Mechanisms and management of diabetic painful distal symmetrical polyneuropathy

Abstract

Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15-20% of diabetic patients may have painful DSPN, but not all of these will require therapy. In practice, the diagnosis of DSPN is a clinical one, whereas for longitudinal studies and clinical trials, quantitative sensory testing and electrophysiological assessment are usually necessary. A number of simple numeric rating scales are available to assess the frequency and severity of neuropathic pain. Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. α-Lipoic acid, an antioxidant and pathogenic therapy, has evidence of efficacy but is not licensed in the U.S. and several European countries. All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment.

Figure 1

A representation of the central spinal and peripheral changes that accompany neuropathy. The existence of a lesion or disease of a peripheral sensory nerve alters the conduction and transmission of sensory messages. The normal transfer of modalities (top right) onto spinal nociceptive specific (NS) and wide-dynamic range (WDR) neurons is changed by ectopic activity, sensory loss, and changes in ion channels. Spinal cord neurons are subject to many receptor-mediated events, but increases in Ca channel function lead to increased transmitter release so that glutamate causes an enhanced activation of AMPA and NMDA receptors. Substance P acts on neurokinin 1 (NK1) receptors to add to the excitation. Reduced spinal inhibition through γ-aminobutyric acid (GABA) and the transporter potassium-chloride transporter member 5 (KCC2) aids enhanced pain messages. Reduced noradrenaline (NA) descending inhibition via α-2 adrenoceptors and increased 5-hydroxytryptamine (5HT) descending excitation via 5HT3 receptors add to the dominance of excitatory transmission. μ-Opioid receptors (MOR) are found on this circuitry.

Figure 2

An overview of the ascending (left) and descending (right) pain pathways. From the spinal cord there are spinoreticular projections and dorsal column pathways to the cuneate nucleus (CN) and nucleus gracilis (NG). Other limbic projections relay in the parabrachial nucleus (PB) and then project to the hypothalamus (Hyp) and amygdala (Am), where central autonomic function and fear/anxiety are processed. Spinothalamic pathways run to the ventrobasal medial (VPM) and lateral (VPL) areas and then run to the somatosensory part of the cerebral cortex (CC) where the location and the sensory components of pain are generated. Limbic brain areas (Am and Hyp) project down to the periqueductal gray (PAG) and to the locus coereleus (LC), A5 and A7 nuclei, and the rostroventral medial medulla (RVM). Thence, descending noradrenaline (NA) inhibition via α-2 adrenoceptors and increased 5-hydroxytryptamine (5HT) descending excitation via 5HT3 receptors modulates spinal cord activity. The changes induced by peripheral neuropathy on these brain functions are depicted together with comorbidities, and genotypic and phenotypic factors are shown.

Figure 3

Treatment algorithm for painful DSPN. Adapted with permission from Tesfaye et al. (65).