Neuropathic pain: pathogenesis and its clinical significance
Neuropathic pain occurs after nerve injury with deleterious changes within the damaged neurons, which subsequently affect the somatosensory system and the downstream regulatory pathways of the central nervous system. A wide variety of neurotransmitters and some substances involved in the development and maintenance of neuropathic pain also play a role in other neurobiological dysfunctions. This partly explains why chronic pain patients have a high co-morbidity of sleep disorders and some psychological disorders such as depression, and why some drugs that are primarily used for one disorder are also effective for others. Neuropathic pain differs from non-neuropathic pain in two ways. First, there is no transduction of neuropathic pain (injurious stimuli need to be converted to electrical impulses). Second, neuropathic pain has a poorer prognosis: damage to major nerves is more likely to lead to chronic pain than damage to non-neural tissues. In addition, neuropathic pain is less well tolerated than non-neuropathic pain to conventional analgesics such as NSAIDs and opioids. However, based on the great commonality between the two in terms of neuropathic alterations and injury pain pathogenesis and treatment characteristics, it is more constructive to understand their nature as different nodes of the same continuum of events.
INTRODUCTION: Pain is a protective mechanism by which the body warns of ongoing or impending tissue damage. According to a 2011 article published by the Institute of Medicine, one third of Americans experience chronic pain, more than people with heart disease, cancer, and diabetes combined. In Europe, the prevalence of chronic pain is 25-30%. Roughly one in five of all chronic pain patients is considered to have neuropathic pain.
The main reason for such a high prevalence of chronic pain patients, especially those with neuropathic pain, is the lack of effective treatment options. Unlike non-steroidal anti-inflammatory drugs and opioids, which have a definite therapeutic effect on patients with non-neuropathic pain, when they are used to treat patients with neuropathic pain, they only have a rather mild effect on some of the population, mainly because the pathogenesis is not precisely understood. In general, specific treatments that target specific pain pathogenesis are significantly more effective than treatments that are based on knowledge of the disease or its cause. This is the reason why many drugs are effective in preclinical trials but have little effect in the clinical setting. In the past decade, several articles have reviewed and analyzed the pathogenesis of neuropathic pain, most of which were directed at neuroscientists; however, it is also quite important for clinicians to understand its pathogenesis, as it can guide future research directions and direct clinical practice.
Physiology and Classification
Four basic elements are required to produce pain following injury to body tissues.
1. transduction: injurious receptors transform noxious stimuli into injurious signals.
2. Transmission: transmission of the injurious signal from the injury site along the nerve fibers to the central nervous system.
3. Transduction or remodeling: modulation of injurious signals at synaptic sites and at the CNS level through upward, downward, or localized facilitation and inhibition transitions.
4. Perception: Integration of cognitive and affective responses to injurious signals that produce pain sensations. This is a key factor in the occurrence of pain in clinical practice.
Although it is possible to define all pain as the same concept, this is too simplistic. In reality pain can be divided into many types and each type has different neurobiological and pathophysiological mechanisms. Most commonly, pain is classified into two main types: neuropathic pain and injurious pain. This typing is extremely important because it not only clarifies the cause of the pain, but also guides the subsequent treatment.
Injury pain can be subdivided into somatic pain and visceral pain. Chronic somatic pain is easily localized because of the high distribution of injury receptors in somatic tissues, but it also often leads to degeneration of this process. In contrast, visceral is insensitive to traditional pain stimuli (e.g., cutting, burning) but very sensitive to ischemia, inflammation, and obstruction.
Neuropathic pain is pain that results from damage or dysfunction of the somatosensory system. In this type of pain, damage to the tissues directly affects the nervous system, leading to ectopic discharges in the transduction parabolic pathway.
Emotion and physiology
The most common misconception about pain is that it is a purely physiological phenomenon. In fact, the term “pain” is synonymous with the integration of all information and expressions, including neurophysiological, psychological, and sociocultural factors. This is the reason why preclinical studies, clinical studies and clinical practice have yielded varying results.
Since pain is influenced by multiple factors, it can also gradually develop into chronic pain when it occurs in patients due to psychological factors such as depression, physical reasons, poor coping skills, weak social adjustment, and job burnout. In addition, situational changes also play a role in pain perception.
The mechanisms of its occurrence can be divided into central and peripheral neural mechanisms. Peripheral mechanisms such as peripheral sensitization, ion channel expression, phenotypic switch, sensory denervation and proliferation of lateral branch nerve fibers, and sympathetic maintenance pain. Central neural mechanisms such as spinal mechanisms, spinal glutamatergic modulation, glial cell activation and inflammatory cytokines, supraspinal central neural mechanisms, etc.
Neuropathic pain and injurious pain: different in nature or different stages of development of the same disease?
It is generally accepted that neuropathic pain and non-neuropathic pain are fundamentally different, but there are still some people who doubt this conclusion and believe that the two diseases are classified only according to natural tendencies. The essential difference between the two has two main aspects.
1. injurious pain requires transduction from a non-electrical signaling pathway to an electrochemical signaling pathway, whereas neuropathic pain simply involves nerve stimulation and does not require transduction.
The prognosis is different: most patients with injurious pain recover to a pain-free state, whereas patients with damage to major nerves are in a long-term painful state.
However there are also many studies proving the presence of many neurotransmitters, neuropeptides, cytokines and enzymes in both pains of different nature. Moreover, the spinal upstream conduction pathways, the supraspinal regions that process pain signals, and the downstream regulatory pathways are identical in neuropathic and non-neuropathic pain. Combined with the fact that these two different properties of pain have many components with overlapping characteristics, the different subtypes of chronic pain can be considered as different nodes of the same continuum.
New therapeutic advances
To enable a deeper understanding of pain mechanisms, to develop treatment and research models, and to develop new analgesics, we need to do the following.
1. develop new animal models that focus on the impact of clinical complications on pain.
2. apply new behavioral assessment tools to measure various aspects of the pain experience.
3. explore the relationship between brain reorganization in the imaging of novel imaging machines and chronic pain, focusing on the altered imaging of pain in response to treatment.
4. detecting biomarkers, genotyping or phenotyping of different pains, allowing us to better understand the heterogeneity of clinical pain and develop individualized treatment plans.
These research advances combined with new drugs produced for individualized patients and specific pain mechanisms are believed to significantly improve the treatment of neuropathic pain in the coming years.