Pregunta 1
Pregunta
Pain types:
1. Nociceptive Pain. Acute, [blank_start]protective[blank_end] and physiological. Somatic (skin, bone, joint, muscle.) pain = [blank_start]throbbing[blank_end], localised. Visceral (large intestine, pancreas.) referred or [blank_start]localised[blank_end].
2. Neuropathic (pathologic) pain. [blank_start]Disengaged[blank_end] from noxious stimuli. Chronic, [blank_start]neuronal[blank_end] damage.
• Related pain syndromes: [blank_start]diabetic[blank_end] neuropathy, post-herpetic, IBS
• Reported pain is [blank_start]greater[blank_end] than physical exam findings.
3. Inflammatory. More acute. [blank_start]Repairing[blank_end], pathological.
4. [blank_start]Dysfunctional[blank_end] pain. Chronic. No neuronal damage, noxious stimuli, or inflammation.
Respuesta
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protective
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throbbing
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localised
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Disengaged
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neuronal
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diabetic
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greater
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Repairing
-
Dysfunctional
Pregunta 2
Pregunta
Molecular mechanisms of pain:
1. Transduction
Stimulation of [blank_start]nociceptors[blank_end]. Uses afferent fibres. [blank_start]High[blank_end] activation threshold eg >45C or <5C. Sensitisation by bradykinin, [blank_start]prostaglandins, interleukins, TNFa,[blank_end] serotonin, can [blank_start]lower[blank_end] threshold.
2. Transmission
Conduction of impulse from periphery to [blank_start]CNS[blank_end] across [blank_start]dorsal[blank_end] horn of spinal cord. Neurotransmitters: [blank_start]Glutamate, Substance P, CGRP.[blank_end] Associated with thalamus and sensorimotor cortex.
3. Perception
Afferent impulse goes to [blank_start]ascending[blank_end] pathways; also associated with thalamus and cortex. [blank_start]Conscious[blank_end] experience: cognition, behaviour
4. Modulation
[blank_start]Suppress[blank_end] transduction, conduction, transmission. Local inhibitory neurons: [blank_start]GABA[blank_end]. Descending pathway is [blank_start]locus coeruleus[blank_end], also affected by the inhibitory substances: [blank_start]Opioids[blank_end], 5HT, NA, endogenous cannabinoids.
Respuesta
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nociceptors
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High
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prostaglandins, interleukins, TNFa,
-
lower
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CNS
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dorsal
-
Glutamate, Substance P, CGRP.
-
ascending
-
Conscious
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Suppress
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GABA
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locus coeruleus
-
Opioids
Pregunta 3
Pregunta
The analgesic ladder (WHO)"
STEP 1 [blank_start]Non-opioid analgesics[blank_end] e.g. paracetamol, NSAIDs
STEP 2 [blank_start]Opioids[blank_end] suitable for moderate pain (or [blank_start]tramadol[blank_end]) ± simple analgesics e.g. codeine, dihydrocodeine
STEP 3 Opioid suitable for [blank_start]severe[blank_end] pain ± simple analgesics e.g. morphine
Respuesta
-
Non-opioid analgesics
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Opioids
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tramadol
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severe
Pregunta 4
Pregunta
Endogenous opioids: [blank_start]Agonists[blank_end] at opioid receptors, eg Beta endorphin, Enkephalin
• Receptors: pre/post [blank_start]synaptic[blank_end] terminals in the [blank_start]apinal[blank_end] cord, limbic system, PNS
• Inhibit [blank_start]transmission[blank_end] - stimulate inhibitory pathways
• Euphoria
All opioid Rs are coupled to [blank_start]inhibitory G proteins[blank_end]. R activation has many [blank_start]intracellular[blank_end] consequences.
Respuesta
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Agonists
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synaptic
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spinal
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transmission
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inhibitory G proteins
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intracellular
Pregunta 5
Pregunta
Opioid Analgesics: Buprenorphine, codeine, fentanyl, morphine, diamorphine (heroin), oxycodone, tramadol.
• Agonists at [blank_start]specific[blank_end] opioid Rs.
[blank_start]Muse-R[blank_end] stimulation (raphe magnus)
• Less activity in [blank_start]GABA[blank_end] neurons = descending 5-HT neurons (brainstem)
• Presynaptic connection = [blank_start]afferent[blank_end] nociceptive neurons (spinal cord)
Inhibition of GABA permits [blank_start]increased[blank_end] firing in [blank_start]descending[blank_end] pathway.
Analgesia: inhibition of release of [blank_start]pain mediators[blank_end] (substance P, NO, glutamate.)
Respuesta
-
specific
-
Muse-R
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GABA
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afferent
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descending
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increased
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pain mediators
Pregunta 6
Pregunta
Opioid analgesia:
Muse R activation = increased pain [blank_start]modulation[blank_end]
Kappa R activation = [blank_start]antagonizes[blank_end] m-mediated analgesia + has unopposed [blank_start]spinal[blank_end] analgesia
Also present on peripheral nerves:
Muse agonists: decrease [blank_start]sensitivity[blank_end] of nociceptive neurons (inflamed tissue)
Kappa receptors: endothelial cells, T lymphocytes, macrophages. Modulate [blank_start]immune[blank_end] response.
Respuesta
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modulation
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antagonizes
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spinal
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sensitivity
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immune
Pregunta 7
Pregunta
All opioids have maximum potency for [blank_start]muse[blank_end] receptors.
Morphine, diamorphine, pethidine, oxycodone, codeine have specificity for [blank_start]kappa and delta[blank_end].
Methadone has [blank_start]NO[blank_end] kappa or delta specificity, [blank_start]only[blank_end] muse.
Fentanyl has no [blank_start]kappa[blank_end] sensitivity, just muse and [blank_start]delta[blank_end].
Naloxone has specificity for muse, less for kappa(but [blank_start]more[blank_end] than most opiods), and some for delta.
Respuesta
-
muse
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kappa and delta
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NO
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only
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kappa
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delta
-
more
Pregunta 8
Pregunta
Other CNS effects:
- Euphoria - Mediated by [blank_start]muse[blank_end], contributes to analgesia
- Dysphorial ([blank_start]kappa[blank_end])
- Respiratory Depression - primary cause of [blank_start]morbidity[blank_end]; depress rhythm generation in [blank_start]medulla[blank_end], desensitize brainstem [blank_start]chemoreceptors[blank_end] (increasing [blank_start]pCO2[blank_end])
- Cough suppression - Antitussive, direct effect on [blank_start]cough center[blank_end] in medulla - [blank_start]codeine, dextromethorphan[blank_end]
Pregunta 9
Pregunta
Peripheral effects:
GI Tract
• increased [blank_start]resting[blank_end] tone (m, k)
• [blank_start]constipation[blank_end] (80%)
• affecst [blank_start]absorption[blank_end] of other drugs
• less stomach [blank_start]motility[blank_end] – anorexia, N&V
Cardiovascular system
• Few effects on heart or circulation
• High dose – depress [blank_start]medullary vasomotor[blank_end] center
• Hypotension (parenteral use of [blank_start]morphine[blank_end])
SEs are dose dependent.
Respuesta
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resting
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constipation
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absorption
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motility
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medullary vasomotor
-
morphine
Pregunta 10
Pregunta
Tolerance and dependence:
[blank_start]Continuous[blank_end] use causes adaptive changes in R function.
• More drug for same effects = [blank_start]tolerance[blank_end]
• [blank_start]Withdrawal[blank_end]= adverse physiological effects (dependence)
Tolerance
• Learned ([blank_start]psychological[blank_end])
• (Adaptive) [blank_start]R downregulation/desensitization[blank_end]
• Most pharmacological effects ([blank_start]not[blank_end] constipation, pupil constriction)
Dependence (withdrawal syndrome, m)
• Anxiety, sweating, craving (12h)
• Rhinorrhea, [blank_start]dilated[blank_end] pupils, yawning, chills, pilo[blank_start]erection[blank_end], [blank_start]hyper[blank_end]ventilation, diarrhoea
• Duration of action varies
Pregunta 11
Pregunta
Cautions and contraindications:
Caution
• Impaired [blank_start]respiratory[blank_end] function (sleep apnea, asthma, COPD?)
• Renal impairment (dose [blank_start]reductions[blank_end])?
• Pregnancy?
Contraindications:
• Raised [blank_start]ICP[blank_end]
• Acute head injury ([blank_start]pupillary responses[blank_end])
Respuesta
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respiratory
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reductions
-
ICP
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pupillary responses
Pregunta 12
Pregunta
Strong opioids are used for pain in palliative care.
Pregunta 13
Pregunta
Tx options:
- Oral [blank_start]morphine[blank_end] generally first-line strong opioid. Active metabolites (from [blank_start]renal[blank_end] impairment) lead to opioid toxicity = excessive [blank_start]sedation[blank_end], confusion, restlessness, hallucinations
- Oral [blank_start]oxycodone[blank_end] is second-line. Risk of toxicity with renal impairment. [blank_start]CYP[blank_end] inhibitors.
- [blank_start]Fentanyl[blank_end] safer option for patients with GFR < 30 mL/min
Respuesta
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morphine
-
renal
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sedation
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oxycodone
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CYP
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Fentanyl