Specific Drugs

• Strong Agonists

  • Phenanthrenes are strong agonists, often effecting in management of severe pain

    • Morphine

    • Hydromorphone (Dilaudid)

    • Oxymorphone (Numorphan)

    • Heroin,  not available in United States

  • Phenylheptylamines:

    • Methadone (Dolophine)

      • Pharmacodynamics:

        • Similar to morphine but 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

          • May have a negative inotropic cardiac effect

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

      • Fentanyl group: fentanyl (Sublimaze), sufentanil (Sufenta), alfentanil (Alfenta), remifentanil (Ultiva) exhibit differences in, for example biodisposition and 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 is 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 and 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 (κ) agonist

  • Benzomorphans:

    • Pentazocine (Talwain); κ agonist and weak μ antagonist

      • Partial agonist/weak antagonist

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

      • High affinity for μ receptors; less for κ 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 --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

        • Sngle, 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; 

1. Way, W.L., Fields, H.L. and Way, E. L. Opioid Analgesics and Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 496-515.

2. Schuckit, M.A. and Segal D.S., Opioid Drug Abuse and Dependence, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2508-2512;

3. Coda, B.A. Opioids, In Clinical Anesthesia, 3rd Edition (Barash, P.G., Cullen, B.F. and Stoelting, R.K.,eds) Lippincott-Ravin Publishers, Philadelphia, New York, 1997, pp 329-358.