Jacewicz/Sweatman - Pain Pathways and Mgmt Flashcards
What are the 2 functional divisions of the anterior lateral spinothalamic tract? Associated nuclei?
- NEO-SPINOTHALAMIC: intensity, location, quality of pain; fast pain that is sharp, well localized, and relayed rapidly to somatosensory cortex -> relayed to lateral pain system
1. Ventral posterior lateral (VPL)
2. Ventral posterior medial (VPM) - PALEO-SPINOTHALAMIC: emo, visceral responses to pain, & influences descending pathway from brainstem that modulate pain; dull, throbbing, poorly localized pain; relayed to medial pain system
1. Dorsal medial (DPM)
2. Intralaminar centromedian (CM)
3. Parafascicular (PF)
What are the peripheral pain sensors?
- Free nerve endings:
1. TEMP via transient receptor potential channels (TRP) -> TRPV1 sensitive to >43o C and Capsaicin, and TRPM8 sensitive to <25o C
2. MECHANICAL
3. CHEMICAL
How is peripheral pain transduced (key fibers and NT’s)?
- A-delta fibers (III): thinly myelinated, transmit temp and mechanical pain, discrete location, fast, sharp pain
- C fibers (IV): unmyelinated, transmit temp, mech, and chemical pain (polymodal), diffuse, slow pain
- A-delta and C-fiber cell bodies are in DRG, and use glutamate, substance P, and calcitonin-gene related peptide (CGRP) as NT’s
1. These NT’s may be released at both central (dorsal horn) and peripheral (skin, other organs) terminals
How does peripheral pain receptor sensitization work?
̧- Stimulation (tissue injury)of nociceptive receptors triggers release of several substances (H+ ion, 5-HT, ATP, bradykinin, prostaglandins) that activate free nerve endings to fire AP back to spinal cord dorsal horn
̧- Activation of nociceptive receptors causes the local (peripheral) release of substance P and CGRP from free N endings at site of injury -> cause release of histamine from mast cells and vasodilation of local blood vessels
- Combo of local tissue injury (inflam) + release of above substances + SP and CGRP sensitizes free nerve ending receptors so threshold for activation is lowered
̧- Inflam chem milieu activates previously silent nociceptive receptors on free N endings, INC temporal and spatial summation of AP’s traveling to dorsal horn
What 2 types of neurons are critical for spinal cord pain processing?
- Nociceptive-specific neurons (SPN’s): neurons in laminae I and II of dorsal horn that only respond to A-delta or C fiber AP’s, and encode only pain
-
Wide dynamic range neurons (WDRN’s): neurons in laminae V of dorsal horn that respond to variety of synaptic inputs encoding pain AND non-pain stimuli
1. Fire AP’s in graded fashion, depending on stimulus intensity (proportional to stimulus freq)
2. > C-fiber AP frequency = > WDRN Ap response
What is wind up (central sensitization)?
- SIGNAL AMPLIFICATION -> repetitive AP’s from C-fibers trigger wind up by:
1. Glutamate activation of WDRN AMPA receptors and CGRP activation of WDRN CGRP receptors lead to WDRN depolarization, and release of Mg2+ block of NMDA channel
2. Enhanced Ca2+ influx through NMDA channel causes insertion of more Na+ channels and blockade of K+ channels in WDRN’s - Substance P activation of NK1 receptors contributes to process by prolonging WDRN depolarization
- Combined activation from these NT’s reduces threshold and INC insertion of receptors in WDRN’s, leading to lowered threshold for firing AP’s
What is the functional consequence of wind up?
- A relatively brief C-fiber stimulation can lead to long-lasting facilitation of the pain pathway stimulated
- This is a partial explanation of why and how patients experience hyperalgesia, and long-lasting, chronic pain
What are three endogenous pain modulation methods?
- GATE CONTROL MECHS: A-beta fibers (Ib, II) activate dorsal column interneurons that INH WDR neurons, blunting activation of the latter neurons in response to A-delta and C-fiber activity
- DESCENDING PATHWAYS: cortex, amygdala, and hypothalamus all impinge on PAG and reticular formation neurons that send descending fibers to modulate lamina II neurons in dorsal horn -> may INH or facilitate pain
- ENDOGENOUS OPIOID: activation of opioid receptors blocks presynaptic voltage-gated Ca2+ channels, and/or opens postsynaptic K+ channels, hyperpolarizing postsynaptic neuron and reducing AP’s
How might the pain pathways result in referred pain? Provide an example.
- Nociceptive receptors in viscera (intrathoracic, pelvic, abdominal organs) synapse on dorsal horn neurons primarily devoted to surface (dermatomal) receptors
- Viscera are sparsely populated by these receptors
- Significant sharing of visceral nociceptive activity with dermatomal system -> REFERRED PAIN
- EXAMPLE: poorly localized nociceptive receptors in heart muscle may generate pain localized to midline L chest, C8-T1 dermatome and neck region
- EXCEPTION: some visceral pain neurons bypass this pathway, and synapse in the intermediate gray zone neurons lying near the central canal
Describe the “newly discovered” visceral pain pathway, and its clinical consequences.
- Some visceral nociceptive receptors send afferent fibers that bypass 2o dorsal horn neurons associated with anterior-lateral spinothalamic tract to synapse on intermediate gray zone neurons near central canal
- These 2o neurons send fibers upward, traveling with dorsal column pathway; distinguished by the fact that they travel very close to midline in dorsal column
- Synapse in VPL of thalamus; 3o fibers redistributed to somatosensory cortex and other pain matrix centers
- Clinical consequences of this pathway = small midline lesions of the dorsal column at the lower thoracic cord alleviates chronic visceral pain, such as cancer pain
What are the 3 families of endogenous opioid peptides in the human body (that we need to know)? What are their precursors, and where are they located?
- Enkephalins, endorphins, dynorphins: regulate CNS activity, incl. pain, thermoregulation, appetitie, reward
- Precursor proteins: preproopio-melanocortin (POMC), preproenkephalin, prepro-dynorphin (multiple peptides from trypsin-like enzyme activity)
-
POMC-producing cells: hypothalamic arcuate nucleus and nucleus tractus solitarius -> project to brainstem, limbic system, and spinal cord (ACTH, alpha-MSH)
1. Expression also in ant/int lobes of pituitary (beta-endorphin), and pancreatic islet cells -
Proenkephalin peptides: in areas of CNS involved in processing of pain info (spinal cord, trigeminal nucleus, PAG), affective beh (amygdala, hippocampus, frontral cerebral cortex), motor control (caudate, globus pallidus), modulation of autonomic control (medulla oblongata), and NE function (median eminence)
1. Circulating proenkephalins from adrenal medulla and exocrine glands of the stomach and intestine - Dynorphins: widely distributed in the CNS; freq co-expressed with other opioid peptides
What are 4 anatomic sites for therapeutic intervention in the pain pathways?
- Interruption of initiating signal in peripheral tissues: NSAIDs modulate signal transduction
- Ascending nerve block with local anesthetics: Na+ channel blockers block signal conduction in nociceptive fibers
- Modulation of transmission at the spinal cord: opioids, anti-depressants, NSAID’s, anti-convulsants, alpha-2 adrenergic agonists modulate transmission of pain sensation in spinal cord by DEC signal relayed from peripheral to central pathways
- Modulation of perception at the cortical level: opioids also modulate central perception of painful stimuli
26-y/o M in MVA. Weakness of R leg, loss of vibratory sensation up to iliac crest, and loss of pin sensation up to umbilicus on opposite side. Up to where do you image to look for a lesion? Where do you suspect the lesion is?
- Thoracic spine -> hemi-section of the spinal cord (aka, Brown-Sequard)
- Lesion suspected at: T10 on the right
What is the site of action of the opioids?
Spinal cord and CNS
What is the MOA of Ketamine?
NMDA antagonist
What is the MOA of the local anesthetics?
- Act at voltage-gated Na+ channels
Name a highly potent opiate often administered via transdermal patch.
- Fentanyl
- Crucial thing with this patch is that it takes time to accumulate a sufficient concentration
- Have to provide analgesia until this thing begins to reach steady-state concentration
Action at which opiate receptor produces respiratory depression?
Mu, OP-3
Which opioids would most likely produce psychotic symptoms that would dissuade abuse?
- Drugs that act on kappa receptor, i.e., Butorphanol
Which opioids are commonly used in combo with acetaminophen? Why?
- Hydrocodone
- Oxycodone
- This diversifies MOA
Death from opiate intoxication is the result of?
- Death from opiate intoxication is the result of: respiratory depression.
- Which of the following is not an AE of pain mgmt with opiate analgesics? Tachycardia. Why might you see tachycardia in a pt to whom you administer opiate? They are still in pain.
- Which of the following is NOT part of the triad of symptoms of opiate overdose? Diarrhea. Pinpoint pupils: opiate overdose, or pontine hemorrhage.
- Which of the following AE’s to opiate therapy would be least likely to disappear as pt becomes drug tolerant? Constipation.
- Which of the following would be most appropriate tx for pt who has become progressively obtunded since last opiate dose? Naloxone; titrate dose.
- Which of the following opioid antagonists can be used to mitigate peripheral AE’s w/o compromising analgesia? Methylnaltrexone —> does not cross BBB due to methyl.
- Which antagonist would be most appropriately used in tx of addiction? Naltrexone b/c good oral bioavailability.
- The mild pain relief from codeine is: due to conversion to morphine. Pt who is ultra-rapid metabolizer of CYP2D6 can have trouble; neonatal deaths from mom taking codeine and breastfeeding.
- Case of man with gastric cancer and admin of crushed tablets. What can you not give? Sustained release oxycodone PGT because crushing would alter the pharmacokinetics of this drug.
- Pt with renal problems. Which med? Hydromorphone tablets bc not metabolized to any pharmacologically active metabolite. Oxycodone is the other opiate most suitable for use in pts with renal insufficiency.
Respiratory depression
Why might you see tachycardia in a pt to whom you administer an opiate?
- Because they are still in pain
- REMEMBER: tachycardia is NOT an AE of pain mgmt with opiate analgesics
What 2 things should you be concerned about in a pt that presents with pinpoint pupils?
- Opiate overdose
- Pontine hemorrhage
What would be the most appropriate tx for a pt who has become progressively obtunded since their last opiate dose?
- Naloxone -> titrate dose
What opioid antagonist can be used to mitigate peripheral AE’s w/o compromising analgesia?
- Methylnaltrexone -> does NOT cross BBB due to methyl group
Which antagonist would be most appropriately used in tx of addiction?
- Naltrexone -> good oral bioavailability
The mild pain relief from codeine is due to…?
- Which antagonist would be most appropriately used in tx of addiction? Naltrexone b/c good oral bioavailability.
- The mild pain relief from codeine is: due to conversion to morphine. Pt who is ultra-rapid metabolizer of CYP2D6 can have trouble; neonatal deaths from mom taking codeine and breastfeeding.
- Case of man with gastric cancer and admin of crushed tablets. What can you not give? Sustained release oxycodone PGT because crushing would alter the pharmacokinetics of this drug.
- Pt with renal problems. Which med? Hydromorphone tablets bc not metabolized to any pharmacologically active metabolite. Oxycodone is the other opiate most suitable for use in pts with renal insufficiency.
Man with gastric cancer and admin of crushed tablets via EG tube. What can you NOT give?
- Sustained release oxycodone PGT because crushing would alter the pharmacokinetics (how the body affects the drug) of the drug
Pt with renal problems who needs analgesia. What can you give?
- Hydromorphone tablets bc not metabolized to any pharmacologically active metabolite
- Oxycodone is the other opiate most suitable for use in pts with renal insufficiency
Why is methadone used in short-term tx of pts experiencing opiate withdrawal symptoms?
- It has a long half-life, so you can space out dosing, and this allows body to become re-acquainted with drug-free state
What attribute of Buprenorphine makes it useful in the tx of opiate addicts?
- Tight receptor binding, bc once bound, it will have persistent effect
What drug is used in the tx of alcohol dependence and craving?
- Naltrexone
Describe the arrival of a pain AP in the spinal cord dorsal horn. What NT’s are involved?
- Incoming AP from periphery activates presynaptic voltage-sensitive Ca2+ channels, leading to Ca2+ influx and synaptic vessicle release
- Released NT’s (glutamate and neuropeptides: CGRP and substance P) act on postsynaptic receptors
- Stimulation of ionotropic glutamate receptors leads to fast postsynaptice depolarization, while activation of o/modulatory receptors mediates slower depolarization
- Postsynaptic depolarization, if sufficient, leads to AP production (singal generation) in 2o relay neuron
Where can the synaptic transmission of pain in the spinal cord dorsal horn be modulated?
- Both pre- AND post-synaptically
- PRE: NE (alpha-2 receptors), GABA (GABA B r’s), and endogenous opiates (endorphin, enkephalin) all INH Ca2+ entry into pre-synaptic terminal -> Ca is essential to promote fusion of transmitter vesicles w/endplate to release transmitters into synaptic cleft
- POST: same players activate K+ channels, leading to INC in K+ conductance, and hyperpolarization of cell, DEC likelihood of depolarization threshold being reached -> onward transmission of pain signal interrupted
How do mu-opioid receptors in the spinal cord work?
- Activation of pre- and post-synaptic mu-opioid receptors by descending and local-circuit INH neurons INH central relaying of nociceptive stimuli
- PRE: mu activation DEC Ca influx in response to incoming AP
- POST: mu activation INC outward K+ conductance, DEC post-synaptic response to excitatory neurotransmission
- BOTH mechanism lead to reduction in likelihood of pain signals being conducted to CNS
Which opioids are partial agonists?
- Pentazocine, Nalbuphine, Buprenorphine, Butorphanol
1. Partial agonists on the mu (OP-3) receptor, and more significant activity on the kappa (OP-2) receptor -> devo w/expectation of avoiding some of the AE’s mediated via OP-3 receptor system - NOTE: do NOT need to memorize potency, but the fentanill series (newer synthetic opioids) are much more potent
1. Tramadol is a weak OP-3 agonist only partially antagonized by Naloxone, suggesting effects on serotonin reuptake more important to clinical action
What are the consequences of opiate overdose?
- COMA: DEC cortical stimulation via thalamus and hypothalamus
- PINPOINT PUPILS: E-W complex CN III nucleus (midbrain)
- RESP DEPRESSION: DEC CO2 sensitivity, DEC RR, DEC tidal volume
- RED BOX: altered mental states, severe perspiration, shock, pulmonary edema, and unresponsiveness
What is the classical view for the recycling of G-protein coupled receptors? How does this cycle vary for Morphine v. Enkephalin?
- Homologous desensitization: receptor activation by agonist triggers receptor activation + desensitization
- Receptor phosphorylation by GRK protein INC receptor affinity for beta-arrestin, enhancing interaxn bt the 2 proteins, and internalization
- Internalized receptors directed to early/sorting endosomes; recycle back to mem or are degraded
- NOTE: endogenous ENKEPHALIN signaling can persist bc relative balance bt desensitization and resensitization; with exogenous MORPHINE, there is a slow persistent desensitization and little recycling, so the overall balance falls in favor of loss of drug activity (poorly mediate endocytosis)
What is the “new” perspective on resensitization? Why is this important?
- Advocacy of resensitization process that can occur w/o need for internalization
- A: receptor dephosphorylation thought to occur at cell surface if GRK2 and beta-arrestin proteins INH w/pharma agents
- This opens up possibility that drugs INH these proteins may be used as a means to maintain potency and efficacy of current opiate agonists in the future
What is the physiologic mechanism behind opiate addiction? Just how addictive are they?
- ADDICTION: activation of opiate receptors in ventral tegmental neurons = disINH of opiate pathways and INC dopaminergic activation in nucleus accumbens
- As addictive as nicotine, but somewhat less than cocaine or amphetamines
- ALL addictive drugs have characteristic acute effects, and induce strong feelings of euphoria and reward
What are the MOA, admin, excretion, and AE’s of Gabapentin/Pregabalin?
- MOA: bind alpha-2-delta subunit of voltage-gated Ca channels, preventing their trafficking to the cell surface in hypersensitization
1. INH neuronal excitability, esp. in dense synaptic connxns of neocortex, amygdala, hippocampus
2. Ectopic activity reduced; normal nerve func unchanged
3. NO effects on GABA-A or -B uptake or degradation - ORAL dosing: gabapentin saturable uptake, pregabalin linear peaks
- EXCRETION: renal (dose adjust in renal compromise)
- Most common AE’s: dizziness, drowsiness
What are the MOA, use, and AE’s for Lamotrigene?
- MOA: blocks Na-channel function
- Useful in neuropathy, stroke, MS, phantom limb
- Dose adjustment in hepatic failure
- BBW for RASH: SJS
- Most common AE’s: diplopia, blurred vision, rarely hematologic toxicity
What are the MOA, use, and AE’s for Carbamezepine?
- MOA: blocks voltage-gated Na-channel function
- Pain relief associated w/blockade of synaptic transmission in trigeminal nucleus
- Potent enzyme inducer (CYP); induces own metabolism -> dose adjustment in hepatic failure
- AE’s: dizziness, drowsiness, rarely agranulocytosis
- NOTE: anticonvulsants carry risk of
What are the MOA, use, and AE’s for Ketamine?
- MOA: NMDA receptor antagonist (NMDA activation usually leads to Ca entry, initiates central sensitization)
- Limited by psychomimetic effects: case reports indicate low epidural doses effective w/o toxicity
- Useful in avoiding respiratory depression
- Particular utility for severe, acute pain
- Anesthetic agent
What are the MOA, use, and AE’s for Dextromethorphan?
- MOA: low affinity NMDA receptor antagonist (NMDA activation usually leads to Ca entry, initiates central sensitization)
- Used for chronic and post-op pain
- Used primarily as antitussive, working in CNS cough center
- Limited by psychomimetic effects at high doses
How can alcohol dependence/craving be treated?
- Alcohol consumption by dependent person elevates dopamine in nucleus accumbens -> beta-endorphin stimulates dopamine release directly (nucleus accumbens) or indirectly (ventral tegmental area) by INH GABA neurons
- Naltrexone: opiate antagonist -> blocks elevation of dopamine levels arising from signals in ventral tegmental area and arcuate nucleus (both of the axns described above)
What CAM agents have the best evidence of activity (table)?
