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Opiates: A Review and the best new

treatment in a century

David M. McDowell, MD

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Heroin and Opiates

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Increased Media Attention

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Increased production in

Afganhastan

Record poppyproduction

reported inAfghanastan

All reports point toincreases in thelikely chaos of thenext two years

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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

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The Opium Poppy

Papaver somniferum

Morphine

Opium

Codeine

Papaverine

Naltrexone

Many other opiods

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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.

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1905

Reacting to an alarming

increase in heroin and

morphine addiction,opium is banned by

Congress.

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1906U.S. Congress passes

the Pure Food andDrug Act requiringcontents labeling onpatent medicines bypharmaceuticalcompanies. As aresult, the

availability of opiatesand opiateconsumerssignificantly declines.

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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.

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The Doctors Dilemma

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ID: 46581,Published in the New Yorker 11/12/2001

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Drug Addiction Treatment Act of 2000

An Amendment

to the Controlled Substances Act

(October, 2000)

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17

Evolving Landscape of Drugs of Abuse

Farming Pharming

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Changing Methods of Distribution

Hand commerce E commerce

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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

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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

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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

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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)

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Types of Receptors

Mu

Kappa

Delta

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Effects Pain Modulation

Mood Regulation

Respiration

Vomiting Center

Pupil Response

Endocrine effects

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Effects of Opiates Desired effects give

way to dependence

Increased number ofreceptors

Suppression of

endogenous opiates

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Physical effects of Opiate

Intoxicationdilated pupils

piloerection (goose bumps)

watery eyes

runny nose Yawning

loss of appetite

Tremors

Panic

Chills Nausea

muscle cramps

insomnia

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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


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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


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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


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Drugs and medications that activateDrugs and medications that activate mumureceptors:receptors:

morphinemorphine heroinheroin

methadonemethadone LAAMLAAM

hydromorphonehydromorphone buprenorphinebuprenorphine

codeinecodeine oxycodoneoxycodone

fentanylfentanyl hydrocodonehydrocodone

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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

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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.

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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

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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

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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

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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

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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

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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?

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Immediate Detox Protocol Anti Withdrawal Agents

Clonidine, Lofexadine

Anti-Nausea Agents

Reglan, Odansetron

Anti-Anxiety Agents

Benzodiazepines, Beta Blockers

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Advantages of Buprenorphine

Legal Issues

Ceiling Effect Difficulty of Overdose

Stabilization

Logistics

Cost effectiveness Dollars

Human Costs

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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

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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

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Two forms of medicine

Suboxone Subutex

Both forms takensublingually

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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!

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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

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Zubieta et al., 2000

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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

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ID: 43331,Published in the New Yorker 2/21/2000

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Transitioning from

Non-specified: 51 (13%)

Heroin 125 (33%)

Rx drugs: 122 (33 %)

Methadone 40 (11%) (dosage issues)

Suboxone 19 (5%)

Combination: 18 (5%)

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Average Initial Dose 14.3 mg

Average Time to detox, for those who have

detoxed3.8 months

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Success Rates Difficult at times to truly assess

The 1/3, 1/3, and 1/3 rule

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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

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Other things can make one feel

good too

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Easy Access: Role of the Internet?Delivered in the Privacy of your Home

Some reasonswhy you shouldconsider using

this pharmacy

Noprescriptionrequired!

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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

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Less Often Discussed Mechanisms

Residential Burglaries

Obituary Shopping

Hotel & residential sneak thefts Supply-chain theft

In-production losses

In-transit lossesReturns/reverse distributorsEmployee pilferage

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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

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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

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Treatment Options

Detoxification

To antagonist maintenance (naltrexone, nelmefene, depotnaltrexone)

To residential therapeutic community

To abstinenceoriented programs (counseling, 12 step programs)

Maintenance

Methadone

Buprenorphine

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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

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It was the first and only time that the

schrieking numbness of existence was

silenced.

--Kurt Vonnegut Jr

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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

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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

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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

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Buprenorphine:

clinical pharmacology

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Other things can make one feel

good too

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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

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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

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RCT BPN vs Meth: RetentionMattick et al 2003 Addictions

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RCT BPN vs Meth: drug useMattick et al 2003 Addictions

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Think Stabilization, thenDetoxification

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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

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Buprenorphine as a gateway to

treatment

Dependent

user

Withdrawalepisode

Buprenorphine

with structured

review

Naltrexonetreatment

Substitutionmaintenancetreatment

Psychosocialinterventions

only

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Barriers to Implementation

Clinician Confusion

Historical precendence regarding opiates

Practical considerations of inductions

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Buprenorphine is very easy to use

in maintenance---it is slightly

more difficult to transition oneonto it

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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.

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The patient must be in

Withdrawal!!!

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Induction Recommendations

Moderate Withdrawal symptoms

COWS score of 10 or greater (other factors

may be involved)

Adjuvant medications may be used

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The patient must be in

Withdrawal!!!

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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.

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Difficulty Managing Transition

Withdrawal unpleasant

Logistical problems

Most often a matter of

reassurance and commonsense.

Many cases andarguments for specializedclinics and times

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Goals

Evaluation

Education

Transition

Appropriate referral (usually back to

referral source)

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Our Experience to Date

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Positive Effectsclinical

impressions Clear headedness

Increased Energy

Less iatrogenic sociopathy

Improved sleep

Mood stability

Aide to therapy

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Patients get their lives back

Documents

Opiates 2008