Understanding Medication-Assisted Treatment for Opioid Use Disorders
Mark Stanford, PhD Santa Clara Valley Medical Center - Addiction Medicine & Therapy Services
Clinical Associate Professor - Stanford University School of Medicine Psychiatry and Behavioral Science
Case Alex is a 44 year old man having difficulty with pain medications Avascular necrosis of left hip for several years, requiring opioid analgesics Also has hepatitis C infection with documented viremia (type 1A) and mild elevation in AST and ALT
Initially treated with percocet, up to 8 tablets q day
Switched to MS Contin due to concern over tylenol exposure
Eventually stabilized on MS Contin 30 mg 2x q daily and
hydrocodone 2 mg to 4 mg q 4 hrs for break-though pain
S/P total hip replacement 6 months ago
After hospital discharge, he was given Rx for percocet by orthopedist
He is currently taking 8 percocets daily
His primary provider has tried unsuccessfully to discontinue the percocets
He no longer has hip pain, but he complains of irritability, malaise, insomnia, generalized body pain, abdominal cramping, diarrhea, sweats and chills when he doesn’t take them
Both the patient and his primary provider are concerned that he has developed an addiction to pain medications
What is your assessment?
Opiates
• Naturally derived from the poppy plant
(opium)
• Broad range of synthetic drugs that bind at
the mu-opioid receptor
• Used therapeutically for:
– Pain relief (analgesia)
– Cough suppression (anti-tussive)
– Anti-diarrheal
Analgesics
• Decrease in sensation of pain.
• Classes:
– Opioid.
• Agonist.
• Antagonist.
• Agonist-antagonist.
– Non-opioids.
• Salicylates.
• NSAIDs.
• Adjuncts.
Opioid Agonists and Antagonists
Agonists Semi-Synthetic Synthetic Partial Antagonists
(naturally Agonists Agonists Agonist
occurring)
Opium diacetylmorphine Methadone Buprenorphine Naloxone
(Heroin)
Paregoric hyrdromorphone Fentany Talwin Naltrexone
(Dilaudid) (Vivitrol,
Nubain Revia)
Morphine hydrocodone Nalline
(Vicodin) Stadol Nalmafene
(Revex)
Codeine oxymorphone Lomotil
(Numorphan, Opana)
oxycodone Demerol
(Percocet, Oxycontin)
Norco tramadol
(acetominephen and (Ultram)
hydrocodone)
What do opioids do?
• Bind to opiate receptors in the brain, spinal cord, and gut
• Block transmission of pain signals
• Produce drowsiness
• Depress respiration
• Cause constipation
• Produce euphoria by stimulating brain regions that mediate pleasure
General Actions of Opioids
• Analgesia
• Respiratory
depression
• Constipation
• Urinary retention
• Cough suppression
• Emesis
• Euphoria/Dysphoria
• Sedation
• Miosis
– Pupil constriction
• Preload & afterload
– Watch for hypotension!
Opioid Medications
Mechanism of Action
The neural basis for craving may involve changes in post synaptic receptor sites as an adaptive response to drug-induced neurotransmitter levels.
normal down regulated up regulated
Craving
Diagnosing Addiction
• Diagnosing Addiction: The 4 “C’s”
– C = Control
– C = Compulsion
– C = Continued use despite consequences
– C = Craving
Koob, G. Scripps. 2014
13
Reminder to Clinicians!
A classic diagnostic feature for chronic relapsing substance use disorders is:
Continued compulsive illicit use despite adverse medical consequences
Biobehavioral precursors to continued compulsive use include severity of opioid withdrawal and persistent craving behaviors including cued reactivity.
14
OPIATE COMPLICATIONS OF USE MANY OF THE COMPLICATIONS OF OPIATE USE ARE DUE TO THE ROUTE OF USE AND THE LIFESTYLE OF THE USER, NOT THE DRUG
• NEUROLOGIC • Toxic amblyopia (optic nerve pathology) • Mononeuropathy (dysfunction of a single nerve) • Polyneuropathy (dysfunction of several nerves) • Meningitis
• PULMONARY • Aspiration • Pneumonia • Lung abscess • Pulmonary emboli (clots going to the lung) • Pulmonary fibrosis (scarring of the lung) • Noncardiogenic pulmonary edema (lung fills with fluid
not as a result of heart dysfunction)
15
OPIATE COMPLICATIONS OF USE • DERMATOLOGIC
• Abscess • Lymphangitis (swelling and dysfunction of the lymph
system)
• HEPATIC • Hepatitis B,C,D,G
• INFECTIONS • Endocarditis • Tetanus in immigrants in California
Opioid Withdrawal
• Severe flu-like symptoms
• Anxiety
• Hyperactivity
• Lacrimation/Tearing
• Rhinorrhea
• Anorexia
• Nausea
• Vomiting
• Diarrhea
• Myalgias
• Muscle spasms
“The greatest problem with pharmacotherapy is the continued myth and misunderstanding about its effectiveness in recovery.”
David Mee-Lee, MD ASAM, 2014.
Pharmacotherapy (aka, Medication-Assisted Treatment)
should be considered an evidence-based practice in the treatment of SUD
like group therapy, CBT, contingency management, or 12-Step facilitation
therapy.
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.
30 years of independent research
shows that . . . .
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
Opioid Addiction: Methadone
What is Methadone? • a long-acting opiate with a slow
onset of action…no rush…
• opiate addicts experience gradual
relief from symptoms of
withdrawal
• opiate naïve users experience
slow onset of sedation
• produces physical dependence
The gold standard for the treatment of opioid addiction: best
abstinence rates: 70-80% blocks craving, blocks euphoria,
normalization of limbic function, sustained functionality
Why Methadone?
• The patient benefits
– addicts are able to quit using heroin and
remain abstinent from compulsive illicit use
– a therapeutic dose enhances patients’
ability to pursue education or employment
– a therapeutic dose enhances patients’
ability to regain/maintain family
relationships
Why Methadone?
• The community benefits
– decreased transmission of HIV and hepatitis C
– decreased criminal activity
– improved pregnancy outcome for opiate
addicted patients
– financial savings
Stabilization
When a patient is on a stabilized dose of methadone, they no longer meet the DSM - 5 diagnostic criteria for opioid addiction.
Stabilization means…
• patient experiences no withdrawal between doses • cravings are minimized • no drowsiness or sedation • no switching to other depressants (benzos alcohol, etc) • 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-5 diagnosis for opioid use disorder
DSM 5 – Opioid Use Disorder
• Taking more opioid drugs than intended. • Wanting or trying to control opioid drug use without success. • Spending a lot of time obtaining, taking, or recovering from the effects of opioid drugs. •Failing to carry out important roles at home, work or school because of opioid use. • Continuing to use opioids, despite use of the drug causing relationship or social problems. • Giving up or reducing other activities because of opioid use. • Using opioids even when it is physically unsafe. • Knowing that opioid use is causing a physical or psychological problem, but continuing to take the drug anyway. • Tolerance for opioids. • Withdrawal symptoms when opioids are not taken • Cravings for opioids.
Characteristics of a Candidate
for Methadone Maintenance
• moderate to severe addiction
• demonstrated inability to achieve/maintain abstinence with other treatment modalities
• physical 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 still persist, including ‘it’s just drug switching’, or ‘you can’t really be in recovery unless you’re drug-free’
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
• Slow onset: no “rush”
• Stabilized physiology, hormones, tolerance
• Long acting: can maintain “comfort” or
normal brain function
Do
se
Re
sp
on
se
Time
“Loaded”
“High”
Normal Range
“Comfort Zone”
“Sick”
Methadone Simulated 24 Hr. Dose/Response
At steady-state in tolerant patient
0
hrs.
24
hrs.
Subjective
w/d Objective w/d
Opioid Agonist Treatment of Addiction - Payte - 1998
A dose level is therapeutic when:
• Physical withdrawal is eliminated
• Craving behaviors are eliminated
• Other opioids are blocked from abuse
• The patient is not over-sedated
• The patient returns to functionality
Second Question:
What is the right dose of
methadone?
A dose is non-therapeutic when:
• 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
0
10
20
30
40
50
60
70
80
90
10 20 30 40 50 60 70 80 90 100
Daily Methadone Dose (in mgs.)
Past
month
heroin
use
(%)
Methadone Is NOT
A Heroin Substitute
sick
normal
high Day 1 Day 2 Day 3 Day 1 Day 2 Day 3
Heroin Methadone
Methadone Pharmacology
• compared to heroin, the patient is
stabilized
Third Question:
How long should patients stay
on methadone?
“Long Enough!!” J. Thomas Payte, MD. Founding Chair, Methadone Treatment Committee, ASAM
Length of Stay in Methadone Correlated
with Better Outcomes
8%
23%
97%
67%
0
20
40
60
80
100
120
P
e
r
c
e
n
t
Pre-
treatment
Admission:
< 6 months
stay
Average
Stay: 6 to
54 months
Long-term:
> 54 months
Relapse to heroin use after MMT-
105 patients who left treatment
% of
relapse
rates
28.9%
82.1%72.7%
57.6%
45.5%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
In Tx. 1 to 3 4 to 6 7 to 9 10 to 12
Months Since Stopping Treatment
Case
• 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 (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 (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.
Fourth Question:
What are the side effects of
methadone?
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, a defect in the reproductive system resulting in impaired gonad function (not as severe as with heroin, may be dose dependent)
• Constipation
• Potential for QTc prolongation on ECG
• Sweating
• Methadone treatment tied to regulated clinic
Methadone and Cardiac Risk: Prolonged QTc
The QT interval represents the time for electrical activation and relaxation of the ventricles. The QT interval measurement is affected by heart rate, so it is mathematically adjusted for this to give a QT-corrected number, or QTc. Usually, a QTc greater than 500 msec raises clinical concerns about possible heart rhythm disturbance.
When the QTc becomes significantly prolonged, the person may be at risk of developing torsade de pointes, or TdP ('twisting of the points‘) and on ECG, looks like undulating peaks twisting about a central axis. This may signal convulsive twitching of heart muscle, or ventricular fibrillation, which can be fatal if emergency care is not provided [Leavitt and Krantz 2003].
CLINICAL GUIDELINES Ann Intern Med, March 17, 2009; 150(6): 417 - 418.
QTc Interval Screening in Methadone Treatment
Recommendation 1 (Disclosure): Clinicians should inform patients of arrhythmia risk when they prescribe methadone. Recommendation 2 (Clinical History): Clinicians should ask patients about any history of structural heart disease, arrhythmia, and syncope.
CLINICAL GUIDELINES Ann Intern Med, March 17, 2009; 150(6): 417 - 418.
QTc Interval Screening in Methadone Treatment
Recommendation 3 (Screening): Obtain a pretreatment electrocardiogram for all patients to measure the QTc interval and a follow-up electrocardiogram within 30 days and annually. Additional electrocardiography is recommended if the methadone dosage exceeds 100 mg/d or if patients have unexplained syncope or seizures.
CLINICAL GUIDELINES Ann Intern Med, March 17, 2009; 150(6): 417 - 418.
QTc Interval Screening in Methadone Treatment
Recommendation 4 (Risk Stratification): If the QTc interval is greater than 450 ms but less than 500 ms, discuss the potential risks and benefits with patients and monitor them more frequently. I f the QTc interval exceeds 500 ms, consider discontinuing or reducing the methadone dose; eliminating contributing factors, such as drugs that promote hypokalemia; or using an alternative therapy. Recommendation 5 (Drug Interactions): Clinicians should be aware of interactions between methadone and other drugs that possess QT interval–prolonging properties or slow the elimination of methadone
Methadone Treatment
Outcomes
• 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
HIV CONVERSION IN METHADONE TREATMENT
0%
5%
10%
15%
20%
25%
In Tx (N=95) Partial Tx
(N=45)
No Tx (N=55)
Tx Status
Metzger, D. et. al 18 month HIV conversion by treatment retention. J of AIDS 6:1993. p.1053
Methadone Treatment Reduces
Criminal Behavior
Drug related arrests significantly decline because MMT
patients reduce or stop buying and using illegal drugs.
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
0
50
100
150
200
250
300
A B C D E F
Before TX
During TX
Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991
Cri
me
Days
Pe
r Y
ea
r
Pregnancy
• Methadone is the 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.
Methadone Treatment Is More Effective With...
• counseling (individual/group)
• therapeutic use of urine testing
• involvement in community recovery groups
• lifestyle changes to support recovery
• mental health evaluation/treatment
• medical assessment/referral
Evidence for Counseling Services in Methadone Maintenance
55% 28% 0% >16 consecutive
weeks of (-)
urines
81% 59% 31% Retention
Methadone
+ Enhanced
Counseling
Methadone +
Std.
Counseling Methadone Outcome
McClellan. Treatment Research Institute. University of Pennsylvania, 2001.
Methadone is a second-line treatment for opioid addiction
The State requires that:
• Patients be at least 18 years of age
• Confirmed history of at least 2 years of addiction to opiates
(i.e. arrest records, treatment failures, etc.) – Does not
apply to pregnant addicts
• Confirmed history of 2 or more unsuccessful attempts in
withdrawal treatment (detox) with subsequent relapse to
opiate use. Does not apply to pregnant addicts.
• Evidence of observed signs of physical dependence
Calif Code of Regs (CCR). Title 9 Narcotic Treatment Programs. 2006
2 types: Subutex and Suboxone
Suboxone, bupe combined with naloxone, is a partial
agonist/antagonist drug.
• “Ceiling effect” and safety
• Displaces other opiates: withdrawal on induction
• t/2 >24 hours
• Blocks craving and euphoria
• Office – based use available
• Sublingual film is administered sublingually as a single
daily dose.
Buprenorphine
Opioid Addiction: Suboxone Film
SUBOXONE indicated for maintenance
treatment. The recommended target
dosage of SUBOXONE is 16/4 mg
buprenorphine/naloxone/day, as a single
daily dose.
The dosage of SUBOXONE
progressively adjusted in
increments/decrements of 2/0.5 mg or
4/1 mg buprenorphine/naloxone to a
level that holds the patient in treatment
and suppresses opioid withdrawal.
Maintenance dose is generally in the range of 4/1 mg
bupe/nalox to 24/6 mg bupe/nalox per day.
0
10
20
30
40
50
60
70
80
90
100
%
Mu Receptor
Intrinsic
Activity
Full Agonist
(e.g. methadone)
Partial Agonist
(e.g. buprenorphine)
Antagonist (e.g. naloxone)
no drug high dose
DRUG DOSE
low dose
Suboxone’s Ceiling Effect
“Ceiling” Effect
Vivitrol (naltrexone)
• Injectable form of Naltrexone
• Once monthly dosing
• FDA approved 2006
• Manufactured by Alkermes, Inc.
• An evidence-based practice - SAMHSA Treatment Improvement Protocol #49: “Incorporating Alcohol Pharmacology into Medical Practice”
Vivitrol
While previous studies have shown the benefit of using
naltrexone as part of a combined behavioral
intervention*, oral naltrexone, “has not been widely
prescribed…at least in part because of inconsistent
adherence with oral therapy.”**
* Donnovan, D., Anton, R. F., Miller, W. R. et al. (2008). Combined pharmacotherapies and behavioral
interventions for alcohol dependence: examination of posttreatment drinking outcomes. Journal of
studies on alcohol and drugs 69(1) 5.
** Kranzler, H. R. (2006). Extended-release intramuscular naltrexone. Drugs 66(13) 1754.
The intramuscular (IM) administration of
naltrexone offers less psychotherapeutic
limitations over its oral form and has led
researchers to conclude that, Vivitrol has
demonstrated efficacy at decreasing
heavy drinking in alcohol-dependency.
Johnson, B.A. (2007). Naltrexone long-acting formulation in the treatment of alcohol
dependence. Therapeutics and clinical risk management 3(5) 741-9.
BENEFITS OF INJECTABLE
NALTREXONE (Vivitrol):
– Reduces cravings
– Decreases impulsivity
– Enhances motivation
– Improves treatment adherence
– Eliminates daily adherence decisions
– Single injection is effective for four weeks
– Rapid onset of therapeutic effect in the first 2
days
Mechanism of Action
Not a narcotic or controlled substance. Not pleasure-producing. Not
addictive. Not aversive.
XR-NTX – Adverse Effects
• Precipitation of opioid w/d
• Injection site reactions
– Should only be administered IM
• Nausea, HA, fatigue
• Most SE – during 1st month of tx
• No significant hepatic toxicity
– Different from oral NTX
– Transient transaminase elevation seen
– Safe in patients with hep C (chronic active)
Preventing Opioid Overdose
Overdose as a cause of death is preventable in the majority of cases because it usually: • Happens to experienced users; • Happens over 1-2 hours, not instantly; • Is frequently witnessed by other users or by other persons present who can take life-saving action; and • Can be treated (reversed) effectively with naloxone.
Opioid Overdose Review
Risk factors for overdose
• Loss of Tolerance: Regular use of opioids leads to greater tolerance, i.e. more is needed to achieve the same effect. Overdoses occur when people start using again following a period of not using (abstinence) such as incarceration, or detox. • Mixing Drugs: Mixing opioids with other drugs, especially depressants such as benzodiazepines (Xanax, Clonopin) or alcohol can lead to an overdose. These combined drugs are “synergistic”, i.e., the effect of taking mixed drugs is greater than the effect one would expect if taking the drugs separately.
Risk factors for overdose
• Variation in strength of ‘street’ drugs: Street drugs may vary in strength and effect based on the purity of the heroin (or other opioid) and the amount of other ingredients used to cut the drug. Users should use small amounts of new batches or inject slowly enough to get a feel of the quality/strength of the drug(s). • Serious illness: If users have a serious illness including HIV/AIDS, liver disease, diabetes and/or heart disease, they are at greater risk for an overdose. Care should be taken when using to check the strength of the drug, avoid mixing drugs and/or using alone.
Main Symptoms of Opioid Overdose
Opioid overdose prevention kit – Opioid antagonist Naloxone
Understanding naloxone
• Naloxone reverses an opiate overdose by blocking opioid receptors in the brain. It wakes a person who is overdosing in 3-5 minutes and will continue working for about 30–90 minutes. After that time, the effect of opioids can return. This 30-90 minute window is usually enough to prevent death even if no further care is provided. • Naloxone will bring on withdrawal symptoms, which will also last 30-90 minutes, in someone who is opioid dependent. • Naloxone has no other effects and cannot be used to get high. • Naloxone will cause no harm if it is injected into a person who is not having an overdose. • Naloxone should be stored at room temperature and kept away from light.
Naloxone – a full opioid antagonist
New naloxone product for “home use” of opioid overdose prevention
5 STEPS FOR RESPONDING TO AN OPIOID OVERDOSE
1. Stimulation • Yell the user’s name. • Shake the person. 2. Call for Help • Call 911. Place them in the Recovery Position: Put the person on his/her side. This will help to keep the airway clear and prevent the person from choking on vomit.
5 STEPS FOR RESPONDING TO AN OPIOID OVERDOSE
3. Check Breathing and Respond • If the person is not breathing, the responder should start by giving a few rescue breaths and then administer naloxone. • If the person is breathing but unresponsive, then the responder should administer naloxone first. 4. Administer Naloxone • Inject 1cc of naloxone into a large muscle such as the upper arm or thigh. Or .4 mg via the Evzio. • If no response in 3-5 minutes, repeat administration.
If EMS has not yet been called, it is urgent to do so now.
5 STEPS FOR RESPONDING TO AN OPIOID OVERDOSE
5. Evaluation and Support • Stay with the overdose survivor and provide reassurance that the drug withdrawal symptoms will decrease in about one hour. Tell them that more drugs (opioids) should not be used now. • Inform EMS of what happened and how much naloxone was given. • Encourage survivor to go to the hospital.
