Motivating Clients for Treatment and Addressing Resistance

Motivating Clients for Treatment and Addressing Resistance

Volume C, Module 2 Opioids: Basics of Addiction; Treatment with Agonists, Partial Agonists, and Antagonists Treatnet Training Volume C: Module 2 Updated 18 October 2007 Module 2: Training goals To describe the: Key components of opiate addiction and its medical / psychiatric consequences Benefits and limitations of methadone as a pharmacotherapy for opiate dependence Benefits and limitations of buprenorphine as a pharmacotherapy for opiate dependence Benefits and limitations of narcotic antagonists for overdose (naloxone) and relapse prevention (naltrexone) for opiate dependence

Module 2: Workshops Workshop 1: Opiates: What they are, problems associated with their use, and medical treatment implications Workshop 2: Opiate addiction treatment with methadone Workshop 3: Opiate addiction treatment with buprenorphine Workshop 4: Opiate Antagonist Treatment: Naloxone for overdose, Naltrexone for relapse prevention Icebreaker: Opiate medication in my country Does your country use opiate medications, and if so, what type of medication? What are the main problems in your

country regarding the use of these medications? 15 Min. Workshop 1: Opiates What they are, problems associated with their use, and medical treatment implications Pre-assessment 10 Min. Please respond to the pre-assessment questions in your workbook. (Your responses are strictly confidential.)

Training objectives At the end of this training you will understand the: 1. 2. 3. 4. Epidemiology of opiate addiction worldwide and its relationship to infectious diseases Basic neurobiology of opiate addiction Medical / psychiatric co-morbidities and treatment strategies for these disorders used with opiate addicts Key issues in engaging opiate addicts into treatment with low threshold approaches Introduction

Global abuse of opiates Overview: Sixteen million (0.4%) of worlds population aged 15-64 abuse opiates Heroin abusers make up about 71% of opiate abusers Opiates account 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.

Annual Prevalence of Opiate Abuse, 2003 - 2005 Trends in Opiate Use Change in Abuse of Heroin and Other Opiates (2004, or latest year available) Opioids Opiate (n) An unlocked door in the prison of identity. It leads to the jail yard. Ambrose Bierce

The Devils Dictionary (1906) Opioid-related problems Most prominent problems are associated with heroin dependence Not all users of heroin develop dependence. Between 1 in 4 to1 in 3 regular users develop dependence Development of heroin dependence usually requires regular use over months (or longer, when use is more irregular) The revolving door Heroin dependence is a chronic, relapsing disorder. It is a dependency

that 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 principle health care objective is to get the patient into treatment, help keep them in treatment, and return them to treatment when relapse occurs. Polydrug use: Patterns and risks Polydrug use is the norm among drug users

Most people who use illicit drugs use a variety of different drugs Heroin users also are heavy users of alcohol and benzodiazepines As CNS depressants, these combinations are especially dangerous and known to be significant contributors to overdose Patients should be advised against the use of these combinations and told of the risks involved Detecting opioid dependence Look for a pattern (not an isolated event): In which a patient frequently runs out of scripts for a prescribed opioid In which a patient is on a high and increases the dose of prescribed opioids In which a patient injects oral medications Of observed intoxication or being in withdrawal

Which presents plausible conditions that warrant prescribed opioids, but with specific requests for medication type and amount In which the patient threatens or harasses staff for a fitin appointment In which a patient alters, steals, or sells scripts In which a patient is addicted to alcohol or other drugs Classification of Opioids Pure Opioid Agonists Semi-synthetic opium papaverine morphine codeine heroin hydromorphone oxycodone

Partial Agonists/Antagonists naltrexone buprenorphine LAAM Synthetic LAAM fentanyl meperidine hydrocodone methadone pentazocine pethidine Opioids: Pharmacology (1) PET scan of opioid receptors Opioids: Pharmacology (2)

3 main families of opioid receptors (, , and )) Agonists including morphine and methadone act on the system, while partial agonists, including buprenorphine, also act at that site but have less of a maximal effect as the dose is increased. Opioid receptors and peptides are located in the CNS, PNS, and GI tract Opioid receptors are inhibitory inhibit release of some neurotransmitters (e.g., 5-HT, GABA, glutamate, acetylcholine) enable the release of dopamine (considered to contribute to the dependence potential of opiates)

Opioids: Pharmacology (3) Heroin Morphine is produced through heroin hydrolysis heroin monoacetylmorphine (MAM) morphine Heroin and MAM are lipophilic, hence more rapid action Heroin excreted in urine as free and conjugated morphine Heroin metabolites are present in urine for approximately 48 hours following use

Morphine: Immediate effects (1) Perception altered, possible delirium Analgesia, to some degree Impaired cognition, though consciousness may be preserved Autonomic nervous system affected Suppression of cough reflex GI system affected Hypothermia Morphine: Immediate effects (2)

Miosis Urinary retention Reduced GI motility Endocrine Non-cardiogenic pulmonary oedema Coma or death (from respiratory depression) Other pruritis; flushed skin; dry mouth, skin, and eyes 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 poor general self-care imprisonment drug impurities or contaminants, BBV Opioids: Long-term effects (2) Possible: Constipation / narcotic bowel syndrome Cognitive impairment from hypoxia as a result of repeated non-fatal overdose

Reproduction and endocrine irregularity Medication-induced headaches Intense sadness (depression, dysthymia) Opioids: Drug Interactions Respiratory depression Toxicity/ Hypotension risk of death Coma CNS Depressants

MAOIs TCAs Betablockers BZDs

Opioids: Considerations for assessment Pregnancy Infectious Diseases 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) Physical exam Signs of opioid dependence: Needle marks on wrists, antecubital fossa, legs (inner thighs), feet, hands, neck Intoxication: pinpoint pupils, nodding off, drowsiness, sweating Withdrawal: restlessness, goosebumps, sweating, increased bowel sounds, lacrimation, sniffles, dilated pupils, muscle tenderness, tachycardia, hypertension Complications from use

The following slides depict complications from use, dependence, and overdose. Courtesy of Dr. John Sherman, St. Kilda Medical Centre Courtesy of Dr. John Sherman, St. Kilda Medical Centre Opioid withdrawal Signs

Yawning Lacrimation, mydriasis Diaphoresis Rhinorrhea, 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 Courtesy of Dr. John Sherman, St. Kilda Medical Centre Progress of the Acute Phase of Opioid Withdrawal Since Last Dose Withdrawal from methadone Onset: 2448 hrs, sometimes more Duration: 1020 days, sometimes more

Severity of signs and symptoms Withdrawal from heroin Onset: 624 hrs Duration: 410 days 0 10 20 Days deCrespigny & Cusack (2003) Adapted from NSW Health Detoxification Clinical Practice Guidelines (2000-2003) Predictors of withdrawal severity

Main predictors Greater Greater regular dose withdrawal Rapidity with which drug is withdrawn severity Also consider 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 (males) or menstrual irregularities (females) Opioid withdrawal scales Withdrawal scales: guide treatment monitor progress of withdrawal (subjective and objective signs) do not diagnose withdrawal but describe severity guide ongoing assessment If the withdrawal pattern is unusual, or the patient is not responding, suspect other conditions.

Opioid withdrawal management Withdrawal management aims to: reverse neuroadaptation by managing tolerance and withdrawal promote the uptake of post-withdrawal treatment options Withdrawal management may occur: as an outpatient

in a residential / treatment setting 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) 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 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 There is 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. Dependent Opioid Use and Treatment Pathways Abstinence Outpatient (drug-free) Psychological counselling Support group Antagonist (e.g., naltrexone) Relapse

Cessation Relapse Prevention Residential (drug-free) Substitution Treatment Withdrawal Management Setting Buprenorphine Methadone (LAAM) SR morphine Medication Speed

Harm Reduction Heroin use Dependence Education about overdose HIV/HCV risk reduction info DSM IV criteria for opioid dependence Tolerance

Withdrawal symptoms on cessation of drug use Increasing quantity or frequency of use Persistent desire for the drug or unsuccessful attempts to cut down Salience of drug use over other responsibilities (most of a patients time involves taking, recovering from, or obtaining drugs) Continued use despite evidence of psychological or social problems 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) Maintenance pharmacotherapies

Methadone Buprenorphine Buprenorphine + Naloxone combination product Naltrexone LAAM Slow-release oral morphine Depot naltrexone 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 Methadone: Clinical properties The Gold Standard Treatment

Synthetic opioid with a long half-life 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) Buprenorphine

Derived from the morphine alkaloid thebaine Partial opioid agonist at opioid receptors Antagonist at k opioid receptor Blocks opioid receptors, diminishes cravings, prevents opioid withdrawal Buprenorphine vs. Methadone

Buprenorphine Advantages Milder withdrawal Convenient (dose every 2/7) Better receptor blocker Relative ease of use, i.e., ready transmission from heroin withdrawal state or methadone Easier to taper than methadone

Wider safety margin Buprenorphine Disadvantages SL route results in reduced bio-availability compared with IV preparations Difficult to reverse respiratory depression if it does occur Increased time required for supervised

dosage (to get dissolution) Rationale for opioid agonist / partial agonist treatment Advantages of opioid agonist / partial agonist medication over heroin Non-parenteral administration Known composition Gradual onset and offset Long-acting Far less reinforcing than heroin

Medically supervised Rationale for opioid agonist treatment (1) 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 Continued Rationale for opioid agonist treatment (2) Opioid agonist treatment (continued) Decreases in criminal activity Decreases in needle sharing and blood-borne virus transmission (including HIV) Improvements in pro-social activities Improvements in mental health

Injecting Drug Use and HIV/AIDS Estimated number of deaths from AIDS up till now: 25 million Estimated number of people with HIV infection in 2002/2003: 42 million Estimated number of additional HIV infections till 2010: 45 million. The threat from HIV / AIDS By 2010, AIDS will have caused more deaths than any disease outbreak in history. Injecting drug use is an important contributor to the spread of HIV.

Estimated Size of IDU Population (1998/2003) N. America 1.43m Caribbean: 0.028m L. America: 0.97m W. Europe: 1.24m MENA:0.44m E. Europe & C. Asia: 3.2m E. Asia & Pacific

2.35m S. & S-E Asia: 3.33m S. SaharanAfrica 0.009m Australia & N. Zealand: 0.19m 10.3m (78%) in developing / transitional countries 91% of the world adult population (4 billion) is covered by the data. Information unavailable for 119 countries. UN Reference Group on HIV/AIDS prevention and care among IDU www.idurefgroup.org 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. Availability of Substitution Treatment 95% + methadone is consumed in developed countries (2002) Substitution treatment is available in few countries outside Europe, North America, and Australia, including: Argentina China

Croatia India Indonesia Iran Kyrgystan Malaysia Moldova Nepal Singapore Thailand Ukraine Thanks to Gerry Stimson US 53% 8.7

tons Spain 11% 1.8 tons Germany 6% 916kg Italy 5%

812kg UK, Canada, Australia, Switzerland, France, Denmark and Belgium, 18% Most of the rest consumed by 8 other countries, mostly in Europe, and Australia Estimated Opiate-Dependent Drug Users in Substitution Treatment per 100,000 Population 200 150 100 50 0 Australia

I taly France China Spain UK Canada I ndia United States Germany Sweden Nepal Netherlands Denmark Thailand Naltrexone

Morphine antagonist, true blockade No direct psychoactive effect No withdrawal experienced upon cessation Reported to reduce cravings in some people Naltrexone: Mechanism of action Fully blocks u receptors, preventing euphoria from opioid use; therefore drug money spent = money wasted Allows extinction of Pavlovian-conditioned response to opiate cues

Prevents reinstatement of opioid dependence, but does not reinforce compliance 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 1 week after cessation of heroin use Optimally effective with motivated individuals who

have higher levels of psychosocial functioning and family support ? ? ? Questions? Comments? Thank you for your time! End of Workshop 1 Volume C, Module 2, Workshop 2: Opiate Addiction Treatment with Methadone Training objectives At the end of this training, you will know: 1.

2. 3. 4. 5. 6. 7. The rationale for opiate agonist therapy Medical withdrawal protocols using methadone The basic purpose and background evidence to support the use of methadone for treating opiate dependence The basic principles of maintenance treatment with methadone Effective practices (evaluation, initial dose and management of dose; tapering procedures, etc.) in the implementation of methadone treatment How to address concurrent use of other drugs and alcohol during methadone treatment

The contraindications and medical interactions with methadone 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 There is 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. 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 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

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) Opioid withdrawal management Withdrawal management aims to:

reverse neuroadaptation by managing tolerance and withdrawal promote the uptake of post-withdrawal treatment options Opioid withdrawal treatment Involves: reassurance and supportive care information hydration and nutrition

opioid pharmacotherapies (e.g., methadone) medications to reduce severity of somatic complaints (analgesics, antiemetics, benzodiazepines, antispasmodics) Progress of the Acute Phase of Opioid Withdrawal Since Last Dose Withdrawal from methadone Onset: 2448 hrs, sometimes more Duration: 1020 days, sometimes more Severity of signs and symptoms Withdrawal from heroin Onset: 624 hrs Duration: 410 days 0

10 Days 20 Methadone: Clinical properties The Gold Standard Treatment Synthetic opioid with a long half-life 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) Intrinsic Activity: Full Agonist, Partial Agonist and Antagonist 100 90 Full Agonist (Methadone) 80 70 Intrinsic Activity 60

Partial Agonist (Buprenorphine) 50 40 30 20 10 Antagonist (Naloxone) 0 -10 -9 -8

-7 -6 Log Dose of Opioid -5 -4 Methadone pharmacokinetics Good oral bioavailability Peak plasma concentration after 2-4 hrs 96% plasma protein bound Mean half-life around 24 hrs Steady state after 3-10 days

Metabolism Cytochrome P450 mediated CYP3A4 main also CYP2D6, CYP1A2, CYP2C9 and CYP2C19 genetic variability risk of drug interactions

Pharmacodynamics Full opioid agonist Main action on mu receptors inhibit adenyl cyclase = cAMP potassium channel opening calcium channel opening also inhibit serotonin reuptake also non-competitive antagonist NMDA receptor 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 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 Minimal reinforcing properties, relative to heroin Counselling and support assists long-term lifestyle changes Legal and affordable reduced participation in crime

Few long-term side effects 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 Maximising 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 Assessment objectives Clarify nature and severity of problems Establish a therapeutic relationship Formulate problems into a treatment plan Core assessment issues

What does the patient want? Is the patient dependent? What is their level of tolerance? Is the patient using / dependent on other drugs? What is their motivation for change? What social supports exist? Are there other co-existing medical and psychiatric conditions? 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 Medical and psychiatric HIV/HCV Pregnancy Other major medical conditions Liver Cardiac Major psychiatric conditions Depression, suicide, psychosis Opioid-related overdose

Psychosocial Relationship with family Relationship with partner Education and employment Criminal justice Living circumstances Sources of income Examination Mental state

Mood Affect Cognition Injection sites Signs of intoxication / withdrawal Stigmata of liver disease Nutritional state Induction stabilisation phase (1) Dose adequacy and drug interactions

Signs of intoxication / withdrawal Frequency of drug use Frequency of sharing Case coordination and management Psychological Social Medical Health / welfare system interaction Induction stabilisation phase (2) Risk Assessment

Drug use practises polydrug OD sharing Sexual practises Safe initial dose

20 - 30mg methadone is generally safe Deaths have occurred with higher starting doses or polydrug use It may be safer to start opioid-dependent polydrug users as inpatients Methadone: Initial Effects and Side-Effects

Relief from physical pain Feeling of wellbeing Constricted pupils Vasodilation Lowered sex drive Nausea and vomiting Loss of appetite Sweating Fluid retention Endocrine changes (loss of libido, menstrual changes) Intense constipation Lowered temperature Bradycardia Hypotension Palpitations Shallow respirations

Poor circulation Itching and skin rashes Recurrent dental problems Polydrug use may cause overdose. Opioid withdrawal scales guide treatment monitor progress

(subjective and objective signs) do not diagnose withdrawal but describe severity guide ongoing assessment If the withdrawal pattern is unusual, or the patient is not responding, suspect other conditions. Opiate withdrawal scale 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 hour not accounted for by room temperature or patient activity 0 no report of chills or flushing

1 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 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 Continued Opiate withdrawal scale 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

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 Continued Opiate withdrawal scale GI Upset: over last hr 0 no GI symptoms 1 stomach cramps

2 nausea or loose stool 3 vomiting or diarrhoea 3 multiple episodes of diarrhoea or vomiting 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 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 Continued Opiate withdrawal scale 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 Gooseflesh skin 0 skin is smooth 3 piloerection of skin can be felt or hairs standing up on arms 5 prominent piloerection Total Score _______ The total score is the sum of all 11 items Initials of persons Completing assessment ___________________ Methadone: Inappropriate dosing Dose too low Withdrawal Flu-like symptoms Runny nose, sneezing

Abdominal cramps, diarrhoea Tremor, muscle spasm, aches, and cramping Yawning, teary eyes Hot and cold sweats Irritability, anxiety, aggression Aching bones Craving Dose too high Intoxicated Drowsy, nodding off Nausea, vomiting Shallow breathing Pinned (pinpoint) pupils Drop in body temperature Slow pulse, low BP, palpitations Dizziness

Stabilisation (1) Rate of Dose Increase Increase 0-10mg methadone per 1-3 days during the first week according to physical assessment and SOWS score Maximum increase of 20-25mg over 1st week Subsequent dose increases should not exceed 10mg per week Continued Stabilisation (2) Rate of Dose Increase gradual increase essential due to long half-life Best outcomes from maintenance doses > 60mg Lethal dose 20mg for children, as low as 50 mg for opioid-nave adults

% of clients using heroin (last 30 days) Relationship between Methadone Dose and Heroin Use Methadone Dose (MG) (Adapted from Ball and Ross, 1991) Stabilisation (3) 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

Other treatment issues Promote compassionate opioid analgesia Health care worker education especially at hospital Role of maintenance treatment in analgesia Encourage good vein care To maintain venous access Important later, if applicable, in the clinical course of HIV infection

Ongoing management issues (1) Monitoring HIV progression Co-infection Cognitive state Mental health Depression Suicide ideation ASPD PTSD Pain management Drug substitution

Ongoing management issues (2) Risk exposure dose compliance with program rules Cost of medication Staff attitudes Characteristics of effective programs Longer duration (2-4 years) Higher doses; > 60mg methadone Accessible prescriber and dispenser Integrated services Quality of therapeutic relationship

Drug interactions-metabolism Methadone Metabolism Cytochrome P450 mediated CYP3A4 main also CYP2D6, CYP1A2, CYP2C9 and CYP2C19, genetic variability CYP3A4 breaks down 50% of drugs Methadone mixed inhibitor may increase other drug levels, e.g., Nifidepine, etc. Opioids: Other Drug Interactions Respiratory depression Toxicity/ Hypotension Coma risk of death

CNS Depressants MAOIs TCAs

Betablockers BZDs Efficacy of methadone concurrent control studies (1) 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 Drug Free "Methadone Group" 71% Percent Drug Free No Methadone Group" 6% Imprisonment rate: Twice as great for placebo group. ( Newman and Whitehill, 1978) Efficacy of methadone concurrent control

studies (2) 34 patients assigned to methadone or no methadone at one clinic Outcomes: Percent drug free Follow-up Time 2 years Percent Drug Free "Methadone Group" 71% Percent Drug Free No Methadone Group" 6%

Five year follow-up: No methadone group offered methadone Those choosing methadone: 89% Those not choosing methadone: 13% 5 died of OD, 2 imprisoned 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) 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

(Schottenfeld R, et al., 1993) Results 65 20 mg % 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

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 3 Gearing MF, Neurotoxicology, 1977 4 Grondblah L, ACTA Psych Scand, 82, 1990 Death Rates in Treated and Untreated Heroin Addicts Annual Rate 8 6.91 7.20 6 4 1.65

2 0.15 0.85 0 Matched Cohort Methadone Voluntary Involuntary Untreated Discharge Discharge Compare the Costs 25,000 Costs are for a 6 month period, per person

No Treatment $21,500 $20,000 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 Relapse to IV Drug Use After Termination of Methadone Maintenance Treatment Percent IV Users 100 82.1% 80 72.7%

57.6% 60 40 20 0 45.5% 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 Cochrane Review OST and HIV Prevention Included studies 33 studies involving 10,400 participants Majority not controlled studies 32 studies used methadone

12 reported doses of 60mg/day or more 8 reported doses of 40-60mg/day 12 did not report doses 2 studies provided methadone in the context of detoxification 24 studies were in the context of a specialist drug & alcohol program Most studies at risk of confounding or bias Relative risk of injecting at follow-up compared to baseline Review: Comparison: Outcome: Substitution treatment of injecting opioid users for prevention of HIV infection 01 Drug use and risk outcomes (follow-up studies)

01 Proportion reporting injecting use Study or sub-category Follow-up n/N Baseline n/N RR (random) 95% CI Weig % 01 Controlled studies Dolan 2003

44/129 82/129 100. 02 Cohort studies Teesson 2006 16/227 177/227 100. 173/326 306/425 215/478

44/69 25/64 38/78 326/326 425/425 296/478 59/69 64/64 78/81 17. 17. 17. 16. 14. 15. 03 Descriptive studies

Camacho 1996 Chatham 1999 Gossop 2000 King 2000 Magura 1991 Schroeder 2006 0.1 0.2 0.5 Favours follow-up 1 2

5 Favours baseline Gowing L, Farrell M, Bornemann R, Sullivan L, Ali R. Substitution treatment of injecting opioid users for prevention of HIV infection. Cochrane Database of Systematic Reviews 2008, Issue 2. 10 Frequency of injecting substitution vs no substitution treatment Review: Substitution treatment of injecting opioid users for prevention of HIV infection Comparison:04 Drug use and risk outcomes - substitution treatment versus no substitution treatment Outcome: 02 Frequency of injecting use

Study Substitution or sub-category N Mean (SD) No substitution N SMD (random) Mean (SD) Weight

95% CI % SMD (random) 95% CI 01 Controlled studies 02 Cohort studies Kwiatkowski 2001 99 28.50(41.30) 216 44.20(49.30)

100.00 -0.33 [-0.57, -0.09] Baker 1995 95 1.20(0.90) 165 2.16(1.17) 50.49 -0.89 [-1.15, -0.62]

Meandzija 1994 63 43.03(95.03) 290 101.48(108.62) 49.51 -0.55 [-0.82, -0.27] 03 Descriptive studies -4 -2

0 2 4 Favours substitution Favours control Gowing L, Farrell M, Bornemann R, Sullivan L, Ali R. Substitution treatment of injecting opioid users for prevention of HIV infection. Cochrane Database of Systematic Reviews 2008, Issue 2. Summary of findings on injecting risk Reduction in injecting drug use associated

with substitution treatment a consistent finding True in terms of: proportion of participants reporting injecting drug use and frequency of injection Benefits may not be sustained after treatment, particularly if treatment cessation is involuntary Lower Rates of HIV Sero-conversion while in treatment

Metzger 1993 Williams 1992 seroconversion 3/100 person years in substitution treatment (10/100 person years not in treatment) 0.7/100 person years in substitution treatment (4.3/100 person years not in treatment) Moss 1992

1.4/100 person years in substitution treatment (3.1/100 person years not in treatment) ? ? ? Questions? Comments? Thank you for your time! End of Workshop 2 Volume C, Module 2, Workshop 3: Opiate Addiction Treatment with Buprenorphine Training objectives At the end of this training you will:

1. 2. 3. 4. 5. 6. Understand medical withdrawal protocols using buprenorphine Know the basic purpose and background evidence to support the use of buprenorphine for treating opiate dependence Know the basic principles of maintenance treatment with buprenorphine Know effective practises (evaluation, initial dose and management of dose; tapering procedures, etc.) in the implementation of buprenorphine treatment Understand how to address concurrent use of other drugs and alcohol during buprenorphine treatment Know contraindications and medication interactions with

buprenorphine 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

Affinity and dissociation Buprenorphine has: high affinity for mu opioid receptor o competes with other opioids and blocks their effects slow dissociation from mu opioid receptor o prolonged therapeutic effect for opioid dependence treatment (contrasts to its relatively short analgesic effects) Abuse potential Buprenorphine is abusable (epidemiological, human laboratory studies show) Diversion and illicit use of analgesic form (by injection) Relatively low abuse potential compared

to other opioids 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 Buprenorphine: Clinical pharmacology Partial agonist high safety profile / ceiling effect

low dependence Tight receptor binding at mu receptor long duration of action slow onset mild abstinence Antagonist at k receptor Subjects Rating of Drugs Good Effect 100 Peak Score 80 60 40

20 0 p 0.5 2 8 16 Buprenorphine (mg) 32 3.75 15

Methadone (mg) 60 Breaths/minute Buprenorphines Effect on Respiration 18 16 14 12 10 8 6 4 2 0 p

1 2 4 Buprenorphine (mg) 8 16 32 Intensity of Abstinence Symptoms Himmelsbach scores 60

Buprenorphine 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 Metabolism and excretion High percentage of buprenorphine bound to plasma protein Metabolised in liver by cytochrome P450

3A4 enzyme system into norbuprenorphine and other metabolites Patient selection: Assessment questions (1) Is the patient addicted to opioids? Is the patient aware of other available treatment options? Does the patient understand the risks, benefits, and limitations of buprenorphine treatment? Is the patient expected to be reasonably compliant? Is the patient expected to follow safety

procedures? Patient selection: Assessment questions (2) Is the patient psychiatrically stable? Is the patient taking other medications that may interact with buprenorphine? Are the psychosocial circumstances of the patient stable and supportive? Is the patient interested in office-based buprenorphine treatment? Are there resources available in the office to provide appropriate treatment?

Patient selection: Issues for consultation (1) Several factors may indicate a patient is less likely to be an appropriate candidate, including: Patients taking high doses of benzodiazepines, alcohol, or other central nervous system depressants Significant psychiatric co-morbidity Multiple previous opioid addiction treatment episodes with frequent relapse during those episodes (may also indicate a perfect candidate) Nonresponse or poor response to buprenorphine treatment in the past Patient selection: Issues for consideration (2)

Pregnancy Currently buprenorphine is a Category C medication. This means it is not approved for use during pregnancy. Studies conducted to date suggest that buprenorphine may be an excellent option for pregnant women. Randomized trials are underway to determine the safety and effectiveness of using buprenorphine during pregnancy. Patient selection: Issues for consideration (3)

Patients with these conditions must be evaluated by a physician for appropriateness prior to buprenorphine treatment: Seizures HIV and STDs Hepatitis and impaired hepatic function Use of alcohol, sedative-hypnotics, and stimulants Other drugs Buprenorphine induction Overview: Goal of induction To find the dose of buprenorphine at which the patient:

discontinues or markedly reduces use of other opioids experiences no cravings has no opioid withdrawal symptoms has minimal / no side effects Buprenorphine induction: For short-acting opioids (1) Patients dependent on short-acting opioids (e.g., heroin, oxycodone): Day 1 Instruct patients to abstain from any opioid use for 12-24 hours (so they are in mild withdrawal at time of first buprenorphine dose) may be easiest to schedule appointment early in day (decrease risk of opioid use prior to

office visit) Continued Buprenorphine induction: For short-acting opioids (2) Patients dependent on short-acting opioids (continued) If patient is not in opioid withdrawal at time of arrival in office, then assess time of last use and consider either having them return another day, waiting in the office until evidence of withdrawal is seen, or leaving office and returning later in the day (with strict instructions to not take opioids while away from the office) Continued Buprenorphine induction: For short-acting opioids (3)

Patients dependent on short-acting opioids (continued) First dose: 2-4 mg sublingual buprenorphine Monitor in office for up to 2 hours after first dose Relief of opioid withdrawal symptoms should begin within 30-45 minutes after the first dose Continued Buprenorphine induction: For short-acting opioids (4) Patients dependent on short-acting opioids (continued)

If opioid withdrawal appears shortly after the first dose, it suggests that the buprenorphine may have precipitated a withdrawal syndrome Clinical experience suggests the period of greatest severity of buprenorphine-related precipitated withdrawal occurs in the first few hours (1-4) after a dose, with a decreasing (but still present) set of withdrawal symptoms over subsequent hours Continued Buprenorphine induction: For short-acting opioids (5) Patients dependent on short-acting opioids (continued)

If a patient has precipitated withdrawal consider: giving another dose of buprenorphine, attempting to provide enough agonist effect from buprenorphine to suppress the withdrawal, or stopping the induction, provide symptomatic treatments for the withdrawal symptoms, and have patient return the next day Can re-dose if needed (every 2-4 hours, if opioid withdrawal subsides and then reappears) Maximum first-day dose of 8/2 mg buprenorphine / naloxone Induction: Patient Physically Dependent on Short-acting Opioids, Day 1 Patient dependent on short-acting opioids? Yes Withdrawal symptoms

present 12-24 hrs after last use of opioids? No Yes Stop; Reevaluate suitability for induction Give buprenorphine/naloxone 4/1 mg, observe Withdrawal symptoms continue or return? No

Yes Yes Repeat dose up to maximum 8/2 mg for first day Withdrawal symptoms relieved? Yes Daily dose established. Withdrawal symptoms No return? No Manage withdrawal symptomatically

Return next day for continued induction. Daily dose established. Buprenorphine induction: For long-acting opioids (1) Patients dependent on long-acting opioids Experience suggests patients should have dose decreases until they are down to 40 mg/d of methadone Begin induction at least 24-36 hours after last dose of methadone Patient should be in mild withdrawal from methadone Give no further methadone once buprenorphine induction is started

Continued Buprenorphine induction: For long-acting opioids (2) Use similar procedure as that described for short-acting opioids (i.e., first dose of 4/1 mg of buprenorphine/naloxone) Expect total first day dose of 8/2 mg sublingual buprenorphine / naloxone Continue adjusting dose by 2-4 mg increments until an initial target dose of 1224 mg is achieved for the second day

Continued dose increases are indicated after the second day to a maximum daily dose of 32/8 mg Induction: Patient Physically Dependent on Long-acting Opioids, Day 1 Patient dependent on long-acting opioids? If LAAM, taper to 50-55 mg for Monday/Wednesday dose Yes 48 hrs after last dose, give buprenorphine 4/1 mg If methadone, taper to 40 mg per day 24 hrs after last dose, give buprenorphine 4/1 mg

Withdrawal symptoms present? No Yes Daily dose established Give buprenorphine 4/1 mg Withdrawal symptoms continue? No Yes Repeat dose up to maximum 12/3 mg/24 hrs

Withdrawal symptoms relieved? No Manage withdrawal symptomatically Yes Daily dose established GO TO INDUCTION FOR PATIENT PHYSICALLY DEPENDENT Buprenorphine induction: For short- or long-acting opioids Patients dependent on short- or long-acting opioids

After the first day of buprenorphine induction for patients who are dependent on either shortacting or long-acting opioids, the procedures are essentially the same On Day 2, have the patient return to the office if possible for assessment and Day 2 dosing Assess if patient has used opioids since they left the office, and adjust dose according to the patients experiences after first-day dosing Induction: Patient Physically Dependent on Short- or Long-acting Opioids, Days 2+ Patient returns to office on 8/2-12/3 mg Yes No

Withdrawal symptoms present since last dose? Maintain patient on 8/2-12/3 mg per day. Yes Increase buprenorphine/naloxone dose to 12/3-16/4 mg Withdrawal symptoms continue? No Withdrawal symptoms return? No

Daily dose established. Yes Administer 4/1 mg doses up to maximum 24/6 mg (total) for second day Withdrawal symptoms relieved? Yes Daily dose established. No Manage withdrawal symptomatically Return next day for continued

induction; start with day 2 total dose and increase by 2/0.5-4/1 mg increments. Maximum daily dose: 32/8 mg Buprenorphine stabilisation / maintenance (1) The patient should receive a daily dose until stabilised Once stabilised, the patient can be shifted to alternate day dosing (e.g., every other day, MWF, or every third day, MTh) Increase dose on dosing day by amount not received on other days (e.g., if on 8 mg/

d, switch to 16/16/24 mg MWF) Buprenorphine stabilisation / maintenance (2) Stabilise on daily sublingual dose Expect average daily dose to be somewhere between 8/2 and 32/8 mg of buprenorphine / naloxone Dose may need to be increased if patient continuing to use heroin or other illicit opioids Higher daily doses more tolerable if tablets are taken sequentially rather than all at once

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 Individuals with better levels of psychosocial functioning and support are optimal candidates for

buprenorphine 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 hospitalisation and cognitive behavioral therapy) Stabilisation / Maintenance No Induction phase completed?

Yes Continued No illicit opioid use? Yes Withdrawal No symptoms present? Yes Compulsion No to use, cravings present? Daily dose established

Yes Continue adjusting dose up to 32/8 mg per day Continued illicit opioid use despite maximum dose? Yes Maintain on buprenorphine/naloxone dose, increase intensity of non-pharmacological treatments, consider if methadone transfer indicated No Daily dose established Withdrawal using buprenorphine (1) Withdrawal in

withdrawal symptoms Long-term efficacy is not known, and is likely limited Studies of other withdrawal modalities have shown that such brief withdrawal periods are unlikely to result in long-term abstinence Withdrawal in 30 day (long-term) Not a well-studied topic Literature on opioid withdrawal can provide guidance; suggests longer, gradual withdrawals more effective

than shorter withdrawals Although there are few studies of buprenorphine for such time periods, buprenorphine has been shown more effective than clonidine over this time period. Withdrawal using buprenorphine (3) Regardless of the buprenorphine withdrawal duration: Consider use of ancillary medications to assist with symptoms of opioid withdrawal (e.g., medications for arthralgias, nausea, insomnia) Overview of safety and side effects

Highly safe medication (under both acute and chronic dosing circumstances) Also safe if inadvertently swallowed by someone not dependent on opioids (because of poor oral bioavailability and the ceiling on maximal effects) Primary side effects: like other mu agonist opioids such as methadone (e.g., nausea, constipation) Anecdotal reports indicate that symptoms may be less severe Precipitated withdrawal (1) The likelihood for buprenorphine- precipitated withdrawal is low Buprenorphine-precipitated withdrawal seen in controlled studies has been mild in intensity and of short duration

Precipitated withdrawal (2) Risk factors that increase the possibility of buprenorphine-related precipitated withdrawal are: higher levels of physical dependence a short time interval between last use of an opioid and first dose of buprenorphine higher first doses of buprenorphine Overdose with buprenorphine

Low risk of clinically significant problems. No reports of respiratory depression in clinical trials comparing buprenorphine to methadone. Buprenorphines 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). Drug interactions with buprenorphine 1. 2. 3. 4. Benzodiazepines and other sedating

drugs Medications metabolised by cytochrome P450 3A4 Opioid antagonists Opioid agonists Benzodiazepines and other sedating drugs (1) Reports of deaths when buprenorphine injected along with injected benzodiazepines Reported from France, where buprenorphine without naloxone tablets are available (appears patients dissolve and inject tablets) Probably possible for this to occur with other sedatives Mechanism leading to death in these cases is not known Not clear if any patients have died from use of sublingual buprenorphine combined with oral benzodiazepine. Most

deaths appear to have been related to injection of the combination of dissolved buprenorphine tablets with benzodiazepine Benzodiazepines and other sedating drugs (2) Note that the combination product (buprenorphine with naloxone, Suboxone) is designed to decrease the likelihood that people will dissolve and inject buprenorphine, so the risk of misuse of buprenorphine with benzodiazepines should be decreased with the availability of buprenorphine / naloxone.

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 Buprenorphines Abuse Potential 100 Placebo Opiate Percent 75

Other 50 25 0 Placebo 1mg 2mg Sublingual Buprenorphine 4mg (From Jasinski et al., 1989) 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) 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 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) Buprenorphine Methadone: Treatment Retention 100 90 80

Percent 70 60 50 40 30 Buprenorphine 20 Methadone 10 0 1

2 4 6 8 10 12 14 16 Week (Strain et al., 1994)

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) 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) Buprenorphine Maintenance / Withdrawal: Mortality Detox/Placebo Buprenorphine Cox regression Dead 4/20 (20%) 0/20 (0%)

2=5.9; p=0.015 (Kakko et al., 2003) Questions? Comments? Thank you for your time! End of Workshop 3 Workshop 4: Opiate Antagonist Treatment: Naloxone for Overdose, Naltrexone for Relapse Prevention Training objectives At the end of this training you will: 1. Understand the neurobiology-conditioning underpinning opiate relapse

2. Understand the rationale for the use of naloxone for opiate overdose 3. Know the protocol for the use of naltrexone for relapse prevention 4. Understand the challenges and limitations of naltrexone treatment Naloxone for Opiate Overdose Naloxone for opiate overdose Naloxone is a medication used to counter the effects of opioid overdose, for example heroin and morphine overdose. Specifically, naloxone is used in opioid overdoses for countering life-threatening depression of the central nervous system and respiratory system. It is marketed under trade names including Narcan, Nalone, and Narcanti.

Continued Naloxone for opiate overdose The drug is derived from thebaine and has an extremely high affinity for -opioid receptors in the central nervous system. Naloxone is a -opioid receptor competitive antagonist, and its rapid blockade of those receptors often produces rapid onset of withdrawal symptoms Continued

Naloxone for opiate overdose Naloxone is injected, usually initially intravenously for fastest action The drug acts after about two minutes, and its effects may last about 45 minutes. Continued Signs of opioid overdose Unconscious (does not respond verbally or by opening eyes when spoken to loudly and shaken gently) Constricted pupils Hypoventilation (respiration rate too slow or tidal volume too low) Cool moist skin

Opioid overdose: Steps to take (1) If an opioid overdose is suspected: Oxygen, if available Naloxone 0.4-0.8mg IV/IMI, (aliquots of 50mcg every 12 minutes may be used IV until arousal sufficient for airway maintenance and adequate ventilation). Dose may be repeated after 2 minutes if no response, to a maximum of 10mg Call ambulance Advise reception of emergency and location If client unwilling to attend hospital, you may need to consider need for detention order if concerns for safety of client Opioid overdose: Steps to take (2) Assess the client Responsiveness Airway open and clear Breathing respiratory rate and volume Circulation carotid pulse

Opioid overdose: Steps to take (3) If unresponsive, respiratory arrest, or hypoventilating Call ambulance Place in lateral coma position if breathing spontaneously Bag and mask, ventilate with oxygen for hypoventilation Naloxone 0.4-0.8mg IV (50mcg aliquots every 12 minutes) or IM if suspect opioid OD Opioid overdose: Steps to take (4) If response is adequate The patient will be fully conscious, oriented, alert, and responsive If response is inadequate or there is no

response to naloxone Continue oxygenation Keep lateral Monitor observations Administer further naloxone Opioid overdose: Steps to take (5) Advise client to go to the hospital for observation +

naloxone infusion If refuses, advise no further drugs or alcohol that day Stay with a responsible person for > 2 hours Provide written information regarding above If client at risk (suicide / effects of drugs) consider detention order Naloxone for opiate overdose Naloxone has been distributed as part of emergency kits to heroin users, and this has been shown to reduce rates of fatal overdose. Projects of this type are underway in San Francisco and Chicago, and pilot projects started in Scotland in 2006. Naltrexone for Relapse Prevention Naltrexone for opiate relapse prevention (1)

Naltrexone is an opioid antagonist treatment medication: It is a pure, potent mu antagonist that can be taken by mouth once daily or every other day, and has minimal side effects. It is neither reinforcing nor addicting and has no potential for abuse or diversion for unprescribed use. Naltrexone for opiate relapse prevention (2) Naltrexone, and its active metabolite 6-- naltrexol, are competitive antagonists at - and -opioid receptors, and to a lesser extent at -opioid receptors. This blockade of opioid receptors is the

basis behind its action in the management of opioid dependence it reversibly blocks or attenuates the effects of opioids. Naltrexone for opiate relapse prevention (3) Naltrexone is not a narcotic It works by blocking the effects of narcotics, especially the high feeling that is produced by opiates It also may block the high feeling that is produced by alcohol It will not produce any narcotic-like effects or cause mental or physical dependence Naltrexone for opiate relapse prevention (4)

Naltrexone will cause withdrawal symptoms in people who are physically dependent on narcotics Naltrexone treatment is started after an individual is no longer dependent on narcotics It is important for an individual to be fully withdrawn from opiates If naltrexone is taken by individuals who are incompletely detoxified from opiates, it can precipitate a rapid and unpleasant withdrawal syndrome Naltrexone for opiate relapse prevention (5)

The length of time between the last dose of opiate and the first dose of naltrexone is important The specific timetable depends on whether the opiate being used was a short-acting opiate (e.g., morphine or heroin) or a long-acting opiate (e.g., methadone) and how long the opiate was used (i.e., days, weeks months) Before starting naltrexone it is important for the treating physician to have this information Naltrexone for opiate relapse prevention (6)

When opiate-dependent individuals desire to be inducted onto naltrexone, it is necessary to first detoxify them from opiates to avoid precipitated withdrawal It is not possible to use the two most effective withdrawal agents, methadone and buprenorphine, because of their agonist properties Therefore, detoxification methods that do not employ methadone and / or buprenorphine must be used Naltrexone for opiate relapse prevention (7) Two commonly used agents are lofexidine and clonidine, both a-adrenergic agonists that

relieve most opioid withdrawal symptoms without producing opioid intoxication or drug reward. Opiate detoxification with these agents is less effective, since they do not relieve many opioid withdrawal symptoms. Therefore, adjunctive medicines often are necessary to treat insomnia, muscle pain, bone pain, and headache. Pre-naltrexone detoxification procedures (1) An appropriate protocol for clonidine is 0.1mg administered orally as a test dose

A dose of 0.2mg might be used initially for patients with severe signs of opioid withdrawal or for those patients weighing more than 200 pounds The sublingual (under the tongue) route of administration also may be used A similar procedure using lofexidine is appropriate; lofexidine produces significantly less hypotension than clonidine Pre-naltrexone detoxification procedures (2) Clinicians should check the patient's blood pressure prior to clonidine administration, and clonidine should be withheld if systolic blood pressure is lower than 90 or diastolic blood pressure is below 60

These parameters can be relaxed to 80/50 in some cases if the patient continues to complain of withdrawal and is not experiencing symptoms of orthostatic hypotension (a sudden drop in blood pressure caused by standing) Pre-naltrexone detoxification procedures (3) Clonidine (0.1 to 0.2mg orally) can then be given every 4 to 6 hours on an as-needed basis Clonidine detoxification is best conducted in an inpatient setting, as vital signs and side effects can be monitored more closely in this environment In cases of severe withdrawal, a standing dose

(given at regular intervals rather than purely "as needed") of clonidine might be advantageous Pre-naltrexone detoxification procedures (4) The daily clonidine requirement is established by tabulating the total amount administered in the first 24 hours, and dividing this into a three or four times per day dosing schedule. Total clonidine should not exceed 1.2mg the first 24 hours and 2.0mg after that, with doses being held in accordance with parameters noted above. The standing dose is then weaned over several days.

Clonidine must be tapered to avoid rebound hypertension. Naltrexone for opiate relapse prevention For oral dosage form (tablets): For treating narcotic addiction: Adults25 milligrams (mg) (one-half tablet) for the first dose, then another 25 mg one hour later. After that, the dose is 350 mg a week. This weekly dose should be divided up according to one of the following schedules:

50 mg (one tablet) every day; or 50 mg a day during the week and 100 mg (two tablets) on Saturday; or 100 mg every other day; or 100 mg on Mondays and Wednesdays, and 150 mg (three tablets) on Fridays; or 150 mg every three days Naltrexone for opiate relapse prevention (1) Side effects Acute opioid withdrawal precipitated (e.g., lethargy, aches, cramps, low energy)

Depression, irritability Anxiety, nervousness Sleeping difficulties Skin rash

Poor appetite Dizziness Precautions If naltrexone ceased and opioid use reinstated, reduced tolerance to opioids increases risk of overdose and death Precipitates withdrawals in opioid-dependent

patients Naltrexone for opiate relapse prevention (2) Patient non-compliance in part due to the absence of any agonist effects is a common problem. Therefore, a favourable treatment outcome requires a positive therapeutic relationship, careful monitoring of medication compliance, and effective behavioural interventions. Effectiveness tends to be dependent on: situation, circumstances, support, commitment of patient

inclusion as part of comprehensive treatment program (including counselling) Long-term treatment efficacy still under investigation While effective for some, inappropriate for others Naltrexone - psychotherapy research Positive results when naltrexone is combined with cognitive behavioural therapy and treatment with the Matrix Model Contingency management also produces large increases in retention on naltrexone Family therapy also promotes successful treatment with naltrexone

Using legal pressure (individuals sentenced to treatment by courts) to mandate people to take naltrexone can greatly increase retention on naltrexone and outcome success Naltrexone for opiate relapse prevention Naltrexone can also be administered as a lowdose implant. These implants can remain effective for 30-60 days. They dissolve slowly and are usually put in under a local anaesthetic in the left iliac fossa. This implant procedure has not been shown scientifically to be successful in "curing" the patient of their addiction, although it does provide a better solution than oral naltrexone for medication compliance reasons.

Conclusion: Naltrexone for opiate addiction (1) Naltrexone, nonselective opioid antagonist Induction issues Retention Depot preparation Better outcomes with specific therapies or legal interventions Conclusion: Naltrexone for opiate addiction (2)

Treatment with opiate agonists (methadone) or partial agonists (buprenorphine) produces far better retention than does naltrexone several studies report by end second week between 39% and 74% left treatment Use of these medications has gained far more acceptance by practitioners than has naltrexone treatment Psychotherapy can substantially improve outcome with these medications as well Naltrexone for alcoholism (2)

Alcohol produces some of its reinforcing properties by releasing the bodys own opiate-like substance (endorphin) Naltrexone can block endorphin An alcoholic who is maintained on naltrexone will not experience endorphin-mediated alcohol-induced euphoria Maintenance on naltrexone will reduce alcohol use Naltrexone for alcoholism (2) Two landmark studies documented that naltrexone can be an effective treatment for treating alcoholics: Volpicelli, W., Alterman, A., Hayashida, M., OBrien, C. Naltrexone in the Treatment of Alcohol Dependence. Archives of General Psychiatry 49:

876-880 (1990) OMalley, S., Jaffe, A., Chang, G., Schottenfeld, R., Meyer, R., Rounsaville, B. Naltrexone and Coping Skills Therapy for Alcohol Dependence. Archives of General Psychiatry 49: 881-887 (1992). OMalley et al. demonstrated that if naltrexone is used with coping skills therapy, relapses are reduced and the severity of the relapse is reduced. Naltrexone for alcoholism (3) For treating alcoholism:

AdultsThe first dose may be 25mg (one-half tablet). After that, the dose is 50 mg (one tablet) every day. Children and teenagers up to 18 years of age Use and dose must be determined by the doctor. For injectable dosage form For treating alcoholism: Adults380 mg once a month injected into the muscle by a doctor. Questions? Comments?

Post-assessment Please respond to the post-assessment questions in your workbook. (Your responses are strictly confidential.) 10 minutes Thank you for your time! End of Workshop 4

Recently Viewed Presentations

  • CS 335 - Computer Networks - University of Lynchburg

    CS 335 - Computer Networks - University of Lynchburg

    Tahoma Arial Century Gothic Wingdings 3 Times New Roman Arial Rounded MT Bold Arial Black Ion 1_Ion 2_Ion 3_Ion Microsoft Clip Gallery CS 335 - Computer Networks Introduction How do we design networks?
  • Chapter 6: Graphs 6.2 The Euler Characteristic

    Chapter 6: Graphs 6.2 The Euler Characteristic

    V-E+R: The Euler Characteristic ANY connected graph drawn on a flat plane with no edge crossings will have the same value for V-E+R: it will always be 2. (We'll talk about why in a minute.) V-E+R: The Euler Characteristic ANY...
  • Life of the Past

    Life of the Past

    DISCOVERY OF THE CELL Robert Hooke- 1st to see cells in a cork. Matthias Schleiden- Saw living cells in plants. Theodor Schwann- Saw living cells in tissues of animals. Rudolf Virchow- Concluded that new cells come from other cells. Cell...
  • Welcome to... ARTful Hour, Gr. K-2 January 2011

    Welcome to... ARTful Hour, Gr. K-2 January 2011

    Kinds of Lines Straight Line (& directionality) Zigzag Line Wavy or Curvy Line Loopy Line Thin Line Thick Line Broken Line Intro to Zentangles The term "Zentangle" was first coined by Rick Roberts and Maria Thomas Maria noticed feelings of...
  • Modules, Credits and Other Animals Modules & Credits

    Modules, Credits and Other Animals Modules & Credits

    Penalties for plagiarism: Academic Misconduct Panel Plagiarised work = 0 marks (also for allowing work to be plagiarised) Repeated plagiarism can lead to termination Passing Modules Need 40% overall for assessment in order to pass a module (60% for music...
  • A Level Physics: Kinematics- Projectiles Objectives:  Spec point

    A Level Physics: Kinematics- Projectiles Objectives: Spec point

    Steps for projectiles: Work on the vertical component first. Identify known values. Identify equation that can be used . Must have the mystery value. Has no other unknown values. Rearrange the equation. Solve for vertical component value. Use the value...
  • John Milton - Cornell College

    John Milton - Cornell College

    The passage from The Odyssey was included to display how Paradise Lost compared to Homer's poem as an epic. Placing them side-by-side shows both how Milton's poem in an epic because he invokes the Muse, but also attempts to surpass...
  • Enzyme Inhibition and Drug Action Malfunction of enzyme

    Enzyme Inhibition and Drug Action Malfunction of enzyme

    Reversible inhibition Competitive Non-competitive Binding to different sites Inhib. can be reversed by increasing [S] Vmax decrease KM unchanged Inhib. and substrate very different structures Difficult to design inhib. Irreversible enzyme inhibitors Often covalent bonds between E and I Enzyme...