Fixed dose combination of low dose pregabalin and duloxetine, or pregabalin monotherapy for neuropathic pain: A double-blind, randomized, parallel-group study

Background: Treatment of neuropathic pain is challenging. Pregabalin and duloxetine are used as first-line therapy. Various international guidelines recommend a combination of first-line agents for the management of neuropathic pain. The objective of this study was to evaluate the efficacy and safety of a fixed-dose combination (FDC) of low-dose pregabalin and duloxetine compared to pregabalin monotherapy at week 7 in patients with moderate to severe neuropathic pain. Methods: This was a phase 3, randomized, double-blind, double-dummy parallel-group non-inferiority study conducted at 17 sites across India. Three hundred and twenty-eight adult patients with moderate to severe neuropathic pain were randomized in a ratio of 1:1 to receive a FDC of pregabalin and duloxetine or pregabalin monotherapy for 7 weeks followed by a one-week follow-up. The pregabalin-duloxetine combination was initiated at 50 plus 20 mg per day and gradually titrated to a maximum of 75mg plus 30mg twice daily. Pregabalin was initiated at 75mg/day and gradually titrated to a maximum of 150mg twice daily. The main efficacy outcome was a mean change in pain intensity at the end of 7 weeks. Results: Two hundred and ninety-eight patients completed the study, 148 in the pregabalin-duloxetine group and 150 in the pregabalin group. The mean change in daily pain at 7 weeks was as follows: -4.49 with FDC and -4.66 with pregabalin (p<0.0001). The non-inferiority of a low-dose FDC compared to pregabalin monotherapy was demonstrated at the end of the study. The incidence of dizziness and somnolence was comparable between both treatments. A higher frequency of peripheral oedema was observed with pregabalin monotherapy than in the FDC group (p>0.05). Conclusions: A FDC of low doses of pregabalin and duloxetine and high dose of pregabalin monotherapy achieved similar analgesia with dizziness, and somnolence as the most frequent adverse event. Trial registration: CTRI/2020/09/027555


Introduction
Neuropathic pain significantly impacts the quality of life and well-being of patient. 1 The financial burden to manage neuropathic pain in the chronic setting is huge on society. 2,3Its prevalence in the general population ranges from 1% to 8%. 4,5][6][7][8][9] Most of these options are effective but come with a few potential side effects.
Pregabalin, a gabapentanoid blocks the presynaptic alpha 2 delta subunit of calcium channels of the dorsal horn.This leads to inhibition of neurotransmitter release from presynaptic neuron. 7,8,10Multiple international societies recommend it as a first-line treatment option for neuropathic pain. 2,6,11][6][7][8][9] Duloxetine, an SNRI modulates pain signals by facilitating descending inhibitory pain pathway. 3,7SNRIs have been found effective in peripheral diabetic neuropathy, 6,8 painful peripheral neuropathy and multiple sclerosis. 12eatment of neuropathic pain with monotherapy has several limitations such as not being effective for all patients, having partial pain relief and increased side effects with higher doses. 8These are the main reasons to use two or more drugs in about 45% of patients. 13,14To overcome these issues, for adequate pain relief without increased adverse effects, combination therapy with two or more medications is required in about half of the patients affected with neuropathic pain.Many international guidelines suggest an addition of another drug from a different pharmacological class when adequate pain control is not achieved with monotherapy.However, the evidence available for combination therapy is limited. 1,2,7,8,9The advantages of combination therapy may be increased efficacy and better tolerability due to the use of smaller doses of individual drugs. 1,9th pregabalin and duloxetine are approved in the treatment of neuropathic pain.The monotherapy with drugs at their standard doses (60mg and 300 mg/day respectively) have shown to provide substantial clinical pain relief in only 40% of patients. 15,16,17ministration of pregabalin and duloxetine combination treatment may provide better pain relief and tolerability than the administration of maximum doses of each drug, especially in patients showing partial response to monotherapy. 18egabalin and duloxetine have different mechanism of action and administration of these drugs in combination rather than monotherapy may potentially provide enhanced pain relief in neuropathic pain due to their complementary actions. 19,20However, there have been no clinical studies on fixed-dose combinations of low-dose pregabalin and duloxetine for the treatment of neuropathic pain.
The objective of our phase 3 study was to assess the potential non-inferiority of fixed-dose combination of low-dose pregabalin and duloxetine compared to pregabalin monotherapy in adults with moderate to severe neuropathic pain.

Study design and setting
This was a multicentre, parallel, randomized, double-blind, double-dummy, non-inferiority trial conducted in adult patients with neuropathic pain enrolled from 17 sites across India.All investigational sites were approved by respective Independent Ethics Committee or Institutional Review Board before the enrolment of any patient in the trial.This trial followed the principles outlined in the Declaration of Helsinki and the trial protocol was approved by the Institutional Ethics Committee and the Drug Controller General of India (CT-06-11/2020).The trial was registered on 2 nd September 2020 with the Clinical Trial Registry of India (Registry identifier: CTRI/2020/09/027555).This trial was conducted from September 2020 to January 2021.

Study population
Four hundred and thirty patients presenting with moderate to severe neuropathic pain and having at least moderate to severe pain intensity ≥ 4 on the numeric pain rating scale (NPRS) during screening at one of the participating centres were assessed and referred to the investigator for enrolment.The pain intensity was measured through 11-point NPRS in which 0 indicated no pain and 10 as the worst possible pain.Eligible adult patients aged 18 to 65 years of age who met inclusion criteria and signed informed consent forms were enrolled.Exclusion criteria included were a history of hypersensitivity to pregabalin or duloxetine or any of its excipients; clinically significant illness in the past three months; type I or II diabetes with glycosylated haemoglobin A1C of >10%; clinically significant electrocardiogram (ECG) abnormalities or QTc ≥450 msec; treated with drugs that impair metabolism of serotonin or serotonergic drugs other than study drugs or corticosteroids within the past four weeks; treated with topical or systemic pain medications within past two weeks; pregnant or lactating women, female with childbearing potential who were neither surgically sterilized nor willing to use medically acceptable contraceptive methods during the study; participated in any other investigational drug trial within the past four weeks and those patients who in the opinion of the investigator either unable to cooperate or unlikely to adhere with any study procedures or not considered a suitable candidate for participation in the study.

Treatment & visit details
The trial period was 7 weeks, and the patients were scheduled for 7 visits (screening, baseline, week 1, week 2, week 3, week 5 and week 7).Patients were screened by the respective site investigator and eligible patients were randomized to receive either test + dummy reference or reference + dummy treatment.The assignment of treatment was as per the pre-determined computer generated, centrally administered randomization scheduled with the help of interactive web response system (IWRS).Each patient received unique randomization code.
Post-screening, three hundred and twenty-eight participants were randomized to receive either fixed-dose combination (FDC) of pregabalin and duloxetine or pregabalin monotherapy.At screening, sociodemographic data and pain intensity were assessed.At baseline, clinical data (significant medical history, concomitant use of other medications), pain intensity and neuropathic pain symptom inventory were collected.
At the baseline visit, all the eligible patients were randomized in a 1:1 fashion to receive either FDC of pregabalin and duloxetine plus dummy of pregabalin (Test group) or pregabalin plus dummy of FDC of pregabalin and duloxetine (Reference group).The study medications were administered in a double-blind, dummy manner.The double-dummy design of the trial was achieved with the placebo formulations of pregabalin plus duloxetine and pregabalin in identical capsule.The investigation product's primary packaging, blinding, labelling and secondary packaging was performed by third party.The investigation packages were given unique number code.At regular monitoring visits, study monitor ensured that the blinding was maintained.The participants, the research staff, and the investigators were all blinded to treatment allocations throughout the study period.One-hundred and sixty-four patients in the test group were initiated with FDC of pregabalin 50mg plus duloxetine 20mg capsule and one-hundred and sixty-four patients in the reference group with pregabalin monotherapy (75mg) capsule in the evening.Patients who responded to assigned treatment continued the same treatment until week 7 and those who were non-responders were up titrated after assessment at consecutive weeks.Patients who were having <30% reduction in pain intensity (based on the 11-point NPRS) were considered non-responders to the assigned treatment.After visit 2, non-responders in both groups were up-titrated at visit 3, visit 4 and visit 5 (Table 1).A telephonic safety follow-up was performed for all the subjects after 1 week (AE 2 days) after the end of the treatment.

Study outcome measures
The primary objective was to assess the mean change in pain intensity based on an 11-point NPRS.
The secondary outcome measures were mean change in NPRS from baseline to weeks 2, 3, and 5; proportion of responders (≥30% improvement in pain (NPRS) from baseline) at week 7; proportion of patients with ≥50% improvement in NPRS from baseline to week 7; mean change in NPSI total score from baseline to end of the treatment; Percentage of patients who required rescue medication for inadequate pain relief (recorded at every visit); Patient Global Impression of Improvement (PGI-I) score at week 7; Clinical Global Impression of Improvement (CGI-I) score at week 7; incidence of treatment-emergent adverse event (TEAE) in test arm against reference arm (recorded at every visit)

Statistical analysis
The study was powered to detect a mean of improvement of 2.5 for Pregabalin and 2.7 for FDC at the end of the study in NPRS with a 2-sided test and 95% power, assuming an SD of 2.3.Non-inferiority margin considered was 33%.This analysis required 139 patients per treatment arm.We assumed around 15% discontinuing during therapy, on that basis a total of 328 patients were planned.
Table 1.Up-titration in Non-responder (<30% reduction in pain intensity based on the 11 point NPRS) patients.

Test Group (FDC Pregabalin + Duloxetine)
Reference Group (Pregabalin) • Visit 3-75 mg plus 20 mg in the evening • Visit 4-75 mg plus 30 mg in the evening • Visit 5-75 mg plus 30 mg in the morning and evening • Visit 3-100 mg in the evening • Visit 4-150 mg in the evening • Visit 5-150 mg in the morning and evening For analyses, we used modified intention-to-treat (mITT) principles.All randomised patients were included in efficacy analyses if they were treated and had a baseline and at least received one dose of study medication and one post-baseline assessment of any efficacy parameter.In safety population analysis, all randomised patients who received at least one dose of study medication were included.
Primary efficacy evaluation, change from baseline (Day 0) to EOT (Week 7) was calculated for NPRS score.It was compared using an independent t-test to test the differences between treatment groups.The non-inferiority was assessed based on the one-sided 97.5% CI (i.e., two-sided 95% CI) approach.A non-inferiority margin of 33% (MoNI -0.8) of the total response was observed for reference.
The secondary efficacy analysis included mean change in NPRS score from baseline to Weeks 2, 3 and 5 and mean change in NPSI total score from baseline to end of week 7, PGI-I and CGI-I score, subjects required rescue medication for inadequate pain relief and incidence of TEAE [dizziness, somnolence and/or peripheral oedema].These endpoints were analyzed using either t-test, Chi-square or Fisher's exact test.
Descriptive statistics were used to summarise the safety measures.Fisher's Exploratory Analysis were performed to determine the frequencies of patients with TEAEs.The analysis of variance (ANOVA) and analysis of covariance (ANCOVA) were performed to determine the difference in the least-squares mean in the magnitude of change in NPRS and NPSI scores between the treatments.All statistical analysis were performed by using SAS software, version 9.4 (SAS Institute Inc., North Carolina, Cary, USA).

Results
A total of 430 patients were screened from all the sites (Figure 1).A total of 328 eligible patients were equally randomized in two groups as test groups (N=164) and reference group (N=164).After randomization, 20 patients withdrew their consent, 7 patients were lost to follow-up, 2 patients discontinued due to adverse events and 1 patient was discontinued by the investigator from the test group.The reasons for discontinuation are mentioned in Figure 1.Thus, total 298 patients completed 7 weeks treatment. 28e demographic characteristics between both treatment groups were comparable.The number of female patients was slightly higher in the reference group compared to the test group.The demographic characteristics are presented in Table 2.The mean patient age at enrolment was 46.5 years.All included patients had an average pain score of at least 4 on NPRS prior to treatment.The mean pain intensity was 6.4.

Primary outcomes
The primary efficacy assessment was to compare the change in NPRS score between the test and the reference group.At the end of week 7, the mean change in NPRS score from baseline was -4.49 and -4.66 with the test and the reference group (p<0.0001)respectively (Figure 2).The lower bound 95% CI for treatment difference was -0.18 which was higher than the non-inferiority margin of -0.8.Therefore, the test treatment was non-inferior to the reference group.These results obtained in the mITT population were supported by those seen in the PP population [95%CI: -0.26, 0.44, p <0.05).

Secondary outcomes
The change in NPRS scores between the test group and the reference group at weeks 2, 3 and 5 from baseline was nonsignificant.In the test group it was -2.49, -3.19 and -3.89 while -2.65, -3.34 and -4.03 in the reference group (p>0.05).
(Figure 2) The percentage proportion of responders between the test and the reference treatment were similar at week 7 (96.20%Vs 98.73%, p>0.05).Similarly, no statistically significant difference was observed at week 7 in the percentage of the patient with ≥50% improvement in pain (84.18%Vs 89.17, p>0.05).No statistically significant difference in mean change in NPSI total score from baseline was observed (-37.57Vs -38.47, p>0.05).
When patients were asked about their global impression of improvement using the PGI-I, patients reported much better to very much better improvement with both treatments.The mean of the PGI-I score at Week 7 was 1.7 and 1.6 between test group and treatment group (p>0.05).
When investigators were asked about their global impression of improvement using the CGI-I, investigators reported much better to very much better improvement with both the treatments.The mean of CGI-I scores at week 7 was 1.6 in both the treatment groups (p>0.05).Table 3 represents the secondary outcome data.

Safety
The percentage of subjects who experienced TEAEs were comparable between the groups.Most of the TEAES were at least possibly related to study treatment.In the reference group, two patients discontinued the treatment due to TEAES while none in the test group discontinued for this reason.Table 4 presents an overall summary of adverse events for the safety population.The major side effects reported in both groups were somnolence, dizziness, and oedema (Table 4).All the reported TEAEs were mild in severity.The incidence of peripheral oedema was higher with the reference treatment as compared to the test treatment (3.11% vs. 0%, p>0.05), although statistically not significant.
No serious adverse events (SAE) were observed in the study.
In additional analysis, significantly more moderate to severe adverse events were observed in the reference group as compared to the test group.Furthermore, early onset of somnolence and gastrointestinal AEs were observed with pregabalin monotherapy compared to FDC of low-dose pregabalin and duloxetine and this difference was significant.
Similarly, significantly, more patients withdrew from the study due to experiencing AE's or needing treatment for AE's in the test group compared to the reference group.

Discussion
Neuropathic pain can be spontaneous or provoked and the patient may complain of paraesthesia, dysesthesia, and loss of normal sensation due to nerve damage. 21The most commonly used option to treat neuropathic pain is pharmacotherapy.However, the complex aetiology of neuropathic pain is the reason for the limited benefit of monotherapy.
The drawback of monotherapy is its limited efficacy and increased adverse effects with the higher dose.Due to tolerability issues, higher doses needed for maximum therapeutic response are not used.Inadequate partial pain relief with the single agent will lead to impaired physical function, impaired sleep, reduced quality of life and higher economic costs of unrelieved pain.
Combination therapy with two or more drugs must be considered to overcome the challenges of managing uncontrolled neuropathic pain with improved analgesic efficacy and reduced overall side effects especially when synergistic interactions are possible for dose reductions of combined drugs. 22In clinical practice, combination therapy is frequently used.Evidence supports the combination of gabapentinoids and antidepressants than a high dose of individual drugs from either class for a reasonable treatment in neuropathic pain.Pregabalin, a gabapentinoid and duloxetine, an antidepressant; should be initiated with lower doses and gradually up-titrated based on the treatment response.
Pregabalin-duloxetine combination shows additive analgesic actions with a better safety profile compared to high-dose pregabalin monotherapy.In clinical practice, lower doses (once daily or twice daily) of pregabalin (50mg, 75 mg) and duloxetine (20mg, 30 mg) are widely co-prescribed by the neurologist.A combination of significantly lower doses of pregabalin-duloxetine has a greater pain relief than for side effects. 23nish expert recommendation reported that a combination of gabapentinoid and SNRI is associated with better pain relief and lesser side effects than a single drug therapy. 24An Indian consensus statement suggests that when managing neuropathic pain management with gabapentinoids as first drug, TCAs such as nortriptyline or SNRIs can be considered as add on therapy and vice versa. 25The American Diabetes Asssociation (ADA) position statement recommends combination of two first line agents from class of gabapentinoids, SNRIs, or TCAs in cases wherein monotherapy fails.Furthermore, it also suggests that tramadol/tapentadol can be added if two drug combinations provide inadequate pain relief. 26e COMBO-DN (Combination vs. Monotherapy of pregabalin and duloxetine in DPN) is one of the largest and well known multinational randomized study conducted in patients with diabetic peripheral neuropathy.It reported outcome of duloxetine and pregabalin monotherapy at high doses versus a combination of these two agents at standard dosing. 27The primary outcome of the study was not achieved as no significant difference was measured between the monotherapy and standard-dose combination therapy.However, secondary outcomes of this trial showed that number of patients who achieved >50% reduction were more in combination treatment compared to high dose monotherapy (52.1% Vs 39.3%, p=0.068) with better tolerability.
The initial evidence indicates the need of additional large clinical trials in neuropathic pain for identifying optimal combination as initial approach.Therefore, we conducted a phase 3 trial on the fixed-dose combination of lower doses of pregabalin (50mg, 75mg) and duloxetine (20mg, 30mg) in adult patients with moderate to severe neuropathic pain.
Our phase 3 trial result suggests that the combination of a low dose of pregabalin and duloxetine provides similar analgesia and better safety in comparison to a high dose of pregabalin (150mg, 300mg) monotherapy.The subjective assessment done by CGI-I and PGI-I was also found similar in both the groups.
Data from the present trial suggest that a combination of low-dose pregabalin and duloxetine could be a combination of choice considering the relatively lesser dose administration for pregabalin without compromising efficacy and safety.Additional evaluation of safety data indicated a clear tolerability advantage of FDC over monotherapy for clinically meaningful adverse events associated with monotherapy.
The efficacy results of previous studies on the combination of pregabalin and duloxetine indicate that a combination therapy might be a reasonable therapeutic approach rather than up-titrating the dose in patients with inadequate pain control or having tolerability problem with a high doses of single first-line agent.The outcome of the present study supports the outcomes of previous studies.
In our trial, there were no significant safety concerns observed in both the treatment groups.The most common adverse effects observed were dizziness and somnolence, which are in line with the currently known profile of these drugs.
In this study, the overall frequency of adverse effects was similar with both treatments, except that patient receiving the pregabalin monotherapy had a higher frequency of peripheral oedema than those receiving the pregabalin-duloxetine combination.Additional analysis also established the safety advantage of FDC in AEs of common concern over monotherapy.
The strength of our study is that it is a double-blind, double-dummy parallel-group design.The use of lower doses of pregabalin and duloxetine in combination reflects current clinical practice.
The limitations of our study include small sample size, shorter duration of the study, and the design of the study which compared a fixed dose combination of pregabalin and duloxetine only with a high dose of pregabalin not with duloxetine.
Patient related outcomes such as sleep interference and emotional functioning were not assessed in our trial.
Nevertheless, the trial results unequivocally shows that a low dose pregabalin-duloxetine combination is non-inferior to high-dose pregabalin monotherapy in management of patients with moderate to severe neuropathic pain.

Conclusion
In patients with moderate to severe neuropathic due to different aetiologies, the analgesic effect demonstrated by FDC of pregabalin (low dose), and duloxetine was comparable to pregabalin (high dose) monotherapy.The FDC was safe and well tolerated.This is the first Indian clinical trial in which FDC of pregabalin and duloxetine was evaluated.Future studies with larger sample sizes, long-term duration and heterogenous population are necessary to understand the clinical outcome with FDC of pregabalin and duloxetine.

Nariman Essmat
Semmelweis University, Budapest, Hungary Subject: Review of Manuscript The manuscript titled "Efficacy and Safety of Fixed-Dose Combination of Pregabalin and Duloxetine for Neuropathic Pain" provides valuable insights into the efficacy and safety of a fixeddose combination (FDC) of pregabalin and duloxetine compared to pregabalin monotherapy for the management of neuropathic pain.The manuscript provides a clear overview of the study's objectives, methods, results, discussion, and conclusions.However, the paper needs minor revision before acceptance.My comments have been addressed as follows: The title does not specify the phase of the study.Including information about the study phase (e.g., phase 3) would be better

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In the abstract: in the method section the authors should clarify the method of pain assessment (numeric pain rating scale (NPRS).

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In the first paragraph of the introduction section, authors should define neuropathic pain according to IASP.

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In the Study Design and Setting section, please mention that the study is in phase III ○ Please add more information for the inclusion criteria

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In the statistical analysis section, please explain how the Non-Inferiority Margin was determined.
○ DPN: give the full name for this abbreviation, no need for an abbreviation as it appears one in the text

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The study was double-dummy; no data was added for the placebo group; please provide supplementary data on this issue

Laith Thamer Al-Ameri
Al-Kindy College of Medicine, University of Baghdad, Baghdad, Baghdad, Iraq Dear Editor, Authors, and Readers, A well-written manuscript and good work, such a trial will add much to what is known and previously written about neuropathic pain.Pregabalin is well known to be equivalent to or superior to many other medications in neuropathic pain management, and additional information is needed about the benefits of and combinations with other medications regarding efficacy and tolerability.
It's worth noting that the manuscript demonstrates strong enrolment criteria, a robust methodology, and the use of appropriate statistical methods, which contribute to the overall quality of the study.
However, the conclusion section needs to be rewritten to represent the results and be more informative.The authors have to mention the result regarding the efficacy and tolerability of both groups (e.g., a low-dose pregabalin-duloxetine combination is non-inferior to high-dose pregabalin monotherapy in the management of patients with moderate to severe neuropathic pain), a statement already mentioned at the end of the discussion.

Denis Dupoiron
Anesthesiology and Pain Department, Institut de Cancérologie de l'Ouest, Angers, France Very good paper, the topic is attractive, the comparative study is well built, and the methodology does not present significant issue.
The outcomes are well presented and relevant.The results validate observations in clinical practice.
Moreover, the discussion is helpful and well conducted.
My only one comment is about limitations, I do think the number of patients included is low.

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?I cannot comment.A qualified statistician is required.
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: neuropathic cancer pain 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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Treatment Specification: Test = Fixed dose combination of Pregabalin and Duloxetine capsule; Reference = Pregabalin capsule.Abbreviation(s): BMI = Body Mass Index; cm= Centimeter; kg= Kilogram; m= Meter; Max = Maximum; Min = Minimum; N = Number of subjects in specified treatment; n = Number of subjects in specified category; NE = Not Evaluable; NPRS = Numeric Pain Rating Scale; NPSI = Neuropathic Pain Symptom Inventory; SD = Standard Deviation.Note 1: Percentages were based on the number of subjects in the specified treatment.Note 2: For continuous variables p-value was calculated using independent t-test and for categorical variables p-value was calculated using Chi-square test.Note 3: NPRS and NPSI measurement were based on Visit 2 (Day 0).Note 4: Safety = Randomized subjects administered with at least one dose of study medication.
Treatment Specification: Test = Fixed dose combination of Pregabalin and Duloxetine capsule; Reference = Pregabalin capsule.Abbreviation(s): E = Number of events in specified category; AE = Adverse event; N = Number of subjects in specified treatment; n = Number of subjects in specified category; SAE = Serious adverse event; TEAE = Treatment emergent adverse event.Note 1: Subjects with multiple events in the same category were counted only once in that category with highest severity.Note 2: Percentages were based on the number of subjects in safety population in specified treatment.Note 3: Medical Dictionary: MedDRA Version 23.0.Note 4: Safety = Randomized subjects administered with at least one dose of study medication.

Table 2 .
Summary of Baseline and Demographics Characteristics -Safety Population.

Table 4 .
Overall Summary of Adverse Event -Safety Population.

Table 3 ,
what was the statistical test used for the calculation of the p-value?It's better to add a table ligand ○In ○ In the conclusion section, it mentioned (In patients with moderate to severe neuropathic due to different aetiologies), please specify the neuropathic pain types that can be treated with this combination ○ 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: PainI 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.
Reviewer Report 13 April 2024 https://doi.org/10.5256/f1000research.143095.r254315© 2024 Al-Ameri L. This is an open access peer review report 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.

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:
1. Al-Ameri LT, Shukri ME, Hameed EK, Marzook AA: Pregabalin versus Gabapentin Efficacy in the Management of Neuropathic Pain Associated with Failed Back Surgery Syndrome.J Korean Neurosurg Soc.2024; 67 (2): 202-208 PubMed Abstract | Publisher Full Text No competing interests were disclosed.Neurosurgery, Neuroanatomy, Clinical Trials, sleep disorders, neuropathy, and Artificial Intelligence in medical fields 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.
This is an open access peer review report 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.