Simple presentation describing opioid dependence and pharmacological treatments

1. Opiod Dependence:
An Epidemic in the U.S.
Selahattin Kurter, M.D.
Assistant Clinical Professor,
Medical College of Wisconsin

2. Opioids in History
• Used for over 3000 years
• Morphine was isolated from opium poppy
in 1806
• Later Codeine was isolated from poppy in
1832
• Synthetic opioid have been manufactured
such as: Demerol, Methadone, and
Propoxyphene

3. Dependence vs. Abuse?
• Opioid Dependence: 3 or more of following in a 12
month period:
• 1. A strong desire or sense of compulsion to take the drug
• 2. Difficulties in controlling drug-taking behavior in terms of its
onset, termination, or levels of use
• 3. A physiological withdrawal state when drug use is stopped or
reduced, as evidenced by: the characteristic withdrawal syndrome
for the substance; or use of the same (or a closely related)
substance with the intention of relieving or avoiding withdrawal
symptoms
• 4. Evidence of tolerance, such that increased doses of the drug are
required in order to achieve effects originally produced by lower
doses
• 5. Progressive neglect of alternative pleasures or interests because
of drug use, increased amount of time necessary to obtain or take
the drug or to recover from its effects
• 6. Persisting with drug use despite clear evidence of harmful
consequences

4. Dependence vs. Abuse?
• Opioid Abuse:
• A. A maladaptive pattern of substance use leading to clinically
significant impairment or distress, as manifested by one (or more)
of the following, occurring within a 12-month period:
1. Recurrent substance use resulting in a failure to fulfill major role
obligations at work, school, or home
2. Recurrent substance use in situations in which it is physically
hazardous
3. Recurrent substance-related legal problems
4. Continued substance use despite having persistent or recurrent
social or interpersonal problems caused by or exacerbated by the
effects of the substance
• B. The symptoms have never met the criteria for Substance
Dependence for this class of substance.

5. Epidemiology
• Estimated number of heroin users in U.S.=
600,000
• Estimated number of persons abusing
opioid (includes prescription pills)= 1
million to 2 million
• 3x more males than females are dependent
• Most common age is 30-40s. However,
common to start in 20’s
• Dependence is expensive $$. May users
turn to criminal activities and/or
prostitution to fund addiction
• Strong correlation of use and risk of HIV

6. Epidemiology
• Estimated cost to society $20 billion per yr.
• Heroin addiction in the United States has
been increasing and currently is believed
to be the highest it has been since the
1970s
• The incidence of emergency
department visits related to
prescription opioid pain medications
has more than doubled between 1994
and 2001

7. Neuropharmacology
• 2 major opioid receptors in brain:
– “Mu” receptor: involved in analgesia,
respiratory depression, constipation ,
and dependence
– “Kappa” receptor: involved analgesia,
diuresis (water regulation), and sedation
Endorphins and Enkephalins are two
naturally occurring opioids of the brain.
They work on both “Mu” and “Kappa”
receptors to reduce pain and help with
brain function

8. Comorbidity
• 90% of opioid addicts have an additional
psychiatric disorder
• Most common are: Major Depression
(30%), Anxiety (20%), Alcohol Disorders,
Antisocial Personality Disorder
• 15% of opioid addicts attempt suicide at
least once in their lives

9. Clinical Effects
• Can be taken orally, snorted, injected IV,
subcutaneous (through the skin)
• Causes a euphoric “high”
• Users feel warm, heaviness or numbness
to extremities, dry mouth, itchy face, and
facial flushing
• After euphoria there is sedation (this is
called “nodding off”)
• Can cause respiratory depression
(decreased rate of breathing), pupil
constriction, constipation, low BP, and low
HR

10. Opiod Intoxication
• Maladaptive behavior patterns (euphoria,
agitation, impaired judgment) with specific
physical symptoms after use:
– Altered mood
– Psychomotor retardation
– Drowsiness
– Slurred speech
– Impaired memory
– Constricted pupils

11. Opiod Withdrawal
• Physical symptoms associated with
cessation of opioids
– Severe muscle cramp, runny nose,
gooseflesh
– Profuse diarrhea, yawning, fever, dilated
pupils, high BP, palpitations
– Restlessness, depression, tremor, N/V
• May start in as little as 6 hrs from last
intake for Morphine/Heroin to 1 or 3 days
for Methadone

12. Opiod Withdrawal
• Withdrawal may last up to 1 wk with most
intense days being days 2 to 3 after intake
• Withdrawal is rarely fatal
• Fatal only in cases where pt have
underlying respiratory or cardiac problems
• Insomnia, depression, and cravings may
last up to months after withdrawal

13. Overdose
• Most death from overdose occurs from
respiratory depression
• Symptoms of overdose:
unresponsiveness, coma, pinpoint pupils,
hypothermia, extremely low BP, and low
pulse
• Treatment is with an opioid blocker called
Naloxone (“Narcan”) which reverses
effects of opioids
• Pt. should be admitted to ICU for
monitoring and respiratory support

14. Methadone
• Synthetic Narcotic taken orally
• Suppresses withdrawal symptoms of
other opioids
• Lasts longer than one day
• Used by clinics for opioid addicts via
“reduction of harm” method
– Reduces IV drug use (Less HIV)
– Produces less “high” or euphoria
– Supposed to reduce criminality and
improve function of addicts

15. What is Buprenorphine?
• Is a synthetic opioid drug being used
increasingly for maintenance and detox of
opioid dependency
• Appears to be considerably safer than
methadone as to respiratory depression
(60-70% safer) 2 deaths out of 70,000* (use
with benzo’s)
• Effective or almost as effective as
methadone for maintenance treatment1
• Easier than methadone to detoxify patients
• Long- half life allows for every other day
dosing

16. What is Buprenorphine?
• May block effect of additional illicit drug
use with concurrent use of Buprenorphine
• Has been suggested for first-line treatment
for opioid substitution

17. History
• Originally licensed in 1978 as an analgesic
(pain killer) under the trade name
Temgesic
• Recognized that it could be used for
treatment of addiction in that year
• However, use for addiction developed in
past few years (past 10 years)
• Approved for opioid dependence in France
(1996), UK (1998), Australia (2000), Israel
and Europe (2001), US (2002)
• Marketed in US as “Subutex”
(Buprenorphine) and
“Suboxone” (Buprenorphine and Naloxone)

18. Mechanism of Action
• Partial Mu opioid receptor agonist and a
Kappa receptor antagonist
• Treatment effects thought to be due to
partial Mu receptor agonism
• Kappa antagonism causes lack of
dysphoria and lack of hallucinations
compared to methadone
• Effects are seen 30-60 minutes after
sublingual intake. Max peek in 1-4 hrs

19. Mechanism of Action
• Long half life (24-36 hrs). Steady state
reached by 3-7 days
• Higher concentration to tissues high in fat
and large blood supply (mainly liver and
brain)
Figure 1:
Receptor Profile
of Mu Opioid
Heroin= Full
agonist
Buprenorphine=
partial agonist
Naloxone=
antagonist

20. FDA Approved Indications
• Opioid Dependency
– Detoxification from Opioids (prevent
symptom severity of withdrawals)
– Maintenance treatment (instead of
Methadone)

21. Administration / Dosing
• Given sublingually (under tongue). If
swallowed, the amount absorbed by the
body is less because liver metabolizes
drug
• With Suboxone (Buprenorphine/ Naloxone)
4:1 ratio. Made to prevent abused injection
of drug- Naloxone will counteract any
euphoria and cause withdrawal symptoms.
Thus, formulation allows for take home

22. Administration / Dosing
• Given daily. Dose between 4-24 mg
• Initially, wait until pt. experiences mild-
moderate withdrawal after stopping opioid
of abuse or methadone.
• Then, start 4-8 mg of Buprenorphine.
Titrate as necessary, depending on
protocol and treatment purpose. Wean if
detoxifying and continue daily treatment if
maintenance treatment

23. Contraindications
• Contraindicated in patients with severe
respiratory, severe liver problems, severe
acute or chronic pain, who breast feed
• Use during pregnancy not recommended.
However, preferred compared to
methadone secondary to less severe
neonatal withdrawal after delivery
(Neonatal Abstinence Syndrome)
• Caution in patients with concurrent use of
benzodiazepines, alcohol, or poly-drug use
(concern for respiratory depression)

24. Respiratory Depression?
Risk of Respiratory Depression with Increasing Dose
0
10
20
30
40
50
60
70
Increasing Opioid Dose--->
OpioidAgonistEffect
Buprenorphine
Methadone,
Heroin
Antagonist
(Naloxone,
Naltrexone)
Respiratory Depression

25. Common Side Effects
• Headache (9%), Constipation (7%),
Tiredness (7%), Insomnia (6%), Sweating
(3%), Nausea (3%)
• Risk of precipitating opioid withdrawal is
20% if converting from Methadone (30-
40mg/day) to Buprenorphine. Should wait
36hrs after last Methadone dose. Should
wait 12 hr after last dose of short acting
opioid.

26. Drug Addiction Treatment Act of
2000
• Legal for outpatient doctors to prescribe
opioids to manage addiction for
maintenance or for short-term detox
• Limited to Schedules III through V med
only - excluding methadone and stronger
opioids
• Allows one physician to treat up to 30
patients

27. Efficacy of Methadone
Treatment
• Opioid treatment programs (OTPs), which
are methadone maintenance programs that
embrace interventions that include
counseling services, vocational resources,
referrals, and appropriate drug monitoring,
have been shown to reduce opioid use and
related crime, increase employment, and
decrease the incidence of human
immunodeficiency virus (HIV) related to
needle sharing6
• Abusers enrolled in such programs gain
improved physical and mental health and
decreased overall mortality for opioid
addiction5

28. Efficacy of Buprenorphine
Compared to Methadone
• A Cochrane Database Study Systematic
Rev 2002.. (meta-analysis)
• OBJECTIVES: To evaluate the effects of
Buprenorphine maintenance against placebo and
methadone maintenance in retaining patients in
treatment and in suppressing illicit drug use
• 13 randomized double placebo controlled studies
• Methodological study design rated as good
• Low dose buprenorphine is not superior to low
dose methadone. High dose buprenorphine does
not retain more patients than low dose
methadone, but may suppress heroin use better.
There was no advantage for high dose
buprenorphine over high dose methadone in
retention (RR=0.79; 95% CI:0.62-1.01)

29. Efficacy of Buprenorphine
Compared to Methadone
• Buprenorphine was statistically
significantly superior to placebo
medication in retention of patients in
treatment at low doses (RR=1.24; 95% CI:
1.06-1.45), high doses (RR=1.21; 95% CI:
1.02-1.44), and very high doses
• Conclusion: Buprenorphine is an effective
intervention for use in the maintenance
treatment of heroin dependence, but it is
not more effective than methadone at
adequate dosages2

30. Efficacy of Buprenorphine
Compared to Methadone
• In another major study- meta-analysis
compared effectiveness of Buprenorphine
relative to methadone1
• 5 randomized double blinded control trials
evaluated (stricter inclusion criteria-
relative to dosing)
• Conclusion: It was more effective than 20-
35mg/day of methadone daily
maintenance.
• Compared to higher dosing of methadone
(50-60mg/day), Buprenorphine was slightly
less effective with relapse prevention
(RR=1.26 95% confidence interval)

31. Buprenorphine in Practice
Who is a good candidate for Buprenorphine:
• Patients who are interested in treatment
• Patients who have no contraindication or
serious concerns to Buprenorphine (no severe
respiratory or liver problems, no concurrent
benzo or serious polydrug (ETOH) use, no
severe chronic pain)
• Patients who can be expected to be compliant
(no acute serious self harm behaviors, no
multiple history of prior relapses after
treatment)

32. Finally…
• Importance of combining psychological
treatments with pharmacologic treatments
can not be stressed more…
• Drug Addiction Treatment Act stipulates
prescribers must attest to their capacity to
refer such patients for appropriate
counseling and other non-pharmacologic
therapy
• Studies clearly indicate a better outcome
when pharmacological and behavioral
therapies are utilized appropriately

33. References
1. Barnett R., Rodgers J.. A Meta-Analysis comparing Buprenorphine to Methadone for
treatment of Opiate Dependence. Addiction. 2001;96:683-690
2. Kaplan and Sadock. Synopsis of Psychiatry. Opioids. Ninth Edition. pp 448-459.
Lippincott Williams and Wilkins. 2003.
3. Kimber J., Mattick RP. Buprenorphine maintenance versus placebo or methadone
maintenance for opioid dependence. University of New South Wales, National Drug
and Alcohol Research Centre. Cochrane Database Systematic Review 2002;
(4):CD002207
4. Law F., Daglish M. The Clinical Use of Buprenorphine in Opiate Addiction: Evidence
and Practice.
5. Office of National Drug Control Policy (ONDCP). Drug Policy Information
Clearinghouse. Heroin Fact Sheet June 2005. Available at:
http://www.whitehousedrugpolicy.gov/publications/factsht/heroin/197335.pdf.
Accessed Nov. 25, 2006
6. Sees KL, Delucchi KL, Masson C, Rosen A, Clark HW, Robillard H, et al. Methadone
maintenance vs. 180-day psychosocially enriched detoxification for treatment of
opioid dependence: a randomized controlled trial. JAMA. 2000;283:1303