Neuropathic pain significantly impacts the quality of life and well-being of patient. ¹ The financial burden to manage neuropathic pain in the chronic setting is huge on society. ^{2 , 3} Its prevalence in the general population ranges from 1% to 8%. ^{4 , 5}

The most effective pharmacotherapeutic classes of drugs in the management of neuropathic pain are gabapentanoids, tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). ^{1 – 3 , 6 – 9} Most of these options are effective but come with a few potential side effects.

Pregabalin, a gabapentanoid blocks the presynaptic alpha 2 delta subunit of calcium channels of the dorsal horn. This leads to inhibition of neurotransmitter release from presynaptic neuron. ^{7 , 8 , 10} Multiple international societies recommend it as a first-line treatment option for neuropathic pain. ^{2 , 6 , 11}

SNRIs are also recommended as a first-line treatment option by multiple guidelines. ^{1 – 3 , 6 – 9} Duloxetine, an SNRI modulates pain signals by facilitating descending inhibitory pain pathway. ^{3 , 7} SNRIs have been found effective in peripheral diabetic neuropathy, ^{6 , 8} painful peripheral neuropathy and multiple sclerosis. ¹²

Treatment of neuropathic pain with monotherapy has several limitations such as not being effective for all patients, having partial pain relief and increased side effects with higher doses. ⁸ These are the main reasons to use two or more drugs in about 45% of patients. ^{13 , 14} To overcome these issues, for adequate pain relief without increased adverse effects, combination therapy with two or more medications is required in about half of the patients affected with neuropathic pain. Many international guidelines suggest an addition of another drug from a different pharmacological class when adequate pain control is not achieved with monotherapy. However, the evidence available for combination therapy is limited. ^{1 , 2 , 7 , 8 , 9} The advantages of combination therapy may be increased efficacy and better tolerability due to the use of smaller doses of individual drugs. ^{1 , 9}

Both pregabalin and duloxetine are approved in the treatment of neuropathic pain. The monotherapy with drugs at their standard doses (60mg and 300 mg/day respectively) have shown to provide substantial clinical pain relief in only 40% of patients. ^{15 , 16 , 17}

Administration of pregabalin and duloxetine combination treatment may provide better pain relief and tolerability than the administration of maximum doses of each drug, especially in patients showing partial response to monotherapy. ¹⁸

Pregabalin and duloxetine have different mechanism of action and administration of these drugs in combination rather than monotherapy may potentially provide enhanced pain relief in neuropathic pain due to their complementary actions. ^{19 , 20} However, there have been no clinical studies on fixed-dose combinations of low-dose pregabalin and duloxetine for the treatment of neuropathic pain.

The objective of our phase 3 study was to assess the potential non-inferiority of fixed-dose combination of low-dose pregabalin and duloxetine compared to pregabalin monotherapy in adults with moderate to severe neuropathic pain.

A total of 430 patients were screened from all the sites ( Figure 1). A total of 328 eligible patients were equally randomized in two groups as test groups (N=164) and reference group (N=164). After randomization, 20 patients withdrew their consent, 7 patients were lost to follow-up, 2 patients discontinued due to adverse events and 1 patient was discontinued by the investigator from the test group. The reasons for discontinuation are mentioned in Figure 1. Thus, total 298 patients completed 7 weeks treatment. ²⁸

The demographic characteristics between both treatment groups were comparable. The number of female patients was slightly higher in the reference group compared to the test group. The demographic characteristics are presented in Table 2. The mean patient age at enrolment was 46.5 years. All included patients had an average pain score of at least 4 on NPRS prior to treatment. The mean pain intensity was 6.4.

Neuropathic pain can be spontaneous or provoked and the patient may complain of paraesthesia, dysesthesia, and loss of normal sensation due to nerve damage. ²¹ The most commonly used option to treat neuropathic pain is pharmacotherapy. However, the complex aetiology of neuropathic pain is the reason for the limited benefit of monotherapy.

The drawback of monotherapy is its limited efficacy and increased adverse effects with the higher dose. Due to tolerability issues, higher doses needed for maximum therapeutic response are not used. Inadequate partial pain relief with the single agent will lead to impaired physical function, impaired sleep, reduced quality of life and higher economic costs of unrelieved pain.

Combination therapy with two or more drugs must be considered to overcome the challenges of managing uncontrolled neuropathic pain with improved analgesic efficacy and reduced overall side effects especially when synergistic interactions are possible for dose reductions of combined drugs. ²² In clinical practice, combination therapy is frequently used.

Evidence supports the combination of gabapentinoids and antidepressants than a high dose of individual drugs from either class for a reasonable treatment in neuropathic pain. Pregabalin, a gabapentinoid and duloxetine, an antidepressant; should be initiated with lower doses and gradually up-titrated based on the treatment response.

Pregabalin-duloxetine combination shows additive analgesic actions with a better safety profile compared to high-dose pregabalin monotherapy. In clinical practice, lower doses (once daily or twice daily) of pregabalin (50mg, 75 mg) and duloxetine (20mg, 30 mg) are widely co-prescribed by the neurologist. A combination of significantly lower doses of pregabalin-duloxetine has a greater pain relief than for side effects. ²³

Danish expert recommendation reported that a combination of gabapentinoid and SNRI is associated with better pain relief and lesser side effects than a single drug therapy. ²⁴ An Indian consensus statement suggests that when managing neuropathic pain management with gabapentinoids as first drug, TCAs such as nortriptyline or SNRIs can be considered as add on therapy and vice versa. ²⁵ The American Diabetes Asssociation (ADA) position statement recommends combination of two first line agents from class of gabapentinoids, SNRIs, or TCAs in cases wherein monotherapy fails. Furthermore, it also suggests that tramadol/tapentadol can be added if two drug combinations provide inadequate pain relief. ²⁶

The COMBO-DN (Combination vs. Monotherapy of pregabalin and duloxetine in DPN) is one of the largest and well known multinational randomized study conducted in patients with diabetic peripheral neuropathy. It reported outcome of duloxetine and pregabalin monotherapy at high doses versus a combination of these two agents at standard dosing. ²⁷ The primary outcome of the study was not achieved as no significant difference was measured between the monotherapy and standard-dose combination therapy. However, secondary outcomes of this trial showed that number of patients who achieved >50% reduction were more in combination treatment compared to high dose monotherapy (52.1% Vs 39.3%, p=0.068) with better tolerability.

The initial evidence indicates the need of additional large clinical trials in neuropathic pain for identifying optimal combination as initial approach. Therefore, we conducted a phase 3 trial on the fixed-dose combination of lower doses of pregabalin (50mg, 75mg) and duloxetine (20mg, 30mg) in adult patients with moderate to severe neuropathic pain.

Our phase 3 trial result suggests that the combination of a low dose of pregabalin and duloxetine provides similar analgesia and better safety in comparison to a high dose of pregabalin (150mg, 300mg) monotherapy. The subjective assessment done by CGI-I and PGI-I was also found similar in both the groups.

Data from the present trial suggest that a combination of low-dose pregabalin and duloxetine could be a combination of choice considering the relatively lesser dose administration for pregabalin without compromising efficacy and safety. Additional evaluation of safety data indicated a clear tolerability advantage of FDC over monotherapy for clinically meaningful adverse events associated with monotherapy.

The efficacy results of previous studies on the combination of pregabalin and duloxetine indicate that a combination therapy might be a reasonable therapeutic approach rather than up-titrating the dose in patients with inadequate pain control or having tolerability problem with a high doses of single first-line agent. The outcome of the present study supports the outcomes of previous studies.

In our trial, there were no significant safety concerns observed in both the treatment groups. The most common adverse effects observed were dizziness and somnolence, which are in line with the currently known profile of these drugs.

In this study, the overall frequency of adverse effects was similar with both treatments, except that patient receiving the pregabalin monotherapy had a higher frequency of peripheral oedema than those receiving the pregabalin-duloxetine combination. Additional analysis also established the safety advantage of FDC in AEs of common concern over monotherapy.

The strength of our study is that it is a double-blind, double-dummy parallel-group design. The use of lower doses of pregabalin and duloxetine in combination reflects current clinical practice.

The limitations of our study include small sample size, shorter duration of the study, and the design of the study which compared a fixed dose combination of pregabalin and duloxetine only with a high dose of pregabalin not with duloxetine. Patient related outcomes such as sleep interference and emotional functioning were not assessed in our trial.

Nevertheless, the trial results unequivocally shows that a low dose pregabalin-duloxetine combination is non-inferior to high-dose pregabalin monotherapy in management of patients with moderate to severe neuropathic pain.

In patients with moderate to severe neuropathic due to different aetiologies, the analgesic effect demonstrated by FDC of pregabalin (low dose), and duloxetine was comparable to pregabalin (high dose) monotherapy. The FDC was safe and well tolerated. This is the first Indian clinical trial in which FDC of pregabalin and duloxetine was evaluated. Future studies with larger sample sizes, long-term duration and heterogenous population are necessary to understand the clinical outcome with FDC of pregabalin and duloxetine.