Download Opioid Abuse and Dependence - Alcohol Medical Scholars Program

Opioid Abuse and Dependence
Maritza Lagos, M.D.
Michigan State University/KCMS
Alcohol Medical Scholars Program
February, 2008
Slide 2
I.
Introduction
A.
Why this is important?
1.
Opioids
a.
Non-medical use of prescription opioids is increasing in US: 12th
graders past 30-day usage: 1% (1991)4 % (2006)1
b.
Less than 40% of physicians trained in medical schools 2
c.
A double-edged sword
Slide 3
1) A cornerstone of pain management
2) Mood-altering properties misuse liability
a)
Serious side effects: sedation, respiratory ↓
b) Tolerance may lead to overdose
c)
↑ physician liability
Slide 4
2.
Physician’s dilemma
a.
Fear of diversion, abuse and dependence (“opiophobia”)
b.
Fear of inadequate treatment of pain (generous prescribers)
In both cases, patient may be failed
c.
3.
B.
Physician’s challenge
a.
Learning clinical aspects and monitoring these conditions
b.
Balanced use so benefits outweigh harms
Goal: Address key concepts, pharmacology, clinical implications of opioids abuse
and dependence (emphasis on prescription opioids), assessment and treatment
Slide 5
C.
This lecture will cover:
1.
History, definitions, and classifications
2.
Pharmacology of opioid medications
3.
Uses of prescription opioids
a.
Medical: analgesia, maintenance treatment for opioid dependence
b.
Non-medical: misuse, diversion, abuse/dependence
1) Abuse
2) Dependence
3) Associated conditions
c.
Assessment and Treatment
Slide 6
II.
Opioids: history, definitions, classification
A.
History:
1.
The use, abuse, and dependence of opioids date back to antiquity 3
2.
Known to Sumerians 4000 BC and Egyptians 2000 BC 4
3.
Medicinal value described in Ebers Papyrus 1600 BC 3
4.
Opium isolated: 1806, heroin: 1898 5
5.
Smoking Opium Exclusion Act in 1909: prohibited importation/use of
opium except medicinal purposes 4
6.
1960s: methadone maintenance therapy 6
Slide 7
B.
Opiates vs. Opioids
1.
Opiates
a.
Natural opium alkaloids: morphine, thebaine, and codeine
b.
Semi-synthetics drugs derived from natural alkaloids 7
c.
1.
diacetylmorphine (derived from morphine): heroin
2.
oxycodone: (OxyContin, Percocet)
3.
hydrocodone: (Vicodin, Lortab)
NOTE: trade names are capitalized, while generic names are not
Slide 8
2.
Opioids: fully synthetic chemical with morphine-like action 4
a.
fentanil: Duragesic patch, Sublimaze
b.
methadone: Dolophine
3.
Common feature of opioids and opiates: bind to opioid receptors
4.
DSM-IV uses the term opioid related disorders 8
5.
“OPIOIDS”: term used in this lecture.
Slide 9
C.
Classification
1.
Pure agonists: bind and activate specific opioid receptor
a.
b.
2.
Full agonist: great affinityfull receptor activation
1.
morphine (MS Contin)
2.
fentanyl (Duragesic patch, Sublimaze)
3.
oxycodone (OxyContin, Percocet)
Partial agonist: less than full activation
1.
butorphanol (Stadol)
2.
pentazocine (Talwin)
Antagonists: bind but do not activate the receptor (competitive inhibition)
Slide 10
3.
a.
Pure: naloxone (Narcan): blocks effects for 3-4 h
b.
naltrexone (ReVia): Blocks opioid effects for 24-72h
Mixed agonist-antagonists: bind and activate one receptor type but not
another
4.
a.
buprenorphine (Buprenex, Subutex): µ agonist and κ antagonist
b.
Nalbuphine (Nubain): µ antagonist and κ agonist
Others: tramadol (Ultram): µ agonist + inhibition of reuptake of NE and
serotonin
Slide 11: Transition
Pharmacology
III.
Slide 12
A.
Opioid receptors: mu, kappa, and delta (out of up to 17 receptors) 9
1.
µ (mu) receptor: prototypical
a.
Activated by morphine
2.
b.
Primary site of action of all prescription opioids10
c.
Distributed: brain, spinal cord, autonomic system and GI
d.
Linked to abuse/dependence
1.
Euphoric effects
2.
Positive reinforcement
κ (kappa) receptor: analgesia, endocrine changes and dysphoria:
for endogenous peptides (endorphins, dynorphins, etc.)
Slide 13: zooming in
B.
Pharmacodynamics: what the drug does to the body 10
1.
Interact with 3 opioid receptors: µ, κ, and δ
2.
Receptors are widely distributed most pronounced effects: CNS and GI
tract
Slide 14: zooming in
3.
Receptors: G protein-coupled family and signal via second messenger
(cyclic AMP) or a K+ ion channel
4.
Alteration of cyclic AMP cellular changesEFFECTS
a.
Desirable: analgesia,↓ diarrhea, cough suppression
b.
Undesirable (side effects): euphoria  positive reinforcement
Slide 15
5.
Effects at the CNS level
a.
Desirable
1.
Analgesia: reason of use
1)
Activation of descending pain control
circuits9
2)
Inhibition of ascending pain transmission
system9
Cough suppression: e.g., dextromethorphan
b.
Undesirable (side effects)
1.
Euphoria and reward:  abuse or dependence
2.
Respiratory depression8 (dose dependent): most serious
3.
Sedation and drowsiness: dangerous if + CNS depressants
4.
Hallucinations, confusion, nightmares
5.
Inhibition of Gonadotropin Releasing Hormone and
Corticotropin Releasing Factor (endocrine effects)4
Slide 16
6.
Effects in the gastrointestinal (GI) tract 9
a.
Desirable: antidiarrheal; inhibits peristalsis (loperamide-Imodium)
b.
Undesirable
1.
2.
Nausea, vomiting: action at chemoreceptor trigger zone
Constipation:↓ secretion, ↓ propulsion and ↑ muscle tone
Slide 17
C.
Pharmacokinetics: what the body does to the opioids10
1.
Absorption
a.
Readily through GI tract (include rectal mucosa)
b.
If lipid soluble  through nasal and buccal mucosa,
skin
2.
Biotransformation: mainly in the liver (variable first-pass
rate)
3.
4.
Distribution and fate
a.
Variable binding to proteins (25%-90%)
b.
Excretion through kidney and GI (bile)
Altered by: Patient’s age, gender, organ dysfunction (liver, kidney) 4
Slide 18
Table: Comparison of a short acting and long acting opioids
Opioid Morphine Methadone Oral bioavailability 35-75%, 85%
Plasma ½ life 2-3.5 h, 24 h
Duration of analgesia 4-6 h, 4-8 h
Accumulation in the body Limited Significant
Intra Muscular/Per Oral potency 6, 2
Biotransformation Liver Liver
Analgesic property M6G D-isomer
Elimination Kidney>>>>GI (<10%) Kidney=GI
Slide 19: transition
Slide 20
IV.
Medical use of opioids
A. Analgesia: morphin (MS Contin), hydromorphone (Dilaudid)
1.
Most powerful and effective analgesic available 11
2.
Less effective for neuropathic pain (e.g. peripheral neuropathy)
3.
Local anesthetic effect (epidural, intrathecal)
4.
Used for general anesthesia: fentanyl
5.
Patient controlled anesthesia: sickle cell anemia patients (infusion pumps)
B. Severe diarrhea: Peripheral action; diphenoxylate (Lomotil) and loperamide
(Imodium)
C. Cough suppressant: D-isomer depresses the cough center. No analgesia10
e.g. dextromethorphan
D. Maintenance treatment of opioid dependence
1.
Long-term administration of long-acting opioids
2.
Methadone: most thoroughly studied and widely used
3.
Use in opioid dependent patients who cannot avoid relapsing to opioid
drugs
4.
Blocks effects of opioids  ↓ reduces illicit opioid use (and prescription
opioid misuse)
Slide 21
V.
Different uses of prescription opioids
A.
Misuse
1.
Patient’s incorrect use
2.
Miss-managed by physicians: the 4 Ds 12
a.
Dated: with changes of standard of practice
b.
Duped: easily manipulated by patients
c.
Disabled: impaired by their own illness
d.
B.
Dishonest: Dealing with drugs  prosecution
Non-medical use13 (illicit)
1.
Using a drug: not prescribed for you
2.
Takes only for the feeling or experience it caused
3.
Does not include: over-the-counter but legitimate use of opioids
4.
Most common class of prescription drugs used illicitly14,15
5.
Illicit use in US: age 12 and older:
a.
2%: past month (2006: current users)13
b.
Lifetime prevalence (opioids other than heroin): 14 % 13
Slide 22
C.
Dependence: DSM-IV8
1.
3+ in same 12 months (definitions to follow)
a.
Tolerance
b.
Withdrawal
c.
Larger amounts and over longer period of time than intended
d.
Persistent desire or unsuccessful efforts to cut down
e.
Much time obtaining, using, or recovering from effects
f.
↓ social/occupational/ recreational activities because of use
g.
Continued use despite physical/psychological problems
Slide 23
D.
Abuse: DSM – IV 8
1.
Not if dependent
2.
1 in 12 months: OH OL
3.
a.
Use despite problems: Obstinate
b.
Use in hazardous situations
c.
Failure to fulfill major role obligations
d.
Legal problems
Abuse trends
a.
Most prevalent: oxycodone, hydrocodone, methadone,
hydromorphon15
Less prevalent: fentanil and buprenorphine 15
Slide 24
4.
Epidemiology: (Figure) Dependence on or abuse of specific illicit drugs in
the past year among persons 12+ : 2006 13
Slide 25
VI.
Conditions Associated with Prescription Opioid Misuse, Abuse, or Dependence
A.
Tolerance
1.
With repeated use
2.
Need of increasing doses to maintain effect
3.
Can see in non-dependent pain patients drug-seeking behavior
4.
Mechanism
a.
Adaptation of receptors
b.
Intracellular mechanisms change (cAMP, G-protein
etc)
5.
Slide 26
Different rates of tolerance to each effect: e.g., respiratory depression
B.
Withdrawal or abstinence syndrome
1.
After cessation or reduction of chronic opioid use
2.
After giving an opioid antagonist
3.
Signs and symptoms opposite to agonist effects
4.
Diagnosis needs: 3+ within minutes to several days
a.
Unhappy mood
b.
Fever
c.
Pupillary dilation
d.
Tearing/runny nose
e.
Yawning
f.
Nausea/vomiting
g.
Diarrhea
h.
Muscle aches
i.
Goose bumps
j.
Sweating
k.
Insomnia
Slide 27
C.
Opiod overdose
1.
Recent use of opioid
2.
May present with perceptual disturbances (hallucinations)
3.
Pinpoint (miosis) or dilated (anoxia: severe) pupils
4.
1+ signs and symptoms
a.
Drowsiness or coma
b.
Slurred speech
c.
Impairment in attention and memory
Slide 28: Transition
Slide 29
VII.
Treatment
A.
Treatment goals
1.
↓ /eliminate use11
2.
↓ risks: overdose, IV use, dependence
3.
Address co-morbid conditions, psychosocial outcomes, somatic needs
Slide 30
B.
Assessment
1.
C.
Diagnosis from interview
a.
Use DSM-IV criteria
b.
Begin by asking life problems
c.
Next, tie-in use of substances, including misuse of medications
d.
Be direct yet empathic and non-judgmental
Laboratory drug testing
1.
Rationale
a.
Helps determine problem if not reported by patient (denial, stigma,
illegality)
b.
2.
If patient knows testing  ↑disclosure
Most urine immunoassays - targeted to morphine and most opiates
(i.e., hydrocodone, hydromorphone, codeine)
a.
Poor specificity for oxycodone
b.
False positive: patient recent food dense in poppyseeds
c.
False negative
d.
1.
Tampering: manipulating urine
2.
Below cut-off concentration: specific calibration
3.
Too late: i.e. after 36 h of last use for short acting
Methadone: Gas liquid chromatography and gas chromatography-
mass spectroscopy (GC/MS)
3.
Best to test: 12-36 hrs after use
4.
Choice of body fluids 2
a.
Urine: higher concentration of compound
b.
Blood: can get blood level
c.
Others: meconium (to indicate fetal exposure to opioids)
Slide 31
D.
Acute intervention
1.
Intoxication/overdose
a.
Severe intoxication: emergency setting 24
1.
Can be fatal: support vital signs (breathing, blood
pressure)
2.
2.
Naloxone: parenteral opioid antagonist
1)
SC/IV: 0.4 mg q 2-3 min.
2)
If no response to 5-10 mg: think other cause
Withdrawal
a.
Distress measured by rating scales 11- 25
1.
CINA: Clinical Institute Narcotic Assessment. Adapted
from Peachey, J.E., and Lei, H. Assessment of opioid dependence with
naloxone. British Journal of Addiction 83(2):193–201, 1988.
2.
COWS: Clinical Opiate Withdrawal Scale. Wesson et al.
1999.
b.
Three main strategies
1.
Methadone substitution with gradual methadone
tapering11
2.
Buprenorphine substitution and gradual tapering25
3.
Treat symptoms only:
1)
Clonidine: suppress symptoms of withdrawal11
2)
Pain: non-steroids
3)
Diarrhea: Imodium
Slide 32
E.
Maintenance treatment for opioid dependence: long acting opioids
1.
When chronic & relapsing condition
2.
Most studies for heroin dependence 27-28
3.
Not well studied for prescription opioid dependence 12 but in use
4.
Goals:
a.
Achieve a stable dose that
1.
Suppresses withdrawal
2.
Decreases craving
3.
b.
Blocks effects of illicit opioids
Facilitate and promote rehabilitation
Slide 33
F.
Pharmacological Treatment
1.
2.
Methadone
a.
Full µ agonist
b.
Dosed once/day
c.
40-60 mg/d: sufficient to block withdrawal symptoms
d.
>60 mg/d: suppresses withdrawal & craving 11
Buprenorphine/Naloxone
a.
µ Receptor partial agonist
b.
Kappa receptor partial antagonist
c.
12-16 mg/d
d.
8-32 mg/d –reduced risk of diversion 25
Slide 34
G.
Psychosocial treatment
1.
Specialized programs
2.
Cognitive behavioral therapy 11
3.
Behavioral therapy
4.
Psychodynamic/interpersonal therapy
5.
Family therapy: identification of conflictive dynamics and enabling
6.
Recovery-oriented therapies
7.
Self-help groups: Narcotics Anonymous - based on 12-step philosophy 11
Slide 35
Summary
A.
Opioids
1.
Excellent pain relievers but associated to misuse/abuse/dependence
2.
Cannot separate therapeutic action from risk of misuse
3.
Risk of tolerance, abuse and dependence
4.
Learn to use it
5.
Monitor effectiveness and side effects
6.
Abuse and dependence are treatable conditions
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