A twelve-week, four-arm, randomized, double-blind, placebo-controlled, phase 2 prospective clinical trial to evaluate the efficacy and safety of an anthroposophic multimodal treatment on chronic pain in outpatients with postpolio syndrome.

Abstract Introduction Chronic pain and fatigue are the main symptoms of postpoliomyelitis syndrome (PPS). This study aimed to evaluate the efficacy and safety of an anthroposophic multimodal treatment for chronic pain in PPS outpatients. Methods A twelve‐week, four‐arm, randomized, double‐blind, placebo‐controlled, phase 2 prospective clinical trial was designed to compare four groups (n = 48): groups A and B received daily active experimental transdermal gel (ETG) or placebo gel (PTG), respectively; groups C and D received weekly external therapies, art therapies, and neurofunctional reorganization, plus either daily ETG or PTG, respectively. The pain symptoms were evaluated through a visual analogue scale (VAS), the McGill questionnaire, and thermography. Quality of life and resilience were evaluated by the WHOQOL‐BREF and Antonovsky sense of coherence questionnaires applied at baseline and after the interventions. Results No related adverse events occurred, and 10% of the patients reports dysphagia improvement. In the groups C and D, pain reduction was statistically significant in both the placebo group (p = .02, d = 1.315) and in the ETG (p = .005, d = 2.035). However, following the week‐to‐week evolution of pain with the concomitant use of the ETG, this significant pain reduction occurred earlier from the 4th week and continued to decrease (p = .016, d = 1.369). In the group that received the complete multimodal treatment, the greatest significant benefit in increasing quality of life occurred in the physical domain and elevation in resilience with an emphasis on meaning and comprehension domains. Conclusions The anthroposophic multimodal treatment group presented both safety and efficacy as an analgesic in the groups that received the nonpharmacological therapies, much earlier when associated with the ETG. The multimodal approach corresponded to the pattern of better efficacy for both pain reduction and improvement in quality of life and resilience.


| INTRODUC TI ON
Pain is one of the leading reasons why people turn to complementary and integrative health approaches, which may help manage pain and other symptoms that are not consistently addressed by prescription drugs and other conventional treatments (Tompkins, Hobelmann, & Compton, 2017). The use of complementary interventions in individuals with chronic pain is increasingly common worldwide, with estimates of their use ranging between 18% and 94% in the US (Breuer, 2010). For individuals with lower back pain, osteoarthritis, and fibromyalgia syndrome, there is a moderate evidence base for the use of acupuncture, meditation, chiropractic manipulation, massage therapy, and yoga (Barbour, 2000;Bronfort, Haas, Evans, Kawchuk, & Dagenais, 2008;Chung, Xu, Eken, & He, 2009;Ernst, 2006;Ernst & Posadzki, 2011;Fouladbakhsh, 2012;Kwon, Pittler, & Ernst, 2006;Manheimer, White, Berman, Forys, & Ernst, 2005;Terry, Perry, & Ernst, 2012). For this reason, the research priorities of the National Anthroposophic medicine (AM) is a whole medical system that is widely used in Europe; it combines integrative approaches and conventional interventions with a number of specific therapeutic treatments involving a wide multiprofessional team, as well natural products (Kienle, Albonico, Baars, & Hamre, 2013;Ministério da Saúde, 2006). The review of the pain literature in the Swiss Health Technology Assessment Report on AM (2006) detected 18 studies from 189 clinical trials and systematic reviews from a wide range of diseases (Albonico, Kiene, & Kienle, 2006). The pain studies were conducted between 1973 and 2005 and evaluated 2,308 patients.
In general, all of the studies showed favorable results, a high level of safety and good cost-effectiveness ratios (Hamre et al., 2007(Hamre et al., , 2010. Vieira et al. (2012) reported an experience with 204 patients in a public outpatient center in Brazil with anthroposophical multimodal treatment for chronic pain by osteoarticular and rheumatic disorders. According to the author, 33.5% of the therapies employed were anthroposophic external therapies (AET) as compresses, bandages, medicinal baths, and clay therapy. From the specific group of 74 patients applying clay therapy, the author reported an improvement in pain management and a decrease in analgesic and anti-inflammatory use in 75% of the patients (Vieira et al., 2012). The AET are conducted usually by anthroposophic nursing specialists that apply skills, processes, and attitudes that belong to anthroposophic knowledge of biographic development throughout the various phases of life in which care is needed (e.g., childhood, disease, disabilities, advanced age), that can promote coping and resilience in the patients.
The many survivors of the polio epidemics that occurred worldwide in the mid-20th century constitute a population of 20 million people at risk of presenting postpolio syndrome (PPS). Since the Global Polio Eradication Initiative was launched in 1988 by the WHO, the number of cases has fallen by over 99%; however, an endemic transmission is continuing in Afghanistan, Nigeria, and Pakistan. The prevalence of PPS among people with polio sequelae has been estimated to be between 22% and 80% (Bosch, 2004). When comparing cohort studies, the prevalence of PPS was 77.2, 68, and 60% for Brazilian, North American, and Swiss population, respectively (Agre et al., 1995;Conde et al., 2009). PPS is characterized by new muscle weakness and/or skeletal muscle fatigue that is persistent for at least 1 year, that is unrelated to other causes, and that occurs at least 15 years after a period of functional stability following the previous acute paralytic poliomyelitis illness. The diagnosis is based on a proper clinical workup in which all other possible explanations for the newly presented symptoms are ruled out (Dalakas, 1995;Dalakas et al., 1986).
Aside from new muscular fatigue, the main symptom is myalgia and joint pain, which are both progressive characteristics of the disease. Other manifestations include cold intolerance, dysphagia and sleep and respiratory disorder, dysphonia, musculoskeletal deformities, psychosocial problems, and restless legs syndrome (Lo & Robinson, 2018;Oluwasanmi et al., 2019).
The clinical and epidemiological aspects of PPS in the Brazilian population were evaluated through two studies performed in 2009 and 2012 (Conde et al., 2009;Quadros et al., 2012). The two studies included 132 and 129 patients with a mean age of 39 years after the onset of the syndrome and after a period of 30-35 years of functional stability. The most common symptoms were fatigue (87.1% and 77.5%), muscle pain (82.4% and 76.0%), and joint pain (72.0% and 79.8%), respectively. Approximately 50% of the cases were severe cases, which were defined as cases with patients who required assistance in walking and/or presented with severe sleep apnea (Quadros et al., 2012).
The pathophysiological framework relating to the genesis of PPS is based on the theory of super training, considering that shortly after an episode of acute poliomyelitis, the remaining motor neurons increase the number of sprouts for the reinnervation of muscle fibers after they have been denervated. About two to three decades after corresponded to the pattern of better efficacy for both pain reduction and improvement in quality of life and resilience.

K E Y W O R D S
anthroposophic medicine, motor system, neurodegenerative diseases, pain, postpolio syndrome the acute episode, there is a tendency to overload this system, that can be accelerated depending on individual factors especially the activities and exercises carried out that promote overuse of the affected muscles. In this case of overuse and super training, an intense metabolic demand in the residual motor units occurs, which then triggers a process of secondary neuronal death (Orsini et al., 2015), and active inflammatory process is present in the spinal cord with increased level of cytokines in the cerebrospinal fluid but without any convincing evidence of viral reactivation (Fiorini et al., 2007).
Another hypothesis for the genesis of PPS is that it results from an autoimmune disorder, a theory that is reinforced by the presence of anti-neurofilament antibodies in the cerebrospinal fluid (Drory et al., 1998). and acupuncture may also contribute to effective treatment to strengthen weakened muscles as well as to decrease pain (Gevirtz, 2006;Shi, 1996). In a controlled clinical trial, the use of a long-term infrared emitter from bioceramic tissue over 4 weeks showed a significant reduction in pain intensity (8.3 ± 2.5 vs. 3.8 ± 2.5) and an improvement in sleep quality measured by polysomnographic examination that demonstrated a significant decrease in the PLM index (11 ± 14 vs. 3.7 ± 6.3) in 12 patient with cold intolerance and restless legs syndrome . A case report showed a positive result of Cannabis sativa oil to control nausea and abdominal pain as somatoform autonomic function disorder of the upper gastrointestinal tract of a eldery SPP patient, becoming a possible pharmacological option for some patients with functional disorders resistant to antiemetic and pain-modulating drugs (Bleckwenn, Weckbecker, & Voss, 2018).
Full-body clinical thermography (telethermography) has recently been used to monitor painful syndromes such as fibromyalgia and chronic adrenal fatigue, associated with chronic inflammatory processes, verified systemic changes due to mechanical overload as well as inflammatory changes in nonmusculoskeletal territories as well as indirect signs of pain-induced sleep disturbance (Biasi, Fioravanti, Franci, & Marcolongo, 1994;Czaplik, Dohmeier, Barbosa Pereira, & Rossaint, 2017).

| Populations
The study was approved by the ethics committee of the Federal University of São Paulo (Clinical Trial Registry No. 925842). We recruited 48 patients who were admitted into the Neuromuscular Disease Outpatient Clinic of the Federal University of São Paulo.
The participants provided written informed consent before study entry.
Inclusion criteria for patients were as follows: adults resident in Brazil aged 20-59-years-old; with confirmed paralytic poliomyelitis; who fulfilled the definition of PPS; had muscle (myofascial) and/or joint pain.
Specific exclusion criteria were as follows: had other diseases that could lead to muscle weakness; neuropathic pain; the use of a wheelchair; or who received any other type of unconventional analgesic therapy. We also excluded patients who did not agree to sign the informed consent form, who failed to perform more than three intervention sessions or who were absent on the initial and/or final evaluation days.

| Study design
A twelve-week, four-arm, randomized, double-blind, placebo-controlled, phase 2 prospective clinical trial was designed to compare the parallel intervention of four groups with pharmacological (transdermal gel) and nonpharmacological anthroposophic clinical interventions (NPAIs).
The 48 PPS patients were randomized into blocks, with randomly selected block sizes (4:8:4:4) using SAS ® version 9.1 (SAS ® Institute), that were divided into four groups. Groups A and B received a daily experimental transdermal gel (ETG) treatment, with either active ingredients or a placebo gel (PTG), respectively; groups C and D received an NPAI weekly, plus a daily ETG or PTG treatment, respectively.

| Interventions
The pharmacological interventions consisted of a nightly application of the ETG in groups A and C or a nightly application of PTG in groups B and D, at a dose of 1 g in the painful regions for 12 weeks.
Each patient received three vials containing 30 g each, with a doser set to 1 g, and each vial was delivered every 4 weeks for use. The

| Data analysis
1. Primary outcome: Pain symptoms and quantitative evaluations were assessed by: 1.1. The unidimensional scale for measure pain intensity assessment: numerical rating scales of visual analogue scale (VAS) (Gould, 2001).
The VAS of pain was applied over the 12 weeks, with completion under the supervision of a group of nurses and/ or physicians from the outpatient clinic, using a straight horizontal scale with numbers, whose extremities were defined as the extreme limits of the symptom of pain oriented from the right ("no pain"-number 0) to the left ("unbearable pain"-number 10). In groups receiving therapies (C and D), the VAS was applied before the sessions and throughout the 12 weeks. In groups that did not receive therapies (A and B), the data were collected by either weekly telephone contact or in person when they arrived to pick up their gel bottles once a month. This assessment consists of questions distributed according to three components: 11 items measuring comprehensibility, 10 items measuring manageability, and eight items measuring meaningfulness (Eriksson & Lindström, 2007).
The questionnaires and thermographies were applied in all groups at baseline and after the 12-week interventions (Figure 1).
A weekly safety evaluation was conducted, based on spontaneous complaints by the study subjects, with a special emphasis on cutaneous allergies.
For the statistical analysis, the Student t test was used for samples that were correlated with a uniform distribution profile, and Wilcoxon nonparametric paired test was used for nonuniform distributions of the data. For a correlation with severity, the Pearson correlation test was used for samples with a regular distribution profile, and a Spearman correlation test was used for simples with an irregular data distribution. The statistical analysis was performed with SAS ® version 9.2. It used the sample power of Minitab (power and sample size) and calculated the main statistical parameters (mean and standard deviation) of the protocol. As we analyzed eight vari-  (Cohen, 1988).

| RE SULTS
Of the 48 recruited patients, we excluded eight patients due to the excessive absence of six patients (one in the ETG group, two in the PTG group, two in the ETG + NPAI group, and one in the PTG + NPAI group) and the lack of attendance for the final evaluation in two patients (one in the PTG + NPAI group and one in the ETG group) in two of the groups. Thus, the sample size for the statistical analyses was 40 patients.
Considering We observed reports of dysphagia improvement in four patients who received therapies (three in the ETG + NPAI group and one in the PTG + NPAI group), which represented 10% of the total sample of 40 patients. We postulated that the PMRN intervention should have contributed more directly to this improvement, as a result of the oral exercises.
The thermographic examinations showed a pattern of alterations that was observed in almost all of the patients. These alterations were maintained before and after the interventions and practically characterized the thermal signature of PPS.
The main findings were a pattern of thermal asymmetry between the upper and lower regions of the body, which showed significant   temperatures and/or stress as signal of mantle (Biasi et al., 1994;Costa, Maia, Brioschi, & Machado, 2017;Larson, Pardo, & Pasley, 2014).

| Pain outcome
The analyses showed a significant reduction in pain in the groups that employed therapies (NPAI), both in the groups accompanied with placebo (VAS p = .021) and in the ETG group (p = .017), according to Table 1.
In the groups without therapies, there was a reduction in the amount of pain of approximately 20.7% in the ETG group (p = .268) and approximately 24.8% in the PTG group (p = .317), but these reductions were not statistically significant, as shown in Table 1. Such findings are consistent with the placebo response rates that are frequently much higher than the often-cited onethird response rate (Turner, Deyo, Loeser, Von Korff, & Fordyce, 1994).
In the groups receiving NPAI, as shown in Table 2

| Quality of life outcome
In the groups that received the NPAI with the addition of the ETG,  Table 3.
Resilience, which was measured by QSCA, was significantly elevated with the use of the transdermal gel, showing a medium effect size (p = .008, d = 0.671). Nevertheless, when the gel was associated with the therapies (NPAI), there was a large effect size (p = .028, d = 0.972) as shown in Table 4.
However, when comparing the concomitant use of the ETG with the therapies versus the use of the gel alone, there was a higher degree of elevation in resilience in the full intervention (Table 4), with an emphasis on meaning (p = .015, d = 0.787) and on comprehension domains (p = .030, d = 0.996) with large effect size.

| CON CLUS ION
We concluded that the multimodal anthroposophic treatment presented both safety and efficacy as an analgesic in the groups that received the nonpharmacological therapies as an independent intervention, but exhibited these properties much earlier when associated with the ETG compared to the placebo gel. In the groups that used

ACK N OWLED G M ENTS
The authors would like to thank Dr. Francoi Hibou and Rodolfo Schleier, formerly of WELEDA AG, Germany and WELEDA BRASIL, for donation of the experimental and placebo topical transdermal gels. We would also like to thank Dr. Alexandre Aldred, who participated in the clinical investigation, especially in conducting the thermography examinations and analyses.

CO N FLI C T O F I NTE R E S T S
None declared.

AUTH O R CO NTR I B UTI O N
Ricardo Ghelman conceived the study, participated in its design,

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available in