New Diabetic Treatment by Alleviation of Autonomic Nervous System Dysfunction Measured as Periosteal Pressure Sensitivity at Sternum Improves Empowerment, Treatment Satisfaction, and Self-Reported Health of People with Type 2 Diabetes: A Randomized Trial.

Purpose: Autonomic nervous system dysfunction (ANSD), for which presently no treatment exists, has a negative impact on prognosis in people with type 2 diabetes (T2D). Periosteal pressure sensitivity (PPS) on sternum may be a measure of autonomic nervous system dysfunction (ANSD). We tested if a non-pharmacological PPS-feedback-guided treatment program based on non-noxious sensory nerve stimulation, known to reduce PPS, changed empowerment, treatment satisfaction, and quality of life in people with T2D, compared to usual treatment. Patients and Methods: Analysis of secondary endpoints in a single center, two-armed, parallel-group, observer-blinded, randomized controlled trial of individuals with T2D. Participants were randomized to non-pharmacological intervention as an add-on to treatment as usual. Endpoints were evaluated by five validated questionnaires: Diabetes specific Empowerment (DES-SF), Diabetes Treatment Satisfaction (DTSQ), quality of life (QOL) (WHO-5), clinical stress signs (CSS), and self-reported health (SF-36). Sample size calculation was based on the primary endpoint HbA1c. Results: We included 144 participants, 71 allocated to active intervention and 73 to the control group. Active intervention compared to control revealed improved diabetes-specific empowerment (p = 0.004), DTSQ (p = 0.001), and SF-36 self-reported health (p=0.003) and tended to improve quality of life (WHO-5) (p = 0.056). The findings were clinically relevant with a Cohen's effect size of 0.5 to 0.7. Conclusion: This non-pharmacological intervention, aiming to reduce PPS, and thus ANSD, improved diabetes-specific empowerment, treatment satisfaction, and self-reported health when compared to usual treatment. The proposed intervention may be a supplement to conventional treatment for T2D.

Pressure pain sensitivity: A new stress measure in children and adolescents with type 1 diabetes?

Type 1 diabetes (T1D) is associated with general- and diabetes-specific stress which has multiple adverse effects. Hence measuring stress is of great importance. An algometer measuring pressure pain sensitivity (PPS) has been shown to correlate to certain stress measures in adults. However, it has never been investigated in children and adolescents. The aim of our study was to examine associations between PPS and glycated hemoglobin (HbA1c), salivary cortisol and two questionnaires as well as to identify whether the algometer can be used as a clinical tool among children and adolescents with T1D. Eighty-three participants aged 6-18 years and diagnosed with T1D were included in this study with data from two study visits. Salivary cortisol, PPS and questionnaires were collected, measured, and answered on site. HbA1c was collected from medical files. We found correlations between PPS and HbA1c (rho = 0.35, P = 0.046), cortisol (rho = -0.25, P = 0.02) and Perceived Stress Scale (rho = -0.44, P = 0.02) in different subgroups based on age. Males scored higher in PPS than females (P < 0.001). We found PPS to be correlated to HbA1c but otherwise inconsistent in results. High PPS values indicated either measurement difficulties or hypersensibility towards pain.

In Ischemic Heart Disease, Reduced Sensitivity to Pressure at the Sternum Accompanies Lower Mortality after Five Years: Evidence from a Randomized Controlled Trial.

Background: Autonomic nervous system dysfunction (ANSD) is associated with negative prognosis of ischemic heart disease (IHD). Elevated periosteal pressure sensitivity (PPS) at the sternum relates to ANSD and sympathetic hyperactivity. Two previous observational case-control studies of the effect of reduction of PPS suggested lower all-cause mortality from IHD and stroke. We now used a specific daily, adjunct, non-pharmacological program of reduction of elevated PPS to test the hypothetical association between the intervention and reduced all-cause mortality in patients with stable IHD in a randomized controlled trial (RCT). Methods: We completed active (n = 106) and passive interventions (n = 107) and compared the five-year mortalities. We also compared the five-year individual all-cause mortality of each participant to approximately 35.000 members of the general population of Denmark. Pooling the mortality data from the active group of the RCT with the two preliminary studies, we registered the mortality following active intervention of 1.168 person-years, compared to 40 million person-years of the pooled general population. Results: We recorded fewer deaths of the active RCT intervention group than of the corresponding control group from the general population (p = 0.01), as well as of the passive RCT intervention group (p = 0.035). The meta-analysis of the three studies together demonstrated reduced 4.2-year all-cause mortality of 60% (p = 0.007). Conclusions: The test of the hypothetical effect of an intervention aimed at the attenuation of ANSD accompanied by a lowered PPS revealed reduced all-cause mortality in patients with stable IHD.

In Type 2 Diabetes Mellitus, normalization of hemoglobin A1c accompanies reduced sensitivity to pressure at the sternum.

Background: The autonomic nervous system (ANS) maintains glucose homeostasis. While higher than normal glucose levels stimulate the ANS toward reduction, previous findings suggest an association between sensitivity to, or pain from, pressure at the chest bone (pressure or pain sensitivity, PPS) and activity of the ANS. A recent randomized controlled trial (RCT) of type 2 diabetes (T2DM) suggested that addition of an experimental, non-pharmacological intervention more effectively than conventional treatment lowered the levels of both PPS and HbA1c. Materials and analyses: We tested the null hypothesis that conventional treatment (n = 60) would reveal no association between baseline HbA1c and normalization of HbA1c in 6 months, related to change of PPS. We compared the changes of HbA1c in PPS reverters who experienced a minimum reduction of 15 units of PPS and in PPS non-reverters who experienced no reduction. Depending on the result, we tested the association in a second group of participants with addition of the experimental program (n = 52). Results: In the conventional group, PPS reverters experienced normalization of HbA1c that corrected the basal increase, thus disproving the null hypothesis. With the addition of the experimental program, PPS reverters experienced similar reduction. The reduction of HbA1c among reverters averaged 0.62 mmol/mol per mmol/mol increase of baseline HbA1c (P < 0.0001 compared to non-reverters). For baseline HbA1c ≥ 64 mmol/mol, reverters averaged 22% reduction of HbA1c (P < 0.01). Conclusion: In consecutive analyses of two different populations of individuals with T2DM, we demonstrated that the higher the baseline HbA1c, the greater the reduction of HbA1c but only in individuals with a concomitant reduction of sensitivity to PPS, suggesting a homeostatic effect of the autonomic nervous system on glucose metabolism. As such, ANS function, measured as PPS, is an objective measure of HbA1c homeostasis. This observation may be of great clinical importance.

Reduction of Pressure Pain Sensitivity as Novel Non-pharmacological Therapeutic Approach to Type 2 Diabetes: A Randomized Trial.

BACKGROUND: Autonomic nervous system dysfunction (ANSD) is known to affect glucose metabolism in the mammalian body. Tradition holds that glucose homeostasis is regulated by the peripheral nervous system, and contemporary therapeutic intervention reflects this convention. OBJECTIVES: The present study tested the role of cerebral regulation of ANSD as consequence of novel understanding of glucose metabolism and treatment target in type 2 diabetes (T2D), suggested by the claim that the pressure pain sensitivity (PPS) of the chest bone periosteum may be a measure of cerebral ANSD. DESIGN: In a randomized controlled trial of 144 patients with T2D, we tested the claim that 6 months of this treatment would reduce PPS and improve peripheral glucose metabolism. RESULTS: In the active treatment group, mean glycated hemoglobin A1c (HbA1c) declined from 53.8 to 50.5 mmol/mol (intragroup p = 0.001), compared with the change from 53.8 to 53.4 mmol/mol in the control group, with the same level of diabetes treatment but not receiving the active treatment (between group p = 0.036). Mean PPS declined from 76.6 to 56.1 units (p < 0.001) in the active treatment group and from 77.5 to 72.8 units (p = 0.02; between group p < 0.001) in the control group. Changes of PPS and HbA1c were correlated (r = 0.37; p < 0.001). CONCLUSION: We conclude that the proposed approach to treatment of T2D is a potential supplement to conventional therapy. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03576430).

Chronic psychological stress seems associated with elements of the metabolic syndrome in patients with ischaemic heart disease.

BACKGROUND AND OBJECTIVES: Chronic psychological stress, the metabolic syndrome (MS) and ischaemic heart disease (IHD) seem closely connected. In this study, we evaluate the association between chronic stress and elements of MS in patients with stable IHD. DESIGN: Cross-sectional cohort study. METHODS: Three hundred and fifty patients with stable IHD were included. Chronic stress was evaluated by the two questionnaires, Major Depression Inventory (MDI) and the psychological wellbeing index WHO-5, as well as by Pressure Pain Sensitivity (PPS), a physiological measure of hyperalgesia at the sternum known to be associated to elements of the chronic stress syndrome. Elements of MS were evaluated by dual-energy X-ray absorptiometry, body weight, HOMA-IR and blood lipids. RESULTS: Depressive symptoms were associated with a high percentage of body fat (ß = 0.179, p = .001), and high level of triglycerides (ß = 0.150, p = .007). Low psychological wellbeing was associated with a high percentage of body fat (ß = -0.165, p = .002) and low level of HDL cholesterol (ß = 0.128, p = .024). Chronic stress measured by PPS was associated with a high percentage body fat (ß = 0.327, p < .001), low body weight (ß = -0.218, p < .001) and low HDL-cholesterol (ß = -0.137, p = .013). Adjusting for several life style factors did not change these results. CONCLUSIONS: In patients with stable IHD, different measures of chronic psychological stress seem associated with a high percentage of body fat and adverse blood lipids independent of several lifestyle factors.

Pressure Pain Sensitivity: Marker for Stress Affecting General Health.

OBJECTIVE: The study examined the links between pressure pain sensitivity (PPS) measured during preventive medical examination of men, their health status and occupation. METHOD: A one year (2015-2016) convenience sampling technique was used to gain primary data from actual medical examination, health records (personal and occupational history) and pressure pain sensitivity (PPS) measured by Ull Meter equipment during preventive medical examination of 371 men of different occupations (average age 43.6±10.4 years, range 19-66 years). Measured PPS values of 60 or more indicate high PPS, contrary PPS values to 40 indicate low PPS. RESULTS: 345 men (93%) were considered healthy (without diagnosis of a disease), 26 men (7%) had positive personal history/symptoms of disease. The average of measured PPS values for the whole group was 36.6±9.5 (first measurement) and 36.7±8.5 (second, repeated measurement), suggesting a high reproducibility of the measurements (r=0.80). Decreased PPS values were measured in men without reported diagnosis of a disease compared to men with diagnosed diseases. Elevated PPS values were measured in men with symptoms of neurocirculatory asthenia (NCA) compared to asymptomatic men and also to men with different diagnosis. The group of men with other than NCA symptoms did not differ significantly in PPS values compared to group of asymptomatic men. Road drivers (177 men) did not differ significantly compared to other occupations (194 men). CONCLUSION: The increased neuropsychological load/stress is connected with increased pain sensitivity to pressure. The PPS method is objective, reliable, simple, and noninvasive evaluation of the impact of stress and may be helpful in assessing medical fitness to work.

Association between pressure pain sensitivity and autonomic function as assessed by a tilt table test.

BACKGROUND: We tested the hypothesis that pressure sensitivity of the sternum (PPS) is associated with autonomic nervous system (ANS) function as assessed by tilt table test (TTT). in patients with stable ischemic heart disease. OBJECTIVES: (1) To evaluate an association between PPS and systolic blood pressure (SBP) and heart rate (HR) responses to TTT; and (2) to test the hypothesis that a reduction of resting PPS raises the PPS, SBP and HR responses to TTT response and lowers risk factors for ANS dysfunction (ANSD). METHODS: Cross-sectional study: In 361 patients with stable ischemic heart disease we measured PPS, SBP, and HR during TTT. Intervention study: We reassessed subjects with persistent stress who concluded a stress intervention trial by a second TTT. RESULTS: Cross-sectional study: Resting PPS and the PPS response to TTT were correlated (r = - 0.37). The PPS response to TTT was correlated with that of SBP (r = 0.44) and HR (r = 0.49), and with the number of risk factors for ANSD (r = - 0.21) (all p < 0.0001). Intervention study: A reduction in resting PPS was associated with an increment in PPS response to TTT (r = - 0.52, p < 0.0001). The greater this increment, the greater was the reduction in ANSD risk factors (r = - 0.23; p = 0.003). CONCLUSION: The results are consistent with the hypothesis that PPS at rest and in response to TTT reflects ANS function.

Diabetes and ischemic heart disease: double jeopardy with regard to depressive mood and reduced quality of life.

The aim of this study was to test i) whether patients having diabetes and ischemic heart disease (IHD), i.e., patients suffering from two chronic diseases, demonstrate a higher degree of chronic stress when compared with patients suffering from IHD alone, and ii) whether suffering from the two chronic diseases results in an elevation in specific elements of the chronic stress concept. A total of 361 participants with IHD were included, of whom 47 suffered from concomitant diabetes. Stress was measured by pressure pain sensitivity (PPS) and by the following questionnaires: the Major Depression Inventory (MDI), the SF-36 Quality of Life questionnaire (SF-36 QOL), the WHO-5 Well-being Index, and the clinical stress signs (CSSs) scale. Participants with diabetes and IHD had a higher MDI score, a lower SF-36 physical component summary score, and a lower score of several sub-measurements of the SF-36 mental component score when compared with patients with IHD without diabetes. No significant differences were observed regarding stress measured by the PPS measure, the WHO-5 Well-being Index, or the number of CSSs. In conclusion, the combination of diabetes and IHD seems to be associated with increased depressive symptoms, lower overall physical QOL, and reduced mental QOL on several sub-elements of the questionnaire. This should be recognized in the management of patients with double diagnoses.

The effect of daily self-measurement of pressure pain sensitivity followed by acupressure on depression and quality of life versus treatment as usual in ischemic heart disease: a randomized clinical trial.

BACKGROUND: Depressive symptoms and reduced quality of life (QOL) are parts of the chronic stress syndrome and predictive of adverse outcome in patients with ischemic heart disease (IHD). Chronic stress is associated with increased sensitivity for pain, which can be measured by algometry as Pressure Pain Sensitivity (PPS) on the sternum. AIM: To evaluate if stress focus by self-measurement of PPS, followed by stress reducing actions including acupressure, can decrease depressive symptoms and increase psychological well-being in people with stable IHD. DESIGN: Observer blinded randomized clinical trial over 3 months of either intervention or treatment as usual (TAU). STATISTICAL ANALYSIS: Intention to treat. METHODS: Two hundred and thirteen participants with IHD were included: 106 to active treatment and 107 to TAU. Drop-out: 20 and 12, respectively. The active intervention included self-measurement of PPS twice daily followed by acupressure as mandatory action, aiming at a reduction in PPS. Primary endpoint: change in depressive symptoms as measured by Major depression inventory (MDI). Other endpoints: changes in PPS, Well-being (WHO-5) and mental and physical QOL (SF-36). RESULTS: At 3 months PPS decreased 28%, to 58, in active and 11%, to 72, in TAU, p<0.001. MDI decreased 22%, to 6.5, in active group vs. 12%, to 8.3 in TAU, p = 0.040. WHO-5 increased to 71.0 and 64.8, active group and TAU, p = 0.015. SF-36 mental score sum increased to 55.3 and 53.3, active and TAU, p = 0.08. CONCLUSIONS: PPS measurements followed by acupressure reduce PPS, depressive symptoms and increase QOL in patients with stable IHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01513824.

Pressure pain sensitivity as a marker for stress and pressure pain sensitivity-guided stress management in women with primary breast cancer.

OBJECTIVES: To validate (1) Pressure Pain Sensitivity (PPS) as a marker for stress and (2) a PPS-guided intervention in women with primary Breast Cancer (BC). METHODS: (1) A total of 58 women with BC were examined before and after 6 months of intervention. A control group of 165 women office employees was divided in a High Stress Group (HSG, n = 37) and a Low Stress Group (LSG, n = 128) to evaluate the association between PPS, questionnaire-related Quality of Life (QOL) and self-evaluated stress. (2) A PPS-guided stress management program (n = 40) was compared to a Psychosocial Group Intervention (PGI, n = 91) and no treatment (n = 86) with respect to a European Organization for Research and Treatment of Cancer (EORTC) questionnaire measured QOL. RESULTS: (1) Resting PPS and changes in PPS during the intervention period correlated significantly to EORTC and Short Form 36 (SF 36) main scores: (all p < 0.05). Between BC, HSG and LSG there was a significant and positive correlation with respect to PPS, SF 36 main scores, depression, and clinical stress scores (all p < 0.05). However, the BC group scored significantly lower than both HSG and LSG (both p < 0.05) with respect to self-evaluated stress. (2) The PPS-guided intervention group improved EORTC main score, pain and nausea, when compared to the control groups (all p < 0.05). CONCLUSIONS: PPS was positively associated with QOL, which was in contrast to self-evaluated stress. PPS-guided intervention improved QOL in women with breast cancer.

The association between changes in pressure pain sensitivity and changes in cardiovascular physiological factors associated with persistent stress.

OBJECTIVES: To evaluate the possible association between pressure pain sensitivity of the chest bone (PPS) and cardiovascular physiological factors related to persistent stress in connection with a three-month PPS-guided stress-reducing experimental intervention programme. METHODS: Forty-two office workers with an elevated PPS (≥ 60 arbitrary units) as a sign of increased level of persistent stress, completed a single-blinded cluster randomized controlled trial. The active treatment was a PPS (self-measurement)-guided stress management programme. Primary endpoints: Blood pressure (BP), heart rate (HR) and work of the heart measured as Pressure-Rate-Product (PRP); Secondary endpoints: Other features of the metabolic syndrome. RESULTS: PPS decreased and changes in PPS after the intervention period were significantly associated with HR, PRP, body mass index (BMI) and visceral fat index (all correlation coefficients > 0.2, p < 0.05). Compared to the control cluster group, the active cluster group obtained a significant reduction in PPS, Low-density lipoprotein (LDL) cholesterol and total number of elevated risk factors (p < 0.05). On an individual level, significant and clinically relevant between-group reductions were observed in respect to BP, HR, PRP, total and LDL cholesterol, and total number of elevated risk factors (p < 0.05). CONCLUSIONS: The stress intervention method applied in this study induced a decrease in PPS which was associated with a clinically relevant decrease in resting blood pressure, heart rate, work of the heart and serum cholesterols.

Pressure pain sensitivity: a new method of stress measurement in patients with ischemic heart disease.

BACKGROUND: Chronic stress is prevalent in patients with ischemic heart disease (IHD) and worsens the long-term prognosis. Chronic stress is vaguely defined, but is associated with depressive symptoms, reduced psychological wellbeing, and reduced quality of life (QOL). Stress seems to induce hyperalgesia.The aim of the present study was to evaluate hyperalgesia by pressure pain sensitivity (PPS) in patients with IHD, and compare PPS to questionnaires measuring depressive symptoms, reduced psychological wellbeing, and QOL as markers of stress. Design. A cross-sectional study of 361 subjects with IHD. METHODS: PPS was measured on the sternum, and compared to the questionnaires: Clinical stress symptoms score (CSS), Major Depression Inventory (MDI), WHO-5 Wellbeing Index, and SF-36 QOL score. RESULTS: PPS correlated to CSS (r = 0.20, p < 0.001), MDI (r = 0.14, p = 0.02), SF-36 mental component summary score (MCS) (r = - 0.10, p = 0.049), SF-36 physical component summary score (PCS) (r = - 0.17, p = 0.001), and self-perceived stress level (r = 0.15, p = 0.006). CSS correlated similarly (r = 0.5-0.7, all p < 0.001). Comparing subjects within the lowest vs. highest tertiles of PPS and CSS, the mean MDI score was 4 vs. 15, WHO-5 was 77 vs. 53, SF-36 PCS was 53 vs. 43, and SF-36 MCS was 58 vs. 46; all p < 0.001. CONCLUSIONS: PPS reflected to a modest degree markers of chronic stress in IHD. PPS and CSS together might be useful as easy-to use tools for evaluating these markers in IHD patients.

The association between pressure pain sensitivity, and answers to questionnaires estimating psychological stress level in the workplace. A feasibility study.

OBJECTIVES: To examine the association between pressure pain sensitivity (PPS) at the sternum as a measure of persistent stress assessed by questionnaires in a working population. METHODS: In 308 office employees PPS measurement was compared to Quality of life questionnaires: SF-36 for general physical and mental health, the Major Depression Inventory (MDI); 50 specific clinical symptoms for persistent stress; subjective evaluation of present and long-term stress level on a 7-point ordinal scale. Repeated measures were used to validate the PPS method. RESULTS: A significant correlation between PPS and a persistent stress condition evaluated from SF-36, MDI and a number of clinical symptoms were found (all p < 0.01). Persons with PPS ≥ 60 units had an elevated health risk profile based on the questionnaires, when compared to persons with PPS ≤ 40 (all p < 0.05) (all odds ratios > 2). When categorizing a person with PPS ≥ 60 as persistently stressed (27% of subject), and using SF-36, MDI and the number of stress signs for risk calculation, the remaining 73% of the subjects, with no elevated health risk factors, were identified with an 80% specificity. During home measurements, with a full day between measurements, between-measurement correlation coefficient was 0.87 and categorization reproducibility 87% (both p < 0.001). CONCLUSIONS: In office workers, the PPS measurement correlated to several QOL questionnaires and was found useful for persistent stress screening. Validation studies demonstrated sufficient reproducibility including during self measurement at home.