For maintenance of antinociception during general anesthesia, we use simultaneously multiple antinociceptive agents, including opioids (Table 1, column II, row A). Use of multiple antinociceptive agents in addition to an opioid creates the opioid-sparing effect of these agents. Each agent targets a different component of the nociceptive system so that together, they suppress more completely nociceptive transmission. The hypnotic agents reduce the ability to perceive pain, and thereby, contribute implicitly to antinociception (Table 1, column III, row A).
During general anesthesia, uncon sciousness is maintained primarily by using a single titratable agent such as propofol or sevoflurane (Table 1, column II, row B). The antinociceptive agents profoundly contribute to unconsciousness by arresting nociceptive-induced arousal (Table 1, column III, row B). Because each of the antinociceptive agents decreases arousal, their combination reduces appreciably the hypnotic dose required to maintain unconsciousness. When considering the use of an inhaled ether to maintain unconsciousness, the fact that less is required when multiple antinociceptive agents are administered is the commonly cited special case of the minimal alveolar concentration–sparing effect of the antinociceptive drugs. Amnesia is maintained by ensuring unconsciousness because a patient who is truly unconscious and not simply unresponsive is also amnestic.
A single muscle relaxant (nicotinic anticholinergic agent) can be used to maintain immobility (Table 1, column II, row C). The GABAergic hypnotic agents contribute to muscle relaxation by blocking α motor neurons at the level of the spinal cord (Table 1, column III, row C). Magnesium, administered as part of an antinociceptive regimen (Table 1, column II, row A), also enhances muscle relaxation significantly (Table 1, column III, row C). In this case, the muscle relaxant dose has to be reduced accordingly.
In addition to standard monitors required for tracking the physiological state during general anesthesia, electroencephalogram monitoring is essential to track level of unconsciousness and to guide hypnotic dosing. The ability to apply our multimodal strategy would be substantially enhanced by a monitor to track level of antinociception and guide dosing of the antinociceptive agents.25 Such monitors are becoming commercially available.60–63 At present, we use heart rate and blood pressure changes as a measure of the nociceptive medullary adrenergic circuit response to nociceptive stimuli.64
To illustrate our multimodal general anesthesia strategy, we summarize the perioperative management of 4 surgeries: laminectomy, total knee replacement, cesarean delivery, and exploratory laparotomy (Table 2). The strategy requires an explicit plan for preoperative, intraoperative, postoperative, and discharge antinociception/pain management. The drug doses and combinations are ones the anesthesiologist chose for the particular case. They are intended solely as examples. The management strategy, anesthetic choices, and anesthetic doses must be adapted to the needs of the individual patient.
The preoperative anesthetic management for the lumbar laminectomy with instrumentation (Table 2, column I) started 30 minutes before the surgery by administering low-dose infusions of dexmedetomidine and magnesium. These infusions, which initiate the patient’s antinociceptive regimen, commonly induce substantial sedation and muscle relaxation. Unconsciousness was induced with propofol and maintained with a low-rate propofol infusion and a low concentration of sevoflurane. After a ketamine bolus, ketamine and lidocaine infusions were added to complete simultaneous multimodal targeting of nociception. Muscle relaxation was maintained with rocuronium, which was reversed with sugammadex before the start of the instrumentation. The magnesium, lidocaine, and dexmedetomidine infusions were stopped 15–30 minutes before the projected end of the surgery to avoid prolonged recovery of consciousness. For postoperative antinociceptive management, a field block was performed by combining ropivacaine, dexmedetomidine, and ketorolac. Half of the volume was administered in the muscle layer along the wound, and the remaining half was administered in the subcutaneous tissue. This field block provided postoperative analgesia for approximately 24 hours.
We (M.N.) used the visual analog scale to allow the patient to describe their level of postoperative pain. Intravenous ketorolac and acetaminophen were the primary agents used for pain control, and morphine was administered to treat breakthrough pain. Before discharge, we counseled the patient on the benefits of taking pain medication on a set schedule and on the potential adverse effects of opioids. Our (M.N.) goal is to discharge patients using just NSAIDs, such as either ketorolac or acetaminophen to control pain.65 This patient was also discharged on pregabalin as he had been taking it for neuropathic pain before his surgery.
The multimodal strategy also applies to surgeries such as total knee replacements (Table 2, column II) and cesarean deliveries (Table 2, column III), which were conducted using regional anesthetic techniques. For the total knee replacement, a low-dose propofol infusion was used for sedation during placement of the spinal and during the surgery. During the cesarean delivery, a low-dose propofol infusion was used for sedation until delivery then discontinued at the end of the surgery. The spinal anesthetics for both cases used a combination of bupivacaine, clonidine, and morphine to achieve multimodal antinociception and muscle relaxation. Both patients received field blocks using a combination of ropivacaine, dexmedetomidine, and ketorolac at the completing of their surgeries before closing the skin incisions. For the field block, the anesthetic solution is injected in a systematic way around the length of the incision. Postoperative pain management relied on ketorolac and acetaminophen, with morphine as the rescue agent after the total knee replacement and tramadol as the rescue agent after the cesarean delivery. Both patients were discharged home on ketorolac 10 mg every 8 hours for 3 days and acetaminophen 1 g every 8 hours for 5 days. In addition to the ketorolac and acetaminophen, the patient who had the total knee replacement was given tramadol 50 mg every 8 hours for breakthrough pain.
For many years after the initial use of ether as the first anesthetic in the 1840s, anesthesiologists relied almost exclusively on this single agent for anesthetic management. With time, anesthesiologists learned that using balanced general anesthesia to create the anesthetic state offered a greater likelihood of achieving the beneficial effects while minimizing side effects. The several undesirable side effects of the opioids and the recent opioid epidemic have catalyzed efforts to develop new balanced anesthesia paradigms, which reduce or eliminate opioid use.10 , 66
For example, a recent review proposes an opioid-free multimodal balanced general anesthesia strategy that provides unconsciousness with amnesia and muscle relaxation while maintaining appropriate tissue perfusion and sympathetic stability to protect organs.10 This strategy emphasizes use of medications other than opioids to create stress-free intraoperative conditions and asserts that analgesia is only important postoperatively and can be achieved with medications other than opioids. In contrast, we believe that nociception should be maintained intraoperatively and postoperatively using multiple antinociceptive agents.
A recent report has summarized the modalities (nonanesthetic and anesthetic adjuncts, and regional techniques) that can be used to reduce opioid use perioperatively.67 Our framework offers a principled approach for designing and implementing multimodal strategies for use in anesthesiology practice. The fundamental feature of our strategy is administration of multiple antinociceptive agents simultaneously to suppress nociceptive trafficking during both general and regional anesthesia (Table 2). Each agent targets a different component of the nociceptive system. Our neural circuit analyses provide a neurophysiologically based approach for understanding the effects of each anesthetic and for choosing the anesthetic combinations (Figures 2–6). As stated in the “Introduction,” surgically induced nociception is the primary reason for administering general anesthesia and the primary source of the patient’s hemodynamic and stress responses. If nociceptive control is adequate, the stress responses will be minimized and sympathetic stability will be achieved. Moreover, our approach also takes account of the implicit effects of the anesthetics being administered (Table 1). Suppression of nociceptive transmission has the significant added benefit of decreasing arousal, which appreciably reduces the hypnotic doses required to maintain unconsciousness and amnesia. We postulate that reduction in hypnotic use may facilitate faster recovery and help reduce the contribution of general anesthesia to postoperative cognitive dysfunction. Similarly, muscle relaxants decrease arousal by decreasing proprioceptive feedback. Under our strategy, opioid use need not be eliminated. Instead, other agents are used along with opioids to achieve antinociception control intraoperatively and pain control postoperatively (Tables 1 and 2).
To achieve adequate postoperative pain control, multimodal pain management has to be continued in the immediate postoperative period and after discharge (Table 2). This formal planning that provides an explicit way to reduce postoperative opioid use requires coordinated management during the perioperative period among the anesthesiology, surgical, and nursing teams. Our experience suggests that this multimodal strategy has important potential. We will test our strategy further in clinical practice and in clinical trial comparisons with existing approaches.
APPENDIX Glossary of Terms
α-2 adrenergic receptor is a subtype of G-protein–coupled, presynaptic receptor through which catecholamines like norepinephrine and epinephrine signal in the central and peripheral nervous systems.
Arousal system (arousal pathways) is (are) a collection of nuclei located primarily in the brainstem and their ascending neuronal projections to the thalamus and cortex that is (are) responsible for creating the awake component of consciousness. Inactivation of these nuclei and/or their pathways is a mechanism for producing unconsciousness.
Basal forebrain (BF) is an area of the cortex located in at the base of the frontal cortex that is a major source of excitatory cholinergic projections to the thalamus and cortex.
Cyclooxygenase (COX) is an important enzyme for biosynthesis of prostaglandins that promote inflammation and fever. COX-1 and COX-2 are 2 important types COX enzymes, the actions of which are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs).
Dorsal raphé is a brainstem area located in the central pons that sends primarily excitatory serotonergic projections to the cortex.
Frequency bands are electroencephalogram frequency ranges that have been established by convention. The commonly used bands, characterized in cycles per second or Hertz (Hz), are as follows: slow-delta, 0.1–4 Hz; theta, 4–7 Hz; alpha, 8–12 Hz; beta, 13–25 Hz; gamma, >25 Hz.
Galaninergic pathways are inhibitory pathways that project from the preoptic area of the hypothalamus onto nearly each one of the major arousal nuclei in the pons and midbrain. The neuropeptide galanin is the neurotransmitter in these pathways.
γ-amino butyric acid is the primary inhibitory neurotransmitter in the central nervous system.
Laterodorsal tegmentum is a brainstem area located in the superior posterior region of the midbrain that is a major source of excitatory cholinergic projections to the thalamus and cortex.
Locus ceruleus is a brainstem area located in the central pons that sends primarily noradrenergic projections to the cortex, central thalamus, BF, and the preoptic area of the hypothalamus.
Neutrophil priming is the process by which polymorphonuclear lymphocytes are activated, and as a consequence, readily degranulate inducing amplification of an inflammatory response.
N-methyl-D-aspartate receptors are a pharmacologically identified subset of glutamate receptors and ion channel proteins that are primarily excitatory.
Nociception is the propagation through the sensory system of potentially noxious and harmful chemical, mechanical, or thermal stimuli. The nociceptive system or pathways consist of the nociceptors in the periphery and in the viscera, the ascending nociceptive pathways and the descending nociceptive pathways. The ascending pathways transmit nociceptive stimuli from the periphery to the spinal cord to the brainstem (medulla and midbrain), the amygdala, the thalamus, and on to the primary and secondary sensory cortices. The brainstem descending component of the nociceptive pathway begins in the periaqueductal gray located in the midbrain, and projects through the rostral ventral medulla in the medulla to the spinal cord. The descending pathways are activated immediately by the nociceptive inputs from the ascending pathways and modulate (upregulate and downregulate) the nociceptive information.
Nociceptors are unspecialized bare nerve cell endings that initiate nociception or pain. Their cell bodies arise in the dorsal horn of the spinal cord and send one axonal process to the periphery and the other to the spinal cord or brainstem through the spinothalamic tract.
NSAIDs are pharmacological agents that block specifically the COX-1 and COX-2 enzymes that play a major role in prostaglandin synthesis. Because prostaglandins are primary mediators of inflammation, NSAIDs are key agents for blocking inflammation and thereby reducing inflammation-induced nociception and pain.
Pain is the conscious perception of nociceptive information.
Parabrachial nucleus is a brainstem area located in the dorsolateral pons that surrounds the superior cerebellar peduncle as it enters the brainstem from the cerebellum. The parabrachial nucleus provides important glutamatergic projections to the central thalamus and the BF.
Pedunculopontine tegmentum is brainstem area located in the superior posterior region of the midbrain that is a major source of excitatory cholinergic projections to the thalamus and to the cortex.
Periaqueductal gray is the midbrain relay of the descending pathways for modulating nociceptive inputs into the central nervous system.
Pyramidal neurons are multipolar, commonly teardrop-shaped excitatory neurons that are located primarily in the amygdala, the hippocampus, and the cortex.
Rostral ventral medulla is a brainstem area located in the upper ventral part of the medulla that relays descending modulation of nociceptive information from the periaqueductal gray to the spinal cord.
Rostral and caudal ventral lateral medulla are brainstem areas located respectively in the upper and lower ventral lateral parts of the medulla. These areas relay sympathetic signals from the nucleus of the tractus solitarius—also in the medulla—to the sympathetic ganglia in the thoracolumbar trucks.
Spindles are waxing and waning oscillations in the 9–15 Hz range that are a defining feature of stage 2 nonrapid eye movement sleep. These oscillations are also observed in the EEG of patients receiving low-dose dexmedetomidine.
Striatum is a general term used to denote the putamen and caudate in the basal ganglia. It plays a critical role in motor control.
Thalamic reticular nucleus is a network of inhibitory neurons that surround the thalamus and modulate nearly all thalamic output, particularly to the cortex.
1. Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med. 2010;363:2638–2650.
2. Lundy JS. Balanced anesthesia. Minn Med. 1926;9:399–404.
3. Hendrickx JF, Eger EI II, Sonner JM, Shafer SL. Is synergy the rule? A review of anesthetic interactions producing hypnosis and immobility. Anesth Analg. 2008;107:494–506.
4. Purves D, Augustine GJ, Fitzpatrick D, Hall WC, Lamantia A, White LE. Purves D, Augustine GJ, Fitzpatrick D, Hall WC, Lamantia A, White LE. Pain. In: Neuroscience. 2012:5th ed. Sunderland, MA: Sinauer Associates, Inc; 209–228.
5. Lake APJ. Balanced anaesthesia 2005: avoiding the transition from acute to chronic pain. South Afr J Anaesth Analg. 2005;11:14–18.
6. McNicol E, Horowicz-Mehler N, Fisk RA, et al; American Pain Society. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain. 2003;4:231–256.
7. Volkow ND, Collins FS. The role of science in the opioid crisis. N Engl J Med. 2017;377:1798.
8. Brown EN, Purdon PL, Van Dort CJ. General anesthesia and altered states of arousal: a systems neuroscience analysis. Annu Rev Neurosci. 2011;34:601–628.
9. Dunn LK, Durieux ME. Perioperative use of intravenous lidocaine. Anesthesiology. 2017;126:729–737.
10. Mulier J. Opioid free general anesthesia: a paradigm shift? Rev Esp Anestesiol Reanim. 2017;64:427–430.
11. Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66:355–474.
12. Rabiner EA, Beaver J, Makwana A. Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans. Mol Psychiatry. 2011;16:826–835.
13. Burn DJ, Rinne JO, Quinn NP, Lees AJ, Marsden CD, Brooks DJ. Striatal opioid receptor binding in Parkinson’s disease, striatonigral degeneration and Steele-Richardson-Olszewski syndrome, A [11C]diprenorphine PET study. Brain. 1995;118(pt 4):951–958.
14. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem. 2004;73:953–990.
15. Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med. 1995;332:1685–1690.
16. Fukuda K. Opioids. 2009.7th ed. New York, NY: Churchill Livingstone.
17. Veinante P, Yalcin I, Barrot M. The amygdala between sensation and affect: a role in pain. J Mol Psychiatry. 2013;1:9.
18. Becerra L, Harter K, Gonzalez RG, Borsook D. Functional magnetic resonance imaging measures of the effects of morphine on central nervous system circuitry in opioid-naive healthy volunteers. Anesth Analg. 2006;103:208–216.
19. Lydic R, Baghdoyan HA. Sleep, anesthesiology, and the neurobiology of arousal state control. Anesthesiology. 2005;103:1268–1295.
20. Mortazavi S, Thompson J, Baghdoyan HA, Lydic R. Fentanyl and morphine, but not remifentanil, inhibit acetylcholine release in pontine regions modulating arousal. Anesthesiology. 1999;90:1070–1077.
21. Griffioen KJ, Venkatesan P, Huang ZG. Fentanyl inhibits GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Brain Res. 2004;1007:109–115.
22. Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008:313–333.
23. Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res. 1999;33:523–533.
24. Seamans J. Losing inhibition with ketamine. Nat Chem Biol. 2008;4:91–93.
25. Purdon PL, Sampson A, Pavone KJ, Brown EN. Clinical electroencephalography for anesthesiologists: part I: background and basic signatures. Anesthesiology. 2015;123:937–960.
26. Boon JA, Milsom WK. NMDA receptor-mediated processes in the parabrachial/Kölliker fuse complex influence respiratory responses directly and indirectly via changes in cortical activation state. Respir Physiol Neurobiol. 2008;162:63–72.
27. Fuller PM, Fuller P, Sherman D, Pedersen NP, Saper CB, Lu J. Reassessment of the structural basis of the ascending arousal system. J Comp Neurol. 2011;519:933–956.
28. Fulwiler CE, Saper CB. Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat. Brain Research. 1984;319:229–259.
29. Akeju O, Song AH, Hamilos AE. Electroencephalogram signatures of ketamine anesthesia-induced unconsciousness. Clin Neurophysiol. 2016;127:2414–2422.
30. Do SH. Magnesium: a versatile drug for anesthesiologists. Korean J Anesthesiol. 2013;65:4–8.
31. Pairu J, Triveni GS, Manohar A. The study of serum calcium and serum magnesium in pregnancy induced hypertension and normal pregnancy. Int J Reprod Contracept Obstet Gynecol. 2015;4:30–34.
32. Gourgoulianis KI, Chatziparasidis G, Chatziefthimiou A, Molyvdas PA. Magnesium as a relaxing factor of airway smooth muscles. J Aerosol Med. 2001;14:301–307.
33. Ruppersberg JP, Kitzing E, Schoepfer R. The mechanism of magnesium block of NMDA receptors. Semin Neurosci. 1994;6:87–96.
34. Seyhan TO, Tugrul M, Sungur MO. Effects of three different dose regimens of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery. Br J Anaesth. 2006;96:247–252.
35. Andrieu G, Roth B, Ousmane L. The efficacy of intrathecal morphine with or without clonidine for postoperative analgesia after radical prostatectomy. Anesth Analg. 2009;108:1954–1957.
36. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437:1257–1263.
37. Sherin JE, Elmquist JK, Torrealba F, Saper CB. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci. 1998;18:4705–4721.
38. Akeju O, Kim SE, Vazquez R. Spatiotemporal dynamics of dexmedetomidine-induced electroencephalogram oscillations. PLoS One. 2016;11:e0163431.
39. Akeju O, Pavone KJ, Westover MB. A comparison of propofol- and dexmedetomidine-induced electroencephalogram dynamics using spectral and coherence analysis. Anesthesiology. 2014;121:978–989.
40. Bautmans I, Njemini R, De Backer J, De Waele E, Mets T. Surgery-induced inflammation in relation to age, muscle endurance, and self-perceived fatigue. J Gerontol A Biol Sci Med Sci. 2010;65:266–273.
41. Arias J, Aller M-A, Arias J-I. Surgical Inflammation. 2013.Madrid, Spain: Bentham Science Publishers.
42. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31:986–1000.
43. Ajmone-Cat MA, Bernardo A, Greco A, Minghetti L. Non-steroidal anti-inflammatory drugs and brain inflammation: effects on microglial functions. Pharmaceuticals (Basel). 2010;3:1949–1965.
44. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–235.
45. Berde C, Strichartz GR. Miller R, Eriksson L, Fleisher L, Wiener-Kronish J, Cohen N, Young W. Local Anesthetics. In: Miller's Anesthesia. 2015:8th ed. Philadelphia, PA: Elsevier; 1028–1053.
46. Wang GK, Strichartz GR. State-dependent inhibition of sodium channels by local anesthetics: a 40-year evolution. Biochem (Mosc) Suppl Ser A Membr Cell Biol. 2012;6:120–127.
47. Hollmann MW, Herroeder S, Kurz KS. Time-dependent inhibition of G protein-coupled receptor signaling by local anesthetics. Anesthesiology. 2004;100:852–860.
48. Miralda I, Uriarte SM, McLeish KR. Multiple phenotypic changes define neutrophil priming. Front Cell Infect Microbiol. 2017;7:217.
49. Hollmann MW, McIntire WE, Garrison JC, Durieux ME. Inhibition of mammalian Gq protein function by local anesthetics. Anesthesiology. 2002;97:1451–1457.
50. Wagman IH, De Jong RH, Prince DA. Effects of lidocaine on the central nervous system. Anesthesiology. 1967;28:155–172.
51. Muth-Selbach U, Hermanns H, Stegmann JU. Antinociceptive effects of systemic lidocaine: involvement of the spinal glycinergic system. Eur J Pharmacol. 2009;613:68–73.
52. Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception: implications for mechanisms of pain. Pain. 2007;131:243–257.
53. Bowery NG, Hudson AL, Price GW. GABAA
receptor site distribution in the rat central nervous system. Neuroscience. 1987;20:365–383.
54. Hemmings HC Jr, Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL. Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci. 2005;26:503–510.
55. Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci. 2008;9:370–386.
56. Purdon PL, Pierce ET, Mukamel EA, et al. Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proc Natl Acad Sci U S A. 2013;110:E1142–E11–51.
57. Lewis LD, Weiner VS, Mukamel EA, et al. Rapid fragmentation of neuronal networks at the onset of propofol-induced unconsciousness. Proc Natl Acad Sci U S A. 2012;109:E3377–E33–86.
58. Ching S, Cimenser A, Purdon PL, Brown EN, Kopell NJ. Thalamocortical model for a propofol-induced alpha-rhythm associated with loss of consciousness. Proc Natl Acad Sci U S A. 2010;107:22665–22670.
59. Flores FJ, Hartnack KE, Fath AB, et al. Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness. Proc Natl Acad Sci U S A. 2017;114:E6660–E6668.
62. Storm H. Med-Storm. 2016.PainMonitor™:Oslo, Norway.
63. Huiku M, Kamppari L, Viertio-Oja H. Surgical Plethysmographic Index (SPI) in Anesthesia Practice. 2014.Helsinki, Finland: General Electric Healthcare.
64. Brown EN, Solt K, Purdon PL, Akeju O. Miller R, Eriksson L, Fleisher L, Wiener-Kronish J, Cohen N, Young W. Monitoring brain state during general anesthesia and sedation. In: Miller’s Anesthesia. 2015:8th ed. Philadelphia, PA: Elsevier; 1524–1540.
65. Clarke R, Derry S, Moore RA. Single dose oral etoricoxib for acute postoperative pain in adults. Cochrane Database Syst Rev. 2014:CD004309.
66. Ljungqvist O, Scott M, Fearon KC. Enhanced recovery after surgery: a review. JAMA Surg. 2017;152:292–298.
67. Kumar K, Kirksey MA, Duong S, Wu CL. A review of opioid-sparing modalities in perioperative pain management: methods to decrease opioid use postoperatively. Anesth Analg. 2017;125:1749–1760.