Comorbidity between pain and mental illness - Evidence of a bidirectional relationship.

BACKGROUND: Pain from various locations in the body and mental illness are common and the comorbidity between the two is well-known although the temporal relationship remains to be determined. Our aim was to follow patients over time to study if pain (here dorsalgia/abdominal pain) or fibromyalgia lead to an increased risk of developing mental illness (here depression/anxiety) and/or the reverse, that is whether patients with mental illness have an increased risk to develop pain or fibromyalgia, compared to the rest of the population. METHODS: This prospective cohort study used the Skåne Healthcare Register, covering all care in the region of Skåne, southern Sweden (population ~1.3 million). The cohort included healthcare consultations in primary care, outpatient specialized care and inpatient care between 2007 and 2016 for all patients without prior registered diagnosis of mental illness or pain, aged 18 or older (n = 504,365). RESULTS: The incidence rate ratio (IRR) for developing mental illness after pain was 2.18 (95% CI = 2.14-2.22) compared to without pain. IRR for developing pain after mental illness was 2.02 (95% CI = 1.98-2.06) compared to without mental illness. Corresponding IRR for developing mental illness after fibromyalgia was 4.05 (95% CI = 3.58-4.59) and for developing fibromyalgia after mental illness 5.54 (95% CI = 4.99-6.16). CONCLUSIONS: This study shows a bidirectional influence of similar magnitude of pain and mental illness, respectively. In monitoring patients with pain or mental illness, a focus on both conditions is thus important to develop appropriate, targeted interventions and may increase the likelihood of improved outcomes. SIGNIFICANCE: We followed a population-based cohort over a period of 10 years, including incident cases of both exposure and outcome and found a bidirectional relationship between pain and mental illness. Clinicians need to pay attention on both conditions, in patients seeking care due to mental illness or pain.

Diurnal variation of flow-mediated vasodilation in healthy premenopausal women.

The present study was designed to test the hypothesis of a diurnal variation of endothelial function. Sixteen healthy, nonsmoking women were studied, each on four occasions during one 24-h period (2:00 PM, 8:00 PM, 2:00 AM, and 8:00 AM). Endothelial function was assessed by ultrasound determinations of flow-mediated vasodilation (FMD%) in the brachial artery. FMD% was contrasted with endothelium-independent vasodilation, i.e., nitroglycerine-induced vasodilation (NTG%). Additionally, plasma concentrations and urinary excretion of nitrate and cGMP were analyzed. FMD% and NTG% displayed diurnal, albeit not parallel, patterns of variation. Whereas FMD% gradually increased from 2:00 PM and peaked at 2:00 AM (means +/- SE: 3.1 +/- 0.4, 4.4 +/- 0.4, 5.1 +/- 0.9, and 3.9 +/- 0.8%), the NTG% demonstrated a nadir at 2:00 AM. Plasma levels and urinary excretion of nitrate and cGMP did not display diurnal variation and no clear association with the variations seen in FMD% and NTG%. This study demonstrates a diurnal variation in both endothelium-dependent and -independent vasodilation in the brachial artery of healthy women. The background and possible implication of such a variation require further studies.

Intrathecal release of nitric oxide in Alzheimer's disease and vascular dementia.

A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of brain damage in dementia. We have recently demonstrated that patients with Alzheimer's disease (AD) and vascular dementia (VaD) display an intrathecal production of proinflammatory cytokines. TNF-alpha, one of these cytokines, leads to the production of nitric oxide (NO), a potent inflammatory mediator, by induction of inducible NO synthase. The aim of the present study was to investigate the intrathecal levels of nitrate, one of the main metabolites of NO, and to relate its levels to the degree of intellectual impairment, in patients with AD and VaD. Twenty patients with early AD and 26 patients with VaD were analyzed with respect to cerebrospinal fluid levels of nitrate by gas chromatography/mass spectrometry. Interestingly, in patients with AD but not VaD, the intrathecal levels of nitrate were significantly and inversely correlated (r = -0.68, p = 0.002) to the degree of intellectual impairment. Our study demonstrates an inverse correlation between the intrathecal levels of nitrate and the degree of cognitive impairment in patients with AD, suggesting a neuroprotective effect of NO in AD.

Intrathecal release of nitric oxide and its relation to final brain damage in patients with stroke.

The potential role of inflammatory mechanisms in the pathophysiology of ischemic brain damage has intensely been discussed. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines early after onset of symptoms. IL-1beta, one of these cytokines, stimulates the production of nitric oxide (NO), a potent inflammatory mediator. The aim of the present study was to investigate the intrathecal levels of nitrate, one of the main metabolites of NO in acute stroke and to relate its levels to brain damage. Stroke patients were prospectively studied with clinical evaluation, radiological assessment and analysis of intrathecal levels of nitrate by gas chromatography/mass spectrometry. In addition, simultaneous analyses of cytokines and of soluble Fas/APO-1 and bcl-2, two proteins regulating apoptosis, were performed. The intrathecal levels of nitrate were not significantly different in stroke patients compared to controls throughout the observation period. However, the intrathecal levels of nitrate increased significantly 3 months after stroke onset compared with the first 3 days. Interestingly, the levels of nitrate measured at stroke onset were negatively correlated to the final size of infarct volume (r = -0.69, p < 0.05) measured by MRI. In addition, patients with large infarcts displayed significantly (p = 0.008) lower levels of nitrate in cerebrospinal fluid compared to patients with small infarcts during the first 3 days after stroke onset. In contrast, the intrathecal levels of nitrate were significantly positively correlated (r = 0.79, p < 0. 001) to the neurological deficit and negatively correlated (r = -0. 76, p < 0.05) to bcl-2, a protein downregulating neuronal apoptosis, in the late stage of the stroke. Early NO production is associated with a smaller infarct volume, suggesting a protective effect, whereas late NO production is associated with severer neurological deficits, suggesting a neurotoxic effect. Treatment trials pertaining to modulate NO production in stroke should take into consideration the dual effect of NO on ischemic brain damage.

Exhaled oral and nasal nitric oxide during L-arginine infusion in preeclampsia.

OBJECTIVE: To determine the effects of the nitric oxide (NO) precursor L-arginine on the airway NO concentration in patients with preeclampsia. METHODS: NO was measured by a noninvasive chemiluminescence technique in air sampled directly from nasal and oral cavities during expiration before and during L-arginine infusion in 9 preeclamptic and 10 control pregnancies. Maternal blood pressure and heart rate were simultaneously recorded, and blood was sampled for analyses of cyclic guanosine monophosphate (cGMP) and nitrate. RESULTS: Basal nasal and orally exhaled NO and the increment in nasal NO concentration during L-arginine infusion were similar in both groups. Basal plasma and platelet cGMP concentrations were similar in both groups. Following L-arginine infusion, plasma cGMP levels were significantly higher in preeclamptics (p < 0.01), while platelet cGMP was unaffected in both groups. Basal plasma nitrate was significantly higher in preeclamptics (p < 0.01), and this difference was not altered following infusion. Blood pressure and heart rate remained unaffected by the procedure in both groups. CONCLUSIONS: Blood pressure did not decrease in the preeclamptics following L-arginine infusion, despite a significant increase in nasal NO sampled during breathhold and a concomitant increase in plasma cGMP, possibly reflecting an endogenous NO production. These results do not support the idea of a generalized decrease in NO production being a major cause of hypertension in preeclampsia.

Whole-body cooling increases plasma endothelin-1 levels in women with primary Raynaud's phenomenon.

To understand better the role of endothelin-1 (ET-1) in the pathogenesis of primary Raynaud's phenomenon (PRP), we investigated the basal ET-1 plasma levels and changes after whole-body cooling in healthy women and those with PRP. The study was performed as an open parallel-group comparison during the month of February. The Raynaud group included 21 female patients (mean age 45.3 years, range 21-57 years) who had had disabling Raynaud's phenomenon for a mean period of 17 years (range 2-26 years). The control group consisted of 25 healthy women (mean age 43.6 years, range 27-56 years). Plasma levels of ET-1 were measured on two separate occasions: once after 30 min of rest at room temperature and after 40 min of whole-body cooling. There were no significant differences in baseline plasma ET-1 levels between the two groups of women. The plasma ET-1 levels increased significantly in the PRP group after cold exposure (mean difference 0.11 pmol l-1, 95% CI 0.005-0.214, P = 0.012). In contrast, the levels of plasma ET-1 in the control group did not change significantly after cold provocation. In conclusion, no differences in plasma basal levels of ET-1 were observed between the two groups. However, women suffering from Raynaud's phenomenon responded with a slight but significant elevation in plasma levels of ET-1 after whole-body cooling, whereas the healthy control subjects did not. The results from the present study confirm previous observations that endothelial dysfunction may be of aetiological importance in PRP.

Non-invasive investigation of endothelium-dependent dilatation of the brachial artery in women with primary Raynaud's phenomenon.

1. Primary Raynaud's phenomenon is characterized by white fingers and toes with impaired perfusion in response to cold or emotional stress. The aetiology has not been clarified. In previous studies we have demonstrated a season-linked inability in women with primary Raynaud's phenomenon to raise their plasma cGMP levels in response to whole-body cooling, suggesting a dysfunction of the L-arginine-NO-cGMP pathway. To further elucidate the possibility of such a defect in patients with primary Raynaud's phenomenon, we determined flow-mediated dilatation of the brachial artery. 2. Twenty-two premenopausal, non-smoking women with primary Raynaud's phenomenon (mean age 39 +/- 8 years) and 23 healthy controls (mean age 41 +/- 7 years) were studied during two winter weeks. The diameter of the right arm brachial artery was measured by high resolution ultrasonography, at rest and during reactive hyperaemia. The investigation was conducted both with the participants at rest at room temperature and after 40 min of whole-body cooling. 3. Both study groups showed a marked attenuation of flow-mediated dilatation during whole-body cooling, which could partly but not solely be explained by a decreased shear rate. There was, however, no significant difference in flow-mediated diameter (D) increase (% flow-mediated dilatation; delta D/D x 100) between primary Raynaud's phenomenon and controls, either at room temperature (7.8 +/- 0.8 and 9.0 +/- 0.8) or in response to whole-body cooling (3.8 +/- 1.2 and 4.4 +/- 0.7). 4. Thus, whole-body cooling markedly impairs flow-mediated dilatation in women. Flow-mediated dilatation is, however, not decreased in women with primary Raynaud's phenomenon at room temperature or during whole-body cooling, indicating that this particular aspect of endothelial function is not impaired in this setting.

Seasonal variations in cyclic GMP response on whole-body cooling in women with primary Raynaud's phenomenon.

1. Primary Raynaud's phenomenon (PRP) is characterized by increased vasoconstrictor tone that develops during exposure to cold. The symptoms are most pronounced during the winter months with low outdoor temperature. The L-arginine-nitric oxide (NO)-cyclic GMP (cGMP) pathway plays an important role in counteracting vasospasm. The aim of the present study was to investigate if the venous cGMP response to whole-body cooling in women with PRP varied with the season of the year. 2. The study was performed as an open parallel-group comparison between women with PRP and healthy female controls during the winter months of February 1994 and 1995 and in the summer month of August 1994. Blood samples were drawn just before and 40 min after whole-body cooling. 3. There were no significant changes in venous cGMP after whole-body cooling in women with PRP during the winter months of February 1994 and 1995. Cold exposure in the summer month of August resulted, however, in a significant increase in venous cGMP (P < 0.01). In contrast, the healthy women responded with a significant increase in venous cGMP on all three test occasions: February 1994 (P < 0.05), August 1994 (P < 0.05) and February 1995 (P < 0.01), 4. A seasonal variation in venous cGMP response to whole-body cooling was observed only in women with PRP. Healthy women responded to cold exposure with an increase in venous cGMP during summer and winter, whereas females with PRP showed an increase only during summer. Results from the present study might indicate seasonal variation in the regulation of constitutive nitric oxide synthetase in women with PRP, which may contribute to new therapeutic approaches.

Plasma nitric oxide metabolite in women with primary Raynaud's phenomenon and in healthy subjects.

Primary Raynaud's phenomenon (PRP) is characterized by cold- or stress-induced transient attacks of impaired skin circulation in fingers and/or toes. PRP displays seasonal variation with less severe symptoms in the summer. The aetiology has not been clarified. The aims of the present study were (a) to assess the influence of cold exposure on the plasma levels of the nitric oxide (NO) metabolite, nitrate, in patients with PRP and in healthy control subjects; and (b) to investigate whether there is a seasonal variation in these plasma levels. In a group of women with PRP and matched control subjects, venous blood was sampled before and at the end of a 40-min period of whole-body cooling. The study was performed with the same protocol on two occasions; once in the winter and once in the summer. A seasonal variation was detected with higher plasma levels of nitrate in the winter than in the summer, both in PRP and in control subjects. However, the plasma level of nitrate was not changed in response to cold exposure on any occasion, either in the patient or in the control group. Our study indicates that NO formation is up-regulated in response to cold weather in both study groups. However, NO formation does not seem to be increased in response to whole-body cooling, either in PRP patients or in healthy subjects. Further investigations are required to reveal whether the observed seasonal variation in NO formation is a universal phenomenon in man.

Cold exposure increases cyclic guanosine monophosphate in healthy women but not in women with Raynaud's phenomenon.

OBJECTIVE: To investigate influence of whole-body cooling on cyclic GMP (cGMP) in women with Raynaud's phenomenon and in healthy women. DESIGN: The study was performed as an open, parallel-group comparison between women with Raynaud's phenomenon and healthy women during the winter month of February. SETTING: The municipality of Västerås (Sweden). PARTICIPANTS: The Raynaud group comprised 24 female patients. The control group consisted of 21 healthy females. MAIN OUTCOME MEASURE: The venous levels of cGMP were measured on three different occasions: just before and after 40 min of whole-body cooling and after 20 min rest at room temperature (21 degrees C). RESULTS: Venous cGMP increased significantly in the control group after cold exposure (mean difference 0.43 pmol mL-1; 95% CI, 0.018-0.848; t = 2.18; df = 20; P = 0.02) and remained at a high level after 20 min rest (mean difference 0.58 pmol mL-1; 95% CI, 0.063-1.108; t = 2.34; df = 20; P = 0.015). In contrast, the levels of venous cGMP in the Raynaud group did not change significantly. The difference in increase between the two groups was significant (P < 0.02). The diastolic blood pressure in the Raynaud group increased after 40 min of whole-body cooling and was still significantly increased (P < 0.001) after 20 min rest at room temperature (21 degrees C). CONCLUSION: These results indicate that women suffering from Raynaud's phenomenon lack the physiological response of cGMP to cold exposure, which may explain their increased vasospastic response.