The effectiveness of complementary and alternative medicine therapy in reducing pain in diabetic neuropathy: A systematic review

Background: Pain is quite often felt in approximately 30 to 50% of people with diabetic neuropathy. As a result, the quality of life is low, indicated by the high morbidity and mortality rates. The availability of symptomatic pharmacological agents has the potential to have side effects and adverse effects in the elderly and in addition to the high risk of addiction. Complementary therapy and alternative medicine in chronic pain are clinically safe, cost-effective, and affordable. However, scientific evidence of its effectiveness is limited. Objective: This systematic review aims to evaluate the intervention modalities and the effectiveness of complementary and alternative medicine therapy in diabetic neuropathy pain. Methods: The searched literature databases included PubMed, ProQuest, ScienceDirect, EBSCO host, DOAJ, Clinical Key for Nursing, and Cochrane. The criteria for the article, among others, focus on complementary therapy and alternative medicine in diabetic neuropathy pain, publications in the last five years, full text, and in English. Results: Fifteen articles were identified in reporting the effectiveness of complementary therapy and alternative medicine in reducing diabetic neuropathy pain, including mindfulness-based stress reduction, mindfulness meditation, relaxation, whole-body vibration, Abzan, aerobic resistance training, nano curcumin, Citrullus colocynthis, dietary, acupuncture, laser, and reflexology. Conclusion: Most scientific evidence reports the effectiveness of complementary and alternative medicine therapies in reducing pain in diabetic neuropathy, thus strengthening its application as an adjunct to conventional medicine is needed.

Both pharmacological and nonpharmacological can treat pain. Pregabalin, Duloxetine, and Gabapentin are recommended as pharmacological treatments for DN pain (American Diabetes Association, 2020), but there is therapeutic intolerance (Spallone, Lacerenza, Rossi, Sicuteri, & Marchettini, 2012), high risk of addiction and side effects may be more severe in elderly (American Diabetes Association, 2020). The best combination therapy for DN pain management is needed (Peltier, Goutman, & Callaghan, 2014). In DN treatment, pain professionals have begun to combine complementary and alternative medicine (CAM) with conventional therapy (Lee & Raja, 2011). This is done in order for DN patients to receive additional therapy to reduce DN pain.
Several types of CAM therapy have advantages, including clinically safe and cost-effective acupuncture (Bašić-Kes et al., 2011), low-risk massage, and mind-body as one of the safest integrative therapies, especially for the elderly group (Bauer, Tilburt, Sood, Li, & Wang, 2016). Despite significant advances in therapy, symptomatic treatment for DN pain is less than optimal (Aslam et al., 2014). Further studies are needed for more effective treatment of DN pain (Tesfaye et al., 2011). RCTs and statistically significant results are required (Lee & Raja, 2011). But there is a gap in understanding the effectiveness of CAM therapy on DN pain. Therefore, this review aims to systematically evaluate the intervention modality and effectiveness of CAM in DN pain. assessed with a mean difference, confidence interval (CI), and p-value, reported in a narrative, qualitative manner by the author and two co-authors.

Ethical Consideration
Ethical Clearance was obtained from the Ethics Committee of the Hasanuddin University Faculty of Medicine with Ethical approval Recommendation Number: 794 / UN4.6.4.5.31 / PP36 / 2020.

Study Selection
Screening on seven databases identified 452 articles with human subjects. 33 duplicated articles, 398 irrelevant to the research question, three articles that were not full text, and three articles that were not English were excluded. Finally, only 15 articles met our review criteria (Figure 1).

Collected Study
These 13 RCT and 2 Pilot study RCT articles describe the effectiveness of CAM therapy in DN pain. Overall, the subjects used (n = 843) were distributed as follows, four studies from Iran, three studies from the United States, two studies from India, and one each from Canada, Pakistan, Turkey, Myanmar, KSA, and Egypt (Table 1).

Assessment of Study Feasibility
Fifteen studies were declared eligible and approved by the authors and two co-authors. However, two studies are not applicable using CASP (Shanb et al., 2020;Win, Fukai, Nyunt, & Linn, 2020).

Risk Bias on the Study
In the assessment of the risk of bias, it was found that the majority were with a moderate risk of bias (9 studies), a low risk of bias (5 studies), and a high risk of bias (1 study).

Characteristics of the CAM Intervention Sample on DN Pain
Most studies reported patients with DN pain, type 2 DM, VAS pain score of 4.83, pain duration of 6 to 12 years (Asadi et al., 2019). Most samples were 105 (Hussain & Said, 2019), with an average age of 59 years and 544 (64%) with the female gender.

Application Technique and Duration of CAM in DN Pain
A total of five studies provided 12 weeks of intervention, namely Mindfulness Meditation (Hussain & Said, 2019), hand and foot exercise (Win et al., 2020), acupuncture with 10-15 minute needle placement, and 20-40 minute needle retention (Chao et al., 2019). Progressive muscle relaxation at home 20 minutes via audio recording (Izgu et al., 2020) and deep tissue laser therapy (DTLT) 2 times a week (Chatterjee et al., 2019).
Five studies demonstrated the shortest duration of the intervention, the vibrating platform-style Whole Body Vibration (WBV) therapy, for four weeks (Kessler, Lockard, & Fischer, 2020). Undergoing therapy in warm water for four weeks every night before going to bed, both feet are soaked in a bath of 5 liters of warm water (Vakilinia et al., 2020). Undergo WBV therapy for six weeks consisting of warm-up, WBV, and cycling gradually over 5-10 minutes (Jamal et al., 2019). Two studies with an intervention duration of 8 weeks were undergoing mindfulness-based stress reduction (MBSR) workshops for eight weeks, 2.5 hours per session (Nathan et al., 2017), and undergoing 80 mg of curcumin nano therapy for eight weeks (Asadi et al., 2019). Four studies demonstrated the longest duration of the intervention: undergoing a combination of resistance-aerobic training for 16 consecutive weeks (Parsa, Hosseini, Bije, & Nia, 2018), following a low-fat plant-based diet for 20 weeks (Bunner et al., 2015); and undergoing 2 mL topical Citrullus colocynthis therapy for 36 weeks (Heydari, Homayouni, Hashempur, & Shams, 2016). Magnetic therapy was administered for 20 minutes/session for 36 weeks (Shanb et al., 2020) and underwent foot reflexology therapy 30 minutes/day for 48 weeks (Ibrahim & Rizk, 2018).

Design, Feasibility, and Bias Risk of the Study
The effectiveness of CAM for reducing DN pain has been identified and evaluated in this systematic review. All studies used an RCT design, with the majority of CAM therapies having a positive effect on DN pain reduction. RCT is the best type of study to determine causal between intervention and effect (Kabisch, Ruckes, Seibert-Grafe, & Blettner, 2011). In this review, the majority of studies were of moderate risk of bias. The unique strengths of randomization, allocating intervention and blinding to prevent bias (J. P. Higgins et al., 2016). However, one study of low-quality show concern for its applicability in clinical implications.

Sample on the Study
Most of the samples had type 2 diabetes, women, pain duration up to 12 years, and a mean age of 59. This is consistent with the previous theory that DN is more common in older adults (> 50 years) because of the time it takes for nerve damage and pain to occur (Zakin, Abrams, & Simpson, 2019), with an increased risk for type 2 DM patients, women, the prevalence of DN increases, and 23.5% after seven years (Iqbal et al., 2018). This suggests the need for early fuses, DN pain symptoms, especially in type 2 DM, to prevent the risk of complications.

Duration of Intervention and Pain Instruments in CAM Application
In this review, most of the studies performed CAM over 12 weeks and for pain instruments using VAS, NPS, NRS, McGill Pain Questionnaire, and LANSS. VAS, SF-MPQ are non-specific pain measurements (Nash, Armour, & Penkala, 2019). NPS and Neuropathic Pain Questionnaire (NPQ) measure the quality and intensity of DN pain (Bašić-Kes et al., 2011). Meanwhile, NRS, LANNS, and McGill Pain Questionnaire are validated, best and oldest measurements of neuropathic pain in a numerical rating scale (Tesfaye et al., 2011). This shows the importance of using proper pain measurement instruments in order to get accurate results.

Effects of CAM interventions on DN pain
The identification and evaluation of CAM interventions show significance in reducing DN pain, including MBSR, meditation, relaxation, WBV, Abzan, aerobic resistance training, and nano curcumin, Citrullus colocynthis, dietary, acupuncture, laser, and reflexology. According to previous studies, CAM intervention in the form of acupuncture and mind-body therapy showed its efficacy for chronic pain (Bauer et al., 2016), reflexology is an alternative non-pharmacological therapy in improving symptoms of peripheral DN (Çakici, Fakkel, Van Neck, Verhagen, & Coert, 2016). The more common plants for the treatment of neuropathic pain include Citrullus colocynthis (Forouzanfar & Hosseinzadeh, 2018). It can be concluded that CAM therapy can be said to be effective in reducing DN pain.
Seven other types of CAM interventions also have the effect of reducing DN pain, such as WBV, Abzan, exercise, relaxation, dietary, nano curcumin, and laser. WBV transfers energy with the benefit of glucose regulation (Baute, Zelnik, Curtis, & Sadeghifar, 2019). The relaxation response increases the brain's response to endorphins (Hassed, 2013). Consumption of a low-fat vegan diet can improve glucose tolerance and insulin sensitivity (Barnard, Scialli, Turner-McGrievy, Lanou, & Glass, 2005), and movement, especially aerobic exercise, has the ability to reduce distraction and pain perception (Baute et al., 2019). However, the most effective intervention in this review is Mindbody spirit meditation therapies, which reduce pain early on and have no side effects. Mind-body, one of the safest integrative therapies (Bauer et al., 2016), can be used in the management of chronic pain, sometimes as a single treatment but more commonly as an adjunct (Hassed, 2013). Ultimately, it can be given as an adjunct or alternative therapy for DN pain.

CAM Intervention Side Effects
Most studies reveal no side effects of CAM. As for the side effects that may occur, it is tolerable and does not require additional intervention. In accordance with previous studies that acupuncture is safe and clinically cost-effective, there is a risk of skin irritation, but this problem is relatively rare and easy to treat (Bašić-Kes et al., 2011). Diet modification, exercise, and lifestyle optimization with minimal side effects (Baute et al., 2019). Although most studies reveal the effect of CAM on reducing DN pain, the quality of the studies is moderate.

Strength and Limitation of the Study
To our knowledge, this is the first systematic review to evaluate the effectiveness of CAM therapy to reduce DN pain. In addition, we assessed the side effects of CAM in order to identify clinically safe interventions to generalize. Although the evaluation results of most CAM interventions have the effect of reducing DN pain, there are several limitations, such as the limited sample due to dropouts, no follow-up to confirm the effect of the intervention, the use of different pain measurement instruments. For this reason, a meta-analysis could not be done.

Conclusion
CAM therapy is effective at reducing DN pain and can be used as an adjunct to conventional treatments. However, further studies are needed with good study quality, large sample, the follow-up to further confirm the effectiveness of CAM interventions in reducing DN pain.

Declaration of Conflicting Interest
The authors declare no conflict of interest.

Funding
The study did not receive specific grants from funding agencies in the public, commercial, or nonprofit sectors.

Author Contribution
Designed and implemented the research (SS and SY), analyzed of the results (SS, SY, and YS), written the manuscript (SS), critically reviewed (SY) and revised the manuscript (SS). All authors agreed with the final version of the manuscript.