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Effects of Opioids on the Respiratory System

(Reference: Miller's Anesthesia, 2-Volume Set, 10e - Chapter 22)

1. Overview

Opioids can affect respiration through multiple mechanisms, and opioid overdose can lead to fatal hypoxia caused by prolonged apnea. Opioid-induced respiratory depression is caused by its suppressive effect on the pontomedullary respiratory center, and is characterized by slow, shallow, and irregular breathing, which in severe cases leads to respiratory arrest. Opioids also impair chemoreflexes and upper airway patency and induce muscle rigidity, sedation, and sleep-disordered breathing, all of which compromise patient outcomes.

2. Effects on Airways (Antitussive Actions)

The antitussive actions of opioids are well known and are central in origin. Opioids blunt or eliminate somatic and autonomic responses to tracheal intubation and allow patients to tolerate endotracheal tube placement without coughing or bucking. Remifentanil (at an effect-site concentration of 2 ng/mL) can suppress coughing induced by extubation after propofol or sevoflurane anesthesia.

Morphine has a depressant effect on respiratory mucus secretion in human bronchi, which is one of the most important defenses against respiratory tract infections; however, morphine had no effect on the beating frequency of nasal cilia in vitro. A sedative dose of morphine (0.1 mg/kg) was associated with increased incidence of pharyngeal dysfunction and discoordinated breathing and swallowing, a combination that impairs airway protection and potentially increases the risk for pulmonary aspiration.

3. Opioid-Induced Cough (Paradox)

Despite their antitussive properties, opioids can paradoxically induce cough. Equipotent boluses of sufentanil 0.3 mcg/kg and fentanyl 3 mcg/kg both increase the incidence of cough, although the incidence and severity of coughing with sufentanil are less than with fentanyl. The incidence of fentanyl-induced cough (100-150 mcg given IV) decreased from 18% to 1.3% when the injection time was increased from 2 seconds to 30 seconds. Lidocaine 1.5 mg/kg administered 1 minute before fentanyl effectively suppresses opioid-induced cough, and a meta-analysis identified 0.5 mg/kg as the lowest effective lidocaine dose. Propofol, alpha-2 agonists (clonidine, dexmedetomidine), beta-2 agonists (terbutaline, salbutamol), and NMDA-receptor antagonists (ketamine, dextromethorphan) are also effective in suppressing fentanyl-induced cough.

In summary, opioids engender potent antitussive properties that help blunt airway responsiveness to endotracheal intubation, but depending on the class of opioid and rate of administration, they may evoke a brief cough that can be subverted by preadministered agents such as lidocaine.

4. Respiratory Depression - The Primary Adverse Effect

The respiratory-depressant actions of opioids represent their most serious adverse effect. Opioids activating the mu-receptor cause dose-dependent depression of respiration, primarily through a direct action on brainstem respiratory centers. Although the preBötzinger complex (PreBötC), the main region of respiratory rhythm-pattern generation, has been known to be the main target of opioid-induced respiratory depression, it was demonstrated that the PreBötC partially mediates opioid effects on respiratory phase timing but does not mediate the opioid-induced depression of respiratory rate.

Activation of the mu-opioid receptor in the caudal medullary raphe region, which is important for regulating pain and respiration, inhibits the ventilatory response to hypercapnia. Polymorphism of the mu-opioid receptor at nucleotide position 118 does not significantly change the susceptibility to the respiratory depressive effect of M6G, which suggests that analgesia and respiratory depression may be mediated by different signal transduction mechanisms activated by the mu-opioid receptor.

5. Effects on CO2 Response and Chemoreflexes

The stimulatory effect of CO2 on ventilation is significantly reduced by opioids, and the pressure of end-tidal carbon dioxide (PetCO2) is increased. Opioids also decrease hypoxic ventilatory drive and induce characteristic changes in respiratory pattern. Plasma fentanyl concentrations of 1.5-3.0 ng/mL are associated with significant decreases in CO2 responsiveness, and when moderately large doses (20-50 mcg/kg or greater) of fentanyl are used, the potential need for postoperative mechanical ventilation should be anticipated. In healthy humans, the EC50 for depression of minute ventilation with remifentanil and alfentanil was 1.17 ng/mL and 49.4 ng/mL, respectively. Fentanyl 1 mcg/kg and remifentanil 0.5 mcg/kg had similar maximum decreases in minute ventilation (~50%), but onset and recovery from ventilatory depression were faster with remifentanil.

6. Effects on Respiratory Rate and Pattern

Respiratory rate is usually drastically decreased in opioid overdose, although hypoxic CNS insult can counter this effect. The prolonged expiratory time in the respiratory cycle induced by opioids frequently results in greater reductions in respiratory rate than in tidal volume. High doses of opioids usually eliminate spontaneous respirations without necessarily producing unconsciousness, and patients receiving high doses of opioids may still be responsive to verbal command and often breathe when directed to do so.

7. Postoperative Respiratory Function

Inadequate postoperative pain relief in the thoracoabdominal region can inhibit deep breathing and cause shallow respiration, leading to postoperative respiratory dysfunction including atelectasis; therefore, opioids can prevent or correct respiratory impairment as a basic component of postoperative analgesia. However, opioids can also dose-dependently depress respiration - the incidence of postoperative opioid-induced respiratory depression was reported to be 0.1%-37%, depending on the route of opioid administration, the type of opioid, the definition and method of monitoring, and the prospective versus retrospective nature of the study.

8. Mechanism of Respiratory Depression

By use of knockout mice and pharmacologic approaches, G-protein-gated inwardly rectifying K+ channels were shown to contribute to respiratory depression by mu-opioid receptors. A major component of the excitatory synaptic drive necessary for respiratory rhythmogenesis is mediated by AMPA-type glutamate receptors, leading to investigations of ampakine therapy to alleviate opioid-induced respiratory depression. 5-HT released from the raphe nuclei potently alters the excitability of respiratory motoneurons in the PreBötC and other brainstem respiratory nuclei, and activation of 5-HT1A receptors with befiradol alleviated fentanyl-induced respiratory depression in rats.

9. Factors Affecting Opioid-Induced Respiratory Depression

The following factors increase the magnitude and/or duration of opioid-induced respiratory depression (Box 22.2 in Miller's):

High dose of opioid
Sleep state
Neonates (morphine easily penetrates the incomplete blood-brain barrier in neonates and infants, producing greater respiratory depression on a weight basis than in adults)
Old age (older patients are more sensitive to the respiratory-depressant effect and experience higher plasma concentrations on a weight basis)
CNS depressants (inhaled anesthetics, alcohol, barbiturates, benzodiazepines, most IV sedatives and hypnotics) - though droperidol, scopolamine, and clonidine do NOT enhance the respiratory-depressant effects of opioids
Hyperventilation/hypocapnia (enhances and prolongs postoperative respiratory depression by increasing brain opioid penetration and decreasing removal via reduced cerebral blood flow)
Respiratory acidosis
Hyperoxia (respiratory depression by remifentanil was more pronounced while inhaling 50% O2 than in normoxia; additionally, pulse oximetry may remain normal during the first minutes of respiratory depression in hyperoxia, masking the condition)
Decreased clearance (reduction of hepatic blood flow, renal insufficiency - as active metabolites of hydromorphone and the morphine metabolite M6G accumulate)

Opioid-induced respiratory depression can also be affected by the patient's original respiratory status - in patients who hyperventilate because of anxiety or pain, even small doses of IV opioids can result in transient apnea because of acute shifts in apneic thresholds.

10. Renarcotization Risk

All opioid agonists with a longer plasma half-life than naloxone have a hypothetical potential for renarcotization with time, especially when a bolus dose of naloxone is used to treat opioid-induced respiratory depression. Overall, opioids exert their primary respiratory depressant effects through mu-receptor activation in the brainstem respiratory center - dose-dependent opioid respiratory depression increases the apneic threshold and reduces the respiratory stimulatory drive of both CO2 and hypoxia.

Source: Miller's Anesthesia, 2-Volume Set, 10e, Chapter 22 - Respiratory Effects of Opioids (pp. 2751-2764)

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Respiratory Depression Doses of Opioids

(Reference: Miller's Anesthesia, 2-Volume Set, 10e - Chapter 22)

Fentanyl

Plasma fentanyl concentrations of 1.5 to 3.0 ng/mL are associated with significant decreases in CO2 responsiveness.
When moderately large doses of 20 to 50 mcg/kg or greater of fentanyl are used, the potential need for postoperative mechanical ventilation should be anticipated.
In healthy volunteers, fentanyl 1 mcg/kg produced a maximum decrease in minute ventilation of approximately ~50% (similar in magnitude to remifentanil 0.5 mcg/kg), but onset and recovery were slower.
Fentanyl >2.9 mcg/kg produces dose-dependent respiratory depression that results in apnea (in contrast to buprenorphine, which reaches a ceiling effect).
In PCA, the optimal demand dose for opioid-naive patients is 40 mcg for fentanyl - doses above this carry a higher risk of respiratory depression.

Remifentanil

The EC50 (concentration producing 50% depression of minute ventilation) for remifentanil is 1.17 ng/mL.
Remifentanil 0.5 mcg/kg (IV bolus) produces a ~50% maximum decrease in minute ventilation - comparable to fentanyl 1 mcg/kg, but with a faster onset and faster recovery.
Respiratory depression by remifentanil 50 mcg infused over 60 seconds is more pronounced under hyperoxia (50% O2) than normoxia, as measured by minute ventilation, PetCO2, and respiratory rate.
When combined with propofol, even low concentrations of both drugs produce a strikingly synergistic and potentially severe respiratory depression. Combined with midazolam, respiratory depression is similarly enhanced.

Alfentanil

The EC50 for depression of minute ventilation with alfentanil is 49.4 ng/mL.

Morphine

A bolus dose of 100 mcg/kg followed by a continuous infusion of 30 mcg/kg/h suppresses resting inspired minute ventilation and increases PetCO2 (as shown in Fig. 22.19 of Miller's).
In PCA, the optimal demand dose for opioid-naive patients is 1 mg morphine - exceeding this increases the risk of respiratory depression.
Morphine can produce greater respiratory depression in neonates than adults on a weight basis, because it easily penetrates the immature blood-brain barrier.
Oxycodone 20 mg orally in opioid-naive healthy volunteers induced significant PetCO2 increase, further potentiated by ethanol co-administration.

Buprenorphine

Buprenorphine produces depression of minute ventilation that levels off at doses higher than 3.0 mcg/kg to approximately 50% of baseline (ceiling effect on respiratory depression).
This contrasts sharply with full agonists like fentanyl, where respiratory depression continues in a dose-dependent manner progressing to apnea at doses >2.9 mcg/kg.
Despite this theoretical ceiling effect, a systematic review reported that in clinical settings, buprenorphine can still cause significant adverse effects on respiratory function.

Sufentanil

Equipotent boluses of sufentanil 0.3 mcg/kg increase the incidence of cough-related respiratory effects, though the incidence and severity are less than with fentanyl 3 mcg/kg.

Tramadol

Analgesic doses of tramadol produce less respiratory depression than other opioids, partly because of its nonopioid receptor-mediated mechanism of action. Tramadol is one-fifth to one-tenth as potent as morphine.

Summary Table

Opioid	Key Respiratory Depression Threshold
Fentanyl	1.5-3.0 ng/mL plasma = decreased CO2 response; >2.9 mcg/kg = apnea; 20-50 mcg/kg = mechanical ventilation anticipated
Remifentanil	EC50 = 1.17 ng/mL; 0.5 mcg/kg = ~50% decrease in minute ventilation
Alfentanil	EC50 = 49.4 ng/mL
Morphine	100 mcg/kg bolus = suppressed minute ventilation + raised PetCO2
Buprenorphine	Ceiling at >3.0 mcg/kg (~50% of baseline) - no apnea even at high doses

Source: Miller's Anesthesia, 10e, Chapter 22 (pp. 2755-2875)

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Cardiovascular Effects of Opioids

(Reference: Miller's Anesthesia, 2-Volume Set, 10e - Chapter 22)

1. General Overview - Hemodynamic Stability

Numerous reports have demonstrated that large doses of opioid, administered as the sole or primary anesthetic, result in hemodynamic stability throughout the operative period. Multiple mechanisms are involved in the ability of opioids to provide perioperative cardiovascular stability: they reduce sympathetic tone and enhance parasympathetic activity, often producing bradycardia but not tachycardia; minimally change cardiac contractility; function generally as antiarrhythmics; potentially act as cardioprotective agents by mimicking ischemic preconditioning; have no significant effect on the coronary circulation; produce modest vascular smooth muscle relaxation - with the exception of morphine-induced hypotension mediated by histamine release; and reduce the surgical stress response through the nervous system and adrenal-pituitary axis, depending on the opioid class.

2. Neurologic (Central) Mechanisms

Key brainstem areas that integrate cardiovascular responses include the nucleus solitarius, the dorsal vagal nucleus, the nucleus ambiguous, and the parabrachial nucleus. The nucleus solitarius and parabrachial nucleus, where enkephalin-containing neurons and opioid receptors are distributed, play an important role in the hemodynamic control of vasopressin secretion. Direct administration of mu-agonists into the CNS of rats most commonly produces hypotension and bradycardia. Most systemically administered opioids reduce sympathetic and enhance vagal/parasympathetic tone. As a consequence, patients who are volume depleted, or who depend on high sympathetic tone or exogenous catecholamines to maintain cardiovascular function, are predisposed to hypotension after opioid administration. The predominant effect of opioids on heart rate is bradycardia, resulting from stimulation of the central vagal nucleus; blockade of sympathetic actions may also play a role in opioid-induced bradycardia.

3. Cardiac Contractility

Opioids have experimentally been shown to affect myocardial contractility, but clinical reports on their effects are scarce. The direct cardiac actions of opioids on myocardial contractile mechanisms are significantly less pronounced than those of many other intravenous and inhaled anesthetics. Key findings for individual drugs are:

Morphine decreases Ca2+ transients and enhances myofilament Ca2+ sensitivity through the delta-1 opioid receptor. In rabbit ventricular myocytes, morphine prolonged action potential duration by increasing L-type Ca2+ current (via delta- and kappa-receptors) and hyperpolarized cardiac resting membrane potential by increasing inwardly rectifying K+ current. Morphine decreased the isometric force of contraction in atrial muscles from both nonfailing and failing human hearts through a naloxone-insensitive mechanism.
Fentanyl produces little or no change in myocardial contractility, and most hemodynamic variables usually remain unchanged even after large doses.
Alfentanil, at clinically achievable concentrations, increases contraction in ventricular cells by increasing the sensitivity of the contractile apparatus to Ca2+. It also ameliorates the negative inotropic effect of TNF-alpha and IL-1beta on rat ventricular myocytes, although this response may not be opioid receptor-mediated.
Remifentanil (target effect-site concentration 2 ng/mL; infusion rate 0.08-0.09 mcg/kg/min) did not affect systolic or diastolic left ventricular function in young healthy subjects during spontaneous breathing.
Sufentanil (bolus 1.5-2.0 mcg/kg) preserves hemodynamic parameters as well as echocardiographic indices of left ventricular systolic and diastolic function in patients with ischemic heart disease.

4. Cardiac Rhythm and Conduction

Opioid-induced bradycardia is primarily mediated by the CNS, but direct effects on cardiac rhythm conduction have also been reported. Many commonly prescribed opioids can uniquely affect the ECG and lead to various cardiac arrhythmias. One of the most significant side effects is QTc interval prolongation, especially in patients with baseline risk for QTc prolongation - a prolonged QTc interval can cause lethal torsades de pointes and ventricular fibrillation.

Methadone has been specifically shown to increase the risk of QTc interval prolongation.
Fentanyl caused a significant increase in QT interval after injection during induction for CABG surgery. However, pretreatment with fentanyl 2 mcg/kg or remifentanil 1 mcg/kg significantly attenuated QTc prolongation associated with laryngoscopy and tracheal intubation during propofol or sevoflurane induction.
Sufentanil and alfentanil have been demonstrated to be devoid of electrophysiologic effects on normal or accessory pathways in patients with Wolff-Parkinson-White syndrome.
Clinically, cardiac conduction disturbances attributable to opioids are not frequently observed but may be more likely in the presence of Ca2+ channel blockers or beta-adrenergic blockers.

5. Coronary Circulation and Cardioprotection

Opioids appear to have no significant effect on coronary vasomotion or myocardial metabolism, do not produce steal phenomena, and do not diminish the ability of large coronary arterioles to respond normally. Opioids can mimic ischemic preconditioning - opioid receptor stimulation results in a reduction in infarct size similar to that produced by ischemic preconditioning in rats. The preconditioning effect is mediated mainly by cardiac kappa- and delta-opioid receptors, while part of remifentanil's protective effect may involve mu-agonist activity outside the heart.

Preconditioning with small doses of intrathecal morphine provides cardioprotection comparable to myocardial ischemic preconditioning, involving mu-, delta-, and kappa-opioid receptors.
Late preconditioning (cardioprotective effects observed 24 hours later) was also produced by morphine-induced activation of opioid receptors in rat hearts.
Postconditioning (protection via brief ischemia/reperfusion at the start of reperfusion) was induced by activation of the delta-opioid receptor.
Clinically, pretreatment with morphine and remifentanil showed beneficial effects in postoperative cardiac troponin release after surgical ischemia-reperfusion and angioplasty.
High-dose opioid-based anesthesia for CABG surgery can maintain myocardial perfusion and O2 supply-demand ratio as well as or better than inhalation-based techniques.

6. Circulatory Reflexes

In experiments using cats, baroreceptor reflexes were well preserved by moderate doses of fentanyl, while high doses of fentanyl depressed baroreceptor reflexes. The oculocardiac reflex (caused by traction of extraocular muscles during strabismus surgery) was significantly augmented by fentanyl, sufentanil, and remifentanil.

7. Vascular Mechanisms

Pharmacologic studies demonstrated direct peripheral vessel smooth muscle relaxation by alfentanil, fentanyl, and sufentanil in the dog. Sufentanil (0.083-0.833 mcg/min infused into the brachial artery) has a direct vasodilatory effect on human vascular tissue that is likely independent of neurogenic or systemic mechanisms.

Remifentanil can cause transient hemodynamic instability in clinical settings. It vasodilates by an endothelium-dependent mechanism (involving prostacyclin and nitric oxide) and an endothelium-independent mechanism (suppression of voltage-dependent Ca2+ channels). In patients with a total artificial heart, remifentanil (0.25 mcg/kg/min) induces dose-dependent and significant systemic vasodilation without significant effects on capacitance vessels, confirming direct vascular effects.

Opioids also affect the pulmonary vasculature: sufentanil and remifentanil have potent vasodepressor activity in the pulmonary vascular bed in cats, responses mediated by histamine and blocked by naloxone.

8. Histamine Release and Hypotension

Morphine causes histamine release by an opioid receptor-independent mechanism - it activates MRGPRX-2, a G-protein-coupled receptor expressed in mast cells, resulting in mast cell degranulation and histamine release. Increases in plasma histamine after morphine cause dilation of terminal arterioles and direct positive cardiac chronotropic and inotropic actions. In patients pretreated with both H1- and H2-antagonists, the cardiovascular responses are significantly attenuated despite comparable increases in plasma histamine.

Codeine and meperidine similarly induce mast cell activation with release of histamine and tryptase, likely via a non-mu-receptor mechanism.

Unlike morphine or meperidine, fentanyl, alfentanil, sufentanil, and remifentanil do NOT produce increases in plasma histamine, and subsequent hypotension is less frequent with their administration.

9. Opioids in Shock

Endogenous opioids contribute to the pathophysiology of hypovolemic shock through central and peripheral sympathetic inhibition, contributing to hypotension during severe hemorrhage. Morphine, however, in an animal model, decreased leukocyte adhesion and vascular permeability in mesenteric microvasculature when given before hemorrhagic shock, suggesting a protective role on the microvasculature. A meta-analysis showed that naloxone therapy for shock was associated with statistically significant hemodynamic improvement in humans, though clinical effectiveness remains controversial.

Comparison Table: CVS Effects by Opioid Drug

Parameter	Morphine	Fentanyl	Alfentanil	Sufentanil	Remifentanil	Methadone	Buprenorphine
Heart Rate	Bradycardia (vagal)	Bradycardia	Bradycardia	Bradycardia	Bradycardia; transient instability	Bradycardia	Bradycardia
Blood Pressure	Hypotension (histamine)	Stable	Stable	Stable	Transient instability / vasodilation	Variable	Minimal change
Myocardial Contractility	Decreased (naloxone-insensitive)	Little/no change	Increased (Ca2+ sensitization)	Preserved	Not affected (at 2 ng/mL TCI)	-	-
Histamine Release	Yes (via MRGPRX-2)	No	No	No	No	No	No
QTc Prolongation	Mild	Yes (CABG induction)	No effect (WPW safe)	No effect (WPW safe)	Attenuates QTc from intubation	Most significant	-
Coronary Circulation	No significant effect	No significant effect	No significant effect	No significant effect	No significant effect	-	-
Cardioprotection (preconditioning)	Yes (mu/delta/kappa)	Partial	-	Yes (kappa/delta)	Yes (mu outside heart)	-	-
Pulmonary Vasculature	-	Attenuates alpha-1 contraction	-	Vasodepressor (histamine-mediated)	Vasodepressor (histamine-mediated)	-	-
Oculocardiac Reflex	-	Augments	-	Augments	Augments	-	-

Comparison Table: Histamine Release Among Opioids

Opioid	Histamine Release	Mechanism	CVS Consequence
Morphine	Yes	MRGPRX-2 activation on mast cells	Hypotension, tachycardia, arteriolar dilation
Codeine	Yes	Non-mu-receptor mast cell activation	Hypotension
Meperidine	Yes	Non-mu-receptor mast cell activation	Hypotension
Fentanyl	No	-	Hemodynamically stable
Alfentanil	No	-	Hemodynamically stable
Sufentanil	No	-	Hemodynamically stable
Remifentanil	No	-	Hemodynamically stable

Source: Miller's Anesthesia, 2-Volume Set, 10e, Chapter 22 - Cardiovascular Effects of Opioids (pp. 2764-2773)

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Endocrinological Effects of Opioids and Stress Responses

(Reference: Miller's Anesthesia, 2-Volume Set, 10e - Chapter 22, pp. 2773-2775)

1. Hormonal Effects

Opioids can induce a variety of endocrinologic responses. In humans, opioids generally increase growth hormone (GH), thyroid stimulating hormone (TSH), and prolactin, and decrease luteinizing hormone (LH), testosterone, estradiol, and oxytocin. The effects of opioids on arginine vasopressin (AVP) and ACTH are conflicting. The primary endocrine disorder that results from opioid misuse is hypogonadism, particularly in males.

Table: Summary of Opioid Effects on Hormones (Table 22.4, Miller's)

Hormone	Effect of Opioids
Growth Hormone (GH)	Increased (↑)
Thyroid Stimulating Hormone (TSH)	Increased (↑)
Prolactin (PRL)	Increased (↑)
Luteinizing Hormone (LH)	Decreased (↓)
Follicle Stimulating Hormone (FSH)	Decreased (↓)
Testosterone	Decreased (↓)
Estradiol	Decreased (↓)
Oxytocin (OT)	Decreased (↓)
ACTH	Conflicting (↑/↓)
Arginine Vasopressin (AVP)	Conflicting (↑/↓)
Cortisol	Decreased (dose-dependent, surgical context)

(↑ = stimulation; ↓ = inhibition; ↑/↓ = conflicting evidence)

2. Opioids and the Surgical Stress Response

Hormonal and metabolic responses to surgical invasion are often extreme and are thought to contribute to operative mortality. Opioids can reduce the stress response by modulating nociception at several levels of the neuraxis, as well as by influencing centrally mediated neuroendocrine responses. The main components of the neuroendocrine stress response are the corticotropin-releasing hormone brain centers (e.g., the paraventricular hypothalamic nucleus) and the locus coeruleus-norepinephrine/autonomic nervous system.

Excessively high levels of stress hormones are considered undesirable because they promote hemodynamic instability and intraoperative and postoperative metabolic catabolism. Endogenous opioid peptides may serve as stress hormones themselves - not just as modulators of other hormones' secretion - which is consistent with the finding that beta-endorphin and ACTH are both derived from the same precursor, preproopiomelanocortin, and are co-secreted in response to stress.

Opioid agonists can modify hormonal responses to surgical trauma in a dose-related fashion through: blockade of ACTH release, suppression of surgically induced increases in plasma cortisol, and attenuation of the pituitary-adrenal response to surgical stress.

Morphine can paradoxically increase some stress-responding hormones by evoking histamine release from mast cells, which can induce catecholamine release from sympathetic nerve endings and the adrenal medulla.

Fentanyl and its congeners are more effective than morphine in modifying hormonal responses to surgery. A randomized controlled trial showed that remifentanil (0.83 mcg/kg/min), when compared with fentanyl (total doses of 12 and 24 mcg/kg), blunts the hypertensive responses and cortisol excretion associated with cardiac surgery, but is associated with more hypotension. In coronary artery bypass grafting, remifentanil (0.25 mcg/kg/min) attenuated the increase in stress hormones (ACTH, vasopressin, epinephrine, and norepinephrine) and inflammatory mediators (IL-6, IL-8, and TNF-alpha) compared with intermittent fentanyl (total dose 2.6 mg).

Large-dose opioids - remifentanil (0.83 mcg/kg/min) or fentanyl (24 mcg/kg) - were associated with lower cortisol secretion and a decreased rate of myocardial infarction after cardiac surgery, compared with small-dose fentanyl (12 mcg/kg). These reports indicate that opioids can efficiently control surgery-induced stress responses, which may affect patient outcomes including morbidity and mortality.

Effects of Opioids on the Gastrointestinal Tract

(Reference: Miller's Anesthesia, 2-Volume Set, 10e - Chapter 22, pp. 2775-2784)

1. General Overview and Mechanism

Gastrointestinal side effects still constitute a major drawback in both acute and chronic use of opioids. The adverse gastrointestinal effects of opioids include nausea, vomiting, altered fluid dynamics, inhibited gastric emptying, inhibited intestinal coordinated propulsive activity, and increased transit time - all of which may contribute to postoperative ileus. Opioid-dependent mechanisms driving these effects are complex, and effects on gastrointestinal motility are believed to involve opioid receptors expressed throughout the myenteric plexus. Both kappa- and mu-receptor agonists regulate cholinergic transmission in the myenteric plexus; kappa-agonists appear to modulate acetylcholine release more potently than mu-agonists by inhibition of N-type voltage-dependent Ca2+ channels via a pertussis toxin-sensitive G protein.

2. Table: Pharmacologic Actions and Clinical Effects on the GIT (Table 22.5, Miller's)

Pharmacologic Action	Clinical Effect
Decreased gastric motility and emptying	Decreased appetite; increased gastroesophageal reflux
Decreased pyloric tone	Nausea and vomiting
Decreased enzymatic secretion	Delayed digestion; hard, dry stools
Inhibition of small and large bowel propulsion	Delayed drug absorption; straining; incomplete evacuation; bloating; abdominal distension; constipation
Increased fluid and electrolyte absorption	Hard, dry stools
Increased nonpropulsive segmental contractions	Spasms; abdominal cramps; pain
Increased anal sphincter tone	Incomplete evacuation

3. Esophagus and Gastric Emptying

In healthy volunteers, morphine (100 mcg/kg) increased the velocity but did not alter the amplitude or duration of primary peristalsis of the esophagus, and decreased the duration and magnitude of swallowing-induced lower esophageal sphincter relaxation. Gastric emptying is delayed by opioids via supraspinal (vagus nerve-mediated), spinal, as well as peripheral mechanisms. Intrathecal morphine (0.4 mg) significantly decreased the gastroduodenal propagation velocity and acetaminophen absorption, and intramuscular morphine (4 mg) gave additional effects. Opioids administered epidurally as well as intrathecally reduce gastrointestinal motility.

Tramadol (1.25 mg/kg IV) has a measurable but smaller inhibitory effect on gastric emptying compared with codeine (1 mg/kg IV) or morphine (0.125 mg/kg IV).

Propofol (0.3 mg/kg bolus and 1.0 mg/kg/h) abolished the decrease of gastric tone induced by morphine (0.1 mg/kg IV), but did not abolish morphine-induced delay of gastric emptying.

4. Reversal of GIT Effects

Naloxone reverses opioid-induced delays in gastric emptying. Methylnaltrexone (0.3 mg/kg) - a quaternary naloxone derivative that does NOT cross the blood-brain barrier - can attenuate morphine (0.09 mg/kg)-induced delays in gastric emptying in healthy volunteers, confirming that a peripheral mechanism is involved in the opioid effect on the gastrointestinal tract. Intravenous (but not intramuscular) metoclopramide (10 mg) can also reverse morphine (10 mg)-induced delays in gastric emptying.

5. Biliary and Hepatic Effects

Opioid agonists increase biliary duct pressure and sphincter of Oddi (choledochoduodenal sphincter) tone in a dose- and drug-dependent manner through opioid receptor-mediated mechanisms. However, the clinical consequences of opioid-induced biliary tract actions are usually minimal.

Although traditional teaching dictates that morphine induces "spasm" of the sphincter of Oddi and should not be used in acute pancreatitis, no studies or evidence exist to indicate morphine is contraindicated for use in acute pancreatitis. Increases in biliary pressure caused by opioids are reversible with naloxone.

Comparing individual drugs at the sphincter of Oddi:

Morphine - increases common bile duct pressure (via sphincter of Oddi spasm)
Meperidine - had no effect on sphincter of Oddi motility
Tramadol - inhibited motility of the sphincter of Oddi
Remifentanil (0.1 mcg/kg/min) - delays drainage of the gall bladder into the duodenum, but the delay is shorter than that reported after morphine or meperidine

6. Comparison Table: Sphincter of Oddi Effects

Opioid	Effect on Sphincter of Oddi / Biliary Pressure
Morphine	Increases biliary duct pressure and sphincter tone (spasm)
Meperidine	No effect on sphincter of Oddi motility
Tramadol	Inhibits sphincter of Oddi motility
Remifentanil	Delays gall bladder drainage, but less than morphine or meperidine

7. Hepatic (Liver) Effects

Opioids produce minimal effects on liver function during anesthesia and surgery. However, in animal models they can affect ischemia-reperfusion injury:

Remifentanil pretreatment attenuates liver injury induced by ischemia-reperfusion in rats, mediated by inducible nitric oxide synthase expression and reactive oxygen species exhaustion, via an opioid receptor-independent mechanism. Remifentanil also significantly attenuated increases in serum aminotransferase levels and histologic liver changes induced by ischemia-reperfusion, possibly via hepatic interleukin-18.
Morphine (IV or intrathecal, 10 minutes before ischemia) protects against ischemia-reperfusion injury after 6 hours of reperfusion in both normal and cirrhotic rat liver, via an opioid receptor-dependent mechanism.

These animal findings suggest possible beneficial effects of opioids in liver surgery, but clinical evidence is not yet established.

8. Nausea and Vomiting (PONV)

Intraoperative use of opioids is a well-known risk factor for PONV. Opioids stimulate the chemoreceptor trigger zone (CTZ) in the area postrema of the medulla, possibly through delta-receptors, leading to nausea and vomiting. Irrespective of the specific opioid administered, opioids increase the risk for PONV in a dose-dependent manner, and the effect appears to last for as long as opioids are used in the postoperative period.

Prevention and treatment strategies:

Propofol in balanced or total intravenous anesthesia significantly reduces the incidence of opioid-induced nausea and vomiting.
Antiemetic prophylaxis should be considered, including anticholinergics, butyrophenones, dopamine antagonists, serotonin antagonists, and acupressure.
Ondansetron (5-HT3 receptor antagonist) is effective for opioid-induced PONV. A meta-analysis confirmed that prophylactic 5-HT3 antagonists significantly reduced PONV in parturients who received intrathecal morphine for cesarean delivery.
Dexamethasone (8 mg IV) prevented nausea and vomiting after epidural morphine (3 mg) for post-cesarean analgesia as effectively as droperidol (1.25 mg IV).
Rolapitant, a potent NK1 receptor antagonist, was effective in reducing emetic episodes after surgery in a dose-dependent manner.
A continuous low-dose naloxone infusion (0.25 mcg/kg/h) ameliorated opioid-induced nausea, vomiting, and pruritus in many patients without adversely affecting analgesia.
Transdermal scopolamine is effective for prophylaxis of nausea and vomiting in parturients receiving intrathecal morphine for cesarean delivery, but is associated with dry mouth and blurry vision.

Source: Miller's Anesthesia, 2-Volume Set, 10e, Chapter 22 (pp. 2773-2784)

Simplify the above content

Here is the simplified version of all the content from Miller's Anesthesia:

Endocrinological Effects of Opioids

1. Hormonal Effects (Simple Version)

Opioids disturb the body's hormone balance. They raise some hormones and lower others:

Hormones that go UP: Growth hormone, TSH (thyroid hormone), Prolactin
Hormones that go DOWN: LH, FSH, Testosterone, Estradiol (female sex hormone), Oxytocin
Uncertain effect: ACTH (stress hormone), Vasopressin (ADH) - studies give mixed results
The most common endocrine problem in long-term opioid users is hypogonadism (low sex hormones), especially in men - causing reduced libido, infertility, and fatigue

Table: Opioid Effects on Hormones (Quick Reference)

Hormone	What It Does	Opioid Effect
Growth Hormone (GH)	Growth, metabolism	↑ Increases
TSH	Controls thyroid	↑ Increases
Prolactin	Milk production	↑ Increases
LH / FSH	Sex gland stimulation	↓ Decreases
Testosterone	Male sex hormone	↓ Decreases
Estradiol	Female sex hormone	↓ Decreases
Oxytocin	Bonding, uterine contraction	↓ Decreases
ACTH	Stress / cortisol control	Mixed (↑/↓)
Vasopressin (ADH)	Water retention	Mixed (↑/↓)

2. Opioids and Surgical Stress - Simplified

Surgery triggers a massive stress response in the body - flooding the blood with stress hormones like cortisol, adrenaline (epinephrine), and ACTH. This is dangerous because it:

Destabilizes blood pressure
Breaks down body proteins (catabolism)
Worsens outcomes after major surgery

Opioids block this stress response. They act on the brain and spinal cord to reduce how much cortisol and adrenaline the body releases during surgery.

Key points:

Fentanyl and its family (remifentanil, sufentanil) block stress hormones better than morphine
Morphine can actually worsen stress hormone release by triggering histamine, which then releases adrenaline from nerve endings
Remifentanil during heart bypass surgery reduced ACTH, vasopressin, adrenaline, noradrenaline, and even inflammatory chemicals (IL-6, IL-8, TNF-alpha) better than fentanyl
Large doses of opioids (remifentanil 0.83 mcg/kg/min or fentanyl 24 mcg/kg) lead to lower cortisol and fewer heart attacks after cardiac surgery, compared to small doses

Bottom line: Opioids are powerful suppressors of the surgical stress response, and the fentanyl family does this more cleanly than morphine.

Effects of Opioids on the Gastrointestinal (GI) Tract

1. How Do Opioids Affect the Gut?

Opioids act on receptors in the gut wall (the myenteric plexus - the gut's own nervous system). This slows down everything - movement, secretion, and emptying. This is one of the most common and troublesome side effects of opioids.

2. GI Side Effects - What Happens and Why

What Opioids Do to the Gut	What the Patient Feels
Slow down stomach emptying	Loss of appetite, acid reflux
Reduce pyloric tone	Nausea and vomiting
Reduce digestive secretions	Slow digestion, hard dry stools
Block small and large bowel movement	Constipation, bloating, abdominal distension, incomplete emptying
Absorb too much water from stool	Hard, dry stools
Increase non-moving (spastic) contractions	Abdominal cramps and spasms
Tighten the anal sphincter	Difficulty passing stool

All of these together can cause postoperative ileus (the bowel stops working after surgery).

3. Esophagus and Stomach - Key Points

Morphine speeds up swallowing movement in the esophagus but reduces lower esophageal sphincter relaxation - meaning the valve between the food pipe and stomach does not open properly, raising reflux risk.
Opioids slow gastric emptying via the brain (vagus nerve), spinal cord, and directly in the gut.
Tramadol causes less gastric emptying delay than codeine or morphine.
Propofol can reverse the direct stomach-slowing effect of morphine, but cannot fully reverse the gastric emptying delay.

4. Reversing Opioid Gut Effects

Naloxone (IV) - reverses gastric emptying delay but also reverses pain relief
Methylnaltrexone - a special form of naloxone that works only in the gut (does not cross the blood-brain barrier), so it treats constipation without reducing pain relief
Metoclopramide (IV only, not IM) - can reverse morphine-induced gastric emptying delay

5. Biliary System (Bile Duct and Gallbladder)

Opioids tighten the sphincter of Oddi (the valve between the bile duct and the small intestine), raising pressure in the bile duct. Different opioids behave differently:

Opioid	Effect on Sphincter of Oddi
Morphine	Causes spasm - raises bile duct pressure significantly
Meperidine	No effect on the sphincter
Tramadol	Relaxes / inhibits the sphincter
Remifentanil	Delays gall bladder drainage, but less than morphine or meperidine

Important clinical point: Although it was traditionally taught that morphine causes sphincter of Oddi spasm and should be avoided in pancreatitis, no clinical evidence supports this contraindication. Morphine can still be used safely in acute pancreatitis for pain relief.

6. Liver Effects

Opioids have minimal effect on normal liver function during surgery.
In animal studies, both remifentanil and morphine protected the liver from ischemia-reperfusion injury (the damage caused when blood supply is restored after a period of blockage) - but whether this translates to humans is not yet proven.

7. Nausea and Vomiting (PONV)

Opioids cause nausea by stimulating the chemoreceptor trigger zone (CTZ) in the brainstem (area postrema). This is a dose-dependent effect - more opioid = more nausea - and it persists as long as opioids are being given postoperatively.

How to prevent/treat opioid-induced nausea:

Treatment	How It Helps
Propofol (TIVA)	Strongly reduces opioid-induced nausea
Ondansetron (5-HT3 blocker)	Directly blocks nausea signals - very effective
Dexamethasone (steroid)	As effective as droperidol for post-cesarean morphine nausea
Rolapitant (NK1 blocker)	Reduces vomiting episodes after surgery
Low-dose Naloxone infusion (0.25 mcg/kg/h)	Reduces nausea, vomiting, and pruritus without reducing pain relief
Scopolamine patch	Works for spinal morphine nausea in obstetrics, but causes dry mouth and blurred vision

Source: Miller's Anesthesia, 2-Volume Set, 10e, Chapter 22 (pp. 2773-2784)

Take miller's anesthesia as reference ,simplify and give other effects of opiods in sentences

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Other Effects of Opioids

(Reference: Miller's Anesthesia, 2-Volume Set, 10e - Chapter 22)

1. Renal and Urinary Effects

On the Kidneys: Opioids can affect kidney function mainly by acting on the brain and nervous system rather than directly on the kidneys. Kappa-opioid receptor agonists reduce the release of vasopressin (ADH - the water-retaining hormone) from the brain, which means the kidneys retain less water. However, fentanyl, sufentanil, alfentanil, and remifentanil do not raise levels of vasopressin, renin, or aldosterone, meaning they largely preserve normal kidney function. Any kidney changes that do occur during opioid anesthesia are most likely due to secondary changes in blood pressure and blood flow, not a direct drug effect.

Interestingly, a study in patients with chronic kidney disease found that remifentanil-based anesthesia was associated with a higher glomerular filtration rate (better kidney function) after surgery, suggesting remifentanil may actually protect the kidneys.

On the Bladder (Urinary Retention): Opioids - especially when given spinally (intrathecal or epidural) - frequently cause urinary retention by relaxing the bladder muscle (detrusor) and reducing the sensation of urge to urinate. This is dose-dependent: after intrathecal sufentanil, normal bladder function returns in 5-8 hours, whereas after intrathecal morphine it takes 14-20 hours. Not all opioids affect the bladder equally:

Opioid	Effect on Bladder (Detrusor)
Morphine (intrathecal)	Suppresses detrusor + reduces urge (14-20 h recovery)
Sufentanil (intrathecal)	Suppresses detrusor + reduces urge (5-8 h recovery)
Fentanyl (IV)	Decreases detrusor contraction
Buprenorphine (IV)	Decreases detrusor contraction
Morphine / Nalbuphine (IV)	Alters bladder sensation only - no detrusor effect

Urinary retention caused by remifentanil can be reversed by a single dose of methylnaltrexone (0.3 mg/kg IV) or naloxone (0.01 mg/kg IV), confirming that peripheral opioid receptors play a role in bladder dysfunction.

2. Effects on the Eyes (Ocular Effects)

Opioids lower intraocular pressure (IOP), making them useful during eye surgery or in patients with glaucoma. Remifentanil (1 mcg/kg) combined with propofol or thiopental effectively prevents the sharp rise in IOP that occurs after succinylcholine and tracheal intubation. In elective surgery, remifentanil reduced IOP from ~13.6 to 7.1 mmHg, and fentanyl reduced it from ~13.7 to 9.7 mmHg. Both opioids lower eye pressure, making them safe and useful when raised IOP is a concern.

3. Immune Effects

Opioids have wide-ranging effects on the immune system, acting on immune cells directly (via mu, delta, and kappa receptors on immune cells) and indirectly via the nervous and hormonal systems. The immune effects of opioids are complex and sometimes contradictory across studies.

General pattern - Opioids tend to SUPPRESS immunity:

Adaptive Immunity (T and B cells):

Reduce T-helper cell function and reduce CD4/CD8 T-cell numbers
Suppress natural killer (NK) cell activity - which is important for killing cancer cells and infected cells
Reduce B-cell antibody responses
Reduce production of pro-inflammatory cytokines (IL-1β, IL-2, TNF-alpha, IFN-gamma)
Increase T-cell death (apoptosis)

Innate Immunity (first-line defence):

Reduce macrophage numbers available to fight infection
Reduce white blood cell migration to sites of infection
Reduce phagocytosis (ability to engulf and destroy bacteria)
Reduce neutrophil killing activity

Drug-specific immune effects worth noting:

Morphine (10 mg IM postoperatively) does not significantly affect NK-cell activity at clinical doses
Tramadol (100 mg IM) actually enhances NK-cell activity - making it potentially better from an immune standpoint
Long-term fentanyl infusion in ICU patients suppressed NK-cell killing ability
Remifentanil (but not sufentanil, alfentanil, or fentanyl) can block neutrophil activation triggered by bacteria, by acting on the kappa-opioid receptor - this may reduce excessive inflammation in sepsis
Morphine suppressed inflammatory markers (IL-6, CD11b, CD18) after cardiac surgery better than fentanyl

4. Effects on Cancer

This is one of the most clinically significant and evolving areas of opioid research. Opioids may affect cancer in both directions - promoting and inhibiting tumour growth - depending on the dose, context, and opioid used.

How opioids might promote cancer:

Opioids (especially via the mu-receptor) may directly stimulate tumour cell growth, invasion, and survival
Overexpression of the mu-opioid receptor has been found in human non-small cell lung cancer, suggesting it promotes tumour growth
Women with a reduced-function variant of the mu-opioid receptor gene (A118G) had lower breast cancer mortality, suggesting that normal mu-receptor activity promotes cancer progression
Morphine can stimulate the growth of new blood vessels into tumours (angiogenesis) through nitric oxide, VEGF, and MAPK pathways - feeding the tumour with blood supply
Opioid-induced immunosuppression (reduced NK cells) may reduce the body's natural ability to destroy cancer cells

How opioids might fight cancer:

Opioids can also activate anti-cancer pathways in certain contexts
Methylnaltrexone (the gut-acting opioid blocker) may help by blocking peripheral mu-receptors that promote cancer while keeping central pain relief intact - and is being studied as a potential cancer therapy when combined with chemotherapy
Activation of delta-opioid receptors in some studies shows anti-tumour effects

Bottom line: The relationship between opioids and cancer is not yet fully understood. General anesthesia with opioids may be associated with higher cancer recurrence rates than regional anesthesia techniques, but this area needs much more clinical research before firm conclusions can be drawn.

5. Effects on Wound Healing

Opioid receptors (mu, delta, kappa) are present in skin cells (keratinocytes) and play a role in normal skin maintenance and wound repair. The effects of opioids on wound healing are mixed:

Delta-receptor activation - promotes keratinocyte migration, which is needed for fast wound closure
Overstimulation of mu, delta, and kappa receptors - can trigger formation of hypertrophic (thick) scars
Peripheral opioid receptors on sensory nerves reduce the release of substance P and CGRP (nerve chemicals important in wound repair), which may interfere with healing
Topical morphine - reduced myofibroblasts and macrophages in closing wounds in rats, resulting in thinner skin and more residual scar tissue - this means topical morphine may impair normal healing
On the other hand, topical opioids in clinical studies have produced good local pain relief and in some cases even facilitated wound healing

Key takeaway: Opioids have real effects at the skin level. While topical opioids offer potential for pain relief in wounds, their effect on healing speed and scar formation is a complex balance that depends on which receptor is activated.

6. Perinatal Effects (Pregnancy and Newborns)

Opioid use in pregnancy has increased dramatically since 2004, making this an important area.

Newborns of mothers taking opioids can experience neonatal abstinence syndrome (NAS) - a withdrawal reaction requiring treatment and monitoring
Opioid birth defects in humans appear minimal in animal models, but true teratogenicity in humans is not well-established
Buprenorphine given to pregnant women acutely suppresses fetal heart rate and movement, and this effect becomes stronger as pregnancy advances
Animal studies show that prenatal opioid exposure leads to reduced brain cortex thickness, abnormal brain development, and hyperactivity in offspring during adolescence - raising serious concerns about long-term neurodevelopmental effects of opioid exposure before birth
The full impact of prenatal opioid exposure on fetal brain development cannot be excluded and requires caution

Quick Summary Table: Other Opioid Effects

System	Main Effect	Key Point
Kidneys	Minimal direct effect; preserves renal function	Remifentanil may protect kidneys; kappa agonists reduce ADH
Bladder	Urinary retention (especially spinal route)	Dose-dependent; reversed by naloxone or methylnaltrexone
Eyes	Lowers intraocular pressure	Useful in glaucoma; both remifentanil and fentanyl reduce IOP
Immune System	Generally suppresses immunity	Tramadol is the exception - it enhances NK-cell activity
Cancer	Complex: may promote or inhibit tumour growth	Mu-receptor promotes cancer; methylnaltrexone may block this
Wound Healing	Mixed: may impair or assist healing	Delta-receptor helps closure; mu-receptor may worsen scarring
Pregnancy/Fetus	Neonatal withdrawal (NAS); possible brain effects	Prenatal exposure may cause hyperactivity and brain development changes in offspring

Source: Miller's Anesthesia, 2-Volume Set, 10e, Chapter 22 (pp. 2784-2796)

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