Nociceptive pain is defined as a physiologic response to tissue damage or potential damage. This can be caused by physical, chemical, or temperature stimuli. Most patients describe nociceptive pain using terms such as sharp, aching, and throbbing. Most nociceptive pain is acute or subacute in nature (lasting <4–6 weeks) with a lower proclivity to become chronic, though it may be implicated in centralized pain states.

Neuropathic pain may also be referred to as neuralgia or nerve pain and results from damage to peripheral nerves or the central nervous system. Most patients tend to describe this type of pain using terms such as burning, stabbing, shooting, electrical, or pins and needles. Patients with neuropathic pain have a high propensity to develop chronic pain syndromes.

Nociplastic pain occurs when persistent pain occurs despite an absence of ongoing tissue injury. It is thought to involve abnormal processing of painful stimuli by the central nervous system and/or abnormal processing of nonpainful stimuli such that they are perceived as pain. This is generally a maladaptive pattern that involves amplification or change of signals to result in an experience of pain. Nociplastic pain itself should not be confused with the phenomenon of central sensitization, although central sensitization may play a role in the development of nociplastic pain.

Each of these 3 primary categories of pain may occur in isolation or simultaneously with one or more other types of pain. ^,,

Four major regions are implicated in the core pain processing network: the primary and secondary somatosensory cortices, the anterior cingulate cortex (ACC), the insula, and the thalamus. ^,,,,

The primary and secondary somatosensory cortices are responsible for processing sensory discriminative aspects of pain and encoding location, intensity, and quality of the stimuli ( Fig. 1 ). The ACC is crucial for the affective motivational dimension of pain while processing the unpleasantness of a painful experience, thus implicated in the emotional response and attention to pain. ^, The insula is responsible for integrating sensory and affective pain components. ^, The anterior insula conducts affective motivational aspects, and the posterior insula conducts sensory discriminative aspects. Lastly, the thalamus serves as the central relay station for all nociceptive and neuropathic information and is thought to filter and modulate any incoming pain signals to then project to cortical regions through different nuclei ( Table 1 ). ^,

Diagram summarizing the main cortical areas that are implicated in pain sensation and interpretation. Amg, amygdala; Cd, caudate; Hi, hippocampus; Ins, insular cortex; LC, locus coeruleus; M1, primary motor cortex; NAc, nucleus accumbens; PAG, periacqueductal gray; PFC, prefrontal cortex; Pu, putamen; RVM, rostral ventral medulla; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; SMA, supplementary motor area; Th, thalamus; TPJ, temporal-parietal junction.

(Reproduced with permission from Martucci et al. )

Pain signals must travel peripherally to centrally located structures, and this occurs via the spinal cord. The dorsal horn laminae represent the first order processing and modulation centers for painful signals to the central nervous system. These directly project to the spinothalamic tract, which is the major ascending pain pathway to the thalamic nuclei. Other pathways in the spinal cord that are involved in pain include the spinoreticular, spinomesencephalic, and spinoparabrachial. These pathways all relay to important cortical structures, as outlined in Table 2 . ^,,,,

There are 3 primary structures categorized in the descending pain modulation system: PAG, rostral ventromedial medulla (RVM), including the nucleus raphe magnus (NRM), and the locus coeruleus (LC). ^,

The PAG is a central hub for descending pain modulation, analogous to the thalamus in the core pain processing network. It coordinates analgesic responses and connects with the RVM. The RVM contains on and off cells that can either upregulate or downregulate pain signals. The RVM importantly includes the NRM, which has serotonergic projections to the dorsal horn of the spinal column thus involved in descending pain inhibition. The LC receives input from the PAG and communicates with the RVM and sends inhibitory signals down the spinal cord. ^,

The PFC is involved in the cognitive aspects of pain processing and is believed to help with pain anticipation and contextualization. The PFC is also implicated in mediating placebo analgesia in cognitive pain modulation. ^,

This descending pain modulation system is detailed in Fig. 2 .

Descending Inhibition pathway of the cortical and spinal cord structures including the thalamus, amygdala, PAG, LC, RVM, and dorsal reticular nucleus (DRt). Additional structures in the amygdala shown are the lateral amygdala (LA), basolateral amygdala (BLA), and central nucleus of the amygdala (CeA). Ascending tracts are labeled with red lines and descending tracts with green lines.

(Reproduced with permission from Ossipov et al. )

The amygdala processes fear and anxiety related to painful stimuli, contributing to the emotional affective aspect and is critical to pain related learning and memory. The basal ganglia are implicated in motor responses to pain and are involved in pain-related reward processing, with contributions to pain chronicity. The cerebellum is involved in pain processing, particularly in motor coordination in response to pain, along with perception and modulation thereof.

There are a multitude of neurotransmitters used in various regions of the brain and spinal cord, specifically for pain transmission and processing. While not a comprehensive list, the following tables ( Tables 3–5 ) highlight important neurotransmitters involved in these processes. ^,

Alterations seen in patients with longstanding chronic pain are demonstrated as neuroplastic changes across various brain regions. Many studies have identified regions that demonstrate typical alterations in this patient population.

Histologically, chronic pain generates neuroinflammation resulting in glial cell activation (microglia and astrocytes), which then can release proinflammatory cytokines and chemokines, contributing to the development of hyperalgesia and allodynia.

Imaging studies reveal that chronic pain is associated with reduced gray matter in the insular cortex, disrupted connectivity with the frontoparietal network, and heightened insular activation during pain processing. Additionally, altered connection patterns are shown in the medial prefrontal cortex (mPFC) and anterior insula.

The hippocampus (CA3 region specifically) shows dendritic atrophy with decreased density and correlates with cognitive impairments. The thalamus tends to show volume loss and altered activity as well.

In the spinal cord, increased synaptic plasticity and heightened responsiveness of the dorsal horn occur through a similar neuroinflammatory process as described earlier. Loss of inhibitory interneurons, along with the formation of maladaptive synaptic connections, amplifies nociceptive transmission. Together with long-term potentiation and wind-up phenomena, these changes contribute to the hyperexcitability of spinal neurons seen in central and chronic pain states. ^,

SCI patients in particular show evidence of regional hyperexcitability, and patients with spinothalamic tract damage have a high risk of increased pain intensity and altered pain modulation. ^,

The clinical history of a patient presenting with centralized pain can be vague and nonspecific, though recognizable patterns may be present. Many patients will report widespread pain, fatigue, mood disturbances, and sleep disturbances, which are typically out of proportion to the known morbidities the patient has. ^,,,

History of stroke, SCI, long-standing psychiatric illness, auto-immune conditions involving the CNS, and uncontrolled chronic metabolic disorders place patients at high risk of developing centralized pain.

Centralized pain encompasses a range of characteristics but is often distinguished from typical nociceptive or neuropathic pain by hallmark features such as allodynia and/or hyperalgesia, diffuse distribution, variable intensity and duration, fatigue, and disturbances in mood or sleep.

While these symptoms may present in patients without centralized pain, having multiple components present increases a clinician’s index of suspicion for centralized pain disorders. ^,