Anticipatory nausea: the role of individual differences related to sensory perception and autonomic reactivity.

BACKGROUND: Anticipatory nausea (AN) during chemotherapy has been difficult to control with conventional antiemetics. AN can lead cancer patients to delay or discontinue chemotherapy, possibly compromising the treatment. PURPOSE: The aim is to investigate the possible influence on the development of AN of individual differences in absorption, somato-sensory amplification, and autonomic perception-measures theorized to be related to sensory perception and autonomic reactivity. METHODS: Prior to treatment, 125 women (M age = 48.5 years) undergoing adjuvant chemotherapy for breast cancer rated their expected severity of side effects and completed the Tellegen Absorption Scale, the Somato-Sensory Amplification Scale, and the Autonomic Perception Questionnaire. AN, as well as anticipatory vomiting (AV), distress, and worry/anxiety, were measured prior to the fourth, sixth, and last cycle of chemotherapy. Posttreatment nausea (PN), vomiting, and fatigue were measured after the first, fourth, sixth, and last cycle. RESULTS: 34% of the women reported AN before 1 or more cycles. When controlling for treatment characteristics and other known predictors, AN was significantly associated with high absorption in addition to severity of PN, pretreatment worry/anxiety, and not receiving radiotherapy between chemotherapy sessions. AV was not associated with any of the variables investigated. Our data suggest that the association is strongest in the early phases of treatment. CONCLUSIONS: Our results partly confirm the results of a previous study showing absorption and autonomic perception as predictors of anticipatory side effects in cancer patients receiving chemotherapy. Individuals high in absorption may be more autonomically reactive to aversive stimuli and, subsequently, more conditionable. Additional radiotherapy could be a competing stimulus, reducing the conditioning of chemotherapy-related nausea. Further studies investigating possible psycho-physiological mechanisms in the development of AN are needed.

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.

Cardiovascular conditioning and anticipatory nausea and vomiting in cancer patients.

Explanations of individual differences in susceptibility to learning of anticipatory nausea and/or vomiting (AN/V) in cancer patients have focused mainly on the patients who develop AN/V. On the basis of conditioning theory, however, one would expect that all patients who experience post-treatment nausea and/or vomiting (PN/V) should develop AN/V. Consistent with findings demonstrating that conditioned responses are more easily established in autonomic-reactive individuals, we have previously reported that patients who do not develop AN/V (noAN/V) are less autonomic reactive than the AN/V patients. Thus, we hypothesized that the noAN/V patients might not show classical conditioning to the same degree and extent as the AN/V patients and that conditioning may be the mediating mechanism in AN/V. This study presents data from 36 patients. Among the 28 patients who experienced PN/V, 16 developed AN/V. We found no systematic group differences in severity of PN/V or antiemetic treatment. Before chemotherapy, all patients were tested in a signaled reaction-time paradigm. We used two different tones (CSs), one of which was always followed by a noise (UCS) as a button-press signal. The patients who later developed AN/V demonstrated significantly shorter reaction times, and also showed enhanced cardiovascular reactivity to the tone followed by the UCS (CS+) in comparison with the nonsignal tone (CS-). The noAN/V patients did not show differential cardiovascular responses to the CS+ and CS-.

Trait anxiety and anticipatory immune reactions in women receiving adjuvant chemotherapy for breast cancer.

We compared peripheral blood cell counts as well as mitogen activity and natural killer-cell activity in women undergoing adjuvant chemotherapy for breast cancer in the hospital prior to chemotherapy with assessment at home 2 days earlier. Patients compared to controls had an increased number of white blood cell counts in the hospital as compared to those at home, mediated by an increased total number of granulocytes. Among patients, those with high compared to low trait anxiety evidenced immune system changes. Total number of monocytes were reduced in patients with high compared to low trait anxiety and natural killer-cell activity tended to be compromised in the high anxiety group. Helper/inducer T-cells isolated from hospital blood samples were lower in patients with high as compared to low trait anxiety, while no difference was observed in samples taken at home. Conditioned nausea was associated with trait anxiety and patients with as compared to without conditioned nausea displayed immune changes similar to changes observed as a function of trait anxiety. State anxiety measured at the hospital did not relate to immune measures. The observed increase in granulocytes is consistent with an interpretation both in terms of conditioning and anticipatory stress. The anticipatory immunosuppression in patients with high compared to low trait anxiety is consistent with the hypothesis that chemotherapy patients may develop conditioned immunosuppression after repeated pairings of treatment-related stimuli with the unconditioned immunosuppressive effect of chemotherapy.

Noradrenergic activity in anticipatory nausea.

Two studies were conducted to examine the hypothesis that noradrenergic activity is a cause of the anticipatory nausea associated with cancer chemotherapy. In the first study concentrations of plasma 3-methoxy-4-hydroxyphenyl-glycol (MHPG) on day 1 of cycle 5 of initial chemotherapy were significantly higher in patients with than without anticipatory nausea. To determine whether elevated MHPG reflected a clinically significant causative role for noradrenergic activity in anticipatory nausea, we conducted a randomized, double-blind, placebo-controlled, crossover trial of clonidine for anticipatory nausea. At a dose of clonidine that produced significant side effects and reductions of plasma MHPG, anticipatory nausea was improved only marginally. These studies do not support a causative role for noradrenergic activity in anticipatory nausea that can be reduced by clonidine with an acceptable therapeutic index.