Brief resume of intended work:

6.1 Need for study: 

Diabetic peripheral neuropathy (DPN) is defined as the presence of symptoms or signs of peripheral nerve dysfunction after the exclusion of other causes.¹The pain affects specific regions of the nervous system, due to failure of the endogenous analgesic mechanisms in the descending spinal pathways that control pain transmission to the brain.²   Pain is a common symptom, can cause anxiety, depression, adversely affect function, and deteriorate the overall quality of life.³ Surveys conducted on Indian patients found the prevalence varied from 26% to 31%, it adds to the humanistic and economic burden.¹ 

Clinical management of diabetic peripheral neuropathic pain (DPNP) is challenging. Historically, DPNP has been treated with tricyclic antidepressants (TCAs), opioid analgesics, and anticonvulsant agents.  Currently two medications- duloxetine and pregabalin are approved by the US Food and Drug Administration for the management of DPNP. The mechanism of action of duloxetine, an antidepressant is reuptake inhibition of both serotonin and norepinephrine in the central nervous system, which increases the activity of these neurotransmitters and subsequently reduces the perception of pain by modulating the pain signals. In contrast, pregabalin, an anticonvulsant agent, has an analgesic mechanism of action that involves binding to the α_2-δ subunit of calcium channels in the hyperexcited afferent neurons, which reduces the release of glutamate, norepinephrine, and substance P, thereby reducing pain signals transmitted from the periphery to the brain.² The major advantage of pregabalin is its relative reliability, easy use and high tolerance in patients with neuropathic pain. 

 At present monotherapy drugs are associated with limited efficacy and dose‐related side effects, combining two drugs with different mechanism may improve analgesic efficacy and reduce overall side effects and hence the study is taken up.

6.2 Review of Literature:   

Chronic, painful diabetic neuropathy is difficult to treat with only symptomatic treatment being available. Prevention of diabetic neuropathy is critical through improved glycemic control. Two oral agents approved by the U.S. Food and Drug Administration (FDA), duloxetine and pregabalin, or gabapentin is usually initially used for pain associated with diabetic neuropathy. No direct comparisons of agents are available, and it is reasonable to switch agents if there is no response or if side effects develop.⁴ 

A randomized cross over study done by Tesfaye et al in 2022 compared the efficacy of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for treating diabetic peripheral neuropathic pain in the UK, showed that all three treatment pathways delivered similar analgesic efficacy both in terms of statistical and clinical significance. It also showed that combination treatment, where needed, was well tolerated and led to significantly better pain relief.⁵

However, a randomized ‘‘COMBO-DN study’’ conducted in Europe in 2013 by Wilhem s, compared efficacy and safety of Duloxetine and pregabalin high-dose monotherapy versus their combination in patients with diabetic peripheral neuropathic pain not responding to standard doses of duloxetine or pregabalin. Even though the primary end point was not achieved, efficacy results consistently favored combination therapy with might be a reasonable clinical option compared to increasing the dose of monotherapy⁶

 A review study by Preston G et al in 2023 on “Painful Diabetic Peripheral Neuropathy: Practical Guidance and Challenges for Clinical Management” highlights the high prevalence of painful diabetic peripheral neuropathy, which is often underdiagnosed and undertreated. Achieving complete pain resolution is rare, with 30-50% reduction considered good. Side effects from medications require careful consideration, and many patients do not respond to primary pharmacotherapy. Hence require a trial-and-error approach.⁷

6.3 Objectives of the study:

          1. To compare the efficacy of Pregabalin with Amitriptyline versus Pregabalin with Duloxetine.                   

          2. To compare the safety of Pregabalin with Amitriptyline versus Pregabalin with             Duloxetine.

Materials and Methods:

7.1 Source of data:

         Patients attending the Outpatient Department of Medicine in Victoria Hospital

         attached to Bangalore Medical College and Research Institute, Bengaluru.

 7.2Methods of Collection of Data:

    A. Study design: Open label, Comparative, non-randomized controlled study.  

    B. Study period:  April 2024 to September 2025 (18 months)

    C. Place of study: The study is planned to be conducted on an Outpatient basis at             the Department of Medicine in Victoria Hospital attached to Bangalore Medical   college and Research Institute, Bengaluru

    D. Sample size:

    Based on study conducted by Tesfaye S et al, adverse events among pregabalin with amitriptyline and pregabalin with duloxetine were 24% and   16% respectively⁵

. Assuming minimum expected difference between 2 groups as 25%.

·       Formula

were, 

P₁ is 24, P₂ is 16,                 

 D is 25

 Z-value for 5% level of significance =1.96

 Z-value for 80% power= 0.84

Substituting,

 n = 40 in each arm.

   Drop Out Rate = 10%

    10% of 40 = 4

Total Sample Size

    40+4=44

 Rounding off to 45 in each arm.

E. Inclusion Criteria:                                          

1.     Patient willing to give informed consent.

2.     Age above 18 years of either gender.

3.     Patients with Type 2 diabetes mellitus having peripheral neuropathic pain screened by Douleur Neuropathic 4 (DN4) questionnaire (Annexure -3c) having total pain intensity of ≥ 4 points on Numeric Rating Scale (NRS-11)

(Annexure-3b) who received monotherapy.

F. Exclusion Criteria:

1.     Patients with history of epilepsy, depression requiring antidepressants medications.

2.     Unstable cardiovascular or serious, hepatic (acute liver injury such as hepatitis or severe cirrhosis), kidney, respiratory diseases, blood disorder, seizure disorder, problems with peripheral vascular disease.

3.     Pregnancy/breastfeeding or planning pregnancy during the course of the study.

4.     Hypersensitivity to study drugs.

 G. Methodology:

After obtaining approval and clearance from the Institutional Ethics Committee, the patients fulfilling the inclusion criteria will be enrolled for the study after obtaining informed consent. (Annexure – 1).

 The demographic details along with the disease-related and pharmacotherapeutic variables with be noted in the Case Record Form with follow up chart (Annexure – II).

Patients with Type 2 diabetes mellitus having peripheral neuropathic pain screened by Douleur Neuropathic 4 (DN4) questionnaire having total pain intensity of    â‰¥ 4 points on NRS-11 who received monotherapy. According to the treating physician choice the selected patients will be given Pregabalin with Amitriptyline or Pregabalin with Duloxetine and divided into Group A and Group B respectively.

·       Group A patients (n=45) will receive pregabalin 50mg with amitriptyline 10mg daily for 6 weeks.

·       Group B patients (n=45) will receive pregabalin 50mg with duloxetine 20mg daily for 6 weeks.

Demographic data, medical history, concomitant medications, physical examination, clinical examination, and details of drug prescription by the treating physician will be recorded in the case record form at baseline visit (Visit 1) (Annexure II).

Follow-up visit will be at the end of 6 weeks (Visit 2). A deviation of ±2 days for follow-ups will be accepted. The detailed schedule of patient visits is as follows -

·       Efficacy in terms of symptom relief will be measured using NRS-11.

·       Safety will be assessed in terms of numbers and severity of adverse events experienced by study participants during treatment.

The detailed schedule of patient’s visits is as follows

Visit 1/Day 0/Baseline assessment:

·       Patients will be given a thorough explanation of the study and written informed consent will be obtained.

·       Patients will be enrolled as per inclusion/exclusion criteria.

·       Details of patients’ demographic characteristics, medical history, detailed physical/clinical examination will be recorded.

·       Clear instructions regarding intake of study medication will be given to patient.

·       Baseline investigations and pain intensity measured using NRS-11 scale.

·       For Patients medication will be given for 6 weeks.

·       Patients will be asked to return for follow up after 6 weeks

Visit 2/At the end of 6 weeks

·       Improvement in symptoms and signs is noted.

·       Pain intensity measured using NRS-11 scale.

·       All observed or spontaneously reported adverse events will be recorded.

·       The study termination form will be completed.

                                      WORK FLOW CHART

  Patients attending the outpatient department  of medicine, Victoria hospital BMCRI.

                                  (n=90)

Assessed for eligibility

·       Written informed consent taken,

·       Demographic data,

·       Medical history and

·       Baseline investigations are done.

Group A

(n=45)

Pregabalin 50mg with Amitriptyline 10mg

Group B

(n=45)

Pregabalin 50mg with Duloxetine 20mg

Follow up:

At the end of 6 weeks

Efficacy: NRS-11 scale

Safety assessment

Relevant statistical tests done

·       Compiling the data &

·       Study termination

  H. Assessment Tools:

  1. Efficacy will be assessed by:

·       Numeric Rating Scale (NRS-11).

·       Insomnia severity Index (Annexure-3d).

           2. Safety will be assessed by:

Number and severity of adverse events recorded as reported by the patient at any time of the study (CDSCO adverse drug reaction reporting form).

I. Outcome measures:

            1.Efficacy parameters:

·       Pain intensity using Numeric Rating Scale (NRS-11).

·       Quality of sleep using Insomnia severity Index.

2.Safety is assessed:

 by monitoring and recording adverse events reported by the patients at any time   of the study (CDSCO adverse drug reaction reporting form). (Annexure 3d)

J. Statistical Analysis:

The data collected will be analyzed statistically using descriptive statistics namely mean, standard deviation, percentage wherever applicable. Independent t - test/Mann-Whitney U Test will be used to determine significant difference between two groups. Paired t - test/Wilcoxon sign rank test will be used to determine significant difference between pre and post intervention. Chi-Square test used to determine association between qualitative variables. P<0.05 will be considered statistically significant, SPSS version 21.0 will be used for data analysis.

7.3 Does the study require any investigation to be conducted on patients or animals specify?

Study does not require any investigation to be conducted on patients or animals.

7.4 Has ethical clearance been obtained from ethics committee of your institution in case of 7.3?

     Institutional Ethics committee clearance awaited.