October 23, 2019

Honest Placebo: Good Medicine for Cancer-Related Fatigue?

A novel approach to one of cancer’s most debilitating effects
The improvement of subjective cancer-related fatigue in cancer survivors by placebo may involve the dopamine system.

This article is part of the 2019 Oncology Special Issue of Natural Medicine Journal. Read the full issue here


Zhou ES, Hall KT, Michaud AL, et al. Open-label placebo reduces fatigue in cancer survivors: a randomized trial. Support Care Cancer. 2019;27(6):2179-2187.

Study Objective

To evaluate the effect of an open-label placebo on cancer-related fatigue (CRF) in cancer survivors and to assess whether personality characteristics or a genetic variation in dopamine catabolism (catechol-O-methyltransferase) affect the placebo response


Randomized trial with participants allocated to either an open-label placebo group (ie, participants were aware they were receiving a placebo) or a non-treatment control group


Forty cancer survivors, all of whom had no evidence of active disease, were at least 6 months post-treatment, scored <43 on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale, and were not being treated or evaluated for any other medical cause of fatigue. The average age of participants was 47.3 years (range 22-74) and most were married (62.5%), non-Hispanic white (87.5%) females (92.5%) who had been diagnosed with breast cancer (55%) an average of 9.3 years previously.


On day 1 of the study, all participants completed 7 questionnaires (FACIT-F, SF-12, POMS-SF, GLTEQ, BIDR-7, LOT-R, and the Subjective Significance Questionnaire) and provided a saliva sample for genetic testing. Participants then met with an investigator for a scripted 15-minute study initiation discussion during which the investigator outlined both the rationale of the study and prior evidence indicating that placebo can improve fatigue. At the end of this discussion, participants opened a sealed envelope indicating their study allocation (either open-label placebo [OLP] or non-treatment control). OLP participants received 120 placebo pills with instructions to take 2 pills twice a day for 22 days.

On day 8 of the study, all participants repeated 3 questionnaires (FACIT-F, GLTEQ, and the Subjective Significance Questionnaire). OLP participants were reminded and encouraged to continue taking their placebo pills.

On day 22 of the study, all participants repeated 5 questionnaires (FACIT-F, SF-12, POMS-SF, GLTEQ, and the Subjective Significance Questionnaire). No data were collected after day 22.

Study Parameters Assessed

  • Fatigue: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
  • Physical and mental health status: Short Form-12 (SF-12)
  • Mood disturbance: Profile of Mood States-Short Form (POMS-SF)
  • Exercise participation: Godin Leisure Time Exercise Questionnaire (GLTEQ)
  • Tendency toward socially desirable responding: Balanced Inventory of Desirable Responding-Version 7 (BIDR-7)
  • Generalized optimism: Life Orientation Test-Revised (LOT-R)
  • Subjective fatigue and overall quality of life: Subjective Significance Questionnaire
  • Catechol-O-methyltransferase (COMT) SNPs rs4680 and rs4818: genetic testing

Primary Outcome Measures

Differences in the questionnaire scores from those in the control group were considered to reflect the influence of placebo.

Key Findings

OLP significantly improved CRF as reflected by changes in the FACIT-F score between days 1 and 8 and days 1 and 22.

Changes in FACIT-F scores were not significantly correlated with measures of socially desirable responding (BIDR-7) or generalized optimism (LOT-R), suggesting that a general tendency to expect the best or to present oneself in the best light are not personality variables associated with OLP responsiveness.

The successful treatment of cancer-related fatigue can be expected to improve quality of life for patients and may also improve their survival.

OLP responsiveness did differ significantly based on the COMT rs4818 genotype, suggesting that the dopamine system may play a role.

The SF-12, POMS-SF, and GLTEQ questionnaires found no significant difference between OLP and control.

The Subjective Significance Questionnaire found significant subjective improvement in fatigue and overall quality of life in response to OLP at day 8, but not day 22.

Practice Implications

CRF is defined as “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.”1

This academic definition, though descriptive in a technical sense, fails to convey a real sense of the human impact of CRF. Nothing compares to the words of actual patients sharing their own experiences: “It is not exhaustion. I’ve been exhausted. I’ve never had fatigue like this. It’s not work fatigue or emotional fatigue. It’s very different. It’s incredible.”2

CRF is inherently different from the fatigue experienced as a part of everyday life. It’s not clearly connected to physical exertion, it’s not relieved by rest or sleep, and it includes additional manifestations such as apathy, cognitive dysfunction, emotional lability, and generalized weakness.2

Formal estimates of the prevalence of CRF have ranged from 4% to 91%, depending on the type of cancer studied and the assessment methods used.3 A more recent estimate suggests that non-trivial CRF is experienced by 45% of cancer patients undergoing treatment and 29% of cancer survivors (ie, CRF persists for years as a long-term problem).4

CRF ranks among the top self-reported concerns of cancer patients and can be so severely disruptive to activities of daily living and quality of life that it consistently ranks as being more troublesome than other cancer-related symptoms like depression, nausea, and pain.5,6 CRF may also predict shorter survival for cancer patients.7,8 As such, the successful treatment of CRF can be expected to improve quality of life for patients and may also improve their survival.

Current treatment options for CRF include exercise, mind-body approaches, psychosocial interventions, and pharmaceutical therapy.9 A strong case can be made that exercise is the most effective of these treatment options.10-12 However, it can be very challenging to get fatigued patients to exercise.

The present results reported by Zhou et al may be helpful in this respect. They independently confirm results from a similar study in 2018 and thus position OLP as an intriguing treatment option for CRF.13 They also suggest that OLP can be leveraged to help patients implement a program of therapeutic exercise. While Zhou et al did not find statistically significant evidence that OLP helped patients to increase their physical activity, it is not unreasonable to suspect that a longer time period would increase this likelihood. Placebo effects have been documented to last as long as 12 months and represent a valid option for patients.14

Finally, when seeking to implement OLP in clinical practice, the clinician’s approach probably matters. Zhou et al were very deliberate in their approach to participants and the way in which they presented information, encouragement, and support. “Belief activation” may be an important element for the success of placebo in clinical practice.15


This study is limited by the preponderance of female participants (92.5%) and the short study period (22 days). Further studies in a more diverse group of subjects with a longer intervention will be needed.


Even when administered open-label, placebo improved subjective cancer-related fatigue compared to no treatment in cancer survivors.

Categorized Under


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