Arch Gen Intern Med 2018 Volume 2 Issue 4
American Diabetes Association (ADA), Diabetes Canada (DC) published updates to the
management of Diabetic peripheral neuropathy (DPN) in 2017 and 2018. National Institute of
Healthcare and excellence (NICE) also updated their guidelines for management of neuropathic
pain in 2018.
This article aims to review the topic given those updates and to highlight similarities as well as
differences in management. The authors will focus on implications and their clinical application
in everyday practice.
Introduction and Background
Diabetic peripheral neuropathy (DPN) is common with
prevalence ranging from 40% to 50% of all patients with long-
standing diabetes . DPN term refers to peripheral nerve
dysfunction and damage in diabetic patients after exclusion of
other causes . The denition encompasses a heterogeneous
group of presentations.
Clinical presentation of DPN could be asymptomatic, typical
neuropathic pain, atypical neuropathic pain, altered or decreased
sensations. Motor or sensorimotor symptoms may present early
on in the form of weakness and wasting. Asymptomatic DPN is
not uncommon. Typical neuropathic pain refers to the typical
presentation of stocking and gloves pain. Atypical neuropathic
pain covers many forms of peripheral neuropathic pain that
varies in site and character. Pain could be refractory to treatment
and affects patient quality of life. Lastly, sensory symptoms
may present in the form of altered or decreased sensations. Both
of which are a risk factor for diabetes complications such as
diabetic foot, ulcers and amputations. Complications of DPN
are signicant causes of morbidity and mortality in the diabetic
The mainstay of treatment should remain on prevention rather
than reversibility. To date, once DPN developed no treatment is
available to reverse the condition or to alter the progression course.
Tight Glycaemic control may be an effective intervention to prevent
or delay the development of the condition in type 1 diabetes. It
may help reduce the clinical neuropathy symptoms and signs in
both types of diabetes [2,4,5]. The focus of treatment of DPN is
currently on improving quality of life and preventing complications
through effective screening, pain control and foot care.
Subclinical and clinical DPN and other classications
Subclinical DPN refers to patients with no symptoms but denite
signs and positive nerve conduction studies. Symptoms of
DPN are absent in up to 50% of diabetic peripheral neuropathy
patients . Clinical DPN refers to patients with both symptoms
Classication of DPN according to nerve distribution includes
polyneuropathy, mononeuropathy, mononeuropathy multiplex
among other presentations. Also, peripheral nerve dysfunction
could be sensory, motor or both if classied according to
Symptoms and signs
In clinic settings, symptoms and signs are both crucial for
screening for and assessing the severity of DPN.
The most frequent presentation of DPN is the symmetrical
sensory pain/impairment that affects lower limbs sooner than
the upper limbs in a classic stocking and gloves’ appearance
. Other symptoms to suggest DPN include atypical pain,
altered sensation, numbness, pins and needles, hot or burning
sensations. More interestingly, painful symptoms could happen
in diabetic patients with or without neuropathy . Neuropathic
motor dysfunction symptoms include muscle weakness, poor
balance and falls.
Signs of neuropathy tested at the bedside include vibration
sensation and altered proprioception, which reect large-bre
function. Also, impairment of pain, light touch, and temperature
which reects small bres’ functions, Any of which could
present as an early sign of neuropathy . Motor signs include
wasting and decreased reexes. Motor and sensorimotor
neuropathy symptoms and signs are all reported and recognised
complications of diabetes.
Both symptoms and signs carry subjective elements and could
be nonspecic. 10 g Monolament and tuning fork had low
and variable diagnostic accuracies with the former sensitivity
reported from 19% to 73% in one systematic review .
Several scoring systems are in place for identication of DPN
cases. The United Kingdom screening test (UKST)  and the
Michigan Neuropathy Screening Instrument (MNSI)  are
among the commonly used tools. The 2 part diagnostic screening
tools consist of simple symptoms and physical examination
scores (Table 1).
A review of diabetic peripheral neuropathy management given recent guidelines
Ehab Hamed*, Mohalall Abdel Monem
Department of Family Medicine, Al Khor Health Centre, Primary Health Care Corporation, Qatar
Accepted on August 28, 2018
Keywords: Diabetes peripheral neuropathy, Neuropathic pain, Diabetes complications.
Citation: Hamed E, Monem MA. A review of diabetic peripheral neuropathy management given recent guidelines updates. Arch Gen Intern
Med. 2018;2(4):1-5. DOI: 10.4066/ 2591-7951.1000060
Arch Gen Intern Med 2018 Volume 2 Issue 4
Either could serve as a gold standard history taking and
examination tools. Both screening tools have better specicity
and sensitivity but are time-consuming. It is not clear though
that these complex systems have benecial outcomes compared
to the simplied screening .
Nerve conduction study and a validated measure of small bre
neuropathy are the gold standards to establish the diagnosis of
typical DPN and to monitor the severity. They are not readily
available in the community and many clinic settings, but they
could play an essential role in at least epidemiological and
research purposes .
Generally, the diagnosis of DPN remains clinical diagnosis.
More than one symptom or sign at presentation or combination
of both are stronger predictors of diabetic neuropathy. Current
guidance from ADA and DC does not support the usage of more
Frequency and mode of bedside assessment
In 2017 statement the American Diabetes Association (ADA)
recommended that all type 2 patients should be assessed with
history taking and bedside testing at the time of diagnosis and at
least annually afterwards. Those with type 1 should be assessed
ve years after diagnosis and again annual testing. Diabetes
Canada (DC) 2018 guidelines seem to agree with the frequency
of check. Both reect on the early presentation of DPN in type
On the mode of testing, The ADA recommends bedside testing
with temp or pinprick sensation and tuning fork to test both
small and large nerve bre functions. 10 g monolament
testing is essential in all patients . DC recommends rapid
screening using either monolament or tuning fork annually
in asymptomatic patients (Table 2). More comprehensive
testing, including scoring systems, could be used for those with
symptoms or positive signs and for research purposes .
Patient with prediabetes might benet from baseline assessment
at the time of diagnosis. A holistic evaluation of diabetic foot
risk should include reviewing skin integrity, vascular systems,
footwear and cardiovascular risk factors.
Investigations and differential diagnoses
History, examination alongside investigations could help
exclude other causes of neuropathy. Symptoms and signs that
would warrant referral include an asymmetrical presentation,
rapid progression and motor more than sensory signs. In
everyday practice, recommended blood tests include serum
B12, folic acid, thyroid functions, complete blood count and
serum electrophoresis .
Patients with diabetes are likely to have B12 and Thyroid-
function abnormalities. B12 deciency is more associated
with malabsorption rather than nutritional deciency .
Specically, In type 2 diabetes population, B12 deciency is
more relevant because of long-term metformin use . On the
other hand, The thyroid stimulating hormone (TSH) was higher
in a Chinese population with DPN, and in another systematic
analysis, subclinical hypothyroidism was associated with more
diabetic complications [16,17]. A periodic check of both B12
and TSH is a reasonable approach in all diabetic patients with
or without neuropathy.
Prevention and tight glycemic control
Prevention approach focuses on glycemic control. In type 1
diabetes near-normal glycemic control reduces the occurrence
of DPN, and patient with intensive treatment showed the
benets of primary prevention for more than ten years . In
Asymptomatic patients mode of assessment Temp or Pinprick
Either Monolament or tuning fork
Symptomatic patients More comprehensive testing
Both Guidelines recommend annual testing of all type 2 patients from diagnosis and type 1 patients 5 years after diagnosis. Healthcare professionals should assess risk
in at least three different sites on each foot.
Table 2: Frequency and mode of assessment.
Symptoms (a) What is the sensation felt?
(b) What is the location of symptoms?
(c) Have the symptoms ever woken patient at night?
(d) What is the timing of symptoms?
(e) How are symptoms relieved?
1. Are your legs and/or feet numb?
2. Do you ever have any burning pain in your legs and/or feet?
3. Are your feet too sensitive to touch?
4. Do you get muscle cramps in your legs and/or feet?
5. Do you ever have any prickling feelings in your legs or feet?
6. Does it hurt when the bed covers touch your skin?
7. When you get into the tub or shower, are you able to tell the hot
water from the cold water?
8. Have you ever had an open sore on your foot?
9. Has your doctor ever told you that you have diabetic neuropathy?
10. Do you feel weak all over most of the time?
11. Are your symptoms worse at night?
12. Do your legs hurt when you walk?
13. Are you able to sense your feet when you walk?
14. Is the skin on your feet so dry that it cracks open?
15. Have you ever had an amputation?
Signs (a) What is the Achilles tendon reex?
(b) What is the vibration sense?
(c) What is the pin-prick sensation?
(d) What is the temperature sensation?
1. Appearance of Feet
3. Ankle Reexes
4. Vibration perception at great toe
Table 1: The United Kingdom screening test (UKST) vs Michigan neuropathy screening instrument (MNSI).
3Arch Gen Intern Med 2018 Volume 2 Issue 4
type 2 tight control is reported as a modestly useful measure for
prevention [1,2]. There is no evidence to date that tight glycemic
control reverses DPN course, but it is paramount for managing
patient cardiovascular risk and preventing complications.
Management of diabetic neuropathy pain
Painful diabetic neuropathy affects 25% to 30% of patients
with diabetes in both hospital and clinic settings. Patients are
reluctant to report their symptoms, and many of them do not
take their medications. Few patients report complete relief
of pain, and 30 to 50 % reduction is considered a meaningful
Medications fall into three categories, anticonvulsants,
antidepressants and opioids. Antidepressants are further divided
into serotonin-norepinephrine reuptake group and tri-cyclic
antidepressants (TCA) group. All categories have their common
share of side effects and signicant adverse events. Anticonvulsants
and antidepressants are more favourable options compared to
opioids because of their less addictive prole.
American Diabetes Association (ADA) treatment guidance
elected two medicines from each treatment group as possible
rst lines. It favours pregabalin and gabapentin as options from
the anticonvulsants group, duloxetine and venlafaxine from the
serotonin-norepinephrine reuptake inhibitor group and nally
nortriptyline and desipramine from the tri-cyclic antidepressants
The guidelines allow physicians to choose according to patient
comorbidities, side effects, drug interaction and cost. Of this
list, FDA approved only pregabalin and duloxetine for the
management of pain in diabetic neuropathy patients .
Canadian Guidelines afrms there is not enough evidence
for comparative effectiveness. It also highlights the same
two medicine as licensed medications in the treatment of the
condition from Health Canada .
Pregabalin and duloxetine numbers needed to treat (NNT) range
from 3.3 to 11 for 30 to 50% of pain reduction. TCA group have
better numbers with NNT falls below three but more side effects.
In other words, about two-thirds of patients may not respond
to treatment, and most patients have a partial response. Other
alternatives include topiramate, venlafaxine, amitriptyline,
nortriptyline and desipramine and topical nitrate spray.
Options from the opioid family include tramadol and tapentadol
with the latter gained the license for treatment of the condition.
Both the ADA and Canadian Guidelines suggest that physicians
should not use opioid agents as rst lines of treatment because
of their higher potential for abuse.
National Institute of Health and Care Excellence (NICE)
suggested a choice of amitriptyline, duloxetine, gabapentin or
pregabalin as the rst line. They advise to switch in between
those agents if the patient is not responding or developing side
effects (Table 2).
NICE recommends referral to a pain specialist in case of
treatment poor response or effect on patient quality of life.
Tramadol is suggested for acute therapy and capsaicin cream
for those patients who have localised pain and don’t want oral
All current guidelines advise a personalised approach with a
low dose start to be tailored to the maximum response with the
least side effects or adverse events. Early rotation or switch to
another agent in treatment failures, side effects or adverse events
(Table 3). Painful diabetic neuropathy (PDN) can be refractory
to conventional pharmacologic therapy .
Other options for pain management
Other options for pain management include surgical
decompression and alternative and complementary medicine
Surgical decompression is an evolving eld. A recent systematic
review suggests it may be benecial in DPN cases, though the
evidence comes from observational studies and more focused
towards upper limb presentations [22,23].
Alternative and complementary medicine approaches with
promising results from the latest literature systematic reviews
include alpha lipoic acid, acetyl-l-carnitine, spinal cord
stimulation and capsacian [24-27]. Acupuncture and chinese
medicines have less evidence to support its use.
Beyond pain management
NICE recommendations stress following a personalised
approach with an agreed treatment plan that takes into account
patient concerns, expectations and health beliefs. It stresses the
importance of assessing the impact on life, explaining plans for
ADA DC NICE
Topical nitrate sprays
Notes 1. The choice should be patient specic
2. Starting dose should be low and titrate up according to the response.
3. In non-responders, healthcare professionals should switch between agents. DC guidance suggests they may also be used
4. Tramadol and Tapentadol carry risks of tolerance, abuse and dependency. They may be considered in people not responsive
to the above medications.
Table 3: Pain management medications in DPN.
Citation: Hamed E, Monem MA. A review of diabetic peripheral neuropathy management given recent guidelines updates. Arch Gen Intern Med.
Arch Gen Intern Med 2018 Volume 2 Issue 4
starting, titrating up doses and monitoring. It follows up on other
coping strategies and rehabilitation programmes and referral to
pain specialists when necessary .
Multifactorial care includes optimisation of cardiovascular
risk factors such as lifestyle, dyslipidemia, HTN, erectile
dysfunction and stress. It is also essential to assess the effect of
pain on psychological status. It may improve patient responses
and adherence to treatment. Diabetic peripheral neuropathy was
associated with a higher risk of depression and anxiety .
Diabetic foot ulcers, infections, gangrenes and amputations are
associated with higher mortality and poor prognosis. 50% of
patients with amputations and foot ulcers die within ve years
. The classic triad of ischemia, neuropathy and infection
caused a casual sequence of trauma, ulcer, and infection in
nearly 72% of amputation cases. While the primary pathology is
diabetic vasculopathy, a ve-year retrospective study reported
neuropathy as the main etiopathogenetic factor for diabetic foot
The term foot care encompasses a patient and physician approach
to screen for neuropathy, vasculopathy and infection signs.
Multidisciplinary team urgent intervention may be required in
the event of ulceration and development of diabetic foot.
Diabetic peripheral neuropathy is a clinical diagnosis that is well
researched with recent updates on management. Combination of
symptoms and signs improves the accuracy of screening and
diagnosis. Healthcare professionals should consider referral
in cases with rapid progression, motor more than sensory
and asymmetrical presentations. Current guidelines suggest
routine blood investigations checks with a focus on vitamin
B12, thyroid function tests and serum electrophoresis. Tight
glycaemic control forms a cornerstone in the prevention or
delay of presentation, and it may prevent complications.
Pain control should be patient centred, regularly monitored
and tailored to minimum effective dose with least side effects.
There is a consensus on the usage of pregabalin, gabapentin,
duloxetine and to less extent venlafaxine and amitryptiline. In
many cases, pain could be refractory to medicine.
A more holistic approach should address the impact of diabetic
neuropathy on a patient’s quality of life, psychological status
and assessment of other cardiovascular risk factors. Screening,
early detection and urgent intervention may help decrease
diabetic foot complications and amputation rates.
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Department of Family Medicine
Al Khor Health Centre
Primary Health Care Corporation