Neuropathic pain
Encyclopedia
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 (paroxysmal) components. The latter are likened to an electric shock. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching. Nociceptive pain, by contrast, is more commonly described as aching.
Up to 7% to 8% of the European population is affected and in 5% of persons it may be severe.
Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.
, a disorder of chronic widespread pain, is potentially a central pain disorder and is responsive to medications that are effective for neuropathic pain. Aside from diabetes (see diabetic neuropathy
) and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster
infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, genetic (gene HCN2
), and immune mediated disorders or physical trauma to a nerve trunk. Neuropathic pain is common in cancer
as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy
, radiation injury or surgery.
. Current knowledge regarding the mechanisms of neuropathic pain is incomplete and is biased by a focus on animal models of peripheral nerve injury.
, aberrant regeneration may occur. Neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and heightened sensitivity to chemical, thermal and mechanical stimuli. This phenomenon is called "peripheral sensitization
".
(STT), which constitutes the major ascending nociceptive pathway. As a consequence of ongoing spontaneous activity arising in the periphery, STT neurons develop increased background activity, enlarged receptive fields and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization is an important mechanism of persistent neuropathic pain.
Other mechanisms, however, may take place at the central level after peripheral nerve damage. The loss of afferent signals induces functional changes in dorsal horn neurons. A decrease in the large fiber input decreases activity of interneurons inhibiting nociceptive neurons i.e. loss of afferent inhibition. Hypoactivity of the descending antinociceptive systems or loss of descending inhibition may be another factor. With loss of neuronal input (deafferentation) the STT neurons begin to fire spontaneously, a phenomenon designated "deafferentation hypersensitivity.”
Neuroglia ("glial cells") may play a role in central sensitization. Peripheral nerve injury induces glia to release proinflammatory cytokines and glutamate which, in turn influence neurons.
In addition to the work of Dworkin, O'Connor and Backonja et al., cited above, there have been several recent attempts to derive guidelines for pharmacological therapy. These have combined evidence from randomized controlled trial
s with expert opinion.
Determining the best treatment for individual patients remains challenging. Attempts to translate scientific studies into best practices are limited by factors such as differences in reference populations and a lack of head-to-head studies. Furthermore, multi-drug combinations and the needs of special populations, such as children, require more study.
It is common practice in medicine to designate classes of medication according to their most common or familiar use e.g. as "antidepressants" and "anti-epileptic drugs" (AED's). These drugs have alternate uses to treat pain because the human nervous system employs common mechanisms for different functions, for example ion channels for impulse generation and neurotransmitters for cell-to-cell signaling.
Favored treatments are certain antidepressants e.g. tricyclics
and selective serotonin-norepinephrine reuptake inhibitor
s (SNRI's), anticonvulsant
s, especially pregabalin
(Lyrica) and gabapentin
(Neurontin), and topical lidocaine
. Opioid
analgesics and tramadol
are recognized as useful agents but are not recommended as first line treatments. Many of the pharmacologic treatments for chronic neuropathic pain decrease the sensitivity of nociceptive
receptors, or desensitize C fibers such that they transmit fewer signals.
Some drugs may exert their influence through descending pain modulating pathways. These descending pain modulating pathways originate in the brainstem.
In animal models of neuropathic pain it has been found that compounds which only block serotonin reuptake do not improve neuropathic pain.
Similarly, compounds that only block norepinephrine
reuptake also do not improve neuropathic pain. Dual serotonin-norepinephrine reuptake inhibitor
s such as duloxetine
, venlafaxine
, and milnacipran
, as well as tricyclic antidepressant
s such as nortriptyline
and desipramine
improve neuropathic pain and are considered first-line medications for this condition.
Bupropion
has been found to have efficacy in the treatment of neuropathic pain.
Tricyclic antidepressants may also have effects on sodium channels.
(Lyrica) and gabapentin
(Neurontin) work by blocking specific calcium channels on neurons and are preferred first-line medications for diabetic neuropathy
. The anticonvulsants carbamazepine
(Tegretol) and oxcarbazepine
(Trileptal) are especially effective in trigeminal neuralgia
. The actions of these two drugs are medicated principally through sodium channels.
Lamotrigine may have a special role in treating two conditions for which there are few alternatives, namely post stroke pain and HIV/AIDS-related neuropathy in patients already receiving antiretroviral therapy.
Several opioids, particularly methadone
, and ketobemidone
possess NMDA antagonism in addition to their µ-opioid agonist properties. Methadone does so because it is a racemic
mixture; only the l-isomer is a potent µ-opioid agonist. The d-isomer does not have opioid agonist action and acts as an NMDA antagonist; d-methadone is analgesic in experimental models of chronic pain. Clinical studies are in progress to test the efficacy of d-methadone in neuropathic pain syndromes.
There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of its NMDA antagonism. It is reasonable to base the choice of opioid on other factors.
can provide relief. A transdermal patch containing lidocaine is available commercially in some countries.
Repeated topical applications of capsaicin, are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers. Nevertheless, benefits appear to be modest with standard (low) strength preparations.
. Unfortunately, strongly held beliefs make discussion of the appropriate use of these substances, in a medical context, difficult. Similar considerations apply to opioids.
A recent study showed smoked marijuana
is beneficial in treating symptoms of HIV
-associated peripheral neuropathy.
Nabilone
is an artificial cannabinoid which is significantly more potent than delta-9-tetrahydrocannabinol (THC). Nabilone produces less relief of chronic neuropathic pain and had slightly more side effects than dihydrocodeine
.
The predominant adverse effects are CNS depression and cardiovascular effects which are mild and well tolerated but, psychoactive side effects limit their use. A complicating issue may be a narrow therapeutic window; lower doses decrease pain but higher doses have the opposite effect.
Sativex
, a fixed dose combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol, is sold as an oromucosal spray. The product is approved in Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis, and for cancer related pain
.
Long-term studies are needed to assess the probability of weight gain, unwanted psychological influences and other adverse effects.
type A (BTX-A) is best know by its trade name, Botox. Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone. Benefits persist for at least 14 weeks from the time of administration.
The utility of BTX-A in other painful conditions remains to be established.
seems to play a major role in neuropathic pain and in the development of opioid tolerance. Dextromethorphan
is an NMDA antagonist at high doses. Experiments in both animals and humans have established that NMDA antagonists
such as ketamine
and dextromethorphan
can alleviate neuropathic pain and reverse opioid tolerance. Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half life (dextrometorphan), weak activity (memantine)or unacceptable side effects (ketamine).
Lesioning operations on the sympathetic branch of the autonomic nervous system
are sometimes carried out.
There are methods of treating sympathetically maintained pain in peripheral tissues. This is done topically to a patient having sympathetically maintained pain at a peripheral site where the pain originates. Wherein the sympathetically maintained pain can be diagnosed by local anesthetic blockade of the appropriate sympathetic ganglion or adrenergic receptor
blockade via intravenous administration of phentolamine
, and rekindled by intradermal injection of norepinephrine
.
A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy. While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (including stabbing and burning pain) as well as neuropathic deficits (paresthesia
), the metanalysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone". There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.
Benfotiamine
is a lipid-soluble form of thiamine that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.
, yoga
, massage
, meditation
, cognitive therapy
, and prescribed exercise. Some pain management specialists will try acupuncture
, with variable results.
Transcutaneous electrical nerve stimulation
(TENS) may be worth considering in chronic neurogenic pain. TENS, with certain electrical waveforms, appears to have an acupuncture-like function.
Infrared photo therapy has been clinically proven to treat neuropathic pain and symptoms. However, recent work has cast doubt on the value of this approach.
Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions for which they might be beneficial.
Infusion pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide are infused. Complications such as, serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted with intrathecal insufion.
There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time. These results must be viewed skeptically since placebo effects cannot be evaluated.
have been reported with targets in the periventricular/periaqueductal grey matter
(79%), or the periventricular/periaqueductal grey matter plus thalamus
and/or internal capsule (87%). There is a significant complication rate which increase over time.
Somatosensory system
The somatosensory system is a diverse sensory system composed of the receptors and processing centres to produce the sensory modalities such as touch, temperature, proprioception , and nociception . The sensory receptors cover the skin and epithelia, skeletal muscles, bones and joints, internal...
. It may be associated with abnormal sensations called dysesthesia
Dysesthesia
Dysesthesia comes from the Greek word "dys", meaning "not-normal" and "aesthesis", which means "sensation" . It is defined as an unpleasant, abnormal sense of touch, and it may be, or not be, considered as a kind of pain...
, which occur spontaneously and allodynia
Allodynia
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...
that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic (paroxysmal) components. The latter are likened to an electric shock. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching. Nociceptive pain, by contrast, is more commonly described as aching.
Up to 7% to 8% of the European population is affected and in 5% of persons it may be severe.
Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.
Cause
Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. FibromyalgiaFibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
, a disorder of chronic widespread pain, is potentially a central pain disorder and is responsive to medications that are effective for neuropathic pain. Aside from diabetes (see diabetic neuropathy
Diabetic neuropathy
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
) and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster
Herpes zoster
Herpes zoster , commonly known as shingles and also known as zona, is a viral disease characterized by a painful skin rash with blisters in a limited area on one side of the body, often in a stripe...
infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, genetic (gene HCN2
HCN2
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 is a protein that in humans is encoded by the HCN2 gene.-Interactions:HCN2 has been shown to interact with HCN1 and HCN4.-Function:...
), and immune mediated disorders or physical trauma to a nerve trunk. Neuropathic pain is common in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, radiation injury or surgery.
Mechanisms
The starting point for neuropathic pain is a lesion or dysfunction within the somatosensory systemSomatosensory system
The somatosensory system is a diverse sensory system composed of the receptors and processing centres to produce the sensory modalities such as touch, temperature, proprioception , and nociception . The sensory receptors cover the skin and epithelia, skeletal muscles, bones and joints, internal...
. Current knowledge regarding the mechanisms of neuropathic pain is incomplete and is biased by a focus on animal models of peripheral nerve injury.
Peripheral
Under normal circumstances, pain sensations are carried by unmyelinated and thinly myelinated nerve fibers, designated C-fibers and A-delta fibers, respectively. After a peripheral nerve lesionLesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
, aberrant regeneration may occur. Neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and heightened sensitivity to chemical, thermal and mechanical stimuli. This phenomenon is called "peripheral sensitization
Sensitization
Sensitization is an example of non-associative learning in which the progressive amplification of a response follows repeated administrations of a stimulus. An everyday example of this mechanism is the repeated tonic stimulation of peripheral nerves that will occur if a person rubs his arm...
".
Central
The (spinal cord) dorsal horn neurons give rise to the spinothalamic tractSpinothalamic tract
The spinothalamic tract is a sensory pathway originating in the spinal cord. It transmits information to the thalamus about pain, temperature, itch and crude touch...
(STT), which constitutes the major ascending nociceptive pathway. As a consequence of ongoing spontaneous activity arising in the periphery, STT neurons develop increased background activity, enlarged receptive fields and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization is an important mechanism of persistent neuropathic pain.
Other mechanisms, however, may take place at the central level after peripheral nerve damage. The loss of afferent signals induces functional changes in dorsal horn neurons. A decrease in the large fiber input decreases activity of interneurons inhibiting nociceptive neurons i.e. loss of afferent inhibition. Hypoactivity of the descending antinociceptive systems or loss of descending inhibition may be another factor. With loss of neuronal input (deafferentation) the STT neurons begin to fire spontaneously, a phenomenon designated "deafferentation hypersensitivity.”
Neuroglia ("glial cells") may play a role in central sensitization. Peripheral nerve injury induces glia to release proinflammatory cytokines and glutamate which, in turn influence neurons.
Mechanisms at light-microscopic and submicroscopic levels
The phenomenon described above are dependent on changes at light-microscopic and submicroscopic levels. Altered expression of ion channels, changes in neurotransmitters and their receptors as well as altered gene expression in response to neural input are at play.Treatments
Neuropathic pain can be very difficult to treat with only some 40-60% of patients achieving partial relief.In addition to the work of Dworkin, O'Connor and Backonja et al., cited above, there have been several recent attempts to derive guidelines for pharmacological therapy. These have combined evidence from randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
s with expert opinion.
Determining the best treatment for individual patients remains challenging. Attempts to translate scientific studies into best practices are limited by factors such as differences in reference populations and a lack of head-to-head studies. Furthermore, multi-drug combinations and the needs of special populations, such as children, require more study.
It is common practice in medicine to designate classes of medication according to their most common or familiar use e.g. as "antidepressants" and "anti-epileptic drugs" (AED's). These drugs have alternate uses to treat pain because the human nervous system employs common mechanisms for different functions, for example ion channels for impulse generation and neurotransmitters for cell-to-cell signaling.
Favored treatments are certain antidepressants e.g. tricyclics
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
and selective serotonin-norepinephrine reuptake inhibitor
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
s (SNRI's), anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
s, especially 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...
(Lyrica) and 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...
(Neurontin), and topical lidocaine
Lidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
. Opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesics and 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...
are recognized as useful agents but are not recommended as first line treatments. Many of the pharmacologic treatments for chronic neuropathic pain decrease the sensitivity of nociceptive
Nociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
receptors, or desensitize C fibers such that they transmit fewer signals.
Some drugs may exert their influence through descending pain modulating pathways. These descending pain modulating pathways originate in the brainstem.
Antidepressants
The functioning of antidepressants is different in neuropathic pain from that observed in depression. Activation of descending norepinephrinergic and serotonergic pathways to the spinal cord limit pain signals ascending to the brain. Antidepressants will relieve neuropathic pain in non-depressed persons.In animal models of neuropathic pain it has been found that compounds which only block serotonin reuptake do not improve neuropathic pain.
Similarly, compounds that only block norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
reuptake also do not improve neuropathic pain. Dual serotonin-norepinephrine reuptake inhibitor
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
s such as duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
, venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
, and milnacipran
Milnacipran
Milnacipran is a serotonin–norepinephrine reuptake inhibitor used in the clinical treatment of fibromyalgia...
, as well as tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s such as nortriptyline
Nortriptyline
Nortriptyline is a second-generation tricyclic antidepressant marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis...
and desipramine
Desipramine
Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
improve neuropathic pain and are considered first-line medications for this condition.
Bupropion
Bupropion
Bupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
has been found to have efficacy in the treatment of neuropathic pain.
Tricyclic antidepressants may also have effects on sodium channels.
Anticonvulsants
PregabalinPregabalin
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...
(Lyrica) and 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...
(Neurontin) work by blocking specific calcium channels on neurons and are preferred first-line medications for diabetic neuropathy
Diabetic neuropathy
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
. The anticonvulsants carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
(Tegretol) and oxcarbazepine
Oxcarbazepine
Oxcarbazepine is a anticholinergic anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy. It is also used to treat anxiety and mood disorders, and benign motor tics...
(Trileptal) are especially effective in trigeminal neuralgia
Trigeminal neuralgia
Trigeminal neuralgia , tic douloureux is a neuropathic disorder characterized by episodes of intense pain in the face, originating from the trigeminal nerve. It has been described as among the most painful conditions known...
. The actions of these two drugs are medicated principally through sodium channels.
Lamotrigine may have a special role in treating two conditions for which there are few alternatives, namely post stroke pain and HIV/AIDS-related neuropathy in patients already receiving antiretroviral therapy.
Opioids
Opioids, also known as narcotics, are increasingly recognized as important treatment options for chronic pain. They are not considered first line treatments in neuropathic pain but remain the most consistently effective class of drugs for this condition. Opioids must be used only in appropriate individuals and under close medical supervision.Several opioids, particularly methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
, and ketobemidone
Ketobemidone
Ketobemidone is a powerful opioid analgesic. Its effectiveness against pain is in the same range as morphine, and it also has some NMDA-antagonist properties imparted by it's metabolite norketobemidone. This makes it useful for some types of pain that don't respond well to other opioids...
possess NMDA antagonism in addition to their µ-opioid agonist properties. Methadone does so because it is a racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture; only the l-isomer is a potent µ-opioid agonist. The d-isomer does not have opioid agonist action and acts as an NMDA antagonist; d-methadone is analgesic in experimental models of chronic pain. Clinical studies are in progress to test the efficacy of d-methadone in neuropathic pain syndromes.
There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of its NMDA antagonism. It is reasonable to base the choice of opioid on other factors.
Topical agents
In some forms of neuropathy, especially post-herpetic neuralgia, the topical application of local anesthetics such as lidocaineLidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
can provide relief. A transdermal patch containing lidocaine is available commercially in some countries.
Repeated topical applications of capsaicin, are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers. Nevertheless, benefits appear to be modest with standard (low) strength preparations.
Cannabinoids
Marijuana's active ingredients are called cannabinoidsCannabinoids
Cannabinoids are a class of chemical compounds that include the phytocannabinoids , and chemical compounds that mimic the actions of phytocannabinoids or have a similar structure...
. Unfortunately, strongly held beliefs make discussion of the appropriate use of these substances, in a medical context, difficult. Similar considerations apply to opioids.
A recent study showed smoked marijuana
Medical cannabis
Medical cannabis refers to the use of parts of the herb cannabis as a physician-recommended form of medicine or herbal therapy, or to synthetic forms of specific cannabinoids such as THC as a physician-recommended form of medicine...
is beneficial in treating symptoms of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-associated peripheral neuropathy.
Nabilone
Nabilone
Nabilone is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It is a synthetic cannabinoid, which mimics the main ingredient of cannabis...
is an artificial cannabinoid which is significantly more potent than delta-9-tetrahydrocannabinol (THC). Nabilone produces less relief of chronic neuropathic pain and had slightly more side effects than dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...
.
The predominant adverse effects are CNS depression and cardiovascular effects which are mild and well tolerated but, psychoactive side effects limit their use. A complicating issue may be a narrow therapeutic window; lower doses decrease pain but higher doses have the opposite effect.
Sativex
Sativex
Nabiximols is a cannabinoid oromucosal mouth spray developed by the UK company GW Pharmaceuticals for multiple sclerosis patients, who can use it to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms. Nabiximols is also being developed in Phase III trials as a...
, a fixed dose combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol, is sold as an oromucosal spray. The product is approved in Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis, and for cancer related pain
Cancer pain
Pain is a symptom frequently associated with cancer. Cancer can cause pain by irritating or damaging nerves, by stimulating nociceptors , or by releasing chemicals that make nociceptors respond to normally non-painful stimuli. Cancer pain may be caused by the tumor itself or by medical...
.
Long-term studies are needed to assess the probability of weight gain, unwanted psychological influences and other adverse effects.
Botulinum toxin type A
Botulinum toxinBotulinum toxin
Botulinum toxin is a protein produced by the bacterium Clostridium botulinum, and is considered the most powerful neurotoxin ever discovered. Botulinum toxin causes Botulism poisoning, a serious and life-threatening illness in humans and animals...
type A (BTX-A) is best know by its trade name, Botox. Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone. Benefits persist for at least 14 weeks from the time of administration.
The utility of BTX-A in other painful conditions remains to be established.
NMDA antagonism
The N-methyl-D-aspartate (NMDA) receptorNMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
seems to play a major role in neuropathic pain and in the development of opioid tolerance. Dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
is an NMDA antagonist at high doses. Experiments in both animals and humans have established that NMDA antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
such as ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
and dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
can alleviate neuropathic pain and reverse opioid tolerance. Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half life (dextrometorphan), weak activity (memantine)or unacceptable side effects (ketamine).
Reducing sympathetic nervous stimulation
In some neuropathic pain syndromes, "crosstalk" occurs between descending sympathetic nerves and ascending sensory nerves. Increases in sympathetic nervous system activity result in an increase of pain; this is known as sympathetically-mediated pain.Lesioning operations on the sympathetic branch of the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
are sometimes carried out.
There are methods of treating sympathetically maintained pain in peripheral tissues. This is done topically to a patient having sympathetically maintained pain at a peripheral site where the pain originates. Wherein the sympathetically maintained pain can be diagnosed by local anesthetic blockade of the appropriate sympathetic ganglion or adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
blockade via intravenous administration of phentolamine
Phentolamine
Phentolamine is a reversible nonselective alpha-adrenergic antagonist. -Mechanism:Its primary action is vasodilation due to α1 blockade....
, and rekindled by intradermal injection of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
.
Dietary supplements
There are two dietary supplements that have clinical evidence showing them to be effective treatments of diabetic neuropathy; alpha lipoic acid and benfotiamine.A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy. While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (including stabbing and burning pain) as well as neuropathic deficits (paresthesia
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
), the metanalysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone". There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.
Benfotiamine
Benfotiamine
Benfotiamine is a synthetic S-acyl derivative of thiamine . After absorption, benfotiamine can be dephosphorylated by cells bearing an ecto-alkaline phosphatase to the lipid-soluble S-benzoylthiamine...
is a lipid-soluble form of thiamine that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.
Other modalities
In addition to pharmacological treatment several other modalities are commonly recommended. While lacking adequate double blind trials, these have shown to reduce pain and improve patient quality of life for chronic neuropathic pain: chiropracticChiropractic
Chiropractic is a health care profession concerned with the diagnosis, treatment and prevention of disorders of the neuromusculoskeletal system and the effects of these disorders on general health. It is generally categorized as complementary and alternative medicine...
, yoga
Yoga
Yoga is a physical, mental, and spiritual discipline, originating in ancient India. The goal of yoga, or of the person practicing yoga, is the attainment of a state of perfect spiritual insight and tranquility while meditating on Supersoul...
, massage
Massage
Massage is the manipulation of superficial and deeper layers of muscle and connective tissue to enhance function, aid in the healing process, and promote relaxation and well-being. The word comes from the French massage "friction of kneading", or from Arabic massa meaning "to touch, feel or handle"...
, meditation
Meditation
Meditation is any form of a family of practices in which practitioners train their minds or self-induce a mode of consciousness to realize some benefit....
, cognitive therapy
Cognitive therapy
Cognitive behavioral therapy is a psychotherapeutic approach: a talking therapy. CBT aims to solve problems concerning dysfunctional emotions, behaviors and cognitions through a goal-oriented, systematic procedure in the present...
, and prescribed exercise. Some pain management specialists will try acupuncture
Acupuncture
Acupuncture is a type of alternative medicine that treats patients by insertion and manipulation of solid, generally thin needles in the body....
, with variable results.
Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation is the use of electric current produced by a device to stimulate the nerves for therapeutic purposes...
(TENS) may be worth considering in chronic neurogenic pain. TENS, with certain electrical waveforms, appears to have an acupuncture-like function.
Infrared photo therapy has been clinically proven to treat neuropathic pain and symptoms. However, recent work has cast doubt on the value of this approach.
Neuromodulators
Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions for which they might be beneficial.
Spinal cord stimulators and implanted spinal pumps
Spinal cord stimulators, use electrodes placed adjacent to, but outside the spinal cord. The overall complication rate is one-third, most commonly due to lead migration or breakage but advancements in the past decade have driven complication rates much lower. Lack of pain relief occasionaly prompts device removal.Infusion pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide are infused. Complications such as, serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted with intrathecal insufion.
There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time. These results must be viewed skeptically since placebo effects cannot be evaluated.
Motor cortex stimulation
Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (dura) has been used to treat pain. The level of stimulation is below that for motor stimulation. As compared with spinal stimulation, which requires a noticeable tingling (paresthesia) for benefit, the only palpable effect is pain relief.Deep brain stimulation
The best long-term results with deep brain stimulationDeep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...
have been reported with targets in the periventricular/periaqueductal grey matter
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...
(79%), or the periventricular/periaqueductal grey matter plus thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
and/or internal capsule (87%). There is a significant complication rate which increase over time.