Duloxetine improves chronic orofacial pain and comorbid depressive symptoms in association with reduction of serotonin transporter protein through upregulation of ubiquitinated serotonin transporter protein.

ABSTRACT: Chronic orofacial pain (COP) is relieved by duloxetine (DLX) and frequently causes depressive symptoms. The aim of this study was to confirm effects of DLX on pain and depressive symptoms, and to associate with their effectiveness in platelet serotonin transporter (SERT) expression, which is a target molecule of DLX and plasma serotonin concentration in COP patients with depressive symptoms. We assessed for the severity of pain and depressive symptoms using the Visual Analog Scale (VAS) and 17-item Hamilton Depression Rating Scale (HDRS), respectively. Chronic orofacial pain patients were classified into 2 groups based on their HDRS before DLX-treatment: COP patients with (COP-D) and without (COP-ND) depressive symptoms. We found that the VAS and HDRS scores of both groups were significantly decreased after DLX treatment compared with those before DLX treatment. Upregulation of total SERT and downregulation of ubiquitinated SERT were observed before DLX treatment in both groups compared with healthy controls. After DLX treatment, there were no differences in total SERT of both groups and in ubiquitinated SERT of COP-D patients compared with healthy controls; whereas, ubiquitinated SERT of COP-ND patients remained downregulated. There were positive correlations between changes of serotonin concentrations and of VAS or HDRS scores in only COP-D patients. Our findings indicate that DLX improves not only pain but also comorbid depressive symptoms of COP-D patients. Duloxetine also reduces platelet SERT through upregulation of ubiquitinated SERT. As the result, decrease of plasma serotonin concentrations may be related to the efficacy of DLX in relieving pain and depression in COP patients.

Collaboration of perioperative management in an adult patient with 22 q 11.2 deletion syndrome: A case report.

A 24-year-old woman diagnosed with 22 q 11.2 deletion syndrome was referred for multiple extractions. Due to the syndrome, the patient had schizophrenia, cardiac anomalies, and maxillofacial complications. This case report suggested that a multidisciplinary team approach is important for perioperative management of patients with 22 q 11.2 deletion syndrome.

Duloxetine attenuates pain in association with downregulation of platelet serotonin transporter in patients with burning mouth syndrome and atypical odontalgia.

OBJECTIVE: The aim of this study was evaluation of the association between severity of pain and expression of total or ubiquitinated serotonin transporter (SERT) protein in patients with burning mouth syndrome and atypical odontalgia (BMS/AO), who were treated by duloxetine. METHODS: Patients with BMS/AO were assessed for severity of pain using the visual analog scale (VAS), and expression of total and ubiquitinated SERT protein in platelets before (baseline) and 12 weeks after duloxetine-treatment. RESULTS: The expression of total and ubiquitinated SERT protein at baseline in all patients (n = 33) were higher and lower, respectively, compared to those in healthy controls. 12 weeks after duloxetine-treatment, there was no difference in the total SERT protein levels between patients (n = 21) and healthy controls. In the 16 patients who could be measured, mean VAS scores and total SERT protein levels were significantly decreased after the treatment, compared to those at baseline. There was tendency for a positive correlation between total SERT protein levels and VAS scores in these patients. CONCLUSIONS: Our findings indicate that duloxetine relieves pain in association with downregulation of platelet SERT expression in patients with BMS/AO.

Evaluation of patients suffered from burning mouth syndrome and persistent idiopathic facial pain using Japanese version PainDETECT questionnaire and depression scales.

BACKGROUND/PURPOSE: Various questionnaires have been validated as methods for screening of neuropathic pain, but none have been established for the orofacial region. Although chronic pain and depression are likely to comorbid, few studies have examined the relationship between orofacial chronic pain and depression. Therefore, we evaluated the potential of the Japanese Version of PainDETECT as an assessment tool for neuropathic pain associated with burning mouth syndrome (BMS) and persistent idiopathic facial pain (PIFP). We also evaluated the depression scale such as Beck's Depression Inventory (BDI: a subjective index) and Hamilton Depression Rating Scale (HDRS: an objective index) with BMS or PIFP. MATERIALS AND METHODS: As a target, we administered the Japanese version of the PainDETECT questionnaire to the BMS (29 patients) and PIFP (17 patients). As a control, patients with post-extraction pain (typical nociceptive pain, (EXT) 16 patients) were also participated. We performed BDI and HDRS with BMS or PIFP. RESULTS: Although PainDETECT final score was significantly higher in BMS [median: 10] compared with PIFP [6] and EXT [5] (p < 0.05), PainDETECT final scores for all groups were lower than the cutoff value for the possibility of neuropathic pain. HDRS was significantly higher in the BMS than the PIFP. There were no significant differences between the BMS and PIFP in BDI. CONCLUSION: Under the limitations of current research design, the Japanese version of the PainDETECT questionnaire does not show sufficient potential as pain assessment tool for patients with BMS and PIFP. BMS is comorbid with depression objectively when compared with PIFP.

Serum Metabolic Profiles of the Tryptophan-Kynurenine Pathway in the high risk subjects of major depressive disorder.

Previous reports have shown that during chronic inflammation, the tryptophan (TRP)-kynurenine (KYN) pathway plays a pivotal role in the onset of depression. The aim of this study was to investigate the characteristics of the serum TRP-KYN pathway metabolite profile in high-risk subjects of major depressive disorder (HRMDD) defined by depression scores. The concentrations of TRP-KYN pathway metabolites {TRP, KYN, 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), kynurenic acid (KYNA) and anthranilic acid (AA)} were assessed in serum from HRMDD, chronic pain disorder patients and healthy controls. In serum from HRMDD, elevated levels of AA and decreased levels of TRP were observed, but the levels of other metabolites were not changed. Furthermore, the change in the AA2nd/AA1st ratio in subjects who progressed from a health. y state to a depressive state was correlated with an increase in the CES-D score. The level of IL-1 receptor antagonist (IL-1RA) was negatively correlated with that of AA. Interestingly, we confirmed AA as a possible biomarker for depression-related symptoms, since the metabolite profiles in the chronic pain disorder group and chronic unpredictable mild stress model mice were similar to those in the HRMDD. These results suggest that AA may be an effective marker for HRMDD.

Valproate intoxication in a patient with bipolar I disorder due to SGLT2 inhibitor-induced weight reduction.

INTRODUCTION: Sodium glucose cotransporter 2 (SGLT2) inhibitors are hypoglycemic agents characterized by a weight loss effect. This effect is likely to increase blood levels of other drugs. Reason for the report: SGLT2 inhibitor-induced weight reduction could bring unexpected side effects of other drugs whose blood concentrations are affected by body weight. However, this interaction between SGLT2 inhibitor and other drugs via weight loss effect has not been reported so far. CASE SUMMARY: I describe the case of a 67-year-old male with bipolar I disorder who was treated with valproate. He was diagnosed with type 2 diabetes mellitus, started treatment with empagliflozin, and his body weight decreased gradually. Two months after he started empagliflozin, he developed hand tremor which was one of the symptoms of valproate intoxication, and his tremor was improved by dose reduction of valproate. It seemed that this symptom was brought mainly by weight loss effect of empagliflozin. These observations suggest the existence of a detour where blood concentrations of some drugs are increased by weight loss due to SGLT2 inhibitors. Clinicians need to be aware of the blood levels of drugs in patients with type 2 diabetes mellitus after starting SGLT2 inhibitors. Graphical abstract.

Effect of antidepressant treatment on plasma levels of neuroinflammation-associated molecules in patients with somatic symptom disorder with predominant pain around the orofacial region.

OBJECTIVE: Burning mouth syndrome (BMS) and atypical odontalgia (AO) are examples of somatic symptom disorders with predominant pain around the orofacial region. Neuroinflammation is thought to play a role in the mechanisms, but few studies have been conducted. We aimed to better understand the role of neuroinflammation in the pathophysiology and treatment of BMS/AO. METHODS: Plasma levels of 28 neuroinflammation-related molecules were determined in 44 controls and 48 BMS/AO patients both pretreatment and 12-week post-treatment with duloxetine. RESULTS: Baseline plasma levels of interleukin (IL)-1ß (p < .0001), IL-1 receptor antagonist (p < .001), IL-6 (p < .0001), macrophage inflammatory protein-1ß (p < .0001), and platelet-derived growth factor-bb (.04) were significantly higher in patients than in controls. Plasma levels of granulocyte macrophage colony stimulating factor were significantly higher in patients than in controls (p < .001) and decreased with treatment (.009). Plasma levels of eotaxin, monocyte chemoattractant protein-1, and vascular endothelial growth factor decreased significantly with treatment (p < .001, .022, and .029, respectively). CONCLUSIONS: Inflammatory mechanisms may be involved in the pathophysiology and/or treatment response of somatic symptom disorders with predominant pain around the orofacial region.

Duloxetine Plasma Concentrations and Its Effectiveness in the Treatment of Nonorganic Chronic Pain in the Orofacial Region.

OBJECTIVE: The purpose of this study was to examine the relationship between the pain-relieving effects of duloxetine and its plasma concentrations in patients with burning mouth syndrome and atypical odontalgia characterized by chronic nonorganic pain in the orofacial region. METHODS: We administered duloxetine to 77 patients diagnosed as having burning mouth syndrome or atypical odontalgia for 12 weeks. The initial dose of duloxetine was established as 20 mg/d and was increased to 40 mg/d after week 2. We evaluated pain using the visual analog scale and depressive symptoms using the Structured Interview Guide for the Hamilton Depression Rating Scale at weeks 0, 2, 4, 6, 8, 10, and 12 and measured plasma concentrations of duloxetine 12 weeks after the start of its administration. RESULTS: Visual analog scale scores were significantly lower 12 weeks after than at the start of the administration of duloxetine (paired t test, t = 6.65, P < 0.0001). We examined the relationship between the rate of decreases in visual analog scale scores and plasma concentrations of duloxetine. There was no significant linear regression or quadratic regression. CONCLUSIONS: Duloxetine significantly relieved pain in patients with chronic nonorganic pain in the orofacial region. However, no relationship was observed between its pain-relieving effects and plasma concentrations.

Five Patients With Burning Mouth Syndrome in Whom an Antidepressant (Serotonin-Noradrenaline Reuptake Inhibitor) Was Not Effective, but Pregabalin Markedly Relieved Pain.

Burning mouth syndrome (BMS) causes idiopathic pain or a burning sensation in clinically normal oral mucosa. Burning mouth syndrome is a chronic disease with an unknown etiology. Burning mouth syndrome is also idiopathic, and a consensus regarding diagnosis/treatment has not been reached yet. Recent studies have supported the suggestion that BMS is a neuropathic pain disorder in which both the peripheral and central nervous systems are involved. Tricyclic antidepressants (nortriptyline and amitriptyline), serotonin-noradrenaline reuptake inhibitors (SNRIs) (duloxetine and milnacipran), and antiepileptic drugs, potential-dependent calcium channel α2δ subunit ligands (gabapentine and pregabalin), are currently recommended as the first-choice drugs for neuropathic pain. In this study, we report 5 patients with BMS in whom there was no response to SNRI (milnacipran or duloxetine), or administration was discontinued because of adverse reactions, but in whom pregabalin therapy markedly reduced or led to the disappearance of pain in a short period. Pregabalin, whose mechanism of action differs from that of SNRIs, may become a treatment option for BMS patients who are not responsive to or are resistant to SNRIs.