Opioid Abuse and Dependence

Maritza Lagos, M.D.

Michigan State University/KCMS

Alcohol Medical Scholars Program

                                                                                                   February, 2008              

Slide 2

1.         I.              Introduction
   1.                                 A.              Why this is important?
   1.                                                              1.              Opioids
   1.                                                                                         a.              Non-medical use of prescription opioids is increasing in US: 12^th graders past 30-day usage: 1% (1991)à4 % (2006)¹
   2.                                                                                         b.              Less than 40% of physicians trained in medical schools ²

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   3.                                                                                         c.              A double-edged sword

   1)      A cornerstone of pain management

   2)      Mood-altering propertiesà misuse liability

   a)       Serious side effects: sedation, respiratory ↓

   b)      Toleranceà may lead to overdose

   c)       ↑ physician liability

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   2.                                                              2.              Physician’s dilemma
   1.                                                                                         a.              Fear of diversion, abuse and dependence (“opiophobia”)
   2.                                                                                         b.              Fear of inadequate treatment of pain (generous prescribers)
   3.                                                                                         c.              In both cases, patient may be failed
   3.                                                              3.              Physician’s challenge
   1.                                                                                         a.              Learning clinical aspects and monitoring these conditions
   2.                                                                                         b.              Balanced use so benefits outweigh harms
   2.                                 B.              Goal: Address key concepts, pharmacology, clinical implications of opioids abuse and dependence (emphasis on prescription opioids), assessment and treatment

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   3.                                 C.              This lecture will cover:
   1.                                                              1.              History, definitions, and classifications
   2.                                                              2.              Pharmacology of opioid medications
   3.                                                              3.              Uses of prescription opioids
   1.                                                                                         a.              Medical: analgesia, maintenance treatment for opioid dependence
   2.                                                                                         b.              Non-medical: misuse, diversion, abuse/dependence

   1)      Abuse

   2)      Dependence

   3)      Associated conditions

   3.                                                                                         c.              Assessment and Treatment

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   2.     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

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                  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

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                                               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 affinityàfull 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)

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      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

      3. III.              Pharmacology

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                     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

                                                  3.              δ (delta) receptor: 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 distributedà 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 àcellular changesàEFFECTS

         a.       Desirable: analgesia,↓ diarrhea, cough suppression

         b.       Undesirable (side effects): euphoria à positive reinforcement

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                                                  5.              Effects at the CNS level

         a.       Desirable

         1.                    Analgesia: the reason of their use

                                                                                                                                                      1)              Activation of descending pain control circuits ⁹

                                                                                                                                                      2)              Inhibition of ascending pain transmission system ⁹

         2.                    Cough suppression: e.g., dextromethorphan

         b.       Undesirable (side effects)

         1.                    Euphoria and reward: à 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

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                                                  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 à 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

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         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