Effect of topical <i>Zingiber cassumunar</i> on painful diabetic neuropathy: a double-blind randomized-controlled trial

Nachapol Jatuten; Phuangthong Piyakunmala; Jiratha Budkaew; Bandit Chumworathayi

doi:10.12688/f1000research.131344.1

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Research Article

Clinical trial

Effect of topical Zingiber cassumunar on painful diabetic neuropathy: a double-blind randomized-controlled trial

[version 1; peer review: 1 approved with reservations]

Nachapol Jatuten¹, Phuangthong Piyakunmala², Jiratha Budkaew², Bandit Chumworathayi ³

PUBLISHED 24 Mar 2023

Author details Author details

¹ Selaphum Hospital, Selaphum District, Roi Et, 45120, Thailand
² Social Medicine, Khon Kaen Hospital, Muang District, Khon Kaen, 40000, Thailand
³ Obstetrics and Gynaecology,, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

Nachapol Jatuten
Roles: Conceptualization, Data Curation, Formal Analysis, Resources, Software, Writing – Original Draft Preparation

Phuangthong Piyakunmala
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology

Jiratha Budkaew
Roles: Project Administration, Resources, Software, Supervision, Validation, Visualization

Bandit Chumworathayi
Roles: Methodology, Supervision, Validation, Visualization, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Plai or Zingiber cassumunar Roxb. was registered into the Thai Traditional Medicine list since 2011. However, there is limited evidence regarding Plai as a treatment in painful diabetic neuropathy (PDN). Therefore, this study aimed to evaluate the efficacy of topical Zingiber cassumunar.
Methods: A RCT was conducted in patients with PDN during February to March 2019. All participants received oral gabapentin 300 mg before bed as a standard regimen. The intervention group (n=16) received Plai balm 15%w/w 0.5 gram to apply on their feet three times a day and the control group (n=15) received placebo balm to similarly apply. Pain score at baseline, 2^nd and 4^th weeks were assessed and compared. Patients’ quality of life, and adverse events, were collected. Mean pain scores before and after treatment in each group and between groups were also analyzed.
Results: At the end of week two and week four, the Plai group showed statistically significant lesser mean pain scores than the placebo group by -1.47 (95%CI: -1.96 to -1.30, p-value < 0.001), and by -1.51 (95%CI: -1.92 to -0.13, p-value = 0.027), respectively. Moreover, the Plai group had more cases number/ percentages with at least 50% pain score reduction than the placebo group [12/16 (75%) vs 3/15 (20%), p-value = 0.004]. However, there was no statistically significant difference in quality of life between the two groups (overall p-value = 0.366). Adverse event was not found in any groups.
Conclusions: Zingiber cassumunar balm (Plai) was efficacious for pain reduction in painful diabetic neuropathy.
Registration: Registered with the Thai Clinical Trials Registry; TCTR20200221001.

Keywords

Painful diabetic neuropathy, Zingiber cassumunar, Plai balm

Corresponding author: Bandit Chumworathayi

Competing interests: No competing interests were disclosed.

Grant information: This study was supported by Khon Kaen Hospital (research grant number KEXP62005). We confirm that the funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2023 Jatuten N et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Jatuten N, Piyakunmala P, Budkaew J and Chumworathayi B. Effect of topical Zingiber cassumunar on painful diabetic neuropathy: a double-blind randomized-controlled trial [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:334 (https://doi.org/10.12688/f1000research.131344.1) First published: 24 Mar 2023, 12:334 (https://doi.org/10.12688/f1000research.131344.1) Latest published: 13 Nov 2023, 12:334 (https://doi.org/10.12688/f1000research.131344.2)

Introduction

Diabetic polyneuropathy is one of the complications of diabetes mellitus. There are many signs and symptoms, such as painful diabetic neuropathy (PDN), orthostatic hypotension, cardiac autonomic neuropathy, foot injuries, and wounds.¹ The incidence of diabetic patients who have developed neuropathy, is approximately 20%. In addition, 50-70% of them must undergo surgery for non-traumatic amputation.²

PDN is the damage of nerves, that causes pain in the limbs. Patients will suffer from aching and feeling like shooting and stabbing pain. These symptoms will occur at the limbs during nighttime, and usually affect daily life activities, sleeping patterns and work, as a result, patient quality of life will be decreased.³^,⁴

Presently, non-steroidal analgesic medicines or opioids have been widely used for symptoms relieving. However, opioids are not only ineffective but have many side effects when treating PDN. Consequently, patients’ quality of life also decreases because of drug’s dosage-administration complexities, and long onset of action.⁵^–⁸ Capsaicin cream is effectively used for pain relief in PDN, but after a week, it might cause severe burn effect and finally require opioids for pain relief.⁹

Plai or Zingiber cassumunar Roxb. is registered on the Thai Traditional Medicine list since 2011,¹⁰ and categorized as a topical anti-inflammatory agent. The important extracted components from Zingiber cassumunar are (E)-4-(3, 4–dimethoxyphenyl) but-3-en-1-ol (compound D), (E)-1-(3, 4-dimethoxyphenyl) but-1, 3-diene (DMPBD) and zerumbone.¹¹ It has also been used for anti-inflammation,¹²^–¹⁵ pain relief,¹⁶^–¹⁹ and local anesthesia.²⁰^–²³

Although there were two successful studies of mixed multi-herbal preparation using Zingiber cassumunar Roxb. as its main component in treating diabetic foot ulcers,²⁴^,²⁵ there still has been no study regarding the use of Plai as a treatment in PDN. Therefore, this study aimed to evaluate the efficacy of a topical Zingiber cassumunar preparation by comparing with placebo on PDN.

Methods

Patients

This study was conducted at Selaphum Hospital, Selaphum District, Roi Et, Thailand. Participants were patients diagnosed with PDN. Neuropathic Pain Diagnostic Questionnaire (Thai version of DN4) was used for pain assessment,²⁶ and monofilament test was used as a sensory screening tool in these patients.⁸ Written informed consent was obtained from all patients.

Recruitment

Patients aged 20-60 years who had been diagnosed with diabetic mellitus for at least 1 year, tested for HbA1c within six months, suffering from pain intensity on a scale as moderate or more [Numerical Rating Scale (NRS), pain score ≥ 4], and with defined positive monofilament test result, were included. Patients who had been diagnosed with diabetic mellitus less than one year, with other caused neuropathy, clinically significant cardiovascular, foot ulcer and/or infection, pregnancy and lactation, and allergy to Plai, were excluded.

Study design and oversight

This double-blind randomized-controlled trial was conducted within four weeks, from the 1^st of February to the 1^st of March 2019. All the authors were involved in the design and performance of the study, which was conducted according to the Declaration of Helsinki. The Khon Kaen Hospital Institute Review Board (KKHIRB) in Human Research (the oversighting IRB for Selaphum Hospital) approved the study protocol on 19^th December 2018 (KE61099). This trial was retrospectively registered with the Thai Clinical Trial Registry (TCTR20200221001) on 19^th February 2020, because “registration before recruitment” was missed, but authors finally registered it within one year after completion. Registration before recruitment is not a prerequisite for KKHIRB or Selaphum Hospital’s study. The study protocol did not differ from the registered one.

Study treatment and procedures

Pain assessment was commenced at week 0 and indicated by using The World Health Organization Quality of Life (WHOQOL-BREF–THAI)²⁷ with NRS, pain characteristic, and pain mapping to follow-up side effect of Plai and its adverse events as baseline. Consequently, patients returned to clinic at the following week one, two, and four, to monitor and assess the accuracy of practice on frequency, and dosage of balms’ use. The patients’ quality of life in week 4 were observed and recorded.

Block-of-four randomization was applied to this study, concealment was done by telephone calls to research assistants. Participants were divided into two groups. All participants received oral gabapentin of 300 mg, one tablet a day before bedtime as a standard regimen. The intervention group (n=16) received Plai balm 15% w/w 0.5 gram to apply on their feet three times a day and the control group (n=15) received the placebo balm to apply similarly.

Endpoints

The mean differences of pain scores in NRS at week two and four between the two groups were the first endpoint. The other endpoint was the comparison of patients’ numbers/percentages who have at least 50% pain reduction at week two and four between the groups. Additionally, The World Health Organization Quality of Life (WHOQOL- BREF–THAI) scores changes at week four were compared between the groups.

Statistical analysis

The preliminary study suggests that the number of participants should be 24-36 people. Consequently, this study recruited 35 participants, which were divided in to two groups. Generalized estimating equation (GEE) was used to analyze the mean differences of pain scores at week two and four. Fisher’s exact test was used to analyze the differences in patients’ numbers/percentages who had at least 50% pain reduction at week two and four between the groups. Independent t-test was used to analyze the differences of The World Health Organization Quality of Life (WHOQOL-BREF–THAI) scores changes at week four between the groups. Mann-Whitney U-test was used to compare skew continuous data.

Results

Study patients

There were 826 diabetic mellitus type 2 patients treated at Selaphum Hospital during the study period. Although 88 of them had developed PDN, only 46 patients were able to participate according to the age criteria. Eleven of them were later excluded by other exclusion criteria. As a result, 35 of them were randomly assigned to each group. The intervention group had 18 participants receiving Plai balm, and the control group had 17 participants receiving placebo balm. Two participants in each group were later excluded due to follow-up loss (Figure 1).

Figure 1. CONSORT flow diagram.

The patients’ characteristics, pain characteristics, and pain mapping of PDN at baseline, were similar among the two groups (Tables 1, 1.1, and 1.2).

Table 1. Baseline characteristics of the patients.

Patients’ characteristics	Plai (n=16)		Placebo (n=15)		P-value
Patients’ characteristics	Number	Percent	Number	Percent	P-value
Age (years)^§					0.064
Lower than 50	2	12.50	4	26.67
51 or more	14	87.50	11	73.33
Mean (±SD)	55.56	(±5.43)	52.87	(±5.57)
Median (min:max)	58	(39:59)	54	(39:59)
Gender**					0.561
Male	7	43.75	6	40.00
Female	9	56.25	9	60.00
Duration of diabetes (years)^¶					0.611
Lower than 5	6	37.50	4	26.67
6 or more	10	62.50	11	73.33
Mean (±SD)	7.50	(±3.29)	8.07	(±2.81)
Median (min:max)	6.50	(3:12)	8.00	(4:12)
Duration of PDN (years)^§					0.662
Lower than 1	8	50.0	8	53.33
2 or more	8	50.0	7	46.67
Mean (±SD)	1.88	(±1.31)	1.67	(±1.05)
Median (min:max)	1.5	(1:6)	8.00	(1:5)
History of hypertension**					0.561
Yes	9	56.25	9	60.00
No	7	43.75	6	40.00
HbA1c at screening^¶					0.534
Mean (±SD)	11.09	(±2.14)	10.59	(±2.22)
Median (min:max)	10.9	(8.3:16.6)	8.00	(7:15.1)
Baseline average daily pain^§					0.280
Mean (±SD)	6.81	(±1.47)	6.33	(±1.59)
Median (min:max)	6.5	(5:10)	6	(5:9)
NSAIDs					0.525
Yes	2	12.50	1	6.67
No	14	87.50	14	93.33
Opioids**					0.475
Yes	1	6.25	2	13.33
No	15	93.75	13	86.67

¶ Independent t-test.

§ Mann-Whitney U-test.

** Fisher’s exact test.

Table 1.1. Baseline pain characteristics of PDN.

Pain characteristics	Plai (n=16)		Placebo (n=15)
	Frequency	Intensity	Frequency	Intensity
	(Percent)	(Mean±SD)	(Percent)	(Mean±SD)
1. Throbbing	6 (37.5)	1.44±0.55	11 (73.33)	1.45±0.52
2. Shooting	12 (75)	1.92±0.79	12 (80.0)	1.33±0.49
3. Stabbing	10 (62.5)	1.70±0.67	4 (26.67)	1.75±0.5
4. Sharp	12 (75)	2±0.60	11 (73.33)	1.36±0.50
5. Cramping	4 (25)	2±0.81	5 (33.33)	2±0.71
6. Gnawing	6 (37.5)	1.83±0.98	6 (40.0)	1±0
7. Burning	7 (43.75)	1.86±0.38	11 (73.33)	1.45±0.68
8. Aching	7 (43.75)	1.43± 0.53	4 (26.67)	1.45±0.53
9. Heavy	5 (31.25)	1.6±0.55	4 (26.67)	2±0.81
10. Tender	3 (18.75)	1.67±0.58	7 (46.67)	2.75±0.5
11. Splitting	2 (12.50)	1.5±0.7	2 (13.33)	2.5±0.71
12. Exhausting	10 (62.5)	1.7±0.67	6 (40.0)	1.83±0.75
13. Fearful	6 (37.5)	1.83±0.75	3 (20.0)	2±1
14. Sickening	15 (93.75)	1.73±0.59	14 (93.33)	1.57±0.85
15. Punishing-Cruel	13 (81.25)	1.54±0.66	12 (80.0)	1.5±0.79

Table 1.2. Baseline pain mappings of PDN.

Pain mappings	Plai (n=16)		Placebo (n=15)
Pain mappings	Number	Percent	Number	Percent
Posterior ankle pain	12	75.00	12	80.00
Lateral ankle pain	12	75.00	12	80.00
Medial ankle pain	10	62.50	10	66.67
Anterior ankle pain	10	62.50	10	66.67
Dorsal forefoot pain	16	100.00	15	100.00
Dorsal great toe pain	16	100.00	15	100.00
Dorsal lesser toe pain	16	100.00	15	100.00
Metatarsal head pain	13	81.25	15	100.00
Plantar great toe pain	16	100.00	15	100.00
Plantar lesser toe pain	12	75.00	14	93.33
Plantar midfoot pain	16	100.00	15	100.00
Heel pain	16	100.00	15	100.00

Primary outcomes

The mean changes of pain scores in each group were significantly decreased. The mean changes of pain score in the Plai group decreased by -3.00 (95%CI: -3.58 to -2.41, p-value <0.001) at week two, and by -3.44 (95%CI: -3.87 to -3.00, p-value <0.001) at week four. The mean changes of pain score in the placebo group also decreased by -1.53 (-95%CI: 2.08 to -0.98, p-value <0.001) at week two, and by -1.93 (95%CI: -2.46 to -1.40, p-value <0.001) at week four (Table 2).

Table 2. Mean changes of NRS scores in each groups.

Groups	Baseline Mean (SD)	Week 2 Mean (SD)	Week 4 Mean (SD)	Week 2		Week 4
Groups	Baseline Mean (SD)	Week 2 Mean (SD)	Week 4 Mean (SD)	Mean change* (95%CI)	P-value	Mean change* (95% CI)	P-value
Plai	6.81 (1.47)	3.81 (1.04)	3.38 (1.02)	-3.00 (-3.58 to -2.41)	<0.001	-3.44 (-3.87 to -3.00)	<0.001
Placebo	6.33 (1.59)	4.8 (1.57)	4.4 (1.40)	-1.53 (-2.08 to -0.98)	<0.001	-1.93 (-2.46 to -1.40)	<0.001

* Paired-T test.

Using GEE analyses by controlling confounding factors (age, sex, quality of life score), showed that the Plai group had statistically significant less pain at week two by -1.47 (95%CI: -1.96 to -1.30, p-value <0.001) when compared to the placebo group. At week four, the Plai group’s pain score was still decreasing and statistically significant less than the placebo group by -1.51 (95%CI: -1.92 to -0.13, p-value <0.027) (Table 2.1).

Table 2.1. Mean of NRS scores differences between groups at week 2 and 4.

NRS differences	Week 2			Week 4
NRS differences	Plai (n=16)	Placebo (n=15)	P-value	Plai (n=16)	Placebo (n=15)	P-value
Mean^a (95%CI)	-1.47 (-1.96 to -1.30)		0.001	-1.51 (-1.92 to -0.13)		0.027

a Generalized estimating equations (GEE).

Secondary outcomes

Numbers/percentages of patients who had at least 50% pain reduction of pain by NRS scores at week four were found significantly more in the Plai group when compared to the placebo group [12/16 (75%) vs 3/15 (20%), p-value = 0.004] (Table 3).

Table 3. Numbers/percentages of patients who had at least 50% pain reduction in each groups at week 4.

Pain reduction amount	Groups		P-value
Pain reduction amount	Plai, n (%)	Placebo, n (%)	P-value
≥50%	12 (75.00)	3 (20.00)	0.004
<50%	4 (25.00)	12 (80.00)	0.004

The overall integration of WHOQOL- BREF–THAI 4 components was used. Physical domain, psychological domain, social relationships, and environmental domain analyzed patients’ quality of life scores at week four. Overall and each domain’s patients’ quality of life scores were no different between the two groups (Table 4).

Table 4. WHOQOL-BREF–THAI scores in each groups at week 4.

WHOQOL-BREF domain	$\bar{X}$	SD	Mean difference	95%CI	P-value
Physical
Plai	14.12	0.60	-1.74	-3.49 to 0.01	0.0504
Placebo	15.87	0.60
Psychological
Plai	20.56	0.96	-0.30	-3.21 to 2.60	0.832
Placebo	20.86	1.05
Social
Plai	10.875	0.24	-0.32	-0.99 to 0.34	0.329
Placebo	11.2	0.22
Environmental
Plai	26.25	0.61	0.52	-1.25 to 2.28	0.555
Placebo	25.73	0.61
Overall
Plai	71.81	1.48	-1.85	-5.98 to 2.28	0.366
Placebo	73.67	1.37

Adverse events

No adverse events such as edema, erythema, papules, pruritus, and burning sensation, were found in this study.

Discussion

This double-blind randomized-controlled trial was conducted in PDN patients who had pain by NRS scores of four or more within four weeks, from the 1^st February to the 1^st March 2019 at Selaphum Hospital, Selaphum District, Roi Et, Thailand. Majority of participants were elderly female patients who had been diagnosed with poor controlled type 2 diabetic mellitus for years. Those patients met the criteria of having PDN, which obviously presented similar pain characteristics and pain mapping between the groups.

Based on this study’s method, all participants received oral gabapentin 300 mg, 1 tablet daily before bed as a standard regimen. The use of Plai balm 15% w/w 0.5 gram significantly showed pain reduction on PDN. The pain scores by NRS were decreased more in the Plai group compared to the placebo group [by mean differences of -1.47 (95%CI: -1.96 to -1.30, p-value <0.001) at week two, and by mean difference of -1.51 (95%CI: -1.92 to -0.13, p-value = 0.027) at week four]. These results derived from the effects of Plai balm on PDN.

Until now (December 2022), there has been no other trial that studied the efficacy of Plai on reducing pain in PDN. However, previous studies had shown that Plai being main component in mixed herbal preparations, is safe²⁴ and effective²⁵ in treating diabetic foot ulcers. Moreover, Plai has local anesthetic²⁰^–²³ and neuroprotective²⁸ effects, in addition to its effects on anti-inflammation¹²^–¹⁵ and pain relief.¹⁶^–¹⁹ These mechanisms in combination, might be the cause of pain reduction. Nevertheless, this study has been the first one to show the effect on PDN. Whether a neuroprotective effect also occurs in the peripheral nerves, is needed to be investigated.

In this study, not only Plai was found to be effective in pain reduction, but also safe with no adverse event reported, neither redness, swelling, burning or rash. These were similar to a systematic review done in 2017 by Chongmelaxme et al.¹⁵ Even in two more recent studies, with very similar application but more mixed herbs, adverse events were still not found.²⁴^,²⁵ However, quality of life scores were not significantly different between groups at week 4, even though the quality-of-life scores were improved in each groups. This could be explained by the standard treatment both groups had received: 300 mg gabapentin, once a day. This might be also the main reason for similar changes in the quality-of-life scores.

Strengths of this study were 1) This has been the first RCT comparing treatment efficacy of Plai to placebo, 2) Pain reduction was found significantly different between the groups, and 3) Pain and quality of life scores were measured, reported, and analyzed using their standard methods. Weaknesses of this study might be that; 1) It has low sample size, 2) Some patients were lost from each group, and 3) Cost-effectiveness was not collected and analyzed. Future research with similar objectives may be conducted with larger sample sizes and more diverse settings.

Conclusion

In conclusion, Zingiber cassumunar balm (Plai) was efficacious and safe for reducing pain in patients with painful diabetic neuropathy (PDN). However, quality of life scores changes in the Plai group were not significantly different from the placebo group.

Data availability

Underlying data

Figshare. Zingiber cassumunar Dataset. DOI: https://doi.org/10.6084/m9.figshare.21805182.v1.²⁹

This project contains the following data:

- This is the dataset of the research titled “Effect of topical Zingiber cassumunar on painful diabetic neuropathy: A double-blind randomized-controlled trial”

Figshare. Zingiber cassumunar Protocol. DOI: https://doi.org/10.6084/m9.figshare.22180675.v1.³⁰

- This is the protocol of an RCT on Zingiber cassumunar for painful diabetic neuropathy (PDN).

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Reporting guidelines

Figshare. Zingiber CONSORT Checklist. DOI: https://doi.org/10.6084/m9.figshare.22046570.v1.³¹

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Acknowledgements

Authors appreciate all supports from Selaphum Hospital, Selaphum District, Roi Et, Thailand, patients, volunteers, and all the staffs of all clinics involving in this study. Authors are grateful to Dr Jitjira Chaiyarit, biostatistician/epidemiologist, in helpful analysis and interpreting of the results. The authors also thank Mr Dirk Krapf for the English editing of the manuscript. This study was scientifically approved by the Postgraduate Committee of Medication Education Center, Khon Kaen Hospital, as the Family Medicine Board thesis of Dr Nachapol Jatuten (NJ). The authors have no financial or other conflict of interests to declare. Ethical justification of this study was also approved by Office of the Khon Kaen Hospital Institute Review Board in Human Research (the oversighting IRB for Selaphum Hospital) on 19^th December 2018 (KE61099).

NJ contributed to the conception, design, data analysis, proposal and manuscript writing. PP contributed to the conception and design, data acquisition, analysis and interpretation of the data, and drafting of the article. JB contributed to the conception, design, and data acquisition. BC contributed to the conception, design, methodological supervision, literature review, and revisions. All authors approved the final version of the manuscript before submission. Underlying data of this study are available via link below (Dataset). This study was also registered in the TCTR database (www.thaiclinicaltrials.org), No. TCTR20200221001.

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20. Anantasan V, Asayakun S: Study on the local anesthetic effect of squeezed Zingiber cassumuna Roxb. Chiang Mai Med. Bull. 1971; 10: 10–23.
21. Khalid MH, Akhtar MN, Mohamad AS, et al.: Antinociceptive effect of the essential oil of Zingiber zerumbet in mice: possible mechanisms. J. Ethnopharmacol. 2011; 137: 345–351. Publisher Full Text
22. Zulazmi NA, Gopalsamy B, Farouk AA, et al.: Antiallodynic and antihyperalgesic effects of zerumbone on a mouse model of chronic constriction injury-induced neuropathic pain. Fitoterapia. 2015; 105: 215–221. PubMed Abstract | Publisher Full Text
23. Chia JSM, Omar Farouk AA, Mohamad AS, et al.: Zerumbone alleviates chronic constriction injury-induced allodynia and hyperalgesia through serotonin 5-HT receptors. Biomed. Pharmacother. 2016; 83: 1303–1310. PubMed Abstract | Publisher Full Text
24. Hirunsirivat S, Tungsukruthai P, Tharavanij T, et al.: Safety of yellow surat cream in healthy participants (clinical trial phase 1). Walailak Procedia. 2019; 1: ic4ir.183.
25. Chumpolphant S, Suwatronnakorn M, Issaravanich S, et al.: Polyherbal formulation exerts wound healing, anti-inflammatory, angiogenic and antimicrobial properties: Potential role in the treatment of diabetic foot ulcers. Saudi J. Biol. Sci. 2022; 29: 103330. PubMed Abstract | Publisher Full Text | Free Full Text
26. Chaudakshetrin P, Prateepavanich P, Chira-Adisai W, et al.: Cross-cultural adaptation to the Thai language of the neuropathic pain diagnostic questionnaire (DN4). J. Med. Assoc. Thail. 2007; 90: 1860–1865.
27. Taboonpong S, Suttharangsee W, Chailangka P: Evaluating psychometric properties of WHO quality of life questionnaire in Thai elderly. J. Gerontol. Geriatric. Med. 2001; 2: 6–12.
28. Kongsui R, Sriraksa N, Thongrong S: The Neuroprotective Effect of Zingiber cassumunar Roxb. Extract on LPS-Induced Neuronal Cell Loss and Astroglial Activation within the Hippocampus. Biomed. Res. Int. 2020; 2020: 4259316.
29. Chumworathayi B: Zingiber cassumunar Dataset. Dataset. figshare. 2023. Accessed on 3^rd January 2023. Publisher Full Text Reference Source
30. Chumworathayi B: Zingiber cassumunar Protocol. figshare. Online resource. Accessed on 27^th February 2023. Publisher Full Text Reference Source
31. Chumworathayi B: Zingiber CONSORT Checklist. figshare. Online resource. Accessed on 8^th February 2023. Publisher Full Text Reference Source

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Version 2

VERSION 2 PUBLISHED 24 Mar 2023

Author details Author details

Nachapol Jatuten
Roles: Conceptualization, Data Curation, Formal Analysis, Resources, Software, Writing – Original Draft Preparation

Phuangthong Piyakunmala
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology

Jiratha Budkaew
Roles: Project Administration, Resources, Software, Supervision, Validation, Visualization

Bandit Chumworathayi
Roles: Methodology, Supervision, Validation, Visualization, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

This study was supported by Khon Kaen Hospital (research grant number KEXP62005). We confirm that the funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

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Published: 13 Nov 2023, 12:334

https://doi.org/10.12688/f1000research.131344.2

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Published: 24 Mar 2023, 12:334

https://doi.org/10.12688/f1000research.131344.1

© 2023 Jatuten N et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Jatuten N, Piyakunmala P, Budkaew J and Chumworathayi B. Effect of topical Zingiber cassumunar on painful diabetic neuropathy: a double-blind randomized-controlled trial [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:334 (https://doi.org/10.12688/f1000research.131344.1)

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PUBLISHED 24 Mar 2023

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Reviewer Report 21 Aug 2023

Fifteen Aprila Fajrin, Clinical and Community Department, Faculty of Pharmacy, Universitas Jember, Jember, East Java, Indonesia

Approved with Reservations

https://doi.org/10.5256/f1000research.144178.r193436

I think the author has conducted this research well. But it needs some explanation for the following area:

There is no detail about the preparation of topical Zingiber cassumunar. And what is the composition of Plai

I think the author has conducted this research well. But it needs some explanation for the following area:

There is no detail about the preparation of topical Zingiber cassumunar. And what is the composition of Plai balm, just Zingiber cassumunar or there are some active plants?
The author needs to explain why patients were excluded from this research and give detailed explanations.
In the result, I found the adverse events, but in the methods, there was no description of how this test was performed and also the assessment.
Almost half of the references are too old, the author can choose another reference that is more up-to-date.
The author needs to explain the limitation of this study.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Molecular Pharmacology, neuropharmacology.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Author Response 20 Nov 2023

Bandit Chumworathayi, Obstetrics and Gynaecology,, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

20 Nov 2023

Author Response

Responses to Reviewer #1
Thank you very much for your kind comments and suggestions. Authors would like to response them as follows.
1.0. I think the author has conducted this ... Continue reading Responses to Reviewer #1
Thank you very much for your kind comments and suggestions. Authors would like to response them as follows.
1.0. I think the author has conducted this research well. But it needs some explanation for the following area:
Response: Thank you for your admiration that we did this research well. More explanations are followed.
1.1. There is no detail about the preparation of topical Zingiber cassumunar. And what is the composition of Plai balm, just Zingiber cassumunar or there are some active plants?
Response: The detail of preparation was added to the Methods, and the composition of Plai balm was as the following table, other active plants (paraffin, Vaseline, camphor, Borneo camphor, menthol, and wintergreen oil) were similar, but with more paraffin and Vaseline added, to the placebo.
Composition
Plai balm 15%w/w
Paraffin 10 g
Vaseline 50 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 15 g
Placebo
Paraffin 15 g
Vaseline 60 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 0 g
1.2. The author needs to explain why patients were excluded from this research and give detailed explanations.
Response: From 11 excluded patients, the detailed explanations, that were lost, are as follows, and we have added them to the Results.
• Did not meet inclusion criteria (foot ulcer, n=2)
• Declined to participate (n=9)
1.3. In the result, I found the adverse events, but in the Methods, there was no description of how this test was performed and also the assessment.
Response: Data about adverse events such as burning sensation and pruritus were collected by history taking and examination at week 1, 2, and 4, similar to the primary outcomes [references number 8 (monofilament test) and 26 (Thai version of DN4)], but edema/ erythema/ papules were collected by visual examination when patient followed up. We have added these processes into the Methods (Study treatment and procedures).
1.4. Almost half of the references are too old, the author can choose another reference that is more up-to-date.
Response: On November 7, 2023, we have re-searched for relevant published papers in PubMed by using the terms “Zingiber cassumunar” AND “painful diabetic neuropathy”, and retrieved zero results. We re-tried with only “Zingiber cassumunar”, and retrieved 85 but no one was relevant. We have tried again in “Google Scholar”, but no one was relevant in this topic too.
1.5. The author needs to explain the limitation of this study.
Response: In addition to weaknesses, we have added accordingly in the last paragraph of the Discussion.
Responses to Reviewer #1
Thank you very much for your kind comments and suggestions. Authors would like to response them as follows.
1.0. I think the author has conducted this research well. But it needs some explanation for the following area:
Response: Thank you for your admiration that we did this research well. More explanations are followed.
1.1. There is no detail about the preparation of topical Zingiber cassumunar. And what is the composition of Plai balm, just Zingiber cassumunar or there are some active plants?
Response: The detail of preparation was added to the Methods, and the composition of Plai balm was as the following table, other active plants (paraffin, Vaseline, camphor, Borneo camphor, menthol, and wintergreen oil) were similar, but with more paraffin and Vaseline added, to the placebo.
Composition
Plai balm 15%w/w
Paraffin 10 g
Vaseline 50 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 15 g
Placebo
Paraffin 15 g
Vaseline 60 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 0 g
1.2. The author needs to explain why patients were excluded from this research and give detailed explanations.
Response: From 11 excluded patients, the detailed explanations, that were lost, are as follows, and we have added them to the Results.
• Did not meet inclusion criteria (foot ulcer, n=2)
• Declined to participate (n=9)
1.3. In the result, I found the adverse events, but in the Methods, there was no description of how this test was performed and also the assessment.
Response: Data about adverse events such as burning sensation and pruritus were collected by history taking and examination at week 1, 2, and 4, similar to the primary outcomes [references number 8 (monofilament test) and 26 (Thai version of DN4)], but edema/ erythema/ papules were collected by visual examination when patient followed up. We have added these processes into the Methods (Study treatment and procedures).
1.4. Almost half of the references are too old, the author can choose another reference that is more up-to-date.
Response: On November 7, 2023, we have re-searched for relevant published papers in PubMed by using the terms “Zingiber cassumunar” AND “painful diabetic neuropathy”, and retrieved zero results. We re-tried with only “Zingiber cassumunar”, and retrieved 85 but no one was relevant. We have tried again in “Google Scholar”, but no one was relevant in this topic too.
1.5. The author needs to explain the limitation of this study.
Response: In addition to weaknesses, we have added accordingly in the last paragraph of the Discussion.
Competing Interests: Authors declare no competing interest. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 20 Nov 2023

Bandit Chumworathayi, Obstetrics and Gynaecology,, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

20 Nov 2023

Author Response

Responses to Reviewer #1
Thank you very much for your kind comments and suggestions. Authors would like to response them as follows.
1.0. I think the author has conducted this ... Continue reading Responses to Reviewer #1
Thank you very much for your kind comments and suggestions. Authors would like to response them as follows.
1.0. I think the author has conducted this research well. But it needs some explanation for the following area:
Response: Thank you for your admiration that we did this research well. More explanations are followed.
1.1. There is no detail about the preparation of topical Zingiber cassumunar. And what is the composition of Plai balm, just Zingiber cassumunar or there are some active plants?
Response: The detail of preparation was added to the Methods, and the composition of Plai balm was as the following table, other active plants (paraffin, Vaseline, camphor, Borneo camphor, menthol, and wintergreen oil) were similar, but with more paraffin and Vaseline added, to the placebo.
Composition
Plai balm 15%w/w
Paraffin 10 g
Vaseline 50 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 15 g
Placebo
Paraffin 15 g
Vaseline 60 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 0 g
1.2. The author needs to explain why patients were excluded from this research and give detailed explanations.
Response: From 11 excluded patients, the detailed explanations, that were lost, are as follows, and we have added them to the Results.
• Did not meet inclusion criteria (foot ulcer, n=2)
• Declined to participate (n=9)
1.3. In the result, I found the adverse events, but in the Methods, there was no description of how this test was performed and also the assessment.
Response: Data about adverse events such as burning sensation and pruritus were collected by history taking and examination at week 1, 2, and 4, similar to the primary outcomes [references number 8 (monofilament test) and 26 (Thai version of DN4)], but edema/ erythema/ papules were collected by visual examination when patient followed up. We have added these processes into the Methods (Study treatment and procedures).
1.4. Almost half of the references are too old, the author can choose another reference that is more up-to-date.
Response: On November 7, 2023, we have re-searched for relevant published papers in PubMed by using the terms “Zingiber cassumunar” AND “painful diabetic neuropathy”, and retrieved zero results. We re-tried with only “Zingiber cassumunar”, and retrieved 85 but no one was relevant. We have tried again in “Google Scholar”, but no one was relevant in this topic too.
1.5. The author needs to explain the limitation of this study.
Response: In addition to weaknesses, we have added accordingly in the last paragraph of the Discussion.
Responses to Reviewer #1
Thank you very much for your kind comments and suggestions. Authors would like to response them as follows.
1.0. I think the author has conducted this research well. But it needs some explanation for the following area:
Response: Thank you for your admiration that we did this research well. More explanations are followed.
1.1. There is no detail about the preparation of topical Zingiber cassumunar. And what is the composition of Plai balm, just Zingiber cassumunar or there are some active plants?
Response: The detail of preparation was added to the Methods, and the composition of Plai balm was as the following table, other active plants (paraffin, Vaseline, camphor, Borneo camphor, menthol, and wintergreen oil) were similar, but with more paraffin and Vaseline added, to the placebo.
Composition
Plai balm 15%w/w
Paraffin 10 g
Vaseline 50 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 15 g
Placebo
Paraffin 15 g
Vaseline 60 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 0 g
1.2. The author needs to explain why patients were excluded from this research and give detailed explanations.
Response: From 11 excluded patients, the detailed explanations, that were lost, are as follows, and we have added them to the Results.
• Did not meet inclusion criteria (foot ulcer, n=2)
• Declined to participate (n=9)
1.3. In the result, I found the adverse events, but in the Methods, there was no description of how this test was performed and also the assessment.
Response: Data about adverse events such as burning sensation and pruritus were collected by history taking and examination at week 1, 2, and 4, similar to the primary outcomes [references number 8 (monofilament test) and 26 (Thai version of DN4)], but edema/ erythema/ papules were collected by visual examination when patient followed up. We have added these processes into the Methods (Study treatment and procedures).
1.4. Almost half of the references are too old, the author can choose another reference that is more up-to-date.
Response: On November 7, 2023, we have re-searched for relevant published papers in PubMed by using the terms “Zingiber cassumunar” AND “painful diabetic neuropathy”, and retrieved zero results. We re-tried with only “Zingiber cassumunar”, and retrieved 85 but no one was relevant. We have tried again in “Google Scholar”, but no one was relevant in this topic too.
1.5. The author needs to explain the limitation of this study.
Response: In addition to weaknesses, we have added accordingly in the last paragraph of the Discussion.
Competing Interests: Authors declare no competing interest. Close
Report a concern

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Version 2

VERSION 2 PUBLISHED 24 Mar 2023

Open Peer Review

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	Invited Reviewers
	1	2
Version 2 (revision) 13 Nov 23	read	read
Version 1 24 Mar 23	read

Fifteen Aprila Fajrin, Universitas Jember, Jember, Indonesia
Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, Indonesia

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Reviewer Report

3 Views

30 Aug 2024 | for Version 2

Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, East Java, Indonesia

3 Views Cite this report Responses(1)

Approved

Relevance to Traditional Medicine: The study focuses on Zingiber cassumunar (Plai), which has been recognized in the Thai Traditional Medicine list since 2011. This adds significant relevance to the research, as it explores a plant with established traditional use.
Scientific Validation: Evaluating the efficacy of topical Zingiber cassumunar is crucial for bridging the gap between traditional knowledge and modern medicine. The study contributes to validating and potentially integrating traditional remedies into contemporary therapeutic practices.
Potential Impact: If the study demonstrates the efficacy of Zingiber cassumunar, it could lead to broader acceptance and usage of this traditional remedy, benefiting both healthcare providers and patients seeking alternative or complementary treatments.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Plant Extracts

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

9 Views

16 Nov 2023 | for Version 2

Fifteen Aprila Fajrin, Clinical and Community Department, Faculty of Pharmacy, Universitas Jember, Jember, East Java, Indonesia

9 Views Cite this report Responses(0)

Approved

Thank you for the revision, I think it is detailed enough to answer all my questions.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Molecular Pharmacology, neuropharmacology.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

10 Views

21 Aug 2023 | for Version 1

Fifteen Aprila Fajrin, Clinical and Community Department, Faculty of Pharmacy, Universitas Jember, Jember, East Java, Indonesia

10 Views Cite this report Responses(1)

Approved With Reservations

I think the author has conducted this research well. But it needs some explanation for the following area:

There is no detail about the preparation of topical Zingiber cassumunar. And what is the composition of Plai balm, just Zingiber cassumunar or there are some active plants?
The author needs to explain why patients were excluded from this research and give detailed explanations.
In the result, I found the adverse events, but in the methods, there was no description of how this test was performed and also the assessment.
Almost half of the references are too old, the author can choose another reference that is more up-to-date.
The author needs to explain the limitation of this study.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Yes
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Molecular Pharmacology, neuropharmacology.

Respond to this report

Responses (1)

Author Response

20 Nov 2023

Bandit Chumworathayi, Obstetrics and Gynaecology,, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

Responses to Reviewer #1
Thank you very much for your kind comments and suggestions. Authors would like to response them as follows.
1.0. I think the author has conducted this research well. But it needs some explanation for the following area:
Response: Thank you for your admiration that we did this research well. More explanations are followed.
1.1. There is no detail about the preparation of topical Zingiber cassumunar. And what is the composition of Plai balm, just Zingiber cassumunar or there are some active plants?
Response: The detail of preparation was added to the Methods, and the composition of Plai balm was as the following table, other active plants (paraffin, Vaseline, camphor, Borneo camphor, menthol, and wintergreen oil) were similar, but with more paraffin and Vaseline added, to the placebo.
Composition
Plai balm 15%w/w
Paraffin 10 g
Vaseline 50 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 15 g
Placebo
Paraffin 15 g
Vaseline 60 g
Camphor 10 g
Borneo camphor 5 g
Menthol 5 g
Wintergreen oil 5 g
Plai oil 0 g
1.2. The author needs to explain why patients were excluded from this research and give detailed explanations.
Response: From 11 excluded patients, the detailed explanations, that were lost, are as follows, and we have added them to the Results.
• Did not meet inclusion criteria (foot ulcer, n=2)
• Declined to participate (n=9)
1.3. In the result, I found the adverse events, but in the Methods, there was no description of how this test was performed and also the assessment.
Response: Data about adverse events such as burning sensation and pruritus were collected by history taking and examination at week 1, 2, and 4, similar to the primary outcomes [references number 8 (monofilament test) and 26 (Thai version of DN4)], but edema/ erythema/ papules were collected by visual examination when patient followed up. We have added these processes into the Methods (Study treatment and procedures).
1.4. Almost half of the references are too old, the author can choose another reference that is more up-to-date.
Response: On November 7, 2023, we have re-searched for relevant published papers in PubMed by using the terms “Zingiber cassumunar” AND “painful diabetic neuropathy”, and retrieved zero results. We re-tried with only “Zingiber cassumunar”, and retrieved 85 but no one was relevant. We have tried again in “Google Scholar”, but no one was relevant in this topic too.
1.5. The author needs to explain the limitation of this study.
Response: In addition to weaknesses, we have added accordingly in the last paragraph of the Discussion.

View more View less

Competing Interests

Authors declare no competing interest.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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[2] 2. Hadden RDM, Thomas PK, Hughes RAC: Diseases of the peripheral nerves.Warrell DA, Cox TM, Firth JD, editors. Oxford Textbook of Medicine. 5 ed.Oxford: Oxford Textbooks; 2010.

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[4] 4. Jensen MP, Chodroff MJ, Dworkin RH: The impact of neuropathic pain on health-related quality of life: review and implications. Neurology. 2007; 68: 1178–1182. Publisher Full Text

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[9] 9. Martini C, Yassen A, Olofsen E, et al.: Pharmacodynamic analysis of the analgesic effect of capsaicin 8% patch (Qutenza™) in diabetic neuropathic pain patients: detection of distinct response groups. J. Pain Res. 2012; 5: 51–59. PubMed Abstract | Publisher Full Text

[10] 10. Nichpanit S, Chantraket R, Visithanon K, et al.: Thai Traditional and Alternative Health Profile: Thai Traditional Medicine, Indigenous Medicine and Alternative Medicine 2011–2013. Bangkok: Kaeo Chao Chom Media and Print Materials Centre; 2014; 1–465.

[11] 11. Panthong A, Kanjanapothi D, Niwatananant W, et al.: Anti-inflammatory activity of compound D {(E)-4-(3',4'-dimethoxyphenyl)but-3-en-2-ol} isolated from Zingiber cassumunar Roxb. Phytomedicine. 1997; 4: 207–212. PubMed Abstract | Publisher Full Text

[12] 12. Laupattarakasem W, Kowsuwon W, Laupattarakasem P, et al.: Efficacy of Zingiber cassumunar ROXB (Plygesal) in the Treatment of Ankle Sprain. Srinagarind Med. J. 1993; 8: 159–164.

[13] 13. Sasinut S: Efficacy of Plai Cream Compared with Diclofenac Gel in osteoarthritis of Knee. Mahasarakham Hosp. J. 2010; 7: 53–60.

[14] 14. Sunyarn N, Parkpoom S, Tanwarat K: The efficacy of Plygesic gel for use in the treatment of osteoarthritis of the knee. J. Med. Assoc. Thail. 2012; 95(Suppl 10): S113–S119.

[15] 15. Chongmelaxme B, Sruamsiri R, Dilokthornsakul P, et al.: Clinical effects of Zingiber cassumunar (Plai): A systematic review. Complement. Ther. Med. 2017; 35: 70–77. PubMed Abstract | Publisher Full Text

[16] 16. Cheechareoan S, Pathanawiriyasirikul T, Manmee C, et al.: Efficacy of Plai Cream in Adult Patients with Muscle Strain: A Randomized, Double-Blind, Placebo-Controlled Trial. J. Med. Assoc. Thai. 2016; 99(Suppl 2): S147–S152.

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Effect of topical Zingiber cassumunar on painful diabetic neuropathy: a double-blind randomized-controlled trial

Abstract

Keywords

Introduction

Methods

Patients

Recruitment

Study design and oversight

Study treatment and procedures

Endpoints

Statistical analysis

Results

Study patients

Figure 1. CONSORT flow diagram.

Table 1. Baseline characteristics of the patients.

Table 1.1. Baseline pain characteristics of PDN.

Table 1.2. Baseline pain mappings of PDN.

Primary outcomes

Table 2. Mean changes of NRS scores in each groups.

Table 2.1. Mean of NRS scores differences between groups at week 2 and 4.

Secondary outcomes

Table 3. Numbers/percentages of patients who had at least 50% pain reduction in each groups at week 4.

Table 4. WHOQOL-BREF–THAI scores in each groups at week 4.

Adverse events

Discussion

Conclusion

Data availability

Underlying data

Reporting guidelines

Acknowledgements

References

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