COMBO-DN: Duloxetine and Pregabalin Combination vs. High-Dose Monotherapy in Patients with DPN who do not Respond to Standard-dose Monotherapy

29 Apr, 22

Introduction

Nearly 50% of diabetes patients suffer with the chronic complication of diabetic peripheral neuropathy (DPN) that is associated with severe un-remitting lower limb pain. DPN negatively affects sleep, functionality and other aspects of quality of life. Nevertheless, clinical management of DPN is a challenging task. Duloxetine and pregabalin are the two drugs that have been approved for the treatment of neuropathic pain associated with diabetes. It is believed that complimentary mode of action for the both the medications may provide additive effect for treating DPN.

Aim

The COMBO-DN (COmbination vs. Monotherapy of pregabalin and dulOxetine in Diabetic Neuropathy) evaluated whether a combination of duloxetine and pregabalin would be superior to the standard doses or high doses of the monotherapy in managing the DPN pain.

Patient Profile

Adult patients who were not receiving any medication for DPN or had completed a 2-week washout period, and had never received any duloxetine or pregabalin, except for a <15-day course of duloxetine or pregabalin treatment (n=804).
Patients also had daily pain (for at least 3 months) due to bilateral peripheral neuropathy associated with type-1 or type-2 diabetes mellitus, beginning in the feet in a relatively symmetrical fashion.
All patients had the diagnosis of DPN, as confirmed by a score of ≥3 on the Michigan Neuropathy Screening Instrument at screening
All patients had to present with a 24-hour average pain severity of ≥4 on the Brief Pain Inventory Modified Short Form (BPI-MSF), and stable glycemic control with glycosylated hemoglobin (HbA1c) ≤12%.

Methods

Study Design

Multinational, randomized, double-blind, parallel-group study

Treatment Strategy

The study period was divided into four phases:
- a 2-week screening and washout period
- an 8-week initial therapy period
- an 8-week combination/high-dose therapy period
- a 2-week taper period
Patients were randomized 1:1:1:1 into 4 parallel groups:
During the initial 8-week period, patients received either 60 mg/day duloxetine (groups 1, 2; n=401) or 300 mg/day pregabalin (groups 3, 4; n=403)
Following this, during the 8-week combination/high-dose therapy period, patients received the following:
- Only non-responders received high dose monotherapy (n=173) 120 mg/day duloxetine (group 1) or 600 mg/day pregabalin (group 4)
- A combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3; n=170)

Outcomes

Primary Outcome

Brief Pain Inventory Modified Short Form (BPI-MSF) 24-hour average pain score

Secondary Outcomes

Other BPI-MSF severity items
The Clinical Global Impression of Improvement scores
The Patient Global Impression of Improvement scores
The Neuropathic Pain Symptom Inventory (NPSI) questionnaire total score, and its 5 subscores (burning spontaneous pain, pressing spontaneous pain, paroxysmal pain, evoked pains, and paraesthesias/dysaesthesias)
The total and anxiety and depression subscale scores of the Hospital Anxiety and Depression Scale (HADS).
The change in BPI-MSF 24-hour average pain during initial therapy period, comparing standard doses of duloxetine (60 mg/day) and pregabalin (300 mg/day), corresponding to half the maximum doses for each drug

Safety Outcomes

Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs, defined as any event resulting in prolonging hospitalization or death, life-threatening experience, severe or permanent disability)

Results

The BPI-MSF average pain did not differ significantly between combination and high-dose monotherapy groups (Fig. 1). The corresponding mean percent change was -39.4% with combination therapy, and -34.3% with high-dose monotherapy.

Fig. 1: Mean change in the BPI-MSF score in the study group

Amongst the high-dose monotherapy group, 46.9% of patients treated with 600 mg/day pregabalin experienced a pain reduction of ≥50% compared to 28.4% treated with 120 mg/day duloxetine
The 50% responder rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068).
At the end of the combination/ high-dose therapy the secondary efficacy outcomes were consistently in favor of the combination therapy, though the differences were not statistically significant. Only the results for the HADS anxiety subscale were significant (mean difference: -0.62; P = 0.049).
Both drugs and their combination were well tolerated in the study population, with no significant differences between the incidence of TEAEs and SAEs.

Conclusions

“COMBO-DN was the first multicentre, fully blinded parallel-group study that addressed an important clinical question for patients with DPN: ‘‘Is it better to increase the dose of the current first-line recommended monotherapy or to combine with another first-line recommended drug early on in patients with insufficient pain relief?”
The findings of the study were in favor of the combination therapy, the same being superior to high-dose monotherapy.
The combination therapy with duloxetine and pregabalin might thus be a reasonable, effective, safe, and well tolerated clinical option, rather than shifting to high-dose monotherapy for patients not responding to standard-dose monotherapy with the individual drugs.

Pain. 2013; 154: 2616–2625.