Choice and the nocebo effect: If a little is good, more is better?

OBJECTIVE: Lack of choice over treatment may increase the nocebo effect, whereby unpleasant side effects can be triggered by the treatment context, beyond any inherent physiological effects of the treatment itself. Excessive choice may also increase the nocebo effect. The current studies tested these possibilities. METHOD: Participants took part in studies ostensibly investigating the influence of beta-blockers (Study 1, n = 71) and benzodiazepines (Study 2, n = 120) on anxiety. All treatments were placebos. In Study 1, participants were randomly allocated to three groups: no-treatment control, no-choice, and choice between two treatments. In Study 2, a ten-choice group was added. Participants were warned about possible treatment side effects. These warned symptoms were assessed, and scores summed. Nocebo effects were evidenced by significantly higher warned symptoms scores in any placebo-treated group compared to the control group. RESULTS: In both studies, the no-choice groups experienced a nocebo effect (S1: p = .003, ηp2= 0.121; S2: p = .022, ηp2= 0.045). A significant nocebo effect was not present in groups who chose between two treatments (S1: p = .424, ηp2= 0.009; S2: p = .49, ηp2= 0.004). In Study 2, choosing between ten treatments resulted in a nocebo effect (p = .006, ηp2= 0.065). CONCLUSION: Lack of choice resulted in the development of nocebo effects, while having a limited choice between two placebos did not generate significant nocebo effects. However, a larger choice between ten placebos generated a nocebo effect of similar magnitude to lack of choice. Facilitating (some) choice in medical care may reduce the development of nocebo effects, but more extensive choice options may not offer similar benefits.

The influence of message framing on nocebo headaches: Findings from a randomized laboratory design.

Attribute framing presents an ethically sound approach for reducing adverse nocebo effects. In past studies, however, attribute framing has not always decreased nocebo effects. The present study used a sham tDCS procedure to induce nocebo headaches to explore factors that may contribute to the efficacy of attribute framing. Participants (N = 174) were randomized to one of three between-subject conditions: a no-headache instruction (control) condition and two conditions in which headaches were described as either 70% likely (negative framing) to occur or 30% unlikely (positive framing) to occur. Results revealed nocebo headaches in both framing conditions, as compared to the control condition. Attribute framing did not influence headache measures recorded during the sham tDCS task, but framing did have a modest influence on one of two headache items completed after the task. Results suggest that attribute framing could have a stronger influence on delayed nocebo effect measures or retrospective symptom reports; a finding that may explain inconsistencies in the existing framing-nocebo effect literature. Exploratory analyses also revealed that low negative affect was associated with stronger nocebo and attribute framing effects, although these effects were found on only a few headache measures. It is concluded that researchers should further investigate the influence of attribute framing on nocebo headaches as a function of both timing and emotional factors.

Using Positive Attribute Framing to Attenuate Nocebo Side Effects: A Cybersickness Study.

BACKGROUND: Side effect warnings can contribute directly to their occurrence via the nocebo effect. This creates a challenge for clinicians and researchers, because warnings are necessary for informed consent, but can cause harm. Positive framing has been proposed as a method for reducing nocebo side effects whilst maintaining the principles of informed consent, but the limited available empirical data are mixed. PURPOSE: To test whether positive attribute framing reduces nocebo side effects relative to negative framing, general warning, and no warning. METHODS: Ninety-nine healthy volunteers were recruited under the guise of a study on virtual reality (VR) and spatial awareness. Participants were randomized to receive positively framed ("7 out of 10 people will not experience nausea"), negatively framed ("3 out of 10 people will experience nausea"), general ("a proportion of people will experience nausea"), or no side effect warnings prior to VR exposure. RESULTS: Receiving a side effect warning increased VR cybersickness relative to no warning overall, confirming that warnings can induce nocebo side effects. Importantly, however, positive framing reduced cybersickness relative to both negative framing and the general warning, with no difference between the latter two. Further, there was no difference in side effects between positive framing and no warning. CONCLUSIONS: These findings suggest that positive framing not only reduces nocebo side effects relative to negative framing and general warnings, but actually prevents nocebo side effects from occurring at all. As such, positive attribute framing may be a cheap and ethical way to reduce nocebo side effects.

A test of psychological and electrodermal changes immediately after the delivery of 3 analgesic treatment messages.

INTRODUCTION: Placebo analgesia often results when a pain reduction treatment message is delivered to a patient or research participant. Little information exists regarding the psychological changes that are immediately triggered by the delivery of a treatment message. OBJECTIVES: This experiment tested the impact of 3 different analgesic treatment messages on the expectations, feelings, and electrodermal activity of participants anticipating a pain stimulus. METHODS: In laboratory sessions, healthy participants (N = 138) were randomly assigned to 1 of 4 conditions in a between-subject design. The design included a no treatment message control condition and 3 treatment message conditions: a standard analgesic message, an analgesic treatment with side-effect message, and a double-blind analgesic message. After the treatment message manipulation, measures were taken of: treatment efficacy expectations, pain experience expectations, pretask anxiety, positive affect, negative affect, and electrodermal activity. RESULTS: Overall, the dependent measures showed relatively few correlations. Furthermore, across all 3 message conditions, treatment-specific expectations were greatly increased compared with the control condition. Finally, participants in the double-blind message condition displayed elevated negative affect. CONCLUSION: All 3 analgesic treatment messages produced a stronger immediate influence on treatment efficacy expectations than on the other dependent measures. Treatment messages can alter negative affect along with expectancies. The low correlations found between dependent measures suggest that different patterns of psychological responses may emerge from analgesic treatment messages depending on contextual factors.

Can Positive Framing Reduce Nocebo Side Effects? Current Evidence and Recommendation for Future Research.

Although critical for informed consent, side effect warnings can contribute directly to poorer patient outcomes because they often induce negative expectations that trigger nocebo side effects. Communication strategies that reduce the development of nocebo side effects whilst maintaining informed consent are therefore of considerable interest. We reviewed theoretical and empirical evidence for the use of framing strategies to achieve this. Framing refers to the way in which information about the likelihood or significance of side effects is presented (e.g., negative frame: 30% will experience headache vs. positive frame: 70% will not experience headache), with the rationale that positively framing such information could diminish nocebo side effects. Relatively few empirical studies (k = 6) have tested whether framing strategies can reduce nocebo side effects. Of these, four used attribute framing and two message framing. All but one of the studies found a significant framing effect on at least one aspect of side effects (e.g., experience, attribution, threat), suggesting that framing is a promising strategy for reducing nocebo effects. However, our review also revealed some important open questions regarding these types of framing effects, including, the best method of communicating side effects (written, oral, pictorial), optimal statistical presentation (e.g., frequencies vs. percentages), whether framing affects perceived absolute risk of side effects, and what psychological mechanisms underlie framing effects. Future research that addresses these open questions will be vital for understanding the circumstances in which framing are most likely to be effective.

The Influence of Side Effect Information Framing on Nocebo Effects.

BACKGROUND: One contributing factor to the development of nocebo effects is information provided about possible side effects. However, nondisclosure of information can be problematic. PURPOSE: We assessed whether positively framed side effect information (highlighting likelihood of not experiencing side effects) can reduce nocebo effects compared to negatively framed information (highlighting likelihood of experiencing side effects). METHODS: One hundred twelve participants took part in research ostensibly assessing the influence of benzodiazepines (actually sham capsules) on anxiety. Participants were randomized to receive a sham capsule with positively or negatively framed information about four side effects, or a no-treatment control condition. Side effect expectations were assessed after information provision. Framed side effects and other unmentioned symptoms were assessed during the session and 24-hr follow-up. RESULTS: Nocebo effects occurred in symptoms presented as side effects (regardless of framing) during the study session and follow-up (ps < .003). At follow-up, there was also a nocebo effect in other unmentioned symptoms (p = .018). Positive framing reduced side effect symptoms compared with negative framing during the study session (p = .037), but this effect was no longer present at follow-up (p = .53). Side effect expectations did not differ between the framing conditions (p = .14). CONCLUSIONS: Positive framing reduced side effects short-term, but not at follow-up. Expectations did not differ between negative and positive framing. Nocebo effects appeared to generalize to other unmentioned symptoms over a 24-hr period. Further research is needed to determine whether the initial impact of positive framing can be maintained over time.

Prior experience with a pain stimulus as a predictor of placebo analgesia.

Placebo effects are important in pain reduction, but the effects are inconsistent. Prior experience with a pain stimulus may moderate placebo analgesia. The current study tests the effect of prior experience with a pain stimulus on placebo analgesia during a laboratory pain task. Healthy normotensive undergraduates (66 women, 68 men) who either did or did not report prior experience with pain from submerging a limb in cold water were enrolled. In the laboratory, an experimenter applied an inert, medicinal-smelling cream to participants' non-dominant hand. Participants randomized to the no-expectation group were told that the cream was a hand cleanser. Participants randomized to the placebo expectation group were told that the cream would reduce the pain associated with the cold pressor task. Participants then completed the cold pressor task and reported their pain on the short form of the McGill Pain Questionnaire. Analysis of variance revealed a main effect of expectation (p < .05), such that participants in the placebo expectation group reported less pain. An interaction was also found between expectation and prior experience (p < .05), such that participants with prior experience with pain from cold water immersion showed no difference in pain reports between expectation groups. In a pain context, prior experience with the pain stimulus may prevent a placebo expectation from reducing the experience of pain.

Affect and exercise: positive affective expectations can increase post-exercise mood and exercise intentions.

BACKGROUND: Prior research has found affect to predict exercise. Little research has examined the causal influence of exercise-related affect on exercise intentions. PURPOSE: The purpose of this study was to test whether expectations about post-exercise affect can be successfully manipulated to produce changes in post-exercise affect and exercise intentions. We also tested whether cognitively elaborating on the expectation would increase the duration of the expectation effect. METHODS: Participants (59 men, 89 women) were exposed to an affective expectation manipulation as well as an elaboration manipulation and then completed 10 min of light-intensity exercise on a stationary bicycle in the laboratory. Participants also completed a 2-week follow-up. RESULTS: Affective expectation participants displayed more positive post-exercise affect and exercise intentions than no-expectation participants (ps < .05). Affective expectation participants who also elaborated on that expectation reported more positive post-exercise affect during the follow-up than the no-elaboration participants (p < .05). CONCLUSION: Expectations about positive post-exercise affect can be experimentally manipulated to increase exercise-related feelings and intentions. The duration of this effect increases when individuals cognitively elaborate on the expectation.

Effects of estrogen and opioid blockade on blood pressure reactivity to stress in postmenopausal women.

Estrogen may influence coronary heart disease risk in women through the effects of endogenous opioids on autonomic control of blood pressure. In a randomized, placebo-controlled trial, we examined the combined effects of estrogen and the opioid antagonist, naltrexone, on blood pressure responses to psychological stress in 42 postmenopausal women. After 3 months of estrogen or estrogen plus progestin (hormone replacement therapy; n = 27) or placebo replacement, participants completed a mental arithmetic task after administration of .7 mg/kg oral naltrexone or placebo. Systolic blood pressure (SBP), diastolic blood pressure, mean arterial pressure and heart rate (HR) were measured at rest and during the arithmetic stressor. Stress produced significant increases in circulatory measures regardless of estrogen condition or opioid blockade (p's < .001). Interestingly, there was an estrogen by naltrexone interaction on SBP reactivity scores [F(1,38) = 4.36, p < .05], where women on estrogen with intact opioid receptors showed the largest SBP responses to stress, compared with all other conditions. This is consistent with some studies of premenopausal women, suggesting that estrogens may alter opioid function during stress. The interaction between estrogen and endogenous opioids may explain sex differences in opioid effects on stress reactivity in younger premenopausal women.

Why does choice enhance treatment effectiveness? Using placebo treatments to demonstrate the role of personal control.

In modern health care, individuals frequently exercise choice over health treatment alternatives. A growing body of research suggests that when individuals choose between treatment options, treatment effectiveness can increase, although little experimental evidence exists clarifying this effect. Four studies were conducted to test the hypothesis that exercising choice over treatment alternatives enhances outcomes by providing greater personal control. Consistent with this possibility, in Study 1 individuals who chronically desired control reported less pain from a laboratory pain task when they were able to select between placebo analgesic treatments. Study 2 replicated this finding with an auditory discomfort paradigm. In Study 3, the desire for control was experimentally induced, and participants with high desire for control benefited more from a placebo treatment when they were able to choose their treatment. Study 4 revealed that the benefit of choice on treatment efficacy was partially mediated by thoughts of personal control. This research suggests that when individuals desire control, choice over treatment alternatives improves treatment effectiveness by enhancing personal control.

Beliefs about expectations moderate the influence of expectations on pain perception.

BACKGROUND: Expectations congruently influence, or bias, pain perception. Recent social psychological research reveals that individuals differ in the extent to which they believe in expectation biases and that individuals who believe in expectation biases may adjust for this bias in their perceptions and reactions. That is, idiosyncratic beliefs about expectations can moderate the influence of expectations on experience. PURPOSE: Prior research has not examined whether idiosyncratic beliefs about expectations can alter the degree to which one's expectations influence pain perception. Using a laboratory pain stimulus, we examined the possibility that beliefs about expectation biases alter pain responses following both pain- and placebo-analgesic expectations. METHODS: Participants' beliefs about expectation biases were measured. Next, participants were randomly assigned to receive either a pain expectation or a placebo-analgesia expectation prior to a cold-pressor task. After the task, participants rated their pain. RESULTS: Beliefs about expectation biases significantly influenced pain reports. Specifically, pain reports were more influenced by provided expectations the less participants believed in expectation biases (i.e., pain expectations resulted in more pain than analgesia expectations). CONCLUSIONS: Beliefs about the expectation bias are an important and under-examined predictor of pain and placebo analgesia.

Concept priming and pain: an experimental approach to understanding gender roles in sex-related pain differences.

Prior research has found that sex differences in pain are partially due to individual variations in gender roles. In a laboratory study, we tested the hypothesis that the presence of covert gender role cues can also moderate the extent to which women and men experience pain. Specifically, we varied gender role cues by asking male and female participants to write about instances in which they behaved in a stereotypically feminine, masculine, or neutral manner. Pain and cardiovascular reactivity to the cold pressor task were then assessed. Results revealed that, when primed with femininity, men reported less pain and anxiety from the cold pressor task than women. However, no differences existed between the sexes in the masculine or neutral prime conditions. The results indicate that covert gender cues can alter pain reports. Further, at least in some situations, feminine role cues may be more influential on pain reports than masculine role cues.

Placebo expectations and the detection of somatic information.

In a laboratory study we examined the hypothesis that placebo expectations enhance the initial identification of placebo-relevant sensations over placebo-irrelevant sensations. Participants (N = 102) were randomly assigned to one of three expectation groups. In the first group, participants ingested a placebo capsule and were told it was caffeine (deceptive expectation). In a second group, participants ingested a placebo capsule and were told it may be caffeine or it may be a placebo (double-blind expectation). Participants in the third group were given no expectation. All participants then tallied the placebo-relevant and placebo-irrelevant sensations they experienced during a 7-min period. Participants in the deceptive expectation group identified more placebo-relevant sensations than placebo-irrelevant sensations. No-expectation participants identified more placebo-irrelevant sensations than placebo-relevant sensations. Participants given the double-blind expectation identified an equal amount of placebo-relevant and irrelevant sensations. The amount of both placebo-relevant and placebo-irrelevant sensations detected mediated the relationship between the expectation manipulation and subsequent symptom reports. These data support the position that expectations cause placebo responding, in part, by altering how one identifies bodily sensations.

Dispositional optimism predicts placebo analgesia.

UNLABELLED: Based on prior research identifying dispositional optimism as a predictor of placebo responding, the present study tested the hypothesis that individuals high in optimism would be more likely to respond to a placebo analgesic. Optimists and pessimists were randomly assigned to a placebo expectation condition or a no expectation condition before a cold pressor task. Blood pressure and heart rate were recorded before and during the cold pressor task, and participant ratings of pain and expectations were obtained immediately after the task. Analysis of the expectation manipulation revealed that the placebo instruction was successful in altering participant expectancy during the cold pressor. Supporting the main hypothesis, dispositional optimism was associated with lower pain ratings in the placebo condition but not in the control condition. Because dispositional optimism can alter placebo responding to laboratory pain, future studies should examine the potential role that this individual difference factor may play in patient responsivity to pharmacological and nonpharmacological treatments for clinical pain. PERSPECTIVE: This study examined the possibility that individual differences can predict placebo analgesia. Participants were randomly assigned to receive either a placebo expectation or no expectation before a cold pressor task. Dispositional optimism was related to less cold pressor pain in the placebo condition as compared with the control condition.

Dispositional optimism and thoughts of well-being determine sensitivity to an experimental pain task.

BACKGROUND: Prior studies with patient samples have found dispositional optimism to be associated with less pain. PURPOSE: We examined the relationship between optimism and experimental pain. It was hypothesized that optimists generally cope with a painful stimulus by mentally disengaging from the pain. However, if optimists are prompted to think about health and well-being prior to the painful event, they are more responsive to the pain. METHODS: Optimists and pessimists were primed with words related to health or with neutral words prior to the cold pressor task. Pain, distress, and cardiovascular reactivity to the cold pressor task were assessed. RESULTS: Dispositional optimism was associated with lower pain sensitivity, distress, and cardiovascular reactivity in the neutral prime condition. In the health prime condition, optimists and pessimists did not differ on any of the dependent measures. CONCLUSIONS: Dispositional optimism is associated with reduced pain for healthy adults encountering a brief pain stimulus. This relationship is eliminated, however, when individuals are primed with thoughts of health and well-being. The results are interpreted as evidence for the use of differential coping strategies by optimists in response to pain.

Further evidence for individual differences in placebo responding: an interactionist perspective.

OBJECTIVE: A prior investigation found that individuals low in optimism are more likely to follow a negative placebo (nocebo) expectation. The present study tested the hypothesis that individuals high in optimism are more likely to follow a positive placebo expectation. METHODS: Individuals (N=56) varying in their level of optimism were randomly assigned to one of three conditions. In the first condition, participants were given the expectation that a placebo sleep treatment would improve their sleep quality (placebo expectation condition). In the second condition, participants engaged in the same sleep treatment activity but were not given the positive placebo expectation (treatment control condition). Finally, a third group did not receive the positive placebo expectation and also did not engage in the placebo sleep treatment (no-placebo control condition). RESULTS: Optimism was positively associated with better sleep quality in the placebo expectation condition (r=.48, P<.05). Optimism scores were not associated with better sleep quality in either the treatment control condition (r=-.17, P=.46) or the no-placebo control condition (r=-.24, P=.35). CONCLUSION: Dispositional optimism relates to placebo responding. This relationship, however, is not manifested in a simple increase or decrease in all types of placebo responding. Rather, it appears that, as optimism increases, response to the positive placebo expectation increases, whereas response to nocebo expectation decreases. It is recommended that future research on personality and placebo effects consider the interaction between situational and dispositional variables.

Opioid analgesia in persons at risk for hypertension.

OBJECTIVE: Acute pain sensitivity is reduced in clinical hypertension, but the precise relationship between pain perception and altered blood pressure control is not well-characterized. A negative correlation between resting blood pressure and pain sensitivity is observed throughout the normotensive range, suggesting links between basic mechanisms of blood pressure control and pain regulation. The opioid peptides are important endogenous analgesic mechanisms, but their role in the hypoalgesia of blood pressure elevations has not been well-established. The current study sought to examine the effects of endogenous opioids on blood pressure-associated hypoalgesia in young adults at risk for hypertension development. METHODS: The effects of the opioid receptor antagonist, naltrexone, on cold pressor pain sensitivity were assessed in young adult men (n = 49) and women (n = 76) with mildly elevated casual blood pressure. RESULTS: Results indicate interactions between hypertension risk and the effects of opioid blockade on pain sensitivity. CONCLUSIONS: These findings suggest exaggerated opioid analgesia in persons at enhanced risk for hypertension and point to important links between altered neuropeptide regulation of pain and altered blood pressure control mechanisms in the early stages of hypertension.

Expectations and placebo response: a laboratory investigation into the role of somatic focus.

It has been theorized that expectations are an important causal determinant of the placebo effect. Placebo expectations, however, do not always yield placebo effects. In a laboratory study, we tested the hypothesis that one's level of somatic focus moderates the effect of placebo expectations on placebo responding. We also varied whether participants were told the placebo was a drug, could either be a drug or placebo, or was a placebo. The results revealed that individuals who thought they were taking a drug (i.e., unconditional expectations) reported more placebo symptoms when they closely focused on their symptoms. Individuals told they may or may not be receiving a drug (i.e., conditional expectations) did not differ from control participants regardless of how closely they attended to their symptoms. The findings have theoretical implications for expectancy models of the placebo effect as well as for practical research comparing the type of expectations held by individuals in clinical trials and clinical practice.

Goal activation, expectations, and the placebo effect.

Motivational factors receive little attention in current theories of the placebo effect. Reasons for this position are reviewed, and an argument is made for reconsidering the influence of motivation on the placebo effect. The authors hypothesize that nonconscious goals alter reactions to a placebo expectation. Specifically, the authors predict that the placebo effect is most likely to occur when individuals have a goal that can be fulfilled by confirmation of the placebo expectation. The authors tested this notion in 5 experiments. The results demonstrate the role of motivation in the placebo effect across a variety of symptom domains and via 4 different goal activation techniques. Moreover, this moderating effect occurred for both positive and negative placebo expectations, across different placebo effect measures, and in brief laboratory experiments as well as in lengthier studies. It is argued that theories regarding the placebo effect should incorporate motivational factors.