot and cold flushes Joint and muscle pain or twitching Insomnia Drug cravings Restlessness/anxiety. 10 Progress of the Acute Phase of Opioid Withdrawal Since Last Dose Severity of signs and symptoms Withdrawal from heroin Onset: 6–24 hrs Duration: 4–10 days 0 Withdrawal from methadone Onset: 24–48 hrs, sometimes more Duration: 10–20 days, sometimes more 10 Days deCrespigny & Cusack (2003) Adapted from NSW Health Detoxification Clinical Practice Guidelines (2000-2003) 20 11 Predictors of Withdrawal Severity Main predictors – Greater regular dose – Rapidity with which drug is withdrawn. Also consider } – – – Greater withdrawal severity Type of opioid used, dose, pattern and duration of use Prior withdrawal experience, expectancy, settings for withdrawal Physical condition (poor self-care, poor nutritional status, track marks) – Intense sadness (dysthymia, depression) – Constipation or ‘Narcotic Bowel Syndrome’ – Impotence (M) or menstrual irregularities (F). Opioids 12 12 Opioid Withdrawal Treatment Involves: reassurance and supportive care information hydration and nutrition medications to reduce severity of somatic complaints (analgesics, antiemetics, clonidine, benzodiazepines, antispasmodics) opioid pharmacotherapies (e.g. methadone, buprenorphine, naltrexone). Opioids 13 13 Opioid Withdrawal Complications Anxiety and agitation Low tolerance to discomfort and dysphoria Drug-seeking behaviour (requesting or seeking medication to reduce symptom severity) Muscle cramps Abdominal cramps Insomnia. Opioids 14 14 Heroin Withdrawal Non-life threatening Commences 6–24+ hours after last use Peaks at around 24–48 hours after use Resolves after 5–7 days. Increasing recognition of the existence of a protracted phase of withdrawal lasting some weeks or months, characterised by reduced feelings of wellbeing, insomnia, dysthymia, and cravings. Opioids 15 15 General Principles of Pharmacotherapies Pharmacodynamics: Agonists – Partial agonists – directly activate opioid receptors (e.g. morphine, methadone) unable to fully activate opioid receptors even with very large doses (e.g. buprenorphine) Antagonists – occupy but do not activate receptors, hence blocking agonist effects (e.g. naloxone). Opioids 16 16 Maintenance Pharmacotherapies Methadone Buprenorphine Naltrexone LAAM Slow-release morphine. Opioids 17 17 Key Outcomes of Maintenance Pharmacotherapy Programs Retention in treatment Facilitates reduction/cessation of opioid use Reduces risky behaviours associated with opioid use Enables opportunity to engage in harm reduction measures Mortality and morbidity Psychological, emotional and physical wellbeing of patients Social costs associated with illicit drug use Crime. Opioids 18 18 Methadone: Clinical Properties The ‘Gold Standard’ Treatment Synthetic opioid with a long half-life μ agonist with morphine-like properties and actions Action – CNS depressant Effects usually last about 24 hours Daily dosing (same time, daily) maintains constant blood levels and facilitates normal everyday activity Adequate dosage prevents opioid withdrawal (without intoxication). Opioids 19 19 Rationale for opioid agonist treatment (1) Advantages of opioid agonist medication over heroin: Non-parenteral administration Known composition Gradual onset and offset Long-acting Mildly reinforcing Medically supervised 20 20 Rationale for opioid agonist treatment (2) Opioid agonist treatment: Most effective treatment for opioid dependence Controlled studies have shown that with long term maintenance treatment using appropriate doses, there are significant: Decreases in illicit opioid use Decreases in other drug use 21 21 Rationale for opioid agonist treatment (3) Opioid agonist treatment (continued): Decreases in criminal activity Decreases in needle sharing and HIV transmission Improvements in prosocial activities Improvements in mental health 22 22 The global response: UN support for good treatment WHO/UNODC/UNAIDS position paper: Substitution maintenance therapy in the management of opioid dependence and HIV/AIDS prevention “Substitution maintenance treatment is an effective, safe and cost-effective modality for the management of opioid dependence. Repeated rigorous evaluation has demonstrated that such treatment is a valuable and critical component of the effective management of opioid dependence and the prevention of HIV among IDUs.” 23 23 Safety Overview Safe medication (acute and chronic dosing) Primary side effects: like other mu agonist opioids (e.g., nausea, constipation), but may be less severe No evidence of significant disruption in cognitive or psychomotor performance with Methadone maintenance No evidence of organ damage with chronic dosing 24 24 Methadone: Advantages of Treatment Suppresses opioid withdrawal Pure – no ‘cutting agents’ present Oral administration (syrup or tablet forms used) Once daily doses enable lifestyle changes Slow reduction and withdrawal can be negotiated with minimal discomfort Counselling and support assists long-term lifestyle changes Legal and affordable – reduced participation in crime Few long-term side-effects. 25 25 Methadone: Disadvantages of Treatment Initial discomfort to be expected during stabilisation phase Opioid dependence is maintained Slow withdrawal (preferably) negotiated and undertaken over a period of months Protracted withdrawal symptoms Can overdose, particularly with polydrug use Daily travel and time commitment Variable duration of action Diversion 26 26 To Maximize Treatment Adherence Address psychosocial issues as first priority emotional stability "chaotic" drug use accommodation income Opioid agonist pharmacotherapy can: address psychosocial instability increase opportunities to directly observe the administration of various HIV therapies 27 27 Drug Use History Primary drug Average daily use (quantity/duration) Time last used Route of administration Age commenced, periods of abstinence Severity of dependence Previous treatment(s) Other drugs Current and previous dependence 28 28 Medical and Psychiatric HIV/HCV Pregnancy Other Liver Cardiac Major major medical conditions psychiatric conditions Depression, suicide, psychosis Opioid related overdose 29 29 Induction Stabilization Phase Dose adequacy and drug interactions signs intoxication/withdrawal frequency of drug use frequency of sharing Case coordination and management psychological social medical health/welfare system interaction 30 30 Safe Initial Dose 20 - 30mg methadone is generally safe Deaths have occurred with higher starting doses or poly-drug use Opioid-dependent polydrug users may be safer to start as inpatients 31 31 Resting Pulse Rate: _______ beats/minute Measured after patient is sitting or lying for one minute 0 pulse rate 80 or below 1 pulse rate 83-100 2 pulse rate 101-120 4 pulse rate greater than 120 Sweating: over past ½ hour not accounted for by room temperature or patient activity 0 no report of chills or flushing 1 Subjectie report of chills or flushing 2 flushed or observable moistness on face 3 beads of sweat on brow or face 4 sweat streaming off face GI Upset: over last ½ hr 0 no GI symptoms 1 stomach cramps 2 nausea or loose stool 3 vomiting or diarrhoea 3 multiple episodes of diarrhoea or vomiting Restlessness Observation during assessment 0 able to sit still 1 reports difficulty sitting still but is able to do so 3 frequent shifting or extraneous movements of legs/arms 5 unable to sit still for more than a few seconds Yawning Observation during assessment 0 no yawning 1 yawning once or twice during assessment 2 yawning three or more times during assessment 4 yawning several times/minute Pupil Size 0 pupils pinned or normal size for room light 1 pupils possibly larger than normal for room light 2 pupils moderately dilated 5 pupils so dilated that only the rim of the iris is visible Anxiety or Irritability 0 none 1 patient reports increasing irritability or anxiousness 2 patient obviously irritable or anxious 4 patient so irritable or anxious that participation in the assessment is difficult Bone or Joint aches If patient was having pain previously, only the additional component attributed to opiates withdrawal is scored 0 not present 1 mild diffuse discomfort 2 patient reports severe diffuse aching of joints/muscles 4 patient is rubbing joints or muscles and is unable to sit still because of discomfort Runny nose or tearing Not accounted for by cold symptoms or allergies 0 not present 1 nasal stuffiness or unusually moist eyes 2 nose running or tearing 4 nose constantly running or tears streaming down cheeks Gooseflesh skin 0 skin is smooth 3 piloerection of skin can be felt or hairs standing up on arms 5 prominent piloerection Tremor observation of outstretched hands 0 no tremor 1 tremor can be felt but not observed 2 slight tremor observable 4 gross tremor or muscle twitching Total Score _______ The total score is the sum of all 11 items Initials of persons Completing assessment ___________________ 32 Relationship between methadone dose and heroin use % of clients using heroin (last 30 days) (adapted from Ball and Ross, 1991) Methadone Dose (MG) 33 33 Stabilisation FREQUENCY OF APPOINTMENTS First 5 -7 days - see every 1-2 days Write prescription till next appointment only Always see the patient before increasing the dose Continue the assessment process, build the therapeutic relationship 34 34 Effective Programs Longer duration (2-4 years). Higher doses - > 60mg methadone. Accessible prescriber and dispenser. Ancillary services. Quality of therapeutic relationship. 35 35 Opioids: Other Drug Interactions Respiratory depression Toxicity/ Hypotension Coma risk of death CNS Depressants MAOIs TCAs Betablockers BZDs 36 36 Efficacy of Methadone Concurrent Control Studies 100 male narcotic addicts randomized to methadone or placebo in a treatment setting Both groups initially stabilized on 60 mg methadone per day. Both groups had dosing adjustments: Methadone could go up or down Placebo – 1 mg per day tapered withdrawal Outcome measures: treatment retention and imprisonment Follow-up Time 2 years Percent DrugFree "Methadone Group" 12/17 Percent DrugFree “No Methadone Group" 1/17 Imprisonment rate: twice as great for placebo group 37 37 Efficacy of Methadone Concurrent Control Studies 34 patients assigned to methadone or no methadone at one clinic Outcomes: percent drug free Follow-up Time 2 years Percent DrugFree "Methadone Group" 12/17 Percent DrugFree “No Methadone Group" 1/17 Five year follow-up: No methadone group offered methadone Those choosing methadone: 8/9 Those not choosing methadone: 1/8 5 Died of ODs, 2 Imprisoned 38 38 Evidence for the Efficacy of Methadone Dose Response Studies Dose Response Trials Retention and illicit opiate use N 212 Methadone Doses 0,20,50 mg Results 50 mg 20 mg 0 Strain, E., et al. Ann. Int. Med. 119:23-27, 1993 N 162 Methadone Doses 20, 60 mg Results 60 mg >20 mg Johnson RE, Jaffe J, Fudala PJ, JAMA, 267(20), 1992 39 39 Evidence for the Efficacy of Methadone Dose Response Studies Outcomes: Retention and illicit opiate use N 225 Methadone Doses 30 and 80 mg Results 80 30 mg Ling et al, Arch Gen Psych, 53(5), 1996 N 140 Methadone Doses 20 and 65 mg Results 65 20 mg Schottenfeld R, et al., 1993 40 40 % I.V. Drug Use Heroin Abuse Frequency Vs. Methadone Dose 80 60 40 20 0 10 20 30 40 50 60 70 80 90 100 Daily Dose In MGS. V.P. Dole, JAMA, VOL. 282, 1989, p. 1881 41 Evidence for the Efficacy of Methadone N 4,776 Treatment Untreated Annual Death Rate 7.0 100 109 3,000 368 Treated Detox MM MM 3.4 8.3 0.8 1.4 Age Adjusted Control 0.6 1 0.3 2 3 3 0.17 4 1 Prescore MJ, US Public Health Report, Suppl 170, 1943 2 Valliant GE, Addictive States, 1992 ¾ Gearing MF, Neurotoxicology, 1977 4 Grondblah L, ACTA Psych Scand, 82, 1990 42 42 Death Rates in Treated and Untreated Heroin Addicts Annual Rate 8 6.91 7.20 6 4 1.65 2 0.85 0.15 0 Matched Cohort Methadone Voluntary Involuntary Untreated Discharge Discharge 43 Compare the Costs 25,000 No Treatment $21,500 $20,000 Costs are for a 6 month period, per person 20,000 15,000 10,000 In Treatment Program $9,825 $8,250 5,000 $1,750 $1,575 0 Untreated Incarceration Adolescent Adult Residential Methadone Drug Free Outpatient 44 Relapse to IV Drug Use After Termination of Methadone Maintenance Treatment Percent IV Users 100 82.1% 80 72.7% 57.6% 60 45.5% 40 20 0 28.9% In Treatment Rate 1-3 Months Later 1 2 3 4-6 Months Later 10-12 Months Later 7-9 Months Later Months Since Drop Out 4 5 6 7 8 9 10 11 12 Ball, JC, Ross A. The Effectiveness of Methadone Maintenance Treatment, Springer-Verlag, New York, 1991 45 Naltrexone Morphine antagonist, true blockade No psychoactive effect Prevents euphoria from opioid use therefore ‘drug money spent = money wasted’ Prevents reinstatement of opioid dependence, although does not reinforce compliance No withdrawal experienced upon cessation Reported to reduce cravings in some people. Opioids 46 46 Naltrexone: Indications for Use Prescribed for the management of opioid dependence by registered prescribers Primary role = relapse prevention Abstinence-based treatment option Non-dependence inducing Commenced at least a week after cessation of heroin use. Opioids 47 47 Opiate Addiction Treatment with Buprenorphine 48 48 Overview Buprenorphine is a thebaine derivative (classified in the law as a narcotic) High potency Produces sufficient agonist effects to be detected by the patient Available as a parenteral analgesic (typically 0.3-0.6 mg im or iv every 6 or more hours) Long duration of action when used for the treatment of opioid dependence contrasts with its relatively short analgesic effects 49 49 Affinity and Dissociation Buprenorphine has: A high affinity for mu opioid receptor competes with other opioids and blocks their effects A slow dissociation from mu opioid receptor – prolonged therapeutic effect for opioid dependence treatment (contrasts to its relatively short analgesic effects) 50 50 Mu efficacy and opiate addiction Full agonist - Super agonist fentanyl morphine/heroin hydromorphone Positive effect = Potentially lethal dose Agonist + partial agonist addictive potential Partial agonist - buprenorphine Antagonist - naltrexone dose Negative effect Antagonist + agonist/partial agonist 51 Buprenorphine: Clinical Pharmacology Partial Agonist high safety profile/ceiling effect low dependence Tight Receptor Binding long duration of action slow onset mild abstinence 52 52 Intensity of abstinence Buprenorphine Himmelsbach scores 60 Morphine 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Days after drug withdrawal 53 53 Buprenorphine Stabilization / Maintenance Stabilize on daily sublingual dose Expect average daily dose will be somewhere between 8/2 and 32/8 mg of buprenorphine/naloxone Higher daily doses more tolerable if tablets are taken sequentially rather than all at once 54 54 Maintenance Treatment Using Buprenorphine Studies conclude: Buprenorphine more effective than placebo Buprenorphine equally effective as moderate doses of methadone (e.g., 60 mg per day) Not clear if buprenorphine can be as effective as higher doses of methadone (e.g., 80-100 mg or more per day), and therefore may not be the treatment of choice for some patients with higher levels of physical dependence 55 55 Buprenorphine Maintenance/Withdrawal Comparison of buprenorphine maintenance vs. withdrawal: Shows both the efficacy of maintenance treatment, and the poor outcomes associated with withdrawal (even when provided within the context of a relatively rich set of psychosocial treatments including hospitalization and cognitive behavioral therapy) 56 56 Precipitated Withdrawal Buprenorphine-precipitated withdrawal seen in controlled studies has been mild in intensity and of short duration The likelihood for buprenorphineprecipitated withdrawal is low, and even when it does occur, it is mild in intensity and short in duration 57 57 Overdose with Buprenorphine Low risk of clinically significant problems No reports of respiratory depression in clinical trials comparing buprenorphine to methadone Buprenorphine’s ceiling effect means it is less likely to produce clinically significant respiratory depression. However, overdose in which buprenorphine is combined with other CNS depressants may be fatal (reviewed later in this section) 58 58 Drug Interactions with Buprenorphine 1. Benzodiazepines and other sedating drugs 2. Medications metabolized by cytochrome P450 3A4 3. Opioid antagonists 4. Opioid agonists 59 59 Diversion and Misuse Four possible groups that might attempt to divert and abuse buprenorphine/naloxone parenterally: 1. Persons physically dependent on illicit opioids 2. Persons on prescribed opioids (e.g., methadone) 3. Persons maintained on buprenorphine/naloxone 4. Persons abusing, but not physically dependent on opioids 60 60 Combination of Buprenorphine plus Naloxone Combination tablet containing buprenorphine with naloxone – if taken under tongue, predominant buprenorphine effect If opioid dependent person dissolves and injects buprenorphine/naloxone tablet – predominant naloxone effect (and precipitated withdrawal) 61 61 Maintenance Treatment Using Buprenorphine Following slides briefly review representative studies: Comparison of different doses of sublingual buprenorphine Buprenorphine-methadone flexible dose comparison Buprenorphine, methadone, LAAM comparison 62 62 Different Doses of Buprenorphine: Opiate Use % Ss With 13 Consecutive Opiate Free Urines 25 20 1 15 4 8 10 16 5 0 Buprenorphine dose (mg) (Ling et al., 1998) 63 Buprenorphine – methadone: treatment retention 100 90 80 Percent 70 60 50 40 Buprenorphine 30 Methadone 20 10 0 1 2 4 6 8 10 12 14 16 Week (Strain et al., 1994) 64 Buprenorphine, Methadone, LAAM:Treatment Retention Percent Retained 100 80 73% Hi Meth 60 58% Bup 40 53% LAAM 20 20% Lo Meth 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Study Week (Johnson et al., 2000) 65 Remaining in treatment (nr) Buprenorphine Maintenance/Withdrawal: Retention 20 15 10 Detox/placebo 5 Buprenorphine 0 0 50 100 150 200 250 Treatment duration (days) 300 350 (Kakko et al., 2003) 66 Buprenorphine Maintenance/Withdrawal: Mortality Detox/Placebo Buprenorphine Cox regression Dead 4/20 (20%) 0/20 (0%) c2=5.9; p=0.015 (Kakko et al., 2003) 67 Questions? Comments? 68