Martin Pain Meds Flashcards
Opioid Full Agonists
Morphine (prototype) Fentanyl Heroin Methadone Hydromorphone Oxymorphone
Opioid partial agonists
Codeine
Hydrocodone
Oxycodone
Opioid mixed agonist/ antagonist
Buprenorphine
Opioid Antagonists
- Naloxone (Narcan)
use for overdose of opioids
Weak Opioid Agonist/Reuptake Inhibitors
Tramadol [Ultraam]: 5-HT uptake blockade, NE uptake blockade, weak mu-receptor agonist
Tapentadol – weak mu receptor agonist & NE reuptake blocker
Non-Opioid Analgesics
Acetaminophen, Aspirin and other NSAIDs, & Selective COX-2 Inhibitors, i.e., Celebrex
Analgesia:
Attenuation of pain perception without the loss of consciousness.
Analgesia is accomplished by raising the pain threshold at the level of the spinal cord and altering the brain’s perception of pain
Patients treated with morphine are still aware of the presence of pain, but the sensation is not unpleasant.
Given to a person who does not have pain, the effects may be unpleasant and may cause nausea and vomiting
Analgesia: Going from 10 –> 0
Pain is a subjective experience.
It is only the patient, not the clinician, who can describe the intensity of pain.
Pain has a sensory and a reactive component:
Sensory
Pain is perceived as a result of direct stimulation of pain receptors.
Reactive
Intensity of pain is dramatically altered by the level of anxiety and the stress response related to the original insult.
Narcotic:
Archaic term, more legal than medical, referring to any substance producing stupor associated with analgesia (usually associated with derivatives of opium).
Opiates:
Natural products and derivatives obtained from the opium poppy (e.g., opium, morphine, heroin, codeine).
Opioids:
The class of compounds that bind to opioid receptors. Includes agonists, antagonists, partial agonists and mixed agonist/antagonists.
Endogenous opioid agonists:
endorphin, enkephalins, dynorphins, and others
Opioids and Their Receptors
All opioid drugs act by binding to specific opioid receptors in the CNS, on nerve terminals in the periphery, on cells in the GI tract, and other locations in the body to produce effects that mimic the actions of endogenous opioid peptide neurotransmitters
Endorphins- b-endorphin
Enkephalins- Met-enkephalin, Leu-enkephalin
Dynorphins- Dynorphin A, Dynorphin B
Synthesis of Endogenous Opioid Peptides
Pro-Opiomelanocortin (POMC) –> ACTH, beta lipotropin –> endorphins, etc.
Mechanism for Opioid-Induced Analgesia
Periaqueductal gray – opiates inhibit GABA release which increases inhibitory nerve activity regulating projections to the medulla that attenuate dorsal horn excitability.
Spinal cord – opiates act presynaptically to block Ca++ influx and neurotransmitter release or postsynaptically to open K+ channels causing hyperpolarization.
mu (μ) opioid receptors (m1, m2)
Endorphins>enkephalins>dynorphins
Supraspinal & spinal analgesia; sedation; inhibition of respiration; slowed GI transit; modulation of hormone & neurotransmitter release
kappa (k) opioid receptors (k1, k2, k3)
Enkephalins> endorphins = dynorphins
Supraspinal & spinal analgesia; modulation of hormone & neurotransmitter release
delta (δ) opioid receptors (d1, d2)
Dynorphins>endorphins>enkephalins
Supraspinal & spinal analgesia; psychomimetic effects; slowed GI transit
Other ligands
endomorphin-1 and -2
Other receptor subtypes
sigma (σ)
TLR-4
ORL-1 (orphanin opioid-receptor-like subtype1):
A cloned “orphan” receptor
similar structure to opioid receptors
different function
no effects on pain, hyperalgesia, or inflammation
different ligands – nociceptin = orphanin FQ
debate still continues
Opioid Receptor Signal Transduction
m, k, d opioid receptors are all GPCR
These receptors can couple to Gi, Gq, and possibly other G proteins
Principle known signal mechanisms:
1. Inhibit cyclic AMP production
- Open G-protein modulated K+ channels allowing K+ efflux from the cell and hyperpolarization, slow IPSP
- Reduce presynaptic Ca++ influx which inhibits neurotransmitter release, glutamate, * Substance P (which mediates pain perception), and others
Receptor Distribution and Function- Brain stem
opioid receptors influence respiration, cough, nausea, & vomiting, BP, pupillary diameter, stomach secretions
Receptor Distribution and Function- Medial thalamus
this area mediates deep pain that is poorly localized
Receptor Distribution and Function- Spinal cord
receptors here are involved with receipt and integration of incoming sensory information, activation of these receptors ** attenuates painful afferent stimuli.
Receptor Distribution and Function- Hypothalamus
receptors in this CNS area affect neuroendocrine secretion.
Receptor Distribution and Function- Limbic system
has a high density of opioid receptors in the amygdala. These receptors influence emotional behavior.
Receptor Distribution and Function- Periphery
– peripheral sensory nerve fibers and nerve terminals, inhibit Ca++ influx and the release of excitatory (glutamate) and pro-inflammatory (Substance P) substances
Receptor Distribution and Function- Immune cells
have opioid receptors, function is largely unknown
opioid receptors and the effects of opioids
(m) mu receptors- important for most of the classical effects described for opioids including:
analgesia
euphoria
miosis
respiratory depression
physiological dependence
reduced GI motility (constipation)
(k) kappa receptors
less involvement in abuse potential and physical dependence
important for effects of non-selective and some of the mixed agonist-antagonist opioids including: butorphanol and nalbuphine
Stimulation of kappa receptors results in:
- dysphoria
psychotomimetic responses (disoriented or depersonalized feelings)
less miosis and respiratory depression than mu agonists
analgesia
sedation
vasodilation
increased urinary output
Opioid Effects: CNS
analgesia - both affective and sensory components of pain are affected
euphoria/dysphoria - due to effects at mu and kappa receptors, respectively
sedation
respiratory depression - * cause of death in overdose (decreased response of brainstem to CO2)
cough suppression - different receptors from those responsible for other opioid actions (sigma ??) Over-the-counter cough suppressant = dextromethophan and codeine also used
- recent ban on OTC cough and cold medications (hydrocodone cough suppressant) sold for use in babies < 2 years old
miosis- due to indirect parasympathetic actions (atropine blocks).
nausea and vomiting - stimulation of the chemoreceptor trigger zone of the brainstem.
Miosis and tolerance
TEST QUESTION
Little or no tolerance develops to this miosis, so all abusers show pinpoint pupils. This is important diagnostically, because many other types of causes of coma and respiratory depression produce dilation of the pupil. Mydriasis occurs in opiate overdose only if asphyxia develops.
Opioid Effects: Cardiovascular System
No major effects on blood pressure or heart rate
Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase the cerebrospinal fluid (CSF) pressure. Therefore, use of * opioids is usually contraindicated in individuals with severe brain injury. *
Opioid Effects: GI System
- Constipation
decreased GI motility secondary to increased tone (due to effects both in the CNS and on the local enteric nervous system).
Little or no tolerance development
- Constipation is a significant problem, especially for patients on chronic therapy
Opioids can also increase biliary tract pressure due to contraction of the gallbladder and constriction of the biliary sphincter
Opioid Effects: Histamine Release
Opioids release histamine from mast cells, causing urticaria, sweating, and vasodilation.
Because opioids can cause histamine-induced bronchoconstriction, asthmatics should not receive the drug.
High Efficacy Opioids
Strong (Full) Agonists: Morphine (prototype) Fentanyl Methadone Heroin
Low Efficacy Opioids
Weak (Partial) Agonists
Codeine
Hydrocodone
Oxycodone
Pharmacokinetics
Most opioids are well absorbed when given SC, IM, or PO
Variable first-pass effect
TEST Q? **Morphine high first pass metabolism, so oral doses must be higher than IV doses. This is reflected in oral:parenteral potency ratio.
- Codeine and oxycodone less first pass metabolism
Most opioids become widely distributed in tissues, CNS, lungs, liver, muscle, and even the *fetus (don’t use during labor)
- Fentanyl highly lipophilic, slowly metabolized, but short acting because distributes to fatty tissues*
Most of these drugs metabolized in liver by Phase II glucuronidation; some metabolites still active, e.g., morphine 6-glucuronide, the major metabolite of morphine, is 2x more potent than morphine.
Morphine: The Prototypic Opioid Analgesic
binds to all opioid receptor subtypes. highest affinity is for mu receptors. low oral:parenteral potency ratio high efficacy for analgesia high abuse potential can produce physical dependence * HIGH ADDICTION POTENTIAL
Clinical Uses of morphine-Analgesia
Best with severe, constant pain. Not as effective with sharp, intermittent pain.
Although dulled, pain is still perceived. Reaction to pain is diminished.
Match drug and dose to the intensity of pain
clinical uses of morphine- Acute Pulmonary Edema
Relief from dyspnea associated with left
ventricular failure may be due to:
reduced perception of shortness of breath
anxiolytic effects ( anxiety)
reduction in cardiac preload and afterload
Morphine is also used as first-line treatment to relieve pain and anxiety associated with * acute myocardial infarction.
clinical uses of morphine- Cough Suppression
Obtained at doses lower than needed for analgesia.
Possibly due to activity at non-opioid (sigma) receptors.
Dextromethorphan (no analgesia)
Codeine (low doses)
clinical uses of morphine- Diarrhea
Obtained at lower doses than needed for analgesia.
Loperamide (Imodium)
Diphenoxylate (+ atropine) (Lomotil)
Difenoxin (+ atropine) (Motofen)
Fentanyl
100-fold more potent than morphine
used in anesthesia and chronic, severe pain
highly lipophilic and has a * rapid onset and short duration of action (15 to 30 minutes)
Administered as IV, epidural injection, or intrathecal injection
Epidural is used for analgesia postoperatively and during labor
An oral transmucosal preparation (cancer patients) and a transdermal patch are also available.
Sufentanil, alfentanil, and remifentanil are similar to fentanyl but only used during anesthesia
Methadone
Synthetic, orally effective opioid
Equally potent with morphine but induces less euphoria and has a *longer duration of action
Used as an analgesic
- Used for controlled withdrawal of dependent abusers of heroin and morphine
- *Orally administered methadone is substituted for injected opioid
- *The patient is slowly weaned from methadone
- *Methadone causes a withdrawal syndrome that is milder but more protracted than that of other opioids
Meperidine (Demerol®)
Synthetic opioid used for acute pain
Binds to both mu and kappa receptors
Causes respiratory depression
Dilates pupils instead of miosis
Not useful for treatment of diarrhea or cough
- Less effects on smooth muscle so can be employed in obstetrics
- Toxic metabolite can accumulate at high doses and cause seizures so it should not be used for chronic treatment (less than 48 hrs)
Heroin
Diacetylmorphine
Schedule I – no legal, medical use
3x more potent than morphine
Greater lipid solubility; gets into brain more rapidly than morphine
More exaggerated euphoria
Converted to morphine in the body but its effects last half as long
Codeine
(mu effects seen starting with low doses; kappa effects at high dose)
Hydrocodone
(relatively pure mu; probably misclassified [a DEA Schedule-III agent])
Oxycodone
relatively pure mu
Derivative of codeine
High oral: parenteral potency ratio (lower 1st pass metabolism)
Sustained release product: OxyContin™
In combination products:
- Oxycodone/acetaminophen (Percocet, others)
- Oxycodone/aspirin (Percodan, others)
Intermediate Efficacy Partial Agonist often combined with NSAIDs to increase analgesic efficacy – These are the most widely prescribed outpatient analgesics
Tylenol with Codeine
Codeine/aspirin (Empirin compound)
Hydrocodone/acetaminophen (Vicodin, Lortab, others)
Oxycodone/acetaminophen (Percocet, others)
Oxycodone/aspirin (Percodan, others)
Mixed Opioid Agonist-Antagonists- more details
Buprenorphine,
These agents have variable actions at different receptor subtypes.
A given agent may be a full agonist at one receptor subtype and a partial agonist at another.
A given agent may be an agonist at one receptor subtype and an antagonist at another.
Partial agonists act as antagonists when given with a full agonist.
Buprenorphine
A partial agonist at mu receptors
Has high affinity for receptors so very slowly dissociates
- Major use is for opioid detoxification
Less severe and shorter duration of withdrawal compared to methadone
Opioid Agonist/Antagonists: Agonist Properties
- analgesia - differs among compounds but are normally used for moderate pain
mu agonist toxicity, including respiratory depression, can be seen at high doses
some (e.g., codeine) elicit psychotomimetic effects (visual hallucinations, dysphoria, nightmares and depersonalization) (kappa receptors)
Opioid Agonist/Antagonists: Antagonist Properties
block the effects of full agonists
- precipitate withdrawal symptoms in physically dependent individuals
Opioid Antagonists
uses
- naloxone (Narcan) short acting; injected
naltrexone (ReVia) long acting; oral - Used to treat opioid overdose
Administration of an antagonist to a patient who is dependent on opioids will precipitate a withdrawal syndrome
useful in treating some drug-free addicts
Opiate Reward Pathways
GABAergic pathways
Dopaminergic pathways
Opiate agonists reduce excitability and transmitter release. This inhibition in the VTA on GABA interneurons or in the NAc reduce GABA-mediated inhibition and increase outflow from the ventral pallidum (VP), which appears to correlate with a positive reinforcing state (enhanced reward).
Opioid Tolerance
Tolerance means higher plasma concentrations must be achieved to obtain the same level of effect
Dose-response curve shifts to the right
Receptors down-regulated and signal transduction pathways desensitized
tolerance (cross-tolerance) can develop to (among) all opioid agonists
rate of development varies among agents but generally develops faster with more potent drugs and/or higher doses
starts with first dose but doesn’t become clinically relevant for 2-3 weeks (@ normal therapeutic doses)
tolerance can be profound (as great as 35-fold)
Opioid Tolerance develops to these effects:
Analgesia
Respiratory depression
Euphoria
Sedation
Opioid Tolerance does not develop to:
Miosis
Constipation
Opioid Dependence
accompanies tolerance development
may include both physical and psychological dependence
withdrawal syndrome is seen upon cessation of drug use or upon treatment with opioid antagonists or mixed agonist/antagonists (precipitated withdrawal).
Symptoms can be almost unbearable
Very rare, but withdrawal can cause death
Opioid Withdrawal: Symptoms
rhinorrhea lacrimation yawning chills piloerection hyperventilation hyperthermia mydriasis vomiting diarrhea anxiety
Opioid Withdrawal: Treatment
from a medical standpoint, no pharmacologic treatment is usually necessary (contrast this with sedative-hypnotic/alcohol withdrawal). Monitor patient.
treat with clonidine (α2-adrenergic agonist)
- reduces cravings
- reduces anxiety symptoms
- reduces sympathetic outflow
Opioid Overdose: Signs/Symptoms
Primary (triad)
lethargy or coma
depressed respiration
pinpoint pupils (normoxic)
Secondary hypotension hypothermia with cold or clammy skin pulmonary edema convulsions (primarily in children) hypoxia with dilated pupils
Opioid Overdose: Treatment
administer opioid antagonist (e.g., naloxone)
support respiration and other vital functions
identify most likely drug
if determined that other drugs were also ingested, treat for the overdose of these drugs accordingly
