Condition
Placebo
Placebo in children
1. Migraine
1.1 Symptomatic treatment a
Analgesics
9 % (7–17)
37–53 %
Triptans
6.1 ± 84.4 % (5–17)
28–65 %
TMS
67 %
1.2. Prophylactic treatment b
All drugs
23.5 ± 8 % (95 % CI 18.3–28.8)
NA
Botulin toxin A
35 %
NA
Acupuncture
38 % (95 % CI 30–47)
NA
Surgery
58 % (37–77)
NA
Anti-CGRP antibodies
33–45 %
NA
Neurostimulationc
12.1–13.5 %
NA
2. Tension-type headache
2.1 Symptomatic treatment a
All drugs
12–51 %
NA
2.2 Prophylactic treatment b
Venlafaxine and mirtazapine
15.4–28 %
NA
Acupuncture
41 %
NA
3. Cluster headache
3.1 Symptomatic treatment d
Triptans
3–17 %
NA
Oxygen
20 %
NA
3.3 Prophylactic treatment e
Steroid suboccipital injections
54.5 %
NA
4.3 Nocebos
Nocebo refers to adverse events (AEs) related to patient’s negative expectations that medical treatment will likely harm instead of heal [36]. Other relevant mechanisms contain prior conditioning and suggestions. Nocebo submits more to the intervention than to the outcome and includes expected AEs or, less frequently, nonspecific effects that cannot be substantiated referring to pharmacological action of the treatment [36, 37]. The term nocebo (“I shall harm”) was introduced in contraposition to the term placebo (“I shall please”), by Kennedy in the early 1960s to distinguish the noxious from the pleasing effects of placebo [1, 38]. Nocebo is related to lower adherence in therapy as well as with high rates of dropouts and significant difficulty in assessing the efficacy and the safety profile of a drug in clinical trials [39, 40]. It has been suggested that dopaminergic, cyclooxygenase/prostaglandins and opioid brain pathways reward circuitries, and decision-making processes play a crucial role in the mechanisms that underlie nocebo [40–43]. Reports from clinicians indicate that the nocebo effects are very prevalent, but the exact magnitude remains elusive [44]. Information disclosure for potential side effects can itself contribute to producing AEs, or detailed and extensive information by physicians can also trigger nocebo AEs. Nocebo adversely influences quality of life and therapy adherence, emphasizing the need for minimizing these responses to the extent possible. Definitively, the content and the way information are presented to patients in clinical trials in both the placebo and active treatment conditions influence nocebo. Evidence further indicates that the informed consent process in clinical trials may also induce nocebo [45]. Like placebo, nocebo shares key functions in pain conditions. Two recent systemic meta-analyses searched for nocebo in trials for prevention of migraine and tension-type headache and revealed that 1 out of 20 patients treated with placebo withdraw treatment due to adverse effects. Additionally, adverse events in placebo groups mirrored the adverse events expected of the active medication studied, confirming that pretrial suggestions induce the adverse events in placebo-treated patients. Therefore, nocebo reduces the study population by 10 % and limits the treatment outcomes in randomized controlled trials for primary headaches. The potential implications of this substantial nocebo effect for both trial designing and clinical practice are discussed below [46].
4.3.1 Nocebo in Migraine RCTs
Reuter and colleagues [47] first investigated nocebo in randomized placebo-controlled trials (RCTs) and found that up to one third of migraineurs treated with placebo experience AEs. In trials for symptomatic migraine treatment that tested the therapeutic efficacy of triptans, 21.9 % of control patients reported at least one AE although treated with placebo. Symptoms were grouped into three categories: migraine-related (symptoms such as nausea, photophobia, and phonophobia), drug-related (symptoms typical of the experimental compound such as chest pressure in response to triptans), and nonspecific or coincidental (symptoms such as sleep disturbance). Thus, symptoms in the placebo group were related to the drug under study and to the symptomatology of migraine, whereas some others had no obvious relation to the condition or treatment [47]. In another review aimed at estimating the placebo response in migraineurs treated with oral triptans, it was found that 23.40–14.05 % of participants treated with placebo reported AEs. Fascinatingly, studies performed in North America showed a higher nocebo frequency than those conducted in Europe [12]. Amanzion and colleagues [37] published an extensive systematic review of nocebo in clinical trials for migraine. This was the first attempt to intensely investigate migraine-related nocebo effects. They investigated the AEs after placebo in RCTs testing NSAIDs, triptans, or anticonvulsants. Their major finding was that nocebo AEs mirrored the AEs expected of the active medication studied precisely. For example, anorexia and memory difficulties, which are typical AEs of anticonvulsants, were present only in the placebo arm of these trials. In other words, nocebo in migraine trials arose from patients’ distrust [37]. However, this important meta-analysis aimed to investigate mechanisms of nocebo in particular, rather than to investigate the magnitude of nocebo in RCTs for migraine. Migraine most likely was used as a vehicle pain condition in this study. For instance, the investigators searched RCTs for migraine trials, both symptomatic and preventive, only if specific anti-migraine agents were tested. Undoubtedly, the results of this meta-analysis confirmed their findings derived from experimental human studies that expectations modulate both nocebo and placebo (the expectation theory of placebo and nocebo) [37].
In another more recent meta-analysis of RCTs for all primary headache disorders, 56 RCTs published in the last decade were analyzed to estimate the frequency of patients treated with placebo who experience any AE (nocebo AE ratio) or discontinued treatment due to AE (nocebo dropout ratio) [36]. In this meta-analysis, all RCTs using any compound, either for acute or for chronic treatment, were included. The aim was to estimate the magnitude of nocebo in headaches in the most clinically relevant manner for both the clinicians and trial designers. In symptomatic treatments (STs) nocebo dropout ratio was limited (0.33 %), but in chronic preventive treatments was increased up to 5 %, showing that 1 out of 20 patients treated for migraine prophylaxis discontinues treatment due to nocebo AEs. Practitioners should be aware of this fundamental nocebo effect, trial designers as well [48].
Stratified analyses in migraine studies revealed that (1) nocebo AEs and nocebo dropout ratios were higher in preventive trials than in symptomatic trials (P < 0.001); (2) nocebo AE ratio varied by year of publication in trials for ST of migraine, decreasing from 22.05 % (95 % CI 16.46–28.21 %) for trials published within 1998–2004 to 14.39 % (95 % CI 10.81–18.39 %) for trials published within 2005–2009 (P < 0.001); (3) nocebo did not change with route of drug administration; (4) no differences were found between studies performed in North America compared with Europe; (5) dropout ratio was lower in the placebo group than in the active drug group (mean difference, 7.09 %; 95 % CI 4.1–10.1 %; P < 0.0001); (6) nocebo rates did not vary with the drug tested, with headache type, or by continent, with one exception. In studies with botulin toxin type A, the dropout ratio was significantly lower than in any other preventive drug (0.92 % vs. 4.75 %); and (7) dropout rates were strongly associated in both treatment groups (r = 0.824; P < 0.0001) [36]. These correlations indicate that the safer a drug is, the less nocebo is induced. These correlations indicate that the safer a drug is, the less nocebo is induced and the less potential AEs the concept form describes in RCTs, the less nocebo is caused. This principal finding is in line with other meta-analyses and with the expectation theory of placebo and nocebo [36, 37].
Another key finding concerns the low nocebo dropout ratio in trials for symptomatic migraine treatment. Even the nocebo AE ratio was limited in STs, compared with nocebo AE ratio in preventive antimigraine treatments, implying that the duration of a pharmaceutical treatment may be essential for nocebo. What makes botulin toxin A to have lower dropout nocebo ratio compared to other anti-migraine treatments remains unclear. The route and the frequency of drug administration, or even a positive expectation related to this particular treatment, may account for this variation. It seems that the frequency and the study protocol for the drug administration may be more important for this variation (every 3 months injections in the head and neck). Notably, placebo responder rate was increased (35.1 % vs. 47.1 %) [22]. Conversely, as noted above, the pooled analysis revealed a positive relation between nocebo and placebo rates [36]. Thus, a high positive expectation for the treatment outcome may also explain the low nocebo dropout rate in botulin toxin type A trials (Table 4.2).
Table 4.2
Nocebos in primary headache disorders
Condition | Nocebo AE ratio | Nocebo AE dropout ratio |
|---|---|---|
1. Symptomatic treatment | ||
Migraine | 18.4 % (15–22.2) | 0.3 % (0.2–0.5) |
Cluster headache | 18.7 % (1.6–28.3) | NA |
2. Prophylactic treatment | ||
Migraine | 42.8 % (34.7–51.4) | 4.7 % (3.3–6.5) |
Tension-type headache | 24 % (4.6–52.2) | 5.4 % (1.3–12.1) |
4.3.2 Nocebo in Tension-Type Headache and Cluster Headache
Like chronic migraine, chronic TTH results in a variety of negative repercussions both on individuals and on society at large [49]. There is no more than one meta-analysis available for nocebo in trials for TTH [36]. Unfortunately, only four RCTs for prophylactic TTH treatments fulfilling the search criteria were found for pooled data analysis. Nocebo AE (24 %, 95 % CI 4.6–52.2 %) and nocebo dropout rates (5.44 %, 95 % CI 1.3–12.1 %) were similar to those estimated in RCTs for migraine prophylaxis, but the limited number of RCTs included in this analysis did not allow extensive meta-regression analyses to reveal specific TTH-related nocebo manipulating cofactors [36]. Unlike TTH and migraine, cluster headache is a rare primary headache disorder affecting more men than women [50]. Only data from two RCTs were analyzed [36]. Like in migraine, the pooled estimate for nocebo AE ratio in RCTs for ST of cluster headache was 18.6 % (95 % CI 1.6–28.3 %). But no good data to estimate the nocebo dropout rate in these RCTs were found [36]. In summary, both TTH and cluster headache share similar size nocebo with migraine in prophylactic treatments (one out of five treated patients) (Table 4.2).
4.4 Clinical Implications
4.4.1 Placebo
Because the placebo effect is part of the overall treatment effect, placebos – even powerful placebos – should not replace treatments [51]. Patients will benefit if physicians exploit relatively powerful placebos either alone or as part of a therapeutic regime. A clear case where placebos might be used for clinical benefit is pain, where placebo effects are almost similar in magnitude to treatment effects [51, 52]. But this is not the case for headache. All available treatments showed significant higher effect compared to placebo, although placebo size was large enough. Along these lines, presented numbers needed to treat, a common outcome measurement in meta-analyses, does not represent the actual power of treatments because the placebo effect is extracted. Apparently, this measurement helps to make cross trial comparisons. But in daily practice both the physician and the patient may modify the treatment power individually. All patients share a motivation to overcome the disease. When the physician understands and manages the patients’ needs and expectations he may improve the disease outcome by triggering this motivation. The skill to touch and amplify the positive patients’ expectations varies substantially among physicians. Eventually, the ancient magician’s spirit to stimulate, motivate, and convince patients is needed to be added into the scientific education in order to better control a medical condition. And because pain perception varies considerably by individuals, this skill becomes more important in the case of headache. In this context, comorbidity with somatoform and mood disorders [53] is also important in headache management. Non-pharmaceutical treatments and alternative treatments show higher placebo effects, together with botulin toxin A. Neurostimulation and treatments with monoclonal antibodies may follow this pattern, but more studies are needed to draw clear conclusions in this matter. Children and adolescents tend to express higher placebo effects as well, indicating that physician may control them easier than adults, as expected (Table 4.1).
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