Specific Drugs

• Strong Agonists:

  • Phenanthrenes-- strong agonists; management of severe pain

    • Morphine

    • Hydromorphone (Dilaudid)

    • Oxymorphone (Numorphan)

    • Heroin -- not available in United States

  • Phenylheptylamines:

    • Methadone (Dolophine)

      • Pharmacodynamics:

        • Similar to morphine, longer acting

        • Reliable following oral administration

        • Compared to morphine, methadone tolerance and physical dependence develops more slowly

        • Following abrupt methadone discontinuation-- withdrawal symptoms less severe than with morphine

      • Useful drug for detoxification in maintenance of chronic, heroin addict

      • Cross-tolerance with heroin (methadone -- prevents addiction-reinforcing heroin actions)

    • Levomethadyl acetate (L-acetylmethadol):

      • Related to methadone: longer half-life

      • FDA approval for use in detoxification clinics

      • Frequency administration: once every two to three days

  • Phenylpiperidines

    • Meperidine (Demerol); fentanyl (Sublimaze): most widely used phenylpiperidines

      • Meperidine: (Demerol)

        •  Significant anticholinergic (antimuscarinic) effects

          • Contraindicated in the presence of underlying tachycardia

        • Risk of seizures: due to accumulation of CNS active metabolite, normeperidine

      • Fentanyl group: fentanyl (Sublimaze), sufentanil (Sufenta), alfentanil (Alfenta), remifentanil (Ultiva)--differences: biodisposition, potency

        • Sufentanil (Sufenta): 5--7 times more potent fentanyl

        • Alfentanil (Alfenta)

          • Less potent fentanyl

          • More rapid acting

          • Shorter duration of action

        • Remifentanil (Ultiva)

          • Rapidly metabolized: tissue cholinesterases resulting in:

            • Extremely short half-life

  • Morphinans: -- Levorphanol (Levo-dromoran) 

    • Synthetic analgesic

    • Similar to morphine

• Mild/Moderate Agonists

  • Phenanthrenes:

    • Codeine, oxycodone (Roxicodone), or codeine, hydrocodone

      • Less efficacious than morphine or have limiting adverse effects

      • Formulations: combination with aspirin or acetaminophen

  • Phenylheptylamines:

    • Propoxyphene -- related to methadone

      • Low analgesic activity

      • Low efficacy: unsuitable for management of severe pain

      • low abuse potential

  • Phenylpiperidines:

    •  Diphenoxylate; diphenoxylate metabolite (difenoxin)

      • Management of diarrhea

      • Used in combination with atropine

      • Limited abuse potential

    • Loperamide

      • Management of diarrhea

      • Limited abuse potential

• Mixed Agonist-Antagonists & Partial Agonists

  • Phenanthrenes:

    • Nalbuphine

      • Kappa (κ) agonist; Mu (μ) antagonist

      • Parenteral administration

      • Possibly less respiratory depression than with morphine

      • When respiratory depression occurs: may be more difficult to reverse with naloxone

    • Buprenorphine:

      • Long acting, potent

      • Partial Mu (μ) agonist

      • Slowed association for receptor = relative naloxone-reversal resistant

  • Morphinans:

    • Butorphanol (Stadol)

      • Analgesic equivalent to buprenorphine (Buprenex) and nalbuphine

      • More sedation

      • Kappa (k) agonist

  • Benzomorphans:

    • Pentazocine (Talwain); k agonist & weak m antagonist

      • Partial agonist/weak antagonist

    • Dezocine (Dalgan)-- related to pentazocine (Talwain)

      • High affinity for m receptors; less for k receptors

      • Also a mixed agonist-antagonist; similar efficacy to morphine

• Miscellaneous:

  • Tramadol (Ultram)

    • Weak (μ) agonist

    • Norepinephrine/serotonin CNS reuptake inhibition

    • Probably acts through active metabolite; analgesic magnitude is similar to propoxyphene

    • Possibly no advantages over older analgesics

•   Antitussives:

  • Most commonly used opioid antitussives in United States:

    • Dextromethorphan

      • Dextrorotatory stereoisomer of methylated levorphanol derivative

      • Essentially free of analgesic/addictive properties

      • Less constipation compared to codeine

    • Codeine

    • These agents exhibit limited adverse effects

      • Use with caution in patients taking MAO inhibitors

•   Opioid Antagonists: pure antagonists

  • Naloxone (Narcan), naltrexone (ReVia), nalmefene (Revex)

    • Naloxone:

      • Oral route administration: poor efficacy;

      • Injectable: short duration of action (1-2 hours)

      • Metabolism: glucuronide-conjugation

    • Naltrexone:

      • Oral route of administration: well absorbed

      • Rapid first pass metabolism

      • Half-life: 10 hours

        • Single, oral dose of 100 mg:  blocked injected heroin effects for 48 hours

    • Nalmefene:

      • Naltrexone derivative

      • Long acting -- half-life 8-10 hours

• Pharmacodynamics:

  • No effect in the absence of agonist

  • IV administration: rapid opioid effect reversal (1-3 minutes)

  • In a patient with acute opioid overdosage, pure opioid antagonists will normalize:

    • Respiration

    • Level of consciousness

    • Pupil size

    • Gastrointestinal motility

  • In an opioid-dependent patient, taking opioids, pure opioid antagonists will  precipitate and immediate withdrawal (abstinence syndrome)

  • No tolerance develops to opioid antagonists/no abstinence syndrome following discontinuation of antagonist treatment

•   Clinical Use:

  • Naloxone: pure antagonist

    • Major Clinical Application:

      • Management of acute opioid overdosage

      • Note short duration of action (coma relapse possible within 1-2 hours; repetitive dosing may be needed)

  • Naltrexone (ReVia): pure antagonist

    • Suggested for drug "maintenance" for addicts in treatment

    • May be useful in management of alcoholism; purported to reduce alcohol craving;