Comparative Efficacy of Tapentadol versus Tapentadol Plus Duloxetine in Patients with Chemotherapy-Induced Peripheral Neuropathy (CIPN): A Randomized Non-Inferiority Clinical Trial

Simple Summary Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication due to treatment with anti-cancer agents. Our aim was therefore to assess the non-inferiority of the analgesic effect and safety of tapentadol alone compared to duloxetine plus tapentadol administered to patients with chemotherapy-induced peripheral neuropathy. The use of tapentadol is a safe and effective analgesic therapy in patients with CIPN. Positive effects of tapentadol were noted on the patients’ quality-of-life assessments. Abstract Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication due to treatment with many commonly used anti-cancer agents. CIPN is a mainly sensory neuropathy that can be characterized by the appearance of motor and autonomic alterations. Clinicians may offer duloxetine (DLX) for patients with cancer experiencing CIPN. Our aim was to assess the non-inferiority of the analgesic effect and safety of tapentadol (TP) alone compared to duloxetine plus tapentadol administered to patients with CIPN. Methods: A total of 114 patients were enrolled in the study and randomized to receive tapentadol in a dosage of 50 to 500 mg/day (n = 56) or tapentadol plus duloxetine in a dosage of 60 to 120 mg/day (n = 58) for a period of 4 weeks. We evaluated the analgesia efficacy, defined as a decrease in pain on the NRS between the first administration and 28 days later. Secondary endpoints included analgesia efficacy at 28 and 42 days, defined by a decrease in DN4 and LEPs, decrease in quality of life, and the incidence of any serious or non-serious adverse events after the first administration. Results: In this randomized, double-blind trial comparing TP and TP plus DLX for CIPN management, TP was feasible and non-inferior to the association with DLX as far as the reduction of pain after chemotherapy at 28 days is concerned. Scores on other rating scales evaluating the quality of life, anxiety and depression, and the characteristics of pain revealed similar improvements associated with tapentadol versus duloxetine at these time points. Conclusion: The use of TP is a safe and effective analgesic therapy in patients with CIPN. Positive effects of TP were noted on the patients’ quality-of-life assessments.

The high success rate of these drugs in cancer treatment has led to a steady increase in the survival rates of patients. As a result, the number of cancer survivors suffering from Patients were excluded if they met any of the following criteria: neuropathy due to other diseases; previous treatment of pain in the week before starting the study; other non-medical intervention/therapy for the treatment of peripheral neuropathy; liver, kidney, or heart failure; contraindications to the drugs to be tested (e.g., TP and/or DLX allergy); and women who were breastfeeding or pregnant (excluded from medical history and/or laboratory tests).

Randomization and Masking
Patients were randomized via computer-generated codes to receive TP or TP plus DLX. All medical staff, as well as patients, were blinded to the treatment group, with the exception of the pharmacist responsible for preparing the blisters. Treatments were prepared in the hospital pharmacy and the investigator was given blisters labelled only "A" and "B". The randomization (1:1) in parallel groups was pre-performed in blocks of random size using a dedicated software available to the University of Campania "Luigi Vanvitelli". The randomization list was delivered to the central pharmacy in charge of preparing the packs.

Procedures
In line with normal prescribing practice, patients received tapentadol in a dosage of 50 to 500 mg/day for a period of 4 weeks (TP group) or tapentadol plus duloxetine in a dosage of 60 to 120 mg/day for a period of 4 weeks (DLX group).
In the TP group, an initial dose of 50 mg of tapentadol was administered. An additional dose of 50 mg was administered at 1 h if the Numerical Rating Scale (NRS) remained > 3/10.
In the DLX group, an initial dose of 60 mg of duloxetine and 50 mg of tapentadol were administered.
In both groups, pain relief was assessed every 7 days to determine whether titration of the drug was necessary. Patients with NRS < 3/10 continued to receive the starting dose. In all other cases, the dose was increased gradually.
If an intolerable adverse event (AE) occurred, symptomatic treatment was guaranteed, and the dose of the drug was eventually reduced.
Patients could not switch between groups until the end of the study; however, they may have chosen to leave the studio for any reason at any time.

Data Collections and Outcomes
Data collections and outcomes were completed by research members who were trained before the study and not involved in the management of the patients.
The primary endpoint was analgesia efficacy, defined as a decrease in pain on the NRS between the first administration and 28 days later. Pain intensity was evaluated also at 42 days.
Secondary endpoints included analgesia efficacy at 28 and 42 days, defined by a decrease in DN4 and LEPs, decrease in quality of life, and the incidence of any serious or non-serious adverse events after the first administration.
Pain intensity was evaluated using the 11-point Numerical Rating Scale (NRS) from 0 (no pain) to 10 (worst possible pain), based on average pain over the past 24 h [14]. The Douleur Neuropathique 4 (DN4) was used for the diagnosis of neuropathic pain if the total score was greater than or equal to 4 [15].
Several techniques are available for the objective evaluation of pain in patients. The laser-evoked potentials (LEPs) is a useful tool to assess conduction via nociceptive nerve fibers Aδ and C and can be used to identify nerve-fiber dysfunction and altered nociception [16][17][18][19]. A MYOQUICK matrix line (Micromed SpA, Treviso, Italy), a system containing a stimulatory neodymium-doped yttrium aluminum garnet (Nd:YAG) laser of wavelength 1064 nm, was used to produce LEPs. The laser pulses were applied at the site where neuropathic pain was reported. Nerve impulses were generated with a series of 40 stimulations in 10 min with an interval between stimulations of 10-20 s. At 3 s after each stimulation, the patients expressed pain level using NRS; for comparison, a value of 4 was assigned to the pain sensation after a pinprick. An electroencephalogram was recorded using a BRAIN QUICK system (Micromed SpA). Electrodes were applied to the scalp in the frontal, central, and parietal midline positions, according to the international 10-20 positioning system. The latencies and amplitudes of the N2 and P2 components of the LEPs were recorded at the central midline (Cz) position, where the LEP signal is maximum.
The severity of cancer-related pain is affected by the development of catastrophic thoughts in patients, such as "my pain will never improve without a doubt". This effect was evaluated using the Pain Catastrophizing Scale (PCS) [20].
The effects of pain on patients' psychiatric symptoms (anxiety and depression) were assessed using the Hospital Anxiety and Depression Scale (HADS) [21]. A HADS score of <20 points was used as a limit for detecting patients with severe depression.
General health status was assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Chemotherapy-Induced Peripheral Neuropathy Questionnaire (EORTC QLQ-CIPN20) [22].
Finally, a self-assessment was performed by patients using Pain Relief Scale (PRS) [24]. Patients determined the effectiveness of TP or TP plus DLX themselves using a 4-point scale: "complete relief", "much relief", "mild relief", and "no change".
During the first visit (randomization time, T0) the following data were carried out: • Remote and proximal anamnestic collection. • Adverse Events (AEs).
The follow-up phase included the evaluation of the patients at 42 days (follow-up time, T42) after the start of treatment.

Sample Size and Statistical Analysis
Our study was designed to demonstrate the non-inferiority of TP to TP plus DLX as far as the change in average pain intensity from baseline to the 28th day of the double-blind treatment period is concerned. As a non-inferiority study, the threshold was based on a clinically meaningful difference in efficacy (NRS T28 -NRS T0 ) between the two treatments of −1.5. From previous studies, the standard deviation of the reduction in pain was estimated to be 2.5.
With a sample size of 90 patients (45 in each group), a 2-group design would have provided at least 80% power to reject the null hypothesis (corresponding to a loss of efficacy greater than or equal to 1.5), in favor of the alternative hypothesis, corresponding to a gain in efficacy or a loss of efficacy of less than 1.5, assuming that the expected mean difference was 0, the common standard deviation 2.5, and the level of significance 2.5%. Assuming a drop-out rate of 10%, a total sample size of 100 patients was required.
Non-inferiority was determined on the basis of a 1-sided mean-equivalence t-test (two 1-sided t-tests approach, TOSTT procedure) [25] on the per-protocol population (primary endpoint: NRS efficacy [NRS T28 -NRS T0 ]). We also compared the efficacy of the TP treatment to TP plus DLX treatment at the different time points (NRS T7 -NRS T0 , NRS T14 -NRS T0 , NRS T21 -NRS T0 and NRS T42 -NRS T0 ) in the per-protocol population using a two-sample Student's t-test.
An analysis of variance (ANOVA) with repeated measures was performed for DN4, HADS, QLQ-CIPN20, PCS, and N2 and P2 latency and amplitude. A chi-squared test was performed for the PRS score.
We compared the incidence of serious and non-serious adverse events between the groups using a chi-squared test.
Demographic and baseline characteristics were compared by a two-sample Student's t test for numeric variables.
All statistical analyses were performed using SAS ® version 9.3 (SAS Institute srl, Milan, Italy).

Patient Characteristics
A total of 114 patients were enrolled in the study and randomized to receive tapentadol in a dosage of 50 to 500 mg/day (n = 56) or tapentadol plus duloxetine in a dosage of 60 to 120 mg/day (n = 58) for a period of 4 weeks (Figure 1). Doses were titrated to adequate pain relief or dose-limiting toxicity on the basis of the clinical response. A total of 108 patients completed the trial. A total of 92.8% (52/56) of patients in the TP group and 96.5% (56/58) of patients in the TP plus DLX group completed the double-blind treatment period; the most common reasons for treatment discontinuation in both treatment groups were a previous treatment (TP group, 1 Demographic and baseline characteristics were comparable between the treatment groups in the overall population, as shown in Table 1. At baseline, no major differences were noted between the two study groups regarding age (52.4 vs. 51.7 years) and sex (20/32 vs. 22/34 male/female).
Patient tumour characteristics of the two groups were well balanced. In the TP group, forty-seven patients (90.4%) had a solid tumour, and the most frequent were breast (40.4%) and digestive system cancer (27.6%). Forty-six patients (88.5%) underwent surgery, and twenty-one patients (40.4%) received radiotherapy. The majority of patients were affected by taxane-induced CIPN (42.3%), followed by platinum-compound-induced CIPN (34.6%). In the TP plus DLX group, eighteen patients (36.7%) presented breast cancer and fourteen (28.6%) digestive cancer. Globally, forty-nine patients (87.5%) had a solid tumour. Surgical treatment was performed forty-nine times (87.5%), while radiotherapy twenty-two times (39.3%). Similarly to the other group, CIPN was diagnosed in twenty-four patients (42.8%) treated with taxanes and in nineteen patients (33.9%) treated with platinum-based drugs.

Patient Characteristics
A total of 114 patients were enrolled in the study and randomized to receive tapentadol in a dosage of 50 to 500 mg/day (n = 56) or tapentadol plus duloxetine in a dosage of 60 to 120 mg/day (n = 58) for a period of 4 weeks (Figure 1). Doses were titrated to adequate pain relief or dose-limiting toxicity on the basis of the clinical response. A total of 108 patients completed the trial. A total of 92.8% (52/56) of patients in the TP group and 96.5% (56/58) of patients in the TP plus DLX group completed the double-blind treatment period; the most common reasons for treatment discontinuation in both treatment groups were a previous treatment (TP group, 1  Demographic and baseline characteristics were comparable between the treatment groups in the overall population, as shown in Table 1. At baseline, no major differences were noted between the two study groups regarding age (52.4 vs. 51.7 years) and sex (20/32 vs. 22/34 male/female).
Patient tumour characteristics of the two groups were well balanced. In the TP group, forty-seven patients (90.4%) had a solid tumour, and the most frequent were breast The duration of treatment was 28 days in both the TP and TP plus DLX treatment groups. The median of the mean total daily dose (TDD) of study drug taken during the treatment was 104.5 mg for tapentadol in the TP group and 51.6 mg for tapentadol plus 78.6 mg for duloxetine in the TP plus DLX group.

Primary Endpoint Pain Intensity
At baseline, all patients showed a NRS ≥ 4. We considered NRS higher than 4 as the optimal cut-off point between mild and moderate pain [26]. This cut-off was identified as the threshold of tolerable pain.
The mean difference between NRS at first administration and NRS at 28 days was −4.21 in the TP group and −4.4 in the TP plus DLX group, with a mean difference in the NRS variation between the groups of 0.19. At days 7, 14, 21, 28, and 42, the mean NRS score was significantly (p < 0.05) reduced from baseline in both the TP and TP plus DLX groups. The reduction in the NRS score from baseline to day 7 (−0.  Table 2 and Figure 2).  Table 2 and Figure 2). Table 2. Study data at baseline (T0) and at 7 (T1), 14 (T2), 21 (T3), 28 (T4), 42 (T5) days after treatment. T0  T1  T2  T3  T4  T5  T0  T1  T2  T3  T4  T5

Quality of Life
At days 7, 14, 21, 28, and 42, the mean QLQ-CIPN20 score was significantly (p < 0.05) reduced from baseline in both the TP and TP plus DLX groups. The reduction in the QLQ-CIPN20 score from baseline to day 7 (−6.

Discussion
In this randomized, double-blind trial comparing TP and TP plus DLX for CIPN management, TP was feasible and non-inferior to the association with DLX as far as the reduction of pain after chemotherapy at 28 days is concerned.
The experience of pain depends on the central processing of ascending (incoming) signals from peripheral tissues, which are modulated by descending inhibitory and facilitatory mechanisms.
The origin of supraspinal (or descending) pain control pathways is from different supraspinal sites. Descending pain control pathways can be facilitatory or inhibitory. They influence the perception of pain and modulate the activity of spinal nociceptors regulating the propagation of signals to the brain. The release of neurotransmitters, such as endogenous opioids, norepinephrine, and serotonin, is involved in endogenous pain modulation. The µ-opioid receptor (MOR) agonists inhibit transmission of pain signals along the ascending pathways and are involved in the modulation of supraspinal pain signals through their action in descending pathways. Norepinephrine inhibits pain through α2 adrenoceptors, while serotonin facilitates or inhibits functions depending on the receptor subtype.
Tapentadol acts both as a MOR agonist and as a norepinephrine reuptake inhibitor (NRI), thereby generating synergistic analgesic action [9,10].
The clinical efficacy of the tapentadol has previously been established in patients with diverse types of painful peripheral neuropathies (PPN), such as postherpetic neuralgia and painful diabetic polyneuropathy [11]. Galiè et al. conducted an open-label, 3-month, prospective study assessing the efficacy of tapentadol in 31 patients with moderate-to-severe neuropathic pain from a CIPN. It was unresponsive to maximum doses of antineuropathic antidepressants and anticonvulsants [12].
According to ASCO guidelines, duloxetine is recommended for clinical practice in patients with painful CIPN [8].
Notably, the present trial showed that tapentadol-treated patients versus tapentadol plus duloxetine recipients with CIPN experienced similar NRS and DN4 pain scores after 28 and 42 days of treatment.
Scores on other rating scales-HADS, QLQ-CIPN20, PRS, and PCS-also revealed similar improvements associated with tapentadol versus duloxetine at these time points.
CINP negatively affects psychological distress and sleep quality in cancer patients treated with chemotherapy [28]. Considering the increasing emphasis given to the quality of life among cancer patients, the association between CIPN and QoL has been largely explored. CIPN negatively influences the QoL of cancer patients by producing unpleasant symptoms, such as anxiety, depression, and sleep disorders [28].
Our data suggest that CIPN has a negative effect on psychological distress and sleep quality in patients treated with chemotherapy. In this study, enhanced QoL is associated with functional recovery and improved sleep quality. This beneficial action of TP probably depends on its peculiar pharmacological action, which is characterized also by a marked noradrenergic activity.
AEs were mild and tolerable. Tapentadol shows fewer typical opioid-induced side effects compared with equianalgesic doses of classical opioids [29]. This favorable tolerability profile is associated with maintenance of QoL and improved compliance.
Neurophysiological endpoints were also assessed via LEPs for studying Aδ and C nerve-fiber transmission involved in afferent nociception [16,18,19,[30][31][32]. Heat impulses produced by a laser were used to selectively stimulate nerve terminals in the epidermis, activate Aδ and C nerve fibers, and evoke potentials recordable via electrodes on the scalp.
LEPs data from our trial in patients with CINP treated with tapentadol or duloxetine revealed a significant reduction in latency and a significant increase in amplitude of N2 and P2 potentials.
We believe that the marked analgesic efficacy of tapentadol, together with available safety data, support the use of this drug for the treatment of CIPN.

Limitations
Our study should minimize most of the common biases. Nevertheless, our study has a number of limitations. Despite the random assignment, there was imbalance between the study arms in the male/female ratio.

Conclusions
The objective of this randomized non-inferiority trial was to demonstrate the efficacy of the tapentadol in reducing the intensity of chemotherapy-induced peripheral neuropathy in patients treated with chemotherapeutic agents. Detailed analysis of the study findings revealed that the study objective was met; that is, the use of the TP is a safe and effective analgesic therapy in patients with CIPN. Clinical efficacy of this formulation was mediated by its action as a µ-opioid receptor agonist and as a norepinephrine reuptake inhibitor. In addition, positive effects of the TP were noted on the patient QoL. Overall, given the high incidence of chemotherapy-induced peripheral neuropathy and the few therapeutic tools available, the clinical value of a safe and effective analgesic therapy, such as the tapentadol, which also considerably improves the patient QoL, is clear.

Author Contributions:
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by P.S., L.G.G. and M.C.P. The first draft of the manuscript was written by P.S. and L.G.G., and all authors commented on previous versions of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding:
No funding or sponsorship was received for this study or publication of this article.

Institutional Review Board Statement:
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of University of Campania "Luigi Vanvitelli"-Naples, Italy (Ethics Committee Code 1154/12).

Informed Consent Statement:
Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The datasets generated during the current study are available from the corresponding author on reasonable request.