Painful and Non-painful Diabetic Neuropathy, Diagnostic Challenges and Implications for Future Management

Troels S. Jensen; Pall Karlsson; Sandra S. Gylfadottir; Signe T. Andersen; David L. Bennett; Hatice Tankisi; Nanna B. Finnerup; Astrid J. Terkelsen; Karolina Khan; Andreas C. Themistocleous; Alexander G. Kristensen; Mustapha Itani; Søren H. Sindrup; Henning Andersen; Morten Charles; Eva L. Feldman; Brian C. Callaghan


Brain. 2021;144(6):1632-1645. 

In This Article

Phenotyping DN and Painful DN and Implication for Treatment

Phenotyping patients with DN versus painful DN may be important for identifying new or better treatments for painful DN. Three studies used the German research network protocol to investigate differences in sensory profiles between painful and non-painful DN.[106,107] In the UK Pain in Neuropathy Study (PiNS),[106] patients with painful DN had more sensory loss, particularly small fibre function, and greater spread of proximal clinical signs compared to those with painless DN. Dynamic brush evoked allodynia was only observed in patients with painful DN. Similar findings were seen in two other studies,[107] one of which also demonstrated a predominant sensory loss to thermal stimuli that correlated to the severity of neuropathic pain and neuropathy. Consistently, painful DN exhibits more extensive sensory function loss, supporting the notion that loss of afferent input, mainly related to small fibre function, is important for the development of neuropathic pain.[70]

Phenotypic profiling may be important for identifying the optimal treatment for patients with painful DN. Current pharmacological therapies for painful DN are insufficient, mainly due to a lack of approved therapies targeting the underlying pain mechanisms.[8,39,108–110] As shown in Figure 5, most of the current symptomatic pharmacological treatments are of poor efficacy with numbers need to treat (NNT) of ~7 for the most frequently used therapies. This means that less than one in seven patients with painful DN obtain a pain sufficient relief. It is worth noting that the studies from which the different symptomatic guidelines were generated[110,112–115] were almost entirely based on patients with painful DN, but without specific sensory profiling. The lack of highly efficacious therapies for painful DN raises the question of whether additional tests such as QST, nerve fibre assessment from skin biopsies, genetic analysis, or other biomarkers[116] may aid in further phenotyping patients to improve clinical trial design and outcome measures.

Figure 5.

Combined numbers needed to treat values for drug classes recommended for painful DN. The circle sizes indicate the relative number of patients, who received active treatment drugs in studies for which dichotomous data were available. Gabapentin ER = gabapentin extended release or enacarbil; NNT = needed to treat; SNRIs = serotonin noradrenaline reuptake inhibitors; TCAs = tricyclic antidepressants. Updated from Finnerup et al.110,111

Recent studies suggest that more precise phenotyping of painful neuropathies, including DN, may identify patient subgroups likely to respond to an existing compound, which otherwise may be ineffective in unselected patients. One randomized controlled trial in peripheral neuropathic pain, including painful DN, stratified patients a priori to test the concept of a mechanism-based treatment.[117] In that study, patients with the so-called 'irritable nociceptor phenotype' based on QST responded better to the sodium-channel blocker oxcarbazepine than those without this phenotype.[117] A recent study Han and colleagues[118] described how carbamazepine, a structural oxcarbazepine analogue, may correct hyperexcitability caused by a novel Nav1.8 mutation in a patient with diabetes and neuropathic pain. This novel mode of action of carbamazepine is similar to that seen in another sodium channel subtype, Nav1.7.[119] These findings may be of value in identifying patients that are more likely to respond to carbamazepine or related compounds, but future studies are needed to clarify this possibility.

The anticonvulsant lacosamide, a Nav1.7 and Nav1.8 sodium channel blocker, has been tested in small trials of patients with painful DN, but did not significantly reduce pain compared to placebo.[120] However, in a recent double-blind placebo controlled cross-over study in patients with Nav1.7-related SFN, lacosamide significantly reduced pain versus placebo.[121] These findings indicate that pharmacological efficacy may be boosted in specific patient subgroups.

Taken together, these studies suggest it may be possible to apply precision medicine to treating neuropathic pain by utilizing detailed phenotypic profiling of DN patients. However, additional studies are needed to clarify the role of detailed phenotyping of diabetic patients, including consideration of specific mechanisms of pharmacological agents.