Perioperative Management o f t h e O p i o i d Tol e r a n t P a t i e n t f o r O r t h o p e d i c Su r g e r y Marchyarn Mahathanaruk, Oscar A. de LeonCasasola,
a
, James Hitt, * MD
DO
a,b,
MD, PhD
a
,
KEYWORDS Opioid tolerance Cellular mechanisms Postoperative pain Opioids Ketamine KEY POINTS Opioid tolerance may occur as early as 2 weeks after therapy is started with opioids. Patients who have received high doses of opioids preoperatively will respond better to therapy with opioids with high intrinsic efficacy, such as sufentanil. Evidence supporting the role of the N-methyl D-aspartate (NMDA) receptor in the development of tolerance suggests the use of NMDA receptor antagonists, such as ketamine, for the management of patients who are not responding to increasing doses of opioids. Epidural techniques with a local anesthetic and higher doses of morphine or sufentanil are effective in the management of postoperative pain in patients with opioid tolerance.
INTRODUCTION
Determining the number of patients with pain in the United States has been a difficult task, because calculations of the prevalence of pain vary depending on definitions of the levels of pain and methods used to quantify it. Recently, however, the Institute of Medicine (IOM) estimated that in 2011 there were 100 million individuals with pain in the United States.1 This calculation was made based on a study that used a World Health Organization (WHO) World Mental Health Survey instrument in 10 developed countries and concluded that approximately 37% of adults have common chronic pain conditions.1 It is noteworthy that these estimates do not include either patients with acute pain or children with pain. This increase in the prevalence of pain was paralleled by an increase in the use of prescription analgesics, including opioids. The National Health and Nutrition Examination Survey (NHANES) showed an increase in
a University at Buffalo Department of Anesthesiology, 252 Farber Hall, 3435 Main Street, Buffalo, NY 14214, USA; b Division of Pain Medicine, Department of Anesthesiology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA * Corresponding author. Division of Pain Medicine, Department of Anesthesiology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: [email protected]
Anesthesiology Clin 32 (2014) 923–932 http://dx.doi.org/10.1016/j.anclin.2014.08.009 anesthesiology.theclinics.com 1932-2275/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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Mahathanaruk et al
the number of Americans using opioids from the 1988 to 1994 period (3.2%) to the 2005 to 2008 period (5.7%).1 Of these individuals, 7% were patients aged 65 years or older. Moreover, according to the White House Action Plan, the number of opioid prescriptions dispensed by retail pharmacies increased by 48%, representing 257 million prescriptions between 2000 and 2009.2 Of the 3.61 billion total prescriptions filled in the United States in 2009, 7% were for opioids.3 Clearly, opioid analgesic use among Americans, particularly individuals aged 65 years and older, has increased in the past 12 years. This increase in opioid use can be explained in part by the progressively increasing number of patients experiencing pain due to osteoarthritis, as members of the “baby boomer” generation have reached the age at which they begin to feel the effect of such conditions.4 A more cautious and thoughtful approach to opioid prescribing is further emphasized by the statistic that an estimated 35 million Americans have misused prescription opioids during their lifetimes, which translates to about 13.9% of the US population.5 In 2011, 6.1 million Americans reported that they misused prescription opioids within the past month. Annual increases in prescription opioid misuse have been reported in all age groups, and an estimated 1.8 million people fit the criteria for substance abuse or dependence.5 Moreover, recent pain therapy recommendations for geriatric patients suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors may be associated with an increase in morbidity and mortality from cardiac and gastric causes, resulting in an increased reliance on opioid analgesics for pain treatment in these patients.6 To add an additional layer of concern, some data suggest that opioid therapy may not result in analgesic benefit and improved function in all patients suffering from osteoarthritis.7 This recent systematic review of the use of traditional opioids in pain due to osteoarthritis concluded that this class of analgesics should not be used routinely for osteoarthritis.7 This information suggests that practitioners should be very cautious when prescribing opioid analgesics and that patients receiving this class of analgesics should be continuously evaluated for therapeutic success as judged by pain and functionality improvement, side effects, adverse events, and aberrant behavior.8 Treatment plans that include opioids should include an exit strategy concept,9 whereby patients who do not show improvement in pain intensity and function after a reasonable opioid trial are quickly identified and titrated off opioid analgesics. This approach is not uniformly implemented by clinicians, and many patients who fail to respond to reasonable doses of opioids are placed on ever higher doses, increasing the risk of tolerance, opioid-induced hyperalgesia, and aberrant behaviors (misuse, abuse, and diversion). Opioid-tolerant patients may present a significant problem for the management of postoperative pain, because patients who have received or self-administered opioids for as little as 2 weeks prior to surgery may exhibit signs of opioid tolerance, resulting in a higher perioperative opioid requirement.10 This increased need for opioid medications may result in undertreatment, which can be misinterpreted as opioid craving or aberrant behavior. Moreover, the risk for physiologic withdrawal may also be present if their daily opioid consumption is abruptly decreased either because they failed to report their actual usage pattern or due to reluctance of health providers to match their preoperative dosing. This is particularly important in those patients who abuse opioids, because their daily opioid intake may be significantly greater than those patients taking them for therapeutic purposes. Moreover, the former patient population may also take other illicit drugs that may have effects on the N-methyl-D-aspartate receptor (NMDA) (eg, phencyclidine [PCP]) or combinations of this agent with other illicit drugs such as marijuana.11
Perioperative Pain Management
Recent studies have helped elucidate the cellular mechanisms of opioid tolerance. This information has been useful in defining protocols for the management of patients with a history of high opioid intake so that these patients may also experience adequate postoperative pain control. SUPRASPINAL MECHANISMS OF OPIOIDS
When opioids are administered via the oral or intravenous (IV) route, they bind the opioid receptors in the brainstem at the periaqueductal gray (PAG) region and the rostral ventromedial (RVM) nucleus. Neurons then project to the medullary reticular formation and the locus coeruleus (the major source of norepinephrine cells in the brain), probably through disinhibition, and inhibition of a tonically active inhibitory interneuron. These descending fibers, collectively known as the descending inhibitory pathways, comprise the dorsolateral funiculus in the spinal cord and project to the dorsal horn, where they synapse with the primary afferent neurons. These descending pain modulatory neurons release neurotransmitters in the spinal cord, especially serotonin (5HT) and norepinephrine (NE). The released NE and 5HT act to modulate the release of pain neurotransmitters, namely glutamate, substance P, calcitonin generelated peptide, and brain-derived neurotrophic factor from the first order (presynaptic) neuron, and decrease the activation of the second-order neurons, namely the spinothalamic tract.12 CELLULAR MECHANISMS OF TOLERANCE
Opioid tolerance occurs as a result of quantitative and qualitative functional phenomena. Progressive loss of active receptor sites from prolonged agonist exposure may result in less fewer sites and decreased opioid analgesic action. Prolonged opioid exposure causes desensitization by uncoupling the opioid receptor from the guanosine triphosphate (GTP)-binding subunit, which decreases agonist-binding affinity.13–15 This is because opioids inhibit adenylyl cyclase via a Gi protein mechanism, which decreases the synthesis of cyclic adenosine monophosphate (cAMP) (ie, a reduction in protein kinase A [PKA]-mediated phosphorylation of intracellular proteins).16 This is, in fact, the underlying neurobiological mechanism by which opioids produce analgesia. However, in the face of opioid tolerance, intracellular cAMP returns to control levels, or may even be increased from the baseline. This is thought to be due to the uncoupling of the opioid receptor from the inhibitory G protein system.17 Thus, the desensitization (a qualitative phenomenon) to agonist binding and the loss in the number of opioid receptors (a quantitative phenomenon) result in higher opioid requirements. Trujillo and Akil18 and Elliot and colleagues19 have also implicated the NMDA receptor in the development of acute tolerance. Moreover, Mayer and colleagues20 reported that opioid tolerance was associated with an increase in the second messenger protein kinase C (PKC), the production of nitric oxide (NO), and NO-activated poly-adenosine diphosphate (ADP) ribose synthetase (PARS)21 activation within the superficial laminae of the dorsal horn. PKC has been shown to regulate the NMDA receptor through phosphorylation, which results in removal of a blocking magnesium ion.22 This modulation of the NMDA receptor by PKC likely plays a key role in the development acute opioid tolerance. In fact, opioid tolerance in rodents can be inhibited by NMDA receptor antagonists, for example noncompetitive antagonists such as MK801, dextromethorphan, ketamine, and phencyclidine, and competitive NMDA receptor antagonists such as LY274614, NPC 17742, and LY235959.23 Success has also been achieved with the use of partial glycine agonists (ACPC), glycine antagonists
925
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Mahathanaruk et al
(ACEA-1328), and nitric oxide synthase inhibitors (L-NNA, L-NMMA, and methylene blue.23 A case report further suggests a for the NMDA receptor in opioid tolerance in people. The authors documented not only pain relief, but also a decrease in opioid requirements in a young patient with a history of heroin abuse after a suicide attempt that resulted in multiple traumatic injuries requiring T12-L1 spinal fusion. During the first 27 hours postoperatively, the patient required a total of 12 g of acetaminophen, 0.9 mg of clonidine, the patient’s home dose of 40 mg of methadone, and up to 430 mg/d of IV morphine without improvement in her pain relief (visual analog scale [VAS], 5–7 out of 10). Ketamine infusion was started at 10 mg/kg/min and then was progressively reduced by steps of 2.5 mg/kg/min, over a period of 45 min, to a final dose of 2.5 mg/kg/min. Improvement in pain relief became evident in the first hour after the beginning of the ketamine infusion (VAS, 2 out of 10), and morphine consumption (patient-controlled analgesia) decreased to 160 mg/d. Ketamine was continued at 2.5 mg/kg/min until the fifth postoperative day and then again for 2 more days after the removal of misplaced screws. The VAS pain score remained at 3 out of 10 or below, and no neurologic sequelae were observed. Upon discharge, the patient left the hospital with a substitution treatment of 40 mg/d methadone.24 The potential use of ketamine in this setting is an important finding, as it has been shown that either a single dose or repeated administration of opioids may lead to activation of the NMDA receptor just as effectively as repeated C-fiber stimulation.25,26 Thus, ketamine, as well as other NMDA receptor antagonists, could be useful in the treatment of acute postoperative pain in patients with opioid tolerance, as it not only reverses morphine tolerance and restores morphine effectiveness,27 but it may also prevent the development of acute tolerance to opioids. An alternative, very exciting strategy is the use of benzamide, a selective PARS inhibitor that has been shown to reduce or even prevent the development of opioid analgesic tolerance and the resultant formation of dark neurons in adult male Sprague-Dawley rats.21 Unfortunately, the development of benzamide has not progressed to human trials or usage to date. The need to treat postoperative pain in patients with opioid tolerance is not only a clinical issue with moral and ethical implications, but also a neurobiological one. Uncontrolled pain produces morphologic changes in the receptive field zone of the spinal cord, leading to chronic pain patients using opioids to experience increased levels of postoperative pain that may result in both higher opioid requirements postoperatively and/or uncontrolled pain even in the face of the administration of increasing doses of opioids.28 Thus, blockade of afferent pain signals before the nociceptive stimulus starts may be even more important in the chronic opioid user patient than in the opioid-naı¨ve patient.29 BACKGROUND ON CLINICAL STUDIES
Clinical studies on opioid-tolerant patients are scarce. Moreover, the phenomenon of cross-tolerance between systemic and intraspinal opioids is a controversial issue due to the design of the studies that have evaluated this phenomenon. Although the authors,30–32 as well as others33 have published data to suggest that people experience cross-tolerance between the oral and intraspinal route, others have not shown the same results.34,35 In the studies by Pfeifer35 and Kossmann,34 patients received 510 mg of epidural morphine and were followed for only 24 hours. Pharmacokinetic data show that high concentrations of morphine are achieved in both the lumbar and cervical cerebrospinal fluid (CSF) of patients receiving similar doses of morphine as those used in the studies by Pfeifer and Kossman 68 hours after lumbar epidural
Perioperative Pain Management
injection.36 These high concentrations may saturate the opioid receptors acutely, masking any down regulation. Thus, cross-tolerance may not be evident after large epidural morphine doses, particularly when pain evaluation and opioid utilization analysis is limited to a 24-hour period. As the authors have documented in their studies,30–32 patients with a history of opioid use not only require higher doses of opioids but also more days of therapy compared with opioid-naı¨ve patients. PROTOCOLS FOR PATIENT CARE IN THE POSTOPERATIVE PERIOD
The Division of Pain Medicine at Roswell Park Cancer Institute has used a multimodal protocol for the perioperative care of patients with a history of opioid use and clinical manifestations of opioid tolerance. The authors’ approach includes the use of gabapentinoids and a selective NSAID. Gabapentin is an antiepileptic medication that is known to modulate the release of excitatory neurotransmitters in the dorsal horn of the spinal cord by modulating the voltage-sensitive calcium channel. Gabapentinoids block this voltage-sensitive ion channel, causing a decreased influx of calcium and a reduced release of excitatory neurotransmitters into the synaptic cleft. In addition to this well-known property of gabapentinoids, they also have been shown to have supraspinal effects, enhancing the descending cortical inhibitory pathways by activating the a-2 adrenoceptor.37 Treatment of rats with oral gabapentin increased concentrations of norepinephrine in the CSF and attenuated postoperative hyperalgesia in a dose-dependent fashion. This effect of gabapentin pretreatment was blocked with specific a-2 receptor antagonists.38 Gabapentin has also been studied in people, and a meta-analysis examined 12 randomized controlled studies and reported reduced pain intensity scores (at 4 hours and 24 hours) and reduced opioid consumption in the immediate postoperative period.39 Pregabalin and gabapentin have a similar mechanism of action, but pregabalin has better bioavailability and penetration into the central nervous system. A prospective, randomized, controlled trial of pregabalin (preoperative dose of 300 mg followed by a 2-week tapering dose schedule) showed reductions in perioperative opioid consumption and a reduced incidence of persistent neuropathic pain at 3 months and 6 months.40 Preoperative celecoxib has also been shown to reduce postoperative pain intensity and to reduce postoperative opioid requirements in a dose-dependent fashion.41 The analysis showed that 400 mg of preoperative celecoxib prolonged the time to rescue medication use compared with placebo (6.6 hours vs 2.3 hours), reduced the need for rescue medication in the first 24 hours (63% vs 91%), and did not change the adverse event incidence.41 If there is a contraindication to the implementation of a perioperative regional anesthesia technique, or the site of surgery is not amenable for this type of therapy, IV patient-controlled analgesia (PCA) is utilized. A basal infusion can be calculated based on the patient’s baseline 24-hour opioid utilization. For this purpose, the authors calculate that a daily dose of 90 mg of oral morphine, 60 mg of oral methadone, 45 mg of oral oxycodone, 12 mg of oral hydromorphone, or 25 mg/h of transdermal fentanyl is equivalent to 2 to 3 mg of IV hydromorphone or 2 to 4 mg/h of IV sufentanil.42 IV breakthrough doses of 20% of the basal infusion dose of hydromorphone or sufentanil are also prescribed. The patient is evaluated every 6 hours after the PCA infusion has been started, and the doses of hydromorphone or sufentanil are adjusted to limit the number of breakthrough boluses to 2 to 3 per hour. In patients with cancer-related pain, acetaminophen (APAP) has been shown to decrease opioid requirements and improve pain and wellbeing in patients treated with moderate doses of opioids.43 Moreover, Sinatra and colleagues44 showed that patients undergoing hip and knee
927
928
Mahathanaruk et al
arthroplasties who were treated with IV APAP differed significantly from the placebo group in pain relief from 15 minutes to 6 hours (P0.21 mg/kg) of dexamethasone decreased opioid consumption to a similar extent ( 0.82 [ 1.30 to 0.42] and 0.85 [ 1.24 to 0.46]), respectively, but there was no benefit with low doses (
a
, James Hitt, * MD
DO
a,b,
MD, PhD
a
,
KEYWORDS Opioid tolerance Cellular mechanisms Postoperative pain Opioids Ketamine KEY POINTS Opioid tolerance may occur as early as 2 weeks after therapy is started with opioids. Patients who have received high doses of opioids preoperatively will respond better to therapy with opioids with high intrinsic efficacy, such as sufentanil. Evidence supporting the role of the N-methyl D-aspartate (NMDA) receptor in the development of tolerance suggests the use of NMDA receptor antagonists, such as ketamine, for the management of patients who are not responding to increasing doses of opioids. Epidural techniques with a local anesthetic and higher doses of morphine or sufentanil are effective in the management of postoperative pain in patients with opioid tolerance.
INTRODUCTION
Determining the number of patients with pain in the United States has been a difficult task, because calculations of the prevalence of pain vary depending on definitions of the levels of pain and methods used to quantify it. Recently, however, the Institute of Medicine (IOM) estimated that in 2011 there were 100 million individuals with pain in the United States.1 This calculation was made based on a study that used a World Health Organization (WHO) World Mental Health Survey instrument in 10 developed countries and concluded that approximately 37% of adults have common chronic pain conditions.1 It is noteworthy that these estimates do not include either patients with acute pain or children with pain. This increase in the prevalence of pain was paralleled by an increase in the use of prescription analgesics, including opioids. The National Health and Nutrition Examination Survey (NHANES) showed an increase in
a University at Buffalo Department of Anesthesiology, 252 Farber Hall, 3435 Main Street, Buffalo, NY 14214, USA; b Division of Pain Medicine, Department of Anesthesiology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA * Corresponding author. Division of Pain Medicine, Department of Anesthesiology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: [email protected]
Anesthesiology Clin 32 (2014) 923–932 http://dx.doi.org/10.1016/j.anclin.2014.08.009 anesthesiology.theclinics.com 1932-2275/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
924
Mahathanaruk et al
the number of Americans using opioids from the 1988 to 1994 period (3.2%) to the 2005 to 2008 period (5.7%).1 Of these individuals, 7% were patients aged 65 years or older. Moreover, according to the White House Action Plan, the number of opioid prescriptions dispensed by retail pharmacies increased by 48%, representing 257 million prescriptions between 2000 and 2009.2 Of the 3.61 billion total prescriptions filled in the United States in 2009, 7% were for opioids.3 Clearly, opioid analgesic use among Americans, particularly individuals aged 65 years and older, has increased in the past 12 years. This increase in opioid use can be explained in part by the progressively increasing number of patients experiencing pain due to osteoarthritis, as members of the “baby boomer” generation have reached the age at which they begin to feel the effect of such conditions.4 A more cautious and thoughtful approach to opioid prescribing is further emphasized by the statistic that an estimated 35 million Americans have misused prescription opioids during their lifetimes, which translates to about 13.9% of the US population.5 In 2011, 6.1 million Americans reported that they misused prescription opioids within the past month. Annual increases in prescription opioid misuse have been reported in all age groups, and an estimated 1.8 million people fit the criteria for substance abuse or dependence.5 Moreover, recent pain therapy recommendations for geriatric patients suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors may be associated with an increase in morbidity and mortality from cardiac and gastric causes, resulting in an increased reliance on opioid analgesics for pain treatment in these patients.6 To add an additional layer of concern, some data suggest that opioid therapy may not result in analgesic benefit and improved function in all patients suffering from osteoarthritis.7 This recent systematic review of the use of traditional opioids in pain due to osteoarthritis concluded that this class of analgesics should not be used routinely for osteoarthritis.7 This information suggests that practitioners should be very cautious when prescribing opioid analgesics and that patients receiving this class of analgesics should be continuously evaluated for therapeutic success as judged by pain and functionality improvement, side effects, adverse events, and aberrant behavior.8 Treatment plans that include opioids should include an exit strategy concept,9 whereby patients who do not show improvement in pain intensity and function after a reasonable opioid trial are quickly identified and titrated off opioid analgesics. This approach is not uniformly implemented by clinicians, and many patients who fail to respond to reasonable doses of opioids are placed on ever higher doses, increasing the risk of tolerance, opioid-induced hyperalgesia, and aberrant behaviors (misuse, abuse, and diversion). Opioid-tolerant patients may present a significant problem for the management of postoperative pain, because patients who have received or self-administered opioids for as little as 2 weeks prior to surgery may exhibit signs of opioid tolerance, resulting in a higher perioperative opioid requirement.10 This increased need for opioid medications may result in undertreatment, which can be misinterpreted as opioid craving or aberrant behavior. Moreover, the risk for physiologic withdrawal may also be present if their daily opioid consumption is abruptly decreased either because they failed to report their actual usage pattern or due to reluctance of health providers to match their preoperative dosing. This is particularly important in those patients who abuse opioids, because their daily opioid intake may be significantly greater than those patients taking them for therapeutic purposes. Moreover, the former patient population may also take other illicit drugs that may have effects on the N-methyl-D-aspartate receptor (NMDA) (eg, phencyclidine [PCP]) or combinations of this agent with other illicit drugs such as marijuana.11
Perioperative Pain Management
Recent studies have helped elucidate the cellular mechanisms of opioid tolerance. This information has been useful in defining protocols for the management of patients with a history of high opioid intake so that these patients may also experience adequate postoperative pain control. SUPRASPINAL MECHANISMS OF OPIOIDS
When opioids are administered via the oral or intravenous (IV) route, they bind the opioid receptors in the brainstem at the periaqueductal gray (PAG) region and the rostral ventromedial (RVM) nucleus. Neurons then project to the medullary reticular formation and the locus coeruleus (the major source of norepinephrine cells in the brain), probably through disinhibition, and inhibition of a tonically active inhibitory interneuron. These descending fibers, collectively known as the descending inhibitory pathways, comprise the dorsolateral funiculus in the spinal cord and project to the dorsal horn, where they synapse with the primary afferent neurons. These descending pain modulatory neurons release neurotransmitters in the spinal cord, especially serotonin (5HT) and norepinephrine (NE). The released NE and 5HT act to modulate the release of pain neurotransmitters, namely glutamate, substance P, calcitonin generelated peptide, and brain-derived neurotrophic factor from the first order (presynaptic) neuron, and decrease the activation of the second-order neurons, namely the spinothalamic tract.12 CELLULAR MECHANISMS OF TOLERANCE
Opioid tolerance occurs as a result of quantitative and qualitative functional phenomena. Progressive loss of active receptor sites from prolonged agonist exposure may result in less fewer sites and decreased opioid analgesic action. Prolonged opioid exposure causes desensitization by uncoupling the opioid receptor from the guanosine triphosphate (GTP)-binding subunit, which decreases agonist-binding affinity.13–15 This is because opioids inhibit adenylyl cyclase via a Gi protein mechanism, which decreases the synthesis of cyclic adenosine monophosphate (cAMP) (ie, a reduction in protein kinase A [PKA]-mediated phosphorylation of intracellular proteins).16 This is, in fact, the underlying neurobiological mechanism by which opioids produce analgesia. However, in the face of opioid tolerance, intracellular cAMP returns to control levels, or may even be increased from the baseline. This is thought to be due to the uncoupling of the opioid receptor from the inhibitory G protein system.17 Thus, the desensitization (a qualitative phenomenon) to agonist binding and the loss in the number of opioid receptors (a quantitative phenomenon) result in higher opioid requirements. Trujillo and Akil18 and Elliot and colleagues19 have also implicated the NMDA receptor in the development of acute tolerance. Moreover, Mayer and colleagues20 reported that opioid tolerance was associated with an increase in the second messenger protein kinase C (PKC), the production of nitric oxide (NO), and NO-activated poly-adenosine diphosphate (ADP) ribose synthetase (PARS)21 activation within the superficial laminae of the dorsal horn. PKC has been shown to regulate the NMDA receptor through phosphorylation, which results in removal of a blocking magnesium ion.22 This modulation of the NMDA receptor by PKC likely plays a key role in the development acute opioid tolerance. In fact, opioid tolerance in rodents can be inhibited by NMDA receptor antagonists, for example noncompetitive antagonists such as MK801, dextromethorphan, ketamine, and phencyclidine, and competitive NMDA receptor antagonists such as LY274614, NPC 17742, and LY235959.23 Success has also been achieved with the use of partial glycine agonists (ACPC), glycine antagonists
925
926
Mahathanaruk et al
(ACEA-1328), and nitric oxide synthase inhibitors (L-NNA, L-NMMA, and methylene blue.23 A case report further suggests a for the NMDA receptor in opioid tolerance in people. The authors documented not only pain relief, but also a decrease in opioid requirements in a young patient with a history of heroin abuse after a suicide attempt that resulted in multiple traumatic injuries requiring T12-L1 spinal fusion. During the first 27 hours postoperatively, the patient required a total of 12 g of acetaminophen, 0.9 mg of clonidine, the patient’s home dose of 40 mg of methadone, and up to 430 mg/d of IV morphine without improvement in her pain relief (visual analog scale [VAS], 5–7 out of 10). Ketamine infusion was started at 10 mg/kg/min and then was progressively reduced by steps of 2.5 mg/kg/min, over a period of 45 min, to a final dose of 2.5 mg/kg/min. Improvement in pain relief became evident in the first hour after the beginning of the ketamine infusion (VAS, 2 out of 10), and morphine consumption (patient-controlled analgesia) decreased to 160 mg/d. Ketamine was continued at 2.5 mg/kg/min until the fifth postoperative day and then again for 2 more days after the removal of misplaced screws. The VAS pain score remained at 3 out of 10 or below, and no neurologic sequelae were observed. Upon discharge, the patient left the hospital with a substitution treatment of 40 mg/d methadone.24 The potential use of ketamine in this setting is an important finding, as it has been shown that either a single dose or repeated administration of opioids may lead to activation of the NMDA receptor just as effectively as repeated C-fiber stimulation.25,26 Thus, ketamine, as well as other NMDA receptor antagonists, could be useful in the treatment of acute postoperative pain in patients with opioid tolerance, as it not only reverses morphine tolerance and restores morphine effectiveness,27 but it may also prevent the development of acute tolerance to opioids. An alternative, very exciting strategy is the use of benzamide, a selective PARS inhibitor that has been shown to reduce or even prevent the development of opioid analgesic tolerance and the resultant formation of dark neurons in adult male Sprague-Dawley rats.21 Unfortunately, the development of benzamide has not progressed to human trials or usage to date. The need to treat postoperative pain in patients with opioid tolerance is not only a clinical issue with moral and ethical implications, but also a neurobiological one. Uncontrolled pain produces morphologic changes in the receptive field zone of the spinal cord, leading to chronic pain patients using opioids to experience increased levels of postoperative pain that may result in both higher opioid requirements postoperatively and/or uncontrolled pain even in the face of the administration of increasing doses of opioids.28 Thus, blockade of afferent pain signals before the nociceptive stimulus starts may be even more important in the chronic opioid user patient than in the opioid-naı¨ve patient.29 BACKGROUND ON CLINICAL STUDIES
Clinical studies on opioid-tolerant patients are scarce. Moreover, the phenomenon of cross-tolerance between systemic and intraspinal opioids is a controversial issue due to the design of the studies that have evaluated this phenomenon. Although the authors,30–32 as well as others33 have published data to suggest that people experience cross-tolerance between the oral and intraspinal route, others have not shown the same results.34,35 In the studies by Pfeifer35 and Kossmann,34 patients received 510 mg of epidural morphine and were followed for only 24 hours. Pharmacokinetic data show that high concentrations of morphine are achieved in both the lumbar and cervical cerebrospinal fluid (CSF) of patients receiving similar doses of morphine as those used in the studies by Pfeifer and Kossman 68 hours after lumbar epidural
Perioperative Pain Management
injection.36 These high concentrations may saturate the opioid receptors acutely, masking any down regulation. Thus, cross-tolerance may not be evident after large epidural morphine doses, particularly when pain evaluation and opioid utilization analysis is limited to a 24-hour period. As the authors have documented in their studies,30–32 patients with a history of opioid use not only require higher doses of opioids but also more days of therapy compared with opioid-naı¨ve patients. PROTOCOLS FOR PATIENT CARE IN THE POSTOPERATIVE PERIOD
The Division of Pain Medicine at Roswell Park Cancer Institute has used a multimodal protocol for the perioperative care of patients with a history of opioid use and clinical manifestations of opioid tolerance. The authors’ approach includes the use of gabapentinoids and a selective NSAID. Gabapentin is an antiepileptic medication that is known to modulate the release of excitatory neurotransmitters in the dorsal horn of the spinal cord by modulating the voltage-sensitive calcium channel. Gabapentinoids block this voltage-sensitive ion channel, causing a decreased influx of calcium and a reduced release of excitatory neurotransmitters into the synaptic cleft. In addition to this well-known property of gabapentinoids, they also have been shown to have supraspinal effects, enhancing the descending cortical inhibitory pathways by activating the a-2 adrenoceptor.37 Treatment of rats with oral gabapentin increased concentrations of norepinephrine in the CSF and attenuated postoperative hyperalgesia in a dose-dependent fashion. This effect of gabapentin pretreatment was blocked with specific a-2 receptor antagonists.38 Gabapentin has also been studied in people, and a meta-analysis examined 12 randomized controlled studies and reported reduced pain intensity scores (at 4 hours and 24 hours) and reduced opioid consumption in the immediate postoperative period.39 Pregabalin and gabapentin have a similar mechanism of action, but pregabalin has better bioavailability and penetration into the central nervous system. A prospective, randomized, controlled trial of pregabalin (preoperative dose of 300 mg followed by a 2-week tapering dose schedule) showed reductions in perioperative opioid consumption and a reduced incidence of persistent neuropathic pain at 3 months and 6 months.40 Preoperative celecoxib has also been shown to reduce postoperative pain intensity and to reduce postoperative opioid requirements in a dose-dependent fashion.41 The analysis showed that 400 mg of preoperative celecoxib prolonged the time to rescue medication use compared with placebo (6.6 hours vs 2.3 hours), reduced the need for rescue medication in the first 24 hours (63% vs 91%), and did not change the adverse event incidence.41 If there is a contraindication to the implementation of a perioperative regional anesthesia technique, or the site of surgery is not amenable for this type of therapy, IV patient-controlled analgesia (PCA) is utilized. A basal infusion can be calculated based on the patient’s baseline 24-hour opioid utilization. For this purpose, the authors calculate that a daily dose of 90 mg of oral morphine, 60 mg of oral methadone, 45 mg of oral oxycodone, 12 mg of oral hydromorphone, or 25 mg/h of transdermal fentanyl is equivalent to 2 to 3 mg of IV hydromorphone or 2 to 4 mg/h of IV sufentanil.42 IV breakthrough doses of 20% of the basal infusion dose of hydromorphone or sufentanil are also prescribed. The patient is evaluated every 6 hours after the PCA infusion has been started, and the doses of hydromorphone or sufentanil are adjusted to limit the number of breakthrough boluses to 2 to 3 per hour. In patients with cancer-related pain, acetaminophen (APAP) has been shown to decrease opioid requirements and improve pain and wellbeing in patients treated with moderate doses of opioids.43 Moreover, Sinatra and colleagues44 showed that patients undergoing hip and knee
927
928
Mahathanaruk et al
arthroplasties who were treated with IV APAP differed significantly from the placebo group in pain relief from 15 minutes to 6 hours (P0.21 mg/kg) of dexamethasone decreased opioid consumption to a similar extent ( 0.82 [ 1.30 to 0.42] and 0.85 [ 1.24 to 0.46]), respectively, but there was no benefit with low doses (
