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Cancer and Non-cancer Fatigue Treated With Bupropion: A Systematic Review

      Abstract

      Context

      Fatigue is a predominant and distressing symptom in cancer and non-cancer conditions for which there is a paucity of recommendations for pharmacological interventions. Bupropion is a novel treatment whose efficacy and safety in the treatment of fatigue are unknown.

      Objectives

      This study aimed to systematically assess the evidence on the efficacy and safety of bupropion in the treatment of fatigue in people with cancer and non-cancer conditions.

      Methods

      PubMed, EMBASE, and Ovid Medline databases were searched up to July 26, 2022. Studies were included if they reported bupropion as an intervention for cancer and non-cancer-related fatigue and used an objective scale to assess symptom outcomes. Experimental and quasi-experimental studies in adult patients published in English were included.

      Results

      This review reports on seven studies (three randomized studies, three non-randomized studies, and one case series) that enrolled a total of 584 patients. Bupropion was tested in five studies for treating cancer-related fatigue and in two studies for treating fatigue in non-cancer conditions. The reviewed studies were heterogeneous in relation to the scales used to assess fatigue. Six out of seven studies reported that bupropion significantly reduced the fatigue burden without causing major adverse effects. These positive results must be taken with caution caused by the small sample sizes and low quality of the studies reviewed.

      Conclusion

      Bupropion may prove to be an effective and safe intervention for fatigue in cancer and non-cancer conditions. A high-quality randomized trial is warranted to test current preliminary results.

      Key Words

      Key Message

      - Bupropion has been used for the treatment of fatigue in cancer and non-cancer conditions.- Preliminary evidence suggests bupropion is an effective intervention for fatigue.- Bupropion has a better safety profile than current interventions for fatigue.

      Introduction

      The Colombian National Cancer Institute has identified cancer-related fatigue (CRF) as one of the top five first-tier high‐priority research areas.
      • Buchanan DR
      • O'Mara AM
      • Kelaghan JW
      • Minasian LM
      Quality-of-life assessment in the symptom management trials of the National Cancer Institute-supported Community Clinical Oncology Program.
      Fatigue is the most common symptom in patients undergoing cancer treatment for advanced cancer and is a ‘pervasive debilitating sensation’ that affects patients’ quality of life and social interaction.
      • Jankowski C
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      NCCN guidelines version 2.2022 cancer-related fatigue.
      ,
      • Whitehead LC
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      The experience of fatigue across long-term conditions: a qualitative meta-synthesis.
      It is an ‘ever present feeling of abject weakness.’
      • Whitehead LC
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      The experience of fatigue across long-term conditions: a qualitative meta-synthesis.
      Even cancer survivors may suffer from fatigue long after recovery.
      • Jankowski C
      • Aranha O
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      • et al.
      NCCN guidelines version 2.2022 cancer-related fatigue.
      ,
      • Fabi A
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      • Fatigoni S
      • et al.
      Cancer-related fatigue: ESMO clinical practice guidelines for diagnosis and treatment.
      The prevalence of CRF varies between cancer populations and assessment tools, but it has been reported as high as 100%.
      • Moens K
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      • Harding R.
      Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review.
      Moreover, fatigue is reported to be a frequent symptom of several non-cancer chronic diseases. For instance, 32%–96% of patients with chronic obstructive pulmonary disease, 42%–82% with chronic heart failure, 13%–100% with end-stage renal disease, 43%–95% with acquired immune deficiency syndrome, 81% with multiple sclerosis, 43%–50% with Parkinson, 50% with primary biliary cirrhosis, and 14% with dementia may experience fatigue.
      • Moens K
      • Higginson IJ
      • Harding R.
      Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review.
      ,
      • Broch L
      • Simonsen CS
      • Flemmen HØ
      • et al.
      High prevalence of fatigue in contemporary patients with multiple sclerosis.
      ,
      • Jones DEJ
      • Gray JC
      • Newton J.
      Perceived fatigue is comparable between different disease groups.
      Sadly, fatigue is a ubiquitous, underreported, underrecognized, and undertreated problem.
      • Jankowski C
      • Aranha O
      • Banerjee C
      • et al.
      NCCN guidelines version 2.2022 cancer-related fatigue.
      ,
      • Kapoor A
      • Singhal MK
      • Bagri PK
      • et al.
      Cancer related fatigue: a ubiquitous problem yet so under reported, under recognized and under treated.
      The unknown pathophysiology and the various fatigue phenotypes affecting the physical, emotional, and cognitive spheres, within and between different conditions, limit treatment options.
      • Ryan JL
      • Carroll JK
      • Ryan EP
      • et al.
      Mechanisms of cancer-related fatigue.
      Several mechanisms underlying fatigue include serotonin dysregulation, vagal afferent activation, muscle metabolism alterations, hypothalamic–pituitary–adrenal axis dysfunction, circadian rhythm disruption, anemia, and cytokine dysregulation.
      • Ryan JL
      • Carroll JK
      • Ryan EP
      • et al.
      Mechanisms of cancer-related fatigue.
      ,
      • Matura LA
      • Malone S
      • Jaime-Lara R
      • Riegel B.
      A systematic review of biological mechanisms of fatigue in chronic illness.
      The latest versions of five international guidelines for CRF recommend exercise, energy conservation, psychological support, sleep optimization, nutrition, and complementary therapies as the best evidence-based interventions.
      • Chapman EJ
      • Martino E Di
      • Edwards Z
      • et al.
      Practice review: evidence-based and effective management of fatigue in patients with advanced cancer.
      The pharmacological treatments currently studied, such as psychostimulants (methylphenidate and modafinil) and corticoids, have been questioned for the adverse effects they cause and the null or moderate benefit they show.
      • Jankowski C
      • Aranha O
      • Banerjee C
      • et al.
      NCCN guidelines version 2.2022 cancer-related fatigue.
      ,
      • Fabi A
      • Bhargava R
      • Fatigoni S
      • et al.
      Cancer-related fatigue: ESMO clinical practice guidelines for diagnosis and treatment.
      ,
      • Chapman EJ
      • Martino E Di
      • Edwards Z
      • et al.
      Practice review: evidence-based and effective management of fatigue in patients with advanced cancer.
      • Mustian KM
      • Alfano CM
      • Heckler C
      • et al.
      Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: a meta-analysis.
      • Belloni S
      • Arrigoni C
      • de Sanctis R
      • et al.
      A systematic review of systematic reviews and pooled meta-analysis on pharmacological interventions to improve cancer-related fatigue.
      Nevertheless, the shortage of clinical staff, the limited availability of caregivers, and the access barriers to non-pharmacological interventions call for the investigation of new pharmacological alternatives.
      Bupropion is an antidepressant that inhibits norepinephrine and dopamine reuptake; it is well tolerated, has a low abuse potential, and produces a stimulant-like effect as a member of the N-alkylated cathinone group.
      • Costa R
      • Oliveira NG
      • Dinis-Oliveira RJ.
      Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects.
      Bupropion has been proposed as an option for fatigue treatment as it increases monoaminergic and dopaminergic tone, reduces tumor necrosis factor-alpha, and produces a concomitant antidepressant effect.
      • Altschuler EL
      • Kast RE
      Bupropion for fatigue and as a tumor necrosis factor-alpha lowering agent in primary biliary cirrhosis.
      A 2015 Cochrane review on CRF treatments found only one case report and one quasi-experimental trial testing bupropion.
      • Mücke M
      • Mochamat Cuhls H
      • Peuckmann-Post V
      • et al.
      Pharmacological treatments for fatigue associated with palliative care.
      A recent network meta-analysis comparing different pharmacological interventions found paroxetine as the most promising treatment and did not find a difference between bupropion and placebo (SMD=−1.185, 95%CI: −3.016 to 0.646).
      • Chow R
      • Bruera E
      • Sanatani M
      • et al.
      Cancer-related fatigue-pharmacological interventions: systematic review and network meta-analysis.
      However, Chow et al.
      • Chow R
      • Bruera E
      • Sanatani M
      • et al.
      Cancer-related fatigue-pharmacological interventions: systematic review and network meta-analysis.
      did not include trials testing bupropion for treating fatigue in non-cancer conditions and their conclusions were based solely on two small single-centered randomized trials.
      • Chow R
      • Bruera E
      • Sanatani M
      • et al.
      Cancer-related fatigue-pharmacological interventions: systematic review and network meta-analysis.
      Before discarding bupropion as a feasible pharmacological intervention for fatigue, an in-depth review of the existing evidence is needed. We conducted a comprehensive systematic literature review on bupropion's efficacy and safety for cancer and non-cancer-related fatigue treatment.

      Methodology

      Objective

      The primary aim was to systematically review all the available studies investigating the effectiveness of bupropion in patients experiencing fatigue. The secondary aim was to evaluate the side effect profile of bupropion.

      Search Strategy

      We developed a search strategy using Medical Subject Headings (MeSH) and keywords related to bupropion treatment for fatigue in non-communicable chronic diseases. We searched three databases (Medline, EMBASE, and PubMed) using the following search string: (Fatigue OR chronic fatigue OR fatigue syndrome OR cancer-related fatigue OR terminal care OR palliative care) AND (Bupropion OR norepinephrine dopamine disinhibitory OR Bupropion Hydrochloride). The systematic review protocol was registered in Prospero CRD42022349833. The search results were downloaded into Endnote software to remove duplicates. Five reviewers (JEC, MFI, NM, LC, and SG) screened abstracts to ensure consistency in eligibility criteria and they reviewed the full texts of the articles whose abstracts had met the criteria. References from selected articles and expert´s recommendations were also included. In the event of disagreements, consensus was reached through discussion among the reviewers. We have reported the results following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)(Fig. 1.).

      Study Selection

      Eligible studies had to 1) be published in a peer-reviewed journal before June 26, 2022; 2) include human participants over 18 years old who experienced fatigue caused by chronic degenerative diseases 3) report an intervention of more than one week with bupropion for symptom treatment; 4) be published in English; 5) use an experimental or quasi-experimental research design, and 6) examine treatment outcomes using a fatigue scale. Given that there is no universal definition of fatigue in chronic conditions apart from cancer, the National Comprehensive Cancer Network (NCCN) definition of CRF was used as reference in the literature search: “Cancer-related fatigue is a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer and/or cancer treatment that is not proportional to recent activity and interferes with usual functioning”.
      • Jankowski C
      • Aranha O
      • Banerjee C
      • et al.
      NCCN guidelines version 2.2022 cancer-related fatigue.
      Gray literature, editorials, commentaries, case series with ten or fewer patients, case studies, and protocols were excluded from the review.

      Data Extraction

      Two reviewers (EQ and SG) independently extracted data into a Microsoft Excel spreadsheet. Data extracted included the year of publication, country, study design, number of participants, inclusion/exclusion criteria, sample characteristics, type of disease, fatigue definition, fatigue assessment, bupropion intervention, comparator, time of follow-up, and efficacy and safety outcomes. To ensure consistency, extracted data were compared between reviewers, and disagreements were discussed until consensus was reached.

      Quality Appraisal

      Two reviewers (LC and MFI) independently assessed each included study for risk of bias. A third reviewer arbitrated possible differences. Randomized controlled trials were evaluated using the Cochrane Collaboration's Risk-of-Bias Tool 2, the Newcastle Ottawa Scale was used for evaluating non-randomized studies, and the Murad et al.’s tool for evaluating the methodological quality of case series.
      • Murad MH
      • Sultan S
      • Haffar S
      • Bazerbachi F.
      Methodological quality and synthesis of case series and case reports.
      No study was disregarded for its quality.

      Data Synthesis and Analysis

      We synthesized the characteristics of the randomized and non-randomized studies in a narrative summary. The primary outcome was fatigue improvement, which was reported using means (or difference in means) ± standard deviations or means with confidence intervals (CIs). The data for each type of study is presented regarding the efficacy and safety of the bupropion intervention. Epidemiological statistics were synthesized as they were reported in the reviewed articles. As a recent meta-analysis had been performed with two randomized studies,
      • Chow R
      • Bruera E
      • Sanatani M
      • et al.
      Cancer-related fatigue-pharmacological interventions: systematic review and network meta-analysis.
      the authors agreed not to perform a meta-analysis unless the search yielded new randomized trials for CRF treatment. In case of finding two or more randomized trials for treating fatigue in non-cancer conditions, a meta-analysis would be performed. All authors were involved in the analysis and interpretation of the results and vouched for their completeness and accuracy.

      Results

      The search process yielded 10,458 studies, of which 400 were duplicates, and 10,047 were deemed ineligible after screening titles and abstracts. One article was added following expert advice. Subsequently, the full texts of eight studies were screened in detail. Of these, one was a protocol and did not meet the eligibility criteria. Fig. 1 depicts the complete screening process. Seven eligible studies were included in the present review.
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      The publication dates ranged from 2004 and 2021 and the sample sizes from 15 to 230 participants. The median number of patients was 83. The length of follow-up ranged from 4 to 12 weeks, with a median of 7.2 weeks. The studies originated from four countries: Canada, the United States, Iran (n=2), and Italy (n=1). Three studies had a randomized design,
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      ,
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      ,
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      three were non-randomized open-label studies,
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      and one was a case series.
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      Overall, two randomized studies had a low risk of bias, and one had some concerns of bias. The non-randomized trials were of moderate (n=1) and low quality (n=2), and the case series was of low quality. Table 1, Table 2, Table 3 presents the quality details by type of study of the seven reviewed studies.
      Table 1Clinical Trial's Risk of Bias Assessment
      StudyBias Arising From the Randomization ProcessBias caused by Deviations From Intended InterventionsBias caused by Missing Outcome DataBias in Measurement of the OutcomeBias in Selection of the 1Total
      Ashrafi, et al (2018)
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      LowLowLowLowLowLow
      Salehifar, et al (2020)
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      LowLowLowSome concernLowSome concern
      Barton (2021)
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      LowLowLowLowLowLow
      Quality tool used: Cochrane risk-of-bias tool for randomized trials Version 2
      Table 2Quality Assessment of Cohorts and Cases-Control studies
      StudyType of StudySelectionComparabilityOutcome / ExposureTotal
      Moss, et al (2006)
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      CohortLowLowLowLow quality
      Pardini, et al (2012)
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      Case-controlLowLowLowLow quality
      Hashash, et al (2020)
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      CohortFairFairFairFair quality
      Quality tool used: The Newcastle-Ottawa Scale
      Table 3Quality Assessment of Case series
      StudySelectionAscertainmentCausalityReportingTotal
      Cullum et al (2004)
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      LowLowLowLowLow quality
      Quality tool used: Murad et al.’s tool.
      • Murad MH
      • Sultan S
      • Haffar S
      • Bazerbachi F.
      Methodological quality and synthesis of case series and case reports.

      Efficacy Outcomes

      The main characteristics of the studies are listed in Table 4. The randomized trials only included patients with CRF; however, CRF was evaluated in heterogeneous populations. Two trials examined CRF in patients receiving treatment at the time of the studies.
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      ,
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      The remaining study investigated sexual desire and fatigue in cancer survivors who could or could not be receiving hormone therapy.
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      Patients on active treatment in the trials were 18 years or older, scored ≥4 out of 10 points on the Brief Fatigue Inventory (BFI), and had several types of cancer, including breast, gastric, prostate, liver, lung, pancreatic, ovarian, and hematologic neoplasms. Cancer stages were not specified.
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      ,
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      Patients were excluded if they had a history of seizures; scored <50 points on the Karnofsky Performance Scale (KPS); had received psychostimulants, erythropoietin, or antidepressants in the last six weeks; were pregnant; had a rheumatologic condition, or had a renal or hepatic failure. Both trials used the BFI and Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale to assess CRF.
      Table 4Characteristics of Bupropion Studies in Fatigue
      StudyNumber of participantsPopulationScaleOutcomesDuration
      Cullum et al (2004)
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      15CancerGCI13 of 15 subjects reported fatigue improvement.4 weeks
      Moss et al (2006)
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      21CancerBFIDecreased cancer-related fatigue (P <0.01) in both the depressed and not depressed group.4 weeks
      Pardini et al (2012)
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      174Multiple sclerosisMFISLower response to reward at baseline predicted higher rates of fatigue remission: (physical fatigue: r= -0.42, P<0.001; mental fatigue: r= -0.62, P<0.001; psychosocial fatigue: r= -0.51, P <0.001) in patients treated with bupropion.12 weeks
      Ashrafi et al (2018)
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      57CancerFACIT-FDecreased cancer-related fatigue. (P<0.001)4 weeks
      Hashash et al (2020)
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      52Crohn's diseaseMFIDecreased cancer-related fatigue. (P< 0.02)12 weeks
      Salehifar et al (2020)
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      30CancerBFI FACIT-FDecreased cancer-related fatigue. (P=0.006).6 weeks
      Barton et al (2021)
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      230Cancer survivorsPROMIS short form 8aFatigue interference with sexual function was not different between groups.9 weeks
      Abbreviations. BFI = The Brief Fatigue Inventory; FACIT-F = The Functional Assessment of Chronic Illness Therapy-Fatigue; MFI = Multidimensional Fatigue Inventory; MFIS = Modified Fatigue Impact Scale; GCI = Global Clinical Improvement; PROMIS = Patient-Reported Outcomes Measurement Information System.
      In the intervention arm of Ashrafi et al.’s study,
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      bupropion doses began with 75 mg for three days and were then titrated to 75 mg twice per day. The comparator arm of both trials was placebo. The primary outcome was CRF improvement; secondary outcomes were anxiety, depression, quality of life, and functionality improvement. Ashrafi et al.
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      found that bupropion improved CRF at week four (+7.0 ± 10.9 vs. +1.0 ± 10.9 [placebo] [P < 0.000]). Secondary outcomes, including depression and performance status, did not show a significant difference between groups. Salehifar et al.
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      found improved CRF levels in the bupropion group measured with the BFI at the end of week six (-1.8 ± 0.9 vs. -0.5 ± 0.7 [placebo] [P = 0.006]). For the FACIT-F scale, the mean fatigue scores for the bupropion group were better but without significant differences. The secondary outcomes favored bupropion intervention at six weeks, with improvement in anxiety and depression (P < 0.001) and ​​performance status (P <0.001).
      In Barton et al.’s
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      randomized trial of cancer survivors, only patients with breast or ovarian cancer diagnoses were included. Patients were selected if they had a decreased libido as determined by desire subscale scores below 3.3 on the Female Sexual Function Index (FSFI). The primary outcome was sexual desire improvement with bupropion over placebo at week nine with 150 mg or 300 mg extended-release daily dose. In the secondary outcomes, fatigue was assessed with the Patient Reported Outcomes Measurement Information System (PROMIS) fatigue scale. Neither dose showed a meaningful improvement in the primary or the secondary outcome. A meta-analysis could not be performed by including Barton et al.’s study
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      because the scales employed were different, and the CRF was appraised as a secondary outcome.
      The non-randomized studies included non-cancer conditions such as Crohn's disease (n=1)
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      and multiple sclerosis (n=1)
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      , as well as patients with cancer of the breast, head, neck, ovary, prostate, uterus, skin, and brain and lymphoma (n=2).
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      ,
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      The primary outcome was fatigue improvement, but none of the studies measured fatigue using the same scale. In Pardini et al.’s
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      multiple sclerosis trial, fatigue was measured using the Modified Fatigue Impact Scale (MFIS), and the patients were included in the study if they had had a score of more than 38 points. In the Crohn's disease trial on sleep and fatigue by Hashash et al.,
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      the participants completed the Multidimensional Fatigue Inventory (MFI), and a cut-off score of 45 points was set as one of the inclusion criteria. In the studies with cancer patients by Moss et al. and Cullum et al,
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      ,
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      the BFI and the Clinical Global Improvement (CGI) scale were used, respectively; the CGI was employed to assess fatigue improvement in addition to the severity of illness.
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      The intervention dosages of bupropion in the four non-randomized studies were between 100 and 300 mg per day. The outcomes were followed for three months in the studies evaluating non-cancer conditions.
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      ,
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      In the studies with cancer patients, bupropion intervention was evaluated after one and three months of treatment.
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      ,
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      Bupropion significantly reduced fatigue, according to the four studies’ results.
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.
      The Crohn's disease trial reported that the brief behavioral treatment of sleep and bupropion lowered the MFI mean score from 56.1 to 48.2 (P ≤ 0.001) and improved sleep quality (P ≤ 0.001). Anxiety and depression measured using the Hamilton Anxiety Rating Scale (HARS) and the Hamilton Depression Rating Scale (HDRS), respectively, also improved (HARS score 10.4 [preintervention] and 5.8 [postintervention], P = 0.008; HDRS score 9.0 [preintervention] and 5.0 [postintervention], P = 0.001).
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      Patients with multiple sclerosis had an improvement in fatigue scores from 47.4 ± 0.6 to 32.1±1.3 after bupropion therapy (P < 0.001) and showed higher reward responsiveness than patients receiving escitalopram or placebo.
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      In the trial with cancer patients, bupropion significantly reduced BFI scores from 7.06 ± 0.95 to 5.14 ± 1.97 (P = 0.01).
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      This improvement was present in patients with and without depression. Patients with depression showed an improvement in HDRS scores from 23.0 ± 3.84 to 14.78 ± 8.79 (P = 0.01).
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      The case series study did not report a statistical analysis, but cancer patients treated with bupropion showed lower symptom burden up to two years after treatment.
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.

      Safety Outcomes

      In the randomized control trial on CRF by Salehifar et al.,
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      three patients were unwilling to continue in the study: two in the intervention group and one in the control group. No adverse effects were observed in either group. In Ashrafi et al.’s
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      randomized control trial on CRF, 17 patients discontinued intervention caused by adverse events, consent withdrawal or loss to follow-up: nine in the intervention arm and eight in the placebo arm. Common and mild adverse effects were anorexia, constipation, nausea, dizziness, and abdominal or back pain. No severe adverse effects were documented, and there was no difference in adverse effects between both groups (P = 0.11). In the trial of Barton et al.,
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      women receiving 300 mg of bupropion once daily reported more headaches at week seven (P = 0.01). No toxicities were documented, and side effects were equally distributed across the 150 mg dose and the placebo arm.
      • Barton DL
      • Pugh SL
      • Ganz PA
      • et al.
      Randomized controlled phase II evaluation of two dose levels of Bupropion Versus Placebo for sexual desire in female cancer survivors: NRG-CC004.
      The non-randomized trials reported a low rate of patients lost to follow-up. Five patients with CRF and two fatigued patients with multiple sclerosis were lost to follow-up.
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      ,
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      No patients missed or discontinued treatment in the Crohn's disease trial.
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      No adverse effect was reported in the three non-randomized trials.
      • Moss EL
      • Simpson JSA
      • Pelletier G
      • Forsyth P.
      An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners.
      • Hashash JG
      • Knisely MR
      • Germain A
      • et al.
      Brief behavioral therapy and Bupropion for sleep and fatigue in young adults with crohn's disease: an exploratory open trial study.
      • Pardini M
      • Capello E
      • Krueger F
      • Mancardi G
      • Uccelli A
      Reward responsiveness and fatigue in multiple sclerosis.
      The case series documented mild and limited cases of headaches, constipation, agitation, blur vision, confusion, pruritus, insomnia, and depression. No epileptic crisis was reported in patients with a history of seizures.
      • Cullum JL
      • Wojciechowski AE
      • Pelletier G
      • Simpson JSA.
      Bupropion sustained release treatment reduces fatigue in cancer patients.

      Discussion

      Fatigue is the most predominant and severe symptom in cancer patients in the last six months of life with a mean Edmonton Symptom Assessment System (ESAS) score of 6–8/10 points.
      • Seow H
      • Barbera L
      • Sutradhar R
      • et al.
      Trajectory of performance status and symptom scores for patients with cancer during the last six months of life.
      Caused by its concurrent occurrence and positive correlation with pain (r = −0.20, P = 0.0012), nausea (r = −0.13, P = 0.04), anxiety (r = −0.27, P < 0.0001), depression (r = −0.19, P = 0.0019), drowsiness (r = −0.24, P = 0.0002), dyspnea (r = −0.17, P = 0.007), anorexia (r = −0.29, P < 0.0001), and insomnia (r = −0.25, P < 0.0001), fatigue is usually underdiagnosed and undertreated.
      • Yennurajalingam S
      • Palmer JL
      • Zhang T
      • Poulter V
      • Bruera E.
      Association between fatigue and other cancer-related symptoms in patients with advanced cancer.
      Furthermore, there appear to be different phenotypes of fatigue depending on the cognitive or motor aspects caused by each chronic degenerative disease, making it challenging to investigate fatigue as a single entity.
      • Feng LR
      • Regan J
      • Shrader JA
      • et al.
      Cognitive and motor aspects of cancer-related fatigue.
      Even placebo had a significant effect on CRF, obtaining a response rate of 29% (95%CI 25–32%) and an improvement of 4.88 points in the FACIT-F Scale score (95%CI +2.45 to +7.29).
      • Junior PNA
      • Barreto CMN
      • de Iracema Gomes Cubero D
      • del Giglio A.
      The efficacy of placebo for the treatment of cancer-related fatigue: a systematic review and meta-analysis.
      These reasons partly explain the lack of consensus and recommendations on pharmacological treatments for fatigue. Previous pharmacological treatments, primarily stimulants, not only had a moderate response but implied a diversion risk.
      • Belloni S
      • Arrigoni C
      • de Sanctis R
      • et al.
      A systematic review of systematic reviews and pooled meta-analysis on pharmacological interventions to improve cancer-related fatigue.
      The network meta-analysis by Chow et al. found paroxetine to be a promising pharmacological intervention for CRF.
      • Chow R
      • Bruera E
      • Sanatani M
      • et al.
      Cancer-related fatigue-pharmacological interventions: systematic review and network meta-analysis.
      In that same line, our systematic review is the first to comprehensively evaluate the literature on bupropion as a treatment for fatigue in cancer and non-cancer conditions. Even though the preliminary data is insufficient to draw conclusions, several findings must be underlined.
      First, six out of seven studies showed a significant improvement in fatigue scores with bupropion over placebo in cancer and non-cancer conditions. The trial that did not show benefit of bupropion in fatigue had the limitation of assessing CRF as a secondary outcome in relation to sexual desire in cancer patients. Although the suboptimal quality of the studies cannot be overlooked, the favorable consistency of the results seems unlikely to be caused by a repeated bias incurred systematically by different authors. Second, bupropion's efficacy was explored in fatigue in non-cancer conditions, and promising results were found. In non-cancer conditions, fatigue is also a common symptom but is inadvertently ignored. The preliminary findings of bupropion reducing fatigue in two different autoimmune diseases are worth exploring in future trials. Third, bupropion was well tolerated and safe. The adverse effects were mild and limited; this characteristic alone could make physicians prefer bupropion over stimulants if the efficacy profile is similar or in special populations such as children and patients with a history of psychiatric disease or drug misuse. For these reasons, we believe a robust and high-quality randomized clinical trial is warranted to investigate the potential role of bupropion and other antidepressants in the treatment of fatigue in cancer and non-cancer conditions. Recently, a multicentered, randomized, double-blind, placebo-controlled, phase III trial protocol researching the efficacy of bupropion in reducing CRF in breast cancer survivors has been published. Also, it will explore the possible benefits of bupropion in depression and quality of life while reporting on the tolerability of the intervention. This trial aims to enroll 422 patients and is currently recruiting participants.
      • Jim HSL
      • Hoogland AI
      • Han HS
      • et al.
      A randomized placebo-controlled trial of bupropion for Cancer-related fatigue: study design and procedures.
      A breakthrough result from this milestone trial could transform our understanding and clinical practice of CRF.

      Limitations

      The review has a number of limitations that should be considered. The search was conducted only in three databases, in one language, and excluded grey literature; therefore, there is a chance of having missed relevant articles. However, the total number of screened articles was high enough to assure that the search was considerably extensive. Our results should be considered hypothesis-generating, given the low methodological quality and the design characteristics of the studies reviewed, especially regarding the non-cancer conditions caused by the paucity of current evidence. Moreover, both randomized trials with positive primary outcomes were single-centered and had a small number of participants (33 patients in total for bupropion intervention).
      • Salehifar E
      • Azimi S
      • Janbabai G
      • et al.
      Efficacy and safety of bupropion in cancer-related fatigue, a randomized double blind placebo controlled clinical trial.
      ,
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      Furthermore, the length of follow-up in the included trials only evaluated short-term ranges, which does not allow for assessment of the long-term effects of bupropion use. Also, bupropion's cost-effectiveness is unknown in fatigue treatment; this unexplored factor may favor or avoid bupropion use in clinical practice if its profile matches other pharmacological options. Future studies should be guided and interpreted through patients’ reported outcomes. It is known that a clinically significant improvement in CRF is a reduction of approximately 10 points in FACIT-F and 4 points in ESAS fatigue scores.
      • Reddy S
      • Bruera E
      • Pace E
      • Zhang K
      • Reyes-Gibby CC
      Clinically important improvement in the intensity of fatigue in patients with advanced cancer.
      In one study with bupropion, the FACIT-F score showed a change of 7 points
      • Ashrafi F
      • Mousavi S
      • Karimi M.
      Potential role of bupropion sustained release for cancer-related fatigue: a double-blind, placebo-controlled study.
      ; this and other related outcomes should be analyzed in regard to patients’ goals.

      Conclusions

      Fatigue is an ever-present symptom underdiagnosed and undertreated in chronic non-communicable diseases that places a significant burden on patients’ quality of life. Bupropion is an atypical antidepressant, well tolerated and with a high safety profile, that has been considered a novel treatment for fatigue caused by its stimulant-like effect. The current studies of suboptimal quality that have used bupropion to treat fatigue in cancer and non-cancer populations have found significant efficacy. Still, the heterogeneous and quasi-experimental design of pilot studies limits their findings and warrants robust and high-quality randomized trials to confirm preliminary results. Future research should focus on pathophysiologic pathways, diagnosis, and treatment of fatigue in non-cancer conditions.

      Submission Declaration

      Disclosures and Acknowledgments The authors thank the authors’ institutions for allowing them to participate in this research, and Dr. Marta Ximena León, for her support. The authors declare that they have no conflict of interest. All authors participated in the research design, analysis of information, and writing of the article, and attest to the veracity and originality of the study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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