Using stratified medicine to understand, diagnose, and treat neuropathic pain

Neuropathic pain (NeuP) is defined as pain arising from a lesion or disease of the somatosensory nervous system[39; 88]. NeuP is common, affecting approximately 6-8% of the general population[14; 86] and currently treatment is inadequate due to both poor drug efficacy and tolerability[38]. Many different types of injury can cause neuropathic pain including genetic (e.g. SCN9A gain of function variants), metabolic (e.g. diabetic polyneuropathy), infective (e.g. HIV associated neuropathy, hepatitis), traumatic and toxic (e.g. chemotherapy induced neuropathy) causes. Such injurious events can impact on anatomically distinct regions of the somatosensory nervous system ranging from the terminals of nociceptive afferents (in small fiber neuropathy) to the thalamus (in post-stroke pain). Classification of neuropathic pain using etiology and location remains an important aspect of routine clinical practice; however, pain medicine is coming to the realization that we need more precision in this classification. The hope is that improved classification will lead to better understanding of risk, prognosis and optimal treatment of NeuP. Patient stratification is the process of identifying subgroups of patients, suffering from a disorder (such as NeuP) in order to better target medical intervention[92]. Such sub-groups may map to a particular pathogenic mechanism but could also simply be a constellation of clinical symptoms and signs or biomarker, which are predictive of treatment response. Personalized medicine aims to target intervention to individual patients and is therefore even more ambitious in scope[68]. Personalized medicine may be possible in rare cases of NeuP (usually associated with specific gene mutations) but for the most part we will discuss stratified pain medicine in this review. Both preclinical and clinical science, have identified an array of pathogenic mechanisms underlying NeuP ranging from ectopic activity in primary afferents to defective central pain modulation pathway (for a comprehensive review see [18]). It is not a new idea that we should be trying to understand pain mechanisms in patients [106; 107] although there are challenges in being able to assess specific mechanisms in individual patients. Stratification aims to achieve patient subgroupings that have utility in terms of diagnosis, prognosis or treatment and this may not relate to a single pathogenic mechanism. Fortunately our armamentarium for identifying patient subgroups (and in some cases directly assaying pathogenic mechanisms) in patients has greatly improved. In the first section of this manuscript we will review the means by which NeuP patients may be stratified and in the second section the potential benefits of stratification. Thomas Lewis said, ‘Diagnosis is a system of more or less accurate guessing, in which the endpoint achieved is a name. These names applied to disease come to assume the importance of specific entities, whereas they are for the most part no more than insecure and therefore temporary conceptions’. He was likely exaggerating for effect but we hope that patient stratification will not only reduce the uncertainty in diagnosis but also help improve prevention, prognostication and treatment.