Review Article Systematic Review of the Use of Phytochemicals for Management of Pain in Cancer Therapy

Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 506327, 8 pages http://dx.doi.org/10.1155/2015/506327 Review Article Systematic Review of the Use of Phytochemicals for Management of Pain in Cancer Therapy Andrew M. Harrison,1 Fabrice Heritier,2 Bennett G. Childs,3 J. Michael Bostwick,4 and Mikhail A. Dziadzko5 1 Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55905, USA 2Department of Anesthesiology, CH du Forez, 42600 Montbrison, France 3Mayo Graduate School, Mayo Clinic, Rochester, MN 55905, USA 4Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN 55905, USA 5Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA Correspondence should be addressed to Mikhail A. Dziadzko; [email protected] Received 10 August 2015; Accepted 1 October 2015 Academic Editor: Sung-Hoon Kim Copyright © 2015 Andrew M. Harrison et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pain in cancer therapy is a common condition and there is a need for new options in therapeutic management. While phytochemicals have been proposed as one pain management solution, knowledge of their utility is limited. The objective of this study was to perform a systematic review of the biomedical literature for the use of phytochemicals for management of cancer therapy pain in human subjects. Of an initial database search of 1,603 abstracts, 32 full-text articles were eligible for further assessment. Only 7 of these articles met all inclusion criteria for this systematic review. The average relative risk of phytochemical versus control was 1.03 [95% CI 0.59 to 2.06]. In other words (although not statistically significant), patients treated with phytochemicals were slightly more likely than patients treated with control to obtain successful management of pain in cancer therapy. We identified a lack of quality research literature on this subject and thus were unable to demonstrate a clear therapeutic benefit for either general or specific use of phytochemicals in the management of cancer pain. This lack of data is especially apparent for psychotropic phytochemicals, such as the Cannabis plant (marijuana). Additional implications of our findings are also explored. 1. Introduction The use of phytochemical therapy for the treatment of cancer pain is further confounded by historical folklore and phy- Pooled prevalence of pain in cancer is greater than 50% [1]. tochemical isolates of poorly defined chemical composition. Thisdataisbasedonasystematicreviewof52research Specificplantsandthephytochemicalsfromtheseplantshave articles (out of a possible 4,737 articles) that spans 40 years of literature and includes patients after curative treatment, been investigated for their anti-inflammatory properties [4]. during cancer therapy, characterized as advanced/metastatic/ One example is the dried fruits of flowering shrub Carissa terminal disease, and/or at all disease stages. One reason carandas. In this case, a specific plant containing potentially for the low article inclusion rate in this systematic review numerous compounds active against pain, as opposed to a (1.1%) is the complex, multifactorial nature of cancer pain, specific phytochemical, was investigated. Numerous plants which includes different mechanisms and targets [2]. In the have also been used in traditional South African medicine context of this multifactorial nature and poor definition of for the treatment of pain [5]. However, rigorous scientific cancer pain, stringent inclusion criteria were another reason investigation into any specific phytochemicals these plants for this low article inclusion rate. Although phytochemical may contain for the specific treatment of pain is lacking. therapy has historically been used as a treatment for can- These examples are in contrast with examples of progress in cer, treatment of cancer pain in general is challenging [3]. chemotherapeutics. 2 BioMed Research International The need for new chemotherapeutic agents with 2.2. Data Sources and Searches. The internationally accepted increased efficacy and decreased toxicity has led tothe Preferred Reporting Items for Systematic Reviews and Meta- development of novel biologicals, such as antibody therapy, Analyses (PRISMA) standard was used for this systematic for the treatment of cancer [6]. This movement has resulted review [17, 18]. A comprehensive search of 4 databases was in some success, such as rituximab for the treatment of conducted: PubMed (the National Library of Medicine), Bcell-mediatedlymphomasandleukemias.Anextractof Ovid/MEDLINE (Wolters Kluwer), Scopus (Elsevier), and Toxicodendron vernicifluum (also known as Rhus verniciflua Web of Science (Thomson Reuters). English abstracts were Stokes and the Chinese lacquer tree) has been shown to searched from each database’s inception through July 01, induce growth inhibition and apoptosis of hepatic tumor cells 2015. The search strategy was designed and conducted in cell culture [7]. Likewise, ursolic acid—found in the waxy with a controlled vocabulary supplemented with keywords peels of fruits, as well as some herbs and spices—has been to search for studies of phytochemicals (“phytotherap*”, demonstrated to induce apoptosis of melanoma cells in cell “phytochemical*”, “plant”, and “plants”), fungochemicals culture [8]. Thus, evidence exists for the use of phytochemi- (mushr*), pain (“pain” and “nociception”), and cancer (“can- cals as novel chemotherapeutic agents. The molecular sig- cer” and “neoplas*”). Case reports, case series, case studies, naling pathways and other mechanisms explaining these controlled trials, and comparative studies were included in observations are slowly being elucidated [9, 10]. For example, this search strategy. Meta-analysis, reviews, commentaries, a variety of natural inhibitors of the STAT3 signaling path- and letters were excluded. All abstracts were screened by way, which results in the induction of apoptosis in both 1 reviewer (Mikhail A. Dziadzko) and potentially relevant hematological and solid tumor cells, have been identified. articles in human subjects were identified for full-text review Examples include betulinic acid, butein, caffeic acid, and cap- by 2 reviewers (Mikhail A. Dziadzko and Bennett G. Childs). saicin. However, the need for more agents with this level of success for the management of chemotherapeutic pain 2.3. Study Selection. A study was eligible for inclusion if it has resulted in other avenues of investigation [11], including examined the use of any phytochemical for the manage- phytochemicals and other natural products [12]. The ration- ment of pain in cancer therapy in human subjects. Only ale for this investigation includes epidemiological data from interventional (nonobservational) studies with controls were dietary intakes and in vitro experimentation. included. Phytochemical derivatives were excluded, as were While investigation into the use of phytochemicals for abstracts and articles not available in English. cancer chemotherapy is limited, exploration of phytochemicals for management of pain in cancer therapy is even 2.4. Data Extraction and Quality Assessment. The primary more lacking. Specific extracts of the plant Swertia corymbosa outcome of this systematic review was response to phyto- have been isolated, identified, and shown to have dose- chemicals in the management of pain in cancer therapy. dependent therapeutic effects in mouse and rat models for The Cochrane Collaboration tool for assessing risk of bias the management of convulsions, sedation, and anxiety [13]. wasutilizedtorankthequalityofthesepapers[19].Briefly, Numerous traditional herbs and phytochemicals have also this tool includes scoring for (1) sequence generation, (2) already been investigated at the level of in vivo experiments allocation concealment, (3) blinding of participants and and some clinical trials for neurodegenerative diseases, such personnel, (4) blinding of outcome assessors, (5) incomplete as Alzheimer’s disease [14]. In the context of these largely outcome data, (6) selective outcome reporting, and (7) other preclinical results, our objective was to perform a systematic sources of bias. The review of all full-text articles for inclusion review of the biomedical literature for the specific use of basedonthisCochraneCollaborationtoolwasperformedby phytochemicals for the management of pain in cancer therapy 2 reviewers (Mikhail A. Dziadzko and Fabrice Heritier). in human subjects. 2.5. Data Synthesis and Analysis. Data abstraction was coor- 2. Methods dinated and performed using the online systematic review 2.1. Background Definitions. One popular definition of phy- software Covidence (Alfred Health, Monash University, Mel- tochemicals (of the Kingdom Plantae) is “bioactive nonnu- bourne,Australia)[20].Foreachstudy,relativeriskwas trient plant compounds in fruits, vegetables, grains, and other calculated by extracting the number of patients with dichoto- plantfoodsthathavebeenlinkedtoreducingtheriskofmajor mous (binary) pain outcomes and comparing between the chronic diseases” [15]. For the purpose of this systematic control and exposure groups. Statistical analysis, as well as review, as described in the search strategy below and the forest plot and stacked bar chart generation, was performed Discussion, fungochemicals (of the Kingdom Fungi) were using JMP (SAS, Cary,

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