Opioids

Teri Martin

[email protected]

November 4, 2003

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

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

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)

Basic Pharmacology of Opioids

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)

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

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

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 CO 2 • Truncal rigidity may complicate  respiration • Respiratory failure the major toxicity of opioids • Analgesia and respiratory depression are inseparable and increase with dose in parallel

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

Major effects of opioids - CNS

• Miosis • Nausea and Vomiting • Cough suppression

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

Symptomatology in Overdose

• Euphoria + + + • Unconsciousness • Respiratory depression • Pulmonary edema • Seizures • Hypothermia • Death

Example Opioids

Morphine, Heroin, Codeine, Fentanyl, Meperidine and Methadone

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

Heroin

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

Codeine

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

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

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  • 0.01 mg/100 mL codeine  • 0.10 mg/100 mL codeine  morphine 20 ng/mL morphine 200 ng/mL morphine

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

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

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

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 

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

Meperidine

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

Normeperidine

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

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

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 populat n • Risk of death during induction into program

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

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

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

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

Opioid antagonists

• • • Naloxone (Narcan®), Naltrexone (Trexan®) 1. Used to reverse respiratory depression 2. Used as a diagnostic test in opioid addicts 3. Used to treat addiction after withdrawal Caution: Naloxone t½ is 1– 2 hours Naltrexone t½ is approximately 10 hours

Tolerance & Withdrawal

Tolerance

• Negligible tolerance to miosis and constipation • High degree of tolerance develops to the central nervous system effects of opioids: • Analgesia, Euphoria, Sedation, Respiratory depress n • • 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

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

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

Abstinence Syndrome

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

Human Performance Impairment

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

Opioids and Driving

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

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

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

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