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BMC Anesthesiology May 2023Although laparoscopic surgery provides earlier recovery, less morbidity and hospital stay, however, severe pain is still a problem after it. Duloxetine has been recently... (Clinical Trial)
Clinical Trial
BACKGROUND
Although laparoscopic surgery provides earlier recovery, less morbidity and hospital stay, however, severe pain is still a problem after it. Duloxetine has been recently used in postoperative pain management. We tested perioperative duloxetine to evaluate its effect on patients undergoing laparoscopic colorectal cancer surgery.
METHODS
Sixty patients were enrolled in this study divided into two equal groups; duloxetine group each patient received an oral duloxetine capsule (60 mg) 1st dose at night before surgery, the 2nd dose 1 h preoperative, and the 3rd dose 24 h postoperative. Placebo group received placebo capsules at the same times. The cumulative morphine consumption in 48 h, postoperative VAS score, quality of recovery (QoR-40 score), sedation, and adverse effects were evaluated.
RESULTS
Duloxetine group had lower VAS scores compared to placebo group, (3 ± 0.69) VS. (4.17 ± 0.83), (2.5 ± 0.6) VS. (4.3 ± 0.9), (2.2 ± 0.7) VS. (3.9 ± 0.6), (1.6 ± 0.7) VS. (3.6 ± 0.8), (1.1 ± 0.8) VS. (3.7 ± 0.7), (0.7 ± 0.7) VS. (3.5 ± 0.8), (0.6 ± 0.7) VS. (3.5 ± 0.8) respectively, P ˂0.01. The cumulative morphine consumption was significantly reduced in the Duloxetine group compared to the placebo group (4.6 ± 2.9 vs. 11.3 ± 1.7 mg), P < 0.01. The total QoR-40 score for duloxetine group was (180.8 ± 4.5) vs. (156 ± 5.9) in placebo group (P < 0.01). Patients in Duloxetine group were more sedated in all the 48 h postoperatively in comparison to placebo group.
CONCLUSIONS
Perioperative duloxetine had reduced postoperative pain, decreased opioid consumption, and improved the quality of recovery in patients undergoing laparoscopic colorectal surgery.
Topics: Humans; Analgesia; Analgesics, Opioid; Colorectal Neoplasms; Double-Blind Method; Duloxetine Hydrochloride; Laparoscopy; Morphine; Pain, Postoperative
PubMed: 37194004
DOI: 10.1186/s12871-023-02119-8 -
Expert Review of Neurotherapeutics Jun 2023Generalized Anxiety Disorder (GAD) is a common psychiatric condition, characterized by the presence of general apprehensiveness and excessive worry. Current management... (Review)
Review
INTRODUCTION
Generalized Anxiety Disorder (GAD) is a common psychiatric condition, characterized by the presence of general apprehensiveness and excessive worry. Current management consists of a range of pharmacological and psychological treatments. However, many patients do not respond to first-line pharmacological treatments and novel anxiolytic drugs are being developed.
AREAS COVERED
In this review, the authors first discuss the diagnostic criteria and epidemiology of GAD. The effective pharmacological treatments for GAD and their tolerability are addressed. Current consensus guidelines for treatment of GAD are discussed, and maintenance treatment, the management of treatment resistance, and specific management of older adults and children/adolescents are considered. Finally, novel anxiolytics under development are discussed, with a focus on those which have entered clinical trials.
EXPERT OPINION
A range of effective treatments for GAD are available, particularly duloxetine, escitalopram, pregabalin, quetiapine, and venlafaxine. There is a limited evidence base to support the further pharmacological management of patients with GAD who have not responded to initial treatment. Although many novel anxiolytics have progressed to clinical trials, translation from animal models has been mostly unsuccessful. However, the potential of several compounds including certain psychedelics, ketamine, oxytocin, and agents modulating the orexin, endocannabinoid, and immune systems merits further study.
Topics: Humans; Anti-Anxiety Agents; Anxiety Disorders; Duloxetine Hydrochloride; Pregabalin; Treatment Outcome
PubMed: 37183813
DOI: 10.1080/14737175.2023.2211767 -
International Journal of Molecular... May 2023Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only...
Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only duloxetine has shown significant but moderate analgesic effect. Since statins, classically used to reduce hypercholesterolemia, have shown antinociceptive effect in preclinical studies on neuropathic pain, we studied whether the antinociceptive efficacy of duloxetine could be synergistically potentiated by rosuvastatin in a model of paclitaxel-induced neuropathy in mice. The astrocytic and microglial responses in the spinal cord of paclitaxel-treated mice were also assessed by measuring GFAP and CD11b proteins, respectively. Paclitaxel treatment did not impair motor coordination and balance in rotarod testing. Rosuvastatin, duloxetine, and the rosuvastatin/duloxetine combination (combined at equieffective doses) dose-dependently decreased mechanical allodynia (ED, von Frey testing) and thermal hyperalgesia (ED, hot plate testing) in paclitaxel-treated mice. Isobolographic analysis showed a superadditive interaction for rosuvastatin and duloxetine, as both the ED and ED for the rosuvastatin/duloxetine combination contained only a quarter of each drug compared to the individual drugs. The rosuvastatin/duloxetine combination reversed paclitaxel-induced GFAP overexpression, indicating that such effects might depend in part on astrocyte inactivation. Results suggest that statins could be useful in synergistically enhancing the efficacy of duloxetine in some chemotherapy-induced neuropathic conditions.
Topics: Mice; Animals; Paclitaxel; Duloxetine Hydrochloride; Rosuvastatin Calcium; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pain Measurement; Neuralgia; Hyperalgesia; Analgesics
PubMed: 37176065
DOI: 10.3390/ijms24098359 -
The Cochrane Database of Systematic... May 2023Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions.
OBJECTIVES
To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache).
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022.
SELECTION CRITERIA
We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm. DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal.
MAIN RESULTS
This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes.
AUTHORS' CONCLUSIONS
Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.
Topics: Adult; Humans; Antidepressive Agents; Chronic Pain; Duloxetine Hydrochloride; Milnacipran; Network Meta-Analysis; Pain Management; Randomized Controlled Trials as Topic
PubMed: 37160297
DOI: 10.1002/14651858.CD014682.pub2 -
Acta Crystallographica. Section E,... Apr 2023Duloxetine hydro-chloride (trade name Cymbalta) is marketed as a single enanti-omer ()--methyl-3-(naphthalen-1-yl-oxy)-3-(thio-phen-2-yl)propyl-am-in-ium chloride,...
Duloxetine hydro-chloride (trade name Cymbalta) is marketed as a single enanti-omer ()--methyl-3-(naphthalen-1-yl-oxy)-3-(thio-phen-2-yl)propyl-am-in-ium chloride, CHNOS·Cl, which is twice as effective as the ()-enanti-omer in serotonin uptake. Here, we report the crystal structure of duloxetine hydro-chloride in its racemic form (space group 2), where it shows significant differences in the mol-ecular conformation and packing in its extended structure compared to the previously reported ()-enanti-omer crystal structure. Mol-ecules of this type, comprising aromatic groups with a single side chain terminated in a protonated secondary amine, are commonly found in active anti-depressants. A Cambridge Structural Database survey of mol-ecules with these features reveals a strong correlation between side-chain conformation and the crystal packing: an extended side chain leads to mol-ecules packed into separated layers of hydro-phobic and ionic hydro-philic phases. By comparison, mol-ecules with bent side chains, such as racemic duloxetine hydro-chloride, lead to crystal-packing motifs where an ionic hydro-philic phase is encapsulated within a hydro-phobic shell.
PubMed: 37151834
DOI: 10.1107/S2056989023003353 -
International Journal of Surgery... Apr 2023The aim was to evaluate the efficacy and safety of duloxetine for postoperative recovery after total knee arthroplasty. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim was to evaluate the efficacy and safety of duloxetine for postoperative recovery after total knee arthroplasty.
METHODS
The following electronic databases were searched for eligible trials: PubMed, EMBASE, Web of Science, Cochrane Library, VIP, Wanfang Data, and China National Knowledge Infrastructure (CNKI). The search was performed from the inception dates to 10 August 2022. Data extraction and quality assessment were performed by two independent reviewers. Standard mean differences or mean differences with 95% CIs for pooled data were calculated. The primary outcomes were pain, physical function, and analgesic consumption. Secondary outcomes included range of motion (ROM) of the knee, depression, and mental health.
RESULTS
This meta-analysis included 11 studies, reporting on a total of 1019 patients. Results of analyses indicated that duloxetine showed a statistically significant reduction in pain at rest at 3 days, 1 week, 2, and 6 weeks and pain on movement at 5 days, 1 week, 2, 4, 6, and 8 weeks. However, there was no statistical significance in pain at rest and on movement at 24 h, 12 weeks, 6 months, and 12 months. Additionally, duloxetine had a significant improvement in physical function, ROM of the knee at 6 weeks, and emotional function (depression and mental health). Moreover, the cumulative opioid consumption at 24 h in the duloxetine groups was lower than in the control groups. But there was no statistical significance for the cumulative opioid consumption over 7 days between the duloxetine groups and controls.
CONCLUSIONS
In conclusion, duloxetine might reduce pain mainly over a time span of 3 days-8 weeks and lower cumulative opioid consumption within 24 h. In addition, it improved physical function, ROM of the knee with a time span of 1-6 weeks and emotional function (depression and mental health).
Topics: Humans; Arthroplasty, Replacement, Knee; Duloxetine Hydrochloride; Analgesics, Opioid; Knee Joint; Pain, Postoperative
PubMed: 37097617
DOI: 10.1097/JS9.0000000000000230 -
The Clinical Journal of Pain May 2023Duloxetine is a serotonin-norepinephrine reuptake inhibitor prescribed for musculoskeletal and other forms of chronic pain. Its dual pharmacologic properties have the...
OBJECTIVE
Duloxetine is a serotonin-norepinephrine reuptake inhibitor prescribed for musculoskeletal and other forms of chronic pain. Its dual pharmacologic properties have the potential to either raise or lower cardiovascular risk: adrenergic activity may increase the risk for acute myocardial infarction (AMI) and stroke, but antiplatelet activity may decrease risk. Gabapentin is another nonopioid medication used to treat pain, which is not thought to have adrenergic/antiplatelet effects. With the current emphasis on the use of nonopioid medications to treat patients with chronic pain, assessing cardiovascular risks associated with these medications among high-risk patients is important.
MATERIALS AND METHODS
We conducted a retrospective cohort study among a 20% sample of Medicare enrollees, aged 65 to 89, with chronic pain who were new users between 2015 and 2018 of either duloxetine (n = 34,009) or gabapentin (n = 233,060). We excluded individuals with cancer or other life-threatening conditions at study drug initiation. The primary outcome was a composite of AMI, stroke, and out-of-hospital mortality. We adjusted for comorbidity differences with time-dependent inverse probability of treatment weighting.
RESULTS
During 115,668 person-years of follow-up, 2361 patients had the composite primary outcome; the rate among new users of duloxetine was 16.7/1000 person-years compared with new users of gabapentin (21.1/1000 person-years), adjusted hazard ratio = 0.98 (95% CI: 0.83, 1.16). Results were similar for the individual components of the composite outcome as well as in analyses stratified by demographic and clinical characteristics.
DISCUSSION
In summary, cohort Medicare patients with non-cancer pain beginning treatment with duloxetine had rates of AMI, stroke, and out-of-hospital mortality comparable to those who initiated gabapentin.
Topics: Humans; Aged; United States; Duloxetine Hydrochloride; Gabapentin; Medicare; Retrospective Studies; Chronic Pain; Stroke; Myocardial Infarction; Hospitals
PubMed: 37094085
DOI: 10.1097/AJP.0000000000001105 -
BMJ (Clinical Research Ed.) Apr 2023The studyTesfaye S, Sloan G, Petrie J, et al. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine... (Randomized Controlled Trial)
Randomized Controlled Trial
The studyTesfaye S, Sloan G, Petrie J, et al. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial. 2022;400:680-90.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/combination-therapy-for-painful-diabetic-neuropathy-is-safe-and-effective/.
Topics: Humans; Diabetic Neuropathies; Pregabalin; Analgesics; Amitriptyline; Duloxetine Hydrochloride; Treatment Outcome; Double-Blind Method; Diabetes Mellitus
PubMed: 37085164
DOI: 10.1136/bmj.p866 -
Epilepsia Open Jun 2023We searched for, from the FDA (Food and Drug Administration-USA)-approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (eg, mild headache, sedation,...
OBJECTIVE
We searched for, from the FDA (Food and Drug Administration-USA)-approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (eg, mild headache, sedation, etc.) and with the ability to cross the blood brain barrier (BBB), using bio-informatics tools (in-silico). This may pave the road for designing clinical trials of such drugs in patients with functional seizures (FS) and other stress-associated disorders.
METHODS
Several databases were used to find all the approved drugs that potentially have interactions with FKBP51 protein [ie, CTD gene-chemical interaction section of FKBP51 protein of Harmonizome of Mayaanlab, DrugCenteral database, PDID (Protein Drug Interaction Database), DGIdb (the Drug Gene Interaction database)]. Other databases were also searched [eg, clinicaltrials.gov; DRUGBANK (the FASTA format of the FKBP51 protein was imported to the target sequencing section of the database to find the associated drugs), and the STITCH database (to find the related chemical interaction molecules)].
RESULTS
After a comprehensive search of the designated databases, 28 unique and approved drugs were identified. Fluticasone propionate and Mifepristone and Ponatinib, Mirtazapine, Clozapine, Enzalutamide, Sertraline, Prednisolone, Fluoxetine, Dexamethasone, Clomipramine, Duloxetine, Citalopram, Chlorpromazine, Nefazodone, and Escitalopram are inhibitors of FKBP5 and have BBB permeability.
SIGNIFICANCE
While the current in-silico repurposing study could identify potential drugs (that are already approved and are widely available) for designing clinical trials in patients with stress-associated disorders (eg, FS), any future clinical trial should consider the pharmacological profile of the desired drug and also the characteristics and comorbidities of the patients in order to foster a success.
Topics: United States; Humans; Sertraline; Fluoxetine; Citalopram; Clomipramine; Duloxetine Hydrochloride
PubMed: 37078238
DOI: 10.1002/epi4.12749 -
Basic & Clinical Pharmacology &... Jul 2023We aimed to unravel potential pharmacokinetic interactions between aripiprazole and duloxetine.
OBJECTIVE
We aimed to unravel potential pharmacokinetic interactions between aripiprazole and duloxetine.
METHODS
Plasma concentrations of aripiprazole in two groups of 78 patients each, receiving aripiprazole as a monotherapy or combined with duloxetine, were compared. A potential impact of duloxetine on the metabolism of aripiprazole was expected in higher plasma concentrations of aripiprazole and higher dose-adjusted plasma concentrations.
RESULTS
Patients co-medicated with duloxetine showed significantly higher plasma concentrations of aripiprazole by 54.2% (p = 0.019). Dose-adjusted plasma concentrations were 45.6% higher (p = 0.001); 12.8% of these patients exhibited aripiprazole plasma concentrations above the upper limit of the therapeutic reference range, in the control group this was only the case for 10.3% of the patients. A positive relationship was found between the daily dose of duloxetine and dose-adjusted plasma concentrations of aripiprazole (p = 0.034). As dehydroaripiprazole concentrations were not available, conclusions for the active moiety (aripiprazole plus dehydroaripiprazole) could not be drawn.
CONCLUSIONS
Combining duloxetine and aripiprazole leads to significantly higher drug concentrations of aripiprazole, most likely via an inhibition of cytochrome P450 CYP2D6 and to a lesser extent of CYP3A4 by duloxetine. Clinicians have to consider increasing aripiprazole concentrations when adding duloxetine to a treatment regimen with aripiprazole.
Topics: Humans; Aripiprazole; Duloxetine Hydrochloride; Antipsychotic Agents; Piperazines; Quinolones; Cytochrome P-450 CYP2D6
PubMed: 37069136
DOI: 10.1111/bcpt.13875