Molecular and immunological origins of catatonia.

Catatonia occurs secondary to both primary psychiatric and neuromedical etiologies. Emerging evidence suggests possible linkages between causes of catatonia and neuroinflammation. These include obvious infectious and inflammatory etiologies, common neuromedical illnesses such as delirium, and psychiatric entities such as depression and autism-spectrum disorders. Symptoms of sickness behavior, thought to be a downstream effect of the cytokine response, are common in many of these etiologies and overlap significantly with symptoms of catatonia. Furthermore, there are syndromes that overlap with catatonia that some would consider variants, including neuroleptic malignant syndrome (NMS) and akinetic mutism, which may also have neuroinflammatory underpinnings. Low serum iron, a common finding in NMS and malignant catatonia, may be caused by the acute phase response. Cellular hits involving either pathogen-associated molecular patterns (PAMP) danger signals or the damage-associated molecular patterns (DAMP) danger signals of severe psychosocial stress may set the stage for a common pathway immunoactivation state that could lower the threshold for a catatonic state in susceptible individuals. Immunoactivation leading to dysfunction in the anterior cingulate cortex (ACC)/mid-cingulate cortex (MCC)/medial prefrontal cortex (mPFC)/paralimbic cortico-striato-thalamo-cortical (CSTC) circuit, involved in motivation and movement, may be particularly important in generating the motor and behavioral symptoms of catatonia.

Establishing reliability and validity for mental health screening instruments in resource-constrained settings: Systematic review of the PHQ-9 and key recommendations.

Mental illness is one of the largest contributors to the global disease burden. The importance of valid and reliable mental health measures is crucial in order to accurately measure said burden, to capture symptom improvement, and to ensure that symptoms are appropriately identified and quantified. This is of particular importance in low and middle-income countries (LMICs), where the burden of mental illness is relatively high, and there is heterogeneity in linguistic, racial, and ethnic groups. Using the PHQ-9 as an illustrative example, this systematic review aims to provide an overview of existing work and highlight common validation and reporting practices. A systematic review of published literature validating the use of the PHQ-9 in LMICs as indexed in the PubMed and PsychInfo databases was conducted. The review included n = 49 articles (reduced from n = 2,349). This manuscript summarizes these results in terms of the frequency of reporting on important procedures and in regards to the types of reliability and validity measured. Then, building off of the existing literature, we provide key recommendations for measure validation in LMICs, which can be generalized for any type of measure used in a setting in which it was not initially developed.

Catatonia in patients with anti-NMDA receptor encephalitis.

AIM: There is a lack of studies related to the frequency, phenomenology, and associated features of catatonic syndrome in patients with anti-NMDA receptor encephalitis (ANMDARE). This study aimed to measure the frequency of catatonia in this condition and to delineate its particular symptoms. METHODS: A prospective study was done with all inpatients who fulfilled the criteria of definite ANMDARE admitted to the National Institute of Neurology and Neurosurgery of Mexico from January 2014 to September 2018. The Bush-Francis Catatonia Rating Scale and Braünig Catatonia Rating Scale were administered at admission. RESULTS: Fifty-eight patients were included and catatonia was diagnosed in 41 of these patients (70.6%). Immobility, staring, mutism, and posturing were the most frequent catatonic signs. Catatonia was associated with delirium, hallucinations, psychomotor agitation, generalized electroencephalography dysfunction, and previous use of antipsychotics. Mortality was present in 10% of the total sample; it was associated with status epilepticus, and was less frequent in the catatonia group. After immunotherapy, all cases showed a complete recovery from catatonic signs. CONCLUSION: This systematic assessment of catatonic syndrome shows that it is a frequent feature in patients with ANMDARE as part of a clinical pattern that includes delirium, psychomotor agitation, and hallucinations. The lack of recognition of this pattern may be a source of diagnostic and therapeutic errors, as most physicians associate catatonia with schizophrenia and affective disorders.

Adverse obstetric and neonatal outcomes complicated by psychosis among pregnant women in the United States.

BACKGROUND: Adverse obstetric and neonatal outcomes among women with psychosis, particularly affective psychosis, has rarely been studied at the population level. We aimed to assess the risk of adverse obstetric and neonatal outcomes among women with psychosis (schizophrenia, affective psychosis, and other psychoses). METHODS: From the 2007 - 2012 National (Nationwide) Inpatient Sample, 23,507,597 delivery hospitalizations were identified. From the same hospitalization, International Classification of Diseases diagnosis codes were used to identify maternal psychosis and outcomes. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were obtained using logistic regression. RESULTS: The prevalence of psychosis at delivery was 698.76 per 100,000 hospitalizations. After adjusting for sociodemographic characteristics, smoking, alcohol/substance abuse, and pregnancy-related hypertension, women with psychosis were at a heightened risk for cesarean delivery (aOR = 1.26; 95% CI: 1.23 - 1.29), induced labor (aOR = 1.05; 95% CI: 1.02 - 1.09), antepartum hemorrhage (aOR = 1.22; 95% CI: 1.14 - 1.31), placental abruption (aOR = 1.22; 95% CI: 1.13 - 1.32), postpartum hemorrhage (aOR = 1.18; 95% CI: 1.10 - 1.27), premature delivery (aOR = 1.40; 95% CI: 1.36 - 1.46), stillbirth (aOR = 1.37; 95% CI: 1.23 - 1.53), premature rupture of membranes (aOR = 1.22; 95% CI: 1.15 - 1.29), fetal abnormalities (aOR = 1.49; 95% CI: 1.38 - 1.61), poor fetal growth (aOR = 1.26; 95% CI: 1.19 - 1.34), and fetal distress (aOR = 1.14; 95% CI: 1.10 - 1.18). Maternal death during hospitalizations (aOR = 1.00; 95% CI: 0.30 - 3.31) and excessive fetal growth (aOR = 1.06; 95% CI: 0.98 - 1.14) were not statistically significantly associated with psychosis. CONCLUSIONS: Pregnant women with psychosis have elevated risk of several adverse obstetric and neonatal outcomes. Efforts to identify and manage pregnancies complicated by psychosis may contribute to improved outcomes.

Alternative treatment strategies for catatonia: A systematic review.

BACKGROUND: Catatonia is a commonly encountered syndrome, affecting 10-20% of various psychiatric populations and carrying significant medical co-morbidities. However, there are few established alternative treatment strategies when benzodiazepines are ineffective and electroconvulsive therapy is unavailable. OBJECTIVE: The authors systematically review evidence for alternative treatment strategies for catatonia using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. METHOD: The authors conducted a search of PubMed database from 1983 to August 2016 to identify articles. Eligible reports presented cases involving treatment of catatonia using modalities other than benzodiazepines or electroconvulsive therapy. RESULTS: The authors identified 72 articles, comprising 98 individual cases. N-methyl-d-aspartate-receptor antagonists, anti-epileptic drugs, and atypical antipsychotic agents appeared to have the largest number of reports supporting their effectiveness and safety in treating catatonia patients. CONCLUSIONS: Based on the case report literature, the authors propose an updated algorithm for catatonia treatment in cases where benzodiazepines fail and electroconvulsive therapy is not available.

Opioid and Opiate Immunoregulatory Processes.

The discovery of the ability of the nervous system to communicate through "public" circuits with other systems of the body is attributed to Ernst and Berta Scharrer, who described the neurosecretory process in 1928. Indeed, the immune system has been identified as another important neuroendocrine target tissue. Opioid peptides are involved in this communication (i.e., neuroimmune) and with that of autoimmunoregulation (communication between immunocytes). The significance of opioid neuropeptide involvement with the immune system is ascertained from the presence of novel δ, µ., and κ receptors on inflammatory cells that result in modulation of cellular activity after activation, as well as the presence of specific enzymatic degradation and regulation processes. In contrast to the relatively uniform antinociceptive action of opiate and opioid signal molecules in neural tissues, the presence of naturally occurring morphine in plasma and a novel µ3 opiate-specific receptor on inflammatory cells adds to the growing knowledge that opioid and opiate signal molecules may have antagonistic actions in select tissues. In examining various disorders (e.g., human immunodeficiency virus, substance abuse, parasitism, and the diffuse inflammatory response associated with surgery) evidence has also been found for the involvement of opiate/opioid signaling in prominent mechanisms. In addition, the presence of similar mechanisms in man and organisms 500 million years divergent in evolution bespeaks the importance of this family of signal molecules. The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.

Catatonia in Neurologic and Psychiatric Patients at a Tertiary Neurological Center.

This study describes the prevalence, phenomenology, treatment, and outcome of neurological patients and psychiatric patients with catatonia at a tertiary neurological center. Clinical variables included nosological diagnoses and complications. Admission length and days with catatonia were used as outcome measures. Of 2,044 patients who were evaluated prospectively, 68 (3.32%) had catatonia, 42 (61.7%) were neurological patients, 19 (27.9%) were psychiatric patients, and 7 (10.2%) had drug-related diagnoses. Of all patients, the ratio of neurological to psychiatric patients was 3:1. Encephalitis was the most common diagnosis (N=26 [38.2%]), followed by schizophrenia (N=12 [17.6%]). Psychiatric patients exhibited a stuporous type of catatonia (15 [83.3%] versus 14 [33.3%], p>0.001), whereas neurological patients exhibited a mixed form of catatonia (25 [59.5%] versus 1 [5.6], p<0.001). Neurological patients had more complications, longer hospitalizations, and more days with catatonia. A total of 56 patients (82.3%) received lorazepam, and 14 patients (20.5%) underwent ECT. Second- and third-line treatments included amantadine, bromocriptine, and levodopa. Catatonia is a prevalent syndrome that can remit with proper and opportune treatment.

Standardised mindfulness-based interventions in healthcare: an overview of systematic reviews and meta-analyses of RCTs.

BACKGROUND: Mindfulness-based therapies are being used in a wide range of common chronic conditions in both treatment and prevention despite lack of consensus about their effectiveness in different patient categories. OBJECTIVE: To systematically review the evidence of effectiveness MBSR and MBCT in different patient categories. METHODS: A systematic review and meta-analysis of systematic reviews of RCTs, using the standardized MBSR or MBCT programs. We used PRISMA guidelines to assess the quality of the included reviews and performed a random effects meta-analysis with main outcome measure Cohen's d. All types of participants were considered. RESULTS: The search produced 187 reviews: 23 were included, covering 115 unique RCTs and 8,683 unique individuals with various conditions. Compared to wait list control and compared to treatment as usual, MBSR and MBCT significantly improved depressive symptoms (d=0.37; 95%CI 0.28 to 0.45, based on 5 reviews, N=2814), anxiety (d=0.49; 95%CI 0.37 to 0.61, based on 4 reviews, N=2525), stress (d=0.51; 95%CI 0.36 to 0.67, based on 2 reviews, N=1570), quality of life (d=0.39; 95%CI 0.08 to 0.70, based on 2 reviews, N=511) and physical functioning (d=0.27; 95%CI 0.12 to 0.42, based on 3 reviews, N=1015). Limitations include heterogeneity within patient categories, risk of publication bias and limited long-term follow-up in several studies. CONCLUSION: The evidence supports the use of MBSR and MBCT to alleviate symptoms, both mental and physical, in the adjunct treatment of cancer, cardiovascular disease, chronic pain, depression, anxiety disorders and in prevention in healthy adults and children.

Catatonia in resource-limited settings: a case series and treatment protocol.

OBJECTIVE: The catatonic syndrome ("catatonia") is characterized by motor and motivation dysregulation and is associated with a number of neuropsychiatric and medical disorders. It is recognizable in a variety of clinical settings. We present observations from the treatment of four individuals with catatonia in Haiti and Rwanda and introduce a treatment protocol for use in resource-limited settings. METHODS: Four patients from rural Haiti and Rwanda with clinical signs of catatonia and a positive screen using the Bush-Francis Catatonia Rating Scale were treated collaboratively by general physicians and mental health clinicians with either lorazepam or diazepam. Success in treatment was clinically assessed by complete remittance of catatonia symptoms. RESULTS: The four patients in this report exhibited a range of characteristic and recognizable signs of catatonia, including immobility/stupor, stereotypic movements, echophenomena, posturing, odd mannerisms, mutism and refusal to eat or drink. All four cases presented initially to rural outpatient general health services in resource-limited settings. In some cases, diagnostic uncertainty initially led to treatment with typical antipsychotics. In each case, proper identification and treatment of catatonia with benzodiazepines led to significant clinical improvement. CONCLUSION: Catatonia can be effectively and inexpensively treated in resource-limited settings. Identification and management of catatonia are critical for the health and safety of patients with this syndrome. Familiarity with the clinical features of catatonia is essential for health professionals working in any setting. To facilitate early recognition of this treatable disorder, catatonia should feature more prominently in global mental health discourse.

Chronic variable stress activates hematopoietic stem cells.

Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the ß3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.

Low degree of formal education and musical experience predict degree of music-induced stress reduction in relatives and friends of patients: a single-center, randomized controlled trial.

OBJECTIVE: To determine the factors that may predict music-induced relaxation in friends and family of patients in the emergency department. BACKGROUND: It remains unclear to date which demographic and experiential factors predict the effectiveness of music-induced relaxation. Furthermore, in-hospital stressors for friends and family of patients rather than patients themselves are underresearched and deserve in-depth investigation to improve this group's experience in health care environments. METHODS: A total of 169 relatives and friends of patients in the emergency department-waiting area completed a series of questionnaires, including the Spielberger State-Trait Anxiety Inventory (STAI), the Music Experience Questionnaire (MEQ), and a demographic survey. They were then randomly assigned to either Case Group (1 hour in the waiting area with classical music in the background) or Control Group (1 hour with no music) before completing a second, identical copy of the STAI to measure change from baseline. Data were analyzed for associations between music intervention, change in STAI scores, MEQ scores, and demographic characteristics. RESULTS: Participants who underwent the music intervention experienced a 9.8% decrease in overall mean State Anxiety, whereas those in the Control Group experienced no change over time (P = 0.001). Higher education significantly inversely correlated with the effectiveness of music intervention: participants with no formal education beyond high school showed a greater overall mean decrease in State Anxiety than those with a college education or beyond in response to classical music (P = 0.006). Furthermore, MEQ scores indicated that the Social Uplift scale (a measure of one's tendency to be uplifted in a group-oriented manner by music) was highly predictive of the effectiveness of music intervention. CONCLUSIONS: Music is an effective and inexpensive means of reducing anxiety in friends and family of patients, who are underresearched in medicine. Moreover, low educational attainment and tendency to respond positively to music in a group setting can predict the effectiveness of music-induced relaxation.

Westphal variant Huntington disease and refractory catatonia: a case report.

A young woman with Westphal variant (juvenile) Huntington disease (HD) also developed catatonia. Catatonia is an underdiagnosed psychomotor syndrome often associated with neurological and psychiatric disorders, but it has rarely been documented in patients with HD. Catatonia usually responds to standard treatment with benzodiazepines and electroconvulsive therapy; however, this patient's catatonic syndrome did not improve until we augmented the standard treatment with amantadine and levodopa. The underlying pathophysiology and a neurochemical hypothesis of HD and catatonia can explain their comorbidity and the refractoriness of catatonia to treatment. Both conditions are linked to dysregulation of neurotransmitters in the striatocortical and corticocortical pathways. This understanding may serve as a guide for the use of nonstandard treatments. Our evidence also suggests that electroconvulsive therapy can be useful and safe in the treatment of HD.

Screening for major depression in post-myocardial infarction patients: operating characteristics of the Beck Depression Inventory-II.

OBJECTIVE: To assess the operating characteristics of the Beck-Depression Inventory-II (BDI-II) and the BDI-II cognitive subscale (BDI-II-cog) in screening for major depression (MDD) in post-myocardial infarction (MI) patients. METHODS: Between October 2003 and July 2005, 131 post-MI patients admitted to an urban academic medical center completed the BDI-II and a semi-structured interview for depression within 72 hours of symptom onset. Sensitivity, specificity, positive and negative predictive values, overall correct classification, and likelihood ratios for various cutoff values on both scales were evaluated by comparing scores to interview diagnosis of MDD. Receiver-operator curves (ROC) were also calculated and area under the curve (AUC) measured. RESULTS: The optimal cutoff value for the BDI-II was > or = 16, with a sensitivity of 88.2% and a specificity of 92.1%. Cutoff values of > or = 3 or > or = 4 were both acceptable for the BDI-II-cog (sensitivity = 88.2% and 82.4%, respectively; specificity = 81.6% and 88.6 %, respectively). AUC was 0.96 for the BDI-II and 0.89 for the cognitive subscale. CONCLUSIONS: Effective depression screening is important in post-MI patients because of depression's independent association with morbidity and mortality following MI. Our results suggest that the BDI-II and its cognitive subscale are effective tools for screening for MDD in post-MI patients.

Detection of depression in cardiac inpatients: feasibility and results of systematic screening.

BACKGROUND: A recent American Heart Association (AHA) Prevention Committee report recommended depression screening of all coronary heart disease patients using 2- and 9-item instruments from the Patient Health Questionnaire (PHQ-2 and PHQ-9) to identify patients who may need further assessment and treatment. Our objective was to assess the feasibility and results of such screening on inpatient cardiac units. METHODS: In September 2007, the PHQ-2 was added to the nursing interview dataset on 3 cardiac units in a general hospital; this screen was completed as part of routine clinical care. Rates and results of depression screening, reasons for patients not being screened, and results of a nursing satisfaction survey were tabulated, and differences in baseline characteristics between screened and unscreened patients were analyzed via chi(2) and independent-samples t tests. RESULTS: For a 12-month period, 4,783 patients were admitted to the cardiac units; 3,504 (73.3%) received PHQ-2 depression screening. Approximately 9% of screened patients had a PHQ-2 score > or =3 and were approached for further depression evaluation (PHQ-9) by a social worker; 74.1% of the positive-screen patients had a PHQ-9 score of > or =10, suggestive of major depression. Nurses (n = 66) reported high satisfaction with the screening process, and mean reported PHQ-2 screening time was 1.4 (+/-1.1) minutes. CONCLUSIONS: Systematic depression screening of cardiac patients using methods outlined by the AHA Prevention Committee is feasible, well-accepted, and does not appear markedly resource-intensive. Future studies should link these methods to an efficient and effective program of depression management in this vulnerable population.

Using the differential from complete blood counts as a biomarker of fatigue in advanced non-small-cell lung cancer: an exploratory analysis.

OBJECTIVE: Fatigue is currently recognized as an undertreated symptom in cancer. To date the association between fatigue and inflammatory activation has not been examined in patients with advanced cancer. Our exploratory investigation considered whether variations in routinely available hematological parameters relate to the severity of fatigue reports. METHODS: Fatigue, white blood cell differential, and hemoglobin concentration were assessed in 44 Stage IIIb and IV non-small-cell lung cancer (NSCLC) patients. Days of survival and the relative timing of treatment discontinuation were also recorded. Relationships between fatigue intensity and length of survival and between fatigue and hematological variables were examined using binomial and linear regressions respectively. RESULTS: When we controlled for effects related to age, gender, and time until treatment termination, more intense fatigue was associated with shorter survival (beta = -.34, p = .03). Lower hemoglobin concentrations were associated with more intense fatigue (beta = -.36, p = .04). When we controlled for the effect attributable to hemoglobin, higher neutrophil (beta = .43, p = .01) and monocyte (beta = .31, p = .05) concentrations were associated with reports of more severe fatigue. SIGNIFICANCE OF RESULTS: This exploratory study provides empiric data showing that the severity of fatigue reported by advanced-stage NSCLC patients is significantly associated with length of survival. Consistent with existing data, linear regression identified a negative association between fatigue intensity and hemoglobin concentration. When we controlled for this effect, further linear regressions identified significant relationships between fatigue and blood concentrations of neutrophils and monocytes. Further, the magnitude of relationship between myeloid cell concentrations and fatigue was similar to the effect size identified for the relationship between hemoglobin and fatigue. Thus, the indirect measure of inflammatory state provided by routinely assessed myeloid cell counts appears to play as strong a role as the established variable, hemoglobin, in accounting for the fatigue reported by this sample of advanced-stage lung cancer patients.

Successful implementation of an alcohol-withdrawal pathway in a general hospital.

BACKGROUND: Although alcohol use and abuse are common among general-hospital inpatients, many patients are inadequately assessed and treated for alcohol withdrawal. OBJECTIVE: The purpose of this study was to determine whether the implementation of a clinical pathway for the treatment of alcohol withdrawal in medical inpatients would result in improvements in clinical practice and patient outcomes. METHOD: Authors retrospectively reviewed 80 patient records (including 40 of those treated before the implementation of a pathway and 40 of those treated after pathway implementation). RESULTS: Assessment procedures and ordering patterns of physicians (medical house staff and staff physicians) shifted in a fashion consistent with the new treatment guidelines. Patient outcomes (e.g., length of stay and the incidence of delirium) improved for those patients who received benzodiazepines within the range of the pathway guidelines. CONCLUSIONS: Timely assessment and staff education can shift prescription patterns, increase patient monitoring, and reduce costs associated with alcohol withdrawal.

Encephalitis and catatonia treated with ECT.

OBJECTIVE: To describe 2 cases of encephalitis with neuropsychiatric symptoms including catatonia, compounded by neuroleptic use for delirious agitation culminating in malignant catatonia responsive to electroconvulsive therapy (ECT). BACKGROUND: Neuropsychiatric symptoms including catatonia can be manifestations of limbic encephalitis and encephalitides of unidentified etiology, including encephalitis lethargica. Catatonic features are often difficult to appraise in this context. This can easily lead to the use of neuroleptics, which may precipitate worsening of catatonia. METHOD: Medical, neurologic, and psychiatric histories, physical examination findings, results of laboratory, imaging and neurophysiologic investigations, and treatment response with medications and ECT were recorded. RESULTS: Both patients showed significant improvement with ECT. CONCLUSIONS: Malignant catatonia can complicate encephalitis lethargica and idiopathic limbic encephalitis, which already carry high mortality rates. When neuroleptics are used for agitation in cases of encephalitis, physicians must be wary of precipitating malignant catatonia and neuroleptics should be discontinued when such a danger emerges. Although lorazepam is helpful in treating catatonia, it may not suffice, as in the cases presented. ECT deserves serious consideration early in the course of malignant catatonia and for catatonia nested in encephalopathy secondary to encephalitis, unresolved with lorazepam.

Nicotine, alcohol and cocaine coupling to reward processes via endogenous morphine signaling: the dopamine-morphine hypothesis.

Pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, nicotine, cocaine and alcohol appear to exert their pleasure providing action via endogenous morphinergic mechanisms. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways, now, in part, via endogenous morphine processes.