opioids/opiates

opioid vs. opiate: opioid

any drug that acts on opioid receptors in the brain/CNS

mainly synthetic drugs

examples: hydrocodone, oxycodone, fentanyl, heroin

opioid vs opiate: opiate

considered a subset of opioids that is naturally derived from the poppy plant

currently, opioid is the common term to describe opiates and opioids

examples: morphine, codeine, opium

endogenous opioid peptides

includes peptide neurotransmitters, opioids, and opioid metabotropic receptors

function is to alleviate stress/pain

targeted by analgesics, some general anesthetics, and drugs of abuse

naturally produced in the CNS and act as neuromodulators

what are the three opioid receptors?

delta, kappa, and mu

all are Gi coupled GPCRs

what are the three classes of the endogenous opioid peptides?

enkephalins

dynorphins

endorphins

pharmacology of endogenous opioids

inhibit glutamate release and inhibit the activation of spinal nociceptive neurons

Gi coupled - includes mu, delta, and kappa

expressed in CNS at sites of pain modulation, and endogenous opioids are released to alleviate pain

• endorphins: delta = mu

• enkephalins: delta > mu

• dynorphins: kappa, sensitize nociceptive signals in dorsal horn

• endomorphins: mu (main target for pain meds)

presynaptically, which opioid receptors are expressed?

all 3 are expressed on primary afferent neurons

postsynaptically, which opioid receptors are expressed?

mu, on spinal nociceptive neurons and peripheral terminals of sensory neurons

what are the sites of action of the opioid receptors?

1. spinal cord (pre and post)

2. supraspinal effects (pre and post)

3. peripheral terminals (post only)

understand this diagram well per dr. missaoui!

how does the direct inhibition in the ascending pathway work?

see image for more details

activation of postsynaptic mu opioid receptor inhibits the neuronal activation/pain transmission

which receptors are the primary therapeutic target of opioid analgesics?

mu

can cause analgesia, euphoria, respiratory depression, and dependence

kappa selective opioid agonists

effective analgesics, but can cause anxiety, panic, delirium, etc

which receptors likely contribute to tolerance?

delta

which receptors are important in sedative and GI effects of opioid agonists?

kappa

full/strong mu OR agonist list

morphine, hydromorphone, oxymorphone, heroin, methadone, fentanyl and its derivatives, mepiridine, levorphanol, dextromethorphan

partial/mild mu OR agonists list

codeine, oxycodone, hydrocodone, propoxyphene, loperamide, diphenoxylate, difenoxin

mixed mu and kappa OR agonists/antagonists list

nalbuphine, buprenorphine, butorphanol, pentazocine, dezocine

mu OR antagonists list

naloxone, naltrexone

metabolism of opioid agonists

morphine and mepiridine are full agonists that can cause seizures

phenanthrenes are converted to nonactive polar glucuronides in the liver and are excreted by the kidneys (except morphine - see above)

phenylpiperidines are metabolized by 3A4 (except mepiridine - see above)

absorption of opioid agonists

generally well absorbed from multiple routes with signficiant first pass metabolism

• the least metabolized: oxycodone, codeine

can include parenteral, rectal, intranasal, transdermal, etc.

CNS effects of opioids

good/desired effects: analgesia, euphoria, cough suppression, sedation sometimes

bad/undesired effects: sedation, respiratory depression, miosis, truncal rigidity, n/v

• respiratory depression is especially a problem in asthma, COPD, increased intracranial pressure

peripheral effects of opioids

CV: bradycardia (except mepiridine = tachycardia), hypotension

GI: constipation, no tolerance development

uterus: reduce uterine tone, prolong baby delivery

renal: urinary retention, reduced renal function

neuroendocrine: regulates relese of LH, ADH, prolactin

pruritis triggered mostly by mu agonists

immune: inhibits lymphocytes, NKs

clinical use of opioids - analgesia

used for severe acute pain

must consider:

• maximal efficacy

• pain is usually self-reported/not quantifiable

• duration of action of therapy

• route of administration

• ADRs

• individual opioid history

also used in chronic pain, but tolerance/dependence is possible with limited efficacy

can be used in terminal illness as well for analgesia

other clinical uses of opioids

anesthesia (alone or adjunct) - pre-op and during surgery

acute pulmonary edema can be alleviated by morphine (not sure how)

diarrhea (loperamide, diphenoxylate, difenoxin)

cough suppression (codeine, dextromethorphan)

potencies of the fentanyl derivatives

sufentanil > fentanyl > alfentanil

alfentanil and remifentanil have short half life and rapid action

mepiridine

has antimuscarinic activity

avoid in tachycardia and in decreased renal function

methadone

long acting, used to treat opioid use disorder (OUD)

used for detox and to lessen withdrawal severity by blocking the rewarding effects of heroin and other drugs

potent NMDA receptor blocker and potent mu OR agonist

used as a morphine alternative in “opiate rotation”

true or false: a patient receiving a partial agonist can also receive a full agonist

false

what will partial agonists do if administered with a full agonist?

they will compete and hinder the full agonist from reaching its maximum effect

true or false: you should not give a mixed agonist to pts receiving a full agonist

true

true or false: all mixed agonists have the potential for negative psychotogenic effects, like delusion and hallucination

true

nalbuphine

mixed kappa agonist and mu antagonist

butorphanol

mixed kappa agonist and partial mu agonist

pentazocine

mixed kappa agonist and weak mu antagonist

buprenorphine

mixed long-acting partial mu agonist and delta/kappa antagonist

used for detox

lower risk for respiratory depression than methadone

naloxone-resistant

tramadol

SERT blocker, weak mu agonist

used in chronic neuropathic pain

no respiratory effects

can cause seizures, nausea

tapentadol

NET blocker

weak mu agonist

codeine

cough suppressant and a partial mu agonist

given at sub-analgesic doses

dextromethorphan (DXM)

full mu agonist cough suppressant

non-habit forming and less constipating than codeine

stereoisomer of levorphanol

levopropoxyphene

cough suppressant stereoisomer of dextropropoxyphene

contraindications of opioids

partial agonists can cause withdrawals in pts receiving full aognists

pre-existing intracranial pressure/head injury

pregnancy

pre-existing pulmonary impairments

pre-existing impaired renal or hepatic function

hypothyroidism or low adrenal activity

opioid antagonists

high affinity for mu receptors

used for management of acute opioid overdose to completely reverse morphone effects

includes naloxone (IV, short-acting) and naltrexone (oral long-acting, maintenance)

opioid tolerance

clinically relevant around 2 weeks into treatment

highest tolerance develops toward analgesia, euphoria, sedation, and respiratory depression

limited tolerance develops with mixed-type opiates/opioid rotation

risk varies with opioid efficacy and DOA

likely involves up-regulation of cAMP pathway, down-regulation/internalization of mu ORs, receptor uncoupling, and NMDA receptors

chronic opioid administration may lead to hyperalgesia

opioid dependence

withdrawal/abstinence syndrome can develop upon d/c of the drug

includes rhinorrhea, lacrimation, yawning, chills, goosebumps, hyperthermia, hyperventilation, n/v/d, mydriasis, muscle aches, anxiety, hostility

opiate administration immediately reverses withdrawal

withdrawal intensity is dependent on half life

• morphine/heroin: peaks 48hrs in, lasts 5 days

• mepiridine/fentanyl: complete within 24hrs

• methadone: peaks 3-5 days, lasts 2 weeks, less intense - used for heroin detox

antagonist-precipitated withdrawal can cause immediate symptoms upon administration of naloxone

abrupt d/c of mixed agonist can cause less severe withdrawals