Opiates

Snapshot

A 22-year-old male is brought into the emergency department by the police due to depressed mental status. He was found in the park with an empty syringe by his side. Vital signs are notable for a respiratory rate of 7 breaths/min. Physical exam is significant for bilateral track marks, and miotic pupils.

Introduction

Opioids act on mu (most important), kappa, and delta transmembrane receptors in the central and peripheral nervous system
- mu, kappa, and delta receptors are Gi protein coupled
  - inhibition of adenylyl cyclase → decrease cAMP concentration → increased K⁺conductance + decreased Ca²⁺ conductance
    - inhibits presynaptic neurotransmitter release
      - prevents release of acetylcholine, norepinephrine, serotonin, glutamate, substance P
    - inhibits postsynaptic depolarization
Endorphines, enkephalins, dynorphins are examples of endogenous opioid peptides
Pharmacokinetics
- morphine, hydromorphone, oxymorphone undergo first pass metabolism
  - morphine gets metabolized to morphine-6-glucoronide, which is highly active (the active analgesic)
- opioids are generally metabolized by liver into inactive glucuronide conjugates
  - after metabolism they get excreted by the kidneys
- codeine, oxycodone, hydrocodone are metabolized by hepatic cytochrome enzymes
  - cytochrome has genetic variability → variable analgesic response
- meperidine can get metabolized to normeperidine N-demethylation
  - normeperidine can lead to anxiety, tremors, seizures
heroin gets metabolized into 6-monoacetylmorphine, which can be detected on urine screening

Clinical Uses

Physicans should assess patient’s pain medication history prior to prescribing opioids

Drug Classification
Subclass	Medication
Agonists	Morphine, fentanyl, meperidine, codeinepain management
Methadone detoxification and maintenance (agonist) treatment of opioid addictionpain managementhas relatively slow onset of action (30 minutes) and long half life (1 day)
Mixed agonist-antagonist	Buprenorphinemaintenance treatment of opioid addictionpain managementwithdrawal symptoms can induce withdrawal symptoms
Antagonists	Naltrexonetreatment of alcohol dependenceprevention of opioid relapseblocks the effects of opioid if used
Methylnaltrexoneopioid-induced constipation
Naloxone opioid overdosefor reversal of opioid depression
Antitussives	Dextromethorphan
Codeine
Others	Tramadolpain management
Butorphanolpain management
Loperamide/dyphenoxylatemanages diarrhea

Side Effects by System

Opiate Pharmacologic Effects by System
System	Side Effect
Central nervous	AnalgesiaEuphoria/dysphoriaMiosistolerance does not develop in miosis SedationCough reflex inhibition
Cardiovascular	VasodilationHypotension
Pulmonary	Respiratory depression
Gastrointestinal	Constipationtolerance does not develop to constipationIncreased tone/pressure in the biliary sphincterNausea and vomiting
Genitourinary	Urinary retentionMay prolong labor
Endocrine	Increases antidiuretic hormone (ADH) and prolactin secretionDecrease luteinizing hormone (LH) secretion
Dermatological	PruritusFlushing

Toxicity

Acute overdose triad
- miosis, respiratory depression, coma
  - respiratory depression due to ↓ response to ↑ pCO₂
Tolerance
- a decrease in pharmacologic effect after prolonged drug usage
  - secondary to down-regulation of opioid receptors
- miosis and constipation are not affected by tolerance
- NMDA receptor antagonists (eg, ketamine) and delta-receptor antagonists have been reported to prevent opioid tolerance
Withdrawal side effects
- pain originating from the CNS
- flu-like symptoms
  - lacrimation, sweating, rhinorrhea, salivation
  - muscle cramps and spasms
- yawning
- diarrhea
Drug specific side-effects
- meperidine (seizures and serotonin syndrome with MAOIs/SSRIs)
  - only opioid to cause mydriasis vs miosis (pinpoint pupils)
nalbuphine (hallucinations)

Contraindications

Head trauma
- ↑ pCO₂ can cause vasodilation and ↑ intracranial pressure
Pulmonary dysfunction
- patient may not be able to compensate for respiratory depression
Liver/kidney dysfunction
- poor excretion mechanisms may result in accumulation
Adrenal/thyroid deficiencies
- opiates may show greater effects
Pregnancy
- fetus may show dependency
- exception is meperidine