Evaluating the efficacy and safety of duloxetine and gabapentin in managing diabetic neuropathy: A systematic review and meta-analysis

Abstract

Background and objective

Painful diabetic neuropathy (PDN) is a common complication of diabetes, characterized by significant pain and functional impairment. Gabapentin and duloxetine are standard treatments. This study compared their efficacy in alleviating pain, improving clinical global impression of change (CGIC), reducing sleep interference, enhancing response rates, and assessing safety.

Methods

A systematic review and meta-analysis was conducted following PRISMA guidelines. A search of Embase, Medline, ScienceDirect, Scopus, Web of Science, and Cochrane databases through May 2024 identified randomized controlled trials comparing gabapentin and duloxetine for PDN. Risk of bias was assessed using the Cochrane RoB2 tool. Data on pain, CGIC, sleep interference, responder rates, and adverse events were analyzed using a random-effects model, with results presented as standardized mean differences and risk ratios with 95% confidence intervals.

Results

Six RCTs with 526 patients (44% female) were included. There was no significant difference between duloxetine and gabapentin in relieving pain (SMD = −0.16, 95% CI [−0.36, 0.03], p = .10, I² = 66%). No significant differences were observed in the overall effect of CGIC (MD = 0.01, 95% CI [−0.07, 0.09], p = .79, I² = 0%), or sleep interference (MD = −0.07, 95% CI [−0.36, 0.23], p = .67, I² = 39%); However, duloxetine showed superiority at week 1 for CGIC (MD = 0.56, 95% CI [0.18, 0.94], p = .003), and week 8 for sleep interference (MD = −0.40, 95% CI [−0.79, −0.01], p = .04, I² = 0%), while gabapentin was superior at week 1 in sleep interference (MD = 0.75, 95% CI [0.11, 1.39], p = .02). No significant differences were observed in responder rates or adverse events.

Conclusion

Gabapentin and duloxetine are effective for PDN, with distinct advantage at different time points. Personalized treatment is recommended, and future research should assess long-term efficacy in diverse populations.

Introduction

Painful diabetic neuropathy (PDN) is a common complication of Diabetes Mellitus (DM) characterized by chronic pain resulting from peripheral nerve damage, after ruling out other potential causes of nerve injury. ¹ This condition typically manifests in the lower extremities, often worsening at night, and may be accompanied by symptoms such as allodynia, hyperalgesia, and paresthesia. Distal symmetrical polyneuropathy is the most prevalent form of PDN. ² Approximately 50% of patients with diabetes develop peripheral neuropathy within 25 years, with a reported prevalence of PDN among Type 2 DM patients with diabetic neuropathy as high as 57.2%.^3,4 The pathophysiological mechanisms underlying PDN are multifactorial and not fully understood, involving prolonged hyperglycemia, obesity, smoking, hypertension, and dyslipidemia. ⁵ While optimal glucose control and lifestyle modifications remain crucial for managing diabetic complications, pharmacological interventions are essential for alleviating PDN symptoms. ⁶ Current clinical guidelines recommend the use of both antidepressants and anticonvulsants for the management of PDN, recognizing the need for effective pharmacological interventions in alleviating neuropathic pain. Duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), has shown efficacy in reducing pain by increasing norepinephrine and serotonin levels in the central nervous system. ⁷ However, its use can be limited by side effects such as nausea, dizziness, and increased blood pressure. In contrast, gabapentin, an anticonvulsant, works by modulating neurotransmitter activity to inhibit the release of excitatory signals, providing pain relief. ² While generally well-tolerated, gabapentin may lead to sedation, dizziness, and the potential for dependency. ⁸ Given the increasing prevalence of PDN and the significant impact it has on patients’ quality of life, it is essential to compare the efficacy and safety of available treatments. This systematic review and meta-analysis aim to compare the efficacy of duloxetine and gabapentin in pain relief, improvement of the Clinical Global Impression of Change, reduction of sleep interference, enhancement of response rates, and evaluation of their safety profiles.

Materials and methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and the pre-specified protocol was registered in PROSPERO (CRD42024544425).

Eligibility criteria

This systematic review included only studies that fulfilled the following criteria: (1) randomized controlled trials (RCTs); (2) studies diagnosing painful diabetic neuropathy; (3) studies evaluating both duloxetine and gabapentin as interventions for PDN; and (4) studies that measured the Visual Analogue Scale (VAS), Clinical Global Impression of Change (CGIC), and Sleep Interference Score. Conversely, review articles, non-English articles, animal studies, non-randomized controlled trials, and articles without full text were excluded.

Search strategy

A detailed search was performed in Embase, Medline, ScienceDirect, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases. The literature was systematically searched from inception until 10 May 2024, without any language restrictions. The following Medical Subject Headings (MeSH) terms and keywords were used in the search: (painful diabetic neuropathy) OR (diabetic neuropathy) AND (duloxetine) AND (gabapentin) AND (randomized controlled trials) OR (clinical trial) OR (controlled study) OR (trial).

Study selection and data extraction

After removing all duplicates, two authors independently started the process of study selection and data extraction, primarily based on the abstract and title, followed by full-text evaluation. Any disagreements were discussed and resolved, and if necessary, a third reviewer was consulted. A data collection sheet was used to extract the following: country, study design, main inclusion and exclusion criteria, type of DM, sample size, patient characteristics, dosage of interventions, duration of interventions, time points of outcome measurements, mean and standard deviation of intended outcomes for both interventions. These outcomes included VAS, CGIC, sleep interference score at baseline and post-intervention, response rate, and adverse events.

Study outcomes

Data on pain, sleep interference, and clinical condition were systematically collected using standardized assessment tools to compare the effects of duloxetine and gabapentin. Data from each scale were recorded at predetermined time points, specifically the 1st, 2nd, 4th, 8th, and 12th weeks. The VAS and the Numerical Pain Rating Scale (NPRS) were used to evaluate the effectiveness of the interventions in alleviating the intense pain associated with PDN. It is noteworthy that while some studies utilized a rating scale of 1 to 10, others used a scale of 1 to 100. To facilitate a consistent analysis, all ratings were standardized to a common scale of 1 to 10. Furthermore, the sleep interference score, which includes six distinct domains, was implemented to assess the efficacy of both interventions in improving the sleep quality of patients with PDN. Improvements in quality of life and overall clinical condition were evaluated using the CGIC. Additionally, response rates were reported in several studies to assess the effectiveness of the interventions. Definitions and thresholds for responder rates varied, with reductions of 25%, 50%, and 75% in VAS from baseline considered across different studies. Finally, adverse events were systematically reviewed and compared between the two intervention groups.

Risk of bias and quality assessment

Following the Revised Cochrane Risk of Bias Tool (RoB2), two authors independently examined the risk of bias for each RCT. The studies were subsequently classified into categories of low risk, high risk, or some concerns based on the overall bias evaluation. In cases of disagreement, discussions were held with a third author to resolve.

Statistical analysis

Data were analyzed using RevMan 5.3 software (Cochrane Collaboration). A 95% confidence interval (CI) was applied, and a p-value of less than 0.05 was considered statistically significant. The statistical methods utilized included inverse variance and a random effects model. Dichotomous data were presented as risk ratios (RR), while continuous data were analyzed using two approaches. For outcomes with differing scores, such as VAS and NPRS for pain assessment, standardized mean differences (SMDs) were calculated. Conversely, if the outcome was assessed using a single scoring system, the mean difference (MD) was utilized. The I² statistic was used to assess statistical heterogeneity among the included studies. If the I² value exceeded 50%, a sensitivity analysis was conducted to identify potential sources of high heterogeneity and to examine its impact on the p-value.

Results

Study selection

A total of 2522 studies were identified through the previously mentioned databases using the specified keywords. After removing 1141 duplicates, 1467 records remained for title and abstract screening. Following this screening process, eligible articles underwent full-text review, resulting in the final inclusion of six studies that met the eligibility criteria for inclusion in this systematic review and meta-analysis.^1,2,5–7,9 (Supplemental Figure 1).

Study characteristics

Details regarding study characteristics can be found in Table 1. The included RCTs^1,2,5–7,9 comprised a total of 526 patients, with females accounting for 231 participants (44%) across both treatment groups. The mean ages in the duloxetine group ranged from 48.37 to 59.7 years, while the gabapentin group ranged from 47.4 to 60.7 years. Moreover, four of the studies were conducted in India,^1,2,7,9 and one each in Iran ⁶ and Bangladesh. ⁵ The types of diabetes mellitus investigated varied among the studies: one focused on type 1 diabetes mellitus (T1DM), ² one on type 2 diabetes mellitus (T2DM), ¹ three addressed both types,^5,7,9 and one study did not report the type of DM investigated. ⁶ The mean VAS baseline range was 5.50 to 7.24 and 5.36 to 7.34 for the duloxetine and gabapentin groups, respectively. Intervention specifics of each study are summarized in Table 2.

Table 1.

Study characteristics.

Study	Country	Study design	Age in years, mean ± SD	Female n (%)	Total number of patients	Type of DM	Pain at baseline (VAS, NPRS)
Khasbage et al.	India	Randomized, parallel group, active-control, open-label trial	Duloxetine 53 ± 8.37	Duloxetine 16 (37.2%)	86	T2DM	Duloxetine 7.24 ± 0.85
			Gabapentin 55.9 ± 10.75	Gabapentin 18 (41.9)			Gabapentin 7.34 ± 1.06
Begum et al.	India	Comparative randomized, double-blind, parallel-group study	Duloxetine 48.37 ± 7.85	Duloxetine 17 (56.7%)	60	T1DM	Duloxetine 5.50 ± 0.68
			Gabapentin 47.40 ± 7.58	Gabapentin 15 (50%)			Gabapentin 5.36±0.79
Ahmad et al.	Bangladesh	Prospective comparative clinical study	Duloxetine 51.32 ± 8.90	Duloxetine 16 (51.6%)	64	T1DM	Duloxetine 6.84 ± 1.07
			Gabapentin 52.21 ± 8.08	Gabapentin 22 (66.7%)		T2DM	Gabapentin 6.70 ± 1.16
Majdinasab et al.	Iran	Prospective, randomized, double-blind, parallel-group trial	Duloxetine 59.7 ± 5.59	Duloxetine 28 (53.8%)	104	NR	Duloxetine 6.1 ± 2.12
			Gabapentin 60.7 ± 5.66	Gabapentin 31 (59.6%)			Gabapentin 6.3 ± 2.00
Sagar et al.	India	Prospective, randomized, double-blind, parallel-group study	Duloxetine 50.21 ± 5.66	30 (50%)	60	T1DM	Duloxetine 6.82 ± 1.16
			Gabapentin 51.32 ± 5.69			T2DM	Gabapentin 6.02 ± 0.66
Devi et al.	India	Randomized, open-label, comparative study	Duloxetine 58.48 ± 8.8	Duloxetine 23 (46%)	152	T1DM	Duloxetine 5.71 ± 1.62
			Gabapentin 57.22 ± 10.5	Gabapentin 15 (30%)		T2DM	Gabapentin 6.01 ± 1.75

SD: Standard deviation, T1: Type 1, T2, Type 2, DM: Diabetes mellitus, VAS: visual analogue scale, NPRS: Numeric Pain Rating Scale.

Table 2.

Intervention details.

Study	Intervention A (Dose)	Intervention B (Dose)	Duration of intervention	Time points of outcome measurement (weeks)	Outcome measurement		Response rate
					Primary effect (pain)	Secondary effect (pain interfering with sleep, QoL, overall clincal state)
Khasbage et al.	Duloxetine (60 mg, QD)	Gabapentin (300 mg, QD)	12 weeks	At the end of weeks 6 and 12	VAS	NDS, DNS, DNE	50% reduction in VAS, NDS, DNS, DNE
Begum et al.	Duloxetine (60 mg, QD)	Gabapentin (300 mg, QD)	12 weeks	VAS: at the end of weeks 4, 8, 12	VAS, SF-MGQ, PGIC	30% reduction in VAS	NR
				SF-MGQ: at week 12
				PGIC: at week 12
Ahmad et al.	Duloxetine (30 mg)	Gabapentin (300 mg)	12 weeks	At the end of weeks 4, 8, 12	NRPS, PGIC, CGIC	NR	NR
Majdinasab et al.	Duloxetine (30 – 60 mg, QD)	Gabapentin (300 - 900 mg, QD)	8 weeks	At the end of weeks 1, 4, 8	VAS	Sleep interference score, CGIC	NR
Sagar et al.	Duloxetine (30 mg, BID)	Gabapentin (300 mg, BID)	12 weeks	At the end of weeks 4, 8, 12	NPRS	Sleep interference score, CGIC	NR
Devi et al.	Duloxetine (20 - 120 mg, QD)	Gabapentin (300 – 1800 mg, QD)	12 weeks	At the end of weeks 4, 8,12	VAS	Sleep interference score, PGIC, CGIC	NR

DLX: duloxetine, GBP: gabapentin, QD: once a day, BID: twice a day, VAS: visual analog scale, SF-MGQ: short form McGill pain questionnaire, NPRS: numerical pain rating scale, PGIC: patient global impression of change, CGIC: clinical global impression of change, NDS: neuropathic disability score, DNS: diabetic neuropathy symptom, DNE: diabetic neuropathy examination, QoL: quality of life, SF-36: short form-36, NR: not reported.

Risk of bias assessment

The risk of bias assessment, conducted using the Rob2 tool, revealed a spectrum of concerns across the included studies (Supplemental Figure 2) and (Supplemental Figure 3). Two studies were classified as having an overall high risk of bias.^5,6 Specifically, in the study by Ahmad et al., three domains were deemed to be at high risk, owing to the use of an inappropriate statistical analysis model, the absence of outcome data for 11% of participants, and insufficient information regarding the blinding process. ⁵ Additionally, Majdinasab et al. exhibited a high risk in domain two due to inadequate reporting on the analytical methods employed. ⁶ The study by Khasbage et al. was deemed to have some concerns due to utilizing an inappropriate method of analysis. ¹ Conversely, three studies were evaluated as having an overall low risk of bias.^2,7,9 A comprehensive summary of the risk of bias data is presented in (Table 3).

Table 3.

Justification of risk of bias assessment.

Study	Domain 1: Randomization process		Domain 2: Deviations from intended intervention		Domain 3: Missing outcome data		Domain 4: Measurement of the outcome		Domain 5: Selection of reported result		Overall risk of bias
Khasbage et al.	Low risk	-	Some concern	An inappropriate analysis method was utilized “per-protocol”	Low risk	-	Low risk	-	Low risk	-	Some concern
Begum et al.	Low risk	-	Low risk	-	Low risk	-	Low risk	-	Low risk	-	Low risk
Ahmad et al.	Some concern	No information is available on the randomization and concealment process	High risk	No information is available on any type of blinding, and the analysis model was inappropriate	High risk	Outcome data were not available for a significant portion of the patients, and there was insufficient evidence to support the absence of bias	High risk	No information is available on the blinding of outcome assessors	Some concern	No information is available on the multiple-used analyses and pre-specified plan	High risk
Majdinasab et al.	Low risk	-	High risk	No information is available on the analysis model	Low risk	-	Low risk	-	Low risk	-	High risk
Sagar et al.	Low risk	-	Low risk	-	Low risk	-	Low risk	-	Low risk	-	Low risk
Devi et al.	Low risk	-	Low risk	-	Low risk	-	Low risk	-	Low risk	-	Low risk

Pain

All six studies evaluated pain intensity using either the VAS or NPRS.^1,2,5–7,9 The pooled analysis indicated no significant overall difference in pain relief between duloxetine and gabapentin (SMD = −0.16, 95% CI [−0.36, 0.03], p = .10, I² = 66%). Upon performing sub group analysis, no significant differences were observed at week 1 (SMD = 0.18, 95% CI [−0.21, 0.56], p = .37), week 4 (SMD = −0.10, 95% CI [−0.34, 0.13], p = .39, I² = 28%), week 8 (SMD = −0.24, 95% CI [−0.59, 0.10], p = .17, I² = 65%), or week 12 (SMD = −0.23, 95% CI [−0.74, 0.29], p = .39, I² = 83%) (Figure 1). A sensitivity analysis excluding the study by Begum et al. ² from all subgroups resulted in a significant reduction in overall heterogeneity (SMD = −0.01, 95% CI [−0.13, 011], p = .83, I² = 0) (Supplemental Figure 4).

Figure 1.

Forest plot of pain at different time points.

Clinical global impression of change

Only four studies among the included RCTs assessed the CGIC.^5–7,9 The pooled analysis indicated no significant difference between duloxetine and gabapentin (MD = 0.01, 95% CI [−0.07, 0.09], p = .79, I² = 0%). A subgroup analysis at various time points revealed a significant advantage for duloxetine at week 1 (MD = 0.56, 95% CI [0.18, 0.94], p = .003). In contrast, no significant differences were noted between the two interventions at week 4 (MD = −0.07, 95% CI [−0.23, 0.08], p = .36, I² = 0%), week 8 (MD = −0.01, 95% CI [−0.12, 0.11], p = .93, I² = 0%), or week 12 (MD = 0.04, 95% CI [−0.15, 0.22], p = .70, I² = 0%) (Figure 2).

Figure 2.

Forest plot of clinical global impression of change at different time points.

Sleep interference score

Only three studies among the included trials assessed and reported the sleep interference score.^6,7,9 The pooled analysis indicated no significant difference between the two interventions (MD = −0.07, 95% CI [−0.36, 0.23], p = .67, I² = 39%). A subgroup analysis across multiple time points revealed a significant advantage for gabapentin over duloxetine at week 1 (MD = 0.75, 95% CI [0.11, 1.39], p = .02) and for duloxetine over gabapentin at week 8 (MD = −0.40, 95% CI [−0.79, −0.01], p = .04, I² = 0%). However, no significant differences were observed at week 4 (MD = 0.06, 95% CI [−0.32, 0.44], p = .77, I² = 0%) or week 12 (MD = −0.28, 95% CI [−0.85, 0.28], p = .33, I² = 0%) (Figure 3).

Figure 3.

Forest plot of sleep interference at different time points.

Response rate

Only two RCTs reported the response rate of participants to each intervention.^1,2 The pooled analysis revealed an overall insignificant difference between duloxetine and gabapentin (RR = 1.03, 95% CI [0.93, 1.14], p = .60, I² = 49%). A subgroup analysis indicated a significant difference favoring duloxetine at week 4 (RR = 1.90, 95% CI [1.07, 3.38], p = .03). However, no statistical differences were observed between the two interventions at week 6 (RR = 0.62, 95% CI [0.36, 1.07], p = .09), week 8 (RR = 1.03, 95% CI [0.94, 1.13], p = .47), or week 12 (RR = 1.02, 95% CI [0.95, 1.11], p = .54, I² = 0%) (Figure 4).

Figure 4.

Forest plot of response rate at different time points.

Adverse events

All included studies reported adverse events related to the interventions.^1,2,5–7,9 The pooled analysis found no significant difference in the incidence of adverse effects between duloxetine and gabapentin in patients with diabetic peripheral neuropathy (RR = 1.19, 95% CI [0.73, 1.94], p = .48, I² = 67%) (Figure 5). Following a sensitivity analysis that excluded the study by Khasbage et al., ¹ a notable reduction in heterogeneity was observed (RR = 1.02, 95% CI [0.68, 1.55], p = .91, I² = 29%) (Supplemental Figure 5). A detailed demonstration of the adverse events reported for each arm throughout the included studies can be identified in Table 4.

Figure 5.

Forest plot of adverse events.

Table 4.

Adverse events.

Adverse events	%
	Duloxetine	Gabapentin
Dizziness	4.5	7.7
Dry mouth	1.9	0
Nausea/vomiting	20.1	9.6
Somnolence	6.5	5.8
Constipation	3.9	0
Headache	1.3	0.6
Anorexia	2.6	0
Weight gain	0	1.9
Insomnia	1.9	0.6
Palpitations	1.9	1.3

A summary of the main findings for all outcomes, including the number of contributing studies, effect estimates, and their interpretation, is presented in Table 5.

Table 5.

Summary of findings.

Outcome	Number of studies (participants)	Effect estimate (95%confidence interval)	Interpretation/summary
Pain	6 studies (n = 526)	SMD = −0.16 (95% CI: −0.36, 0.03)	No overall difference between duloxetine and gabapentin in pain relief
Clinical global impression of change	4 studies (n = 328)	MD = 0.01 (95% CI: −0.07, 0.09)	Duloxetine and gabapentin showed no significant overall difference in CGIC, suggesting comparable overall clinical benefit
Sleep interference score	3 studies (n = 264)	MD = −0.07 (95% CI: −0.36, 0.23)	No overall difference between duloxetine and gabapentin in improving sleep disturbances
Response rate	2 studies (n = 146)	RR = 1.03 (95% CI: 0.93, 1.14)	There was no significant difference between duloxetine and gabapentin in achieving higher responder rates
Adverse events	6 studies (n = 526)	RR = 1.19 (95% CI: 0.73, 1.94)	There was no significant difference between duloxetine and gabapentin in terms of safety profiles or incidence of adverse events

CGIC: clinical global impression of change, SMD: standardized mean difference, MD: mean difference, RR: risk ratio.

Discussion

In this systematic review and meta-analysis, no significant overall differences were detected between duloxetine and gabapentin regarding pain relief, CGIC, sleep interference scores, response rates, or adverse events. These findings align with those of Ko et al., who reported similar outcomes. ¹⁰ In contrast, Jiang et al. reported duloxetine as superior in reducing adverse effects and sleep interference, though pain and CGIC were similar. ¹¹ Notably, our methodological approach differs from previous meta-analyses, which primarily relied on endpoint measurements for outcome assessment. Instead, we incorporated subgroup analyses and evaluated outcomes across multiple time points.

Duloxetine and gabapentin operate via distinct mechanisms. Duloxetine inhibits pain transmission by enhancing serotonergic and noradrenergic activity in descending pathways.^7,12–17 Gabapentin binds to the α2δ subunit of voltage-gated calcium channels, reducing excitatory neurotransmitter release and neuronal hyperexcitability.^2,18,19 Pharmacokinetically, duloxetine follows first-order kinetics, with proportional plasma increases and delayed onset, requiring patient education and monitoring.^20–22 Gabapentin exhibits nonlinear zero-order kinetics, complicating dose titration and necessitating careful monitoring.^22–24

The American Academy of Neurology (AAN) recommends both drugs for PDN management. ²⁵ According to AAN guidelines, the recommended dose for duloxetine ranges from 40 to 60 mg, which was implemented in most of the included RCTs, except for Ahmad et al. ⁵ and Sagar et al., ⁷ where a suboptimal dose of 30 mg was used. . For gabapentin, the AAN suggests a dose of 900 to 3600 mg, though most RCTs did not adhere to this range. These deviations from the recommended doses may impact the therapeutic response to the medications.

The choice between duloxetine and gabapentin depends on both pharmacological properties and patient-specific factors. Clinicians should assess medical history, comorbidities, potential drug interactions, and side effect profiles.^10,11,26 Duloxetine may be preferred in patients with coexisting depression or anxiety, offering dual benefits for pain and mood. ²⁷ In contrast, gabapentin may be more suitable for those with insomnia, essential tremors, or restless leg syndrome, where it provides added therapeutic value. ¹¹

Although no difference was observed between the two interventions in improving pain, clinically relevant trends were observed across different time points. At week one, gabapentin exhibited a numerically greater, though statistically non-significant reduction in pain scores compared to duloxetine. This observation may suggest a faster onset of analgesic action, consistent with its potential role in acute neuropathic pain exacerbations. ²⁸ In contrast, duloxetine demonstrated a modest yet insignificant advantage in pain reduction by week four to 12. This pattern may reflect its proposed cumulative benefits in chronic pain management.^17,26 The absence of statistical significance between the two medications, suggests comparable overall efficacy in pain management.

CGIC Analysis revealed a significant advantage for duloxetine in the first week, likely due to its mood-enhancing effects, which contribute to early perceived improvements in well-being. This underscores the importance of balancing immediate relief with sustained therapeutic needs in managing PDN. ¹³ In contrast, gabapentin’s increasing, yet insignificant, efficacy by the fourth week suggests delayed onset, with more pronounced benefits over time

Gabapentin showed greater improvement in sleep interference at week one, while duloxetine demonstrated superior efficacy by week eight. By week 12, differences between the two were no longer significant, though duloxetine retained a slight, non-significant edge. Gabapentin’s early benefit may be linked to its sedative properties, which can reduce sleep disruption shortly after treatment begins. ²⁹ In contrast, duloxetine’s delayed effects likely reflect its gradual impact on mood and overall symptom control.^13,26,30 These findings suggest that the choice between the two should consider both the urgency of sleep symptom relief and the need for long-term management, particularly in patients with PDN and associated sleep disturbances.

Temporal response patterns showed that duloxetine achieved a significantly higher response rate than gabapentin at week 4, pointing to an earlier onset of clinical benefit. However, this difference diminished over time. By weeks 6, 8, and 12, response rates between the two treatments were comparable, indicating similar long-term effectiveness. Although there was moderate heterogeneity overall, the significant subgroup difference suggests that timing may influence the relative benefits of each drug. These results underscore duloxetine’s early advantage while reinforcing the overall comparable efficacy of both medications, emphasizing the need to consider patient-specific factors when choosing between them.

The two medications demonstrated comparable adverse effect profiles, with nausea, vomiting, somnolence, and dizziness representing the most frequently reported side effects for both treatments (Table 4). Gabapentin offered better gastrointestinal tolerability, with lower rates of nausea and vomiting. However, it was associated with a slightly higher incidence of dizziness compared to duloxetine. Notably, although multiple studies reported similar adverse events within the duloxetine group,^1,2,6 Ahmed et al. identified peripheral edema as one of the most common side effects associated with duloxetine use. ⁵ Interestingly, a single case of transient ejaculatory dysfunction was documented at the end of treatment by Sagar et al. ⁷ These findings suggest duloxetine may be preferable when minimizing dizziness is a priority, while gabapentin might be better suited for patients with gastrointestinal sensitivity. Furthermore, for individuals at an increased risk of heart failure or stroke, duloxetine may be favored, as gabapentin has been hypothesized to be associated with increased cardiovascular event risk during long-term use. ³¹

This systematic review and meta-analysis has several limitations. Two included studies carried a high risk of bias, which may affect the reliability of the findings.^5,6 Evidence beyond 12 weeks was limited, restricting assessment of long-term outcomes. Additionally, inadequate reporting of comorbidities hindered evaluation across specific patient subgroups. Finally, a substantial degree of irreducible heterogeneity was observed among the included studies, potentially limiting the interpretability of the pooled results. Future high-quality RCTs with larger samples, extended follow-up, and detailed comorbidity data are needed to improve generalizability and support personalized treatment strategies for diabetic peripheral neuropathy.

Conclusion

Duloxetine and gabapentin show comparable overall efficacy and safety in managing pain, CGIC scores, sleep interference, and responder rates, with only time-specific differences in effectiveness. Both are effective options for treating PDN. Clinicians should base their choice on individual patient risks, preferences, and lifestyle factors to optimize outcomes and support adherence.

ORCID iD

Mumen H. Halabi https://orcid.org/0009-0002-4513-2819