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Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) primarily used in the treatment of major depressive disorder and fibromyalgia. The aim of this study was to formulate and evaluate controlled-release Milnacipran tablets using hydrophilic polymers (HPMC K4M, HPMC K100M) and polyacrylate polymers (Eudragit RS100, Eudragit RL100) to enhance antidepressant activity. A total of 15 formulations (F1-F15) were developed using a direct compression method. "The micromeritic properties of the formulation blends were assessed." The compressed tablets were evaluated for various parameters such as hardness, friability, weight uniformity, and drug content, all of which met the required standards. The study concluded that both Eudragit and HPMC polymers effectively controlled the release of Milnacipran, making the formulations suitable for oncedaily administration, potentially improving patient compliance and therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Background Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown. Objective To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal. Design This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682). Setting We analysed trials from all settings. Participants We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache. Interventions We included all antidepressants. Main outcome measures Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial. Results We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled (n = 83) and parallel armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most 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. 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 for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Limitations The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects. Conclusions There is only reliable evidence for duloxetine in the treatment of chronic pain. 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. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. Future work There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance. Study registration This study is registered as PROSPERO CRD42020171855. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? Chronic pain is pain that lasts for more than 3 months. Over one-third of people across the world experience chronic pain. This often has a detrimental impact on people’s mood, disability and well-being. Antidepressants are often prescribed to reduce pain, but we are not sure which antidepressants work best for different types of pain, or whether they are safe. We wanted to find out whether antidepressants were effective and safe for management of chronic pain. What did we do? We searched for studies that had compared any antidepressant with any other treatment for any type of chronic pain (except headache). We compared all the treatments against each other using a statistical method called network meta-analysis. This method allows us to rank the treatments in order of best to worst for each outcome. What did we find? We found 176 studies that included a total of 28,664 people with chronic pain. Most of the studies (83/176) compared an antidepressant with a placebo (which looks like the real medicine but does not have any medicine in it). The evidence from our analysis suggests that: Duloxetine is the antidepressant that we have the most confidence in. It was the best antidepressant for reducing pain and improving physical function. A standard dose of duloxetine was equally as effective for reducing pain as a high dose of duloxetine. Milnacipran was also effective at reducing pain, but we are not as confident in this result as in the one for duloxetine because there were fewer studies with fewer people involved. Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review, and even for duloxetine and milnacipran, we do not know the long-term effects. It is important to recognise that the lack of evidence for the majority of antidepressants in this review does not necessarily equal a lack of benefit. Rather, this means that the large, high-quality trials required for us to be certain of an antidepressant’s effectiveness have not been undertaken. Altogether, although duloxetine and milnacipran are effective, the results of this review should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. These conclusions were informed by our patient and public involvement group. Scientific summary 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 examining all antidepressants across all chronic pain conditions. Objectives Our objective was to assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events and withdrawal. Search methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions up until 4 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 the study was required to be double-blind. RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) were included but rated as at high risk of bias. We excluded RCTs where the follow-up was < 2 weeks and those with < 10 participants in each trial arm. We included any antidepressant at any dose, for any indication but used primarily for treatment of people with chronic pain and compared to placebo or active intervention. Participants We included adults (aged 18 years or older) reporting primary or secondary pain in any part of their body (except headache) as their primary complaint, that matched the International Association for the Study of Pain definition of chronic pain (i.e. at least 3 months’ duration). We included all trials regardless of the severity of participants’ chronic pain, although we extracted whether severity was part of the inclusion criteria of the individual studies. We excluded studies where the participants’ primary pain condition was headache or migraine. Data collection and analysis Two authors separately screened, extracted data and judged risk of bias. We synthesised the data using Bayesian network meta-analysis (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. We primarily used the Confidence in Network Meta-Analysis (CINeMA) framework and ‘Risk Of Bias due to Missing Evidence in Network meta-analysis’ (ROB-MEN) tool 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 Grading of Recommendations, Assessment, Development and Evaluations (GRADE) to assess the certainty of the evidence. Main results This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (n = 83) and parallel-armed (n = 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 NMAs. 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 trials, 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 For pain relief, duloxetine standard dose showed a small to moderate effect for substantial pain relief [odds ratio 0.91, 95% confidence interval (CI) 0.56 to 0.84] and continuous pain intensity [standardised mean difference (SMD) −0.31, 95% CI −0.39 to −0.24]. For pain intensity, milnacipran standard dose also showed a small effect (SMD −0.22, 95% CI −0.39 to 0.06) with moderate-certainty evidence. For mood, mirtazapine had a moderate effect (SMD −0.5, 95% CI −0.78 to −0.22), while duloxetine showed a small effect (−0.16, 95% CI −0.22 to −0.1); however, it is important to note that most trials 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 equally 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, there is reliable evidence for only duloxetine in the treatment of chronic pain. 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. Data for all other antidepressants were of 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 and safety of any antidepressant. Study registration This study is registered as PROSPERO CRD42020171855. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.

Milnacipran is a dual serotonin and norepinephrine reuptake inhibitor, clinically used for the treatment of major depression or fibromyalgia. Currently, there are no studies reporting the pharmacokinetics (PK) of milnacipran after intraperitoneal (IP) injection, despite this being the primary administration route in numerous experimental studies using the drug. Therefore, the present study was designed to investigate the PK profile of IP-administered milnacipran in mice and compare it to the intravenous (IV) route. First a liquid chromatography–mass spectrometry (LC-MS/MS) method was developed and validated to accurately quantify milnacipran in biological samples. The method was used to quantify milnacipran in blood and brain samples collected at various time-points post-administration. Non-compartmental and PK analyses were employed to determine key PK parameters. The maximum concentration (Cmax) of the drug in plasma was at 5 min after IP administration, whereas in the brain, it was at 60 min for both routes of administration. Curiously, the majority of PK parameters were similar irrespective of the administration route, and the bioavailability was 92.5% after the IP injection. These findings provide insight into milnacipran's absorption, distribution, and elimination characteristics in mice after IP administration for the first time and should be valuable for future pharmacological studies. [ABSTRACT FROM AUTHOR]

(1) Background: Milnacipran is a typical serotonin–norepinephrine reuptake inhibitor and has been shown to have analgesic effects in several pain models. However, its antihyperalgesic effect in cisplatin-induced neuropathy remains unknown. We examined the effects of intraperitoneal (IP) milnacipran on allodynia in cisplatin-induced peripheral neuropathic mice. (2) Methods: Peripheral neuropathy was induced by injecting cisplatin (2.3 mg/kg/day, IP) six times, on every other day. Saline or milnacipran (10, 30, 50 mg/kg, IP) were then administered to the neuropathic mice. We examined mechanical allodynia using von Frey hairs at preadministration and at 30, 60, 90, 120, 180, 240 min and 24 h after drug administration. We also measured the dorsal root ganglion (DRG) activating transcription factor 3 (ATF3) to confirm the analgesic effects of milnacipran. (3) Results: For the milnacipran groups, the decreased paw withdrawal thresholds to mechanical stimuli were significantly reversed when compared to the preadministration values and the values in the saline-injected control group (p < 0.0001). Milnacipran administration to cisplatin-induced peripheral neuropathic mice resulted in a significant suppression of neuronal ATF3 activation (p < 0.01). (4) Conclusions: Milnacipran given via IP injection attenuates mechanical allodynia in mouse models of cisplatin-induced poly-neuropathic pain. These effects were confirmed by significant suppression of neuronal ATF3 activation in the DRG. [ABSTRACT FROM AUTHOR]

Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3–4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 μL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors (p < 0.05), which generally normalized in MLN-treated rats (p < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is a chronic disease that causes neuronal plasticity and increased hypothalamic pituitary adrenal (HPA) axis of stress disorders. The change in metabolism is reportedly associated with inadequate response to antianxiety and antidepressant agents. Objective: This study aimed to determine the effect of milnacipran antidepressants on anxiety-like behavior in mice with diabetes mellitus. Methods: Male ICR mice were divided into naive, stress, diabetes mellitus (DM), DM + stress groups to measure anxiety-like behavior. Diabetes mellitus was induced using alloxan, and electric footshock stress was used as a stressor for 14 consecutive days. Anxiety-like behavior was measured using the light-dark box (LDB) and elevated plus maze (EPM) test at days 0, 7 and 14. The antidepressant milnacipran (MIL) was given for 7 days, on days 8 to 14. On day 14, evaluation of anxiety-like behavior after administration of MIL was carried out in all groups using LDB and EPM tests. Results: The results showed that administration of milnacipran effectively ameliorated anxiety-like behavior in the non-DM, but not in the DM group, using the LDB test. A similar result was demonstrated in the EPM test showing the non-DM group's attenuation after milnacipran administration. Conclusion: The present results indicate that there is an inadequate attenuation of the anxiety-like behavior after treatment with milnacipran in diabetes conditions.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the presynaptic neuronal uptake of serotonin and norepinephrine and prolong the effects of the monoamines in the synaptic cleft within the central nervous system, leading to increased postsynaptic receptor activation and neuronal activities. Serotonin-norepinephrine reuptake inhibitors can have multiple clinical indications, including as the first-line agents for the management of depression and anxiety, and as analgesics in the treatment of chronic pain. The effects of reuptake inhibition of norepinephrine and serotonin are often dose-dependent and agent-dependent. There are five FDA-approved serotonin-norepinephrine reuptake inhibitors (desvenlafaxine, duloxetine, levomilnacipran, milnacipran and sibutramine) currently being marketed in the United States. As the COVID-19 pandemic significantly increased the incidence and prevalence of anxiety and depression across the country, there are significantly increased prescriptions of these medications perioperatively. Thus, anesthesiologists are more likely than ever to have patients administered with these agents and scheduled for elective or emergency surgical procedures. A thorough understanding of these commonly prescribed serotonin-norepinephrine reuptake inhibitors and their interactions with commonly utilized anesthetic agents is paramount. There are two potentially increased risks related to the continuation of SNRIs through the perioperative period: intraoperative bleeding and serotonin syndrome. SNRIs have some off-label uses, more new indications, and ever-increasing new applications in perioperative practice. This article aims to review the commonly prescribed serotonin-norepinephrine reuptake inhibitors and the current clinical evidence regarding their considerations in perioperative anesthesia and analgesia.

Currently, in various world regions, the prevalence of depressive and anxiety disorders due to the impact of coronavirus infection is repeatedly increased compared to that in previous years. Among the predictors of their development during the pandemic, there are COVID-19 symptoms, a history of mental disorders, as well as restrictive measures, and financial losses.The paper describes three clinical cases of depressive disorders during the COVID-19 pandemic, with the depiction of the anamnesis, somatic and mental status, the patholopsychogical qualification of the condition, and the justification of a therapy regimen. The multifactorial stressor effect of the COVID-19 pandemic has provoked an exacerbation of depression in a male patient with a history of affective disorder; the development of a nosogenic depressive reaction of demoralization in a female patient with coronavirus pneumonia; the worsening of somatization dysthymia in a female patient of involutional age. The timely recognition of depression and its treatment with currently available antidepressants have contributed to the achievement of high-quality remission, the increase of stress resistance, and the improvement of quality of life in the patients.

Selective serotonin reuptake inhibitors (SSRI)-induced apathy syndrome occurs in 5–20% of patients taking these drugs.Objective: to investigate the possibility and advantages of switching patients with SSRI-induced apathy to treatment with a SSRI and norepinephrine reuptake inhibitor.Patients and methods. The investigation enrolled 105 depressive patients without psychotic symptoms, who were observed to develop symptoms of SSRI-induced apathy during SSRI antidepressant monotherapy for at least 6 months. The patients were randomized to groups: 1) 35 patients were switched to milnacipran (Ixel 50–100 mg/day) with simultaneous antidepressant replacement; 2) 35 patients were prescribed milnacipran with a 2-week gradual discontinuation of the previous SSRI; 3) 35 patients were switched to combined therapy with milnacipran 50–100 mg/day and sulpiride (Eglonyl 50 mg/day). The latter was prescribed to test the hypothesis for the benefits of combined correction of SSRI-induced apathy syndrome. The duration of the investigation was 3 months. Changes in the condition of the patients were assessed during their visits before and 1, 2, 4, 8, and 12 weeks after changing therapy. The efficiency of antidepressant therapy was studied using the 21-item Hamilton Depression Rating Scale (HDRS-21) and the Clinical Global Impression (CGI) rating scale; the changes in the severity of asthenic manifestations were examined according to a subjective asthenia assessment (Multidimensional Fatigue Inventory (MFI-20)). The UKU side effect rating scale was used to verify side effects.Results and discussion. A significant (p

Introduction Fibromyalgia is a chronic pain disorder characterized by widespread pain, fatigue, and sleep disturbances. The purpose of this study was to compare how well duloxetine, pregabalin, and milnacipran worked for fibromyalgia patients in terms of pain management, quality of life, and sleep quality. Methodology A prospective cohort research study with 193 fibromyalgia patients was carried out at the Abbas Institute of Medical Sciences, Muzaffarabad, Pakistan. For a total study duration of nine months, participants were prescribed milnacipran, pregabalin, or duloxetine for six months, and followed up monthly for an additional three months after completing therapy. At baseline and at the conclusion of the study, measures of pain intensity, quality of life (Fibromyalgia Impact Questionnaire, FIQ), and sleep quality (Pittsburgh Sleep Quality Index, PSQI) were taken. Analysis of variance (ANOVA) and paired t-tests were among the statistical studies carried out. Results Significant improvements in pain, quality of life, and sleep quality were shown by all three drugs. The most significant benefits were from duloxetine, which dramatically reduced pain and improved sleep and quality of life (p < 0.05). Pregabalin was less successful at improving quality of life than it was at reducing pain and promoting better sleep. Milnacipran had less of an effect on quality of life but showed modest effectiveness in managing fatigue and reducing discomfort. Due to moderate side effects, such as nausea and dizziness, duloxetine had greater rates of discontinuation. Conclusion Duloxetine was the most effective treatment, improving pain, quality of life, and sleep quality. Pregabalin is beneficial for pain and sleep management, while milnacipran remains a viable option for those with predominant fatigue. These results support the use of these medications in fibromyalgia treatment., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Abbas Institute of Medical Sciences issued approval 7412/AIMS/2023, dated: December 12, 2023. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Faizan Ejaz et al.)

Objectives: To summarise and evaluate Cochrane reviews of pharmacological therapies for adults with fibromyalgia syndrome (FMS) pain., Methods: Systematic search of Cochrane Database of Systematic Reviews to May 2024. Generic quality assessment used AMSTAR-2 criteria, validity checks of potentially critical factors in evaluation of analgesic efficacy, and assessment of susceptibility of results to publication bias. Pain outcomes were participant-reported pain relief of ≥ 30% or ≥ 50%, or PGIC much or very much improved., Results: Twenty-one reviews (87 trials, 17,631 patients) were included. All rated moderate (15) or high-quality (6) using AMSTAR-2 and at least seven of eight critical pain criteria were met by 13 of 21 reviews. Diagnosis of FMS used recognised criteria. Seven reviews found no trials (carbamazepine, clonazepam, lamotrigine, phenytoin, oxycodone, topiramate, or valproate), seven had limited and inadequate data (antipsychotics, cannabinoids, combination therapy, gabapentin, lacosamide, monoamine oxidase inhibitors, NSAIDs), and two were subject to publication bias (amitriptyline, SSRI). Mirtazapine had moderate evidence of no effect. Duloxetine, milnacipran, and pregabalin had moderate/good evidence of substantial pain relief for 4-12 weeks in around 1 in 10 adults with moderate or severe FMS pain, without evidence of efficacy beyond six months. Serious adverse events were no more common than with placebo. There was no evidence about who might benefit or experience adverse events. There was no substantial efficacy evidence for other medicines., Conclusions: Duloxetine, milnacipran, and pregabalin had good evidence that about 1 person in 10 with moderate or severe pain experienced pain intensity reduction by at least 50%., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the presynaptic neuronal uptake of serotonin and norepinephrine and prolong the effects of the monoamines in the synaptic cleft within the central nervous system, leading to increased postsynaptic receptor activation and neuronal activities. Serotonin-norepinephrine reuptake inhibitors can have multiple clinical indications, including as the first-line agents for the management of depression and anxiety, and as analgesics in the treatment of chronic pain. The effects of reuptake inhibition of norepinephrine and serotonin are often dose-dependent and agent-dependent. There are five FDA-approved serotonin-norepinephrine reuptake inhibitors (desvenlafaxine, duloxetine, levomilnacipran, milnacipran and sibutramine) currently being marketed in the United States. As the COVID-19 pandemic significantly increased the incidence and prevalence of anxiety and depression across the country, there are significantly increased prescriptions of these medications perioperatively. Thus, anesthesiologists are more likely than ever to have patients administered with these agents and scheduled for elective or emergency surgical procedures. A thorough understanding of these commonly prescribed serotonin-norepinephrine reuptake inhibitors and their interactions with commonly utilized anesthetic agents is paramount. There are two potentially increased risks related to the continuation of SNRIs through the perioperative period: intraoperative bleeding and serotonin syndrome. SNRIs have some off-label uses, more new indications, and ever-increasing new applications in perioperative practice. This article aims to review the commonly prescribed serotonin-norepinephrine reuptake inhibitors and the current clinical evidence regarding their considerations in perioperative anesthesia and analgesia. [ABSTRACT FROM AUTHOR]

The effects of psychotropic agents such as fluvoxamine, fluoxetine, paroxetine, milnacipran, and fluphenazine on dopamine formation from p-tyramine catalysed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared with the effects on dopamine formation from p-tyramine by CYP2D6.1. Michaelis constants (Km) and maximal velocity (kcat) values for dopamine formation and inhibition constants (Ki) of the psychotropic agents were determined. For CYP2D6.39, the kcat values for fluvoxamine, fluoxetine, and milnacipran, but not for paroxetine and fluphenazine, gradually increased with increasing concentrations, indicating activation of the catalysed reaction. Fluphenazine competitively inhibited dopamine formation catalysed by all variants, with a higher Ki value for CYP2D6.10. Among the three compounds that have a trifluoromethyl group in their chemical structure, only fluvoxamine and fluoxetine, as well as milnacipran that does not have this group, decreased Km values and/or increased kcat values for dopamine formation, suggesting that the group may not be essential for the activation. These findings indicate that substitution of amino acids at positions 34 and 486 can affect the affinity (Km) and enzymatic activity (kcat), respectively, for milnacipran and that the effect of substitution of arginine to cysteine at the 296th position on the activation would be effector dependent. [ABSTRACT FROM AUTHOR]