Hyperalgesia
Encyclopedia
Hyperalgesia is an increased sensitivity to pain
, which may be caused by damage to nociceptor
s or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior
, the evolved
response to infection.
Opioid-induced hyperalgesia
may develop as a result of long-term opioid use in the treatment of chronic pain
. Various studies of humans and animals have demonstrated that primary or secondary hyperalgesia can develop in response to both chronic and acute exposure to opioids. This side effect can be severe enough to warrant discontinuation of opioid treatment.
(PAF) which comes about in an inflammatory
or an allergic
response. This seems to occur via immune cells interacting with the peripheral nervous system
and releasing pain-producing chemicals (cytokine
s and chemokine
s).
One unusual cause of focal hyperalgesia is platypus venom
.
Long term opioid (e.g. heroin, oxycodone) users and those on high-dose opioid medications for the treatment of chronic pain, may experience hyperalgesia and experience pain out of proportion to physical findings, which is a common cause for loss of efficacy of these medications over time. As it can be difficult to distinguish from tolerance, opioid-induced hyperalgesia
is often compensated for by escalating the dose of opioid, potentially worsening the problem by further increasing sensitivity to pain. Chronic hyperstimulation of opioid receptors results in altered homeostasis of pain signalling pathways in the body with several mechanisms of action involved, one major pathway being through stimulation of the nociceptin receptor
, and blocking this receptor may therefore be a means of preventing the development of hyperalgesia.
Stimulation of pain fibers in a pattern consistent with that from inflammation
switches on a form of amplification
in the spinal cord
, long term potentiation. This occurs where the pain fibres synapse to pain pathway, the periaqueductal grey. Amplification in the spinal cord may thus be another way of producing hyperalgesia.
The release of proinflammatory cytokine
s such as Interleukin-1 by activated leukocytes triggered by lipopolysaccharides, endotoxin
s and other signals of infection
also increases pain sensitivity as part of sickness behavior
, the evolved response
to illness.
and neuropathic pain
, and consequently may respond to standard treatment for these conditions, using various drugs such as SSRI or tricyclic antidepressants, non-steroidal antiinflammatory drugs, glucocorticoids, gabapentin
or pregabalin
, NMDA antagonists, or atypical opioids such as tramadol
. Where hyperalgesia has been produced by chronic high doses of opioids, reducing the dose may result in improved pain management. However as with other forms of nerve dysfunction associated pain, treatment of hyperalgesia can be clinically challenging, and finding a suitable drug or drug combination that is effective for a particular patient may require a certain amount of trial and error.
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, which may be caused by damage to nociceptor
Nociceptor
A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.-History:...
s or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior
Sickness behavior
thumb|350px|right|[[Michael Peter Ancher|Ancher, Michael]], "The Sick Girl", 1882, [[Statens Museum for Kunst]]Sickness behavior is a coordinated set of adaptive behavioral changes that develop in ill individuals during the course of an infection....
, the evolved
Evolutionary medicine
Evolutionary medicine or Darwinian medicine is the application of modern evolutionary theory to understanding health and disease. It provides a complementary scientific approach to the present mechanistic explanations that dominate medical science, and particularly modern medical education...
response to infection.
Types
Hyperalgesia can be experienced in focal, discrete areas, or as a more diffuse, body-wide form. Conditioning studies have established that it is possible to experience a learned hyperalgesia of the latter, diffuse form. The focal form is typically associated with injury, and is divided into two subtypes:- Primary hyperalgesia describes pain sensitivity that occurs directly in the damaged tissues.
- Secondary hyperalgesia describes pain sensitivity that occurs in surrounding undamaged tissues.
Opioid-induced hyperalgesia
Opioid-induced hyperalgesia
Opioid-induced hyperalgesia or opioid-induced abnormal pain sensitivity is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even...
may develop as a result of long-term opioid use in the treatment of chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
. Various studies of humans and animals have demonstrated that primary or secondary hyperalgesia can develop in response to both chronic and acute exposure to opioids. This side effect can be severe enough to warrant discontinuation of opioid treatment.
Causes
Hyperalgesia is induced by platelet-activating factorPlatelet-activating factor
Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC is a potent phospholipid activator and mediator of many leukocyte functions, including platelet aggregation and degranulation, inflammation, and anaphylaxis...
(PAF) which comes about in an inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
or an allergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
response. This seems to occur via immune cells interacting with the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
and releasing pain-producing chemicals (cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s and chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s).
One unusual cause of focal hyperalgesia is platypus venom
Platypus venom
The platypus is one of the few mammals to produce venom. Males have a pair of spurs on their hind limbs. The male's pair of spurs spits out a cocktail of poisons that, while excruciatingly painful, is not lethal to most animals.-Spur and crural gland:...
.
Long term opioid (e.g. heroin, oxycodone) users and those on high-dose opioid medications for the treatment of chronic pain, may experience hyperalgesia and experience pain out of proportion to physical findings, which is a common cause for loss of efficacy of these medications over time. As it can be difficult to distinguish from tolerance, opioid-induced hyperalgesia
Opioid-induced hyperalgesia
Opioid-induced hyperalgesia or opioid-induced abnormal pain sensitivity is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even...
is often compensated for by escalating the dose of opioid, potentially worsening the problem by further increasing sensitivity to pain. Chronic hyperstimulation of opioid receptors results in altered homeostasis of pain signalling pathways in the body with several mechanisms of action involved, one major pathway being through stimulation of the nociceptin receptor
Nociceptin receptor
The nociceptin receptor or NOP also known as the orphanin FQ receptor or kappa-type 3 opioid receptor is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a G protein-coupled receptor whose natural ligand is known as nociceptin or orphanin FQ, a 17 amino acid...
, and blocking this receptor may therefore be a means of preventing the development of hyperalgesia.
Stimulation of pain fibers in a pattern consistent with that from inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
switches on a form of amplification
Amplifier
Generally, an amplifier or simply amp, is a device for increasing the power of a signal.In popular use, the term usually describes an electronic amplifier, in which the input "signal" is usually a voltage or a current. In audio applications, amplifiers drive the loudspeakers used in PA systems to...
in the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, long term potentiation. This occurs where the pain fibres synapse to pain pathway, the periaqueductal grey. Amplification in the spinal cord may thus be another way of producing hyperalgesia.
The release of proinflammatory cytokine
Proinflammatory cytokine
A proinflammatory cytokine is a cytokine which promotes systemic inflammation.Examples include IL-1 and TNF alpha....
s such as Interleukin-1 by activated leukocytes triggered by lipopolysaccharides, endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
s and other signals of infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
also increases pain sensitivity as part of sickness behavior
Sickness behavior
thumb|350px|right|[[Michael Peter Ancher|Ancher, Michael]], "The Sick Girl", 1882, [[Statens Museum for Kunst]]Sickness behavior is a coordinated set of adaptive behavioral changes that develop in ill individuals during the course of an infection....
, the evolved response
Evolutionary medicine
Evolutionary medicine or Darwinian medicine is the application of modern evolutionary theory to understanding health and disease. It provides a complementary scientific approach to the present mechanistic explanations that dominate medical science, and particularly modern medical education...
to illness.
Treatment
Hyperalgesia is similar to other sorts of pain associated with nerve damage such as allodyniaAllodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
and neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
, and consequently may respond to standard treatment for these conditions, using various drugs such as SSRI or tricyclic antidepressants, non-steroidal antiinflammatory drugs, glucocorticoids, gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
or pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
, NMDA antagonists, or atypical opioids such as tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
. Where hyperalgesia has been produced by chronic high doses of opioids, reducing the dose may result in improved pain management. However as with other forms of nerve dysfunction associated pain, treatment of hyperalgesia can be clinically challenging, and finding a suitable drug or drug combination that is effective for a particular patient may require a certain amount of trial and error.