Placebo Effects on Stress, but Not on Pain Reports. A Multi-Experiment Study

BackgroundContextual factors, such as participant/experimenter sex may moderate the placebo effects. We tested whether the participant and experimenter sex modulated placebo effects on experimentally induced pain and associated stress.ObjectiveTo investigate if (i) participant sex and (ii) experimenter sex influence placebo analgesia and subjective and physiological stress in two experiments employing a within-subjects and a mixed design, respectively. Placebo effects were investigated in pain reports, stress, and blood pressure.MethodsParticipants received painful stimulations and a placebo cream. In Experiment One (N = 59) participants underwent a placebo condition (PC) and a natural history condition (NHC) in random order. A placebo cream was applied in the PC and then the heat stimulation temperature was surreptitiously lowered. Identical stimulations were administered in the NHC, but with no cream, no information, and no lowered temperature. In Experiment Two, participants (N = 93) were randomly assigned to three groups receiving either a placebo cream with surreptitiously lowered intensity of electric stimuli (Placebo, PG), a placebo cream (Cream-Control, CCG) without changing the stimuli, or lowered intensity, but with no cream (Pain-Control, PCG) in a mixed design. All participants in both experiments received the same stimuli in the post-test as in the pre-test. Four experimenters (two females) in Experiment One, and five experimenters (two females) in Experiment Two conducted the studies.ResultsNo placebo effect was seen on pain. However, there were placebo effects on stress, moderated by participant and experimenter sex: in Experiment One males in the PC had lower diastolic blood pressure (DBP) compared to males in the NHC. Participants in the PC had lower DBP compared to the NHC when tested by a female. In Experiment Two, participants expected more cream effectiveness when a female experimenter administered it, and reported lower stress in the PG compared to the PCG when tested by females.ConclusionOur findings highlight a distinction between placebo effects on pain and on associated stress. Secondly, female experimenters recorded lower physiological and subjective stress, higher effectiveness expectations, and lower pain from both sexes compared to male experimenters. Possible reasons for the failure to find a pain placebo effect are discussed.

No Influence of Nonivamide-nicoboxil on the Peak Power Output in Competitive Sportsmen

Recent studies have shown that the oxygenated hemoglobin level can be enhanced during rest through the application of nonivamide-nicoboxil cream. However, the effect of nonivamide-nicoboxil cream on oxygenation and endurance performance under hypoxic conditions is unknown. Therefore, the purpose of this study was to investigate the effects of nonivamide-nicoboxil cream on local muscle oxygenation and endurance performance under normoxic and hypoxic conditions. In a cross-over design, 13 athletes (experienced cyclists or triathletes [age: 25.2±3.5 years; VO2max 62.1±7.3 mL·min−1·kg−1]) performed four incremental exercise tests on the cycle ergometer under normoxic or hypoxic conditions, either with nonivamide-nicoboxil or placebo cream. Muscle oxygenation was recorded with near-infrared spectroscopy. Capillary blood samples were taken after each step, and spirometric data were recorded continuously. The application of nonivamide-nicoboxil cream increased muscle oxygenation at rest and during different submaximal workloads as well as during physical exhaustion, irrespective of normoxic or hypoxic conditions. Overall, there were no significant effects of nonivamide-nicoboxil on peak power output, maximal oxygen uptake or lactate concentrations. Muscle oxygenation is significantly higher with the application of nonivamide-nicoboxil cream. However, its application does not increase endurance performance.

EFFECTIVENESS OF LIDOCAINE CREAM FOR REDUCING PAIN SENSATION OF PRE INJECTION OF SUBCUTANEOUS LIDOCAINE IN LUMBAL PUNCTURE DIAGNOSTIC AND THERAPEUTIC PROCEDURES

Background: Lumbar puncture is one of the methods that is quite often performed for various purposes. There is no global agreement regarding the use of local anesthesia in subcutaneous or topical infiltration prior to LP. Topical anesthesia injection in lumbar puncture still cause pain, there should be needing additional topical anesthesia. Aim: To compare the effectiveness between lidocaine cream and placebo cream prior lidocaine subcutaneous injection to reduce pain sensation in LP procedures. Methods: The study was conducted in July-October 2019, randomized and clinical trial (RCT) by sampling technique using block randomization method. Sample was divided into two group. Pain scale was assessed when the needle touched the skin, subcutaneously and overall in both groups. Data analysis using SPSS ver 22 for windows. Results: The average age of subjects is 38.50±14.43 years and majority are women (57.9%). There is significance difference of pain scale between groups when needle touched the skin (p=0,035), meanwhile, there is not significance difference when needle subcutaneously (p=0,061) and overall (p=0,182) in both groups. Conclusion: Lidocaine cream has been shown to be significantly more effective in reducing pain pre lidocaine subcutaneous injection compare to placebo cream when needle touched the skin.

Neural effects of placebo analgesia in fibromyalgia patients and healthy individuals

ABSTRACTPlacebo analgesia is hypothesized to involve top-down engagement of prefrontal regions that access endogenous pain inhibiting opioid pathways. Fibromyalgia (FM) patients have neuroanatomical and neurochemical alterations in pathways relevant to placebo analgesia. Thus, it remains unclear whether placebo analgesic mechanisms would differ in FM patients compared to healthy controls (HCs). Here, using placebo-analgesia-inducing paradigms that included verbal suggestions and conditioning manipulations, we examined whether behavioral and neural placebo analgesic responses differed between 32 FM patients and 46 age- and sex-matched HCs. Participants underwent a manipulation scan, where noxious high and low heat were paired with the control and placebo cream, respectively, and a placebo experimental scan with equal noxious heat temperatures. Before the experimental scan, each participant received saline or naloxone, an opioid receptor antagonist. Across all participants, the placebo condition decreased pain intensity and unpleasantness ratings, decreased activity within the right insula and bilateral secondary somatosensory cortex, and modulated the Neurologic Pain Signature. There were no differences between HCs and FM patients in pain intensity ratings or neural responses during the placebo condition. Despite the perceptual and neural effects of the placebo manipulation, prefrontal circuitry was not activated during the expectation period and the placebo analgesia was unaltered by naloxone, suggesting placebo effects were driven more by conditioning than expectation. Together, these findings suggest that placebo analgesia can occur in both HCs and chronic pain FM patients, without the involvement of opiodergic prefrontal modulatory networks.

Effectiveness of Lidocaine Cream for Reducing Pain Sensation of Pre Injection of Subcutaneous Lidocaine in Lumbal Puncture Diagnostic and Therapeutic Procedures

Background: Lumbar puncture is one of the methods that is quite often performed for various purposes. There is no global agreement regarding the use of local anesthesia in subcutaneous or topical infiltration prior to LP. Topical anesthesia injection in lumbar puncture still cause pain, there should be needing additional topical anesthesia. Aim: To compare the effectiveness between lidocaine cream and placebo cream prior lidocaine subcutaneous injection to reduce pain sensation in LP procedures. Methods: The study was conducted in July-October 2019, randomized and clinical trial (RCT) by sampling technique using block randomization method. Sample was divided into two group. Pain scale was assessed when the needle touched the skin, subcutaneously and overall in both groups. Data analysis using SPSS ver 22 for windows. Results: The average age of subjects is 38.50±14.43 years and majority are women (57.9%). There is significance difference of pain scale between groups when needle touched the skin (p=0,035), meanwhile, there is not significance difference when needle subcutaneously (p=0,061) and overall (p=0,182) in both groups. Conclusion: Lidocaine cream has been shown to be significantly more effective in reducing pain pre lidocaine subcutaneous injection compare to placebo cream when needle touched the skin.

Single-Blind Placebo-Controlled Response Test with Phenytoin 10% Cream in Neuropathic Pain Patients

Background: Phenytoin cream applied topically has been explored in neuropathic pain conditions. In several case series, phenytoin 5% and 10% cream could reduce pain in a clinically relevant way with a fast onset of action within 30 min, and with positive effects on sleep. Objective: To evaluate a single-blind placebo-controlled response test (SIBRET) for use in clinical practice. Materials and Methods: Patients with localized neuropathic pain, having an equal pain intensity in at least 2 areas (e.g., both feet), and a pain intensity of at least 4 on the 11-point numerical rating scale (NRS), were selected to perform the SIBRET. In one area, placebo cream consisting of the base cream was applied, and on the other area, phenytoin 10% cream was applied with separate hands to avoid contamination. Responders were defined as patients who experienced within 30 min at least 2-points difference as scored on the NRS, between the phenytoin 10% and the placebo cream applied areas, in favor of the former. Responders were subsequently prescribed phenytoin 10% cream. Results: Of the 21 patients, 15 patients (71.45%) were classified as responders. The mean pain reduction after 30 min as measured with the NRS in the phenytoin 10% cream area was 3.3 (SD: 1.3) and in the placebo cream area 1.2 (SD: 1.1). The difference of the mean percentage pain reduction between phenytoin 10% cream and placebo cream was 33.2% (SD: 17.6, p < 0.001). Using a 50% reduction on the NRS as a full response criterion, we could identify 57.1% of responders on phenytoin 10% cream and only 9.5% responders on placebo cream. Conclusions: The SIBRET helps patients and clinicians to quickly identify the appropriate treatment and can thus be seen as an important contributor to the domain of personalized medicine in pain. These results can also be regarded as a proof of principle for the analgesic activity of 10% phenytoin cream.

Artichoke Polyphenols Produce Skin Anti-Age Effects by Improving Endothelial Cell Integrity and Functionality

Artichoke is a characteristic crop of the Mediterranean area, recognized for its nutritional value and therapeutic properties due to the presence of bioactive components such as polyphenols, inulin, vitamins and minerals. Artichoke is mainly consumed after home and/or industrial processing, and the undersized heads, not suitable for the market, can be used for the recovery of bioactive compounds, such as polyphenols, for cosmetic applications. In this paper, the potential skin anti-age effect of a polyphenolic artichoke extract on endothelial cells was investigated. The methodology used was addressed to evaluate the antioxidant and anti-inflammatory activities and the improvement of gene expression of some youth markers. The results showed that the artichoke extract was constituted by 87% of chlorogenic, 3,5-O-dicaffeoylquinic, and 1,5-O-dicaffeoylquinic acids. The extract induced important molecular markers responsible for the microcirculation and vasodilatation of endothelial cells, acted as a potential anti-inflammatory agent, protected the lymphatic vessels from oxidative damage by ROS formation, and enhanced the cellular cohesion by reinforcing the tight junction complex. In addition, the artichoke extract, through the modulation of molecular pathways, improved the expression of genes involved in anti-ageing mechanisms. Finally, clinical testing on human subjects highlighted the enhancement by 19.74% of roughness and 11.45% of elasticity from using an artichoke extract cosmetic formulation compared to placebo cream.

Topical Phenytoin Cream Reduces Burning Pain Due to Small Fiber Neuropathy in Sarcoidosis

We present a patient case of burning pain and sleep disturbances due to small fiber neuropathy (SFN) in sarcoidosis, treated successfully by topically applied phenytoin 10% cream. Using a single blind, placebo-controlled response test, the patient identified that within a 10 minute period phenytoin 10% cream provided a pain reduction of 50%, while placebo cream did not reduce pain at all. Subsequently, the patient was prescribed phenytoin 10% cream and used this cream for several weeks. Burning pain was reduced by 50% to 60%, resulting in a much improved sleep. The onset of analgesia starts around five minutes after the application of phenytoin 10% cream and in this case lasts for around 20 hours. Plasma levels of phenytoin, measured in 15 comparable patients were below the level of detection, ruling out systemic analgesia. Our hypothesis is that topical phenytoin influences epidermal targets such as nociceptors, small nerve fibers and keratinocytes, all which play a role in the pathogenesis of pain in SFN.

The mu-opioid receptor gene OPRM1 as a genetic marker for placebo analgesia

The aim of the present study was to examine if genetic factors associated with pain perception could predict the placebo analgesic response in healthy volunteers. 296 participants (182 women) were randomized to either a placebo group receiving placebo cream with information that the cream was an effective painkiller, or to a natural history group receiving no treatment. Pain was induced by contact heat stimuli. Genotyping for the mu-opioid receptor gene OPRM1, the serotonin transporter gene 5-HTT, and the dopamine-metabolizing gene COMT was performed. Individuals with the OPRM1 A/A genotype reported significantly higher placebo responses compared to individuals with the */G variant. No clear effect of the 5-HTT or COMT was observed. The OPRM1 A/A had a predictive accuracy of 92.5% in identification of placebo responders. Our data indicate that the OPRM1 rsl799971 A/A genotype can be used as a reliable identification marker for placebo analgesia.