Pain

Pain is an unpleasant sensory and emotional experience. The International Association for the Study of Pain (IASP) defines it as <em>an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage</em>. The 2020 wording replaced the 1979 definition, which tied pain more closely to tissue damage. This entry treats pain as a biological, psychological and social phenomenon. It covers the neurons that detect harmful stimuli, the central nervous system that processes them, and the brain regions that give pain its emotional character. It also covers why pain is useful, why it sometimes outlasts injury, and how it is measured and treated.

Pain matters because it is one of the most common reasons people seek medical care. Acute pain warns of injury and drives protective behavior, while chronic pain can become a disease in its own right, with large effects on function, mood and economic productivity. Pain also sits at the center of major public-health debates, including the opioid crisis, unequal access to analgesia, and the search for safer drugs.

The article moves from definitions and nociception through the neural pathways, sensitization, and classification of pain. It then turns to psychological modulation, biological function and genetics, the history of theory, and clinical assessment. The final sections cover pharmacological and non-drug treatment, opioid policy, new drug development, the global burden, and open questions.

Definition and conceptual boundaries

For most of the late twentieth century, the working definition of pain was the one adopted by the International Association for the Study of Pain (IASP) in 1979. It described pain as an unpleasant sensory and emotional experience linked to actual or potential tissue damage, "or described in terms of such damage." A 14-member IASP presidential task force, chaired by Srimathi Raja and drawing on basic and clinical researchers from several countries, spent about two years revising it. The revised definition, published in Pain in 2020, reads: "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." Two changes matter most. The revision lowered the emphasis on tissue damage as the defining cause. It also removed the phrase "described in terms of such damage." That removal allows people who cannot speak, including infants, some people with dementia, and nonhuman animals, to be assessed through other validated indicators of pain, such as facial expression, posture, and behavior. The task force also took account of criticism that the older notes were redundant and imprecise. The etymology of the word, from Middle English peine, Anglo-French, Latin poena (penalty), and Greek poinē (payment, penalty), was added to the revised text.

Pain and nociception

The revised definition separates pain from nociception. The IASP defines nociception as the neural process of encoding noxious stimuli: the activation and transmission of signals from nociceptors through the peripheral and central nervous system. Nociception is a physical event in the nervous system; pain is a conscious, subjective state. The 2020 notes state that pain and nociception are different phenomena and that pain cannot be inferred solely from activity in sensory neurons. The two can therefore dissociate in both directions. Nociception without pain is common: a reflexive withdrawal from a hot object, or a rise in blood pressure during surgery under anaesthesia, can occur without conscious pain. Pain without a corresponding nociceptive input is also documented, for example in phantom limb pain, in some neuropathic states, and in conditions in which the brain generates pain signals without ongoing peripheral activation. The distinction is central to measurement, because a physiological signal of nociception cannot by itself establish how much pain a person is experiencing.

The six notes

The 2020 definition is accompanied by six notes, which carry much of its practical content. First, pain is always a personal experience, shaped to varying degrees by biological, psychological, and social factors. Second, pain and nociception are different phenomena, as described above. Third, through their life experiences individuals learn the concept of pain, so the word and its meaning are acquired rather than innate. Fourth, a person's report of an experience as pain should be respected. Fifth, verbal description is only one of several ways to express pain, and an inability to communicate does not rule out the possibility that a human or nonhuman animal is in pain. Sixth, although pain usually serves an adaptive role, it may have adverse effects on function and on social and psychological well-being. The notes thus treat pain as a subjective experience that is biologically grounded, socially shaped, and sometimes harmful in itself, rather than as a simple readout of tissue injury.

Boundaries with related concepts

Pain is usually distinguished from several neighbouring terms. Discomfort denotes a milder, less intense unpleasantness, often without a clearly identified source, and is not the same as the sharper and more threatening quality associated with pain. Suffering is a broader concept that can include pain but extends to distress, fear, loss of meaning, and the impact of a condition on a person's life; the revised notes' emphasis on adverse effects on function and well-being reflects this wider frame, although suffering is not formally defined by the IASP. Itch is treated as a separate sensation with partly overlapping neural pathways: some itch is transmitted by dedicated fibres and is provoked by mediators such as histamine, and pain can inhibit itch at the spinal level. Keeping these terms apart matters for diagnosis, for choosing outcome measures, and for interpreting animal studies, where behavioural responses such as scratching or guarding must be read with care.

Peripheral detection: nociceptors and noxious stimuli

Nociceptors and their location

Nociceptors are the sensory endings that respond to stimuli capable of damaging tissue. They are not encapsulated end-organs of the kind found in touch receptors. They are the free nerve endings of primary sensory neurons, which belong to the peripheral nervous system. The cell bodies of these pseudounipolar neurons lie in the dorsal root ganglia along the spinal cord and, for the face, head and oral cavity, in the trigeminal ganglion. One axonal branch extends to the periphery, where its terminals are distributed in skin, muscle, joints, tendons, blood vessels, the cornea, the dental pulp and the viscera. The other branch enters the central nervous system. Because the terminals are so widely distributed, the site of a nociceptor's ending largely determines where a pain is felt.

Classes of noxious stimuli

Nociceptors are commonly grouped by the stimuli they respond to. Mechanical nociceptors respond to intense pressure, pinching and stretching, and most have high thresholds, so they are largely silent to gentle touch. Thermal nociceptors respond to heat above roughly 43 °C and to cold intense enough to threaten tissue. Chemical nociceptors respond to protons (acidic conditions) and to a range of substances released during injury and inflammation, including bradykinin, histamine, potassium ions and ATP. Many nociceptors are polymodal, meaning they respond to more than one class of stimulus.

The best-characterized polymodal receptor is TRPV1, a member of the transient receptor potential family of cation channels. It was cloned in 1997 and identified as the receptor for capsaicin, the pungent compound in chili peppers. TRPV1 opens in response to noxious heat, acidic conditions and capsaicin, so it integrates thermal and chemical cues in a single molecule. Other channels contribute to the same task. TRPA1 responds to irritant compounds such as allyl isothiocyanate (the pungent component of mustard oil) and to some cold stimuli. TRPV2 is activated only at higher temperatures than TRPV1. Acid-sensing ion channels (ASICs) detect protons, and P2X3 receptors detect extracellular ATP.

Fiber types and conduction speed

Nociceptive axons fall into two main groups, distinguished by myelination and conduction velocity. A-delta fibers are thinly myelinated and conduct at roughly 5 to 30 m/s. They mainly respond to mechanical and thermal stimuli, and their activity produces a sharp, pricking sensation that is well localized, often called first pain. C fibers are unmyelinated and conduct at roughly 0.5 to 2 m/s. Most C fibers are polymodal. Their slow signaling produces a dull, burning and diffuse sensation, often called second pain, which tends to follow the initial sharp sensation after a stimulus such as a burn or a blow. The two-phase pattern is most easily noticed after a pinprick or a sudden injury. The division is a simplification, however, because the response properties of A-delta and C fibers overlap, and the quality of the final sensation depends heavily on central processing. Large-diameter low-threshold mechanoreceptors, which signal light touch, do not normally signal pain.

Transduction and action potential generation

A noxious stimulus is converted into an electrical signal by transduction. Mechanical stimuli act on mechanically gated channels, including members of the Piezo and TRP families. Heat, acid and chemicals act on thermosensitive or ligand-gated channels such as TRPV1 and ASICs. Ion influx depolarizes the nerve ending and produces a receptor (generator) potential whose size grows with stimulus intensity. When this depolarization reaches threshold, voltage-gated sodium channels open and generate an action potential, which then propagates along the axon toward the spinal cord.

Three sodium channel isoforms, Nav1.7, Nav1.8 and Nav1.9, are most closely associated with nociceptors. Nav1.8 is largely restricted to peripheral sensory neurons and contributes substantially to the upstroke of the action potential in many nociceptors. Nav1.7 is thought to amplify small depolarizations toward threshold. Genetic and pharmacological work on these channels is discussed in other sections. Stimulus intensity is encoded mainly by firing frequency and by the number of fibers recruited. On reaching the spinal cord, the central branches of these axons enter the dorsal root and synapse in the dorsal horn. Trigeminal fibers similarly synapse in the spinal trigeminal nucleus. These central connections are the subject of the next section.

Transmission to the spinal cord and brain

Synaptic relay in the dorsal horn

Nociceptive signals travel from the periphery along the central branches of primary sensory neurons, which enter the spinal cord through the dorsal roots. Their terminals mostly synapse in the superficial dorsal horn, the sensory-processing region of the central nervous system that is organized into numbered laminae. Lamina I (the marginal zone) and the deeper lamina V receive much of the direct nociceptive input, and lamina II (the substantia gelatinosa) contains many local interneurons. Thinly myelinated Aδ fibres and unmyelinated C fibres both reach the dorsal horn, and they differ in the transmitters they release.

Most primary afferent terminals release glutamate, which acts quickly through AMPA and NMDA receptors on second-order neurons. Glutamate is the main source of fast excitation and is especially associated with the rapid, sharp component of pain. Substance P, a neuropeptide co-released mainly from C-fibre terminals, acts on neurokinin-1 (NK1) receptors. Its effect is slower and longer-lasting, and it is released most strongly during intense or high-frequency stimulation. Substance P can potentiate glutamate release and promote the internalization of NK1 receptors. Lamina I projection neurons carry many NK1 receptors, which is why they are central to this transmission. Inhibitory neurotransmitters such as GABA and glycine, released from local interneurons, act at the same synapses and determine how much of the incoming signal passes on. Experimental work also suggests that substance P can enhance feed-forward inhibition, which may partly explain its antinociceptive effects in some circuits.

Ascending pathways to the thalamus

Second-order neurons send their axons across the midline in the anterior white commissure and ascend in the contralateral anterolateral white matter. The main route is the spinothalamic tract, whose lateral component carries pain and temperature information to the ventral posterior nuclei of the thalamus. Other routes include the spinoreticular, spinomesencephalic, and spinoparabrachial pathways. The spinoparabrachial route, which includes lamina I NK1 neurons, projects to the parabrachial nucleus and onward to the amygdala and hypothalamus, and it is thought to contribute to the affective and autonomic aspects of pain. Facial pain is carried by the trigeminal system, which follows an analogous route through the brainstem to the thalamus. Thalamic relay neurons then project to the cerebral cortex and to subcortical structures.

Cortical and subcortical processing

The brain does not process pain in a single location. Neuroimaging and lesion studies have consistently implicated the primary and secondary somatosensory cortices, which contribute to localization, intensity, and sensory-discriminative features. The posterior insula and the anterior insula, together with the anterior cingulate cortex, are associated with the unpleasant and motivational qualities of pain and with attention to it. The amygdala contributes to the emotional learning and fear responses that shape pain, and prefrontal regions are involved in evaluation and cognitive control. These structures are also active during many non-painful tasks, so their activation does not identify pain specifically. This is why the "pain matrix" idea is now treated with caution, a point discussed further in the measurement and research sections of this entry. The cortex itself is composed of the cerebral cortex, which is reached through thalamocortical projections.

Descending modulation from the brainstem

Signals do not flow only upward. The periaqueductal gray (PAG) in the midbrain and the rostral ventromedial medulla (RVM) in the brainstem form a descending system that can suppress or amplify transmission in the dorsal horn. The PAG receives input from the prefrontal and anterior cingulate cortices and from the amygdala and hypothalamus, which provides a route for cognitive and emotional states to influence pain. The PAG projects to the RVM, and the RVM projects to the superficial dorsal horn. Within the RVM, so-called ON-cells are activated by noxious stimuli and facilitate pain-related transmission, whereas OFF-cells are suppressed by such stimuli and normally inhibit it. Serotonergic and noradrenergic projections, including those from the locus coeruleus, contribute to the same modulation. Opioids acting in the PAG are thought to produce analgesia largely by disinhibiting this output. The balance between inhibition and facilitation can shift after injury or during chronic pain, which links the descending system to the central sensitization described elsewhere in this entry.

Sensitization and neural plasticity

Sensitization describes changes in which the nervous system becomes more responsive, so that stimuli that are normally harmless, or only mildly noxious, can produce pain. Changes of this kind are usually divided into peripheral sensitization, which occurs in the tissue and at the nerve endings, and central sensitization, which occurs in the spinal cord and brain. Both are considered important reasons why pain can persist after the original injury has begun to heal.

Peripheral sensitization

Inflammation releases a broad set of neuroactive substances. Reviews list kinins (such as bradykinin), prostanoids (such as prostaglandins), proinflammatory and anti-inflammatory cytokines, neurotrophins including nerve growth factor, neuropeptides, nitric oxide, histamine, serotonin, and proteases among the mediators that can activate or sensitize nociceptive neurons. These substances may act alone or together, and their combined effect is to lower the threshold at which the nerve endings fire, so that weaker stimuli are enough to trigger signals. In rat joints, injecting the cytokine TNF-α produced long-lasting sensitization of both Aδ and C fibers, and in osteoarthritis, nerve growth factor released during cartilage breakdown, bone remodeling, and synovial inflammation has been linked to mechanical hyperalgesia.

Sensitization also changes the nerve cell itself. Voltage-gated sodium channels can be moved to the membrane in greater numbers and gate with altered kinetics, which favors repetitive action-potential firing. Inflammatory signals can further increase the transcription of genes encoding pronociceptive ion-channels, receptors, and signaling molecules in the dorsal root ganglion. Because these changes outlast the immediate inflammatory episode, they provide a plausible basis for sensitivity that persists after healing.

Central sensitization

Central sensitization is generally defined as an elevated responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold input, arising from plasticity within the central nervous system. Persistent or intense firing of C fibers drives repeated transmitter release in the dorsal horn of the spinal cord. Glutamate mediates fast excitatory transmission at these first sensory synapses, while substance P and neurokinin A mediate slower excitatory potentials. Repeated input from small-diameter afferents produces a progressive increase in dorsal horn discharge known as wind-up. Wind-up depends on activation of NMDA receptors, and it is widely used as an experimental model of central sensitization. Sensitization can also alter presynaptic release: NMDA receptors on primary afferent terminals can regulate the release of downstream transmitters, which affects hyperalgesia.

Central sensitization shares features with long-term-potentiation (LTP), a persistent strengthening of synaptic transmission first described in the hippocampus. NMDA-receptor-dependent LTP has been reported at spinal dorsal horn synapses as well as in the anterior cingulate and insular cortex. Its expression involves changes in the number and properties of AMPA and NMDA receptors and in voltage-gated calcium channels. Blocking NMDA-dependent LTP has produced analgesia in animal models of chronic pain. However, LTP expressed at a single synapse is unlikely by itself to explain widespread pain, secondary hyperalgesia, or allodynia, and glial cells in the dorsal horn may help it spread across circuits.

A related mechanism involves loss of inhibition. Glycinergic and GABAergic inhibitory interneurons normally gate nociceptive traffic, and blocking or chronically losing glycinergic transmission in the spinal cord produces allodynia and hyperalgesia in experimental models. The proinflammatory cytokine interleukin-1β can induce LTP at glycinergic synapses on GABAergic interneurons, which may weaken inhibition and so amplify the output of projection neurons.

Maladaptive plasticity in the brain and glia

Plasticity is not confined to the spinal cord. Supraspinal regions, including the anterior cingulate cortex and insular cortex, show synaptic potentiation and large-scale reorganization that is thought to contribute to the unpleasantness and persistence of pain. Nerve injury and inflammation also activate immune and glial responses, both in the dorsal root ganglia and in the dorsal horn, where satellite cells and astrocyte-like glia alter neuronal excitability. These glia and immune-derived signals are therefore considered part of the maladaptive plasticity that sustains chronic pain, although their precise contributions remain under study.

Hyperalgesia and allodynia

Sensitization accounts for the two main signs of pain hypersensitivity. Hyperalgesia is an exaggerated response to noxious stimuli, while allodynia is pain evoked by stimuli that would normally be innocuous, such as light touch. Peripheral changes in nerve endings are often invoked to explain heightened sensitivity at the injury site, whereas central changes, which alter how normal input is processed, are invoked to explain allodynia and secondary hyperalgesia that spreads beyond the injured area. Central sensitization is therefore considered an important reason why pain can become decoupled from the intensity or duration of the peripheral stimulus, and why in many clinical syndromes pain no longer serves a protective function.

Acute and chronic pain

Pain is most often sorted by its time course. Acute pain is generally understood as a short-lived warning that accompanies a particular injury or illness, and it tends to fade as tissue heals. Chronic pain is pain that outlasts that healing window. The distinction matters for diagnosis, treatment, and research, because the two forms appear to involve partly different biology and carry different prognoses.

Defining the boundary

Much of the modern definition of chronic pain comes from the International Association for the Study of Pain (IASP) taskforce that worked on the ICD-11 classification. In ICD-11, chronic pain is defined as pain that persists or recurs longer than 3 months and is subdivided into seven categories: chronic primary pain and six types of chronic secondary pain. The three-month threshold was chosen partly because it is clear and easy to apply. This simple definition with a temporality criterion allows chronic pain to be clearly recognizable independently of other descriptors such as pain intensity, impact on functionality and pain-related distress. The classification itself was built to cover chronic pain only, and excludes acute pain.

Although the time criterion is simple, the categories are not. Chronic pain may also be described as biopsychosocial. The ICD-11 text notes that biological, psychological and social factors contribute to the pain syndrome.

Chronic primary pain as a disease

The most significant change in ICD-11 is the separation of chronic primary pain from pain that is secondary to a known condition. Chronic primary pain is now considered a disease in itself, and not a mere symptom of an underlying disease. Its diagnostic criteria require more than duration alone. Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability, and the diagnosis applies only when the pain is not better accounted for by another condition. The authors deliberately avoided etiological labels: the category was designed to be agnostic with regard to etiology, which sidesteps older terms such as "nonspecific" or "functional" that define a condition by what it lacks. Secondary categories cover cancer-related pain, post-surgical or post-traumatic pain, neuropathic pain, secondary musculoskeletal, visceral, and headache or orofacial pain. Post-surgical and post-traumatic pain is defined as pain that develops after a surgical procedure or a tissue injury (involving any trauma, including burns) and persists at least 3 months after surgery or tissue trauma.

How acute pain becomes chronic

Not all acute pain resolves. Pain that lasts beyond the expected recovery period is sometimes described as entering a chronic phase, and the transition has been studied most closely in low back pain and after surgery. In one large United States primary-care cohort, overall transition rate to chronic LBP at six months was 32%, and a systematic review found that 2% to 48% (median, 26%) of patients with acute LBP in primary care settings transition to chronic LBP. Surgery offers a rare chance to study the process prospectively, because the precise timing of the physical insult and ensuing pain are known in advance.

Risk factors fall into several groups. A recent review lists patient demographics, phenotypic trait variations, acute pain characteristics (i.e., acute pain intensity/severity, duration, and cumulative trauma exposure), and psychosocial factors as predictors. Psychological variables have been among the most consistently linked. In one systematic review, fifteen (83%) of the articles reported an association between psychosocial factors and chronicity. Depression and fear-avoidance are the most frequently implicated, and a total of 5 of the studies (29%) demonstrated that depression was a possible predictor and 6 (35%) of the studies found fear-avoidance to be associated with chronicity. Other reviews point to concurrent or past pain may be the greatest risk factor for development of chronic pain, which suggests that earlier pain experiences can prime later persistence.

Biological mechanisms proposed for this transition include increases in membrane excitability of peripheral and central nerve fibers, synaptic plasticity, and loss of the function of descending inhibitory pain fibers, along with immune involvement. These processes are discussed in the sections on sensitization and neural plasticity, and the timing is not fully settled. Researchers note that this process occurs some period after the onset of acute pain, and that both acute and chronic pain mechanisms may arise simultaneously in individuals with persistent pain.

Open questions

Whether early intervention can prevent chronicity remains uncertain. Studies of perioperative multimodal analgesia have produced mixed results, and other studies fail to show this benefit. For this reason, the field has moved toward early identification of people at high risk and biopsychosocial management rather than relying on a single drug strategy. Key unresolved issues include why some people with healed tissue continue to hurt, and how clinicians can predict this in individual patients rather than in groups.

Mechanistic classification: nociceptive, neuropathic, and nociplastic pain

Three mechanistic descriptors

The International Association for the Study of Pain (IASP) divides pain by mechanism into three descriptors. Nociceptive pain is the form that arises when tissue is actually or potentially damaged and the nociceptors that detect that damage are activated. Its name reflects a contrast with the other two categories: it describes pain occurring when the somatosensory nervous system is functioning normally. Common examples include the pain of a bone fracture, a burn, or inflammation of a joint. Its subtypes, somatic and visceral, are discussed in the section on common clinical conditions.

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system. The IASP treats it as a clinical description rather than a formal diagnosis, and it requires a demonstrable lesion or a disease that meets established neurological criteria. Postherpetic neuralgia, which persists after shingles has damaged nerves, and painful diabetic neuropathy, in which chronic high blood glucose injures peripheral nerves, are typical examples. The distinction between the two categories rests on where the signal originates: in nociceptive pain the sensory system works properly, whereas in neuropathic pain the fault lies in the nerves or neural circuits themselves, whether peripheral or central.

Nociplastic pain was first proposed in 2016 and formally adopted by the IASP in 2017. It is defined as pain arising from altered nociception without clear evidence of actual or threatened tissue damage that activates peripheral nociceptors, and without evidence of a disease or lesion of the somatosensory system. Because the definition is framed by exclusion, it identifies pain by what it is not. Its proposed mechanism is sensitization of pain processing, particularly central sensitization in which neurons in the spinal cord and brain become more responsive, together with altered descending pain modulation. Fibromyalgia is the condition most often cited as an example, and widespread musculoskeletal pain without a clear structural cause is another.

Operational criteria and their limits

For musculoskeletal conditions, criteria for possible nociplastic pain require a minimum of four features: pain lasting more than three months, a regional, multifocal, or widespread distribution, pain that cannot be fully explained by nociceptive or neuropathic mechanisms, and clinical signs of pain hypersensitivity in the painful region. A vignette-based study found satisfactory reliability and moderate criterion validity, with high specificity (about 89%) but only moderate sensitivity (about 69%), and its authors called for testing in real clinical settings. Neuropathic and nociplastic pain share features such as hypersensitivity and spontaneous pain, which makes them hard to separate in practice. No evidence-based diagnostic test currently exists for nociplastic pain, and the IASP itself describes it as a mechanism rather than a diagnosis.

The debate over nociplastic pain

Nociplastic pain remains contested. Critics argue that the concept is too broad, that it may be applied as a catch-all category, and that its use can discourage clinicians from searching for occult peripheral causes, such as small-fibre neuropathy or low-grade inflammation that current tests cannot detect. A further objection is that the sensitization it invokes is generally shown to depend on continuing noxious input, such as nerve injury, so persistent pain without any peripheral trigger is difficult to explain. Critics also ask why most people with similar injuries recover while only some develop persistent pain, a question that any theory of chronic pain must answer. Some argue that a pain state with no protective function would conflict with the view that pain has evolved as a defensive signal. Supporters reply that the category captures a large group of patients whose pain cannot be attributed to tissue or nerve damage, and that the mechanism can be inferred from clinical signs. The debate also concerns overlap with the chronic primary pain category in the ICD-11 system, which treats chronic pain as a condition in its own right.

Mixed pain states

The three categories are not always mutually exclusive. The University of California, San Francisco's pain program notes that some patients present with both nociceptive and neuropathic features, while others show neither evidence of tissue damage nor a lesion of the nervous system. A patient with cancer may have tumour invasion of tissue, nerve compression, and chemotherapy-induced neuropathy at the same time. A person with chronic low back pain may have a disc that compresses a nerve root while also experiencing widespread sensitization. Assigning a single mechanism in such cases is often an approximation. Clinicians therefore tend to treat the components separately, and the mechanism-based framework is best understood as a guide to likely drivers of pain and to treatment choices, rather than as a fixed diagnostic scheme.

Common clinical pain conditions

Clinical pain is usually grouped by the body region or organ system involved and by the disease that produces it. These categories overlap. One patient may have several, and a single disease may produce pain through more than one route.

Headache disorders

Headache is among the most common pain complaints. Estimates from the Global Burden of Disease 2021 study put tension-type headache at about 2.0 billion people and migraine at about 1.2 billion. Tension-type headache is the more prevalent of the two, but migraine causes greater disability. Migraine is thought to involve activation of trigeminal sensory afferents that innervate the meninges and the walls of cerebral blood vessels. Calcitonin gene-related peptide released from these fibers, together with neurogenic inflammation of the dura, contributes to the pain. Some patients also experience an aura, which is thought to reflect a slowly propagating wave of cortical depolarization. Migraine treatments reflect this model. Triptans act on 5-HT1B/1D receptors to constrict dilated vessels and reduce neuropeptide release, while gepants block the CGRP receptor.

Musculoskeletal pain

Musculoskeletal pain accounts for most of the pain-related disability in adults. Low back pain, defined as pain between the lower margin of the 12th rib and the gluteal folds, ranks first among causes of years lived with disability worldwide. An estimated 619 million people had it in 2020. In most cases the cause is nonspecific. Imaging rarely identifies a single structural lesion that explains the pain, and episodes tend to recur. Osteoarthritis, which involves cartilage loss, subchondral bone change, and synovial inflammation, mainly affects the knee and hip. Radiographic severity correlates only weakly with pain intensity, which suggests that synovitis, bone marrow changes, and central sensitization contribute substantially. Both conditions are major drivers of disability and of demand for rehabilitation services.

Visceral pain

Visceral pain arises from the thoracic, abdominal, and pelvic organs. It is typically triggered by distension of hollow organs, ischemia, inflammation, or smooth-muscle spasm. Visceral afferents are sparse and mostly unmyelinated, so the pain is poorly localized, often dull or cramping, and frequently accompanied by nausea, sweating, or other autonomic signs. Referred pain is a defining feature. Visceral and somatic afferents converge on the same second-order neurons in the dorsal horn, and the brain projects the visceral signal onto the skin or muscle supplied by those neurons. Cardiac ischemia can be felt in the left arm, jaw, or chest wall. Gallbladder disease can produce pain in the right shoulder, and kidney stones in the flank and groin.

Cancer pain

Cancer pain can arise from several sources. Tumor invasion of bone, nerves, or soft tissue is one. Compression of nerves or the spinal cord is another. Chemotherapy-induced peripheral neuropathy, radiotherapy-related mucosal injury, and pain after surgery or diagnostic procedures also contribute. Pooled estimates suggest that roughly two-thirds of people with advanced cancer have significant pain. Because of this burden, cancer pain has long been a central concern of palliative care, and the stepwise analgesic approach that the World Health Organization developed was originally framed around it. Treatment is often complicated by the need to address several mechanisms at once.

Pain in specific diseases

In sickle cell disease, vaso-occlusive crises occur when sickled red cells, which contain polymerized hemoglobin S, obstruct small blood vessels. The resulting ischemia, reperfusion injury, endothelial activation, and inflammation cause severe pain, most often in the bones, chest, and abdomen, that can last for days. Crises are a leading reason for hospital admission in affected patients, and some develop persistent pain with features of central sensitization.

In rheumatoid arthritis, an autoimmune disease, pain comes mainly from synovitis and joint destruction. Pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1 sustain the inflammation, which causes prolonged morning stiffness and swelling. Many patients also report pain that persists despite low inflammatory activity on laboratory measures. This residual pain may reflect nociplastic or centrally sensitized mechanisms and is an important target of management.

Psychological, social, and cultural modulation

Pain intensity is shaped by cognitive and emotional states as well as by the signals that arrive from tissue. Experimental work has shown that where a person directs attention, what they expect, and how they feel can change both the reported intensity and the activity in pain-processing pathways, including the spinal cord.

Attention and distraction

Attention is one of the most reliable modulators of pain in laboratory studies. Focusing on a painful stimulus generally increases its perceived intensity, while a demanding competing task tends to reduce it. Neuroimaging studies from the early 2000s, such as work by Bantick and colleagues using fMRI, linked attention to pain with activity in the anterior cingulate cortex and related cortical regions. In 2012, Sprenger and colleagues used high-resolution fMRI of the human cervical spinal cord during thermal pain and a working-memory task. They found that spinal responses to pain fell when participants were more absorbed in the task, that the size of this spinal reduction predicted the behavioral analgesia, and that the effect depended on endogenous opioid signalling, which indicates that distraction acts partly by inhibiting incoming signals before they reach the brain. Distraction is not uniformly effective, however. Reviews have found that distractors unrelated to pain can be less effective than pain-related tasks, possibly because participants are less motivated by them, and people with chronic unexplained pain may show weaker attentional modulation, so the effect varies with the person and the pain condition.

Emotion, mood, and chronic pain

Anxiety, fear, catastrophic thinking about pain, and depression are closely tied to the experience of pain. Fear of movement and of re-injury can lead to avoidance, deconditioning and reduced activity, which in turn may worsen disability. Anxiety can heighten the perceived intensity of acute pain, and depression is common among people with persistent pain, with each condition often making the other more severe. The relationship runs in both directions: pain can cause sleep loss, withdrawal and low mood, while mood disorders can lower pain thresholds and reduce the capacity to cope. Several of these links are thought to involve shared neural circuits, such as the prefrontal cortex, insula, amygdala and the hypothalamic–pituitary–adrenal stress axis. The clinical implication, which underlies much of the psychological treatment of chronic pain, is that emotional state is part of the pain problem rather than merely a reaction to it.

Expectation, placebo, and nocebo

Expectation is one of the most studied modulators of pain. A placebo, an inert treatment given with the belief that it relieves pain, can produce measurable analgesia. The effect has been studied for decades with the opioid antagonist naloxone, which reverses part of the placebo response, indicating the involvement of endogenous opioids. Later imaging studies, including a 2005 PET study using receptor binding, showed increased mu-opioid receptor activity in regions such as the prefrontal cortex, nucleus accumbens and insula during placebo analgesia. Research with the cholecystokinin antagonist proglumide suggested that cholecystokinin opposes opioid-mediated placebo analgesia, and that blocking it can enhance the placebo response. The reverse process, the nocebo effect, is produced by negative expectations, and work from the same research line suggests that verbal warnings of increased pain can generate anticipatory anxiety that activates cholecystokinin and facilitates pain transmission. Anxiety-reducing drugs such as benzodiazepines have been reported to block nocebo hyperalgesia, which supports the role of anxiety in this pathway. These findings indicate that expectation acts through identifiable neurochemical systems, although the effect sizes vary and many mechanisms remain incompletely understood.

Culture, language, and learning

Culture shapes how pain is named, displayed, tolerated and treated. The International Association for the Study of Pain notes that upbringing and social values influence the expression of pain, with some societies encouraging open expression and others teaching restraint. A qualitative pilot study comparing four ethnic groups in the United States reported that participants differed in whether they defined pain as a primarily physical or emotional experience, and in how openly they discussed symptoms. Some work on Japanese populations describes a culturally encouraged stoicism in which people may feel pain as intensely as others while showing less of it. Comparative clinical studies have also found differences in pain language: a study of American and Nepali patients found that Nepali patients used more metaphors when describing their pain. A systematic review of chronic pain research found that between-country differences in pain beliefs, coping and catastrophizing exist for some domains but not all, suggesting that culture interacts with, rather than fully determines, pain appraisal.

Learning also shapes the concept of pain. Through observation, social instruction and prior experience, people form expectations about what pain means and how it should be responded to, and these expectations can influence both the reported experience and the choice of care. This makes pain assessment sensitive to the cultural context of both patient and clinician. Documented disparities show that some patient groups, including African American patients in several studies, have had their pain underestimated or undertreated, which indicates that cultural and clinical bias can affect the care that pain patients receive, not only their self-report.

Biological function and evolution

Pain is best understood as a protective system. Its most basic role is to make an organism withdraw from a damaging stimulus, guard the injured region, and reduce activity while tissue heals. Acute pain therefore has clear adaptive value: it turns a threat to the body into an immediate behavioural priority. Experimental work in fish illustrates this. Injuries reduce normal activity, and these changes are blocked when analgesic drugs are given first, which suggests that the response is organised around protecting the animal rather than being a simple reflex.

Evidence from people who cannot feel pain

The clearest human evidence for pain's protective role comes from congenital insensitivity to pain (CIP), a rare inherited condition. CIP has several genetic causes. Loss-of-function mutations in SCN9A, which encodes the Nav1.7 sodium channel in sensory neurons, typically produce a form with normal intelligence and a loss of smell. Mutations in NTRK1 produce a related but broader disorder, NTRK1 congenital insensitivity to pain with anhidrosis, in which people also cannot sweat and often have intellectual disability. In this form, the ability to sense pain, including visceral pain, is absent, while touch, vibration and joint position remain normal. The consequences are repeated injuries: biting of the tongue, lips and fingertips, unnoticed skin wounds and infections, fractures that fail to heal properly, and recurrent joint dislocations. Because the body cannot signal damage, these patients often depend on constant external monitoring to stay safe. The genetic basis of these conditions is discussed in the genetics section, but the clinical picture makes the point here: the absence of a warning signal leaves tissue damage unchecked.

Conservation across vertebrates

The machinery that detects noxious stimuli is widely shared among animals. Reviews by Lynne Sneddon and colleagues describe teleost fish whose nociceptors, innervated by the trigeminal nerve, are physiologically similar to those of higher vertebrates. Fish also have opioid receptors and endogenous opioids in the brain and spinal cord, and morphine reduces both nociceptive responses and avoidance learning. Fish possess fewer unmyelinated C fibres than mammals, yet the electrophysiological properties of their nociceptors are nearly identical to those of higher vertebrates, which suggests that these properties evolved early in vertebrate history. Substance P has been detected in the dorsal horn of cartilaginous fish, and reptiles express mu- and delta-opioid receptors in relevant brain regions. Birds, by contrast, are not affected by the burning sensation of capsaicin, a difference attributed to sequence changes in the TRPV1 receptor.

Invertebrates show the same logic at a simpler level. Comparative reviews argue that all animals studied possess nociceptors, and that the molecular basis of nociception is conserved where it has been examined. In the fruit fly Drosophila, the painless gene encodes a TRP channel that is an evolutionary homologue of the mammalian TRPA1 channel. The sea slug Aplysia has become a model for the sensitization of nociceptors that underlies aversive memory and hyperalgesia. Taken together, these findings suggest that many elements of the system predate the vertebrates. Differences between species, such as the cold-sensing requirements of terrestrial animals, are usually interpreted as adaptations to particular environments rather than as fundamental changes in design.

Debates about nonhuman animals

Whether nonhuman animals feel pain is less settled than whether they detect noxious stimuli. The central question is whether a reaction to tissue damage reflects only nociception, an unconscious detection process, or a conscious and unpleasant experience. Fish provide the most debated case. Some authors argue that the evidence is substantial, pointing to nociceptors, analgesic-reversible changes in behaviour and physiology, and higher brain activity during noxious stimulation. Others argue that fish have no awareness at all, while some propose that they may also feel fear. A survey of responses to one target article in the journal Animal Sentience found that most commentators did not take a firm position. A 2022 review proposed that many commonly used measures, including reactions in spinal preparations or decerebrate animals, cannot distinguish sentience from reflex, and suggested instead tests such as operant tasks, working-memory tasks, and self-reporting approaches.

These disagreements have practical consequences for animal welfare, research regulation and food production, and so they bear on ethics as well as on neuroscience. The underlying problem is methodological: a central nervous system response can be measured, but the subjective quality of a feeling cannot be observed directly, and any inference from behaviour to experience depends on assumptions about what the behaviour means.

Genetic and individual variation

SCN9A and the Nav1.7 channel

The most direct genetic link to pain runs through SCN9A, which encodes the Nav1.7 subunit of a voltage-gated sodium channel. The protein is highly expressed in pain-sensing neurons, and it is strongly expressed in nociceptive neurons. Because the channel's contribution to nociception depends on how a mutation alters its function, the same gene can produce opposite clinical pictures. Bi-allelic loss-of-function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythromelalgia (PE).

In CIP, the defect is typically inherited in a recessive pattern. Affected individuals do not feel pain in response to noxious stimuli. By 2011, over 30 loss-of-function variants in SCN9A had been identified and reported to cause CIP. The 2006 mapping studies in consanguineous families argued that the channel is an essential and non-redundant requirement for nociception in humans. Yet the loss of the channel was not catastrophic: loss of Nav1.7 did not lead to lethality nor any significant disability, although CIP patients are anosmic because the channel is also expressed in olfactory epithelium. Gain-of-function variants produce the reverse. In PE, the primary symptoms are severe chronic burning pain sensations in the hands and feet, and these mutations enhance channel activation. The discovery that Nav1.7 is required for pain in humans made it a prominent target for analgesic drug development, a line of work described in the pharmacological sections of this entry.

Heritability of chronic pain

Twin and family studies consistently find that chronic pain is partly heritable, though the estimates vary widely with the phenotype and design. Family cluster studies suggest that the heritability for chronic pain ranges from 6.7% to 30%, whereas twin studies demonstrate a heritability of 27%–59% for chronic pain. Twin designs estimate heritability by comparing how often monozygotic and dizygotic co-twins share a condition, using a formula in which the heritability of chronic pain can then be estimated as h² = 2(r_mz – r_dz), where r is the concordance rate. Estimates also depend on the pain site: heritability was substantially higher for chronic pain rather than acute back pain, with the heritability mostly attributed to genes expressed in the brain.

Heritability can also change over time. In a study of 961 female twins followed for 12 years, heritability for chronic pain was 63% at baseline and 55% at follow-up. However, the underlying genetic structure shifted: one genetic factor explained 62% of variance in chronic pain at baseline and 11% at follow-up. Genetic influences are also shared across conditions. One twin analysis of several chronic pain syndromes found a common latent factor with an estimated heritability of 66% of the underlying latent variable. Overlap with mood disorders has been reported as well: in one study of female twins, a latent trait linking chronic widespread pain and major depression showed 86% heritability.

Gene discovery and the limits of genetic explanation

Despite these heritability estimates, identifying specific pain-related genes has proved difficult. One review described the search for "pain genes" as slow and generally disappointing despite the relatively large heritable component. Genome-wide association studies have mostly detected only small effects by single nucleotide variants, and the genetic contribution is thought to arise from the cumulative effect of many SNVs. Rare, highly penetrant variants have been found mainly in congenital conditions. A review of genetics in pain notes that more than 20 genes have been identified for congenital insensitivity to pain.

Heritability estimates also have limits. Even in monozygotic twins, environmental and psychological factors have been found to play a substantial role, and in one study of temporomandibular pain cognitive and emotional variables may supersede genetic factors in the manifestation of painful TMD. The same mutation can also produce variable outcomes; in the SCN9A literature, the phenotype that results from a given mutation might vary significantly. In practice, pain variation is best understood as the product of interactions among many genes, environmental exposures, and individual experience, rather than of any single determinant.

Sex and age differences

Sex differences in pain are among the more consistently reported individual variations, although their size and mechanisms are debated. A widely cited review found that the direction of sex differences in pain responses across multiple stimulus modalities and pain measures is highly consistent, with women showing greater sensitivity than men. At the same time, the magnitude (and statistical significance) of the sex difference varies across measures, as it does across published studies. Clinically, women are more likely to be diagnosed with chronic painful conditions, such as headache, musculoskeletal pain, abdominal pain, arthritis, as well as fibromyalgia, and temporomandibular disorder. Some conditions, however, show the reverse pattern; a few painful conditions are more likely to affect men (e.g., cluster headache).

The mechanisms remain unresolved. Experimental work suggests that sex/gender differences are found in conditioned modulation (stronger in men) and temporal summation (greater in women). Hormonal contributions are uncertain: one systematic review concluded that the involvement of hormonal and physiological factors is either inconsistent or absent. Responses to treatment also vary by sex in ways that are hard to generalize. Reviews report that findings regarding sex differences in responses to pharmacologic and non-pharmacologic pain treatments are inconsistent. Partly because of such uncertainty, this has led many to conclude that women are at risk for under-treatment of their pain.

Age effects are less well characterized in the sources reviewed. Twin research suggests that both sex and age influenced the heritability of neck pain, which indicates that the genetic component of a given pain condition may itself change across the lifespan. Whether comparable age-related patterns hold across pain types, and how they affect analgesic response, remains less clearly established.

History of theories and research

For most of Western history, pain was discussed as part of a wider account of the senses rather than as a separate subject. Classical thinkers, including Aristotle, treated it within the general sense of touch. The idea that pain had its own dedicated route became more explicit in the early modern period. René Descartes described a mechanical model in which a sensory cue pulled on a tube running from the body to the brain and opened a gate along it. This account was published posthumously in 1664, and it kept the picture of pain as a message sent along fixed channels.

In the 19th century, physiologists began testing such ideas experimentally and formalized them as the specificity theory. It held that each sensory modality, such as touch, heat, cold, or pain, had its own receptors and fibers, with free nerve endings serving as the pain receptors. Later work by Max von Frey refined this view in the late 19th century. The specificity theory identified real anatomical structures, but it could not account for phantom limb pain or for the wide variability of pain felt from the same stimulus. A rival account, the pattern theory, was proposed by Alfred Goldscheider in 1894. It argued that pain arose from the summation of sensory input, so that almost any stimulus could hurt if it was intense enough, and that the summation occurring in the dorsal horn of the spinal cord determined whether a stimulus was painful. The pattern theory explained some observations the specificity theory could not, but it had difficulty explaining why some patients felt severe pain from minimal stimulation. Over the following decades, these two positions were gradually displaced by models that combined peripheral and central factors.

The most influential of these was the gate control theory, proposed in 1965 by the psychologist Ronald Melzack and the neurophysiologist Patrick Wall, working at MIT. They suggested that a gating mechanism in the spinal cord could modulate the transmission of nociceptive signals to higher centers. In their account, input from large-diameter fibers carrying non-painful information could close the gate and reduce the pain signal, while the brain could exert descending influence on the gate. The theory reconciled elements of the specificity and pattern views, and it offered a physiological explanation for the observed effects of psychological factors on pain. The reception was initially hostile; Melzack later recalled that the idea was met with scorn. In 1968 Melzack extended the framework by arguing that pain is subjective and multidimensional because several parts of the brain contribute to it at the same time. Gate control also stimulated research that led to the discovery of endogenous opioids such as endorphins and enkephalins, although later work refined the original anatomical details.

Melzack's subsequent work went further. Beginning with studies of phantom limb pain in the late 1980s and early 1990s, he proposed the neuromatrix theory, in which a widely distributed network of neurons representing the body and the self generates characteristic patterns of impulses. In a 2001 account, he described pain as the output of this body-self neuromatrix, which is genetically determined but shaped by sensory experience, and which can generate pain even without sensory input, as in some chronic conditions. Alongside these theoretical developments, functional brain imaging from the 1990s onward allowed researchers to observe networks of regions active during pain, which seemed to support a more distributed view of pain processing than the older models of dedicated pathways. The neuromatrix idea has been both influential and debated, particularly over how far it can be tested directly.

Clinical thinking was also reshaped in the 1990s, when pain was promoted as a "fifth vital sign" alongside temperature, pulse, respiration, and blood pressure. The phrase was introduced by James Campbell, president of the American Pain Society, in an address that sources date to late 1995 or 1996. The Veterans Health Administration adopted the idea in 1999, and in 2000 the Joint Commission made pain assessment a condition of accreditation. The campaign was later reassessed. The Joint Commission reported that the phrase had been removed from its accreditation materials by 2004, and by 2017 several bodies, including the American Medical Association and the Centers for Medicare and Medicaid Services, had withdrawn their advocacy for it. Critics argued that treating pain as a routine vital sign encouraged a focus on numerical scores that contributed to overprescribing, a claim that the Joint Commission has disputed, saying it never formally endorsed the concept. The episode illustrates how a measurement framework can shift clinical priorities in ways that its proponents did not fully anticipate.

Measurement and assessment

Pain is assessed in two main ways: by asking the person to rate it, and by observing behaviour when the person cannot give a reliable report. Because the 2020 definition treats the person's report as central, self-report remains the reference standard wherever it is possible, and observational tools are used as substitutes rather than as the default.

Self-report instruments

The simplest tools are one-dimensional. The visual analogue scale (VAS) is usually a 10-cm line on which the patient marks intensity between no pain and the worst imaginable pain. The numerical rating scale (NRS) asks for a whole number from 0 to 10, and verbal rating scales use graded words such as "mild" or "severe." One review notes that the NRS is favored for ease of administration in clinical and research settings, and that acute pain at rest and during movement can be reliably assessed with such one-dimensional tools. Their limitation is that they capture intensity and little else.

The McGill Pain Questionnaire (MPQ), developed by Ronald Melzack and Warren Torgerson in the 1970s, was designed to capture the quality of pain as well as its strength. It contains 78 descriptors arranged in groups, so that patients choose words such as "burning," "shooting," or "agonizing," and the choices are summed into a Pain Rating Index. A short form and a present-pain-intensity rating are also used. Because word choice itself is treated as informative, the MPQ is more time-consuming than the NRS and is used mainly in research and specialist settings.

Observational scales

For infants, young children, and adults with dementia or other conditions that limit speech, clinicians rely on scales scored by observers. The Face, Legs, Activity, Cry and Consolability (FLACC) scale was developed in 1997 for postoperative pain in preverbal children; it scores five categories from 0 to 2, giving a total from 0 to 10. The Pain Assessment in Advanced Dementia (PAINAD) scale, published in 2003, uses five observable domains (breathing, negative vocalization, facial expression, body language, and consolability) and was designed for nonverbal older adults in residential care. Other tools include the Abbey Pain Scale, the Discomfort Scale for Dementia of the Alzheimer's Type, and the Checklist of Nonverbal Pain Indicators. A systematic review of reviews identified a large number of such instruments and recommended a shorter list, including the Abbey and PAINAD scales, for people with dementia. Validity is not uniform across populations: one review found that FLACC, when applied to older adults with dementia, produced inconsistent reliability and validity, partly because many of the behaviours it records are not typical of that group.

The search for objective measures

No objective test for pain is in routine clinical use. Physiological signals such as heart rate variability and skin conductance reflect autonomic activity, but they are also shaped by anxiety, attention, and context. Facial action coding and reflex testing provide complementary information but are complex to apply. Neuroimaging has identified brain patterns associated with pain, yet a 2025 umbrella review of systematic reviews found that no single biomarker has achieved clinical validation for chronic pain, and most of the included reviews were rated as low or critically low quality. Inflammatory markers such as CRP, IL-6, and TNF-α showed the most consistent associations with chronic musculoskeletal pain, but the evidence for clinical use is limited. A recurring problem is that neuroimaging "pain signatures" developed with experimentally induced pain in healthy volunteers do not reliably generalize to sustained clinical pain. For these reasons, biomarkers remain research tools and are not yet a substitute for self-report or validated observation. See biomarker and diagnosis for the broader problem of validation.

Functional impact and severity

Pain intensity alone is an incomplete measure of severity. Clinicians and researchers also assess how pain interferes with sleep, mood, work, household tasks, and social activities, and many chronic-pain studies treat this interference as a primary outcome alongside intensity. The two dimensions often diverge: a person with low-intensity but constant pain may be more disabled than someone with severe but brief pain. For this reason, functional measures are routinely combined with intensity ratings, and outcomes are expressed in terms of quality-of-life and disability as well as pain scores. Mood is assessed in parallel, since depression and anxiety-disorders are common in people with persistent pain and can influence both self-reported intensity and daily functioning.

Pharmacological management

The most influential framework for drug treatment of pain is the analgesic ladder that the World Health Organization published in 1986 for cancer pain. It described three steps: non-opioid drugs, with or without adjuvants, at the first step; a weak opioid added at the second; and a strong opioid, with or without the earlier drugs, at the third. Escalation was meant to occur only if pain persisted. The authors recommended aspirin, with paracetamol as the alternative, at step one; codeine at step two; and morphine at step three. Its later history is contested. A 2022 critique in the British Journal of Anaesthesia noted that the report could not cite literature showing that weak opioids were clinically effective, and that the weak/strong labels were misapplied to chronic non-cancer and postoperative pain, contributing to opioid harm. The 2018 WHO update removed explicit advocacy of weak opioids. Other reviewers point out that the ladder was never revised to reflect newer formulations and that its efficacy has not been tested in large trials, so its benefit remains uncertain.

Non-opioid analgesics: NSAIDs and acetaminophen

Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, and naproxen, act mainly by inhibiting cyclooxygenase (COX) enzymes, which convert arachidonic acid into prostaglandins. Lower prostaglandin levels reduce the sensitization of peripheral nociceptors during inflammation, which accounts for their analgesic, anti-inflammatory, and antipyretic actions. The same inhibition explains their main harms. Prostaglandins in the gastric wall support mucus secretion, mucosal blood flow, and bicarbonate production, so their suppression is linked to dyspepsia, ulceration, and bleeding. In the kidney, prostaglandins dilate afferent vessels and help maintain perfusion when the renin–angiotensin system is activated. Blocking them can cause hemodynamically mediated acute kidney injury, which is most likely in older adults, people with chronic kidney disease or heart failure, and those taking diuretics or renin–angiotensin inhibitors. Less common forms include acute interstitial nephritis, and long-term use has been associated with chronic kidney disease. Selective COX-2 inhibitors reduced gastroduodenal lesions in trials but were associated with cardiovascular thrombotic risk, and all prescription NSAIDs carry a boxed warning for cardiovascular and gastrointestinal events.

Acetaminophen (paracetamol) is an effective analgesic and antipyretic with weak peripheral anti-inflammatory activity. Its precise mechanism has not been fully worked out; COX inhibition in the central nervous system is thought to contribute. Because it does not produce the antiplatelet effect of aspirin, it is often preferred when bleeding is a concern. At doses that approach the degree of COX inhibition produced by ibuprofen, it can share NSAID-like gastrointestinal and blood pressure effects. Its most serious hazard is hepatotoxicity in overdose.

Opioids

Opioids act principally on mu-opioid receptors (MOR), G protein-coupled receptors that are distributed in the spinal dorsal horn, brainstem, thalamus, and limbic structures. Activation hyperpolarizes neurons and reduces neurotransmitter release from primary afferent terminals, which dampens nociceptive transmission. Opioids remain the most effective drugs for severe acute pain, such as fractures and postoperative pain, and are a mainstay for severe cancer pain. Their adverse effects arise largely from the same receptor acting in other regions. In the pons and medulla, MOR activation depresses respiratory rhythm and blunts the ventilatory response to rising carbon dioxide and falling oxygen, which is the usual cause of death in overdose. Naloxone can reverse this effect, but very high doses can produce convulsions that naloxone does not always relieve. Other common effects include nausea through the chemoreceptor trigger zone, constipation from slowed gut motility, and histamine release that can lower blood pressure. Tolerance, in which higher doses are needed for the same effect, and physical dependence develop with repeated use. In neuropathic pain, opioids often give less relief, which can push clinicians toward higher doses and increases the risk of dependence.

Adjuvant analgesics

Adjuvants are drugs developed for other purposes that relieve certain types of pain, especially neuropathic pain. Tricyclic antidepressants such as amitriptyline and serotonin–noradrenaline reuptake inhibitors such as duloxetine raise monoamine levels in the synapse, which strengthens descending inhibition of spinal nociceptive transmission. Their analgesic effect often occurs at doses below those used for depression and is partly independent of mood change. Anticonvulsants such as gabapentin and pregabalin bind the α2δ subunit of voltage-gated calcium channels, reducing the release of excitatory neurotransmitters from sensitized neurons. They are used for postherpetic neuralgia and painful diabetic neuropathy, and their adverse effects include sedation, dizziness, and weight gain. Topical agents include lidocaine, which blocks sodium channels locally, and high-concentration capsaicin, which desensitizes TRPV1-expressing nociceptors. Overall, benefit from adjuvants is usually partial, and drug choice is individualized, often combining several classes.

Non-pharmacological and interventional treatment

Exercise, physical therapy and rehabilitation

Exercise-based rehabilitation is the most widely endorsed non-drug approach for chronic musculoskeletal pain. In a Cochrane-based review of chronic low back pain, exercise reduced pain and improved function compared with no treatment or usual care, with low- to moderate-quality evidence. The benefit was clinically significant in the short term (six to 12 weeks) but less pronounced six months after treatment completion, which means that programs need ongoing reinforcement to hold their effect. Guideline bodies have followed this line of evidence. The American College of Physicians' 2017 guideline recommended exercise as the first-line non-pharmacological treatment for chronic non-specific or radicular low back pain.

Evidence on which type of exercise works best is less settled. Network meta-analyses have found that Pilates, strength, core-based and mind-body programs can outperform aerobic work for pain, and a Tai Chi-focused analysis ranked Tai Chi highest. However, the 2021 physical therapy guideline concluded that there is no clear evidence of superiority of one exercise type or approach over another when exercise protocols are directly compared. Dose is also debated: one network meta-analysis favoured sessions of 15–30 minutes, three times weekly, over at least 16 weeks, while another suggested that programs of up to eight weeks work best, so the optimal parameters remain unresolved. Physical therapy guidance also emphasises pain neuroscience education alongside other physical therapy interventions, such as exercise or manual therapy.

Psychological approaches

Cognitive behavioral therapy (CBT) is the most commonly used psychological treatment for chronic pain. A 2024–2025 meta-analysis of 13 randomized trials (1,679 patients) found that significant improvements were observed in pain intensity (SMD = −0.44) and functional disability (SMD = −0.41) when CBT was combined with exercise, relative to usual care or other non-drug controls. For low back pain specifically, an overview of reviews found that CBT outperformed waiting-list or usual care for pain and disability, and that it is also more effective than some standalone active treatments such as physiotherapy and exercise, but less effective than surgery.

Acceptance and commitment therapy (ACT) and mindfulness-based programs form a second group. A BMJ-published review of 24 trials (2,505 participants) reported that ACT produced little evidence of pain reduction or reduced anxiety, yet it did improve pain interference, disability, depression and quality of life. Mindfulness-based stress reduction has been studied as an alternative to CBT, with trial protocols aiming to compare the two directly on disability and distress. The overall picture is that psychological therapies consistently improve how patients function and cope, even when they change pain intensity less.

Interventional procedures

Interventional procedures aim to interrupt pain signals at specific sites. Epidural steroid injections, nerve blocks and radiofrequency ablation are widely used to stop pain signals reaching the brain, but current guidelines provide conflicting recommendations for their use. The evidence is mixed by procedure. A 2025 BMJ rapid recommendation panel graded the evidence and found that there was no high certainty evidence for any procedure, and that low- and moderate-certainty evidence showed no meaningful relief for axial or radicular spine pain compared with sham procedures. Trials of conventional lateral branch radiofrequency ablation have likewise shown no specific effect over sham, whereas some alternative techniques showed greater and more sustained pain reduction. By contrast, an older systematic review rated transforaminal epidural steroid injections as strong for short-term and moderate for long-term relief in lumbar radicular pain. Procedures also differ in their risk profile: in cervicogenic headache, radiofrequency ablation was associated with a low complication rate, whereas steroid injections gave relief that could recur within weeks.

Neuromodulation and multidisciplinary care

Neuromodulation uses electrical stimulation to alter pain processing. Transcutaneous electrical nerve stimulation (TENS), which applies electrodes to the skin, has been studied widely, but several back pain guidelines do not recommend it; one comparison lists it among passive modalities that are not recommended. Spinal cord stimulation, which places electrodes in the epidural space to deliver pulses that may modulate dorsal horn activity, is generally reserved for selected neuropathic pain and persistent pain after spinal surgery; it typically begins with a trial period before any permanent implant. Its benefits and hardware complications vary across studies.

Multidisciplinary pain clinics bring together physicians, physical therapists, psychologists and nurses, usually combining several of the approaches above. The rationale is that disability often reflects physical, psychological and social factors together, so single-modality care may fall short. Evidence for the clinic model is stronger for program structure than for any single component.

Opioid crisis, regulation, and access

Opioids have long been used for severe pain, but the scale of prescribing in the United States expanded sharply from the 1990s. Opioid prescribing ramped up heavily from 1995 to 2010 is a claim I've phrased differently below: prescribing grew steeply in that window, with billions of prescriptions dispensed. Newly reformulated products such as OxyContin, together with a pain advocacy movement that encouraged more aggressive pain treatment, helped drive a steep rise in opioid use. Doctors had traditionally been wary of long-term opioid therapy for chronic conditions such as back pain, osteoarthritis and headache, so this shift marked a change in clinical practice as well as in marketing.

Overdose deaths rose in successive waves rather than in one event. Between 1999 and 2010 the rate of opioid-involved overdose deaths roughly doubled, from 2.9 to 6.8 per 100,000 people. Around 2011 the CDC described deaths from prescription painkillers as an epidemic, and federal and state authorities began to tighten prescribing. Heroin deaths then climbed steeply after about 2010, and from 2016 synthetic opioids, led by illicitly manufactured fentanyl, became the largest category of opioids involved in overdose deaths. Between 1999 and 2020, roughly 565,000 Americans died from opioid-involved overdoses, and total annual drug overdose deaths first passed 100,000 in 2021.

Regulatory responses have included clinical guidelines, state-level legal limits, prescription monitoring programs, and changes to product labeling and promotion. The CDC's 2016 guideline for chronic pain was replaced in 2022 by a broader document covering acute, subacute and chronic pain in adults, with twelve recommendations grouped into four areas: whether to start opioids, how to select drugs and doses, how long to prescribe and follow up, and how to assess and reduce risk. The 2022 guideline explicitly excludes pain related to sickle cell disease and cancer and care for patients receiving palliative or end-of-life treatment, and it states that its recommendations should not be applied as inflexible standards of care.

Whether restricting prescriptions reduced deaths is contested. The standard account holds that expanded prescribing fueled addiction and overdoses, and that prescribing restrictions can reduce these harms. Critics, including the libertarian Cato Institute, argue that the link between prescription volume and deaths is weaker than assumed, partly because deaths have been driven increasingly by illicit fentanyl and because toxicology tests cannot always distinguish prescription from illicit fentanyl. Some analyses report that opioid prescribing fell by roughly half during the 2010s while overdose deaths continued to rise, and some researchers have raised the possibility that restrictions shifted patients toward more dangerous illicit supply. These findings remain debated, and many of the studies are observational.

Estimates of economic cost also vary widely with method. The CDC put the 2017 cost of opioid use disorder and fatal opioid overdose at about $1,021 billion, with $550 billion attributed to fatal overdoses. A congressional Joint Economic Committee analysis that adapted the CDC method estimated nearly $1.5 trillion for 2020. Earlier estimates from the White House Council of Economic Advisers, which counted productivity losses and the value of statistical lives, were lower in dollar terms but still exceeded $500 billion a year. Costs also fall unevenly, with a large share of health care spending borne by public programs such as Medicaid.

The crisis has also created a tension between limiting misuse and ensuring adequate analgesia. Health-equity guidance from public health bodies states that disparities in access to pain care must be addressed, and the 2022 CDC guideline stresses that patients with pain should still receive appropriate treatment. Critics of restrictive policies argue that tapering and abrupt dose reductions have left some patients with unmanaged pain, while supporters respond that inadequate attention to risk has itself caused harm. Balancing these concerns remains a central challenge for prescribers, regulators and patients.

New drug development and emerging therapies

Nav1.8 is a voltage-gated sodium channel concentrated in nociceptors, so blocking it can dampen pain signals at their source without acting on opioid receptors. The first drug to reach patients on this basis is suzetrigine, sold as Journavx. On January 30, 2025, the FDA approved suzetrigine under the brand name Journavx for the treatment of moderate to severe acute pain in adults, representing the first new class of analgesic approved for this indication in over 25 years. The regulatory decision leaned on data from 2191 adults with moderate to severe pain (mean score ~7 on a 0-10 scale) following full abdominoplasty (Trial 1) or bunionectomy (Trial 2). Dose-response data were clear-cut: only the top dose separated from placebo, while lower doses did not separate from placebo. The evidence base is narrow. Trial data for moderate to severe pain reach no further than about two weeks of use, and the drug is intended for pain that starts suddenly (often from trauma or surgery) and is expected to last less than three months. Its use in chronic pain remains under study.

Regulators have also set out how non-opioid drugs for persistent pain should be tested. The origin of this work lies in the SUPPORT Act, which requires the FDA to issue guidance to help address challenges related to developing non-opioid treatments for pain management. The chronic-pain draft was released on September 11, 2025, and a later version, labelled Revision 1 and dated May 2026, is now in circulation. Its phase 3 advice is detailed. The agency proposes at least one randomized, double-blind, parallel-group superiority trial, supplemented by additional studies that may evaluate efficacy or long-term safety. Candidate indications may be condition-specific, group-specific, and general chronic pain. To limit the effect of spontaneous fluctuation, enrolment should select participants with pain of appropriate intensity and chronicity (e.g., at least 3 months). Sponsors can also show whether a product avoids opioid initiation, eliminates ongoing opioid use, or reduces opioid dosage while maintaining pain control.

Gene-silencing approaches are, for the most part, still preclinical. In rodent models, viral vectors carrying small interfering RNAs against NaV1.7 have lowered the channel's expression in neurons of the dorsal root ganglion, and these approaches have resulted in significant attenuation of mechanical and thermal hyperalgesia in rodent models of neuropathic pain, with some effects lasting for several weeks following a single administration. Targeting happens in the spinal cord as well. A dCas9-KRAB construct delivered intrathecally results in the epigenetic repression of Nav1.7 gene expression, and in one rat study a spinal TRPV1-targeting siRNA attenuated behavioural hyperalgesia. Selectivity is a key appeal: in the NaV1.7 work, animals kept normal sensation even as hypersensitivity improved. Approaches aimed at the brain are less mature. Herpes simplex virus-derived vectors have been used to reach brainstem pain control circuits, and gene transfer has been tried in cancer patients with severe pain, although recent studies have demonstrated their efficacy in modulating key molecular targets involved in nociceptive signaling, both in preclinical models and early-phase clinical trials. Delivery methods and long-term safety still need work, as further research is anticipated to refine the delivery strategies and ensure clinical safety.

Other non-opioid strategies are more exploratory. Ziconotide, a peptide derived from cone snail venom, has been approved for severe chronic pain when given intrathecally, and newer venom-derived peptides are being screened for analgesic activity. Some groups are also trying to disrupt protein–protein interactions inside nociceptors that help sustain sensitization, with the aim of reducing pain without the systemic effects of opioids. These approaches remain at an early stage, and their clinical value is not yet established.

Global burden and public health

Chronic pain is one of the largest sources of health loss worldwide, although its measured size depends on how it is defined. One widely cited estimate holds that about one adult in five, roughly 1.5 billion people, lives with chronic pain, and that prevalence rises with age Globally, it is estimated that about one in five, or about 1.5 billion people, suffer from chronic pain (CP), with prevalence increasing with age. Burden is usually quantified as years lived with disability (YLD), and Global Burden of Disease analyses place chronic pain conditions among the top contributors to years lived with disability (YLD) globally. Low back pain dominates these figures. A 2021 analysis found that low back pain remains the leading cause of years lived with disability globally. The Lancet Rheumatology estimated that 619 million people worldwide suffered from low back pain in 2020 (nearly 10% of the world's population), and by 2050, that number is expected to reach 843 million. Once population size and age structure are set aside, the rate has edged down, but the absolute number of affected people keeps growing. Neck pain and osteoarthritis also rank among the leading causes of disability, though lower on the list low back pain is in 1st place, with neck pain coming in 4th and osteoarthritis coming in 13th.

Economic costs

The costs fall on health systems, employers, and individuals alike. For the United States, low back and neck pain were estimated at US$134 billion in 2016. In Brazil, low back pain was associated with about 100 absent workdays per person each year, and productivity losses accounted for nearly four-fifths of the national cost low back pain accounted for 100 days absent from work per person per year between 2012 and 2016, with productivity losses accounting for nearly 80% of the country's annual cost of low back pain (US$2.2 billion). A 2019 global estimate of economic losses attributable to occupational ergonomic risk factors for low back pain reached US$216.1 billion, and the costs and disability were distributed unevenly: High-income countries bore >70% of global economic burden, whereas middle-income countries experienced >70% of global YLD. Workforce effects are central. For working-age populations, low back pain forces more people out of the workplace than any other chronic health condition. Headache disorders show a similar pattern. In the 2019 Global Burden of Disease study they were ranked as the world's third leading cause of disability, and top cause in young adults, and their disability translates into lost productivity. Across chronic pain more broadly, the costs include health system expenditures, productivity losses, reduced quality of life, and informal care. Pain also overlaps with mental health: chronic low back pain is associated with increased depression, and depression is linked to increased disability and worse recovery in individuals with low back pain.

Unequal access to analgesics

Access to analgesics is distributed very unevenly. While opioids are often oversupplied and overprescribed in high-income countries, there are significant inequities as many low- and middle-income countries (LMICs) experience severe shortages. One analysis describes the imbalance in stark terms: the richest 10% in the world reside in countries receiving almost 90% of all available opioids, while 50% of the poorest in the world reside in countries receiving just 1% of all available opioids. The WHO model list has long included these drugs. Opioid analgesics have appeared on the list since the first edition was published in 1977, and the current list names five opioids to be essential medicines, including codeine, fentanyl, loperamide, methadone, and morphine. Listing a drug does not guarantee that patients can obtain it. In Ethiopia, for example, morphine is included in the list of essential medicines, millions of people with chronic diseases do not have access to opioids. Cost is another barrier, since in lower-income settings opioids are often unaffordable for both individual patients and health-care institutions. Barriers also include regulatory and attitudinal factors, such as the absence of training, fear of dependence and diversion, problems in sourcing, and restrictive prescribing rules.

Universal health coverage and policy

Within the framework of universal health coverage, WHO member states have committed to ensuring that access to pain treatment is needs-based and not dependent on stage of illness. Practice has fallen short of that commitment. Despite the low cost of opioids, most people worldwide who would benefit do not receive them. Pain has also been marginal in global health priorities. Despite being the leading cause of disability worldwide, low back pain and other musculoskeletal conditions have not featured prominently on the global health agenda. Primary care integration is affected by the same gap, given continued reliance on low-value health care, and the burden falls heavily on disadvantaged groups, with disproportionate impact on disadvantaged and culturally diverse populations. Whether a country includes pain in its national health strategy, and how it finances analgesics, rehabilitation, and specialist services, therefore strongly shapes who receives care.

Unresolved questions and research frontiers

Whether nociplastic pain is a valid category

Nociplastic pain was added to the IASP scheme as a third mechanism alongside nociceptive and neuropathic pain, and it is the most contested part of that scheme. The central objection is that it describes pain persisting without tissue damage or a nerve lesion, yet the central sensitization it involves has been shown to depend on continuing noxious input, such as nerve injury. Critics therefore ask whether a lesion or peripheral input is hidden somewhere, even when none is visible. Because the concept does not explain why only some patients with pain go on to develop this persistent form, it is also difficult to test as a general theory of chronic pain.

Another objection concerns function. If the definition holds, the pain arises from altered nociceptors without requiring any noxious input, which would mean it serves no protective purpose, a claim some clinicians find hard to reconcile with evolutionary biology. The category has also been criticized for its clinical use. Its defenders describe it as a mechanism rather than a diagnosis, and critics warn that adherence to the label may reduce vigilance for occult organic causes of pain.

Validation work is ongoing. A vignette study reported satisfactory reliability and criterion validity for IASP criteria, and a prospective cohort in knee osteoarthritis proposed refinements, but other authors note that the reliability and validity of the IASP criteria and grading system have not been tested adequately in real-world settings. Some researchers also propose that nociplastic features are a continuous, additive component of pain rather than a discrete category, as seen in osteoarthritis or rheumatoid arthritis with prominent central sensitization.

Why pain persists after healing

The transition from acute to persistent pain remains poorly explained. Although pain is normally a protective signal, the reasons why it becomes a disabling and often lasting condition are a matter of scientific debate. Several hypotheses have been advanced, including ongoing peripheral input, central plasticity, and psychological and social factors, but none has been established as a reliable predictor for individual patients. Identifying prognostic markers that can be validated across populations, and that can guide preventive treatment before chronicity sets in, is therefore a major research goal.

Measuring pain objectively in nonverbal people

Assessment is hardest in patients who cannot communicate. The IASP has stated that the inability to communicate verbally does not exclude the possibility that a person is experiencing pain, yet in patients with disorders of consciousness, accurate assessment and management of pain is one of the most significant challenges, because these individuals often cannot reliably communicate their suffering. Neuroimaging has shown that the brain can process noxious stimuli in some such patients. Studies report that pain-related brain activation appears to increase with the level of consciousness, and that some cortical activation can be seen even in patients in unresponsive wakefulness syndrome. These findings are hard to interpret, however. Autonomic reactions to harmful stimuli must be distinguished from the conscious experience of unpleasantness, and the degree of residual function needed for each component of pain is not yet clear.

Proposed solutions include electrophysiological markers. Laser-evoked potentials and EEG can be recorded quickly at the bedside, and one study found that variability in the interval between evoked components may represent an objective measure of pain processing. Behavioural scales remain the main clinical tool, and experts increasingly call for multimodal assessment strategies that combine behavioural scales with objective physiological and neurophysiological measures. None of these has yet been validated for routine clinical use, and the same problem applies in animal research, where pain is still largely inferred from behaviour.

Translating animal findings into human treatments

Many analgesics that work in rodents fail in people. Analgesic development has been described as characterized by a high attrition rate, in which drugs effective in rodents fail in clinical trials. For drug development as a whole, a 2023 narrative review states that the failure rate for translating drugs from animal testing to human treatments remains above 92%, and that most of these failures reflect unexpected toxicity or a lack of efficacy. Pain research has its own difficulties. Animal models of pain are often blamed for their low predictivity for analgesic efficacy in humans, and human trials are themselves confounded by placebo responses and variable patient populations.

Explanations focus on biological divergence. One critique argues that clinical failures are largely attributable to heavy reliance on mouse models, which assumes that pain pathways are evolutionarily conserved, and it notes that the dorsal root ganglion, the starting point of the nociceptive circuit, shows fundamental differences between species. Redundancy in human neurons can also undermine strategies that target a single molecule. Proposed responses include human experimental pain models, organoid platforms, and multiple rodent models and testing methods to better capture human complexity. Whether these approaches will close the gap between laboratory and clinic remains open.

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