F1000ResearchF1000Research2046-1402F1000 Research LimitedLondon, UK10.12688/f1000research.131344.1Research ArticleArticlesEffect of topical
Zingiber cassumunar on painful diabetic neuropathy: a double-blind randomized-controlled trial
[version 1; peer review: 1 approved with reservations]
JatutenNachapolConceptualizationData CurationFormal AnalysisResourcesSoftwareWriting – Original Draft Preparation1PiyakunmalaPhuangthongConceptualizationData CurationFormal AnalysisFunding AcquisitionInvestigationMethodology2BudkaewJirathaProject AdministrationResourcesSoftwareSupervisionValidationVisualization2ChumworathayiBanditMethodologySupervisionValidationVisualizationWriting – Review & Editinghttps://orcid.org/0000-0003-1214-1962a3
Selaphum Hospital, Selaphum District, Roi Et, 45120, Thailand
Social Medicine, Khon Kaen Hospital, Muang District, Khon Kaen, 40000, Thailand
Obstetrics and Gynaecology,, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailandbchumworathayi@gmail.com
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.
Painful diabetic neuropathyZingiber cassumunarPlai balmKhon Kaen HospitalKEXP62005This 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.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.
MethodsPatients
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.
ResultsStudy 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).
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).
Baseline characteristics of the patients.
Patients’ characteristics
Plai (n=16)
Placebo (n=15)
P-value
Number
Percent
Number
Percent
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
PDN=painful diabetic neuropathy.
Independent t-test.
Mann-Whitney U-test.
Fisher’s exact test.
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
Baseline pain mappings of PDN.
Pain mappings
Plai (n=16)
Placebo (n=15)
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).
Mean changes of NRS scores in each groups.
Groups
Baseline Mean (SD)
Week 2 Mean (SD)
Week 4 Mean (SD)
Week 2
Week 4
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).
Mean of NRS scores differences between groups at week 2 and 4.
NRS differences
Week 2
Week 4
Plai (n=16)
Placebo (n=15)
P-value
Plai (n=16)
Placebo (n=15)
P-value
Meana(95%CI)
-1.47 (-1.96 to -1.30)
0.001
-1.51 (-1.92 to -0.13)
0.027
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).
Numbers/percentages of patients who had at least 50% pain reduction in each groups at week 4.
Pain reduction amount
Groups
P-value
Plai, n (%)
Placebo, n (%)
≥50%
12 (75.00)
3 (20.00)
0.004
<
50%
4 (25.00)
12 (80.00)
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).
WHOQOL-BREF–THAI scores in each groups at week 4.
WHOQOL-BREF domain
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 safe
24 and effective
25 in treating diabetic foot ulcers. Moreover, Plai has local anesthetic
20–23 and neuroprotective
28 effects, in addition to its effects on anti-inflammation
12–15 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.
This is the dataset of the research titled “Effect of topical
Zingiber cassumunar on painful diabetic neuropathy: A double-blind randomized-controlled trial”
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.
ReferencesTesfayeSSelvarajahD:
The Eurodiab study: what has this taught us about diabetic peripheral neuropathy?Curr. Diab. Rep.2009;9:432–434.
1995468710.1007/s11892-009-0070-1HaddenRDMThomasPKHughesRAC:
Diseases of the peripheral nerves.WarrellDACoxTMFirthJD, editors.
Oxford Textbook of Medicine.5 ed.Oxford:
Oxford Textbooks;2010.Centre for Clinical Practice at NICE (UK):
Neuropathic Pain: The Pharmacological Management of Neuropathic Pain in Adults in Non-specialist Settings.London:
National Institute for Health and Care Excellence, (UK);2013.JensenMPChodroffMJDworkinRH:
The impact of neuropathic pain on health-related quality of life: review and implications.Neurology.2007;68:1178–1182.
10.1212/01.wnl.0000259085.61898.9eSchmaderKE:
Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy.Clin. J. Pain.2002;18:350–354.
1244182810.1097/00002508-200211000-00002O'ConnorAB:
Neuropathic pain: quality-of-life impact, costs and cost effectiveness of therapy.PharmacoEconomics.2009;27(2):95–112.
10.2165/00019053-200927020-00002AttalNCruccuGBaronR:
EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision.Eur. J. Neurol.2010;17:1113–e88.
10.1111/j.1468-1331.2010.02999.xHartemannAAttalNBouhassiraD:
Working Group on the Diabetic Foot from the French-speaking Society of Diabetology. Painful diabetic neuropathy: diagnosis and management.Diabetes Metab.2011;37(5):377–388.
10.1016/j.diabet.2011.06.003MartiniCYassenAOlofsenE:
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.
2253609210.2147/JPR.S30406NichpanitSChantraketRVisithanonK:
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.PanthongAKanjanapothiDNiwatananantW:
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.
2319547710.1016/S0944-7113(97)80069-4LaupattarakasemWKowsuwonWLaupattarakasemP:
Efficacy of
Zingiber cassumunar ROXB (Plygesal) in the Treatment of Ankle Sprain.Srinagarind Med. J.1993;8:159–164.SasinutS:
Efficacy of Plai Cream Compared with Diclofenac Gel in osteoarthritis of Knee.Mahasarakham Hosp. J.2010;7:53–60.SunyarnNParkpoomSTanwaratK:
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.ChongmelaxmeBSruamsiriRDilokthornsakulP:
Clinical effects of
Zingiber cassumunar (Plai): A systematic review.Complement. Ther. Med.2017;35:70–77.
2915407110.1016/j.ctim.2017.09.009CheechareoanSPathanawiriyasirikulTManmeeC:
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.ManimmanakornNManimmanakornABoobphachartD:
Effects of
Zingiber cassumunar (Plai cream) in the treatment of delayed onset muscle soreness.J. Integr. Med.2016;14:114–120.
2698843210.1016/S2095-4964(16)60243-1KlaphajoneJChutarattanakulNLeeP:
Efficacy of topical plai (
Zingiber Cassumunar) cream extract for symptomatic relief of delayed onset muscle soreness.Chiang Mai Med. J.2017;56:69–79.WisuitiprotVBumrungchaichanaWKaewtaiN:
Effectiveness of a Plai Oil Prepared by Thai Traditional Medicine Process in the Treatment of Myofascial Pain Syndrome: A Randomized Placebo Controlled Trial.J. Health Sci. Med. Res.2019;37:207–215.
10.31584/jhsmr.201954AnantasanVAsayakunS:
Study on the local anesthetic effect of squeezed
Zingiber cassumuna Roxb.Chiang Mai Med. Bull.1971;10:10–23.KhalidMHAkhtarMNMohamadAS:
Antinociceptive effect of the essential oil of
Zingiber zerumbet in mice: possible mechanisms.J. Ethnopharmacol.2011;137:345–351.
10.1016/j.jep.2011.05.043ZulazmiNAGopalsamyBFaroukAA:
Antiallodynic and antihyperalgesic effects of zerumbone on a mouse model of chronic constriction injury-induced neuropathic pain.Fitoterapia.2015;105:215–221.
2620504510.1016/j.fitote.2015.07.011ChiaJSMOmar FaroukAAMohamadAS:
Zerumbone alleviates chronic constriction injury-induced allodynia and hyperalgesia through serotonin 5-HT receptors.Biomed. Pharmacother.2016;83:1303–1310.
2757017310.1016/j.biopha.2016.08.052HirunsirivatSTungsukruthaiPTharavanijT:
Safety of yellow surat cream in healthy participants (clinical trial phase 1).Walailak Procedia.2019;1:ic4ir.183.ChumpolphantSSuwatronnakornMIssaravanichS:
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.
3572123110.1016/j.sjbs.2022.103330PMC9198379ChaudakshetrinPPrateepavanichPChira-AdisaiW:
Cross-cultural adaptation to the Thai language of the neuropathic pain diagnostic questionnaire (DN4).J. Med. Assoc. Thail.2007;90:1860–1865.TaboonpongSSuttharangseeWChailangkaP:
Evaluating psychometric properties of WHO quality of life questionnaire in Thai elderly.J. Gerontol. Geriatric. Med.2001;2:6–12.KongsuiRSriraksaNThongrongS:
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.ChumworathayiB:
Zingiber cassumunar Dataset.Dataset.
figshare.2023. Accessed on 3
rdJanuary 2023.
10.6084/m9.figshare.21805182.v1Reference SourceChumworathayiB:
Zingiber cassumunar Protocol. figshare. Online resource.Accessed on 27
thFebruary 2023.
10.6084/m9.figshare.22180675.v1Reference SourceChumworathayiB:
Zingiber CONSORT Checklist. figshare. Online resource.Accessed on 8
thFebruary 2023.
10.6084/m9.figshare.22046570.v1Reference Source10.5256/f1000research.144178.r193436Reviewer response for version 1FajrinFifteen Aprila1Referee
Clinical and Community Department, Faculty of Pharmacy, Universitas Jember, Jember, East Java, Indonesia
Competing interests: No competing interests were disclosed.
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
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
Is the study design appropriate and is the work technically sound?
Yes
Are the conclusions drawn adequately supported by the results?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
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.
ChumworathayiBanditKhon Kaen University, Thailand
Competing interests: Authors declare no competing interest.
7112023
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.