Sensory profiles are heterogeneous in neuropathic pain disorders, and subgroups of patients respond differently to treatment.
To further explore this, patients in the COMBO-DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8-week therapy with either duloxetine or pregabalin, and after subsequent 8-week combination/high-dose therapy. Exploratory post hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items
In patients not responding to initial 60 mg/d duloxetine,
- adding 300 mg/d pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain,
- whereas maximizing the duloxetine dose to 120 mg/d appeared more beneficial regarding paresthesia/dysesthesia.
In contrast, adding 60 mg/d duloxetine to 300 mg/d pregabalin in case of nonresponse to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/d
Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items.
Mean Brief Pain Inventory average pain improved in all clusters during combination/high-dose therapy
However, in patients with severe pain, the treatment effect showed a trend in favor of high-dose monotherapy,
combination therapy appeared to be more beneficial in patients with moderate and mild pain (not significant)
These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.
Evidence suggests that in painful diabetic neuropathy, only a few drugs achieve greater than 30% reduction in pain in more than 50% of patients
Even though the COmbination vs Monotherapy of pregaBalin and dulOxetine in Diabetic Neuropathy Study (COMBO-DN study), a large, multinational combination treatment trial investigating duloxetine in combination with pregabalin in painful diabetic neuropathy , indicated that such a combination therapy might be a reasonable clinical option, the study failed to meet its primary objective.
some studies showed that lidocaine and morphine act differently on the different neuropathic pain symptoms and dimensions assessed with quantitative sensory testing (QST) and/or specific neuropathic pain questionnaires
The main objective of the present investigation was to further explore these hypotheses on the basis of complementary and exploratory analyses of data from the COMBO-DN study
In these exploratory analyses, we further compared the effects of duloxetine and pregabalin, administered alone or in combination, on the different dimensions of neuropathic pain.
The present exploratory analyses of data collected in the COMBO-DN study suggest that duloxetine and pregabalin have different effects on distinct neuropathic pain components in diabetic peripheral neuropathy.
Furthermore, subgroups of patients responded differently to the administration of these 2 drugs when given alone or in combination.
These results from a prospective evaluation of pain symptoms in a large number of patients with the same neuropathic pain etiology as well as from post-hoc cluster analyses tend to confirm the advantages of sensory phenotyping in clinical trials
the superior analgesic efficacy (based on the change in overall BPI 24-hour average pain) of 60 mg/d duloxetine for initial pain treatment was also reflected by greater effects on the different NPSI dimensions, with the exception of the evoked pain dimension
Interestingly, when examining the changes in the dimensions more closely, and when comparing the maximum doses of both drugs with their fixed combination of 60 mg/d duloxetine plus 300 mg/d pregabalin in the combination/high-dose therapy period, our data also indicated different effects of the drugs, depending on the pain dimension.
Combining pregabalin with duloxetine in patients not responding to an initial treatment with duloxetine alone was particularly beneficial on the evoked pain and pressing pain dimensions, whereas the feeling of abnormal sensations in the painful area as assessed by the paresthesia/dysesthesia dimension appeared to be more susceptible to maximizing the dosage of duloxetine
In contrast, combining duloxetine with pregabalin in patients not responding to pregabalin alone induced a more homogenous decrease in the different neuropathic pain components, which was slightly larger than for patients treated with high-dose pregabalin
Our findings also indicate that neither 60 mg/d nor 120 mg/d of duloxetine should be regarded as similar “monotherapies” when compared with 300 mg/d and 600 mg/d of pregabalin, respectively.
Taken together, our data are in line with suggestions that the heterogeneity of neuropathic pain syndromes should be taken into account in the consideration of treatment strategies
some drugs (eg, lidocaine, morphine, botulinum toxin) have a preferential action on some neuropathic symptoms, suggesting that symptoms or combinations of symptoms depend on different mechanisms
Thus, our data confirming the heterogeneity of patients within a single etiology tend to support that grouping patients based on sensory symptoms and signs rather than on etiology may be a meaningful way to improve response to pharmacological treatment
From a practical point of view, these exploratory data suggest that patients with painful diabetic neuropathy in whom insufficient pain relief is obtained after 8-week treatment with 60 mg/d duloxetine might benefit from combination treatment by adding 300 mg/d pregabalin, particularly if they present with a high intensity of pressing pain and evoked pain
In contrast, maximizing the duloxetine dose to 120 mg/d might be the better therapeutic option when paresthesia/dysesthesia is the main issue
For initial pregabalin nonresponders, increasing the pregabalin dose to 600 mg/d or combination treatment with 60 mg/d duloxetine might both be reasonable clinical options
However, our tentative practical conclusions should be regarded with caution, because several limitations should be considered with regard to the interpretation of our data.
First, treatment response to duloxetine, pregabalin, or their combination does not entirely depend on sensory phenotypes. Other factors influencing drug metabolism and susceptibility, including psychological trait and state variables or prior treatment experiences, should be taken into account
Second, the lack of a placebo group is an important drawback, because it cannot be excluded that some of the differences reported here were not specific
The present exploratory analyses further support the hypothesis that variability in sensory profiles exists across patients with diabetic peripheral neuropathic pain
In essence, the identification of subgroups of patients with distinct pain characteristics at baseline and their differential responses to duloxetine and pregabalin, alone or in combination, is encouraging, and indicates that heterogeneity in the patient population should be taken into account for a more stratified or even personalized treatment approach.