Prevention and treatment of anticipatory chemotherapy-induced nausea and vomiting in pediatric cancer patients and hematopoietic stem cell recipients: Clinical practice guideline update.

This 2021 clinical practice guideline update provides recommendations for preventing anticipatory chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. Recommendations are based on systematic reviews that identified (1) if a history of acute or delayed CINV is a risk factor for anticipatory CINV, and (2) interventions for anticipatory CINV prevention and treatment. A strong recommendation to optimize acute and delayed CINV control in order to prevent anticipatory CINV is made. Conditional recommendations are made for hypnosis, systematic desensitization, relaxation techniques, and lorazepam for the secondary prevention of anticipatory CINV. No recommendation for the treatment of anticipatory CINV can be made.

Oxytocin, social factors, and the expression of conditioned disgust (anticipatory nausea) in male rats.

Disgust has been proposed to have evolved as a means to rid the body and mouth of noxious substances and toxins, as well as to motivate and facilitate avoidance of contact with disease-causing organisms and infectious materials. Nonemetic species, such as the rat, show distinctive facial expressions, including the gaping reaction, indicative of nausea-based disgust. These conditioned disgust responses can be used to model anticipatory nausea in humans, which is a learned response observed following chemotherapy treatment. As social factors play a role in the modulation and expression of conditioned disgust responses in rats, and the nonapeptide, oxytocin (OT), is involved in the modulation of social behavior, the present study examined the effects of an OT antagonist, L-368 899, on the development and expression of socially mediated conditioned disgust in male rats. When administered 10 min before testing in a distinct context (different from the original conditioning context), L-368 899 (5 mg/kg) significantly decreased gaping behavior in rats that were conditioned with a social partner. LiCl-treated rats administered L-368 899 before testing also showed decreased social initiations toward their social partner. These findings suggest that OT may play a role in the modulation and expression of socially mediated conditioned disgust in rats.

Impairment of lithium chloride-induced conditioned gaping responses (anticipatory nausea) following immune system stimulation with lipopolysaccharide (LPS) occurs in both LPS tolerant and LPS non-tolerant rats.

Anticipatory nausea is a classically conditioned response to a context that has been previously paired with toxin-induced nausea and/or vomiting. When injected with a nausea-inducing drug, such as lithium chloride (LiCl), rats will show a distinctive conditioned gaping response that has been suggested to be an index of nausea. Previous studies have found that immune system activation with an endotoxin, such as lipopolysaccharide (LPS), attenuates LiCl-induced conditioned gaping in rats. The present study examined the acquisition of LiCl-induced conditioned gaping in rats that were either LPS tolerant or LPS non-tolerant, as little is known about the effects of endotoxin tolerance on learning and memory. Male Long-Evan rats were given four systemic injections of LPS (200 µg/kg) or isotonic saline (NaCl) to induce LPS tolerance, indexed with 24 h changes in body weight following treatment. The animals were then given 4 acquisition trials in a LiCl-induced conditioned gaping paradigm. On conditioning days animals were treated with LPS (200 µg/kg) or saline followed 90 min later by injection of LiCl (127 mg/kg) or saline and then placed in a distinctive context for 30 min and their behavior video-recorded. On a drug free test day all animals were again placed in the distinctive context for 10 min and behavior was video-recorded. Gaping responses were scored for all acquisition days and the test day. Spleen and body weights were also obtained for all rats at the end of the experiment. Gaping responses were attenuated in rats treated with LPS in both the LPS tolerant and LPS non-tolerant groups. There were significant negative correlations between spleen weight as well as spleen/body weight ratios, and levels of conditioned gaping responses in LiCl treated rats, but not control rats. These results show that LPS interferes with learning/memory in the anticipatory nausea paradigm in rats that are both LPS tolerant and LPS non-tolerant.

Risk factors at pretreatment predicting treatment-induced nausea and vomiting in Australian cancer patients: a prospective, longitudinal, observational study.

PURPOSE: Despite significant advances in antiemetic management, almost 50% of cancer patients still experience nausea and vomiting during treatment. The goal of antiemetic therapy is complete prevention of treatment-induced nausea and/or vomiting (TINV); however, realisation of this goal remains elusive, thus supplementary strategies identifying patients at high risk must be employed in the interim. Consequently, we examined TINV incidence and its risk factors, including patient, clinical and pretreatment quality of life (QOL)/psychological factors. METHODS: Two hundred newly diagnosed cancer patients beginning combined treatment participated in this prospective, longitudinal, observational study. QOL (including TINV), psychological adjustment, and patient/clinical characteristics were examined at pretreatment, on-treatment (8 weeks ± 1 week) and post-treatment. RESULTS: Overall, 62% of patients experienced TINV, with TIN incidence (60%) doubling that of TIV (27%). Eight independent risk factors predicted 73% of TIN incidence: high premorbid/anticipatory NV, moderately/highly emetogenic chemotherapy (M/HEC), longer treatment (>3 months), female gender, surgery prior to adjuvant chemotherapy ± radiotherapy, private health insurance and low emotional functioning (pretreatment). Six independent risk factors predicted 77% of TIV incidence: premorbid/anticipatory vomiting, M/HEC, female gender, cancer resection and low role functioning (pretreatment). CONCLUSIONS: TINV still represents a very major concern for patients. Several pretreatment risk factors for the development of TIN and TIV, respectively, were identified. Patients about to undergo cancer treatment, particularly combined treatment involving emetogenic chemotherapy and surgery, should be screened for these factors with a view to modifying standard pretreatment/maintenance antiemetic therapy. Furthermore, and consistent with recent research, it is recommended that more comprehensive interventions combining antiemetics with other effective pharmacological (e.g. anxiolytics) and non-pharmacological approaches (e.g. acupuncture, relaxation techniques) be considered by clinicians in attempts to improve control of TIN and TIV (and overall QOL) for their patients. In this way, optimal holistic care will be ensured for cancer patients by clinicians providing conventional oncology treatment.

Anticipatory nausea and vomiting.

A commonly reported consequence of post-treatment nausea or vomiting is the development of anticipatory nausea and vomiting (ANV). In most published work, nausea is reported to occur before chemotherapy drugs are administered by approximately 20% of patients at any one chemotherapy cycle and by 25-30% of patients by their fourth chemotherapy cycle. Most studies in adult patients strongly support the view that the development of ANV involves elements of classical conditioning. The best method to avoid development of ANV is to adequately prevent both vomiting and nausea from the first exposure to chemotherapy. If anticipatory side effects develop, behavioral treatment techniques, such as systematic desensitization, have been shown effective. Benzodiazepines used in combination with behavioral techniques or antiemetics may also be useful. The evidence on which these conclusions are based is reviewed in this article.

A randomized trial of nurse-administered behavioral interventions to manage anticipatory nausea and vomiting in chemotherapy.

PURPOSE: Chemotherapy side effects diminish quality of life and can lead to treatment delay. Nausea and vomiting can occur prior to chemotherapy because of classical conditioning. We studied the effects of 20-minute behavioral interventions, administered by oncology nurses, of higher intensity (mindfulness relaxation-MR) or lower intensity (relaxing music-RM), on anticipatory nausea and vomiting (ANV). PATIENTS AND METHODS: Patients undergoing chemotherapy for solid tumors were randomized to MR (N = 160), RM (N = 159), or standard care SC (N = 155). Subjects were mostly female (91.8%) and white (86.1%) with breast cancer (85%). Most patients had early stage disease (Stage I: 26%; II: 52.9%; III: 19%; IV: 0.1%). Anticipatory nausea and vomiting were assessed at the midpoint and end of the chemotherapy course using the Morrow Assessment of Nausea and Emesis (MANE). RESULTS: Compared to SC, there was reduced anticipatory nausea at the midpoint of chemotherapy in those receiving MR (OR 0.44, 95% CI 0.20-0.93) and RM (OR 0.40, 95% CI 0.20-0.93), controlling for age, sex, cancer stage, and emetogenic level of chemotherapy. There was no difference between treatment groups in anticipatory nausea at the end of chemotherapy or in anticipatory vomiting and postchemotherapy nausea and vomiting at either time point. CONCLUSION: A brief nurse-delivered behavioral intervention can reduce midpoint ANV associated with chemotherapy.

Exposure to a context previously associated with nausea elicits conditioned gaping in rats: a model of anticipatory nausea.

Following one or more chemotherapy treatments, many patients report that they experience anticipatory nausea. This phase of nausea has been interpreted as a classically conditioned response where a conditional association develops between the contextual clinic cues and the nausea and/or vomiting that developed following treatment. Although rats do not vomit, they display a distinctive gaping reaction when exposed a flavored solution previously paired with a toxin. Here we report that, even in the absence of a flavored solution, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium (Experiment 1 with a distinctive odor and Experiment 3 without a distinctive odor), a low dose of lithium (Experiment 2) or provocative vestibular stimulation (Experiment 2). These results suggest that the conditioned gaping reaction in rats is selectively elicited by nausea-paired contextual stimuli, as well as flavors. This rat model of anticipatory nausea may serve as a valuable preclinical tool to evaluate the effectiveness of anti-nausea treatments and the side effect of nausea produced by newly developed pharmaceutical compounds intended for other clinical treatments.

Pavlovian conditioning of nausea and vomiting.

Cancer patients undergoing cytotoxic drug treatment often experience side-effects, the most distressing being nausea and vomiting. Despite antiemetic drugs, 25-30% of the chemotherapy patients report these side-effects when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea and anticipatory vomiting. The present paper summarizes the evidence that anticipatory vomiting is acquired by Pavlovian conditioning, and, consequently, may be alleviated by conditioning techniques. To explore the mechanisms that induce and alleviate conditioned nausea and vomiting further, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea was demonstrated. Cortisol and tumor-necrosis factor-alpha were elevated as endocrine and immunological correlates of nausea. Data in the rotation-induced motion sickness model indicated that gender is an important moderator variable to be considered in further studies. The paper concludes with a review of applications of the demonstrated conditioning principles as interventions to ameliorate distressing anticipatory nausea or anticipatory vomiting in cancer patients undergoing chemotherapy.

Overshadowing and latent inhibition of context aversion conditioning in the rat.

A review is presented of experimental studies, using rats as the subjects, that were designed to establish an animal model of the clinical phenomenon of anticipatory nausea. Experiments 1 and 2 demonstrated that pairing a distinctive context with an illness-inducing injection of lithium chloride endowed the context with new properties, consistent with the proposal that classical conditioning had established an association between the context as the conditioned stimulus and nausea as the unconditioned stimulus. The conditioned response to the context constitutes a form of anticipatory nausea. Experiment 3 examined overshadowing, showing that the presence of a novel salient cue (a flavour) during context conditioning reduced the magnitude of the aversion conditioned to the context. Experiments 4-7 examined the effects of giving exposure to the context prior to conditioning. They demonstrated a latent inhibition effect, that is, a reduction in the magnitude of the aversion in pre-exposed animals. It is suggested that these ways of modulating conditioned aversions could form the basis of interventions for use in the chemotherapy clinic. Anticipatory nausea is assumed to be a consequence of the formation of an association between the cues that constitute the clinic and the drug-induced nausea experienced in their presence. By restricting the development of this association, latent inhibition and overshadowing procedures should be effective in alleviating the problem of anticipatory nausea.

The continuing problem of post chemotherapy nausea and vomiting: contributions of classical conditioning.

Despite continuing improvements in antiemetic therapies, nausea and vomiting following chemotherapy treatments for cancer remain significant clinical problems for many patients. The role of classical conditioning in patients' anticipatory nausea is well known, but little attention has been paid to possible conditioning effects on post treatment nausea. The present study statistically examined the contribution of anticipatory (conditioned) nausea to patients' subsequent post treatment nausea. Forty early stage breast cancer patients who developed anticipatory nausea were analyzed. Results revealed a significant correlation between the intensity of anticipatory nausea in the clinic prior to their treatment infusion and subsequent post treatment nausea during the 24 h after the infusion. These results provide support for the hypothesis that, once established, conditioned nausea may contribute to the severity of subsequent post treatment nausea in patients receiving repeated cycles of chemotherapy for cancer. The results suggest the importance of considering the contribution of conditioning process to nausea and other post treatment side effects.

Latent inhibition of rotation chair-induced nausea in healthy male and female volunteers.

OBJECTIVES: Pre-exposure to an environment in which a nausea-inducing body rotation will subsequently be given constitutes a latent inhibition procedure that might act to reduce anticipatory and postrotation nausea. METHODS: This was tested in 24 healthy subjects randomly assigned to receive no pre-exposure (group 0), a single pre-exposure (group 1), or three pre-exposures (group 3). Rotation was standardized as 5 x 1 minute rotation, but the subjects could terminate it on request. Nausea was determined on a 7-item symptom rating scale before, during, and after rotation on days 3 and 4, whereas anticipatory nausea was measured before presumed rotation on day 5. Saliva cortisol and tumor necrosis factor alpha (TNF-alpha) levels were determined at baseline before, directly, and 15 and 30 minutes after rotation every day, and before presumed rotation on day 5. RESULTS: Pre-exposure significantly reduced the degree of anticipatory nausea on day 5. Cortisol levels increased with rotation and were higher at baseline on days 4 and 5, but subjects habituated from day 3 to day 4; levels were lower in women than in men. In contrast, TNF-alpha decreased with rotation but showed no habituation. For both cortisol and TNF-alpha, no effects on postrotational nausea were found. CONCLUSION: It is concluded that repetitive pre-exposure (latent inhibition) reduces anticipatory but not postrotation nausea; behavioral measures (rotation time) and measures of acute stress (cortisol, TNF-alpha) do not respond to latent inhibition. Thus, Pavlovian conditioning rules are effective in healthy humans with anticipatory nausea but not with postrotation nausea. Hormonal responses--TNF-alpha decrease with stress, compensatory cortisol increase--and gender-related effects on learning and habituation are discussed with regard to psychophysiological and psychoimmunological processes.

Anticipatory nausea in cyclical vomiting.

BACKGROUND: Cyclical Vomiting Syndrome (CVS) is characterised by discrete, unexplained episodes of intense nausea and vomiting, and mainly affects children and adolescents. Comprehending Cyclical Vomiting Syndrome requires awareness of the severity of nausea experienced by patients. As a subjective symptom, nausea is easily overlooked, yet is the most distressing symptom for patients and causes many behavioural changes during attacks. CASE PRESENTATION: This first-hand account of one patient's experience of Cyclical Vomiting Syndrome shows how severe nausea contributed to the development of anticipatory nausea and vomiting (ANV), a conditioned response frequently observed in chemotherapy patients. This conditioning apparently worsened the course of the patient's disease. Anticipatory nausea and vomiting has not previously been recognised in Cyclical Vomiting Syndrome, however predictors of its occurrence in oncology patients indicate that it could complicate many cases. CONCLUSION: We suggest a model whereby untreated severe and prolonged nausea provokes anxiety about further cyclical vomiting attacks. This anxiety facilitates conditioning, thus increasing the range of triggers in a self-perpetuating manner. Effective management of the nausea-anxiety feedback loop can reduce the likelihood of anticipatory nausea and vomiting developing in other patients.

Involving women with breast cancer in the development of a patient information leaflet for anticipatory nausea and vomiting.

As chemotherapy regimens increase in toxicity and changes in service provision move towards a more ambulatory outpatient basis, patients are often coping with side effects of treatment in isolation. Despite advances in pharmacological control, for some patients nausea and vomiting can be problematic. For some this can develop into anticipatory nausea and vomiting (ANV), which can severely effect the patients physical and psychological well-being. It is well recognised that the giving of realistic and understandable information is paramount to empower patients in their individual coping. A plethora of literature supports the use of Patient Information Leaflets as a means to educate and empower patients within their treatment trajectory. This paper discusses the authors' experiences in developing a Patient Information Leaflet, designed to assist breast cancer patients in understanding and coping with the symptoms of ANV. The patient's needs were sought to add clarity to the development and design of the leaflet. The authors conclude that developing a Patient Information Leaflet was a major undertaking in terms of time and resources.

Behavioural interventions and psychological aspects of care during chemotherapy.

Numerous studies have reported the deleterious impact that the side effects of cytotoxic chemotherapy can exert on the quality of life in patients with cancer. Nausea and vomiting consistently feature as the most distressing aspects of cancer therapy. Uncontrolled emesis can cause patients to abandon treatment and the poor public image of chemotherapy may lead others to refuse treatment altogether. Anticipatory nausea and vomiting can also develop in patients and this may persist for many years after successful completion of treatment. There are several behavioural interventions that are effective in ameliorating or preventing these unpleasant side effects. Consequently, psychological support should be provided as an integral part of good patient management, alongside appropriate antiemetic and anxiolytic drugs. As we can identify the characteristics of those patients more at risk from severe emesis and the development of anticipatory problems, there are good arguments for the most effective drug therapy (rather than the cheapest) being given to them prophylactically, together with relaxation techniques.

Psychological factors predicting nausea and vomiting in breast cancer patients on chemotherapy.

A series of 100 breast cancer patients were included in a study to test the hypothesis that incidence of anticipatory nausea and vomiting during chemotherapy and towards the end of a patient's course of treatment is influenced by patient expectation, anxiety level and coping response. The role of psychological factors in postinfusional nausea and vomiting was also examined. Incidence of postinfusional and anticipatory nausea was high overall, with vomiting less frequently reported; 43% of patients reported nausea or vomiting before treatment at some stage over their chemotherapy cycles and 77% reported post-treatment symptoms. Anticipatory nausea was described by 47% of those experiencing it as being of moderate or severe intensity at some point throughout chemotherapy. Postinfusional side-effects were more intense; 21 and 10 patients, respectively, described severe or very severe levels as occurring at some point during their treatment. The majority of patients experiencing postinfusional symptoms indicated that these persisted for more than 24 h and were worse a day or two after chemotherapy administration. Incidence of anticipatory nausea or vomiting was found to relate directly to experience of nausea or vomiting during preceding cycles. Psychological variables were associated with symptoms of anticipatory nausea mid-treatment, but not with postinfusional symptoms. In particular, trait anxiety and a baseline expectation that nausea would be experienced during treatment were predictive in a multivariate model. Despite this, the overwhelming factor influencing ANV and PNV both mid- and towards the end of treatment was that of previous experience of the symptoms at earlier courses.

Prevalence of anticipatory nausea and other side-effects in cancer patients receiving chemotherapy.

98 patients receiving chemotherapy for cancer were interviewed to determine the prevalence of anticipatory nausea and vomiting, anxiety and dietary changes. Among those who had received at least four treatments 41% reported at least mild anticipatory nausea (AN). For 24% this was a moderate to severe problem, which was significantly associated with a high level of anxiety about treatment. Prevalence at this level was independent of whether the subject was receiving treatment as an in- or an outpatient. Anticipatory vomiting (AV) was reported by only 12 patients, of whom 11 were women; this was the only effect of gender found in the sample. Independence between moderate AN and AV was also suggested by a difference in type of event triggering the effect: predominantly odours for AN and thoughts of the treatment for AV. Changes in diet after commencing chemotherapy were reported by 50% of patients who had received at least four treatments. These most commonly took the form of aversions to meat and then to coffee, and were attributed most frequently to changes in taste and then to loss of appetite.

Persistent symptoms among survivors of Hodgkin's disease: an explanatory model based on classical conditioning.

Persistent symptoms of nausea, distress, and vomiting triggered by reminders of cancer treatment were examined among 273 Hodgkin's disease survivors, 1 to 20 years posttreatment. Prevalence rates were high for distress and nausea but low for vomiting. Retrospective report of anticipatory symptoms during treatment was the strongest predictor of persistent symptoms, suggesting that treatment-induced symptoms are less likely to persist if conditioning does not occur initially. Time since treatment was also a significant predictor, with patients more recently treated more likely to experience persistent symptoms. Thus, an explanatory model based on classical conditioning theory successfully predicted presence of persistent symptoms. Symptoms also were associated with ongoing psychological distress, suggesting that quality of life is diminished among survivors with persistent symptoms. Recommendations for prevention and treatment of symptoms are discussed.

Effectiveness of biofeedback and relaxation training in reducing the side effects of cancer chemotherapy.

Assessed the effectiveness of electromyographic (EMG) and skin-temperature (ST) biofeedback and relaxation training (RT) in reducing the aversiveness of cancer chemotherapy. Eighty-one cancer patients, equated on several individual-difference variables, were randomized to one of six groups formed by a 3 (EMG Biofeedback, ST Biofeedback, No Biofeedback) x 2 (RT, No RT) factorial design. Outcome was assessed with physiological, patient-reported, and nurse-reported indices taken over five consecutive chemotherapy treatments. RT patients showed decreases in nausea and anxiety during chemotherapy and physiological arousal after chemotherapy. EMG and ST biofeedback reduced some indices of physiological arousal but had no other effects on chemotherapy side effects. These findings suggest that RT can be effective in reducing the adverse consequences of chemotherapy and that the positive effects found for biofeedback in prior research were due to the RT that was given with the biofeedback, not to the biofeedback alone.

Specific response expectancies predict anticipatory nausea during chemotherapy for breast cancer.

Clinical research has demonstrated that large numbers of chemotherapy patients continue to experience nausea in the clinic prior to infusions. A better understanding of the mechanisms responsible for such anticipatory nausea (AN) is likely to provide critical information for identifying intervention targets. In the present study the authors investigated the contribution of expectancy, history of nausea, and distress to AN in 60 women with Stage I or II breast cancer receiving standard adjuvant chemotherapy. The predictors were each independently associated with AN (p < .05). However, only expectations significantly predicted AN in simultaneous regression analyses. Results suggest that interventions to reduce AN during chemotherapy should target patients' expectations.

Anticipatory nausea and vomiting in cancer patients.

The present study reports on a mediating mechanism for anticipatory nausea and vomiting (ANV) in cancer chemotherapy. ANV is usually explained as a classically conditioned response. However, conditioning models have failed to explain individual variation in ANV susceptibility. On the basis of the positive correlation between degree of autonomic reactivity (AR) and conditionability, it is proposed that individual AR is predictive of ANV development. Of the 31 patients who participated in the study, 74% experienced postinfusion nausea and vomiting (PNV). Of the 23 patients who experienced PNV, 52% developed ANV. AR was recorded in a habituation paradigm before chemotherapy treatment was initiated. The patients in the ANV group showed significantly increased sympathetic reactivity as compared with the no-ANV group, implying that AR is a mediator of ANV development.