Week 7 - Pain Physiology & Opioids Flashcards
What is the definition of acute pain?
The direct result of tissue damage or potential damage and is a symptom
- Well defined onset and clear pathology
- Protect from tissue damage and allow time for healing
- Frequently observable tissue damage
- Usually adequately treated by pharmacological and treatment methods
- It is useful and protective
What are the four components of nociception?
Transduction
Transmission
Modulation
Perception
What are nociceptors?
Specialized class of primary afferents that respond to intense, noxious stimuli in skin, muscles, joints, viscera, and vasculature
- respond to multiple energy forms (thermal, mechanical, and chemical) that produce injury
- provide info to CNS regarding location and intensity of noxious stimuli
- are inactive until they are stimulated by sufficient energy to reach the threshold
What are the types of nociceptors?
C Fibers: unmyelinated, burning pain from heat stimuli and pain from sustained pressure
A Fibers Type 1 (Beta and some delta): myelinated, responsive to heat, mechanical, and chemical stimuli (polymodal), fast pain (>2m/sec)
A Fibers Type II (Delta): first pain sensation from heat (15m/sec)
What is the sensitization of nociceptors?
Increased responsiveness of peripheral neurons responsible for pain transmission to heat, cold, mechanical, or chemical stimuli
*frequently occurs and is attributed to the release of inflammatory mediators
What functions as a relay center for nociceptive and other sensory activity?
The spinal dorsal horn
Where does the perception of sensory-discriminative of peripheral painful stimuli occur (i.e. location and intensity of pain)?
Forebrain Somatosensory Cortex
Where does the perception of motivation-affective components of pain occur?
Limbic Cortex (Amygdala) and Thalamus
What modulates (either depress or facilitate) the integration of painful information in the spinal dorsal horn?
Descending projections originating from Periaqueductal Gray-Rostral Ventromedial Medulla system
What are the ascending pathways for pain transmission?
From spinal cord to sites in the brainstem and thalamus – important for perception and integration of nociceptive information
- Spinothalamic Tract (direct projections to thalamus)
- Spinomedullary and Spinobulbar Projections (direct projections to homeostatic control regions in medulla/brainstem)
- Spinohypothalamic Tract (direct projections to the hypothalamus and ventral forebrain)
What are the descending pathways of pain modulation?
Originate from supraspinal regions and promote or supress nociceptive transmission through the dorsal horn
- Descending Inhibition Pathway
- Descending Facilitation Pathway
What are the inhibitory neurotransmitter effects on pain?
- GABA (cerebral cortex, basal ganglia, cerebellum, spinal cord): increases Cl- which hyperpolarizes
- ACh: increases K+ conductance in peripheral PNS
- Dopamine: most likely inhibitory by acting on adenylate cyclase
- Norepi: RAS & hypothalamus (inhibitory)
- Epi: RAS (inhibitory)
- Glycine (spinal cord): increases Cl-
- Endorphins: excitatory for descending inhibitory pathway that inhibits pain transmission
- Serotonin: inhibitory in the brain
- Histamine: hypothalamus and RAS (inhibitory)
What are the excitatory neurotransmitters effects on pain?
- Glutamate (hippocampus, outer layer of cerebral cortex, substantia gelatinosa): learning and memory (recall), central pain transduction, and excitotoxic neuronal injury
- Inotropic Glutamate Receptors (NMDA receptors): ligand operated channel opens - influx of Na+, membrane depolarization
What is the mechanism of action of opioids?
Act as agonists at specific opioid receptors at presynaptic and postsynaptic sites in the CNS (brainstem and spinal cord) and the periphery
- Mimic the actions of the endogenous ligands (Enkephalins, Endorphins, and Dynorphins) by binding to opioid receptors, resulting in the activation of the antinociceptive system
- do not alter responsiveness of peripheral nerves to noxious stimuli nor impair impulse transmission
What state do opioids need to be in order to bind to the receptor?
Needs to be in the ionized state for strong binding to occur
Only levorotatory forms of the opioids exhibit agonist activity
What is the principal effect of opioid receptor activation?
A decrease in neurotransmission
- this occurs largely by presynaptic inhibition of neurotransmitter release (ACh, Dopamine, Norepi, Substance P)
- postsynaptic inhibition of evoked activity may also occur
What are the intracellular biochemical events initiated by occupation of opioid receptors with an opioid agonist?
Increased K+ conductance (hyperpolarization) and/or Ca++ channel inactivation
Leads to immediate decrease in neurotransmitter
*opioid receptor-mediated inhibition of adenylate cyclase is not responsible for immediate effect but may have a delayed effect (via reduction in cAMP)
Opioid cross the blood brain barrier based on what? (4)
- Molecular size (smaller is better)
- Lipid solubility (lipid soluble is better)
- Non-ionized is better
- Protein binding (greater protein bound = less drug available to cross)
What are the types of opioid receptors? What endogenous opioid bind to each type?
Mu – Endorphins and Endomorphins
Delta – Endorphins and Enkephalins
Kappa – Dynorphins
*the opioid-receptor-like 1 (ORL1) is involved in pain response and opioid tolerance
Where are opioid mu receptors located?
Brain: cortex, thalamus, striatum, periaqueductal gray, and rostra ventromedial medulla
Spinal cord: substantia gelatinosa
Peripheral sensory neurons
Intestinal tract
What are the actions of opioid mu receptors?
- Sedation
- Analgesia
- Physical Dependence
- Respiratory Depression (Mu2)
- Miosis
- Euphoria
- Reduced GI motility
- Vasodilation
- Mu1 = low abuse potential
- Mu2 = physical dependence
What are agonists at the mu receptors?
Endorphins
Morphine
Synthetic opioids
Where are opioid kappa receptors located?
Brain: hypothalamus, periaqueductal gray, and claustrum
Spinal Cord: substantia gelatinosa
Peripheral sensory neurons
*high intensity painful stimulation may be resistant to kappa receptor effects (as compared to mu)
What are the actions of opioid kappa receptors?
- Analgesia
- Anticonvulsant effects
- Dissociative and delirium
- Diuresis
- Dysphoria
- Miosis
- Sedation
- Reduces shivering
*low abuse potential
What are agonists at the kappa receptor?
Dynorphins
Where are opioid delta receptors located?
Brain: pontine nuclei, amygdala, olfactory bulbs, cortex
*NO spinal cord or peripheral sensory
What are the actions of opioid delta receptors?
- Analgesia
- Antidepressant effects
- Convulsant effects
- Physical dependence
- Respiratory depression
What are agonists at the delta receptor?
Enkephalins
What are the general side effects of opioids?
- Sedation (precursor to respiratory depression)
- Respiratory depression (usually prevented by intense pain)
- N/V (treat with antiemetics)
- Decreased GI motility (leads to constipation)
- Euphoria
- Anti-tussive (codeine)
- Miosis (pupillary constriction)
- Pruritis
- Biliary spams (mostly morphine - cautious use in gallbladder surgeries)
- Myoclonus/Seizure (high dose)
- Chest wall rigidity (high doses, given quickly IV)
What are the cardiovascular effects of opioids?
- Orthostatic hypotension
- Bradycardia due to increased activity of vagal nerves (may directly stimulate SA node as well - decreased vulnerability to VF)
- Peripheral vasodilation due to histamine release
- Protect myocardium from ischemia (kappa receptors mostly – enhance resistance to oxidative stress)
What is the onset, duration, and T1/2 of Morphine?
Onset = 15-30 min Duration = ~4-6 hours T1/2 = 2-3 hours
- Only 23% unionized so only a small amount gets into CNS
- Minimal cross to BBB due to poor lipid solubility, highly ionized at pH 7.4, high protein binding, and quick glucuronidation
What are the effects of morphine?
- Analgesia
- Euphoria
- Sedation
- Diminished ability to concentrate
- Nausea
- Feeling of body warmth
- Heaviness of extremities
- Mouth dryness
- Pruritus (especially nose) (mu receptor effect – not histamine related)
- Influences the motivation-effective aspect of pain
- Biliary spasm (increases phasic wave frequency of sphincter of Oddi)
How does morphine produce analgesia?
Classic Mu opioid receptor agonist
- Brain (Central) – mu1 – periaqueductal gray, locus coeruleus, medullary nuclei
- Sends descending inhibitory signals
- Spinal Level – mu2
- presynaptic inhibition of primary afferents (decrease in substance P)
- postsynaptic hyperpolarization of interneurons (substantia gelatinosa) – decreases afferent transmission of nociception
Central and spinal synergy
How does gender affect morphine?
Morphine exhibits greater analgesic potency and slower speed of offset in women than men
*higher post-op opioid consumption in men compared to women
What are the respiratory effects of morphine?
- Causes respiratory depression (onset of resp depression parallels onset of analgesia)
- Shifts the CO2 response curve to the right to resting PaCO2 and to apnea (protects pt from receiving too much morphine)
- Slower RR and normal tidal volume
- Decreased ventilatory response to hypoxia/hypoxemia
*hypercarbia will enhance CNS effect (decreases ionization)
How does morphine induce N/V?
By direct stimulation of the chemoreceptor trigger zone (CTZ)
What occurs with prolonged use of morphine?
Tolerance develops with continued exposure
Hyperalgesia may develop
*Patients show signs and symptoms of withdrawal with it is discontinued
How is morphine metabolized?
70% in liver via glucuronidation
- M-3-glucuronide (75-85%): inactive metabolite
- M-6-glucuronide (5-10%): active metabolite – 10x more potent than morphine
*liver disease has minimal effect on metabolism of morphine (reduced hepatic blood flow reduces clearance)
How is morphine eliminated?
Excretion of metabolites via the kidneys
- M6G is secreted by organic ion transporters in kidneys and is impaired in renal disease – M3G also accumulates
- Patients with renal insufficiency may develop prolonged sedation or coma due to M6G accumulation
What are the pharmacokinetics of Hydromorphone (Dilaudid)?
Morphine Derivative – ~5x more potent than morphine
1-2mg IV Hydromorphone = 10-20mg IV Morphine
IV: onset in 5 minutes and peaks in 10-20 minutes
PO: 2-4mg Q4-6H – onset 20-40 min and peaks in 1.5 hours
Metabolized via glucuronidation in the liver
What is Codeine?
Morphine Derivative – prodrug that is converted to morphine via CYP2D6
- low affinity for opioid receptors
- Analgesic effect due to ~10% conversion to morphine
- Less 1st pass metabolism when taken orally
Commonly mixed with acetaminophen:
- Tylenol #3 (30mg codeine + 300mg Tylenol)
- Tylenol #4 (60mg codeine + 300mg Tylenol)
What is Hydrocodone?
Derivative of codeine
- Similar in potency to oral morphine and similar duration of analgesic action
- Commonly combined with acetaminophen
- Used to treat acute pain associated with illness or injury
- Metabolized via CYP2D6 to hydromorphone
What is oxycodone? What are the dosages?
Morphine Derivative – 2x as potent as oral morphine with similar duration of analgesia
- Less 1st pass metabolism than morphine
- Metabolized via CYP2D6/CYP3A4
Percocet (Oxycodone + 325mg acetaminophen)
- Adults 5-15mg (1-3 tabs) Q6H
- Peds 0.05-0.15mg/kg Q4-6H
Oxycotin (sustained release tablets) – taken whole, get bolus “high” when crushed
- 10-20mg Q12H
- 80-120mg for opioid tolerant pts (cancer)
What are the opioid antagonists?
Naloxone (Narcan) – use for opioid OD
Naltrexone (Antabuse) – long acting, not used for an OD but rather for maintenance treatment of opioid dependence
Nalmefene – equipotent to naloxone, 15-25mcg every 5 min IV – longer duration than naloxone
Where does Naloxone act and how is it administered?
Competitive antagonist at mu, kappa, and delta opioid receptors
Admin IV, intranasal, or SQ
*Peak effect in 1-2 minutes
What is the dose of Naloxone for a slow/partial reversal and for “code blue”?
Adult Dose = 0.5-1.5mcg/kg (40-100mcg) for slow/partial reversal of unwanted opioid side effects
Standard ampule = 0.4mg (400mcg) – give full ampule (400mcg) in a “code blue” respiratory depression or narcotic overdose
-Will reverse excessive opioid induced respiratory depression
**Duration of action = 30-40 min and T1/2 = 65 min (adults) and 3hr (neonates) — what is the T1/2 of opioid - may need to redose
What is Meperidine and its properties?
Synthetic Opioid – 1/10th potency of morphine but has faster onset (more lipid soluble)
- Acts on mu and kappa opioid receptors
- Less bradycardia and respiratory depression than equianalgesic dose of morphine
- Some LA activity (sensory/motor block – block Na+ channel)
- Dysphoric/Psychomimetic effects from kappa receptor
- Less biliary pressure effect
- Greater histamine release than morphine
- Metabolized in liver (CYP2D6/CYP3A4)– active metabolite Normeperidine T1/2 14-21 hours (can lead to seizures/delirium)
What is the primary clinical use of Meperidine?
Very useful for post-op shivering – kappa receptor stimulation and alpha2 activation
- does cause N/V
- Clonidine and Burophanol better at decreasing shivering
What may occur with the administration of meperidine to patients receiving antidepressant drugs? What are the symptoms of it?
Serotonin Syndrome – meperidine inhibits reuptake of serotonin
Manifests as:
- Delirium - altered mental status, agitation, excitement and confusion
- Fever - tachycardia, tachypnea, autonomic hyperactivity, diaphoresis
- Convulsions - neuromuscular hyperactivity, tremor, clonus, myoclonus, hyper-reflexia, and pyramidal rigidity
Where does fentanyl act and how does it compare to morphine?
It is almost completely mu receptor agonist
50-100x more potent than morphine
*100 mcg Fentanyl = 10 mg Morphine
Effects and side effects are similar at equianalgesic doses
- no direct reduction in myocardial contractility (BP will drop if pain relieved and SNS slows down, acts on baroreceptors to slow HR)
- no histamine release
What is the onset of fentanyl?
Onset of effects in 3-5 minutes IV
- more rapid brain equilibration than morphine (highly lipid soluble)
- Lipid solubility 816 = 80% to Vascular Rich Group
*Rapid onset of analgesia = rapid respiratory depression
Explain fentanyl’s context-sensitive half-time
During prolonged infusions inactive tissue sites become saturated with fentanyl – This tissue reservoir replaces fentanyl eliminated by hepatic metabolism – leads to slow decrease in plasma concentrations when infusion is discontinued
Depends on length of administration:
1 min infusion = T1/2 5 min
1 hour infusion = T1/2 20 min
8 hour infusion = T1/2 250 min (4hr)
What effects do opioids have on inhaled anesthetics?
- Increased opioid allows reduced Iso concentration (MAC)
- MAC reduction may be greater than 75%
- MAC reduction occurs at moderate plasma levels of opioid concentration
- Iso can NOT be eliminated
*Fentanyl upon induction will reduce MAC requirements for inhaled anesthetic
What are the infusion doses of fentanyl?
Loading Dose = 8-12 mcg/kg (500-850 mcg in 70kg pt)
Maintenance Dose = 1-2 mcg/kg/hr
Where does alfentanil act and how does it compare to morphine and fentanyl?
Almost completely mu receptor agonist
10x as potent as morphine
1/10 - 1/4 as potent as fentanyl
1000mcg Alfentanil = 100mcg Fentanyl = 10mg Morphine
*effects/side effects similar at equianalgesic dose
How is fentanyl metabolized?
100% hepatic extraction – CYP3A4
inactive metabolites
- clearance directly correlated to liver blood flow
- decreased with P450 inhibitors
What is the onset of Alfentanil?
Extremely rapid onset ~1-2 minutes
- 90% unbound is unionized at pH 7.4
- Rapidly crosses B:B barrier
*rapid onset = rapid onset of respiratory depression
How is alfentanil metabolized?
~30-50% in the liver
- Inactive metabolites
- Clearance is directly proportional to liver blood flow
- Reduced with P450 inhibitors
- Metabolism is lower in elderly and CHF – decreased blood flow to liver
What is the context-sensitive T1/2 for alfentanil?
Depends on length of admin but less affected than fentanyl
1 min infusion = T1/2 1 min
1 hour infusion = T1/2 30 min
8 hour infusion = T1/2 50 min
What is the dosing for alfentanil?
Loading dose = 35-70 mcg/kg
*2,500-5,000mcg in 70kg pt – comes in 500mcg/mL
Maintenance infusion = 0.25-0.5 mcg/kg/min
Where does remifentanil act and how does it compare to fentanyl?
Almost completely mu receptor agonist
Equipotent to Fentanyl – 50 mcg Remifentanil = 50 mcg Fentanyl
What is the onset of remifentanil?
very rapid onset ~1 minute
What is the metabolism and clearance of remifentanil?
Metabolism is by non-specific plasma esterases (NOT pseudocholinesterase)
Clearance is CONSTANT and not affected by liver flow, renal failure, or length of infusion
*no residual analgesia – need long acting opioid before turning off
What is the context-sensitive T1/2 of Remifentanil?
Independent of length of infusion
1 min infusion = T1/2 3 min
1 hour infusion = T1/2 3 min
8 hour infusion = T1/2 3 min
*Duration ~6-9 min after infusion turned off
What is the dosing for remifentanil?
Infusion is the only way to use remifentanil
- Loading dose = 1-2 mcg/kg (70-140mcg)
- Infusion = 0.05-0.25 mcg/kg/min
*UIHC: mix 4 mcg/mL for non-intubated cases and 10 mcg/mL for intubated/GA cases
What is the mechanism behind opioid tolerance and hyperalgesia?
Prolonged exposure to opioid activates NMDA glutamate receptors via second messenger mechanisms and also downregulates spinal glutamate transporters
-the resultant high synaptic concentrations of glutamate and NMDA receptor activation contributes to tolerance and hyperalgesia
**treat with small doses of ketamine (NMDA antagonist)
What characteristics of opioids do you look at when choosing and dosing an opioid?
Onset – percent non-ionized
Control of effects – protein binding %
Duration – clearance/elimination T1/2
Potency – partition coefficient
What opioids are used as spinal opioids?
Morphine or Fentanyl – must be preservative free!
- Act on mu receptors in the dorsal horn to produce analgesia
- Admin intrathecally (directly into cerebro-spinal fluid) for chronic pain
- Admin intrathecally or epidurally for acute pain
- morphine controls pain well and produces less sedation and resp depression for the same amount of analgesia
- however, resp depression, N/V, sedation, and itching still frequently occur
What is the result of opioid synergism?
Opioid + Benzo or Opioid + Propofol
Can cause significantly greater respiratory depression, obtundation, and respiratory arrest at much lower doses than those given when agents are admin alone
- shown with ALL opioids
- fast onset opioids are that much more dangerous secondary to lack of time for onset of side effects
What opioids have active metabolites?
Morphine (M6G) Hydrocodone (hydromorphone) Meperidine (normeperidine) Oxycodone (oxymorphone) Codeine (morphine) Tramadol (o-desmethyl-tramadol (M1))
What are the advantages and disadvantages of opioid mixed agonist/antagonist?
Partial agonists at all 3 receptors
Advantages:
- Ability to produce analgesia with limited respiratory depression
- Low potential for physical dependence
Disadvantages:
- Have ceiling effect – increase dose doesn’t increase additional response
- Once antagonized, difficult to then use opioid agonist
What is Butrophanol?
Mixed opioid agonist-antagonist
- low affinity for mu receptors to produce antagonism
- moderate affinity for kappa receptors to produce analgesia and anti-shivering effects
- minimal affinity for sigma receptor so incidence of dysphoria is low
What is Buprenorphine?
Mixed opioid agonist-antagonist
- affinity for mu receptors 50x greater than morphine with slow dissociation from these receptors – prolonged duration
0. 3mg buprenorphine = 10mg morphine - Can be used post-op for moderate to severe pain
- Can be placed in epidural space – high lipid solubility and affinity for opioid receptors limits cephalad spread thus likelihood of resp depression
- Antagonist effects reflect ability to displace opioid agonists from mu receptors
What is the mechanism of action of NSAIDs?
Inhibit the biosynthesis of prostaglandins by preventing the substrate arachidonic acid from binding to the COX enzyme active site
- COX 1: catalyzes production of prostaglandins that are involved in numerous physiologic functions and production of proaggregatory thromboxane A2
- COX 2: expression induced by inflammatory mediators in many tissues and has a role in mediation of pain, inflammation, and fever
*in addition to peripheral blockade of prostaglandin synthesis, central inhibition of COX2 may play an important role in modulation nociception
What are the general effects of NSAIDs on platelet function?
Inhibit the activity of COX1 thus the production of thromboxane A2 that is responsible for platelet aggregation
What are the general effects of NSAIDs on GI tract?
Upper GI: endoscopic ulcers and sometimes serious ulcer complications including perforation and bleeding
Increased Risk Factors for GI complications:
- High Dose
- Older age
- H-pylori infection
- Concomitant use of low-dose ASA, anticoagulants, or corticosteroids
What are the general effects of NSAIDs on CV system?
Increased risk of MI, HF, and HTN
- COX inhibition disturbs balance between COX2 mediated production of proaggregatory thromboxane in platelets and antiaggregatory prostaglandin I2 in endothelial cells
- Naproxen has safer profile
What are the general renal effects of NSAIDs?
Changes in excretion of Na+
Changes in tubular function
Potential for interstitial nephritis
Reversible renal failure due to alterations in filtration rate and renal plasma flow
*all except ASA decrease GFR (occurs more frequently in pts with CHF or renal disease)
What are the general pulmonary effects of NSAIDs?
Patients with allergic rhinitis, nasal polyposis, and/or history of asthma are at increased risk for anaphylaxis
*due to the inhibition of prostaglandin synthesis in local tissues
Highly selective COX2 inhibitors as an alternative to ASA/other NSAIDs suggested for pts with ASA-exacerbated respiratory disease
What is the mechanism of action of Acetaminophen?
Antipyretic and analgesic but has no anti-inflammatory action
Central analgesic effect mediated through activation of descending serotonergic pathways – may inhibit prostaglandin synthesis via COX3
Spinal cord level - antagonize neurotransmission by NMDA, substance P, and nitric oxide pathways
What is the dosing for Acetaminophen?
Excellent Bioavailability
PO: 325-650 mg Q4-6H (do not exceed 4,000mg)
IV provides around 4 hours of effective analgesia
*Combination of Acetaminophen and an NSAID may offer superior analgesia compared with either drug alone
What is the oldest and most widely used medicinal compound around the world?
Aspirin
*derivative of salicylic acid – rapidly metabolized by plasma esterases
What is aspirin predominantly used to treat?
Cardiovascular and cerebrovascular disease
What is the mechanism of action of aspirin?
Irreversibly blocks the action of the COX enzymes preventing production of prostaglandins
*leads to prolonged inhibition of platelet aggregation
How do steroids treat pain?
Its anti-inflammatory action results in decreased production of various inflammatory mediators that play a major role in amplifying and maintenance of pain perception
-Also possibly by inhibition of phospholipase A2 as well as changes in cell function induced by glucocorticoid receptor activation
Glucocorticoids>Corticosteroids in anti-inflammatory
How does dexamethasone affect post-op pain management?
Patients treated with dexamethasone experience less post-op pain
- Require less post-op opioid
- Longer time to first analgesic dose
- Need less rescue analgesia
- Shorter PACU stays
What is Capsaicin?
Transient receptor potential vanilloid (TRPV1) channel agonist
- TRPV1 receptor is markedly reduced in inflammatory conditions and is present on unmyelinated C fibers in the periphery
- Activation of TRPV receptors releases high-intensity impulses and releases substance P, which results in the initial phase of burning – continued release of substance P in presence of Capsaicin leads to depletion and subsequent decrease in C fiber activation
What is Capsaicin used for?
Temporary relief of pain from arthritis, myalgias, arthralgias, and neuralgias
Treatment of postherpetic neuralgis (Shingles), intermetatarsal neuroma, erythromelalgia, and HIV associated neuropathy
