Opioid (Narcotic) Analgesics and Antagonists

strong analgesics (mu agonists)

morphine

codeine

fentanyl

heroin

hydrocodone

hydromorphone

merperidine

methadone

oxycodone

hydrocodone

vicodin

lortab

norco

oxycodone

percocet

oxycontin ER

partial agonists and mixed agonist/antagonist analgesics

pentazocine (talwin)

buprenorphine (buprenex, subutrex, suboxone)

butorphanol (stadol)

tramadol (ultram)

tapentadol (nucynta)

opioid antagonists

naloxone

naltrexone

methylnaltrexone

alvimopan

naloxegol

term derived from opium

opiate

term for having properties similar to drugs derived from opium

opioid

technically means “sleep inducing” but is commonly taken to mean opioid

narcotic

what is the essential moiety of morphine molecule

phenyl N methyl piperidine

substitutions for morphine

methyl, acetyl, allyl or methylcyclopropyl

methyl substitution in phenyl N methyl piperidine

methyl at position 3 or 6

codeine: 3 - 0 methyl morphine

more slowly metabolized

acetyl substitution in phenyl N methyl piperidine

acetyl at position 3 or 6

heroin: 3,6 diacetyl morphine

acetylation makes it more lipid soluble, can cross BBB easily

allyl or methylcyclopropyl substitution in phenyl N methyl peperidine

sub at position 17, confers antagonist

pain pathway spinal tract

nociceptor synapses on interneuron in dorsal gray matter of spinal cord

crosses over and STT travels up contralaterally to synapse in thalamus

third order neuron synapses in sensory cortex and limbic system

where does opioid act on the pain pathway

primarily the opioid acts on the ascending fiber in the thalamic synapse to the third order neuron

• acts on same receptor as enkephalins (mu/opioid receptors)

can also act on dorsal horn of spinal cord to decrease transmission of pain through spinal analgesia by injected morphine into substantia gelatinosa

STT pathway

nociceptor sends signal through to dorsal root ganglion, substance p released to receptors and signal travels up STT

descending neuron releases enkephalin to inhibit substance P release

turns off transmission of pain impulse

mu receptors are located in the

brainstem

spinal cord

limbic areas

mu receptors mediate

supraspinal analgesia

spinal analgesia

sedation

respiratory depression

euphoria and dependence

k receptors are located in the

brainstem and spinal cord

lesser extent: limbic system

kappa receptors mediate

some spinal analgesia and supraspinal analgesia

miosis

sedation

dysphoria

presynaptic inhibition effects on ascending pathway

blocks Ca channels to prevent NT release

postsynaptic inhibition effects on ascending pathway

prevent postsynaptic neuron from hyperpolarizing

inhibit ascending pain pathway drugs

acetaminophen

NSAIDs

lidocaine

capsaicin

menthol

opioids

cannabinoids

ketamine

drugs that facilitate descending pain modulation

antiepileptics (gabapentinoids, sodium channel agents)

antidepressants

cannabinoids

ketamine

common amino acid chain in opioids

tyr-gly-gly-phe-met

morphine effects

CNS depressant

analgesia, floating dream-like state sedation and mental clouding

relief of anxiety and apprehension

euphoria

• sometimes 10% dysphoria (anxiety, apprehension, hallucination)

• more common in females than males

morphine overdose

graded depression of cortical function

mental clouding and sedation → hypnosis or stupor → coma → death

pathways underlying rewarding properties of opioids

by activating mu receptors you get reinforcement effect from nucleus accumbens

opioids and nausea

due to stimulation of chemoreceptor trigger zone in medulla

• may involve vestibular system

• more common in ambulatory pts

• tolerance develops so CRTZ desensitizes

opioids and depression of respiration toxicity

major toxic effect - usual cause of death

levels of CO2 and O2 drive us to breath, chemoreceptors detect these levels

opioids wipe out CO2 drive for respiration by decreasing CO2 receptor sensitivity

• build up of CO2 goes undetected

DO NOT GIVE OXYGEN TO PT, low O2 levels keeps the pt breathing and if you supply with O2 they will stop breathing

opioids and therapeutic respiratory depression

used for pulmonary edema with unpleasant symptoms of air hunger (think HF, lung fluid build up)

gives partial relief in acute pulmonary edema by alleviating patient’s conscious awareness of respiratory distress

opioid poisoning tell-tale sign

pin point constricted pupils

• due to nucleus of Edinger-Westfall (CN III)

use naloxone, it is an antagonist

antitussive effect of opioids

depression of cough control center in the medulla

morphine not usually used because it is too intense

codeine is used

lowering of seizure threshold use of opioids

use with caution in seizure-prone patients

can induce more seizures, need to titrate

endocrine disturbances of opioids

decreased secretion of gonadotropins, corticosteroids and prolactin

females leads to menstrual disturbances

impotence in males

opioid effects on smooth muscle

increased tone of circular smooth muscle

decrease in propulsive movements of longitudinal muscle

decreased intestinal motility = constipation

urine retention = need catheterization

bronchoconstriction = issues in asthmatic and COPD pts

increased biliary pressure due to constriction of bile duct = gallstone attacks

opioid cardiovascular effects

orthostatic hypotension due to release of histamine and interference w hemostatic reflexes

cutaneous vasodilation due to release of histamine, can experience pruritis (relieve with H1 histamine antags)

increased CSF pressure from buildup of CO2

• use in caution in pts with head injuries

how does opioids impact skeletal muscle and immunosuppression

rigidity at high doses

seen with chronic usage - complicate immunocompromised patients or may contribute to pathogenesis of immune disorders

pharmacokinetics of morphine

IM, IV, SC

abuse = snort

less potent orally due to significant first pass effect in liver, oral products need much higher dose

therapeutic standard dose of IM or SC morphine

10 mg

pharmacokinetics specifics of morphine

t1/2 = 2-3 hours

duration of analgesia is 4-6 hours

excretion 90% in urine 10% in feces

• morphineglucuronide

major drug interactions with morphine

additive effects with other CNS depressants (alcohol, barbiturates, antipsychotics)

MAO inhibitors - severe hyperpyrexia and coma

abuse with amphetamines and cocaine = speedball

other analgesics (ibuprofen, acetaminophen, aspirin) - enhanced analgesic effect

antihistamines (hydroxyzine)

tricyclic antidepressants and SNRI’s = enhance analgesic effects, used in chronic/severe pain

opioid poisoning symptoms

CNS depression - stupor or coma

depressed depth and rate of respiration

pin point pupils

• if pt is hypoxic pupils may be dilated

treatment of opioid poisoning

support respiration mechanically

• admin of O2 will cause apnea, do not do

administer narcotic antagonist naloxone (NARCAN)

common uses of morphine and related drugs

moderate-severe pain

tx of chronic pain

adjuncts to surgical anesthesia

antitussives

antidiarrheals

dyspnea of LHF and pulmonary edema

abuse

morphine sulfate salt MOI

absorbed from GI tract, not as effective orally because of first pass metabolism

10mg subQ, IM ; 5mg IV

PCA standard form (patient controlled analgesia)

spinal analgesia - mu receptors

codeine (phosphate or sulfate salt) MOI

orally effective

30-60mg

weak opioid agonist, metabolized to morphine

mild-moderate pain, like a bad sprained ankle, and antitussive dose is 15mg, which is lower than analgesic dose of codeine

used in combo with acetaminophen

hydromorphone (dilaudid)

oral, more severe pain

10x more potent than morphine

oxycodone (percocet)

used orally in combo w acetaminophen/aspirin/ibuprofen

oxycontin: sustained release oral preparation for severe chronic pain, oxycodone only

hydrocodone (vicodin)

used orally for mild moderate pain and as an antitussive

used in combo w acetaminophen/aspirin/ibuprofen

meperidine

synthetic drug, oral and parenteral

1/10 the potency of morphine

post operative pain control, problems with shivering

short acting - 1-3 hours, not appropriate for long term pain management

active metabolite normeperidine - can cause seizures

heroin (diacetylmorphine)

more potent and euphoric than morphine

duration of action 4-6 hrs

abuse

common taken by injection, snorting or smoking

methadone

opioid agonist, used as analgesic to treat opioid addiction

orally effective, less euphoric high and longer duration of action - 12-24 hrs

methadone substitution - high enough dose to suppress opioid withdrawal

methadone maintenance therapy - maintained on methadone indefinitely while on counseling

• can be dispensed through licensed clinics

fentanyl

potent mu agonist for pain management, 100x more potent than morphine

can be absorbed through the skin with patches, lozenge for tx of severe breakthrough pain in chronic pts

carfentanil 10,000x more potent than morphine

main drug for opioid poisoning

naloxone

adulterants appearing in street opioids: designer opioids

fentanyl analogs

nitazenes (benzimidazoles)

cychlorphine

adulterants appearing in street opioids non-opioids

xylazine (tranq)

medetomidine

opioid combination products issues

have to worry about pt taking too much opioid

have to worry about acetaminophen toxicity

vicodin

5mg hydrocodone + 500mg acetaminophen, do not exceed 8/day or else toxic

buprenorphine

partial agonist at mu receptors and possible kappa receptors

• doesn’t fully activate the receptor

mild-moderate pain, abuse potential is much lower

can suppress sx of withdrawal in opioid addict

• used in tx of opioid addiction/opioid use disorder

• #1 drug for opioid use disorder

tramadol

weak mu agonist, can inhibit reuptake of serotonin and norepi

pain relieving activity, mild-moderate pain

do not use for severe pain

lower abuse potential

tapentadol

similar to tramadol with more opioid activity

agonist at mu receptors, inhibits reuptake of NE and 5-HT

naloxone

drug of choice for opioid overdose

parenteral to be effective DO NOT GIVE ORALLY

ER usually given IV, also has nasal sprays

pt can go into opioid withdrawal immediately

naltrexone

long acting orally effective antagonist

used to decrease craving of alcohol in alcoholics

DO NOT GIVE MORPHINE WITH NALTREXONE, WILL NOT WORK

long acting drug of 24 hrs

naloxegol

long acting opioid antagonist

blocks opioid receptors, does not get absorbed from GI tract

used to treat opioid induced constipation

opioid withdrawal tolerance

tolerance readily develops to the euphoric, sedative, and analgesic effects

does not develop to miosis, constipation

characteristics of acute withdrawal syndrome

craving for drug

anxiety, insomnia

dilation of pupils

severe GI hypermotility

HTN and tachycardia

goose flesh

yawning and sweating

manage opioid withdrawal

cold turkey

withdrawal lasts 48-72 hours

wean patient off drug

methadone

substitution

maintain on methadone, requires methadone clinic

buprenorphine

acute withdrawal - clonidine suppresses symp overreactivity