Week 2-Pain & Opioids Flashcards
What is the definition of pain?
Physical, emotional, and psychological condition that does not necessarily correlate to the degree of tissue damage present.
What are components of the phenomenon known as pain?
Sensory-discriminative & Motivational-affective
Define sensory-discriminative.
component of pain depends on ascending projections of tracts (including the spinothalamic and trigeminothalamic tracts) to the cerebral cortex. Sensory processing at these higher levels results in the perception of the quality of pain (pricking, burning, aching), the location of the painful stimulus, and the intensity of the pain.
Define motivational-affective.
responses to painful stimuli include attention and arousal, somatic and autonomic reflexes, endocrine responses, and emotional changes
What effect does pain have on society?
Great cost to society in treatment and loss of production
What are nociceptors?
Pain receptors, Specialized class of primary afferents that respond to intense, noxious stimuli in skin, muscles, joints, viscera, and vasculature.
What stimuli do nociceptors respond to?
Respond to thermal, mechanical, and chemical stimuli
What information do nociceptors provide to the CNS?
location and intensity of the stimuli
Nociceptors are generally ________________
Generally inactive until stimulated by enough energy to reach the stimulus threshold
What are the four components of nociception (The experience of pain involves a series of complex neurophysiologic processes)?
transduction, transmission, modulation, and perception.
Nociception is the ________system’s response to certain harmful or potentially harmful stimuli
sensory nervous system
Define transduction.
Process by which noxious stimuli (heat, cold, mechanical distortion) are converted to nerve electrical impulses in sensory nerve endings
Define transmission.
Conduction of those impulses to the CNS (dorsal horn of the spinal cord and thalamus which has projections to cingulate, insular, somatosensory cortices)
Define modulation.
Process of altering pain transmission–CNS/PNS inhibitory & excitatory mechanisms
Define perception.
Mediated through the thalamus acting as the central relay station for incoming pain signals and the primary somatosensory complex which serves to discriminate specific sensory experiences
Does the occurrence of pain depend on all four steps of nociceptive process? What is an example of when this wouldn’t occur?
No
For example, pain from trigeminal neuralgia occurs in the absence of transduction of a chemical stimulus at a nociceptor reflecting axonal discharges initiated at the site of a compressed or demyelinated nerve. Modulation of pain impulses may not occur if specific nervous system tracts are injured. For example, phantom limb pain occurs in the absence of nociception or nociceptors (pain receptors).
Specific types of nociceptors react to ________.
different stimuli
What is the reaction of the alpha delta peripheral nerve fibers?
Fast pain (sharp pain)
Is the alpha delta peripheral nerve fibers myelinated or unmyelinated?
Myelinated
What is the fiber diameter of the alpha delta peripheral nerve fibers?
2-5 mm
What is the reaction of the C peripheral nerve fibers?
Slow pain (+cold, throbbing, burning)
Is the C peripheral nerve fibers myelinated or unmyelinated?
Unmyelinated
What is the fiber diameter of the C peripheral nerve fibers?
0.4-1.2
Cell damage results in disruption of phospholipid membrane causes the release of _______________ to became various eicosanoids which include prostaglandins
arachidonic acid that is acted upon by intracellular COX enzymes (cyclo-oxygenase)
Ascending pathways: How do nerve endings respond?
Nerve endings responding to noxious stimulus (chemical mediators) send signals (action potentials) from site of injury to the dorsal horn (1st order neuron)
Where are the noxious pain signals sent?
dorsal horn (1st order neuron)
Ascending pathways: What happens after 1st order neurons synapse with 2nd order neurons?
- Main neurotransmitter: Substance P
- Relay area of spinal cord: substantia gelatinosa part of the Rexed laminae- grey matter dense with other interneurons
Ascending pathways: What is the main neurotransmitter after the 1st and 2nd order synapse?
Substance P
Ascending pathways: What is the relay order of the spinal cord?
substantia gelatinosa
Ascending pathways: What is the cross process of 2nd order neurons?
- cross (decussate) to contralateral side to enter spinothalamic tract to ascend to brain (thalamus) Pain, temperature, itch
- Other ascending tracts, some ipsilateral
Ascending pathways: Where do 2nd order neurons connect?
2nd Order neurons connect at the thalamus (relay station in the brain) to relay with 3rd order neurons (thalamocortical)
Ascending pathways: What is the result of 2nd order neurons connect at the thalamus, in response to pain?
- Location & Discrimination of pain
- Impulse to specific area of brain related to anatomic injury
Ascending pathways: What response to pain is found in Cingulate and Insular Cortices (via the amygdala)?
- Deep, dull pain that is poorly localizes
- Emotional, affective component (fear, anxiety, depression)
What is the function of the descending pathway of pain?
Responsible for controlling/inhibiting pain
Descending pathway: What are the priority neurotransmitters involved?
Serotonergic/adrenergic (NE) neurotransmitters
Descending pathway: What are the two major anatomical pathways located?
Periaqueductal grey (PAG) & Rostral Ventromedial Medulla (RVM)/Nucleus Raphe Magnus
Descending pathway: Where is Periaqueductal grey (PAG) located?
midbrain
Descending pathway: Where is Rostral Ventromedial Medulla (RVM)/Nucleus Raphe Magnus located?
brainstem
Descending pathway: Where does the Periaqueductal grey (PAG) receive signals from?
Receives signals from autonomic cortex, thalamus, amygdala
Descending pathway: Where does the Rostral Ventromedial Medulla (RVM)/Nucleus Raphe Magnus receive signals from?
Receives signal from PAG
Descending pathway: What is the major neurotransmitter of the Periaqueductal grey (PAG)?
Norepinephrine
Descending pathway: What is the major neurotransmitter of the Rostral Ventromedial Medulla (RVM)/Nucleus Raphe Magnus?
Serotonin
Descending pathway: Where does the PAG/RVM system modulate pain?
dorsal horn
Descending pathway: What is the function of the dorsal horn in relation to the PAG/RVM system?
- Stimulate an interneuron to release endogenous opioid: enkephalins
- Prevent release of Substance P thus inhibiting nociceptive pain transmission
Descending pathway: What is stimulated by the dorsal horn?
interneuron
Descending pathway: What does the PAG/RVM system contribute to?
PAG/RVM system contributes to hyperalgesia & allodynia (stimuli that is not normally painful)
Descending pathway: What is the relationship of the PAG/RVM system to pain management?
major site of opioid based analgesia:
The direct inhibitory effects of μ receptors
& The modulating effects of κ receptors
What is the mechanism for chronic pain development?
Chronic pain occurs if the conditions associated with inflammation do not resolve, resulting in sensitization of peripheral and central pain signaling pathway and increased pain sensations to normally painful stimuli (hyperalgesia) and the perception of pain sensations in response to normally nonpainful stimuli (allodynia)
Define peripheral sensitization.
Increased responsiveness of peripheral neurons responsible for pain transmission to heat, cold, mechanical, or chemical stimulation.
What is released during peripheral sensitization?
multitude inflammatory mediators
Where do peripheral sensitization mediators work?
Mediators can work directly on nociceptive nerves or activate inflammatory cells to release chemicals
What key chemicals are involved in peripheral sensitization?
bradykinin, prostaglandin E2, histamine, cytokines thromboxane, endo-cannabinoids
What various receptors are involved in peripheral sensitization (5)?
TRPV1, purinergic, metabotropic, glutamatergic, ion channels
What is gate theory?
Larger, faster Aβ fibers override/close the gate of the pain transmission sent by smaller, slower Aδ and C fibers in the dorsal horn (mechanism for massage, acupuncture, nerve stimulators)
Where does gate theory occur?
dorsal horn
What are some types of pain?
Neuropathic and Visceral
Define neuropathic pain.
Persists after injury/healing and can be difficult to manage
What changes to the neuron result from neuropathic pain (3)?
Blocking/scarring of axon regeneration, Hyperalgesia, allodynia
What is the characterized difference between visceral and somatic pain?
While somatic pain is easily localized with distinct sensations, visceral pain is diffuse and poorly localized.
Visceral pain is associated with _____________
stronger emotional responses
How is viscera unique?
that each organ receives innervation from two nerves (pelvic and spinal or vagal and spinal)
Which fibers are effected in visceral pain?
Predominantly Aδ and C fibers
Spinal visceral nociceptors ________ neurons in dorsal root ganglion same as ______ nociceptors (get referent pain).
afferent; somatic nociceptors
How is visceral nociceptors activated?
stretching, spasm, distinction, ischemia (not cutting or burning)
What relation does viscera have with the vagus nerve?
Thoracic and abdominal visceral co-innervated with vagus nerve (Autonomic and emotional component)
Pain perception by _______weeks gestation
23 weeks
What is known about the threshold of pain for neonates and infants?
Newborns and young children have lower thresholds for pain & exaggerated responses
Neonates subjected to pain can have ___________.
long term sequalae
What is opium?
- Mixture of alkaloids from the papaver somniferum plant (poppy)
- Use 300 BC; Morphine isolated in 1803
What is opiates?
Any naturally occurring opioid derived from opium
What is a narcotic?
From Greek meaning “to numb or deaden”. Used to denote an opioid but used to describe drugs of addition (Even nonopioids)
What is opioid?
Refers to all exogenous substances, natural and synthetic, that bind specifically to opioid receptors and produce at least some agonists (morphine liked) effects
What is the general MOA of opioid agonists?
Mimic actions of endogenous ligands that bind to opiate receptors
What are examples of opiate receptors?
Enkephalins, endorphins, dynorphins
What is the relation of GABA and opioid receptors?
GABA receptors in the limbic system have opioid receptors: presynaptic inhibition of GABA thus increasing dopamine (pleasure)
What type of receptors do opioids typically bind?
G-coupled receptor class
What affect can be seen by agonists binding to various opioid receptors (G protein receptors)?
Decreased neurotransmission:
- decrease K+ conductance/efflux (hyperpolarize-decrease excitability)
- Close Ca++ sensitive voltage channels presynaptic (suppress substance P and affect neurotransmitters as NE, ACh)
- 2nd messenger functions
What other receptors can opioids modulate?
May modulate NMDA receptors
Review G coupled protein receptors.
Slide 25
Review pain signals and their relationship of action potential.
Slide 26
Our bodies cope with certain amount of pain by releasing ___________.
endogenous opioids
What are the three major families of endogenous opioids (3)?
Enkephalins, Dynorphins & Endorphins.
How do endogenous opioids exert it’s effects?
Endogenous opioids exert their effects by binding to opioid receptors, which are abundantly present in the central and peripheral nervous systems.
What are the three major types of opioid receptors?
µ (mu), δ (delta) & k (kappa)
How do opioid receptors vary?
Receptors vary in their cellular distribution, their relative affinity for various opioid ligands, and their contribution to specific opioid effects.
Review endogenous opioid effects.
Slide 29
What are synthetic opioids?
While naturally-derived opioids can only reach a certain potency, the synthetically-produced opioids are refined and processed to be much more powerful.
What are some examples of synthetic opioid agonists (7)?
Fentanyl, Hydrocodone, Hydromorphone, Methadone, Meperidine, Oxycodone, Oxymorphone
What is important to know about methadone? What type of pain is it best to help treat (2)?
is not only a potent μ-receptor agonist but also a potent antagonist of the NMDA receptor as well as norepinephrine and serotonin reuptake inhibitor. These properties make Methadone useful for treatment of both nociceptive and neuropathic pain.
What effect does pain have on the endocrine system (5)?
Stimulates neuroendocrine stress response, increase adrenergic neural activity and plasma catecholamines and sympathetic tone and hypothalamic-mediated reflexes
What effect does pain have on the CV system? What can it precipitate?
CV effects include hypertension, tachycardia which increase myocardial oxygen demand which can precipitate myocardial ischemia and infarction
What effect does pain have on the respiratory system?
- increase minute ventilation in response to the overall increase in body oxygen consumption and increases tissue oxygenation
- When surgery involves the abdominal or thoracic cavities, respiratory effects can include hypoventilation, decreased tidal volume, ability to cough, and the development of atelectasis
What are some other response to pain (3)?
anxiety, sleep disturbances, and depression
How are opioid receptors classified?
according to the ligands originally found to bind them or from their tissue of origin: μ, κ, δ
What are the locations of opioid receptors?
Brain, Spinal cord and Outside the CNS
Where are opioid receptors located in the brain (5)?
Periaqueductal gray, locus coeruleus, amygdala, hypothalamus, rostral ventral medulla
Where are opioid receptors located in the spinal cord (2)?
Interneurons and primary afferent neurons in the dorsal horn (substantia gelatinosa)
Where are opioid receptors located in the CNS (2)?
Sensory neurons and immune cells
What is the target of mu opioid receptors?
Principally responsible for supraspinal and spinal analgesia
What does Mu1 produced?
produces analgesia
What does Mu2 produced?
hypoventilation, bradycardia, and physical dependence
What is the characteristics of Kappa opioid receptors?
- Less respiratory depression than μ
- Less analgesia for high intensity pain
- Inhibition of neurotransmitter release via Ca++ channels (dopamine)
What medication class is kappa receptors the primary site of action?
opioid agonist-antagonist
What is the result of negative reinforcers and kappa opioid receptors?
Negative reinforcers producing conditional aversive effects in reward centers (antidepressant effects).
What are the functions of the delta opioid receptors?
- Respond to endogenous enkephalins
- Weakly modulate μ receptors
Morphine as well as Meperidine may provoke release of histamine, which plays a major role in producing _________.
hypotension
Other opioids generally produce a dose-dependent bradycardia by _________
increasing the centrally mediated vagal stimulation.
All opioids can cause itching via ___________
pruritoceptive neural circuits
Autonomic nervous system regulated by ________. Why is this important?
hypothalamus, Area with opioid receptors
Explain why we are transitioning to opioid free anesthesia. Specifically the mu agonist effects that support this change.
- μ agonists: most effective treating “second pain” by unmyelinated C-fibers as opposed to “first pain” Aδ-fibers
- Not all pain may be suppressed leading to tachycardia and hypertension
What are the most common cardiovascular side effects of opioids?
- Orthostatic hypotension & Bradycardia
- Cardioprotective effects (oxidative/ischemic stress)
What causes orthostatic hypotension from opioids?
- decrease in sympathetic tone
- Myocardial depression or hypotension unlikely with normovolemia
What causes bradycardia from opioids? What medication does not have this effect and why?
- Increase vagal (CN X) nerve activity- medulla
- Not meperidine (atropine-like effects)
What blood pressure effect could occur with morphine? What can be used to help prevent?
+/- histamine with morphine- causes decrease BP
-Pretreat with H1/H2 blocker (does not attenuate histamine release but the associated BP drop)
What is the most significant side effect of opioids?
Occurs simultaneously with analgesic effects
suppression of ventilation,
What effect does pain from surgery have on opioid respiratory effects?
Pain from surgery will counteract (may titrate opioids to RR)
What causes suppression of ventilation with opioids?
Agonist effect at mu2 receptors, leading to a direct depressant effect on the brainstem ventilation centers (pons/medulla)
What are the primary factors that lead to respiratory depression?
- Decreased responsiveness/sensitivity to CO2
- Prolonged pauses with breathing (apnea) -Not compensated with increased Tv
- From decreased of ACh from neurons (offset respiratory depression with physostigmine- not analgesia)
Depression of ventilation is _________ & _________ (but conscious)
rapid and can persist for hours
What directly causes increased airway pressures? What indirectly does?
Increased airway pressures to the direct bronchial smooth muscle constriction (opiate/ACh-mediated) and indirectly from histamine
Drug interactions: What affect occurs with opioid agonists and nitrous oxide?
cardiovascular depression (reduced cardiac output and BP and increase cardiac filling pressures)
Drug interactions: What affect occurs from opioids and benzos?
Decreased SVR and BP (+ ventilatory depression! Something you will see clinically)
Ventilatory depressant effects of opioids may be exaggerated by what other drugs (4)?
amphetamines, phenothiazines, MAOIs, and tricyclic antidepressants
What medications can help with cough suppression? How?
Codeine & Dextromethorphan (OTC)
-Suppress cough center (medullary)
What impact on cough can occur with fentanyl, sufentanil and alfentanil? What is this called?
cough reflex, (“fentanyl cough”)
Opioids: _________ precedes analgesia
Sedation
What effect do opioids have on the CNS?
Decreased CBF and possibly ICP (increase ICP: often counteracted by PaCO2/hypoventilation)» Caution in patients with head injury
-EEG resembles sleep despite overt seizure/myoclonus movement
Miosis
What cause miosis to develop with opioids?
excitatory ANS component: Edinger-Westphal nucleus of oculomotor nerve (CN III)- antagonized by atropine (Merperdine is a little different)
What is one CNS way to assess opioid level intraoperatively?
Pupillary constriction
What CNS effect will be seen with morphine & hypoxemia?
mydriasis (dilation)
What can a rapid bolus of opioids produce?
generalized skeletal muscle rigidity
Rigidity produced by opioids becomes a problem when? What is the most likely due to?
Chest wall rigidity: problems ventilating (More likely due to laryngeal musculature contraction)
What opioid drugs do you genuinely see rigidity as a side effect with?
Mainly seen with fentanyl and its derivatives
What opioid has the highest risk of rigidity?
Incidence after moderate dose of Sufentanil ranges from 84% to 100%
What can be used to treat rigidity?
Treatment with neuromuscular blocking drugs or opioid antagonism (Naloxone)
What phenomenon is rigidty similar to?
Due to ⬇️ GABA and resultant ⬆️ dopamine (same mechanism for the euphoria)
Opioids: Clonic skeletal muscle activity (myoclonus) may resemble ________
grand mal seizures
What effect can opioids have on the biliary tract?
Can cause spasm of biliary smooth muscle causing an increase in biliary pressure
What is biliary pain offten confused with?
angina pectoris
How does biliary pain manifest?
Manifested as epigastric distress or biliary colic
During surgery, opioid-induced spasm of the sphincter of Oddi can be reversed with _____ or ____
Naloxone or Glucagon 2 mg IV
What impact do opioids have on the GI tract? What impact does it have in anesthesia?
Opioids also decrease gastric motility and prolong gastric emptying time, which may cause constipation.
Can lead to increased risk of aspiration.
How do opioids cause N/V?
Opioid-induced N&V is caused by direct stimulation of the chemoreceptor trigger zone (CTZ)- area postrema/medulla
What impact on the urinary system can be produced by opioids? What can be used to treat it?
-urinary retention, Increased tone and peristaltic activity of the ureter – treated with atropine
How do opioids cause Urinary urgency?
produced by opioid-induced augmentation of the detrusor muscle and is offset by the enhancement of the urinary sphincter tone, making voiding difficult
What cutaneous changes can be observed by morphine?
- Morphine causes cutaneous blood vessels to dilate resulting in flushed face, neck, and upper chest
- Caused in part by histamine release
What impact do opioids have on the placenta?
Readily transported across the placenta, neonatal depression (also dependency)
What are the hormonal changes associated with opioids?
Prolonged opioid therapy may influence the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis, leading to endocrine and immune effects
What is the principle manifestation of overdose?
ventilatory depression: apnea
What is the triad that is associated with opioid overdose?
miosis, hypoventilation, and coma
What can be administered for overdose? What may occur in this situation?
Administration of an opioid antagonist such as Naloxone may precipitate acute withdrawal in dependent patients
Major limitation for repeated use of opioids; __________ develops among opioids
Cross tolerance
What is tolerance?
Increased amount needed for effect (usually 2-3 weeks)
What side effects will a patient on opioids not develop tolerance to?
NOT miosis, bowel motility (constipation)
What is dependence?
Develop a psychological and physiological need (usually 25 days but as soon as 48 hrs)
What can be occur with dependence?
Withdrawal symptoms (Clonidine used to attenuate)
What is the MOA of opioid tolerance/dependence?
Opioid receptors become desensitized, the blocking of cAMP pathways recover with long term exposure and upregulate
Prolonged opioid exposure also activates _______
NMDA receptors (ketamine)
