ConquerFear-group: Feasibility study with pilot results of a psychological intervention for fear of cancer recurrence delivered in groups.

OBJECTIVE: ConquerFear has been found to effectively reduce fear of cancer recurrence (FCR). Group interventions may be particularly effective for the treatment of FCR and could lower overall costs. Our objectives were therefore to adapt ConquerFear into a group format (ConquerFear-Group, CF-G), and to evaluate its feasibility, acceptability, and preliminary efficacy. METHODS: Eligible patients had completed treatment for breast cancer 3 months to 5 years previously, were ≥18 years, and scored ≥22 on the Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF). The manual was first evaluated with seven patients (Pilot 1), adjusted in accordance with feedback from the patients, therapists, and the original ConquerFear developers. After further evaluation with eight patients (Pilot 2), and subsequent adjustments, the preliminary efficacy of the final manual was evaluated with 27 patients, randomized in blocks to CF-G (N = 13) or active control (AC) (relaxation training) (N = 14) (Pilot 3). The primary outcome was the FCRI total score. Secondary outcomes included general distress, quality-of-life, and process outcomes pertaining to metacognitions, decentering, and worry. All measures were completed at baseline, post-treatment, and at 3 and 6 months follow-up. RESULTS: Adjustments of the original ConquerFear manual (Pilot 1 and 2) included changes in the order of treatment components, simplified exercises, and shortened homework. Compared with ACs, CF-G participants reported greater reductions in FCRI total scores from baseline to post-treatment (Hedges's g = 0.59, p = 0.004), 3 months (g = 0.50, p = 0.026), and 6 months later (g = 0.93, p = 0.043). Differences corresponding to medium-to-large effect sizes (Pilot 3). Although non-significant, group differences concerning reductions in general distress and maladaptive metacognitions corresponded to small-to-medium effect sizes (g = 0.40-0.61; ps = 0.40-0.61). CONCLUSIONS: CF-G appears feasible and potentially efficacious in treating FCR in a breast cancer population. These preliminary results are promising but need to be confirmed in a larger randomized trial.

Neurotransmitter systems involved in placebo and nocebo effects in healthy participants and patients with chronic pain: a systematic review.

The investigation of neurotransmitter systems in placebo and nocebo effects has improved our understanding of these phenomena. Yet, most studies involve healthy participants. Because the pain modulatory system may differ in healthy participants and patients with chronic pain, it is important to investigate the evidence for neurotransmitter involvement in placebo and nocebo effects in each of these populations. PubMed, Embase, and Scopus databases, and the Cochrane Library were searched for articles investigating the endogenous opioid, endocannabinoid, dopaminergic, oxytocinergic, vasopressinergic, and cholecystokininergic (CCKergic) systems in placebo and nocebo effects in pain. Twenty-eight placebo and 2 nocebo studies were included. Vote counting was used to balance the number of positive vs negative findings. In healthy participants, the endogenous opioid, endocannabinoid, and vasopressinergic systems were involved in placebo effects, whereas findings on the dopaminergic and oxytocinergic systems were mixed. In patients with chronic pain, only 4 studies investigated neurotransmitters showing no involvement of the endogenous opioid system and mixed findings regarding the dopaminergic system. As to nocebo effects, 2 studies suggest that the CCKergic system is involved in nocebo effects in healthy participants. Overall, research has come a long way in specifying the neurotransmitter systems involved in placebo effects in healthy participants. Yet, evidence for the involvement of neurotransmitter systems in placebo effects in patients with chronic pain and in nocebo effects in healthy participants and patients is scarce. Based on the existing evidence, this systematic review suggests that knowledge obtained in healthy participants may not necessarily be transferred to chronic pain.

Dopaminergic tone does not influence pain levels during placebo interventions in patients with chronic neuropathic pain.

Placebo effects have been reported in patients with chronic neuropathic pain. Expected pain levels and positive emotions are involved in the observed pain relief, but the underlying neurobiology is largely unknown. Patients with neuropathic pain are highly motivated for pain relief, and as motivational factors such as expectations of reward, as well as pain processing in itself, are related to the dopaminergic system, it can be speculated that dopamine release contributes to placebo effects in neuropathic pain. Nineteen patients with neuropathic pain after thoracic surgery were tested during a placebo intervention consisting of open and hidden applications of the pain-relieving agent lidocaine (2 mL) and no treatment. The dopamine antagonist haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) were administered to test the involvement of dopamine. Expected pain levels, desire for pain relief, and ongoing and evoked pain were assessed on mechanical visual analog scales (0-10). Significant placebo effects on ongoing (P ≤ 0.003) and evoked (P ≤ 0.002) pain were observed. Expectancy and desire accounted for up to 41.2% and 71.5% of the variance in ongoing and evoked pain, respectively, after the open application of lidocaine. We found no evidence for an effect of haloperidol and levodopa/carbidopa on neuropathic pain levels (P = 0.071-0.963). Dopamine seemed to influence the levels of expectancy and desire, yet there was no evidence for indirect or interaction effects on the placebo effect. This is the first study to suggest that dopamine does not contribute to placebo effects in chronic neuropathic pain.

Lessons Learned From Nocebo Effects in Clinical Trials for Pain Conditions and Neurodegenerative Disorders.

It has been demonstrated that patients in the placebo arm of a clinical trial may experience adverse events (AEs), which may lead to nonadherence and dropout. However, so far, it is unknown to which extent this phenomenon is observed consistently across different diseases such as pain and neurodegenerative disorders.The current review shows for the first time that different diseases share a common risk for patients in terms of a negative outcome: a large percentage of placebo-treated patients experience AEs in pain conditions (up to 59%) and neurodegenerative disorders (up to 66%). In addition, the rate of patients who discontinue because of AEs is up to 10% and 11% in pain conditions and neurodegenerative disorders, respectively.We highlight methodological shortcomings with the aim of suggesting how the detection and reporting of AEs can be improved in future trials. The insights from the current review should be taken into consideration when designing clinical trials to tailor individualized treatments.

Placebo, nocebo, and neuropathic pain.

Over the last decade, the apparent increase in placebo responses in randomized controlled trials (RCTs) of neuropathic pain have complicated and potentially limited development and availability of new effective pain medication. Placebo analgesia and nocebo hyperalgesia effects are well described in nociceptive and idiopathic pain conditions, but less is known about the magnitude and mechanisms of placebo and nocebo effects in neuropathic pain. In neuropathic pain, placebo treatments have primarily been used as control conditions for active agents under investigation in RCTs and these placebo responses are typically not controlled for the natural history of pain and other confounding factors. Recently, mechanistic studies that control for the natural history of pain have investigated placebo and nocebo effects in neuropathic pain in their own right. Large placebo analgesia but no nocebo hyperalgesic effects have been found, and the underlying mechanisms are beginning to be elucidated. Here we review placebo and nocebo effects and the underlying mechanisms in neuropathic pain and compare them with those of nociceptive and idiopathic pain. This allows for a novel discussion on how knowledge of psychological, neurobiological, and genetic factors underlying well-controlled placebo effects may help improve the information that can be obtained from and potentially restore the utility of RCTs.

Experimental orofacial pain and sensory deprivation lead to perceptual distortion of the face in healthy volunteers.

Patients suffering from persistent orofacial pain may sporadically report that the painful area feels "swollen" or "differently," a phenomenon that may be conceptualized as a perceptual distortion because there are no clinical signs of swelling present. Our aim was to investigate whether standardized experimental pain and sensory deprivation of specific orofacial test sites would lead to changes in the size perception of these face areas. Twenty-four healthy participants received either 0.2 mL hypertonic saline (HS) or local anesthetics (LA) into six regions (buccal, mental, lingual, masseter muscle, infraorbital and auriculotemporal nerve regions). Participants estimated the perceived size changes in percentage (0 % = no change, -100 % = half the size or +100 % = double the size), and somatosensory function was checked with tactile stimuli. The pain intensity was rated on a 0-10 Verbal Numerical Rating Scale (VNRS), and sets of psychological questionnaires were completed. HS and LA were associated with significant self-reported perceptual distortions as indicated by consistent increases in perceived size of the adjacent face areas (P ≤ 0.050). Perceptual distortion was most pronounced in the buccal region, and the smallest increase was observed in the auriculotemporal region. HS was associated with moderate levels of pain VNRS = 7.3 ± 0.6. Weak correlations were found between HS-evoked perceptual distortion and level of dissociation in two regions (P < 0.050). Experimental pain and transient sensory deprivation evoked perceptual distortions in all face regions and overall demonstrated the importance of afferent inputs for the perception of the face. We propose that perceptual distortion may be an important phenomenon to consider in persistent orofacial pain conditions.

Painful stimulation and transient blocking of nerve transduction due to local anesthesia evoke perceptual distortions of the face in healthy volunteers.

UNLABELLED: Anecdotally, orofacial pain patients sometimes report that the painful face area feels "swollen." Because there are no clinical signs of swelling, such illusions may represent perceptual distortions. In this study, we examine whether nociceptive stimulation can lead to perceptual distortion of the face in a way similar to that of local anesthesia. Sixteen healthy participants received injections of .4 mL hypertonic saline to induce short-term nociceptive stimulation, .4 mL mepivacaine (local anesthetic) to transiently block nerve transduction, and .4 mL isotonic saline as a control condition. Injections were administered in both the infraorbital and the mental nerve regions. Perceptual distortions were conceptualized as perceived changes in magnitude of the injected areas and the lips, and they were measured using 1) a verbal subjective rating scale and 2) a warping procedure. Prior to the study, participants filled in several psychological questionnaires. This study shows that both nociceptive stimulation (P < .05) and transient blocking of nerve transduction (P < .05) can lead to perceptual distortion of the face. A test-retest experiment including 9 new healthy subjects supported the results. Perceptual distortions were positively correlated with the psychological variable of dissociation in several conditions (P < .05). Perceptual distortions may therefore be influenced by somatosensory changes and psychological mechanisms. PERSPECTIVE: Knowledge of the factors that influence the perception of the face is important to understand the possible implications of perceptual distortions in orofacial pain disorders (and possibly other chronic pain states). Such information may ultimately open up new avenues of treatment for persistent orofacial pain.