“The whole purpose of education is to turn mirrors into windows.”
– Sydney Harris

Pain – Definitions and Terms

Pain is defined as:

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

 

 

Understanding Pain:

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Definitions and Terms Related to Pain:

 

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.

 

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

 

Allosteric modulators (AMs)

Allosteric modulators (AMs) bind to receptor allosteric sites which are topographically different comparative to that of the orthosteric sites, where a receptor’s ligand binds. Upon binding, AMs modify the configuration of receptors to either enhance or reduce the effectiveness and/or potency of ligands that bind to the orthosteric sites and trigger receptor-driven actions. Thus, rather than directly activating receptors, AMs instead “fine-tune” the effects of ligands that bind to orthosteric sites.

 

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 α2adrenergic 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.

 

Alpha-2 (α2) adrenergic receptor agonists

Alpha-2 adrenergic receptor agonists inhibit adenylyl cyclase activity, inhibit norepinephrine release from presynaptic neurons and reduces brainstem vasomotor center-mediated CNS activation. The a-2 adrenergic receptor agonists are used to treat high blood pressure, attention-deficit/hyperactivity disorder; pain and panic disorders as well as symptoms of cigarette craving as well as opioid, benzodiazepine, and alcohol withdrawal. Common a-2 adrenergic receptor agonists include clonidine (Catapres) and lofexidine (Lucemyra) and also tizanidine (Zanaflex), a medication commonly used as a muscle relaxer.

 

Apoptosis:

Apoptosis is a form of programmed cell death that physiologically plays a role in embryogenesis, cell differentiation, proliferation/homeostasis and as a defensive mechanism to remove infected, mutated, or damaged cells. Under normal conditions, a balance between apoptosis and cell survival is important in the development of multicellular organisms and in the regulation and maintenance of cell populations in tissues. In fact, dysfunction of the apoptotic program is implicated in a variety of pathological conditions. Thus, impaired apoptosis can result in cancer, auto-immune disorders such as Lupus or Rheumatoid Arthritis and the spread of viral infections. Excessive apoptosis can lead to neurodegenerative disorders such as Alzheimers and Parkinson’s Disease and cardiovascular disease.

 

Aromatherapy

Aromatherapy is “the use of essential oils from plants (flowers, herbs, or trees) as therapy to improve physical, mental, and spiritual well-being.”

 

Autacoids

Autacoids can be defined as locally produced modulating factors, influencing locally the function of cells and/or tissues, which are produced on demand and which subsequently are metabolized in the same cells and/or tissues. PEA (palmitoylethanolamide) is an example of an autocoid.

 

Bioavailability

Bioavailability refers to the proportion of a drug or other substance which enters the blood circulation when introduced into the body via inhalation, through the skin or through ingestion etc. For example, the bioavailability of a substance introduced directly into the vein by injection is, by definition, 100%.

 

Biomarker

A biomarker is any measurable substance, structure, or process in the body or its products that influences or predicts the incidence ot outcome of a disease.

 

Biopsychosocial Model of Pain

The biopsychosocial model identifies pain as a unique, multidimensional experience influenced by a person’s physical, psychological, and sociocultural domains. Each domain plays a significant role in the dynamic process of the patient’s pain experience. Though described individually, these domains are continuously interacting with each other to shape the patient’s pain experience. The physical (bio-) domain addresses nociception, wherein a physiological event (e.g., injury) engages the nervous system to stimulate pain receptors. The neural signals are contextualized by the patient, who actively makes meaning of the event. The psychological (psycho-) domain determines the unique pain experience of the patient, including cognitive (beliefs, self-efficacy, cognition, and coping), affective (depression, anxiety, and anger), and personality factors. The sociocultural (socio-) domain refers to circumstances that can influence the patient’s perception, beliefs, and expectations of pain and involve the interaction between the patient and external influences. These include learned behavior through observation (social learning mechanism), social support (operant learning mechanism), and cultural beliefs (respondent learning mechanism).

 

Cell Signaling

Cell signaling is part of any communication process governing basic activities of cells including the coordination of activity between cells. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis.

 

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 refers to the increased nerve connections (synapses) and associated hyper-responsiveness established in somatosensory nerves in the dorsal horn of the spinal cord following intense and prolonged peripheral noxious stimuli, tissue injury or nerve damage. This heightened synaptic nerve transmission leads to a reduction in pain threshold which leads to greater pain with less stimulation, an amplification of pain responses and a spread of pain sensitivity to non-injured areas.

 

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

CGRP is a 37-amino-acid neuropeptide identified in 1982 with diverse biological functions in the peripheral and in the central nervous system. The role of CGRP in migraine pathophysiology has  led to the development of small molecule CGRP receptor antagonists for acute and preventive treatment of migraine and monoclonal antibodies against CGRP mechanisms for migraine prevention. To what extent CGRP is involved in non-headache pain conditions is not fully understood or whether CGRP antagonism may represent a useful therapeutic approach for the treatment of chronic pain is yet unknown.

 

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

Cytokines are small intracellular regulatory proteins that are released by immune cells in the event of damage or injury and have a specific effect on the interactions and communications between cells. Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes).

 

Cytokines can be pro-inflammatory or anti-inflammatory and they play an important role in the development and maintenance of chronic pain. Cytokines sensitize peripheral nociceptors (nerve endings – see below) and trigger pain signals to the spinal cord, but they may also cross the blood brain barrier and participate in central sensitisation processes in the spinal cord and brain.

 

Pro-inflammatory cytokines including interleukin (IL)-6, IL-8, IL-17, tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) promote inflammation, while anti-inflammatory cytokines including IL-4, IL-10, and IL-13, reduce inflammation and promote healing. An imbalance or excessive production of cytokines has been linked to different diseases and symptoms, ranging from fever to death and atherosclerosis to cancer. Dysregulation of pro-inflammatory cytokines has also been linked to sickness behavior, such as pain perception, cognitive impairment, depression, and other neurologically related effects. It has been suggested serum levels of cytokines are potential biomarkers in diseases, such as in rheumatoid arthritis.

 

Examples of cytokines relevant to pain include Tumour Necrosis Factor (TNF), Interleukin 1 (IL-1), and Interleukin 6 (IL-6) and others. IL-6 appears to be the best biomarker for the presence of chronic systemic inflammation and nerve pain and your physician may use blood tests to monitor IL-6 levels.

 

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.

 

Foods for Special Medical Purposes (FSMPs)

Foods for Special Medical Purposes (FSMPs) are a new class of therapeutics, which can be used under medical supervision to treat diseases and alleviate symptoms. FSMPs are intended to provide nutritional support to persons who suffer from a specific disease, disorder or a medical condition, as a part of their dietary management.

 

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

 

Interleukins

Interleukins are cytokines made by one leukocyte and act on other leukocytes. There are both pro-inflammatory cytokines and anti-inflammatory interleukins.

Interleukins: Pro-Inflammatory

IL-1β is released primarily by monocytes and macrophages as well as by nonimmune cells, such as fibroblasts and endothelial cells, during cell injury, infection, invasion, and inflammation.  IL-1β is also expressed in nociceptive dorsal root ganglion (DRG) neurons in the spinal cord. IL-1β expression follows crush injury to peripheral nerve and after trauma to microglia and astrocytes in the central nervous system (CNS) where it can produce hyperalgesia.  IL-1β increases production of other pro-inflammatory cytokines including substance P and prostaglandin E2 (PGE2) in other neuronal and glial cells.

IL-6 has been shown to play a central role in the neuronal reaction to nerve injury including nerve regeneration.  IL-6 is also involved in microglial and astrocytic activation as well as in regulation of neuronal neuropeptides expression. Research indicates that IL-6 contributes to the development of neuropathic pain behavior following a peripheral nerve injury. IL-6 is sometimes used as a biomarker for systemic inflammation.

 

Interleukins: Anti-Inflammatory

Major anti-inflammatory interleukins include interleukin (IL)-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13. Other anti-inflammatory cytokines include Leukemia Inhibitory Factor, interferon-alpha, IL-6, and transforming growth factor (TGF)-β but they are categorized as either anti-inflammatory or pro-inflammatory cytokines, under various circumstances. Specific cytokine receptors for IL-1, TNF-α, and IL-18 also function as inhibitors for pro-inflammatory cytokines.

 

Intrinsic Activity

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 a result of a particular opioid having higher intrinsic activity and greater therapeutic effect while occupying a lower percentage of available opioid receptors, it will develop tolerance more slowly than an opioid with lower intrinsic activity. So there is an inverse relationship to an opioid’s intrinsic activity and the rate at which it develops tolerance: the higher its intrinsic activity, the longer the opioid takes to develop tolerance.

 

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:

The neural responses of encoding and processing noxious stimuli

 

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.

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.

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. Exemplified by fibromyalgia, nociplastic conditions also include chronic visceral pain, chronic headaches and facial pain, and chronic musculoskeletal pain. 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):

The NSAIDs are analgesics for mild to moderate pain and are usually the first type of analgesic taken for pain along with acetoaminophen (not an NSAID). NSAIDs work by inhibiting two enzymes that are responsible for inflammation and pain, cyclooxygenase-1 and cyclooxygenase-2 (Cox-1 and Cox-2). NSAIDs that inhibit both Cox-1 and Cox-2 are considered non-selective NSAIDs (ns-NSAIDs) whereas NSAIDs that inhibit only Cox-2 are referred to as selective Cox-2 inhibitors.

 

NSAIDs that are available over the counter (OTC) without prescription include ibuprofen (Advil, Motrin) and naproxen (Naprosyn, Anaprox, Aleve) and aspirin. Prescription versions of the OTC NSAIDs are available and usually covered by insurance. Other common prescription NSAIDs include diclofenac (Voltaren), Mobic (meloxicam) and others.

 

Topical NSAIDs:

Topical NSAIDs in many cases are equally effective for pain control and are the recommended first choice to begin treatment with an NSAID. There are many effective OTC topical creams with NSAIDs. Prescription NSAIDs include diclofenac (Voltaren Gel, Pennsaid and Flector Patches). Compounded topical medications used for pain usually consist of a combination of different medications with analgesic properties, in addition to diclofenac

 

Nutraceutical

The term “nutraceutical,” derived from “nutrition” and “pharmaceutical,” refers to a product that is isolated from herbs, botanicals or foods that has physiological benefit by supporting the structure or function of the body or providing protection against diseases. Nutraceuticals are directed at improving health, preventing or reducing the impact of disease, suppressing the aging process and increasing life expectancy. Nutraceuticals are generally sold in medicinal form as a supplement rather than as a food. This definition encompasses a wide range of compounds: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandular materials, and metabolites.

 

 

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).

 

Peripheral Sensitization

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 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 localised to the site of injury.

 

Phantom:

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

 

Pharmacodynamics:

Pharmacodynamics considers processes such as receptor binding type and location, alterations in signal transduction, and cross-tolerance – including how medications work.

 

Pharmacokinetics:

Pharmacokinetics considers how the production of metabolites, alterations in metabolic enzyme activity, and modulation of drug transporter expression or function are addressed – including how quickly medications are eliminated.

 

PPAR

PPAR receptors (Peroxisome Proliferator-Activated Receptor) belong to the PPARG nuclear receptor family which has three different isoforms (PPAR𝛼, PPAR𝛽/𝛿, and PPAR Υ). These nuclear receptors are members of the steroid receptor superfamily which behave as transcription factors in the regulation of processes concerning inflammation, metabolism, regulating energy expenditure and storage, atherosclerosis, cell differentiation, and proliferation. Activation of PPARG by its ligands reduces cytokines such as TNF𝛼 and NF-𝜅𝛽 in monocytes, inhibiting inflammation.

Endogenous ligands at PPARs include fatty acids and N-acylethanolamines (NAEs) such as the endocannabinoid, anandamide (AEA), N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA).  PPAR agonist drugs which act upon PPAR receptors are used for the treatment of metabolic syndrome, mainly for lowering triglycerides (dyslipidemia) and blood sugar (diabetes). Probiotics may help control PPARγ, ‘‘the master regulator of adipogenesis’’ and TNF-α in inflammation.

Moreover, studies suggest that the PPAR signalling system may modulate pain, anxiety and cognition. PPARs also regulate inflammatory processes and PPAR agonists have anti-inflammatory effects in models of chronic inflammation. The phytocannabinoid, Beta-caryophyllene (BCP), acts on PPAR-γ  in the suppression of inflammation.

 

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)

Temporal summation, also referred to as “wind-up,” occurs when a painful stimulus is continuously repeated lasting more than 10 seconds, the pain will integrate and become more painful by increasing pain intensity at the end of the stimulus train. Temporal summation is a measure of increased central nervous system pain and an important mechanism related to central sensitization. Difficult to block with conventional analgesics or anaesthetic procedures, it is a very powerful pain mechanism associated with repetitive activation of C nerve fibers and dorsal horn wide-dynamic range neurons. Temporal summation can be elicited with mechanical or thermal stimulation in the skin, musculoskeletal structures, and viscera. In clinical bedside testing, temporal cutaneous summation can be assessed by tapping the skin with a nylon filament.

 

The NMDA receptor plays a key role in temporal summation, but is very difficult to block even when using general anaesthesia or epidural analgesia. Many animal studies have shown that wind-up in dorsal horn neurons are inhibited by NMDA receptor antagonists as well as by antagonists of the glycine site in the NMDA receptor channel complex. Temporal summation in chronic pain patients is efficiently inhibited by NMDA receptor antagonists in patients with surgical incisions, postherpetic neuralgia, phantom limb pain, chronic postsurgical neuropathic pain and fibromyalgia.

 

Drugs showing an inhibitory effect on temporal summation include dextromethorphan (Delsym), ketamine, amantadine, imipramine, gabapentin (Neurontin) and venlafaxine (Effexor).

 

 

Tissue Necrosis Factor (TNF-α):

Tissue Necrosis Factor (TNF-α), also known as cachectin, is an inflammatory cytokine that plays a key role in pain. TNF also acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways (pathways that regulate cell death and reabsorption), NF- kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). TNF-α receptors are present in both neurons and glia. TNF-α plays important roles in both inflammatory and neuropathic hyperalgesia.

 

TRPV (Transient receptor potential channels, of the vanilloid subtype (TRPV)

TRPV Transient receptor potential channels, of the vanilloid subtype (TRPV), act as sensory moderators, including pain. They are activated by compounds (ligands), either endogenous (endocannabinoids such as anandamide and PEA) or  exogenous (capsaicin). They are also triggered by heat, mechanical and osmotic stress.  TRPV channels are found in smooth muscle cells, endothelial cells lining blood vessels, as well as in peri-vascular nerves that accompany blood vessels.

 

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)

Temporal summation, also referred to as “wind-up,” occurs when a painful stimulus is continuously repeated lasting more than 10 seconds, the pain will integrate and become more painful by increasing pain intensity at the end of the stimulus train. Temporal summation is a measure of increased central nervous system pain and an important mechanism related to central sensitization. Difficult to block with conventional analgesics or anaesthetic procedures, it is a very powerful pain mechanism associated with repetitive activation of C nerve fibers and dorsal horn wide-dynamic range neurons. Temporal summation can be elicited with mechanical or thermal stimulation in the skin, musculoskeletal structures, and viscera. In clinical bedside testing, temporal cutaneous summation can be assessed by tapping the skin with a nylon filament.

The NMDA receptor plays a key role in temporal summation, but is very difficult to block even when using general anaesthesia or epidural analgesia. Many animal studies have shown that wind-up in dorsal horn neurons are inhibited by NMDA receptor antagonists as well as by antagonists of the glycine site in the NMDA receptor channel complex. Temporal summation in chronic pain patients is efficiently inhibited by NMDA receptor antagonists in patients with surgical incisions, postherpetic neuralgia, phantom limb pain, chronic postsurgical neuropathic pain and fibromyalgia.

Drugs showing an inhibitory effect on temporal summation include dextromethorphan (Delsym), ketamine, amantadine, imipramine, gabapentin (Neurontin) and venlafaxine (Effexor).

 

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

For more information, please contact Accurate Clinic.

 

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