Topic Resources
According to the International Association for the Study of Pain (IASP), pain is defined as an “unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage (1).
There are several key concepts in understanding pain:
The experience of pain is always subjective.
Individuals learn the concept of pain through experiences.
Individuals' biomedical, psychological, and social contexts influence their experience of pain.
The IASP emphasized that an individual’s report of pain should always be respected, and that verbal description of pain is only one way to communicate pain. In fact, the inability to communicate does not negate the possibility of experiencing pain.
Pain has sensory and emotional components and is often classified as acute or chronic. Acute pain is frequently associated with anxiety and hyperactivity of the sympathetic nervous system (eg, tachycardia, increased respiratory rate and blood pressure, diaphoresis, dilated pupils). Chronic pain generally does not involve sympathetic hyperactivity but may be associated with other comorbidities (eg, fatigue, sleep disturbances, dissatisfaction with social roles, changes in mood, anxiety).
Pain is the most common reason patients seek medical care, and chronic pain, defined as pain lasting more than 3 months, impacts a large portion of the population. In 2023, the Centers for Disease Control and Prevention estimated that almost 25% of adults in the United States had chronic pain and approximately 7% had high-impact chronic pain (2), meaning their chronic pain significantly restricted daily activities. Population studies consistently show higher incidences of chronic pain in females and older adults. The most common locations of pain are the lower extremity, followed by the back, the upper extremities, and the head (3).
References
1. Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976-1982. doi:10.1097/j.pain.0000000000001939
2. Lucas JW, Sohi I. Chronic Pain and High-Impact Chronic Pain in U.S, Adults, 2023. National Center for Health Statistics. NCHS Data Brief No. 518, November 2024.
3. Yong RJ, Mullins PM, Bhattacharyya N. Prevalence of chronic pain among adults in the United States. Pain. 2022;163(2):e328-e332. doi:10.1097/j.pain.0000000000002291
Pathophysiology and Classification of Pain
While there are no universally agreed upon ways to classify pain, there are several frameworks that can be used.
The timing of pain (ie, its onset, persistence, fluctuation, and duration) is the basis for classifying it as acute or chronic.
Acute pain, which usually occurs in response to tissue injury, results from activation of peripheral pain receptors and their specific A delta and C sensory nerve fibers (nociceptors). Acute pain is typically sudden in onset and is time-limited, lasting less than 1 month but sometimes up to 3 to 6 months.
Chronic pain related to ongoing tissue injury is presumably caused by persistent activation of these fibers. However, the severity of tissue injury does not always predict the severity of chronic or acute pain, and chronic pain can occur in the absence of tissue damage. Chronic pain can be secondary to an underlying disease (eg, cancer) or primary (ie, it can be a disease in and of itself) (1). Chronic pain may also result from ongoing damage to or dysfunction of the peripheral or central nervous system (which causes neuropathic pain). Pain is classified as chronic if it persists for more than 3 months to 6 months (1).
Chronic pain can also be understood using a pathophysiologic model, which classifies pain as nociceptic, neuropathic, or nociplastic based on known or hypothesized mechanisms (2).
Nociceptive pain (pain caused by tissue injury) may be somatic or visceral; it is due to activation of peripheral pain receptors and includes pain due to inflammation. Somatic pain receptors are located in skin, subcutaneous tissues, fascia, other connective tissues, the periosteum and endosteum, and joint capsules. Stimulation of these receptors usually produces sharp or dull localized pain, but burning is not uncommon if the skin or subcutaneous tissues are involved. Visceral pain receptors are located in most viscera and the surrounding connective tissue. Visceral pain due to obstruction of a hollow organ is poorly localized, deep, and sometimes cramping and may be referred to remote cutaneous sites. Visceral pain due to injury of organ capsules or other deep connective tissues may be more localized and sharp. Examples of causes of nociceptive of pain include osteoarthritis and pain due to acute trauma, cancer, and rheumatologic conditions.
Neuropathic pain refers to pain caused by injury to either the central or peripheral nervous system and is often characterized by pain in a dermatome, a territory controlled by an area of the brain or a peripheral nerve. Neuropathic pain is sometimes associated with paresthesias and is often described as shooting, burning, or tingling. Neuropathic pain conditions may be accompanied by neurologic deficit. Examples of neuropathic pain include diabetic neuropathy, trigeminal neuralgia, and postherpetic neuralgia.
Nociplastic pain is a more recently described third category that is distinct from nociceptive and neuropathic pain and is still poorly understood. It is thought to be due to a dysfunction of the central nervous system resulting in altered processing of pain signals. Nociplastic pain tends to be more diffuse, widespread, and may be associated with fatigue, gastrointestinal symptoms, sleep disturbances, and cognitive dysfunction. Fibromyalgia is an example of nociplastic pain. Nociplastic pain is also thought to play a role in conditions such as temporomandibular disorder and long COVID syndrome.
Many pain syndromes are multifactorial and can be considered mixed states. For example, chronic low back pain and most cancer pain syndromes have a prominent nociceptive component but may also involve a neuropathic component (due to nerve damage). It has been estimated that the prevalence of mixed pain among patients with chronic pain in primary care and orthopedic settings may be more than 50% (3). However, chronic pain as a whole is best understood within the context of the biopsychosocial model. According to this model, the experienced intensity of chronic pain—regardless of type—is modulated to a highly variable degree by psychological factors. Thoughts and emotions have an important role in the perception of pain. Many patients who have chronic pain also have psychological distress, especially depression and anxiety. Because certain syndromes characterized as psychiatric disorders (eg, some somatic symptom disorders) are defined by self-reported pain, patients experiencing unexplained pain are often misdiagnosed with a psychiatric disorder and are thus deprived of appropriate care.
Pain impairs multiple cognitive domains including attention, memory, concentration, and content of thought, possibly by demanding cognitive resources. (For a concise description of the 3 main categories of pain, see Figure 2. Illustrative drawing showing the various manifestations of neuropathic, nociceptive, and nociplastic pain, along with treatment considerations, 2.)
Pain processing: transduction, transmission, modulation, and perception
Normal pain processing entails a process of transduction, transmission, modulation, and finally perception. When acute pain becomes chronic, there are abnormal changes in the pain-processing pathway that are contributed to by premorbid risk factors and genetics.
Transduction is the process of activation, by noxious stimulation, of the subtype of primary afferent neuron, known as a nociceptor. This activation may occur whether there is actual or potential tissue damage because inflammatory mediators can be produced in both situations. Nociceptors are located throughout the body except for the brain. Nociceptors are either large and myelinated A delta fibers, responsible for acute sharp pain, or small and unmyelinated C fibers causing a slow-onset, dull, lingering, or achy pain. Nociceptors are typically polymodal and capable of responding to different stimuli (thermal, mechanical, or chemical) depending on their location in the body.
There are many receptors involved in nociception. Perhaps the best known receptor family comprises membrane-based transient receptor potential (TRP) ion channels. These receptors and others help activate and sensitize other nociceptors. Inflammatory mediators can stimulate nociceptors directly or sensitize them to more readily respond to noxious stimuli and increase neuronal excitability. Sensitization reduces the threshold of activation and increases the response rate to harmful stimulation caused by tissue insult and inflammation. Tissue injury can also stimulate nociceptors directly.
Transmission is the process of conveying the signal to the central nervous system (CNS). Both C and A delta fibers can transmit signals. This signal enters the spinal cord at the dorsal root ganglia and synapses in the dorsal horn. Second-order neurons then carry the transmission to the central nervous system via the lateral spinothalamic tract and medial spinothalamic tract. These tracts project to the thalamus. The lateral spinothalamic tract projects to the ventral posterolateral nucleus of the thalamus, and the medial spinothalamic tract projects to the medial thalamus. The lateral tract carries information about the intensity and location of pain. The medial tract carries the unpleasant emotional perception of pain and autonomic information. Finally, third-order neurons transmit signals from the thalamus to cortical regions that process the localization, perception, and emotional components of pain.
Modulation is an endogenous process that enhances or diminishes the transmission of pain signals in the periphery, spinal cord, and brain. Mechanisms thought to be responsible for this phenomenon include segmental inhibition, the endogenous opioid system, and the descending inhibitory nerve signals. In addition, cognitive and coping strategies also play a role in altering pain perception. Segmental inhibition, originally part of the “gate theory” described by Melzack and Wall, is the process whereby nearby sensory neurons carrying nonpainful signals stimulate inhibitory neurons that reduce transmission of pain (4). This explains why rubbing an injury reduces the sensation of pain. Noxious stimuli carried by A delta and C fibers and neurons in the dorsal horn of the spinal cord can be blocked when large myelinated nerve fibers (A delta) that sense nonnoxious stimuli stimulate inhibitory pathways in the spinal cord that suppress transmission of pain signals in small, unmyelinated C fiber afferents. Endogenous opioids (enkephalins, endorphins, and dynorphins) bind to the opioid receptors in the pain pathway and modulate the pain signal. Finally, the descending inhibitory pathway controls the transmission of noxious signaling by stimulating release of serotonin and norepinephrine to dampen the pain signal in the dorsal horn.
Perception is the conscious experience of pain, shaped by sensory, emotional, and cognitive processes. The thalamus acts as a central relay, distributing pain signals to key brain regions:
The somatosensory cortex processes the sensory-discriminative aspect, encoding pain location, intensity, and quality.
The insular cortex integrates pain perception with autonomic and emotional responses, shaping the subjective pain experience.
The anterior cingulate cortex (ACC) mediates emotional distress, suffering, and pain-related motivation.
The prefrontal cortex (PFC) influences pain perception through attention, expectations, and cognitive modulation.
The limbic system, including the amygdala and hippocampus, links pain to fear, anxiety, and memory, affecting long-term pain responses.
Pain perception is highly variable, influenced by psychological state, attention, prior experiences, and social context. Factors like anxiety or catastrophizing can amplify pain, while distraction or cognitive control can diminish it. Chronic pain conditions, such as central sensitization, involve maladaptive neuroplastic changes, leading to persistent pain perception even in the absence of ongoing nociceptive input.
Pain-Processing Pathway
Normal pain processing entails a process of transduction, transmission, modulation, and finally perception. GABA = gamma-aminobutyric acid. |
Pathophysiology and classification references
1. Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976-1982. doi:10.1097/j.pain.0000000000001939
2. Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021;397(10289):2082-2097. doi:10.1016/S0140-6736(21)00393-7
3. Ibor PJ, Sánchez-Magro I, Villoria J, Leal A, Esquivias A. Mixed Pain Can Be Discerned in the Primary Care and Orthopedics Settings in Spain: A Large Cross-Sectional Study. Clin J Pain. 2017;33(12):1100-1108. doi:10.1097/AJP.0000000000000491
4. Jabbur SJ, Saadé NE. From electrical wiring to plastic neurons: evolving approaches to the study of pain. Pain. 1999;Suppl 6:S87-S92. doi:10.1016/S0304-3959(99)00141-4
Key Points
Pain may be defined as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.
Pain is a subjective experience that is influenced by biomedical, psychological, and social factors.
Acute pain is a short-term response to tissue injury lasting less than 3 months, whereas chronic pain persists for over 3 months and may occur without ongoing tissue damage.
Three main categories of pain mechanisms are nociceptive (due to tissue injury), neuropathic (from nerve injury), and nociplastic (related to central nervous system dysfunction).
Many pain syndromes can be multifactorial and are considered mixed states.
Normal pain processing entails a process of transduction, transmission, modulation, and finally perception.
