Effects of sex on placebo effects in chronic pain participants: a cross-sectional study.

ABSTRACT: Sex-related differences can influence outcomes of randomized clinical trials and may jeopardize the effectiveness of pain management and other therapeutics. Thus, it is essential to understand the mechanistic and translational aspects of sex differences in placebo outcomes. Recently, studies in healthy participants have shed light on how sex-related placebo effects might influence outcomes, yet no research has been conducted in a patient population. Herein, we used a tripartite approach to evaluate the interaction of prior therapeutic experience (eg, conditioning), expectations, and placebo effects in 280 chronic (orofacial) pain patients (215 women). In this cross-sectional study, we assessed sex differences in placebo effects, conditioning as a proxy of prior therapeutic effects, and expectations evaluated before and after the exposure to positive outcomes, taking into account participant-experimenter sex concordance and hormonal levels (estradiol and progesterone assessed in premenopausal women). We used mediation analysis to determine how conditioning strength and expectations impacted sex differences in placebo outcomes. Independent of gonadal hormone levels, women showed stronger placebo effects than men. We also found significant statistical sex differences in the conditioning strength and reinforced expectations whereby reinforced expectations mediated the sex-related placebo effects. In addition, the participant-experimenter sex concordance influenced conditioning strength, reinforced expectations, and placebo effects in women but not in men. Our findings suggest that women experience larger conditioning effects, expectations, and placebo effects emphasizing the need to consider sex as a biological variable when placebo components of any outcomes are part of drug development trials and in pain management.

Prior Therapeutic Experiences, Not Expectation Ratings, Predict Placebo Effects: An Experimental Study in Chronic Pain and Healthy Participants.

INTRODUCTION: Many clinical trials fail because of placebo responses. Prior therapeutic experiences and patients' expectations may affect the capacity to respond to placebos in chronic disorders. OBJECTIVE: The scope of this study in 763 chronic orofacial pain and healthy study participants was to compare the magnitude and prevalence of placebo effects and determine the putative role of prior therapeutic experiences vs. expectations. METHODS: We tested placebo propensity in a laboratory setting by using 2 distinct levels of individually tailored painful stimulations (high pain and low pain) to reinforce expectations and provide a hypoalgesic experience (conditioning phase). Afterwards, both levels of pain were surreptitiously set at a moderate pain level to test for placebo effects (testing phase). Pain and expectation ratings were assessed as primary outcomes using visual analog scales. RESULTS: In both chronic pain and healthy participants, placebo effects were similar in magnitude, with the larger prevalence of responders in the healthy participants. Although chronic pain participants reported higher pain relief expectations, expectations did not account for the occurrence of placebo effects. Rather, prior experience via conditioning strength mediated placebo effects in both pain and healthy participants. CONCLUSIONS: These findings indicate that participants with chronic pain conditions display robust placebo effects that are not mediated by expectations but are instead directly linked to prior therapeutic experiences. This confirms the importance of assessing the therapeutic history while raising questions about the utility of expectation ratings. Future research is needed to enhance prediction of responses to placebos, which will ultimately improve clinical trial designs.

Modeling Learning Patterns to Predict Placebo Analgesic Effects in Healthy and Chronic Orofacial Pain Participants.

Successfully predicting the susceptibility of individuals to placebo analgesics will aid in developing more effective pain medication and therapies, as well as aiding potential future clinical use of placebos. In pursuit of this goal, we analyzed healthy and chronic pain patients' patterns of responsiveness during conditioning rounds and their links to conditioned placebo analgesia and the mediating effect of expectation on those responses. We recruited 579 participants (380 healthy, 199 with temporomandibular disorder [TMD]) to participate in a laboratory placebo experiment. Individual pain sensitivity dictated the temperatures used for high- and low-pain stimuli, paired with red or green screens, respectively, and participants were told there would be an analgesic intervention paired with the green screens. Over two conditioning sessions and one testing session, participants rated the painfulness of each stimulus on a visual analogue scale from 0 to 100. During the testing phase, the same temperature was used for both red and green screens to assess responses to the placebo effect, which was defined as the difference between the average of the high-pain-cue stimuli and low-pain-cue stimuli. Delta scores, defined as each low-pain rating subtracted from its corresponding high-pain rating, served as a means of modeling patterns of conditioning strength and placebo responsiveness. Latent class analysis (LCA) was then conducted to classify the participants based on the trajectories of the delta values during the conditioning rounds. Classes characterized by persistently greater or increasing delta scores during conditioning displayed greater placebo analgesia during testing than those with persistently lower or decreasing delta scores. Furthermore, the identified groups' expectation of pain relief acted as a mediator for individual placebo analgesic effects. This study is the first to use LCA to discern the relationship between patterns of learning and the resultant placebo analgesia in chronic pain patients. In clinical settings, this knowledge can be used to enhance clinical pain outcomes, as chronic pain patients with greater prior experiences of pain reduction may benefit more from placebo analgesia.

The Placebo Phenomenon: A Narrow Focus on Psychological Models.

The placebo effect is a complex phenomenon that can be described from neurobiological, psychosocial, and epistemological perspectives. Different leaders in the field have proposed multiple theories and models that attempt to describe both the nature and the mechanisms of action underlying placebo effects. This article focuses on the most relevant psychological models that have been suggested for characterizing the different mechanisms underlying the placebo effect. We outline how the dynamic psychoneurobiological aspects of the placebo phenomenon can be a potential reliable and useful tool in daily clinical practice for illness and symptom management within a wide variety of specialties and health-care practices.

The Role of Patient-Practitioner Relationships in Placebo and Nocebo Phenomena.

INTRODUCTION: Placebo and nocebo effects form part of all therapeutic environments and play a significant role in the effectiveness of treatment outcomes. Patient expectancies drive these phenomena, which can be shaped through contextual factors including verbal suggestions, conditioning, and social observation. OBJECTIVES: This review seeks to identify the biopsychosocial factors of the patient-practitioner interaction that play a role in the development of placebo and nocebo effects, as well as the anthropological elements of the biodynamic process of relating that are meaningful in the development of expectancies. METHODS: We conducted a narrative review of frameworks of the placebo and nocebo effect, including the impact of expectancies and interpersonal relationships in the context of healing and the clinical setting. RESULTS: Expectancies leading to placebo and nocebo effects can be modified by macro and micro factors, such as culture and society, as well as individual psychobiological traits, respectively. The developmental sociobiological adaptations that form and consolidate mindsets and meaningful contexts play an important role in shaping patient expectancies, as well as patients' conscious and subconscious reactions to signs and actions taking place within the clinical environment. Practitioner characteristics, like empathy, friendliness, and competence, favor the formation of positive expectancies. Caring and warm patient-practitioner interactions can enhance the therapeutic value of clinical encounters when patients' positive expectancies are actively encouraged and engaged. CONCLUSION: A patient-centered approach rooted in demonstrating care and empathy can positively enhance a patient's experience within the clinical environment and activate psychosociobiological adaptations associated with the placebo phenomenon. Pain patients could particularly benefit from non-invasive approaches for improving treatment effectiveness and quality-of-life.

Placebo hypoalgesic effects in pain: Potential applications in dental and orofacial pain management.

Placebo and nocebo effects are present within every treatment and intervention, and can be purposefully enhanced and reduced, respectively, in order to improve patients' clinical outcomes. A plethora of research has been conducted on the mechanisms of placebo hypoalgesia and nocebo hyperalgesia in experimental and clinical settings. However, its implications in particular clinical settings such as orthodontic pain management remain underexplored. We conducted a search of the literature regarding placebo analgesia, orthodontic pain management, and orofacial and dental pain. Articles were qualitatively assessed and selected based on the scope of this narrative review. Although no studies investigating the extent of the implications of the placebo and nocebo phenomena in the orthodontic clinical setting were found, we herein present a comprehensive review on the influences of placebo and nocebo effects in experimental and clinical pain management, as well as on the potential for engaging placebo-related endogenous pain modulation for orthodontic pain management. Ethical considerations for the clinical application of placebos are discussed, and future research directions are presented.

Nocebo and pain: An overview of the psychoneurobiological mechanisms.

INTRODUCTION: Nocebo effects are defined as adverse events related to negative expectations and learning processes that are involved in the modulation of the descending pain pathways. Research over the last couple of decades has illustrated that behavioral, psychoneurobiological and functional changes occur during nocebo-induced pain processing. OBJECTIVES: We aimed to review published human and non-human research on algesia and hyperalgesia resulting from negative expectations and nocebo effects. METHODS: Herein, we searched and comprehensively reviewed scientific literature providing informative knowledge about the psychoneurobiological bases of the nocebo effect in the field of pain with an emphasis on how pain processes are shaped by both cognitive and non-cognitive factors. RESULTS: Negative expectations are formed through verbal suggestions of heightened pain, prior nociceptive and painful experiences and observation of pain in others. Susceptibility to the nocebo effect can be also influenced by genetic variants, conscious and nonconscious learning processes, personality traits and psychological factors. Moreover, providers' behaviors, environmental cues and the appearance of medical devices can induce negative expectations that dramatically influence pain perception and processing in a variety of pain modalities and patient populations. CONCLUSION: Importantly, we concluded that nocebo studies outline how individual expectations may lead to physiological changes underpinning the central integration and processing of magnified pain signaling. Further research is needed to develop strategies that can identify nocebo-vulnerable pain patients in order to optimize the psychosocial and therapeutic context in which the clinical encounter occurs, with the ultimate purpose of improving clinical outcomes.

Nocebo effects in clinical studies: hints for pain therapy.

INTRODUCTION: Nocebo-induced algesic responses occurring within clinical contexts present a challenge for health care practitioners working in the field of pain medicine. OBJECTIVES: Following the recent research on algesic nocebo effects, the scope of this review is to develop ethically acceptable strategies to help avoid, or at least reduce, nocebo responses within clinical settings. METHODS: We reviewed relevant clinical studies that depict how patient-practitioner interactions may contribute to the reduction of nocebo responses. RESULTS: A strong algesic nocebo effect may adversely impact a patient's condition by causing decreases in both the efficacy and effectiveness of interventions, as well as by promoting treatment nonadherence and discontinuation. These effects may be triggered through multiple channels and can lead to significant alterations in a patient's perception of pain, consequently producing a weakening of the specific positive effects of pharmacological, psychological, or physical pain-management interventions. CONCLUSION: To minimize nocebo effects in clinical settings, we identified and discussed five contextual aspects relevant to the treatment of patients with chronic pain: (1) negative patient-clinician communication and interaction during treatment; (2) emotional burden of patients during treatment with analgesic medication; (3) negative information provided via informational leaflets; (4) cued and contextual conditioning nocebo effects; and (5) patient's lack of positive information. Through an understanding of these elements, many preventive and ethically acceptable clinical actions can be taken to improve multidisciplinary pain treatment outcomes.

Complementary and Alternative Medicine Use and Latina Breast Cancer Survivors' Symptoms and Functioning.

Complementary and alternative medicine (CAM) is used widely in cancer populations, particularly among women, and has shown promise for addressing symptom and functioning outcomes. Few studies to date have evaluated CAM use and associations over time with symptoms and function among Latina breast cancer survivors. We administered a baseline (N = 136) and follow-up (n = 58) telephone survey in Spanish or English assessing Latina breast cancer survivor demographics, physical function, anxiety, depression, fatigue, satisfaction with social roles, and both CAM activities and devotional and spiritual practices. About one-third of our sample (35% baseline; 36% follow-up) reported using CAM (yoga, meditation, massage, or herbal/dietary supplements). We assessed devotional and spiritual practices separately from CAM (church attendance, prayer, religious groups, and reading devotional and religious texts); the majority of Latina survivors reported devotional and spiritual practices (80% baseline; 81% follow-up). At baseline, CAM demonstrated a positive association with better physical functioning and lower depression. In contrast, CAM use at the time of follow-up appeared to be related to lower levels of satisfaction with social roles and physical function. In longitudinal analyses, devotional and spiritual practices at baseline significantly predicted lower anxiety, depression, and fatigue at follow-up. Findings suggest CAM plays a complex and not always linear role in symptoms and function outcomes for Latina breast cancer survivors. These findings contribute to the literature on longitudinal CAM use and associations with symptom and functioning outcomes among Latina breast cancer survivors.