Pharmacologicrxof opiates 2012

1. PHARMACOLOGIC TREATMENT
OF
OPIATE DEPENDENCE
Paula Colescott MD
Diplomat of The American Board of Addiction Medicine
Board Certification in Internal Medicine

2. Objectives
The student will understand:
• The Brain changes in the addict
• The Historical Approaches of Treatment
• Agonist Treatment
• Blockade of the Opiate Receptor
• Those who qualify for
Buprenorphine/Naltrexone
• The Clitheroe Protocol

3. In Reflection
• 25 yo Native Female, IV heroin user ,being
released from Hiland Prison. She is tremulous
as she tells me she doesn’t think she can stay
clean.
• 30 yo white female, narcotic/heroin user, who
is in RSAT @ Hiland Prison. She confides to
me that despite treatment she fears her
inability to resist relapse.

6. W
H
Y

7. OPIUM
1898
1804
1832

8. OPIATES
Derived from extracts of the juice of opium poppy.
OPIOIDS
Any exogenous substance that acts as an agonist at any of
several receptors
Neurobiology of Addiction
George F. Koob

9. Take a Drug Change Your Brain
DRUG ADDICTION IS A COMPLEX ILLNESSDRUG ADDICTION IS A COMPLEX ILLNESS
www.drugabuse.gov

11. Steward, 1987, p. 166
“It’s staying off that is the hard part. It
takes a lot of willpower. But seeing
smack eats away at your willpower; it
makes it very hard. When I stop I just
feel vacant with no direction or
energy and that lasts for months.’

12. Behavioral Mechanisms
of Addiction
“The special role the drug comes to play in the
personality organization of these patients. They
have not successfully established familiar defensive,
neurotic, characterological or other common
adaptive mechanisms as a way of dealing with their
distress. Instead, they have resorted to the use of
opioids as a way of coping with a range of problems
including ordinary human pain, disappointment,
anxiety, loss, anguish, sexual frustration, and other
suffering”

13. Opioids relieve emotional pain
and this is one of the behavioral
mechanisms implicated in the
addiction cycle
(Khantzian, 1985, 1990, 1997)

19. Opioid Intoxication
1st Profound euphoria the rush
Visceral sensations, a facial flush, deepening of the voice. The
rush is resistant to tolerance.
2nd The High feeling of well-being over several
hours, no tolerance
3rd The Nod state of escape from reality ranging
from sleepiness to virtual unconsciousness
4th Being Straight User no longer experiencing
the rush or nod or high, but also not in withdrawal. This can
last up to 8 h following an injection or smoking of heroin.

21. NATURAL REWARDS
DISPLACED
SPIRITUALLY
PHYSICALLY
SOCIALLY
INTELLECTUALLY
EMOTIONALLY
Salient

22. Substance Dependence (brief)
• Organization around acquisition, use, recovery from
effects, of the drug—behavior is rewarding
• Dosage and frequency not the issue
• Consequences are the issue
• Adaptation and deterioration are hallmarks
• Ambivalence is the psychodynamic
– Loss of CONROL

23. WITHDRAWAL

24. Acute Withdrawal
5-7 Days
• Runny nose, sneezing,
• Sweating, yawning
• Restless, insomnia
• Piloerection, myalgia
• Twitching, arthralgia
• Abd. Cramps, diarrhea
• Vomiting, dehydration
• Tachycardia, HBP, Fever
• Psychosis
• Autonomic rebound locus ceruleus
•

25. Protracted (1-12 months) Abstinence
• Anergia, Anhedonia
• Sleep disturbance
• Poor appetite
• Emotional lability/dysphoria
• Stress incompetence
• Drug craving, obsession
• Muscle aches and pains
• Reduced libido, impotence
• Dopaminergic deficiency,
nucleus accumbens, VTA

26. WHY TREAT OPIOID DEPENDENCE WITH
OPIOID AGONISTS?
Repeated Exposure
Neuronal Adaptation
Tolerance, physical dependence, craving
Chronic relapsing nature of opioid dependence

27. Natural History of Narcotic Addiction:
Male Heroin Addicts
• Hser et al.,2001

28. Therapeutic Options Available to Benjamin Rush, MD

29. Coming in For Treatment

30. Medical Withdrawal from Opioids
1. Cold Turkey
2. Symptomatic Medications/Social Support
Clonidine, ibuprofen, hydoxyzine, methocambanol, loperamide…
3. Taper ( Goodman & Gilman: 20-50% decrease/day)
4. Federally regulated methadone clinic
5. Ultra-Rapid Opioid Detox (UROD), Rapid Opioid Detox
6. Buprenorphine –(suboxone/subutex)
7. Blockade of the Opiate Receptor ?
Medical Withdrawal or “Detox” is not treatment

31. OPIATES
Just Detox Alone
And then
Aftercare??

33. Treatment Overview of
Opioid Dependence
DEATH
HARM REDUCTION
OPIOID
REPLACEMENT
Methadone or buprenorphine
ABSTINENCE
< 20% CAN ACHIEVE THIS
Naltrexone
Needle Exchange Program

34. Is Clean & Sober too Much to ask with
Opiates??
Opioid
Replacement
Methadone=76%
Buprenorphine=?
Abstinence
Detox only
3% @ 1 yr
MJ Kreek
<20% in
lifetime
WA state MDs
85% @ 10
yrs.

35. New History
1960-70s Dole, Nyswander, and Kreek
• Proposed addiction to be a change in brain from
prolonged exposure to opiates
• Started evaluating methadone in the early 1960s
• Methadone for dependence/addiction Rx in special clinics

36. Buprenorphine
(Subutex)
Orphan drug developed by NIDA and private
pharmaceutical interest over 25 years

37. 2000 Drug Addiction Treatment Act
• Addiction is a chronic disease
• Physicians may offer buprenorphine treatment, as a
replacement therapy in their office “OBOT” –Office Based
Opioid Therapy (need 8h CME)
• PCP knows the patient, the family, “the story”
• Reduces stigma, increases access to care
• Aligns addiction with other chronic relapsing conditions
(asthma, HBP, DM, Obesity, depression, mental illness, etc.)

38. Cognitive Behavioral Therapies
Substance abuse is related to maladaptive
social learning/adverse life situations.
• Improve interpersonal
&Coping skills
– Evaluating feelings,
thoughts
• Self-efficacy
– Teach problem solving
Reduce risk of relapse
– Triggers, cues
– Coping with urges
“As a Man thinks, so is he”
Solomon

39. Is Buprenorphine an Opioid?
Yes

40. Is Buprenorphine an Analgesic?
• Yes
• 20-40 X as potent as morphine
• Analgesic in US, Buprenex (IV/IM), for decades
• Worldwide use for pain as Temgesic
• There is no FDA approval for pain(SL), but it is
prescribed to pain patients “off-label”
[problematic]

41. Opioid Receptors and Effect of Agonist
Mu1 (μ1) analgesia, euphoria
Mu2 (μ2)
constipation, respiratory
depression
Kappa spinal analgesia, dysphoria
Delta unknown

42. Receptor Binding at Mu receptor
Agonist
Partial Agonist
Antagonists
Morphine-like effect, increasing dose
increases effect
Morphine-like effect with strong receptor
affinity, slow dissociation, ceiling effect
(bup)
No effect in absence of an opiate or opiate
dependence (e.g., naltrexone)

43. Function at Receptors: Full Agonists
Mu
receptor
Full agonist binding …
 activates the mu receptor at higher levels
with higher doses
 is highly reinforcing
 is the most abused opioid type
 includes, oxycodone, morphine,methadone, others
Slide Courtesy of John T. Pichot, MD

44. Opioid Receptor Partial Agonists
Mu
receptor
 activates the receptor at lower levels but
plateaus at lower levels
 is relatively less reinforcing
 is a less abused opioid type
 includes buprenorphine
Partial agonist binding …
Slide Courtesy of John T. Pichot, MD

45. Full Agonist
Bound to Receptor
Bup affinity is higher
Therefore
Full Agonist is displaced
Partial Agonist (Bup) Receptor Affinity
Mu
Receptor
• Strength: Drug physically binds to a receptor
 Buprenorphine affinity is very strong and it will
displace full agonists like morphine and methadone
 Can precipitate withdrawal
Slide Courtesy of John T. Pichot, MD

46. Receptor Dissociation
• Speed (slow or fast) of disengagement or uncoupling
of a drug from the receptor
• Buprenorphine’s dissociation is slow
– Blocks other opioids (ie morphine) from binding
– Prolonged therapeutic effect (> 24 hours)
Mu
Receptor
Bup dissociation is slow
Therefore
Full Agonists can’t bind
Slide Courtesy of John T. Pichot, MD

47. 0
10
20
30
40
50
60
70
80
90
100
2 mg 16 mg 32 mg
Dose
%ReceptorOccupancy
Source: Greenwald, MK et al, Neuropsychopharmacology 28, 2000-2009, 2003.
μ
Effects of Buprenorphine Maintenance Dose on
Mu Opioid Receptor Availability
27 to 47%
85 to 92%
94 to 98%

48. Benefits of Buprenorphine
• Mild withdrawal syndrome
• Prolonged therapeutic effect
• Safe and effective as an analgesic
• Blockade of “illicit” opioids
• Greater safety margin compared to methadone
• Decreased risk of abuse and diversion with
combination tablet
• Efficacy comparable to methadone

49. “Normal”
Withdrawal
Effects of IV Heroin without
Buprenorphine
High
Opiate
Effects
Rush

50. Usual Effect of Buprenorphine Induction in an
Opiate Dependent Patient
“Normal”
Withdrawal
High
Opiate
Effects

51. “Normal”
Withdrawal
Effects of Using Heroin while on
Buprenorphine
High
Attenuated
rushOpiate
effects

52. CESAR FAX
U n i v e r s i t y o f M a r y l a n d , C o l l e g e P a r k
A Weekly FAX from the Center for Substance Abuse Research
April 9, 2012
Vol. 21, Issue 14
Northeastern and Southern Regions of Country Account for
Largest Increases in Buprenorphine Found in Law Enforcement Drug Seizures
2003 2004 2005 2006 2007 2008 2009 2010
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
831
1,689
4,161
3,856
West
Midwest
Northeast
South
Estimated Number of Buprenorphine Reports,
U.S. Law Enforcement-Seized Drug Exhibits Analyzed by Forensic Laboratories,
by U.S. Census Region*, 2003-2010
*Northeast: CT, MA, ME, NH, NJ, NY, PA, RI, VT
South: AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA WV
Midwest: IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, WI
West: AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, WY
Buprenorphine estimates for the South and West regions do not meet the DEA’s standard of precision and reliability.

53. Who is Appropriate for
Buprenorphine Treatment?

54. Patient Selection:
10 Assessment Questions
• Is the patient dependent/addicted to opioids?
• Does the Client live in Anchorage?
• Is the patient aware of other available treatment
options?
• Does the patient understand the risks, benefits, and
limitations of buprenorphine treatment?
• Is the patient expected to be reasonably compliant,
with all treatment modalities?
• Is the patient able to follow safety procedures?

55. Patient Selection:
10 Assessment Questions
• Is the patient psychiatrically stable?
• Is the patient taking other medications that may
interact with buprenorphine?
• Are the psychosocial circumstances of the patient
stable and supportive?
• Is the patient interested in office-based
buprenorphine treatment?
• Are there resources available in the office to provide
appropriate treatment, and support?
• Do they have a means of paying for the Suboxone?

56. Less Likely to be an Appropriate Candidate:
• High BNZ doses, alcohol, other CNS depressants
• Significant psychiatric co-morbidity
• Multiple addiction treatment episodes (+ -??)
• Actively or chronic suicidal or homicidal ideation
• Needs that cannot be addressed with existing office-
based resources or through referrals
• High daily doses of methadone ( 40mg+/day)
• Poor social support system—Cannot be living with IV
opiate user . Cannot be employed by Business linked to
drug use

57. How do you determine Dependence?
DSM-IV requirements:
3 or more needed x 12 months
– Tolerance
– Withdrawal
– Larger amt. longer period than intended
– Any unsuccessful effort / persistent desire to cut down
/control substance use
– A lot of time spent obtaining / recovering
– Important social, occupational, or recreational
activities given up / reduced
– Continuation despite consequences caused or
exacerbated by the substance

58. Narcotic / Alcohol Dependent
• Do CIWA and COWS scale
• Treat according to the CIWA/ETOH protocol
• This patient is NOT a candidate for suboxone
• This patient is a good candidate for
NALTREXONE maintenance once they finish
withdrawing from ETOH.
• They can be made comfortable with BZDs,
clonidine, phenergan or zofran

59. The Narcotic/Alcohol Dependent
• Suboxone possible If
– they contract to remain in residential treatment for
90 days
– Their counselors confirm their investment in recovery
– They have no underlying psych co-morbidity
– Upon release they have a stable living situation
– Upon release they remain in IOP
– Upon release they have the finances to obtain
suboxone consistently.
– They agree to be on a monitored ANTABUSE
PROGRAM

60. $$
Subutex: 2 mg: $14.49.
#30 $173.49
8mg: $20.99
#30 $317.49
CARRS—6/2010