Opioids are a mainstay of treatment for pain worldwide. Pruritus, a common side effect of opioids, is a patient dissatisfier that limits their use in many clinical settings. Both parenteral and neuraxial administration of opioids frequently evoke pruritus. The ability of opioids to suppress pain while causing itch continues to perplex clinicians and researchers alike. Several mechanisms have been proposed to explain how opioids can give rise to pruritus, but specific knowledge gaps perpetuate debate. This review summarizes the clinical burden of opioid-induced pruritus and emphasizes recent discoveries of peripheral and central mechanisms for opioid-induced pruritus, particularly with respect to scientific and conceptual advances in spinal cord circuitry and mast cell biology. The mechanisms and effectiveness of existing medications used for clinical management of pruritus will be evaluated, and we will highlight the emerging preclinical utility of selective κ-opioid receptor agonists, such as nalfurafine, for the management of opioid-induced pruritus.

Opioids have been used to control pain for millennia. Today, they are used for numerous types of pain, including acute, chronic, preoperative, perioperative, and postoperative, and cancer pain.1  One route of opioid administration that is frequently used is the neuraxial (epidural and intrathecal) route of administration. Neuraxial opioids are frequently administered for abdominal and lower extremity surgeries.2–6  Although neuraxial analgesia is associated with improved postoperative outcomes such decreased length of hospital stay7–9  and extended dosing for acute pain control,3,5,9  it is also associated with many side effects, particularly pruritus.10–13  Oral and parenteral opioid analgesia are other routes used in ambulatory and inpatient settings whenever neuraxial administration is not possible. In contrast to the neuraxial route of opioid administration, the oral and parenteral routes are less frequently associated with pruritus.14,15 

The purpose of this review is to assess the incidence of opioid-induced pruritus among different routes of opioid medication and to summarize the most recent advances in treatments. New treatments stem from new knowledge in the mechanistic underpinnings of opioid-induced pruritus due to novel insights in spinal cord circuitry and mast cell biology. Based on these mechanisms, we weigh the appropriateness of existing therapies for opioid-induced pruritus.

Although neuraxial opioids are frequently used in acute perioperative pain, they also have side effects. These side effects include pruritus,10–13  nausea (25%), sedation (17%), urinary retention (19%), and, very rarely, respiratory depression (3%).9,16,17  Although pruritus is occasionally observed with parenteral opioid use,18,19  it is an extremely common side effect of neuraxial opioids, with an incidence ranging from 30 to 85%, depending on the dose and lipophilicity of the opioid administered.12,20,21  Dose-response relationships between spinal morphine, analgesic duration, and pruritus have indicated that escalating doses of morphine improve analgesia but are correlated with higher incidences and severity of pruritus.22,23  This relationship suggests that the duration of analgesia of neuraxial morphine can be improved with increased doses but xst be weighed against increasing side effects.

Because of the widespread use of neuraxial opioids in the childbirth setting, opioid-induced pruritus is most frequently observed among obstetric patients16,24–26  (table 1), where it has an incidence of up to 85%,20  and is primarily dose-dependent.22,23  Pruritus is also frequently reported among orthopedic patients receiving neuraxial opioids (30 to 70%)37,38  for Enhanced Recovery after Surgery. The incidence of pruritus in patients receiving neuraxial morphine is more common among female patients (60 to 85%),16,24–26  which mirrors the incidence and burden of chronic pain that also disproportionately affects women.32  Differences in estrous cycle, which could affect the sensitivity of the μ-opioid receptor to opioid drugs,39  have been proposed to underlie these differences, yet the extent to which nonbiologic factors could also contribute to disparities in experiences of pruritus warrants further investigation.

Table 1.

Incidence of Parenteral and Neuraxial Opioid-induced Pruritus

Incidence of Parenteral and Neuraxial Opioid-induced Pruritus
Incidence of Parenteral and Neuraxial Opioid-induced Pruritus

Although it is less common than neuraxial opioid–induced pruritus, parenteral opioid–induced pruritus has been observed in 10 to 50% of patients, particularly in the setting of patient-controlled analgesia (PCA)15,27,40,41  and among patients receiving IV morphine for vasoocclusive crisis in sickle cell disease.42  Thus, in contrast to neuraxial opioid–induced pruritus, which is observed after a single dose of opioids, parenteral opioid–induced pruritus is mostly observed after extended dosing.15,27,40,41  Among pediatric patients on PCA, pruritus was the most common reason for switching medications to another opioid class: for example, from morphine to a semisynthetic opioid such as hydromorphone.27  In these settings, the development of pruritus may be associated with central sensitization to opioids that may occur independently of tolerance to opioid-induced analgesia.43  Proposed mechanisms include sensitization of itch-responsive circuits within the spinal dorsal horn after chronic use.43  In particular, central, but not peripheral, μ-opioid receptors have recently been implicated in modulation of dermatitis and lymphoma-induced chronic itch.44  Further research is necessary to elucidate the contribution of these central pathways to chronic opioid-induced pruritus. Thus, although pruritus is most common after neuraxial opioid administration, it also poses a troublesome side effect for a small number of patients, such as those on PCA for postoperative pain management.

Polymorphisms of OPRM1 on Opioid-induced Analgesia and Pruritus

Sequencing of the human μ-opioid receptor (OPRM1) gene, which encodes for the μ-opioid receptor, indicates that certain polymorphisms may be associated with protection against the side effect of pruritus.28,46  For example, genetic association studies have focused on the A118G polymorphism of OPRM1.28,46  The recessive G allele in this polymorphism is associated with lower incidences of pruritus among obstetric patients receiving epidural (4.8%) and spinal (0 to 50%) morphine.28,46  This variant is further associated with reduced sensitivity to the analgesic effects of opioids,47  suggesting that the A118G polymorphism may give rise to a μ-opioid receptor that is generally less responsive to opioid medications. However, given the heterogeneity among clinical populations receiving opioid analgesia and their self-reported experiences for both pain and itch, many of these studies are underpowered to provide definitive conclusions about these polymorphism relationships.48,49  In mice, distinct splice variants of the u-opioid receptor isoform consisting of exons 1-3 and 8-9 (MOR1D) and exons 1-4 (MOR1), have been shown to differentially modulate morphine-induced itch and morphine-induced analgesia, respectively.50  However, the contributions of these splice variants have not been characterized in humans. Additional large population genetic association studies are necessary to further assess the clinical significance and utility of identifying genetic variations on acute postoperative pain management and risk for opioid-related side effects.

Differences in Opioid Medications and Pruritus

Opioid-induced pruritus is observed after the use of intrathecally administered hydrophilic opioids (such as morphine) and lipophilic opioids (such as fentanyl and sufentanil).29,51  The high incidence of pruritus after morphine (60 to 85%)10,11,13,19,30  and lipophilic opioids (60 to 90%)29,51  suggests a common μ-sensitive pathway modulates pruritus in response to these medications (table 1). However, a key difference between these two classes of opioid drugs is the onset and duration of pruritus; pruritus occurs within hours and lasts up to several days in patients receiving epidural and spinal morphine.30,31  With lipid-soluble opioids, the onset of pruritus can occur as rapidly as within minutes of administration and persists up to several hours.25,29  These differences in onset and duration reflect the pharmacokinetics of these intrathecally administered opioid medications. Microdialysis studies in pigs32  (using equimolar doses of morphine, fentanyl, and sufentanil) have revealed that spinal exposure to morphine was greater than lipophilic opioids because of morphine’s low spinal cord distribution volume and slow clearance into the plasma. Fentanyl and sufentanil, in contrast, have been found to rapidly clear into the plasma and epidural fat, respectively, reducing their spinal bioavailability.32  In a clinical study examining the clearance of opioid medications from the cerebrospinal fluid (CSF), volunteers received an intrathecal injection of both morphine and fentanyl (50 μg each). The ratio of morphine to fentanyl in the CSF was found to increase over time (reaching 4:1 within 2 h).52  The solubility of morphine compared to lipid-soluble opioids, such as fentanyl, clearly affect the bioavailability and thus onset and duration of opioid analgesia and its side effects. Furthermore, the bioavailability of neuraxial morphine supports its suitability for acute postoperative pain, such as for Enhanced Recovery after Surgery53  and in obstetric settings54 ; however, its long elimination time must be considered against its delayed adverse effects, such as pruritus.

It has been proposed that release of histamine underlies opioid-induced pruritus,55  although the route of administration might lead to differential impact of mast cells on pruritus (fig. 1). Intramuscular and subcutaneous morphine have been shown to evoke pruritus and vasodilation at the injection site.56  One study that performed in vivo microdialysis in human skin found that intradermal injections of morphine led to dose-dependent increases in local histamine and itch sensations.57  Similarly, examination of blood samples from patients with parenteral exposure to opioids has also revealed an elevation in histamine levels.33–35  Last, in vitro studies in both human and rodent models have confirmed that opioids, such as morphine, act directly on mast cells to drive degranulation and histamine release.58–60 

Fig. 1.

Proposed mechanisms of opioid-induced pruritus. This review summarizes mechanisms by which opioids could drive pruritus in the skin, dorsal root ganglia, and spinal cord dorsal horn. In the skin, systemic opioids can cause mast cell degranulation through activation of mas-related G protein–coupled receptor X2 (MRGPRX2) on mast cells. Neuraxial opioids are proposed to drive itch through spinal neurons containing the μ-opioid receptor in the spinal cord dorsal horn.

Fig. 1.

Proposed mechanisms of opioid-induced pruritus. This review summarizes mechanisms by which opioids could drive pruritus in the skin, dorsal root ganglia, and spinal cord dorsal horn. In the skin, systemic opioids can cause mast cell degranulation through activation of mas-related G protein–coupled receptor X2 (MRGPRX2) on mast cells. Neuraxial opioids are proposed to drive itch through spinal neurons containing the μ-opioid receptor in the spinal cord dorsal horn.

Close modal

Only recently, however, has it become clear how opioids could directly activate mast cells. Morphine was recently found to induce mast cell degranulation through activation of mas-related G protein-coupled receptor X2 (MRGPRX2), a primate-exclusive G protein–coupled receptor, rather than canonical opioid receptors (such as the μ-opioid receptor).58  Binding of opioids to MRGPRX2 leads to increases in intracellular calcium in mast cells.58  This is thought to occur through the phospholipase Cβ pathway, which results in the release of mediators, such as histamine.61  MRGPRX2 is implicated in itch and pain,62  and the restricted expression of MRGPRX2 on mast cells, which can be activated in the absence of atopy,61  such as by direct binding of opioids,58  establishes a mechanism for how opioids can directly act on mast cells to give rise to pruritus (fig. 2). The expression of MRGPRX2 on mast cells may also underlie anaphylaxis after opioid administration, which comprised 2.6% of all cases of anaphylaxis caused by anesthetics.63  For these reasons, MRGPRX2 should be considered a target for IgE-independent allergic reactions to perioperative drugs such as morphine administered subcutaneously and intravenously.

Fig. 2.

Systemic and neuraxial opioid–induced pruritus are separately modulated. Systemic (oral, subcutaneous, and parenteral) morphine may drive pruritus through the engagement of mas-related G protein–coupled receptor X2 (MRGPRX2) on mast cells. Neuraxial (epidural and intrathecal) opioid-induced pruritus, on the other hand, is likely driven by spinal neurons containing the μ-opioid receptor, because less than 0.01% of the peak concentration detected in the cerebrospinal fluid is detected in the plasma after neuraxial opioid administration.

Fig. 2.

Systemic and neuraxial opioid–induced pruritus are separately modulated. Systemic (oral, subcutaneous, and parenteral) morphine may drive pruritus through the engagement of mas-related G protein–coupled receptor X2 (MRGPRX2) on mast cells. Neuraxial (epidural and intrathecal) opioid-induced pruritus, on the other hand, is likely driven by spinal neurons containing the μ-opioid receptor, because less than 0.01% of the peak concentration detected in the cerebrospinal fluid is detected in the plasma after neuraxial opioid administration.

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However, for neuraxial opioids, the evidence that a mast cell–dependent mechanism underlies pruritus is less compelling. In humans, the neuraxial administration of fentanyl, a lipophilic and synthetic opioid, evokes pruritus, even though fentanyl does not cause mast cell degranulation and histamine release as morphine does.60,64–66  Furthermore, clinical plasma concentrations of morphine are orders of magnitude smaller than CSF concentrations after neuraxial morphine administration (less than 0.01%),67,68  and the concentration of morphine detected in the plasma is likely insufficient to cause mast cell degranulation, as suggested by in vitro studies (fig. 2).58–60  Mast cell–mediated pruritus after the local injection of opioids, as seen after intradermal injections of morphine, is restricted to the site of injection57  and does not explain how neuraxial opioids, frequently administered into lumbar segments, evoke pruritus in other dermatomes, including those innervating facial regions.10,11,13  Last, genetically modified mice lacking mast cells scratch at levels similar to controls in response to intrathecal morphine.36  Therefore, a mast cell-dependent mechanism does not explain the prevalence and spread of neuraxial opioid–induced pruritus. Taken together, although there is evidence that histamine release may cause itch from peripheral (subcutaneous, oral, and intravenous) opioids, this process is unlikely to contribute to neuraxial opioid–induced pruritus.

With neuraxial morphine-induced itch, it has been proposed that the nervous system could be responsible for mediating the sensation of itch12,69  (fig. 2). The analgesic benefits of opioids are mediated through the nervous system70,71 ; therefore, it is proposed that pruritus, another sensory symptom, may also be mediated through neurons. Although both intrathecal and epidural opioids cause pruritus,10,11  pruritus occurs more commonly with the intrathecal route of administration; a review of 11 trials by Simmons et al.72  found the average relative risk of developing pruritus in combined spinal analgesia relative to epidural analgesia to be 1.80 (95% CI, 1.22 to 2.65).72  This supports the possibility that pruritus occurs because of a direct effect of the opioid within the neuraxis.

Further evidence for a neuronal mechanism for pruritus is the observation that opioid lipophilicity is associated with the onset and severity of pruritus among patients. For example, lipophilic opioids, such as fentanyl, which more readily cross the blood–brain barrier, are associated with a more rapid onset and shorter duration of pruritus than hydrophobic opioids such as morphine,12,21,25,73  consistent with a neuronal mechanism of action. These clinical observations further support the idea that two separate mechanisms underlie opioid-induced pruritus arising from different routes of administration (fig. 2): systemic opioids activate mast cells to drive itch through histamine release, whereas neuraxial opioids act on CNS pathways to cause itch.

Opioid-induced Pruritus Mediated by Primary Afferents

Primary sensory neurons respond directly to itch-inducing agents. For example, a class of transient receptor potential cation channel subfamily V member 1 (TRPV1)-containing C-fibers that innervate the skin expresses the histamine receptor, which can be activated by histamine.74,75  Upon activation with histamine, these neurons transmit pruriceptive information to the superficial layers of the spinal cord, and this information ascends through the spinothalamic tracts to target the primary sensory and cingulate cortices.76  Thus, if opioid-induced pruritus causes the release of histamine, then peripheral opioid-induced itch may occur through this pathway (fig. 1). Consistent with this view, intradermal injection of the μ-opioid receptor agonist D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) elicits itch in mice that is abrogated with the ablation of TRPV1-expressing fibers.56  Another channel expressed by primary afferents is transient receptor potential cation channel, subfamily A, member 1 (TRPA1), which has also been implicated in acute and chronic itch.77,78  However, the contribution of TRPA1 to peripheral opioid-induced itch is unlikely because TRPA1-deficient mice exhibit normal histamine-evoked itch.77,78  These findings suggest that for subcutaneous, oral, and intravenous opioids, itch likely occurs through TRPV1, and not TRPA1, sensory neurons after the release of histamine from mast cells.33–35  However, given the weak association between neuraxial opioids and histamine release,60,64–66  histamine receptor–expressing sensory neurons are not likely to be involved in neuraxial opioid–induced pruritus.

Presently, neuraxial opioids are not believed to act directly on μ-opioid receptor expressing sensory neurons to elicit itch. Conditional deletion of the μ-opioid receptor from TRPV1 and somatostatin neurons, which have been implicated in itch signaling, did not affect intrathecal morphine–induced itch in mice.45  In support of this view, other studies have suggested that rather than direct modulation of these peripheral sensory neurons, neuraxial opioids may influence pruriceptive processing centrally. One study, performed in rats, identified that neuraxial morphine augmented the activity in trigeminothalamic tract neurons in response to itch stimuli.79  Trigeminothalamic tract neurons are analogous to spinothalamic tract neurons in the spinal cord but relay information pertaining to the head and neck regions rather than the body. It was found that intrathecal morphine caused these neurons to increase their ongoing activity to pruritogens applied to the skin.79  Intrathecal morphine also enhanced responses to innocuous mechanical stimuli, suggesting that opioids may also cause sensitization to touch-evoked itch.79  Another study in mice also examined the role of TRPV1 antagonists and neuraxial morphine-induced itch.80  In this study, it was observed that the intrathecal delivery of a TRPV1 antagonist reduced morphine-induced itch in mice. Together, these studies suggest that neuraxial morphine can evoke sensitization of central pathways, leading to an enhancement of responsiveness within these circuits to peripheral stimulation.

Opioid Pharmacology as a Key to Understanding Spinal Circuitry

It is curious that opioids suppress pain but evoke itch. Conversely, intense pain can also suppress itch.81,82  Previously, it was believed that itch occurs because of a reduction in pain signaling.44  However, detailed pharmacologic investigations have largely ruled out this theory.50,83  Several studies have shown that μ-opioid agonists, such as morphine, elicit itch, but δ- and κ-opioid receptor agonists, which also produce analgesia,84  do not cause scratching behavior.69,83,85  Instead, selective κ-opioid receptor agonists have been shown to suppress itch in preclinical models86–88  and have been approved to treat chronic pruritus in Japan.89  Notably, μ and κ-opioid receptors often exert opposing effects in several regions of the central nervous system; whereas μ-opioid receptor agonists produce analgesia, euphoria, and itch, κ-opioid receptor agonists are antipruritic and dysphoric.90,91  Clearly, a simple model whereby a suppression of pain is sufficient to evoke itch does not explain these observations. The differential roles of these opioid receptors and their agonism in the context of itch underscores that opioid-induced pruritus is a complex and active process.

Spinal Disinhibition Causes Neuraxial Opioid–induced Itch in Preclinical Models

The mechanisms of opioid-induced itch at the level of the dorsal horn have only recently begun to be examined. One study in mice suggested that neuraxial morphine causes itch through activation of gastrin-releasing peptide receptor neurons in the dorsal horn,50  an excitatory population that is involved in mediating itch (fig. 3).92,93  This study suggested that neuraxial morphine triggers heterodimerization of the μ-opioid receptor with gastrin-releasing peptide receptor.50  After heterodimerization, the authors proposed that itch occurs after the activation of excitatory downstream pathways involving phospholipase Cβ3 and an increase in intracellular calcium.50  However, recent sequencing94,95  and neurochemical studies36,45  cast doubt on this conclusion. Opioids typically signal through Gαi-coupled G protein–coupled receptors, resulting in potassium efflux and hyperpolarization, which inhibits neuronal activity.96,97  Thus, the conclusion that neuraxial opioid–induced itch occurs through dimerization of the μ-opioid receptor and gastrin-releasing peptide receptor is controversial.69 

Fig. 3.

Mechanisms of action of proposed therapies for neuraxial opioid–induced pruritus. Antagonists (naloxone) of the μ-opioid receptor are proposed to act on μ-opioid receptor–expressing inhibitory neurons to relieve pruritus. Propofol may potentiate the inhibitory action of these inhibitory neurons to suppress itch. Mixed antagonist–agonists (nalbuphine and butorphanol) inhibit itch through antagonism of the μ-opioid receptor and agonism of the κ-opioid receptor. Dopamine and serotonin receptor antagonists (droperidol and ondansetron, respectively) are thought to exert their action on spinal neurons, although this has not been tested directly. GABA, γ-aminobutyric acid.

Fig. 3.

Mechanisms of action of proposed therapies for neuraxial opioid–induced pruritus. Antagonists (naloxone) of the μ-opioid receptor are proposed to act on μ-opioid receptor–expressing inhibitory neurons to relieve pruritus. Propofol may potentiate the inhibitory action of these inhibitory neurons to suppress itch. Mixed antagonist–agonists (nalbuphine and butorphanol) inhibit itch through antagonism of the μ-opioid receptor and agonism of the κ-opioid receptor. Dopamine and serotonin receptor antagonists (droperidol and ondansetron, respectively) are thought to exert their action on spinal neurons, although this has not been tested directly. GABA, γ-aminobutyric acid.

Close modal

Alternatively, molecularly defined inhibitory neurons have been implicated in the modulation of itch. For example, inhibitory neurons containing dynorphin and neuropeptide Y have been shown to be important for the inhibition of chemical88,98,99  and mechanical itch,100,101  respectively. When either dynorphin neurons or neuropeptide Y neurons are lost during development, mice show spontaneous scratching behavior suggesting that these populations are involved in the tonic inhibition of itch.88,98–101  In a recent study, selective removal of the μ-opioid receptor from inhibitory neurons (neurons that produce γ-amino butyric acid [GABA]) abolished opioid-induced itch in a mouse model.45  A second study focused on a subset of inhibitory neurons containing dynorphin, the endogenous peptide for the κ-opioid receptor.36  In this study, the expression of the μ-opioid receptor was found to be required for morphine-induced itch.36  κ-opioid signaling alleviated morphine-induced itch in both mice and nonhuman primates.36  Therefore, emerging evidence highlights that opioids could cause itch through inhibition of inhibitory neurons; rather than through heterodimerization between the μ-opioid receptor and gastrin-releasing peptide receptor, there is now compelling evidence that opioids cause itch through a mechanism of neuronal disinhibition (fig. 3).

These two recent studies, from two independent groups, highlight the role of inhibitory neurons in the spinal cord as the crucial mediators of opioid-induced itch. To date, they provide the most compelling evidence for how a spinal mechanism is responsible for neuraxial opioid–induced itch.

Given the dose-dependent nature of opioid-induced pruritus, clinicians have managed to control unwanted side effects by tightly titrating the dose needed to optimize analgesia.102  Multimodal analgesia has also been shown to be effective at both managing pain and reducing opioid side effects through synergy between multiple agents.103  For example, the combination of local anesthetics, such as bupivacaine, with opioid analgesics reduces the severity of pruritus in the immediate postoperative period.51,73  However, despite efforts to reduce the dose of opioids administered and to apply a multimodal approach to neuraxial analgesia, pruritus as a side effect persists for some people. Common and modern treatment options for these patients are described below (table 2).

Table 2.

Frequently Prescribed Treatments for Opioid-induced Pruritus

Frequently Prescribed Treatments for Opioid-induced Pruritus
Frequently Prescribed Treatments for Opioid-induced Pruritus

Histamine Receptor Antagonists

The role of antihistamines in neuraxial opioid–induced pruritus is contested. Antihistamines reduce diaphoresis and wheal-and-flare responses to parenteral opioids,34  and many providers continue to use antihistamines to manage pruritus induced by opioids. Nevertheless, the appropriateness of this practice in the setting of neuraxial opioid–induced pruritus is questionable.124  Several studies indicate that histamine receptor antagonists, such as diphenhydramine and promethazine, reduce itch in obstetric patients who receive neuraxial opioids.104.124–127  However, antihistamines have also been shown to cause sedation,19,105,106  and it has been observed that the sedating effects of antihistamines have caused patients to verbally deny itch but continue to scratch or that patients report itchiness in between periods of sleep.10,104,106  Thus, it is possible that the apparent reduction in itch with antihistamine treatment seen in some studies may, in fact, be secondary to drowsiness.128 

Comparisons between the effectiveness of mixed κ agonist–μ antagonist and antihistamines for the management of neuraxial opioid–induced pruritus have revealed major limitations of antihistamine treatment for this form of pruritus.104,125,126,129–131  In spite of these limitations, they continue to be prescribed for both peripheral and central opioid-induced pruritus.12,127  Given new evidence that spinal neurons mediate neuraxial opioid–induced pruritus,45,36,69  antihistamines likely have no role in the treatment of neuraxial opioid–induced pruritus, but they may have a key role in the treatment of subcutaneous, oral, and intravenous morphine–induced pruritus.

μ-Opioid Receptor Antagonists

To date, the most effective treatments for opioid-induced pruritus have included pharmacologic agents that antagonize the μ-opioid receptor, which pose disadvantages in that they can reverse analgesia.107,132  Clinically, μ-opioid receptor antagonists have also been shown to be effective for the management of parenteral opioid–induced pruritus.129  For patients on parenteral opioid therapy, such as patients with sickle cell disease, the coadministration of the opioid analgesic and its antagonist helps to mitigate pruritus,42  particularly when small doses are infused (e.g., naloxone 0.25 to 2 μg · kg–1 · h–1 intravenous push).133,134  Naloxone is also effective at reducing wheal-and-flare responses caused by morphine.135  These findings highlight the utility of μ-opioid receptor antagonists in the management of peripherally mediated and histamine-dependent opioid induced pruritus.

μ-Opioid receptor antagonists are also effective for the treatment of pruritus induced by neuraxial opioid administration.12,13  Naloxone and naltrexone are direct opioid receptor antagonists often used to reduce both the frequency and the severity of pruritus evoked by neuraxial opioid analgesia.132  Unfortunately, these antagonists, at doses that are clinically effective at reversing pruritus, may also reverse the analgesic effects of opioids41  (e.g., complete reversal for opioid-induced respiratory depression at doses of naloxone 0.1 mg/kg intravenous push).108  In nonhuman primates, the one-time administration of a selective μ-opioid receptor antagonist, such as nalmefene, produced a 10-fold rightward shift in both morphine-induced scratching and analgesia.83  Furthermore, the mean pKB (an estimate of antagonist affinity) of nalmefene was found to be similar for both scratching and thermal nociception endpoints,83  indicative of a circumscribed window for the management of itch without affecting analgesia by μ-opioid receptor antagonism, making these agents suboptimal for the treatment of pruritus in obstetric patients. Thus, optimal doses of μ antagonists, such as naloxone or naltrexone, to relieve clinical pruritus often come with a risk-benefit discussion with patients about their preferential priorities on pain control versus itch.

Alternatively, mixed opioid receptor agonists, such as nalbuphine (1 to 5 mg IV)136  and butorphanol (0.2 to 2 mg IV)137  are also clinically effective therapies for neuraxial opioid–induced pruritus.19,107,138  They are frequently used due to their improved ability to manage pruritus without reducing analgesia compared to selective μ-opioid receptor antagonists.107  Nalbuphine is a mixed antagonist of the μ-opioid receptor and agonist of the κ-opioid receptor, and because of its partial antagonism of the μ-opioid receptor, reversal of analgesia remains a concern.109  Another potential limitation of nalbuphine is its sedating side effect,19,133  although this is only observed when a high dose (10 mg/70 kg) is used,139  which is beyond the range used to manage pruritus clinically.24  In contrast, butorphanol is a partial agonist of both the μ- and κ-opioid receptors. Similar to nalfurafine, butorphanol has also been reported as an effective treatment of opioid-induced pruritus, particularly among pediatric patients.140,141  Thus, nalfurafine and butorphanol may pose therapeutic advantages over selective μ-antagonists because of their agonism of the κ-opioid receptor and the ability to directly modulate spinal itch circuits.

Notably, both opioid antagonists and mixed agonist–antagonists are effective for other clinical instances of pruritus, including those associated with systemic disease or of dermatologic origin. Nalbuphine, for example, is effective at managing pruritus among patients with end stage renal disease142,143  and contact dermatitis.144  These observations suggest that different forms of pruritus (spanning from systemic disease to drug-induced) converge on a common itch pathway that depend on central opioid signaling, likely centered upon the involvement of endogenous endorphin and dynorphin tone. Like many drugs frequently used in clinical anesthesia practice, the use of nalbuphine for the clinical management of opioid-induced pruritus is off-label.145  Given the effectiveness of nalbuphine for the prevention and severity of pruritus,19  a new drug indication of nalbuphine for opioid-induced pruritus could facilitate its widespread use within clinical practice.

Selective κ-Opioid Receptor Agonists

The dynorphin–κ-opioid receptor system has been heavily implicated in itch. Pharmacologic and genetic manipulations of spinal dynorphin-expressing neurons in freely behaving animals have uncovered that spinal dynorphin is required for the inhibition of itch.88,99  In rodent and nonhuman primate models, selective κ-opioid receptor agonists, such as nalfurafine, have been shown to be important for the inhibition of several forms of chemical, immunologic, and drug-induced (including opioid-induced) itch.87,146,147  Clinically, nalfurafine (2.5 or 5.0 μg per os)148  has been shown to be effective for the treatment of uremic and cholestatic pruritus in Japan.89 

Emerging evidence in preclinical models, involving both mice and nonhuman primates, indicate that the intrathecal and systemic administration of κ-opioid receptor agonists can reduce morphine-induced itch without reducing morphine-induced analgesia.36,87,149  In preclinical models, nalfurafine has been found to restore dynorphin signaling disrupted by neuraxial μ-opioid receptor agonists, such as morphine.36  These preclinical findings indicate that selective κ-opioid receptor agonists should be further considered for opioid-induced pruritus in the future.

Presently, however, nalfurafine does not have approval by the European Medicines Agency (Amsterdam, The Netherlands) or Food and Drug Administration (Silver Spring, Maryland) for clinical use in Europe and the United States, respectively.150  One concern has been its sedating effects, which has been observed after long-term use in dogs,151  but this has not been a consistent finding in other animal models and in patients.87,148,152  In European trials, nalfurafine (5 μg per os) did not significantly reduce the severity of uremic pruritus compared to placebo over 8 weeks.151  However, one key difference between the studies conducted in Europe151  and Japan153  was the duration of the trial (weeks compared to days, respectively), and notably, in the European trials, both the nalfurafine-treated and placebo groups exhibited significant reductions in self-reported visual analogue scale intensities of pruritus over the course of the study.151  Given the incidence of opioid-induced pruritus in the postoperative setting, the effectiveness of nalfurafine may be more evident in acute settings, although further clinical trials in perioperative and acute care settings is necessary.

Serotonin Receptor Antagonists

5-Hydroxytryptamine receptor antagonists are frequently used to treat postoperative nausea and vomiting. Both of these side effects are observed in postoperative patients who receive neuraxial morphine.154,155  Several studies have revealed that prophylaxis with a 5-hydroxytryptamine receptor antagonist (such as ondansetron, ranging from 4 to 8 mg IV) does not significantly reduce the incidence of pruritus.20,110–114,154  A systematic review by Bonnet et al.115  of 15 randomized controlled trials suggests that 5-hydroxytryptamine receptor antagonists may reduce the intensity of opioid-induced pruritus but also concluded that the trials included in the systematic review, such as small studies that favor the publication of positive findings, may have suffered from publication bias. Thus, there is still a lack of consensus on the clinical effectiveness of 5-hydroxytryptamine receptor antagonists in opioid-induced pruritus.115,156 

The mechanism by which 5-hydroxytryptamine receptor antagonists such as ondansetron alleviate itch is not clear. 5-Hydroxytryptamine receptor immunoreactivity has been observed in the spinal dorsal horn,157  and the endogenous source of serotonin is thought to originate from descending fibers arising within the brainstem.158  Depletion of supraspinal serotonin has been shown to alleviate pruritogen-induced itch in rodents,159  which may partially explain how antagonism of 5-hydroxytryptamine receptor reduces opioid-induced itch. However, spinal neurons expressing 5-hydroxytryptamine receptor and the μ-opioid receptor have been found to comprise nonoverlapping populations,95  making it unlikely that agents such as ondansetron could directly reduce the activity of neurons responsible for opioid-induced itch. In rhesus monkeys, ondansetron has also been found to be ineffective at reducing morphine-induced itch, even at high doses that caused extrapyramidal effects.69  Given these conflicting reports between human and animal models and the lack of a cellular basis for how serotonin and opioid signaling could converge, 5-hydroxytryptamine receptor antagonists are currently not considered front-line therapies for opioid-induced pruritus and likely have a limited role in prophylaxis against opioid-induced pruritus.

Propofol

The effectiveness of subhypnotic doses of propofol (10 to 30 mg IV) for the treatment of opioid-induced pruritus remains controversial. In one double-blind trial, propofol (10 mg IV) was observed to reduce morphine-induced pruritus compared to placebo (85% compared to 16%, respectively).160  The patients in this study had received either epidural or spinal morphine for a variety of surgical procedures including gynecologic, gastrointestinal, thoracic, and orthopedic surgery.160  Another study also reported that propofol (10 mg IV) protected against pruritus after intrathecal morphine for arthroplasty surgery.116  However, Warwick et al.117  did not confirm these findings in a double-blind study of obstetric patients; propofol (10 to 20 mg IV) had no effect on the onset or severity of pruritus after intrathecal morphine. Age and sex differences among these studies may account for the variable effectiveness of the similar doses of propofol used to mitigate neuraxial morphine-induced pruritus. These studies further underscore that pruritus disproportionately occurs in younger and female obstetric patients,16,24–26  who may be less responsive to the antipruritic effects of propofol. Another possibility for the observed differences across studies is that the dose of propofol used may not have been adequate to achieve clinical effect. Thus, although propofol has been observed to reduces incidence of pruritus in patients receiving morphine for a variety of elective surgeries,116.160 its benefit in the treatment of opioid-induced pruritus within the obstetric population remains questionable.117 

Recent work in rodents have revealed that neurons producing GABA are required for neuraxial opioid–induced itch,36,45  and the administration of propofol, through potentiation of GABA receptors, may enhance the ability of these neurons to dampen excitatory spinal circuits92  involved in itch transmission. Additional dose-response studies are necessary to identify the appropriate dose of propofol for management of pruritus without sedation.

Gabapentin

Gabapentin has been shown to be effective for several forms of pruritus in systemic disease, including uremic pruritus, pruritus in multiple sclerosis, and pruritus of unknown origin.118,119,161  Its use in the treatment of neuraxial opioid–induced pruritus is less clear. Preoperative gabapentin (1,200 mg per os) has been found to significantly delay the onset and reduce the incidence and severity of intrathecal morphine–induced pruritus in patients undergoing orthopedic surgery162  and prolong the onset of pruritus in patients receiving spinal morphine for unilateral hernia repair.120  However, a lower dose (600 mg) was not found to significantly decrease the incidence of pruritus compared to placebo and was associated with urinary retention.163  Further pharmacologic studies in preclinical and clinical models are necessary to characterize the mechanism of action of gabapentin within the nervous system. However, recent efforts have noted the safety concerns associated with gabapentin in the perioperative setting; the risks of adverse effects and lack of significant analgesic effect on postoperative pain suggest that the use of gabapentin for opioid-induced pruritus should also be avoided.121,164 

Dopamine D2 Receptor Antagonists

Droperidol (1.25 mg IV), a short-acting, potent dopamine receptor antagonist, has been shown in several studies to be effective at reducing the incidence and severity of neuraxial opioid–induced pruritus and has previously been used for postoperative nausea and vomiting.104,122,165  However, dopamine receptor antagonists have been reported to be effective only when small doses of opioids are administered. Sedation has been shown to increase with escalating doses of droperidol (2.5 to 5 mg IV), which may confound its antipruritic effects.122  Given the broad influences of supraspinal dopamine signaling on the functions of spinal and dorsal root ganglion neurons, the antipruritic effects observed may be nonspecific.123  Emerging evidence indicates that low doses of droperidol may be safely used; however, clinical use of droperidol in a perioperative setting is limited by an Food and Drug Administration black box warning because of its risk for sudden cardiac death.166  The warning will likely preclude any clinical adoption of droperidol to treat opioid-induced pruritus.

Emerging Treatments for Opioid-induced Pruritus and Future Directions

All existing treatment options for opioid-induced pruritus have undesirable side-effect profiles. Furthermore, many of these treatments are used empirically and off-label. Because of the limitations of currently available treatments, some patients or providers may elect to forgo analgesia or opt for suboptimal analgesia that excludes neuraxial opioids, but these practices can lead to unnecessary pain and suffering.167  Recent success in preclinical models suggests that nalfurafine, a selective κ-opioid receptor agonist, may be used to manage opioid-induced pruritus without limiting opioid-induced analgesia,36  but further basic, translational, and clinical research is required before recommendations for clinical use in opioid-induced pruritus can be made. Optimization of opioid analgesia and development of improved therapies for opioid-induced pruritus have the potential to significantly improve the clinical standards of care for patients who receive opioids for the management of perioperative pain and experience pruritus as an unwanted side effect.

Conclusions

Pruritus after neuraxial opioids remains a highly common and dissatisfying side effect. Advancements in the understanding of mast cell biology and neuronal itch circuitry have provided clues as to how opioids can induce analgesia and evoke pruritus. Existing evidence suggests that parenteral opioids cause pruritus through histamine release, whereas neuraxial opioid–induced pruritus occurs through a mechanism of neuronal disinhibition in the spinal cord dorsal horn. The differential modulation of peripheral and neuraxial opioid–induced pruritus by mast cells and neurons, respectively, further highlight the complexity of the side effects of opioid use. Emerging evidence suggests that pruritus arises because of the dysregulation of opioid-sensitive pathways involving μ- and κ-opioid receptor signaling, which parallels other forms of chronic, systemic, and drug-induced pruritus. Ultimately, a richer understanding of the genetic, molecular, and cellular underpinnings of opioid-induced pruritus may provide a basis upon which to develop improved therapies that can manage pain but do not cause itch.

Research Support

Supported by the Virginia Kaufman Endowment Fund; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (Bethesda, Maryland) grant No. AR063772; National Institute of Neurological Disorders and Stroke, National Institutes of Health grant No. NS096705 (to Dr. Ross); National Research Service Award grant No. F31 F31NS113371; and National Institute of General Medical Sciences, National Institutes of Health grant No. T32GM008208 (to Dr. Nguyen).

Competing Interests

The authors declare no competing interests.

1.
Dowell
D
,
Haegerich
TM
,
Chou
R
:
CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016
MMWR Recomm Rep
.
2016
;
65
:
1
49
2.
Sarma
VJ
,
Boström
UV
:
Intrathecal morphine for the relief of post-hysterectomy pain: A double-blind, dose-response study.
Acta Anaesthesiol Scand
.
1993
;
37
:
223
7
3.
Fassoulaki
A
,
Gatzou
V
,
Petropoulos
G
,
Siafaka
I
:
Spread of subarachnoid block, intraoperative local anaesthetic requirements and postoperative analgesic requirements in caesarean section and total abdominal hysterectomy.
Br J Anaesth
.
2004
;
93
:
678
82
4.
Dualé
C
,
Frey
C
,
Bolandard
F
,
Barrière
A
,
Schoeffler
P
:
Epidural versus intrathecal morphine for postoperative analgesia after caesarean section.
Br J Anaesth
.
2003
;
91
:
690
4
5.
Chadwick
HS
,
Ready
LB
:
Intrathecal and epidural morphine sulfate for post-cesarean analgesia: A clinical comparison.
Anesthesiology
.
1988
;
68
:
925
9
6.
Grant
CRK
,
Checketts
MR
:
Analgesia for primary hip and knee arthroplasty: The role of regional anaesthesia.
Cont Educ Anaesth Crit Care Pain
.
2008
;
8
:
56
61
7.
de Leon-Casasola
OA
,
Karabella
D
,
Lema
MJ
:
Bowel function recovery after radical hysterectomies: Thoracic epidural bupivacaine-morphine versus intravenous patient-controlled analgesia with morphine: A pilot study.
J Clin Anesth
.
1996
;
8
:
87
92
8.
Jørgensen
H
,
Wetterslev
J
,
Møiniche
S
,
Dahl
JB
:
Epidural local anaesthetics versus opioid-based analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after abdominal surgery.
Cochrane Database Syst Rev
.
2000
:
CD001893
9.
Chestnut
DH
:
Efficacy and safety of epidural opioids for postoperative analgesia.
Anesthesiology
.
2005
;
102
:
221
3
10.
Ballantyne
JC
,
Loach
AB
,
Carr
DB
:
Itching after epidural and spinal opiates.
Pain
.
1988
;
33
:
149
60
11.
Szarvas
S
,
Harmon
D
,
Murphy
D
:
Neuraxial opioid–induced pruritus: A review.
J Clin Anesth
.
2003
;
15
:
234
9
12.
Kumar
K
,
Singh
SI
:
Neuraxial opioid–induced pruritus: An update.
J Anaesthesiol Clin Pharmacol
.
2013
;
29
:
303
7
13.
Ganesh
A
,
Maxwell
LG
:
Pathophysiology and management of opioid-induced pruritus.
Drugs
.
2007
;
67
:
2323
33
14.
Werawatganon
T
,
Charuluxanun
S
:
Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery.
Cochrane Database Syst Rev
.
2005
:
CD004088
15.
Hong
D
,
Flood
P
,
Diaz
G
:
The side effects of morphine and hydromorphone patient-controlled analgesia.
Anesth Analg
.
2008
;
107
:
1384
9
16.
Yurashevich
M
,
Habib
AS
:
Monitoring, prevention and treatment of side effects of long-acting neuraxial opioids for post-cesarean analgesia.
Int J Obstet Anesth
.
2019
;
39
:
117
28
17.
Mugabure Bujedo
B
:
A clinical approach to neuraxial morphine for the treatment of postoperative pain.
Pain Res Treat
.
2012
;
2012
:
612145
18.
Tarcatu
D
,
Tamasdan
C
,
Moryl
N
,
Obbens
E
:
Are we still scratching the surface?: A case of intractable pruritus following systemic opioid analgesia.
J Opioid Manag
.
2007
;
3
:
167
70
19.
Jannuzzi
RG
:
Nalbuphine for treatment of opioid-induced pruritus: A systematic review of literature.
Clin J Pain
.
2016
;
32
:
87
93
20.
Yeh
HM
,
Chen
LK
,
Lin
CJ
,
Chan
WH
,
Chen
YP
,
Lin
CS
,
Sun
WZ
,
Wang
MJ
,
Tsai
SK
:
Prophylactic intravenous ondansetron reduces the incidence of intrathecal morphine–induced pruritus in patients undergoing cesarean delivery.
Anesth Analg
.
2000
;
91
:
172
5
21.
Shah
MK
,
Sia
AT
,
Chong
JL
:
The effect of the addition of ropivacaine or bupivacaine upon pruritus induced by intrathecal fentanyl in labour.
Anaesthesia
.
2000
;
55
:
1008
13
22.
Jiang
CJ
,
Liu
CC
,
Wu
TJ
,
Sun
WZ
,
Lin
SY
,
Huang
FY
,
Chao
CC
:
Mini-dose intrathecal morphine for post-cesarean section analgesia.
Ma Zui Xue Za Zhi
.
1991
;
29
:
683
9
23.
Sultan
P
,
Halpern
SH
,
Pushpanathan
E
,
Patel
S
,
Carvalho
B
:
The effect of intrathecal morphine dose on outcomes after elective cesarean delivery: A meta-analysis.
Anesth Analg
.
2016
;
123
:
154
64
24.
Tubog
TD
,
Harenberg
JL
,
Buszta
K
,
Hestand
JD
:
Prophylactic nalbuphine to prevent neuraxial opioid–induced pruritus: A systematic review and meta-analysis of randomized controlled trials.
J Perianesth Nurs
.
2019
;
34
:
491
501.e8
25.
Wells
J
,
Paech
MJ
,
Evans
SF
:
Intrathecal fentanyl-induced pruritus during labour: The effect of prophylactic ondansetron.
Int J Obstet Anesth
.
2004
;
13
:
35
9
26.
Charuluxananan
S
,
Somboonviboon
W
,
Kyokong
O
,
Nimcharoendee
K
:
Ondansetron for treatment of intrathecal morphine–induced pruritus after cesarean delivery.
Reg Anesth Pain Med
.
2000
;
25
:
535
9
27.
DiGiusto
M
,
Bhalla
T
,
Martin
D
,
Foerschler
D
,
Jones
MJ
,
Tobias
JD
:
Patient-controlled analgesia in the pediatric population: Morphine versus hydromorphone.
J Pain Res
.
2014
;
7
:
471
5
28.
Tsai
FF
,
Fan
SZ
,
Yang
YM
,
Chien
KL
,
Su
YN
,
Chen
LK
:
Human opioid μ-receptor A118G polymorphism may protect against central pruritus by epidural morphine for post-cesarean analgesia.
Acta Anaesthesiol Scand
.
2010
;
54
:
1265
9
29.
Gulhas
N
,
Erdil
FA
,
Sagir
O
,
Gedik
E
,
Togal
T
,
Begec
Z
,
Ersoy
MO
:
Lornoxicam and ondansetron for the prevention of intrathecal fentanyl-induced pruritus.
J Anesth
.
2007
;
21
:
159
63
30.
Waxler
B
,
Dadabhoy
ZP
,
Stojiljkovic
L
,
Rabito
SF
:
Primer of postoperative pruritus for anesthesiologists.
Anesthesiology
.
2005
;
103
:
168
78
31.
Slappendel
R
,
Weber
EW
,
Benraad
B
,
van Limbeek
J
,
Dirksen
R
:
Itching after intrathecal morphine: Incidence and treatment.
Eur J Anaesthesiol
.
2000
;
17
:
616
21
32.
Ummenhofer
WC
,
Arends
RH
,
Shen
DD
,
Bernards
CM
:
Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil.
Anesthesiology
.
2000
;
92
:
739
53
33.
Ennis
M
,
Schneider
C
,
Nehring
E
,
Lorenz
W
:
Histamine release induced by opioid analgesics: A comparative study using porcine mast cells.
Agents Actions
.
1991
;
33
:
20
2
34.
Philbin
DM
,
Moss
J
,
Rosow
CE
,
Akins
CW
,
Rosenberger
JL
:
Histamine release with intravenous narcotics: Protective effects of H1 and H2-receptor antagonists.
Klin Wochenschr
.
1982
;
60
:
1056
9
35.
Baldo
BA
,
Pham
NH
:
Histamine-releasing and allergenic properties of opioid analgesic drugs: Resolving the two.
Anaesth Intensive Care
.
2012
;
40
:
216
35
36.
Nguyen
E
,
Lim
G
,
Ding
H
,
Hachisuka
J
,
Ko
M-C
,
Ross
SE
:
Morphine acts on spinal dynorphin neurons to cause itch through disinhibition.
Sci Transl Med
.
2021
;
13
:
eabc3774
37.
Kaye
AD
,
Urman
RD
,
Cornett
EM
,
Hart
BM
,
Chami
A
,
Gayle
JA
,
Fox
CJ
:
Enhanced recovery pathways in orthopedic surgery.
J Anaesthesiol Clin Pharmacol
.
2019
;
35
(
suppl 1
):
35
9
38.
Szarvas
S
,
Chellapuri
RS
,
Harmon
DC
,
Owens
J
,
Murphy
D
,
Shorten
GD
:
A comparison of dexamethasone, ondansetron, and dexamethasone plus ondansetron as prophylactic antiemetic and antipruritic therapy in patients receiving intrathecal morphine for major orthopedic surgery.
Anesth Analg
.
2003
;
97
:
259
63
39.
LaBella
FS
,
Kim
RS
,
Templeton
J
:
Opiate receptor binding activity of 17-α-estrogenic steroids.
Life Sci
.
1978
;
23
:
1797
804
40.
Woodhouse
A
,
Hobbes
AFT
,
Mather
LE
,
Gibson
M
:
A comparison of morphine, pethidine and fentanyl in the postsurgical patient-controlled analgesia environment.
Pain
.
1996
;
64
:
115
21
41.
Gan
TJ
,
Ginsberg
B
,
Glass
PS
,
Fortney
J
,
Jhaveri
R
,
Perno
R
:
Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate.
Anesthesiology
.
1997
;
87
:
1075
81
42.
Koch
J
,
Manworren
R
,
Clark
L
,
Quinn
CT
,
Buchanan
GR
,
Rogers
ZR
:
Pilot study of continuous co-infusion of morphine and naloxone in children with sickle cell pain crisis.
Am J Hematol
.
2008
;
83
:
728
31
43.
Schmelz
M
,
Paus
R
:
Opioids and the skin: “Itchy” perspectives beyond analgesia and abuse.
J Invest Dermatol
.
2007
;
127
:
1287
9
44.
Ikoma
A
,
Steinhoff
M
,
Ständer
S
,
Yosipovitch
G
,
Schmelz
M
:
The neurobiology of itch.
Nat Rev Neurosci
.
2006
;
7
:
535
47
45.
Wang
Z
,
Jiang
C
,
Yao
H
,
Chen
O
,
Rahman
S
,
Gu
Y
,
Zhao
J
,
Huh
Y
,
Ji
RR
:
Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition.
Brain
.
2021
;
144
:
665
81
46.
Pettini
E
,
Micaglio
M
,
Bitossi
U
,
De Gaudio
AR
,
Degl’Innocenti
DR
,
Tofani
L
,
Limatola
V
,
Adembri
C
,
Di Filippo
A
:
Influence of OPRM1 polymorphism on postoperative pain after intrathecal morphine administration in Italian patients undergoing elective cesarean section.
Clin J Pain
.
2018
;
34
:
178
81
47.
Sia
AT
,
Lim
Y
,
Lim
EC
,
Goh
RW
,
Law
HY
,
Landau
R
,
Teo
YY
,
Tan
EC
:
A118G single nucleotide polymorphism of human μ-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia.
Anesthesiology
.
2008
;
109
:
520
6
48.
Wong
CA
,
McCarthy
RJ
,
Blouin
J
,
Landau
R
:
Observational study of the effect of μ-opioid receptor genetic polymorphism on intrathecal opioid labor analgesia and post-cesarean delivery analgesia.
Int J Obstet Anesth
.
2010
;
19
:
246
53
49.
Kung
CC
,
Chen
SS
,
Yang
HJ
,
Lai
CJ
,
Chen
LK
:
Pharmacogenetic study of pruritus induced by epidural morphine for post cesarean section analgesia.
Taiwan J Obstet Gynecol
.
2018
;
57
:
89
94
50.
Liu
XY
,
Liu
ZC
,
Sun
YG
,
Ross
M
,
Kim
S
,
Tsai
FF
,
Li
QF
,
Jeffry
J
,
Kim
JY
,
Loh
HH
,
Chen
ZF
:
Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids.
Cell
.
2011
;
147
:
447
58
51.
Mulroy
MF
,
Larkin
KL
,
Siddiqui
A
:
Intrathecal fentanyl-induced pruritus is more severe in combination with procaine than with lidocaine or bupivacaine.
Reg Anesth Pain Med
.
2001
;
26
:
252
6
52.
Eisenach
JC
,
Hood
DD
,
Curry
R
,
Shafer
SL
:
Cephalad movement of morphine and fentanyl in humans after intrathecal injection.
Anesthesiology
.
2003
;
99
:
166
73
53.
Tang
J
,
Churilov
L
,
Tan
CO
,
Hu
R
,
Pearce
B
,
Cosic
L
,
Christophi
C
,
Weinberg
L
:
Intrathecal morphine is associated with reduction in postoperative opioid requirements and improvement in postoperative analgesia in patients undergoing open liver resection.
BMC Anesthesiol
.
2020
;
20
:
207
54.
Sutton
CD
,
Carvalho
B
:
Optimal pain management after cesarean delivery.
Anesthesiol Clin
.
2017
;
35
:
107
24
55.
Galloway
KS
,
Yaster
M
:
Pain and symptom control in terminally ill children.
Pediatr Clin North Am
.
2000
;
47
:
711
46
56.
Melo
H
,
Basso
L
,
Iftinca
M
,
MacNaughton
WK
,
Hollenberg
MD
,
McKay
DM
,
Altier
C
:
Itch induced by peripheral μ opioid receptors is dependent on TRPV1-expressing neurons and alleviated by channel activation.
Sci Rep
.
2018
;
8
:
15551
57.
Blunk
JA
,
Schmelz
M
,
Zeck
S
,
Skov
P
,
Likar
R
,
Koppert
W
:
Opioid-induced mast cell activation and vascular responses is not mediated by μ-opioid receptors: An in vivo microdialysis study in human skin.
Anesth Analg
.
2004
;
98
:
364
70
58.
Lansu
K
,
Karpiak
J
,
Liu
J
,
Huang
XP
,
McCorvy
JD
,
Kroeze
WK
,
Che
T
,
Nagase
H
,
Carroll
FI
,
Jin
J
,
Shoichet
BK
,
Roth
BL
:
In silico design of novel probes for the atypical opioid receptor MRGPRX2
Nat Chem Biol
.
2017
;
13
:
529
36
59.
Grosman
N
:
Histamine release from isolated rat mast cells: Effect of morphine and related drugs and their interaction with compound 48/80
Agents Actions
.
1981
;
11
:
196
203
60.
Hermens
JM
,
Ebertz
JM
,
Hanifin
JM
,
Hirshman
CA
:
Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone.
Anesthesiology
.
1985
;
62
:
124
9
61.
Porebski
G
,
Kwiecien
K
,
Pawica
M
,
Kwitniewski
M
:
Mas-related G protein–coupled receptor-X2 (MRGPRX2) in drug hypersensitivity reactions.
Front Immunol
.
2018
;
9
:
3027
62.
Meixiong
J
,
Anderson
M
,
Limjunyawong
N
,
Sabbagh
MF
,
Hu
E
,
Mack
MR
,
Oetjen
LK
,
Wang
F
,
Kim
BS
,
Dong
X
:
Activation of mast-cell-expressed mas-related G-protein-coupled receptors drives non-histaminergic itch.
Immunity
.
2019
;
50
:
1163
71.e5
63.
Laxenaire
MC
,
Moneret-Vautrin
DA
,
Widmer
S
,
Mouton
C
,
Guéant
JL
,
Bonnet
MC
,
Bricard
H
,
Facon
A
,
Lesage
F
,
Valfrey
J
:
[Anesthetics responsible for anaphylactic shock. A French multicenter study.]
Ann Fr Anesth Reanim
.
1990
;
9
:
501
6
64.
Rosow
CE
,
Moss
J
,
Philbin
DM
,
Savarese
JJ
:
Histamine release during morphine and fentanyl anesthesia.
Anesthesiology
.
1982
;
56
:
93
6
65.
Warner
MA
,
Hosking
MP
,
Gray
JR
,
Squillace
DL
,
Yunginger
JW
,
Orszulak
TA
:
Narcotic-induced histamine release: A comparison of morphine, oxymorphone, and fentanyl infusions.
J Cardiothorac Vasc Anesth
.
1991
;
5
:
481
4
66.
Flacke
JW
,
Flacke
WE
,
Bloor
BC
,
Van Etten
AP
,
Kripke
BJ
:
Histamine release by four narcotics: A double-blind study in humans.
Anesth Analg
.
1987
;
66
:
723
30
67.
Sjöström
S
,
Tamsen
A
,
Persson
MP
,
Hartvig
P
:
Pharmacokinetics of intrathecal morphine and meperidine in humans.
Anesthesiology
.
1987
;
67
:
889
95
68.
Bernards
CM
,
Shen
DD
,
Sterling
ES
,
Adkins
JE
,
Risler
L
,
Phillips
B
,
Ummenhofer
W
:
Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids: Part 1. Differences among opioids.
Anesthesiology
.
2003
;
99
:
455
65
69.
Ko
MC
:
Neuraxial opioid–induced itch and its pharmacological antagonism.
Handb Exp Pharmacol
.
2015
;
226
:
315
35
70.
Pathan
H
,
Williams
J
:
Basic opioid pharmacology: An update.
Br J Pain
.
2012
;
6
:
11
6
71.
Pan
Z
,
Hirakawa
N
,
Fields
HL
:
A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin.
Neuron
.
2000
;
26
:
515
22
72.
Simmons
SW
,
Taghizadeh
N
,
Dennis
AT
,
Hughes
D
,
Cyna
AM
:
Combined spinal-epidural versus epidural analgesia in labour.
Cochrane Database Syst Rev
.
2012
;
10
:
CD003401
73.
Asokumar
B
,
Newman
LM
,
McCarthy
RJ
,
Ivankovich
AD
,
Tuman
KJ
:
Intrathecal bupivacaine reduces pruritus and prolongs duration of fentanyl analgesia during labor: A prospective, randomized controlled trial.
Anesth Analg
.
1998
;
87
:
1309
15
74.
Shim
WS
,
Oh
U
:
Histamine-induced itch and its relationship with pain.
Mol Pain
.
2008
;
4
:
29
75.
Davidson
S
,
Giesler
GJ
:
The multiple pathways for itch and their interactions with pain.
Trends Neurosci
.
2010
;
33
:
550
8
76.
Schmelz
M
,
Schmidt
R
,
Bickel
A
,
Handwerker
HO
,
Torebjörk
HE
:
Specific C-receptors for itch in human skin.
J Neurosci
.
1997
;
17
:
8003
8
77.
Wilson
SR
,
Nelson
AM
,
Batia
L
,
Morita
T
,
Estandian
D
,
Owens
DM
,
Lumpkin
EA
,
Bautista
DM
:
The ion channel TRPA1 is required for chronic itch.
J Neurosci
.
2013
;
33
:
9283
94
78.
Wilson
SR
,
Gerhold
KA
,
Bifolck-Fisher
A
,
Liu
Q
,
Patel
KN
,
Dong
X
,
Bautista
DM
:
TRPA1 is required for histamine-independent, Mas-related G protein–coupled receptor-mediated itch.
Nat Neurosci
.
2011
;
14
:
595
602
79.
Moser
HR
,
Giesler
GJ
, Jr
:
Itch and analgesia resulting from intrathecal application of morphine: Contrasting effects on different populations of trigeminothalamic tract neurons.
J Neurosci
.
2013
;
33
:
6093
101
80.
Sakakibara
S
,
Imamachi
N
,
Sakakihara
M
,
Katsube
Y
,
Hattori
M
,
Saito
Y
:
Effects of an intrathecal TRPV1 antagonist, SB366791, on morphine-induced itch, body temperature, and antinociception in mice.
J Pain Res
.
2019
;
12
:
2629
36
81.
Liu
T
,
Ji
RR
:
New insights into the mechanisms of itch: Are pain and itch controlled by distinct mechanisms?
Pflugers Arch
.
2013
;
465
:
1671
85
82.
Graham
DT
,
Goodell
H
,
Wolff
HG
:
Neural mechanisms involved in itch, itchy skin, and tickle sensations.
J Clin Invest
.
1951
;
30
:
37
49
83.
Ko
MC
,
Naughton
NN
:
An experimental itch model in monkeys: Characterization of intrathecal morphine–induced scratching and antinociception.
Anesthesiology
.
2000
;
92
:
795
805
84.
Woolf
CJ
:
μ and
δ
opioid receptors diverge.
Cell
.
2009
;
137
:
987
8
85.
Ko
MC
,
Lee
H
,
Song
MS
,
Sobczyk-Kojiro
K
,
Mosberg
HI
,
Kishioka
S
,
Woods
JH
,
Naughton
NN
:
Activation of κ-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys.
J Pharmacol Exp Ther
.
2003
;
305
:
173
9
86.
Kamei
J
,
Nagase
H
:
Norbinaltorphimine, a selective κ-opioid receptor antagonist, induces an itch-associated response in mice.
Eur J Pharmacol
.
2001
;
418
:
141
5
87.
Ko
MC
,
Husbands
SM
:
Effects of atypical κ-opioid receptor agonists on intrathecal morphine–induced itch and analgesia in primates.
J Pharmacol Exp Ther
.
2009
;
328
:
193
200
88.
Kardon
AP
,
Polgár
E
,
Hachisuka
J
,
Snyder
LM
,
Cameron
D
,
Savage
S
,
Cai
X
,
Karnup
S
,
Fan
CR
,
Hemenway
GM
,
Bernard
CS
,
Schwartz
ES
,
Nagase
H
,
Schwarzer
C
,
Watanabe
M
,
Furuta
T
,
Kaneko
T
,
Koerber
HR
,
Todd
AJ
,
Ross
SE
:
Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.
Neuron
.
2014
;
82
:
573
86
89.
Cowan
A
,
Kehner
GB
,
Inan
S
:
Targeting itch with ligands selective for κ opioid receptors.
Handb Exp Pharmacol
.
2015
;
226
:
291
314
90.
Pfeiffer
A
,
Brantl
V
,
Herz
A
,
Emrich
HM
:
Psychotomimesis mediated by κ opiate receptors.
Science
.
1986
;
233
:
774
6
91.
Pan
ZZ
:
μ-Opposing actions of the κ-opioid receptor.
Trends Pharmacol Sci
.
1998
;
19
:
94
8
92.
Sun
YG
,
Chen
ZF
:
A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
Nature
.
2007
;
448
:
700
3
93.
Pagani
M
,
Albisetti
GW
,
Sivakumar
N
,
Wildner
H
,
Santello
M
,
Johannssen
HC
,
Zeilhofer
HU
:
How gastrin-releasing peptide opens the spinal gate for itch.
Neuron
.
2019
;
103
:
102
117.e5
94.
Sathyamurthy
A
,
Johnson
KR
,
Matson
KJE
,
Dobrott
CI
,
Li
L
,
Ryba
AR
,
Bergman
TB
,
Kelly
MC
,
Kelley
MW
,
Levine
AJ
:
Massively parallel single nucleus transcriptional profiling defines spinal cord neurons and their activity during behavior.
Cell Rep
.
2018
;
22
:
2216
25
95.
Häring
M
,
Zeisel
A
,
Hochgerner
H
,
Rinwa
P
,
Jakobsson
JET
,
Lönnerberg
P
,
La Manno
G
,
Sharma
N
,
Borgius
L
,
Kiehn
O
,
Lagerström
MC
,
Linnarsson
S
,
Ernfors
P
:
Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types.
Nat Neurosci
.
2018
;
21
:
869
80
96.
Al-Hasani
R
,
Bruchas
MR
:
Molecular mechanisms of opioid receptor-dependent signaling and behavior.
Anesthesiology
.
2011
;
115
:
1363
81
97.
Torrecilla
M
,
Quillinan
N
,
Williams
JT
,
Wickman
K
:
Pre- and postsynaptic regulation of locus coeruleus neurons after chronic morphine treatment: A study of GIRK-knockout mice.
Eur J Neurosci
.
2008
;
28
:
618
24
98.
Ross
SE
,
Mardinly
AR
,
McCord
AE
,
Zurawski
J
,
Cohen
S
,
Jung
C
,
Hu
L
,
Mok
SI
,
Shah
A
,
Savner
EM
,
Tolias
C
,
Corfas
R
,
Chen
S
,
Inquimbert
P
,
Xu
Y
,
McInnes
RR
,
Rice
FL
,
Corfas
G
,
Ma
Q
,
Woolf
CJ
,
Greenberg
ME
:
Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice.
Neuron
.
2010
;
65
:
886
98
99.
Huang
J
,
Polgár
E
,
Solinski
HJ
,
Mishra
SK
,
Tseng
PY
,
Iwagaki
N
,
Boyle
KA
,
Dickie
AC
,
Kriegbaum
MC
,
Wildner
H
,
Zeilhofer
HU
,
Watanabe
M
,
Riddell
JS
,
Todd
AJ
,
Hoon
MA
:
Circuit dissection of the role of somatostatin in itch and pain.
Nat Neurosci
.
2018
;
21
:
707
16
100.
Acton
D
,
Ren
X
,
Di Costanzo
S
,
Dalet
A
,
Bourane
S
,
Bertocchi
I
,
Eva
C
,
Goulding
M
:
Spinal neuropeptide Y1 receptor–expressing neurons form an essential excitatory pathway for mechanical itch.
Cell Rep
.
2019
;
28
:
625
39.e6
101.
Bourane
S
,
Duan
B
,
Koch
SC
,
Dalet
A
,
Britz
O
,
Garcia-Campmany
L
,
Kim
E
,
Cheng
L
,
Ghosh
A
,
Ma
Q
,
Goulding
M
:
Gate control of mechanical itch by a subpopulation of spinal cord interneurons.
Science
.
2015
;
350
:
550
4
102.
Sultan
P
,
Gutierrez
MC
,
Carvalho
B
:
Neuraxial morphine and respiratory depression: Finding the right balance.
Drugs
.
2011
;
71
:
1807
19
103.
Ngan Kee
WD
,
Khaw
KS
,
Ng
FF
,
Ng
KK
,
So
R
,
Lee
A
:
Synergistic interaction between fentanyl and bupivacaine given intrathecally for labor analgesia.
Anesthesiology
.
2014
;
120
:
1126
36
104.
Horta
ML
,
Morejon
LC
,
da Cruz
AW
,
Dos Santos
GR
,
Welling
LC
,
Terhorst
L
,
Costa
RC
,
Alam
RU
:
Study of the prophylactic effect of droperidol, alizapride, propofol and promethazine on spinal morphine-induced pruritus.
Br J Anaesth
.
2006
;
96
:
796
800
105.
Anwari
JS
,
Iqbal
S
:
Antihistamines and potentiation of opioid induced sedation and respiratory depression.
Anaesthesia
.
2003
;
58
:
494
5
106.
Roth
T
,
Roehrs
T
,
Koshorek
G
,
Sicklesteel
J
,
Zorick
F
:
Sedative effects of antihistamines.
J Allergy Clin Immunol
.
1987
;
80
:
94
8
107.
Cohen
SE
,
Ratner
EF
,
Kreitzman
TR
,
Archer
JH
,
Mignano
LR
:
Nalbuphine is better than naloxone for treatment of side effects after epidural morphine.
Anesth Analg
.
1992
;
75
:
747
52
108.
Rzasa Lynn
R
,
Galinkin
JL
:
Naloxone dosage for opioid reversal: Current evidence and clinical implications.
Ther Adv Drug Saf
.
2018
;
9
:
63
88
109.
Kendrick
WD
,
Woods
AM
,
Daly
MY
,
Birch
RF
,
DiFazio
C
:
Naloxone versus nalbuphine infusion for prophylaxis of epidural morphine-induced pruritus.
Anesth Analg
.
1996
;
82
:
641
7
110.
Charuluxananan
S
,
Kyokong
O
,
Somboonviboon
W
,
Narasethakamol
A
,
Promlok
P
:
Nalbuphine versus ondansetron for prevention of intrathecal morphine–induced pruritus after cesarean delivery.
Anesth Analg
.
2003
;
96
:
1789
93
111.
Sarvela
PJ
,
Halonen
PM
,
Soikkeli
AI
,
Kainu
JP
,
Korttila
KT
:
Ondansetron and tropisetron do not prevent intraspinal morphine- and fentanyl-induced pruritus in elective cesarean delivery.
Acta Anaesthesiol Scand
.
2006
;
50
:
239
44
112.
Yazigi
A
,
Chalhoub
V
,
Madi-Jebara
S
,
Haddad
F
,
Hayek
G
:
Prophylactic ondansetron is effective in the treatment of nausea and vomiting but not on pruritus after cesarean delivery with intrathecal sufentanil-morphine.
J Clin Anesth
.
2002
;
14
:
183
6
113.
Siddik-Sayyid
SM
,
Aouad
MT
,
Taha
SK
,
Azar
MS
,
Hakki
MA
,
Kaddoum
RN
,
Nasr
VG
,
Yazbek
VG
,
Baraka
AS
:
Does ondansetron or granisetron prevent subarachnoid morphine-induced pruritus after cesarean delivery?
Anesth Analg
.
2007
;
104
:
421
4
114.
Kyriakides
K
,
Hussain
SK
,
Hobbs
GJ
:
Management of opioid-induced pruritus: A role for 5-HT3 antagonists?
Br J Anaesth
.
1999
;
82
:
439
41
115.
Bonnet
MP
,
Marret
E
,
Josserand
J
,
Mercier
FJ
:
Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: A quantitative systematic review.
Br J Anaesth
.
2008
;
101
:
311
9
116.
Törn
K
,
Tuominen
M
,
Tarkkila
P
,
Lindgren
L
:
Effects of sub-hypnotic doses of propofol on the side effects of intrathecal morphine.
Br J Anaesth
.
1994
;
73
:
411
2
117.
Warwick
JP
,
Kearns
CF
,
Scott
WE
:
The effect of subhypnotic doses of propofol on the incidence of pruritus after intrathecal morphine for caesarean section.
Anaesthesia
.
1997
;
52
:
270
5
118.
Anand
S
:
Gabapentin for pruritus in palliative care.
Am J Hosp Palliat Care
.
2013
;
30
:
192
6
119.
Yesudian
PD
,
Wilson
NJ
:
Efficacy of gabapentin in the management of pruritus of unknown origin.
Arch Dermatol
.
2005
;
141
:
1507
9
120.
Akhan
A
,
Subasi
FD
,
Bosna
G
,
Ekinci
O
,
Pamuk
H
,
Batan
S
,
Ateser
RY
,
Turan
G
:
Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal morphine–induced pruritus.
North Clin Istanb
.
2016
;
3
:
53
9
121.
Kharasch
ED
,
Clark
JD
,
Kheterpal
S
:
Perioperative gabapentinoids: Deflating the bubble.
Anesthesiology
.
2020
;
133
:
251
4
122.
Horta
ML
,
Ramos
L
,
Gonçalves
ZR
:
The inhibition of epidural morphine-induced pruritus by epidural droperidol.
Anesth Analg
.
2000
;
90
:
638
41
123.
Wood
PB
:
Role of central dopamine in pain and analgesia.
Expert Rev Neurother
.
2008
;
8
:
781
97
124.
McNicol
E
,
Horowicz-Mehler
N
,
Fisk
RA
,
Bennett
K
,
Gialeli-Goudas
M
,
Chew
PW
,
Lau
J
,
Carr
D
;
Americal Pain Society
.
Management of opioid side effects in cancer-related and chronic noncancer pain: A systematic review.
J Pain
.
2003
;
4
:
231
56
125.
Liao
CC
,
Chang
CS
,
Tseng
CH
,
Sheen
MJ
,
Tsai
SC
,
Chang
YL
,
Wong
SY
:
Efficacy of intramuscular nalbuphine versus diphenhydramine for the prevention of epidural morphine-induced pruritus after cesarean delivery.
Chang Gung Med J
.
2011
;
34
:
172
8
126.
Eldor
J
,
Fishelev
V
,
Levine
S
,
Guedj
P
,
Dudakova
I
:
Prevention of epidural morphine pruritus by intramuscular promethazine in parturients.
Reg Anesth
.
1994
;
19
:
433
4
127.
Millington
GWM
,
Collins
A
,
Lovell
CR
,
Leslie
TA
,
Yong
ASW
,
Morgan
JD
,
Ajithkumar
T
,
Andrews
MJ
,
Rushbook
SM
,
Coelho
RR
,
Catten
SJ
,
Lee
KYC
,
Skellett
AM
,
Affleck
AG
,
Exton
LS
,
Mohd Mustapa
MF
,
Levell
NJ
:
British Association of Dermatologists’ guidelines for the investigation and management of generalized pruritus in adults without an underlying dermatosis, 2018
Br J Dermatol
.
2018
;
178
:
34
60
128.
Kamei
J
,
Hirano
S
,
Miyata
S
,
Saitoh
A
,
Onodera
K
:
Effects of first- and second-generation histamine-H1-receptor antagonists on the pentobarbital-induced loss of the righting reflex in streptozotocin-induced diabetic mice.
J Pharmacol Sci
.
2005
;
97
:
266
72
129.
Dunteman
E
,
Karanikolas
M
,
Filos
KS
:
Transnasal butorphanol for the treatment of opioid-induced pruritus unresponsive to antihistamines.
J Pain Symptom Manage
.
1996
;
12
:
255
60
130.
Somrat
C
,
Oranuch
K
,
Ketchada
U
,
Siriprapa
S
,
Thipawan
R
:
Optimal dose of nalbuphine for treatment of intrathecal-morphine induced pruritus after caesarean section.
J Obstet Gynaecol Res
.
1999
;
25
:
209
13
131.
Juneja
MM
,
Ackerman
WE
, 3rd
,
Bellinger
K
:
Epidural morphine pruritus reduction with hydroxyzine in parturients.
J Ky Med Assoc
.
1991
;
89
:
319
21
132.
Miller
JL
,
Hagemann
TM
:
Use of pure opioid antagonists for management of opioid-induced pruritus.
Am J Health Syst Pharm
.
2011
;
68
:
1419
25
133.
Kjellberg
F
,
Tramèr
MR
:
Pharmacological control of opioid-induced pruritus: A quantitative systematic review of randomized trials.
Eur J Anaesthesiol
.
2001
;
18
:
346
57
134.
Maxwell
LG
,
Kaufmann
SC
,
Bitzer
S
,
Jackson
EV
, Jr
,
McGready
J
,
Kost-Byerly
S
,
Kozlowski
L
,
Rothman
SK
,
Yaster
M
:
The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: A double-blind, prospective, randomized, controlled study.
Anesth Analg
.
2005
;
100
:
953
8
135.
Levy
JH
,
Brister
NW
,
Shearin
A
,
Ziegler
J
,
Hug
CC
, Jr
,
Adelson
DM
,
Walker
BF
:
Wheal and flare responses to opioids in humans.
Anesthesiology
.
1989
;
70
:
756
60
136.
Charuluxananan
S
,
Kyokong
O
,
Somboonviboon
W
,
Lertmaharit
S
,
Ngamprasertwong
P
,
Nimcharoendee
K
:
Nalbuphine versus propofol for treatment of intrathecal morphine–induced pruritus after cesarean delivery.
Anesth Analg
.
2001
;
93
:
162
5
137.
Lawhorn
CD
,
McNitt
JD
,
Fibuch
EE
,
Joyce
JT
,
Leadley
RJ
, Jr
:
Epidural morphine with butorphanol for postoperative analgesia after cesarean delivery.
Anesth Analg
.
1991
;
72
:
53
7
138.
Lee
H
,
Naughton
NN
,
Woods
JH
,
Ko
MC
:
Effects of butorphanol on morphine-induced itch and analgesia in primates.
Anesthesiology
.
2007
;
107
:
478
85
139.
Goletiani
NV
,
Mendelson
JH
,
Sholar
MB
,
Siegel
AJ
,
Skupny
A
,
Mello
NK
:
Effects of nalbuphine on anterior pituitary and adrenal hormones and subjective responses in male cocaine abusers.
Pharmacol Biochem Behav
.
2007
;
86
:
667
77
140.
Gunter
JB
,
McAuliffe
J
,
Gregg
T
,
Weidner
N
,
Varughese
AM
,
Sweeney
DM
:
Continuous epidural butorphanol relieves pruritus associated with epidural morphine infusions in children.
Paediatr Anaesth
.
2000
;
10
:
167
72
141.
Bailey
AG
,
Valley
RD
,
Freid
EB
,
Calhoun
P
:
Epidural morphine combined with epidural or intravenous butorphanol for postoperative analgesia in pediatric patients.
Anesth Analg
.
1994
;
79
:
340
4
142.
Hawi
A
,
Alcorn
H
, Jr
,
Berg
J
,
Hines
C
,
Hait
H
,
Sciascia
T
:
Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus.
BMC Nephrol
.
2015
;
16
:
47
143.
Reszke
R
,
Szepietowski
JC
:
End-stage renal disease chronic itch and its management.
Dermatol Clin
.
2018
;
36
:
277
92
144.
Inan
S
,
Torres-Huerta
A
,
Jensen
LE
,
Dun
NJ
,
Cowan
A
:
Nalbuphine, a κ opioid receptor agonist and μ opioid receptor antagonist attenuates pruritus, decreases IL-31, and increases IL-10 in mice with contact dermatitis.
Eur J Pharmacol
.
2019
;
864
:
172702
145.
Smith
MC
,
Williamson
J
,
Yaster
M
,
Boyd
GJ
,
Heitmiller
ES
:
Off-label use of medications in children undergoing sedation and anesthesia.
Anesth Analg
.
2012
;
115
:
1148
54
146.
Umeuchi
H
,
Togashi
Y
,
Honda
T
,
Nakao
K
,
Okano
K
,
Tanaka
T
,
Nagase
H
:
Involvement of central μ-opioid system in the scratching behavior in mice, and the suppression of it by the activation of κ-opioid system.
Eur J Pharmacol
.
2003
;
477
:
29
35
147.
Togashi
Y
,
Umeuchi
H
,
Okano
K
,
Ando
N
,
Yoshizawa
Y
,
Honda
T
,
Kawamura
K
,
Endoh
T
,
Utsumi
J
,
Kamei
J
,
Tanaka
T
,
Nagase
H
:
Antipruritic activity of the κ-opioid receptor agonist, TRK-820
Eur J Pharmacol
.
2002
;
435
:
259
64
148.
Kozono
H
,
Yoshitani
H
,
Nakano
R
:
Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch® capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus.
Int J Nephrol Renovasc Dis
.
2018
;
11
:
9
24
149.
Akiyama
T
,
Carstens
MI
,
Piecha
D
,
Steppan
S
,
Carstens
E
:
Nalfurafine suppresses pruritogen- and touch-evoked scratching behavior in models of acute and chronic itch in mice.
Acta Derm Venereol
.
2015
;
95
:
147
50
150.
Mores
KL
,
Cummins
BR
,
Cassell
RJ
,
van Rijn
RM
:
A review of the therapeutic potential of recently developed G protein-biased κ agonists.
Front Pharmacol
.
2019
;
10
:
407
151.
European Medicines Agency
Assessment report: Winfuran. European Medicines Agency
.
Committee for Medicinal Products for Human Use
,
2013
152.
Brust
TF
,
Morgenweck
J
,
Kim
SA
,
Rose
JH
,
Locke
JL
,
Schmid
CL
,
Zhou
L
,
Stahl
EL
,
Cameron
MD
,
Scarry
SM
,
Aubé
J
,
Jones
SR
,
Martin
TJ
,
Bohn
LM
:
Biased agonists of the κ opioid receptor suppress pain and itch without causing sedation or dysphoria.
Sci Signal
.
2016
;
9
:
ra117
153.
Kumagai
H
,
Ebata
T
,
Takamori
K
,
Muramatsu
T
,
Nakamoto
H
,
Suzuki
H
:
Effect of a novel κ-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: A phase III, randomized, double-blind, placebo-controlled study.
Nephrol Dial Transplant
.
2010
;
25
:
1251
7
154.
Grangier
L
,
Martinez de Tejada
B
,
Savoldelli
GL
,
Irion
O
,
Haller
G
:
Adverse side effects and route of administration of opioids in combined spinal-epidural analgesia for labour: A meta-analysis of randomised trials.
Int J Obstet Anesth
.
2020
;
41
:
83
103
155.
Norris
MC
,
Grieco
WM
,
Borkowski
M
,
Leighton
BL
,
Arkoosh
VA
,
Huffnagle
HJ
,
Huffnagle
S
:
Complications of labor analgesia: Epidural versus combined spinal epidural techniques.
Anesth Analg
.
1994
;
79
:
529
37
156.
George
RB
,
Allen
TK
,
Habib
AS
:
Serotonin receptor antagonists for the prevention and treatment of pruritus, nausea, and vomiting in women undergoing cesarean delivery with intrathecal morphine: A systematic review and meta-analysis.
Anesth Analg
.
2009
;
109
:
174
82
157.
Morales
M
,
Battenberg
E
,
Bloom
FE
:
Distribution of neurons expressing immunoreactivity for the 5HT3 receptor subtype in the rat brain and spinal cord.
J Comp Neurol
.
1998
;
402
:
385
401
158.
Marinelli
S
,
Vaughan
CW
,
Schnell
SA
,
Wessendorf
MW
,
Christie
MJ
:
Rostral ventromedial medulla neurons that project to the spinal cord express multiple opioid receptor phenotypes.
J Neurosci
.
2002
;
22
:
10847
55
159.
Zhao
ZQ
,
Liu
XY
,
Jeffry
J
,
Karunarathne
WK
,
Li
JL
,
Munanairi
A
,
Zhou
XY
,
Li
H
,
Sun
YG
,
Wan
L
,
Wu
ZY
,
Kim
S
,
Huo
FQ
,
Mo
P
,
Barry
DM
,
Zhang
CK
,
Kim
JY
,
Gautam
N
,
Renner
KJ
,
Li
YQ
,
Chen
ZF
:
Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling.
Neuron
.
2014
;
84
:
821
34
160.
Borgeat
A
,
Wilder-Smith
OH
,
Saiah
M
,
Rifat
K
:
Subhypnotic doses of propofol relieve pruritus induced by epidural and intrathecal morphine.
Anesthesiology
.
1992
;
76
:
510
2
161.
Gunal
AI
,
Ozalp
G
,
Yoldas
TK
,
Gunal
SY
,
Kirciman
E
,
Celiker
H
:
Gabapentin therapy for pruritus in haemodialysis patients: A randomized, placebo-controlled, double-blind trial.
Nephrol Dial Transplant
.
2004
;
19
:
3137
9
162.
Sheen
MJ
,
Ho
ST
,
Lee
CH
,
Tsung
YC
,
Chang
FL
:
Preoperative gabapentin prevents intrathecal morphine–induced pruritus after orthopedic surgery.
Anesth Analg
.
2008
;
106
:
1868
72
163.
Chiravanich
W
,
Oofuvong
M
,
Kovitwanawong
N
:
Single dose of gabapentin for prophylaxis intrathecal morphine–induced pruritus in orthopedic surgery: A randomized controlled trial.
J Med Assoc Thai
.
2012
;
95
:
186
90
164.
Verret
M
,
Lauzier
F
,
Zarychanski
R
,
Perron
C
,
Savard
X
,
Pinard
AM
,
Leblanc
G
,
Cossi
MJ
,
Neveu
X
,
Turgeon
AF
;
Canadian Perioperative Anesthesia Clinical Trials (PACT) Group
.
Perioperative use of gabapentinoids for the management of postoperative acute pain: A systematic review and meta-analysis.
Anesthesiology
.
2020
;
133
:
265
79
165.
Horta
ML
,
Vianna
PT
:
Effect of intravenous alizapride on spinal morphine-induced pruritus.
Br J Anaesth
.
2003
;
91
:
287
9
166.
Jackson
CW
,
Sheehan
AH
,
Reddan
JG
:
Evidence-based review of the black-box warning for droperidol.
Am J Health Syst Pharm
.
2007
;
64
:
1174
86
167.
Arendt
K
,
Segal
S
:
Why epidurals do not always work.
Rev Obstet Gynecol
.
2008
;
1
:
49
55