REVIEW ARTICLES
`Neurokinin-1 receptor antagonists in the prevention
`of postoperative nausea and vomiting
`P. Diemunsch1*†, G. P. Joshi2 and J.-F. Brichant3
`1Department of Anesthesiology, Hautepierre University Hospital, 1, Avenue Molie`re, 67000 Strasbourg,
`France. 2Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical
`Center, Dallas, TX, USA.3Department of Anesthesiology and Intensive Care, Service d’Anesthe´sie—
`Re´animation Chirurgicale, University Hospital of Lie`ge, Belgium
`*Corresponding author. E-mail: pierre.diemunsch@chru-strasbourg.fr
`Despite major advances, emesis remains a major problem in the context of cancer chemother-
`apy and in the postoperative period. A better understanding of the relevant neurocircuitry,
`especially the central pattern generator responsible for emesis and the central role of
`substance P , led to the development of a new class of antiemetics: the neurokinin-1 (NK1)
`receptor antagonists. Aprepitant is the first NK1 receptor antagonist approved for use in post-
`operative nausea and vomiting, but several other compounds are currently being investigated
`for their potential as antiemetics in the postoperative and cancer chemotherapy settings.
`Br J Anaesth2009; 103: 7–13
`Keywords: antagonists, NK1 receptor, aprepitant; complications; substance P; vomiting, nausea
`Nausea and vomiting
`Nausea is an unpleasant sensation that refers to an incli-
`nation to vomit. Retching is an involuntary effort to vomit
`that does not result in ejection of gastric contents.
`Vomiting is the forceful expulsion of gastrointestinal con-
`tents from the stomach through the mouth. Motor changes
`during vomiting involve both respiratory and gastrointesti-
`nal muscles. Before expulsion of the gastric contents, the
`glottis is closed, the diaphragm and the muscles of the
`abdominal wall contract whereas the oesophagus contracts
`longitudinally and the gastro-oesophageal sphincter zone
`relaxes. This results in the expulsion of the gastric con-
`tents that is facilitated by a retrograde contraction of the
`cervical oesophagus and a relaxation of the portion of the
`diaphragm that surrounds the oesophagus. This motor act
`is coordinated by brainstem structures.
`Primarily recognized as a protective reflex occurring in
`response to the ingestion of hazardous compounds (emesis
`was used as a therapeutic tool in ancient civilizations),
`8
`vomiting is in fact a distressing symptom and a particularly
`unpleasant side-effect associated with various medical inter-
`ventions.
`15 Emesis remains a critical problem during recov-
`ery from surgical procedures, particularly in the ambulatory
`setting, in anticancer cytotoxic therapy, and in circumstances
`involving motion and vestibular disturbances (e.g. Me´ nie`re’s
`disease). Vomiting can also occur in natural circumstances
`where its benefits remain obscure (e.g. pregnancy sickness).
`Postoperative nausea and vomiting
`Every year, more than 100 000 000 patients are anaesthe-
`tized throughout the world. Nausea and vomiting are two
`of the most common and distressing symptoms that can
`follow procedures requiring anaesthesia.
`54 59 Attempts to
`quantify the distress caused by postoperative nausea and
`vomiting (PONV) have led to North American and
`German or Turkish patients declaring that they would be
`prepared to spend up to 100 US$ (75E or £70) to avoid
`them.29 45 Although PONV is usually self-limiting and not
`lethal, it can lead to significant clinical problems. They
`include increased postoperative pain, dehydration, electro-
`lyte imbalance, dehiscence of surgical wounds, haemor-
`rhage, oesophageal rupture, and aspiration pneumonia, the
`most severe complications being rare. In addition, PONV
`imposes an economic burden by extending recovery room
`stay, delaying discharge from hospital, and increasing
`unanticipated admissions of surgical outpatients.
`28 33
`PONV has been associated with the use of general
`anaesthetics since the introduction of general anaesthesia.1
`In the chloroform and ether era, the incidence of PONV
`was as high as 80%. Despite improvements in the preven-
`tion of PONV and development of new drugs, the current
`†Declaration of interest. P.D. has acted as a lecturer, consultant,
`investigator, and coordinator of clinical studies promoted by Glaxo,
`Marion Merrell Dow, Roche, Pro Strakan, Merck.
`# The Author [2009]. Published by Oxford University Press on behalf of The Board of Directors of the British Journal of Anaesthesia. All rights reserved.
`For Permissions, please email: journals.permissions@oxfordjournal.org
`British Journal of Anaesthesia103 (1):7–13 (2009)
`doi:10.1093/bja/aep125 Advance Access publication May 19, 2009
`HELSINN EXHIBIT 2051
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
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`overall incidence of PONV is estimated to be /C2430%.26
`This incidence can reach 70% in groups of high-risk
`patients.63 06 1 Up to 21% of patients will experience
`nausea and vomiting in the recovery room, for which they
`will receive antiemetic drugs.
`44 47 65 In studies that dis-
`tinguish between nausea and vomiting, the incidence of
`nausea ranges from 38% to 52% and that of vomiting
`from 21% to 33% during the first 24 postoperative
`hours.
`3 – 5 21 48When the study period is extended to 72 h,
`the incidence of nausea ranges from 10% to 72% and that
`of vomiting from 10% to 17%.
`12 66 Many methodological
`differences may explain such large ranges. Although
`nausea and vomiting have been for long considered as
`steps of the same process, some data suggest that the
`pathophysiology of the two events may differ. Indeed, risk
`factors for PONV are different.
`22 66
`Neurocircuitry involved in emesis
`Vomiting may be triggered by various inputs or a combi-
`nation of inputs. Considering PONV, enterochromaffin
`cells in the stomach and intestine release serotonin.
`Serotonin binds to 5-hydroxytryptamine type 3 (5-HT 3)
`receptors in the gastrointestinal tract. This binding results
`in stimulation of vagal afferents in the gastrointestinal tract
`that conduct impulses reaching brainstem structures
`located between the levels of the obex and the nucleus
`ambiguous, such as the area postrema. Located on the
`dorsal surface of the medulla oblongata at the caudal end
`of the fourth ventricle, the area postrema has a critical role
`in the central mechanism of vomiting. In addition to
`receiving vagal inputs, this highly vascularized structure
`can detect emetic agents in the blood and in the cerebro-
`spinal fluid as it lacks a blood–brain barrier. Therefore,
`the area postrema is considered as a chemoreceptor trigger
`zone. The area postrema has neurones that project to the
`medial part of the nucleus tractus solitarius, the subnucleus
`gelatinosus. The nucleus tractus solitarius also receives
`inputs from the vagus nerve and from the enterochromaf-
`fin, the vestibular, and the limbic system. From the
`nucleus tractus solitarius, efferent neurones reach the
`rostral nucleus, the nucleus ambiguous, the ventral respir-
`atory group, and the dorsal motor nucleus of the vagus. It
`has been proposed that these latter structures are driven by
`an ‘afferent relay station’ that integrates the outputs from
`the neurones in the nucleus tractus solitarius.
`Thus, the central structures involved in the patho-
`physiology of vomiting are disseminated throughout the
`medulla oblongata of the brainstem,
`34 making it inap-
`propriate to group them in a precise anatomical entity as a
`‘vomiting centre’.24 42 The structures are scattered in the
`Bo¨ tzinger complex (a region of the brainstem also critical
`for respiratory rhythmogenesis) and are designated as the
`‘central pattern generator for vomiting’.
`Neurotransmitter receptor systems involved in the
`mediation of signals leading to nausea and vomiting
`include dopaminergic (D
`2), cholinergic (muscarinic), his-
`taminergic (H1) serotonergic (5-HT3), and neurokinin NK1
`systems. The corresponding receptors are potential targets
`for antiemetic drugs. Even if the numerous neurochemicals
`involved in the neurocircuitry of emesis may not have
`been fully identified, the two main inputs to the central
`pattern generator are from the abdominal vagal afferents
`via the nucleus tractus solitarius
`46 and from the chemocep-
`tive trigger zone located in the area postrema.39
`Experimental development of the neurokinin-1
`(NK1) receptor antagonists
`The introduction of selective 5-HT3 receptor antagonists
`or serotonin type 3 receptor antagonists has incontestably
`represented a major advance in the control of acute emesis
`associated with cytotoxic therapy and surgery. However,
`further improvement is still needed. An attractive strategy
`to block emesis, irrespective of its eliciting stimulus,
`would be to treat patients with a pharmacological agent
`able to depress the activity of neurones within the medul-
`lary emetic circuitry. Chemicals acting as partial (e.g. bus-
`pirone and ipsaspirone) or full (e.g. 8-OH-DPAT and SUN
`8399) agonists of the 5-HT1A receptor have shown broad-
`spectrum antiemetic activity in several species without
`marked adverse effects.
`53 These compounds were expected
`to be clinically relevant. Unfortunately, most investigations
`in various animal models have shown that 5-HT1A recep-
`tor agonists usually exhibit weak antiemetic properties
`against cisplatin-induced emesis; therefore, their clinical
`development was not considered pertinent at that time.
`Thus, the pharmacological quest to make available a
`highly effective broad-spectrum antiemetic has led neuro-
`scientists to investigate the role of neurotransmitter
`systems other than the serotonergic system.
`Special attention has been focused on the role of tachy-
`kinins since they have been immunohistologically ident-
`ified in the dorsal vagal complex of the ferret, an area
`regarded as essential in the elicitation of vomiting. The
`emetic action of the tachykinin, substance P, was reported
`by Carpenter and colleagues
`9 in 1984. Its role within the
`medullary emetic circuitry was demonstrated by Andrews
`and Bhandari2 in 1993 using resinferatoxin, an ultra-potent
`capsaicin analogue that exhibits antiemetic properties in
`the ferret against both centrally and peripherally acting
`emetic agents. Andrews and Bhandari suggested that resin-
`feratoxin exerts its antiemetic activity by depleting sub-
`stance P at a central site in the emetic pathway. Upon
`these results, potent and highly selective non-peptide NK1
`receptor antagonists that cross the blood–brain barrier and
`antagonize the central effects of substance P were devel-
`oped as tools for investigation of the physiological role of
`substance P in emesis. Besides emesis, other potential
`indications foreseen for such compounds included pain,
`migraine, rheumatoid arthritis, inflammatory bowel
`disease, asthma, and chronic bronchitis.
`Diemunsch et al.
`8
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`Tachykinins are members of a family of neuropeptides
`able to rapidly promote a contractile action in smooth
`muscles and sharing the common C-terminal sequence
`Phe-Xaa-Gly-Leu-MetNH2. These compounds include
`substance P (for pain) and neurokinins A and B (NKA
`and NKB). They exert their biological activity through
`three G-protein-coupled receptor subtypes, identified as
`NK1, NK2, and NK3 receptors. 55 According to the
`Montreal nomenclature,37 the NK1 receptor is defined as
`the mediator of the biological activity encoded by the
`C-terminal sequence of tachykinins, for which substance P
`is a more potent agonist than NK
`A or NKB. Since sub-
`stance P is believed to exert a key role within the central
`emetic circuitry, selective NK1 receptor antagonists were
`expected to express potent antiemetic activity.
`The nucleus tractus solitarius lying ventrally to the area
`postrema in the so-called subnucleus gelatinosus is a good
`candidate for the site of action of NK1 receptor antagon-
`ists. Extensive substance P-like immunoreactivity has
`been identified in this region and the tachykinins have
`been proposed as transmitters in vagal afferents.
`19 20 51
`Experimentally, the substance P-induced discharge of
`action potentials of single nucleus tractus solitarius neur-
`ones recorded in slices of ferret brain stem is inhibited by
`HSP-117, an NK1 receptor antagonist with potent antie-
`metic activity.
`63 These results and the data from positron
`emission tomography studies in rhesus monkeys23 suggest
`that NK1 receptor antagonists exert their main antiemetic
`action by depressing the neural activity of nucleus tractus
`solitarius neurones, that is, within the central emetic cir-
`cuitry. A contribution from peripheral sites is also possible
`as peripheral injection of sendide, a peptide-based NK1
`receptor antagonist, is active against cisplatin-induced
`emesis in the ferret and this is likely to be through a gas-
`trointestinal tract site of action.
`58 The proposed mechan-
`ism involves a block of the NK1 receptors located on
`vagal terminals in the gut decreasing the intensity of the
`emetic afferent message transmitted to the medullary
`emetic circuitry. This peripheral effect of NK1 receptor
`antagonists might be similar to that of the 5-HT
`3 receptor
`antagonists on the serotonergic activation of vagal term-
`inals. This hypothesis remains to be confirmed.
`Clinical applications of the NK1 receptor
`antagonists
`In animals and in humans, the numerous transmitters
`involved in the emetic process accounts for the incomplete
`efficacy of single-drug therapies for nausea and vomiting
`of various aetiologies. Maybe due to their central role on a
`potential, final common pathway, the NK1 receptor antag-
`onists have offered the prospect of a broader spectrum
`antiemetic activity than the 5HT
`3 receptor antagonists,
`dopamine receptor antagonists, anticholinergic agents, and
`corticosteroids. As with pain management,
`64 the efficacy
`of NK1 receptor antagonists in treatment of nausea and
`vomiting is optimized by combining it with other antie-
`metics from different classes.
`Data from published clinical studies seem to confirm
`the usefulness of the NK1 receptor antagonists in man, in
`two types of indications: cancer-chemotherapy-induced
`nausea and vomiting (CINV) and PONV. In contrast, the
`NK1 receptor antagonists were shown to be less effective in
`motion-induced nausea, either alone or in combination
`with a 5-HT
`3 receptor antagonist.62 The investigational
`NK1 receptor antagonists studied include GR205171 (vofo-
`pitant, GlaxoSmithKline), CP-122721 (Pfizer), CJ-11974
`(Pfizer), L-754030 (aprepitant, Merck), and its prodrug
`MK 0517 or L-758298 (fosaprepitant). Numerous other
`compounds are under investigation, including casopitant
`(GlaxoSmithKline), maropitant (Pfizer), netupitant (Helsinn
`Healthcare), rolapitant or SCH 619734 (Schering-Plough),
`T 2328 (Mitsubishi Tanabe Pharma), and vestipitant
`(GlaxoSmithKline).
`NK1 receptor antagonists in
`chemotherapy-induced nausea and vomiting
`The prevention of CINV remains the main target in the
`development of new antiemetics. In this setting, the
`design of several placebo-controlled trials allowed com-
`parison between NK1 receptor antagonist, 5-HT
`3 receptor
`antagonist (usually ondansetron), a combination of a
`5-HT3 receptor antagonist plus dexamethasone, a combi-
`nation of a NK1 receptor antagonist with either dexa-
`methasone alone or with a 5-HT
`3 receptor antagonist plus
`dexamethasone (three antiemetics).16 The recent classifi-
`cation of the antineoplastic agents used in chemotherapy
`into four groups according to their emetogenicity
`35 and
`the better comprehension of the different categories of
`emetic events during CINV allows for better comparisons
`between older and newer prevention and treatment
`regimens.
`In the study arms where a NK1 receptor antagonist was
`administered alone, it proved either ineffective
`(GR205171, 5 or 25 mg i.v.)
`25 or not superior to ondanse-
`tron (L-758298, 60 or 100 mg i.v),11 in the control of
`acute CINV after high doses of cisplatin. Except for this
`setting, the NK1 receptor antagonists have shown dramatic
`antiemetic activity in cisplatin-treated patients. This is true
`for the prevention of acute CINV in association with a
`5-HT
`3 receptor antagonist or with a 5-HT3 receptor antag-
`onist plus dexamethasone.
`For the prevention of delayed CINV, a single prophylac-
`tic dose of NK1 receptor antagonist (CP-122721) proved
`effective in six out of the seven patients (86%), whereas
`the combination with a 5-HT 3 receptor antagonist and
`dexamethasone brought about this result in eight out of
`10 patients (80%).49 The NK1 receptor antagonists alone
`proved significantly superior to ondansetron alone in the
`NK1 receptor antagonists in the prevention of PONV
`9
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`prevention of vomiting and nausea on days 2–7 after cis-
`platin administration.35
`The first NK1 receptor antagonist to be marketed in the
`USA and Europe is aprepitant (Emend* Merck) in an oral
`presentation. Aprepitant administration is part of the 2008
`clinical recommendations of the European Society for
`Medical Oncology for the prophylaxis of CINV.
`38 Its
`pharmacokinetics have been described by Majumdar and
`colleagues.56 After an oral dose, aprepitant bioavailability
`is 60–65%. Absorption is not affected by food and the
`serum half-life is 4 h. The drug crosses the blood–brain
`barrier.
`36 It is metabolized in the liver, primarily by
`CYP450 3A4 enzymes, and is excreted in both urine and
`faeces. Aprepitant potentially competes with other drugs
`for the same metabolic pathway: the clinical implications
`are minor except for co-administered corticosteroids, the
`dose of which should be reduced.
`57
`Compared with standard therapy (ondansetron plus
`dexamethasone), oral aprepitant 125 mg before cisplatin
`followed by aprepitant 80 mg on days 2–5 after the treat-
`ment brings better and more sustained protection against
`CINV over multiple cycles. Comparing the time course of
`the antiemetic effect of aprepitant with that of ondansetron
`or granisetron and that of the combination of the NK1
`receptor antagonist and a 5HT
`3 receptor antagonist,
`Hesketh and colleagues41 showed that serotonin may be
`more influential in acute CINV (8–12 h), whereas sub-
`stance P plays the major role in delayed symptoms. The
`same authors showed that addition of aprepitant to a 5HT
`3
`receptor antagonist plus corticosteroid regimen abolished
`the effect of female gender on the success rate of CINV
`prophylaxis.40 The i.v. prodrug, fosaprepitant, is converted
`to aprepitant within about 30 min: 115 mg of fosaprepitant
`i.v. is equivalent to 125 mg oral aprepitant.50
`Casopitan (GlaxoSmithKline) is still under evaluation.
`Phase II and III studies showed that casopitan 90–50 mg
`i.v./p.o. in combination with ondansetron and dexametha-
`sone reduces CINV in patients receiving moderately, and
`also highly, emetogenic chemotherapy.
`7 However, the
`observed improvements seem to be related mainly to
`vomiting and less to nausea control.
`NK1 receptor antagonists in PONV
`Early studies
`The first clinical study of an NK1 receptor antagonist in
`the context of PONV was published in 1999. In this con-
`trolled randomized trial in the setting of treatment of
`established PONV after laparoscopic or open hyster-
`ectomy, Diemunsch and colleagues
`17 showed vofopitant or
`GR205171 25 mg i.v. as a single agent to be superior to
`placebo for complete control of nausea and vomiting. This
`benefit was maintained throughout the entire 24 h study
`period. The proportion of patients requiring rescue
`medication during the 24 h after drug administration was
`also less after treatment with GR205171 (61% vs 83%
`after the placebo). Neither difference across groups for
`pain severity or need for analgesics (P¼0.2) nor major
`adverse event was observed in this study.
`Comparing CP-122721 200 mg orally with ondansetron
`4 mg i.v. and with the combination of the two agents in
`the prevention of PONV, Gesztesi and colleagues
`32 found
`no differences for postoperative nausea scores among the
`three groups, but a significantly lower incidence of emetic
`episodes when CP-122721 was part of the prophylactic
`regimen. The combination of CP-122721 and ondansetron
`provided no additional benefit. These results were pub-
`lished as an abstract only. The same group published
`additional data in 2000
`31 showing, in a dose-ranging
`approach, that oral CP-122721 200 mg was more effective
`than oral CP-122721 100 mg. In this controlled random-
`ized trial that involved 277 patients presenting for total
`abdominal hysterectomy, the combination of CP-122721
`and ondansetron significantly prolonged the time to the
`administration of the first rescue antiemetic drug when
`compared with either drug alone, and prevented the occur-
`rence of emesis in 98% of the patients. Nevertheless,
`patient satisfaction was no different than after ondansetron
`4 mg. There was no significant difference between the
`morphine requirement in the CP-122721 and placebo
`groups during the initial 24 h postoperative period. The
`only clinically significant adverse event attributed to
`CP-122721 during the 72 h follow-up period was an
`increased incidence of headache (22% vs 2% in the
`placebo group;P,0.05).
`In another study published so far as an abstract only,
`oral casopitant 50 mg or placebo was given 60 min before
`anaesthesia along with ondansetron 4 mg i.v. injected
`before induction, in 570 patients receiving opioids peri-
`operatively. In the casopitant group, the complete response
`rate (no vomiting and no rescue) was better than in the
`placebo group (57%vs 43%; P,0.05), irrespective of the
`postoperative opioid used. Conversely, no difference for
`nausea was found between the groups.
`10
`Aprepitant in PONV
`In a randomized, multicentre, double-blind phase III trial,
`922 patients undergoing open abdominal surgery were
`allocated randomly to receive one of the three antiemetic
`treatments before the operation: oral aprepitant 40 mg, oral
`aprepitant 125 mg, or i.v. ondansetron 4 mg, or matching
`placebos for the prevention of PONV. All oral medications
`were given within 3 h of anticipated induction of anaesthe-
`sia and i.v. ondansetron or placebo was infused over 2–5
`min immediately before induction, according to the
`approved prescribing information. Complete response was
`achieved in 64% of patients in the aprepitant 40 mg group
`(odds ratio of aprepitant to ondansetron, 1.4; lower bound
`of the one-sided 95% CI, 1.08), 63% in the aprepitant
`Diemunsch et al.
`10
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`125 mg group (odds ratio, 1.4; lower bound of the one-
`sided 95% CI, 1.04), and 55% in the ondansetron group,
`showing aprepitant (40 or 125 mg) being non-inferior to
`ondansetron (4 mg) in achieving complete response (i.e.
`no vomiting and no use of rescue therapy) for 24 h after
`surgery. Aprepitant was significantly more effective than
`ondansetron for preventing vomiting at 24 h (percentage
`of patients with no vomiting 84%, 86%, and 71%, respect-
`ively, in the aprepitant 40 mg, aprepitant 125 mg, and
`ondansetron groups); and at 48 h post-surgery (percentage
`of patients with no vomiting 82%, 85%, and 66%, respect-
`ively, in the aprepitant 40 mg, aprepitant 125 mg, and
`ondansetron groups); and in reducing nausea severity in
`the first 48 postoperative hours.
`14 The most commonly
`reported adverse events were pyrexia, constipation, head-
`ache, and bradycardia with no differences between the
`groups. No major adverse effect attributable to aprepitant
`was observed.
`In another study based on a similar design, aprepitant
`was superior to ondansetron for prevention of vomiting in
`the first 24 and 48 h, but no significant differences were
`observed between aprepitant and ondansetron for nausea
`control, use of rescue antiemetic, or complete response.
`27
`A post hocanalysis of the pooled data from these two ran-
`domized active-controlled trials was performed on 541
`patients in the aprepitant 40 mg group, 532 patients in the
`aprepitant 125 mg group, and 526 patients in the ondanse-
`tron group, in a modified intention-to-treat analysis This
`analysis showed that in the 24 h after surgery, aprepitant
`40 mg was more effective than ondansetron for all five
`endpoints evaluated [no significant nausea (56.4% vs
`48.1%), no nausea (39.6%vs 33.1%), no vomiting (86.7%
`vs 72.4%), no nausea and no vomiting (38.3%vs 31.4%),
`and no nausea, no vomiting, and no use of rescue (37.9%
`vs 31.2%); P,0.035 for the odds ratio for each compari-
`son] (Fig. 1). Comparisons of prophylactic antiemetics
`should take into account the potential influence of rescue
`therapy on either nausea or vomiting since once rescue
`medication is taken, a lack of nausea, vomiting, or both
`may be due to the prophylactic antiemetic, the rescue
`therapy, or both. Therefore, the most relevant endpoint of
`antiemetic prophylaxis is its ability to provide complete
`protection from vomiting, nausea, and the need for rescue
`therapy. More patients taking aprepitant achieved this
`complete protection compared with those taking ondanse-
`tron, with the best results seen in the aprepitant 40 mg
`group. Aprepitant 125 mg tended to show similar or
`slightly reduced effects compared with aprepitant 40 mg,
`suggesting a plateau in response and the recommended
`and approved dose of oral aprepitant for PONV prophy-
`laxis is 40 mg.
`13
`Specific advantages of aprepitant in the PONV setting
`include its oral formulation, easily administered for pro-
`phylaxis along with the premedication, the possible use of
`an i.v. form (fosaprepitant) for treatment of established
`PONV, the possibility to save the other validated antie-
`metics as rescue drugs since a change in therapeutic class
`is recommended in the case of failure of prophylaxis, and
`possible specific advantages due to the long-lasting effect
`of this drug. This particular point has been recently docu-
`mented in the orthopaedic inpatient setting
`67 but may be
`even more important in the outpatient setting.
`Safety
`Safety of the NK1 receptor antagonists in man has never
`been a concern in the clinical studies, and all the investi-
`gational drugs were well tolerated, with no drug-related
`toxicity. No adverse events were reported that would pre-
`clude further studies of NK1 receptor antagonists in man.
`One exception, however, has been a serious episode of
`dizziness possibly related to oral L-754030 (400 mg).
`Similarly an increased incidence of mild or moderate
`headaches was observed after oral CP-122721 (200 mg) in
`the dose-ranging study. Despite the implication of sub-
`stance P in pain mechanisms, no obvious effects on pain
`threshold or on analgesia were observed in the human
`PONV studies. This is contrary to the results of one
`study
`18 which showed that the NK1 receptor antagonist
`CP-99994 was effective in pain reduction after third molar
`extraction.
`Other potential indications of the NK1 receptor antagon-
`ists include asthma, anxiety, arthritis, migraine, schizo-
`phrenia, glaucoma and ocular hypotension, neural injury,
`and stroke. Recent evidence of prevention of adhesions
`related to laparoscopic surgery by intraperitoneal adminis-
`tration of aprepitant may be of particular interest.
`52 It is so
`far unknown, as to whether the doses required to treat
`CINV and PONV may provoke specific side-effects related
`to the potential wide-spectrum activity of the NK1
`receptor antagonists.
`0
`20
`40
`60
`80
`100% of patients
`Aprepitant 40 mg (n=541)
`Aprepitant 125 mg (n=532)
`Ondansetron 4 mg (n=526)
`No
`significant
`nausea
`(VRS 4)
`No
`nausea
`(VRS=0)
`No nausea and
`no vomiting
`No nausea,
`no vomiting,
`and
`no rescue
`*
`***
`*
`Fig 1 Percentage of patients in the combined modified intent-to-treat
`population with efficacy endpoints accounting specifically for nausea, by
`treatment group. VRS, verbal rating scale. *An odds ratio
`(aprepitant:ondansetron) .1.0, P,0.05 in favour of aprepitant (from
`Diemunsch and colleagues).13
`NK1 receptor antagonists in the prevention of PONV
`11
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`Conclusion
`More research is needed to determine the optimal dose of
`the NK1 receptor antagonists in PONV, the optimal associ-
`ations with other antiemetics, and the place of these drugs
`in the prevention, the rescue schemes, or both for PONV
`and also their use in paediatric patients. Some putative
`specific benefits bettering terms of superior efficacy for
`the prevention of nausea and delayed vomiting than other
`classes of antiemetics represent directions for further
`work. Also, the possible role of pharmacogenomics in the
`individual response to the NK1 receptor antagonists in
`PONV, as observed for the 5-HT
`3 receptor antagonists,
`needs to be explored.43 60
`Funding
`Only intramural departmental sources.
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