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)ŕ4 % (2006)1

b.              Less than 40% of physicians trained in medical schools 2   

Slide 3

c.              A double-edged sword

1)      A cornerstone of pain management

2)      Mood-altering propertiesŕ misuse liability

a)       Serious side effects: sedation, respiratory ↓

b)      Toleranceŕ may lead to overdose

c)       ↑ physician liability

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2.              Physician’s dilemma

a.              Fear of diversion, abuse and dependence (“opiophobia”)

                                                               b.              Fear of inadequate treatment of pain (generous prescribers)

                                                      c.              In both cases, patient may be failed                                                             

3.              Physician’s challenge                                                                                        

a.              Learning clinical aspects and monitoring these conditions

                                                               b.              Balanced use so benefits outweigh harms

B.              Goal: Address key concepts, pharmacology, clinical implications of opioids abuse

           and dependence (emphasis on prescription opioids), assessment and treatment

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                  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

1.                    diacetylmorphine (derived from morphine): heroin

2.                    oxycodone: (OxyContin, Percocet)

3.                    hydrocodone: (Vicodin, Lortab)

c.       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.

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C.              Classification                                        

1.              Pure agonists: bind and activate specific opioid receptor

a.       Full agonist: great affinityŕfull receptor activation

1.                    morphine (MS Contin)

2.                    fentanyl (Duragesic patch, Sublimaze)

3.                    oxycodone (OxyContin, Percocet)

b.       Partial agonist: less than full activation

1.                    butorphanol (Stadol)

2.                    pentazocine (Talwin)                                        

2.              Antagonists: bind but do not activate the receptor (competitive inhibition)

Slide 10

a.       Pure: naloxone (Narcan): blocks effects for 3-4 h

b.       naltrexone (ReVia): Blocks opioid effects for 24-72h                                         3.              Mixed agonist-antagonists: bind and activate one receptor type but not

another

a.       buprenorphine (Buprenex, Subutex): µ agonist and κ antagonist

b.       Nalbuphine (Nubain): µ antagonist and κ agonist                                        

4.              Others: tramadol (Ultram): µ agonist + inhibition of reuptake of NE and

            serotonin

Slide 11: Transition

III.              Pharmacology

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

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                                       

2.              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 distributedŕ 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 ŕcellular changesŕEFFECTS

a.       Desirable: analgesia,↓ diarrhea, cough suppression

b.       Undesirable (side effects): euphoria ŕ 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: ŕ 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.                 Nausea, vomiting: action at chemoreceptor trigger zone

2.                    Constipation:↓ secretion, ↓ propulsion and ↑ muscle tone

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C.              Pharmacokinetics: what the body does to the opioids10                                        

1.              Absorption

a.       Readily through GI tract (include rectal mucosa)

b.       If lipid soluble ŕ through nasal and buccal mucosa,

     skin                                        

 2.              Biotransformation: mainly in the liver (variable first-pass

            rate)                                        

3.              Distribution and fate

a.       Variable binding to proteins (25%-90%)

b.       Excretion through kidney and GI (bile)                                        

4.              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 ˝ 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 ŕ ↓ reduces illicit opioid use (and prescription opioid misuse)

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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.       Dishonest: Dealing with drugs ŕ prosecution           

B.              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

a.       Use despite problems: Obstinate

b.       Use in hazardous situations

c.       Failure to fulfill major role obligations

d.       Legal problems                                        

3.              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

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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 ŕdrug-seeking behavior                            4.              Mechanism

a.       Adaptation of receptors

b.       Intracellular mechanisms change (cAMP, G-protein etc)                                        

5.              Different rates of tolerance to each effect: e.g., respiratory depression

Slide 26           

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.              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           

C.              Laboratory drug testing

1.       Rationale

a.       Helps determine problem if not reported by patient (denial, stigma, illegality)

b.       If patient knows testing ŕ ↑disclosure

2.       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

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

d.       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.                    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                    

2.              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.                    Blocks effects of illicit opioids

b.       Facilitate and promote rehabilitation

Slide 33            

F.              Pharmacological Treatment                                         

1.              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                                        

2.              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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