Treatment of diabetic neuropathy in the

lower limb
Signs and symptoms of diabetic neuropathy may precede the onset of
diabetes.
LYNNE TUDHOPE, MB ChB, MMed (Surg), BA
Registered Vascular Surgeon and Endovascular Specialist, Montana and Wilgers Hospitals, Pretoria
Lynne Tudhope is President of the Diabetic Foot Working Group of South Africa and an editorial board member for diabetes in the Journal of Wound
Healing of South Africa. She has been an invited speaker at numerous international congresses on the diabetic foot. She has a special interest in
endovascular treatment of the neuroischaemic diabetic foot and heads the multidisciplinary foot clinics at Montana and Wilgers hospitals in Pretoria.
Correspondence to: Lynne Tudhope (ltudhope@[Link])

Diabetic peripheral neuropathy (DPN) is defined as ‘the presence or even foot drop, usually asymmetrical at initial presentation. The
of symptoms and/or signs of peripheral nerve dysfunction in classic signs of motor neuropathy are a high medial arch, claw toes
people with diabetes after exclusion of other causes: the diagnosis and metatarsal head prominence with fatty pad thinning.
cannot be made without a clinical examination’. In fact, many of
these symptoms and signs may precede the onset of diabetes.
Any patient who walks into
Classification the room in spite of extensive
The classification of diabetic neuropathy can be done in several
plantar ulceration has sensory
ways: clinical presentation (symmetrical, focal or multifocal, or neuropathy.
painful, paralytic and ataxic), type of fibres affected (motor, sensory,
autonomic), or painful or non-painful.
Symptoms of autonomic neuropathy in the diabetic foot usually
The commonest presentation of peripheral neuropathy in diabetes include dry, cracked skin, nail changes, transient mottling and
is that of chronic sensorimotor neuropathy. This has an insidious discoloration of the skin and cold feet.
onset, with most patients describing symptoms of burning pain,
Confirmed clinical neuropathy, as diagnosed by a physician skilled
stabbing, shooting pain, hyperaesthesia or paraesthesiae. There
in the proper examination technique, should also be backed up with
is also commonly an exacerbation of symptoms at night. At the
the necessary quantitative sensory testing (e.g. electrophysiological
other end of the spectrum, patients may describe a feeling of
tests, autonomic tests, etc). However, this does not mean that a
total numbness in the feet and lower leg. Any patient who walks
basic neurological examination cannot be done by any health care
into the room in spite of extensive plantar ulceration has sensory
worker in the field, trained in the proper manner to identify the
neuropathy (Fig. 1).
diabetic foot at risk.
Muscular pain secondary to injury to the motor neurons can
The two most prominent changes in a patient with mild diabetic
present as night cramps, spasm or a dull ache. Motor signs and
distal neuropathy is a reduced or absent ankle reflex and distal
symptoms include imbalance when walking and ankle weakness
gradient loss of large and small sensory fibre modalities, the so-
called ‘stocking-and-glove’ sensory loss (Fig. 2).
Gradient loss to cold perception can be tested with a tip therm,
which is used to assess whether the patient can distinguish
between hot and cold tips on the skin surface. Examination with
a 128 Hz tuning fork is the most practical way to check for the
presence or absence of vibratory sensation in the feet, while the
10 g monofilament applied perpendicularly to the skin surface for
2 seconds in various sites is a straightforward way of detecting a
lack of sensation.

Treatment
The non-modifiable risk factors for the development of DPN
include age of the patient and the duration of diabetes. Young et
al., in the UK neuropathy study, showed that patients in the 20 -
29-year age group had an incidence of 5% DPN in contrast to 44%
DPN in the 70 - 79-year group. Likewise in the Spanish neuropathy
Fig. 1. A large ulcer with surrounding callus on a neuropathic diabetic study, there was a 14% incidence among those diabetics who had
foot showing previous toe amputation and deformity of the foot. This had the disease for less than 5 years, while DPN reached nearly 50%
patient experienced no pain or discomfort when walking. in those who had been diagnosed more than 20 years previously.

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Many anticonvulsants have been shown to reduces pain intensity in two ways. It acts
be effective in the management of DPN. as opioid agonist and as an activator of
Although the exact mechanism of benefit monoaminergic spinal inhibition of pain.
remains unknown for some of these Treatment should begin with 50 mg per day
drugs, they probably stabilise nerve fibre and be increased slowly to the maximum
membranes and so suppress paroxysms of dose of 100 mg four times a day.
pain.
A 5% lidocaine patch applied to areas of
Carbamazapine is most effective maximal peripheral pain for weeks at a
in relieving the sharp, lancinating time until symptoms are under control,
component of neuropathic pain rather has been shown to be effective in DPN.
than dull constant pain. Although it is Mood, walking ability, normal work and
well tolerated initially, 30 - 40% of patients sleep all show considerable improvement.
will discontinue treatment within 1 year
because of side-effects. Dosages of 200 mg Antioxidants
three times per day are effective. Alpha-lipoic acid given intravenously at a
Gabapentin, related structurally to dose of 600 mg per day reduces neuropathic
γ-aminobutyric acid, can be titrated up to symptoms and deficits. Conversely,
a daily dose of 3 600 mg until a meaningful the results from oral use have not been
reduction in pain is reported. A starting convincing. In both the ALADIN II and
Fig. 2. The stocking and glove distribution of dose of 300 mg at night can be increased ALADIN III studies no improvement was
diabetic distal symmetrical polyneuropathy every 3 - 5 days until a thrice-daily dosage noted on oral treatment regimens. The
A distal dying back of the nerve fibres occurs, is attained. Most adverse effects of the initial improvement in symptoms noted in
resulting in the involvement of the hands and drug abate after 10 days of treatment. the first 3 weeks of ALADIN III occurred
feet in this pattern. These are commonly drowsiness, fatigue only during the intravenous dosage phase
and imbalance. Gabapentin has no of the study.
Modifiable risk factors in the disease interaction with other medications.
process include hyperglycaemia, hyper- Topical agents
tension, hypercholesterolaemia, heavy Topical agents can also control symptoms
alcohol abuse and smoking. In fact, The management in patients with DPN. Capsaicin, the
hyperglycaemia has been shown to be the
strongest risk factor for the development of DPN must take active agent in chilli, depletes substance
P, a neuropeptide necessary for the
of DPN. In both the DCCT (Diabetes into account that propagation of pain, when applied to the
Control and Complications Trial) and the
UKPDS (United Kingdom Prospective neuropathic pain is skin surface as a cream. The major adverse
effect of capsaicin is its tendency to
Diabetes Study), it was conclusively
demonstrated that better glucose control
commonly constant produce stinging, erythema and warmth
at the application site. At best, capsaicin
prevents or slows the progression of and associated cream produces only mild to moderate
diabetic neuropathy.
with paroxysmal pain relief.
The management of DPN must take
into account that neuropathic pain is exacerbation of Another mode of treatment involves the
application of an adhesive clear plastic
commonly constant and associated with pain that does not dressing on the dorsum of the foot from
paroxysmal exacerbation of pain that
does not follow a specific pattern. This can follow a specific the medial to the lateral aspect. This can
bring about an immediate amelioration in
present a challenge in management for pattern. pain with muffling of the affected nerve
even the most skilled physician. endings.
Although improved glycaemic control is
proposed to control DPN, the expected Pregabalin possesses anticonvulsant, Spinal cord stimulation
pain reduction does not always correlate anxiolytic and analgesic properties. The Spinal cord stimulation of the thoracic
with an improved HbA1C level. In fact, advantage of this drug over gabapentin and lumbar epidural space of patients
some patients often experience increased is the rapid improvement in pain in only with DPN has proven effective in relieving
pain as better glucose control is achieved. 1 - 2 days. An effective dose is usually pain in extremely refractive patients.
only attained if twice-daily medication is Neuropathic pain increases dramatically
The treatment of DPN includes taken starting at 75 mg bd and increasing when the stimulator is turned off and pain
pharmacological and psychological the dose up to 300 mg bd. It is important relief returns when it is reactivated.
approaches. Firstly, the clinician must to note that pregabalin is cleared by the
make the patient aware that there is no kidney, so reduced dosages are required in
magic pill or treatment available that will Acupuncture
patients with creatinine clearances of less
take away all the pain; a 40% reduction than 60 ml/min. Traditional acupuncture gives prolonged
in pain is considered a good response to pain relief in up to 77% of patients with
treatment. Duloxetine has proven efficacy as an DPN. Most patients are able to reduce or
antidepressant and reduces the pain stop other pain medication.
Tricyclic antidepressants still serve as intensity of DPN. It works better in
the mainstay for treatment of DPN. combination with other classes of drugs Surgery
Amitriptyline in a therapeutic dosage such as tramadol hydrochloride.
range of 25 - 150 mg per day, with most or Surgical decompression of nerves in the
all the drug taken at night, remains a first- Tramadol hydrochloride is an effective foot has been promoted as a treatment
line agent in the treatment algorithm. and unique pharmacological agent that option for DPN. Although more than

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240 surgeons have been trained in this

technique in Europe, there is no evidence
Table I. Risk categorisation system
to support this therapy. This procedure will Category Risk profile Check-up frequency
work when the pain is caused by a nerve 0 No sensory neuropathy Once a year
entrapment but is definitely of no benefit 1 Sensory neuropathy Once every 6 months
in true DPN (see Fig. 3).
2 Sensory neuropathy and signs of Once every 3 months
peripheral vascular disease and/or
Tricyclic foot deformities

antidepressants 3 Previous ulcer Once every 1 - 3 months

still serve as economically sound policy of preventing amputations done in diabetics are preceded
the mainstay for foot problems before they happen, but will by foot ulceration, it is of paramount
also enable patients to receive appropriate importance that ulcers are prevented.
treatment of DPN. treatment from the start, before limb Foot deformities, callus formation and
loss occurs. Risk stratification (Table I) poorly fitting shoes are all aspects of DPN
is extremely important from the outset, in the foot that need regular treatment and
Routine assessment by a and patient education and wearing the adjustment.
health care professional/ right footwear are all areas of expertise
that trained podiatrists will offer their
podiatrist patients.
Conclusion
DPN has been labelled the ‘forgotten
It is of the utmost importance that every The American Diabetic Association has
complication of diabetes’. Although the
diabetic, newly diagnosed or long- estimated that 50% of foot ulcers could be
clinical manifestations and treatment are
standing, be assessed regularly by a avoided if both the patient and the health
far advanced in comparison with a decade
trained podiatrist who is accredited as a care professional fulfil their respective
ago, better methods to prevent the onset
‘dia-podiatrist’. This will not only be an responsibilities. Knowing that 85% of all

Fig. 3. Algorithm for the treatment of diabetic peripheral neuropathy. (Algorithm of the French Pain Society 2009 as presented by G Mick at the First
Middle East Regional Diabetes Summit.)

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and progression of the disease need to be as a matter of urgency. A stepwise progression of neuropathy. Ann Intern Med 1995;
researched. treatment plan addressing all aspects of 122: 561-568.
foot care, together with pharmacological Richter RW, Portenoy R, Sharma U, et al. Relief
If ulceration and amputation are to be of painful diabetic peripheral neuropathy with
control of severe neuropathic pain, will
avoided in the insensate foot, then clinician pregabalin: A randomized, placebo-controlled trial.
enable diabetic patients with DPN to have J Pain 2005; 6(4): 253-260.
and patient education must be addressed
functionality and quality of life.
Tanenberg RJ, Donofrio PD. Neuropathic problems
Traditional Further reading of the lower limbs in diabetic patients. In: Levin ME,
O’Neil LW, Bowker JH, et al., eds. The Diabetic Foot,
acupuncture gives Boulton AJM, Gries FA, Jervell JA. Guidelines
for the diagnosis and outpatient management of
7th ed. Philadelphia: Mosby Elsevier, 2008.

prolonged pain diabetic peripheral neuropathy. Diabet Med 1998; UK Prospective Diabetes Study Group. Effect of
intensive blood glucose control with metformin
15: 508-514.
relief in up to 77% Boulton AJM, Vinik AI, Arezzo J, et al. Diabetic
on complications in patients with type II diabetes:
UKPDS 34. Lancet 1998; 352: 854-865.
of patients with neuropathies: A statement by the American Diabetes
Association. Diabetes Care 2005; 28:1480-1481. Zareba G. Pregabalin: A new agent for the treatment

DPN.
of neuropathic pain. Drugs Today (Barc) 2005; 41(8):
DCCT Research Group. The effect of intensive 509-516.
diabetes therapy on the development and

In a nutshell
• Weight loss and depression are important manifestations of DPN.
• When treating DPN remember that you are managing a patient.
• Start medication slowly and in low doses.
• Explain potential side-effects to the patient at the first visit.
• Emphasise that complete relief of symptoms is rare and that a 50 - 75% improvement is considered substantial.
• I f pain persists after 6 weeks of therapy, increase medication to maximal dose and add a second or even third medication to the regimen.
Make sure that the patient is not smoking and check blood pressure, glucose and cholesterol.

Single Suture
More evidence against aspirin for primary prevention
In 1998, researchers in Scotland began a large trial of low-dose aspirin for adults without clinical cardiovascular disease. The results,
now published, suggest that 100 mg of enteric-coated aspirin a day is no more effective than placebo at preventing serious vascular
events including heart attacks, strokes and revascularisation procedures. These adults had an ankle brachial index below 0.95, indicating
a higher risk of cardiovascular disease than the general population of Scotland. Even so, aspirin did not save lives during more than 8
years of follow-up, or protect participants from symptomatic disease. Aspirin caused significantly more major bleeds than placebo (1.71,
0.99 - 2.97), some of which were fatal.
The weight of evidence is now balanced against low-dose aspirin for primary prevention, says an editorial. This trial had its flaws, as
most trials do, but if aspirin has any prophylactic effect in this population, it is likely to be small. The harms are more obvious. These
researchers screened nearly 30 000 adults aged 50 - 75 to find the 4 914 with a reduced ankle brachial index. They managed to randomise
3 350. Around 70% of participants were women.
Gerald F, et al. JAMA 2010; 303: 841-848.

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