European Journal of Cardiovascular Medicine

Diabetic Peripheral Polyneuropathy (DPN) is a common and debilitating complication of diabetes mellitus, characterized by progressive nerve damage due to chronic hyperglycaemia, metabolic disturbances, and microvascular dysfunction [1]. It typically presents with symmetrical sensory symptoms such as tingling, burning, pain, and numbness, starting in the distal extremities (e.g., toes and feet) and gradually progressing proximally in a "stocking-glove" distribution [2-4].

In advanced cases, motor weakness, loss of proprioception, and autonomic dysfunction may occur, increasing the risk of foot ulcers, infections, and amputations. Management focuses on glycaemic control, symptom relief (e.g., with anticonvulsants, antidepressants, or analgesics), and preventive foot care to reduce complications [5, 6]. Early diagnosis and intervention are crucial to slowing progression and improving the quality of life for affected individuals.

Therapeutic options for Diabetic Peripheral Polyneuropathy (DPN) focus on glycaemic control, symptom management, and slowing disease progression [7]. Tight blood glucose regulation through lifestyle modifications, oral hypoglycaemics, or insulin therapy is foundational to prevent further nerve damage. For neuropathic pain, first-line pharmacologic treatments include anticonvulsants (e.g., pregabalin, gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine), and tricyclic antidepressants (e.g., nortriptyline) [8, 9]. 

Existing evidence comparing the efficacy and safety of pregabalin plus nortriptyline (Preg-Nort) versus pregabalin plus duloxetine (Preg-Dul) in diabetic peripheral neuropathy (DPN) is limited but suggests that both combinations may provide superior pain relief compared to monotherapy, with differing side effect profiles [10-12]. Some studies indicate that Preg-Nort may offer better analgesic effects in certain patients due to nortriptyline’s strong noradrenergic modulation, but it carries a higher risk of anticholinergic side effects (e.g., dry mouth, constipation, sedation). In contrast, Preg-Dul may be better tolerated, with duloxetine’s dual serotonin-norepinephrine reuptake inhibition providing synergistic pain control while posing fewer anticholinergic risks, though nausea and dizziness are common [10-12].

A few small trials suggest comparable efficacy between the two combinations, but Preg-Dul may be preferlred in patients with comorbid depression or anxiety due to duloxetine’s additional antidepressant effects [10-12]. Larger, well-controlled studies are needed to definitively establish the optimal combination, but current evidence supports individualized treatment based on patient comorbidities, tolerability, and response.

This study aims to address the research question: "How does the combination of Pregabalin with Nortriptyline compare to Pregabalin with Duloxetine in terms of efficacy and safety for patients with Diabetic Peripheral Polyneuropathy (DPP)?" The hypothesis posits that the combination of “Pregabalin and Nortriptyline” will provide greater pain relief and improved quality of life, with a comparable safety profile, than the combination of Pregabalin and Duloxetine in managing DPP.

The objective of this randomized controlled trial was “to evaluate and compare the efficacy, in terms of pain reduction and functional improvement, and the safety, based on adverse effects and tolerability, of these two therapeutic combinations in patients suffering from DPP.”  

Study Design

This was a “randomized, double-blind, controlled trial” comparing the efficacy and safety of “Pregabalin plus Nortriptyline (Preg-Nort) versus Pregabalin plus Duloxetine (Preg-Dul)” in patients with Diabetic Peripheral Polyneuropathy (DPP).

Participants

Patients aged 18-75 years with a confirmed diagnosis of DPP were recruited from multiple centers. Inclusion criteria included a history of diabetes mellitus for at least 5 years, presence of symptomatic DPP for at least 6 months, and a baseline pain score of ≥4 on “the Numeric Pain Rating Scale (NPRS).” Exclusion criteria included severe renal or hepatic impairment, history of drug or alcohol abuse, and concurrent use of other neuropathic pain medications.

The diagnosis of PDPN was primarily clinical, based on “a history of neuropathic pain and confirmatory examination findings, establishing deficits associated with neuropathy.” Patients with history of pain and numbness in hands and feet in "gloves and stocking" pattern will be included [13].

Interventions

Participants were randomly assigned to one of two treatment groups:

• Pregabalin + Nortriptyline (P+N): Pregabalin 75 mg/day and Nortriptyline 10 mg/day.
• Pregabalin + Duloxetine (P+D): Pregabalin 75 mg/day and Duloxetine 20 mg/day.

Both groups received their respective treatments for 12 weeks. The dosages were titrated up over the first 4 weeks to reach the target dose.

Outcomes

The primary outcome was the change in pain intensity measured by the VAS (visual analogue scale) from baseline to 12 weeks. Secondary outcomes included ISI, HADS-Scale and the incidence of adverse effects.

VAS score: Scores were based on self-reported measures of pain intensity ranging from 0: no pain to 10: worst pain. A higher score indicates greater pain intensity [14, 15].

Mean Insomnia Severity Index Score (ISI): The 7-item ISI self-report questionnaire assesses insomnia's nature, severity, and impact. The usual recall period is the "last month" and the dimensions evaluated are "sleep onset, maintenance, and early morning awakening problems, sleep dissatisfaction, sleep difficulties interfering with daytime functioning, sleep difficulties being noticed by others, and sleep related distress." Each item is scored on a 5-point Likert scale "0 = no difficulty, 4 = very severe problem" for a total score of 0 to 28. "Absence of insomnia (0–7), sub-threshold insomnia (8–14), moderate insomnia (15–21), and severe insomnia (22–28)" comprise the overall score [16].

Hospital Anxiety and Depression Scale – Anxiety score: Patients with physical health issues are assessed for anxiety and depression using the self-report "Hospital Anxiety and Depression Scale (HADS)." The HADS has 14 questions, 7 of which are about anxiety and 7 on depression. Question scores range from 0 to 3, with subscale scores up to 21. The scores for each HADS subscale are totaled to give an anxiety (HADS-A) or depression (HADS-D) score or a total score. "0-7 is normal, 8-10 is borderline, while 11-21 is abnormal [17].”

Safety assessments: The number and percentage of patients reporting at least one adverse event during the treatment protocol were assessed. Drug related adverse events will be defined as those adverse events that were related or possibly related to the study therapy. The frequently reported events were recorded.

Randomization and Blinding

Participants were randomly assigned to treatment groups using a computer-generated randomization sequence. Allocation concealment was ensured using sealed, opaque envelopes. Both participants and investigators were blinded to the treatment assignments.

Sample Size

With reported decrease in VAS of 1.48 ± 0.91 in group P + N and 2.27 in group P + D [14], minimum sample size required to achieve power of 95% with alpha value of 0.05 was found to be 68. To manage with 15% possible attrition rate, 80 patients were recruited with 40 patients in each group.

Statistical Methods

The data was compiled and coded on a Microsoft Excel spreadsheet (version- 365). Data analysis was performed using Statistical Package for Social Sciences (SPSS) for Windows version 24.0 (SPSS Inc., Chicago, IL). Descriptive analysis was performed using “frequency and proportions for categorical variables and mean ± SD for continuous variables”. Mean clinical score was expressed as mean ± SD and was compared between two groups using an unpaired t-test. “Chi-square or Fisher’s exact test” was used for comparison of categorical data such as gender, frequency of patients with ADR, etc. A p-value of less than 0.05 was taken as a measure of statistical significance.

Ethical Considerations

The study was approved by “the Institutional Ethics Committee” (vide Letter No: 1427/IEC/IGIMS/2024). Written informed consent was obtained from all participants before enrolment

Follow-Up

Participants were followed up at 4, 6-, 8-, 10-, and 12-weeks post-randomization. Pain assessments and adverse effect monitoring were conducted at each follow-up visit.   

A total of 212 individuals were assessed for eligibility; of these, 132 were excluded for failing to meet inclusion criteria (n = 124) or declining to participate (n = 8), resulting in 80 participants available for randomization. The participants were randomly assigned to one of two groups: P+D and P+N, with all participants in both groups receiving the assigned intervention. During follow-up, 7 participants from the P+D group and 4 from the P+N group were lost, either before or after the first visit at 4 weeks. In the analysis phase, data from 36 participants in the P+D group and 38 in the P+N group were analysed [Figure 1]. 

Table 1: Comparison of Baseline Demographic and Clinical Characteristics between P + D versus P + N Group

“Values expressed as percentage for categorical data and mean ± SD for continuous data. P values are from the Fisher exact test.  P+D: Pregabalin + Duloxetine; P+N: Pregabalin + Nortriptyline; BMI: body mass index; HbA1c: glycated haemoglobin; FBS: fasting blood glucose; TG: triglyceride; LDL: low-density lipoprotein; HDL: high-density lipoprotein.”  

The table compares baseline demographic and clinical characteristics between P+D and P+N groups, showing no significant differences (p > 0.05) in gender distribution, age, glycaemic control (FBS, HbA1c), lipid profiles (TG, Chol, LDL, HDL), diabetes duration, or BMI categories, indicating well-matched groups at baseline. Both groups had a similar proportion of females (~89%), mean ages around 56–57 years, and comparable metabolic parameters, with slightly higher (but statistically insignificant) insulin use in the P+D group (27.78% vs. 15.79%, p=0.3993). [Table 1]

Table 2: Comparison of Pain Severity using VAS Scale between P + D versus P + N Group

At baseline, both groups had similar pain scores (P+D: 7.26 ± 1.54 vs. P+N: 7.39 ± 1.92, p=0.750), confirming comparable initial pain levels. However, by 4 weeks, the P+D group showed significantly greater pain reduction (4.18 ± 1.21 vs. 4.88 ± 1.35, p=0.022), a trend that persisted at 6 weeks (3.22 ± 0.94 vs. 4.17 ± 1.18, p<0.001), 8 weeks (3.06 ± 0.88 vs. 3.53 ± 1.01, p=0.037), and 10 weeks (2.80 ± 0.81 vs. 3.24 ± 0.93, p=0.034). Although the difference at 12 weeks narrowed (2.41 ± 0.70 vs. 2.76 ± 0.83, p=0.054), the P+D group consistently demonstrated superior pain relief throughout most follow-ups, suggesting that P+D may provide faster and more effective analgesia compared to P+N in diabetic peripheral neuropathy. The diminishing significance at 12 weeks may indicate converging long-term efficacy, though early advantages favour P+D. [Table 2]

Table 3: Comparison of Insomnia Severity Index between P + D versus P + N Group

At baseline, both groups had similar ISI scores (P+D: 10.32 ± 2.19 vs. P+N: 10.19 ± 2.06, p=0.793), indicating comparable initial insomnia levels. However, at 4 weeks, the P+N group showed significantly greater improvement in insomnia (7.91 ± 1.87 vs. 9.67 ± 2.05, p=0.0002), suggesting that nortriptyline may provide faster relief for sleep disturbances compared to duloxetine when combined with pregabalin. By 8 and 12 weeks, the differences between groups diminished (8 weeks: 6.36 ± 1.51 vs. 6.79 ± 1.60, p=0.238; 12 weeks: 5.55 ± 1.32 vs. 5.96 ± 1.44, p=0.205), indicating that both combinations ultimately achieved similar long-term improvements in insomnia. [Table 3]

Table 4: Comparison of HADS-A between P + D versus P + N Group

At the start, the P + D and P + N groups had similar levels of HADS-A (p=0.928440). Both groups' anxiety levels went down from 4 weeks to 12 weeks, but the changes were not statistically significant (p=0.449964 at 4 weeks, p=0.666023 at 8 weeks, and p=0.720123 at 12 weeks). During the study, both therapies may have helped reduce anxiety, but neither was significantly more efficient. [Table 4] 

Table 5: Comparison of HADS-D between P + D versus P + N Group

At the start, the P + D and P + N groups had similar HADS-D (p=0.871352). At 4 weeks, the results were the same (p=0.845719). The P+D group had a much lower HADS-D score than the P+N group after 8 weeks (p=0.048742), and this difference stayed the same after 12 weeks (p=0.029147). This indicates that over time, the P+D intervention cut down on HADS-D scores more than the P+N intervention. [Table 5]

Table 6: Comparison of Adverse Effects (Depression Score) between P + D versus P + N Group

Nausea and vomiting were more common in P + D, while dry mouth was more common in P + N. [Table 6]

The two groups were very similar in age, fasting blood sugar, cholesterol, as well as BMI distribution, and 89% of them were women. The amount of insulin and oral diabetes drugs used was about the same, but P + N people used them more. From four weeks to twelve weeks, the P+D group's pain got a lot better. In the P+D group, ISI was much less severe at 4 weeks, but it got worse over time. HADS-A follows a similar pattern in both groups at all times. Between 8 and 12 weeks, there was a significant decrease in HADS-D level. More people in the P+D group had nausea and vomiting, while more people in the P+N group had dry mouth. Over time, the P+D intervention led to improvement in pain, anxiety, and depression.

The observed therapeutic outcomes can be explained by the distinct pharmacodynamic mechanisms of P+D versus P+N in neuropathic pain management. Pregabalin, a calcium channel α2-δ ligand, modulates presynaptic neurotransmitter release, particularly glutamate, norepinephrine, and substance P, thereby reducing neuronal hyperexcitability. Duloxetine, a SNRI, potentiates descending inhibitory pain pathways by enhancing synaptic concentrations of serotonin and norepinephrine in the central nervous system, while also addressing comorbid depressive symptoms through its dual monoaminergic action. This synergistic combination (P+D) likely results in more comprehensive neuromodulation, leading to superior and sustained analgesia, as evidenced by the significant early and sustained reductions in VAS scores [18, 19]. In contrast, while nortriptyline—a TCA—also inhibits norepinephrine reuptake and exhibits sodium channel-blocking properties that contribute to neuropathic pain relief, its broader anticholinergic, antihistaminergic, and antiadrenergic effects may limit tolerability (e.g., dry mouth, sedation) and reduce long-term adherence. Furthermore, duloxetine’s more selective pharmacologic profile and favorable side-effect kinetics may explain the P+D group’s better balance between efficacy and tolerability, particularly in patients with concurrent mood disorders. These mechanistic distinctions underscore why P+D demonstrated superior pain control and potentially greater applicability in diabetic neuropathy, where both pain and affective comorbidities frequently coexist. Further pharmacogenetic and receptor-binding studies could refine patient-specific selection between these regimens [18, 19].

This backs up earlier research like Zakerkish et al. (2017), which showed that there was no significant difference between duloxetine and nortriptyline in how well they relieved DNP pain [20]. Both studies show that duloxetine is a good choice for TCA-affected people, even though it may cost more than nortriptyline.

Our results back up Bayani et al.'s (2021) opinion that both duloxetine and nortriptyline can help with DNP. Similar to what we found, Bayani et al. also found that both medicines made the pain a lot less severe. Both of our patients did well with duloxetine and nortriptyline, and their study showed that they didn't have any major side effects [21]. These drugs for neuropathic pain have been shown to work consistently in different studies. This means they can be trusted in real life.

Begum et al. (2023) compared pregabalin to duloxetine and nortriptyline. This helped us learn more about how to treat neuropathic pain. Our study only looked at duloxetine and nortriptyline. However, Begum et al. think that pregabalin may also be an option, though it works in a different way [14]. The study by Khajuria et al. (2021) that looked at postherpetic neuralgia and compared pregabalin and nortriptyline shows that the same results are true for other types of neuropathic pain [19]. Our work backs up earlier research that duloxetine and nortriptyline can be used to treat diabetic neuropathic pain. Several studies have shown that these drugs are safe and effective, but they also stress the need for individualized care that takes into account each patient's tolerance and side effects. Neuropathy pain management is always changing, so more research is needed to make treatments better and help patients get better results.

There are a few limitations with our work. It's possible that the sample size was too small to find small but clinically important differences between the treatment groups. Second, the length of the study may not be long enough to see long-term effects and treatment sustainability, but it is long enough for beginning observations. Third, measuring pain, insomnia, anxiety, and sadness based on self-reports may add bias. The study's participants were mostly women, which means it might not work as well with a more diverse group of people. Finally, the patient's lifestyle, drug compliance, and other therapies were not properly managed, which could have had an effect on the results. To fix these problems, future studies should use larger and more diverse groups of people, longer follow-up times, objective tests, and controls for confounding variables.

Our study shows that pregabalin + duloxetine reduces pain and depression intensity in diabetic peripheral neuropathic pain better than nortriptyline. The pregabalin with duloxetine treatment improved pain and depression over 12 weeks; however, sleeplessness intensity decreased over time. Anxiety decrease was similar with both therapies. The adverse effect profiles differ, with higher nausea and vomiting in the pregabalin plus duloxetine group and more dry mouth in the nortriptyline group. These data help clinicians choose diabetic peripheral neuropathic pain treatments.  

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