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.

Comprehension of written texts for the assessment of clinical competence and decision making in people with mild to moderate Alzheimer disease.

BACKGROUND: Clinical competence is the term used to describe an individual's capacity to express a choice regarding their participation in clinical procedures or experimental studies. Understanding the information provided is a prerequisite but consent forms are often lengthy and complicated. Alzheimer's disease patients may be vulnerable in written comprehension, due to cognitive deficits, but unfortunately to date, a specific evaluation of this ability is not included in periodical assessments. METHODS: One hundred thirty Italian patients with Alzheimer's disease were compared with 130 controls in a comprehension task involving a simplified informed consent form. Their performance in this task was compared with their performance with two other types of reading material (a testament and a history text). In addition, the performance of a subgroup of very mild patients in this test was compared with their performance in a widely used interview for the assessment of clinical competence (MacArthur Competence Assessment Tool for Clinical Research). RESULTS: Good sensitivity and specificity of the cut-offs identified consent form and the other texts as good instruments for evaluation of written comprehension. The comprehension of consent form may be compromised since the early stages of Alzheimer's disease. Nevertheless, a simplified, written text may help patients in comparison with interviews (MacCAT-CR). Better performance was correlated to the standard of education and better cognitive functions. CONCLUSION: Deficits regarding the comprehension of written texts and the consent form may be early in Alzheimer's disease patients and need to be investigated during periodical neuropsychological assessment. Comprehension may be facilitated by means of specific simplification strategies.

Correction to: Comprehension of written texts for the assessment of clinical competence and decision making in people with mild to moderate Alzheimer disease.

The above article was published online with missing author. The additional author is Michele Scandola.

When words hurt: Verbal suggestion prevails over conditioning in inducing the motor nocebo effect.

Perception and behavior are strongly influenced by the verbal information conveyed by other individuals (e.g., verbal suggestion) and by learning (e.g., conditioning). This influence is well represented by the placebo and nocebo effects, in which positive verbal suggestion associated with positive conditioning induces beneficial outcomes (placebo effect), while the opposite is true for the negative counterpart (nocebo effect). It is still unclear whether verbal suggestion and conditioning exert distinctive roles in influencing perception, behavior and motor system activity when they occur in opposite directions. To this purpose, fifty-three healthy volunteers were assigned to four groups characterized by either congruent or incongruent verbal suggestion and conditioning. Participants were asked to perform a force motor task by pressing a piston as strongly as possible. Transcranial magnetic stimulation over the primary motor cortex was used to record motor evoked potentials (MEP) and cortical silent period (CSP) from the muscle involved in the task. We found that negative verbal suggestion counteracted positive conditioning and induced sense of weakness, effort, and force decrements. MEP amplitude was stable, whereas the CSP duration shortened in all the groups throughout the procedure, indicating the involvement of cortical inhibitory circuits, independently of the type of verbal suggestion or conditioning. Our findings highlight a prevalent role of verbal suggestion over conditioning in determining a worsening (nocebo effect) but not an improvement (placebo effect) of motor performance. These results suggest that words associated with treatments should be chosen carefully to avoid negative outcomes, especially in sports and clinical settings.

Oral prolonged-release Oxycodone-Naloxone: analgesic response, safety profile, and factors influencing the response in advanced cancer patients.

BACKGROUND: Oxycodone-Naloxone (OXN) aims to reduce opioid-related constipation while being successfully analgesic. METHODS: We evaluated the analgesic response, prevalence, and severity of side effects in 176 cancer patients with moderate to severe pain and treated with OXN. Patients were followed for 28 days and evaluated every seven. Pain intensity, changes of therapy, and adverse drug reactions were recorded at each visit. The primary efficacy endpoint was the proportion of responders (≥30% reduction of pain intensity from baseline to final) and final average pain score ≤4 on a 0-10 scale. RESULTS: Average and worst pain intensity, and breakthrough pain (BTP) prevalence decreased over time and 81.3% of patients were responders. The starting daily dose of OXN was raised from 25.1±13.0 mg to 44.1±29.9 mg, and dose escalation >5%/day was observed in 19.4% of patients; 40.8-46.2% and 11.0-17.0% experienced any and severe grade of constipation during the follow-up visit, respectively. Digestive system tumor, thyroid endocrinopathies, psychological irritability, and BTP increased the risk of analgesic non-response. CONCLUSIONS: OXN had strong analgesic effect in moderate to severe cancer pain patients: the safety profile is in line with the common adverse effects of opioids and severe constipation was uncommon. This article is protected by copyright. All rights reserved.

The Burden of Opioid Adverse Events and the Influence on Cancer Patients' Symptomatology.

CONTEXT: Opioids are frequently used for the treatment of moderate-to-severe pain and their use may produce a number of unwanted adverse events (AEs). OBJECTIVES: The objective of this study was to understand the burden of opioid-induced AEs in cancer patients with pain after the introduction of strong opioids (WHO Step III). METHODS: This is a cohort study derived from a randomized controlled trial involving 498 cancer patients with pain who received strong opioids. During 28-day follow-up, we analyzed frequency, intensity, and changes over time of the main opioid-induced AEs; the influence of previous pain therapy on AEs; and the relationships between the presence of AEs and analgesic response. RESULTS: After starting strong opioids, dry mouth, nausea, and vomiting immediately increased and persisted over time, constipation continued to increase, while drowsiness and confusion tended to decrease. Patients previously treated with weak opioids had more frequent and severe AEs. While at all observation points the percentage of patients without AEs was 37%-39%, considering all the five scheduled visits, from Day 3 to Day 28, 17% of patients never experienced any AEs, while 48% of patients had four or more concomitant AEs. Patients with no AEs experienced significantly lower pain intensity. CONCLUSION: Opioid introduction induces various AEs that persist over time and worse patients' symptomatology. Moreover, there seems to be a different expression of the opioid toxicity among patients, and a possible interaction between AEs and the analgesic response. The balance between the opioids analgesic effect and induced toxicity is fundamental in deciding the best management for pain in cancer patients.

The interplay of exercise, placebo and nocebo effects on experimental pain.

Over the last few decades, placebo, and nocebo effects in general, have been investigated at rest. This proposed study explores whether they could work even when the experience of pain occurs during a movement. Exercise itself can have a hypoalgesic effect, suggesting that placebo- and exercise-induced hypoalgesia could foster pain reduction. In the present study, we investigated the interplay of exercise, placebo and nocebo effects on pain. To this aim, we developed a machine-controlled isotonic motor task to standardize the exercise across participants and used a well-validated model of placebo and nocebo manipulations with reinforced expectations via a conditioning procedure including visual cues paired with heat painful stimulations. Participants reported expectations and pain on a trial-by-trial basis. We found that the standardized isotonic exercise elicited a reduction of pain intensity. Moreover, both exercise and placebo induced comparable hypoalgesic effects. When the exercise was added, placebo and nocebo effects were influenced by expectations but were not affected by fatigue or sex differences. Exercise-, placebo- and nocebo-induced pain modulation are likely to work through distinct mechanisms and neurophysiological research is needed to fully exploit the implications for sport, rehabilitation and pain management.

Prevalence, characteristics and treatment of chronic pain in elderly patients hospitalized in internal medicine wards.

BACKGROUND: Chronic pain is a frequent characteristic of elderly people and represents an actual and still poorly debated topic. OBJECTIVE: We investigated pain prevalence and intensity, and its pharmacological therapy in elderly patients hospitalized in 101 internal medicine wards. METHODS: Taking advantage of the "REgistro POliterapie Società Italiana Medicina Interna" (REPOSI), we collected 2535 patients of whom almost a quarter was older than 85 years old. Among them, 582 patients were affected by pain (either chronic or acute) and 296 were diagnosed with chronic pain. RESULTS: Patients with pain showed worse cognitive status, higher depression and comorbidities, and a longer duration of hospital stay compared to those without pain (all p < .0366). Patients with chronic pain revealed lower level of independency in their daily life, worse cognitive status and higher level of depression compared to acute pain patients (all p < .0156). Moreover, most of them were not treated for pain at admission (73.4%) and half of them was not treated with any analgesic drug at discharge (50.5%). This difference affected also the reported levels of pain intensity. Patients who received analgesics at both admission and discharge remained stable (p = .172). Conversely, those not treated at admission who received an analgesic treatment during the hospital stay decreased their perceived pain (p < .0001). CONCLUSIONS: Our results show the need to focus more attention on the pharmacological treatment of chronic pain, especially in hospitalized elderly patients, in order to support them and facilitate their daily life after hospital discharge.

Nonresponsiveness and Susceptibility of Opioid Side Effects Related to Cancer Patients' Clinical Characteristics: A Post-Hoc Analysis.

BACKGROUND: The response to opioids is not always positive in cancer patients. A considerable proportion of patients do not respond (nonresponders [NRs]) or experience severe toxicity. The aim of this analysis was to assess the role of demographic characteristics, pain features, comorbidities, and ongoing therapy on the lack of efficacy and on the occurrence of severe adverse drug reactions (ADRs). METHODS: This is a post-hoc analysis of a randomized controlled trial that involved 520 patients and aimed to evaluate the efficacy and safety of 4 strong opioids. Patients who presented with unchanged or worsened pain compared to the first visit were considered to be NRs. As for toxicity, severe ADRs with an incidence of greater than 10% were evaluated. Univariate and multivariate logistic models were used. RESULTS: 498 patients were analyzed. Liver metastases and breakthrough pain (BTP) were found to increase the risk for nonresponse. Conversely, a high basal pain intensity significantly decreased the same risk. Constipation risk was worsened by previous weak opioid therapy but decreased with aging and with the use of transdermal opioids. Risk for drowsiness was aggravated by bone metastases and concomitant treatment with anticoagulant, antidiabetic, and central nervous system drugs. Risk for confusion increased with antidiabetics, antibiotics, and previous weak opioid therapy but decreased when fentanyl was used. Occurrence of nausea increased in patients with a high rating on the Karnofsky Performance Status Index. Risk for xerostomia was higher in women and in patients treated with antidiabetic or long-term opioids. CONCLUSIONS: Several clinical variables are correlated with opioid response in cancer patients. In particular, the presence of BTP is associated with nonresponse. Additionally, patients who receive polypharmacological therapy are more likely to experience opioid adverse events.

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.

Placebo and Nocebo Effects: The Advantage of Measuring Expectations and Psychological Factors.

Several studies have explored the predictability of placebo and nocebo individual responses by investigating personality factors and expectations of pain decreases and increases. Psychological factors such as optimism, suggestibility, empathy and neuroticism have been linked to placebo effects, while pessimism, anxiety and catastrophizing have been associated to nocebo effects. We aimed to investigate the interplay between psychological factors, expectations of low and high pain and placebo hypoalgesia and nocebo hyperalgesia. We studied 46 healthy participants using a well-validated conditioning paradigm with contact heat thermal stimulations. Visual cues were presented to alert participants about the level of intensity of an upcoming thermal pain. We delivered high, medium and low levels of pain associated with red, yellow and green cues, respectively, during the conditioning phase. During the testing phase, the level of painful stimulations was surreptitiously set at the medium control level with all the three cues to measure placebo and nocebo effects. We found both robust placebo hypolagesic and nocebo hyperalgesic responses that were highly correlated with expectancy of low and high pain. Simple linear regression analyses showed that placebo responses were negatively correlated with anxiety severity and different aspects of fear of pain (e.g., medical pain, severe pain). Nocebo responses were positively correlated with anxiety sensitivity and physiological suggestibility with a trend toward catastrophizing. Step-wise regression analyses indicated that an aggregate score of motivation (value/utility and pressure/tense subscales) and suggestibility (physiological reactivity and persuadability subscales), accounted for the 51% of the variance in the placebo responsiveness. When considered together, anxiety severity, NEO openness-extraversion and depression accounted for the 49.1% of the variance of the nocebo responses. Psychological factors per se did not influence expectations. In fact, mediation analyses including expectations, personality factors and placebo and nocebo responses, revealed that expectations were not influenced by personality factors. These findings highlight the potential advantage of considering batteries of personality factors and measurements of expectation in predicting placebo and nocebo effects related to experimental acute pain.

Changes in perception of treatment efficacy are associated to the magnitude of the nocebo effect and to personality traits.

The nocebo effect in motor performance consists in a reduction of force and increase of fatigue following the application of an inert treatment that the recipient believes to be effective. This effect is variable across individuals and it is usually stronger if conditioning -exposure to the active effect of the treatment- precedes a test session, in which the treatment is inert. In the current explorative study we used a conditioning procedure to investigate whether subjective perception of treatment effectiveness changes between the conditioning and the test session and whether this change is related to dispositional traits and to the nocebo-induced reduction of force. Results showed that 56.1% of participants perceived the treatment as more effective in the test than in the conditioning session, had a more pronounced reduction of force, felt more effort and sense of weakness and were characterized by lower levels of optimism and higher anxiety traits compared to the other 43.9% of participants, who conversely perceived the treatment as less effective in the test session than in the conditioning. These findings highlight for the first time a link between changes in perception of treatment effectiveness, personality traits and the magnitude of the nocebo response in motor performance.

Modulation of inhibitory corticospinal circuits induced by a nocebo procedure in motor performance.

As recently demonstrated, a placebo procedure in motor performance increases force production and changes the excitability of the corticospinal system, by enhancing the amplitude of the motor evoked potentials (MEP) and reducing the duration of the cortical silent period (CSP). However, it is not clear whether these neurophysiological changes are related to the behavioural outcome (increased force) or to a general effect of expectation. To clarify this, we investigated the nocebo effect, in which the induced expectation decreases force production. Two groups of healthy volunteers (experimental and control) performed a motor task by pressing a piston with the right index finger. To induce a nocebo effect in the experimental group, low frequency transcutaneous electrical nerve stimulation (TENS) was applied over the index finger with instructions of its detrimental effects on force. To condition the subjects, the visual feedback on their force level was surreptitiously reduced after TENS. Results showed that the experimental group reduced the force, felt weaker and expected a worse performance than the control group, who was not suggested about TENS. By applying transcranial magnetic stimulation over the primary motor cortex, we found that while MEP amplitude remained stable throughout the procedure in both groups, the CSP duration was shorter in the experimental group after the nocebo procedure. The CSP reduction resembled previous findings on the placebo effect, suggesting that expectation of change in performance diminishes the inhibitory activation of the primary motor cortex, independently of the behavioural outcome.