Nocebo response in dentistry: A systematic review and meta-analysis of adverse events in analgesic trials of third molar removal.

BACKGROUND: The nocebo response refers to the phenomenon where non-specific factors, including negative verbal suggestion and treatment expectations, cause adverse events (AE) following a placebo treatment. Non-specific factors are also likely to influence AE occurrence following administration of active pharmacological treatments. OBJECTIVE: This meta-analysis aimed to estimate the nocebo response in dentistry by assessing the AEs prevalence in placebo- and active arms of randomised controlled trials (RCTs) assessing analgesic treatment following third molar (M3) surgery. METHODS: A systematic search was performed in PubMed, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials. Eligible studies had to report the number of patients experiencing at least one drug-related AE (patients with AE ≥ 1) separately for the active and placebo arms. The proportion of patients with AE ≥ 1 and drug-related dropouts were pooled, and risk differences (RDs) between patients in the placebo- and active arm were calculated. RESULTS: In 50 independent RCTs of 47 identified articles, the pooled rates of patients with AE ≥ 1 were 22.8% in the placebo arm and 20.6% in the active arm. The pooled rates of drug-related dropout were 0.24% in the placebo arm and 0.08% in the active arm. There were no significant RDs in patients with AE ≥ 1 and drug-related dropouts. CONCLUSION: These results show that patients in the placebo arm reported AEs to the same extent as patients receiving active treatment, suggesting that most AEs in analgesic medication following M3 surgery may be attributed to the nocebo phenomenon.

What is the nocebo effect and does it apply to dentistry?-A narrative review.

BACKGROUND: Evidence for the nocebo effect, a phenomenon characterised by suboptimal treatment efficacy, worsening of symptoms, or the occurrence of adverse events caused by an individual's negative treatment expectations, is growing across a multitude of medical fields. However, little attention has been paid to patients' negative expectations and the nocebo effect within dentistry. AIM: This review summarises essential evidence of the nocebo phenomenon especially in relation to pain and drug administration. Subsequently, an overview of the current evidence of the nocebo phenomenon in the dental field is presented. METHODS: A PubMed search was performed using keywords related to "nocebo," "placebo," "expectations," and "dentistry." In addition to the articles selected from the search, placebo/nocebo researchers and dental researchers added important references from their respective fields. RESULTS: Although research on the nocebo effect in dentistry is limited, available current evidence suggests that the factors, which is related to the nocebo effect are likely to play a role in dental practice. CONCLUSION: Preliminary evidence from the review warrants further investigation into the nocebo effect in dentistry. Finally, based on the general knowledge of the nocebo effect, the review indicates fruitful arrays of research into the nocebo effect in dentistry.

Nocebo belief and attitudes towards side effect disclosure: A general population-based online survey in Europe and North America.

BACKGROUND: With evidence for large nocebo effects in pain, guidelines for nocebo-minimizing strategies regarding side effect disclosure are emerging. While the ethical implications and effectiveness of such strategies have been the subject of investigations, the perspective of healthcare users are missing despite the stakes for patient autonomy. METHODS: In an online survey, 2766 adults (≥18 years) from a general population sample in Europe and North America responded to questions related to nocebo familiarity, nocebo beliefs and attitudes towards side effect disclosure. RESULTS: Only 474 (17%) were familiar with nocebo terminology, while 1379 (50%) were familiar with the concept of nocebo side effects. Belief in nocebo side effects was not well-established; 738 (31%) agreed that side effect information could increase side effect occurrence. Nocebo belief was associated with more negative attitudes towards side effect disclosure and 1962 (73%) indicated that positive framing was an acceptable way of disclosing side effect information. In general, the majority of participants (65-76%) held positive attitudes towards the disclosure of all potential side effects and 2309 (84%) favoured patient autonomy over nonmaleficence. Although the general patterns were similar in the European and North American sample, the latter showed stronger nocebo belief and stronger positive attitudes towards side effect disclosure. CONCLUSIONS: The study found a consistent, moderate association between nocebo belief and attitudes towards nondisclosure, alongside positive attitudes towards the use of framing. Together with the discovered discrepancy between nocebo familiarity and nocebo belief, these findings have implications for the implementation of nocebo education and risk framing strategies. SIGNIFICANCE STATEMENT: This is the first large-scale, general population-based study to contribute to the scientific discussion about nocebo side effects from the perspective of healthcare users. The findings have implications for the discussion on how to handle the medical and ethical problem of nocebo side effects in clinical practice.

The desire for side-effect information in pain treatment: an experimental analysis of contextual and individual difference factors.

ABSTRACT: Informing patients about potential side effects of pain treatment is a requirement that protects patients and aids decision making, but it increases the likelihood of unwanted nocebo side effects. If patients do not desire all side-effect information, it may be possible to ethically reduce nocebo effects through authorized concealment of side effects, whereby patients and clinicians engage in shared decision-making to regulate the disclosure of side-effect information. Currently, there is no experimental data clarifying the factors that causally influence desire for side-effect information in pain treatment. In 2 cross-sectional, between-subjects scenario experiments (experiment 1 N = 498, experiment 2 N = 501), 18 to 79-year-old community adults learned about a lower back pain treatment, and potential side-effect severity, frequency, and duration were manipulated. Individual differences in information avoidance were also recorded. In both experiments, participants reported high desire for side-effect information, but the desire was reduced when side effects were described as less severe, less frequent, and participants scored high in information avoidance. Results were not moderated by participants' level of contact with the health care system, chronic health condition, or clinical pain history. Additional analyses indicated that low side-effect severity and frequency lessen desire for side-effect information because these variables reduce belief that side-effect information will be needed in the future and lower feelings of anticipated regret. The experiments identify situational and individual-difference factors that decrease the desire for side-effect information and provide evidence on when and for whom it may be useful for physicians to engage in shared medical decision-making with the goal of reducing nocebo side effects.

Placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease and healthy participants.

ABSTRACT: The role of placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease (AD) is largely unknown, with only few studies in the area. Therefore, this study aims to investigate to which extent placebo analgesia and nocebo hyperalgesia effects are present in patients experiencing mild-to-moderate AD. Twenty-one patients with AD (test population) and 26 healthy participants (HP; design validation) were exposed to thermal pain stimulation on 3 test days: Lidocaine condition (open/hidden lidocaine administration), capsaicin condition (open/hidden capsaicin administration), and natural history (no treatment), in a randomized, within-subject design. Open lidocaine and open capsaicin were accompanied by verbal suggestions for pain relief and pain increase, respectively. Expected pain and actual pain intensity were measured on a numerical rating scale (0-10). Placebo and nocebo effects were calculated as pain differences in open-hidden lidocaine and capsaicin, respectively, controlled for no treatment. Healthy participants obtained a placebo effect ( P = 0.01) and a trend for a nocebo effect ( P = 0.07). Patients with AD did not obtain a placebo effect ( P = 0.44) nor a significant nocebo effect ( P = 0.86). Healthy participants expected lower and higher pain with open vs hidden lidocaine and capsaicin, respectively ( P < 0.001). The same expectation effects were seen in patients with AD (open vs hidden lidocaine, P = 0.008; open vs hidden capsaicin, P < 0.001). With a well-controlled experimental setting, this study suggests that patients with AD may not experience placebo analgesia effects. Nocebo hyperalgesia effects in patients with AD needs further research. These findings may have implications for the conduction of clinical trials and the treatment of patients with AD in clinical practice.

Importance of blinding and expectations in opioid-induced constipation: evidence from a randomized controlled trial.

OBJECTIVES: Previous studies have found little association between objective measures and the subjective experience of opioid-induced constipation. The subjective experience of opioid-induced constipation may be influenced by treatment expectations. While most trials control for treatment expectations through blinding, success rate is generally low. This study aimed to explore the association between objective measures and the subjective experience of opioid-induced constipation, while considering blinding success and treatment expectations, and other psychological factors. METHODS: Data from a randomized, double-blinded, placebo-controlled crossover trial including 21 healthy male participants was analyzed. Participants received either placebo, tapentadol, or oxycodone (in equipotent doses) for 14 days. They were assessed on objective and subjective measures of opioid-induced constipation (gastrointestinal transit time and the Patient Assessment of Constipation-Symptoms questionnaire, respectively), treatment guesses to indicate blinding success, and psychological factors. RESULTS: There was a strong association between objective and subjective measures of opioid-induced constipation when participants were treated with oxycodone (r=0.676, p=0.006). Furthermore, participants were able to guess that they received active treatment when treated with oxycodone (p<0.001), suggesting that treatment expectations may have influenced the subjective experience of symptoms. Finally, patterns of moderate associations between opioid-induced constipation and other psychological factors emerged, although none reached significance (p>0.05). CONCLUSIONS: Results indicate that treatment expectations could play an important role in the subjective experience of opioid-induced constipation, and support the importance of assessing blinding success in study trials. Besides expectations, other psychological factors may be associated with opioid-induced constipation.