Opioids

1. Opioids Teri Martin teri.martin@jus.gov.on.ca November 4, 2003

2. Outline • What are opioids? • Basic pharmacology of opioids • Symptomatology associated with overdose • Examination of specific opioids • Morphine, Heroin, Codeine • Fentanyl, Meperidine, Methadone • Opioid antagonists • Tolerance and withdrawal

3. Opium • Exudate of the opium poppy (Papaver somniferum) • Has been known and used for 2000 to 6000 years • Known to relieve pain, diarrhea, produce euphoria • Addiction to opium became commonplace • Serturner isolated and purified morphine in 1803 • Semisynthetic compounds (Heroin – 1874) • Fully synthetic opioids (Meperidine – 1939) • Medicinal and recreational uses firmly established

4. Opiates vs. Opioids Opiates – compounds that are extracted from the opium poppy, Papaver somniferum (e.g. morphine) Opioids –natural and semi-synthetic compounds derived from opium as well as entirely synthetic compounds which mimic the actions of morphine (e.g. methadone)

5. Basic Pharmacology of Opioids

6. Receptor Activity • Agonists – activate one or more opioid receptors (e.g. Morphine) • Antagonists – occupy receptors and prevent agonist binding (e.g. Naloxone) • Mixed agonist-antagonists – agonist activity at one type of receptor and antagonist activity at another type of receptor (e.g. Buprenorphine)

7. Opioid Receptors • Mu () • Located at supraspinal and spinal sites • Analgesia and respiratory depression • Mioisis, euphoria, reduced g.i. motility • Kappa () • Dorsal horn of spinal cord and brain stem • Analgesia, miosis, sedation

8. Opioid Receptors • Delta () • Binding sites for endogenous peptides • Analgesia, dysphoria, delusions, hallucinations • Sigma () • Binding is not limited to opioids • Not antagonized by naloxone • Central excitation • Tachycardia, hypertension, hallucinations

9. Major effects of opioids - CNS • Analgesia • Pain relief occurs both by raising the threshold for pain perception and by increasing pain tolerance • Respiratory depression •  sensitivity of the respiratory center to CO2 • Truncal rigidity may complicate  respiration • Respiratory failure the major toxicity of opioids • Analgesia and respiratory depression are inseparable and increase with dose in parallel

10. Major effects of opioids - CNS • Euphoria • Relaxed and dreamy state • Mental clouding • Dysphoria may occur in place of euphoria • Sedation • More likely to occur in the elderly • Less likely to occur with synthetic opioids • Additive with other CNS depressants

11. Major effects of opioids - CNS • Miosis • Nausea and Vomiting • Cough suppression

12. Peripheral effects of opioids • Gastrointestinal tract • Constipation a long recognized effect of opioids • High density of opioid receptors in GI tract • Motility decreased in the stomach • Peristalsis diminished in large intestine • Cardiovascular • Bradycardia, otherwise no significant effects on the heart, on cardiac rhythm or on blood pressure

13. Symptomatology in Overdose • Euphoria + + + • Unconsciousness • Respiratory depression • Pulmonary edema • Seizures • Hypothermia • Death

14. Example Opioids Morphine, Heroin, Codeine, Fentanyl, Meperidine and Methadone

15. Morphine • Primary constituent of crude opium • Strong agonist and prototypical narcotic analgesic • Used in the treatment of moderate-severe pain • t½ range: 1-6 hours

16. Heroin • Synthetic • Morphine derivative (diacetylmorphine) •  penetration of the blood-brain barrier • t½ approximately 5 minutes  6-MAM • No accepted medical uses in North America

17. Codeine • Minor constituent of opium • First-pass effect < morphine • Used in the treatment of mild-moderate pain • t½ range: 2 – 4 hours • 1/10th – 1/6th analgesic potency of morphine • Used in combination with other analgesics • Antitussive action > morphine

18. Heroin Morphine Codeine 6-MAM Morphine Morphine, Heroin or Codeine? Morphine can arise in the blood and urine through the administration of morphine itself or through the metabolism of heroin or codeine

19. Morphine, Heroin or Codeine? • The presence of 6-MAM is definitive evidence that heroin was administered • In vivo: 6-MAM quickly disappears from blood • Ex vivo: 6-MAM hydrolyzes spontaneously • The absence of 6-MAM does not exclude the possibility that heroin was administered

20. Morphine, Heroin or Codeine? • If morphine has arisen from codeine, and is present in  blood concentrations, there should be correspondingly  codeine concentrations • Theoretically, 10-20% of codeine  morphine • 0.01 mg/100 mL codeine  20 ng/mL morphine • 0.10 mg/100 mL codeine  200 ng/mL morphine

21. Case Example • 35 year old male, recent release from prison • Found dead in room at group home • Recent injection site at antecubital fossae • Syringe found under the body of the male • Blood morphine concentration – 175 ng/mL • 6-MAM detected in the blood • 6-MAM not detected in the urine • Suggests a rapid fatal intoxication with heroin

22. Fentanyl • Used as a pre-medicant before surgery and in the treatment of moderate-severe pain • Relative potency with morphine – 50-100x  • t½ range: 3 – 12 hours

23. Transdermal Delivery of Fentanyl • Ideal opioid for transcutaneous administration: • Lipophilic – penetrates keratinous layers of skin • Low molecular weight – penetration, diffusion • High potency – minimizes contact area of delivery • Relatively constant blood concentrations • Less frequent administration despite short t½ • Non-invasive and convenient

24. Case Example: Fentanyl • 42 year old woman in hospital • Rx: hydromorphone  morphine  fentanyl • Fentanyl patch provided excellent analgesia • Abdominal pain – requested heating pad • 2 h later: obtunded, miosis, shallow respiration • Heating pad had slipped over fentanyl patch • Increased release of fentanyl from drug reservoir • Increased skin blood flow  increased systemic 

25. Fentanyl in the news • October 23, 2002 - 117 hostages died in a Moscow theatre after special police units use an incapacitating gas to end 3 day stand-off • Agent used was stated to be related to fentanyl • Evidence for opioid intoxication: • Survivors were successfully treated with antagonists • Respiratory failure and aspiration among fatalities

26. Meperidine • Demerol®, Pethidine (UK) • Synthetic, structurally unrelated to morphine • Used in the treatment of moderate-severe pain • t½ range: 2-5 hours

27. Normeperidine • Pharmacologically active metabolite • Toxicity of normeperidine > meperidine • Causes central nervous system stimulation • Agitation • Hyperreflexia • Tremors • Seizures • t½ is 15-30 hours  accumulation • Renal impairment  accumulation

28. Methadone • Synthetic • Long acting • Analgesic potency and efficacy  morphine • t½ range: 13-47 hours, x = 25 hours • Orally effective, may also administer i.v. • Agonist, primarily at mu-receptor • No active metabolites

29. Methadone Maintenance Therapy • Treatment for opioid addiction • Suppress withdrawal symptoms • Reduce drug-seeking behaviour • Two major concerns with MMT • Diversion of methadone to non-treatment populatn • Risk of death during induction into program

30. Diversion of Methadone • Oral methadone mixed with Tang® • Dilutes and deters against injection • Ingested in the presence of a pharmacist • Carry privileges extended after long-term therapy • Diversion of methadone results in: • Accidental deaths of young children (Kool-Aid®) • Deaths among teenage + young adult party-goers • Population of illicit methadone-users

31. Induction of Methadone Rx Increased risk of death when initiating therapy: • Risk of death is greater than before treatment • Daily dosing and long t ½  accumulation • Clinical tolerance to opioids is subjective • Concomitant use of other drugs

32. Case Example • 18 year old male at a party night before • Offered some “orange drink” by stranger • 1 hour post-administration, became unconscious • 2 hours post-administration, +++ vomiting • Helped home to bed after 4 hours • 17 hours post-ingestion, found VSA

33. Case Example • Death in hospital • Antemortem samples seized and submitted • Postmortem blood methadone 0.03 mg/100 mL • Methadone detected in vomit stains on bed-sheets • COD: Methadone intoxication • Methadone-provider at party charged with manslaughter and criminal negligence causing death

34. Opioid antagonists • Naloxone (Narcan®), Naltrexone (Trexan®) • Used to reverse respiratory depression • Used as a diagnostic test in opioid addicts • Used to treat addiction after withdrawal • Caution: Naloxone t½ is 1– 2 hours • Naltrexone t½ is approximately 10 hours

35. Tolerance & Withdrawal

36. Tolerance • Negligible tolerance to miosis and constipation • High degree of tolerance develops to the central nervous system effects of opioids: • Analgesia, Euphoria, Sedation, Respiratory depressn • Requires increased dosages in long-term users •  survivability at high blood concentrations • Conclusions about toxicity of opioids cannot be drawn on measurement of blood levels alone

37. Tolerance • Extent of tolerance will be dependent upon: • Individual variability • Amount of opioid received • Frequency of administration • Tolerance in patients  tolerance in addicts • Cross tolerance exists between opioids

38. Extent of Tolerance • Administration of 60 mg of codeine (in combination with 600 mg acetaminophen) to 32 subjects resulted in plasma codeine concentrations up to 0.02 mg/100 mL • Blood codeine concentrations in 8 deaths attributed solely to codeine intoxication were 0.14 mg/100 mL to 0.56 mg/100 mL • Gjerde and Morland (1991) measured codeine in the blood of an impaired driver at a blood concentration of 0.26 mg/100 mL

39. Lacrimation Yawning Chills Gooseflesh Hyperventilation Diarrhea Insomnia Hostility Hyperthermia Mydriasis Muscle aches Vomiting Abstinence Syndrome Exaggerated rebound to the pharmacological effects of the opioids:

40. Human Performance Impairment

41. Opioids and Driving • Information on opioids and driving tends to arise from laboratory studies • Studies of the effects of opioids on actual driving (closed-course or “real world”) are rare

42. Opioids and Driving • Central nervous system depressants can cause: • Drowsiness • Dizziness • Confusion • Incoordination • Effects are dose-dependent • Effects will be additive with ethanol

43. Example Case • 24 year old woman observed driving • Vehicle was witnessed to drive up onto the shoulder numerous times as well as wandering into the oncoming lane • Vehicle was subsequently described as driving “completely” into the oncoming lane where collision with two other cars occurred

44. Example Case • At hospital, staff located a plastic bag in the driver’s sock containing 14 white tablets identified as Endocet® (Oxycodone) • Speech was slurred, she appeared “dopey” and she drifted off to sleep numerous times • Hospital urine drug screen was positive for opiates, benzodiazepines and cannabinoids

45. Example Case: Challenges • The presence of opioids, cannabinoids and benzodiazepines in the urine indicate past exposure to these drugs • The symptoms observed by the nurses (slurred speech and sleepiness) could indicate the presence of these drugs but may also be attributable to other things • Interpretation complicated by lack of literature and by tolerance to benzos and opioids