Accurate Education – Pain Definitions and Terms

Adaptogens

Adaptogens are defined as herbal preparations that increase attention and endurance in fatigue, and reduce stress-induced impairments and disorders related to the neuro-endocrine and immune systems.

Adipokines 

Adipokines are molecules that are considered “regulatory,” in that they drive or regulate physiologic activities such as inflammation. These bioactive molecules are released from enlarged visceral fat cells (adipocytes) into systemic circulation which then promote generalized, systemic inflammation, insulin resistance, blood vessel cell dysfunction, hypertension, and atherosclerosis. They also activate immune cells to release even more inflammatory  cytokines (see below). 

Agonists

An “agonist” is an agent or medication that binds to a receptor on a cell that in turn triggers a response from the receptor. Agonists may be classified as a full, partial or antagonist.

Full agonists bind tightly to the opioid receptors and undergo significant conformational change of the receptor to produce maximal effect. Examples of full opioid agonists include codeine, fentanyl, heroin, hydrocodone, methadone, morphine, and oxycodone.

Partial agonists cause less conformational change to the receptor and therefore less receptor activation than full agonists. At low doses, both full and partial opioid agonists may provide similar effects. However, when the dose of partial agonists increases, the analgesic activity will plateau, and further increases in doses will not provide additional relief but may increase the adverse effects. Examples of partial agonists include buprenorphine (Belbuca and Suboxone0, butorphanol (Stadol), and tramadol (Ultram).

Antagonists bind to a receptor but do not result in activation of the receptor so that cellular response occurs. An example of an opioid antagonist is naloxone (Narcan) which attaches to opioid receptors but blocks any activation or cellular response.  This blockade is most effective if the antagonist, naloxone,  has greater affinity to the receptor than another opioid such as morphine, so that it “kicks off” the other medication from the receptor. Affinity can be likened to magnetism – a strong magnet cannot be pushed away by a weaker magnet. This is what makes naloxone an effective opioid overdose medication – when given to someone with too much opioid such as morphine or heroin in their system creating an overdose situation, the naloxone which has higher affinity to the opioid receptors than morphine or heroin kicks off the morphine or heroin, replacing it but, at the same time, blocking any further receptor activity and cellular response and reversing the symptoms of overdose.

There are also mixed agonists/antagonists, that demonstrate varying activity depending on the opioid receptor and the location of the receptor, and also by varying the dose. An important example is buprenorphine, which acts as a full agonist on the mu-opioid receptors in the pain-related areas of the brain and spinal cord but as a partial agonist on the mu-opioid receptors in the brainstem respiratory center. This is why there is a “ceiling effect” of buprenorphine with regard to respiratory depression, making it a safer opioid with respect to overdose risk. Other examples of mixed agonists/antagonists include butorphanol, nalbuphine, and pentazocine.

Also, some opioids are agonists at one or more opioid receptors but also antagonists at other opioid receptors. For example, buprenorphine is a partial agonist at mu-opioid receptors but an antagonist at another opioid receptor, the kappa-opioid receptor. This mechanism of buprenorphine activity is thought to explain why buprenorphine has antidepressant properties and may reduce opioid tolerance and central sensitivity.

Allodynia:

A painful response to a normally innocuous, or non-painful stimulus

Allodynia is a term that describes the experience of pain from a stimulus which does not normally provoke pain. Like hyperalgesia, allodynia can be a consequence of central sensitization. It is also commonly accompanies fibromyalgia, diabetic neuropathy and chronic headaches. An example is a patient with diabetic neuropathy whose feet are sensitive to putting on socks.

For more information:Assessment and Management of Central Sensitization

Alpha-2 (α₂) adrenergic receptor

The alpha-2 (α₂) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR). Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α₂–adrenergic receptor in the central and peripheral nervous systems.

There are 2 subtypes of adrenergic receptors , α and β. Each has both excitatory and inhibitory effects based upon where that receptor is located. When acting centrally within the locus ceruleus in the brain, for example, α-2 agonists produce sedation, reduced pain (analgesia), and euphoric effects as well as reduce acute opioid withdrawal symptoms. Additionally, when acting in the dorsal horn of the spinal cord, they can also reduce pain.

Central pain:

A subset of neuropathic pain caused by a lesion or disease of the central somatosensory nervous system

Central pain is pain arising from a lesion in the central nervous system – such as thalamic pain following stroke – or deafferentation pain (stemming from loss or interruption of sensory nerve fiber transmissions.

Central Pain Syndrome

Central pain syndrome is de!ned by the National Institute of Neurological Disorders and Stroke (NINDS) as “a neurological condition caused by damage to or dysfunction of the central nervous system.” Central Pain Syndrome can occur as a result of stroke, multiple sclerosis, neoplasm, epilepsy, CNS trauma, or Parkinson’s disease. Patients with central pain syndrome may experience localized pain, burning, and/or numbness in speci!c parts of the body, or throughout the body.

Central Sensitization:

Central sensitization can be an important contributing process to the chronic pain experience. It is a process associated with many chronic pain syndromes, especially fibromyalgia, chronic headaches, interstitial cystitis, irritable bowel syndrome and also chronic neck and back pain.

For more information:Central Sensitization

CGRP

Chronic Pain

Chronic pain is inconsistently defined but is generally considered to be pain that persists beyond the normal course of healing, with a time frame usually defined as 3 months or longer.

Chronic Pain Syndrome

Chronic Pain Syndrome is chronic pain associated with signi!cant psychosocial dysfunction. The psychosocial problems may include depression, drug dependence, anxiety, and other manifestations including pain complaints that are out of proportion to the physical findings. Chronic pain syndrome is not synonymous with chronic pain.

Cytokines

Deafferentation pain:

Pathological pain condition associated with a partial or complete loss of sensory input from a part of the body after lesions in somatosensory pathways, often as a result of reorganization in the central nervous system. Common examples include phantom limb pain and brachial plexopathy.

Descending modulation:

The process by which pathways that descend from the brain to the spinal cord modify incoming somatosensory information so that the perception of and reactions to somatosensory stimuli are altered, resulting in increased or decreased pain.

Dysesthesias

electric shock phenomenon

Ectopic discharge:

Trains of ongoing electrical nerve impulses that occur spontaneously without stimulation or originate at sites other than the normal location (or both). This phenomenon typically occurs after nerve injury.

Ephaptic transmission:

The phenomenon by which two independent nerves communicate with each other through an artificial synapse, which often develops after injury to the insulating myelin sheath that normally prevents crosstalk between parallel nerves.

 

Glial Cells

Glial cells, sometimes called neuroglia or glia, are non-neuronal cells (not nerve cells) found in the central and peripheral nervous system.  The role of glia include synapse formation, synapse maturation, and plasticity and the rapid conduction of action potentials, as well as immunological functions in the nervous system. Glial cells are generally distinguished in subclasses based on their diverse morphology and function. These include microglia, the immunocompetent and specialized brain macrophages; astrocytes, which represent the major glial component in the CNS and constitute up to 20–50% of the brain volume; NG2-glia, a peculiar type of glial cells that receive direct synaptic input from neurons; Schwann cells and oligodendrocytes form layers of myelin around neuronal axons in the peripheral and central nervous system, respectively.

Glial cells function to maintain balance in nerve activity, they form myelin (the coating of some nerve cells), and provide support and protection for neurons (nerve cells). Glial cells are derived from the immune system, the most common of which are microglia cells and astrocytes. Glia cells provide a supportive matrix for nerve cells, supplying nutrients and oxygen and aid in the repair of damaged cells. However, when activated by excitatory neurotransmitters released from nearby neurons, glial cells also are important in the evolution and maintenance of chronic nerve pain. They may play a role in opioid function including opioid-induced hyperalgesia and opioid tolerance.

It is believed that pathologic glial cell activation plays a significant role in the evolution of fibromyalgia pain, central sensitization and other chronic pain syndromes. Early studies suggest that medications or supplements that inhibit glial activation may reduce the development of chronic nerve pain or reduce the severity of existing nerve pain.

For more information: Neurobiology of Pain, Palmitoylethanolamide (PEA)

Hyperalgesia:

Hyperalgesia is an exaggerated, increased painful response to a stimulus which is normally painful. Hyperalgesia can be a consequence of central sensitization and is also thought to occur with chronic exposure to opioids, although the clinical significance of this is uncertain.

For more information:Assessment and Management of Opioid Induced Hyperalgesia

Hyperesthesia:

increased sensitivity to mild painful stimuli.

Hyperpathia

pain produced by subthreshold stimuli

Inflammatory Pain

Inflammatory pain derives from damage-induced inflammation to somatic or visceral tissues (actual damage). It can be acute or chronic, depending on the nature of the underly- ing disease. While the former still has a protective purpose, as it limits movements and further damage until the repair is completed (adaptive pain), the latter lacks any biological purpose (maladaptive pain)

Inflammatory pain is the result of nociceptor activation by multiple inflammatory mediators released from immune cells, mainly mast cells. When chronic, this leads to the development of nerve inflammation that brings about subsequent neuro-chemical changes, like wind-up and long-term potentiation, as well as translational and transcriptional modifications (e.g., lower activation threshold of nociceptors and increased expression of functional proteins involved in pain processing). The resulting increased firing rate of the first peripheral nerve and secondary nerve in the spinal cord leads to peripheral and central sensitization, respectively). Ths is the main feature of prolonged inflammatory pain which leads to primary or secondary hyperalgesia (i.e., increased severity perception of painful stimuli at the site of, or distant to the stimulus) and allodynia (a painful perception to non-painful  stimuli).

The pain associated with arthritis is sometimes referred to as inflammatory pain due to the underlying component of inflammation contributing to the pain and disease process. While not strictly a separate type of pain, arthritis pain is often treated differently due to the focus on reducing inflammation thereby reducing the associated pain. Recent research however show us that the pain and disease process of arthitis also involves the underlying bone of the affected joint and there is a neuropathic component to the pain of arthritis. The use of neuropathic pain agents has been shown to be helpful in arthritis pain. Treating arthritis with NSAIDs offers both analgesic and inflammatory benefits although the dosage and duration of treatment may vary between the two (see:NSAIDs).

For more information:  Arthritis and CAM Treatment of Arthritis

Ionotropic Receptor

The nervous system utilizes two types of receptors: metabotropic and ionotropic receptors. Ionotropic receptors, also called neurotransmitter-gated or ligand-gated channels, are ion channels that open in response to the binding of a neurotransmitter. They are primarily located along the dendrites or cell body, but they can be present anywhere along the neuron if there is a synapse. A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity.

 

Medication Abuse and Misuse

These two terms are widely used, yet their definitions are as varied as there are individuals using them. The unfortunate consequence of this is a grave lack of understanding regarding their incidence, risks and consequences. For the purposes of this web site, the following definitions apply:

Medication Abuse:

“Medication Abuse” is defined as the use of a drug for purposes other than as indicated or prescribed. “Purposes other than as indicated or prescribed” include using a medication such as a pain medication for sleep, anxiety, to improve mood or to get high.

Medication Misuse:

“Medication Misuse” is defined as the use of a drug for purposes as indicated or prescribed, but at doses other than as indicated or prescribed. Medication misuse includes taking a prescription medication as previously or routinely prescribed, but without a current prescription. It also includes taking a currently prescribed medication at doses higher than as prescribed.

Metabolism

Metabolism refers to the life-sustaining chemical transformations within the cells of living organisms. The three main purposes of metabolism are the conversion of food/fuel to energy to run cellular processes, the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and some carbohydrates, and the elimination of wastes. These chemical transformations are mediated by enzymes and allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transport of substances into and between different cells.

Metabolism is usually divided into two categories: catabolism, the breaking down of organic matter and anabolism, the building up of components of cells such as proteins and nucleic acids. Usually, breaking down components releases energy and building up components consumes energy.

Metabolites

Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, catalytic activity of their own (usually as a cofactor to an enzyme), defense, and interactions with other organisms.

Metabolomics

Metabolomics is the scientific study of chemical processes involving metabolites. Specifically, metabolomics is the “systematic study of the unique chemical fingerprints that specific cellular processes leave behind”, the study of their small-molecule metabolite profiles. Metabolomics is the study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms. Collectively, these small molecules and their interactions within a biological system are known as the metabolome.

 

Metabotropic Receptor

A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: metabotropic and ionotropic receptors. Ionotropic receptors, also called neurotransmitter-gated or ligand-gated channels, are ion channels that open in response to the binding of a neurotransmitter. They are primarily located along the dendrites or cell body, but they can be present anywhere along the neuron if there is a synapse.

Microbiome

The term “microbiome” refers to the microbial community, including all the microbes – bacteria, fungi, protozoa and viruses – that live on and inside the human body. It also refers to the genetic material of all all these microbes. The number of genes in all the microbes in one person’s microbiome is 200 times the number of genes in the human genome.

 

Mixed Pain

Currently, pain types are defined as being either nociceptive, neuropathic or nociplastic pain but it has been proposed that certain pain conditions exist that fail to fit into any of these 3 categories and instead represent a mixed picture that is separate or overlapping to these three. The term “mixed pain” has not been formally defined despite its common use in pain literature. A 2019 publication proposed the following definition: “Mixed pain is a complex overlap of the different known pain types (nociceptive, neuropathic, nociplastic) in any combination, acting simultaneously and/or concurrently to cause pain in the same body area. Either mechanism may be more clinically predominant at any point of time. Mixed pain can be acute or chronic.”

Neuropathic pain (“Nerve Pain”):

The International Association for the Study of Pain (IASP)’s 1994 definition of neuropathic pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system”proved debatable, specifically related to the term “dysfunction” which was considered to be too broad and imprecise. The IASP Special Interest Group on Neuropathic Pain (NeuPSIG) subsequently proposed a new definition of neuropathic pain in 2008, as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” This was later modified to include  “neuropathic pain is a clinical description (and not a diagnosis).

Nerve pain is usually perceived as burning, electric, shock-like, tingling or sharp and may start at one location and shoot, or “radiate” to another location (like sciatica). Neuropathic pain can be “peripheral,”  (outside the central nervous system),”  like carpal tunnel pain or “central,” originating in the spinal cord or brain.  Neuropathic pain is often a disease process, not simply the symptom of one.

For more information:  Assessment and Management of Neuropathic Pain

Neuroplasticity:

Changes in neural pathways and synapses that result from bodily injury or changes in behavior, the environment, or neural processes. This is consistent with the concept that the brain is a dynamic organ that constantly changes in response to internal and outside events throughout life.

Nociception:

Nociceptive pain:

Nociceptive pain is by far the most common type of pain. It is defined by the IASP as “pain that arises from actual or threatened damage to non-neural tissue and is due to activation of peripheral nerve endings (nociceptors) in response to noxious stimulation. The term nociceptive pain includes pain associated with active inflammation and is designed to contrast with neuropathic pain.

Nociceptive pain is caused by activation of neural pathways in response to damaging or potentially damaging stimuli to body tissue such as occurs with chemical or mechanical trauma or burns.  It is usually described as a sharp, aching, or throbbing pain. Nociceptive pain is further divided into “visceral” pain, originating from the organs inside the body,  and “somatic” pain, originating from muscles, bone and skin. Visceral pain is often vague, difficult to describe and hard to localize. Nocicptive pain is usually a symptom of a disease process.

 

Nociplastic Pain

In 2017, the International Association for the Study of Pain (IASP) adopted a third mechanistic descriptor of pain,  “nociplastic pain,”  defined as “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.” Nociplastic pain reflects changes in function of nociceptive (pain) pathways such as those that contribute to central sensitization. Augmented central nervous system pain and sensory processing with altered pain modulation are suggested to be the mechanism of nociplastic pain.

A more contemporary definition of Nociplastic Pain is “pain due to sensitization of the nervous system, without a sufficient underlying anatomical abnormality to explain the severity of pain. The basis of nociplastic pain is complex and highly dependent on psychological factors such as catastrophizing, low perception of self-efficacy, and neuroticism, all of which act as predictors for this type of pain.

Nociplastic pain may be manifest in various organ systems, is often perceived as being more widespread rather than localized and is commonly associated with central nervous system symptoms of fatigue, difficulties with cognition and sleep, and other somatic symptoms; all features that contribute to considerable suffering.It has been theorized that dysfunction of the endocannabinoid system may contribute to persistent pain in these conditions. 

Nootropics

Nootropics or “smart drugs” are substances that serve to enhance cognition or improve brain performance.

Noxious stimulus:

A stimulus that damages or threatens to damage normal tissues

NSAIDs (Non-Steroid Anti-Inflammatory Drugs):

Pain

Pain is defined as:

“an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

Paresthesias:  numbness or tingling

Partial Agonist

Intrinsic activity is a proportional constant quantifying the extent of functional change produced by a receptor-mediated response system following binding of a drug. A drug with high intrinsic activity at a particular receptor is considered a full agonist, a drug with low intrinsic activity is considered a partial agonist, and a drug that binds to a receptor and exhibits zero activity is defined as an antagonist. Importantly, a drug can reach a full biological response in many signaling systems (e.g., a full analgesic effect) despite having only partial intrinsic activity (thus it is a partial agonist at the receptor) or occupying only a fraction of receptors.

In tissues with a high number of surplus receptors (‘receptor reserve’), partial agonists can activate sufficient signal processes to achieve an effect comparable to full agonists. The characterization of a drug as a full or partial agonist thus needs to be interpreted carefully and has to consider the functional state of the respective receptor system. There is evidence that the functional opioid receptor reserve differs among the diverse neuronal populations that mediate distinct effects of opiate drugs. Clinically, this means that an opioid classified as a partial agonist at the receptor may be indiscernible from a full agonist with regard to one biological response (e.g., analgesia) and may indeed have a partial effect with regard to another biological response (e.g., respiratory depression).

As defined by the IASP (International Association for the Study of Pain), “peripheral sensitization” is the “Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields.”

It is initiated when the peripheral terminals of pain receptors (nociceptors) are exposed to noxious stimulus, for example, inflammatory mediators in traumatically damaged tissue. Ongoing stimulation results in a lowering of the activation threshold and thus an increase in responsiveness of nociceptors. Peripheral sensitization generally requires on going peripheral pathology for the sensitization to be maintained and is generally localized to the site of injury.

Phantom:

Pain perceived to arise from a body part that has been amputated

Pharmacodynamics:

Pharmacokinetics:

Protease-activated receptor-1 (PAR1)

Protease-activated receptor-1 (PAR1) has been implicated as a potential regulator of inflammatory and neuropathic pain. PAR1 is a member of a family of four G-protein coupled receptors that are activated by serine proteases and are typically found in high concentrations at an injury site. Expression of PAR1 has been confirmed on neurons, astrocytes, and microglia, all of which are cells known to contribute to pain. Yet the role of PAR1 in the initiation and maintenance of pain is still not clear.

“Referred” Pain

Referred pain often makes establishing a diagnosis challenging. When the pain originates in one location but is perceived in, or travels to, another location the process is termed “referred” pain. Many people with chronic low back pain also experience “sciatica,” pain that originates in the low back and travels down one or both legs – a common example of referred pain.

The source of referred pain is often difficult to identify accurately. “Sciatica,” so named after the sciatic nerve implying that pain traveling from the low back into the lower extremities is generated by compression or other pathology of the sciatic nerve. Unfortunatly, it not so simple. Many tissues have the capacity to refer pain to a different location. Best known of the referred pains are the dermatomal patterns of pain generated from a specific nerve root in the lower back that give rise to specific patterns of pain from the low back to the great toe for example. This is a “true” sciatica, referred pain from the sciatic nerve. 

However other tissues in the back including the facet joints in the spine, muscles and fascia (the tissue surrounding muscles) can also refer pain to the lower extremities. Referred nerve pain is likely to be perceived as typical neuropathic pain: burning, electric, tingling and usually well localized. Referred pain from the facet joints is more likely to be sharp or dull and aching and likely to be more vaguely localized, usually not below the knees. This case in point underscores the need to evaluate any pain carefully, especially referred pain, to establish an accurate diagnosis. If the diagnosis is wrong, the treatment is unlikely to be effective as many patients victimized by unsuccessful lumbar surgery for “sciatic” pain  will testify to.

Signalling: Upstream and Dounstream Signalling

When a ligand, such as a morphine molecule, attaches to a cell receptor such as the mu-opiod receptor, it triggers a “signalling pathway” in which a cascade of other actions occur. This activity is best described on this “signalling“ reference page.

Sympathetically maintained pain:

Pain that is enhanced or maintained by a functional abnormality of the sympathetic nervous system, such as functional sympathetic afferent coupling or increased expression of adrenergic receptors at the peripheral terminals of nociceptive afferent fibers.

 

Temporal Summation (or Wind-up)

Visceral Pain:

The pain associated with internal organs and tissues is referred to as “visceral” pain. It tends to be somewhat vague when attempting to localize where it arises and it is often perceived as dull, aching or cramping although it may be burning or sharp and stabbing. Visceral pain is often perceived in a different location than where the problem originates (see “referred pain,” below). For example, the pain associated with a heart attack is often perceived down the left (or right) arm. Visceral pain does not generally respond well to neuropathic pain agents though it may respond well to NSAIDs, especially menstrual pain.

Wind-up (or Temporal Summation)