Tratamentos farmacológicos para fadiga em pacientes com doença inflamatória intestinal: uma revisão integrativa

MORAIS, Tayane; COUTO, Genalva; ROCHA, Raquel; SANTANA, Genoile

doi:10.1590/S0004-2803.24612025-081

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Sumário

REVIEW ARTICLE • Arq. Gastroenterol. 62 • 2025 • https://doi.org/10.1590/S0004-2803.24612025-081 linkcopiar

Tratamentos farmacológicos para fadiga em pacientes com doença inflamatória intestinal: uma revisão integrativa

Autoria SCIMAGO INSTITUTIONS RANKINGS

Contexto: Em pacientes com Doença Inflamatória Intestinal (DII), a fadiga é um problema debilitante e pode estar associada a distúrbios do sono, ansiedade, depressão, anemia, uso de esteroides sistêmicos e fase ativa da doença. Além disso, a fadiga também afeta as condições de trabalho desses pacientes, pois está associada ao absenteísmo e é motivo de afastamento do trabalho, superando consultas médicas e dores abdominais. Atualmente, não existem terapias farmacológicas bem estabelecidas para a fadiga, tornando-a um assunto de crescente interesse em pesquisa.

Objetivo: Este estudo teve como objetivo realizar uma revisão integrativa dos tratamentos farmacológicos para fadiga em pacientes com DII.

Métodos: Os critérios de inclusão incluíram artigos completos publicados de 1º de janeiro de 2017 a 31 de dezembro de 2024. Os estudos elegíveis tiveram que incluir a avaliação da fadiga como objetivo principal e discutir tratamentos farmacológicos para fadiga em pacientes com DII. As bases de dados utilizadas foram PubMed, Lilacs, SciElo e Cochrane e os descritores foram (inflammatory bowel disease) AND (fatigue) AND (drug therapy).

Resultados: Foram identificados 294 estudos, dos quais dez preencheram os critérios de inclusão, compreendendo 2.935 pacientes (1.664 com doença de Crohn, 1.215 com colite ulcerativa e 56 com síndrome do intestino irritável). A vitamina B12 não demonstrou eficácia no alívio da fadiga em pacientes com DII. Altas doses de tiamina oral reduzem a fadiga, mas estudos usando uma dose de 300 mg/dia de tiamina não mostraram o mesmo efeito. Os sintomas de fadiga foram reduzidos com o uso de vedolizumabe, upadacitinibe e modafinila. Estudos que avaliam tratamentos farmacológicos para fadiga na DII permanecem limitados e os dados disponíveis ainda são insuficientes. O estabelecimento de terapias farmacológicas eficazes para fadiga nesses pacientes pode levar a um melhor bem-estar físico e emocional, a interações sociais e à empregabilidade aprimoradas, além de reduzir os encargos financeiros associados ao manejo da fadiga. Mais ensaios clínicos randomizados e revisões sistemáticas são necessários para avançar na compreensão das intervenções farmacológicas para fadiga na DII.

Palavras-chave:
Doença inflamatória intestinal; doença de Crohn; retocolite ulcerativa; fadiga; terapia medicamentosa; doença crônica

Year	Authors	Article Title	Country	Language	Kind of study	Study period
2017	Scholten et al.	Overuse of vitamin B₁₂ does not reduce fatigue in patients with IBS^a or IBD^b: a randomized double-blind placebo-controlled trial	Netherlands	English	Randomized, double-blinding, placebo-controlled trial.	8 weeks
2020	Bager et al.	Randomized clinical trial: high-dose oral thiamine versus placebo for chronic fatigue in patients with quiescent IBD.	Denmark	English	Randomized, placebo-controlled clinical trial, crossover intervention design, triple blinding (participant, caregiver, and investigator)	12 weeks
2021	Moradi et al.	The effects of spirulina supplementation (Arthrospira platensis) on anthropometric indices, blood pressure, sleep quality, mental health, fatigue status, and quality of life in UC patients: a randomized, double-blind, placebo-controlled trial	Iran and UK	English	Randomized, double-blind, placebo- controlled study	8 weeks
2022	Bager et al.	Long-term maintenance treatment with 300 mg thiamine for fatigue in IBD patients: results from an open-label extension of the TARIF trial	Denmark	English	Randomised, open-label, placebo-controlled study. Long-term extension study of an early high-dose thiamine study.	39 weeks
2022	Truyens et al.	Effect of 5-hydroxytryptophan on fatigue in quiescent IBD: a randomized controlled trial	Belgium	English	Multicenter randomized, placebo-controlled study.	8 weeks
2023	Bager et al.	B vitamins, related vitamins, and metabolites in patients with quiescent inflammatory bowel disease and chronic fatigue treated with high-dose oral thiamine	Denmark	English	Randomized, double-blind, placebo-controlled crossover study	12 weeks
2023	Danese et al.	Induction and maintenance therapy with upadacitinib improves abdominal pain, bowel urgency, and fatigue in patients with ulcerative colitis: a post hoc analysis of phase 3 data	United States of America, Argentina, Australia, Austria, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czech Republic, Denmark, Egypt, Estonia, France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Republic of Korea, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Serbia, Singapore, Slovakia, Slovenia, South Africa, Spain, Sweden, Switzerland, Taiwan, Peru, Ukraine and United	English	A multicenter, randomized, double-blind, placebo-controlled induction study to evaluate the efficacy and safety of upadacitinib (ABT-494) in subjects with moderately to severely active ulcerative colitis.	52 weeks
2023	Steenholdt et al.	Trajectories of health-related quality of life and fatigue during vedolizumab therapy in inflammatory bowel disease	Denmark	English	Cohort study of patients with biologically refractory IBD treated with vedolizumab	54 weeks
2024	Moulton et al.	Modafinil for severe fatigue in inflammatory bowel disease: a prospective case series	United Kingdom	English	Prospective case series	24 months
2024	Ghosh et al.	Impact of induction and maintenance therapy with upadacitinib on health-related quality of life, fatigue, and work productivity in patients with moderately to severely active Crohn’s disease	United States of America, Argentina, Australia, Austria, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czech Republic, Denmark, Egypt, Estonia, France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Republic of Korea, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Serbia, Singapore, Slovakia, Slovenia, South Africa, Spain, Sweden, Switzerland, Taiwan, Peru, Ukraine and United Kingdom.	English	A Multicenter, Randomized, Double-Blind, Placebo-Controlled Maintenance and Long-Term Extension Study of the Efficacy	52 weeks

Year	Authors	Sample	Disease activity/scale	Limitations
2017	Scholten et al.	95 participants (56 with IBS^a, 20 with CD^b and 19 with UC^c), 70 (73.7%) were female and the mean age was 41 years.	Disease activity has not been evaluated.	A limitation of this study may be the cutoff point used for vitamin B₁₂ deficiency. The present study used <150 pmol/L as the cutoff point for vitamin B12 deficiency, but there is no consensus on the cutoff point for vitamin B₁₂ deficiency. Finally, serum vitamin B₁₂ is not the most sensitive marker for measuring vitamin B₁₂ status, which could indicate vitamin B₁₂ deficient subjects in the study.
2020	Bager et al.	40 patients (20 with CD and 20 with UC). Group 01 had 20 patients (mean age 38 years, and 17 (85%) were female). Group 02 had 20 patients (mean age 36 years and 18 (90%) were female).	All patients were in disease remission.(HBICD^d e CSCAI^e)	Young patient cohort, single-center design, and exclusion criteria (patients with actual chronic disease were excluded without defining an epidermal growth factor receptor cutoff, but patients with rheumatoid arthritis were included).
2021	Moradi et al.	73 patients with UC. The group that used Spirulina had 36 patients (mean age 37.8 years and 18 (50%) were female). The placebo group had 37 patients (mean age 39.5 years and 20 (54.0%) were female	Light to moderate active(SSCCAI^f)	The study did not evaluate the dose-dependent efficacy of spirulina supplementation, which means that one cannot infer sucha relationship. Intervention time was potentially insufficient to cause anthropometric changes.
2022	Bager et al.	40 patients, 35 (87.5%) were female and the mean age was 37 years (20 with CD and 20 with UC).	All patients were in disease remission.(HBICD and CSCAI)	Young patient cohort, single-center design, and exclusion criteria (patients with actual chronic disease were excluded without defining an epidermal growth factor receptor cutoff, but patients with rheumatoid arthritis were included).
2022	Truyen et al.	166 patients, 94 (56.6%) were female, and the mean age was 39 years. 84 patients had CD, and 82 had a diagnosis of UC	All patients were in disease remission. (SHBI^g)	Remission was defined based on clinical criteria and biochemical indices; however, ongoing subclinical inflammation, which could be related to fatigue, has not been evaluated.Sleeping quality was unrated, so it is impossible to relate fatigue burden to sleep quality in this study cohort.
2023	Bager et al.	40 patients (20 with CD and 20 with UC). Group 01 had 20 patients (mean age 38 years, and 17 (85%) were female). Group 02 had 20 patients (mean age 36 years and 18 (90%) were female).	All patients were in disease remission.(HBICD^d e CSCAI^e)	The study itself, regarding the post-analysis of B vitamins and related vitamins, has some limitations. The study included primarily women. The sample size seemed appropriate, as the primary results were clear. Furthermore, the control group was very similar to the intervention group. However, a larger sample size may have revealed more significant results in this B vitamin substudy.
2023	Danese et al.	Total de 988 pacientes com diagnóstico de colite ulcerativa, of which 372 (37.65%) were female. The average age of the patients was 41.5 years.	Moderately to severely active ulcerative colitis, defined by an adapted Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3 (confirmed by central reader)	Limitations of this study include the generalizability of the findings to patients with mild colitis and the lack of granularity in the measurement of abdominal pain and bowel urgency. Therefore, it is difficult to assess patients who may benefit most from a reduction in pain or urgency.
2023	Steenholdt et al.	The study population comprised 79 patients with IBD (40% women), but fatigue was only assessed in one subgroup (30 patients, 21 with ulcerative colitis and 9 with Crohn’s disease).	Clinical remission in patients with Crohn’s disease was defined as Harvey-Bradshaw Index (HBI) < 5, and in ulcerative colitis as Simple Clinical Colitis Activity Index (SCCAI) ≤ 2.	The main limitation of the study is the limited number of patients and the retrospective collection of recorded data. Furthermore, fatigue assessments were implemented later and this subcohort was therefore small and the findings exploratory. Disease activity was assessed objectively after 1 year of VDZ therapy, or at treatment failure, preferably by endoscopy, but with a minority being assessed by other measures reflecting clinical practice.
2024	Moulton et al	Total of 10 patients - 8 females and 2 males in the series, mean age was 33.7 years (SD, 8.4). 8 patients were diagnosed with Crohn’s disease and 2 with ulcerative colitis.	Eight patients had Crohn’s disease and 2 patients had ulcerative colitis. Does not mention a scale to assess disease activity.	Small sample size, limited duration of follow-up, lack of randomization, lack of measurement of fatigue impact, lack of follow-up fecal calprotectin measurement, lack of control group and lack of blinding, and require replication in a randomized controlled trial.
2024	Ghosh et al.	A total of 1,523 patients (all diagnosed with Crohn’s disease) were evaluated for induction and maintenance of Crohn’s disease. Of these, 845 were male. The age ranged from 18 to 75 years.	Patients with active disease were used as eligibility criteria. The study observed disease remission with the drug upadacitinib. Remission was assessed by endoscopy (Simplified Endoscopic Score for Crohn’s Disease - SES-CD) and clinical remission was defined based on average daily stool frequency and average daily abdominal pain score (CDAI). Clinical remission by CDAI was defined as CDAI <150.	The trials had certain limitations as the findings cannot be generalized to real-world settings and to patients with milder CD who were not represented in the sample.
TABLE 2. Evaluation of selected articles (continued).
Year	Authors		Scales to measure fatigue		Main results related to fatigue
2017	Scholten et al.		Checklist Individual Strength.Visual Analogue Scale.Fatigue Impact Scale.	Based on the study, it was not possible to confirm the expected unconventional effect onfatigue after 8 weeks of excess treatment with oral vitamin B₁₂ (there was no significant reduction in scores based on the questionnaires used to measure fatigue, when compared to placebo).
2020	Bager et al.		Inflammatory Bowel Disease Fatigue Scale (IBD-F)	The study showed that high doses of oral thiamine had a significant beneficial effect in reducing fatigue after 4 weeks. Cross-analysis identified an average reduction of 4.5 points in scores on the questionnaire used to assess fatigue after thiamine.
2021	Moradi et al.		Fatigue Severity Scale (FFS)	Despite the study identifying an improvement in quality of life after the intervention period with the use of spirulina supplementation but there was no significant reduction in fatigue.
2022	Bager et al.		Inflammatory Bowel Disease Fatigue Scale (IBD-F)	No beneficial effect was identified in reducing fatigue after using thiamine 300 mg for 12 weeks and following these patients for 6 months, as 66% reached a normal level of fatigue in relation to the period before the intervention.
2022	Truyens et al.		Chronic Illness Fatigue Therapy (FACIT-F)	5-Hydroxytryptophan did not reduce fatigue in patients with IBD when compared with placebo after 8 weeks of intervention.
2023	Bager et al.		Inflammatory Bowel Disease Fatigue Scale (IBD-F)	Flavin mononucleotide (FMN) concentration was lower in patients with chronic fatigue compared with patients without fatigue (p = 0.02). Patients with chronic fatigue who reported a positive effect on fatigue after 4 weeks of high-dose thiamine treatment had a statistically significantly lower level of riboflavin after thiamine treatment (p = 0.01).
2023	Danese et al.		Chronic Illness Fatigue Therapy (FACIT-F)	Significant and clinically meaningful improvements in fatigue were observed in patients treated with upadacitinib at week 2, fatigue improved further by week 8 of induction, and improvements were sustained through 52 weeks of maintenance treatment compared with placebo. The results of this study showed that upadacitinib has a long-term positive impact on the relief of abdominal pain, bowel urgency, and fatigue among patients with moderately to severely active ulcerative colitis when compared with placebo.
2023	Steenholdt et al.		Visual Analogue Scale - Fatigue	Quality improves rapidly and predicts subsequent meaningful clinical-objective efficacies of vedolizumab at the end of induction and one year. Fatigue improves slowly after remission is achieved.
2024	Moulton et al		IBD Fatigue Assessment Scale (IBD-FAS)	Six of 10 patients had a 50% or greater improvement from baseline IBD-FAS score. Although all 10 patients were severely fatigued at baseline, only 2 patients were still in the severe fatigue range after treatment. Modafinil dramatically improved IBD fatigue, suggesting that centrally available dopamine deficiency may be a significant cause of IBD fatigue.
2024	Ghosh et al.		Chronic Illness Fatigue Therapy (FACIT-F)	In patients with active Crohn’s disease, upadacitinib treatment relative to placebo significantly improved fatigue, quality of life, and work productivity as early as Week 4. These effects were sustained through 52 weeks of maintenance.

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[TFN1] IBS: irritable bowel syndrome^a. IBD: inflammatory bowel disease^b.