Opioids Flashcards
Opiate
Naturally occurring
Morphine & Codeine
Semi-Synthesized Opioid
Heroin
Modified natural occurring opiate form (Morphine or Codeine)
Synthetic Opioids
Contain a phenanthrene nucleus
Synthesized rather than modified
Created from scratch; completely man-made
Derivatives: Methadone (recent resurgence; long half-life), Benzomorphan, & Phenylpiperidine
Fentanyl, Sufentanil, Alfentanil, & Remifentanil
Different w/ regards to potency, rate of plasma equilibrium, and action site
Opium Classes
Phenanthrenes - Morphine, Codeine, & Thebaine
Benzylisoquinolines - Papaverine & Noscapine
Opioid Receptor Locations
Primarily located central in brain and spinal cord
Receptors throughout body involved w/ pain perception, impulses, & responses
Peripheral receptors - least likely site
Injecting opioid at pain site Ø to minimal response d/t no peripheral receptors
MOA
GPCR
Decrease neurotransmission
Mimics actions of endogenous ligands (enkephalins, endorphins, dynorphins, NE)
Post-synaptic attach to GPCRs 2nd messenger causes increased K+ conductance = decreased function
Endogenous Pain Modulation
Survival benefit
Substances: Endorphins, enkephalins, dynorphins, norepinephrine
Natural response to modulate pain
Pre-synaptic inhibit release ACh, dopamine, NE, and substance P
Who hypothesized pain perception r/t brain?
Rene Descartes
Treatise of Man
Chronic Pain
Receptors can be located peripherally at pain site and initiated anywhere along the pain pathway
Opioids not the best drugs to treat
What substances are released at site that send pain signal when cell destruction occurs?
Substance P Calcitonin gene-related peptide Serotonin Histamine Swelling causes pain on nerves Neuro-electrical stimulation creates nerve impulse
Pain Pathway
Injury/damage to cell → substances release → neuro-electrical stimulation/impulse → 1st order neuron → DRG → synapse at 2nd order neuron in spinal cord → transmission to midbrain → 3rd order neuron → signal to associated part experiencing the pain (4th order neuron) → motor response → Fight or flight response triggered
Spinal reflex arc
Opioid Agonist Role
Produce analgesia - block pain pathway transmission
Do NOT cause:
Loss of touch
Loss or proprioception (perception or awareness of the position and movement of the body)
Loss of consciousness (in appropriate doses)
Where are pain fibers located?
Rexed lamina 1, 2, & 5
Located in substantia gelatinosa of the dorsal horn
Another Receptor Site
NMDA receptors
In regards to MOA, Opioids do not…
Block nerve impulses (only LA)
Alter afferent nerve ending responsiveness to noxious stimulation
Brain Receptors
Periaqueductal gray - recognized pain and tells body to release endogenous substances
Locus coeruleus - r/t alertness (same receptor site as Dexmedetomidine)
Rostral ventral medulla - motor response
Spinal Cord Receptors
Primary afferent and interneurons of the dorsal horn
Where pain signals transmitted
Mu Receptors
Principally responsible for supraspinal and spinal analgesia
Mu1 - analgesia (supraspinal and spinal), euphoria, miosis, bradycardia, urinary retention
Mu2 - analgesia (spinal), ventilation depression, physical dependence, consitipation
Delta Receptors
Response to endogenous ligands known as enkephalins & may serve to modulate Mu receptor activity
Analgesia (supraspinal and spinal), respiratory depression, physical dependence, urinary retention, and constipation
Kappa Receptors
Activation results in inhibition of neurotransmitter release
Analgesia (supraspinal and spinal)
Dysphoria, sedation
Miosis
Diuresis
Lesser extent - hypoventilation and high-intensity pain
Agonist-antagonist often act primarily on K receptors (limited response; not full efficacy)
Low abuse potential
Metabolism
Most metabolized in liver
Exception: Remifentanil
Active metabolites must be conjugated to inactivate
Small dose effects terminated through redistribution
Metabolism terminates effects of multiple doses and infusions
Excretion
Primarily kidneys
Cardiovascular Effects
Bradycardia w/ sustained BP
Impaired SNS response - orthostatic hypotension, venous pooling, & histamine release
Does not sensitize the heart of catecholamines
Synergism w/ other drugs often causes myocardial effects (Benzodiazepines & nitrous oxide)
Cardiac protectant effect - enhances myocardial resistance to oxidative and ischemic stresses (Sigma & Kappa receptors)
Respiratory Effects
Dose-dependent ventilation depression (Mu & delta receptors in the brainstem)
Regulate breathing rate & rhythm
Decreased responsiveness to CO2 - less acetylcholine & right shift in CO2 response curve
Decreased RR accompanied by TV compensation (slow, deep breaths)
Bronchial - decrease ciliary action & increase airway resistance (bronchial smooth muscle & histamine release)
Cough Suppression
Medullary cough centers depression
Codeine - bulky substitution on number 3 carbon position
Dextromethorphan - dextrorotary - cough suppression w/out analgesia or respiratory depression
Narcotic on induction (primarily Fentanyl) may stimulate cough reflex
CNS Effects
NOT anesthetics; awareness possible
Most effective for visceral and dull pain
Sedative & euphoric effects
Analgesic effects - inhibit ascending transmission of nociceptive information & activate descending pathways
Vasodilation - increased CBF & possibly ICP
Use cautiously in head trauma patients - alter wakefulness, miosis, ventilation depression, increased sensitivity when blood-brain barrier compromised
Do NOT alter neuromuscular blocking drug effects
Miosis d/t action on autonomic nervous system component of Edinger-Westphal nucleus of oculomotor nerve - antagonized by atropine or Naloxone
Muscle Rigidity
NO effect on nerve conduction - cannot cause muscle contraction
Skeletal muscle hypertonus “truncal rigidity” r/t Mu receptors acting on dopamine & GABA channels
Resistance d/t laryngeal musculature contracture
Sedation
Morphine induces sedation that precedes analgesia
Unresponsive patient not necessarily pain free
Biliary Tract
Biliary smooth muscle & Oddi sphincter spasm
Glucagon 2mg IV will reverse smooth muscle spasm, does not antagonize analgesic effects
Pancreatic duct contraction - increase in amylase & lipase levels (mimics acute pancreatitis)
Morphine NOT appropriate after cholecystectomy - Dilaudid or Fentanyl instead
GI Effects
Decreased gastric motility, propulsive activity, & emptying time - increase aspiration risk or delay drug absorption
Opioid-induced constipation (can be debilitating in chronic users)
Methylnatrexone can antagonize effects
N/V
Primary patient complaint
Stimulation of chemoreceptor trigger zone in medulla - serotonin type 3 (5 hydroxytriptamine or 5-HT3) & dopamine type 2 receptors
Increased GI secretions & delayed gastric emptying
N/V not common in recumbent patient - vestibular effect?
GU Effects
Opioid-induced augmentation of detrusor muscle tone results in urgency
Enhanced urinary sphincter tone makes voiding difficult
Cutaneous Changes
Causes blood vessels to dilate - warm, flushed skin Histamine release (not an allergy) -conjunctival erythema, pruritis, itching, rash, urticaria Especially intrathecal (epidural/spinal) Morphine - more long-term effects as compared to Fentanyl
Placental Transfer
Readily crosses placenta - results in neonatal depression
Morphine greater than meperidine
Chronic use can cause neonatal physical dependence
Naloxone may precipitate NAS
Drug Interactions
Cholinergic system - positive opioid analgesia modulator
Ventilatory effects can be exaggerated by other drugs: Amphetamines, Phenothiazines, MOAIs, Tricyclics, Benzodiazepines
Overdose
Ventilation depression - slow, deep breathing
TRIAD: Miosis, hypoventilation, coma
Hypotension and seizures develop if arterial hypoxemia persists
Treatment - mechanical ventilation, supplemental oxygen, antagonist to reverse
Reflex Coughing
“Provocation” of coughing - cause unclear
Imbalance b/w sympathetic and vagal nerve innervation (SNS/PSNS)
Juxtacapillary irritant receptors stimulation
Fentanyl, sufentanil, & alfentanil
NOT seen w/ Morphine or Hydromorphone
Tolerance/Dependence
Cross-tolerance can occur b/w all opioids
Tolerance w/out physical dependence possible, but not vice versa
Pharmacodynamic tolerance - receptor desensitization & down regulation, cAMP up-regulation (Morphine 2-3 weeks - much quicker w/ more potent drugs)
Everything except miosis & bowel motility - all or nothing
Long-term opioid use activates NMDA receptors - down regulates spinal glutamate receptors
Withdrawal Abstinence Syndrome
Initial symptoms - yawning, diaphoresis, lacrimation
Insomnia & restlessness common
Cramps, N/V, and diarrhea peak at 72hrs then decline in the next 7-10 days (up to 2 weeks)
Tolerance quickly lost during withdrawal
Morphine
STANDARD to compare all other opioids
Produces analgesia, euphoria, sedation, decreased concentration
Nausea, body warmth, pruritis (nose), dry mouth, extremity heaviness
Increases pain threshold & modifies noxious stimulation perception
Effective against visceral, muscles, joints - against slow, dull pain when given preemptively
Morphine PK
Onset 15-30min (slow compared to other opioids)
Only small portion reaches CNS - poor lipid solubility, high ionization degree, protein binding, rapid liver conjugation
Increased CBF d/t vasodilation
Accumulates rapidly in kidneys, liver, & muscle
NO first-pass effect in the lungs
Primary metabolism - conjugation w/ glucuronic acid
Significant renal metabolism
Morphine Metabolites
75% morphine-3-glucuronide (inactive)
5-10% morphine-6-glucuronide (active)
Normorphine
Morphine-6-Glucuronide
Active Morphine metabolite
More potent than Morphine
Longer duration of action
High analgesic potency 65x higher than Morphine
Codeine
Know implications for patient coming into surgery
Naturally occurring opioid
Elimination half-life 3-3.5hrs
PRODRUG - inactive compound metabolized in body to produce drug (Morphine)
Morphine 10x more potent than Codeine
Meperidine
Basis for most drugs used now
Synthesized in 1939 - phenylpiperdine ring
Several analogues (structurally similar) - Fentanyl, Sufentanil, Alfentanil, Remifentanil
Structurally similar to Atropine - mild antispasmodic effects
Mu receptor agonist
Primary use: Anti-shivering postoperatively
Stimulates KAPPA receptors
High doses - negative cardiac inotropic effects & histamine release
Meperidine PK
1/10 as potent as Morphine
Duration of action 2-4hrs
Similar sedation, euphoria, nausea, vomiting, ventilation depression
Extensive first pass metabolism by liver - limits oral usefulness
Meperidine Metabolites
90% demethylization to normeperidine
Normeperidine active - needs to be broken down
10% hydrolysis to meperidinic acid
Normeperidine
Meperidine active metabolite Half as active as Meperidine Elimination half-life 15hrs >30hrs in renal failure Increased sensitivity in elderly Eventually undergoes hydrolysis to meperidinic acid
Meperidine Elimination
Excretion
pH dependent
Decreased renal function can result in metabolites accumulation
Meperidine SE
Similar to Atropine d/t structural
Mydriasis (dilated pupils) & increase HR
High doses - decrease myocardial contractility
Delirium & seizures reflects normeperidine accumulation (high CNS effects)
Serotonin syndrome in patients taking MAO inhibitor or Fluoxetine
Less biliary tract spasm
Withdraw develops more rapidly & shorter duration
Elimination half-life 2-4hrs
Opioid Potencies
Tramadol/Meperidine 1/10 MORPHINE Buprenorphine 0.3mg IM = 10mg Morphine Methadone 1/4 (long-acting) Hydromorphone 5x Fentanyl 75-125x
Fentanyl Analogue Potencies
MOST POTENT
Sufentanil 5-10x more potent than Fentanyl
Fentanyl 75-125x more potent than Morphine
Remifentanil (similar to Fentanyl)
Alfentanil (less potent than Fentanyl)
LEAST POTENT
Fentanyl Analogue Vd
Fentanyl 4L/kg
Sufentanil 2L/kg
Alfentanil 0.6L/kg
Remifentanil 0.35L/kg
Fentanyl Analogue Ionization
Alfentanil 90% non-ionized
Remifentanil 58%
Sufentanil 20%
Fentanyl 10%
Fentanyl Analogue pKa
Fentanyl pKa 8.4
Sufentanil 8.1
Remifentanil 7.1
Alfentanil 6.5
Fentanyl
Most widely used opioid analgesic in anesthesia
Phenylpiperidine ring
75-125x more potent than Morphine
Fentanyl PK
Rapid onset 1-3min
Shorter duration
Lipid soluble
Redistribution terminates single dose effect
1st pass uptake in lungs
Metabolism: N-dealkylation & hydroxylation
Minimal metabolites
Longer elimination half-time than Morphine
Vd 4L/kg more than 80% leaves the plasma < 5min
Elderly prolong elimination d/t ↓ clearance
Highly protein-bound
Cirrhosis does not prolong elimination half-time
Context sensitive half-life increases w/ infusion > 2hrs
Fentanyl Dose
Block sympathetic stim 1-3mcg/kg (prior to anesthesia induction) Analgesia 1-3mcg/kg Surgical as sole anesthetic 50-150mcg/kg Peds PO 15-20mcg/kg (pre-op sedation) Transdermal available
Fentanyl SE
Similar profile to Morphine
“Secondary peaks” d/t 1st pass lung uptake
True allergy extremely rare - does not evoke histamine release; hypotension unlikely
Bradycardia more prominent
Associated w/ modest ICP increases
Seizure activity; myoclonus (inhibitory neurons inhibition)
Sufentanil
Thienyl Fentanyl analogue
5-10x more potent than Fentanyl
Sufentanil PK
Extensive protein binding
Rapid redistribution terminates effects
Significant 1st pass pulmonary uptake
Metabolism: N-dealkylation & O-demethylation
Active metabolite - Desmethyl Sufentanil
Clearance sensitive to hepatic blood flow
Normal renal function important to clearance
Sufentanil Dose
Analgesia 0.1-0.4mcg/kg
Longer duration & less respiratory depression
Chest wall rigidity after induction doses
Alfentanil
pKa 6.5
Less potent than Fentanyl
Shorter duration
Alfentanil PK
Rapid onset & offset 90% non-ionized Bound by alpha 1 glycoproteins Vd 0.6L/kg Metabolism: Piperidine N-dealkylation to Noralfentanil & Amide N-dealkylation to N-Phenylpropionamide
Alfentanil Dose
Blunt stim 15mcg/kg
Noxious stim 30mcg/kg
Induction (unconsciousness) 150-300mcg/kg
Combination w/ inhalation anesthetic 15-150mcg/kg/hr
Alfentanil SE
More significant ↓ BP
Diminished N/V incidence
Acute dystonia (avoid in untreated Parkinson’s patients)
Remifentanil
Selective Mu agonist
Similar potency to Fentanyl
ESTER linkage
Synergistic w/ Propofol
Brief action, titratable, does not accumulate, & rapid recovery
Cases requiring transient profound analgesic effect - retrobulbar block, direct laryngoscopy, tracheal intubation, NSGY head pins
Remifentanil PK
Small Vd Rapid clearance Context sensitive half-life = 4min Metabolism: Non-specific plasma esterases No active metabolites Unchanged w/ renal or hepatic failure
Remifentanil Dose
Induction 0.25-1mcg/kg bolus prior to induction agent
Analgesia 0.05-0.2mcg/kg/min
Sedation 0.05-0.1mcg/kg/min in combination w/ 2mg Midazolam
Remifentanil SE
N/V
Ventilation depression
↓ systemic BP
Administer longer acting opioid to treat post-op analgesia
Hyperalgesia 2nd to acute opioid tolerance (Ketamine or Magnesium to block)
“Seizure-like” activity
Hydromorphine (Dilaudid)
5x more potent than Morphine
Slightly shorter duration
Less hydrophilic - faster onset, more sedation, less euphoria
Alternative to treat moderate to severe pain
Side effects: Agitation & myoclonus
Methadone
Synthetic opioid Oral opioid in chronic pain settings Withdrawal & drug suppression Half-life 12hrs Variation*
Methadone Dose
1/4 dose Morphine
20mg IV produces post-op analgesia >24hrs
Methadone SE
Ventilation depression Miosis Constipation Biliary tract spasm Sedative & euphoric effects less
Methadone Chronic Pain Treatment
Low abuse potential
NMDA antagonist activity potentially beneficial to treat neuropathic pain
Disadvantage - prolonged & unpredictable half-life
Drug accumulation & ventilation depression
Tramadol
Synthetic Codeine analog
Weak/moderate Mu agonist
Less potent than Morphine
Less addictive chronic pain treatment option
Enhances descending inhibitory pathway function
Tramadol Metabolism
CYP450
Metabolite O-desmethyltramadol (modest analgesic effects)
Tramadol Disadvantages
Interacts w/ Coumadin
Drug-related seizures (may lower threshold)
High N/V incidence
Ondansetron (Zofran) may interfere w/ analgesic component 5-hydroxytryptamine reuptake
Heroin
Synthetic opioid More rapid onset Rapidly penetrates the CNS where hydrolyzed to active metabolites - Monoacetylmorphine & Morphine Less nausea ↑ physical dependence liability
Opioid Agonist-Antagonist
Bind to Mu receptors but produce limited responses or no effect
Analgesia w/ limited ventilation depression
“Ceiling effect”
Patients who cannot tolerate pure agonist
Butorphanol
Limited intraoperative use
Resembles Pentazocine 20x agonist effects & 10-30x antagonist effects
Low Mu receptor affinity - produces antagonism
Moderate Kappa receptor affinity - analgesia & anti-shivering
Butorphanol PK
Rapidly absorbed after IM injection Metabolized in liver Excretion primarily via bile Hydroxybutorphanol - inactive metabolite Elimination half-life 2.5-3hrs
Butorphanol SE
Sedation, nausea, diaphoresis
Dysphoria
Ventilation depression
↑ catecholamine response (HR, BP, CO, PAP - pulmonary artery pressure)
Mild biliary & GI tract symptoms
Concomitant opioid agonist limits effects
Withdrawal following acute discontinuation in chronic therapy
Nalbuphine
Chemically r/t Oxymorphone & Naloxone Morphine analgesic properties 1/4 antagonist Nalorphine Metabolized in liver Elimination half-life 3-6hrs Antagonist effects at Mu receptors Admin prior to opioid may diminish effects peri-op After opioid admin reserves 2-3hrs ventilation depression BUT maintain analgesia
Nalbuphine SE
Sedation most common
Less dysphoria than Butorphanol
Ventilation depression has ceiling effect (30mg)
Catecholamine stimulation effects - beneficial in cardiac patients needing sedation & analgesia
Buprenorphine
Derived from Thebaine
Potent 0.3mg IM = 10mg Morphine
Post-op pain r/t cancer, renal colic, MI
Buprenorphine SE
Drowsiness, N/V, ventilation depression
Resistance to Naloxone antagonism
Dysphoria unlikely
Low abuse risk
Opioid Antagonists
Substitute alkyl group for methyl group
Pure Mu antagonists - Naloxone, Naltrexone, & Nalmefene
Naloxone
Treat opioid induced hypoventilation, ventilation depression in neonate, deliberate drug overdose, suspected physical dependence
Short half-life 30-45min
Metabolism: liver conjugation w/ glucuronic acid
Naloxone 3-glucuronide (metabolite)
Naloxone Dose
IV 1-4mcg/kg
PCA 5mcg/kg/hr fix ventilation depression w/out affecting analgesia
PO 1/5 as potent d/t 1st pass hepatic metabolism
Naloxone SE
Analgesia reversal
Titrate to maintain analgesia and reverse hypoventilation
N/S
Increased SNS activity - sudden pain onset, tachycardia, hypertension, pulmonary edema, cardiac dysrhythmia
Fetal withdrawal
Naltrexone
Oral antagonist w/ sustained effects >24hrs
Used to treat alcoholism
Nalmefene
Pure opioid antagonist
Naltrexone 6-methylene analogue
Nalmefene PK
Prophylactic treatment decreases N/V and pruritis in PCA patient
Primary advantage - longer duration
Metabolized in liver by hepatic conjugation
Pulmonary edema SE
Nalmefene Dose
15-25mcg until effect achieved
MAX 1mcg/kg
Equipotent to Naloxone
Methylnaltrexone
Quaternary opioid receptor agonist
Highly ionized - difficult to penetrate CNS
Attenuates Morphine induced delayed gastric emptying
Decreases nausea incidence
Opioid Allergy
TRUE opioid allergies = rare
- Histamine release, orthostatic hypotension, N/V
Fentanyl does not cross-react w/ Morphine derivatives
Immune Modulation
Opioid receptors present on immune cells
Immunosuppression (NK cell depression) following prolonged exposure or abrupt withdrawal
Pain itself can impair immune function
PCA
Alternative to intermittent bolus
Allows patient to address own analgesia
Advantages: ↓ healthcare provider workload, ↑ patient satisfaction, ↓ opioid consumption, & inherent safety
Marginally improved analgesia, but ↑ pain satisfaction
Remifentanil PCA 1st labor stage provides analgesia w/ minimal neonatal effects
Neuraxial Opioids
Intrathecal opioids target Mu receptors in substantia gelatinosa in the spinal cord
NO sympathectomy, sensory block, or weakness
Epidural placement - Mu receptors & systemic absorption & minimal to no IV administration
Epi enhances intrathecal Morphine effects
PK: Uptake into fat systemic absorption & diffusion across dura & less lipid soluble more likely to stay in CNS
SE: Pruritis, N/V, urinary retention, & ventilation depression (classic signs), sedation, myoclonus (rare), herpes virus reactivation, miosis, nystagmus, vertigo, delayed gastric emptying, priapism, spinal cord damage dose dependent
