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Neuropathy
Neuropathy is usually short for peripheral neuropathy, meaning a disease of the peripheral nervous system. Strictly speaking, however,
neuropathy is any disease that affects any part of the nervous system.
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Types
The four major forms of nerve damage are polyneuropathy, autonomic neuropathy, mononeuropathy, and mononeuritis multiplex. The most common form is
peripheral polyneuropathy, which mainly affects the feet and legs.
Often the form of neuropathy is further broken down as to cause (see below), or other type, such as small fiber peripheral neuropathy, which is
idiopathic.
There are other less common forms of neuropathy, for example Enteric Neuropathy
Peripheral neuropathy is not a disease in itself, but a symptom or a complication of other underlying conditions. Peripheral nerves, either singly
or in groups, are damaged through lack of circulation, chemical imbalance, trauma, or other factors.
- Ruth Werner, LMP, NCTMB A Massage Theraist's Guide to Pathology; Third Edition Copyright 2005
Causes
Aside from
diabetes (see Diabetic neuropathy), the common causes of neuropathy are
herpes zoster infection,
HIV-
AIDS, toxins, alcoholism, chronic
trauma (such as repetitive motion disorders) or acute trauma (including surgery), various neurotoxins and autoimmune conditions such as celiac disease,
which can account for approximately 16% of small fiber neuropathy cases. Neuropathic
pain is common in
cancer as a direct result of the cancer on
peripheral nerves (e.g., compression by a tumor), as a side effect of many chemotherapy drugs, and as a result of electrical injury. In many cases
the neuropathy is "idiopathic," meaning no cause is found.
Symptoms
Neuropathy often results in numbness, abnormal sensations called dysesthesias and allodynias that occur either spontaneously or in reaction to external
stimuli, and a characteristic form of
pain, called neuropathic
pain or neuralgia, that is qualitatively different from the ordinary nociceptive
pain
one might experience from stubbing a toe or hitting a finger with a hammer.
Neuropathic
pain is usually perceived as a steady burning and/or "pins and needles" and/or "electric shock" sensations. The difference is due to the
fact that "ordinary" pain stimulates only pain nerves, while a neuropathy often results in the firing of both pain and non-pain (touch, warm, cool)
sensory nerves in the same area, producing signals that the spinal cord and brain do not normally expect to receive.
Treatment of Neuropathic Pain
Neuropathic
pain can be very difficult to treat. Sometimes strong opioid analgesics may provide only partial relief. Opioid analgesics are to be
considered only as a tertiary treatment. Several classes of medications not normally thought of as analgesics are often effective, alone or in
combination with opioids and other treatments. These include tricyclic antidepressants such as amitriptyline (Elavil®), anticonvulsants such as
gabapentin (Neurontin®) and pregabalin (Lyrica®).
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. Compounds such as duloxetine, venlafaxine, and milnacipran
that block both serotonin reuptake and norepinephrine reuptake do improve neuropathic pain. Antidepressants usually reduce neuropathic pain more
quickly and with smaller doses than they relieve
depression. Antidepressants therefore seem to work differently on neuropathic pain than on
depression, perhaps by activating descending norepinephrinergic and serotonergic pathways in the spinal cord that block
pain signals from ascending
to the brain.
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. The newer anticonvulsants gabapentin and pregabalin appear to work by blocking calcium channels in damaged peripheral
neurons. Tricyclic antidepressants may also work on sodium channels in peripheral nerves. The anticonvulsants carbamazepine (Tegretol®) and
oxcarbazepine (Trileptal®), especially effective on trigeminal neuralgia, are thought to work principally on sodium channels.
In general, the antidepressants seem to be most effective on continuous burning
pain, while the anticonvulsants seem to work best on sudden,
lancinating, "shock-like" pains that appear to involve large numbers of peripheral nerves improperly firing together.
In some forms of neuropathy, especially post-herpes neuralgia, the topical application of local anesthetics such as lidocaine can provide relief. A
transdermal patch containing 5% lidocaine is available. Ketamine in a transdermal gel is also frequently effective when the neuropathy is localized.
Neurontin 100mg/g PLO gel is also effective for treating peripheral neuropathy, including Carpal Tunnel Syndrome. Capsaicin cream can be beneficial
in several neurogenic
pain disorders, which causes release of the pain neurotransmitter Substance P, and eventually reduces the availability of
Substance P.
Transcutaneous electrical nerve stimulation (TENS) is worth a trial in chronic neurogenic pain. Some pain management specialists will try acupuncture,
with variable results. TENS, with certain electrical waveforms, appears to have an acupuncture-like function.
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. Reducing the sympathetic nerve activity in the
painful region with local nerve blocks or systemic medications such as the alpha-blocker clonidine may provide relief. Other drugs, known for their
ability to desensitize cardiac tissue, include beta-blockers such as propanolol and calcium channel blockers such as verapamil.
The NMDA receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance, and many 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 usually associated with unacceptable side effects.
Several opioids, particularly methadone, have NMDA antagonist activity in addition to their μ-opioid agonist properties that seems to make them effective
against neuropathic pain, although this is still the subject of intensive research and clinical study. Methadone has this property because it is a racemic
mixture; one stereo-isomer is a μ-opioid agonist; the other is a NMDA antagonist.
A recent study showed smoking marijuana is beneficial in treating
HIV-associated periphial neuropathy.
In addition to pharmacological treatment there are several other modalities that help some cases. While lacking double blind trials, these have shown
to reduce
pain and improve patient quality of life particularly for chronic neuropathic pain: Interferential Stimulation; Acupuncture; Meditation;
Cognitive Therapy; and prescribed exercise.
In more recent years, infrared photo therapy has been used to treat neuropathic symptoms. Photo therapy devices emit near infrared light typically at
a wavelength of 890nm. This wavelength is believed to stimulate the release of nitric oxide, an endothelium-derived relaxing factor into the
bloodstream, thus vasodilating the capilaries and venuoles in the microcirculatory system. This increase in circulation has been shown effective in
various clinical studies, to decrease
pain and improve sensation in diabetic and non-diabetic patients. Note that the U.S. FDA has
not approved any infrared photo therapy devices to treat neuropathy.
Alternative Medicine Treatments
There are 2 dietary supplements that have clinical evidence showing them to be effective treatments of diabetic neuropathy; alpha lipoic acid and
benfotiamine. In several studies using a variety of dosages and routes of administration, alpha lipoic acid was found to reduce the various symptoms
of peripheral diabetic neuropathy. A recent review of the published data determined “ALA should be considered as a treatment option for patients with
peripheral diabetic neuropathy.” Also a recent study using orally administered alpha lipoic acid found that 600 mg once a day caused a marked reduction
in the symptoms of diabetic neuropathy including stabbing
pain, burning pain, paresthesia, and asleep numbness of the feet. 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. 400 mg a day was the most commonly studied dose.
(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Neuropathy)
Pregabalin: An Antiepileptic Agent Useful for Neuropathic Pain
Authors: Blommel ML, Blommel AL.
West Virginia Center for Drug and Health Information, Morgantown, WV 26506-9520, USA.
PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of pregabalin are reviewed. SUMMARY:
Pregabalin is the first drug to receive approved labeling from the Food and Drug Administration (FDA) for the treatment of painful diabetic neuropathy
and postherpetic neuralgia and is the first antiepileptic agent to receive FDA-approved labeling since 1999. Pregabalin is the pharmacologically active
S-enantiomer of racemic 3-isobutyl gamma-aminobutyric acid. Pregabalin has demonstrated efficacy in the management of neuropathic pain associated with
diabetic peripheral neuropathy, postherpetic neuralgia, and as adjunctive therapy for adult patients with partial onset seizures. Its exact mechanism of
action is unknown. Pregabalin is rapidly absorbed and exhibits linear pharmacokinetics after oral administration. The lack of hepatic metabolism and
lack of interaction with cytochrome P-450 isoenzymes explain the absence of drug interactions with pregabalin. Several clinical studies have demonstrated
pregabalin's efficacy for each of the FDA-approved indications, with dizziness and somnolence reported as the most common adverse events. Pregabalin
has been designated as a Schedule V controlled substance because of its potential for abuse and dependence. The starting dosage for patients with
neuropathic pain associated with diabetic peripheral neuropathy is 50 mg three times daily and may be increased to 300 mg daily within one week based
on efficacy and tolerability. The starting dosage for patients with partial-onset seizures is 75 mg twice daily or 50 mg three times daily and may be
increased to 600 mg daily based on individual response and tolerability. CONCLUSION: Pregabalin may be beneficial for the treatment of neuropathic pain
or partial-onset seizures in patients who do not respond to conventional treatments or cannot tolerate their adverse effects.
Journal: Am J Health Syst Pharm. 2007 Jul 15;64(14):1475-82.
Adapted from PubMed; click here to access full journal article.
Iatrogenic Axillary Neuropathy After Intramuscular Injection of the Deltoid Muscle
Authors: Davidson LT, Carter GT, Kilmer DD, Han JJ.br>
Department of Physical Medicine and Rehabilitation, University of California-Davis Medical Center, 4860 Y Street, Sacramento, CA 95817, USA.
A previously healthy 26-yr-old male presented for an electrodiagnostic evaluation with complaints of significant right deltoid muscle atrophy and
shoulder abduction weakness after receiving an intramuscular (IM) deltoid injection of an antiemetic 4 wk earlier. Electrodiagnostic evaluation
confirmed an acute axillary neuropathy. We hypothesize that direct mechanical trauma to the anterior branch of the axillary nerve resulted in axillary
mononeuropathy with axonal loss, although chemically induced nerve injury cannot be excluded. Injections in and about the shoulder complex are performed
routinely for the purposes of vaccination, IM medication administration, deltoid trigger-point injections, and intra-articular and bursal steroid
injections. Although such injections are considered routine office procedures, there is increased risk of neurovascular injury if they are performed
incorrectly. The purpose of this brief report is to make practitioners aware of the potential for axillary neuropathy with such procedures, to review
the salient anatomy, and to propose a potential guideline for clinical practice to minimize iatrogenic axillary neuropathy.
Journal: Am J Phys Med Rehabil. 2007 Jun;86(6):507-11.
Adapted from PubMed; click here to access full journal article.
Auditory Neuropathy: An Update
Authors: Gibson WP, Sanli H.
Sydney Cochlear Implant Centre, University of Sydney, Sydney, Australia. gibsonwp@unwired.com.au
OBJECTIVES: To describe the round window electrocochleography (RWECochG) and electric auditory brainstem responses (EABR) in ears affected by auditory
neuropathy (AN), and to determine if these electrophysiological tests can predict the outcome following cochlear implant surgery. METHODS: A longitudinal
study of all pediatric cochlear implant patients between 1994 and 2005 was undertaken. Speech perception outcomes after cochlear implantation and
electrophysiological data were collected prospectively and analyzed. Some otoacoustic emissions (OAE) data were collected retrospectively during the
neonatal period. All subjects were tested using round window electrocochleography (RWEcochG), auditory brainstem responses (ABR), and implant-evoked
electric auditory brainstem responses (EABR). The auditory neuropathy (AN) group consisted of 39 children (78 ears) which had present OAE and absent or
grossly abnormal ABR (a broad N1 component only). RESULTS: All 78 ears from the 39 AN children showed large cochlear microphonics (CM) and an abnormal
positive potential (APP) using RW ECochG. A further 21 children showed large CM and APP but had not been tested for OAE. In total, 60 children were
discovered to have APP among 435 pediatric patients who received a cochlear implant. Electrically evoked ABR (EABR) from the implanted ear were normal
in 45 and abnormal in 15. 46 age matched patients without large CM and APP were used as a control group. Two year postimplant scores (Melbourne categories)
were: 6.27 (APP and normal EABR), 2.25 (APP and abnormal EABR) and 5.37 (control group). Mann-Whitney U Test for nonparametric data was used to test for
significant difference at significance level p < 0.005 (two tailed). The APP ears which provided normal EABR had significantly better outcomes after
cochlear implantation than APP ears which had abnormal EABR. Furthermore, the APP ears which provided normal EABR performed significantly better after
cochlear implant surgery than the control group of patients with no OAE, appropriate ABR results and normal EABR. CONCLUSIONS: Ears affected by AN
provide large CM and APP on RW ECochG. The presence of normal EABR may indicate a significantly better outcome after cochlear implant surgery than for
those APP ears which had abnormal or absent EABR. Based on these findings it is suggested that the presence of APP and/ or OAE in 75% of the ears which
have absent or abnormal ABR may not indicate a pathological condition affecting the auditory nerve or synapse but only survival of outer hair cells
despite extensive loss of inner hair cells.
Journal: Ear Hear. 2007 Apr;28(2 Suppl):102S-106S.
Adapted from PubMed; click here to access full journal article.
Microvascular Tissue Plasminogen Activator is Reduced in Diabetic Neuropathy
Authors: Hafer-Macko CE, Ivey FM, Sorkin JD, Macko RF.br>
Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA. cmacko@grecc.umaryland.edu
BACKGROUND: Abnormalities of endogenous fibrinolysis are linked to diabetic macrovascular disease; whether key vascular endothelial regulatory proteins,
such as tissue plasminogen activator (tPA), are altered in diabetic neuropathy microvasculature is unknown. This neuropathologic case: control study
investigates the hypothesis that tPA expression is regionally deficient in microvessels in human diabetic neuropathy. METHODS: tPA and von Willebrand
factor (vWF), a vascular endothelial cell marker, are detected on vascular endothelium by immunoperoxidase methods with specific antibodies on formalin
fixed paraffin embedded sural nerve biopsies from six diabetic and six axonal neuropathy control nerves without vasculopathy. The proportion of
microvessels in each nerve region expressing tPA is determined by the ratio of tPA positive vessels/total vWF positive vessels on serial sections.
RESULTS: tPA expression is lower in diabetic neuropathy cases compared to controls in all regions, including epineurial (62.4 +/- 8.6% vs 91.0 +/- 1.6%,
p < 0.02) and endoneurial microvessels (51.7 +/- 7.1% vs 91.5 +/- 2.9%, p < 0.001). CONCLUSIONS: These results demonstrate a four- to sixfold
increase in the number of peripheral nerve microvessels lacking immunodetectable tissue plasminogen activator in the epineurial and endoneurial vessels
in
diabetes, suggesting that impaired endogenous fibrinolysis might contribute to microvascular ischemia in human diabetic neuropathy.
Journal: Neurology. 2007 Jul 17;69(3):268-74.
Adapted from PubMed; click here to access full journal article.
Fentanyl Buccal Tablet for the Relief of Breakthrough Pain in Opioid-Tolerant Adult Patients with Chronic Neuropathic Pain: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
Authors: Simpson DM, Messina J, Xie F, Hale M.
Mount Sinai School of Medicine, New York, New York 10029, USA. david.simpson@mssm.edu
BACKGROUND: Patients with chronic noncancer pain, including neuropathic pain, may have transitory exacerbations of pain (median duration, 60 minutes),
termed breakthrough pain (BTP), that may reach peak intensity within minutes. Typical short-acting oral opioids may not provide sufficiently rapid
relief (30- to 60-minute onset of analgesia). The fentanyl buccal tablet (FBT) provides a rapid onset of analgesia (10-15 minutes) by enhancing fentanyl
absorption across the buccal mucosa. OBJECTIVE: This study evaluated the efficacy and tolerability of FBT in opioid-tolerant patients with BTP associated
with chronic noncancer neuropathic pain. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in men and women aged 18 to
80 years who were opioid tolerant; had a >/= 3-month history of chronic persistent neuropathic pain associated with diabetic peripheral neuropathy,
postherpetic neuralgia, traumatic injury, or complex regional pain syndrome; and reported having episodes of BTP. After an open-label titration period
to identify an effective FBT dose (the dose at which the patient reported receiving adequate pain relief within 30 minutes after administration of a
single tablet of that dose during at least 2 of 3 BTP episodes), patients were randomly assigned to treat 9 consecutive episodes of BTP over the next 21
days with 1 of 3 double-blind dose sequences of FBT and placebo tablets. Pain intensity (PI) (rated on an 11-point pain scale, from 0 = no pain to 10 =
worst pain) and other outcomes were assessed before dosing and for 2 hours after dosing. The primary efficacy measure was the sum of PI differences
(PIDs) for the first 60 minutes (SPID(60)). Secondary efficacy measures included the proportion of BTP episodes with >/= 33% and >/= 50%
improvement in PI from baseline; PID at other time points (5, 10, 15, 30, 45, 60, 90, and 120 minutes after dosing); pain relief (PR) at the same time
points (rated on a 5-point Likert scale from 0 = none to 4 = complete); proportion of BTP episodes with meaningful PR; time to meaningful PR; and
proportion of BTP episodes in which supplemental medication was required after administration of study drug. Adverse events (AEs) spontaneously reported
by the patient or elicited by the investigator were recorded throughout the study. RESULTS: Of 102 patients in the open-label titration period, 80
identified an effective dose of FBT and 79 entered the double-blind phase. Of these 79 patients, 77 (97%) completed the study and 75 (95%) were
evaluable for efficacy. Of the 79 patients who entered the double-blind phase, 63% were women and 92% were white; their mean (SD) age was 48.3 (10.42)
years, and their mean weight was 96.8 (33.42) kg. Baseline demographic and pain characteristics were similar between the overall population and the
double-blind population. SPID(60) was significantly greater for BTP episodes treated with FBT compared with those in which placebo was administered
(mean [SE], 9.63 [0.75] vs 5.73 [0.72], respectively; P < 0.001). Significant differences between FBT and placebo were seen beginning at 10 minutes
for PID (mean, 0.740 [0.149] vs 0.427 [0.081]; P < 0.047) and PR (mean, 0.561 [0.087] vs 0.324 [0.056]; P < 0.001). A >/= 33% improvement
in PI from baseline was seen in a greater proportion of BTP episodes treated with FBT compared with placebo from 10 minutes (9% vs 3%; P = 0.008)
through 2 hours (66% vs 37%; P < 0.001). Patients were almost 4 times less likely to require supplemental opioids when BTP episodes were treated
with FBT compared with placebo (odds ratio = 0.28; 95% Cl, 0.18-0.42). AEs were reported by 64 (63%) of 102 patients. The most commonly reported AEs
were those typical of opioids (nausea [13%], dizziness [13%], somnolence [10%], and vomiting [5%]) and occurred more often during the dose-titration
phase (55/102 [54%]) than during the double-blind phase (22/79 [28%]). CONCLUSION: In these opioid-tolerant patients with chronic neuropathic pain who
identified an effective FBT dose, FBT had a rapid onset of action and was effective and well tolerated in the treatment of BTP.
Journal: Clin Ther. 2007 Apr;29(4):588-601.
Adapted from PubMed; click here to access full journal article.
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