ORIGINAL ARTICLE

Anticipatory nausea and vomiting

Joseph A. Roscoe & Gary R. Morrow & Matti S. Aapro &

Alexander Molassiotis & Ian Olver

Received: 8 June 2010 /Accepted: 16 August 2010 /Published online: 30 August 2010# Springer-Verlag 2010

Abstract A commonly reported consequence of post-treatment nausea or vomiting is the development ofanticipatory nausea and vomiting (ANV). In most publishedwork, nausea is reported to occur before chemotherapydrugs are administered by approximately 20% of patients atany one chemotherapy cycle and by 25–30% of patients bytheir fourth chemotherapy cycle. Most studies in adultpatients strongly support the view that the development ofANV involves elements of classical conditioning. The bestmethod to avoid development of ANV is to adequatelyprevent both vomiting and nausea from the first exposure tochemotherapy. If anticipatory side effects develop, behav-ioral treatment techniques, such as systematic desensitiza-tion, have been shown effective. Benzodiazepines used incombination with behavioral techniques or antiemetics mayalso be useful. The evidence on which these conclusions arebased is reviewed in this article.

Keywords Anticipatory nausea and vomiting

Introduction

Anticipatory nausea and vomiting (ANV), also referred to asconditioned, learned or psychological nausea and vomiting, iswidely believed to be a learned response to chemotherapy that25% of patients develop by the fourth treatment cycle[34, 35]. It appears to link psychological, neurological, andphysiological systems [8]. The risk of ANV tends to increasewith the number of cycles received [30], and the symptomsmay persist long after the completion of chemotherapy [20].ANV is difficult to control by pharmacological means,whereas behavioral therapies, most notably systematicdesensitization, can be used to effectively treat it.

The development of ANV best fits a Pavlovian condi-tioning model [16, 30, 50] shown below as Fig. 1. Thereare no data about the development, clinical course, ortreatment of anticipatory side effects that are at variancewith this model. In this conditioning model, a conditionedstimulus (CS) (e.g., the sight of a nurse) is paired with anunconditioned stimulus (e.g., chemotherapy), which reliablyproduces an unconditioned response (UR) (e.g., nausea).Following the conditioning period (repeated chemotherapytreatments), the CS is able, over time, to provoke aconditioned response identical to the UR. In the situation ofa patient receiving chemotherapy, he/she finds him/herself atthe treatment location surrounded by unfamiliar sights,sounds, and smells. In addition, various psychological,cognitive, and social factors are present during this experi-ence. These stimuli become associated with the chemotherapytreatment and the subsequent nausea and vomiting (NV) thatfollow the chemotherapy infusion. After repeated chemother-apy cycles in which these stimuli are paired with theexperience of subsequent nausea, they acquire the ability totrigger a response of nausea or vomiting even before thereceipt of chemotherapy (i.e., ANV).

J. A. Roscoe (*) :G. R. MorrowJames P. Wilmot Cancer Center,University of Rochester School of Medicine and Dentistry,601 Elmwood Avenue, Box 704, Rochester, NY 14642, USAe-mail: joseph_roscoe@urmc.rochester.edu

M. S. AaproIMO Clinique de Genolier,1272 Genolier, Switzerland

A. MolassiotisCancer & Supportive Care, University of Manchester,Manchester, UK

I. OlverCancer Council Australia,Sydney, NSW, Australia

Support Care Cancer (2011) 19:1533–1538DOI 10.1007/s00520-010-0980-0

Predicting ANV

Table 1 shows risk factors shown to be involved in thedevelopment of ANV. From a clinical standpoint, youngerpatients who have experienced severe and frequent nausea/vomiting after their prior treatments are at particularly highrisk for the development of ANV. While the conditioningmodel is well accepted, cognitive factors, such as anxiety,self absorption, and response expectancies, can be involvedin ANV development [4, 33, 35, 55, 60]. Anxiety mayaffect the development of NV at least in part throughnegative expectancies [4, 5, 22, 56], since expectancieshave been shown to affect the generation of conditioningeffects [24, 44, 53].

Hickok et al. [19] evaluated the role of patients'expectations of nausea in the development of ANV infemale cancer patients receiving their first course ofchemotherapy. Of a total of 63 patients, 20 (32%) expectedto experience nausea, and 12 (19%) reported ANV beforethe third cycle. Pretreatment expectations predicted ANVat cycle 3 (Spearman's r=0.41, P=0.001). Anticipatorynausea (AN) developed in 40% of patients who expectednausea, 13% of those who were uncertain whether theywould develop it, and none of those who did not expectnausea. Logistic regression indicated that expecting nau-sea was the strongest predictor (χ2=13.15, P<0.001) ofactually developing nausea.

In another study, the effects of changes in familyrelationships (cohesion, expression, and conflict) onpatients' physical adjustment to chemotherapy were exam-ined. A total of 233 married cancer patients completedquestionnaires consisting of measures of family relation-ships and chemotherapy-related nausea symptoms at twoassessments. An increase in family conflict was associatedwith an increased duration of post-treatment nausea (PTN)and greater severity of AN for younger adult patients butnot for older adult patients. An increase in family conflictwas also associated with a greater severity of AN for femalepatients but not for male patients. These findings suggestthat intervention programs to help reduce family conflictand anxiety may be beneficial for younger adult andfemale patients [23].

Table 1 Risk factors for ANV

Age less than 50

Nausea/vomiting after last chemotherapy session

Expectations of post-treatment nausea

Anxiety (both state and trait)

Susceptibility to motion sickness

Sweating or feeling warm all over after last chemotherapy session

Fig. 1 Classical conditioning ofnausea and vomiting

1534 Support Care Cancer (2011) 19:1533–1538

Anticipatory emesis and the experimental setting

While there is no completely satisfactory laboratory model forANV, some translational research on ANV has been con-ducted using a body rotation model as a nausea-inducingstimulus in humans and a conditioned gaping response in rats[18, 26] in an attempt to develop better prevention andtreatment interventions in addition to preventing post-treatment nausea and vomiting. Studies using the rotationmodel suggest that an overshadowing procedure could behelpful in reducing the development of ANV [50]. Over-shadowing is a technique whereby the subject is conditionedin an adverse experimental setting to respond to a strongstimulus, and then the stimulus is withdrawn at the nextexposure to the adverse experience. Overshadowing has alsobeen examined in a small study of cancer patients. In thatstudy, 16 cancer patients were assigned to one of two groups:with overshadowing (OV+) and without overshadowing(OV−). At the start of all infusions of two consecutivechemotherapy cycles A and B (acquisition), OV+ subjectsdrank a distasteful saline beverage (the overshadowing CS),whereas group OV− drank water. All patients received waterin cycle C (test). As expected, in cycle C (test), no patient ofgroup OV+ showed AN, whereas two patients of groupOV− developed AN [48]. In the experimental animal settingsexamining the gaping response in rats, certain conditioningtechniques, including overshadowing [18, 47, 51], systemictreatment with lipopolysaccharide [10], tetrahydrocannabinol[38], and manipulation of the endocannabinoid system [46]have been examined with inconsistent results. Tetrahydro-cannabinol and cannabidiol have also been effective inreducing conditioned retching in a Suncus murinus model(musk shrew) [39]. Conditioning procedures in other animalmodels have been successfully used to alleviate nausea andvomiting [12, 25].

Appropriate control of acute and delayed emesisreduces ANV

One of the largest observational series evaluating ANVcomprises data from 574 chemotherapy patients whoreceived granisetron as their antiemetic treatment duringrepeat cycle chemotherapy. Per treatment cycle, fewer than10% of patients displayed symptoms of AN, and 2% orfewer had symptoms of anticipatory vomiting [2].

This implies that the rate of ANV is much less thanobserved in older studies, which used less satisfactoryantiemetic programs. Two examples of conditions leadingto ANV are given to illustrate the issue. One such exampleis a report by Wilcox et al. in the early 1980s. The authorsstudied 52 women treated with cyclophosphamide, metho-trexate, and 5-fluorouracil (CMF) adjuvant chemotherapy

for breast carcinoma. Among the 52 patients, ANVoccurred in 17 (33%), while acute and delayed emesiswas experienced by 46 (88%). Of the 52 patients, ten (19%)discontinued CMF adjuvant chemotherapy because ofnausea and vomiting; seven of the ten (70%) hadexperienced anticipatory vomiting [57].

Another example of poor acute control leading to a highprevalence of ANV is a report of women receiving CMF or5-fluorouracil/doxorubicin/cyclophosphamide (FAC). Antie-metic therapy included one corticoid plus ondansetron (in theFAC regimen) or one corticoid plus thiethylperazine (in theCMF regimen). For at least one cycle of chemotherapy,86.1% and 91.7% patients in the FAC protocol experiencedvomiting and nausea, respectively, 11.1% had anticipatoryvomiting, and 30.6% had AN. In the CMF protocol, 79.6%had post chemotherapy vomiting, and 71.7% had postchemotherapy nausea associated with at least one cycle. Inthis group, 7.4% had anticipatory vomiting, and 16.6% hadAN. A high proportion of patients suffered anticipatoryanxiety in both groups (75% in FAC, 74.1% in CMF). Thestimuli most frequently associated with the appearance ofanticipatory emesis were olfactory stimuli and cognitivestimuli [15].

There is some preliminary data that the relationshipbetween ANV and post-treatment nausea may be bi-directional as indicated by findings from 40 early-stagebreast cancer patients who developed AN. A significantcorrelation between the intensity of AN in the clinic prior totheir treatment infusion and subsequent post-treatmentnausea during the 24 h after the infusion was found in 40early-stage breast cancer patients who had developed ANshowing that, once established, conditioned nausea maycontribute to the severity of subsequent post-treatmentnausea in patients receiving repeated cycles of chemother-apy for cancer [7]. It is also of interest that in adult patients,anticipatory immunomodulation (AIM) has also beenobserved and that some results suggest that ANV andAIM also occur in pediatric cancer patients and showfeatures of a conditioned response [49].

Treatment of ANV

Psychological intervention and ANV

Behavioral interventions are especially appropriate toaddress ANV because it is a conditioned response, andthey are best implemented prior to the complete/fulldevelopment of the undesired conditioned response [16].Evidence suggests that behavioral intervention can reduceANV, decrease levels of anxiety and distress, and to a lesserextent decrease cancer-related pain and nausea [36]. Thetechniques have varied, including hypnosis [29, 42] and

Support Care Cancer (2011) 19:1533–1538 1535

biofeedback [9], yoga [40], and many variations ofrelaxation methods [16]. It is of interest that even if anxietylevels of the patients are not always influenced, thesetechniques can control ANV [52]. As a learned phenome-non, ANV is treatable by means of behavioral approachesbased on learning principles. Research on the behavioraltreatment of conditioned adverse effects of chemotherapyhas centered on three principal approaches: progressivemuscle relaxation training (PMRT), systematic desensitiza-tion (SD), and hypnosis. PMRT appears to exert its greatesteffects against adverse events that develop after adminis-tration of chemotherapy [31], although when combinedwith guided imagery, it has shown efficacy in reducingANV [58].

SD is commonly used to treat learning-based difficulties,such as fears and phobias, and is particularly effective forANV. One way in which phobias may develop is by meansof the classical conditioning mechanism described previ-ously. In many respects, anticipatory side effects displaycharacteristics of phobic behaviors, although the match isfar from perfect. SD involves the counter-conditioning ofa response incompatible with those stimuli that typicallyelicit a maladaptive reaction. In terms of ANV, the theorypredicts that these symptoms would be reduced if patientscould be taught an incompatible response (such asprogressive muscle relaxation), rather than the condi-tioned response of NV, in response to the conditionedstimuli (the clinic; the nurse). This treatment has beeneffective in over half the patients to whom it is administered[13, 34].

Hypnosis/suggestion has been used successfully toprevent AN related to chemotherapy [29, 42] and to reducenausea following chemotherapy [21, 45, 54, 61]. Althoughhypnosis was the first psychological technique used tocontrol ANV, few controlled studies have been done. It hasmost often been used with children and adolescents, whichmay be because children are more readily hypnotized thanadults [16, 27, 34, 37, 45].

Acupuncture/acupressure

According to the National Institutes of Health ConsensusDevelopment Panel, acupuncture is effective for thetreatment of postoperative and chemotherapy-related nau-sea and vomiting [1]. Several studies, including a system-atic review, have shown efficacy of acupuncture andacupressure in reducing chemotherapy-related nausea [11,14, 17, 32, 43]. No studies, however, have found anydefinitive evidence supporting the use of acupunctureand acupressure in alleviating ANV. One potentiallyrelated study reported benefit for the use of acupuncturein treatment of “nervous vomiting” in a dental setting[59].

Benzodiazepines and ANV

Razavi et al. [41] conducted a double-blind, placebo-controlled study designed to assess the usefulness of addinglow-dose alprazolam (0.5 to 2 mg/day) to a psychologicalsupport program including progressive relaxation trainingdesigned to prevent ANV in 57 women undergoingadjuvant chemotherapy for stage II primary breast cancer.At the second evaluation, the results showed a higher rateof AN (18% vs 0%) in the placebo compared with thealprazolam arm (P=0.038). These differences were no moresignificant at each of the further assessments. Significantdifferences were found for the intake of hypnotics at eachassessment visit, with the rate of hypnotic users beingsignificantly higher in the placebo (19%) compared withthe alprazolam (0%) arm at the fourth assessment (P<0.05).The authors concluded that the adjunct of alprazolam to apsychological support program delays the occurrence ofAN and controls sleeping problems secondary to adjunctchemotherapy.

Malik et al. [28] conducted a randomized trial toevaluate the efficacy of lorazepam in managing anticipa-tory, acute, and delayed emesis induced by high doses ofcisplatin. A total of 180 events involving cisplatinadministration (100 mg/m2 as a 24-h continuous infusion)were randomized to receive metoclopramide along withdexamethasone and clemastine with or without lorazepam.Lorazepam significantly reduced the incidence of AN andvomiting (P<0.05) as well as acute emesis (P=0.05)induced by cisplatin. Mild sedation and amnesia weresignificantly more common in patients receiving loraze-pam (P<0.001). The authors concluded that lorazepamincreases the efficacy of metoclopramide against cisplatin-induced anticipatory, acute, and delayed nausea andvomiting.

Conclusions

This review updates work published in 2005 [3]. In 1998 andagain in 2005, the Antiemetic Subcommittee of the

Table 2 Guideline for managing anticipatory nausea and vomiting inpatients receiving chemotherapy or radiation therapy

Anticipatory nausea and vomiting should be managed bypsychological techniques

MASCC level of confidence: High

MASCC level of consensus: High

Use of benzodiazepines may be useful in preventing the development ofANVwhen used in conjunctionwith antiemetics (no new data since 2003)

MASCC level of confidence: Moderate

MASCC level of consensus: High

1536 Support Care Cancer (2011) 19:1533–1538

Multinational Association of Supportive Care in Cancer(MASCC) stated [3, 6] that the best treatment for anticipa-tory emesis is the control of acute and delayed emesis so thatANV does not develop. Based on the above review of theliterature, the 2009 panel reaffirms that earlier recommenda-tions add the adjunctive suggestions shown in Table 2.Unfortunately, the use of behavioral interventions willremain difficult to implement, as most patients are treatedin settings where the needed expertise is not available.

References

1. NIH Consensus Conference (1998) Acupuncture. JAMA280:1518–1524

2. Aapro MS, Kirchner V, Terrey JP (1994) The incidence ofanticipatory nausea and vomiting after repeat cycle chemotherapy:the effect of granisetron. Br J Cancer 69:957–960

3. Aapro MS, Molassiotis A, Olver I (2005) Anticipatory nausea andvomiting. Support Care Cancer 13:117–121

4. Andrykowski MA (1990) The role of anxiety in the developmentof anticipatory nausea in cancer chemotherapy: a review andsynthesis. Psychosom Med 52:458–475

5. Andrykowski MA, Redd WH, Hatfield AK (1985) Developmentof anticipatory nausea: a prospective analysis. J Consult ClinPsychol 53:447–454

6. Antiemetic Subcommittee of the Multinational Association ofSupportive Care in Cancer (1998) Prevention of chemotherapy-and radiotherapy-induced emesis: results of Perugia ConsensusConference. Ann Oncol 9:811–819

7. Bovbjerg DH (2006) The continuing problem of post chemother-apy nausea and vomiting: contributions of classical conditioning.Auton Neurosci 129:92–98

8. Burish TG, Carey MP (1986) Conditioned aversive responses incancer chemotherapy patients: theoretical and developmentalanalysis. J Consult Clin Psychol 54:593–600

9. Burish TG, Shartner CD, Lyles JN (1981) Effectiveness ofmultiple muscle-site EMG biofeedback and relaxation training inreducing the aversiveness of cancer chemotherapy. BiofeedbackSelf Regul 6:523–535

10. Chan MY, Cross-Mellor SK, Kavaliers M, Ossenkopp KP (2009)Lipopolysaccharide (LPS) blocks the acquisition of LiCl-inducedgaping in a rodent model of anticipatory nausea. Neurosci Lett450:301–305

11. Collins KB, Thomas DJ, Collins KB, Thomas DJ (2004) Acupunc-ture and acupressure for the management of chemotherapy-inducednausea and vomiting. [Review] [29 refs]. J Am Acad Nurse Pract16:76–80

12. Davey VA, Biederman GB (1998) Conditioned antisickness:indirect evidence from rats and direct evidence from ferrets thatconditioning alleviates drug-induced nausea and emesis. J ExpPsychol Anim Behav Process 24:483–491

13. Elam CL, Andrykowski MA (1991) Admission interview ratings:relationship to applicant academic and demographic variables andinterviewer characteristics. Acad Med 66:S13–S15

14. Ezzo J, Vickers A, Richardson MA, Allen C, Dibble SL, Issell B,Lao L, Pearl M, Ramirez G, Roscoe JA, Shen J, Shivnan J,Streitberger K, Treish I, Zhang G (2005) Acupuncture-pointstimulation for chemotherapy-induced nausea and vomiting. JClin Oncol 23:7188–7198

15. Fernandez-Marcos A, Martin M, Sanchez JJ, Rodriguez-LescureA, Casado LMJ, Diaz-Rubio E (1996) Acute and anticipatoryemesis in breast cancer patients. Support Care Cancer 4:370–377

16. Figueroa-Moseley C, Jean-Pierre P, Roscoe JA, Ryan JL, Kohli S,Palesh OG, Ryan EP, Carroll J, Morrow GR (2007) Behavioralinterventions in treating anticipatory nausea and vomiting. J NatlCompr Cancer Netw 5:44–50

17. Gardani G, Cerrone R, Biella C, Galbiati G, Proserpio E,Casiraghi M, Arnoffi J, Meregalli M, Trabattoni P, Dapretto E,Giani L, Messina G, Lissoni P (2007) A progress study of 100cancer patients treated by acupressure for chemotherapy-inducedvomiting after failure with the pharmacological approach. Miner-va Med 98:665–668

18. Hall G, Symonds M (2006) Overshadowing and latent inhibitionof context aversion conditioning in the rat. Auton Neurosci129:42–49

19. Hickok JT, Roscoe JA, Morrow GR (2001) The role of patients'expectations in the development of anticipatory nausea related tochemotherapy for cancer. J Pain Symptom Manage 22:843–850

20. Hursti T, Fredikson M et al (1992) Association between personalitycharacteristics and the prevalence and extinction of conditionednausea after chemotherapy. J Psychosoc Oncol 10:59–77

21. Jacknow DS, Tschann JM, Link MP, Boyce WT (1994) Hypnosisin the prevention of chemotherapy-related nausea and vomiting inchildren: a prospective study. J Dev Behav Pediatr 15:258–264

22. Jacobsen PB, Andrykowski MA, Redd WH, Die-Trill M, HakesTB, Kaufman RJ, Currie VE, Holland JC (1988) Nonpharmaco-logic factors in the development of posttreatment nausea withadjuvant chemotherapy for breast cancer. Cancer 61:379–385

23. Kim Y, Morrow GR (2003) Changes in family relationships affectthe development of chemotherapy-related nausea symptoms.Support Care Cancer 11:171–177

24. Kirsch I (1997) Specifying nonspecifics: psychological mecha-nisms of placebo effects. In: Harrington A (ed) The placebo effect:an interdisciplinary exploration. Harvard University Press, Cam-bridge, pp 166–186

25. Lett BT (1983) Pavlovian drug-sickness pairings result in theconditioning of an antisickness response. Behav Neurosci 97:779–784

26. Limebeer CL, Krohn JP, Cross-Mellor S, Litt DE, Ossenkopp KP,Parker LA (2008) Exposure to a context previously associatedwith nausea elicits conditioned gaping in rats: a model ofanticipatory nausea. Behav Brain Res 187:33–40

27. Mackenzie A, Frawley GP (2007) Preoperative hypnotherapy inthe management of a child with anticipatory nausea and vomiting.Anaesth Intensive Care 35:784–787

28. Malik IA, Khan WA, Qazilbash M, Ata E, Butt A, Khan MA(1995) Clinical efficacy of lorazepam in prophylaxis of anticipa-tory, acute, and delayed nausea and vomiting induced by highdoses of cisplatin. A prospective randomized trial. Am J ClinOncol 18:170–175

29. Marchioro G, Azzarello G, Viviani F, Barbato F, Pavanetto M,Rosetti F, Pappagallo GL, Vinante O (2000) Hypnosis in thetreatment of anticipatory nausea and vomiting in patientsreceiving cancer chemotherapy. Oncology (Huntingt) 59:100–104

30. Matteson S, Roscoe JA, Hickok J, Morrow GR (2002) The role ofbehavioral conditioning in the development of nausea. Am JObstet Gynecol 185:S239–S243

31. Molassiotis A, Yung HP, Yam BMC, Chan FYS, Mok TS (2002)The effectiveness of progressive muscle relaxation training inmanaging chemotherapy-induced nausea and vomiting in Chinesebreast cancer patients: a randomized controlled trial. Support CareCancer 10:237–246

32. Molassiotis A, Helin AM, Dabbour R, Hummerston S (2007) Theeffects of P6 acupressure in the prophylaxis of chemotherapy-relatednausea and vomiting in breast cancer patients. Complement TherMed 15:3–12

33. Montgomery GH, Tomoyasu N, Bovbjerg DH, Andrykowski MA,Currie VE, Jacobsen PB, Redd WH (1998) Patients' pretreatment

Support Care Cancer (2011) 19:1533–1538 1537

expectations of chemotherapy-related nausea are an independentpredictor of anticipatory nausea. Ann Behav Med 20:104–109

34. Morrow GR, Roscoe JA (1997) Anticipatory nausea and vomiting:models, mechanisms and management. In: Dicato M (ed) Medicalmanagement of cancer treatment induced emesis. Martin Dunitz,London, pp 149–166

35. Morrow GR, Roscoe JA, Kirshner JJ, Hynes HE, Rosenbluth RJ(1998) Anticipatory nausea and vomiting in the era of 5-HT3antiemetics. Support Care Cancer 6:244–247

36. Mundy EA, DuHamel KN, Montgomery GH (2003) The efficacyof behavioral interventions for cancer treatment-related sideeffects. Semin Clin Neuropsychiatry 8:253–275

37. Olness K (1981) Imagery (self-hypnosis) as adjunct therapy inchildhood cancer: clinical experience with 25 patients. Am JPediatr Hematol/Oncol 3:313321

38. Parker LA, Kemp SW (2001) Tetrahydrocannabinol (THC) interfereswith conditioned retching in Suncus murinus: an animal model ofanticipatory nausea and vomiting (ANV). NeuroReport 12:749–751

39. Parker LA, Kwiatkowska M, Mechoulam R (2006) Delta-9-tetrahydrocannabinol and cannabidiol, but not ondansetron,interfere with conditioned retching reactions elicited by alithium-paired context in Suncus murinus: An animal model ofanticipatory nausea and vomiting. Physiol Behav 87:66–71

40. Raghavendra RM, Nagarathna R, Nagendra HR, Gopinath KS,Srinath BS, Ravi BD, Patil S, Ramesh BS, Nalini R (2007) Effectsof an integrated yoga programme on chemotherapy-inducednausea and emesis in breast cancer patients. Eur J Cancer Care(Engl) 16:462–474

41. Razavi D, Delvaux N, Farvacques C, De Brier F, Van Heer C,Kaufman L, Derde M-P, Piccart M (1993) Prevention ofadjustment disorders and anticipatory nausea secondary toadjuvant chemotherapy: a double-blind, placebo- controlledstudy assessing the usefulness of alprazolam. J Clin Oncol11:1384–1390

42. Redd WH, Andresen GV, Minagawa RY (1982) Hypnotic controlof anticipatory emesis in patients receiving cancer chemotherapy.J Consult Clin Psychol 50:14–19

43. Reindl TK, Geilen W, Hartmann R, Wiebelitz KR, Kan G,Wilhelm I, Lugauer S, Behrens C, Weiberlenn T, Hasan C,Gottschling S, Wild-Bergner T, Henze G, Driever PH (2006)Acupuncture against chemotherapy-induced nausea and vomitingin pediatric oncology. Interim results of a multicenter crossoverstudy. Support Care Cancer 14:172–176

44. Rescorla RA (1988) Pavlovian conditioning: it's not what youthink. Am Psychol 43:151–160

45. Richardson J, Smith JE, McCall G, Richardson A, Pilkington K,Kirsch I (2007) Hypnosis for nausea and vomiting in cancerchemotherapy: a systematic review of the research evidence. Eur JCancer Care (Engl) 16:402–412

46. Rock EM, Limebeer CL, Mechoulam R, Piomelli D, Parker LA(2008) The effect of cannabidiol and URB597 on conditionedgaping (a model of nausea) elicited by a lithium-paired context inthe rat. Psychopharmacology (Berl) 196:389–395

47. Sansa J, Artigas AA, Prados J (2007) Overshadowing andpotentiation of illness-based context conditioning. Psicológica28:193–214

48. Stockhorst U, Wiener JA, Klosterhalfen S, Klosterhalfen W, Aul C,Steingruber HJ (1998) Effects of overshadowing on conditionednausea in cancer patients: an experimental study. Physiol Behav64:743–753

49. Stockhorst U, Spennes-Saleh S, Korholz D, Gobel U, SchneiderME, Steingruber HJ, Klosterhalfen S (2000) Anticipatory symptomsand anticipatory immune responses in pediatric cancer patientsreceiving chemotherapy: features of a classically conditionedresponse? Brain Behav Immun 14(3):198–218

50. Stockhorst U, Enck P, Klosterhalfen S (2007) Role of classicalconditioning in learning gastrointestinal symptoms. World JGastroenterol 13:3430–3437

51. Symonds M, Hall G (1999) Overshadowing not potentiation ofillness-based contextual conditioning by a novel taste. AnimLearn Behav 27:379–390

52. Vasterling J, Jenkins RA, Tope DM, Burish TG (1993) Cognitivedistraction and relaxation training for the control of side effectsdue to cancer chemotherapy. J Behav Med 16:65–80

53. Voudouris NJ, Peck CL, Coleman G (1990) The role ofconditioning and verbal expectancy in the placebo response. Pain43:121–128

54. Walker LG, Dawson AA, Pollet SM, Ratcliffe MA, Hamilton L(1988) Hypnotherapy for chemotherapy side effects. Br J ExpClin Hypn 5:79–82

55. Watson M (1993) Anticipatory nausea and vomiting: broadeningthe scope of psychological treatments. Support Care Cancer1:171–177

56. Watson M, McCarron J, Law M (1992) Anticipatory nausea andemesis, and psychological morbidity: assessment of prevalenceamong out-patients on mild to moderate chemotherapy regimens.Br J Cancer 66:862–866

57. Wilcox PM, Fetting JH, Nettesheim KM, Abeloff MD (1982)Anticipatory vomiting in women receiving cyclophosphamide,methotrexate, and 5-FU (CMF) adjuvant chemotherapy for breastcarcinoma. Cancer Treat Rep 66:1601–1604

58. Yoo HJ, Ahn SH, Kim SB, Kim WK, Han OS (2005) Efficacy ofprogressive muscle relaxation training and guided imagery inreducing chemotherapy side effects in patients with breast cancerand in improving their quality of life. Support Care Cancer13:826–833

59. Yugin L, Yugin L (1989) Treating patients with nervous vomitingin the dental office by point-stimulating therapy. Spec Care Dent9:27–28

60. Zachariae R, Paulsen K, Mehlsen M, Jensen AB, Johansson A,von der Maase H (2007) Anticipatory nausea: the role ofindividual differences related to sensory perception and autonomicreactivity. Ann Behav Med 33:69–79

61. Zeltzer LK, Dolgin MJ, LeBaron S, LeBaron C (1991) Arandomized, controlled study of behavioral intervention for chemo-therapy distress in children with cancer. Pediatrics 88:34–42

1538 Support Care Cancer (2011) 19:1533–1538