•  Analgesia

  • Opioids most effective: severe, constant pain

  • Opioids less effective: sharp, intermittent pain

  • Selection and evaluation of opioids-- Factors:

    • Route of Administration (oral or parenteral)

    • maximal efficacy

    • therapy duration

    • previous experience

• Management of cancer pain; pain associate with other terminal illnesses -- Principles

  • adequate treatment

  • concerns about dependence and tolerance -- secondary consideration

  • fixed-interval opioid administration: more effective than dosing on demand

    • slower released dosage forms (new) -- may provide longer and more consistent analgesia levels

  • Addition of stimulants (e.g. amphetamines): enhance opioid analgesic effects

  • clonidine (alpha₂ adrenergic receptor andagonist): may be useful in pain management

•  Obstetrical labor:

  •  minimize fetal/neonatal opioid depression

  • opioid depression: reversible by naloxone

  • phenylpiperidine agents (e.g. meperidine): may produce less depression, especially respiratory depression in the newborn compared to morphine

• Renal/Biliary Colic:

  • adequate pain relief: strong agonist opioid required

  • increased dosages may be necessary to overcome increased pain secondary to increased smooth muscle tone

•  Acute Pulmonary Edema:

  • IV morphine: relieves dyspnea secondary to pulmonary edema

  • Possible mechanism of action:

    • reduced awareness of shortness of breath

    • reduced patient anxiety

    • reduced preload (decreased vascular venous tone)

    • reduced afterload (decreased peripheral resistance)

•  Cough:

  • cough suppression:occurs at lower doses than for opioid analgesia

  • reduced usage of opioids for cough suppression: due to newer non-analgesic, nonaddictive synthetic agents

• Diarrhea:

  • all diarrhea controllable with opioids

  •  if diarrhea secondary to infection, treat the infection with appropriate chemotherapy

  • current antidiarrheals utilize agents selected for the gastrointestinal tract with limited CNS actions

•  Opioids and Anesthesia:

  • Anesthetic Premedication-- advantageous because of:

    • sedative properties

    • anxiolytic properties

    • analgesic properties

• Intraoperative Use --general:

  • adjuncts to other anesthetics

  • at high doses: primary anesthetic component

    • cardiovascular surgery

    • other high-risk surgery (desire to minimize cardiovascular depression)

• Intraoperative Use -- regional

  • epidural

  • subarachnoid spaces

  • long-lasting analgesia:

    • catheter inserted into the epidural space

      • analgesia following morphine or other strong opioid agonist

      • respiratory depression may occur -- requiring naloxone

      • common side effects: pruritus, nausea, vomiting-- naloxone reversible

• Other Routes of Administration:

  • rectal suppositories

  • epidural: action of the spinal level

  • transdermal patch -- systemic effects;

    • stable drug plasma levels

    • better pain control -- no need for repeated parenteral injections

    • fentanyl -- most successful opioid for transdermal use; effective for management to constant pain associated with malignancies

  • intranasal: limited use {patients who cannot tolerate oral medication or repeated parenteral drug injections

  • patient controlled analgesia (PCA) -- common use

    • patient typically use intravenous injection

    • effective in postoperative pain management; less opioid may be used

    •  potential problems:

      • equipment malfunction including improper programming/set up which may lead to improper drug delivery

•  Toxicities/Side effects:

  •  Tolerance and physical dependence

    • Tolerance:

      • clinical appearance: two-three weeks following frequent administration of therapeutic doses

      • large doses -- short intervals: most rapid tolerance development

      • small doses -- long intervals: least rapid tolerance development

• Cross-tolerance:

  • individuals tolerant to morphine effects are also tolerant to other opioid agonists

  • Examples:

    • meperidine, morphine, methadone, and related compounds exhibit cross-tolerance to:

      1. analgesic action

      2. euphoriant effects

      3. site of actions

      4. restaurateur effects

• Physiologic Dependence:

  •  Failure to administer drug: leads to withdrawal or abstinence syndrome (significant rebound from pharmacologic opioid effects).

• Antagonist-precipitated withdrawal: rapidly developing, powerful abstinence syndrome cause by administration of naloxone or another antagonist

•  Psychologic Dependence:

  • Basis of compulsive use:

    • euphoria

    • sedation

    • indifference to stimuli

    • abdominal effects -- likened to intense sexual orgasm

  •  Despite the risk of opioid dependence, adequate pain relief should never be withheld just because the opioid has potential for abuse or because of the more complicated prescribing requirements for narcotics.

• Prescribing Principles and Guidelines:

  1. early establishment of therapeutic goals; limits physiologic dependence potential; involve patients in this process

  2. attempt to limit drug dosage to the established therapeutic level

  3. particularly for chronic pain management consider alternatives to opioids

  4. frequently re-evaluate therapeutic needs for opioids use

•  Management/Treatment of Opioid Overdosage:

  • Diagnosis --

    • may be straightforward (known addict; miosis; needle marks)

    • may be difficult (comatose patients -- known history available)

  • Treatment --

    • intravenous naloxone-- rapid coma reversal if due to opioid overdose (no effect if coma is due to overdose with a sedative hypnotic)

•  Contraindications/Therapeutic Cautions:

  • for patients receiving the opioid agonists:

    • do not administer a mixed agonist-antagonist (e.g. pentazocine): withdrawal may be precipitated;

    • diminishment of analgesia may occur

  •   in patients with head injuries: opioids may induce a further increase in intracranial pressure

  • Pregnancy:

    •  pregnant women chronically using opioids:

      •  fetus may become physiological independent in utero

      • withdrawal symptoms may appear in the early postpartum time frame

      • management of fetal withdrawal symptoms:

        • mild: management with diazepam

        • more severe: oral methadone; tincture of opium (paregoric)

  • Patients with impaired lung function:

    • acute respiratory failure: may be precipitated by opioid-mediated respiratory depression

  • Patients with impaired hepatic or renal function:

    •   half-life may be prolonged in patients with impaired renal function; e.g. morphine and its active metabolite morphine-6-glucuronide may accumulate (reduction in dosage)

    •   since the liver is the primary metabolic site for morphine and related compounds, very use in patients with pre-hepatic coma may be inappropriate

  •  Patients with endocrine disorders:

    • Adrenal-insufficiency (Addison's disease)or hypothyroidism (myxedema): prolonged, exaggerated opioid responses

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

          • 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)--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)evorphanol

    • synthetic analgesic

    • similar to morphine

• Mild/Moderate Agonists

  • Phenanthrenes:

    • ccodeine, oxycodone (Roxicodone), ahead 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 (k) agonist; Mu (m) 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 (m) 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 (m) 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

        • single, oral dose of 100 mg: they 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;