CTIM Journal

Introduction

One of the most common chronic complications of patients with type 2 diabetes, diabetic neuropathy has an impact on quality of life and is highly costly in healthcare [1, 2]. The burning, tingling or shooting variety of pain from neuropathic pain can cause reduced mobility and psychological distress [3]. Regulatory agencies worldwide approved duloxetine, an SNRI, as an antidepressant used for the management of diabetic neuropathic pain; however, its efficacy as monotherapy has also been reported to show only modest benefits in several randomized trials [4,5]. In addition, the therapy may not sufficiently improve the condition, and frequent side effects may limit its long-term use.

Over the past couple of years, there has been a focus on adjunctive therapies that may contribute to the therapeutic effects provided by the currently available pharmacological therapies. Even though alpha-lipoic acid (ALA) is a naturally occurring antioxidant, it has been reported to attenuate oxidative stress and improve nerve conduction in diabetic patients [6, 7]. Also, preclinical studies have shown that ALA has anti-inflammatory effects, reduces reactive oxygen species and might help the alleviation of neuropathic pain [8]. On a clinical scale, small-scale trials have suggested that ALA may alleviate symptoms when taken together with standard neuropathic pain medication [9, 10]. Nevertheless, very little comparative data exists to determine the efficacy of duloxetine when combined with ALA versus duloxetine alone in diabetic neuropathy.

Because the mechanism rationale for a synergistic effect of the neuromodulatory actions of duloxetine along with the antioxidant properties of ALA was what motivated the design of this study, they directly compared the two regimens. In that, we hypothesized that there would be more reduction in pain intensity and more improvement in nerve conduction parameters and QOL outcomes with the combination therapy versus duloxetine monotherapy. This multicenter trial adheres strictly to a code of ethics and rigorous methodologies with the aim of providing clinically relevant data, which may help provide optimal treatment in the field of diabetic neuropathy.

Methods

Study Design and Participants

This was an open-label, randomized controlled trial conducted between January 2021 and December 2024 at four tertiary care centres in Karachi, Pakistan. All participating centres received approval of the study protocol by their institutional boards, and written informed consent of all participants was obtained. The trial adhered to the Declaration of Helsinki and Good Clinical Practice [11].

As participants, adults aged 40–70 years were eligible with type 2 diabetes mellitus according to the American Diabetes Association criteria [12] and a clinical diagnosis of diabetic neuropathy confirmed by nerve conduction studies. Patients with active cardiovascular disease or medical history of major psychiatric disturbances, including psychosis or suicidal tendency, were excluded from this study if they had significant hepatic or renal impairment. The use of other neuropathic pain medications or antioxidants was not permitted at the time of the study.

Randomization and Interventions

This was a phase 3, randomized, 1:1 computer-generated ratio stratified by center trial. Duloxetine was given at 60 mg daily to the duloxetine group, and the same dose of duloxetine plus 600 mg daily of oral alpha-lipoic acid to the combination group. Treatment duration was 12 weeks for both groups. Pill count at each follow-up visit was assessed as compliance.

Sample Size

Prior studies were based on a mean difference of 1.5 points on the Visual Analog Scale (VAS) to represent clinically significant differences [13, 14]. The performed calculation assumed a standard deviation (SD) of 1.8, an alpha error of 0.05, and a power of 80%, and the sample size needed per group was about 90 subjects per group. After taking account of the expected dropout rate of 10%, we enrolled 100 patients in each arm, yielding a total of 200 patients. Nevertheless, 224 patients were finally enrolled to further enhance statistical reliability and to compensate for possible intercenter variations.

Outcome Measures

Change on the 10 cm Visual Analog Scale (VAS) neuropathic pain intensity between baseline and 12 weeks was the primary outcome. Secondary outcomes included:

Changes in the Diabetic Neuropathy Quality of Life (DN-QOL) score.

Nerve conduction velocity (NCV) measurements of the sural and peroneal nerves.

Adverse events were recorded and assessed in terms of safety and tolerability.

Investigator-blinded assessments were performed at baseline, week 4, week 8 and week 12.

Statistical Analysis

SPSS version 26 (IBM Corp., Armonk, NY, USA) was used to analyze data. Categorical variables were presented as percentages and continuous as mean ± SD. Intergroup comparisons of continuous outcomes were carried out by means of an independent t test and the chi square test for categorical variables. Changes over time were evaluated within groups with a repeated measures ANOVA. Statistical significance was declared if p value was less than 0.05. The intention-to-treat principle was adhered to during all the analyses.

Results

Participant Flow and Baseline Characteristics

A total of 238 patients were screened, of whom 224 met the inclusion criteria and were randomized equally between the two treatment arms. Twenty patients (9%) were lost to follow-up, with 210 patients completing the study (105 in the duloxetine group and 105 in the combination group). Baseline demographics and clinical characteristics were comparable between groups (Table 1).

Table 1: Baseline Demographics and Clinical Characteristics

There were no statistically significant differences in baseline characteristics between the two groups, indicating effective randomization.

Primary Outcome: Change in VAS Pain Scores

At 12 weeks, the combination therapy group demonstrated a significantly greater reduction in mean VAS pain scores compared to the duloxetine monotherapy group.

• Duloxetine group: mean VAS score reduced from 7.8 ± 1.0 to 5.7 ± 1.2 (Δ = 2.1 ± 1.3).
• Combination group: Mean VAS score reduced from 7.9 ± 0.9 to 4.7 ± 1.0 (Δ = 3.2 ± 1.1).

The between-group difference was statistically significant (p < 0.001) (Figure 1).

Figure 1: Mean VAS Pain Scores Over 12 Weeks

Secondary Outcomes

Quality of Life

The DN-QOL score improved in both groups, with the combination group showing a significantly higher mean improvement (Δ = 15.6 ± 4.2) compared to the duloxetine group (Δ = 10.3 ± 3.8; p < 0.001).

Nerve Conduction Velocity (NCV)

NCV improved modestly in both groups; however, the combination group demonstrated a statistically significant increase compared to monotherapy (sural nerve: 42.5 ± 4.6 m/s vs. 39.0 ± 4.8 m/s; p = 0.002).

Adverse Events

Adverse events were mild and transient, with no statistically significant differences in frequency between groups. The most common adverse events included nausea, dizziness, and dry mouth (Table 2).

Table 2: Primary and Secondary Outcome Measures.

Figure 2: Distribution of Adverse Events

Additional Analyses

A repeated measures ANOVA confirmed a significant time-treatment interaction for VAS scores (F = 12.3, p < 0.001). Subgroup analyses based on age, duration of diabetes, and baseline HbA1c revealed consistent benefits of combination therapy across all subgroups. No serious adverse events related to the study medications were recorded.

Discussion

The combination of duloxetine and alpha-lipoic acid results in better results of pain relief and functional improvement in diabetic neuropathy patients compared to duloxetine monotherapy, and this is shown in this randomized controlled trial. Our hypothesis is consistent with and extends previous observations in smaller studies [9, 10, 15], and the statistically significant greater reductions in VAS pain scores and improvement in DN-QOL scores in the combination group support the hypothesis.

Mechanistic Insights

Duloxetine’s action as an SNRI modulates central pain pathways by preferentially increasing synaptic availability of serotonin and norepinephrine [16]. Although limited efficacy as a stand-alone therapy in diabetic neuropathy is likely due to the multifactorial pathogenesis of nerve damage in which oxidative stress is central, its use as an adjuvant therapy has been investigated in some patients with diabetic neuropathy [17]. As a potent antioxidant, alpha-lipoic acid helps mitigate oxidative stress and in turn may enhance nerve conduction velocities, as has occurred [7, 18]. The combination, therefore, targets both the neurochemical and oxidative components of diabetic neuropathy.

Clinical Implications

Our results suggest that alpha-lipoic acid could be used as an adjunctive agent with duloxetine and provide better symptomatic control of diabetic neuropathy. In particular, these results are highly relevant since diabetic neuropathy is a major cause of morbidity and many patients do not obtain adequate pain relief with current monotherapies [2, 5]. In addition, this suggests that combination therapy holds promise in a real-world clinical setting.

Comparison with Previous Studies

Duloxetine alone has been reported to have modest benefits in recent meta-analyses and small-scale trials and a few studies have exhibited beneficial effects of ALA with no direct comparison of the two regimens [13, 14, 19]. The combination regimen is superior to the single regimen, as perpicted by our study with a relatively large sample size and multicenter design. Further work on the long-term neuroprotective effects of the improvements in NCV observed in the combination group also suggests that they deserve further exploration [20].

Strengths and limitations

There are two major strengths of this trial: it was randomized, the sample size of this trial was calculated with the previous literature and it strictly adhered to ethical guidelines. However, the study was not blinded, although blinded outcome assessors were used. Moreover, as the duration of the intervention is relatively short (particularly when compared with the duration of treatment needed for known therapeutic interventions), it is not possible to assess long-term therapeutic effect and sustainability. These findings were confirmed to follow future studies with extended follow-up and in a placebo-controlled setting to explore the underlying molecular mechanisms [21].

Subgroup and Sensitivity Analyses

Subgroup analyses confirmed that the benefits of combination therapy were consistent regardless of patient age, diabetes duration, or glycemic control. Sensitivity analyses excluding patients with protocol deviations yielded similar results, supporting the robustness of our findings.

Future Directions

Ongoing research should explore whether combination therapy may delay the progression of neuropathic changes over time and whether similar benefits are observed in patients with other forms of peripheral neuropathy. Furthermore, studies investigating the optimal dosing regimen and potential pharmacodynamic interactions between duloxetine and ALA could refine clinical protocols.

Overall, the present study adds to the growing body of evidence supporting a multimodal therapeutic approach for diabetic neuropathy, addressing both neurochemical imbalances and oxidative stress-mediated nerve damage. (Approximately 1000 words)

Conclusion

To summarize, these multicenter randomized controlled trials show more definitive benefit with combined duloxetine and alpha-lipoic acid than with duloxetine monotherapy on pain reduction, improvement in primary measures of nerve conduction and quality of life in patients with diabetic neuropathy. The large reduction in pain scores (VAS) and significant improvements in DN-QOL metrics, along with the increased nerve conduction velocity in the combination group, suggests that a dual mechanism way of targeting both neurotransmitter imbalances and oxidative stress may have the potential to help patients. As diabetic neuropathy is a chronic and debilitating disease state, these findings represent an optimal therapeutic strategy. For this, longer-term studies are necessary to evaluate long-term benefits and if such effects also serve as neuroprotective. Thus, combination therapy may be an option clinician choose to improve the patient's outcome in diabetic neuropathy and provide broader management of this challenging condition.

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