Search

Tramadol is a weak opioid that produces analgesic effect via both the μ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

Although opioids have potent analgesic properties, their use is associated with side effects, including opioid-induced constipation (OIC). This study investigated the incidence of OIC based on the Rome IV diagnostic criteria in patients using opioid analgesics for chronic non-cancer pain and to explore and compare the risk factors for the development of OIC in opioid analgesic users.We surveyed patients aged 20 years or more living in Japan via the internet; who had been using opioid or non-opioid analgesics (N = 500 each) for at least 3 months for relief from chronic non-cancer musculoskeletal pain (low back pain or osteoarthritis); and who provided electronic consent to participate in and complete the survey. The groups were matched for age and sex.Of the patients using opioid analgesics, 89% were taking weak opioids. The proportion of patients perceiving constipation was comparable between the opioid and non-opioid analgesic groups (34% vs 29%, respectively); however, a significantly higher proportion of patients in the opioid group, compared to the non-opioid group, reported self-assessed constipation (40% vs 18%, respectively) after using an analgesic and fulfilled two or more symptoms of the Rome IV diagnostic criteria for constipation (28% vs 19%, respectively). A higher proportion of patients were taking prescribed medicine for constipation in the opioid group compared with the non-opioid group (33% vs 18%, respectively). Low back pain, but not opioid strength and scheduled dosing, was identified as a risk factor for OIC among various covariates assessed in the logistic regression analysis in 81 patients with OIC and Rome IV diagnosis vs 419 patients without OIC in the opioid group.Use of opioid analgesics, including weak opioids, for treating chronic non-cancer musculoskeletal pain is associated with OIC. This finding highlights the need for appropriate treatment of constipation in patients with chronic non-cancer pain in Japan.UMIN000043985.

BACKGROUND Artificial intelligence–assisted interactive health promotion systems are useful tools for the management of musculoskeletal conditions. OBJECTIVE This study aimed to explore the effects of web-based video patient education and strengthening exercise therapy, using a mobile messaging app, on work productivity and pain in patients with chronic low back pain (CLBP) receiving pharmacological treatment. METHODS Patients with CLBP were randomly allocated to either the exercise group, who received education and exercise therapy using a mobile messaging app, or the conventional group. For patient education, a web-based video program was used to provide evidence-based thinking regarding the importance of a cognitive behavioral approach for CLBP. The exercise therapy was developed in accordance with the recommendations for alignment, core muscles, and endogenous activation, including improvement of posture and mobility for proper alignment, stimulation and/or strengthening of deep muscles for spinal stability, and operation of intrinsic pain for the activation of endogenous substances by aerobic exercise. Both groups continued to receive the usual medical care with pharmacological treatment. The end points were changes in work productivity, pain intensity, quality of life, fear of movement, and depression. The observation period for this study was 12 weeks. An analysis adjusted for baseline values, age at the time of consent acquisition, sex, and willingness to strengthen the exercise therapy was performed. RESULTS The exercise and conventional groups included 48 and 51 patients, with a mean age of 47.9 years (SD 10.2 years; n=27, 56.3% male patients) and 46.9 years (SD 12.3 years; n=28, 54.9% male patients) in the full analysis set, respectively. No significant impact of these interventions on work productivity was observed in the exercise group compared with the conventional group (primary end point: Quantity and Quality method; 0.062 vs 0.114; difference between groups −0.053, 95% CI −0.184 to 0.079; P=.43). However, the exercise group showed consistently better trends for the other end points than did the conventional group. Compared with the conventional group, the exercise group showed a significant improvement in the symptoms of low back pain (3.2 vs 3.8; difference between groups −0.5, 95% CI −1.1 to 0.0; P=.04), quality of life (EuroQoL 5 Dimensions 5 Level: 0.068 vs 0.006; difference between groups 0.061, 95% CI 0.008 to 0.114; P=.03), and fear of movement at week 12 (−2.3 vs 0.5; difference between groups −2.8, 95% CI −5.5 to −0.1; P=.04). CONCLUSIONS This study suggests that patient education and strengthening exercise therapy using a mobile messaging app may be useful for treating CLBP. This study does not reveal the effect of therapeutic interventions on CLBP on work productivity. Thus, further research is required to assess work productivity with therapeutic interventions. CLINICALTRIAL University Hospital Medical Information Network Clinical Trials Registry UMIN000041037; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046866

Purpose As the cancer survivors increase, patients using long-term and high-dose opioids are also increasing. Therefore, the promotion of appropriate use is important. This study investigated the actual status of opioid prescriptions in Japan and identified factors associated with long-term, high-dose prescription. Methods We conducted a case-control study using a hospital-based administrative claims database. Patients with a diagnosis of cancer and prescriptions of opioids were included. Patients who received continuous opioid for less than 183 days were defined as the “control,” and patients who received continuous opioid at higher dose levels (≥ 120 mg/day of oral morphine equivalent) for 183 days or more were defined as the “case.” The case was subdivided into two groups: those with the duration of less than 730 days (case I) and 730 days or more (case II). After describing factors possibly associated with long-term, high-dose opioid prescription, ordinal logistic regression analysis was conducted. Results We included 19,176 patients; of these, 13,517 were in the control, 111 were in the case I, and 682 were in the case II. The analysis showed that distant metastasis, back pain, dose of opioids, non-opioid analgesics, prescription, and chemotherapy during the opioid prescriptions were significantly associated with long-term, high-dose opioid prescription. Conclusion Four percent of the study population were prescribed long-term, high-dose opioids, and several comorbidities and concomitant medications were identified as associated factors. Opioids might be also prescribed for non-cancer chronic pain. It is necessary to properly distinguish the type of pain and to use opioids safely and appropriately.

Chika Sakai,1 Toshinaga Tsuji,1 Toru Nakai,1 Yuki Namba,1 Hirokazu Mishima,1 Masakazu Fujiwara,2 Hisato Matsunaga3 1Medical Affairs Department, Shionogi & Co. Ltd, Osaka, Japan; 2Data Science Office, Shionogi & Co. Ltd, Osaka, Japan; 3Department of Neuropsychiatry, Hyogo College of Medicine, Hyogo, JapanCorrespondence: Toshinaga TsujiMedical Affairs Department, Shionogi & Co. Ltd, 3-1-8, Doshomachi, Chuo-ku, Osaka-shi, Osaka, 541-0045, JapanTel +81 6 6209 7412Fax +81 6 6202 2239Email toshinaga.tsuji@shionogi.co.jpPurpose: To better understand the treatment of comorbid depression in adults with attention-deficit/hyperactivity disorder (ADHD) by investigating the prescription patterns of antidepressants, anxiolytics, and hypnotics after commencing ADHD medication.Patients and Methods: In this retrospective observational study in Japan, the data of patients initiating ADHD medication while already receiving antidepressants (ADHD group) and of patients prescribed antidepressants but not diagnosed with ADHD (control group) were extracted from an electronic medical record database. Additionally, one-to-one matching for patients in both groups was performed using sex, age, baseline dosage of antidepressants, and any comorbid psychiatric disorders as covariates. The observation period included a 1-month baseline period and a 6-month follow-up period. The percentage of patients prescribed antidepressants and the mean prescribed dosages were compared between matched-cohort groups. Prescriptions for anxiolytics and hypnotics were also assessed.Results: In the matched cohorts, consisting of 239 patients in the ADHD group and 239 patients from the unmatched control cohort of 10,485, the percentage of patients prescribed antidepressants decreased from baseline in both groups to 94.1% in the ADHD group and 89.5% in the control group during the first month of follow-up, and 77.0% and 78.7%, respectively, during the last month. There were no significant differences between groups in the percentages of patients prescribed antidepressants or in the mean prescribed dosages of antidepressants at any time point over the follow-up period. Prescribed dosages of anxiolytics and hypnotics tended to be lower in the ADHD group.Conclusion: The two groups were medicated similarly with respect to their depressive symptoms over 6 months. Our results suggest that in patients with ADHD and comorbid depression, which is more likely to be more severe than in depression without ADHD, depressive symptoms are managed following initiation of add-on ADHD medication, without requiring higher antidepressant dosages than in patients with depression only.Keywords: attention-deficit/hyperactivity disorder, MDD, antidepressants, anxiolytics, hypnotics

Introduction Comorbid psychiatric conditions in children and adolescents with attention-deficit hyperactivity disorder (ADHD) occur frequently, complicate management, and are associated with substantial burden on patients and caregivers. Very few systematic reviews have assessed the efficacy and safety of medications for ADHD in children and adolescents with comorbidities. Of those that were conducted, most focused on a particular comorbidity or medication. In this systematic literature review, we summarize the efficacy and safety of treatments for children and adolescents with ADHD and comorbid autism spectrum disorders, oppositional defiant disorder, Tourette’s disorder and other tic disorders, generalized anxiety disorder, and major depressive disorder. Methods We searched MEDLINE, Embase, and ClinicalTrials.gov (to October 2019) for studies of patients (aged

Background The SecA DEAD (Asp-Glu-Ala-Asp) motor protein uses binding and hydrolysis of adenosine triphosphate (ATP) to push secretory proteins across the plasma membrane of bacteria. The reaction coordinate of nucleotide exchange is unclear at the atomic level of detail. Methods We performed multiple atomistic computations of the DEAD motor domain of SecA with different occupancies of the nucleotide and magnesium ion sites, for a total of ~1.7 μs simulation time. To characterize dynamics at the active site we analyzed hydrogen-bond networks. Results ATP and ADP can bind spontaneously at the interface between the nucleotide binding domains, albeit at an intermediate binding site distinct from the native site. Binding of the nucleotide is facilitated by the presence of a magnesium ion close to the glutamic group of the conserved DEAD motif. In the absence of the magnesium ion, protein interactions of the ADP molecule are perturbed. Conclusions A protein hydrogen-bond network whose dynamics couples to the occupancy of the magnesium ion site helps guide the nucleotide along the nucleotide exchange path. In SecA, release of magnesium might be required to destabilize the ADP binding site prior to release of the nucleotide. General significance We identified dynamic hydrogen-bond networks that help control nucleotide exchange in SecA, and stabilize ADP at an intermediate site that could explain slow release. The reaction coordinate of the protein motor involves complex rearrangements of a hydrogen-bond network at the active site, with perturbation of the magnesium ion site likely occurring prior to the release of ADP.

Insertion and release of a solute into and from a cylindrical vessel comprising biopolymers is a fundamental function in biological systems. In earlier works, we reported that the solvent-entropy (SE) effect plays imperative roles for insertion. Here we show that release is also achievable by the SE effect: the solute can be moved from an entrance at one end of the vessel to an exit at the other end using a continuous variation of the vessel geometry. Since the SE effect is rather insensitive to the solute–solvent affinity, our result may provide a clue to the ‘multidrug efflux’ of TolC.

AcrB, a homotrimer, is the pivotal part of a multidrug efflux pump. A "functionally rotating" picture has been proposed for the drug transport by AcrB, but its mechanism remains unresolved. Here, we investigate the energetics of the whole functional rotation cycle using our theoretical methods. We find that the packing efficiency of AcrB is ununiform, and this ununiformity plays imperative roles primarily through the solvent-entropy effect. When a proton binds to or dissociates from a protomer, the packing properties of this protomer and its two interfaces are perturbed overall in the direction that the solvent translational entropy is lowered. The packing properties of the other two protomers are then reorganized with the recovery or maintenance of closely packed interfaces, so that the solvent-entropy loss can be compensated. The functional structural change by an isolated protomer would cause a seriously large free-energy increase. By forming a trimer, any free-energy increase caused by a protomer is always canceled out by the free-energy decrease brought by the other two protomers via the mechanism mentioned above. The functional structural rotation is thus accomplished using the free-energy decrease arising from the transfer of only a single proton per cycle. The similarities to F1-ATPase are also discussed.

We show how to characterize the native-structure models of a protein using our free-energy function F which is based on hydration thermodynamics. Ubiquitin is adopted as an example protein. We consider models determined by the X-ray crystallography and two types of NMR model sets. A model set of type 1 comprises candidate models for a fixed native structure, and that of type 2 forms an ensemble of structures representing the structural variability of the native state. In general, the X-ray models give lower F than the NMR models. There is a trend that, as a model deviates more from the model with the lowest F among the X-ray models, its F becomes higher. Model sets of type 1 and those of type 2, respectively, exhibit two different characteristics with respect to the correlation between the deviation and F. It is argued that the total amount of constraints such as NOEs effectively taken into account in constructing the NMR models can be examined by analyzing the behavior of F. We investigate structural characteristics of the models in terms of the energetic and entropic components of F which are relevant to intramolecular hydrogen bonding and to backbone and side-chain packing, respectively.

The multidrug efflux pump of Escherichia coli is the tripartite complex consisting of the polytopic inner membrane protein AcrB, periplasmic adaptor protein AcrA, and outer membrane channel TolC. AcrB is in charge of the principal part of pumping drugs out of the cell from the inner membrane or periplasm through the TolC channel. AcrB comprises three porotomers with different conformations which are in access (A), binding (B), and extrusion (E) states along the drug transport cycle, respectively. A three-step “functionally rotating” picture has then been proposed for the transport of drugs: Each protomer exhibits a sequential structural change represented as (A, B, E)→(B, E, A)→(E, A, B)→(A, B, E) by utilizing the proton-motive force. Up to now, MD simulations have been performed extensively to elucidate the rotating mechanism. However, they are focused on particular aspects or elementary processes in the functional rotation cycle. The mechanism of the functional rotation and energetics of the whole cycle remain unresolved. Here we investigate the packing structure of AcrB in terms of the entropic effect originating from the translational displacement of water molecules or hydrocarbon groups constituting nonpolar chains of lipid molecules. The theoretical method, which consists of the integral equation theories for simple and molecular fluids combined with the morphometric approach, allows us to analyze solvation properties of the trimer as well as each protomer by accounting for the polyatomic structures in atomic details. We find that the packing in AcrB is highly asymmetric and the solvent-entropy effect is crucially important. We construct a physical picture for the mechanism of conformational rotation elucidating how each protomer achieves such a drastic conformational change using only a small free energy ∼8kBT.

Insertion and release of a solute into and from a vessel comprising biopolymers is a fundamental function in a biological system. A typical example is found in a multidrug efflux transporter. "Multidrug efflux" signifies that solutes such as drug molecules with diverse properties can be handled. In our view, the mechanism of the multidrug efflux is not chemically specific but rather has to be based on a physical factor. In earlier works, we showed that the spatial distribution of the solute-vessel potential of mean force (PMF) induced by the solvent plays imperative roles in the insertion∕release process. The PMF can be decomposed into the energetic and entropic components. The entropic component, which originates from the translational displacement of solvent molecules, is rather insensitive to the solute-solvent and vessel inner surface-solvent affinities. This feature is not shared with the energetic component. When the vessel inner surface is neither solvophobic nor solvophilic, the solvents within the vessel cavity and in the bulk offer almost the same environment to any solute with solvophobicity or solvophilicity, and the energetic component becomes much smaller than the entropic component (i.e., the latter predominates over the former). Our idea is that the multidrug efflux can be realized if the insertion∕release process is accomplished by the entropic component exhibiting the insensitivity to the solute properties. However, we have recently argued that the entropic release of the solute is not feasible as long as the vessel geometry is fixed. Here we consider a model of TolC, a cylindrical vessel possessing an entrance at one end and an exit at the other end for the solute. The spatial distribution of the PMF is calculated by employing the three-dimensional integral equation theory with rigid-body models in which the constituents interact only through hard-body potentials. Since the behavior of these models is purely entropic in origin, our analysis is focused on the entropic component. We show that the entropically inserted solute can be released by a continuous variation of the vessel geometry which forms a time-dependent entropic force continuing to accelerate the solute motion to the exit. Solutes with a wide range of sizes are entropically released using the same vessel-geometry variation. The results obtained are fairly general and also applicable to the efflux pump protein AcrB and ATP-binding cassette transporter.