Is It Time to Redefine Neuropathic Pain?

It is increasingly clear in clinical practice and scientific research that the current definition of neuropathic pain is not sufficiently inclusive of the neuropathic pain conditions. I would like to propose a revision of the definition of neuropathic pain from “pain caused by a lesion or diseases of the somatosensory nervous system” to “pain caused by a lesion or diseases of the sensory nervous system.” This is inspired by the need to cover not only neuropathic pain conditions that are a direct consequence of a lesion or diseases affecting the somatosensory system but also those that are a direct consequence of a lesion or diseases affecting the visceral sensory system.

Neuropathic pain has been defined as “pain that arises as a direct consequence of a lesion or diseases affecting the somatosensory system” by the International Association for the Study of Pain (IASP) (https://www.iasp-pain.org/GlobalYear/NeuropathicPain) [1]. The definition has played an important role in guiding research and patient care. It helps researchers to investigate the epidemiology, mechanisms, therapeutic strategies, preventive measures, and clinical outcomes of various neuropathic pain conditions. It also guides clinicians to diagnose and treat neuropathic pain in their daily practice. Furthermore, it provides a framework to impact the International Classification of Diseases (ICD), particularly the latest ICD-11 revision (https://icd.who.int/en), which recognizes and includes many neuropathic pain conditions for the first time [2].

It is increasingly recognized, however, that this definition has significant limitations. It may have missed a significant class of neuropathic pain conditions that are not a direct consequence of a lesion or diseases affecting the somatosensory system but a direct consequence of a lesion or diseases affecting the visceral sensory system. For example, visceral abdominal pain due to diabetic autonomic neuropathy has been well recognized and documented [3,4] and is clearly neuropathic. Similarly, chronic visceral pain due to multiple abdominal surgeries or chronic pancreatitis, among other conditions, may also have a significant neuropathic component. One piece of direct evidence comes from the fact that autonomic neuropathy with reduced intraepidermal nerve fiber density was observed in patients with gastrointestinal dysmotility and abdominal pain [5]. Indirect evidence comes from observations that patients with abdominal pain after abdominal surgeries or chronic pancreatitis may respond to visceral nerve blocks, radiofrequency ablation, or spinal cord stimulation [6,7]. Furthermore, many medications used to treat neuropathic pain, such as tricyclic antidepressants and anticonvulsants, are also commonly recommended for chronic visceral hyperalgesia or visceral pain [6].

Similar to abdominal visceral pain, refractory angina may also have a significant neuropathic component. Refractory angina refers to long-lasting symptoms (for >3 months) due to established reversible ischemia, which cannot be controlled by escalating medical therapy with the use of second- and third-line pharmacological agents, bypass grafting, or stenting. Patients with refractory angina who have failed medical, interventional, and surgical therapies to treat their coronary artery disease are often characterized by negative objective findings on an electrocardiogram or in cardiac enzymes and are commonly regarded as “completely vascularized” by cardiologists [8,9]. Thus, refractory angina may be considered as primarily a neuropathic pain condition that is caused by possible visceral sensory nerve injury due to coronary artery insufficiency or ischemia or during cardiac surgeries or procedures. In this context, visceral nerves (thoracic sympathetic nerves and, less likely, the vagal nerve–mediated parasympathetic nerves) are most likely responsible for the refractory angina. Indeed, several lines of evidence support this hypothesis. First, the possibility of microvascular disease causing refractory angina is less likely in absence of the cardiac enzymes and other objective findings [10]. Second, stellate ganglion block [11,12] or surgical sympathectomy [13,14] significantly improved patients’ symptoms and quality of life. These observations strongly argue against the likelihood of central causes of chest pain. Third, spinal cord stimulation, developed primarily to treat neuropathic pain conditions, has shown efficacy in mitigating refractory angina in multiple studies, including randomized controlled trials [8,15]. In fact, neuromodulation by spinal cord stimulation has been incorporated into the treatment algorithms for refractory angina in a recent update published by the European Heart Journal [9]. Collectively, this evidence, although indirect, supports the notion that a neuropathic component of refractory angina cannot be excluded and should be further investigated.

In the current IASP definition, only the somatosensory nervous system is explicitly referred to, not the visceral sensory system. Thus, redefining neuropathic pain is warranted. One of the ways of redefining neuropathic pain is to simply change the word “somatosensory” to “sensory” to cover not only neuropathic pain conditions that are a direct consequence of a lesion or diseases affecting the somatosensory system but also those that are a direct consequence of a lesion or diseases affecting the visceral sensory system.