Opioid Analgesics

Opioids
Opioids bind to opioid receptors to produce analgesia.
There are four major types of opioid receptors (shown in the next
slide)
All these receptors are GPCRs

Reduces cAMP by inhibiting AC (Gi)

Inhibits voltage-gated Ca channels (presynaptic terminals)
Activates inwardly rectifying K channels (postsynaptic terminals)
These processes causes membrane hyperpolarization and decreases
neuronal excitability.

Opioid activation inhibits the presynaptic release and postsynaptic

response of to excitatory neurotransmitters from nociceptors

Organ System Effects

CNS
In general, they decrease cerebral blood flow, cerebral oxygen
consumption, and ICP if normocarbia is maintained via
artificial ventilation
Almost no effect on EEG patterns although large doses are
associated with slow wave activity
Seizures have been associated with the meperidine metabolite
normeperidine.
Nausea
Via stimulation of chemoreceptor trigger zone
May also have a vestibular component as ambulation tends to increase
incidence
Noted more in smaller doses

Organ System Effects

CNS
Analgesia
Affect both the physical and emotional aspects of pain

Sedation
Occurs more in the elderly than in young healthy individuals.
If combined with centrally acting depressants like sedatice-hypnotics, it
can result in very deep sleep
More closely related with phenanthrene derivatives (e.g. morphine)

Organ System Effects

Respiratory
Respiratory depression
Due to opioid binding in the neurons in the respiratory centers of the
brainstem
Particularly RR
Increases Paco2 and blunts the response to CO2
Apneic threshold is increased and hypoxic drive is decreased

Histamine induced bronchospasm with morphine and

meperidine
Truncal rigidity
Most apparent when high doses of highly lipid soluble opioids (e.g.
fentanyl, sufentanil, remifentanil, and alfentanil) are given rapidly
Can be prevented with the concomitant use of neuromuscular blockers

Organ System Effects

Cardiovascular
Used alone, they generally have few direct effects on the
heart
Meperidine increases the heart rate due to its structural
similarity with atropine
Morphine, fentanyl, sufentanil, remifentanil, and alfentanil
induce vagus nerve mediated bradycardia at very large doses
Decrease in BP due to bradycardia, vasodilation, and
decreased sympathetic reflexes
More pronounced when used with benzodiazepines (fentanyl and
sufentanil are further associated with decreased CO)
Bolus doses of morphine, hydromorphone, and meperidine can induce
histamine release causing a significant drop in BP

Organ System Effects

Cardiovascular
Intraoperative hypertension in large dose opioid or nitrous
oxide-opioid
Inadequate depth of anesthesia
tx: addition of other anesthetic agents
If HPN persists, add vasodilators or antihypertensives

Gastrointestinal
Biliary colic
Due to opioid induced contraction of the Sphincter of Oddi

Organ System Effects

Gastrointestinal
Biliary spasm
Can mimic common bile duct stone on cholangiography
Reversed by naloxone or glucagon

Constipation
Due to reduced GI motility
Other GI effects are decreased by tolerance except for constipation
Development of peripheral opioid antagonists (methylnaltrexone,
alvimopan) increases GI motility especially in patients who need
chronic opioid use

Other Effects
Miosis
Not affected by tolerance so it is a valuable indicator of
toxicity even in highly tolerant addicts

Temperature regulation
receptor activation results in hypothermia
receptor activation results in hyperthermia

Tolerance
Develops most readily when large doses are given at short
intervals

Opioid agonists
Morphine

Prototypical opioid
Action on 1 is responsible for analgesia
Action on 2 is responsible for respiratory depression
Spinal analgesia is mediated by the receptor
Given orally (there is first pass effect), rectally, via IM, IV, and
intrathecally
Morphine is metabolized by the liver via conjugation with glucuronic
acid
T is ~2h
Excretion is renal. Most of what is excreted has been metabolized

Opioid agonists
Levorphanol

Has affinity for MOR, DOR, and KOR

Available for oral, intravenous, and intramuscular administration
Effects are like morphine but with decreased nausea and vomiting
T:12 16 hours

Meperidine
Predominantly MOR
Strong analgesic action
Sometimes causes CNS excitation (tremors, muscle twitching,
seizures)
Due to accumulation of the metabolite normeperidine (t 15 20h)

Opioid agonists
Meperidine
Has well-known local anesthetic properties particularly noted after epidural
administration
IV administration markedly increases HR
Does not cause as much constipation as morphine due to its greater ability to
cross the CNS therefore needing lower concentrations to produce analgesia
Absorbed by all routes of administration
Rate of absorption may become erratic after IM

Metabolized chiefly in the liver

T = 3h
Not recommended for use longer than 48h due to accumulation of
normeperidine

Opioid agonists
Fentanyl and its congeners
Fentanyl and sufentanil

Relatively short time to peak analgesia

Rapid termination after small boluses
Minimal direct depressant effects on myocardium
MAC sparing has the ability to significantly decrease the dosing
requirement for volatile agents

Muscle rigidity is more commonly seen in fentanyl and its congeners

after administration of high doses
Respiratory depression is more rapid than in other agonists but also
has shorter duration
High doses can cause neuroexcitation and seizure-like activity(rare)

Opioid agonists
Fentanyl and its congeners
Minimal effects on ICP when Paco2 is not allowed to rise
Only mildly decreases HR and BP primary anesthetic for
patients with poor cardiac function
These drugs do not release histamine
Highly lipid soluble and therefore crosses BBB easily
Time to peak analgesic effectis around 5 minutes compared to
morphine and meperidine (15 minutes)
Fentanyl is ~100x more potent than morphine; sufentanil is
~1000x more potent than morphine

Opioid agonists
Remifentanil

Potency is similar to that of fentanyl

Pharmacological properties are similar to fentanyl and sufentanil
Analgesia occurs within 1-1.5 minutes.
Remifentanil is metabolized in the plasma t ~ 8 20 minutes
Elimination is independent of hepatic metabolism and renal excretion
No prolongation of effect with repeated dosing or prolonged infusion
Primary metabolite has 0.025-0.05% of the potency of the parent compound

For short, painful procedures that require intense analgesia

Opioid agonists
Methadone
Long acting MOR agonist with pharmacological properties similar to
morphine
Miotic and respiratory depression are seen > 24h after administration
Absorbed well in the GI tract
Undergoes extensive biotransformation in the liver and is excreted in
the urine and bile along with the unchanged drug.
Mount excreted in the urine is increased when urine is acidified.
T 15 40h
Rifampicin and phenytoin accelerate drug metabolism
Associated with prolonged QT onterval

Opioid agonists
Tramadol
Synthetic codeine analog
Weak MOR agonist
Part of its analgesic effect is due to inhibition of
norepinephrine and serotonin uptake
As effective as morphine for mild to moderate pain BUT NOT
for chronic and severe pain
68% bioavailability when given as a single oral dose and 100%
bioavailable when given IM.

Opioid agonists
Tramadol
Side effects: nausea, vomiting, dizziness, dry mouth, sedation,
headache.
Respiratory depression is less when compared with morphine
Constipation is less than in codeine
Can cause or exacerbate seizures

Not entirely reversible by naloxone

Respiratory depression is reversible by naloxone
Use of naloxone increases risk of seizure in patients exposed to
tramadol

Has been shown to reinitiate physical dependence in those

previously dependent on opioids