Medical App Treatment of Non-Specific Low Back Pain in the 12-month Cluster-Randomized Controlled Trial Rise-uP: Where Clinical Superiority Meets Cost Savings.

Purpose: Non-specific low back pain (NLBP) exerts a profound impact on global health and economics. In the era of Web 3.0, digital therapeutics offer the potential to improve NLBP management. The Rise-uP trial introduces a digitally anchored, general practitioner (GP)-focused back pain management approach with the Kaia back pain app as the key intervention. Here, we present the 12-months evaluation of the Rise-uP trial including clinical and economic outcomes, patient satisfaction and behavioral tracking analysis. Methods: The cluster-randomized controlled study (registration number: DRKS00015048) enrolled 1237 patients, with 930 receiving treatment according to the Rise-uP approach and 307 subjected to standard of care treatment. Assessments of pain, psychological state, functional capacity, and well-being (patient-reported outcome measures; PROMs) were collected at baseline, and at 3-, 6-, and 12-months follow-up intervals. Health insurance partners AOK, DAK, and BARMER provided individual healthcare cost data. An artificial intelligence (AI)-driven behavioral tracking analysis identified distinct app usage clusters that presented all with about the same clinical outcome. Patient satisfaction (patient-reported experience measures; PREMs) was captured at the end of the trial. Results: Intention-to-treat (ITT) analysis demonstrated that the Rise-uP group experienced significantly greater pain reduction at 12 months compared to the control group (IG: -46% vs CG: -24%; p < 0.001) with only the Rise-uP group achieving a pain reduction that was clinically meaningful. Improvements in all other PROMs were notably superior in patients of the Rise-uP group. The AI analysis of app usage discerned four usage clusters. Short- to long-term usage, all produced about the same level of pain reduction. Cost-effectiveness analysis indicated a substantial economic benefit for Rise-uP. Conclusion: The Rise-uP approach with a medical multimodal back pain app as the central element of digital treatment demonstrates both, clinical and economic superiority compared to standard of care in the management of NLBP.

[Attitudes toward digital tools in pain medicine : Survey of German Pain Society health professional members and members of self-help groups]. / Einstellung zur digitalen Medizin im Schmerzbereich : Eine Umfrage unter Ärzten und Patienten der Deutschen Schmerzgesellschaft und Patientenorganisationen.

Digital medicine has increasing influence on the German healthcare system. In times of social distancing during the ongoing coronavirus disease 2019 (COVID-19) pandemic, digital tools enable health professionals to maintain medical care. Furthermore, digital elements have potential to provide effective guideline-oriented treatment to a broad range of patients independently from location and time. This survey was used to assess the attitudes of members of the German Pain Society (health professionals) and of associated self-help groups (patients) towards digital medicine. It was sent out as an online survey to health professionals in September 2020 and to patients in February 2021. The survey referred especially to present usage, attitude and potential concerns regarding particular digital elements. Furthermore, technical affinity was assessed. In total, 250 health professionals and 154 patients participated in the survey. The results show that-although digital elements are already known-a substantial proportion of health professionals still lack broad transfer to regular treatment. The potential of digital tools seems to be recognized by both groups; interestingly, patients consider digital medicine as more useful than health professionals. Nevertheless, concerns about for example data security or digital competence remain in both groups. Taken together, our results indicate that disruptive changes, as the implementation of digital medicine in the healthcare system, have to be guided by intense education and channeled by political policies in order to successfully integrate digital elements into medicine on a long-term basis. This would be in favor for all involved parties and is demanded especially by patients.

Migraine attacks as a result of hypothalamic loss of control.

Migraine is a complex neurological disorder affecting approximately 12% of the population. The pathophysiology is not yet fully understood, however the clinical features of the disease, such as the cyclic behaviour of attacks and vegetative symptoms, suggest a prominent role of the hypothalamus. Previous research has observed neuronal alterations at different time points during the migraine interval, specifically just before the headache is initiated. We therefore aimed to assess the trajectory of migraineurs' brain activity over an entire migraine cycle. Using functional magnetic resonance imaging (fMRI) with pseudo-continuous arterial spin labelling (ASL), we designed a longitudinal intra-individual study to detect the rhythmicity of (1) the cerebral perfusion and (2) the hypothalamic connectivity over an entire migraine cycle. Twelve episodic migraine patients were examined in 82 sessions during spontaneous headache attacks with follow-up recordings towards the next attack. We detected cyclic changes of brain perfusion in the limbic circuit (insula and nucleus accumbens), with the highest perfusion during the headache attack. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval towards the attack, then collapsing during the headache phase. The present data provide strong evidence for the predominant role of the hypothalamus in generating migraine attacks. Due to a genetically-determined cortical hyperexcitability, migraineurs are most likely characterised by an increased susceptibility of limbic neurons to the known migraine trigger. The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system. Repetitive psychosocial stress, one of the leading trigger factors reported by patients, might make the limbic system even more vulnerable and lead to a premature triggering of a migraine attack. Potential therapeutic interventions are therefore suggested to strengthen limbic circuits with dedicated medication or psychological approaches.

Digital Treatment of Back Pain versus Standard of Care: The Cluster-Randomized Controlled Trial, Rise-uP.

PURPOSE: Non-specific low back pain (NLBP) causes an enormous burden to patients and tremendous costs for health care systems worldwide. Frequently, treatments are not oriented to existing guidelines. In the future, digital elements may be promising tools to support guideline-oriented treatment in a broader range of patients. The cluster-randomized controlled "Rise-uP" trial aims to support a General Practitioner (GP)-centered back pain treatment (Registration No: DRKS00015048) and includes the following digital elements: 1) electronic case report form (eCRF), 2) a treatment algorithm for guideline-based clinical decision making of GPs, 3) teleconsultation between GPs and pain specialists for patients at risk for development of chronic back pain, and 4) a multidisciplinary mobile back pain app for all patients (Kaia App). METHODS: In the Rise-uP trial, 111 GPs throughout Bavaria (southern Germany) were randomized either to the Rise-uP intervention group (IG) or the control group (CG). Rise-uP patients were treated according to the guideline-oriented Rise-uP treatment algorithm. Standard of care was applied to the CG patients with consideration given to the "National guideline for the treatment of non-specific back pain". Pain rating on the numeric rating scale was the primary outcome measure. Psychological measures (anxiety, depression, stress), functional ability, as well as physical and mental wellbeing, served as secondary outcomes. All values were assessed at the beginning of the treatment and at 3-month follow-ups. RESULTS: In total, 1245 patients (IG: 933; CG: 312) with NLBP were included in the study. The Rise-uP group showed a significantly stronger pain reduction compared to the control group after 3 months (IG: M=-33.3% vs CG: M=-14.3%). The Rise-uP group was also superior in secondary outcomes. Furthermore, high-risk patients who received a teleconsultation showed a larger decrease in pain intensity (-43.5%) than CG patients (-14.3%). ANCOVA analysis showed that the impact of teleconsultation was mediated by an increased training activity in the Kaia App. CONCLUSION: Our results show the superiority of the innovative digital treatment algorithm realized in Rise-uP, even though the CG also received relevant active treatment by their GPs. This provides clear evidence that digital treatment may be a promising tool to improve the quality of treatment of non-specific back pain. In 2021, analyses of routine data from statutory health insurances will enable us to investigate the cost-effectiveness of digital treatment.

Less Pain, Better Sleep? The Effect of a Multidisciplinary Back Pain App on Sleep Quality in Individuals Suffering from Back Pain - a Secondary Analysis of App User Data.

PURPOSE: Mobile health solutions are finding their way into health systems. The Kaia app has been shown to be able to reduce back pain in two studies. Since pain often comes along with disturbed sleep and both symptoms are strongly related we investigated whether the Kaia app training is associated with improved sleep quality. METHODS: User data of individuals with back pain were collected in two app versions (cohort 1: N = 180; cohort 2: N = 159). We analyzed the ratings of sleep quality and pain intensity on a 11-point numeric ratings scale (NRS; 0-10) both at the beginning of usage (baseline: BL) and on the individual last day of usage (follow-up: LU) within a 3-month training program. RESULTS: In both cohorts, we found a significant reduction in pain intensity from BL to LU (cohort 1: MBL = 4.80; SD = 1.59 to MLU = 3.75; SD = 1.76, Δpain = -1.04; SD = 2.12; t(158) = 6.207; p<.001/cohort 2: MBL = 4.20; SD = 1.98 to MLU = 3.65; SD = 1.78; Δpain = -0.50; SD = 2.04; t(147) = 3.001; p = 0.003) and a significant improvement of sleep quality (cohort 1: MBL = 5.76; SD = 2.12 to MLU = 6.56; SD = 1.72; Δsleep = t(158) = 4.310; p < 0.001/cohort 2: MBL = 6.08; SD = 2.08 to MLU = 6.76; SD = 1.55; Δsleep = 0.67; SD = 2.13; sleep: t(147) = 3.825; p < 0.001). Interestingly, improvement of sleep quality was not fully mediated by pain reduction. CONCLUSION: Our analysis underlines the relationship between pain and sleep in the clinical context. Improvement of sleep quality came along with pain reduction and vice versa. Further study should explain the exact mechanisms of action which are associated with the improvement of both symptom parameters.

Is there a right control condition in mHealth trials? A critical view on pain medicine.

When mobile health (mHealth) applications (apps) are investigated, the question of the proper control condition arises. Normally, the randomized controlled trial (RCT) is seen as the gold standard when testing efficacy of clinical interventions. Yet, mHealth apps rarely comprise innovative treatments but rather provide established treatments digitally. The classical RCT utilizing a placebo or waiting group condition may not always be the suitable methodology, since non-treatment is not appropriate if a disease urges treatment and the development of chronic disease needs to be prevented. The present commentary discusses conceivable control conditions in mHealth trials and illustrates their limitations.

App-based multidisciplinary back pain treatment versus combined physiotherapy plus online education: a randomized controlled trial.

Non-specific low back pain (LBP) is one of the leading causes of global disability. Multidisciplinary pain treatment (MPT) programs comprising educational, physical, and psychological interventions have shown positive treatment effects on LBP. Nonetheless, such programs are costly and treatment opportunities are often limited to specialized medical centers. mHealth and other digital interventions may be a promising method to successfully support patient self-management in LBP. To address these issues, we investigated the clinical effects of a multidisciplinary mHealth back pain App (Kaia App) in a randomized controlled trial (registered at German Clinical Trials Register under DRKS00016329). One-hundred one adult patients with non-specific LBP from 6 weeks to 1 year were randomly assigned to an intervention group or a control group. In the intervention group, the Kaia App was provided for 3 months. Control treatment consisted of six individual physiotherapy sessions over 6 weeks and high-quality online education. The primary outcome, pain intensity, was assessed at 12-week follow-up on an 11-point numeric rating scale (NRS). Our per-protocol analysis showed no significant differences between the groups at baseline (Kaia App group: M = 5.10 (SD = 1.07) vs. control group: M = 5.41 (SD = 1.15). At 12-week follow-up the Kaia App group reported significantly lower pain intensity (M = 2.70 (SD = 1.51)) compared to the control group (M = 3.40 (SD = 1.63)). Our results indicate that the Kaia App as a multidisciplinary back pain app is an effective treatment in LBP patients and is superior to physiotherapy in combination with online education.

Short-term alternating temperature enhances histamine-induced itch: a biphasic stimulus model.

Itch is the major symptom of many allergic or inflammatory skin diseases; yet it is still difficult to measure objectively. Human studies on the physiology and pathophysiology of the itch sensation (e.g. functional magnetic resonance imaging studies) have been hampered by the lack of an efferent and manageable "on-off" stimulus. Here, a short-term temperature-modulated human histamine itch model is presented. In nine healthy right-handed male volunteers (age 29+/-2.6 years), 1% histamine dihydrochloride was used in the skin prick model as standard itch stimulus on the right forearm with subsequent thermal modulation of the target skin area using a Medoc TSA II NeuroSensory Analyzer thermode. Modulation occurred in rapid alternating order from 32 degrees C (neutral) to 25 degrees C (slight cold) and vice versa; each temperature block lasted 20 seconds. Subjective itch ratings were recorded using a computerized visual analog scale (VAS) and - for qualitative assessment - the Eppendorf Itch Questionnaire (EIQ). All subjects reported localized itch sensations without pain; mean VAS itch intensity was 50.6+/-3.5% during the 25 degrees C blocks and 33.8+/-3.9% during the 32 degrees C blocks (P<0.0001). Also, mean EIQ ratings were significantly higher related to the 25 degrees C blocks. In spite of the common knowledge that intensive cold can inhibit itch sensation, a reproducible, significant enhancement of histamine-induced itch by short-term moderate temperature decrease could be shown. This effect might be explained by peripheral and central adaptation processes triggered by alternating afferent activity patterns and might be used - owing to its "on/off" characteristics-in future itch physiology studies such as functional magnetic resonance imaging.

The burden of neuropathic pain: results from a cross-sectional survey.

BACKGROUND: There are few published data on the treatment patterns and burden of neuropathic pain. We have investigated this in a large, observational, cross-sectional survey. METHODS: We surveyed 602 patients with neuropathic pain recruited from general practitioners in six European countries. Physicians recorded demographic and treatment information, including prescription medications. Patients completed Brief Pain Inventory (BPI) severity and interference questions, the EuroQol (EQ-5D), and questions about their productivity, non-prescription treatments, and frequency of physician visits. The BPI Pain Severity score (range: 0-10) is the mean of worst, least, average, and current pain ratings, with scores of 4-6 and 7-10 considered moderate and severe, respectively. We evaluated the impact of pain severity on functioning using analysis of variance models and chi2 tests. RESULTS: Mean (SD) age was 62.9 (14.4) years (50% female). Most patients reported moderate (54%) or severe (25%) pain. Nearly all patients (93%) were prescribed medications for their neuropathic pain: analgesics (71%); anti-epileptics (51%); antidepressants (29%); sedatives/hypnotics (15%). Seventy-six percent visited their physician at least once in the past month. Employment status was affected in 43% of patients; those employed missed a mean (SD) of 5.5 (9.8) workdays during the past month. Pain severity was associated significantly (P<0.001) with poorer EQ-5D scores (mild=0.67, moderate=0.46, severe=0.16), greater disruption of employment status (mild=24%, moderate=48%, severe=54%), and more frequent physician visits (% with one or more visits: mild=66%, moderate=79%, severe=83%). CONCLUSIONS: Patients with neuropathic pain visit their physician frequently and report substantial pain that interferes with daily functioning despite receiving treatment.

Optimal duration of PET studies with 18F-fluoroethyl-diprenorphine.

UNLABELLED: The tracer 6-O-(2-(18)F-fluoroethyl)-6-O-desmethyldiprenorphine (18F-FDPN) provides enhanced flexibility to PET studies of the opioidergic system because the label has a longer half-life than the label of 11C-diprenorphine. Here we evaluated the ideal length of PET studies with 18F-FDPN. METHODS: 18F-FDPN binding kinetics were quantified with protocols of different lengths by use of a 1-tissue or a 2-tissue compartment model for different volumes of interest. Furthermore, the effects of scanning duration were assessed by parametric analyses. RESULTS: A 90-min protocol resulted in less than 10% bias in distribution volume (DV) relative to the full-length protocol. Correlation analyses of the DV estimates for the full-length protocol and the shortened protocols showed good replication of DV estimates for regions with both low and high levels of binding at schedules of up to 90 min. CONCLUSION: Data sampling in dynamic 18F-FDPN PET acquisitions should not be shorter than 90 min to maintain reliable estimates of DV.

COMT Val108/158Met genotype affects the mu-opioid receptor system in the human brain: evidence from ligand-binding, G-protein activation and preproenkephalin mRNA expression.

Recent data from [(11)C]carfentanil ligand-PET indicate that in the human brain, the availability of mu-opioid (MOP) receptor binding sites is affected by the Val(108/158)Met polymorphism of the catechol-O-methyltransferase (COMT) gene. This prompted us to validate the impact of COMT Val(108/158)Met on MOP receptors in human post-mortem brain. [(3)H]DAMGO receptor autoradiography was performed in frontal cortex, basal ganglia, thalamus and cerebellum (8 Met/Met, 6 Met/Val, 3 Val/Val). With respect to genotype, numbers of MOP binding sites in COMT Met(108/158) homozygous and Val(108/158)Met heterozygous cases were higher than in Val(108/158) homozygous. Differences were significant in the caudate nucleus (Val/Met vs. Val/Val), nucleus accumbens (Val/Met vs. Val/Val) and the mediodorsal nucleus of the thalamus (Met/Met vs. Val/Val). In the thalamus, this was corroborated by DAMGO-stimulated [(35)S]GTPgammaS autoradiography. Moreover, stepwise multiple regression taking into account various covariables allowed to confirm the COMT genotype as the most predictive factor in this structure. As a mechanism how COMT might exert its action on MOP receptors, it has been suggested that at least in striatopallidal circuits COMT Val(108/158)Met impacts on enkephalin, which is capable of reciprocally regulating MOP receptor expression. Thus, we assessed preproenkephalin mRNA by in situ hybridization. In the striatum, mRNA levels were significantly higher in COMT Met(108/158) homozygous cases indicating that MOP binding sites and enkephalin are regulated in parallel. Moreover, the transcript was not detectable in the thalamus. Thus, mechanisms other than an enkephalin-dependent receptor turnover must be responsible for COMT-related differences in MOP binding site availability in the human brain.

Quantification of [18F]diprenorphine kinetics in the human brain with compartmental and non-compartmental modeling approaches.

6-O-(2-[(18)F]fluoroethyl)-6-O-desmethyldiprenorphine ([(18)F]FDPN) is a nonselective opiate ligand that binds to postsynaptic micro, kappa and delta opiate receptors. Due to the longer half-life of F-18, compared to C-11, labeling DPN with F-18 allows for alternative experimental protocols and potentially the evaluation of endogenous opioid release. The applicability of this compound to assorted experimental protocols motivated the evaluation of [(18)F]FDPN kinetics with compartmental and non-compartmental models. The results indicate that a two-tissue compartmental model best characterizes the data obtained following a bolus injection of [(18)F]FDPN (120-min scanning protocol). Estimates of distribution volume (DV) were robust, being highly correlated for the one-tissue compartmental model as well as the invasive Logan model and the basis function method. Furthermore, the DV estimates were also stable under a shortened protocol of 60 min, showing a significant correlation with the full protocol. The binding potential (BP) values showed more variability between methods and in some cases were more sensitive to protocol length. In conclusion, this evaluation of [(18)F]FDPN kinetics illustrates that DV values can be estimated robustly using compartmental modeling, the basis function method or the invasive Logan modeling approach on a volume of interest level. BP values were also found to correlate with DV values; however, these results should be interpreted with the understanding that specific binding in the reference region (occipital region) may exist.