Clinical Use: opioid analgesics in pain management
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 agonist): may be useful in pain management
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
adequate pain relief: strong agonist opioid required
increased dosages may be necessary to overcome increased pain secondary to increased smooth muscle tone
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 suppression occurs at lower doses than for opioid analgesia
Reduced usage of opioids for cough suppression: due to newer non-analgesic, non-addictive synthetic agents
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
Anesthetic Premedication-- advantageous because of:
Sedative properties
Anxiolytic properties
Analgesic properties
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
Tolerance and physical dependence
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
Individuals tolerant to morphine effects are also tolerant to other opioid agonists
Examples:
Meperidine, morphine, methadone, and related compounds exhibit cross-tolerance to:
analgesic action
euphoriant effects
site of actions
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
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:
Early establishment of therapeutic goals; limits physiologic dependence potential; involve patients in this process
Attempt to limit drug dosage to the established therapeutic level
Particularly for chronic pain management consider alternatives to opioids
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 -- no 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
pregnant women chronically using opioids:
fetus may become physiologically dependent 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, 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
Phenanthrenes-- strong agonists; management of severe pain
Hydromorphone (Dilaudid)
Oxymorphone (Numorphan)
Heroin -- not available in United States
Methadone (Dolophine)
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
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
less potent fentanyl
more rapid acting
shorter duration of action
rapidly metabolized: tissue cholinesterases resulting in:
extremely short half-life
Morphinans: -- Levorphanol (Levo-dromoran)
Synthetic analgesic
Similar to morphine
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
Management of diarrhea
Limited abuse potential
Mixed Agonist-Antagonists & Partial Agonists
Phenanthrenes:
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
long acting, potent
partial Mu (m) agonist
slowed association for receptor = relative naloxone-reversal resistant
Morphinans:
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:
weak (m) agonist
norepinephrine/serotonin CNS reuptake inhibition
probably acts through active metabolite; analgesic magnitude --similar to propoxyphene
possibly no advantages over older analgesics
Most commonly used opioid antitussives in United States:
dextrorotatory stereoisomer of methylated levorphanol derivative
essentially free of analgesic/addictive properties
less constipation compared to 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)
Oral route administration: poor efficacy;
Injectable: short duration of action (1-2 hours)
Metabolism: glucuronide-conjugation
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
naltrexone derivative
long acting -- half-life 8-10 hours
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
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;
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.
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;
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.