11: Opioids

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CHAPTER 11 Opioids

Christopher L. Ciarallo, MD

1 What is an opiate? An opioid? A narcotic?

Opiates are analgesic and sedative drugs that contain opium or an opium derivative from the poppy plant (Papaver somniferum). Opiates include opium, morphine, and codeine.

An opioid is any substance with morphinelike activity that acts as an agonist or antagonist at an opioid receptor. Opioids may be exogenous or endogenous (such as the endorphins) and may be natural, derived, or completely synthetic.

The term narcotic is not specific for opioids and refers to any substance with addictive potential that induces analgesia, euphoria, or altered sensorium.

2 What are endogenous opioids?

The endorphins, enkephalins, and dynorphins are the three classes of endogenous peptides that are derived from prohormones and are functionally active at opioid receptors. Although their physiologic roles are not completely understood, they appear to modulate nociception. Endorphins are not limited to the central nervous system and may even be expressed by activated leukocytes. A fourth class, the nociceptins, is currently being investigated.

3 Differentiate opioid tolerance, dependence, and abuse

Tolerance is a diminution in the physiologic effects of a substance resulting from repeated administration. Dependence may be physical or psychological and refers to the repeated use of a substance to avoid withdrawal symptoms. Tolerance may be necessary to establish the diagnosis of dependence. Abuse refers to the habitual use of a substance despite adverse consequences, including social and interpersonal problems.

4 Name the opioids commonly used in the perioperative setting, their trade names, equivalent morphine doses, half-lives, and chemical classes

See Table 11-1.

TABLE 11-1 Comparison of Commonly used Opioids

5 Describe the various opioid receptors and their effects

See Table 11-2.

TABLE 11-2 Opioid Receptor Subtypes

Opioid Receptor Subtype	Agonists	Agonist Response
Mu-1 (μ-1)	Enkephalin β-endorphin Phenanthrenes Phenylpiperidines Methadone

Supraspinal analgesia

Urinary retention

Mu-2 (μ-2)

Phenylpiperidines

Spinal analgesia

Respiratory depression

Kappa (κ)

Spinal analgesia (κ-1)

Supraspinal analgesia (κ-2)

Delta (δ)

Spinal analgesia (δ-1)

Supraspinal analgesia (δ-2)

Respiratory depression

Urinary retention

Sigma (σ)
(no longer classified as opioid receptor) Pentazocine

Modified from Stoelting RK, Miller RD: Basics of Anesthesia, ed 4, New York, 2000, Churchill Livingstone, p 71.

6 What is an opioid agonist-antagonist?

Drugs such as pentazocine, butorphanol, buprenorphine, and nalbuphine were initially thought to be μ- and κ-receptor agonists. However, they are now classified as μ- and κ-receptor partial agonists. These drugs provide analgesia but with less euphoria and risk of dependence compared with pure agonists. Agonist-antagonists in general cause less respiratory depression than agonists and may reverse the respiratory depression and pruritus caused by pure agonists.

7 Explain the mechanism of action, duration, and side effects of the opioid antagonist naloxone

Naloxone is a μ-, κ-, and δ-receptor antagonist that will reverse the effects of agonist drugs. The peak effect occurs within 1 to 2 minutes of intravenous administration. The duration of action is between 30 and 60 minutes and may be shorter than the duration of the offending opioid agonist. Incremental doses of 0.5 to 1 mcg/kg should be used initially to reverse respiratory depression to minimize the side effects such as acute opioid withdrawal, severe hypertension, ventricular dysrhythmias, or pulmonary edema.

8 Describe the various routes of administration of opioids

Typical routes of administration include oral, intravenous, intramuscular, epidural, subarachnoid, and rectal. Intranasal, nebulized, and subcutaneous may also be used. Lipophilic opioids such as fentanyl are also available in transdermal, transmucosal, and sublingual formulations.

9 What are the typical side effects of opioids?

Opioid side effects include respiratory depression, nausea and vomiting, pruritus, cough suppression, urinary retention, and biliary tract spasm. Some opioids may induce histamine release and cause hives, bronchospasm, and hypotension. Intravenous opioids may cause abdominal and chest wall rigidity. Most opioids, with the notable exception of meperidine, produce a dose-dependent bradycardia.

10 Which opioids are associated with histamine release?

Parenteral doses of meperidine, morphine, and codeine have been associated with histamine release and resultant cutaneous reactions and hypotension. The incidence and severity, at least with morphine, appears to be dose dependent.

11 Describe the mechanism of opioid-induced nausea

Opioids bind directly to opioid receptors in the chemotactic trigger zone in the area postrema of the medulla and stimulate the vomiting center. They exert a secondary effect by sensitizing the vestibular system. The incidence of nausea and vomiting is similar for all opioids and appears irrespective of the route of administration.

12 What is methylnaltrexone and what potential role does it have in opioid therapy?

Methylnaltrexone is a peripheral opioid receptor antagonist derived from naltrexone. It is a charged, polar molecule that is unable to cross the blood-brain barrier. Methylnaltrexone has been approved in the United States for palliative care use in the treatment of opioid-induced constipation. A related drug, alvimopan, has been approved in an oral form for the treatment of postoperative ileus after bowel resection.

13 Describe the cardiovascular effects of opioids

As a group opioids have minimal effects on the cardiovascular system. With the exception of meperidine, they cause a dose-dependent bradycardia through vagal nucleus stimulation. Other than the myocardial depressant activity of meperidine, opioids have minimal inotropic effect on the myocardium. Some opioids may induce histamine release and significantly reduce systemic vascular resistance (SVR), but most effect only a moderate reduction of SVR, even at anesthetic doses.

KEY POINTS: Opioids

1. Common opioid side effects include nausea, pruritus, bradycardia, urinary retention, and respiratory depression.

2. Morphine and meperidine should be used with caution in patients with renal failure because of the risk of prolonged ventilatory depression and seizures, respectively.

3. Neuraxial opioids and local anesthetics act synergistically to provide analgesia with reduced side effects.

4. Naloxone should be titrated in incremental doses for opioid-induced respiratory depression and may require repeated dosing for reversal of long-acting opioid agonists.

5. Opioid equianalgesic conversions are approximations, and they do not account for incomplete opioid cross-tolerance.

14 Describe the typical respiratory pattern and ventilatory response to carbon dioxide in the presence of opioids

Opioids reduce alveolar ventilation in a dose-dependent manner. They slow the respiratory rate and may cause periodic breathing or apnea. Graphically opioids shift the alveolar ventilatory response–to–carbon dioxide curve down and to the right. Accordingly, for a given arterial carbon dioxide level the alveolar ventilation will be reduced in the presence of opioids. Furthermore, an increase in arterial carbon dioxide will not stimulate an appropriate increase in ventilation. Opioids also impair the hypoxic ventilatory drive (Figure 11-1).

Figure 11-1 Ventilatory response to PaCO₂ in the presence of opioids.

15 Describe the analgesic onset, peak effect, and duration of intravenous fentanyl, morphine, and hydromorphone

See Table 11-3.

TABLE 11-3 Comparison of Commonly used Intravenous Opioids

16 Explain how fentanyl can have a shorter duration of action but a longer elimination half-life than morphine

Elimination half-lives correspond with duration of action in a single-compartment pharmacokinetic model. Lipophilic opioids such as fentanyl are better represented by a multicompartment model since redistribution plays a much larger role than elimination in determining their duration of action.

17 Explain the concept of context-sensitive half-time and its relevance to opioids

Context-sensitive half-time is the time required for a 50% reduction in the plasma concentration of a drug on termination of a constant infusion. This time is determined by both elimination and redistribution, and it varies considerably as a function of infusion duration for commonly used opioids (Figure 11-2).

Figure 11-2 Context-sensitive half-times of commonly used opioids as a function of infusion duration.

(Adapted from Egan TD et al: The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers, Anesthesiology 79:881, 1993.)

18 Explain why morphine may cause prolonged ventilatory depression in patients with renal failure

A morphine dose of 5% to 10% will be excreted unchanged in the urine. The remainder is primarily conjugated in the liver as morphine-3-glucuronide (50% to 75%) and morphine-6-glucuronide (10%), of which 90% is renally excreted. Morphine-3-glucuronide is inactive, but morphine-6-glucuronide is approximately 100 times more potent than morphine as a μ-receptor agonist.

19 Which opioids may be associated with seizure activity in patients with renal failure?

Hydromorphone and meperidine are associated with seizure activity in patients with renal failure. Rarely the metabolites hydromorphone-3-glucuronide and normeperidine can accumulate in renal failure and promote myoclonus and seizures.

20 What is remifentanil and how does it differ from other opioids?

Remifentanil is an ultrashort-acting opioid with a duration of 5 to 10 minutes and a context-sensitive half-time of 3 minutes. It contains an ester moiety and is metabolized by nonspecific plasma esterases. Although remifentanil is most commonly administered as a continuous infusion, it has been used as an intravenous bolus to facilitate intubation but with a significant incidence of bradycardia and chest-wall rigidity. Remifentanil has been shown to induce hyperalgesia and acute opioid tolerance, and its use should be questioned in patients with chronic pain syndromes.

21 Describe the metabolism of codeine

Codeine is metabolized by cytochrome P-450 2D6 (CYP2D6) and undergoes demethylation to morphine. Genetic polymorphisms in the CYP2D6 gene lead to patient stratification into poor metabolizers, extensive metabolizers, and ultrafast metabolizers. Poor metabolizers may obtain marginal analgesia from codeine, whereas ultrafast metabolizers may have up to 50% higher plasma concentrations of morphine and morphine-6-glucuronide than the extensive metabolizers. Ultrafast metabolizers may be at significant risk of opioid intoxication and apnea with typical perioperative doses of codeine.

22 What are some particular concerns with methadone dosing?

As methadone has a particularly long and variable half-life, repeated dosing may lead to excessive plasma levels, particularly on days 2 to 4 after initiating therapy. Methadone acts both as an agonist at μ-opioid receptors and as an antagonist at the N-methyl-d-aspartate (NMDA) receptor. NMDA-receptor antagonism may potentiate the μ-receptor effects and prevent opioid tolerance. Finally, methadone may prolong the electrocardiographic QT interval and increase the risk of torsades de pointes. Expert panel recommendations include a baseline electrocardiogram (ECG) and a follow-up ECG at 30 days and annually while continuing methadone.

23 What is tramadol?

Tramadol is a codeine analog that acts as a μ-, δ-, and κ-receptor agonist and a reuptake inhibitor of norepinephrine and serotonin. It is a moderately effective analgesic with a lower incidence of respiratory depression, constipation, and dependence than other μ-receptor agonists. Rarely tramadol may induce seizures, and it is contraindicated in patients with a preexisting seizure disorder.

24 What are some of the unique characteristics of meperidine?

Unlike other opioids, meperidine has some weak local anesthetic properties, particularly when administered neuraxially. Meperidine does not cause bradycardia and may induce tachycardia, perhaps related to its atropine-like structure. As a κ-receptor agonist, meperidine may be used to suppress postoperative shivering. Notably meperidine is contraindicated for use in patients taking monoamine oxidase inhibitors because the combination may lead to serotonin toxicity, hyperthermia, and death.

25 Describe the site and mechanism of action of neuraxial opioids

Neuraxial opioids bind to receptors in Rexed lamina II (substantia gelatinosa) in the dorsal horn of the spinal cord. Activation of μ-receptors appears to reduce visceral and somatic pain via γ-aminobutyric acid–mediated descending pain pathways. Activation of κ-receptors appears to reduce visceral pain via inhibition of substance P. The effect of δ-receptors is not entirely elucidated but appears minimal in some animal models.

26 Discuss the effect of lipid solubility on neuraxial opioid action

Lipophilic opioids diffuse across spinal membranes more rapidly than hydrophilic opioids. As a result, they have a more rapid onset of analgesia. However, they also diffuse across vascular membranes more readily, typically resulting in increased serum concentrations and a shorter duration of action. Hydrophilic opioids achieve greater cephalo-caudal spread when administered into the epidural or subarachnoid space. They attain broader analgesic coverage than lipophilic opioids but may result in delayed respiratory depression following cephalad spread to the brainstem.

27 Are opioid receptors exclusively in the central nervous system?

No. Peripheral opioid receptors exist on primary afferent neurons, but they are functionally inactive under normal conditions. Tissue inflammation may induce opioid receptor up-regulation and signaling efficiency.

28 Describe the advantages of combining local anesthetics and opioids in neuraxial analgesia

Despite their analgesic benefits, epidural local anesthetics have troublesome side effects such as motor blockade and systemic hypotension. Epidural opioids are burdened with causing pruritus and nausea. Combined, opioids and local anesthetics function in a synergistic manner to provide analgesia with attenuated side effects.

29 What is DepoDur and how is it different from other neuraxial opioids?

DepoDur is an opioid agonist that consists of lipid-based particles with internal morphine vesicles (DepoFoam). It is approved only for single-dose epidural use and may provide up to 48 hours of analgesia. Except for the epidural test dose, DepoDur may not be coadministered with local anesthetics because of the risk of accelerated morphine release. No other medication may be dosed within the epidural space for 48 hours after DepoDur administration.

SUGGESTED READINGS

1. Coda B.A. Opioids. In Barash P.G., Cullen B.F., Stoelting R.K., editors: Clinical anesthesia, ed 5, Philadelphia: Lippincott Williams & Wilkins, 2006.

2. Crawford M.W., Hickey C., Zaarour C., et al. Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery. Anesth Analg. 2006;102:1662-1667.

3. Fukuda K. Intravenous opioid anesthetics. In Miller R.D., editor: Anesthesia, ed 6, Philadelphia: Elsevier, 2005.

4. Gillman P.K. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth. 2005;95:434-441.

5. Kirchheiner J., Schmidt H., Tzvetkov M., et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7:257-265.

6. Krantz M.J., Martin J., Stimmel B., et al. QTc interval screening in methadone treatment: the CSAT consensus guideline. Ann Intern Med. 2009;150:387-395.

7. Moss J., Rosow C.E. Development of peripheral opioid antagonists: new insights into opioid effects. Mayo Clin Proc. 2008;83:1116-1130.

8. Smith H.S. Peripherally-acting opioids. Pain Physician. 2008;11:S121-S132.

9. Viscusi E.R., Martin G., Hartrick C.T., et al. Forty-eight hours of postoperative pain relief after total hip arthroplasty with a novel, extended-release epidural morphine formulation. Anesthesiology. 2005;102:1014-1022.

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