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References | PMC9875301 | |||
Abstract | PMC10107656 | |||
Introduction | HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA | Lomitapide is a microsomal triglyceride transfer protein inhibitor for patients with homozygous familial hypercholesterolaemia. Due to its mechanism of action, potential hepatic effects of lomitapide are of clinical interest. This study aimed to determine the long‐term hepatic safety of lomitapide. | PMC10107656 | |
Methods | HEPATIC FIBROSIS, LIVER FIBROSIS | Data were aggregated from the pivotal phase 3 and extension phase clinical trial with lomitapide (median 5.1 years; serum total bilirubin, transaminases, cytokeratin‐18 [CK‐18] and enhanced liver fibrosis [ELF] score, fat‐soluble vitamins and essential fatty acids), 8‐year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER) and real‐world evidence from a cohort of patients treated with lomitapide in Italy (hepatic elastography, and FIB‐4 score for hepatic fibrosis). | PMC10107656 | |
Results | hepatic stiffness, fibrosis | FIBROSIS, HY'S LAW CASE | In the phase 3 trial and the LOWER registry, any asymptomatic excursions in liver transaminase levels were not associated with elevations in bilirubin, and no Hy's law cases were detected in up to 8 years follow‐up. There were no clinically relevant increases among hepatic biomarkers CK‐18, CK‐18 fragments or ELF score and fat‐soluble vitamins and essential fatty acids remained above normal levels. In 34 patients treated in Italy with lomita pide for more than 9 years, elevations in hepatic fat were mild‐to‐moderate; hepatic stiffness remained normal, and the mean FIB‐4 score remained below the fibrosis threshold value of 2.67. | PMC10107656 |
Conclusions | These data indicate that the hepatic safety of lomitapide remains favourable with no clinically significant elevations in hepatic biomarkers and hepatic stiffness remained normal for more than 9 years follow‐up. | PMC10107656 | ||
Phase 3 trial | NCT00730236; extension phase: NCT00943306; LOWER: NCT02135705.
Italian Working Group on Lomitapide; for MEDLINE indexing: Angelo Baldassare Cefalù, Alessia Di Costanzo, Simone Bini, Antonina Giammanco, Maurizio Averna, Gabriella Iannuzzo, Giuliana Fortunato, Marco Gentile, Maria Donata Di Taranto, Arturo Pujia, Tiziana Montalcini, Chiara Pavanello, Laura Calabresi, Giovanni Battista Vigna, Marco Bucci, Katia Bonomo, Tiziana Sampietro, Francesco Sbrana, Patrizia Suppressa, Carlo Sabbà, Fabio Fimiani, Arturo Cesaro, Paolo Calabrò, Fulvio Ventura, Sergio D'Addato, Livia Pisciotta, Stefano Bertolini, Marcello Arca
| PMC10107656 | ||
Abbreviations | fatty liver | FATTY LIVER, LIVER FIBROSIS | alanine aminotransferaseaspartate aminotransferasebody mass indexconfidence intervalcytokeratin‐18docosahexaenoic aciddrug‐induced liver injurydiscriminative scoreeicosapentaenoic acidenhanced liver fibrosis scorefull analysis setfibrosis‐4hyaluronic acidhigh‐density lipoprotein cholesterolhomozygous familial hypercholesterolaemiainterquartile rangelipoprotein apheresisliver function testslow‐density lipoprotein cholesterolLomitapide Observational Worldwide Evaluation Registrymajor adverse cardiovascular eventmicrosomal triglyceride transfer proteinnon‐alcoholic fatty liver diseasenon‐alcoholic steatohepatitispropeptide of type III procollagenPacific Biomarkers Inc.proprotein convertase subtilisin/kexin type 9 inhibitorstandard deviationtotal cholesteroltriglyceridesmetalloproteinase 1upper limit of normalvery‐low‐density lipoproteins
| PMC10107656 |
Key points | hepatocellular damage, fibrosis | HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA, HEPATOCELLULAR DAMAGE, FIBROSIS | Lomitapide is an effective treatment for patients with homozygous familial hypercholesterolaemia which acts independently of the LDL receptor. As an inhibitor of the microsomal triglyceride transfer protein, lomitapide has been associated with a mild‐to‐moderate accumulation of hepatic fat. However, this did not translate into clinically meaningful increases in biomarkers of hepatocellular damage and hepatic imaging for fibrosis remained normal during long‐term follow‐up. | PMC10107656 |
INTRODUCTION | DILI, liver abnormalities, hepatotoxicity, liver damage, cirrhosis, cholestasis, steatohepatitis, drug‐induced liver injury | HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA, HOFH, CIRRHOSIS, LIVER DAMAGE, LIVER FIBROSIS, CHOLESTASIS, HEPATIC STEATOSIS, HEPATIC STEATOSIS, STEATOHEPATITIS | Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor indicated as an adjunctive therapy for low‐density lipoprotein cholesterol (LDL‐C) lowering in patients with homozygous familial hypercholesterolaemia (HoFH). Lomitapide reduces LDL‐C by a mean of 50.0%–76.6%Idiosyncratic hepatotoxicity is an unpredictable form of drug‐induced liver injury (DILI). It has varying delays to onset, occurs in the therapeutic dose range for the causative agent, and is characterised by high levels of liver transaminases and/or alkaline phosphatase and cholestasis.Hepatic steatosis is among the most common liver abnormalities,None of the types of long‐term liver damage outlined above have been observed during the clinical use of lomitapide in HoFH. However, as discussed, lomitapide has the potential to cause hepatic steatosis, and the question remains whether there is the development of steatohepatitis and subsequent liver fibrosis or cirrhosis over the long term. The current report includes previously unpublished hepatic safety data from several sources with the aim of gaining a better understanding of the long‐term hepatic safety of lomitapide. | PMC10107656 |
PATIENTS AND METHODS | The data described in this paper are derived from three different sources (Table | PMC10107656 | ||
Phase 3 clinical trial and long‐term extension study of lomitapide in patients with | NAFLD, beta‐carotene, fibrosis | LIVER FIBROSIS, COLD, FIBROSIS, CHRONIC LIVER DISEASE | The details of phase 3 clinical trial and its long‐term extension have been published before.Data from the clinical trial programme were used to evaluate mean liver transaminase levels and instances of Hy's law. For biomarker analysis, stored serum samples from the phase 3 trial were analysed by Pacific Biomarkers Inc (PBI). Measurements were conducted on cytokeratin‐18 (CK‐18), CK‐18 fragments, tissue inhibitor of metalloproteinase 1 (TIMP‐1), amino‐terminal propeptide of type III procollagen (P3NP) and hyaluronic acid (HA). Upper and lower limits of quantitation for the assays were determined by PBI. For CK‐18 and CK‐18 fragments, duplicate tests were conducted on matching aliquots 6 months apart to assess the stability of the samples in cold storage.Values for TIMP‐1, P3NP and HA can be used to calculate an individual patient's enhanced liver fibrosis (ELF) score. The ELF score correlates with the degree of fibrosis in chronic liver disease.In the present study, ELF was calculated using the formula provided by Guha et alELF scores derived by this method have a negative value. For NAFLD, indication of some degree of fibrosis is suggested by values greater than −0.6415. For ELF scores, above this figure, there is a 72% positive and 66% negative predictive value for fibrosis with a sensitivity of 80% and a specificity of 56%.Values for HA, P3NP, TIMP‐1 and ELF during lomitapide treatment were compared to those at baseline using a paired t‐test.Fat‐soluble vitamins and essential fatty acids were also measured as patients receiving lomitapide need to be on a low‐fat diet with <20% energy from fat due to the inhibitory effect of lomitapide on chylomicron formation in the intestine. It is important that these micronutrients are maintained at or above the normal level. Vitamins A, vitamin D and beta‐carotene were assessed by measuring serum concentrations of the individual nutrients. Vitamin E was reported as the ratio of vitamin E/total lipids (total cholesterol plus triglycerides). Levels of vitamin K were assessed directly by measuring the ratio of uncarboxylated osteocalcin/total osteocalcin. The fatty acid profile included serum levels of all essential fatty acids. All patients receiving lomitapide also received vitamin E and essential fatty acid supplements (daily amounts: vitamin E 400 IU, eicosapentaenoic acid [EPA] 110 mg, docosahexaenoic acid [DHA] 80 mg, alpha‐linolenic acid 220 mg and linoleic acid 200 mg). | PMC10107656 |
Lomitapide Observational Worldwide Evaluation Registry ( | LOWER is a global, prospective, observational registry assessing long‐term safety and effectiveness of lomitapide in clinical practice. | PMC10107656 | ||
Italian patient cohort sub‐analysis from the Pan European Observational Study conducted by the Italian and European Working Group on Lomitapide in | hepatic steatosis | LIVER, PATHOLOGY, LIVER FIBROSIS, HEPATIC STEATOSIS | The Pan European Observational Study has been published previously.Investigators were asked to retrieve all available hepatic ultrasound and elastography performed on the dates closest to the baseline and last follow‐up visit. The degree of hepatic steatosis was classified as mild, moderate or severe according to the criteria of local examiners. Liver elastography was measured and reported as velocity of transmission of a shear wave through the liver in kPa. Normal elastography results are in the range of 2–7 kPa.Laboratory tests were conducted according to each patient's individual visit schedule. Serum or plasma samples were analysed using local chemical pathology laboratory protocols. Among the laboratory parameters collected, hepatic biomarkers were analysed, including Fibrosis‐4 (FIB‐4). The FIB‐4 score is a simple, non‐invasive biomarker for liver fibrosis.Regardless of study, all patients provided an informed consent. All studies were conducted according to the principles of the Declaration of Helsinki. | PMC10107656 |
RESULTS | PMC10107656 | |||
Transaminases and Hy's law analysis | ±, Twenty‐nine | HOFH | Twenty‐nine HoFH patients in the pivotal phase 3 trial (follow‐up ≤1.5 years) were monitored for elevations in transaminases and any possible elevations in bilirubin (Figure Mean aminotransferase and bilirubin levels from the pivotal phase 3 trial in HoFH. Values represent means ± standard deviation. ULN for bilirubin (all patients) is 1.2 mg/dl; ULN for ALT in females is 33 and males is 40 IU/L; ULN for AST in females is 36 and males is 43 IU/L. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.In addition, a modest and gradual decrease in mean body weight (from 73.5 ± 18.1 kg at baseline to 67.8 ± 13.0 at week 78; p = .004) was observed (Figure Similarly, among the 214 patients in the FAS of the LOWER registry treated over an 8‐year period with lomitapide 5–40 mg/day (Figure In the 34 Italian patients reported here (genetic status reported in Table | PMC10107656 |
Biomarkers of hepatic safety | NAFLD, NASH, fibrosis, steatohepatitis | INFLAMMATION, FIBROSIS, STEATOHEPATITIS | During treatment with lomitapide in the pivotal phase 3 and extension trials, circulating levels of CK‐18 and CK‐18 fragments were measured as biomarkers of hepatic inflammation and indicators of non‐alcoholic steatohepatitis (NASH). Mean levels of CK‐18 and CK‐18 fragments exhibited statistically significant mean increases from baseline to week 26, and then remained relatively stable between weeks 26 and 126 (Figure CK‐18 fragments (A) and ELF component (B) biomarkers during lomitapide treatment in the long‐term extension study. Values represent mean (95% CI) CK‐18 and extracellular matrix markers in patients with follow‐up data. *For HA and TIMP‐1, statistically significant mean elevations over baseline were only evident for HA at week 56 (12.4 ng/ml [95% CI: 1.5, 23.3] Evaluating ELF at the individual patient level showed that there were five patients with ELF scores >−0.6415 post‐baseline through week 78. These elevated scores were mostly at single timepoints—one patient at week 26 (−0.5510), two patients at week 56 (−0.3357 and −0.5731), one patient at week 78 (−0.4715), and one patient at weeks 26, 56 and 78 (−0.3317, −0.3787 and −0.1195). For this latter patient, hepatic fat content was 0.86% at baseline, 11.85% at week 26 and 0.39% at week 56, indicating that NAFLD was not present in this patient. One subject had ELF >−0.6415 at baseline but not thereafter. No subjects exhibited ELF scores that would exceed the threshold whereby the odds of having either moderate or severe fibrosis would exceed the odds of not having moderate or severe fibrosis. During the study, none of the patients underwent post‐baseline liver biopsy due to liver‐related safety concerns. | PMC10107656 |
hepatic stiffness | In the present study, FIB‐4 scores were calculable in 25 patients belonging to the Italian cohort with baseline and follow‐up data on platelet levels and transaminases, ALT and AST. FIB‐4 results showed no significant increase in mean FIB‐4 scores from baseline for up to 110.4 months (>9 years; exposure range 1.4–110.4 months, median exposure 31.3 months; Figure FIB‐4 scores by months of treatment with lomitapide in patients with baseline and follow‐up data (One patient (patient 1) had elevated baseline and follow‐up FIB‐4 scores >2.67 (4.78 and 4.37, respectively). A further patient (patient 7) with an elevated baseline FIB‐4 score of 2.20 showed a modest increase to >2.67 (2.79) at follow‐up. In these two cases, the patients were > 65 years old (77 and 66 years old, respectively; Figure Patient 16 also had elevated baseline and follow‐up FIB‐4 scores >2.67 (3.12 and 4.65, respectively; Figure In all cases, elevated FIB‐4 scores were set against a background of normal liver transaminases. For patients 7 and 16, FIB scores >2.67 were associated with normal hepatic stiffness measured by elastography <7.0 kPa (Table | PMC10107656 | ||
Hepatic Imaging | ±, hepatic stiffness, hepatic steatosis, fibrosis | FIBROSIS, EVENT, HEPATIC STEATOSIS, HOFH | The baseline characteristics of 34 HoFH patients from the Italian cohort are reported in Table Baseline characteristics of a real‐world cohort of HoFH patients from ItalyAbbreviations: BMI, body mass index; HDL‐C, high‐density lipoprotein cholesterol; IQR, interquartile range; LDL‐C, low‐density lipoprotein cholesterol; MACE, major adverse cardiovascular event; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; TC, total cholesterol; TG, triglycerides.Ultrasound and transient elastography were used to evaluate hepatic steatosis and hepatic stiffness (fibrosis), respectively. Of the total cohort (Change in ultrasound data in the Italian cohort (
In patients with elastography data at last follow‐up visit (n = 21), hepatic stiffness was normal in all patients treated with lomitapide for up to 117.4 months (9.8 years) with a mean of 4.9 ± 0.9 kPa (Figure Hepatic stiffness according to liver elastography by months of exposure to lomitapide in patients with follow‐up elastography data ( | PMC10107656 |
Fat‐soluble vitamins and essential fatty acids | beta‐carotene | In the phase 3 trial, levels of fat‐soluble vitamins remained relatively stable through week 78 of phase 3 study. Mean vitamin E levels (which were supplemented with 400 IU vitamin E daily) decreased by −1.2 mg/dl from baseline to weeks 26 and 78, but values did not fall below the normal range (Table The fat‐soluble vitamins A, D and K, and beta‐carotene, which were not supplemented in the diet, were measured throughout the study. Mean levels of vitamins A, D and K, increased from baseline to weeks 28 and 78, while beta‐carotene decreased slightly or remained unchanged. Mean levels of essential fatty acids (supplemented in the diet according to the prescribing information) decreased over time compared to baseline in the phase 3 study. However, there were no shifts to below‐normal levels in the fatty acids linoleic acid, alpha‐linolenic acid, arachidonic acid, EPA and DHA during 78 weeks of treatment (Table | PMC10107656 | |
Apheresis schedules | In the phase 3 study, 18 (62.1%) patients were on LA at baseline. At week 26, three (16.7%) had stopped LA and three (16.7%) had reduced their apheresis frequency. In the Italian cohort, median LDL‐C levels decreased by 58% from 276.5 mg/dl (IQR 196.0–386.2) to 131.0 mg/dl (66.6–228.5) at last visit ( | PMC10107656 | ||
DISCUSSION | NAFLD, hepatic alterations, hepatic inflammation, cirrhosis, fibrosis, liver disease, hepatic stiffness, NASH, hepatic steatosis, liver inflammation, metabolic syndrome, steatohepatitis | HOFH, GENETIC CONDITION, CVD, LIVER, CIRRHOSIS, LIVER DAMAGE, LIVER FIBROSIS, FIBROSIS, EVENT, LIVER DISEASE, METABOLIC SYNDROME, HEPATIC STEATOSIS, EVENTS, HEPATIC FIBROSIS, STEATOHEPATITIS | In the present study, we examined the long‐term hepatic safety of lomitapide based on a range of data available from various sources, which enabled the evaluation of follow‐up for more than 9 years. The data show that lomitapide results in some hepatic alterations, but that overall, there were no clinically meaningful signals of liver damage.Liver transaminases are routinely measured in patients receiving lomitapide for HoFH. In the present analysis of data from multiple sources, a minority of patients experienced increases in liver transaminase levels >3xULN. In LOWER, the majority of first events occurred within the first 12 months of treatment and all first events occurred within 20 months, which coincides with the period of lomitapide dose titration. The transaminase profile for lomitapide is similar to the profile seen in the early years with statins and has not been associated with an increase in other hepatic events with either medication. The number of hepatic transaminase elevations >3x ULN that persist >4 weeks despite dose reduction or interruption has remained unchanged since 2019.Evaluation of liver safety included assessment of biomarkers of liver inflammation, CK‐18 and CK‐18 fragments, in samples taken from patients in the phase 3 trial up to 126 weeks (>2 years). Studies have demonstrated that circulating levels of CK‐18 and CK‐18 fragments are correlated with the degree of hepatocyte apoptosis.Levels of HA, P3NP, and TIMP, and the ELF score (which combines all three independent markers) have been shown to correlate with the extent of hepatic fibrosis in several different conditions.The biomarker results were further supported by the analysis of FIB‐4 scores. FIB‐4 score is a useful, non‐invasive marker of liver fibrosis that uses a calculation based on platelet and transaminase levels to provide a validated measure of the risk of liver fibrosis.A FIB‐4 score above 2.67 is considered predictive for clinically meaningful fibrosis in NAFLD in all age groups >35 years old.Data from the Italian cohort also provided the opportunity to evaluate the effect of lomitapide on the liver using hepatic imaging (ultrasound and/or elastography) in patients exposed to long‐term treatment (more than 9 years). There was evidence of a mild to moderate increase in hepatic fat, which is not unexpected due to the mode of action of lomitapide that reduces the formation of VLDL and thereby the export of triglycerides from the liver, leading to a reduction in LDL‐C. However, elastography data demonstrated that the mild to moderate increase in hepatic fat observed in the HoFH patients treated with lomitapide did not translate into an increase in hepatic stiffness or fibrosis. Therefore, the long‐term, real‐world evidence in this cohort of 34 patients with >9 years support the notion that there are no signs of steatohepatitis or fibrosis in HoFH patients treated with lomitapide to date.The results described above indicate that, despite alterations in some liver parameters with lomitapide treatment, no HoFH patient progressed to develop NASH or cirrhosis. One hypothesis is that the mechanism of hepatic steatosis seen in some patients receiving lomitapide may be different to hepatic fat accumulation consequent to metabolic syndrome or genetic conditions. Hepatic fat accumulation is multi‐factorial, and contributing processes include MTP inhibition (e.g. lomitapidePatients receiving lomitapide were on a low‐fat diet with <20% energy from fat, with vitamin E and essential fatty acids supplemented to maintain normal levels. Data from the phase 3 trial, were collected on the fat‐soluble vitamins A, D, E and K, beta‐carotene and essential fatty acids. During the study period, there were no deficiencies in any of these key micronutrients and some increased slightly, indicating that the supplementation levels were sufficient, and no additional fat‐soluble vitamins required supplementation. The observed decrease in the mean levels of vitamin E from baseline to weeks 26 and 78 is not unexpected given the profound lipid‐lowering effect with lomitapide and the fact that vitamin E is transported to the peripheral tissues via LDL‐C.At baseline, patients in the Italian cohort had high LDL‐C levels (mean [IQR] 276.5 mg/dl [196.0–386.2 mg/dl]), despite having access to statins, ezetimibe, apheresis and PCSK9 inhibitors. More than half of patients had experienced a major adverse cardiovascular event by the time of their pre‐lomitapide baseline assessment. This represents a population with a high risk of cardiovascular events driven by very high cholesterol levels that are not controlled with standard lipid‐lowering therapy, which is a classic hallmark of HoFH. We noted in this cohort that only 35% were receiving apheresis at baseline, which is lower than that documented in some past studies.The present study has several limitations. Validation of CK‐18, CK‐18 fragments and ELF have been conducted in NAFLD and NASH.In conclusion, the MTP inhibitor lomitapide can cause temporary elevations in liver transaminases and mild to moderate accumulation of hepatic fat. Across the data sets analysed, biomarkers of hepatic inflammation or fibrosis do not suggest progressive liver disease over the course of the study and hepatic elastography remained normal after more than 9 years of lomitapide treatment. HoFH patients are at high risk of CVD events and premature mortality due to their extremely high LDL‐C exposure since birth. | PMC10107656 |
FUNDING INFORMATION | The phase 3 trial, extension phase study and the LOWER registry were funded by Amryt Pharmaceuticals DAC. The Italian study was funded as an investigator‐initiated study grant from Amryt Pharma. | PMC10107656 | ||
CONFLICT OF INTEREST | SOB | DL has received consultancy fees and/or honoraria from Amryt, Sanofi and Aegerion. LD has received consultancy fees and/or honoraria from Amgen, Akcea, Amryt, Pfizer, SOBI, Aurora Biopharma and Sanofi. SOB is an employee of Amryt Pharmaceuticals DAC. MA has received consultancy fees and/or honoraria from Akcea/Ionis, Alfasigma, Amgen, Amryt, Daichi‐Sankyo, Novartis, Pfizer, Regeneron, Sanofi. | PMC10107656 | |
ETHICS APPROVAL | The studies described were performed in accordance with the Helsinki Declaration of 1964, and its later amendments. All studies received institutional review board approval. All patients provided informed consent for study participation and publication of related data. | PMC10107656 | ||
REGISTRATION | MAY | Phase 3 trial: NCT00730236 reg. 8 August 2008; extension: NCT00943306 reg. 22 July 2009; LOWER: NCT02135705 reg. 12 May 2014. | PMC10107656 | |
Supporting information |
Data S1
Click here for additional data file. | PMC10107656 | ||
ACKNOWLEDGEMENTS | The authors thank Dr Nigel C Eastmond of Eastmond Medicomm Ltd for medical writing and editorial assistance with the collation of data and the preparation of this manuscript. Medical writing and editorial support was funded by Amryt Pharmaceuticals DAC. The authors thank the LOWER steering committee for provision of the 8‐year data set from LOWER registry. | PMC10107656 | ||
REFERENCES | PMC10107656 | |||
Background | postoperative pain | Thoracoscopic surgical techniques continue to advance, yet the intensity of postoperative pain remains significant, impeding swift patient recovery. This study aimed to evaluate the differences in postoperative pain and recuperation between patients receiving intrathecal morphine paired with low-dose bupivacaine and those administered general anesthesia exclusively. | PMC10691143 | |
Methods | NRS, pain | GROUP B, COMPLICATIONS | This randomized controlled trial enrolled 100 patients, who were allocated into three groups: Group M (5 μg/kg morphine intrathecal injection), Group B (5 μg/kg morphine combined with bupivacaine 3 mg intrathecal injection) and Group C (intrathecal sham injection). The primary outcome was the assessment of pain relief using the Numeric Rating Scale (NRS). Additionally, intraoperative remifentanil consumption was quantified at the end of the surgery, and postoperative opioid use was determined by the number of patient-controlled analgesia (PCIA) compressions at 48 h post-surgery. Both the efficacy of the treatments and any complications were meticulously recorded. | PMC10691143 |
Results | Postoperative NRS scores for both rest and exercise at 6, 12, 24, and 48 h were significantly lower in groups M and B than in group C ( | PMC10691143 | ||
Conclusion | pain | Intrathecal administration of morphine combined with bupivacaine has been shown to effectively ameliorate acute pain in patients undergoing thoracoscopic surgery. | PMC10691143 | |
Trial registration | The trial was registered on ClinicalTrials.gov: ChiCTR2200058544, registered 10/04/2022. | PMC10691143 | ||
Keywords | PMC10691143 | |||
Background | pain, lung tumors, trauma | LUNG TUMORS, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS | Video-assisted thoracoscopic surgery (VATS) has emerged as the principal surgical intervention for lung tumors [The evolution of surgical techniques and the integration of robotics have substantially reduced the extent of surgical trauma, supplanting traditional open surgery with less invasive methods. A solitary intrathecal injection of small-dose morphine is straightforward to administer and capable of delivering profound analgesia at low doses, accompanied by a scant number of postoperative complications. However, the delayed onset of intrathecal morphine, with its peak effect materializing after 6 h [The objective of our research was to assess the analgesic effectiveness of intrathecal morphine in patients undergoing VATS. We specifically confirmed that the combination of intrathecal morphine and bupivacaine surpasses intrathecal morphine alone in pain relief. Additionally, we observed that this combination diminished the intraoperative consumption of remifentanil and lessened the requirement for rescue analgesics during the first 48 h post-surgery. Furthermore, we documented the complications associated with each analgesic approach. | PMC10691143 |
Methods | PMC10691143 | |||
Ethics and registration | This study was approved by the Medical Ethics Committee in Affiliated Hospital of Yangzhou University, Jiangsu, China (Protocol/serial number: 2022-YKL3-08–002) on 8 March 2022. All study subjects gave informed consent for all treatments and investigations. All procedures in the study involving human participants were performed in accordance with the ethics standards of the institutional and national research committee and with the Helsinki Declaration and its later amendments or comparable ethics standards. The study was conducted and reported in accordance with the Consolidating Standards of Reporting Trials (CONSORT) 2010 statement. This trial was registered at the Chinese Clinical Trial Registry ( | PMC10691143 | ||
Patients inclusion and exclusion criteria | Subjects to be enrolled in the study were selected prior to an elective VATS procedure. | PMC10691143 | ||
Subject inclusion criteria |
An elective thoracoscopic lobectomy scheduled,The surgical procedure to be performed under general anaesthesia,Age from 18 to 64 years,Body Mass Index (BMI) from18 to 30 kg/mASA physical status classification system class I-II. | PMC10691143 | ||
Subject exclusion criteria | Psychiatric, opioid abuse, Allergies | CARDIAC DISEASES, HEPATIC INSUFFICIENCY, RENAL FAILURE, DISEASE, MORPHINE ALLERGY, ADVERSE REACTION, COAGULOPATHY, CHRONIC PAIN, ALLERGIES |
Allergies to the local anesthetics, morphine, or drugs used in the study,Cardiac diseases, hepatic insufficiency, and renal failure,Subject’s refusal to participate in the study,Inability to understand what the study is about,Previous cardiothoracic surgery,Any contraindication to intrathecal injection (morphine allergy, coagulopathy, patient refusal),Patients with a history of chronic pain,Preoperative opioid use and/or history of opioid abuse,Psychiatric disease.Patients were also excluded when failure to operate intrathecal anaesthesia, discontinuation of an intravenous analgesic pump due to a serious adverse reaction, and change of procedure. | PMC10691143 |
Procedures | postoperative nausea and vomiting, NRS | GROUP B, STERILE, STERILE, CAVITY, INFILTRATED | After patients were admission, oxygen was administered and ECG, HR, NBP and SPOThe enrolled patients were randomized by random number method into three groups: Group M (5 μg/kg morphine intrathecal injection), Group B (5 μg/kg morphine combined with bupivacaine 3 mg intrathecal injection) and Group C (intrathecal sham injection). Patients were randomly allocated 1: 1: 1 with three treatment groups using a set of computer-generated random numbers kept in sealed envelopes by an investigator not involved in clinical care. Blocks were performed before induction of general anaesthesia, and patients were not informed of their group assignments. The three groups were intrathecal injection morphine, morphine and bupivacaine, or intrathecal sham injection. The anaesthetist conducting the anaesthetic was not blinded to treatment.Group M: Under standard monitoring, patients were placed in the left lateral position and the skin of the low back was disinfected with 0.45–0.55% povidone-iodine disinfectant centred on the L2-3 gap and sterile cavity wipes were laid. 1% lidocaine 2 ml was infiltrated locally and a type II lumbar puncture needle (5#) was used to perform an intrathecal puncture in the L2-3 space. The cerebrospinal fluid was drained freely and morphine hydrochloride 5 μg/kg was injected into the subarachnoid space within 15 s. Morphine hydrochloride configuration: dilute 1 mg morphine hydrochloride (1 mg/ml) with 0.9% sodium chloride to 10 ml (0.1 mg/ml) and inject into a 3 ml syringe after drawing at 5 μg/kg using a 1 ml syringe. Retract cerebrospinal fluid diluted to 3 ml for subarachnoid injection.Group B: The procedure for subarachnoid puncture was the same as that for M group. 5 μg/kg of morphine hydrochloride (morphine preparation was the same as that for M group) combined with 0.75% bupivacaine 0.4 ml (3 mg) was withdrawn and diluted to 3 ml of cerebrospinal fluid for subarachnoid injection.Group C: After the patient has cooperated in the position, the anaesthetist applies finger pressure to the skin to simulate intrathecal injection.The 10°Trendelenburg position was used in all three groups. The flat position was resumed 20 min after completion of the operation to achieve a high plane block. Sterile dressings were given to cover the lumbar back after completion of the puncture operation in all three groups. The upper boundary of the plane of anaesthesia was measured with an alcohol swab 10–15 min after administration.For all three groups, general anaesthesia was induced with 0.05 mg/kg midazolam, 0.4 μg/kg sufentanil and 1.5–2.0 mg/kg propofol. Cisatracurium 0.2 mg/kg was given to facilitate double-lumen bronchial tube intubation. Propofol administration was adjusted to target a Bispectral Index between 40 and 60. Cisatracurium was infused at 0.05 ~ 0.10 mg·kgPostoperative analgesia: All three groups received PCIA after awakening in the PACU with the same settings: sufentanil 2 μg/kg and azasetron 10 mg diluted to 100 ml with 0.9% NaCl. PCA dose, 2 ml, lockout interval 15 min. If the PCA device was fully used (NRS > 4 after three consecutive effective compressions), then aminotriol ketorolac 30 mg is administered intramuscularly for remedial analgesia. In case of postoperative nausea and vomiting, metoclopramide 10 mg is administered intramuscularly. | PMC10691143 |
Measurement | nausea/vomiting, itching, drowsiness, irritable, Pruritus, nausea and vomiting, vomiting, pain, over-sedation, cough, pruritus, Nausea, NRS, urinary retention | PRURITUS, ADVERSE EVENTS | Patients’ baseline data, surgery and anaesthesia were collected. Mean blood presssure and heart rate at eight time points were recorded: After patient admission (T0), 10 min after intrathecal block (T1), 1 min after double-lumen tracheal intubation (T2), 1 min before surgical cut (T3), 1 min after surgical cut (T4), 5 min after surgical cut (T5), at the end of surgery (T6) and 30 min after extubation (T7). IVPCA sufentanil consumption in 48 h and NRS at 1, 6, 12, 24 and 48 h postoperatively were recorded. Intra-operative consumption of remifentanil and propofol was recorded. Additionally, common side effects (sedative effect, nausea/vomiting, and pruritus) and some recovery indicators were recorded.For sedation, the Ramsay Sedation Score was used: 1 score: irritable; 2 score: awake, quiet and cooperative; 3 score: drowsy, but able to follow commands and respond with agility; 4 score: in a state of drowsiness, can be awakened quickly; 5 score: in a state of light sleep, unresponsive to calls and responsive to stronger stimuli (e.g., tapping); and 6 score: in a state of deep sleep, not waking up to calls. If the score is greater than 4, the patient is over-sedated, and 15 μg of nalmefene is given intravenously for over-sedation. Nausea and vomiting were classified as three grades: asymptomatic, symptomatic without treatment, and symptomatic with treatment. Gastrografin 10 mg intramuscularly was given, and haloperidol 0.63–1.25 mg intravenously was given for unrelieved nausea and vomiting, which was repeated once every 8 h if necessary.Pruritus was classified as asymptomatic, symptomatic without treatment and symptomatic with treatment, 10 mg of propofol was given for itching with the maximum dose not exceeding 50 mg. 10 mg of cetirizine tablets were given orally if itching persisted.All patients were given a preoperative urinary catheter, which was removed on the second day. If urinary retention occurred after removal of the urinary catheter, hot compresses and massage were used, and the catheter was reintroduced if it could not be relieved.All results were recorded by an anaesthetist who had no knowledge of the subgroups. The scores of Quality of Recovery-15 (QoR-15) is the recently developed to validate short-form postoperative recovery evaluation. QoR-15 questionnaire has 15 questions that assess patient-reported postoperative health status using a 11-point numerical rating scale that leads to a minimum score of 0 (poor recovery) and a maximum score of 150 (excellent recovery). QoR-15 was obtained 24 h and 48 h after surgery in this trail.The primary outcome was the pain scores at rest and with cough at 48 h after surgery. Secondary outcomes were intraoperative propofol and remifentanil consumption, intraoperative haemodynamic variables, postoperative rescue analgesic requirements and adverse events; and postoperative recovery indicators. | PMC10691143 |
Statistical analysis | blood loss, pruritus, pain | BLOOD LOSS, DISEASE | Variables were summarized as mean ± SD for normally distributed continuous variables (including demographic profile of the patients, duration of surgery, fluid intake and output, hemodynamic changes, Intra-operative remifentanil use, propofol use, first feeding time, first time out of bed, QoR-15 score), and intergroup comparisons were performed using one-way analysis of variance (ANOVA). Median (25th to 75th percentile) for continuous variables with evidence of nonnormality or for ordinal variables (Hospital stay days, blood loss, pain scores, cumulative amount of IVPCA sufentanil used, time of first analgesic request, post-operative extubation time), comparisons between groups were made using the Kruskal–Wallis test. Frequency counts and percentages for categorical variables were analysed using the Pearson’s chi-squared test (sex, ASA physical status, underlying disease, chest drain days, nausea/vomiting) or Fisher’s exact test (pruritus). Statistical analysis was performed using statistical software SPSS (25.0; IBM Corp., Armonk, NY, USA). The 95% confidence intervals of the median differences were estimated by bootstrap method based on resampling through Python version 2.7.6. The significance level was set at | PMC10691143 |
Sample size considerations | pain | 48 h post-operative coughing on the NRS scores was defined as a clinically meaningful effect. Assuming a standard deviation of 2 for each of the three pain score outcomes on the basis of a preliminary study. The pretest result was an NRS score of 1.3 for group M, 1.2 for group B and 3.3 for group C at 48 h postoperative coughing. A sample size of 20 patients per group had 90% power to detect effectiveness of intrathecal morphine and intravenous analgesic pumps on all three primary outcomes at the 0.05 significance level. To allow for some individuals not completing the trial, 33 patients were recruited in each treatment group. | PMC10691143 | |
Discussion | chronic pain, pain | CHRONIC PAIN | This prospective, interventional, single-blind, randomized study reveals that the combination of intrathecal morphine and bupivacaine offers effective analgesia for patients undergoing VATS. Compared to conventional general anesthesia, this anesthesia approach delivered superior pain control during the first 48 h post-surgery, leading to a lower cumulative consumption of IVPCA sufentanil and a reduced necessity for rescue analgesics over the same period. Compared to conventional general anesthesia, this anesthesia approach delivered superior pain control during the first 48 h post-surgery, leading to a lower cumulative consumption of IVPCA sufentanil and a reduced necessity for rescue analgesics over the same period. Aligning with prior research, our findings suggest that intrathecal morphine and bupivacaine are viable alternatives to epidural blocks, particularly for thoracoscopic procedures that necessitate higher levels of analgesia. The expedited administration process of morphine and bupivacaine intrathecal injections, as opposed to the longer duration required for intrathecal morphine alone, potentially renders them more suitable for clinical use. Our results corroborate that a singular intrathecal injection of low-dose morphine in conjunction with bupivacaine can effectively bridge the gap in analgesia due to the gradual onset of intrathecal morphine’s effects [Intrathecal morphine, when used alongside sufentanil and combined with an epidural infusion of bupivacaine and fentanyl in the thoracic segment, has been demonstrated to provide analgesic effects equivalent to those achieved in post-thoracoscopic analgesia [In our study, we utilized the 10 Trendelenburg position, ensuring rapid intrathecal drug administration within 15 s to aid the dispersion of the agents to the thoracic region. The sensory block level was assessed with an alcohol swab, achieving a blockade up to the T2 dermatome prior to anesthesia induction. This effectively corresponded with the T2 to T10 dermatomal pain regions implicated in VATS incisions, providing effective analgesia during the operation and minimizing the necessity for the intraoperative opioid remifentanil.The study by Dhawan et al. [As the ERAS paradigm advances, the adoption of accelerated-track anesthesia is increasingly recommended. This strategy emphasizes prompt postoperative awakening, expeditious extubation, and early mobilization. Referencing Table The Quality of QoR-40 is recognized as a significant measure of patient health status during the initial postoperative phase [This study is not without its limitations. Foremost, the relatively modest sample size and the exclusion of high-risk patients may introduce a degree of bias into the findings. Additionally, the investigation was confined to a single dose of ITM at 5 μg/kg, precluding a comparative analysis across a spectrum of dosages.The experiments of this group are continuing and will further explore the appropriate dose to apply to the patient. Finally, the scope of this research was limited to the assessment of early postoperative recovery quality, neglecting the potential effects on long-term recuperation and the development of chronic pain in patients. For the long-term effects, the results of studies using multi-centre and large samples may be more convincing, and our group is also trying to collaborate with a number of hospitals to conduct multi-centre studies, and expects to demonstrate satisfactory results in the future. | PMC10691143 |
Acknowledgements | Assistance with the study: the authors gratefully thank the Departments of Anaesthesiology and cardiothoracic surgery. Affiliated Hospital of Yangzhou University in Yangzhou, Jiangsu for allowing and supporting this study. | PMC10691143 | ||
Authors’ contributions | Miao GUO, Suhong TANG and Dawei YANG helped to design and conduct the study. Yixin WANG and Fengxia LIU analysed the data and approved the final manuscript. Miao GUO, Lin WANG and Jianyou ZHANG wrote and handed in the final manuscript. The authors read and approved the final manuscript. | PMC10691143 | ||
Funding | Project of Yangzhou Municipal Science and Technology Bureau (YZ2022109). | PMC10691143 | ||
Availability of data and materials | The datasets analyzed during the current study are available from the corresponding author upon reasonable request. | PMC10691143 | ||
Declarations | PMC10691143 | |||
Ethics approval and consent to participate | The study was approved by the Medical Ethics Committee at the Affiliated Hospital of Yangzhou University (Protocol/serial number: 2022-YKL3-08–002). All study subjects gave informed consent for all treatments and investigations. All procedures in the study involving human participants were performed in accordance with the ethics standards of the institutional and national research committee and with the Helsinki Declaration and its later amendments or comparable ethics standards. | PMC10691143 | ||
Consent for publication | Not applicable. | PMC10691143 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10691143 | ||
References | PMC10691143 | |||
Background | CHRONIC DISEASES | Effective emotional regulation is recognized as essential to a good mental health of people with chronic diseases, and Mind–body and Art Therapies (MBATs) could have a positive effect on emotional regulation skills in this population. Thus, we aimed to evaluate the effect of MBATs on emotional regulation as measured by the Difficulties in Emotion Regulation Scale (DERS) questionnaire. | PMC10536705 | |
Methods | chronic somatic illnesses, body-focused, chronic somatic illness | DISORDER, DISEASE | A convergent mixed approach nested in a pragmatic superiority two arms parallel randomized controlled trial was conducted. French speaking adults with one or more chronic somatic illnesses and not suffering from a chronic psychiatric disorder unrelated to one of their chronic somatic illness were included. At inclusion, non-directive interviews were conducted, followed by an initial DERS assessment. The same combination of evaluation was implemented after 6 months of activity (T1). After inclusion, each participant was randomized within either the intervention group (G1) or the control group (G2) following a controlled wait-list design by use of a pregenerated randomization list. Staff and patient were blinded to this list until the initial evaluation was completed, after which the trial was conducted in an open-label fashion. Participants chose 2 mediations: one creativity-focused (art-therapy, writing workshop, theatre of life, vocal workshop) and one mind–body-focused (mindfulness meditation, Pilates, shiatsu, ayurvedic massages). G1 started their mediations immediately after inclusion, while G2 started 6 months later. Primary outcome was the change in means at 6 months in the overall DERS score compared between each group. Non-directive interviews were carried out at the inclusion and after 6 months of MBATs. A continuous inductive analysis was carried out on gathered material in G1 to explore the participants' experiences regarding their disease and their perceived changes associated to the intervention. | PMC10536705 |
Results | A total of 150 patients was randomized (75 per groups) at the end of the study. At T1, 133 patients filled out the final questionnaire (67 in G1 vs 66 in G2) and 112 interviews were analysed (54 in G1 vs 58 in G2). All 150 patients were analysed (intention to treat) using a multiple imputation approach. The mean DERS score at T0 was equal to 82.8 ± 21.1 and 85.0 ± 20.2 in G1 and G2 respectively. On average, at T1, the score decreased in the G1 (Δ = -4.8, SD = 21.3) and in G2 (Δ = -0.11, SD = 17.8). The difference in decrease, however, was not statistically significant ( | PMC10536705 | ||
Conclusions | chronic disease | CHRONIC DISEASE | This study only partially supports benefits on MBAT on emotional regulation skills enhancement in patients with chronic disease receiving MBATs, as measured by the DERS scale. | PMC10536705 |
Trial registration | The protocol was registered on Clinical Trials (NCT02911207). | PMC10536705 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12906-023-04173-8. | PMC10536705 | ||
Keywords | PMC10536705 | |||
Introduction | chronically ill, anxiety, depressive symptoms | CHRONICALLY ILL | According to the World Health Organization, for the first time, a large part of the world's population can expect to live into their sixties and beyond [A large panel of methods are used in TPE [Art therapy experiences have showed a decrease in anxiety symptoms [Regarding mind–body therapies, meditation and Pilates have shown interesting effects on chronically ill patients, especially in reducing anxiety and depressive symptoms [However, data regarding the efficiency of MBATs on emotional regulation is lacking [More specifically, our study aimed to 1) quantitatively measure the effect of MBATs on emotional regulation in chronic patients and 2) to describe qualitatively the emotional change experienced by patients, and more specifically their feelings, cognitions and behaviours to get a better understanding of the quantitative findings. | PMC10536705 |
Methods | We used a concurrent triangulation mixed methods design based on a 1:1 allocation ratio within a pragmatic randomized clinical trial with two parallel groups, one benefiting from the intervention immediately (G1) and the other starting the intervention six months later (G2). The degree of pragmatism in our trial is presented with the PRECIS-2 tool [Pragmatism of the EVAD trial | PMC10536705 | ||
Population | chronic somatic illnesses, chronic somatic illness | DISORDER, RECRUITMENT | The included patients were adults with one or more chronic somatic illnesses, who had given their consent, who spoke French, who were able to carry out a creative and physical activity and who had no chronic psychiatric disorder unrelated to a chronic somatic illness, and had been offered participation in MBATs proposed within the FCS. Additionally, advertising in local press was set up to bolster recruitment. All participants had been informed by a clinical department of Nantes University Hospital or had read about the research in the local press. The inclusion period spanned from August to September 2016. | PMC10536705 |
Randomization procedure | DISEASE | The study used a randomized controlled wait-list design. All participants attended an initial evaluation of 1 h at inclusion (T0), which consisted of a non-directive interview focused on the patient’s experience of the disease, followed by an initial emotional regulation assessment (T0). After the initial evaluation, each participant was randomized within one of the two following groups: immediate intervention group (G1) and delayed intervention group (G2). The randomization list was created with Microsoft Excel software by the statistician, without blocking, before the investigators made the inclusions. Staff who included participants and made treatment allocations were blinded to this list until the initial evaluation was completed, after which the trial was conducted in an open-label fashion. | PMC10536705 | |
Intervention | MBATS proposed by the FCS in usual care setting, as described in Table Type of activities tested | PMC10536705 | ||
Quantitative emotional regulation assessment | The Difficulties in Emotion Regulation Scale (DERS), developed by Gratz & Roemer in 2004, is the Gold Standard to assess emotional regulation [Participants had to indicate how often each item applied to themselves, with responses ranging from 1 to 5, where 1 is almost never and 5 is almost always. The scale yields a total score (range 36 – 180), where higher scores indicate a greater degree of impairment in emotional regulation. Reverse items are recoded so that higher scores in every case indicate greater difficulties in emotional regulation. The DERS has demonstrated excellent internal consistency, with Cronbach's alpha coefficients higher than 0.90 for the overall score and > 0.80 for each of the 6 dimensions and excellent construct validity [In the absence of a Metropolitan French version, we chose to adapt the DERS from the Swiss [ | PMC10536705 | ||
Quantitative analysis | The characteristics of the study population were described using descriptive statistics. The analysis was performed with an intent-to-treat approach, i.e. on all patients randomized to the initial group regardless of their participation in activities. Missing data regarding the outcome were dealt with by implementing a multiple imputation approach with a predictive mean matching method. Five datasets were generated and pooled in the analysis. Data were described with frequency or percentage for qualitative variables, and with mean and standard deviation for quantitative variables. Data from the DERS questionnaires were described by item and the overall score and sub-scores were calculated.The comparison of groups G1 and G2 between T1 and T0 was carried out by calculating the difference in means in the overall DERS score within each group. The differences were presented with their 95% confidence interval in brackets. The statistical significance of these differences was tested with Student's t-test. Alongside the comparison of the global DERS score, we also compared with the same procedure the evolutions of each of the DERS sub-scores between groups. In order to investigate the effect of assiduity on the results, we also performed a unplanned subgroup analysis, using the same procedure as described above. This analysis was based on the comparison of the subset of patients who participated in 80% or more of the planned sessions at T1 with the control group used in the main analysis. In case of multiplicity of test, the inflation of error risk was accounted using the Benjamini Hochberg correction [Considering the most pessimistic effect observed in the literature [ | PMC10536705 | ||
Qualitative analysis | DISEASE | Non-directive interviews were carried out at the inclusion to explore the participants' experiences regarding their disease, and after 6 months of MBATs to explore the participants' perceived changes associated to the intervention. The interviews were conducted by 4 investigators trained in TPE and 5 medical residents, all of whom had benefited from a 5-day training. These in-depth interviews, which lasted for an hour, respected the rules of confidentiality and anonymity and were recorded to allow a complete verbatim transcript of the responses. The interviews focused on the two following open-ended questions: “After 6 months of MBATs, where are you on your path to live with the disease?” and “In which areas of your life have you seen changes linked to the activities you have performed?”.A qualitative content analysis was undertaken, which involved a continuous inductive analysis carried out to establish categories that go further than the ones based on the initial hypotheses of the DERS, in order to better understand and explain changes in emotional regulation.All interviews (The analysis was conducted according to the following steps: (i) the transcribed interviews were read thoroughly, in order to achieve an overview of data and approach experimental themes; (ii) units of meanings linked to emotional regulation were identified and coded; (iii) coded data was condensed and abstracted within each of the categories, which were simultaneously elaborated, and (iv) the content of each interview was organized between each category [All the 112 interviews were coded in the SPHINX QUALI software. The verbatim are reported within quoting marks and in italics. Modifications made for clarity are indicated within brackets. Translation was made freely from French to English by a non-native speaker. | PMC10536705 | |
Ethics and regulation | MAY | All the requirements of French Law were fully complied with. An ethics committee (Comité de Protection des Personnes – Tours – Région Centre-Ouest 1) endorsed the protocol on June 28, 2016. The protocol and the database were registered on May 12, 2016 by the French National Data Protection Committee (CNIL) according to the requirements of the declaration of conformity. The protocol was registered on Clinical Trials under the reference NCT02911207. | PMC10536705 | |
Availability of data and materials | The dataset(s) supporting the conclusions of this article is(are) available upon request to the authors. | PMC10536705 | ||
Results | A total of 150 patients were included at T0 (75 in G1 and 75 in G2). The flowchart of the inclusion process is displayed in Fig. Flowchart of the studyAmong those patients, 78% (Patients’ characteristics (After 6 months (T1), 133 patients filled out the final questionnaire (67 and 66 patients for G1 and G2 respectively). In the intervention group, 63% (47 of 75) of the participants completed 80% or more of their activity program. There were no socio-demographic discrepancies between patients who carried out 80% and more of program activities and the others within the intervention group (Table Differences between patients who carried out 80% or more of program activities and the ones who did not, within the intervention group | PMC10536705 | ||
Quantitative results | PMC10536705 | |||
Evolution of the DERS sub-scores | In the overall sample, none of the 6 DERS sub-scores were significantly improved by the intervention. In patients who followed 80% or more of their activity program, we observed a significant decrease in the impulse dimension in the intervention group compared to the control group (-2.6 vs -0.13, | PMC10536705 | ||
Effects on impulse | In the DERS, Impulse focuses on difficulties to control oneself in a negative emotional context. Half of the interviewees (51%, 57/112) described a better control of their impulsive behaviours (verbatim 1). | PMC10536705 | ||
Effects on awareness | In the DERS, awareness assesses the extent to which individuals are able to monitor one’s emotions. Half of the participants (51%, 57/112) reported an improvement in their ability to listen to their feelings, to better perceive and identify their emotions (verbatim 2). Furthermore, the majority of the participants (66%, 74/112) described a better ability to analyse sensations, thoughts, issues and self-limiting behaviours (verbatim 3). | PMC10536705 | ||
Effects on clarity | Clarity assesses an individual’s ability to identify, distinguish and describe specific emotion. Nearly half of the participants (47% of the interviewees, 53/112) reported a better understanding of their emotions and how they impacted on their physical symptoms (verbatim 4). | PMC10536705 | ||
Effects on acceptance | CHRONIC ILLNESSES | Acceptance is focused on an individual’s ability to accept one's emotional response. Only 12% (14/112) of them spontaneously reported a better acceptance of their emotions after 6 months of intervention. However, the majority of the participants (69%, 77/112) described a better acceptance of their difficulties and chronic illnesses (verbatim 5). | PMC10536705 | |
Effects on strategy | EVENTS, DISEASE | Strategy assesses an individual’s ability to implement emotional regulation strategies in a negative emotional context. A large majority of participants (87%, 98/112) reported having implemented new emotional regulation strategies. We identified either cognitive (77%, 86/112) or behavioural strategies (74%, 83/112).Among the most quoted cognitive strategies was the ability to put things into perspectives, with a greater focus on positive aspects of their life (51%, 58/112). The participants described a more positive relationship to their body and disease, but also a better future outlook (68%, 77/112) (verbatim 6). Most of the participants (84%, 94/112) reported an increased self-awareness of their aspirations, deep needs, values and capacities for action (verbatim 7). Regarding engagement in new behaviours, several participants (38%, 42/112) talked about making important decisions to meet their deepest needs and aspirations (verbatim 8).Among the behavioural strategies, breathing techniques were used by the majority of the participants (58%, 65/112). The participants also kept using in their daily life techniques learned during the interventions: meditation, yoga, singing, self-massages, Pilates, drawing, and writing (verbatim 9). Another new strategy implemented by the patients was emotion expression. For example, 69% (77/112) of the participants allowed themselves to feel and express their emotions more often, without repressing them, in particular by letting themselves cry. During the 6 months that lasted the interventions, 35% (39/112) of the participants were able to release previously repressed emotions, often related to past psycho-traumatic life events (verbatim 10). Finally, 57% of the participants (64/112) reported new relational strategies by being more assertive, communicating their emotions better and expressing their needs or disagreements (verbatim 11). | PMC10536705 | |
Discussion | chronically ill, ’ emotional skills, cancer | CHRONICALLY ILL, CANCER | Our study is the first to evaluate the effect of MBATs on emotional regulation in chronically ill patients by use of a randomized clinical trial design. Our main quantitative analysis was inconclusive as it did not show a favourable effect of MBATs on emotional regulation, compared to the control intervention, as measured by the DERS questionnaire. However, a statistically significant difference was observed between participants who completed at least 80% of their activity program and the control group. Conversely, the qualitative analysis supported a positive effect of MBATs on emotional regulation: nearly half of the participants reported an improvement in their impulsiveness, emotional awareness and emotional clarity. Moreover, most of the participants reported having implemented new emotional regulation strategies.Regarding qualitative data, as no comparisons were planned between groups, every interviewee that had participated in MBAT interventions was interviewed and no patient from control group was. It is thus impossible to differentiate between our program’s effectiveness and the natural evolution of chronically ill patients’ emotional skills in a qualitative manner. Only the comparison between the qualitative and quantitative results in the intervention group was conducted and the difference in results observed between both approach need to be discussed.Several hypotheses can be put forward to explain these discrepancies. First, regarding our quantitative results, the intervention could have had a real effect on emotional regulation in participants, adequately measured but limited in size. Based on the existing literature, our study was designed to detect a between-group difference of 19 points [Second, this apparent paradox could be explained by changes that may have not been detected by the DERS. This could be due to limitations of the tool itself, or by the fact that the improvements reported by the participants only limitedly correspond to the emotional regulation model proposed by Gratz and Romer [Third, these discrepancies could be a result of effect dilution. Indeed, our intervention strategy relied on various MBATs and was applied to a rather heterogeneous study population. Indeed, the choice of this study population and the variety of activities was decided according to the pragmatic nature of the trial, which aimed at reproducing the conditions in which these interventions were already offered to chronically ill patients in Nantes within the FCS. However, the cost of this flexibility could have been paid on different aspects of the study. First, the heterogeneity of the studied population (pathologies’ type and duration, for example) may have contributed to a highly variable impact on patients’ emotional regulation. Some might have experienced an important benefit from it while others didn’t, partly due to the lack of adaptation of the intervention to their specific needs. On the other hand, the multiplication of interventions led to a multiplication of instructors, whose ability to elicit engagement amongst participants regarding the proposed content may have been unequal. All these elements may have led to the pooling of various effects of the different MBATs on various patient profiles, and thus turning effect of a particularly efficient MBAT on a particular clinical context indistinguishable, as our sample size did not permit stratification on each MBAT.When we limited our analysis to highly adherent patients, we observed a stronger and significant effect. This observation in the most adherent population is coherent with the elements described above, as the most adherent patients may have been the patients which found the best match between their personal situation, the proposed MBATs and the personality of their instructors, therefore boosting their will to pursue the intervention program to its end and get the most out of it. Unfortunately, a posteriori analysis revealed that the adherent participants did not differ from the rest of our sample, ruling out the possibility of detecting early on who could benefit the most of our intervention strategy.Finally, several limitations that could have had an impact on our results must be noted. First of all, we evaluated the effect of our MBT-based intervention after 6 months, which could be too short for developing significant changes in emotional regulation. Therefore, the participants may have notice small and encouraging changes that couldn’t yet have a sizeable effect that could be measured by the DERS. Another limitation is that the qualitative methodology involved undirected interviews, which means that the interviewers did not specifically question the participants on the dimensions identified in the DERS. Only the dimensions in which the participants observed or perceived major changes, were thus covered by the qualitative analysis. A last limitation to be noted is the subjectivity of one of the qualitative analysts, which was deeply involved in the diffusion and structuration of MBATs in our local setting. Despite efforts to adopt a neutral stance, this positive bias towards MBATs should be acknowledged.Some encouraging evidence is available regarding the effectiveness of MBT in improving some components involved in emotional regulation or similar concepts. A mapping review reported that art therapy interventions in cancer patients improved emotional condition [To our knowledge, our study is the first to assess impact of MBATs on emotional regulation as assessed by the DERS in a population of chronically ill patients. Existing research is mainly focused on the evaluation of alternatives to MBT in improving emotional regulation, for example Emotion Regulation Group Therapy, Acceptance and Commitment Therapy, Dialectical Behaviour Therapy and Cognitive Behavioral Therapy, showing evidences regarding their capacity to significantly improve emotional regulation ability [ | PMC10536705 |
Conclusion | chronically ill | CHRONICALLY ILL | The quantitative results of this study did not support the causal effect of MBATs on patients' emotional regulation. However, the qualitative part of our mixed methods study highlighted a wild range of potential benefits of these complementary therapies in the population of chronically ill patients regarding their ability to regulate their difficulties. Further research using larger sample sizes, issued from a more homogeneous population, testing a restricted set of MBATs with experienced trainers is needed to fully state on MBATs’ benefits regarding emotional regulation. | PMC10536705 |
Acknowledgements | Pierre Caillault | The authors would like to thank the following contributors for their essential participation to this study: Mathilde Bourgueil, Catherine Greffier, Erwan Rabiller, Myrtille Richard, Cécile Ferriot, Clément Le Glatin, Claire Fesquet, Pierre Caillault, Marianne Bourdon, Lise Gross and everyone at the Fabrique Créative de Santé. | PMC10536705 | |
Authors’ contributions | Conceptualization: ALR, EA, BL, LM. Data curation: ALR, EA, PC, GB, ML, BL, LM. Formal Analysis: ALR, ML, MD, EA, GB, PC, BL, LM. Funding acquisition: ALR, ML, EA, BL, LM. Investigation: ALR, ML, MD, GB, BL. Methodology: ALR, EA, BL, LM. Project administration: ALR, ML, BL, LM. Resources: ALR, ML, BL, LM. Software: EA, GB, PC, BL. Supervision: ALR, ML, BL, LM. Validation: ALR, ML, PC, BL, LM. Visualization: ALR, ML, BL, LM. Writing – original draft: ALR, ML, MD, LG, EA, GB, PC, BL, LM. | PMC10536705 | ||
Funding | This study was funded by the "Direction Générale de l'Offre de Soins" (PREPS 2015 / 15–0304 / EVAD).This study was supported by a grant from the French Ministry of Health (PREPS 2015 / 15-0304 / EVAD). | PMC10536705 | ||
Availability of data and materials | Data are available in supplementary materials (Additional file | PMC10536705 | ||
Declarations | PMC10536705 | |||
Ethics approval and consent to participate | Informed consent was obtained from all subjects and/or their legal guardian(s). All methods were carried out in accordance with relevant guidelines and regulations. The study was approved by the French ethics committee “Comité de Protection des Personnes TOURS—Région Centre—Ouest 1” (FDA IRB n°IORG0008143) on July 30, 2016 (n° 2016-S9). | PMC10536705 | ||
Consent for publication | Not Applicable. | PMC10536705 | ||
Competing interests | The authors declare no competing interests. | PMC10536705 | ||
References | PMC10536705 | |||
Key Points | PMC10167565 | |||
Question | Does pharmacogenetics-informed ( | PMC10167565 | ||
Findings | depressive disorder, depressive symptoms | ADVERSE EFFECTS | In this randomized clinical trial of 111 patients with major depressive disorder, dosing based on preemptive pharmacogenetic testing led to faster attainment of therapeutic plasma concentrations and potentially fewer and less severe adverse effects. No effect on depressive symptoms was found. | PMC10167565 |
Meaning | These findings indicate that pharmacogenetics-informed dosing of tricyclic antidepressants can be safely applied and contributes to personalized antidepressant treatment. | PMC10167565 | ||
Importance | ADVERSE EFFECTS | Evidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects. | PMC10167565 | |
Objective | MDD, unipolar major depressive disorder | To determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD). | PMC10167565 | |
Design, Setting, and Participants | Depression, unipolar nonpsychotic MDD, bipolar or psychotic disorder, comedications | DISORDER | This randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications. | PMC10167565 |
Intervention | In the PIT group, the initial TCA dosage was based on | PMC10167565 |
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