Opioid Tolerance in Critical Illness

Home , Opioid rotation, Opioid withdrawal, Pain tolerance

The new england journal of medicine

Review Article

Julie R. Ingelfinger, M.D., Editor Opioid Tolerance in Critical Illness

J.A. Jeevendra Martyn, M.D., Jianren Mao, M.D., Ph.D., and Edward A. Bittner, M.D., Ph.D.

ritically ill patients in the intensive care unit (ICU) require From the Department of Anesthesiology, urgent and complex interventions that expose them to twice as many Critical Care, and Pain Medicine, Massa- 1 chusetts General Hospital, Shriners Hos- medications as the number encountered on general medical wards. Opioids pital for Children, and Harvard Medical C School — all in Boston. Address reprint have been the mainstay of pain control and sedation in the ICU, despite substantial adverse consequences that continue to plague their use.2 Long-term opioid use leads requests to Dr. Martyn at the Department of Anesthesia, Critical Care, and Pain to tolerance (i.e., less susceptibility to the effects of the opioid, which can result Medicine, Massachusetts General Hospi- in a need for higher and more frequent doses to achieve the same analgesic effect), tal, 51 Blossom St., Rm. 206, Boston, MA physical dependence, and opioid-withdrawal symptoms during weaning and con- 02114, or at jmartyn@mgh.harvard.edu. tributes to the development of chronic pain later and opioid-induced hyperalgesia N Engl J Med 2019;380:365-78. (a paradoxical hypersensitivity to pain).3-5 Opioid tolerance can be seen during DOI: 10.1056/NEJMra1800222 Copyright © 2019 Massachusetts Medical Society. all types of critical illnesses; the magnitude, however, seems exaggerated in patients who have had major trauma (e.g., burn injury), in patients requiring prolonged mechanical ventilation, and in pediatric patients.6-8 The development of tolerance is due in part to the large doses needed to control pain in these critically ill patients. However, the inflammatory response to opioids themselves, seen in patients in the medical ICU and those in the surgical ICU, plays an important role in tolerance. This review describes the indications for opioid therapy in patients in the ICU, opioid signal transduction during short-term and long-term use, the role of inflammation and opioid-mediated innate immune responses in tolerance, and current and potential mitigation strategies for opioid tolerance. Sedative–anxio- lytic drugs, which are adjuncts to analgesia, are not within the scope of this review.

Tissue and Spinal Cord Responses to Injury Most patients in the ICU have some form of tissue injury that causes local and often systemic inflammatory responses. These responses launch a cascade of events, including release of proinflammatory substances and activation of spinal cord N-methyl-d-aspartate (NMDA) receptors (Fig. 1).9 Concomitantly, endogenous antinociceptive mechanisms also become operative. Centrally, the inhibitory opi- oidergic, serotonergic, and noradrenergic pathways are activated, which can reduce nociception. Leukocytes released at the injury site secrete endogenous opioid peptides that interact with the injury-induced opioid receptors that are up-regulated along nerve terminals and reduce pain.10 However, injury-induced reduction of inhibitory control over pain by means of glycine and γ-aminobutyric acid receptors enhances central sensitization.11 These local and central changes lead to exaggerated basal and procedural pain, referred to as hyperalgesia (exaggerated responses to painful stimuli such as a pinprick) and allodynia (pain responses to nonpainful stimuli such as touch).9,10 These changes are consistent with the body’s need to produce essential warning signs and withdrawal responses during nociception.

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Anterior cingulate cortex

Cortex

Enhanced Insula neuronal excitability Peripheral Thalamus sensory neuron

Hypothalamus Interneuron Second-order Glia in Amygdala neuron proinflammatory state Locus coeruleus

Periaqueductal Induced release gray matter of chemokines and cytokines

Spinal cord

Immune cells (e.g., macrophages Dorsal-root BLOOD VESSEL ganglion and lymphocytes)

Infiltration of immune cells Peripheral sensory neuron Opioid Peripheral-tissue peptides injury

Nerve-membrane Release of chemokines, sensitization purinergic substances, opioid peptides Opioid receptor SITE OF INJURY up-regulation Pain pathways Transmission from peripheral-tissue injury (ascending tract) Modulation to periphery (descending tract)

Figure 1. Sites of Action of Opioids and Effects of Injury on Modulation of Nociception. Sites of action of opioids for pain relief include the brain (cortex, thalamus, hypothalamus, locus coeruleus, amygdala, and periaqueductal gray matter), spinal cord, and peripheral-nerve membrane. Transmission of pain sensation (nociception) from the peripheral-tissue injury to the central nervous system occurs through the ascending spinothalamic tract to the thalamus and then to the somatosensory cortex (orange). Descending inhibitory tracts (blue) from the brain and other regions, including the rostroventral medulla, modulate nociception. Nociception can be amplified by dorsal-root ganglia and changes in the dorsal horn of the spinal cord (top inset). The afferent neurons are sensitized by the sprouting of new axons around the cell bodies of dorsal-root ganglia, as well as by infiltrating macrophages, which release inflammatory substances. Neuron projections from dorsal-root ganglia to the dorsal horn amplify the pain by the release of other pro-nociceptive mediators (e.g., calcitonin gene–related peptide), activation of N-methyl-d-aspartate receptors, and the increase in glutamate levels. Second-order neurons transmit these signals upstream to the brain (orange). Injury to tissues (bottom inset) results in local and often systemic inflammatory responses, which prime the peripheral sensory neurons and dorsal-root ganglia to exaggerated nociception by up-regulation or modulation of ligand-gated and voltage-gated ion channels. Mu-opioid receptors are newly expressed throughout the nerve membrane. Extravasated circulating leukocytes (e.g., macrophages and lymphocytes) release proinflammatory mediators, further sensitizing the neurons to pain. These leukocytes also release antinociceptive endogenous opioid peptides, which bind to the up-regulated opioid receptors on the nerve, attenuating pain.

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Indications for Opioid Use demoralization, and is a risk factor for subse- and Consequences quent post-traumatic stress disorder.22,23 Both of Inadequate Analgesia patients and family members report pain as the most stressful experience during their time in the Moderate-to-severe pain, which generally accom- ICU and after discharge.24 Some patients, particu- panies critical illness, is often distressing and larly those who have undergone major surgery, frequently underrecognized.12 The underlying ill- have persistent pain after discharge from the ICU ness or surgery, placement of penetrating inva- that contributes to a reduced quality of life.25 sive tubes or catheters, and other routine inten- Risk factors for the development of persistent sive care procedures are recognized sources of pain are poorly controlled, high-intensity, acute pain.13 Patients in the ICU often cannot commu- pain; preoperative pain or anxiety; long-term nicate about their pain because of the combined opioid use; a relatively long ICU stay; and major effects of endotracheal intubation, sedation, neu- surgery.26 romuscular blockers, altered mental status, physical restraints, and other disease-related compli- Side Effects of Opioid Therapy cations. Therefore, it is imperative for caregivers to assess pain severity reliably through the use Side effects of opioid therapy are categorized as of standardized pain-assessment tools validated either peripheral (e.g., constipation, urinary reten- for use in the ICU.14 Although opioids represent tion, and bronchospasm) or central (e.g., over the primary pharmacologic therapy for moderate- sedation, respiratory depression, hypotension, to-severe pain, there are numerous other indica- nausea, truncal rigidity, and cough suppression). tions for opioid use, including sedation (Table S1 Opioid-induced vasodilatation and hypotension in the Supplementary Appendix, available with the can increase fluid requirements after trauma.27 full text of this article at NEJM.org). Analgesia- In contrast, vasodilatation can be beneficial dur- first sedation (also known as analgosedation) ing disease-, anxiety-, and pain-induced hyper- is a strategy for managing pain and discomfort tension. The respiratory and cough-suppressive that relies on analgesic agents first, before seda- effects can also be beneficial in the ICU setting tives such as benzodiazepines. Analgesia-first (Table S1 in the Supplementary Appendix). Other sedation results in improved outcomes, includ- detrimental effects that are often overlooked in- ing fewer days on a ventilator, as compared with clude inappropriate immune modulation through combined analgesic–sedative regimens,15,16 and neuroendocrine pathways or direct effects has been recommended in clinical practice guide- through receptors that are present on immuno- lines for the ICU.2 cytes.28,29 That opioids impair immune function Unrelieved pain affects physiological and psy- has aroused concern during the care of patients chological function and is associated with both with cancer in the ICU,30 but the role of opioids short- and long-term consequences, most of which in cancer recurrence is far from clear.31 The are due to exacerbation of the stress responses negative effect of intolerable pain on immune induced by catecholamines, glucocorticoids, and function is well documented; however, the more antidiuretic-hormone release.17,18 Stress activation immediate concern is the alleviation of pain and of the hypothalamic–pituitary–adrenal axis and suffering and avoidance of their deleterious con- the renin–angiotensin–aldosterone axis can lead sequences.31 to fluid retention, generalized edema, and hyper- Opioids can contribute to delirium, poor tension. Other adverse consequences of stress sleep quality, and unintended sedation; this is include impaired tissue oxygenation, wound heal- particularly true in patients in the ICU, because ing, and immunity17,18; increased myocardial and of altered drug clearance, concomitant drug total oxygen consumption and muscle catabo- therapy, and central metabolic dysfunction. The lism; and neuroinflammatory priming.19-22 Unre- strategy of analgesia-first sedation in trauma and lieved pain has psychological consequences, in- burn populations in the ICU has been associated cluding anxiety, depression, impaired sleep, and with a reduced risk of delirium,32 whereas opioids

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in combination with benzodiazepines, particu- permeability of the P-glycoprotein–controlled larly in the elderly, have been associated with an blood–brain barrier, reducing the efficacy of some increased risk of delirium.33 Conversely, com- opioids. plete lack of sedation can result in more cases of 34 delirium than sedation with daily interruption, Pharmacodynamic Components although the lack of sedation may simply result of Opioid Tolerance in more cases of delirium being identified. Metabolite Contributions Pharmacokinetic Components Opioid metabolism can result in metabolites of Opioid Tolerance that enhance or antagonize the analgesic effect or have no pharmacologic effect. In the case of Pharmacokinetic studies of opioid use during morphine, the parent drug is active, although its critical illness are limited. Autoinduction of metabolites have contrasting effects: normor- cytochrome P-450 enzyme and enhanced drug phine is inactive, and morphine-6-glucuronide is clearance do not occur with long-term opioid more potent than morphine, whereas morphine- use and therefore cannot explain dose escalation 3-glucuronide is considered to have hyperalgesic (i.e., the need to increase the dose to maintain effects that oppose the analgesic effects of mor- equipotent analgesic effects).35 However, cyto- phine and of morphine-6-glucuronide.40 During chrome P-450 inducers increase clearance of renal failure or dose escalation of morphine (or some drugs (e.g., methadone), resulting in sub- hydromorphone), as seen in the ICU, markedly therapeutic plasma levels, which may be mis increased morphine-3-glucuronide levels can interpreted as pharmacodynamic tolerance (i.e., counteract the analgesic potency of morphine tolerance due to changes in sites of action).36 and morphine-6-glucuronide.40 The hyperalgesic Similarly, during the hyperdynamic phase of effects of morphine-3-glucuronide are simulta- trauma and compensated sepsis, the enhanced neously opioid receptor–dependent and opioid elimination kinetics of “flow dependent” drugs receptor–independent, as shown in a study in- (e.g., fentanyl and morphine) could cause dose volving knockout mice41 and studies involving escalation.37 naloxone.28 The receptor-independent effects are Inflammation increases the expression of mediated by activation of both microglia toll-like 28 α1-acid glycoprotein, an acute-phase reactant pro- receptors and NMDA receptors. The magnitude tein, which binds some drugs. Since methadone of the contribution of morphine-3-glucuronide

has a high affinity for α1-acid glycoprotein, there to a deficiency of analgesia is controversial. is a decreased free fraction of methadone in the plasma.36,38 Despite minimal binding of fentanyl Opioid-Receptor Signaling during 36,38 Short-Term and Long-Term Opioid Use and morphine to α1-acid glycoprotein, tolerance still occurs. Thus, increased glycoprotein Most clinically used opioids act through mu- binding contributes minimally to opioid dose opioid receptors, which belong to the G-protein– escalation. The P-glycoprotein transporter that is coupled receptors family, and transmit downstream present in brain capillaries controls drug efflux signals through heterotrimetric Gαβγ-proteins. from the central nervous system. Long-term ad- When an opioid binds to the mu-opioid receptor, ministration of oxycodone, morphine, and alfen- the receptor-associated Gαβγ-protein dissociates tanil, but not methadone, up-regulates P-glyco- into Gα and Gβγ subunits. Concomitantly, the protein expression, causing decreased drug mu-opioid receptor becomes phosphorylated by penetration in the central nervous system and G-protein–coupled receptor kinase,3 which re- attenuated analgesia.36 Similarly, tumor necrosis cruits β-arrestin protein and binds it to the recep- factor α increases expression and activity of tor, sometimes leading to receptor internalization P‑glycoprotein.39 Together, these observations (Fig. 2). These processes lead to desensitization imply that critical illness–related cytokine re- (conversion from a responsive-receptor state to a lease and opioid administration may tighten the decreased-signaling state), which partly explains

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A Short-Term Treatment B Long-Term Treatment

EXTRACELLULAR Opioid

Opioid Opioid Desensitized receptor Ca2+ opioid receptor

Gβ P P Gα GRK P GRK P Gγ K+ P P Adenylate β-arrestin β-arrestin G protein cyclase Internalization Activation Recycling

β-arrestin

Reduced effect P P P Receptor degradation

P Reduced P Downstream P downstream signaling signaling Increased levels of adenylate cyclase, β-arrestin protein kinase C, protein kinase A, and NMDA

Tolerance and Analgesic effects Hyperalgesia insufficient analgesia

INTRACELLULAR

Figure 2. Opioid-Receptor Signaling during Short-Term Therapy and Long-Term Therapy. In short-term treatment, the binding of an opioid to its receptor (Panel A) causes downstream G-protein–coupled receptors, composed of Gαβγ subunits, to dissociate into Gα and Gβγ subunits. The dissociated G-protein subunits inhibit voltage-gated calcium channels by means of reduced transmitter release, activate inward-rectifying potassium channels (causing hyperpolarization of the membrane), and inhibit downstream adenylate cyclase enzymes, decreasing cyclic adenosine monophosphate levels. These events reduce excitability and nociception and result in analgesic effects. When an opioid binds to its receptor, it becomes an immediate substrate for phosphorylation by G-protein–coupled receptor kinase (GRK), which leads to recruitment and binding of β-arrestin protein to the receptor. This results in desensitization and sometimes endocytosis of the receptor; each of these events decreases the responses to opioids, inducing tolerance and insufficient analgesia. Opioid-receptor signaling terminates when the opioid is displaced from the receptor. After the stimulus (i.e., the agonist) is withdrawn, the desensitized receptor recovers over time (minutes to hours, depending on the agonist), Gα rebinds to Gβγ and once again forms Gαβγ, and the endocytosed receptor is reexpressed on the plasma membrane in a resensitized state. In long-term treatment (Panel B), escalating doses of opioids and concomitant persistent activation of the receptor lead to aggravation of the tolerance by receptor-dependent and receptor-independent intracellular signaling changes, which include up-regulation of the anti- opioid (pro-nociceptive) signaling pathways. The sustained β-arrestin binding to the receptor often leads to internalization, degradation, and down-regulation of membrane receptor number, further decreasing response to opioids. Receptor down-regulation occurs with some opioids (e.g., fentanyl) but not others (e.g., morphine). Phosphorylation by other kinases (e.g., protein kinases A and C), increased adenylate cyclase activity (with increased cyclic adenosine monophosphate levels), activation of N-methyl-d-aspartate (NMDA) receptor, and down-regulation of glutamate receptors (increased glutamate levels) are all implicated in the imbalance between pro-nociceptive and antinociceptive pathways, which results in attenuated analgesic effects, aggravated pain behaviors, increased tolerance, and opioid- induced hyperalgesia.

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acute tolerance.42 The desensitized receptors re- tion of analgesia, increased tolerance, and opioid- cover over time (minutes to hours, depending on induced hyperalgesia. the agonist) after the stimulus has been withdrawn, and the endocytosed receptors are re- Innate Immune Responses cycled to the plasma membrane in a resensitized in the Central Nervous System state. Long-term opioid use leads to exaggerated Injury- or inflammation-related pain can become opioid tolerance, which is characterized by esca- aggravated or long-lasting, features that cannot lating dose requirements to maintain analgesia, be explained by neuronal activation alone. In the and subsequently contributes to opioid-induced central nervous system, the glia (astroglia and hyperalgesia. Tolerance to the analgesic effects microglia) play a major role in central sensitiza- of opioids (and euphoria) develops faster than tion.3,28 Persistent activation of the dorsal horn tolerance to respiratory depression, which ex- of the spinal cord by the injury-induced barrage plains the increased risk of hypoventilation with of nociceptive input and the associated release of dose escalation during tolerance. Both duration damage-associated molecular patterns (DAMPs) and dose appear to affect the development of activate glia, which release inflammatory me- tolerance; infusions induce tolerance faster than diators that enhance the excitability of adjacent intermittent therapy.43 The potent opioid remi- neurons (Fig. 3).48 Although acute stress results fentanil induces tolerance more quickly than the in stress-induced analgesia, persistent sympa- less potent meperidine. Persons with substance- thetic overactivity leads to stress-induced hyper- use disorder who are receiving maintenance algesia.49 Repetitive stress can also lead to cen- therapy with methadone or buprenorphine are tral and peripheral leukocyte priming and release observed to have opioid-induced hyperalgesia, of inflammatory mediators,21,22,28 causing exag- which is absent in those who are not receiving gerated pain behaviors.50,51 The stress-induced opioids.44 catecholamine surge releases immunocytes, in- Prominent signaling changes develop during cluding phenotypical inflammatory M1 mono- the continued presence of exogenous or endoge- cytes (as opposed to antiinflammatory M2 nous ligands because the central nervous system monocytes). This release compounds inflamma- has intrinsic mechanisms to prevent overstimu- tory-mediator responses.52 Stress-associated glu- lation or understimulation. The typical response cocorticoid release can function as DAMPs, pro- of G-protein–coupled receptors to chronic ago- moting activation of the glia.22,53 Superimposition nists is receptor internalization and down-regula- of bacterial inflammation and release of patho- tion together with intracellular signaling chang- gen-associated molecular patterns further aug- es, leading to decreased analgesia.45,46 Additional ment leukocyte-related toll-like receptor activa- cellular adaptations during long-term opioid tion and cytokine release, which can lead to use include induction of systems that attenuate nociceptor sensitization.54 Systemic inflammatory analgesic effects. These systems elicit adaptive diseases can also lead to neuroinflammation,55,56 responses to persistent opioid-induced inhibitory with selective breakdown of the blood–brain bar- downstream signaling.45 The adaptations encom- rier to inflammatory M1 monocytes, which fur- pass the activation of NMDA receptors, down- ther exaggerate neuroinflammation, modulating regulation of glutamate transporter, conversion both mood and nociception.20-22 from a state of decreased to a state of increased Opioids, even in the absence of systemic in- adenylate cyclase activity3 (Fig. 2), and increased flammation, cause neuroinflammation by activat- transduction through other nociception chan- ing toll-like receptors in glia and other immune nels.3,4 The formation of opioid-receptor hetero cells that permeate the blood–brain barrier.3,28,52 dimers that bind opioids has also been impli- The cytokine release from activated immune cells cated in opioid-induced hyperalgesia.47 Thus, leads to exaggerated nociception; antagonism of activation of the analgesia-attenuating system at toll-like receptors or their knockout in mice abro- multiple sites during long-term opioid therapy gates the hyperalgesia.28,46 Similarly, specific an- leads to an imbalance between pro-nociceptive tagonists of putative inflammatory mediators and antinociceptive pathways, resulting in reduc- (e.g., interleukin-1β) attenuate hyperalgesia. Other

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Opioids Injury or infection (e.g., PAMPs, DAMPs)

TLR4 Activation of pathways (NF-κB, ERK, p38) Activation of pathways (NF-κB, JNK) Activated microglia Reactive astroglia cell

• Chemokines • Purinergic substances Induced release of • Cytokines • CGRP proinflammatory • ATP • Glutamate substances • Nitric oxide • Inflammasome

Inhibited glutamate transporter

SECOND-ORDER NEURON PERIPHERAL SENSORY NEURON

Central sensitization Peripheral sensitization Glutamate receptor and hyperalgesia Glutamate accumulation and binding

Figure 3. Cross Talk between Neuronal and Non-Neuronal Cells during Injury and Inflammation. Non-neuronal cells (e.g., astroglia and microglia) can modify pain perception through the production and release of pro-nociceptive mediators. Opioids, injury, cancer, chemotherapy, stress, and other causes of sterile or microbial inflammation can induce the release of damage-associated molecular pathogens (DAMPs) and pathogen-associated molecular patterns (PAMPs). DAMPs and PAMPs cause inflammasome release, which leads to the transition of microglia to an active state and astroglia to a reactive state. The “switched on” glia release inflammatory substances through activation of toll-like receptors (TLRs) and their downstream signaling proteins (Jun N-termi- nal kinase [JNK], nuclear factor κB [NF-κB], extracellular signal-regulated kinase [ERK], and p38 mitogen-activated protein kinase [p38]). Peripheral macrophages infiltrate the central nervous system because of selective breakdown of the blood–brain barrier, and they contribute to the inflammatory responses. The released proinflammatory substances (inflammasomes, ATP, and calcitonin gene–related peptide [CGRP]) sensitize the pre- and postsynaptic central neurons, leading to a vicious cycle characterized by the need for more opioids and more sensitization and more glia inflammation. The end result is a marked exaggeration of nociception, severe opioid tolerance, peripheral and central sensitization, and opioid-induced hyperalgesia.

factors that contribute to central sensitization and use of opioids) that can lead to activation of include age, sex, and concomitant inflammatory the glia in patients in the ICU and can exaggerate conditions (e.g., those caused by cancer and pain behaviors, tolerance, and opioid-induced hy- chemotherapy). Notably, greater opioid tolerance peralgesia, creating a vicious cycle of dose es- seems to develop in pediatric patients7,8; this calation and worsening pain (Figs. 3 and 4).50,51 may be related to less inhibition in the dorsal Thus, tolerance appears to reflect a desensitiza- horn and more facilitation by the rostroventral tion of receptor-mediated antinociceptive path- medulla than in adults.57 Thus, there are multi- ways, whereas opioid-induced hyperalgesia in- ple factors (e.g., inflammation, infection, stress, volves induction of pro-nociceptive glial–neuronal

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A Short-Term Treatment B Long-Term Treatment Dose Level

Analgesia

Normal

Hyperalgesia Tolerance to Pain

Dose Frequency Dose Frequency

Typical dose level and frequency Typical dose Typical tolerance to pain Dose level and frequency in cases of Dose in cases of Pain tolerance in cases of injury or inflammation injury or inflammation injury or inflammation

Figure 4. Short-Term and Long-Term Opioid Therapy and Effects of Inflammation or Injury on Pain Threshold. In Panel A, short-term opioid administration (light blue) provides sufficient analgesia with no or minimal opioid tolerance (pink). In cases of inflammation or injury, as compared with uninjured states, the analgesic potency of the opioid (i.e., the threshold for pain) is decreased, resulting in hyperalgesia; short-term administration of higher doses (dark blue) provides sufficient analgesia but for a shorter duration (purple), requiring more frequent doses (dark blue). Panel B shows that in an uninjured patient with long-term exposure to opioids, the analgesic potency decreases (pink) and the duration of opioid-induced analgesia also decreases with each dose, requiring an increase in dose frequency. Long-term opioid administration will result in induction of antinociceptive mechanisms, resulting in hyperalgesia; even higher doses of opioids (light blue) do not restore complete analgesia (pink). During opioid-induced hyperalgesia in an injured patient, exaggerated pain sensitivity occurs at the injured and uninjured areas. Any cause of systemic inflammation or neuroinflammation (e.g., infection, cancer, diabetes, stress, or chemotherapy) decreases the analgesic potency and the duration of analgesic effects and leads to earlier development of opioid-induced hyperalgesia; even high doses (dark blue) result in minimal analgesia (purple) because of decreased analgesic potency.

pathways. Clinical observations confirm that and S3 in the Supplementary Appendix). Patients hyperalgesia in persons with critical illnesses who have not previously received opioids usually can be more profound than hyperalgesia in the have a good response to opioid analgesics, general population.6,7 Further understanding of whereas those with prolonged exposure (illicit or this phenomenon should help explain why sim- prescribed) may have opioid tolerance on admis- ple and routine procedures can cause pain in sion to the ICU, confounding therapy.44,58 Four patients in the ICU and will allow for more em- case scenarios are discussed in Appendix S1 and pathic and better care of patients in the ICU. Table S4 in the Supplementary Appendix.

Daily Interruption of Sedative Infusions Strategies to Mitigate Opioid Tolerance and Opioid-Induced Interrupted infusions of analgesics and seda- Hyperalgesia tives, as compared with uninterrupted infusions, allow patients to be more awake (without iatro- Strategies for mitigating opioid tolerance and genic coma), yield improved assessment and opioid-induced hyperalgesia include reducing the treatment of pain with fewer days on a ventila- dose of analgesics and the duration of treatment tor, lessen psychological distress, and do not by interrupting infusions of sedative or analgesic increase the incidence of cardiovascular and agents daily or modulating infusions on the basis other outcomes.59-62 Conversion to intermittent of analgesic assessment and sedation scores, by bolus therapy or patient-controlled analgesia using multimodal analgesic agents (nerve blocks should be instituted as early as possible. Pro- and nonopioid analgesics), and by rotating analge- longed coadministration of a benzodiazepine and sic agents sequentially (Table 1, and Tables S2 morphine was shown to exacerbate opioid toler-

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63 ance ; therefore, reducing benzodiazepine use Table 1. Strategies for Mitigating Opioid Tolerance or Opioid-Induced may mitigate tolerance and delirium. Alternative Hyperalgesia.* nonanalgesic drugs could be used for sedation Appropriate use of opioids and potentiation of opioid effects. Use of valid assessment scales of pain before and during administration of the analgesic drug Neuraxial and Non-Neuraxial Analgesia Use of intermittent opioid therapy (oral or intravenous) rather than continuous Neuraxial (thoracic or lumbar epidural) analge- infusions, when possible sic techniques provide effective analgesia while Opioid rotation reducing opioid exposure and tolerance, pulmo- Use of remifentanil for short-term analgesia (because of potent induction nary morbidity, duration of mechanical ventila- of opioid-induced hyperalgesia), except when rapid offset of effect is tion, and the incidence of postoperative ileus. required, as in evaluation of head injury They also render patients more awake and able Minimal use of benzodiazepines (because of delirium and potential to adhere to physical therapy regimens.64,65 Indi- opioid-induced hyperalgesia associated with long-term use) cations for epidurals include thoracic or major Avoidance of excessive dose escalation; supplementation of opioid with abdominal surgery, chest wall trauma, or pul- nonopioid analgesics monary contusion. Despite possible contraindi- Addition of methadone to attenuate or delay opioid tolerance cations in critically ill patients (e.g., administra- Coadministration of nonopioid analgesics as rescue therapy during procedures tion of anticoagulant therapy), epidurals can be or to potentiate the effects of opioids

placed safely before — and continued during N-methyl-d-aspartate receptor antagonists (ketamine) — anticoagulant administration. Other regional α2-Adrenergic receptor agonists (clonidine or dexmedetomidine) or non-neuraxial analgesic techniques with cath- Gabapentinoids (gabapentin or pregabalin) eters are as effective as epidural administration of analgesics in selected patients. Non-neural Continuous administration of nerve blocks by means of a catheter blocks include paravertebral block for rib frac- Neuraxial: thoracic or lumber epidural blocks for thoracic, abdominal, or bilateral leg analgesia tures or after thoracotomy, as well as transversus abdominis block for surgery of the lower Regional: brachial plexus block for arm analgesia; femoral or obturator block or both, with or without sciatic nerve block for lower-limb analgesia abdomen.65 Ultrasound-guided nerve blocks have Local: paravertebral block for rib fractures or chest-tube–associated pain; been safely performed even in patients in the transversus abdominis block for lower abdominal surgery ICU who have had clinically significant coagu- 66 Prevention or reversal of opioid-induced hyperalgesia and opioid-withdrawal lopathy. symptoms Tapering of opioid dose when pain score goal is achieved (10–20% dose Opioid Rotation reduction every 1–4 days) Opioid rotation (i.e., administration of a differ- Use of valid withdrawal assessment scales ent opioid to control pain) generally mitigates Use of adjuncts to opioids (ketamine, dexmedetomidine, or gabapentinoids tolerance. A single gene encodes the mu-opioid [gabapentin or pregabalin]) receptor, but during gene expression some exons Use of methadone are excluded from the final messenger RNA. Reduction of inflammation Consequently, several receptor subtypes can co- Scheduled acetaminophen therapy exist (e.g., mu1 and mu2) owing to alternative exon splicing. One receptor subtype may under- Short-term use of ketorolac† go desensitization to one opioid, leaving other * The nonopioid strategies that are listed are usually used in combination with subtypes available for a new opioid; hence, the opioids; dosing regimens and routes of drug administration are provided in rationale for opioid rotation for the restoration Tables S2 and S3 in the Supplementary Appendix. of analgesic efficacy and decreased doses.67 Dur- † Other nonsteroidal antiinflammatory drugs (e.g., ibuprofen) have limited use in the intensive care unit because of cardiovascular, nephrotoxic, and gastro- ing opioid rotation, the dose of the new opioid intestinal side effects. is derived empirically because opioid conversion tables (used for calculations of opioid equiva- lence) may be inapplicable in a patient in whom morphine and hydromorphone therapy involves tolerance has developed, particularly during the the properties of the morphine-3-glucuronide coadministration of nonopioid adjuvants (e.g., metabolite, which counteract the analgesic effects dexmedetomidine or ketamine).67 Another expla- of morphine and morphine-6-glucuronide.40 Re- nation for the efficacy of drug rotation during placing morphine and hydromorphone with an-

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other opioid that has inactive metabolites (e.g., traditional nonsteroidal antiinflammatory drugs fentanyl or methadone) will decrease morphine- (e.g., ibuprofen), which are nonselective cyclo- 3-glucuronide levels, allowing more effective oxygenase inhibitors, are not conventionally analgesia by the second drug. used in the ICU because of their side effects. Ketorolac is effective as an opioid-sparing agent, Multimodal Analgesia and short-term ketorolac use does not increase In multimodal pain management, multiple non- postoperative bleeding.75 opioid drugs can be used in combination with or in place of opioids to target various nociceptive Future Directions for pathways in the peripheral or central nervous Prevention and Treatment system.68,69 This approach produces additive and of Opioid Tolerance even synergistic effects of the analgesic agents and reduces the adverse effects of opioids. Only The basic and translational development of forth- the common nonopioid analgesics available for coming opioid-receptor–targeted and nonopioid- pain control are discussed here (Table 1, and receptor–targeted pain therapies unrelated to Table S3 in the Supplementary Appendix).69 patients in the ICU has been recently reviewed.76 Ketamine induces analgesia largely by block- Several approaches presented in that review show ing the NMDA receptors, but it also has modula- promise for mitigating tolerance and hyperalgesia tory roles by means of cholinergic, aminergic, in the ICU. We will highlight three approaches. and opioid systems.70 Since NMDA-receptor hy- peractivity underlies a key mechanism of opioid Modulation of Immune Responses tolerance and opioid-induced hyperalgesia, keta Studies have suggested that inflammasome and mine effectively ameliorates these conditions.70 toll-like receptor activation mediated by DAMPs Additional advantages include opioid sparing, critically affects the glial response to both tissue minimal respiratory depression without psycho injury and opioids.3,28,48 Toll-like receptor activa- tomimetic effects (at lower levels),69,70 and the tion can be regulated by racemic naloxone or a antidepressant effects of ketamine metabolites.71 stereoselective naloxone isomer, (+)-naloxone.28

Clonidine, an α2-adrenergic agonist, has mod- For example, dextromorphine exerts a stereose- est analgesic, sedative, antihypertensive, and lective action over levomorphine in the activation opioid-sparing effects and has also been used to of glia; opioid-receptor agonists, including mor- mitigate opioid-induced hyperalgesia and with- phine, activate toll-like receptors but are antago- drawal symptoms during opioid weaning.72 Dex- nized by (+)-naloxone.28 Thus, (−)-naloxone and medetomidine is more potent and has a shorter (+)-naloxone could be used to differentiate be- half-life than clonidine, and doses can easily be tween the role of an opioid in analgesia and ac- adjusted according to the response.69 tivation of toll-like receptors, making it possible The gabapentinoids gabapentin and pregaba- to lessen the inflammatory responses to tissue lin are commonly used adjuncts for multimodal injury and opioid exposure without antagonizing analgesia. The involvement of multiple sites of opioid-induced analgesia. Specific inflammasome action is probably responsible for their superior inhibitors may also be used to modulate glia- pain relief.69 Common dose-related side effects mediated exaggerated nociception and opioid include sedation, dizziness, and confusion, and tolerance, without broadly inhibiting immunity.77

their opioid potentiation can cause respiratory The neuronal α7 nicotinic acetylcholine recep- arrest.73 tor agonists have been shown to attenuate micro glia activation52,78 and to have protective effects on Other Nonopioid Drugs inflammation induced by critical illnesses.79,80

Acetaminophen is a weak analgesic but is com- Moreover, α7 nicotinic acetylcholine receptor monly incorporated in multimodal analgesic activation attenuates inflammatory and neuro- strategies for opioid sparing because it blocks pathic pain and opioid-induced hyperalgesia in 74 78,79,81 the central production of prostaglandins. Par- rodent models. Therefore, α7 nicotinic acetyl- enteral acetaminophen causes hypotension. Doses choline receptor agonists could be useful in the are reduced or not administered during hepatic reduction of both critical illness–related inflam- dysfunction, malnutrition, or dehydration. The mation and pain.

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Cannabinoids cardiac QT interval can occur with cytochrome The role of endocannabinoids in anxiety, stress, P-450 inhibitors or low magnesium levels. Meth- and pain is well documented,82,83 but the useful- adone is used cautiously in the ICU because of ness of exogenous cannabinoids in stress-induced its unpredictable half-life and cardiac toxicity.91,92 hyperalgesia and opioid-sparing in patients in Methadone is a racemic mixture of two stereo- the ICU is unknown. In addition, cannabinoids isomers (l-methadone and d-methadone), with regulate inflammatory responses in preclinical l-methadone being 8 to 50 times as potent as models.82 The analgesic efficacy of cannabi- d-methadone36; therefore, in patients in the ICU noids, their interactions (additive or synergistic) who do not have a response to other opioids, the with opioids, and their abuse potential when usefulness of l-methadone or methadone, which combined with opioids for pain control in pa- produces analgesia through multiple sites of ac- tients in the ICU are topics for future study. tion that differ in potency, is not clear.36,88,90

Buprenorphine with or without Naloxone Other Drugs and Considerations and Methadone Lidocaine, β-adrenoceptor antagonists, magne- Buprenorphine, an opioid analgesic agent, is cur- sium, tricyclic antidepressants, and other drugs rently used (with or without naloxone) as replace- have been used as analgesic adjuncts to decrease ment therapy in persons with substance-use dis- opioid doses. Their long-term safety and efficacy orders and for the treatment of chronic pain.84 in the ICU have not been well established in ran- Although it is a weak analgesic for patients who domized, controlled trials. Selective serotonin- do not have opioid dependency, it has shown reuptake inhibitors and serotonin–norepinephrine promise in patients with opioid dependency be- reuptake inhibitors have antinociceptive effects, cause it reverses opioid-induced hyperalgesia.84 but mortality is higher among patients who use Opioid-induced hyperalgesia is partially related them before ICU admission than among patients to increased interaction of dynorphins with the who do not.93 Antipsychotic agents are currently kappa-opioid receptor; buprenorphine blocks the used in the ICU as adjuncts to opioids, but their binding of dynorphins to the kappa-opioid recep- use has not been studied systematically. Multiple tor and attenuates opioid-induced hyperalgesia.85,86 drugs are often administered simultaneously, Furthermore, buprenorphine, although a partial and in cases of organ dysfunction, the altered opioid agonist, has high affinity for opioid re- drug disposition increases the risk of additive, ceptors and thereby blocks other opioids from synergistic, or antagonistic drug interactions, activating the same receptors. Although few underscoring the importance of reviewing all studies have directly compared the analgesic ef- medications.94 Hepatic disease mildly affects the fects of buprenorphine and methadone, buprenor- dispositions of morphine and fentanyl, and their phine may be superior in cases of renal failure elimination depends on hepatic blood flow; because of extrarenal excretion.87 Thus, pragmatic therefore, the drugs are useful in hepatic dysfunc- clinical protocols are needed to guide the use of tion but not in low-flow states.95 Remifentanil, buprenorphine and naloxone in patients in the although rapidly cleared even in cases of organ ICU who are progressing toward opioid toler- dysfunction, quickly induces tolerance and opioid- ance and for those already receiving buprenor- induced hyperalgesia.91 phine or naloxone therapy before admission. Methadone, another opioid analgesic, mitigates Conclusions opioid-induced hyperalgesia by inhibiting NMDA receptors and serotonin-reuptake activity and There are many indications for opioid use in per- blocking adenylate cyclase overactivity, which is sons with critical illnesses. However, long-term partly responsible for the withdrawal symptoms.36,88 opioid use has detrimental effects, including The major downside of methadone is its variable analgesic tolerance, which drives dose escalation metabolism, intra- and interindividually. During and leads to opioid-induced hyperalgesia. Pain opioid rotation or opioid weaning, methadone management (analgesia) in patients in the ICU, doses must be adjusted to maintain sufficient who are more vulnerable than the general popu- alleviation of symptoms while avoiding side ef- lation to both exaggerated tolerance and the del- fects.88-90 Oversedation and prolongation of the eterious effects of opioids, has been a challenge

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for decades, and methods to mitigate the risks among critically ill patients. Furthermore, the associated with opioid administration are unre- translational application of pain therapies tar- solved. The etiologic factors (i.e., cell types and geted to opioid receptors and those targeted to receptors, sex, extremes of age, and the underly- nonopioid receptors is currently being studied ing inflammation- and opioid-induced immune in the general population and provides a road responses) that contribute to these maladaptive map for strategies to mitigate opioid tolerance responses have not been well characterized and in persons with critical illnesses. pose a barrier to improving analgesic therapy in Disclosure forms provided by the authors are available with cases of critical illness. A more nuanced under- the full text of this article at NEJM.org. standing of the way critical illness and inflam- We thank Ethan Sanford, M.D., Derek Hursey, Pharm.D., Me- lissa Gorman, M.S.N., C.C.R.N.-K., and M. Tréjeeve Martyn, mation affect the body’s response to opioids M.D., for their comments and critiques on an earlier version of could lead to tremendous reduction in morbidity the manuscript.

References 1. Cullen DJ, Sweitzer BJ, Bates DW, acteristics of an unrecognized symptom distress syndrome survivors. Ann Am Burdick E, Edmondson A, Leape LL. Pre- in surgical and trauma versus medical Thorac Soc 2017;14:839-41. ventable adverse drug events in hospital- intensive care unit patients. Anesthesiol- 23. Finan PH, Goodin BR, Smith MT. The ized patients: a comparative study of in- ogy 2007;107: 858-60. association of sleep and pain: an update tensive care and general care units. Crit 13. Puntillo KA, Max A, Timsit JF, et al. and a path forward. J Pain 2013;14:1539- Care Med 1997;25:1289-97. Determinants of procedural pain inten- 52. 2. Barr J, Fraser GL, Puntillo K, et al. sity in the intensive care unit: the Euro- 24. Novaes MA, Knobel E, Bork AM, Clinical practice guidelines for the man- pain study. Am J Respir Crit Care Med Pavão OF, Nogueira-Martins LA, Ferraz agement of pain, agitation, and delirium 2014;189:39-47. MB. Stressors in ICU: perception of the in adult patients in the intensive care unit. 14. Chanques G, Pohlman A, Kress JP, patient, relatives and health care team. Crit Care Med 2013;41:263-306. et al. Psychometric comparison of three Intensive Care Med 1999;25:1421-6. 3. Roeckel LA, Le Coz GM, Gavériaux- behavioural scales for the assessment of 25. Baumbach P, Götz T, Günther A, Ruff C, Simonin F. Opioid-induced hyper- pain in critically ill patients unable to Weiss T, Meissner W. Prevalence and algesia: cellular and molecular mecha- self-report. Crit Care 2014;18:R160. characteristics of chronic intensive care- nisms. Neuroscience 2016;338: 160-82. 15. Faust AC, Rajan P, Sheperd LA, Alva- related pain: the role of severe sepsis and 4. Chu LF, Angst MS, Clark D. Opioid- rez CA, McCorstin P, Doebele RL. Impact septic shock. Crit Care Med 2016;44:1129- induced hyperalgesia in humans: molecu- of an analgesia-based sedation protocol 37. lar mechanisms and clinical considera on mechanically ventilated patients in a 26. Jiang X, Orton M, Feng R, et al. tions. Clin J Pain 2008;24:479-96. medical intensive care unit. Anesth Analg Chronic opioid usage in surgical patients 5. Puntillo KA, Naidu R. Chronic pain 2016;123: 903-9. in a large academic center. Ann Surg 2017; disorders after critical illness and ICU- 16. Devabhakthuni S, Armahizer MJ, 265:722-7. acquired opioid dependence: two clinical Dasta JF, Kane-Gill SL. Analgosedation: 27. Wibbenmeyer L, Sevier A, Liao J, et al. conundra. Curr Opin Crit Care 2016;22: a paradigm shift in intensive care unit se- The impact of opioid administration on 506-12. dation practice. Ann Pharmacother 2012; resuscitation volumes in thermally injured 6. Bittner EA, Shank E, Woodson L, 46:530-40. patients. J Burn Care Res 2010;31:48-56. Martyn JA. Acute and perioperative care 17. Chapman CR, Tuckett RP, Song CW. 28. Hutchinson MR, Shavit Y, Grace PM, of the burn-injured patient. Anesthesiol- Pain and stress in a systems perspective: Rice KC, Maier SF, Watkins LR. Exploring ogy 2015;122:448-64. reciprocal neural, endocrine, and immune the neuroimmunopharmacology of opioids: 7. Anand KJ, Willson DF, Berger J, et al. interactions. J Pain 2008;9:122-45. an integrative review of mechanisms of Tolerance and withdrawal from pro- 18. Tennant F. The physiologic effects of central immune signaling and their im- longed opioid use in critically ill children. pain on the endocrine system. Pain Ther plications for opioid analgesia. Pharma- Pediatrics 2010;125(5):e1208-e1225. 2013;2:75-86. col Rev 2011;63:772-810. 8. Wang Y, Mitchell J, Moriyama K, et al. 19. Finnerty CC, Mabvuure NT, Ali A, 29. Gudin JA, Laitman A, Nalamachu S. Age-dependent morphine tolerance devel- Kozar RA, Herndon DN. The surgically Opioid related endocrinopathy. Pain Med opment in the rat. Anesth Analg 2005; induced stress response. JPEN J Parenter 2015;16:Suppl 1:S9-S15. 100:1733-9. Enteral Nutr 2013;37: Suppl: 21S-29S. 30. Carmona-Bayonas A, Jiménez-Fonseca 9. Mendell JR, Sahenk Z. Painful sen- 20. Wohleb ES, McKim DB, Sheridan JF, P, Castañón E, et al. Chronic opioid ther- sory neuropathy. N Engl J Med 2003;348: Godbout JP. Monocyte trafficking to the apy in long-term cancer survivors. Clin 1243-55. brain with stress and inflammation: a novel Transl Oncol 2017;19:236-50. 10. Stein C. Opioid receptors. Annu Rev axis of immune-to-brain communication 31. Juneja R. Opioids and cancer recur- Med 2016;67: 433-51. that influences mood and behavior. Front rence. Curr Opin Support Palliat Care 11. Meisner JG, Marsh AD, Marsh DR. Neurosci 2015;8: 447. 2014;8:91-101. Loss of GABAergic interneurons in lami- 21. Fonken LK, Weber MD, Daut RA, et al. 32. Pandharipande P, Cotton BA, Shin- nae I-III of the spinal cord dorsal horn Stress-induced neuroinflammatory prim- tani A, et al. Prevalence and risk factors contributes to reduced GABAergic tone and ing is time of day dependent. Psychoneuro- for development of delirium in surgical neuropathic pain after spinal cord injury. endocrinology 2016;66: 82-90. and trauma intensive care unit patients. J Neurotrauma 2010;27:729-37. 22. Anderson BJ, Mikkelsen ME. Stress- J Trauma 2008;65:34-41. 12. Chanques G, Sebbane M, Barbotte E, ing the brain: the immune system, hypo- 33. Pisani MA, Murphy TE, Araujo KL, Viel E, Eledjam JJ, Jaber S. A prospective thalamic-pituitary-adrenal axis, and psy- Van Ness PH. Factors associated with per- study of pain at rest: incidence and char- chiatric symptoms in acute respiratory sistent delirium after intensive care unit

376 n engl j med 380;4 nejm.org January 24, 2019 The New England Journal of Medicine Downloaded from nejm.org at Australian and New Zealand College of Anaesthetists on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. Opioid Tolerance in Critical Illness

admission in an older medical patient 48. Ji RR, Chamessian A, Zhang YQ. Pain Regional anesthesia and analgesia after population. J Crit Care 2010;25(3):540.e1-7. regulation by non-neuronal cells and in- surgery in ICU. Curr Opin Crit Care 2017; 34. Strøm T, Martinussen T, Toft P. A pro- flammation. Science 2016;354:572-7. 23:430-9. tocol of no sedation for critically ill pa- 49. Donello JE, Guan Y, Tian M, et al. A 65. De Pinto M, Dagal A, O’Donnell B, tients receiving mechanical ventilation: peripheral adrenoceptor-mediated sympa- Stogicza A, Chiu S, Edwards WT. Region- a randomised trial. Lancet 2010;375:475-80. thetic mechanism can transform stress- al anesthesia for management of acute 35. Schaller SJ, Alam SM, Mao J, et al. induced analgesia into hyperalgesia. An- pain in the intensive care unit. Int J Crit Pharmacokinetics cannot explain the in- esthesiology 2011;114:1403-16. Illn Inj Sci 2015;5:138-43. creased effective dose requirement for 50. de Goeij M, van Eijk LT, Vanelderen P, 66. Wiebalck A, Grau T. Ultrasound im- morphine and midazolam in rats during et al. Systemic inflammation decreases aging techniques for regional blocks in their extended administration alone or in pain threshold in humans in vivo. PLoS intensive care patients. Crit Care Med combination. J Pharm Pharmacol 2017; One 2013;8(12):e84159. 2007;35: Suppl: S268-S274. 69:82-8. 51. Nyland JE, McLean SA, Averitt DL. 67. Webster LR, Fine PG. Review and cri- 36. Kharasch ED. Current concepts in Prior stress exposure increases pain be- tique of opioid rotation practices and as- methadone metabolism and transport. haviors in a rat model of full thickness sociated risks of toxicity. Pain Med 2012; Clin Pharmacol Drug Dev 2017;6:125-34. thermal injury. Burns 2015;41:1796-804. 13:562-70. 37. Han T, Harmatz JS, Greenblatt DJ, 52. Chavan SS, Pavlov VA, Tracey KJ. 68. Kohler M, Chiu F, Gelber KM, Webb Martyn JA. Fentanyl clearance and volume Mechanisms and therapeutic relevance of CA, Weyker PD. Pain management in crit- of distribution are increased in patients neuro-immune communication. Immunity ically ill patients: a review of multimodal with major burns. J Clin Pharmacol 2007; 2017;46: 927-42. treatment options. Pain Manag 2016;6: 47:674-80. 53. Frank MG, Watkins LR, Maier SF. 591-602. 38. Bista SR, Haywood A, Hardy J, Lobb Stress-induced glucocorticoids as a neuro- 69. Kumar K, Kirksey MA, Duong S, Wu M, Tapuni A, Norris R. Protein binding of endocrine alarm signal of danger. Brain CL. A review of opioid-sparing modalities fentanyl and its metabolite nor-fentanyl Behav Immun 2013;33: 1-6. in perioperative pain management: meth- in human plasma, albumin and α-1 acid 54. Chiu IM, Heesters BA, Ghasemlou N, ods to decrease opioid use postoperative- glycoprotein. Xenobiotica 2015;45:207-12. et al. Bacteria activate sensory neurons ly. Anesth Analg 2017;125: 1749-60. 39. Bauer B, Hartz AM, Miller DS. Tumor that modulate pain and inflammation. 70. Mion G, Villevieille T. Ketamine phar- necrosis factor alpha and endothelin-1 Nature 2013;501:52-7. macology: an update (pharmacodynamics increase P-glycoprotein expression and 55. Fusco M, Skaper SD, Coaccioli S, Var- and molecular aspects, recent findings). transport activity at the blood-brain bar- rassi G, Paladini A. Degenerative joint CNS Neurosci Ther 2013;19:370-80. rier. Mol Pharmacol 2007;71:667-75. diseases and neuroinflammation. Pain 71. Costi S, Van Dam NT, Murrough JW. 40. Smith MT. Neuroexcitatory effects of Pract 2017;17:522-32. Current status of ketamine and related morphine and hydromorphone: evidence 56. Gatson JW, Liu MM, Rivera-Chavez therapies for mood and anxiety disorders. implicating the 3-glucuronide metabo- FA, Minei JP, Wolf SE. Serum levels of Curr Behav Neurosci Rep 2015;2:216-25. lites. Clin Exp Pharmacol Physiol 2000;27: neurofilament-H are elevated in patients 72. Wang JG, Belley-Coté E, Burry L, et al. 524-8. suffering from severe burns. J Burn Care Clonidine for sedation in the critically ill: 41. Roeckel LA, Utard V, Reiss D, et al. Res 2015;36:545-50. a systematic review and meta-analysis. Morphine-induced hyperalgesia involves 57. Verriotis M, Chang P, Fitzgerald M, Crit Care 2017;21:75. mu opioid receptors and the metabolite Fabrizi L. The development of the noci- 73. Quintero GC. Review about gabapen- morphine-3-glucuronide. Sci Rep 2017;7: ceptive brain. Neuroscience 2016;338:207- tin misuse, interactions, contraindications 10406. 19. and side effects. J Exp Pharmacol 2017;9: 42. Porreca F, Cowan A, Raffa RB, Tal- 58. Huxtable CA, Roberts LJ, Somogyi 13-21. larida RJ. Estimation in vivo of the recep- AA, MacIntyre PE. Acute pain manage- 74. McDaid C, Maund E, Rice S, Wright K, tor constants of morphine in naive and ment in opioid-tolerant patients: a grow- Jenkins B, Woolacott N. Paracetamol and morphine-tolerant rats. Life Sci 1982;31: ing challenge. Anaesth Intensive Care selective and non-selective non-steroidal 2355-8. 2011;39:804-23. anti-inflammatory drugs (NSAIDs) for 43. Dumas EO, Pollack GM. Opioid toler- 59. Kress JP, Pohlman AS, O’Connor MF, the reduction of morphine-related side ance development: a pharmacokinetic/ Hall JB. Daily interruption of sedative in- effects after major surgery: a systematic pharmacodynamic perspective. AAPS J fusions in critically ill patients undergo- review. Health Technol Assess 2010;14: 2008;10:537-51. ing mechanical ventilation. N Engl J Med 1-153, iii-iv. 44. Compton P, Charuvastra VC, Ling W. 2000;342:1471-7. 75. Wick EC, Grant MC, Wu CL. Postop- Pain intolerance in opioid-maintained 60. Kress JP, Gehlbach B, Lacy M, Pliskin erative multimodal analgesia pain man- former opiate addicts: effect of long-act- N, Pohlman AS, Hall JB. The long-term agement with nonopioid analgesics and ing maintenance agent. Drug Alcohol De- psychological effects of daily sedative in- techniques: a review. JAMA Surg 2017; pend 2001;63:139-46. terruption on critically ill patients. Am J 152:691-7. 45. Cahill CM, Walwyn W, Taylor AMW, Respir Crit Care Med 2003;168:1457-61. 76. Knezevic NN, Yekkirala A, Yaksh TL. Pradhan AAA, Evans CJ. Allostatic mech- 61. Nassar APJ, Park M. Sedation proto- Basic/translational development of forth- anisms of opioid tolerance beyond desen- cols versus daily sedation interruption: coming opioid- and nonopioid-targeted sitization and downregulation. Trends a systematic review and meta-analysis. pain therapeutics. Anesth Analg 2017; Pharmacol Sci 2016;37:963-76. Rev Bras Ter Intensiva 2016;28:444-51. 125:1714-32. 46. Waxman AR, Arout C, Caldwell M, 62. Shehabi Y. The golden hours of ICU 77. Boriushkin E, Wang JJ, Li J, Bhatta M, Dahan A, Kest B. Acute and chronic fen- sedation: the clock is ticking. Crit Care Zhang SX. p58(IPK) Suppresses NLRP3 tanyl administration causes hyperalgesia Med 2018;46:490-1. inflammasome activation and IL-1β pro- independently of opioid receptor activity 63. Song L, Wang S, Zuo Y, Chen L, Martyn duction via inhibition of PKR in macro- in mice. Neurosci Lett 2009;462:68-72. JA, Mao J. Midazolam exacerbates mor- phages. Sci Rep 2016;6:25013. 47. Costantino CM, Gomes I, Stockton phine tolerance and morphine-induced 78. Bagdas D, Gurun MS, Flood P, Papke SD, Lim MP, Devi LA. Opioid receptor het- hyperactive behaviors in young rats with RL, Damaj MI. New insights on neuronal eromers in analgesia. Expert Rev Mol Med burn injury. Brain Res 2014;1564:52-61. nicotinic acetylcholine receptors as targets 2012;14:e9. 64. Capdevila M, Ramin S, Capdevila X. for pain and inflammation: a focus on α7

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nAChRs. Curr Neuropharmacol 2018;16: 85. Vanderah TW, Gardell LR, Burgess 91. Hayhurst CJ, Durieux ME. Differential 415-25. SE, et al. Dynorphin promotes abnormal opioid tolerance and opioid-induced hyper- 79. Ren C, Tong YL, Li JC, Lu ZQ, Yao YM. pain and spinal opioid antinociceptive algesia: a clinical reality. Anesthesiology The protective effect of alpha 7 nicotinic tolerance. J Neurosci 2000;20:7074-9. 2016;124: 483-8. acetylcholine receptor activation on criti- 86. Horan P, Taylor J, Yamamura HI, Por- 92. Krantz MJ, Martin J, Stimmel B, Mehta cal illness and its mechanism. Int J Biol reca F. Extremely long-lasting antagonistic D, Haigney MC. QTc interval screening in Sci 2017;13:46-56. actions of nor-binaltorphimine (nor-BNI) methadone treatment. Ann Intern Med 80. Chavan SS, Tracey KJ. Essential neuro- in the mouse tail-flick test. J Pharmacol 2009;150: 387-95. science in immunology. J Immunol 2017; Exp Ther 1992;260: 1237-43. 93. Ghassemi M, Marshall J, Singh N, 198:3389-97. 87. Davis MP. Twelve reasons for consider- Stone DJ, Celi LA. Leveraging a critical 81. Abbas M, Rahman S. Effects of alpha-7 ing buprenorphine as a frontline analgesic care database: selective serotonin reup- nicotinic acetylcholine receptor positive in the management of pain. J Support On- take inhibitor use prior to ICU admission allosteric modulator on lipopolysaccha- col 2012;10:209-19. is associated with increased hospital mor- ride-induced neuroinflammatory pain in 88. Elefritz JL, Murphy CV, Papadimos TJ, tality. Chest 2014;145:745-52. mice. Eur J Pharmacol 2016;783:85-91. Lyaker MR. Methadone analgesia in the 94. Feng XQ, Zhu LL, Zhou Q. Opioid 82. Ueda M, Iwasaki H, Wang S, et al. critically ill. J Crit Care 2016;34:84-8. analgesics-related pharmacokinetic drug Cannabinoid receptor type 1 antagonist, 89. McCance-Katz EF, Sullivan LE, Nal- interactions: from the perspectives of evi- AM251, attenuates mechanical allodynia lani S. Drug interactions of clinical im- dence based on randomized controlled and thermal hyperalgesia after burn in- portance among the opioids, methadone trials and clinical risk management. J Pain jury. Anesthesiology 2014;121:1311-9. and buprenorphine, and other frequent- Res 2017;10:1225-39. 83. Woodhams SG, Chapman V, Finn DP, ly prescribed medications: a review. Am 95. Choi L, Ferrell BA, Vasilevskis EE, Hohmann AG, Neugebauer V. The canna- J Addict 2010;19: 4-16. et al. Population pharmacokinetics of binoid system and pain. Neuropharma- 90. Moody DE. Metabolic and toxicologi- fentanyl in the critically ill. Crit Care Med cology 2017;124:105-20. cal considerations of the opioid replace- 2016;44:64-72. 84. Chen KY, Chen L, Mao J. Buprenor- ment therapy and analgesic drugs: metha- Copyright © 2019 Massachusetts Medical Society. phine-naloxone therapy in pain manage- done and buprenorphine. Expert Opin ment. Anesthesiology 2014;120:1262-74. Drug Metab Toxicol 2013;9:675-97.

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378 n engl j med 380;4 nejm.org January 24, 2019 The New England Journal of Medicine Downloaded from nejm.org at Australian and New Zealand College of Anaesthetists on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.