Peripheral neuropathy
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7335.466 (Published 23 February 2002) Cite this as: BMJ 2002;324:466All rapid responses
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I can confirm it.
MS Contin 30 mg 2x/day
Competing interests: No competing interests
“NMDA receptor antagonists in the management of
peripheral neuropathic pain”
Peripheral nerve injury due to various etiologies may lead to a state
of chronic and severe intractable pain in a proportion of patients. This
type of pain is usually referred to as neuropathic pain. The mechanisms
causing neuropathic pain caused by peripheral nerve injury have been the
subject of extensive clinical and fundamental investigation over the last
few years. Several types of peripheral mechanisms have been described.
Despite its varied etiologies, neuropathic pain conditions share
certain clinical characteristics. It includes the clinical components of
allodynia, hyperalgesia, and hyperpathia.(1) Evidence from the basic
sciences suggests that hyperalgesia and allodynia following peripheral
nerve damage is not only due to an increased sensitivity of peripheral
nociceptors in the affected area, but also due to N-methyl-D-aspartate
(NMDA) receptor mediated changes in synaptic excitability in the dorsal
horn of the spinal cord.(2,3,4) Neuropathic pains can be poorly responsive
to opioid analgesia.(5) Patients will, therefore, not always be
completely relieved by a standard pharmacological management like the
stepwise approach of the World Health Organization analgesic ladder.(6)
Clinical evidence has proven that NMDA receptor antagonists reduce pain
caused by nerve injury.
Ketamine is, an N-methyl-D-aspartate receptor antagonist, widely used
as an anesthetic agent. Individual case reports and subsequent studies
have provided convincing evidence that treatment with subanesthetic doses
of ketamine relieves chronic pain due to peripheral neuropathy in some
patients. The administration of low dose ketamine (both oral and
parentral) has been shown to reduce postherpetic neuralgia,(7,8) stump or
phantom limb pain,(9) central pain,(10) orofacial pain,(11) and cancer
pain.(12)
Low-affinity NMDA channel blocker like dextromethorphan has been used
in the treatment of painful diabetic neuropathy.(13)
Although drugs like anticonvulsants, especially gabapentin and
carbamezapine, and tricyclic antidepressants, especially amitriptyline
are used to treat painful neuropathy, one must consider the use of NMDA
receptor antagonists whenever there is a triad of allodynia, hyperalgesia
and hyperpatheia in these patients.
References:
1. H. Merskey, Classification of chronic pain - descriptions of
chronic pain syndromes and definition for terms. Prepared by IASP
subcommittee on taxonomy. Pain 1986: (Suppl 3): 216-25.
2. A.H. Dickenson, Neurophysiology of opioid poorly responsive pain.
Cancer Surv 21 (1994), pp. 5-16.
3. A.H. Dickenson, V. Chapman and G.M. Green, The pharmacology of
excitatory and inhibitory amino acid mediated events in the transmission
and modulation of pain in the spinal cord. Geretzal Pharmacol 28 (1997),
pp. 633-638.
4. A. Dray and L. Urban, New pharmacological strategies for pain
relief. Ann Rev Pharmacol Toxicol 36 (1986), pp. 253-280.
5. A.H. Dickenson, Neurophysiology of opioid poorly responsive pain.
Cancer Surv 21 (1994), pp. 5-16.
6. World Health Organization (WHO). Cancer pain relief. Geneva: WHO,
1986:19.
7. P.K. Eide, A. Stubaugh, I. Oye and H. Breivik, Continuous
subcutaneous administration of the N-methyl-D-aspartic acid (NMDA)
receptor antagonist ketamine in the treatment of post-herpetic neuralgia.
Pain 61 (1995), pp. 221-228.
8. P. Klepstad and P.C. Borchgrevink, Four years treatment with
ketamine and a trial of dextromethorphan in a patient with severe post-
herpetic neuralgia. Acta Anaesthesiol Scand 41 (1997), pp. 422-426.
9. L. Nikolajsen, P.O. Hansen and T.S. Jensen, Oral ketamine therapy
in the treatment of post amputation stump pain. Acta Anaesthesiol Scand 41
(1997), pp. 427-429.
10. J. Persson, G. Axelsson, R.G. Hallin and L.L. Gustafsson,
Beneficial effects of ketamine in a chronic pain state with allodynia,
possibly due to central sensitization. Pain 60 (1995), pp. 217-222.
11. L.C. Mathisen, P. Skjelbred, L.A. Skoglund and I. Oye, Effect of
ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain.
Pain 61 (1995), pp. 215-220.
12. P.G. Fine, Low dose ketamine in the management of opioid
nonresponsive terminal cancer pain. J Pain Symptom Manage 17 (1999), pp.
296-300.
13. Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB, High-dose
oral dextromethorphan versus placebo in painful diabetic neuropathy and
postherpetic neuralgia. Neurology 1997 May: 48(5):1212-8.
Competing interests: No competing interests
We want to congratulate Dr Hughes for his excellent review of
peripheral neuropathy.(1) Recently we have come across a case of
diabetic Amyotrophy with some important clinical lessons which we want to
share with your readers.
70 yr old male was referred by the GP for increasing weakness and
pain in legs predominantly on right side and mainly affecting thighs for
the previous 2 months. In this period he had lost 4 Kg of weight and was
becoming depressed because of constant pain. On specific questioning he
admitted to vascular claudication limiting his walking distance to 10
meters. Mother had diabetes. He smoked 20 per day before stopping 40 years
ago after smoking for 15 years. Alcohol consumption was 3-4 Units/ Wk
On Examination : Eyes revealed background diabetic retinopathy and
some macular edema. Neurologically upper limbs were perfectly normal. Lowe
limbs examination revealed atrophy of both thighs and right leg. Power
was grade 4/5 in hip flexors but was 5/5 in other muscle groups. Rt knee
and both ankle jerks were absent. Plantars were bilaterally flexors. Pain
and touch was impaired on the outer aspect of Rt thigh and Rt leg. Touch
was also impaired in both feet. Vibration sense was impaired upto iliac
crest on both sides. Fasciculations were noted in right calf.
On Investigations: Blood Glucose was 15 mmol/L. Normocytic
normochromic anemia was detected. Urea and electrolytes were normal. Vit
B12 and Folate levels were normal. LFT including protein electrophoresis
was normal. CRP and plasma viscosity was normal. Carotid Doppler failed to
detect any significant stenosis.
The patient was treated with insulin and made a remarkable recovery.
Weight increased, walking improved and pain stopped.
Thus Diabetic Amyotrophy can be a rewarding presentation if
diagnosed early and treated apppropriately. It has been misdiagnosed as
rupture tendon and unnecessary surgical exploration has been done.(2)
1. Hughes R A C.Peripheral Neuropathy.BMJ 2002;324:466-469
2. Bhandankar R, Sudheer K, Rogers A.Diabetic amyotrophy masquerading
as quadriceps tendon rupture: a wordof caution. J R Coll Surg Edinb 2001
;46(6):375-6
Competing interests: No competing interests
Dear Sir,
This is in response to the review on Peripheral neuropathy by
Richard A C Hughes
BMJ 2002; 324: 466-469
In developing countries particularly in the Asian region one of the major causes of peripheral neuropathy is Hansen’s disease (Leprosy). And it is a classic example of an infectious neuritis.
Although many believe leprosy to have been eliminated by year 2000, it still continues to be a major public health problem and contributes significantly to the loss of quality of life.
Leprosy is often called a “skin disease” but, it is important to recognize, that there is a type of leprosy in which ONLY nerves are involved, with no skin manifestations; namely “Polyneuritic Leprosy” or “Pure neural Leprosy”.
The diagnosis of this condition is difficult and often requires a nerve biopsy to determine the histological type of leprosy. For this reason, “Neuritis in Leprosy” is a most important subject.
It is now a well accepted fact that the affinity of M. leprae for Schwann cells and the property of M. leprae to grow in cooler sites of the body have made certain segments of nerve trunks vulnerable. Trauma that supervenes the inflammation and swelling severely aggravates the nerve damage.1
Neuritis in leprosy can present acutely and is an emergency, presenting symptoms vary but classically characterized by severe pain along the affected nerve with or without loss of function, and manifest by sensory impairment, parasthesia, nerve enlargement, nerve tenderness, paresis (weakness) and /or amyotrophy and later form nerve abscesses. Worse still is when the nerve damage occurs silently without any of the warning symptoms2 and can only be recognized by regular monitoring of voluntary muscle and sensory testing. This type involvement is called “quiet nerve paralysis”2
Pain in acute leprous neuritis is the “cry of the dying nerves” and requires prompt and immediate attention. Early recognition and starting treatment with corticosteroids particularly Prednisolone controls the inflammation and prevent or limit disabilities.
Acute neuritis can occur at any phase of the illness but characteristically seen in a small proportion of patients at diagnosis, during the early course of treatment (6 months to 1 year), seen in association with Reactions in leprosy or may even be the sole manifestation of a reaction.3
The reactive phase in all forms of leprosy produces intraneural caseous necrosis in tuberculoid disease and microabscesses in lepromatous disease, causing much irreversible damage to nerves. The steroid treatment that is administered during the reactive phase helps greatly to stop further damage, although the damage already done to nerves is not always reversible. Preventive measures like detecting the disease before nerve trunks are infected and offering prompt and adequate antiLeprosy therapy as early as possible will helped to reduce the prevalence of deformities.
And in case the disease has progressed to administering steroids along with anti leprosy therapy to prevent active inflammation and or fibrosis of the nerve will reduce the prevalence of nerve damage significantly.3
The WHO Expert Committee on Leprosy Committee pointed out the need for improved management of reactions and neuritis and prevention of leprosy-related disabilities and impairments, and recommends that antileprosy activities should become an integral part of general health services and should involve communities to the fullest extent possible.4
Once damaged these nerves can persist to have paresthesias which may manifest as positive neurologic phenomena such as burning, tingling commonly described in the Asian region as “Jhum Jhum” and these symptoms are well controlled with tricyclic antidepressants such as amitryptalline.5, 6
As electrophysiological studies do not contribute any additional information as to the etiology of this treatable cause of peripheral neuropathy and preventable cause of neuronal damage and disability, great care is to be given towards the early detection of this condition.
It would therefore be appropriate to consider a SLIT SKIN SMEAR examination for presence of Acid fast bacilli, although this may be positive and indicative of the disease only in a small proportion of patients, but would still be a useful Stage 1 investigation in peripheral neuropathy in countries with high prevalence of leprosy.
And a nerve biopsy or Cytological needle aspiration as a stage 2 investigation in suspected pure neural leprosy cases.
References:
1. Theuvenet WJ et al: Cytological needle aspiration for the diagnosis of pure neural leprosy. Indian J Lepr. 1996 Jan-Mar;68(1):109-12.
2.Jaiswal AK, Shetty MK et al:Steroid therapy in recent "quiet nerve paralysis" in pure neuritic leprosy. Indian J Lepr 1991 Apr-Jun;63(2):223-5.
3.Job C K Pathology and pathogenesis of leprous neuritis; a preventable and treatable complication. Int J Lepr Other Mycobact Dis. 2001 Jun;69(2 Suppl):S19-29.
4. WHO Expert Committee on Leprosy. World Health Organ Tech Rep Ser 1998;874:1-43
5. Lemaster JW, John O, Roche PW. 'Jhum-jhum'--a common paraesthesia in leprosy. Lepr Rev 2001 Mar;72(1):100-1
6. Basnyat B, Zimmerman M, Sleggs J, Vaidhya H. Jhum-jhum is a symptom. Lancet 1999 Jun 12;353(9169):2074
Competing interests: No competing interests
Symptom control in painful neuropathy can be very difficult and
discouraging for both patient and doctor. Dr Hughes rightly points out
that anticonvulsants are first line therapy, and mentions alternatives,
but stops short of endorsing the use of opioid analgesics.This is a
shame:in carefully selected patients, the use of this drug class can help
to provide considerable improvements in quality of life.
Competing interests: No competing interests
Living with autonomic neuropathy
Dear Madam
I am writing this in hope that it may be published in your personal
column where it may be brought to the attention of both diabetologists and
neurologists. I will start by giving a brief description of my medical
history and present condition.
I am now 37 and was diagnosed with type I diabetes 25 years ago. I
was, no doubt, a typical rebellious teenager, and used my diabetes as a
means of losing weight before my eating disorder developed fully. I had
very soon the first signs of neuropathy in my feet and this was rapidly
followed by what was later diagnosed as autonomic neuropathy in my stomach
and bowels. I lost the sense of feeling in my legs below the knees and the
autonomic neuropathy in the gastrointestinal tract worsened. Sweating on
eating certain foods, postural hypotension, lazy bladder syndrome (before
kidney failure) became more serious. I am now very much aware of these
symptoms but when all these things were happening, it really took a long
time for my specialists to recognise them. Ten years ago I developed
retinopathy and lost my sight totally over the relatively short period of
nine months and two years later I went into end stage renal failure.
Having been on haemodialysis for only ten months under the care of
the renal team at St Mary’s in London, I had a double kidney and pancreas
transplant by the renowned surgeon Mr Nady Hakim. Three and a half years
later my kidney failed and I am now back on haemodialysis. After six and a
half years however my pancreas is still functioning. To my surprise, most
of the classic complications of diabetes have improved markedly since my
transplant and I can actually feel my toes although I lost two of them
earlier through infection.
That is my medical history to date and now I would like to tell you
briefly what it is actually like living with autonomic neuropathy.
I still suffer today from sweating when I eat. Even the smell of food
can trigger the sweating. It is usually all over the head, down the neck,
and the front of my chest. It varies with the foods I eat but in an
average meal there will be something that will trigger the sweat glands
and not my salivary glands, which should happen. This is a most unpleasant
feeling. Obviously spicy and hot foods are to be avoided but there are
often hidden triggers in most foods. I did think that after the transplant
this problem would have improved slightly but this has not however been
the case with me. Obviously the problems with the lazy bladder changed
with the advent of dialysis.
My main problem now is therefore my blood pressure. Sitting blood
pressure for me will usually be around 80/50 mmHg. This can quite easily
fall to 60/30 mmHg on standing, which of course means that I faint. In
fact the higher my blood pressure is to begin with the greater the drop
when standing. This can be a daily occurrence and on really bad days it
can happen more than once. Over the last six years I have fractured my
shoulder, elbow, ankle (I was in plaster for five months), my knee and
little finger. This latter is still giving me a lot of pain down that side
of my hand. Now that I am back on dialysis the problem has been
exacerbated and the lowest recording to date was 25/19 mmHg. On this
occasion I was unconscious and indeed after many of my thrice-weekly
dialyses I faint when I come off the machine and usually I have to wait
for up to one hour until my blood pressure rises to 70/40 mmHg before I
can leave the hospital. It really makes life very difficult and
unfortunately leaves me with no other option than to use a wheelchair for
most of the time. Having to use my wheelchair so much is causing problems
with the muscles in both my back and legs.
I feel very strongly about the lack of awareness of autonomic
neuropathy, which can be so debilitating especially for someone who is
blind. I do see a leading consultant in this field at the National
Hospital for Neurology and Neurosurgery although I do not seem to have any
alternative other than to tolerate the situation. I have tried several
medications for this condition without success and the side effects have
been quite serious. At the moment I dread going to dialysis as the feeling
of losing consciousness whilst being dialysed lying down seems to be far
worse than simply fainting. A situation from which I will come round
almost straight away, stay on the ground for a couple of minutes and then
slowly get up. Since I have been hypotensive for many years my body has
adapted to standing with an unusually low blood pressure at which most
people would be unable to stand.
I am wondering if any other specialists have come across such severe
cases of this problem and if so how do they manage it. As I have already
said it is very debilitating and has restricted my lifestyle as an
independent person.
May I also bring to your attention the problems of having autonomic
neuropathy in my entire gastrointestinal tract?
This can start high in my oesophagus after swallowing where certain
foods will not descend by normal peristalsis and after taking a drink the
food is brought back up in a bolus. Going further down the tract food or
liquid will then remain outside the stomach, which leaves me distended
until it eventually enters the stomach where gastroparesis occurs. At
times the food will begin to ferment, which leaves me with sulphur
smelling eructation from the stomach. The usual pattern after this will
lead to either severe constipation or nocturnal diarrhoeal incontinence.
As with the eructation, the wind can also be of an unpleasant odour.
Living with all these eating difficulties has never been easy. I am sure
this has been made worse by my history of an eating disorder; a condition
which is now becoming more common and more often recognised in female
adolescent diabetics. I now eat very little so as to try and avoid the
digestive problems and not to worsen the hypotension.
I would like to think that this letter might be of some use to both
diabetic specialists and neurologists. I have to live with my problems but
this is not made any easier with the demands that dialysis makes on my
fluid restriction and the special renal diet. When all my symptoms first
presented it took a long time for a diagnosis to be made, as there was so
little known and there are still few effective treatments although the
tests to obtain a reliable diagnosis are now effective. Having had
however, many internal investigations of my digestive tract with no
abnormalities other than fermented food, one can at least rule out any
additional issues.
I have learnt to live with these problems but as you can gather it is
neither easy for me nor for those around me due to my constant fainting. I
hope that my letter has made it clear how difficult it is to live with the
complications associated with autonomic neuropathy. I learnt very early
about my diabetes and yes, I did suffer with nearly all the complications
except those associated with the cardiovascular system, despite being a
smoker for several years (I have not smoked for three years) and never
having drunk alcohol.
I shall end this letter here in the hope that at least part of it
will be published so that those concerned with the treatment of diabetes
can have a clearer picture of some of the problems of having to live with
this dreadful condition.
Yours faithfully
Johanna Cheetham
Competing interests:
None declared
Competing interests: No competing interests