Medical Manuscript
American Journal of Hospice
Is There a Role for 5-HT3 Receptor
Antagonists in the Treatment of
Opioid-Induced Pruritus?
Saima Rashid, MD1, Disha D. Trivedi, MD2, Mudher Al-Shathir, MD3,
Marie Moulton, MSIV1, and Steven J. Baumrucker, MD, FAAFP, FAAHPM4
Abstract
Pruritus is an unpleasant irritation symptom that can be related to various systemic and dermatological conditions. Although
underreported, pruritus is a common adverse event noted after use of opioid pain medications. This article reviews the current
understanding of the mechanism of opioid-induced pruritus (OIP) and various pharmacological therapies. 5-Hydroxytryptamine 3
(5-HT3) receptor antagonists are potentially effective for treating OIP and may be a valuable treatment option if further controlled
studies are encouraging.
Keywords
pruritus, opioid, ondansetron, neuraxial, receptors
Introduction
Pruritus (or itch) is a sensation that arises from the superficial
layers of the skin or the mucous membrane that provokes an urge
to scratch. It is a common symptom of many skin disorders and
systemic diseases such as cholestatic liver disease, chronic renal
failure, diabetes mellitus, myxedema, multiple sclerosis, and
cerebral tumors. In all, 10% to 50% of patients with generalized
pruritus may have underlying systemic diseases.1 Although not
life-threatening, pruritus can affect quality of life.
Opioid analgesics are used to manage moderate to severe
acute and chronic pain; the occurrence of pruritus is reported to
be 10% to 50% following intravenous administration of opioids
and 20% to 100% after neuraxial administration.2-6 In a clinical
setting where comfort is paramount, opioid-induced pruritus
(OIP) represents a significant problem in palliative care, requir-
ing additional medications, opioid rotation, or reduction/dis-
continuation of dosage.
The mechanism of OIP is enigmatic; however, it is hypothe-
sized that pruritus arises from stimulation of peripheral and
central “itch” neurons.7 This article reviews the mechanism
of pruritus, the currently used pharmacological therapies for
pruritus, and the proposed use of 5-hydroxytryptamine 3
(5-HT3) antagonists.
Neurophysiology of Opioid Receptors
and Pruritus
Opioid-induced pruritus is explained by a multitude of mechan-
isms including modulation of the serotonergic pathway,
& Palliative Medicine®
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stimulation of the “itch center” in the brain, medullary dorsal
horn activation, and inhibitory transmitter antagonism.8 Sev-
eral molecules are believed to induce pruritus, including hista-
mine, 5-HT3, substance P, trypsin, opioid, and prostaglandin
(PG) E2.9-12 Studies show that both pain and itch sensations are
possibly mediated by a group of C-fibers with thin axons and
excessive terminal branching.13,14
Mu and K Opioid Receptors
Experiments on animals and the well-documented clinical
response to Mu-opioid receptor antagonists in humans suggest
a central Mu-opioid-receptor-mediated mechanism as the pri-
mary cause of OIP.12,15,16 It has been noted that spinally admi-
nistered Mu-opioid receptor agonists cause segmental pruritus.
Therefore, itch is perceived without the activation of primary
afferent neurons. Central inhibitory effects of opioids can
explain the onset of pruritus. Spinal neurons that signal pruritic
1
Department of Pulmonary and Critical Care, Mercy Health, Cincinnati, OH,
USA
2
Fawcett Memorial Hospital, Port Charlotte, FL, USA
3
Department of Pulmonary and Critical Care, Mercy Health, Cincinnati, OH
4
Hospice and Palliative Medicine, Wellmont Health System, Kingsport, TN,
USA
Corresponding Author:
Steven J. Baumrucker, MD, FAAFP, FAAHPM, Hospice and Palliative Medicine,
Wellmont Health System, 4485 W Stone, Ste 200, Kingsport, TN Tennessee
37660, USA.
Email: hospicedoc@charter.net
2 American Journal of Hospice & Palliative Medicine® XX(X)
information to the thalamus do not have spontaneous activity
unlike pain processing spinal neurons, which can be sponta-
neously active.15 On the contrary, K-opioid agonists such as
nalbuphine have been noted to have reduced Mu-opioid-
induced pruritus in humans.17
Histamine Release
Mast cell degranulation induced by administration of opioids is
less likely to be a major mechanism behind OIP.18 When admi-
nistered, intravenous morphine releases histamine, causing
wheal formation in the ipsilateral extremity.19 However, in
vitro techniques demonstrated that morphine-induced hista-
mine release did not involve opioid receptors.20 Also, hista-
mine release does not occur following administration of
neuraxial opioids, reinforcing the idea that the pathogenesis
of OIP is minimally affected by the release of histamine.21 The
treatment success observed by antihistamines may be due to its
sedative effects.20
Dopamine Receptors
Studies have demonstrated the efficacy of dopamine receptor
antagonists such as droperidol and alizapride in reducing
OIP.19,22 This suggests central dopamine receptors may also
contribute to pruritus or interact with m-opioid receptors to
cause pruritus.
Prostaglandins
Prostaglandin E1 and E2 release inhibitors such as diclofenac
and tenoxicam, which reduced pruritus in patients receiving
neuraxial opioids.23,24 This suggests PG E1 and E2 release is
associated with OIP. However, studies have also concluded
that cyclooxygenase 2 inhibitors do not contribute toward
reduction in OIP.12
Serotonin (5-HT3) Receptors
There is substantial literature on the relationships between
serotonin and opioid neurotransmitter systems. Both opioid
agonists and serotonin modulate pain perception and prur-
itus. Exogenous opioid-induced analgesia is noted to be
inhibited by ondansetron.25 This effect of ondansetron indi-
cates that some opioid-mediated effects depend on seroto-
ninergic neurotransmission. It has been suggested in
anesthesia literature that ondansetron is efficacious in the
prophylaxis of pruritus induced by intravenous and intrathe-
cal administration of opioids.1
A study done on rats in vivo suggests that the long-lasting C
neurons with high-frequency firing in dorsal root ganglion are
sensitive to 5-HT and are responsible for conveying pruritic
information to the spinal cord.10
Other Mechanisms
Gamma-amino butyric acid and glycine receptor antagonists in
central nervous system (CNS) have also been suggested as
potential factors in the development of OIP.26 Although the
pathophysiology is not completely understood, animal models
have shown attenuation of pruritus when an analog such as
strychnine (a glycine receptor agonist) is administered.27
Treatment Options/Modalities
Topical Agents
Capsaicin, antihistamines, and corticosteroids are commonly
used for dermatological conditions; however, the true mechan-
ism for treating OIP related to systemic conditions remains
unclear.28
Systemic Therapy
Mu-opioid receptor antagonists. Maxwell et al examined patients
receiving IV morphine continuously with concomitant nalox-
one at a rate of 0.25 mg/kg/h and demonstrated a significant
decrease in OIP. It was suggested, however, that higher doses
of naloxone could result in reversal of analgesia.29
Naloxone has low bioavailability when administered orally.
In contrast, nalmefene is orally bioavailable, a more potent
antagonist at opioid receptors, and is metabolized slowly. Thus,
nalmefene is a more effective treatment option in patients with
cholestatic liver disease, which is felt to be secondary to per-
ipheral stimulation of mu-opioid receptors.30 Naltrexone is also
orally bioavailable; potential adverse effects include
hepatotoxicity.31
K-opioid receptor agonists. Nalbuphine, both as bolus and as
infusion, has been found to decrease the incidence of OIP when
administered prophylactically. Butorphanol administered epi-
durally by continuous infusion with bupivacaine and morphine
has been found to decrease pruritus as compared to bupivacaine
and morphine alone. However, the possibility of significant
sedation with K-opioid receptor agonists is of concern.7
Anesthetic agents. Prophylactic intravenous propofol has shown
to decrease pruritus following intrathecal and epidural admin-
istration of morphine. The mechanism by which propofol may
reduce OIP may involve a decrease in posterior horn trans-
mission in the spinal cord.32 Some investigators have found
that a subhypnotic dose is ineffective to prevent OIP, so its use
is limited.7
Histamine receptor antagonists. Histamine receptor antagonists,
for example, diphenhydramine, reduce OIP, likely secondary to
their sedative effects, thus interrupting the pruritus-scratch
cycle.21,33
Dopamine receptor agonists. As previously stated, droperidol
reduces OIP but increases somnolence in patients.17
Rashid et al
Other drugs. Epinephrine and clonidine have not shown worth-
while benefits, but this may be partly due to the limited number
of test patients.17 Epidural prednisone, intravenous tenoxicam,
and rectal diclofenac have shown some efficacy in preventing
neuraxial OIP; however, few trials were performed to prove
their significance.12
5-Hydroxytryptamine 3 Receptor
Antagonists
5-Hydroxytryptamine 3 receptor is characterized as ligand-
gated ion channel. 5-Hydroxytryptamine 3 receptors are
located on neurons in CNS and also on peripheral neurons.
Ondansetron, granisetron, and dolasetron are drugs that act
as antagonists at 5-HT3 serotonin subtype receptor. Drugs
within this group differ in their properties with respect to
selectivity of receptor binding, potency, dose–response rela-
tionships, and duration of action.34 Ondansetron, the most
commonly prescribed antagonist, has a peak concentration
of onset of approximately 15 minutes. 35 Studies on rats
suggest that the long-lasting C-neurons with high-frequency
firing at the dorsal root ganglion are sensitive to 5-HT and are
responsible for conveying pruritic information to the spinal
cord.10 According to this pathway, 5-HT3 antagonists may be
useful in treating OIP.
Ondansetron’s mechanism of action is predominately mediated
centrally, ameliorating central symptoms like postoperative
nausea or after chemotherapy/radiation.36 Although ondansetron
is well tolerated, common adverse effects include headache,
constipation, abdominal discomfort, and arrhythmias.37
A prospective, randomized, double-blind, placebo-
controlled study by Iatrou et al assessed the efficacy of pro-
phylactic administration of ondansetron and dolasetron for the
prevention of intrathecal morphine-induced pruritus. A total of
105 patients were randomized into 3 groups: 4 mg ondansetron
intravenously, 12.5 mg dolasetron intravenously, or 5 mL pla-
cebo 30 minutes before administration of spinal anesthesia with
hyperbaric bupivacaine and morphine for urologic, orthopedic,
or vascular surgery. Patients were evaluated for incidence and
severity of pruritus at multiple time intervals. Patients who
received 5-HT3 antagonists reported significantly less total
severity of pruritus compared with placebo during the first 8
hours. Severe pruritus was observed only in patients within the
placebo group. This concluded that the prophylactic use of
ondansetron and dolasetron reduced the incidence and severity
of intrathecal morphine-induced pruritus.38
A systemic review of 15 randomized control trials by Bon-
net et al revealed that prophylactic administration of intrave-
nous ondansetron decreased the incidence, intensity, and need
for treatment of pruritus following administration of mor-
phine.35 This study also revealed that ondansetron adminis-
tered after neuroaxial lipophilic opioids such as fentanyl had
no effect on mitigating pruritus. However, the incidence of
pruritus decreased in patients given ondansetron after neu-
roaxial administration of minimally lipophilic opioid such
as morphine.35
3
A meta-analysis by Wang et al showed that prophylactic
administration of ondansetron meaningfully reduced the inci-
dence of neuroaxial morphine-induced pruritus in nonobstetric
patients; however, no decrease was seen in obstetric popula-
tion.39 This is consistent with a randomized double-blind study
done by Siddik-Sayyid et al on 113 patients with pruritus after
subarachnoid morphine for management of pain after cesarean
delivery. One group of patients received ondansetron and the
other received diphenhydramine. The results concluded that
ondansetron was as effective as diphenhydramine in relieving
pruritus, however, up to 50% of patients required naloxone for
primary failure or recurrence of pruritus in both arms.33
A randomized controlled trial compared treatment with pen-
tazocine with ondansetron in patients who received intrathecal
morphine following cesarean delivery. K-opioid agonist, pen-
tazocine, was noted to be superior to ondansetron for the treat-
ment of moderate to severe pruritus induced by intrathecal
morphine. However, ondansetron administration provided a
lower recurrence of OIP.40
Administration of granisetron and ondansetron reduced the
severity of pruritus, the use of rescue antipruritic medications,
and improved patient satisfaction after receiving subarachnoid
morphine or fentanyl in a randomized trial of cesarean delivery
patients. Although there was improved satisfaction with gran-
isetron over ondansetron, there was no difference in overall
incidence of pruritus, nausea, vomiting, and visual analogue
pain scores between the 2 groups.41 Notably, patients in both
arms received a lipophilic opioid and then were given 5-HT3
antagonist therapy significantly after delivery. As noted by
Bonnet et al, the fast-acting fentanyl binds 5-HT3 receptors and
decreases the overall availability of 5-HT 3 receptors for
antagonist interaction.35 The improved satisfaction of granise-
tron over ondansetron may be due to the faster onset of gran-
isetron, binding 5-HT3 receptors more rapidly compared to
ondansetron. This remains unclear but appears worth further
investigation.
Conclusion
5-hydroxytryptamine 3 antagonists can be used to treat OIP,
but studies have not shown their superiority over Mu-opioid
antagonists or K-opioid agonists. However, as symptom relief
is a primary goal in palliative care patients, any medication
used to relieve pruritus that also reverses analgesia (eg, a cen-
trally acting m-opioid receptor antagonist) would likely be
counterproductive.
It is important to note that many previous studies were
powered to detect a difference in incidence and not reduction
in severity of pruritus, therefore showing modest favorable
results for prophylactic ondansetron. Also, many of these stud-
ies are based on findings from peripartum patients who have a
higher incidence of OIP, possibly owing to the effects of estro-
gen.35 Studies solely based on prophylaxis or treatment of OIP
in palliative care patients are lacking. Further randomized trials
to evaluate the use of 5-HT3 antagonists for OIP are warranted.
4 American Journal of Hospice & Palliative Medicine® XX(X)
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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