Why Would Anyone Treat Drug Addiction With Drugs? Methadone Maintenance Treatment: Fighting Fire With Fire? Mark Stanford, Ph.D. Sangeetha Raghuraman, M.D. SCVHHS Dept Alcohol & Drug Svcs Addiction Medicine Div. 2008
Case Presentation 50 yr old with poorly controlled diabetes. Despite patients best efforts to control his blood sugars, he continues to run high. Patient has voiced concerns to his physician that his dose of insulin is too low
Case Presentation (cont.) His physician s response was You re just substituting an addiction to sugar with an addiction to insulin. You just need to make a choice to eat the right foods and exercise more!
Case Presentation (cont.) When the patient objected, arguing that he needed his insulin to control his diabetes, the physician relented, but informed the patient that he was only going to prescribe insulin for a few weeks and then he would gradually reduce the dose until it was discontinued.
Methadone Maintenance: History 1950 s-1960 s: NYC epidemic heroin use By 1961 death related to heroin injection became #1 cause of death in 15-35 yr old age group Cost to health care system of 100 billion/yr Treatment options: incarceration, civil commitment, and therapeutic communities Methadone for detox in the 1950 s, but relapse rates >90%
Methadone Maintenance: History 1964: Dole and Nyswander (Rockefeller University) pilot study with 6 long term addicts. Morphine failed as a maintenance medication Methadone successfully treated drug craving Eventually all 6 patients stabilized and were able to plan for the future, secure jobs.
Methadone Maintenance: 1964 6 patients History 1971: Returning Vietnam veterans with heroin addiction led Nixon to establish Special Office for Drug Abuse Prevention 1998 179,000 MM patients nationwide 1995 IOM report estimated 500,000 to 1 million heroin users in U.S. = only 19-36% of heroin users are enrolled in methadone treatment.
30 years of independent research shows that.... The success of MMT in reducing crime, death, disease and drug use is well documented. -Death rates among persons on MM 30% less than for those not on treatment Institute of Medicine. 1995.
581 Male Heroin Addicts Followed for 33 Years Hser et al., 2001
Methadone Maintenance Since the mid-1960 s, methadone maintenance has been the gold standard for the treatment of opioid dependence. -JAMA. 2005. 294(8);961-3
DADS Addiction Medicine Division 3 clinics: Central Valley Clinic (on the VMC campus) East Valley Clinic (East San Jose at Alexian) South County Clinic (San Martin) 571 patients: 510 maintenance 50 medically managed withdrawal 7 Suboxone (buprenorphine) patients 4 Perinatal patients
Based on the science, how is addiction currently defined? A brain disease expressed as a compulsive behavior The continued abuse of drugs despite negative consequences A chronic, potentially relapsing disorder NIDA. 2004
ADDICTION AS A CHRONIC ILLNESS Chronic relapsing condition which untreated may lead to severe complications and death.
ADDICTION AS A CHRONIC ILLNESS It is treatable but not curable. Adjustment to diagnosis is part of patient s task. There is a wide spectrum of severity. Retention in treatment is key. Best treatment is integrated.
Addiction is a Chronic Illness Because: It has both a genetic and environmental basis influencing its development and manifestation Recovery from it is often a long-term process requiring repeated treatments Relapses can occur during or after successful treatment episodes Participation in self-help support programs during and following treatment can be helpful in sustaining long-term recovery
Addiction Diagnosed Any 1 of: DSM-IV Abuse recurrent use causing failure to fulfill major role obligations at work/home/school recurrent use when physically hazardous recurrent substance-related legal problems continued use despite persistent social/interpersonal problems due to substance use DSM-IV Dependence Any 3 of: tolerance withdrawal uses more or longer than intended unable to cut down use consumes a great deal of time important social/work activities given up continued use despite mental or health problems known to be caused by substance
Stabilization When a patient is on a stabilized dose of methadone, they no longer meet the DSM IV diagnostic criteria for opioid addiction.
Signs of Stabilization abstinence from opioids no switching to other depressants (benzos alcohol, etc) participation in counseling treatment disassociation from drug-using friends and family members involvement with healthy people and activities
What is Methadone? a long-acting opiate with a slow onset of action no rush not particularly addicting opiate addicts experience gradual relief from symptoms of withdrawal opiate naïve users experience slow onset of sedation produces/perpetuates physical dependence
Why use Methadone? The addicted patient benefits addicts are able to quit using heroin and remain abstinent a therapeutic dose enhances patients ability to pursue education or employment a therapeutic dose enhances patients ability to regain/maintain family relationships
Why Use Methadone? (cont) Society benefits decreased transmission of HIV and hepatitis C decreased criminal activity improved pregnancy outcome for opiate addicted patients financial savings
Characteristics of a Candidate for Methadone Maintenance moderate to severe addiction demonstrated inability to achieve/maintain abstinence with other treatment modalities physiological dependence on opiates for longer than one year OR any pregnant woman with evidence of physical dependence on opiates
Methadone maintenance: an evidence-based medical treatment Stigmatized in spite of saving many lives and lots of money Urban legends persist, including it s just another drug.
Four questions patients ask: Is methadone better than heroin? What is the right dose of methadone? How long should patients stay on methadone? What are the side effects of methadone?
First question: Is methadone better than heroin? Legal Avoids needles Known amount ingested (this is what patients already know, but there is more to it )
Methadone Simulated 24 Hr. Dose/Response At steady-state in tolerant patient Dose Response Loaded High Normal Range Comfort Zone Subjective w/d Sick Objective w/d 0 hrs. Time 24 hrs. Opioid Agonist Treatment of Addiction - Payte - 1998
Is methadone better than heroin? Legal Avoids needles Known amount ingested Slow onset: no rush Long acting: can maintain comfort or normal brain function Stabilized physiology, hormones, tolerance
Four questions patients ask: second question Is methadone better than heroin? What is the right dose of methadone? How long should patients stay on methadone? What are the side effects of methadone?
How Much???? Enough!!! Tom Payte, MD
What is the right dose? Eliminate physical withdrawal Eliminate craving Comfort/function: usually trough is 400-600 ng/ml, peak no more than twice the trough. (see stars on the next graph) Not over-sedated Blocking dose
Methadone Simulated 24 Hr. Dose/Response At steady-state in tolerant patient Dose Response Loaded High Normal Range Comfort Zone Subjective w/d Abnormal Normality trough Sick Objective w/d 0 hrs. Time 24 hrs. Opioid Agonist Treatment of Addiction - Payte - 1998
A Non-therapeutic Dose Jeopardizes the success of treatment. Sub-therapeutic dosing (under-dosing) results in physical discomfort and ongoing use. Over-dosing causes physical discomfort and over-sedation.
Effectiveness of Methadone Treatment: Dose Adequacy 90 80 Past month heroin use (%) 70 60 50 40 30 20 10 0 10 20 30 40 50 60 70 80 90 100 Daily Methadone Dose (in mgs.) Adapted from V. Dole (1989) JAMA, 282, p. 1881
Methadone Is NOT A Heroin Substitute
Methadone Pharmacology compared to heroin, the patient is stabilized high Day 1 Day 2 Day 3 Day 1 Day 2 Day 3 normal sick Heroin Methadone
Stabilization means patient experiences no withdrawal between doses cravings are minimized no drowsiness or sedation no euphoria if other opioids are used because the opioid receptors are blocked no medically significant or subjectively intolerable side effects no longer meets DSM IV diagnosis for opioid dependency
Four questions patients ask: third question Is methadone better than heroin? What is the right dose of methadone? How long should patients stay on methadone? What are the side effects of methadone?
How Long??? Long Enough!! Tom Payte, MD
Relapse to heroin use after MMT- 105 patients who left treatment 90% % 80% I V 70% 60% 50% 57.6% 72.7% 82.1% U S E R S 40% 45.5% 30% 20% 28.9% 10% 0% In Tx. 1 to 3 4 to 6 7 to 9 10 to 12 Months Since Stopping Treatment Adapted from: Ball & Ross, 1991.
How Long For Methadone Treatment? 120 P e r c e n t 100 80 60 40 20 97% 67% 23% 8% 0 Pretreatment Admission: < 6 months stay Average Stay: 6 to 54 months Long-term: > 54 months Adapted from: Ball & Ross, 1991.
Four questions patients ask: fourth question Is methadone better than heroin? What is the right dose of methadone? How long should patients stay on methadone? What are the side effects of methadone?
Opiate effects - physical Predictable physical effects of administering opiates: Tolerance: the body becomes efficient in processing the drug and requires ever higher doses to produce the desired effect. Dependence: when the drug is discontinued there are typical withdrawal signs and symptoms.
Side effects of methadone: General opiate effects: Sedation/stimulation Maintained phys. dependence (stable) Hypogonadism (not as severe as with heroin, may be dose dependent) Constipation Slight QTc prolongation on ECG (Martell etal) Sweating Methadone treatment tied to regulated clinic
What is the QT and Why Does It Matter? When the heart contracts it emits an electrical signal, which can be recorded on an electrocardiogram (ECG). On a paper readout strip, the ECG produces a characteristic waveform with the different parts designated by letters - such as Q, R, S, and T The QT interval represents the time for electrical activation and relaxation of the ventricles, which is measured in fractions of a second, or milliseconds (msec). It is an indicator of either healthy or abnormal heart rhythm.
What is the QT and Why Does It Matter? When the QTc becomes significantly prolonged, the person may be at risk of developing a particularly rapid, abnormal heart rhythm, called torsade de pointes, or TdP. This literally means 'twisting of the points' and is represented on the ECG by undulating peaks twisting about a central axis. This may signal convulsive twitching of heart muscle, or ventricular fibrillation, which can cause death if emergency care is not provided [Leavitt and Krantz 2003].
Case Reports Are Inadequate There have been various case reports of QTc interval prolongation and serious arrhythmia, TdP, in patients prescribed methadone. These cases often, but not always, appear to be more commonly associated with higher-dose treatment (> 200 mg/day) [Pearson and Woosley 2005]. In the majority of those involving typical MMT doses, additional medications, illicit drug use, and/or clinical conditions such as low potassium levels were noted as contributing factors.
Case Reports Are Inadequate An examination of all methadone adverse-event cases reported to the FDA spanning more than 3 decades found only a 0.29% incidence of QT prolongation and 0.79% incidence of TdP. [Pearson and Woosley 2005]. They conceded that it was impossible to be "absolutely certain if methadone caused or contributed to the prolonged QT and TdP." Therefore, while case reports can be of use in signaling a possible problem, in themselves they are weak evidence of methadone being a primary or even significant contributor to cardiac disturbances.
Treatment Outcome Data Treatment Outcome Data 4-5 fold reduction in death rate reduction of drug use reduction of criminal activity engagement in socially productive roles reduced spread of HIV excellent retention Joseph et al, 2000, Mt. Sinai J.Med., vol67, # 5, 6
Outcomes Methadone Reduces: overall and overdose deaths Illicit drug use criminal behavior spread of infectious diseases (HIV, HCV and TB) Is not a cure
HIV CONVERSION IN TREATMENT 25% 20% 15% 10% Tx Status 5% 0% In Tx (N=95) Partial Tx (N=45) No Tx (N=55) Source: Metzger, D. et. al 18 month HIV conversion by treatment retention. J of AIDS 6:1993. p.1053
Methadone Treatment Reduces Criminal Behavior Drug offense arrests decline because MMT patients reduce or stop buying and using illegal drugs. Arrests for predatory crimes decline because MMT patients no longer need to finance a costly heroin addiction, and because treatment allows many patients to stabilize their lives and return to legitimate employment. Hubbard, R.J. Treatment Outcomes Prospective Study, op. cit; J.C. Ball. The Criminal Justice System and Opiate Addiction. NUIDA Research Monograph 86.
Crime among 491 patients before and during MMT at 6 programs 300 Crime Days Per Year 250 200 150 100 50 Before TX During TX 0 A B C D E F Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991
Pregnancy MMT treatment of choice for pregnant, opioid-abusing women. Efforts to avoid intra-uterine fetal withdrawal, including split dose. Neonatal withdrawal occurs within 72 hours, at least 45% need treatment. Breastfeeding recommended if not HIV positive.
Pain in patients on MMT Methadone is prescribed for pain treatment in twice or three times daily doses. Up to 60% of MMT patients have chronic pain (Jamison 2000, Rosenblum 2003) Split doses may be indicated.
Methadone Treatment Is More Effective With... counseling (individual/group) urine testing involvement in community recovery groups lifestyle changes to support recovery mental health evaluation/treatment medical assessment/referral
Evidence for Counseling In Methadone Maintenance The dose of these services can determine treatment outcomes McLellan et al., 1993: 6-month randomized clinical trial three levels of psychological services methadone alone methadone plus standard counseling services methadone plus enhanced services (counseling, medical/psychiatric, employment, and family therapy)
Evidence for Counseling Services in Methadone Maintenance Outcome Methadone Methadone + Std. Counseling Methadone + Enhanced Counseling Retention 31% 59% 81% >16 consecutive weeks of (-) urines 0% 28% 55%
A FEW WORDS ABOUT BUPRENORPHINE Ceiling effect and safety Displaced other opiates: withdrawal on induction Sublingual tablet Schedule 3(methadone is 2) One form combined with naloxone Office based use available
Slide: courtesy Reckitt Benkiser
Buprenorphine is a Partial Agonist 100 90 80 Full Agonist (e.g. methadone) % Mu Receptor Intrinsic Activity 70 60 50 40 30 20 Partial Agonist (e.g. buprenorphine) 10 0 no drug low dose Antagonist (e.g. naloxone) high dose DRUG DOSE
Differences in Precipitated Syndromes Buprenorphine will precipitate withdrawal only when it displaces a full agonist off the mu receptors % Mu Receptor Intrinsic Activity 100 90 80 70 60 50 40 30 20 10 Full agonist (e.g. heroin) A Net Decrease in Receptor Activity if a Partial Agonist displaces the Full Agonist Partial agonist (e.g. buprenorphine) 0 no drug low dose high dose DRUG DOSE
Receptor Affinity Affinity is the strength with which a drug physically binds to a receptor Buprenorphine affinity is very strong and it will displace full agonists like heroin and methadone Note receptor binding strength (strong or weak) is NOT the same as receptor activation (agonist or antagonist) Mu Receptor Bup affinity is higher Bound to receptor Therefore, Full Agonist is displaced Judith Martin, MD. COMP 2004
Receptor Dissociation Dissociation is the speed (slow or fast) of disengagement or uncoupling of a drug from the receptor Buprenorphine s dissociation is slow Therefore Buprenorphine stays on the receptor a long time and blocks heroin or methadone from binding Mu Receptor Bup dissociation is slow Therefore, Full Agonists can t bind Judith Martin, MD. COMP 2004
100 Buprenorphine, Methadone, LAAM: Treatment Retention Percent Retained 80 60 40 20 0 73% Hi Meth 58% Bup 53% LAAM 20% Lo Meth 1 2 3 4 5 6 7 8 9 1011121314151617 Study Week Johnson et al, 2000
Methadone Maintenance Treatment Fighting Fire With Fire? Yes! In some cases, it s the best way to stop an otherwise out of control and devastating situation!
Websites for more info on Medication-Assisted Treatment www.aatod.org www.drugabuse.gov/nidahome.html www.comproviders.com