Opioids

Overview

• Opioids suppress pain by their action on the brain, spinal cord, and peripheral nervous system
• Opioids provide a vital part of the analgesic component of total intravenous anesthesia
• The sensation of pain is altered, threshold for pain is increased, and the affective response to pain is altered as well
• Opioids are more effective against pain arising in the viscera than other non-opioid analgesics
• Opioids work best before the painful stimulus occurs
• The analgesia produced by opioids is not associated with predictable or consistent LOC, loss of touch, or proprioception
• Opioids are weak bases
• Opioids are used for
• o Analgesia
• o Anesthesia
• o Sedation
• Major Side Effects
• o Respiratory Depression
• o Pruritis
• o Delayed gastric emptying
• o Nausea and Vomitiing
• o Constipation
• o Urinary retention
• o Tolerance
• o Physical dependence

Relative Potencies of commonly used Opioids

Source: Stoelting, Robert K., and Ronald D. Miller. Basics of Anesthesia. New York: Churchill Livingstone, 2006.

Pharmacokinetics

• The pharmacokinetic profile of opioids can be described using a three-compartment model
• Important Pharmacokinetic Variables
• o Morphine
• § Vd_ss = 3-5 L/kg
• § Clearance = 15-30 mL/kg/min
• § Alpha Elimination Half-life = 1-2.5 min
• § Beta Elimination Half-life = 2-4 hours
• § 20-40% protein bound
• o Fentanyl
• § Vd_ss = 3-5 L/kg
• § Clearance = 10-20 mL/kg/min
• § Alpha Elimination Half-life = 1-2 min
• § Beta Elimination Half-life = 2-4 hours
• § 84% protein bound
• o Sufentanil
• § Vd_ss = 2.5-3.0 L/kg
• § Clearance = 10-15 mL/kg/min
• § Alpha Elimination Half-life = 1-2 min
• § Beta Elimination Half-life = 2-3 hours
• § 93% protein bound
• o Alfentanil
• § Vd_ss = 0.4-1.0 L/kg
• § Clearance = 4-9 mL/kg/min
• § Alpha Elimination Half-life = 1-3 min
• § Beta Elimination Half-life = 1-2 hours
• § 92% protein bound
• o Remifentanil
• § Vd_ss = 0.2-0.3 L/kg
• § Clearance = 30-40 mL/kg/min
• § Alpha Elimination Half-life = 0.5-1.5 min
• § Beta Elimination Half-life = 0.7-1.2 hours
• § 80% protein bound

• Metabolism
• o Morphine
• § Morphine mainly undergoes metabolism by conjugation in the liver, but it also undergoes extrahepatic metabolism by the kidneys
• § Main metabolite is morphine-3-gluconuride, which is inactive
• § Morphine-6-gluconuride makes up 10% of the metabolites
• M6G is a more potent m-receptor agonist than morphine, and its duration of action is similar
• Beware, M6G can prolong the action of morphine, especially in renal failure!
• o Fentanyl
• § First-pass metabolism by the lungs is an important pathway of elimination
• § Metabolized by the liver by N-dealkylation and hydroxylation
• § Primary metabolite is Norfentanyl
• present in the urine 48 hours after IV administration
• o Sufentanil
• § Like fentanyl, sufentanil undergoes significant first-pass pulmonary metabolism
• § Only a small amount of sufentanil (20%) exists in the nonionized form
• § Major metabolic pathways include N-dealkylation, oxidative O-demethylation, and aromatic hydroxylation.
• o Alfentanil
• § Main metabolic pathways are similar to sufentanil
• § Metabolites have little opioid activity
• o Remifentanil
• § Characterized by its unique ester linkages
• § Undergoes rapid hydrolysis by blood and tissue-nonspecific esterases
• § Main metabolite has little opioid activity
• § Is NOT metabolized by pseudocholinesterase
• § No significant pulmonary metabolism
• Drug Specific Details
• o Morphine
• § IV administration ® peak effect in 15-30 min. (twice as long as fentanyl)
• § Morphine has poor penetration into the CNS
• relatively poor lipid solubility
• rapid metabolism (conjugation with glucuronide)
• o Fentanyl
• § Single dose of fentanyl IV has a more rapid onset and shorter duration of action than morphine - due to greater lipid solubility of fentanyl, facilitating passage across the BBB
• § Short duration of action of a single dose of fentanyl reflects its rapid redistribution into lean body mass
• § -With continuous infusion or multiple administrations, context-sensitive halftime increases, with a large increase after 2 hours (due to saturated, inactive tissue sites behaving as reservoirs)
• § -Although regarded as very rapid, there is a significant delay between peak plasma concentration and effect - effect-site equilibration time between blood and brain is 6.4 minutes
• o Sufentanil
• § Twice as lipid soluble as fentanyl
• § Rapid redistribution to inactive tissues terminates effect of small doses, but like fentanyl, sufentanil can accumulate with repeated dosing or continuous infusion
• § Context sensitive half-time of sufentanil << fentanyl
• o Alfentanil
• § One third the duration of action of fentanyl
• § More rapid onset of action than fentanyl and sufentanil (1.4 min) after IV administration ® due to low pK (90% nonionized at physiologic pH)
• § WIDE interindividual variation in metabolism
• o Remifentanil
• § Analgesic potency similar to fentanyl
• § Susceptible to hydrolysis by nonspecific plasma and tissue esterases (not pseudocholinesterase) to inactive metabolites, resulting in:
• Precise and rapidly titratable effects due to rapid onset/offset
• Noncumulative effects resulting in rapid recovery after discontinuation of IV infusion
• § Context sensitive half-time is independent of duration of infusion (4 min.)

Pharmacodynamics

• Opioids are agonists at stereospecific opioid receptors inside and outside the CNS, and mimic endogenous opioid receptor ligands
• Opioid receptor binding by an agonist results in a decrease in neurotransmission ® usually from presynaptic inhibition of neurotransmitter release, and increased potassium conductance (resulting in hyperpolarization of neurons)
• o Depression of cholinergic transmission in the CNS may account for its analgesic effects (as well as side effects)
• Opioid Receptors are G protein-coupled receptors, and when activated ® inhibit adenyl cyclase and calcium and potassium channels ® decrease in neuronal activity
• CNS
• o Opioids produce analgesia, drowsiness, changes in mood, euphoria and mental clouding
• o Opioids are not true anesthetics, as they do not reliably produce LOC
• o Postoperative titration of morphine frequently induces sedation that precedes the onset of analgesia (thus frequent, intermittent boluses 5-7 minutes apart allows evaluation of effect). Sleep may occur before pain is relieved!
• o Fentanyl can reduce the MAC of isoflurane by 80% (61% reduction of MAC with sevoflurane), but there is a sub-MAC ceiling effect - in other words, opioids cannot reach 100% MAC alone
• o Fentanyl, sufentanil, alfentanil, or remifentanil given with propofol reduces the concentration of propofol required to cause LOC
• o Fentanyl displays marked synergism with BDZs in producing hypnosis and depression of ventilation
• o Remifentanil may have a sedative or hypnotic effect independent of analgesia (can lower the BIS in a dose-dependent manner, unlike other opiates)
• o In otherwise healthy patients, opiates produce a modest decrease in the CMRO₂ and ICP (due to cerebral vasoconstriction), but CBF is unchanged or slightly increased
• o In patients with head injury, opioids must be used with caution since a depression of ventilation and a resultant accumulation in CO­₂ can result in an increase in ICP.
• o Remifentanil produces generalized tonic-clonic seizure-like activity in otherwise healthy adults, as does morphine after epidural or intrathecal administration
• o Opiate induced muscle rigidity (especially of the thoracoabdominal muscles) often occurs just as the patient has LOC
• § Can cause vocal cord closure resulting in difficulty in bag and mask ventilation (most common with fentanyl or sufentanil)
• § Thought to be due to opioid receptor interaction with dopaminergic and GABA responsive neurons
• § Adverse effects of muscle rigidity include:
• Cardiac ® increased CVP, PAP, PVR
• Respiratory ® decrease in compliance, FRC, ventilation, hypercapnia, hypoxemia
• Misc. ® increased O₂ consumption, and ICP
• § Nondepolarizing muscle relaxants, and opioid antagonists can help attenuate rigidity
• Respiratory System
• o Beneficial Effects
• § Opiates work well at preventing hyperventilation induced by anxiety or pain (by decreasing pain and central ventilatory drive)
• § Can prevent postoperative respiratory dysfunction caused by pain
• § Antitussive
• § Can depress the upper airway, tracheal, and lower respiratory tract reflexes (good for laryngoscopy/intubation)
• § Opioids blunt or eliminate somatic and autonomic responses to tracheal intubation
• § Can help avoid bronchoconstriction in asthma
• o Adverse Effects
• § Dose-dependent respiratory depressant effects of opioids are their most serious adverse effect, and seem to act directly on brainstem respiratory centers through the m₂ receptor
• § Incidence of serious adverse events related to respiratory depression is 0.1-1%
• § The hypercapnic ventilatory response is inhibitied, resulting in an increase in the apneic threshold and resting end-tidal PCO₂
• § Hypoxic ventilatory drive decreased as well
• § Beware, high doses of opioids can eliminate spontaneous respirations without producing LOC ® tell your patients to breath!
• § Peak onset of respiratory depression is about 30 min. for morphine and 5-10 min. for fentanyl, and can persist for several hours
• § Sufentanil produces shorter-lasting respiratory depression and longer-lasting analgesia than fentanyl
• § Beware, the combination of remifentanil and propofol is synergistic in producing SEVERE depression of ventilation
• Cardiovascular system
• o Opiates produce hemodynamic stability throughout the perioperative period
• o Particular effect on the hemodynamic profile depends on the opiate:
• § Alfentanil is less reliable than fentanyl or sufentanil in blocking increases in HR and BP during (i.e. induction of anesthesia, sternotomy, etc.)
• § Morphine may cause histamine release, which can cause a decrease in systemic blood pressure (esp. with rapid IV administration of large doses)
• § Morphine may cause bradycardia due to parasympathomimetic effects
• § Fentanyl, when given with a BDZ, can cause significant bradycardia
• § Synthetic and short-acting opioids do not cause histamine release
• o The combination of an opioid with NO₂ or BDZ causes decreased BP, which does not happen when drugs are given alone

Uses

• Analgesia
• o Fentanyl ® 1-2 mg/kg IV dose
• o Remifentanil ® 0.05-2.0 mg/kg/min
• § advantage of remifentanil is rapid recovery from ventilatory depression or excessive sedation
• § CAUTION - longer acting opioid needed before cessation of remifentanil to ensure analgesia post-op
• o Use of an opioid before painful surgical stimulation may decrease the subsequent amount of opioid required in the postoperative period (preemptive analgesia)
• Anesthesia
• o Fentanyl ® 50-150 mg/kg IV
• § produces stable hemodynamics when used alone, but there is the possibility of incomplete LOC
• o Remifentanil ® 1 mg/kg IV
• § Induces anesthesia in 60-90 sec
• Sedation in critically ill patients
• o Remifentanil can be uniquely used in this setting due to rapid onset/offset

Side Effects/Contraindications

• Ventilatory depression
• Pruritis (especially of the face)
• o pronounced during intrathecal and epidural opioid use, but can be counteracted by droperidol (1.25 mg), propofol (20 mg) or alizapride (100 mg)
• Opioids (esp. morphine) decrease peristaltic activity and enhance the tone of the pyloric sphincter, causing delayed gastric emptying and intestinal stasis.
• Opiates can cause urinary retention due to increased bladder sphincter tone
• Nausea and Vomiting
• o Caused by direct stimulation of dopamine receptors in the chemoreceptor trigger zone in the floor of the fourth cerebral ventricle
• o Intraoperative opioids are a risk factor for PONV
• Tolerance and Physical Dependence
• o Major limitations of opioids
• o Tolerance usually develops in about 25 days with analgesic doses of morphine.
• § Tolerance to depression of ventilation develops, but opioids retain their miotic and constipating effects
• § Long term tolerance (opioid insensitivity) may persist for months to years in some patients
• o Physical dependence may occur after 48 hours of continuous medication.
• § Physical dependence is characterized by a typical withdrawal syndrome: diaphoresis, insomnia, restlessness, abdominal cramps, N/V, and diarrhea ® peaks in 72 hours, and lasts for about 7-10 days