*Review* **Lifestyle and Pain following Cancer: State-of-the-Art and Future Directions**

**Astrid Lahousse 1,2,3,4,\* , Eva Roose 2,3,4 , Laurence Leysen 1,2,3,4, Sevilay Tümkaya Yilmaz 2,3 , Kenza Mostaqim 2,3,4, Felipe Reis 3,5,6, Emma Rheel 2,3,7, David Beckwée 2,4 and Jo Nijs 2,3,8,9**


**Abstract:** This review discusses chronic pain, multiple modifiable lifestyle factors, such as stress, insomnia, diet, obesity, smoking, alcohol consumption and physical activity, and the relationship between these lifestyle factors and pain after cancer. Chronic pain is known to be a common consequence of cancer treatments, which considerably impacts cancer survivors' quality of life when it remains untreated. Improvements in lifestyle behaviour are known to reduce mortality, comorbid conditions (i.e., cardiovascular diseases, other cancer, and recurrence) and cancer-related side-effects (i.e., fatigue and psychological issues). An inadequate stress response plays an important role in dysregulating the body's autonomic, endocrine, and immune responses, creating a problematic back loop with pain. Next, given the high vulnerability of cancer survivors to insomnia, addressing and treating those sleep problems should be another target in pain management due to its capacity to increase hyperalgesia. Furthermore, adherence to a healthy diet holds great anti-inflammatory potential for relieving pain after cancer. Additionally, a healthy diet might go hand in hand with weight reduction in the case of obesity. Consuming alcohol and smoking have an acute analgesic effect in the short-term, with evidence lacking in the long-term. However, this acute effect is outweighed by other harms on cancer survivors' general health. Last, informing patients about the benefits of an active lifestyle and reducing a sedentary lifestyle after cancer treatment must be emphasised when considering the proven benefits of physical activity in this population. A multimodal approach addressing all relevant lifestyle factors together seems appropriate for managing comorbid conditions, side-effects, and chronic pain after cancer. Further research is needed to evaluate whether modifiable lifestyle factors have a beneficial influence on chronic pain among cancer survivors.

**Keywords:** cancer survivor; chronic pain; lifestyle; diet; obesity; physical activity; stress; sleep

**Citation:** Lahousse, A.; Roose, E.; Leysen, L.; Yilmaz, S.T.; Mostaqim, K.; Reis, F.; Rheel, E.; Beckwée, D.; Nijs, J. Lifestyle and Pain following Cancer: State-of-the-Art and Future Directions. *J. Clin. Med.* **2022**, *11*, 195. https://doi.org/10.3390/ jcm11010195

Academic Editor: Giustino Varrassi

Received: 30 November 2021 Accepted: 23 December 2021 Published: 30 December 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Cancer has overtaken vascular diseases as the leading cause of death in high-income countries [1]. On top of that, it is expected that the global cancer burden will grow 47% by 2040 [2]. Despite these appalling numbers, cancer survivorship has fortunately increased to 70% in developed countries, mainly due to early detections and treatment advances [3].

Different definitions for cancer survivor (CS) exist, but according to a systematic review of Marzorati et al., (2017), the most widely used definition is: "being a CS, starts on the day of diagnosis and continues until the end of life" [4]. Three cancer survivorship phases can be distinguished: "acute survivorship" (i.e., early-stage or time during curative treatment), "permanent survivorship" (i.e., living with cancer or also called the palliative stage), and "extended survivorship" (i.e., cured but not free of suffering) [4]. This article focuses on the extended survivorship phase since it is difficult for cancer survivors (CSs) to recognize themselves as 'cured' if they continue to suffer after treatment completion [4]. Unfortunately, in this phase, an important proportion of these CSs will face unwanted and debilitating adverse effects that arise or persist beyond primary treatment, which is frightening and should therefore be dealt with seriously [5].

Chronic pain is one of these and occurs in 40% of CSs [6]. Chronic pain is defined by the International Association for the Study of Pain (IASP) as pain that persists or recurs for longer than three months [7]. Unrelieved pain can have considerable adverse consequences on a CSs' quality of life [6]. Therefore, providing CSs with optimal pain treatments is essential to reduce their psychological, physical, and socio-economic impact [6]. Although several initiatives attempted to increase awareness about (post) cancer pain (e.g., the Global Year Against Cancer Pain in 2008 promoted by IASP), chronic pain in CSs remains undertreated, misunderstood, and highly prevalent [6].

Nowadays, the National Comprehensive Cancer Network guidelines [8] advise pharmacological and non-pharmacological treatments for pain during cancer treatment, but after treatment, a decrease of pain medication is recommended to avoid the risk of addiction, misuse, and adverse effects such as opioid-induced hyperalgesia and sleeping disruptions. Unfortunately, shifting towards non-pharmacological treatments remains challenging for many oncologists since they are used to treat patients with acute pain associated with cancer or its therapy [9]. However, the aggressive and curative treatments, including surgery, chemo-, radio- and or maintenance therapy, are not the only factors contributing to the transition of acute to chronic pain. Other factors such as young age at diagnosis, depression, anxiety, low education, and negative lifestyle behaviour (e.g., high body mass index (BMI), low physical activity levels, high alcohol consumption, etc.) might have an impact as well [10–12]. Unfortunately, not all these factors are treatable or modifiable. However, new evidence on healthy lifestyle behaviour demonstrates promising results on pain, quality of life, cancer recurrence, psychological well-being [13–16]. A healthy lifestyle is defined as actions or method one initiate to achieve optimum health and lower the risk of disease or early death [17], which underlines the need to target (pain) multimodally and tailor treatment according to the CS's needs [18]. Therefore, the purpose of this paper is to review and update knowledge on chronic pain and modifiable lifestyle factors in CSs and to discuss the beneficial impact of modifiable lifestyle factors on chronic pain after cancer (Figure 1).

**Figure 1.** Discussed modifiable lifestyle factors in cancer survivors and might contribute to chronic pain after cancer (Creates with BioRender.com (accessed on: 26 November 2021)). **Figure 1.** Discussed modifiable lifestyle factors in cancer survivors and might contribute to chronic pain after cancer (Creates with BioRender.com (accessed on: 26 November 2021)).

#### **2. Methods 2. Methods**

The best evidence regarding lifestyle behaviour and chronic pain in CSs was retrieved in PubMed and Web of Science up to September 2021. Relevant articles were selected by combining the following keywords: CS, chronic pain, lifestyle factors, risk factors, smoking, dietary intake, physical activity, obesity, medication, distress, stress, sleep disorders. To be included, articles had to meet the following criteria: (1) display original data in CSs; (2) address the aims of this review; (3) be published as full articles; and (4) written in English, Dutch, German or French. The following criteria were applied for exclusion: (1) articles reporting animal studies; and (2) studies with the following study design: case reports, congress proceedings, abstracts, letters to the editor, opinions or edito-The best evidence regarding lifestyle behaviour and chronic pain in CSs was retrieved in PubMed and Web of Science up to September 2021. Relevant articles were selected by combining the following keywords: CS, chronic pain, lifestyle factors, risk factors, smoking, dietary intake, physical activity, obesity, medication, distress, stress, sleep disorders. To be included, articles had to meet the following criteria: (1) display original data in CSs; (2) address the aims of this review; (3) be published as full articles; and (4) written in English, Dutch, German or French. The following criteria were applied for exclusion: (1) articles reporting animal studies; and (2) studies with the following study design: case reports, congress proceedings, abstracts, letters to the editor, opinions or editorials.

#### rials. **3. State-of-the-Art**

#### *3.1. Pain*

**3. State-of-the-Art** *3.1. Pain* Chronic cancer-related pain represented in the International Classification of Diseases (ICD-11) differs from the pain of other chronic pain populations [19]. Chronic pain in CSs is caused by damage of primary cancer, its metastasis or its treatment, inducing Chronic cancer-related pain represented in the International Classification of Diseases (ICD-11) differs from the pain of other chronic pain populations [19]. Chronic pain in CSs is caused by damage of primary cancer, its metastasis or its treatment, inducing chronic secondary pain syndromes such as musculoskeletal and neuropathic pains [7]. That can persist over time if no adequate pain management was provided initially [7].

chronic secondary pain syndromes such as musculoskeletal and neuropathic pains [7]. That can persist over time if no adequate pain management was provided initially [7]. Glare et al., (2014) published a comprehensive overview of the types of treatmentrelated cancer pain arising after the curative treatments [19]. For example, post-operative syndromes might occur after surgery, such as phantom pain after amputation, post-mastectomy pain and other complications [19]. Furthermore, chemo- and radiotherapy can also cause adverse effects. Chemotherapy, for example, can cause symmetrical painful numbness, burning, and tingling in both hands and feet. On top of that, it could also lead to osteoporosis, osteonecrosis, arthralgias, and myalgia. Radiotherapy can lead to serious adverse effects caused by ionising radiation, inducing reactive oxygen species (ROS) production, and DNA and regulatory proteins damage to targeted cells. These provoke apoptosis and increased inflammation in the exposed cells and the neighbouring cells by Glare et al., (2014) published a comprehensive overview of the types of treatmentrelated cancer pain arising after the curative treatments [19]. For example, post-operative syndromes might occur after surgery, such as phantom pain after amputation, post-mastectomy pain and other complications [19]. Furthermore, chemo- and radiotherapy can also cause adverse effects. Chemotherapy, for example, can cause symmetrical painful numbness, burning, and tingling in both hands and feet. On top of that, it could also lead to osteoporosis, osteonecrosis, arthralgias, and myalgia. Radiotherapy can lead to serious adverse effects caused by ionising radiation, inducing reactive oxygen species (ROS) production, and DNA and regulatory proteins damage to targeted cells. These provoke apoptosis and increased inflammation in the exposed cells and the neighbouring cells by radiation-induced bystander effects, possibly leading to plexopathies and osteoradionecrosis [19,20]. Maintenance therapy like aromatase inhibitors can produce arthralgia and myalgia [19]. In addition to these

adverse effects, health care providers have to evaluate new arising or aggravating pain complaints with caution because these can indicate a recurrence or a second malignant tumour [19].

Despite the existing guidelines, chronic pain remains underrecognized and mistreated in the extended survivorship phase [5]. Under recognition might be due to: (1) patients' belief that pain is inevitable and uncontrollable, causing them not to report pain to their physicians; and/or (2) physicians' poor knowledge of pain assessment methods [21]. Mistreatment of pain, on the other hand, might be due to: (1) suboptimal communication between CSs and physicians; (2) non-adherence of the patients due to misconception of pain medication; and/or (3) lack of knowledge or confidence of the physicians in applying pain management guidelines in the clinical field [22]. Moreover, CSs typically are insufficiently informed about the origin of their pain, the possibilities of pain relief, and how they can access support when needed, which might affect their happiness of having survived and beaten cancer [23–25].

Over the last decade, the education provided to CSs made a shift from a biomedical pain management, falling short in explaining persistent pain, to a biopsychosocial pain management [26]. This is in concordance with recent findings of the multidimensional aspect of pain [23]. Psychosocial factors, such as cognitive appraisals and expectations, are cornerstones in the patient's pain experience and might bring patients in a downward spiral if not considered [27]. The underlying mechanism can be explained by the fact that psychological factors and pain sensations share similar brain activity, such as the prefrontal cortex, thalamus, hypothalamus, and amygdala and might subsequently affect the descending nociceptive pathways of the periaqueductal grey and rostro-ventral medulla [28]. So, depressive mood, anxiety, and cognitions play an essential role in pain modulation, and the understanding of its mechanism is primordial for appropriate assessment and treatment [10,28]. One cognitive appraisal that gained attention in the past years is perceived injustice (PI) [29,30]. It is demonstrated that people experiencing PI, attribute blame to others for their suffering, have the tendency to interpret their losses as severe and irreparable, and experience a sense of unfairness [29] (*e.g., someone who never smoked yet was diagnosed with lung cancer*). A systematic review showed significant associations between PI and worse pain-related outcomes, including more intense pain, more disability, and worse mental health [31]. These along with lower quality of life are seen in breast CSs with higher PI scores, and PI rather than pain catastrophizing mediates the relationship between pain and quality of life [32]. A more intense expression in terms of their suffering and loss is seen due to increased maladaptive pain behaviour. In turn, this increases the likelihood of being prescribed opioids [29,33]. People displaying more maladaptive pain behaviour affect clinicians' decision to prescribe opioids [34]. Considering the known long-term adverse effects of long-term opioid use [9] and the possibility of developing opiate-induced hyperalgesia [35], PI seems to be a new perspective that should be further investigated in the future.

Other factors that also play a vital role in chronic pain after cancer are associated with patients' healthy lifestyle behaviour. Addressing modifiable lifestyle factors is essential to prevent recurrence of cancer, adverse effects, mortality, as well as improving quality of life and pain relief [36,37]. These factors' impacts and their relationship with pain in CSs are discussed in detail in the following sections of this paper (Figure 2).

**Figure 2.** Evidence of modifiable lifestyle factors contributing to chronic pain in cancer survivors. Abbreviations: CBT(-I): Cognitive behavioural therapy (Insomnia); CBSM: Cognitive Behavioural Stress Management; MA: Meta-analysis; MBSR: Mindfulness-based Stress Reduction; OR: Odds Ratio. **Figure 2.** Evidence of modifiable lifestyle factors contributing to chronic pain in cancer survivors. Abbreviations: CBT(-I): Cognitive behavioural therapy (Insomnia); CBSM: Cognitive Behavioural Stress Management; MA: Meta-analysis; MBSR: Mindfulness-based Stress Reduction; OR: Odds Ratio.

#### *3.2. Lifestyle Behaviour 3.2. Lifestyle Behaviour*

#### 3.2.1. Stress

3.2.1. Stress Stress has been categorised as "the health epidemic of the 21st century" by the World Health Organization (WHO) [38]. It has been defined as a state, whether an actual or perceived event disturbs the physiological homeostasis or the psychological well-being [39,40]. About 12.6% of CSs will develop a lifetime cancer-related post-traumatic stress disorder [41]. Additionally, during survivorship, a substantial proportion of CSs are confronting lingering adverse events and/or experiencing an intense fear of recurrence, both causing anxiety and major distress [42]. Cancer-related distress is defined as a state during which CS cannot deal with their cancer, treatment, or adverse effects due to interference of a multifactorial unpleasant psychological, social, spiritual, or physical event. Distress can transfer normal feelings to disabling problems such as panic attacks, depression, anxiety, existential crises [43]. The presence of chronic stress or distress sustains the overproduction of pro-inflammatory cytokines, which in turn induces fatigue, sleep disorders, depression, and symptoms of sickness [44]. The other stress-related mechanisms behind a heightened inflammation level are higher stress-induced sympathetic activity or a dysregulated hypothalamic-pituitary-adrenal axis (and associated cortisol dysbalance as a characteristic feature of long-term stress exposure) [44,45]. New insights also point out that distress in CSs changes the function and/or structure of some areas of the brain, such as the thalamus, amygdala, prefrontal cortex, hippocampus, subgenual area, hypothalamus, basal ganglia and insula, which are mainly the same areas associated with chronic pain [28,46]. Understanding these changes may open new treatment perspectives and en-Stress has been categorised as "the health epidemic of the 21st century" by the World Health Organization (WHO) [38]. It has been defined as a state, whether an actual or perceived event disturbs the physiological homeostasis or the psychological well-being [39,40]. About 12.6% of CSs will develop a lifetime cancer-related post-traumatic stress disorder [41]. Additionally, during survivorship, a substantial proportion of CSs are confronting lingering adverse events and/or experiencing an intense fear of recurrence, both causing anxiety and major distress [42]. Cancer-related distress is defined as a state during which CS cannot deal with their cancer, treatment, or adverse effects due to interference of a multifactorial unpleasant psychological, social, spiritual, or physical event. Distress can transfer normal feelings to disabling problems such as panic attacks, depression, anxiety, existential crises [43]. The presence of chronic stress or distress sustains the overproduction of pro-inflammatory cytokines, which in turn induces fatigue, sleep disorders, depression, and symptoms of sickness [44]. The other stress-related mechanisms behind a heightened inflammation level are higher stress-induced sympathetic activity or a dysregulated hypothalamic-pituitary-adrenal axis (and associated cortisol dysbalance as a characteristic feature of long-term stress exposure) [44,45]. New insights also point out that distress in CSs changes the function and/or structure of some areas of the brain, such as the thalamus, amygdala, prefrontal cortex, hippocampus, subgenual area, hypothalamus, basal ganglia and insula, which are mainly the same areas associated with chronic pain [28,46]. Understanding these changes may open new treatment perspectives and enhance the quality of provided interventions for distress among CSs.

hance the quality of provided interventions for distress among CSs. Early screening of distress might enhance treatment response [42,47]. As stated in the systematic review of Syrowatka et al., (2017), several predictors for distress after cancer could be identified according to the provided treatment, sociodemographic characteristics, comorbidities, and modifiable lifestyle factors (Table 1, Figure 2) [42]. Interestingly, pain is one of the manageable risk factors for distress creating a problematic back loop because distress, in turn, promotes pain by dysregulating the autonomic, endocrine, and Early screening of distress might enhance treatment response [42,47]. As stated in the systematic review of Syrowatka et al., (2017), several predictors for distress after cancer could be identified according to the provided treatment, sociodemographic characteristics, comorbidities, and modifiable lifestyle factors (Table 1, Figure 2) [42]. Interestingly, pain is one of the manageable risk factors for distress creating a problematic back loop because distress, in turn, promotes pain by dysregulating the autonomic, endocrine, and immune response [44,48]. This vicious cycle can be interrupted by cognitive behavioural stress management (CBSM) consisting of aspects of cognitive behavioural therapy (CBT) [49–51] or, more precisely, coping skills for stress management combined with relaxation training [45,52–54]. According to recent published systematic reviews and meta-analyses, CBT has a beneficial effect on cortisol secretion, distress, anxiety, depression, emotional wellbeing, and negative thoughts in CSs [49–51]. Mindfulness-based stress reduction (MBSR) and yoga have also shown promising results on distress in CSs (Figure 2) [52–54].

#### 3.2.2. Sleep

Insomnia is one the most frequently experienced survivorship concerns and is characterised by difficulty with sleep initiation, duration, consolidation, and quality, resulting in daytime impairments and distress. These difficulties have to occur at least three times a week for more than one month [55]. Insomnia affects more than 30% of CSs years after treatment ending [56–58]. The two-fold higher prevalence rate in comparison to the general population can be attributed to the emotional consequences of cancer diagnosis, the direct effects of cancer treatment, and its side-effects [56]. Among cancer patients, prevalence numbers of insomnia are the highest in breast and gynaecologic cancers compared to prostate cancer [56]. Breast CSs are particularly vulnerable to insomnia due to fear of recurrence, endocrine therapy, and other hormonal changes related to breast cancer treatment [59–61]. Due to hormonal changes, about 85% of breast CSs will report hot flushes, night sweats and arthralgia, resulting in multiple awakenings throughout the night [62,63]. Moreover, breast CSs with hot flushes and (joint) pain are respectively 2.25 (95% CI 1.64–3.08) and 2.31 (95% CI 1.36–3.92) more likely to develop sleep problems (Table 1, Figure 2) [64]. On the other hand, in non-cancer populations, insomnia forms a higher risk for developing future chronic pain disorders compared to chronic pain leading to new insomnia cases [65]. Sleep problems lower pain thresholds and exacerbate response to painful stimuli by dysregulating the immune system, hypothalamus-pituitary-adrenal axis, monoaminergic pathways, and endogenous substances (adenosine, nitric oxide, melatonin, and orexin), which will, for example, increase the pro-inflammatory state [66].

Based on compelling efficacy data, CBT for insomnia (CBT-I) is the gold standard treatment for insomnia (Figure 2) [67]. CBT-I addresses cognitive and behavioural factors that perpetuate insomnia using a multi-component treatment that includes sleep hygiene, stimulus control, sleep restriction, cognitive therapy and relaxation training [68]. The efficacy of CBT-I in CSs was investigated by a systematic review of Johnson et al., (2016) [57] in which they demonstrated that CBT-I improves insomnia symptom severity, sleep efficiency, sleep onset latency, and wake after sleep onset in CSs. The same research question was investigated specifically in breast CSs by a recent review of Ma et al., (2021) [69], in which moderate to large treatment effects were found with clinically significant effects lasting up to one year after therapy for insomnia symptom severity, sleep efficiency and sleep onset latency. Even though solid evidence has shown that CBT-I improves sleep in CSs [57], it remains underused and not readily available in the community or clinical settings [70]. Barriers on the provider level are a shortage of CBT-I specialists and a lack of physician training about sleep [71,72]. On the patient level, barriers include limited understanding of the consequences of insomnia, limited awareness of available treatment options and lack of treatment adherence due to the possible burdensome treatment format [73,74]. There is no doubt about the effectiveness of CBT-I in CSs. However, future studies are needed to investigate the optimal integration of the CBT-I components before adding to the pain management.

#### 3.2.3. Diet

#### Dietary Intake

Dietary recommendations have only recently been brought into the picture for CSs treatment; therefore, the literature is sparse and limited to breast CSs. However, nutritional guidelines have been introduced by the National Cancer Institute, American Cancer Society, Academy of Nutrition to encourage CSs to start a healthy and prudent diet [13,75]. Unfortunately, the adherence is low because CSs have no guarantee that their prognosis will improve by adopting a healthy diet [76]. According to a meta-analysis of cohort

studies, a Western diet, which is characterised by a high consumption of eggs, red meats, and processed foods, is associated with a higher risk of mortality (odds ratio = 1.51; 95% CI 1.24–1.85) and cancer recurrence (odds ratio = 1.34; 95% CI 0.61–2.92) in CSs [77]. However, weak evidence suggests that CSs may be able to reduce their mortality and cancer recurrence rate by switching to a healthy diet that consists of fruits, vegetables, fish, and whole grains after diagnosis [78]. A healthy diet is usually rich in anti-oxidative, antiinflammatory, endothelial protective, metabolic substances, which affect tumour growth and promote cancer apoptosis [79]. As advised by different associations, nutritional counselling should be provided by registered dietitians specialised in oncology [13].

Furthermore, ongoing research shows that food could have both an adverse and a beneficial influence on chronic pain. A recent systematic review revealed that studies examining whether diet influences chronic pain in CSs are essentially lacking (Table 1) [80]. Nevertheless, evidence in breast CSs points out some significant relation between pain and nutrition. A network meta-analysis for therapeutic options for aromatase inhibitorassociated arthralgia in breast cancer has suggested that omega-3 fatty acids might be effective in reducing pain severity scores and pointed out the need for further evaluation for omega-3 fatty acids as well as vitamin D (Table 1) [81]. Additionally, a cross-sectional study showed clearly that breast CSs who were well-nourished or anabolic according to category A of the patient-generated subjective global assessment (PG-SGA) had fewer pain symptoms than those who were malnourished category B of PG-SGA [82].

As discussed earlier, nutritional sciences are only now beginning to address chronic pain in CSs. However, why should "diet" be advised in chronic pain management to CSs? Knowing the benefits and drawbacks of various diets for survivors with chronic pain could be the key to finding a clear answer. The most important vision of implementing a specific diet in pain management is based on using regulatory effects of nutrition on several pain mechanisms with no or bare minimum side effects. This could provide a long-term, sustainable, and cost-effective pain management alternative for CSs. Therefore, in the future, interdisciplinary collaboration across researchers and clinicians is needed to unravel the role of nutrition in pain-related mechanisms and its implications on pain reduction in CSs. Currently, the lack of evidence supporting the added value of dietary interventions for chronic pain management in CSs precludes to advise its use (Figure 2).

#### Obesity

Obesity is a condition characterised by an increase in body fat [83,84]. At the neurobiological level, obesity is considered to cause pain through various mechanisms, including inflammation and hormone imbalance [85]. At the mechanical level, obesity can also cause pain by structural overloading [84,86], which can lead to altered body posture and joint misuse [87]. The latest review in taxane- and platinum-treated CSs demonstrated a good-to-moderate relationship between obesity and higher severity or incidence of chemotherapy-induced peripheral neuropathy (CIPN), with moderate evidence showing diabetes did not increase incidence or severity of CIPN [88]. Furthermore, a systematic review with meta-analyses of Leysen et al., (2017) demonstrated that breast CSs with a BMI > 30 have a higher risk (odds ratio = 1.34, 95% CI 1.08–1.67) of developing pain (Table 1, Figure 2) [12]. However, more research is needed to determine the long-term impact of obesity among the expanding population of CSs [89]. Studies looking at the link between changes in body mass index, fat mass, inflammatory markers, and chronic pain might help us better comprehend the relationship between these variables in the CS population. Additionally, well-designed, high-quality randomised controlled trials on the effect of combined weight loss/pain therapies are required to inform patients and clinicians on how to personalise the approach to reduce chronic pain prevalence, intensity, or severity in CSs through obesity management (Figure 2).

#### 3.2.4. Smoking

Smoking tobacco and, to a lesser extent, e-cigarettes is well-known to negatively influence cancer's prognosis and forms a major risk factor for various cancer types and several other chronic diseases [90–92]. Smoking cessation has a favourable effect on treatment efficacy, psychological well-being and general quality of life [93]. The National Comprehensive Cancer Network offers a guideline for smoking cessation, consisting of pharmacotherapy (e.g., nicotine replacement therapy or varenicline) and behaviour therapy (Figure 2) [47,94]. This program is more successful when initiated at the time of diagnosis because an early start avoids more adverse effects [90]. Patients who continue to smoke have a higher likelihood of facing post-operative complications due to (wound) infections, failed reconstruction and tissue necrosis, which could lead to prolonged hospitalisation [95,96]. Unfortunately, a big proportion of young CSs continue to smoke after their diagnosis. Approximately 25.2% of CSs aged 18 to 44 years were current smokers compared to 15.8% in the general population [97]. Thus, during the survivor phase, additional support should be provided to target patients' barriers to smoking cessation to prevent cancer recurrence.

Pain might be one of the barriers to smoking cessation in CSs [98]. An observational study by Aigner et al., (2016) demonstrated that when patients experience higher pain levels, they usually smoke a larger number of cigarettes during these days and initiate fewer attempts to quit smoking [98]. This can be explained by the fact that nicotine produces an acute analgesic effect, making it much harder for them to stop due to the rewarding sensation they experience [99]. Despite its short-term analgesic effect, tobacco smoking sustains pain in the long-term [93]. This underlines the importance of incorporating antismoking medications in CSs with pain to avoid relapse during nicotine withdrawal [99]. Moreover, pain management should be added to the counselling aspect to enhance the patient's knowledge, which in turn, might improve their adherence to the whole smoking cessation program [98]. Furthermore, the 5As (Ask, Advise, Assess, Assist, Arrange) approach, which assesses the willingness of the patient to quit smoking, is no longer recommended since studies have demonstrated that smokers who did not feel ready to quit smoking at the same rate as those who wanted to [100]. The model with the most promising results might be "opt-out", during which health care providers offer counselling and pharmacotherapy to all smokers, which is more ethical [101]. However, research on how to integrate this approach in current cancer care for CSs is needed.

#### 3.2.5. Alcohol Consumption

Similar to smoking, alcohol consumption is a preventable risk factor for liver, oesophageal, colorectal, breast, head, neck, and many other cancers [102]. It is established that excessive or binge drinking enhances the likelihood of cancer recurrence, bad prognosis, or death [77]. Despite this, up to now, no evidence supports or refutes that drinking with moderation (≤1 drink for women and ≤2 drinks for men per day) is associated with a lower risk of cancer [103–105]. On top of this, some studies show a reduction in risk due to moderate alcohol intake, which might be explained by confounders, and/or the anti-cancer effect of polyphenols (present in wine) [106] or phytoestrogen and polysaccharides (present in beer) that lower free testosterone, inducing prostate cancer [107,108]. However, these small benefits are quickly outweighed by other harms of alcohol consumption. Furthermore, a growing trend in alcohol intake among CSs is observed, but no explanation for this trend could be found [109]. Nevertheless, alcohol consumption can initiate people to smoke or smoke even more [109]. Combining both multiplies their adverse effects because alcohol slows down the body's capacity to eliminate the carcinogenic chemicals of smoking [97,109,110]. These findings highlight the importance of increasing CSs' awareness about these lifestyle factors.

The impact of alcohol use on pain is poorly investigated in CSs, but according to one systematic review of two cohort studies, the risk of developing pain can be reduced by alcohol use (Table 1) [12]. This finding might be misleading due to the fact that alcohol has an acute analgesic effect [111]. In non-cancer populations, studies demonstrated that this analgesic effect diminishes over time, and there is an association between chronic pain and alcohol consumption [112]. This pain might be evoked by developing alcoholic neuropathy, musculoskeletal disorders, or alcohol withdrawal [112]. Conversely, chronic pain increases the risk of alcohol abuse [113]. Nevertheless, psychosocial factors are also highly present in patients with alcohol abuse and can be attributed to abnormalities in the reward system of the brain [114]. Additionally, a recently published study demonstrated that chronic pain patients with high levels of pain catastrophising are more likely to be heavy drinkers [115]. General advice on alcohol consumption after cancer is currently not possible due to the high variability of results in different CSs. Therefore, health care providers should tailor their advice according to cancer types and patients [116]. Within that view, an overview of recommendations regarding individualised alcohol consumption for each CS type could support clinicians in doing so, yet such evidence-based recommendations are currently lacking (Figure 2).

#### 3.2.6. Physical Activity

Being physically active after a cancer diagnosis improves CSs' survival rate by 30% [117–119], which underlines that healthy behaviour during the extended survival phase is essential [117]. The American College of Sports Medicine, American Cancer Society and the US Department of Health and Human Services developed exercise guidelines that advise every CS to engage weekly in 75 min of vigorous-intensity or 150 min of moderateintensity aerobic physical activity [90,120,121]. For instance, the evidence demonstrated that supervised physical activity reduces cancer-related fatigue, depression, and increases quality of life, cardiovascular and musculoskeletal fitness in CSs [14–16]. Additional beneficial effects of physical activity were also seen on musculoskeletal pain and stiffness in breast CSs taking aromatase inhibitors for a long period (Table 1, Figure 2) [81,122,123]. However, only few CSs attain the recommended physical activity levels, with pain being an important limiting factor [116,124]. Inappropriate beliefs regarding the expected outcome of physical activity represent a major barrier for CSs to engage in physical activity programs. For example, some breast CSs fear that resistance exercises can aggravate cancer-related lymphedema, which is proven to be wrong as resistance exercises are perfectly safe in this group and do not increase lymphedema [125], others might fear that exercise can exacerbate their pain, which was refuted by systematic reviews with meta-analyses in CSs and a Cochrane review in chronic non-cancer pain populations, demonstrating that physical activity has a small positive effect on pain (Table 1, Figure 2) [123,126,127]. Despite all this evidence, patients' adherence to physical activity remains low and remains a bottleneck in current care [128]. Therefore, how to reduce a sedentary lifestyle in CSs with chronic pain should be more thoroughly investigated and implemented in guidelines, and patients should be better informed about the benefits of an active lifestyle [128].

Identifying predictors of adherence will offer the possibility to provide personalised guidance to CSs who are less likely to adhere to exercise, which will undoubtedly lead to better treatment outcomes [129]. According to a systematic review, behavioural (i.e., motivation) and sociodemographic predictors (i.e., distance and social support of the family or therapists) should be addressed [130]. To improve CSs' exercise motivation or lifestyle behaviours, motivational interviewing can be used [131]. During this patient-centred approach, five different stages can be distinguished: pre-contemplation, contemplation, preparation, action, and maintenance. In each stage, behaviour changes will be tackled differently [130,131]. A Cochrane review concluded that exercise interventions with determined goals, graded activity, and behaviour change reached the highest adherence in CSs [118]. Behavioural graded activity is such an intervention that combines these three components and aims (i.e., determined goals, graded activity, and behaviour change) to target patients' difficulties and complaints during their daily living [132]. This approach might enhance patients' willingness to adhere to healthy behaviour compared to other exercise interventions. Additionally, in recent years, alternative therapies such as mindfulnessbased approaches, hypnosis and yoga gained importance and demonstrated significant

beneficial effects on quality of life, psychological distress, anxiety, depression, fear of cancer recurrence, fatigue, sleep, and pain [133–135]. Obviously, mindfulness-based approaches and yoga fit into the 'stress management' category as well, and therefore potentially serve two lifestyle factors (i.e., stress and physical therapy). However, more research is needed to find the optimal approach for higher long-term adherence to an active lifestyle in CSs.

**Table 1.** Evidence of lifestyle factors on pain in cancer survivors. Abbreviations: AIA: Aromatase Inhibitor-associated Arthralgia; C: Cohort; CI: Confidence Interval; CIPN: Chemotherapy-Induced Peripheral Neurotoxicity; CS: Cross-sectional Study; ES: Effect Size; I<sup>2</sup> : Heterogeneity; MD: Mean Difference; OR: Odds Ratio; *p*: *p*-value; RCT: Randomized Controlled Trial; SMD: Standardized Mean Difference; SORT: Strength of Recommendation Taxonomy.




#### **4. Future Directions for Scientists**

First, it is recommended that researchers make a clear distinction between CSs' phases when initiating and reporting studies in CSs. Currently, the term CS is too globally used, making it difficult to compare or combine results of studies due to their high heterogeneity. An individual in palliative care has different needs than an individual that is cured of cancer; however, both are CSs according to the most widely used definition [4]. A distinction between the different phases has been described by Mullan et al., in 1985 [138]. Unfortunately, these terms are not frequently used in the literature [138] even though a clear distinction between phases could help clinicians to communicate more easily and to provide the appropriate care to patients' needs according to their phase in the survival of cancer.

Second, most studies were performed on Caucasian breast CSs with high socioeconomic status. This population is more likely to have a higher adherence and willingness to change their lifestyle habits [139]. However, to reach a better understanding of barriers for lifestyle changes, research needs to be performed among CS populations with diverse socio-economic backgrounds. This way, oncological care for CSs can be more tailored to patients of different gender, race, and socio-economic capacities.

Third, future studies regarding lifestyle factors in CSs should more thoroughly account for possible confounders. Indeed, research studying a particular lifestyle factor should not only be adjusted for age, gender, education, and so forth, but also for other established lifestyle factors, which might be a considerable confounder. Furthermore, the effects of lifestyle factors in CSs are most often observed over a short period, preventing to draw conclusions regarding long-term impact of lifestyle factors in CSs. More research is warranted to observe the long-term effects of pain management and healthy lifestyle interventions in CSs.

#### **5. Future Directions for Clinicians**

The literature indicates that implementing healthy lifestyle habits in CSs has low compliance rates [140]. A barrier that might cause low adherence to healthy lifestyle behaviours is the burdensome treatment format of most behavioural interventions [73,74]. Therefore, stepped care models might provide clinicians with a possible solution to improve the feasibility and deliver care efficiently [141]. In existing stepped care models, the first step is typically a form of self-management therapy (e.g., recommendations) with the possibility to progress to the highest step of six to eight individual sessions with a specialist, if needed [142,143]. For example, a recent study in CSs demonstrated that more than 50% of CSs with insomnia benefit form a one-hour group-delivered session that empowers CSs by teaching them about sleep health and provides specific information on how to adapt their sleep behaviours [142]. Interestingly, they found that CSs who had experienced sleep problems for a shorter period and perceived less burden from their sleep problems were most likely to benefit from the one-hour program, suggesting that it is crucial to identify CS with sleep problems as soon as possible to enhance the efficacy of low-intensity interventions [142]. However, further research is warranted before implementing stepped care for the other lifestyle factors. In addition, systematic reviews demonstrated promising findings for virtual therapy, suggesting that virtual interventions might be a possible option to enhance access to care, which solves the distance issue [69,137,144].

Furthermore, to reduce the treatment burden, clinicians should perform early screenings and identify negative predictors to improve patients' self-efficacy to sustain a healthy lifestyle. Developing evidence-based guidelines, including algorithms with practical triage and referral plans to other healthcare professionals, will improve survivorship care. Enhancing the productivity of oncological care by 2025 is of utmost importance because there will be a shortage of oncologists due to the growing cancer population [145]. Besides that, many clinicians have difficulties providing the ideal pain management plan and delivering health promotion guidance due to a lack of knowledge [22]. Supplementary support and educational interventions should be organized for health care providers to enhance their expertise and confidence in this field.

Another recommendation for future clinical practice is considering the use of pain neuroscience education as a way to decrease the threatening nature of pain, catastrophic thinking and fear-avoidance beliefs in CSs [146]. Cancer patients indicate themselves that they have insufficient knowledge regarding pain during or after cancer, what the possibilities of pain relief are and how they can access support when needed [24,25]. When comparing pain knowledge between CSs, healthy controls and caregivers, CSs had the lowest pain knowledge of the three groups [147]. Education about pain is underused in the field of oncology and non-existent in the survivorship phase [148]. Pain neuroscience education can clear the path for more active approaches to pain management, including providing lifestyle interventions. Manuals with guidelines for clinicians on how to explain pain following cancer [146], including accounting for perceived injustice during pain neuroscience education [149], are available to support clinicians in doing so.

Lastly, this state-of-the-art paper underlines once more the complexity of managing chronic pain in CSs. As discussed previously, adopting a healthy lifestyle might have a beneficial influence on the chronic pain of CSs. Unfortunately, there is currently a lack of research about the effectiveness of modifiable lifestyle factors on pain. Moreover, pain in CSs should be targeted on cognitive, behavioural, sensory and emotional levels due to its complexity [18]. Therefore, all pain interventions should be multidisciplinary and personalized for each CS [19].

#### **6. Conclusions**

Emerging evidence shows that CSs find it challenging to receive optimal treatment plans for their burdens, and support or reinforcement to maintain a healthy lifestyle. Therefore, it is crucially important to prepare clinicians well, so they can provide guidance along and after primary treatment. For chronic pain in CSs, it is primordial to identify factors that contribute to the transition of acute to chronic pain in CSs because chronic pain remains underrecognized and mistreated in this population. Furthermore, a proper definition between CSs' phases should be developed for optimal research and treatment. In the clinical field, new psychosocial factors and modifiable lifestyle factors should be targeted to improve pain relief in CSs.

Modifiable lifestyle factors and their impact on pain have been discussed in depth in this paper and are, for instance, stress, insomnia, diet, obesity, smoking, alcohol consumption and physical activity. First, an inappropriate stress response promotes pain by dysregulating the autonomic, endocrine, and immune response creating a problematic back loop because pain is a manageable risk factor for distress. The stress response can be managed by CBSM, CBT, MBSR and yoga. Second, sleep and pain also form a vicious cycle (sleep problems exacerbate response to nociceptive stimuli and pain can disturb sleep quality) that CBT-I can break. Third, guidelines recommend prudent diets in CSs. However, more research is needed to unravel the role of nutrition and obesity in CSs. Fourth, alcohol consumption and smoking are both negative lifestyle behaviours that impact patients' general health. Smoking cessation should consist of behaviour therapy and medication. Last, physical activity demonstrates its beneficial impact in several systematic reviews. However, the adherence is low and new treatment strategies such as motivational interviewing or BGA should be investigated in CSs to increase treatment outcomes in the long-term.

In the future, there will be an insufficient number of professionals (oncologists) due to the growing cancer population [150,151]. Therefore, it is a priority that researchers refine current treatment plans and define the benefits of modifiable lifestyle factors and their impact on chronic pain in CSs.

**Author Contributions:** Conceptualization, A.L., E.R. (Eva Roose), L.L., S.T.Y., K.M., F.R., E.R. (Emma Rheel), D.B., and J.N.; methodology, A.L. and J.N.; software, A.L.; validation, A.L., E.R. (Eva Roose), L.L., S.T.Y., K.M., F.R., E.R. (Emma Rheel), D.B., and J.N.; investigation, A.L., E.R. (Eva Roose), L.L., S.T.Y., and J.N.; writing—original draft preparation, A.L., E.R. (Eva Roose), L.L., S.T.Y., K.M., F.R., E.R. (Emma Rheel), D.B., and J.N.; writing—review and editing, A.L., L.L., S.T.Y., F.R., and J.N.; visualization, A.L.; funding acquisition, A.L., E.R. (Eva Roose), L.L., S.T.Y., E.R. (Emma Rheel), and J.N. All authors have read and agreed to the published version of the manuscript.

**Funding:** A.L. is a research fellow funded by the Research Foundation Flanders (Fonds Wetenschappelijk Onderzoek-FWO), Belgium (grant number 11B1920N). E.R. is funded by Stand Up to Cancer (Kom op tegen Kanker-KOTK), a Belgian cancer charity (project code ANI251). L.L. is a postdoctoral research fellow appointed on 2 funded projects, one by the Research Foundation Flanders (FWO) (grant number G040919N) and one by Stand up to Cancer (KOTK-project code ANI251). S.T.Y. is funded by the Ministry of National Education of the Turkish State as scholarship student for her Ph.D. research program. J.N. and E.R. are holders of a chair on oncological rehabilitation funded by the Berekuyl Academy/European College for Decongestive Lymphatic Therapy, the Netherlands.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** We thank K. Ickmans (Vrije Universiteit Brussel) for creating Figure 1 with BioRender.com.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

### **References**


**Annelie Gutke 1,\* , Karin Sundfeldt 2,3 and Liesbet De Baets <sup>4</sup>**


**Abstract:** During their lifespan, many women are exposed to pain in the pelvis in relation to menstruation and pregnancy. Such pelvic pain is often considered normal and inherently linked to being a woman, which in turn leads to insufficiently offered treatment for treatable aspects related to their pain experience. Nonetheless, severe dysmenorrhea (pain during menstruation) as seen in endometriosis and pregnancy-related pelvic girdle pain, have a high impact on daily activities, school attendance and work ability. In the context of any type of chronic pain, accumulating evidence shows that an unhealthy lifestyle is associated with pain development and pain severity. Furthermore, unhealthy lifestyle habits are a suggested perpetuating factor of chronic pain. This is of specific relevance during lifespan, since a low physical activity level, poor sleep, or periods of (di)stress are all common in challenging periods of women's lives (e.g., during menstruation, during pregnancy, in the postpartum period). This state-of-the-art paper aims to review the role of lifestyle factors on pain in the pelvis, and the added value of a lifestyle intervention on pain in women with pelvic pain. Based on the current evidence, the benefits of physical activity and exercise for women with pain in the pelvis are supported to some extent. The available evidence on lifestyle factors such as sleep, (di)stress, diet, and tobacco/alcohol use is, however, inconclusive. Very few studies are available, and the studies which are available are of general low quality. Since the role of lifestyle on the development and maintenance of pain in the pelvis, and the value of lifestyle interventions for women with pain in the pelvis are currently poorly studied, a research agenda is presented. There are a number of rationales to study the effect of promoting a healthy lifestyle (early) in a woman's life with regard to the prevention and management of pain in the pelvis. Indeed, lifestyle interventions might have, amongst others, anti-inflammatory, stress-reducing and/or sleep-improving effects, which might positively affect the experience of pain. Research to disentangle the relationship between lifestyle factors, such as physical activity level, sleep, diet, smoking, and psychological distress, and the experience of pain in the pelvis is, therefore, needed. Studies which address the development of management strategies for adapting lifestyles that are specifically tailored to women with pain in the pelvis, and as such take hormonal status, life events and context, into account, are required. Towards clinicians, we suggest making use of the window of opportunity to prevent a potential transition from localized or periodic pain in the pelvis (e.g., dysmenorrhea or pain during pregnancy and after delivery) towards persistent chronic pain, by promoting a healthy lifestyle and applying appropriate pain management.

**Keywords:** chronic pelvic pain; endometriosis; pelvic girdle pain; lifestyle factors; pain management; physical activity/exercise; (di)stress; sleep; diet; smoking

**Citation:** Gutke, A.; Sundfeldt, K.; De Baets, L. Lifestyle and Chronic Pain in the Pelvis: State of the Art and Future Directions. *J. Clin. Med.* **2021**, *10*, 5397. https://doi.org/10.3390/ jcm10225397

Academic Editors: Jo Nijs, Felipe Reis and Laxmaiah Manchikanti

Received: 12 October 2021 Accepted: 16 November 2021 Published: 19 November 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

During their lifespans, women are at a high risk for experiencing pain complaints in the pelvic region due to gynecologic and obstetric reasons. Indeed, hormonal changes in the menstruation cycle are typically associated with pain in the pelvis [1]. Most women experience pain for one or more days of the menstruation period, for which pain killers or hormonal contraceptive pills are the first-choice treatment. However, this pharmacological treatment is not sufficient for pain reduction in an important subgroup of women [2], resulting in recurrent or persistent pelvic pain, such in women who experience endometriosisrelated pelvic pain [3]. Severe dysmenorrhea (pain during the menstrual period) is a cardinal symptom of endometriosis and is known to have a high social impact as it is often associated with absence from school or work [1]. Apart from endometriosis-related pelvic pain, pain in the pelvis also occurs in relation to pregnancy and childbirth [4]. Such pregnancy-related pelvic girdle pain (PGP) is suggested to relate to both hormonal, musculoskeletal and biomechanical changes [4,5]. The pain intensity is often severe enough to hinder pregnant women or women in the postpartum period to participate in activities of daily living, including work [4,6–8]. Since pharmacological treatment is not the first choice for pain management for many pregnant or breast-feeding women, other conservative approaches, such as physical therapy, are generally applied [4,9]. However, this care is not considered successful in appropriately alleviating pain in a subgroup of women with PGP, or is not consistently offered to women with PGP [10].

Indeed, women experiencing pain in the pelvis (endometriosis-related pelvic pain and pregnancy-related PGP) are not consistently guided towards appropriate treatment for their pain complaint. It is even more disturbing that these women are often told that their experienced pain should be considered 'normal', and inextricably linked to being a woman [3,11]. Apart of being unethical, such a message also contributes to the fact that many women seek too little help for a pain complaint that may be treatable [10]. This might result in the fact that an initial pain experience, e.g., experienced during menstruation or pregnancy or immediately following childbirth, evolves towards persistent pain in the pelvis.

To improve this current practice, knowledge on adequate treatment approaches for reducing pain in women with pain in the pelvis is required. It is furthermore believed that adequate strategies to prevent an increase in pain during periods of life in which a hormone or pregnancy-related pain can be foreseen, are of even greater importance. In this context, the effect of lifestyle changes on pain has received more attention in recent years. There are many possible causes for pain in the pelvis, and in this review we focus on two common disorders related to specific painful events during lifespan of women to point out the possibility to prevent development of chronic pain. However, to understand why a healthy lifestyle might be effective in reducing pain in women with endometriosis-related pelvic pain and pregnancy-related PGP, more information about the pathophysiology of these conditions is first provided.

#### *1.1. Endometriosis-Related Chronic Pelvic Pain*

Endometriosis is, with a reported prevalence around 10%, a very common condition among women of childbearing age, and one of the most common structural causes of chronic pelvic pain [3,12]. It is classically defined as an estrogen-dependent, chronic inflammatory condition in which the endometrium of the uterus grows outside the uterus by implantation of endometrial cells and creates an inflammatory response of the surrounding tissue. Both superficial lesions on the peritoneum, ovarian endometriosis and a more aggressive deep infiltrating type that may obstruct the intestines or bladder, have been reported [13]. In this context, increasing evidence suggests that endometriosis should be considered a systemic disease, not only restricted to the pelvis [3]. Indeed, endometriosis is reported to co-exist with other conditions such as irritable bowel syndrome, mental health disorders, central sensitization and pain conditions (fibromyalgia, migraine), and immunological conditions (e.g., rheumatoid arthritis, multiple sclerosis) [13,14]. Given

these multiple facets of endometriosis, its diagnosis is currently very challenging [13], resulting commonly in a delay in diagnosis of multiple years [3,13,15,16].

Variable clinical symptoms are related to endometriosis. Typical pain symptoms in women with endometriosis are (a)cyclic pelvic pain, dysmenorrhea and pain at ovulation [3,13,15]. This may be combined with radiating pain to the lower back, groin and thighs, as well as deep intercourse pain [3]. Bladder problems, difficulties in emptying the bowel and infertility can be attributed to endometriosis as well [17]. Given these debilitating symptoms, endometriosis might affect a woman's physical, mental and social well-being, her quality of life and her work ability [18]. These, in turn, are related to higher levels of psychological distress. Furthermore, poorer sleep quality, endometriosis-related fatigue and physical deconditioning are reported in women suffering from endometriosis [19].

Current first-line treatment for endometriosis is conservative pharmacological care, and surgical procedures when pharmacological options are ineffective or with deep infiltrating endometriosis. However, for a large group of women, endometriosis recurs after surgical treatment or are ineffective, as evident from the large rate of (50%) [3]. In this context, the link between the grade of laparoscopic detected lesions and level of symptoms is also inconsistent [3]. This emphasizes the value of looking beyond tissue-related aspects and to look for treatment options addressing the mechanisms underlying symptom development. Therefore, it seems valuable to take a closer look into the lifestyle of women suffering symptomatic endometriosis. As endometriosis is considered an inflammatory and estrogen-dependent disease, targeting lifestyle factors that influence these factors can open the path for multiple conservative treatment options for women with endometriosis-related pelvic pain (e.g., dietary intervention, physical activity, sleep management). Thereby, the anti-inflammatory effect of a healthy lifestyle might positively influence pain perception given the association between inflammatory mediators and peripheral as well as central sensitization [20].

#### *1.2. Pregnancy-Related Pelvic Girdle Pain*

Pregnancy-related PGP is reported by 50% of pregnant women globally [4,5,10]. PGP is classified by its pain location, i.e., between the posterior iliac crest and the gluteal fold, most commonly around the sacroiliac joints and/or pubic bone, sometimes with radiating pain in the thighs, with onset close to, or within three weeks of delivery [5]. For the classification of PGP, it is recommended that the pain is reproduced during clinical pain provocations tests and that it is associated with, and time-dependent on, weight bearing activities. Typical symptoms of PGP, both during and after pregnancy are a decrease in endurance in standing, walking, and sitting (often within 30 min of activity) [4,21] which lead to limitations in daily functioning [6–8], and at work [4,22]. Since PGP is mostly related to pregnancy, it is expected to disappear when pregnancy-related changes disappear after birth [6], which is true for the majority of women [23]. However up to 11 years after pregnancy, 10% of women report persistent and per definition chronic PGP [8]. The etiology of PGP is multifactorial. One suggested cause of PGP is inefficient neuromuscular control [4,5] related to hormonal changes during pregnancy. However, a systematic review of evidence on whether this results in pelvic instability causing PGP is low [24]. In women with PGP, higher prevalence rates of prenatal anxiety and depressive symptoms are reported in comparison to pregnant women without pain [25,26]. This co-occurrence of pain with anxiety and depression continues in women with chronic PGP, who also seem to have less general self-efficacy than women who recovered from PGP after pregnancy [8]. Furthermore, from a recent cohort study [27], lack of physical activity was added as a predisposing factor for pain in the lumbo-pelvic area in pregnancy together with the hitherto reported previous history of pain in the lumbo-pelvic area, low job satisfaction, and increased weight during pregnancy [4].

In general, the evidence is low for the effectiveness of interventions for PGP [4,9]. As PGP treatment, acupuncture shows the most coherent findings in the literature [4,9,28]. Other suggested treatment strategies are the application of a pelvic belt and exercises [4,9].

In recent years, a cognitive behavioral approach and self-management strategies have been proposed for women with PGP [29]. In the above-described context, it seems valuable to take a closer look into the lifestyle factors of women suffering from PGP.

#### *1.3. Lifestyle Factors in Chronic Pain in the Pelvis*

Within the chronic pain field, there is cumulating evidence that unhealthy lifestyle factors such as physical inactivity, increased psychological distress, poor sleep, unhealthy diet, and smoking are associated with chronic pain severity and sustainment [30–32]. A proposed mechanism underlying the association between lifestyle and pain in this regard is related to inflammatory mediators. For example, it is known that in chronic pain patients, disturbed sleep modulates the endogenous inhibitory pain control system, produces changes in the hypothalamic-pituitary-adrenal axis and induces aberrant inflammatory reactions [33]. Specifically in relation to pregnancy, an increase in inflammatory biomarkers in sleep-deprived pregnant women in comparison to non-pregnant has been reported [34]. Even after pregnancy, an inflammatory response with increased cytokine levels is associated with short sleep duration [35].

Within the field of pain in the pelvis, the scientific literature points towards the role of lifestyle on pain. Being overweight/obese or experiencing emotional distress during pregnancy have been associated with less recovery at 3–6 months after pregnancy when the natural course of PGP is over [36]. In women with chronic PGP, level of physical activity, exercises, sleep quality and distress are associated with pain perception [8]. Regarding lifestyle factors and endometriosis, poor sleep quality is reported to be associated with pelvic pain [37].

An increased understanding of the role of exercise, insomnia, diet, and other lifestyle factors on the perception of pain in women with pain in the pelvis is assumed to provide treatment opportunities to optimize current care. Of even greater importance, such understanding on the role of lifestyle factors in the development and maintenance of pain in the pelvis, can provide invaluable knowledge on how we might develop prevention strategies for severe pain in the pelvis. This is of utmost importance, since it can be theorized that painful experiences early in a woman's life that are not handled according to the best of knowledge, might be a reason why higher rates of chronic pain in women as compared to men are reported [38,39]. Therefore, in the early stages, when pain in the pelvis can be expected, there is a window of opportunity to take the right preventive actions, with good pain management strategies, and possibly by advocating a healthy lifestyle.

This review aims to give an overview of the best evidence on the role of lifestyle factors in the development or maintenance of pain in the pelvis in women related to common painful events during their lifespan. Since very few studies are published in the field, a systematic review was not considered feasible. A best-evidence review was considered the appropriate format to explore the field and to present a research agenda. A best-evidence synthesis of the effect of lifestyle interventions on women with pain in the pelvis is provided. The best evidence knowledge is reviewed in a way such that clinicians can integrate the evidence into their daily clinical routine. In addition, the state-of-the-art overview also serves clinical researchers in building upon the best evidence for designing future trials, implementation studies, and to develop new innovative studies.

#### **2. State-of-the-Art**

For this best-evidence review, the following lifestyle factors were defined a priori: physical (in)activity, exercise, sleep, psychological distress, food intake, tobacco use, smoking and alcohol consumption. With regard to the interventions for these lifestyle factors, only active interventions such as exercise, psychologically informed approaches, cognitive behavioral therapy, dietary interventions (focusing on altering food uptake) and multimodal approaches, were considered. Studies on surgical procedures, pharmaceutical treatment in isolation (including supplements e.g., vitamin supplements), Chinese medicine and passive treatments such as acupuncture, in isolation, were not eligible.

A nonsystematic search of scientific studies was performed in MEDLINE (PubMed), and web-of-science from their inception to August 2021, using the following search terms: ((endometriosis OR pelvic girdle pain OR lumbopelvic pain) AND (physical activity OR exercise\* OR insomnia OR sleep OR stress OR diet OR nutrition OR smoking OR tobacco OR alcohol). The searches were conducted by two researchers (AG and LDB) independently. To minimize selection bias and to ensure high quality evidence was selected, systematic reviews and meta-analyses in accordance with PRISMA guidelines were preferred. If these were not available, narrative, and critical reviews were selected. Recent high-quality prospective studies and randomized clinical trials (RCTs) not already included in systematic reviews were also included, as well as information from large population-based cohorts.

Physical activity and exercise were defined as any bodily movement generated by skeletal muscles resulting in energy expenditure above resting levels [40]. The use of the terms 'physical activity' and 'exercise' in the included studies was not consistently in accordance with published definitions [40], and the terms were sometimes used interchangeably. Therefore, this review was not able to differentiate between interventions for either of them.

To retrieve all relevant articles within the area of PGP, a search was done for both PGP and lumbopelvic pain (LPP), since the latter term is often used when the studies do not distinguish between PGP and combined pain from the lumbar and pelvic areas [41]. Some authors have used the term low back pain (LBP) for pain in the lumbar area and evaluated the subgroup with LBP separately e.g., Weis et al., [42], which is also presented separately in our review.

#### **3. Endometriosis-Related Chronic Pelvic Pain and Lifestyle Factors**

Seven systematic reviews were found that were prepared and outlined in accordance with the PRISMA guidelines. Of these reviews, four provided a narrative synthesis of their data due to study heterogeneity (design, research questions, outcomes, interventions, etc.). Three studies performed a meta-analysis. Characteristics of the included systematic reviews and meta-analyses, together with their main results and level of evidence (if applicable) are outlined in Table 1.

In the text that follows, the results of the systematic reviews and meta-analyses are described, together with the results of narrative/critical reviews and recent original studies.


26





29

#### *3.1. Physical Activity and Exercise*

Two systematic reviews reported on endometriosis and physical activity/exercise. Hansen and colleagues (2021) studied the recent evidence on the impact of exercise on pain perception in women with endometriosis [43]. No general positive effect of exercise on pain could be concluded. However, the included studies were generally of high risk of bias. Ricci et al. (2016) studied the role of physical activity on the risk for endometriosis [44]. In their meta-analysis, women with endometriosis performing recent physical activity, and women performing physical activity in the past, were included. The pooled estimate of adjusted odds ratios for current exercise indicated a significantly protective effect of exercise, but the overall estimates did not reach levels of significance. Furthermore, the review did not specify the influence of physical activity on pain symptoms. The aforementioned results are in line with the results of the earlier published narrative review of Bonocher et al. (2014) that assessed the relationship between physical exercise and the prevalence and/or improvement of symptoms associated with endometriosis [50].

The data available are inconclusive regarding the benefits of physical exercise on the risk of endometriosis, and no firm data exist on the added value of physical activity on pain in women with endometriosis.

#### *3.2. Psychological Distress*

One systematic review was found that assessed the effectiveness of psychological and mind-body interventions to improve pain, psychological distress, sleep and fatigue in women with endometriosis [48]. The studies assessed the value of yoga, mindfulness, relaxation training, cognitive behavioral therapy combined with physical therapy, Chinese medicine combined with psychotherapy, and biofeedback. No firm conclusions could be drawn given the high variety of interventions and designs. Most studies were considered pilot studies. However, the results of the studies suggested that psychological and mindbody interventions are promising avenues to decrease pain, anxiety, depression, distress, and fatigue in women with endometriosis.

#### *3.3. Sleep*

No systematic nor narrative reviews on the role of insomnia on pain in women with endometriosis were found, nor on the effectiveness of sleep interventions on pain symptoms in women with endometriosis. No recent original prospective cohort studies or intervention studies regarding this topic were found.

Arion et al., (2020) performed a quantitative analysis of sleep quality in women with surgically confirmed endometriosis to assess which variables were associated with poorer sleep [51]. Based on regression analyses, the following factors were independently associated with poorer sleep: functional quality of life, more depressive symptoms and painful bladder syndrome. In a former cross-sectional study on the sleep quality of women with endometriosis and the relation between sleep quality and pressure pain thresholds, sleep quality was significantly poorer in women with endometriosis compared to women without endometriosis [52]. Furthermore, the pressure pain threshold in the greater trochanter and abdomen was significantly lower in women with endometriosis when compared to women without endometriosis, which is indicative of an increased central sensitivity; however, there was no difference in pain intensity between women with and without endometriosis.

#### *3.4. Diet*

Huijs and Nap (2020) performed a literature search to gain insights into the role of nutrients on the symptoms of women with surgically or magnetic resonance imaging/ultrasound confirmed endometriosis [45]. Using the GRADE criteria, the quality of the evidence in this review turned out to be low to very low. It was suggested that the intake of additional fatty acids, antioxidants and a combination of vitamins and minerals could have a positive effect on endometriosis-associated symptoms.

Nirgianakis et al., (2021) performed a systematic review on the effectiveness of dietary interventions in the treatment of endometriosis [46]. Changes in endometriosis-associated symptoms measured with pain scales or patient-reported quality of life outcomes were the outcomes of interest in this systematic review. Different dietary interventions were assessed, including: supplementation of vitamin D; supplementation of vitamins A, C, and E; supplementation of omega-3/6, quercetin, vitamin B3, 5-methyltetrahydrofolate calcium salt, turmeric, and parthenium; Mediterranean diet; low-FODMAP diet; low nickel diet; gluten-free diet, and individual diet changes. Most studies identified a positive effect of the dietary intervention on endometriosis symptoms. However, all studies were of moderate and/or high-risk risk of bias limiting the validity of the results. Furthermore, it was not possible based on the available evidence to identify certain subcategories of patients, which would be more likely to benefit from a dietary intervention. In addition, it was not possible, based on the current literature, to identify specific dietary interventions that would ameliorate certain endometriosis-associated symptoms. Therefore, it was concluded that more, and especially higher quality original studies, are needed to draw conclusions on the effectiveness of dietary intervention on pain in women with endometriosis.

Recently, Qi et al., (2021) performed a systematic review and dose-response meta-analysis to investigate the association between dairy products and the risk of endometriosis, and to evaluate the amount of dairy intake affecting the risk of endometriosis [47], though the effect on pain perception was not taken into consideration. Based on the meta-analysis results, the authors concluded that the intake of dairy products was associated with a reduction in endometriosis when the average daily intake was three servings or more. When analyzed according to the specific type of dairy product, it was suggested that females with a higher high-fat dairy and cheese intake were at lower risk of endometriosis. Regarding butter intake, it was suggested that high intake was related to an increased risk of endometriosis. All studies included in this meta-analysis were of high quality, as based on the Newcastle-Ottawa Scale [53].

Additionally, Helbig et al., (2021) performed a literature search for articles from 2000 onwards to answer the question whether diet influences the risk for and progression of endometriosis or whether it influences the postoperative condition [54]. This review did not take the effect of diet on pain symptoms into account. Based on the evidence, it was suggested that fish oil capsules in combination with vitamin B12 were associated with a positive effect on endometriosis symptoms (particularly of dysmenorrhea). It was reported that alcohol and increased consumption of red meat and trans-fats were associated with a negative effect on endometriosis. The results of the studies listed with regard to fruit and vegetables, dairy products, unsaturated fats, fibre, soy products and coffee were not clear.

In conclusion, no high-qualitative prospective data on the role of diet (which food products and in which amounts) in the development and maintenance of pain in women with endometriosis are available. Furthermore, no firm data exist on the added value of dietary interventions on pain in women with endometriosis, given the low study quality of currently existing trials.

#### *3.5. Tobacco/Alcohol Use*

One systematic review and meta-analysis studied the relation between tobacco smoking and endometriosis risk. No evidence for an association between tobacco smoking and risk of endometriosis was found [49]. When subgroups were considered, i.e., never smokers vs. former smokers, current smokers, moderate smokers or heavy smokers, no statistically significant associations were reported.

#### **4. Pelvic Girdle Pain and Lifestyle Factors**

Seven systematic reviews were found that evaluated lifestyle intervention for PGP prepared and outlined in accordance with the PRISMA guidelines. Of these reviews, five studies performed a meta-analysis. Characteristics of the included systematic reviews and meta-analyses, together with their main results and level of evidence are outlined in Table 2.





34


for details on risk of bias, refer to original study.

35

In the text that follows, the results of the systematic reviews and meta-analyses are described, together with the results of narrative/critical reviews and recent original studies.

#### *4.1. Physical Activity and Exercise*

Seven systematic reviews, performed according to PRISMA, reported on physical activity/exercise as management of PGP. Weis et al., (2020) conducted two systematic reviews on systematic reviews and RCTs to assess the effectiveness of chiropractic care options including exercises commonly used for pregnancy-related PGP, LPP and LBP during pregnancy [55] and postpartum [42]. For PGP in pregnancy, there was inconclusive evidence that an exercise program was more effective to decrease pain and disability compared with standard treatment [55]. For LPP, it was found that exercise had unclear outcomes on improvements in function (moderate strength evidence), and that exercise reduced the prevalence of LPP. This latter was reported in most included systematic reviews. For LBP, studies had inconclusive strength evidence with favorable outcomes on decreased pain and disability. From a systematic review focusing on the postpartum period [42], there was moderate evidence with no clear outcomes to suggest exercise as treatment for or prevention of PGP, since only one of three included systematic reviews stated the additional effect of exercises at reducing pain and disability. No firm conclusion could be drawn for LPP, but the authors reported some evidence which indicated that exercises could relieve LPP. There were no results for LBP postpartum. Davenport et al., (2019) performed a systematic review to investigate the relationship between the performance of prenatal exercises and PGP, LPP as well as LBP [56]. Based on very low-to-moderate quality evidence, prenatal exercise compared to no exercise during pregnancy did decrease pain severity in pregnancy and at postpartum but did not reduce the odds of suffering from PGP, LPP and LBP either in pregnancy or at postpartum.

Almousa et al., (2018) evaluated the effectiveness of stabilizing exercises in PGP during pregnancy and postpartum in a systematic review [57]. They concluded that there was limited evidence that stabilizing exercises decreased pain and improved quality of life during pregnancy and postpartum. Shiri et al., (2018) did a meta-analysis of RCTs to study the value of exercise in the prevention of PGP and LBP [58]. They concluded that exercise reduced the risk of LBP in pregnancy by 9% but that exercise had no effect on PGP or LPP. Additionally, exercise prevented new episodes of sick leave due to LPP. Liddle and Pennick (2015) performed a systematic review according to Cochrane Collaboration's tool to update the evidence on the effects of any intervention including exercise to prevent or treat PGP, LPP or LBP during pregnancy [4]. Low-quality evidence showed no significant difference in the prevalence of PGP or LBP from exercise. Low-quality evidence showed that any land-based exercise significantly reduced pain and disability from LBP. Moderate-quality evidence showed reduced the prevalence of LPP from 8–12 weeks of exercises.

Tseng et al., (2015) aimed to synthesize evidence from RCTs on the effectiveness of exercise on LPP in postpartum women [59]. Based on four RCTs they concluded that there was some evidence to indicate the effectiveness of exercise for relieving LPP but more trials were need to ascertain the most effective postpartum exercise programs.

Even though not proven to reduce the risk of developing PGP [56,58], a recent systematic review on physical activity and exercise in relation to pregnancy reported decreased severity of PGP and LPP [56]. Davenport et al. reported their intervention results separated as 'exercise only' or 'exercise plus co-intervention' [56], which could explain the somewhat different result to another recent systematic review that reported inconclusive, although favorable, evidence for exercises in pregnancy [55] as well as at postpartum [42]. These latest results confirm the most recent Cochrane review on exercise in pregnancy for LPP and LBP, but not the previous result of no effect for PGP [4]. The newer result, that exercise can reduce the severity of PGP, may be explained by more studies to build evidence on. Likewise, the number of studies to build the evidence on is probably the explanation of some other previously limited [57], inconclusive evidence [59] reported. The recent results confirm an earlier narrative review on LBP and PGP by Stuge (2015), where it was

concluded that there is evidence of moderate quality that exercise reduced pain intensity but not prevalence [60].

Various types of exercises including general physical activity, low impact aerobic exercise such as walking, stabilizing exercises, resistance training, and other forms of exercises such as Yoga, or the combination of different exercises, have been evaluated for their effectiveness in PGP, LPP and LBP in the included systematic reviews. Systematic reviews usually include all exercise types together. Only one identified systematic review differentiated exercise only from exercise with co-interventions [56], but no significant difference between pooled estimates could be seen (pregnancy *p* = 0.24; postpartum *p* = 0.70). At this time, there is insufficient evidence to determine whether one type of exercise is superior to another or whether exercise should be combined with other interventions and, in that case, which co-intervention(s). One identified systematic review that focused on group training for LPP reported no effect as treatment of LPP among pregnant women but reported group training to be effective after pregnancy [61].

From four population-based cohort studies in Brazil, it was reported that 41.9% of 3827 pregnant women reported LBP of any type, and 10% of women during pregnancy reached recommended levels of physical activity [62]. The authors concluded that meeting the recommended levels of physical activity during pregnancy was associated with less activity limitation related to LBP during pregnancy. However, physical activity levels, either before (β coefficient: 0.07; 95% CI, −0.25 to 0.38) or during pregnancy (β coefficient: −0.07; 95% CI, −0.46 to 0.33), were not associated with pain intensity, care seeking, and postpartum LBP [62]. After pregnancy, physical activity level was continuously suboptimal for many women [63]. Recently, it was reported that sedentary behavior after birth was associated with persistent LPP in primiparas, but not multiparas [64]. The authors interpreted this to be a result of multiparas needing to be more active when raising an older child.

#### *4.2. Psychological Distress*

No systematic nor narrative reviews on the effectiveness of (di)stress interventions on pain symptoms in women with PGP were found.

In a recent systematic review on prognostic factors, experiencing emotional distress during pregnancy was associated with less recovery and severe pelvic girdle syndrome at 6 months after pregnancy, when the natural course of PGP is over (*n* = 40,029; Adjusted Odds Ratio (AOR) 1.3, 95% CI (1.1–1.5) [36]. The findings need to be taken with caution since quality of evidence according to GRADE was low to very low. Distress during pregnancy has also been associated with chronic PGP after delivery [65]. The conclusion is that there are indications that distress can affect PGP and its course and that this needs to be studied in more detail both within a prevention as well as a curative context.

#### *4.3. Sleep*

There was no identified systematic review regarding the effect of sleep management on PGP. Among pregnant women with pain in the lumbopelvic area, a high-pain group reported worse emotional health and poorer sleep quality than controls without pain [66]. Sleep disturbance has also been associated with persistent PGP and LPP at 4 months after pregnancy, even after adjustment for possible confounding variables such as BMI, parity, age, and history of LPP [67]. Sleep impairment related to quantity and adequacy of sleep has been associated with women with moderate disability from persistent PGP after pregnancy [68]. Different to these results, in a recent study the moderate or severe sleeping complaints associated with PGP disappeared after adjustment for depression [69]. This might be explained by the comorbidity of PGP and depression [26]. Many women experience disturbed sleep during pregnancy due to continuous hormonal-related changes of the body, need of nocturia and movement from the fetus. It is also known that around 50% of women get disturbed sleep during the first years of parenthood due to nighttime feeding and nocturnal awakening among infants [70,71].

To conclude, there is no evidence of sleep interventions for PGP. However, concerning the prevalence of sleep disturbance in relation to pregnancy and early childhood of women, there are indications of the importance of sleep as a lifestyle factor in women with chronic PGP.

#### *4.4. Diet*

There was no identified systematic review on the effectiveness of dietary interventions in the treatment of PGP. However, if an unhealthy diet leads to a high body mass index (BMI) there are some associations to consider. A systematic review reported an association between a BMI of 25 or more and having persistent PGP 12 weeks after pregnancy (*n* = 179; AOR 2.1, 95% CI 1.0–4.5) [36]. From the same study, it was reported that obese women (BMI 30 or more) had higher odds to have persistent pelvic girdle syndrome (*n* = 27,025; AOR 1.8, 95% CI 1.5–2.0) and severe pelvic girdle syndrome at 6 months (*n* = 27,025; AOR 1.6, 95% CI 1.1–2.4). Pre-pregnancy BMI > 25 was shown as a risk factor for chronic PGP in another recent systematic review [72]. Since interaction between factors could not be done in a multivariate analysis, the results should be taken with care [72].

Lifestyle intervention of physical activity in general in relation to pregnancy and postpartum are often focused on BMI as an outcome [73,74]. Effectiveness of a combination of diet and physical activity consistently showed a reduction in mean gestational weight gain during pregnancy and postnatal weight retention [75]. There were no reports on musculoskeletal pain of the studied groups, but from a coherent literature on PGP it is can be assumed that about 50% of the women had PGP in pregnancy and around 25% had persistent PGP after birth [4]. A major part of women used walking as physical activity intervention in the studies that reported types of physical activity [76,77]. Interesting to consider is whether professional individualized exercise advice would have further improved the outcomes.

Although no systematic review on PGP and diet was identified, there seems to be promising results of intervention for a combination of diet and physical activity in relation to pregnancy that needs further exploration of possible effects on chronic PGP.

#### *4.5. Tobacco/Alcohol Use*

There was no identified systematic review regarding the effect of tobacco or alcohol interventions on PGP.

In a systematic review on prognostic factors, Wuytack et al. reported an association with occasional smoking (*n* = 38,865; AOR 1.3, 95% CI 1.0–1.6), but not daily smoking, in women with pelvic girdle syndrome at 6 months postpartum [36].

#### **5. Future Directions for Clinical Practice**

In line with the World Health Organization's (WHO), a stronger focus towards a healthy lifestyle is recommended, i.e., being physically active for better health and for preventing noncommunicable diseases such as diabetes, cancer, and cardiovascular disease [78]. In the action plan for the prevention of long-term disability from LBP [79] and chronic pain in general across the lifespan [80], a positive health concept as an overarching strategic approach is emphasized. In this, a positive health concept entails, among others, learning to cope with a chronic health problem through self-management strategies. A healthier lifestyle promoting physical activity and staying active despite pain, maintaining a healthy weight, and promoting mental health, are in this context primary prevention strategies for chronic disability [79,80]. When specifically looking into the results of this state-of-the-art paper on lifestyle factors and their role in women with pain in the pelvis, only a few recommendations can be made based on the available literature. Regarding physical activity and exercise, encouraging women to be physically active and to exercise is supported to some extent. Nonetheless, because physical activity and exercises of different intensity, frequency, duration, and type were used in the available evidence, no specific recommendations regarding this point can be made. The available evidence on lifestyle

factors such as sleep, (di)stress, diet, and tobacco/alcohol use for women with pain in the pelvis is inconclusive, since very few studies are available, and the studies which are available are of general low quality. Furthermore, most studies did not focus on the role of targeting lifestyle factors with the aim of improving pain in the pelvis. Therefore, no specific recommendations on the application of management strategies for these lifestyle factors can be provided.

We can, however, approach pain management in women with pain in the pelvis from a modern pain management point of view, which includes the management of lifestyle factors. Indeed, modern pain management implies change in the focus from pain reduction to pain management, i.e., managing thoughts and feelings related to pain (i.e., catastrophic worry), thereby influencing knowledge about pain [81–83] and providing opportunities for behavioral change towards a more active and healthier lifestyle. It also implies accurate self-management, which supports autonomy, and includes educational and supportive interventions to increase the skills and confidence for persons in pain to manage their health problems [84].

For women who are prone to pain experiences early in life, as related to menstruation [85] and pregnancy [4], learning healthy pain management is a priority. This includes the assessment and management of the individual woman with pain in the pelvis, taking into account her history, her present context and framing her messages into biopsycho-social and bio-inflammatory-psychological perspectives [29,86–90]. In this context, it is important for women who experience pain (cyclic pain from menstruation, local pregnancy-related pain, persistent pain at postpartum) to learn to approach activity despite pain. Indeed, physical activity has been described as a way to achieve exercise-induced analgesia [85,91] and as a strategy to promote self-efficacy (because of the experience of self-control [92], which is highly important given the relation between low self-efficacy and the development of disability [84]. In the context of pain in the pelvis, it has been shown that women with chronic PGP have less general self-efficacy than women who recovered from PGP after pregnancy [8]. From chronic pain science, it is known that physical activity additionally might have sleep improving [93], stress-reducing [94] and general anti-inflammatory effects [95], which are all relevant for optimal pain management [96]. Importantly, the intensity, volume, duration and type of activity that is most appropriate to reach these effects in women with pain in the pelvis are not firmly studied [97].

Nonetheless, it is known that pain is considered an important barrier against physical activity in women with pain in the pelvis [98]. For example, it is reported that women with PGP during pregnancy are less likely to exercise regularly [99]. Walking is the most chosen physical activity during pregnancy [77], but it is also the most painful physical activity when suffering from PGP [9]. Thus, decreased physical activity in pregnancy could be partly explained as a consequence of PGP. Importantly, women need to be guided into alternative physical activities and exercises when walking is painful. Therefore, in order to motivate women with pain in the pelvis to uptake physical activity despite tolerable levels of pain, and to reach a behavioral change, the use of a person-centred approach is essential [89]. A person-centred approach may increase the alliance between the care provider and the woman with pain in the pelvis, and subsequently lead to better adherence, improvements in general health and satisfaction [100]. It is important to approach the worries and concerns related to physical activity and exercise, e.g., how to interpret pain-increasing physical activity, which is different for a nociceptive versus nociplastic dominant pain mechanism. Pain neuroscience education is a known strategy that can reduce worries about pain by informing the individual mechanism of the experienced pain and is considered essential before starting physical activity interventions [81]. However, although it has been proven effective in several chronic pain populations, the evidence in women with chronic pain in the pelvis is still nonexistent [101].

#### *Prevention of Chronic Pain in the Pelvis Prevention of Chronic Pain in the Pelvis*

[101].

During the woman's lifespan there are windows of opportunity to prevent the transition from localized and periodic pain in the pelvis (dysmenorrhea or from pregnancy) into chronic pain (Figure 1). During the woman's lifespan there are windows of opportunity to prevent the transition from localized and periodic pain in the pelvis (dysmenorrhea or from pregnancy) into chronic pain (Figure 1).

when suffering from PGP [9]. Thus, decreased physical activity in pregnancy could be partly explained as a consequence of PGP. Importantly, women need to be guided into alternative physical activities and exercises when walking is painful. Therefore, in order to motivate women with pain in the pelvis to uptake physical activity despite tolerable levels of pain, and to reach a behavioral change, the use of a person-centred approach is essential [89]. A person-centred approach may increase the alliance between the care provider and the woman with pain in the pelvis, and subsequently lead to better adherence, improvements in general health and satisfaction [100]. It is important to approach the worries and concerns related to physical activity and exercise, e.g., how to interpret pain-increasing physical activity, which is different for a nociceptive versus nociplastic dominant pain mechanism. Pain neuroscience education is a known strategy that can reduce worries about pain by informing the individual mechanism of the experienced pain and is considered essential before starting physical activity interventions [81]. However, although it has been proven effective in several chronic pain populations, the evidence in women with chronic pain in the pelvis is still nonexistent

*J. Clin. Med.* **2021**, *10*, x FOR PEER REVIEW 20 of 29

**Figure 1.** Women are exposed to pain in the pelvis during their lifespan in relation to hormonal changes and pregnancy. Lifestyle can influence the pain experience during the lifespan. **Figure 1.** Women are exposed to pain in the pelvis during their lifespan in relation to hormonal changes and pregnancy. Lifestyle can influence the pain experience during the lifespan.

> Pre-existing pro-inflammatory states increase the risk of chronification of pain [102]. During adolescence [103], and in relation to pregnancy [104], comorbid disorders of the urogenital systems are common and require attention. Early pain management with behavioral changes may reduce the risk of the transition towards chronic nociplastic pain in such cases, as was suggested from a systematic review (based on low to very lowquality evidence) [94]. Pre-existing pro-inflammatory states increase the risk of chronification of pain [102]. During adolescence [103], and in relation to pregnancy [104], comorbid disorders of the urogenital systems are common and require attention. Early pain management with behavioral changes may reduce the risk of the transition towards chronic nociplastic pain in such cases, as was suggested from a systematic review (based on low to very low-quality evidence) [94].

> Regarding the risk of chronic PGP, women at risk can be identified during pregnancy by a clinical assessment. The number of positive pain provocations tests is an established predictor of chronic PGP [8,105]. Pain provocation tests, as measures of increased pain sensitivity, have also been suggested as indicators of systematic inflammation [90]. Widespread pain, a characteristic feature of central sensitization [106], has been identified as the strongest predictor for a poor long-term outcome in women with PGP [107]. Regarding the risk of chronic PGP, women at risk can be identified during pregnancy by a clinical assessment. The number of positive pain provocations tests is an established predictor of chronic PGP [8,105]. Pain provocation tests, as measures of increased pain sensitivity, have also been suggested as indicators of systematic inflammation [90]. Widespread pain, a characteristic feature of central sensitization [106], has been identified as the strongest predictor for a poor long-term outcome in women with PGP [107]. Moreover, it is reported that eleven years after PGP onset, women with chronic PGP show more concern and depression then women who recover from the PGP after pregnancy [8]. This observation supports the idea of cognitive-emotional sensitization in women with chronic PGP [108]. Therefore, clinical assessment in women with pregnancy-related PGP needs to contain at least pain provocation tests: a pain drawing to assess widespread pain and an evaluation of concern and depression [109,110]. This way, women at risk for chronic pain are identified and preventive interventions targeting the appropriate underlying mechanism might avoid the development of long-term pain [111].

> The promotion of a healthy physical activity level during pregnancy, when women are extra prone to lifestyle changes [112], might improve health-promoting physical activity after childbirth [113]. Importantly, mothers' habits, including a healthy lifestyle, have demonstrated a positive effect on the offspring, as healthy role modelling behaviors for infants [74,87,112]. Current guidelines advise healthy pregnant women to follow the general guidelines of weekly, evenly distributed, physical activity which last 150 min, performed at a moderate intensity, plus two times per week resistance training [87]. Due to anatomical and physiological changes, as well as foetal requirements, some modification of exercise habits may be necessary. Reported barriers related to physical activity after pregnancy

have been related to capability (e.g., limitation in healthcare providers' skills in providing lifestyle support), opportunity (support from partners) and motivation (e.g., identifying benefits of exercise) [74]. Therefore, it is important to focus on these barriers during pregnancy, and to find solutions on how to remove those obstacles [80]. In this context, it is known that women with PGP having a lack of knowledge and lack of support and knowledge from healthcare providers when seeking care, experience unmet needs [10,114,115]. Indeed, education and advice have been reported to positively influence pain, disability and/or sick leave [116].

It is common for pregnant women to seek knowledge and advice on the internet. However, it has been shown that bad advice flourishes and increases worries [117]. Therefore, women need guidance in what knowledge to trust and how to individualize it for their specific situation. This underlines the necessity for physical activity interventions and exercise regimes in pregnant women, guided by health care professionals with adequate education [86]. Indeed, expert advice and experiences on therapeutic exercise (with or without co-interventions) during pregnancy is proven effective [118]. In clinical practice, transcutaneous electric nerve stimulation and belts are common tools to support pain self-management, with some evidence to support their use in PGP [4,9]. They are generally seen as pain reduction tools but would rather be seen as tools to encourage appropriate physical activity, as they enable physical activity at a tolerable pain level.

Lastly and importantly, the promotion of a healthy lifestyle does not exclude the assessment of local nociception-inducing mechanisms in clinical examination and medical assessment, in order to identify and treat specific symptoms related to disorders causing pain in the pelvis.

#### **6. Future Directions for Research**

Women with pelvic pain due to severe dysmenorrhea are currently often told that their pain should be considered normal. In women with PGP during pregnancy or after delivery, pain is often considered a normal consequence of pregnancy and childbirth. Due to this narrow view on pain management, many women are undertreated for complaints that can be treatable. Since pain in the pelvis is associated with suffering, disability and a low health-related quality of life [115,119,120], there is an urgent need to better understand how to alleviate the suffering of women with pain in the pelvis, and to gain knowledge on adequate strategies to prevent (chronic) pain in the pelvis. This state-of-the-art review clearly shows that firm evidence on the role of lifestyle on pain, and on the effectiveness of lifestyle interventions on pain symptoms in women with pain in the pelvis, are essentially lacking. Therefore, we present a research agenda (Figure 2).

#### *6.1. Pain Neuroscience Education: A Prerequisite for Sustained Lifestyle Adaptations in Women with Pain in the Pelvis?*

It could be theorized that teaching women the science behind pain and the mechanisms related to pain in the pelvis (such as lifestyle factors) could be a strong protective factor for developing chronic pain in the pelvis throughout life and for intrinsically motivating them for a sustained engagement in a healthy lifestyle. Thereby, pain neuroscience education in the treatment of women with pelvic pain might provide women in pain with the necessary information to reach a sustained change towards a more active and healthier lifestyle. However, what pain neuroscience education in women with pelvic pain should look like, and whether it is effective in changing beliefs and behaviors, and subsequently in decreasing pain, should be a primary topic of research.

In this context, many questions related to pain education in women need to be considered. When during lifespan would it be optimal to educate women on pain which can appear in relation to menstruation or in relation to pregnancy and at postpartum? This question is of relevance as menstruation and pregnancy should not be medicalized, nor should be neglected. The delivery mode of pain education related to menstruation and pregnancy should also be considered. Can it be added to the curriculum in secondary school, or should the message be spread at a societal level to reach all stakeholders? In

this context, it is also pertinent to study the societal and health care providers' ideas and beliefs about pain in the pelvis. A reflection on which women would need to be educated is another relevant topic in this regard; all women versus women experiencing painful menstruation or PGP, versus women who are mothers experience pelvic pain? Furthermore, the content of the education to achieve the highest impact on women should be explored. Information on all former topics can be studied using quantitative and qualitative research approaches. This way, the barriers for optimal pain care on a patient's, healthcare provider's and societal level can be identified, and necessary content for pain neuroscience education for women with pain in the pelvis can be defined. *J. Clin. Med.* **2021**, *10*, x FOR PEER REVIEW 22 of 29

**Figure 2.** Research agenda of the potential working mechanisms of lifestyle factors on pain reduction in chronic pain in the pelvis, in parallel with potential management options. **Figure 2.** Research agenda of the potential working mechanisms of lifestyle factors on pain reduction in chronic pain in the pelvis, in parallel with potential management options.

#### *6.1. Pain Neuroscience Education: A Prerequisite for Sustained Lifestyle Adaptations in Women with Pain in the Pelvis? 6.2. A Broad View on Pain in Women with Pain in the Pelvis*

It could be theorized that teaching women the science behind pain and the mechanisms related to pain in the pelvis (such as lifestyle factors) could be a strong protective factor for developing chronic pain in the pelvis throughout life and for intrinsically motivating them for a sustained engagement in a healthy lifestyle. Thereby, pain neuroscience education in the treatment of women with pelvic pain might provide women in pain with the necessary information to reach a sustained change towards a more active and healthier lifestyle. However, what pain neuroscience education in women with pelvic pain should look like, and whether it is effective in changing beliefs and Young menstruating women's pain experiences need to be better understood in the development of disability and chronic pain in the pelvis. A better understanding of the role of multiple factors, such as lifestyle, genetic, psychosocial and patho-anatomical factors as predictors for severe pain in the pelvis would create opportunities for developing early preventive and curative strategies. The underlying effects related to lifestyle interventions in endometriosis-related pelvic pain, such as an estrogen-dependent and an anti-inflammatory effect, need to be further explored. Such information is necessary to develop the specific content for pain neuroscience education programs in women with pain in the pelvis.

behaviors, and subsequently in decreasing pain, should be a primary topic of research. In this context, many questions related to pain education in women need to be considered. When during lifespan would it be optimal to educate women on pain which can appear in relation to menstruation or in relation to pregnancy and at postpartum? This question is of relevance as menstruation and pregnancy should not be medicalized, nor should be neglected. The delivery mode of pain education related to menstruation and pregnancy should also be considered. Can it be added to the curriculum in secondary school, or should the message be spread at a societal level to reach all stakeholders? In this In the context of pregnancy-related pain, the pregnancy period is a period characterized by sleep deprivation, hormonal and psychological emotional changes, and less physical activity. For women after childbirth, pelvic floor trauma is an additional challenge in relation to lifestyle, besides those factors mentioned during pregnancy that all may prevail after pregnancy. Through shared neurophysiological mechanisms, these factors may contribute to the development of PGP in pregnancy and chronic PGP which lasts at postpartum. In this, the dominant pain mechanism in pregnancy-related PGP needs to be better

context, it is also pertinent to study the societal and health care providers' ideas and beliefs

menstruation or PGP, versus women who are mothers experience pelvic pain? Furthermore, the content of the education to achieve the highest impact on women should be explored. Information on all former topics can be studied using quantitative and qualitative research approaches. This way, the barriers for optimal pain care on a patient's, healthcare provider's and societal level can be identified, and necessary content for pain

neuroscience education for women with pain in the pelvis can be defined.

understood. Since widespread pain, a characteristic feature of central sensitization [106], has been identified as the strongest predictor of poor long-term outcome in women with PGP [107], more studies on the role of central sensitization in the development of chronic PGP are needed to develop preventive strategies and individually tailored interventions (e.g., personalized pain education and behavior treatment).

Furthermore, the potential of lifestyle adaptations, adapted to pregnancy, as an opportunity for preventing and decreasing the impact of PGP after pregnancy must be explored. Research on how current treatments for lifestyle interventions such as cognitive behavioral therapy as a sleep intervention [121], can be adapted specifically for women with pain in the early time periods following childbirth, is of high priority. Indeed, women ask for more knowledge and support on strategies to (self-)manage pain in relation to pregnancy [10,115]. Therefore, studies on the content and delivery method of pain management programs in women with pregnancy-related pain in the pelvis are needed, i.e., how can treatment be implemented with potential barriers to approaching a healthy lifestyle (e.g., common sleep deprivation due to pregnancy or young children)? In terms of delivery form, management by means of mobile-and-internet-delivered programs for prevention, as well as pain management programs, must be further explored.

It is of interest to explore which barriers towards a healthy lifestyle exist in women with pain in the pelvis. It is, for example, of interest to explore whether transcutaneous electric nerve stimulation can be used as a nonpharmacological treatment to influence central sensitization in women with cyclic or periodic pain [122], and be an effective treatment for staying active and exercising during painful periods. Pelvic floor disorders as a consequence of childbirth need to be identified and managed, not only for the problems themselves but also as barriers to exercise. It is known that pregnancy and vaginal delivery are among the main risk factors for urinary and faecal incontinence [104], and that urinary incontinence affects exercise participation in one in two symptomatic women. Pelvic floor disorders including urinary and faecal incontinence, and pelvic floor prolapse are reported barriers to exercise with a moderate or great effect in 39% of women (95% Cl: 22%, 57%) [123]. Therefore, it is clear that women with pelvic pain should always be approached in a multidimensional way, by a multidisciplinary team. Indeed, chronic pain in the pelvis requires competences from multiple disciplines that involve physiotherapists, midwives, gynecologists, psychologists, occupational therapists, and pain specialized medical doctors.

Finally future research on PGP should consider the recent published core outcome set of PGP to enable future compilation of results in systematic reviews [110]. To strengthen the quality of the evidence, future studies would benefit from designing and presenting results in accordance with accepted reporting standards (e.g., CONSORT and PRISMA).

#### **7. Conclusions**

During their lifespans, many women are exposed to pain in the pelvis in relation to menstruation and pregnancy, which is often considered normal and inherently linked to being a woman. This leads to insufficient treatment. Severe dysmenorrhea, as seen in endometriosis and pregnancy-related PGP, has a great impact on daily activities, school attendance and work ability. Lifestyle factors such as a low physical activity level, poor sleep, or periods of (di)stress are all common in these challenging periods of women's life.

Based on this state-of-the-art review, encouraging women with pain in the pelvis to be physically active and to exercise is supported to some extent. Clinicians are suggested to use a window of opportunity to prevent a potential transition from localized or periodic pain in the pelvis (e.g., pain during pregnancy and after delivery or severe dysmenorrhea) towards persistent chronic pain, by encouraging a healthy physical activity level and applying appropriate pain management. The available evidence on lifestyle factors such as sleep, (di)stress, diet, and tobacco/alcohol use is, however, inconclusive; very few studies are available, and the studies which are available are of general low quality.

Research to disentangle the relationship between lifestyle factors, such as physical activity level, sleep, diet, smoking, and psychological distress, and the experience of pain

in the pelvis is highly needed. Studies which address the development of management strategies for adapting lifestyle, which are specifically tailored to women with pain in the pelvis, and take hormonal status, life events and context into account, are required.

**Author Contributions:** Conceptualization, A.G. and L.D.B.; methodology, A.G. and L.D.B.; validation, A.G., K.S. and L.D.B.; writing—A.G. and L.D.B.; writing—review and editing, A.G., K.S. and L.D.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** Swedish state under the agreement between the Swedish government and the county council, the ALF-agreement (KS).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

