Opioid Use During the Perianesthesia Period ...

Opioid Use During the Perianesthesia Period: Nursing Implications JONI BENNETT, BSN, RN KATHLEEN R. WREN, PhD, CRNA RICHARD HAAS, MS, EdM, CRNA Opioids are used extensively for pain management during the perianesthesia period. These compounds exhibit varying degrees of agonism and antagonism at ␮, ␬, and ⌬ opioid receptors. Stimulation of these receptors cause similar and distinctive actions such as analgesia, euphoria, dysphoria, and respiratory depression. It is imperative that perianesthesia nurses have a clear understanding of opioid receptor site physiology so that maximum analgesic effects are obtained while side effects are minimized. © 2001 by American Society of PeriAnesthesia Nurses.

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PIUM, DERIVED FROM the cultivar poppy papavera somniferum, has been used for analgesia since the Neolithic Period of prehistoric man. Excavated ancient settlements of the Cortaillod culture in Switzerland showed poppy cultivation dating from 3200 to 2600 BCE (Before Common Era). The word opium is derived from the Greek word opion (meaning juice) because it is the milky juice extract from this plant’s immature seed pod that yields the substance known in those cultures as the “destroyer of grief and pain.”1 In 1804, Friedrich Serturner extracted morphine from the poppy plant, with the discovery of codeine following later. Additionally, opioid compounds have been developed by modifying the morphine complex. These agents include hydromorphone, oxymorphone, hydrocodone, and oxycodone. Other opioid agents such as meperidine, fentanyl, and methadone are synthetically produced.2 Late 19th century Victorian England used opium freely because it was sold without prescription by pharmacists. The recommended use for the drug was indicated by the names that were given to the opiate tonics that were produced and sold. For example, “Mother’s Helper” and “Infant Quietness” were solutions used to sedate small children and babies.3

Today, most opiates (excluding morphine) are produced synthetically. The effects of all opiates, both natural and synthetic, are mediated through stimulation of specific opioid receptors located throughout the body. The stimulation of these receptors results in a plethora of reactions that depends on the subclass of the activated opioid receptor. Perianesthesia nurses who administer opioids should have a clear understanding of these receptors to produce maximum analgesic effects while minimizing side effects. OPIOID RECEPTOR DESIGN AND FUNCTION

It is important to look at the molecular events presumed to occur in opioid receptor stimulation to

Joni Bennett, BSN, RN, was a student in the Nursing Anesthesia Program when she wrote this article; Kathleen R. Wren, PhD, CRNA, is an Assistant Professor; and Richard Haas, MS, EdM, CRNA, is an Assistant Professor for the Nursing Anesthesia Program at the School of Nursing, Medical College of Georgia, Augusta, GA. Address correspondence to Kathleen R. Wren, PhD, CRNA, Nursing Anesthesia Program EB-226, School of Nursing, Medical College of Georgia, 1120 15th St, Augusta, GA 30912. © 2001 by American Society of PeriAnesthesia Nurses. 1089-9472/01/1604-0003$35.00/0 doi:10.1053/jpan.2001.25564

Journal of PeriAnesthesia Nursing, Vol 16, No 4 (August), 2001: pp 255-258

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understand the mechanisms by which opiates elicit their pharmacologic effects. Opioid receptors are G protein– coupled receptors and helical in shape. The majority of these receptors are located on primary afferent presynaptic terminals. When the receptor is activated, release of excitatory neurotransmitters such as acetylcholine, dopamine, norepinephrine, and substance P is inhibited. Postsynaptic depolarization may also be inhibited.4 Activation of the opioid receptors also increases the transport of potassium out of the cell, resulting in hyperpolarization. Hyperpolarization is a state in which the resting membrane potential of the cell is moved away from threshold. During times of membrane hyperpolarization, cells are less able to generate an action potential and release neurotransmitters. This prevents propagation of the pain impulse. Calcium channel inactivation can also inhibit neurotransmitter release and pain transmission because calcium must be present to release neurotransmitter vesicles.5 When pain transmission to higher centers of the brain is inhibited, pain perception decreases. Opioid receptors also show up- and downregulation. Downregulation occurs when the body makes less receptors or the receptors themselves become less sensitive. Thus, when opioids are present in large quantities over an extended period of time, the body decreases the number of receptors present or reduces the sensitivity of the receptors. This phenomena may explain the development of tolerance during habitual or prolonged use of opioid medications.5 Upregulation occurs when the body increases the number of receptors. Upregulation of ␮ receptors can occur during chronic cocaine use. Chronic exogenous intake of cocaine decreases enkephalin production in the brain. When enkephalin production falls, the body increases the number of receptor sites to be better able to detect the lower enkephalin level. These empty enkephalin receptor sites in the brain may contribute to the cravings for cocaine.6 OPIOID RECEPTORS

In general, opioid receptors prefer to bind with opiate compounds. Binding studies of opioid receptors show that there are isolated subclasses of opioid receptors. These subclasses are designated as ␮, ␬, and ⌬ and show effects specific to receptor type (Table 1). ⌺ and ⑀ receptors were once subclasses of opioid receptors; however, studies have

Table 1. Receptor Site Effects Effect

␮ Receptor

␬ Receptor

Analgesia Mental status

⫹⫹⫹ Euphoria

⫹⫹⫹ 0 Sedation Dysphoria Dysphoria ⫹ ⫹ ⫺⫺ ⫺ ⫺⫺ ⫺⫺ ⫹⫹

Respiratory depression Gastrointestinal motility Acetylcholine release Dopamine release Urinary retention

⫹⫹⫹ ⫺⫺⫺ ⫺⫺ ⫺⫺ ⫹⫹

⌬ Receptor

NOTE. ⫹⫹⫹, large positive effect; ⫹⫹, moderate positive effect; ⫹, small positive effect; ⫺⫺⫺, large negative effect; ⫺⫺, moderate negative effect; ⫺, small negative effect. Data from references 2, 4, 5, 8, and 10.

shown stimulation of these receptors is not reversed with naloxone, and they have since been reclassified as nonopioid receptors.4 It is the true opioid receptors (␮, ␬, ⌬) that are of greatest concern to perianesthesia providers because of the vast repertoire of opioid agonists that are available for patient administration during the perianesthesia period.

␮ Receptors ␮ Opioid receptors are located in the brain, spinal cord, and periphery. Stimulation of ␮ receptors produces analgesia and feelings of euphoria. The euphoric effects are thought to be caused by the binding and inhibition of inhibitory dopaminergic presynaptic neurons in the pleasure centers of the limbic system. Analgesia is produced by a different mechanism. ␮ Receptors are found in great quantity throughout the mid-brain in regions involved in pain perception; they are also thought to be associated with analgesia attributed to the ␮ agonist morphine. Opioids produce analgesia by stimulation of specific inhibitory neurons in the mid-brain and spinal cord. Once ␮ receptors are occupied by opioids, associated neurons release norepinephrine and activate descending inhibitory nerve tracts in the spinal cord to prevent noxious stimuli from reaching areas in the brain responsible for pain perception. Norepinephrine also diminishes substance P release, reducing pain transmission. Norepinephrine also inhibits dorsal horn neuron response to nociceptive stimuli.7 Other effects produced by stimulation of ␮ receptors include sedation, spinal analgesia, supraspinal (above the level of the spinal cord) an-

OPIOID USE DURING THE PERIANESTHESIA PERIOD algesia, respiratory depression, and constipation because of slowed gastrointestinal peristalsis.8 Several subclasses of ␮ receptors have been identified: ␮, ␮-1 (supraspinal and peripheral analgesia), ␮-2 (spinal cord level), and ␮-3. The effects and clinical significance of the ␮ subclasses are still being delineated. Interestingly, the ␮-3 subtype is found in human macrophage cells and granulocytes (white blood cells). The exact role of this receptor in immune function and central nervous system pathology is still being studied.9 Drugs used in the perianesthesia setting that stimulate the ␮ opioid receptors include morphine, fentanyl, sufentanil, and alfentanil.10 Endogenous opioids (enkephalins and endorphins) also bind to these sites and are responsible for the body’s innate analgesia system. Researchers hypothesize that a better understanding of the body’s own analgesia system may lead to significant advances in the ability to treat chronic pain syndromes. It may be possible in the future to stimulate the body’s endogenous opioids in ways that are now only vaguely understood.8

␬ Receptors ␬ Opioid receptors are another subtype of opioid receptor and have a myriad of effects as well. Activation of these receptors produces analgesia at and above the level of the spinal cord. Stimulation of ␬ receptors can also produce sedation, miosis, and dysphoria.4 Dysphoria reactions are not always recognizable because patients may seem calm and sedated on the outside and experience intense feelings of doom and dread on the inside. Many times patients are unable to verbalize these feelings. This syndrome is termed inner storm. In a study of 9 nondependent opioid abusers, the subjects were given opioid agonists and asked to describe any feelings of dysphoria and euphoria. Through neuroimaging, the study found anatomically distinct changes in the pattern of regional cerebral blood flow that may account for the emotional side effects. Butorphanol, a ␬ agonist and ␮ antagonist, was found to produce more dysphoria and increase blood flow to the temporal lobes bilaterally. Hydromorphone (␮ agonist), however, was associated with euphoria and showed marked increases in cerebral blood flow to the structures in the limbic system.11 Dysphoric reactions commonly occur with pentazocine, thus limiting its use in the perioperative period.

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Nalbuphine, a ␬ receptor agonist, is also a ␮ receptor antagonist (agonist/antagonist). This agent has been shown to have nearly the same analgesic effect as morphine on a milligram-to-milligram basis.5 Further, at a dose of 15 milligrams, nalbuphine’s respiratory depressant effect ceases. This makes the use of nalbuphine efficacious in reversing the respiratory depression induced via a relative overdose of ␮ opiates.12,13 Of crucial importance is the reversal of the respiratory component without the renewal of painful stimuli associated with the administration of nalaxone for similar purposes. ⌬ Receptors ⌬ Opioid receptors have properties that are less known. ⌬ Receptor stimulation may produce epileptic or convulsant effects. Stimulation of ⌬ receptors with high-dose morphine is possible, and although extremely rare, it is thought to contribute to the seizure activity seen with extremely high doses of morphine administration. Selective ⌬ agonists at low doses consistently produce seizure activity in animals. This mechanism is presumed to occur through the inhibition of the neurotransmitter gamma-aminobutyric acid (GABA). Inhibition of GABA leads to an excitatory effect. Anticonvulsant agents may not be able to suppress opioidinduced seizure activity; however, opioid-induced seizure activity may be obliterated by the administration of naloxone. This reinforces the theory that ⌬ opioid receptors may be responsible for the seizure activity.8 IMPLICATIONS FOR PRACTICE

Pain assessment and management is an important component of perianesthesia nursing practice, and opioid agonists are frequently the drug of choice for pain management during this period. Unfortunately, the use of these agents is not without detrimental effects. Stimulation of ␮ receptors may cause respiratory depression, which is inconsequential most times, but becomes of greater concern in those patients with marginal respiratory function: eg, moderate to severe states in chronic obstructive pulmonary disease (COPD), neuromuscular dysfunction, morbid obesity, or premature neonates and infants. ␮ Receptor stimulation may also cause nausea, retching, or vomiting, which can lead to wound dehiscence, loss of ocular contents, or electrolyte imbalance.

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Table 2. Sites of Opioid Activity Receptor Types Medication

Morphine Methadone Fentanyl Sufentanil Alfentanil Butorphanol Pentazocine Nalbuphine Ketamine

␮

␬

⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫺ Partial ⫺

⫹

⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹

⌬

⫹

⫹

NOTE. ⫹, agonist; ⫺, antagonist. Data from references 2, 4, 5, 8, and 10.

␬ Agonists are more likely to cause dysphoria when compared with ␮ agonists. Even so, dysphoria at any time during the perioperative period is undesirable. Avoidance of ␬ agonists in patients who are more likely to experience dysphoria during periods of disinhibition (such as those with post-traumatic stress disorder) would seem judicial (Table 2). Administration of an agonist and/or antagonist agent requires special considerations. The efficacy of a pure ␮ agonist may be reduced if administered after an agonist/antagonist. Thus, the analgesic

effects of morphine (␮ agonist) may be reduced when given after nalbuphine (␬ agonist/␮ antagonist). Of greater concern is the administration of an agonist/antagonist agent in patients who have developed physical dependence to ␮ receptor agonists. Physical dependence is attributed to physiologic changes in the body that develop after prolonged exposure to ␮ agonists. It is manifested by the appearance of a withdrawl syndrome during periods of abstinence or ␮ agonist reversal.14 Thus, if nalbuphine is administered to a cancer patient who has been receiving morphine and fentanyl for pain control over a length of time, a physical withdrawl syndrome will most likely be precipitated. Agonist/antagonist agents should be avoided in these situations. CONCLUSION

Opioid receptors are involved in innumerable functions in the body. At present, researchers are just scratching the surface to understanding these receptors in the body. It is important for perianesthesia professionals to have up-to-date knowledge of these receptors when administering opiate medications. Analgesic drug selection must be based on sound physiologic principles and the needs of the patient.

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8. Reisine T, Pasternack G: Opioid analgesics and antagonists, in Hardman JG, Limbird LE (eds): Goodman & Gilman’s: The Pharmacologic Basis of Therapeutics (ed 9). New York, NY, McGraw-Hill, 1996, pp 521-555 9. Makman MH: Neurotransmitter and neuroimmune regulation, 1998. Available at http://www.ca.aecomm.yu.edu/sggd/ pages/faculty/makman.htm. Accessed January 1999 10. Chick M: Opioid agonists and antagonists, in Nagelhout JJ, Zaglaniczny KL (eds): Nurse Anesthesia. Philadelphia, PA, Saunders, 1997, pp 441-451 11. Schlaepfer TE, Strain EC, Greenberg BD, et al: Site of opioid action in the human brain: Mu and kappa agonists’ subjective and cerebral blood flow effects. Am J Psychol 155:470-473, 1998 12. DeSouza EB, Schmidt WK, Kuhar MJ: Nalbuphine: An autoradiographic opioid receptor binding profile in the central nervous system of an agonist/antagonist analgesic. J Pharmacol Exp Ther 244:391-402, 1988 13. Julie RM: Nalbuphine antagonism of opiate-induced respiratory depression. Anes Rev 12:29-32, 1985 14. McClain BC: Organization of pain management services for children, in Raj PR (ed): Practical Management of Pain (ed 3). St Louis, MO, Mosby, 2000, p 65