8/9/2019 Opiates 2008
1/102
Opiates: A Review and the best new
treatment in a century
David M. McDowell, MD
8/9/2019 Opiates 2008
2/102
Heroin and Opiates
8/9/2019 Opiates 2008
3/102
Increased Media Attention
8/9/2019 Opiates 2008
4/102
Increased production in
Afganhastan
Record poppyproduction
reported inAfghanastan
All reports point toincreases in thelikely chaos of thenext two years
8/9/2019 Opiates 2008
5/102
Opioids constitute a class of drugs found within opiumOpioids constitute a class of drugs found within opium(opiates) as well as semi-synthetic and synthetic compounds(opiates) as well as semi-synthetic and synthetic compounds
that resemble the structure and/or function of the naturallythat resemble the structure and/or function of the naturally
occurring formsoccurring forms
General Opioid PharmacologyGeneral Opioid Pharmacology
8/9/2019 Opiates 2008
6/102
The Opium Poppy
Papaver somniferum
Morphine
Opium
Codeine
Papaverine
Naltrexone
Many other opiods
8/9/2019 Opiates 2008
7/102
8/9/2019 Opiates 2008
8/102
8/9/2019 Opiates 2008
9/102
Early 1900s
U.S. has a widespread
problem with opiates
fueled by former civilwar veterans still
opiate dependent (the
soldiers disease) and
readily available otcremedies.
8/9/2019 Opiates 2008
10/102
1905
Reacting to an alarming
increase in heroin and
morphine addiction,opium is banned by
Congress.
8/9/2019 Opiates 2008
11/102
1906U.S. Congress passes
the Pure Food andDrug Act requiringcontents labeling onpatent medicines bypharmaceuticalcompanies. As aresult, the
availability of opiatesand opiateconsumerssignificantly declines.
8/9/2019 Opiates 2008
12/102
December 14, 1914
The passage of Harrison NarcoticsAct which aims to curb drug(especially cocaine but also heroin)abuse and addiction. It requiresdoctors, pharmacists and others
who prescribed narcotics toregister and pay a tax.
8/9/2019 Opiates 2008
13/102
The Doctors Dilemma
8/9/2019 Opiates 2008
14/102
8/9/2019 Opiates 2008
15/102
ID: 46581,Published in the New Yorker 11/12/2001
8/9/2019 Opiates 2008
16/102
Drug Addiction Treatment Act of 2000
An Amendment
to the Controlled Substances Act
(October, 2000)
8/9/2019 Opiates 2008
17/102
17
Evolving Landscape of Drugs of Abuse
Farming Pharming
8/9/2019 Opiates 2008
18/102
Changing Methods of Distribution
Hand commerce E commerce
8/9/2019 Opiates 2008
19/102
Prescription Opioids
Fastest growing drug abuse Usually used orally but may be crushed & snorted
or injected
Injection less likely with combo products, more
likely with Oxycontin Schedule III products available via Internet but not
Schedule II
More frequent source: medicine cabinets &prescriptions
Believed to be safer than illicit street drugs
8/9/2019 Opiates 2008
20/102
Epidemiology
In 2001, 8 million persons abusedprescription pain relievers at least onceduring previous 12 months
In 2004, this had jumped to 11.4 million
Between 1994-2001, narcotic analgesicabuse more than doubled
In 2002, prescription drugs were second onlyto marijuana as most commonly abuseddrugs
8/9/2019 Opiates 2008
21/102
8/9/2019 Opiates 2008
22/102
Potential subpopulations of prescription
Opioid Abusers Persons who abuse or are dependent on only
prescription opioids
Abusers of other opioids, e.g., heroin, when they cannotget their drug of choice
Polydrug abusers
Pain patients who develop abuse or dependence
problems on these drugs in the course of legitimate
medical treatment
8/9/2019 Opiates 2008
23/102
Why Has the Abuse of PrescriptionDrugs Been Increasing?
Increasing numbers of prescriptions (greateravailability)
Attention by the media & advertising(television and newspaper)
Easier access (e.g. internet availability)
Improper knowledge & monitoring (adverseeffects go unrecognized)
8/9/2019 Opiates 2008
24/102
8/9/2019 Opiates 2008
25/102
Types of Receptors
Mu
Kappa
Delta
8/9/2019 Opiates 2008
26/102
Effects Pain Modulation
Mood Regulation
Respiration
Vomiting Center
Pupil Response
Endocrine effects
8/9/2019 Opiates 2008
27/102
Effects of Opiates Desired effects give
way to dependence
Increased number ofreceptors
Suppression of
endogenous opiates
8/9/2019 Opiates 2008
28/102
Physical effects of Opiate
Intoxicationdilated pupils
piloerection (goose bumps)
watery eyes
runny nose Yawning
loss of appetite
Tremors
Panic
Chills Nausea
muscle cramps
insomnia
8/9/2019 Opiates 2008
29/102
8/9/2019 Opiates 2008
30/102
1.1. Full agonists:Full agonists:
Occupy the receptor and activate that receptorOccupy the receptor and activate that receptor
Increasing doses of the drug produce increasingIncreasing doses of the drug produce increasing
effects until a maximum effect is achieved (receptor iseffects until a maximum effect is achieved (receptor is
fully activated)fully activated)
Most abused opioids are full agonistsMost abused opioids are full agonists
General Opioid PharmacologyGeneral Opioid Pharmacology
8/9/2019 Opiates 2008
31/102
2.2. Partial agonists:Partial agonists:
Bind to and activate receptor (like a full agonist)Bind to and activate receptor (like a full agonist)
Increasing dose does not produce as great an effect asIncreasing dose does not produce as great an effect as
does increasing the dose of a full agonistdoes increasing the dose of a full agonistless of aless of a
maximal effect is possiblemaximal effect is possible
General Opioid PharmacologyGeneral Opioid Pharmacology
8/9/2019 Opiates 2008
32/102
3.3. Antagonists:Antagonists:
Bind to receptors but donBind to receptors but dont activate the receptort activate the receptor
Block the receptor from activation by full and partialBlock the receptor from activation by full and partial
agonistsagonists
General Opioid PharmacologyGeneral Opioid Pharmacology
8/9/2019 Opiates 2008
33/102
General Opioid PharmacologyGeneral Opioid Pharmacology
Drugs and medications that activateDrugs and medications that activate mumureceptors:receptors:
morphinemorphine heroinheroin
methadonemethadone LAAMLAAM
hydromorphonehydromorphone buprenorphinebuprenorphine
codeinecodeine oxycodoneoxycodone
fentanylfentanyl hydrocodonehydrocodone
8/9/2019 Opiates 2008
34/102
Opioid Agonist Treatment: MethadoneOpioid Agonist Treatment: Methadone
Advantages of opioid agonist medication over heroinAdvantages of opioid agonist medication over heroin
Non-parenteral administrationNon-parenteral administration
Known compositionKnown composition
Gradual onset and offsetGradual onset and offset
Long-actingLong-acting
Mildly reinforcingMildly reinforcing
Medically supervisedMedically supervised
8/9/2019 Opiates 2008
35/102
Opioid Agonist Treatment: MethadoneOpioid Agonist Treatment: Methadone
Dole and NyswanderDole and Nyswander
Proposed addiction to be a change in brain fromProposed addiction to be a change in brain from
prolonged exposure to opiatesprolonged exposure to opiates Looked for an orally active, long acting opiate thatLooked for an orally active, long acting opiate that
would manage withdrawal and cravingwould manage withdrawal and craving
Started evaluating methadone in the earlyStarted evaluating methadone in the early1960s1960s
Dole VP,Dole VP, NyswanderNyswanderM. A medical treatment for diacetylmorphine (heroin)M. A medical treatment for diacetylmorphine (heroin)
addiction: A clinical trial with methadone hydrochloride. JAMA 193: 80-84, 1965.addiction: A clinical trial with methadone hydrochloride. JAMA 193: 80-84, 1965.
8/9/2019 Opiates 2008
36/102
TheThe dosedose of psychosocial services can determineof psychosocial services can determine
outcomesoutcomes
6-month RCT with three levels of non-pharmacological6-month RCT with three levels of non-pharmacological
services:services: methadone alonemethadone alone
methadone plus standard counseling servicesmethadone plus standard counseling services
methadone plus enhanced services (counseling,methadone plus enhanced services (counseling,
medical/psychiatric, employment, and familymedical/psychiatric, employment, and family
therapy)therapy)
McLellanMcLellan AT, et al. The effects of psychosocial services in substance abuseAT, et al. The effects of psychosocial services in substance abusetreatment. JAMA 269(15):1953-1959, 1993treatment. JAMA 269(15):1953-1959, 1993
Methadone EfficacyMethadone Efficacy
8/9/2019 Opiates 2008
37/102
Opioid antagonist (no effects in non-dependent person,Opioid antagonist (no effects in non-dependent person,
precipitated withdrawal in opioid dependent person)precipitated withdrawal in opioid dependent person)
Effectively blocks effects of opioids (e.g., heroin)Effectively blocks effects of opioids (e.g., heroin)
Now available in a depot form (though not approved for thisNow available in a depot form (though not approved for this
use--it is widely accepted)use--it is widely accepted)
NaltrexoneNaltrexone PharmacologyPharmacology
8/9/2019 Opiates 2008
38/102
8/9/2019 Opiates 2008
39/102
Highly effective in controlled, inpatient studiesHighly effective in controlled, inpatient studies
Compliance and treatment retention are generally poor inCompliance and treatment retention are generally poor in
outpatient clinical trialsoutpatient clinical trials
Compliance is better in motivated patients (e.g., physicians,Compliance is better in motivated patients (e.g., physicians,
business professionals)business professionals)
WashtonWashton AM et al. Successful use ofAM et al. Successful use ofnaltrexonenaltrexone in addicted physicians and businessin addicted physicians and business
executives. Adv Alcoholexecutives. Adv Alcohol SubstSubst Abuse 4:89-96, 1984Abuse 4:89-96, 1984
NaltrexoneNaltrexone EfficacyEfficacy
8/9/2019 Opiates 2008
40/102
Very safe in usual dose rangeVery safe in usual dose range
Higher than usual doses may produce increases in liverHigher than usual doses may produce increases in liver
function tests (function tests (LFTsLFTs))
Most commonly reported side effects are abdominal complaintsMost commonly reported side effects are abdominal complaints
andand dysphoriadysphoria (although both are rare)(although both are rare)
((PfohlPfohl et al. 1986)et al. 1986)
NaltrexoneNaltrexone Safety and Side EffectsSafety and Side Effects
8/9/2019 Opiates 2008
41/102
Alpha 2 adrenergic agonist (anti-hypertensive - primaryAlpha 2 adrenergic agonist (anti-hypertensive - primary
indication)indication)
Effective in diminishing opioid withdrawal signs, less effectiveEffective in diminishing opioid withdrawal signs, less effective
at decreasing subjective withdrawal symptomsat decreasing subjective withdrawal symptoms
Usual dosing for opioid withdrawal is three times per dayUsual dosing for opioid withdrawal is three times per day
Side effects: hypotension, reports of sedation/abuseSide effects: hypotension, reports of sedation/abuse
(Anderson et al. 1997., Conway and(Anderson et al. 1997., Conway and BalsonBalson 1993)1993)
ClonidineClonidine
8/9/2019 Opiates 2008
42/102
Help! I have a patient in
front of me who is
medically stable, but isscreaming, wailing,
and claims he is in
opiate withdrawal!
What do I do?
8/9/2019 Opiates 2008
43/102
Immediate Detox Protocol Anti Withdrawal Agents
Clonidine, Lofexadine
Anti-Nausea Agents
Reglan, Odansetron
Anti-Anxiety Agents
Benzodiazepines, Beta Blockers
8/9/2019 Opiates 2008
44/102
8/9/2019 Opiates 2008
45/102
Advantages of Buprenorphine
Legal Issues
Ceiling Effect Difficulty of Overdose
Stabilization
Logistics
Cost effectiveness Dollars
Human Costs
8/9/2019 Opiates 2008
46/102
Buprenorphine A partially synthetic
opioid
Partial agonist at the opiate receptor
- Occupies 70% of thereceptor
High affinity for the receptor
-Binds more tightly to opiatereceptors than other opiates
8/9/2019 Opiates 2008
47/102
Mode of administration
Sublingual tablets
0.4, 2 & 8 mg tablets
available tablets take 3 to 5
minutes to dissolve
only get ~ half effectif swallowed
Other means ofdelivery are on thehorizon
8/9/2019 Opiates 2008
48/102
Two forms of medicine
Suboxone Subutex
Both forms takensublingually
8/9/2019 Opiates 2008
49/102
Duration of effects
Quick onset of action: 3060 min
Peak effects: 1 4 hours
Duration of action is dose related
In general 2-3 days!
8/9/2019 Opiates 2008
50/102
Classification of Opioids
Drug Dose
Full Agonists: Heroin, morphine,
methadone, codeine
Partial Agonists: Buprenorphine
Antagonists: Naltrexone, naloxone
Threshold for respiratory
depression
SizeofO
piateAgonistEffe
ct.
.
100
0
8/9/2019 Opiates 2008
51/102
Zubieta et al., 2000
8/9/2019 Opiates 2008
52/102
Advantages of Buprenorphine
Buprenorphine binds more tightly to the receptor than anyother opiate
It is a partial mu agonist, occupying that receptor only 70%-also kappa antagonist
Ceiling effect protects against overdosebut also limitsdegree of agonist effectceiling effect approximately 32 mg
Withdrawal easier than from methadone or heroin
Maintained patients describe;
Clear headedness
Increased energy
Improved sleep & mood stability
Easier to engage in therapy
8/9/2019 Opiates 2008
53/102
8/9/2019 Opiates 2008
54/102
ID: 43331,Published in the New Yorker 2/21/2000
8/9/2019 Opiates 2008
55/102
8/9/2019 Opiates 2008
56/102
Transitioning from
Non-specified: 51 (13%)
Heroin 125 (33%)
Rx drugs: 122 (33 %)
Methadone 40 (11%) (dosage issues)
Suboxone 19 (5%)
Combination: 18 (5%)
8/9/2019 Opiates 2008
57/102
Average Initial Dose 14.3 mg
Average Time to detox, for those who have
detoxed3.8 months
8/9/2019 Opiates 2008
58/102
Success Rates Difficult at times to truly assess
The 1/3, 1/3, and 1/3 rule
8/9/2019 Opiates 2008
59/102
Our Process Pts make appointment
Come in for initial evaluation appointment and
instruction. Induction is scheduled Pt comes in for induction, which takes an average
of 3 hours
Pt returns within a week for check up
Pt is refered to a provider, and other treatments
Pts take a urine toxicology exam every visit
8/9/2019 Opiates 2008
60/102
Other things can make one feel
good too
8/9/2019 Opiates 2008
61/102
8/9/2019 Opiates 2008
62/102
8/9/2019 Opiates 2008
63/102
8/9/2019 Opiates 2008
64/102
8/9/2019 Opiates 2008
65/102
Easy Access: Role of the Internet?Delivered in the Privacy of your Home
Some reasonswhy you shouldconsider using
this pharmacy
Noprescriptionrequired!
8/9/2019 Opiates 2008
66/102
Commonly known Mechanisms of
Diversion Illegal sale of prescriptions by physicians;
Illegal sale of prescriptions by pharmacists;
Doctor Shopping by individuals who visit numerousphysicians to obtain multiple prescriptions;
Illegal substitutions or shorting by pharmacists;
Theft, forgery, or alteration of prescriptionsRobberies & thefts from pharmacies & thefts ofinstitutional drug supplies
Internet sales
8/9/2019 Opiates 2008
67/102
Less Often Discussed Mechanisms
Residential Burglaries
Obituary Shopping
Hotel & residential sneak thefts Supply-chain theft
In-production losses
In-transit lossesReturns/reverse distributorsEmployee pilferage
8/9/2019 Opiates 2008
68/102
Mechanisms of Diversion by Middle
& High School Students
Thefts from family medicine cabinets
Drug switching at home Drug trading at school
Thefts & robberies of medicationsfrom classmates
8/9/2019 Opiates 2008
69/102
Prevalence of Co-Morbid Chronic
Pain & Substance Abuse 10-30% of adult population has chronic pain
10-15% background rate of substance abuse
2-9 million in US with both conditions 30-60% have chronic pain
0.6-1.2 million with pain & opioid addiction
Cost of care is approx. 10 times that of average pt,3 times major depression
8/9/2019 Opiates 2008
70/102
Treatment Options
Detoxification
To antagonist maintenance (naltrexone, nelmefene, depotnaltrexone)
To residential therapeutic community
To abstinenceoriented programs (counseling, 12 step programs)
Maintenance
Methadone
Buprenorphine
8/9/2019 Opiates 2008
71/102
Opiate Addiction
Pharmacotherapy Agonists Methadone, LAAM
Partial Agonists Buprenorphine
Antagonists Naltrexone
Anti-Withdrawal Methadone; Buprenorphine
Clonidine: rapid detox using
Buprenorphine, Naltrexone,
& Clonidine
Anti-Craving Clonidine or Lofexidine
8/9/2019 Opiates 2008
72/102
8/9/2019 Opiates 2008
73/102
It was the first and only time that the
schrieking numbness of existence was
silenced.
--Kurt Vonnegut Jr
8/9/2019 Opiates 2008
74/102
8/9/2019 Opiates 2008
75/102
8/9/2019 Opiates 2008
76/102
Initial Assessment
Categories
Patient in stable recovery
Patient on maintenance therapy
Patient actively abusing Covariates
What is the substance of abuse?
Co-morbid mental illness?
Social supports
U i l P ti
8/9/2019 Opiates 2008
77/102
Universal Precautions-OR-
How to Structure a Program Clinical Assessment
Physical exam, including skin
Pill counts Lab tests
LFTs, CBC, HIV
Urine toxicology Prescription monitoring program data
Significant other reports, medical records
T t t I
8/9/2019 Opiates 2008
78/102
Treatment Issues
Age
Adolescent
Adult
Elderly
Drug History
New onset of drug abuse
Relapser
Chronic poly substance
abuser
Route
Oral
Intranasal
Injector
Comorbidity
Psychiatric
Chronic pain
Who is the Patient
8/9/2019 Opiates 2008
79/102
Buprenorphine:
clinical pharmacology
8/9/2019 Opiates 2008
80/102
Other things can make one feel
good too
8/9/2019 Opiates 2008
81/102
Understanding the Receptor Buprenorphine binds more tightly to the
receptor than any other opiate
It is a partial agonist, occupying thatreceptor only 70%
This partial agonist effect allows for more
normal opiate regulation Muffin Tin analogy
8/9/2019 Opiates 2008
82/102
8/9/2019 Opiates 2008
83/102
8/9/2019 Opiates 2008
84/102
Maintenance Treatment
RCTs comparing BPN to Methadone mainly done inspecialist clinics
Systematic reviews
West, ONeal & Graham 2000, Substance Abuse
Barnett, Rodgers & Bloch 2001Addictions
Mattick et al 2002: Cochrane review (>13 RCTs, >1000 patients)
Main outcomes: heroin use & treatment retention
8/9/2019 Opiates 2008
85/102
RCT BPN vs Meth: RetentionMattick et al 2003 Addictions
8/9/2019 Opiates 2008
86/102
RCT BPN vs Meth: drug useMattick et al 2003 Addictions
8/9/2019 Opiates 2008
87/102
8/9/2019 Opiates 2008
88/102
Think Stabilization, thenDetoxification
8/9/2019 Opiates 2008
89/102
Buprenorphine is abusable (epidemiological, human
laboratory studies show)
Diversion and illicit use of analgesic form (byinjection)
Relatively low abuse potential compared to other
opioids
Abuse Potential
8/9/2019 Opiates 2008
90/102
Buprenorphine as a gateway to
treatment
Dependent
user
Withdrawalepisode
Buprenorphine
with structured
review
Naltrexonetreatment
Substitutionmaintenancetreatment
Psychosocialinterventions
only
8/9/2019 Opiates 2008
91/102
Barriers to Implementation
Clinician Confusion
Historical precendence regarding opiates
Practical considerations of inductions
8/9/2019 Opiates 2008
92/102
Buprenorphine is very easy to use
in maintenance---it is slightly
more difficult to transition oneonto it
8/9/2019 Opiates 2008
93/102
The Induction Phaseour
current method Patient must be in withdrawal
Begin with 2-4 milligrams of suboxone
Administer 2-4 mg every hour until
symptomatic relief.
8/9/2019 Opiates 2008
94/102
The patient must be in
Withdrawal!!!
8/9/2019 Opiates 2008
95/102
Induction Recommendations
Moderate Withdrawal symptoms
COWS score of 10 or greater (other factors
may be involved)
Adjuvant medications may be used
8/9/2019 Opiates 2008
96/102
The patient must be in
Withdrawal!!!
8/9/2019 Opiates 2008
97/102
Barriers to Office Based
Induction(Induction, NOTMaintenance) Addicted patients are not trusting
and come to the office not insufficient withdrawal and mustwait.
Addicted patients do not understandthe directions and come in terriblewithdrawal vomiting all over thewaiting room
Addicted patients use opiatesduring the induction phase andcreate a precipitated withdrawal.
8/9/2019 Opiates 2008
98/102
Difficulty Managing Transition
Withdrawal unpleasant
Logistical problems
Most often a matter of
reassurance and commonsense.
Many cases andarguments for specializedclinics and times
8/9/2019 Opiates 2008
99/102
Goals
Evaluation
Education
Transition
Appropriate referral (usually back to
referral source)
8/9/2019 Opiates 2008
100/102
Our Experience to Date
8/9/2019 Opiates 2008
101/102
Positive Effectsclinical
impressions Clear headedness
Increased Energy
Less iatrogenic sociopathy
Improved sleep
Mood stability
Aide to therapy
8/9/2019 Opiates 2008
102/102
Patients get their lives back