The Roles of Endogenous Opioids in Placebo and Nocebo Effects: From Pain to Performance to Prozac.

Placebo and nocebo effects have been well documented for nearly two centuries. However, research has only relatively recently begun to explicate the neurobiological underpinnings of these phenomena. Similarly, research on the broader social implications of placebo/nocebo effects, especially within healthcare delivery settings, is in a nascent stage. Biological and psychosocial outcomes of placebo/nocebo effects are of equal relevance. A common pathway for such outcomes is the endogenous opioid system. This chapter describes the history of placebo/nocebo in medicine; delineates the current state of the literature related to placebo/nocebo in relation to pain modulation; summarizes research findings related to human performance in sports and exercise; discusses the implications of placebo/nocebo effects among diverse patient populations; and describes placebo/nocebo influences in research related to psychopharmacology, including the relevance of endogenous opioids to new lines of research on antidepressant pharmacotherapies.

Introduction to the Volume: The Journey Ahead.

The endogenous opioid system (EOS) is complex. The line of research contributing to our current body of knowledge about this system is diverse, as are the ways in which endogenous opioids affect human health and behavior. This chapter serves as an introduction to the edited volume. It includes commentary about the current public discourse related to opioids, the rationale for this book, and the unique contributions of each chapter within this volume.

Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2.

PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.

Development of mirror pain following trigeminal nerve injury: a case report and review of neuropathic mechanisms.

Following injury to a peripheral nerve, patients may complain of pain over the distribution of the same contralateral nerve, a phenomenon referred to as contralateral pain or mirror pain (MP). Symptoms of MP usually begin after the neuropathic pain from the original nerve injury has become chronic. Chronic neuropathic pain can lead to sensitization and spread of pain. Because the diagnosis of MP can be missed, patients may undergo multiple treatment procedures that prove to be ineffective in relieving the pain. This article presents a case of MP that appeared approximately 20 months following inferior alveolar nerve injury that occurred during placement of a dental implant in the region of the first molar. Acutely painful nerve injuries must be aggressively treated to prevent changeover to a chronic pain state characterized by sensitization and spread of pain beyond the initial injury. Consequently, clinicians need to begin effective, early pain management to prevent the changeover to chronic pain that has become centralized and refractive to treatment.

Insulin resistance and adipose-derived hormones in young men with untreated obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) increases the risk for insulin resistance (IR). The mechanisms that link the two are not clear and are frequently confounded by obesity. OSA is associated with alterations in adipose-derived hormones (adipokines) that increase IR; however, previous studies have focused on middle-aged and older adults. The objective of this study was to determine if IR and alterations in adipokines exist in young men with OSA, independent of obesity. METHODS: Subjects were assigned into the following groups based on body mass index and presence of OSA: obese with OSA (OSA, n = 12), obese without OSA (NOSA, n = 18), and normal weight without OSA (CON, n = 15). Fasting blood was obtained for batch analysis of biomarkers of IR. The homeostasis model assessment (HOMA) method was used to assess IR. RESULTS: HOMA and leptin were higher in the OSA group than the CON group. There were no differences in insulin, tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) between the OSA and NOSA groups. Adiponectin was lower in the OSA group vs. NOSA and CON; however, when controlled for central abdominal fat (CAF), the difference was nullified. When controlled for total body adiposity, however, CAF was 24 % higher in the subjects with OSA vs. subjects without OSA. CONCLUSIONS: These findings suggest that excess CAF in young men with OSA may contribute to risk for type 2 diabetes indirectly by a degree that would otherwise not be reached through obesity, although further research is needed.

Synthesis of epitaxial metal oxide nanocrystals via a phase separation approach.

Perovskite phase instability of BiMnO3 has been exploited to synthesize epitaxial metal oxide magnetic nanocrystals. Thin film processing conditions are tuned to promote the breakdown of the perovskite precursor into Bi2O3 matrix and magnetic manganese oxide islands. Subsequent cooling in vacuum ensures complete volatization of the Bi2O3, thus leaving behind an array of self-assembled magnetic Mn3O4 nanostructures. Both shape and size can be systematically controlled by the ambient oxygen environments and deposition time. As such, this approach can be extended to any other Bi-based complex ternary oxide system as it primarily hinges on the breakdown of parent Bi-based precursor and subsequent Bi2O3 volatization.

Altered ventilatory responses to exercise testing in young adult men with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a disorder characterized by repetitive obstructions of the upper airway. Individuals with OSA experience intermittent hypoxia, hypercapnia, and arousals during sleep, resulting in increased sympathetic activation. Chemoreflex activation, arising from the resultant oscillatory disturbances in blood gases from OSA, exerts control over ventilation, and may induce increases in sympathetic vasoconstriction, contributing to increased long-term risks for hypertension (HTN) and cardiovascular disease (CVD). METHODS: To evaluate whether OSA elicits exaggerated ventilatory responses to exercise in young men, 14 overweight men with OSA and 16 overweight men without OSA performed maximal ramping cycle ergometer exercise tests. Oxygen consumption (VO(2)), ventilation, (V(E)), ventilatory equivalents for oxygen (V(E)/VO(2)) and carbon dioxide (V(E)/VCO(2)), and V(E)/VCO(2) slope were measured. RESULTS: The VO(2) response to exercise did not differ between groups. The V(E), V(E)/VCO(2), V(E)/VO(2) were higher (p< 0.05, 0.002, and p<0.02, respectively) in the OSA group across all workloads. The V(E)/VCO(2) slope was greater in the OSA group (p<0.05). The V(E)/VCO(2) slope and AHI were significantly correlated (r=0.56, p<0.03). Thus, young, overweight men with OSA exhibit increased ventilatory responses to exercise when compared to overweight controls. This may reflect alterations in chemoreflex sensitivity, and contribute to increased sympathetic drive and HTN risk.

Potential clinical use of cardiopulmonary exercise testing in obstructive sleep apnea hypopnea syndrome.

There is growing evidence linking obstructive sleep apnea hypopnea syndrome (OSAHS) with multiple cardiovascular and metabolic diseases. Exercise testing is generally available and routinely used to provide valuable information on cardiopulmonary function in healthy and diseased populations. This review summarizes and integrates recent findings on exercise testing in OSAHS and discusses the potential mechanisms that may contribute to the responses that seem to differentiate these patients from apparently healthy subjects and patients with other cardiopulmonary diseases. Although exercise testing is widely used in the evaluation and diagnosis of coronary artery disease patients, recent studies showed distinctive cardiopulmonary responses in OSAHS that raise the possibility of similar applications in this disorder, as well. Several studies illustrated in this review found that OSAHS patients have a reduced exercise capacity, as shown by low peak oxygen uptake achieved. Also, their exercise HR response was reported as significantly lower than in healthy peers, suggesting chronotropic incompetence. Exercise blood pressure response were atypical as well. OSAHS patients had increased systolic and diastolic BP during exercise and a persistently elevated systolic BP during the early post-exercise recovery period. Possible explanations for these responses include cardiac dysfunction, impaired muscle metabolism, chronic sympathetic over-activation, and endothelial dysfunction. Early identification of OSAHS using cardiopulmonary exercise testing (CPXT) shows promise for selecting patients at risk for this disorder in the clinical setting. A uniform definition and measurement of OSAHS together with more rigorous trials are necessary to establish the utility of exercise responses in clinical settings.

Attenuated heart rate recovery following exercise testing in overweight young men with untreated obstructive sleep apnea.

STUDY OBJECTIVE: To evaluate whether cardiovascular responses to maximal exercise testing and recovery are altered with obstructive sleep apnea (OSA) in overweight young adult men. DESIGN: Three sedentary subject groups were recruited: Overweight with OSA (OSA), overweight without OSA (No-OSA), and normal weight without OSA (Control). Presence of OSA was screened via portable diagnostic device. Body composition was measured with dual-energy X-ray absorptiometry. Subjects performed maximal ramping exercise testing (RXT) on a cycle ergometer with 5 minutes of active recovery. Exercise measurements included heart rate (HR), blood pressure (BP), respiratory exchange ratio (RER), and oxygen consumption (VO2). Recovery HR was converted to a HR difference (HR(diff)) calculation (HR(peak) - HR(each minute recovery)), and BP was converted to a recovery ratio for each minute. SETTING: The study was carried out on the campus of Virginia Tech, Department of Human Nutrition, Foods, and Exercise, Blacksburg, Virginia. PARTICIPANTS: 14 OSA, 16 No-OSA, and 14 Control volunteers. INTERVENTION: N/A. MEASUREMENTS AND RESULTS: In OSA subjects, HR recovery was significantly attenuated compared to the No-OSA and Control groups throughout recovery (P = 0.009). No differences were noted in the HR or BP response to exercise in any group. The VO2, adjusted for fat-free soft tissue mass, did not differ between groups. CONCLUSIONS: We found that OSA elicits alterations in the cardiovascular response post exercise, reflected by an attenuated HR recovery. This may indicate an imbalance in the autonomic regulation of HR. Exercise tests may provide utility in risk stratification for those at risk for OSA.

Unique cardiopulmonary exercise test responses in overweight middle-aged adults with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by repetitive nighttime obstructions of the upper airway that induce hypoxemia, hypercapnia, sympathetic activation, and arousals. This disorder induces cardiovascular autonomic imbalance and contributes to the development of hypertension. While the diagnostic and prognostic utility of exercise testing is well established in cardiology, the clinical utility of the exercise test in screening for OSA has not been carefully explored. To explore this potential application, we contrasted cardiopulmonary responses to exercise testing in patients recently diagnosed with OSA with apparently healthy counterparts of similar physical inactivity history, age, and body habitus. METHODS: Twenty-three normotensive overweight adults with OSA [apnea-hypopnea index (AHI)=24.7+/-13.5 events h(-1); body mass index (BMI)=33.1+/-5.5 kg m(-2); age=45.6+/-10.7 years] and nine apparently healthy controls of similar age and morphology (BMI=29.5+/-5.5 kg m(-2); age=40.2+/-8.1 years; AHI=4.9+/-0.1) completed a maximal ramping cardiopulmonary exercise tolerance test on a cycle ergometer. Measures included oxygen consumption (VO(2)pk), ventilation (V(E)), heart rate (HR), blood pressure (BP), cardiac output (Qc), and stroke volume (SV). RESULTS: Age, BMI, rest HR, rest BP, rest and exercise cardiac index (QI), rest and exercise stroke volume index (SVI), and V O(2)pk were not different between OSA patients and controls (p>0.05). Exercise heart rate was significantly lower and diastolic BP higher in the OSA group (p<0.05). In the physically active recovery (low-load pedaling), systolic BP recovery was delayed (p<0.05) in the OSA group while diastolic BP tended to remain higher (p=0.056). CONCLUSION: Patients with OSA have a distinctive response to graded exercise, characterized by a blunted HR response, markedly delayed systolic BP response in early recovery, and elevated diastolic BP in both exercise and early recovery. Clinical trials are justified to determine the clinical utility of graded exercise testing to independently inform clinical decision-making for triaging patients to diagnostic polysomnography.

Hypertension research in sleep apnea.

Obstructive sleep apnea (OSA) is characterized by repetitive partial and total collapse of the upper airway that induces stressful arousals throughout sleep to reestablish breathing. Although estimates vary, prevalence has been reported as high as 20% in the adult population. OSA is common in several chronic diseases, the most common of which is obesity. Evidence is strong that OSA increases the risk of hypertension and both fatal and nonfatal cardiovascular events. Several mechanisms linking OSA to hypertension have been proposed, with increased sympathetic activation implicated as the prime mediator. This review summarizes recent data on the influence of OSA on blood pressure, the effect of standard OSA therapy on improving blood pressure, and the potential of lifestyle modification for further decreasing hypertension risk. Challenges confronting the investigation of blood pressure outcomes in response to treatment in OSA patients are discussed.

Myofascial pain of the temporomandibular joint: a review of the behavioral-relaxation therapies.

This paper reviews the behavioral-relaxation treatments of myofascial pain-dysfunction syndrome. The evidence indicates that this pain (located around the oral cavity) is due to muscle hyperactivity, most commonly of the lateral pterygoids. Research concerning relaxation techniques (i.e. progressive muscle relaxation and electromyographic feedback) has indicated the following: (a) in analogue research, normal healthy controls can learn to relax their muscles of mastication profoundly even during stress, and (b) in case reports, relaxation treatments are helpful clinical interventions, especially for pain patients who are not depressed, and who have not had the pain for more than a few years. Well controlled research is the next, essential step.

High versus low intensity acupuncture analgesia for treatment of chronic pain: effects on platelet serotonin.

The 26 chronic pain patients were tested in a baseline plus cross-over design. Half of the subjects were first treated with high intensity acupuncture; then they were treated with low intensity acupuncture. For the other 13 subjects the treatment order was reversed. In the first treatment sequence subjects reported lower pain estimates and engaging in more activities of daily living during treatment with high intensity acupuncture--but not with low intensity acupuncture. In addition, under high intensity acupuncture (i.e. with low pain levels), subjects had higher levels of platelet serotonin; this last finding is consistent with recent research which implicates central serotonin in pain control. The results of the second treatment sequence were ambiguous.

The submaximal effort tourniquet test: its use in evaluating experimental and chronic pain.

The submaximal effort tourniquet test has been widely used to evaluate experimental and chronic pain; however, there has been great variation in the manner in which the test has been applied. The present study systemitically evaluates how different levels of exercise duration and effort affect subjects' report of pain. The data indicate the following: (1) the manner in which the exercise is performed has an important effect on subjects' rating of pain, and (2) under all conditions studied, the pain ratings do not increase as a linear function of time. Both findings warrant precautions when using the submaximal effort tourniquet test to study experimental and chronic pain.

The pain profile: a computerized system for assessment of chronic pain.

A computer-based system to assess and quantify three components of the chronic pain experience is described. The system produces a Pain Profile and classification for each patient based on a mathematical comparison of the pathophysiologic, psychological and behavioral aspects of chronic pain. This computer-based evaluation assists the researcher in analyzing the relative importance of the chronic pain components and helps direct the clinician to the appropriate emphasis of therapy.

Radiofrequency thermoneurolysis of peripheral nerves for control of trigeminal neuralgia.

Radiofrequency thermoneurolysis (RFTN) was performed in the peripheral infraorbital and inferior alveolar nerves of eight patients with paroxysmal trigeminal neuralgias. Pain severity as measured by tourniquet test and global estimate was significantly reduced in seven of eight patients. The sharp, paroxysmal component of neuralgia was controlled in all seven successes although significant pain was recurring in two patients one year post-operatively. Neurosensory threshold responses to tactile-discriminative stimuli were not permanently changed from pre-lesion levels but pain detection and pain tolerance threshold responses to mechanical pin-pressure and thermal stimuli were significantly raised, suggesting that RFTN is more selective for small myelinated and unmyelinated fibers. This procedure was found to be safe, effective, simple, and predictable on the basis of diagnostic blocks. Results suggest that it is a temporary control measure which nevertheless can be repeated. It may also prove useful as a test to identify those patients who may experience anesthesia dolorosa. It is suggested for patients with toxic responses to medical therapy and as an alternative to more invasive surgeries for the long-term management of trigeminal neuralgia.

Acupuncture and chronic pain mechanisms: the moderating effects of affect, personality, and stress on response to treatment.

The present study, part of a larger project investigating neurophysiological and psychosocial factors affecting response to acupuncture for chronic pain, compares responders and non-responders to acupuncture on a series of variables assessing personality, affect and stress. Subjects were 40 patients with pain beneath the waist level longer than 6 months duration selected from the roles of the Multidisciplinary Pain Clinic. Responders, defined as 50% or more reduction in pain estimate for greater than two weeks, were found to be less depressed, less passive and overly conventional, have shorter duration of pain, endorse less frequent exposure to stressors, and have less serious non pain-related illnesses. The findings are viewed as linking the intractability of pain states with psychosocial factors which may interfere with response to somatic modes of therapy or which may interfere via alterations of tonic neurohumoral factors. The study also in seen as supporting the importance of considering psychological variables in evaluating patients for pain treatment strategies and suggests inclusion of such variables in investigating response to other modalities of treatment for chronic pain.

Acupuncture and chronic pain mechanisms.

Forty patients with chronic pain below the waist level not amenable to conventional medical and/or surgical treatment were randomly assigned to one or two different methods of acupuncture, after studying the underlying pain mechanisms using a Multidisciplinary Pain Clinic approach and the differential spinal block (DSB). One group received acupuncture needling in the classical acupuncture points referred to as meridian loci needling (MLN) and the other group received tender area needling (TAN) with needles inserted in the dermatomal distribution of the painful areas. The responses between the two groups showed no significant difference. Results were then related to the predetermined somatopsychological basis of the individual's pain problems as classified by the DSB. A group of patinets in whom pain relief occurred upon subarachnoid injection of 0.25% procaine followed by sympathetic blockade or 0.5% procaine injection followed by hypalgesia without motor loss, also reported maximum subjective improvement in their pain level following acupuncture therapy performed at a later time. The other group of patients in whom pain persisted despite sensory and motor blockade (1% procaine) responded very poorly to acupuncture therapy. DSB was found to be complimentary to acupuncture therapy in that it facilitated patient selection for the therapy.