Efficacy of Duloxetine With Arthrocentesis in the Management of TMJ Internal Derangement.

Temporomandibular joint (TMJ) arthrocentesis is one of the most commonly used non-invasive surgical interventions in the treatment of refractory pain and dysfunction associated with internal derangement. Several adjunctive therapies have been used in combination with arthrocentesis in an attempt to increase its efficacy and long-term maintenance. Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor which is used in different chronic pain conditions. This study aimed to assess the efficacy of duloxetine in combination with arthrocentesis compared with arthrocentesis alone. Twenty-eight patients with chronic TMJ pain were included and randomly allocated into 2 groups (control and study groups). The control group included patients who underwent TMJ arthrocentesis only, and the study group included patients who underwent arthrocentesis followed by giving duloxetine (30 mg) orally twice daily for 3 months. Pain, maximum mouth opening, and level of anxiety and depression were assessed preoperatively and followed at regular intervals of 1 week, 1 month, 3 months, and 6 months postoperatively. Pain was significantly reduced in both groups at all postoperative intervals and was significantly lower in the study group than the control group at 6 months. Maximum mouth opening increased significantly in both groups, but the difference between them was not significant. Level of anxiety and depression was significantly decreased in both groups, with no statistically significant difference between them. The results of this study indicate that duloxetine in combination with arthrocentesis may provide effective and long-term pain control; however, its use is associated with a higher risk of adverse events.

The use of antineuropathic medications for the treatment of chronic pain.

Chronic pain syndromes cost the US healthcare system over $600 billion per year. A subtype of chronic pain is neuropathic pain (NP), which is defined as "pain caused by a lesion or disease of the somatosensory system," according to the International Association for the Study of Pain (IASP). The pathophysiology of neuropathic pain is very complex, and more research needs to be done to find the exact mechanism. Patients that have preexisting conditions such as cancer and diabetes are at high-risk of developing NP. Many NP patients are misdiagnosed and receive delayed treatment due to a lack of a standardized classification system that allows clinicians to identify, understand, and utilize pain management in these patients. Medications like tricyclic antidepressants, serotonin-norepinephrine reuptake Inhibitor (SNRIs), and gabapentinoids are first-line treatments followed by opioids, cannabinoids, and other drugs. There are limited studies on the treatment of NP.

Antidepressant use and colorectal cancer morbidity and mortality: A dose-response meta analysis.

The risk of colorectal cancer associated to antidepressant use remains unclear. The purpose of this meta-analysis was to investigate the risk of colorectal cancer associated to antidepressant use.Medline, Embase, Web of Science, and Cochrane Database were accessed from the dates of their establishment to October 2018, to collect study of antidepressant use and colorectal cancer morbidity and mortality. Then a meta-analysis was conducted using Stata 12.0 software.A total of 11 publications involving 109,506 participants were included. The meta-analysis showed that antidepressant use was not associated with colorectal cancer morbidity (relevant risk (RR): 0.97; 95% confidence interval (CI): 0.94-1.01) and mortality (RR: 1.08; 95% CI: 0.99-1.17). Subgroup analysis showed selective serotonin reuptake inhibitor (RR: 0.99; 95% CI: 0.96-1.03) or serotonin norepinephrine reuptake inhibitor (RR: 1.04; 95% CI: 0.86-1.26) were not associated with colorectal cancer risk; however, TCA was associated with colorectal cancer risk decrement (RR: 0.92; 95% CI: 0.87-0.98). Furthermore, the results also showed that antidepressant use was not associated with colorectal cancer risk in Europe and North America (RR: 0.97; 95% CI: 0.92-1.02) and Asia (RR: 1.00; 95% CI: 0.95-1.26). Additionally, a dose-response showed per 1 year of duration of antidepressant use incremental increase was not associated with colorectal cancer risk (RR: 0.96; 95% CI: 0.87-1.09).Evidence suggests that antidepressant use was not associated with colorectal cancer morbidity and mortality. The cumulative duration of antidepressant use did not utilized played critical roles.

Adjunctive vortioxetine for SSRI-resistant major depressive disorder: a real-world chart review study

Objective: Selective serotonin reuptake inhibitors (SSRIs) are the cornerstone of treatment of major depressive disorder (MDD). However, non-response is common, often necessitating combination strategies. The present study assessed the efficacy of vortioxetine as an add-on therapy in patients with SSRI-resistant MDD. Methods: The charts of 36 adult outpatients with DSM-IV-TR MDD who had not achieved a response after at least 8 weeks of treatment with an SSRI were reviewed retrospectively. Subjects were treated with vortioxetine (5-20 mg/day) for 8 weeks added to the current SSRI. The main outcome measures were change from baseline in total Hamilton Scale for Depression (HAM-D) score and the rate of response (a 50% or greater reduction in HAM-D score and a Clinical Global Impression ‐ Improvement module [CGI-I] score of 1 or 2 at endpoint). HAM-D scores ≤ 7 were considered as remission. Additional outcome measures included the Snaith-Hamilton Pleasure Scale (SHAPS) and the Scale for Suicide Ideation (SSI). Results: 32 patients completed the 8 weeks of treatment. At 8 weeks, a significant reduction in HAM-D score was observed (p ≤ 0.001), with response obtained by 41.7% and remission by 33.3% of patients. Significant reductions in SHAPS and SSI were also observed (p ≤ 0.001 for both scales). Conclusions: Adjunctive vortioxetine may be useful and well-tolerated in stage I treatment-resistant depression. However, the limitations of this study (such as small sample size, absence of randomization and control group, retrospective design, etc.) must be considered.

Efficacy and safety of duloxetine versus placebo in adolescents with juvenile fibromyalgia: results from a randomized controlled trial.

BACKGROUND: Currently, there are no medications approved for the treatment of juvenile fibromyalgia (JFM). We evaluated the safety and efficacy of duloxetine 30/60 mg once daily (QD) versus placebo in adolescents with JFM. METHODS: In this Phase 3b, multisite (US, Argentina, Puerto Rico, and India) trial, patients aged 13-17 years with JFM and a score of ≥4 on the Brief Pain Inventory-Modified Short Form: Adolescent Version (BPI) 24-h average pain severity score were randomized to duloxetine or placebo for the 13-week double-blind period. The starting duloxetine dose was 30 mg, with a target dose of 60 mg QD, as tolerated. The primary endpoint was the mean change in 24-h average pain severity of the Brief Pain Inventory (BPI) from baseline to Week 13, analyzed using mixed-model repeated measures (MMRM) technique. Secondary measures were BPI severity and interference scores; treatment response (≥30%, ≥50% reductions on BPI average pain severity); Pediatric Pain Questionnaire; Clinical Global Impression of Severity: Overall and Mental Illness scales; Functional Disability Inventory: child and parent versions; Children's Depression Inventory; Multidimensional Anxiety Scale for Children; and safety and tolerability. Continuous secondary efficacy measures were analyzed using analysis of covariance or MMRM, and categorical data using Cochran-Mantel-Haenszel test and Fisher's exact test, where appropriate. RESULTS: A total of 184 patients with JFM received duloxetine (N = 91) or placebo (N = 93), of which 149 patients (81.0%) completed the 13-week double-blind treatment period. Baseline characteristics were comparable between groups; majority of the patients were Caucasian (77.17%) and females (75.0%), with a mean age of 15.53 years. For the primary measure, BPI average pain severity, the mean change was not statistically different between duloxetine and placebo (- 1.62 vs. -0.97, respectively; p = .052). For secondary efficacy outcomes, statistically significantly more duloxetine- versus placebo-treated patients had a treatment response (≥30% and ≥50% reductions on BPI average pain severity) and improvement of the general activity and relationships items on the BPI interference subscale. The percentage of patients reporting at least 1 treatment-emergent adverse event was higher in the duloxetine versus placebo groups (82.42% vs. 62.37%, respectively; p = .003). The overall safety profile of duloxetine in this study was similar to that reported previously in duloxetine pediatric trials of other indications. CONCLUSIONS: The primary study outcome, mean change in 24-h BPI average pain severity rating from baseline to Week 13, did not significantly improve with duloxetine compared to placebo in patients with JFM. However, significantly more patients on duloxetine compared to placebo had a ≥30% and ≥50% reduction in pain severity. There were no new safety concerns related to duloxetine in the study population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01237587 . Registered 08 November, /2010.

A probable case of movement disorder (Tardive dyskinesia) due to duloxetine treatment.

Tardive dyskinesia and tardive dystonia are caused by dopamine receptor blocking agents, mostly antipsychotics and sometimes antidepressants or calcium channel blockers. Duloxetine is a serotonin-noradrenaline reuptake inhibitor used in the treatment of diabetic neuropathic pain and fibromyalgia, as well as major depression. In this case, we aimed to discuss the tardive dyskinesia-like appearance of a patient using duloxetine due to fibromyalgia.

Milnacipran: serotonin-noradrenaline reuptake inhibitor approved for fibromyalgia may be a useful antidepressant.

OBJECTIVE: Milnacipran is a serotonin noradrenaline reuptake inhibitor (SNRI) approved for treatment of fibromyalgia in Australia, but is used for depression in Europe and elsewhere. This paper will briefly review milnacipran and its utility in psychiatry for the treatment of depression. CONCLUSION: Milnacipran is a dual reuptake inhibitor of noradrenaline and serotonin, with greater effect on noradrenaline than serotonin, in contrast to the related drugs venlafaxine, desvenlafaxine and duloxetine. Rapidly absorbed irrespective of food, milnacipran has a half-life of approximately 8 hours, reaches steady state in 2 days and is excreted renally. Milnacipran helps a minority of patients with fibromyalgia by reducing pain and fatigue. It is also an effective antidepressant with efficacy comparable to venlafaxine and duloxetine, and a side effect profile characteristic of SNRIs. The dose range is 50-200 mg, in divided doses. Milnacipran may be useful for patients with depression and pain, and endogenous depression characterised by anergia, psychomotor retardation and hypersomnia. Caution is necessary in the presence of heart disease, hypertension, renal impairment, epilepsy, glaucoma, bipolar disorder, and bleeding tendency. Milnacipran is likely to be a useful late antidepressant option in treatment-resistant patients, as well as those with chronic pain, anergia and hypersomnia.

Comparative study of the effects of venlafaxine and duloxetine on chemotherapy-induced peripheral neuropathy.

OBJECTIVE: One of the complications of chemotherapy is peripheral neuropathy. Various studies have shown that potent norepinephrine and serotonin reuptake inhibitors such as gabapentin, venlafaxine and duloxetine have therapeutic effects on neuropathy. The aim of this study was to compare the effects of venlafaxine vs. duloxetine on chemotherapy-induced peripheral neuropathy. METHODS: In this clinical trial, cancer patients who were suffering from chemotherapy-induced peripheral neuropathy comprised the study population. They were randomly assigned to three pharmacotherapy groups including venlafaxine, duloxetine and placebo. Cranial, sensory, motor neuropathies as well as neuropathic pain were evaluated on day 1, week 2, and week 4 after enrollment. RESULTS: Grade of cranial, motor, sensory and neuropathic pain decreased significantly in venlafaxine and duloxetine groups. This reduction was more considerable in duloxetine group compared to venlafaxine group (P < 0.05). CONCLUSION: Duloxetine seems to be more effective than venlafaxine in decreasing the symptoms of chemotherapy-induced peripheral neuropathy. Duloxetine was more effective than venlafaxine in decreasing motor neuropathy and neuropathic pain grade.

Duloxetine and escitalopram for hot flushes: efficacy and compliance in breast cancer survivors.

Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) might be an effective treatment for hot flushes (HFs) in breast cancer survivors (BCSs). This study aims to compare the efficacy and tolerability of duloxetine (SNRI) versus escitalopram (SSRI) in reducing frequency and severity of HFs in BCSs and to assess the effect on depression. Thirty-four symptomatic BCSs with emotional impairment received randomly duloxetine 60 mg daily or escitalopram 20 mg daily for 12 weeks. Patients were asked to record in a diary HF frequency and severity at baseline and after 4 and 12 weeks of treatment. Depression was evaluated through validated questionnaires (Beck Depression Inventory and Montgomery Asberg Depression Rating Scale) at baseline and after 4 and 12 weeks of treatment. Both drugs showed a significant reduction of HF frequency and severity after 12 weeks of treatment with no significant difference between the two groups. A significant improvement in depression symptoms was observed at the end of the study period within both the groups, without difference between the two drugs. In conclusion, escitalopram and duloxetine are both effective treatment for the relief of HFs in BCSs, with similar beneficial effect. A significant improvement of depression was obtained with no major side effects.

Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors Are Not Associated With Bleeding or Transfusion in Cardiac Surgical Patients.

BACKGROUND: Selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) use is known to alter platelet activation and aggregation leading to impairment in hemostasis. Previous studies are ambiguous with regard to bleeding, transfusion, and perioperative complications in patients undergoing cardiac surgery. The purpose of this study was to evaluate the risk of perioperative bleeding, transfusion, morbidity, and mortality in cardiac surgical patients taking SSRI/SNRIs compared with propensity-matched controls. METHODS: Adult patients undergoing cardiac surgery with cardiopulmonary bypass at our institution between January 1, 2004, and December 31, 2014, were eligible for study inclusion. Patients taking SSRI/SNRI medications at the time of surgery were identified and compared against all other patients not taking SSRI/SNRI medications to produce well-matched groups via propensity score analysis. Patients taking SSRI/SNRI medications were matched in a 1:1 ratio to control patients not taking these medications based on an internally estimated propensity score. Primary outcomes included perioperative blood transfusion, chest tube output, and reoperation for bleeding. Secondary outcomes included postoperative complications (renal failure, stroke or transient ischemic accident, prolonged mechanical ventilation, and perioperative myocardial infarction), intensive care unit (ICU) and hospital length of stay (LOS), and 30-day mortality. RESULTS: A total of 1417 pairs of SSRI/SNRI patients and matched controls were retained for analysis. Between SSRI/SNRI patients and matched controls, there was no significant difference in postoperative chest tube output (median, 750.0 vs 750.0 mL; P = .860) or reoperation for bleeding (2.8% vs 2.5%; P = .892). Perioperative transfusion rates across all time points and blood product type were not significantly different between groups, with the overall perioperative transfusion rate for SSRI/SNRI patients 66.5% vs 64.9% for matched controls (P = .697). Patients in the SSRI/SNRI group had a higher rate of prolonged mechanical ventilation (13.1% vs 8.6%; P = .002), longer ICU LOS (median, 25.5 vs 23.8 hours; P < .001), and longer hospital LOS (median, 6.0 vs 5.0 days; P < .001). Remaining mortality and outcome data were similar between groups. CONCLUSIONS: SSRI/SNRI use was not associated with an increased risk of bleeding or transfusion in patients undergoing cardiac surgery. While there was prolonged mechanical ventilation and increased ICU/hospital LOS in the SSRI/SNRI group, it is unclear that this finding is the result of such medications or rather associated with the underlying psychiatric condition for which they are prescribed. The results of this study suggest that perioperative interruption of SSRI/SNRIs to reduce the risk of perioperative bleeding and transfusion is unwarranted and may risk destabilization of patients' psychiatric condition.

Comparison of Bioavailability of Single-Dose Extended-Release Venlafaxine Capsules in Obese Patients Before and After Gastric Bypass Surgery.

STUDY OBJECTIVE: The extended-release (ER) form of venlafaxine is preferred because of improved patient adherence, but the immediate-release (IR) form is frequently used after Roux-en-Y gastric bypass (RYGB) surgery because of concerns for malabsorption. The objective of this study was to determine whether a statistically significant and predictable change in the bioavailability of venlafaxine ER capsules occurs after RYGB. DESIGN: Prospective nonblinded single-dose pharmacokinetic study. SETTING: Clinical research unit at a large tertiary care medical practice. PATIENTS: Ten adult pre-bariatric surgery patients who met the criteria for noncomplicated RYGB were enrolled and served as their own controls. INTERVENTIONS: Patients were administered one venlafaxine ER 75-mg capsule at two visits-the first visit at least 1 week before undergoing RYGB and the second visit 3-4 months after RYGB. Blood samples were collected at predetermined intervals over 48 hours after each dose, and the pharmacokinetics of venlafaxine were measured. MEASUREMENTS AND MAIN RESULTS: Plasma levels of venlafaxine and its primary metabolite, O-desmethylvenlafaxine (ODV), were compared at baseline and 3-4 months after RYGB. The areas under the serum concentration-time curves from 0-24 hours (AUC0-24 ) for venlafaxine (mean ± SD 734 ± 602 vs 630 ± 553 ng·hr/ml, p=0.22) and ODV (mean ± SD 894 ± 899 vs 1083 ± 972 ng·hr/ml, p=0.07) were similar before and after RYGB. Using a bioequivalence approach, differences in pre-RYGB and post-RYGB values of AUC0-24 , peak serum concentration, and time to peak serum concentration were not statistically significant for either venlafaxine or ODV. CONCLUSION: This study suggests that RYGB does not significantly alter the amount of venlafaxine or its active metabolite, ODV, absorbed from a venlafaxine ER capsule or the time over which it is absorbed.

Panicolytic-like effect of tramadol is mediated by opioid receptors in the dorsal periaqueductal grey.

Tramadol is a synthetic opioid prescribed for the treatment of moderate to severe pain, acting as agonist of µ-opioid receptors and serotonin (5-HT) and noradrenaline (NE) reuptake inhibitor. This study evaluated the effects of tramadol in rats submitted to the elevated T-maze (ETM), an animal model that evaluates behavioural parameters such as anxiety and panic. Male Wistar rats were intraperitoneally (i.p.) treated acutely with tramadol (16 and 32mg/kg) and were submitted to the ETM. Tramadol (32mg/kg) promoted a panicolytic-like effect. Considering that dorsal periaqueductal grey (dPAG) is the main brain structure related to the pathophysiology of panic disorder (PD), this study also evaluated the participation of 5-HT and opioid receptors located in the dPAG in the panicolytic-like effect of tramadol. Seven days after stereotaxic surgery for implantation of a cannula in the dPAG, the animals were submitted to the test. To assess the involvement of 5-HT1A receptors on the effect of tramadol, we combined the 5-HT1A receptor antagonist, WAY100635 (0.37nmol), microinjected intra-dPAG, 10min prior to the administration of tramadol (32mg/kg, i.p.). WAY100635 did not block the panicolytic-like effect of tramadol. We also associated the non-selective opioid receptor antagonist, naloxone, systemically (1mg/kg, i.p.) or intra-dPAG (0.5nmol) administered 10min prior to tramadol (32mg/kg, i.p.). Naloxone blocked the panicolytic-like effect of tramadol in both routes of administrations, showing that tramadol modulates acute panic defensive behaviours through its interaction with opioid receptors located in the dPAG.

Fatigue-related impairments in oculomotor control are prevented by norepinephrine-dopamine reuptake inhibition.

Fatigue-induced reductions in saccade velocity have been reported following acute, prolonged exercise. Interestingly, the detrimental impact of fatigue on oculomotor control can be prevented by a moderate dose of caffeine. This effect may be related to central catecholamine upregulation via caffeine's action as an adenosine antagonist. To test this hypothesis, we compared the protective effect of caffeine on oculomotor control post-exercise to that of a norepinephrine-dopamine reuptake inhibitor. Within a placebo-controlled crossover design, 12 cyclists consumed placebo, caffeine or a norepinephrine-dopamine reuptake inhibitor (bupropion) during 180 minutes of stationary cycling. Saccades, smooth pursuit and optokinetic nystagmus were measured using infrared oculography. Exercise fatigue was associated with an 8 ± 11% reduction in the peak velocity of prosaccades, and a 10 ± 11% decrement in antisaccade peak velocity. Optokinetic nystagmus quick phases decreased in velocity by 15 ± 17%. These differences were statistically significant (p < 0.05). Norepinephrine-dopamine reuptake inhibition and caffeine prevented fatigue-related decrements in eye movement velocity. Pursuit eye movements and visual attention were unaffected. These findings show that norepinephrine-dopamine reuptake inhibition protects oculomotor function during exercise fatigue. Caffeine's fatigue-reversing effects on eye movements appear to be mediated, at least in part, via modulation of central catecholamines.

SSRI and SNRI use during pregnancy and the risk of persistent pulmonary hypertension of the newborn.

AIM: The use of selective serotonin reuptake inhibitors (SSRIs) in late pregnancy may be associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). Limited data are available on the risk of PPHN associated with serotonin norepinephrine reuptake inhibitors (SNRIs). We aimed to quantify both associations. METHODS: Using data from the Quebec Pregnancy Cohort between 1998 and 2009, we included women covered by the provincial drug plan who had a singleton live birth. Exposure categories were SSRI, SNRI and other antidepressant use; non-users were considered as the reference category. Generalized estimating equation models were used to obtain risk estimates and 95% confidence intervals (CIs). Confounding by indication was minimized by adjusting for history of maternal depression/anxiety before pregnancy. RESULTS: Overall, 143 281 pregnancies were included; PPHN was identified in 0.2% of newborns. Adjusting for maternal depression, and other potential confounders, SSRI use during the second half of pregnancy was associated with an increased risk of PPHN [adjusted odds ratio (aOR) 4.29, 95% CI 1.34, 13.77] compared with non-use of antidepressants; SNRI use during the same time window was not statistically associated with the risk of PPHN (aOR 0.59, 95% CI 0.06, 5.62). Use of SSRIs and SNRIs before the 20th week of gestation was not associated with the risk of PPHN. CONCLUSIONS: Use of SSRIs in the second half of pregnancy was associated with the risk of PPHN. Given our results on SNRIs and the lack of statistical power for these analyses, it is unclear whether SNRI use during pregnancy also increases the risk of PPHN.

Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor.

AIM: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. METHODS: The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. RESULTS: Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex. CONCLUSION: Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.

MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy.

PURPOSE: Previous pilot data suggested that venlafaxine could prevent acute and chronic oxaliplatin-related neuropathy. The purpose of this randomized, placebo-controlled, double-blinded pilot study was to obtain additional data to support conducting a phase III trial to test the use of venlafaxine to prevent oxaliplatin neurotoxicity. METHODS: Fifty patients, scheduled to undergo oxaliplatin-based therapy (FOLFOX) for stages II-III (67%) or stage IV (33%) colon cancer, were randomized to receive venlafaxine extended release (37.5 mg) or placebo, twice daily, through their last dose of oxaliplatin and then titrated off. Neurotoxicity was evaluated via several patient- and physician-reported measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) instrument. RESULTS: Baseline patient characteristics were equivalent for the two arms, with a median age of 60 years. There was a trend toward benefit for the venlafaxine arm, when evaluated by the oxaliplatin-specific neuropathy scale and by acute neuropathy measures of throat discomfort and discomfort swallowing cold liquids, the latter only for the first two oxaliplatin doses. These trends were outweighed by a lack of any such trends in all other measurements including the following: (1) the CIPN20 sensory subscale (P = 0.55, primary endpoint), physician-completed NCI CTCAE assessment, or cumulative administered oxaliplatin doses (median 716 vs 631 mg for placebo and venlafaxine, respectively, P = 0.34). CONCLUSIONS: The present study neither supports the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice nor the initiation of a phase III trial to investigate venlafaxine in this setting.

The anti-inflammatory activity of duloxetine, a serotonin/norepinephrine reuptake inhibitor, prevents kainic acid-induced hippocampal neuronal death in mice.

Duloxetine (DXT), a potent serotonin/norepinephrine reuptake inhibitor, is widely used in the treatment of major depressive disorder. In the present study, we examined the effects of DXT treatment on seizure behavior and excitotoxic neuronal damage in the mouse hippocampal CA3 region following intraperitoneal kainic acid (KA) injection. DXT treatment showed no effect on KA-induced behavioral seizure activity. However, treatment with 10mg/kg DXT reduced KA-induced neuronal death in the hippocampal CA3 region at 72h after KA administration, and treatment with 20 and 40mg/kg DXT showed a noticeable neuroprotection in the hippocampal CA3 region after KA injection. In addition, KA-induced activations of microglia and astrocytes as well as KA-induced increases of TNF-α and IL-1ß levels were also suppressed by DXT treatment. These results indicate that DXT displays the neuroprotective effect against KA-induced excitotoxic neuronal death through anti-inflammatory action.