Comparative Study of the Effects of Duloxetine and Venlafaxine on Acute Symptomatic Taxane-induced Neuropathy in Breast Cancer Patients: A Randomized Clinical Trial

Abstract

Introduction

Chemotherapeutic agents have the potential to induce neurotoxicity, resulting in a range of symptoms, including mild paresthesia, neuropathic pain, pronounced ataxia, and significant impairment. Taxane-induced neuropathy (TIN) is a prevalent adverse effect and a significant constraint of Taxane-based chemotherapy protocols in treating breast cancer. In this current study, we aim to compare the effects of Venlafaxine and Duloxetine in taxane-induced Neuropathy as well as the quality of life, Depression, and Anxiety in Breast cancer Patients.

Methods

The present study investigated breast cancer patients who experienced acute neuropathic pain after receiving paclitaxel treatment, a chemotherapeutic agent. The participants were allocated randomly into two groups, one receiving Venlafaxine and the other receiving Duloxetine. The participants underwent assessments for anxiety, depression, pain, neuropathy, quality of life, and neuropathic pain through the administration of questionnaires at the commencement of the study and after ten weeks following the intervention.

Results

Both groups exhibited decreased neuropathic pain, with the venlafaxine group significantly reducing McGill’s pain score. Although, the result is not suggestive of a difference between venlafaxine and duloxetine impact on any variables scores.

Conclusion

Duloxetine and Venlafaxine effectively treat neuropathic symptoms such as paraesthesia, tingling, and itching. Venlafaxine is also beneficial for relieving pain associated with neuropathy.

This trial was retrospectively registered on 1.1.2023 at irct.ir (trial registration ID: IRCT20220115053723N1). URL: https://www.irct.ir/trial/62540/pdf.

Key summary points.

• Neuropathy is a common side effect of paclitaxel (a chemotherapeutic agent for cancers) which may lead to decreased patients’ life satisfaction and treatment discontinuation.

• Both venlafaxine and duloxetine reduce neuropathic pain in breast cancer patients treated with paclitaxel.

1. Introduction

Chemotherapeutic agents have the potential to induce neurotoxicity, resulting in the manifestation of various adverse effects such as paresthesia, neuropathic pain, pronounced ataxia, and significant disability. Chemotherapy-induced peripheral neuropathy (CINP) is a common adverse effect of chemotherapy that significantly impairs patients’ quality of life and may result in early treatment discontinuation.1

Paclitaxel, or Taxol, is an antineoplastic drug used to treat various tumors, including breast, head, ovarian, lung, and neck. Taxanes cause neurotoxicity as a result of their effects on microtubules.2–4 Chemotherapy with Taxanes (such as Paclitaxel and Docetaxel) has been associated with CINP in over 80% of patients.5 Although the majority of neurological symptoms tend to improve within a few months following the cessation of Taxol, it is noteworthy that only approximately fifty percent of patients experiencing Paclitaxel-induced CINP achieve recovery within a timeframe of four to six months.6,7 Numerous neuroprotective agents have been studied in animals and humans to mitigate paclitaxel’s neurotoxicity.8–12

Antidepressants have been examined in multiple studies investigating chemotherapy-induced neuropathies, as they have demonstrated analgesic properties and the ability to facilitate neurotransmission. Given the predominant focus of existing research on oxaliplatin-induced neuropathies,8,9,11–17 we decided to compare the effects of Venlafaxine and Duloxetine in breast cancer patients with Taxane-induced neuropathy and their effects in Quality of life, Depression and anxiety to compensate for the lack of sufficient evidence.

1.1. Methods and materials

1.1.1. Study design

A randomized, double-blind, parallel-group clinical trial was conducted to examine the efficacy of Venlafaxine versus Duloxetine for treating acute taxol-induced neuropathy in 60 breast cancer patients at Imam Khomeini Hospital in Tehran between 2018 and 2020. All methods were approved under the ethical standards of the Research Council of Tehran University of Medical Sciences with the registration number IRCT20220115053723N1. All participants signed a written informed consent to participate in this study according to the Helsinki Statement’s provisions and were advised that they might withdraw from the study at any moment without repercussions to their therapy.

1.1.2. Participants

Total of 88 individuals diagnosed with breast cancer and experiencing acute taxane-induced neuropathy, specifically within a time frame of 4 weeks from the onset of symptoms, were enrolled as participants in this clinical trial. In the initial week, eight patients declined to proceed with the treatment regimen due to apprehensions regarding potential drug interactions (four patients in each group). Additionally, twenty participants withdrew from the study due to adverse drug effects (eleven patients in Duloxetine and nine in Venlafaxine groups).

The inclusion criteria was: 1) patients with breast cancer who were treated with Taxol (paclitaxel) or Taxotere (docetaxel) for twelve weeks, with acute (onset of symptoms within 4 weeks) peripheral neuropathy and neuropathic pain confirmed by expert examination, 2) pain score three or more according to McGill questionnaire, 3) Hospital anxiety and depression scale score less than 20 according to hospital anxiety and depression scale (HADS) questionnaire, and 4) Neuropathic score more than 3 in Douleur Neuropathique 4 (DN4) questionnaire. Patients with metastatic breast cancer, progressive paralytic symptoms, pregnancy, breastfeeding, less than three months life expectancy, in addition to those who were currently under treatment with anticonvulsive, antidepressant (TCA-SSRI-SNRI), and opioid drugs, were excluded.

1.1.3. Intervention

Two groups of female patients who met the inclusion criteria for neuropathic pain were randomly assigned to receive a package containing either 37.5 mg of Venlafaxine or 30 mg of duloxetine. The medication was administered once daily for one week. Subsequently, in the event that the patient exhibited favorable tolerance to the medication, the dosage was augmented to 75 mg of Venlafaxine and 60 mg of duloxetine for a further duration of nine weeks.

1.1.4. Outcomes

At the beginning of the trial (prior to medication treatment) and ten weeks after medication administration, the patients completed McGill questionnaire, Douleur Neuropathique 4 (DN4) questionnaire, hospital anxiety and depression scale (HADS) questionnaire, and quality of life questionnaire to assess pain, neuropathy, anxiety and depression, and quality of life, respectively. All of the questionnaires were validated for the Iranian population. The DN4 questionnaire (Cronbach: 0.852) was used to assess neuropathy. It consists of two sections: a question and an examination section. Questions elicit information about the nature of pain, such as burning, painful cold, or electric shock, as well as pain associations, such as tingling, pins and needles, numbness, or itching. Exams assess hypoesthesia to touch or pinpricks and if the pain is induced by brushing. A positive response earns a score of 1, while a negative response earns a score of 0. The maximum possible score is ten. A score higher than 4 is suggestive of neuropathy.

The 15-item QLQ questionnaire version 1 (Cronbach: 0.84) was used to assess the quality of life. The patient assigns a score of 1–4 to each of the first 14 questions. The higher the patient’s score on the first 14 questions, the lower the patient’s quality of life. In question 15, the patient’s overall quality of life is rated on a scale of 1–7, with one being very poor and seven excellent.

The HADS questionnaire (Cronbach: 0.78), which contains 14 items, was used to assess hospital anxiety and depression. Seven questions probe depression, and seven questions probe anxiety. Each item is assigned a score between 0 and 3. Anxiety and depression are indicated by a total score of 11 or higher in each section. A score of 8–10 indicates borderline depression and anxiety, while a score of 0–7 indicates no depression or anxiety.

We used the short-form McGill questionnaire to assess pain (Cronbach: 0.85). This questionnaire consists of 15 descriptors: 11 sensory (questions 1–11) and four affective (questions 12–15), which determine the intensity of pain from 0 (indicating no pain) to 3 (indicating severe pain). Higher scores indicate more severe pain. Additionally, one item for current pain severity, PPI (Present Pain Intensity), and one visual analog scale (VAS) to demonstrate the overall pain intensity score.

1.1.5. Safety

The patients were provided with information regarding the potential adverse effects of the medication, which encompassed symptoms such as nausea, constipation, insomnia, dizziness, fatigue, and headache. Additionally, patients were provided with the clinic’s contact information to facilitate prompt consultation if experiencing any adverse effects. Furthermore, they underwent an examination during each visit. If the patient experienced adverse drug reactions or intolerance, their treatment was terminated and subsequently excluded from the study.

1.2. Statistical analysis

The SPSS Version 26 was utilized for all statistical analyses (IBM, Armonk, NY, USA). Patients in Venlafaxine group and Duloxetine group were compared with regard to the study’s primary and secondary outcome indicators. We reported Grouping variables by frequency and percentage and continuous variables by mean and standard deviation. Analysis of covariance (ANCOVA) was utilized to compare mean differences of each score to compare to which extent each of the two medications changed the scores. A p-value of <0.05 was considered statistically significant.

2. Results

The study enrolled 88 patients with breast cancer who also suffered from Taxane-induced neuropathy. Twenty patients were excluded from the study due to adverse drug reactions. Thirty-one patients received Venlafaxine, while twenty-nine received Duloxetine (Fig. 1). The mean age of patients treated with Venlafaxine was 42.5 ± 12.7, and of patients treated with Duloxetine was 37.5 ± 12.0. The average course of Taxane used in patients treated with Venlafaxine was 4.9 ± 1.3, and in patients treated with Duloxetine was 4.2 ± 1.5 (Table 1). A preliminary comparison of the Duloxetine and Venlafaxine groups revealed no significant difference in the mean of variables between the two groups at the beginning of the study (Table 2).

Fig. 1.

Flow diagram of the study.

Table 1.

Mean age and number of previous taxane-based treatment courses of each group at the beginning of the study.

	All (N:60)	Venlafaxine (N:31)	Duloxetine (N:29)	P-value
	Mean (SD)	Mean (SD)	Mean (SD)
Age	40.05 (12.52)	42.48 (12.7)	37.44 (12)	0.228
Taxane course	4.43 (1.46)	4.83 (1.3)	4.20 (1.5)	0.161

N: number, SD: standard deviation.

Table 2.

Scores of quality-of-life questionnaire, hospital anxiety and depression scale, McGill pain score and DN4 score for each of the groups, at the beginning and after the trial.

	Venlafaxine (N:31) Mean (SD)	Duloxetine (N:29) Mean (SD)	P-value
QLQ score	33.97 (7.97)	29.69 (9.16)	.060
HADS score	14.77 (2.97)	13.96 (3.48)	.339
McGill pain score	3.19 (0.83)	3.03 (0.78)	.448
DN4 score	5.26 (1.69)	4.90 (1.52)	.387

N: number, SD: standard deviation, QLQ: quality-of-life questionnaire, HADS: hospital anxiety and depression score, DN4: Douleur Neuropathique 4.

After treatment with Venlafaxine, there was a noticeable improvement in patients’ neuropathic pain (DN4) criteria (p-value< 0.01). McGill’s pain criteria also significantly changed following Venlafaxine treatment (p-value< 0.01). The quality-of-life score and HADS score remained relatively unchanged (p-value> 0.05).

While Neuropathic pain (DN4) significantly decreased following duloxetine treatment (p-value< 0.05), The patients’ quality of life score, McGill’s pain score, and HADS score remained relatively unchanged (p-value> 0.05) (Table 3).

Table 3.

Comparison of each questionnaires’ score between two arms of the study at the beginning of the trial.

		Duloxetine (N:29)		Venlafaxine (N:31)
		Mean (SD)	P-value	Mean (SD)	P-value
QLQ score	Before	33.97 (7.97)	0.65	29.69 (9.16)	0.47
	After	34.39 (6.58)		28.38 (5.85)
HADS score	Before	14.77 (2.97)	0.27	13.96 (3.48)	0.07
	After	13.16 (2.43)		12.86 (3.48)
McGill pain score	Before	3.19 (0.83)	0.001	3.03 (0.78)	0.16
	After	2.55(0.62)		2.76 (0.74)
DN4 score	Before	5.26 (1.69)	0.004	4.90 (1.52)	0.02
	After	4.58 (1.02)		4.21 (1.26)

N: number, SD: standard deviation, QLQ: quality-of-life questionnaire, HADS: hospital anxiety and depression score, DN4: Douleur Neuropathique 4.

Comparing Venlafaxine and Duloxetine, the difference between the two groups’ amount of change among none of the variables reached statistical significance (neuropathic pain (p-value = 0.974), pain (p-value = 0.154), anxiety and depression (p-value = 0.503), and quality of life (p-value = 0.402)). We also evaluated the relationship between the change of each of the variables. The only significant relationship was between neuropathic pain and quality-of-life scores (p-value = 0.012, Pearson’s correlation = 0.323).

Complications in the venlafaxine group included nausea (11%), insomnia (8%), and constipation (6%), whereas, in the duloxetine group, nausea (15%), fatigue (15%), headache (15%), and dizziness (12%) were reported.

3. Discussion

The present study aimed to assess and compare the therapeutic effectiveness of Duloxetine and Venlafaxine in managing chemotherapy-induced neuropathy. Both medications have demonstrated efficacy in relieving neuropathic symptoms characterized by pain, numbness, and tingling sensations. However, there was a lack of significant enhancement in the patient’s quality of life, specifically in the cohort that was administered duloxetine, throughout the therapeutic intervention. Even among the participants who were administered duloxetine, there was a marginal decline in the quality of life; however, this decline did not reach statistical significance. The present investigation revealed no statistically significant disparity between the two cohorts at the commencement of the study. The research encompassed 68 participants, and no statistically significant complications were detected in either cohort. Within the Duloxetine group, a notable 13% of patients elected to discontinue their treatment regimen due to experiencing dizziness and nausea symptoms. This proportion was observed to be comparatively higher than that observed within the Venlafaxine group.

Previous studies have reported the effectiveness of these medications in treating neuropathy.18,19 However, these studies had limitations, such as small sample size, lack of assessment for depression and anxiety, and not reporting the difference in pain scores between the two groups.20–25

In 2013 Smith et al. conducted a study to assess the effects of Duloxetine on Taxol- and oxaliplatin-induced peripheral neuropathy in 231 patients. At a daily dose of 60 mg, Duloxetine significantly improved quality of life and decreased pain compared to placebo which was in line with our study’s findings.12 In Smiths’ study, patients were examined at the end of week 4 with a BPISF (Brief Pain Inventory-Short Form) questionnaire. The study did not mention using additional analgesics and opioids, patients’ performance status, and side effects. The patients were followed for four months, which was longer than our trial. At the beginning of the study, depression and anxiety were not assessed (it is essential because Duloxetine is an antidepressant drug). Also, 41 percent of the participants experienced adverse effects; However, it is not stated how many patients were removed from the study due to adverse medication reactions.

Duloxetine and Venlafaxine were compared in two groups of patients in a study conducted by Dr. Farshchian et al. in 2018 on 110 patients with chemotherapy-induced neuropathy caused by various chemotherapeutic agents including Taxol, oxaliplatin, and bortezomib.16 After receiving 30 mg of daily duloxetine or 37.5 mg of daily venlafaxine for four weeks, both groups experienced a reduction in neuropathy. The duloxetine group experienced a greater reduction in neuropathic pain than the venlafaxine group. No severe drug adverse effects were reported. The main adverse effects of venlafaxine included nausea, constipation, and insomnia, while duloxetine group mainly experienced dizziness, fatigue, and headache. 11 percent of venlafaxine group and 8 percent of duloxetine group discontinued the treatment due to adverse effects. Follow-up was performed using EMG-NCV. Simultaneous use of analgesics, anticonvulsants, or opioids was not assessed. Additionally, patients’ anxiety and depression levels were not assessed.

In 2020, Natsuki Kato et al. performed a valuable study on mice; Gabapentin and Duloxetine were shown to effectively prevent neuropathic pain in mice treated with Oxaliplatin and Paclitaxel by inhibiting Extracellular Signal-Regulated Kinase Phosphorylation. However, no such study has been conducted on humans comparing the effects of Venlafaxine and Duloxetine on neuropathic pain prevention.10

According to the present study, Duloxetine and Venlafaxine effectively treat neuropathic symptoms such as paraesthesia, tingling, and itching. Venlafaxine is beneficial for relieving pain associated with neuropathy as well as Duloxetine. Nevertheless, there was no substantial improvement in the quality of life of the patients, particularly in the group that received duloxetine, throughout the course of treatment based on QLQ questionnaire. It is worth considering that the patients were undergoing weekly chemotherapy treatment; this heavy treatment itself can reduce the quality of life of the patients regardless of the improvement of neuropathy.26,27

Then, Venlafaxine is recommended as the initial treatment option for individuals experiencing acute neuropathy resulting from Taxanes, primarily due to its superior tolerability, lower financial burden, and greater therapeutic efficacy. If venlafaxine is well-tolerated after one week, the daily dosage may be escalated to 75 mg. If a patient experiences intolerance or adverse effects to venlafaxine, it may be beneficial to consider administering Duloxetine at a dosage of 60 mg to help alleviate neuropathic symptoms. Numerous contemporary and prior investigations have substantiated the efficacy of Venlafaxine and Duloxetine in mitigating the manifestations of pain and neuropathy induced by chemotherapy interventions. It is noteworthy, however, that each chemotherapy drug’s distinct mechanisms of action give rise to neuropathy in a disparate manner. The primary objective of this study was to assess and contrast the effectiveness of these two pharmaceutical interventions in alleviating the neuropathic symptoms commonly associated with the administration of Taxanes.

Due to highly specified inclusion criteria, our study inevitably had a limited sample size of participants. Constructing questionnaires to evaluate the distinct neuropathic symptoms linked to individual chemotherapeutic medications is advisable. The present study focused on patients who experienced neuropathy symptoms, thus limiting the generalizability of the findings to the prophylaxis of neuropathy associated explicitly with chemotherapy. We suggest conducting a study to evaluate the effectiveness of these medications as a prophylactic treatment for neuropathic symptoms.

4. Conclusion

Both venlafaxine and duloxetine demonstrated significant efficacy in treating neuropathic pain among patients. No discernible distinction was observed in terms of their impact on neuropathic pain. The group administered venlafaxine showed a notable enhancement in their McGill pain score. The administration of these drugs did not yield any discernible effect on the patient’s anxiety and depression scores. The study observed a marginal improvement in the quality of life among patients in the venlafaxine group, whereas a decline was noted among those in the duloxetine group. However, it is essential to note that these changes did not reach statistical significance.

Data availability statement

Due to patient confidentiality, the datasets created during the current investigation are not publicly available but are available upon reasonable request from the corresponding author.