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Biennial Review of Pain

Placebo 2.0: the impact of expectations on analgesic treatment outcome

Bingel, Ulrike

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doi: 10.1097/j.pain.0000000000001981
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  • Global Year 2020

1. Expectations drive placebo and nocebo effects

Experimental and clinical evidence from the past decades indicates that patients' expectations about treatment benefits are crucial modulators of health and treatment outcomes (for comprehensive reviews see Refs. 12, 31, 37, 43, 58, and 95). The pivotal role of expectation is best illustrated by experimental or clinical trials involving placebo (inactive) treatments. Changes in health outcomes (eg, pain) after a placebo treatment cannot be explained by specific properties of a drug. Instead, as seminal work by Donald Price, Irving Kirsch, and other pioneers in the field were able to demonstrate, they are critically determined by patients' expectations regarding the (drug) treatment85,86 in addition to natural fluctuations (ie, natural course) of the underlying condition.

Meta-analyses of placebo-controlled randomized clinical trials in different diseases have shown that a large proportion of symptom improvement can be attributed to placebo effects.56,83 Placebo effects have been observed in various physiological systems and medical conditions,95 but their effect size seems to vary between systems and conditions. The effects of positive expectations are particularly strong in studies on pain and depression, where up to 70% of overall treatment effects can be attributed to placebo effects.80,90 Meta-analyses of experimental placebo analgesia studies that allow for a dissociation of expectation effects and natural fluctuations in pain, which is not feasible using a classic randomized controlled trial design, corroborate large and clinically relevant effect sizes of positive expectation on pain.107

Importantly, expectations can also have a negative effect on treatment outcome, which is commonly referred to as nocebo effect. The role of negative expectations in driving the occurrence of unwanted side effects in placebo groups is being increasingly acknowledged.20,29 In fact, large proportions of adverse events and symptoms reported by patients in clinical trials may not be caused by the drug itself. This is suggested by the observation that adverse events in placebo arms of drug trials not only resemble those of active treatments in frequency of occurrence, but also in the nature of the symptoms.3,87,89

The key role of negative expectations in pain perception is corroborated by experimental nocebo studies, indicating that the mere expectation of more intense or more frequent pain can modulate pain sensitivity at the behavioural and neural level.6,21,47,97,100,104 Negative expectations also play a key role in the development and maintenance of new symptoms, as highlighted in a recent study by the Benedetti group on pain at high altitude. Study volunteers who were informed by a fellow participant that the high altitude may lead to hypobaric hypoxia headache showed a significant increase in the prevalence and intensity of headache and salivary cyclooxygenase activity, a core factor in prostaglandin synthesis.16 Similarly, expectations of increasing sensitivity to pain over time can counter the naturally occurring habituation to repetitive painful stimulation in healthy volunteers.92

2. The impact of expectation on active (analgesic) treatments

Expectations not only determine the response to inert treatments. Cumulating clinical and experimental evidence indicates that expectations can also substantially modulate the efficacy and tolerability of active medical treatments, including pharmacotherapy.

Positive treatment expectation has, for instance, been shown to double the analgesic effect of the opioid remifentanil21 (Fig. 1) and to substantially enhance the effect of the acute antimigraine drug rizatriptan.57 For analgesic treatments, up to 50% of the treatment response can be attributed to expectation and not to the pharmacodynamic effect of the administered drug.4,7,21,71 Similar effects have been reported for other treatments, including psychotropic drugs30,78 but also for nonpharmacological interventions. Positive expectations predict outcomes in multimodal treatment programs for chronic pain34 and surgical procedures8,91 as well as the effect of deep brain stimulation on motor performance in Parkinson disease.30

Figure 1.
Figure 1.:
Expectation modulates opioid analgesia. In this study, the effect of a fixed concentration of the µ-opioid agonist remifentanil on heat pain stimuli was assessed under no expectations, positive (analgesic) treatment expectations, and negative (hyperalgesic) treatment expectations. Positive treatment expectancy doubled the analgesic effect of remifentanil. By contrast, negative treatment expectancy completely abolished the analgesic efficacy of the opioid. Adapted from Bingel et al.21

By contrast, negative expectation can reduce the therapeutic effect of pharmacological treatments21,40 and substantially contribute to the development of unwanted side effects.20,29 This was, for instance, made evident using cross-lagged panel analyses in pharmacologically treated patients with rheumatoid arthritis, where side effects were linked to patients' beliefs about arthritis medication.81 Thorough analyses of the side-effect profiles of placebo groups in clinical trials have shown that both the quality and quantity of reported side effects in these placebo groups are similar to those of the active treatment groups.3,38,53,79,89 Furthermore, switching from trademark to generic drugs with identical compounds is frequently associated with an increase in adverse events and therefore often leads to treatment discontinuation,44 an effect that has recently also been discussed to impact the switch from reference biologics to biosimilar products.9

3. Treatment effects revisited: expectation impacts pain and analgesic treatment outcomes

Based on the experimental and clinical evidence outlined above, it can be concluded that expectations significantly shape pain and analgesic treatment outcomes including the efficacy and tolerability of analgesics (Fig. 2). It therefore seems reasonable to propose that expectations themselves should be systematically assessed, and their effects integrated into current standard treatment regimens. Such strategy promises to optimize analgesic treatment outcomes and to prevent or reduce the misuse of analgesics (as currently seen in the endemic use of opioids) and the burden of unwanted side effects. However, the attempt to use the effects of expectation in the clinical context is still in its infancy. The main obstacle for a systematic exploitation of patients' expectations in standard clinical practice is our limited understanding of the mechanisms underlying these expectations, their impact on treatment outcomes, and how these effects interact with actual (eg, pharmacological) treatment effects. In the following, I highlight current concepts but also key challenges and key-open research questions in the field that need be addressed.

Figure 2.
Figure 2.:
Treatment expectation impacts pain and analgesic treatment outcomes.

4. Psychological determinants of treatment expectation

Patient's treatment expectation can be instantiated in various ways: through verbal information (eg, from healthcare professionals), through prior treatment experience or observational learning, but also by characteristics of the therapeutic context or the therapeutic intervention itself (Fig. 3). Verbal information regarding the expected effects of treatments is conveyed by various sources. Both direct verbal communication with healthcare professionals but also written information as part of informed consent procedures or medication leaflets have been shown to shape patients' treatment expectations and treatment outcomes including treatment efficacy21,57 and tolerability.79,89 Digital and social media play an increasingly important role in providing health-related information.36,113 Treatment expectations are further determined by prior treatment experiences. Using associative learning paradigms, pretreatment experiences have been shown to induce or enhance treatment expectation, which can involve implicit and explicit learning processes and conscious awareness to varying degrees.54,55 For instance, pain relief after placebo treatments can successfully be induced by verbal instructions alone, yet the effect is stronger and more sustainable if verbal instructions are combined with the experience of pain reduction, which is usually—unbeknown to the participant—experimentally induced using conditioning procedures.33 Recent evidence indicates that these effects of prior treatment experiences can generalize over time and across different types of treatments and can thus contribute to both positive and negative intervention effects.59,118

Figure 3.
Figure 3.:
Treatment expectation: the influence of prior information, state, and trait factors. Treatment expectation is determined by prior information available to the patient to predict health outcome. This information can be provided by others (eg, healthcare professionals), prior first-hand treatment experience, or the observations of significant others (eg, other patients). Patient-related trait and state factors are assumed to influence an individual's treatment expectation and the interaction between expectation and analgesic treatment outcome. Examples of such factors are an individual's anxiety and stress level, or variations in one's neurobiological makeup (eg, brain connectivity).

Repeated exposure to pharmacological agents can induce a response that mimics the effects of the drug itself, although only a placebo is given. This phenomenon is also referred to as pharmacological conditioning1,39,48,60 and can comprise both the desired effects of a drug (eg, pain relief) and adverse effects (eg, respiratory depression in the case of an opioid drug). Importantly, treatment experiences do not have to be acquired through first-hand experience. Experimental studies indicate that observing positive or negative treatment effects on pain in others can affect treatment expectation and outcome.28,63,108,116 Treatment expectations are also shaped by the characteristics of the therapeutic context and features of the medical setting, such as the appearance of the healthcare provider or the clinical environment.105 Furthermore, characteristics of the treatment itself play a role.77 For instance, invasive interventions (eg, acupuncture, surgery) induce stronger treatment expectations and subsequently greater health benefits than less invasive treatments, such as oral treatments (eg, pills).76 In a similar vein, active placebos (ie, treatments involving the application of a pharmacological substance that induces perceivable [side] effects but with no effect on the target symptom) can induce stronger placebo effects than inert placebos.88 These findings encourage further investigations to explore how treatment features can be tailored to maximize positive treatment expectations.19

5. Neurobiological mechanisms of expectation effects on pain

Experimental studies involving placebo and nocebo conditions have begun to unravel the mechanisms that mediate the effects of positive and negative treatment expectation on pain and analgesic treatments (Fig. 4). Evidence from neuroimaging studies indicates that placebo analgesia involves descending pain modulatory pathways, including the dorsolateral prefrontal cortex (DLPFC), rostral anterior cingulate cortex, and periaqueductal gray,84,109,111 which modulate the activation of pain-processing brain areas such as the insula and somatosensory cortices,65 and even the spinal cord42 in a top-down fashion. Critically, activity in the DLPFC precedes and scales with activity changes in other pain modulatory areas,111 prevents the extinction of once learned placebo analgesia,96 and transient lesioning of the DLPFC reduces placebo analgesia.66 Furthermore, degeneration and reduced connectivity of the frontal lobes in Alzheimer disease are associated with compromised or complete loss of expectation induced analgesia.15 Together, these findings suggest that the DLPFC is important for initiating and maintaining the effect of treatment expectation on pain. Recent evidence suggests that the anterior insula integrates expectation and nociceptive processing.45,46,65 Its functional properties comprising cognitive, affective, and nociceptive aspects and its role in detecting and steering autonomic functions35 make this brain region an ideal candidate to integrate expectation and its effect on subjective and physiological treatment outcomes.

Figure 4.
Figure 4.:
Central nervous system mechanisms underlying expectation and its effects on health outcomes. Physiological changes in response to treatment expectation have been observed in various bodily systems. The CNS mechanism initiating and mediating these effects is best characterized for the effects of positive expectation on pain perception, which has been associated with prefrontal, limbic, and descending pain modulatory pathways. Partly overlapping neural circuitry is assumed for expectation effects on negative mood. The mechanisms underlying the effects of expectation on other bodily systems are unclear to date. Figure modified from Enck et al.43 CNS, central nervous system.

Although previous smaller-scale studies have convincingly linked placebo analgesia with dampened nociceptive processing including the spinal cord, a recent large-scale single-participant meta-analysis of functional magnetic resonance imaging studies of placebo analgesia highlights that this mechanism is not sufficient to explain the behavioural effects.117 Although this meta-analysis confirmed moderate analgesic effects of placebo treatments on experimental pain in healthy volunteers, only rather small effects of placebo treatments on the “neurological pain signature,”110 a validated measure that tracks levels of nociceptive pain, were observed. This suggests that a large proportion of placebo effects is mediated through brain mechanisms that are independent of a modulation of bottom-up nociceptive processing and rather involve cognitive–evaluative and emotional appraisal of pain.

Regarding the involved neurotransmitters, endogenous opioids have been shown to be pivotal for the implementation of placebo analgesia.17,26,41,72 In addition, mesolimbic dopaminergic pathways have been linked to placebo analgesia, although their specific role remains unclear.101 Increased dopaminergic neurotransmission in the striatum has been observed during placebo analgesia, and an individual's placebo analgesic response was shown to correlate with reward responsiveness100 and structural properties of the striatum.99 However, pharmacological blocking of placebo-related activity using haloperidol had no behavioral effect on placebo analgesia in healthy volunteers114 or patients with chronic neuropathic pain.102 Although the results of these pharmacological studies have to be interpreted with caution due to their rather small sample sizes, this suggests that the role of the dopaminergic mesolimbic reward system in placebo analgesia is more complex and might not be directly involved in the analgesic effect induced by positive expectation but may be related to associated processes, such as reward processing or the acquisition (learning) of analgesic treatment experiences.

So far, most studies in the context of pain have focused on the effects of positive expectation, whereas mechanisms underlying negative expectations on pain (ie, nocebo hyperalgesia) have received only little attention, which may at least partly be explained by the significant ethical and clinical constraints that are associated with the deliberate induction of negative expectations, particularly in patients. Findings from first studies investigating negative expectancy effects suggest that expectations that amplify pain are associated with increased activity in sensory pain areas, including the spinal cord.47,104 However, the exact neurobiological mechanisms underlying this amplification of nociceptive information are largely unexplored. Pharmacological studies have linked nocebo hyperalgesia to an activation of the endogenous cholecystokinin system, a system that is tightly related to anxiety, which is a powerful modulator of nocebo hyperalgesia.14 Imaging studies have shown increased activity and functional connectivity of the hippocampus and the amygdala21,64 lending further support for a role of anxiety-related circuitry in nocebo hyperalgesia.

Taken together, despite more than 2 decades of neuroimaging research in the field of placebo analgesia, the detailed neurobiological mechanisms underlying the effects of positive and negative expectation on pain and analgesic treatment outcomes are far from being understood. This particularly relates to the distinct role of the mesolimbic reward system and its interplay with the prefrontal cortex and nociception-related brain circuitry and the question whether the same or potentially different neural circuitry mediates the effects of positive compared to negative expectancy. Furthermore, it is unknown whether the described mechanisms underlying expectation effects on acute experimental pain observed during a single experimental session are also responsible for the effects of expectations over longer periods (as, for instance, in randomized controlled trials in chronic pain patients) and how chronic pain conditions that are known to be associated with changes in brain structure and function5,10,23 affect these circuitry and the mechanisms underlying expectation on analgesic outcome in pain patients.

6. The challenge: interindividual differences in the effects of expectation on pain and analgesia

Expectation effects on health outcomes vary considerably among individuals in both experimental and clinical scenarios. Insights into a patient's responsiveness to positive expectation manipulations would have immediate implications for routine clinical care. For instance, a lower dose of analgesics might be required in patients who can sufficiently engage endogenous pain modulatory pathways under positive expectations, whereas higher doses are needed in patients who cannot, as has already been shown for patients with Alzheimer disease.15 Knowledge about trait and state factors that modulate, or even predict, an individual's effect of expectation on health outcomes is therefore crucial to optimally adapt therapeutic decisions in a personalized manner. So far, interindividual differences have only been investigated in studies with relatively small sample sizes, which might explain the conflicting results.43 Psychological studies have shown that anxiety, stress, and negative affect can modulate an individual's response to positive and negative treatment expectations on pain.73–75 State anxiety can enhance the effect of negative treatment expectation in models of nocebo hyperalgesia,27 and reduce the effect of positive expectation on opioid analgesia.21 These findings indicate that anxiety hampers the effects of positive expectation and promotes negative ones. The modulatory effect of anxiety has been shown to involve hyperactivity of the hypothalamic–pituitary–adrenal axis.14 With respect to more persistent personal characteristics or traits, there is evidence suggesting that negative affect, including anxiety disorders and depression, play a role.70,97 Furthermore, an individual's desire for pain relief seems to shape the influence of expectations,106 which represents an interesting link to value- and reward-related processes.

The responsiveness to placebo manipulations has also been linked to interindividual neurobiological differences (eg, brain structure and function). There is first evidence to support the notion that the structural and functional connectivity of the brain at rest can at least in part predict the influence of expectation on pain and analgesia. White matter integrity within and between DLPFC and key areas in the pain modulatory network, such as rostral anterior cingulate cortex and periaqueductal gray, are known to explain interindividual differences in placebo analgesia.103 Likewise, several fMRI studies have shown that resting-state functional connectivity of the prefrontal cortex and other brain regions at baseline can predict the response to psychological and pharmacological treatments in chronic pain conditions.10,22,51,52,69,98 Also, genetic factors such as genetic variation in pain modulatory neurotransmitter pathways (eg, the endogenous opioid, cannabinoid, or dopaminergic systems) contribute to an individual's response to treatment expectations on pain.49,50

To date, our ability to predict an individual's treatment expectation in a specific clinical situation and, importantly, dynamic changes in these expectations over time, is still limited. Targeting expectations in a personalized manner can, however, only be successful if we gain a better understanding of these interindividual differences. Joint international research efforts and pooled analyses of existing data are expected to help the identification of patient-related variables that modulate or even predict the individual's responsiveness to the effects of positive and negative expectation on pain and analgesic treatment outcomes.

7. Uncharted territories: how do the effects of expectation and active (pharmacological) treatment combine or interact?

One of the crucial, yet unanswered, questions is whether the effects of expectation and treatment (eg, a specific pharmacological agent) combine in an additive or interactive manner (Fig. 5). Depending on the drug, its pharmacological mechanisms and expectation that triggers endogenous neurobiological cascades may combine in an additive manner for one substance/treatment, but in an interactive fashion for another. The so-called balanced placebo designs93 (Fig. 5), which include both placebo and active treatment, provide the unique opportunity to delineate the mechanisms and effects of treatment expectation, the treatment itself, and their interaction.

Figure 5.
Figure 5.:
Balanced placebo design to investigate additive vs interactive effects of expectation and treatment. In these paradigms, the pharmacological treatment and expectations are both varied in a 2 × 2 factorial design with the factors “treatment” (yes/no) and “expectation” (yes/no) (A). This allows for the isolation of mechanisms and effects of treatment expectation (placebo > control) and pharmacodynamic effects of the drug (hidden > control). Although comparing open and hidden applications would reveal the impact of expectation on treatment efficacy, only the full 2 × 2 factorial design allows to differentiate between additive and interactive effects of expectation and treatment (B).

A recent review of the existing balanced-placebo designs involving analgesic treatments strongly suggests the existence of interactive/multiplicative effects, which can result in synergistic, but also subadditive effects of treatment expectations and pharmacological analgesia.24

A more detailed understanding of potential interactions of expectation and specific analgesic treatments is important for 2 reasons. First, in real-life clinical scenarios, treatments are inherently associated with a patient's expectation. To tailor the combination of active treatment and expectation optimization strategies to the individual, knowledge regarding their combined effect is crucial. Second, a more detailed understanding of the interaction of pharmacological treatments and treatment expectation has tremendous implications for the design and interpretation of randomized placebo-controlled studies because these are conceptually built on the fundamental (but potentially false) assumption of solely additive effects of expectation and treatment.

8. Uncharted territories: how can treatment expectations be systematically targeted in clinical settings?

As outlined above, much more can and needs to be understood regarding the mechanisms underlying treatment expectations and their physiological effects on analgesic treatment outcomes. However, I propose that the existing evidence for a substantial contribution of expectancy effects on analgesic treatment outcome is already compelling enough to demand that treatment expectations need to be targets of systematic interventions in the clinical context to improve analgesic treatment outcomes. Patients' outcome expectations are dynamic constructs that are generated based on prior information available to the individual to predict treatment outcome involving varying levels of implicit and explicit learning and awareness.55,94 In other words, treatment expectations are malleable and can be systematically altered by modulating the available treatment information that—as outlined above—can stem from various sources (for practical recommendations see Table 1).

Table 1
Table 1:
Strategies to optimize expectation effects, adopted from Enck et al.,43 Bingel et al.,20 and Colloca and Barsky.25

Verbal information is omnipresent in clinical care. Optimizing treatment information by providing verbal instructions to increase patients' positive expectations in the clinical context is therefore an easy-to-use strategy. As exemplified in the open–hidden drug paradigms, this should start by something as simple as providing “open” medication, ie, making sure that patients are properly informed about the analgesic properties of the drug, its mechanism, and intended effect. Further promising tools are brief psychological interventions that could be used by healthcare professionals to optimize patients' expectations.

Such strategy has proven successful in various experimental studies, and initial studies in the clinical context support the feasibility and effectiveness of such strategy as demonstrated for the recovery after myocardial infarction82 or heart surgery91 or the optimization of pain management after breast18 or knee surgery.62 Influencing treatment expectations by the careful use of language and provision of appropriate information regarding the expected treatment effect should be considered as an important feature of pain management, as is already highlighted in national treatment guidelines.61

Prior treatment experiences represent strong modulators of treatment expectation and its effect on analgesic treatment outcomes. However, although the experience of treatment efficacy can easily be modulated and successfully boost treatment responses in experimental settings, the use of such a strategy in a clinical setting can be difficult, given that often no efficient treatment is available to induce a positive treatment experience, particularly in chronic pain conditions. However, physicians and healthcare professionals should be aware of the potentially detrimental effects of negative prior treatment experiences that can generalize over time and treatment approaches.59,118 Assessing prior treatment experiences and patients' preferences regarding an analgesic treatment represents an important step towards integrating an individual's treatment experiences into the treatment regimen. The systematic modulation of treatment experience including pharmacologically conditioned responses may be challenging and not yet feasible in chronic pain conditions. However, such strategy may be helpful in acute pain, where pharmacologically conditioned analgesia after the repetitive exposure to nonopioid and opioid analgesics has been successfully documented in experimental trials,2,13 and nonpharmacological approaches (eg, relaxation techniques) could be systematically coupled with pharmacological analgesics to harness learned analgesia in subsequent treatments events. Novel and visionary approaches even consider/explore how learning mechanisms in combination with open-label placebos can be used to increase the potency of methadone in treatment seeking opioid use disorder.11

Interestingly, experimental studies indicate that treatment expectations do not have to be acquired through first-hand experience, but that a similar effect can be achieved through observing treatment benefits in others.28,108 If these findings translate into clinical populations, observational learning might provide a particularly useful strategy to enhance treatment expectations in cases where treatments have failed in the individual or where there is no effective treatment available. Future experimental and clinical studies should investigate if and how the observation of treatment success of another patient can be used to enhance positive treatment expectations and subsequent treatment outcome in clinical populations. Witnessing another patient's treatment success could be implemented by means of standardized video observation, as such a strategy—if proven successful—provides the opportunity for translation into clinical context.

Obviously, there is a plethora of further possibilities of how variables of the treatment setting and treatment context, as well as information provided through leaflets, consent forms, etc., could be modulated to support the development of positive outcome expectations. But, as for the 3 strategies outlined above, although prior experimental work strongly supports the usefulness of their modulation, patient studies are needed to explore their actual effect and cost-effectiveness of these strategies.

Although I advocate the systematic use of strategies to increase positive treatment expectations, it needs to be pointed out that overoptimistic attitudes—if purposely induced by the physician or healthcare professional—are neither helpful, nor ethical. In fact, violations of expectations,32,115 which from a probabilistic perspective become more likely the more extreme and unrealistic expectations are, could have a negative impact not only on the patient–physician relationship, but also the treatment effect (here analgesia) itself. It is thus important that therapeutic modifications of outcome expectations are adjusted to an individual's existing expectation and realistic outcome scenarios (for review, see Kube et al.67).

We also need to acknowledge that information provided to the individual is not linearly translated into an expectation and that this translation process differs from individual to individual.112 Furthermore, a substantial proportion of patients is remarkably reluctant to change or adopt expectations despite conflicting evidence available to the individual, and distorted, unhelpful expectations are a hallmark of mental disease such as major depression that often accompanies chronic pain conditions.68 The mechanisms underlying these phenomena and specifically strategies how to overcome such “immunization” of beliefs for the benefit of the patient should be an essential target of future research activities.

Targeting expectations in a truly personalized manner strongly relies on the more fine-grained mechanistic understanding of expectations and their top-down effect on subjective, behavioural, and physiological treatment outcomes. Further, context-, treatment, and patient-related variables, including ethnocultural differences, that modulate or even predict the effect of an individual's expectation on analgesic treatment oucome at a given time-point need to be identified.

9. Key open questions and uncharted territories regarding the mechanisms and effects of treatment expectation on health and treatment outcome

Although the effects of expectations have been documented in various health conditions, and pioneering studies have started to unravel their underpinning mechanisms, the following fundamental questions need to be answered before their potential can be better translated into the clinical context:

Psychological and neurobiological mechanisms

  1. Are there shared or distinct mechanisms underlying the effects of positive and negative expectations on pain?
  2. Do these mechanisms differ between healthy volunteers and patients?
  3. Does treatment expectation affect subjective/patient-reported and objective (physiological/behavioral) outcomes differently?
  4. How do the effects of treatment expectation combine with the effects of a pharmacological treatment? Are these additive or interactive—potentially synergistic—effects, and does this interplay vary depending on the type of treatment?

Interindividual differences

  1. Which psychological and physiological state and trait factors modulate an individual's treatment expectation and its effect on health outcomes? Can these factors help us to predict these effects?

Targeting treatment expectation in the clinical context

  1. How can treatment expectations be systematically targeted in different systems and conditions? How much information is needed to form treatment expectations and how should this information be presented to the individual/patient?

Conflict of interest statement

The author has no conflicts of interest to declare.

Acknowledgements

The author would like to thank Katja Wiech for continuous support and scientific exchange, May Schäflein for help with creating the figures, and Katharina Schmidt for editing the manuscript. This work was inspired and funded by CRC/TRR Treatment Expectation; Germany Research Foundation—Project-ID 422744262—TRR 289. Gefördert durch die Deutsche Forschungsgemeinschaft (DFG)—Projektnummer 422744262—TRR 289.

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