Efficacy of the complementary therapies in the management of cancer pain in palliative care: A systematic review

Objective: to synthesize the knowledge and to critically evaluate the evidences arising from randomized controlled trials on the efficacy of the complementary therapies in the management of cancer pain in adult patients with cancer in palliative care. Method: a systematic review guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The search for articles in the MEDLINE, ISI Web of Knowledge, CENTRAL Cochrane, and PsycINFO databases, as well as the manual search, selection of studies, data extraction, and methodological assessment using the Cochrane Bias Risk tool were performed independently by two reviewers. Results: eight hundred and fifteen (815) studies were identified, six of them being selected and analyzed, of which three used massage therapy, one study used a combination of progressive muscle relaxation and guided imaging, and another two studies used acupuncture. Most of the studies had an uncertain risk of bias (n=4; 67%). Conclusion: while the evidence from the studies evaluating the use of massage therapy or the use of progressive muscle relaxation and guided imaging for the management of cancer pain in these patients demonstrated significant benefits, the other two studies that evaluated the use of acupuncture as a complementary therapy showed contradictory results, therefore, needing more research studies to elucidate such findings.


Introduction
The latest report on the global cancer burden in the world, according to the GLOBOCAN 2018 estimates, has estimated about 18.1 million new cases of cancer and 9.6 million deaths due to malignant neoplasms in 2018 (1) .
Reaching alarming levels, cancer is a contemporary global public health problem, being the second leading cause of mortality in several countries (2) . Estimates from the World Health Organization (WHO) indicate that, in 2030, cancer will reach approximately 27 million incident cases worldwide, 17 million deaths, and 75 million people with annual diagnosis (3) . The greatest effect will be noticeable in low-and middle-income countries. For each year of the 2020-2022 triennium, in Brazil the occurrence of 625 thousand new cancer cases was estimated (4) .
Cancer pain is a symptom related to multiple factors, defined as "simultaneous sensations of acute and chronic pain, of different levels of intensity, associated with the invasive spread of tumor cells in the body; a consequence of the cancer treatment, including chemotherapy, or cancer-related conditions; being generally described as imprecise, hurting, frightening or as an unbearable sensation, with episodes of intense sensations, accompanied by difficulties to sleep, irritability, depression, suffering, isolation, hopelessness, and helplessness" (5) . Although the WHO Analgesic Scale has been widely used (6)(7) , approximately 40% to 50% of the cancer pain cases have inadequaterelief due to their multi-factorial nature (8) . There is still a shortage of effective pain management schemes for many cancer patients, especially those in palliative care (9)(10) . Thus, a combination of pharmacological and non-pharmacological treatment modalities for cancer pain should be the standard care, due to the complexity of this symptom (10)(11) .
Palliative care was defined in 1990 and redefined in 2002 by the WHO as an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other physical, psychosocial, and spiritual problems (12) . Nurses play an important role in palliative care, with responsibility for providing information, counseling, and education to the patients and their families in maintaining the home/hospital dyad (13) . Due to the strong bond with patients and for being at the frontline of care, they are in the best position for handling the cancer symptom clusters (13)(14)(15) . It is highlighted that, for many cancer patients in palliative care, drug therapy is insufficient for pain relief or does not match the patient's choice (11) . Thus, it becomes essential to use complementary therapies (CTs) in addition to the conventional ones for cancer pain management (11,(15)(16) .

Alternative Medicine (NCCAM) defines Complementary
Alternative Medicine as a set of practices, medical and health care systems for individuals who are not considered part of conventional medicine (17) . The CTs cover techniques aimed at prevention, promotion, treatment, and recovery, in order to integrate the physical, mental, and spiritual dimensions of the human being. There are several ways to classify these therapies. The NCCAM categorizes them mainly as: use of natural products; body and mind practices; and body-based manipulation practices (17) . Over the past three decades, the use of CTs has increased considerably both in pediatric patients (18)(19)(20)(21)(22) and in the adult population (23)(24)(25)(26) . However, the efficacy of the CTs for cancer pain management in adults with cancer in palliative care is still a gap in the scientific literature (11) .
In this sense, this study aimed to synthesize the knowledge and to critically evaluate the evidence from

Method
This study is a systematic review of the literature, which was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
In order to guarantee the reliability of the data and methodological transparency, we filed the registration in the International Prospective Register of Systematic  (28) .
The Boolean operators AND and OR were used to obtain restrictive and additive combinations, respectively.
In addition, the search was carried out using identified descriptors and with a broader sense, without using the database filters to preserve significant samples and ensure less risk of losses. This strategy justifies the small number of studies selected in view of the sample obtained, added to the fact that we establish the RCT as an inclusion criteria as a design to encompass the strongest evidence for decisionmaking into clinical practice (28) . Figure 1 shows the final search strategy processed in the respective databases. (TS || =("Adult" AND "Cancer Patients" OR "Advanced Cancer Patients" AND "Neoplasms" OR "Cancer" AND "Palliative Care" OR "Palliative Medicine" OR "Hospices") AND TS=("Complementary Therapies" OR "Therapies, Complementary" OR "Complementary Medicine" OR "Alternative Medicine" OR "Alternative Therapies" OR "Non-pharmacological Interventions") AND TS=("Cancer Pain" OR "Cancer-Associated Pain" "OR "Cancer-Related Pain" OR "Neoplasm Related Pain" OR "Tumor Associated Pain" OR "Oncological Pain" OR "Oncology Pain") AND TS=("Randomized Controlled Trial" OR "Controlled Clinical Trial" OR "Clinical Trial" OR "Random Allocation" OR "Double-blind Method" OR "Single-blind Method"))  The studies were classified according to the risk of bias as follows: "Low" if all the main domains were classified as "low risk"; "Uncertain" if one or two main domains were classified as "uncertain risk"; and "high" if more than two main domains have been classified as "uncertain" or "high risk". When no information was available, we assign "uncertain risk" (33) .
As most of the studies evaluated showed significant methodological differences, it was decided to perform a qualitative synthesis of the data in this systematic review.

Reference
The total number of research participants among the included studies was 609 patients, with samples varying from 24 to 380 patients. Regarding the use of complementary therapies embraced in the included studies, it was verified that three studies used massage therapy (35)(36)(37) , one study used a combination of progressive muscle relaxation and guided imaging (40) ; and another two studies (38)(39) evaluated the use of acupuncture for cancer pain management in adult patients with advanced cancer in palliative care.
Regarding the follow-up time, all the studies showed a short-term follow-up, with the protocols varying from a single day (36,40) ; one week (38) ; two weeks (37) , three weeks (39) , to a maximum of 4 weeks (35) .
With regards to the risk of bias in the studies to be selected and assessed by the Cochrane Collaboration Bias Risk tool, it was verified that, in most of them (83%), the reliability of the results can be questioned, either because they present a risk of uncertain bias (n=4; 67%) (35)(36)(37)(38) or for exhibiting a high risk of bias (n=1; 17%) (40) . Only one study was classified as being at low risk for bias, with all the domains scored in this category (Figure 4).  We observed that four of the included studies (36)(37)(38)40) , corresponding to 67% of the sample, displayed high risk for bias for the "blinding of the participants and the team involved" domain (performance bias). Two studies (35)(36) , corresponding to 33% of the sample, displayed an uncertain risk of bias for the "blinding of outcome evaluators"

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domain (detection bias), and another two other (38,40) also exhibited an uncertain bias risk for the "other sources of bias" domain. It should be noted that all six studies were classified as low risk for bias for the "incomplete outcomes" and "report of selective outcomes" domains, representing low attrition and publication bias, respectively.

Discussion
The clinical use and assessment of the potential benefits of the complementary therapies in the treatment of cancer patients has recently increased in both pediatric (18)(19)(20)(21)(22) and adult patients (23)(24)(25)(26) . Among the manipulation practices based on the body, the therapeutic massage stands out as the most commonly used complementary therapy modality (41)(42) .
In this review, half of the included studies used massage therapy as CT (35)(36)(37) . Another study used a combination of progressive muscle relaxation and interactive guided imaging (40) ; and another two studies (38)(39)  two demonstrated a beneficial effect (36)(37) and one study showed no statistically significant differences (35) .
In summary, a study (36) suggested that the massage can be more effective than simple touch in reducing cancer pain and improving mood immediately after the treatment sessions. However, the sustained benefits of the massage in this population were less evident. Likewise, another study (37) revealed that the combination of massage therapy and exercise showed to be effective in immediately reducing cancer pain, distress, and suffering, as well as improving mood in patients with terminal cancer.
Corroborating to the beneficial findings of the articles in the sample of our review, in other previous studies, the therapeutic massage has been shown to increase blood and lymphatic circulation, decrease inflammation and edema, relax muscles, increase dopamine and serotonin levels and also the number of lymphocytes (41)(42)(43)(44) . In addition, from the reduction of cortisol levels, which are inversely associated with the activity of NK cells, and from the increase in serotonin and dopamine levels, which lead to a reduction in cortisol release (44) .
Other research studies on massage therapy have also shown improvements in pain, nausea and other symptoms, immediately and over time (45)(46) . The most consistent effect of massage has been to reduce the subjective degrees of anxiety, which can be more sensitive than the objective indicators for relaxation/ arousal (42) . In addition, a number of qualitative studies corroborate this potential of the massage to promote relaxation and feelings of well-being (41,47) .
Additionally, a systematic review identified six RCTs related to the relaxing effects of aromatherapy massage.
Three of these studies involved cancer patients and compared massage with and without the addition of essential oils. These studies suggest that aromatherapy massage may have a mild transient anxiolytic effect.
However, there was no evidence of a sustained effect over time, and no beneficial effect on depression (48) .
Contrary to the aforementioned findings, a study in our review found that adding lavender essential oil did not appear to increase the beneficial effects of the massage (35) . In line with this finding, there is a previous study that also did not detect statistically significant changes on cancer symptoms over time (49) . A recent systematic review pointed out that, when compared to ordinary massage alone, aromatherapy massage does not provide significant effectiveness in improving anxiety among cancer patients in palliative care (50) . It should be noted that one of the main limitations in examining the effectiveness of manual massage in cancer patients is the lack of standardization of its application (technique and dosage) and the difficulty of including a control group (51) .
In our review, the results of the study that evaluated the use of MR-IGI (progressive muscle relaxation and interactive guided image) was considered as an effective adjuvant in the relief of suffering related to cancer pain in these patients (40) . In line with this result is a randomized clinical trial that evaluated the effects of muscle relaxation and guided image in 80 women with breast cancer, before and after stress periods, specifically chemotherapy, radiotherapy, and surgery.
The results revealed that the use of this complementary therapy modality changed important responses of the immune system, leading to an increase in the number of activated T cells and in the NK cells' activity (52) . A pilot RCT conducted with 40 hospitalized cancer patients who investigated the contribution of PMR + IGI to pain relief, found significant differences in pain intensity in 31% of the PMR + IGI group versus 8% in the control group (53) .
As for the studies in our review that tested the use of acupuncture (38)(39) , they exhibited divergent results.
While a study indicated that si guanxue acupuncture plus the commonly used acupuncture points (PC6; ST36; SP6) tends to be effective in reducing cancer pain (38) , another study pointed out that, although the treatment with IA appeared to be viable and safe for patients with advanced cancer, it did not demonstrate significant differences in the groups (experimental and control) Rev. Latino-Am. Enfermagem 2020;28:e3377.
mainly due to the control group (Sham IA) limitation (39) . The authors concluded that auricular acupuncture was effective in reducing cancer pain in patients undergoing chemotherapy (7) . Acupuncture is one of the most popular forms of complementary medicine (29,55) and its use is mainly linked to improving the psychological symptoms through sympathomimetic pathways (56) . Traditional

Moreover
Chinese Acupuncture (TCA) is used as a complement to the conventional treatment for several pathological conditions and its focus is to relieve symptoms by reorganizing the body's energy, aiming at leading to selfhealing (55) . Sham Acupuncture (SA), also called placebo, can be understood as an intervention performed in a false way, as it is performed outside the points established by the TCA (57) . The scarcity of research studies with acceptable controls that actually mimic all aspects of the tested intervention has been the main methodological problem presented by the studies that use acupuncture as a therapy (29,57) .
This systematic review has some limitations.

Conclusion
The evidence from these six RCTs, mainly in three studies that evaluated the use of the massage therapy for cancer pain management in adults with cancer in palliative care, showed to be effective and promising for pain reduction. However, although the three studies that addressed massage therapies have positive results and the qualitative analysis of the review suggests the benefit of this practice in reducing cancer pain, the need for further studies with representative samples and rigorous methodological designs is highlighted in order to confirm such findings, since the three studies were evaluated with uncertain bias risk. Due to the fact that they exhibit opposite results, the two studies that evaluated the use of acupuncture as a complementary therapy were insufficient to accurately assert the efficacy of such therapy on the reduction of cancer pain, mainly because they differ on the methodological aspects (type of acupuncture, application techniques, and evaluated acupuncture points), therefore needing to get more evidence to elucidate such findings.