Pain & Opioids - EMILY Flashcards
What is pain?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
How is pain perceived?
Nociception
What is anti-nociception?
Absence of response to a normally painful stimulus
What is analgesia?
Absence of pain in response to a stimulation which would normally be painful
What is general anesthesia?
Drug-induced unconsciousness characterized by controlled but reversible depression of the CNS and perception
How is pain classified (4)?
-Duration
-Pathogenesis
-Location
-Severity
What are the 3 types of pain?
-Nociceptive pain
-Inflammatory pain
-Neuropathic pain
What do inflammatory mediators (prostaglandins, leukotrienes) activate?
They activate silent (high threshold) nociceptors and nociceptor sensitization
What do antidepressants target?
Perception of pain in the cerebral cortex
What do opioids target?
Perception of pain in the cerebral cortex and modulation of pain in the spinal cord
What do alpha-2 agonists target?
modulation of pain in the spinal cord
What do local anesthetics target?
Transmission of pain through sensory (afferent) nerves
What is spinal facilitation of pain (wind up)?
High frequency action potentials train the second order neurons in the spinal cord to respond more vigorously to subsequent stimulation
Does general anesthesia prevent nociception?
No, so pre-emptive analgesia is needed to stop spinal facilitation of pain
What is the difference between pain and nociception?
Pain has a conscious component while nociception does not
Why is it important to provide analgesia before surgery?
Because general anesthetics are not analgesics
What are descending inhibitory pathways?
Decrease neurotransmitter release from primary afferents and reduce excitability of secondary neurons
What endogenous molecules are produced to cause descending inhibition?
-Serotonin
-Norepinephrine
-Dopamine
-GABA
-Opioids
-Cannabinoids
What are 3 physiological pain inhibition mechanisms?
-Endogenous opioid agonists
-Upregulation of peripheral opioid receptors at site of injury
-Migration of opioid-producing leukocytes to site of injury
What are the 4 possible sites of analgesia?
- Block Peripheral nociceptors
- Prevent transmission to spinal cord
- Prevent transmission to brain
- Enhance descending inhibitory pathways
What is the most effective way to prevent and treat pain?
Affect all the different levels of pain conduction (balanced or multimodal approach)
What are the 3 major types of opioid receptors?
-Mu
-Kappa
-Delta
Where are opioid receptors expressed?
-CNS/PNS
-Intestinal tract
-Immune cells
Opioid receptors are ___-protein coupled receptors
G
What is the MOA for opioid receptor activation?
-Decreased cAMP formation and adenylyl cyclase inhibition
-Inhibition of Ca2+ channels in presynaptic neurons (reduced NT release)
-Increased K+ outflow in postsynaptic neurons (hyperpolarization)
What does activation of Mu receptors do?
-Analgesia, sedation, euphoria**
-Respiratory depression
-Increased vagal (parasympathetic) tone
-Increased locomotor activity in horses
What does activation of kappa receptors do?
-Mild analgesia, sedation, dysphoria**
-Diuresis
What does activation of delta receptors do?
Mild analgesia
Which receptor agonist would you pick for a severely painful patient?
Mu agonist
Which drugs are full Mu agonists?
-Morphine
-Hydromorphone
-Fentanyl
-Methadone
-Etorphine
Which drugs are partial Mu agonists?
-Buprenorphine
-Tramadol
-+/- butorphanol
Which drugs are full kappa agonists?
-Etorphine
-Butorphanol
Which drug is a partial kappa agonist?
Morphine
Which drug is a full delta agonist?
Etorphine
What to opioid receptors do when activated in primary afferent neurons?
Inhibit calcium inflow leading to decreased NT release
What are some clinical uses of opioids?
-Analgesic
-Sedative
-Antitussive
-Antidiarrheal
Which opioids would you select for a patient in severe pain?
-Morphine
-Methadone
-Hydromorphone
-Fentanyl
Which opioids would you select for a patient in mild/moderate pain?
-Buprenorphine
-Butorphanol
-Tramadol
When could you give opioids for a patient that is undergoing surgery?
-Pre-anesthetic
-Intra-operative
-Post-operative
What is the effect of giving opioids in combination with sedatives or anesthetics?
Causes additive/synergistic sedative and analgesic effects
What are some formulations of opioids that aren’t injectable?
-Morphine sustained-release tablets
-Fentanyl patch
-Buprenorphine (buccal transmucosal)
-Butorphanol tablets
-Tramadol tablets
-Hydrocodone liquid
What is the most problematic adverse effect of opioids?
Respiratory depression leading to apnea, especially during anesthesia and in neonates
What is another clinically important adverse effect of opioids?
Constipation/ileus. This is especially important to consider in horses since it can make them colic at high doses
What are some other adverse effects of opioids that are less significant?
-Severe pruritus
-Histamine release leading to vasodilation and hypotension
-CNS excitation/dysphoria/seizures
Why should a horse undergoing a head procedure not be given butorphanol?
Butorphanol can cause twitches which makes doing the procedure difficult
What are some pharmacokinetic considerations of opioids?
-Many opioids undergo high first pass metabolism resulting in poor oral bioavailability
-Metabolized by liver and excreted by kidneys, can be affected by hepatic or renal disease
Why are non-injectable forms of opioids limited?
Because of the high first pass effect and poor bioavailability. Better to give as an injection or as a CRI
What is opioid receptor expression upregulated by locally?
Inflammatory cytokines
Which opioid receptor primarily gets upregulated by inflammatory cytokines?
Mu > kappa > delta
Which two types of patients would the use of opioids not be recommended in?
-Patients with chronic kidney disease
-Pregnant patients
What is considered the “gold standard” opioid? Why?
Morphine. It’s safe, effective and cheap
Morphine is a Mu _______ and kappa partial ________
Agonist; agonist
Hydropmorphone is a Mu _________
Agonist
What is another use of hydropmorphone?
It is an emetic
Methadone is a Mu ________, an NMDA _________, and a NE and serotonin reuptake ________
Agonist; antagonist; inhibitor
What is a benefit of using methadone instead of other mu agonists?
It causes fewer CNS effects and less vomiting, especially in cats
What are some other benefits of methadone?
-More effective against chronic pain
-Doesn’t cause histamine release when administered
Fentanyl is a synthetic Mu ________
Agonist
Fentanyl is 100x more potent than morphine. What does this mean for its reversal?
It has very high receptor affinity, meaning that reversal may be more difficult
Fentanyl has a wide safety margin in dogs, but what can happen with a large overdose?
Fatal apnea
Buprenorphine is a partial Mu _______ and a kappa ________
Agonist; antagonist
What will happen if buprenorphine is given with other opioids?
It will displace them and anti-nociceptive effects won’t be as strong
Can buprenorphine be fully reversed by naloxone?
Not completely
Butorphanol is a kappa _______ and a Mu _________ (or partial agonist)
Agonist; antagonist
What does butorphanol provide effective analgesic for?
Mild/moderate pain
What does a low dose of butorphanol cause?
Sedation
What does a high dose of butorphanol cause?
Analgesia
Should you give butorphanol with a Mu agonist?
Probably not cause it can reduce the Mu agonists effects
What else is butorphanol?
-Antiemetic
-Antitussive
Tramadol is a multimodal analgesic. What are its functions?
-Mu agonist
-Serotonin reuptake inhibitor
-NE reuptake inhibitor
-Muscarinic antagonist
Why is tramadol not recommended to be used as the sole analgesic in dogs?
It is a pro-drug that has to be metabolized to function. Individual differences in metabolic activity in dogs drastically alter its effectiveness as an analgesic
Which species is better at metabolizing tramadol more consistently?
Cats
The reversal of opioids occurs via:
Competitive opioid receptor antagonists
What is the most commonly used opioid reversal drug?
Naloxone
Naloxone is a competitive antagonist of all opioid receptors, but greatest for which one?
Mu
Naloxone is a GABA _________. What can this cause?
Antagonist. Can cause seizures
How should naloxone be given?
Small doses IV every 1-3 mins to reverse respiratory depression. IM/SQ will have slower onset of action
Which opioid is not ideal for use in cats?
Morphine
Which opioids can only be given as an injectable?
-Morphine
-Hydromorphone
-Methadone
What is an important consideration when dispensing opioids?
They are drugs of abuse and must be tracked with a TPP
