Dr. Sapiah Sapuan Consultant Neurologist Hospital Sultanah

Dr. Sapiah Sapuan
Consultant Neurologist
Hospital Sultanah Aminah Johor Bahru
A 52-year-old man presents with bilateral
lower extremity pain.
}  The pain is described as sharp and needle
like, increases when he stands.
}  He also experiences pain with any touch,
including fabric.
}  The pain has been present for ~ 6 months
and is not relieved with NSAIDs.
}  He was diagnosed with diabetes 6 years.
}  At the time of diagnosis, his HbA1c was
12.3%.
} 
} 
“the presence of symptoms and/or signs of
peripheral nerve dysfunction in people with
diabetes after the exclusion of other causes”
No neuropathy
10%
Asymptomatic
40%
Symptomatic
50%
} 
Progressive
◦  Distal Symmetrical polyneuropathy
◦  “Small fibre” neuropathy
} 
Reversible
◦  Mononeuropathies
◦  Acute diffuse painful neuropathy
} 
Pressure Palsies
◦  Median nerve ( carpal tunnel)
◦  Ulnar nerve
◦  Common peroneal nerve
PDN is a common complication of diabetes
and can affect many aspects of life
}  Severely limit patients’ daily functions
}  PDN affects 16% of patients with diabetes;
}  Unreported (12.5%)
}  and untreated (39%)
} 
Hyperglycemia is highly correlated with the
development and progression of
neuropathies
}  Tight glycaemic control will reduce the
incidence of neuropathy by 60%.
}  However, even in patients with long-term
excellent glycemic control, the lifetime
incidence of PDN remains 20%
} 
} 
Other risk factors thought to be associated
with diabetic neuropathy are
◦  hyperlipidemia,
◦  hypertension,
◦  cigarette smoking,
◦  consumption of alcohol,
◦  and weight.
The pain is often described as “tingling,”
“numbness,” or “increased due to touch”
}  also be described as “burning,” “electrical,” or
“stabbing with paraesthesia”, “hyperesthesia,”
and “deep aching”
}  typically greater at night
}  typically develops in the feet and lower legs;
}  may also involve the hands
} 
may reveal a decrease in vibratory sensation
}  or altered superficial pain and temperature
sensation
}  A simple vibratory sensation exam consists of
a tuning fork placed on the bony prominence
}  Superficial pain sensation is tested with a
pinprick
} 
signs of decreased arterial flow, reduced
reflexes, deformities, ulcers, or slow-healing
wounds.
}  Signs of decreased arterial flow include:
} 
◦  absence of foot pulses,
◦  decrease in skin temperature,
◦  lack of skin hair,
◦  and bluish skin color.
◦  Deformities include claw toes and Charcot’s
arthopathy is a late sign
} 
By exclusion:
◦  chronic inflammatory demyelinating polyneuropathy
(CIDP),
◦  B12 deficiency,
◦  hypothyroidism,
◦  Uremia
◦  Drugs
◦  toxin
first step in the management of PDN is
glycaemic control
}  and correction of any other metabolic
derangements
}  strict glycaemic control - not only decreased
the incidence of neuropathy, but also slowed
its progressions by 57%
}  No agent will provide 100% pain relief
}  treatment was considered successful if
patients obtained a 50% reduction in pain
} 
• 
Pharmacologic Agents:
§  Anticonvulsants, antidepressants, opioids, antiarrhythmics,
cannabinoids, aldose reductase inhibitors, protein kinase C
beta inhibitors, antioxidants (α-lipoic acid), transketolase
activators (thiamines and allithiamines), topical medications
(analgesic patches, anesthetic patches, capsaicin cream,
clonidine), and others
• 
Nonpharmacologic Modalities:
§  Infrared therapy, shoe magnets, exercise, acupuncture,
external stimulation (transcutaneous electrical nerve
stimulation), spinal cord stimulation, biofeedback and
behavioral therapy, surgical decompression, and intrathecal
baclofen
• 
MEDLINE and EMBASE
◦  1960 to August 2008
◦  Relevant, fully published, peer-reviewed articles
◦  MeSH term “diabetic neuropathies” and its text
word synonyms and key words for the therapeutic
interventions of interest (see published guideline
for full list of terms)
} 
} 
} 
} 
At least two authors reviewed each article for
inclusion.
Risk of bias was determined using the classification
of evidence for each study (Classes I–IV).
Strength of practice recommendations were linked
directly to levels of evidence (Levels A, B, C, and U).
Conflicts of interest were disclosed.
Inclusion criteria:
2234 abstracts
-  Articles dealing with
PDN, describing the
intervention clearly,
reporting study completion
rates, defining the
outcome measures clearly
Exclusion criteria:
-  Case reports and review
papers
79 articles
Conclusions:
• Based on consistent Class I evidence, pregabalin is established as
effective in lessening the pain of PDN .
• Pregabalin also improves QOL and lessens sleep interference, though
the effect size is small.
Recommendation:
• If clinically appropriate, pregabalin should be offered for the treatment
of PDN (Level A).
Conclusion:
•  There is conflicting Class III evidence for the effectiveness of
topiramate in treating PDN.
Recommendation:
•  There is insufficient evidence to support or refute the use of
topiramate for the treatment of PDN (Level U).
Conclusions:
•  Based on 1 Class I study, gabapentin is probably effective in
lessening the pain of PDN.
•  Based on 2 Class II studies, sodium valproate is probably effective
in treating PDN.
Recommendation:
•  Gabapentin and sodium valproate should be considered for the
treatment of PDN (Level B).
•  Although sodium valproate may be effective in
treating PDN, it is potentially teratogenic
•  potential adverse effects such as weight gain and
potential worsening of glycemic control, this drug
is unlikely to be the first treatment choice for
PDN.
Conclusions:
•  Lamotrigine is probably not effective in treating PDN.
•  Based on Class II evidence, oxcarbazepine is probably not effective in
treating PDN.
•  Based on Class III evidence, lacosamide is possibly not effective in
treating PDN.
•  The degree of pain relief afforded by anticonvulsant agents is not
associated with improved physical function.
Recommendation:
• 
Oxcarbazepine, lamotrigine, and lacosamide should probably not be
considered for the treatment of PDN (Level B).
Conclusions:
•  Based on 3 Class I and 5 Class II studies, the antidepressants amitriptyline,
venlafaxine, and duloxetine are probably effective in lessening the pain of PDN .
•  Venlafaxine and duloxetine also improve QOL.
•  Venlafaxine is superior to placebo in relieving pain when added to gabapentin.
Recommendations:
•  Amitriptyline, venlafaxine, and duloxetine should be considered for the
treatment of PDN (Level B). Data are insufficient to recommend one of these
agents over the others.
•  Venlafaxine may be added to gabapentin for a better response (Level C).
Conclusions:
•  Based on one Class I study, dextromethorphan is probably effective in
lessening the pain of PDN and improving QOL.
•  Based on Class II evidence, morphine sulphate, tramadol, and
oxycodone controlled-release are probably effective in lessening the
pain of PDN.
•  Dextromethorphan, tramadol, and oxycodone controlled-release have
moderate effect sizes, reducing pain by 27% compared with placebo.
Recommendation:
•  Dextromethorphan, morphine sulphate, tramadol, and oxycodone
should be considered for the treatment of PDN (Level B). Data are
insufficient to recommend one agent over the other.
•  Tramadol is associated with substantial adverse events
(e.g., sedation in 18%, nausea in 23%, and constipation in
21%).
•  The use of opioids can be associated with the development
of novel pain syndromes such as rebound headache.
•  Chronic use of opioids leads to tolerance and frequent
escalation of dose.
Conclusions:
•  Based on Class I and Class II evidence, capsaicin cream is probably
effective in lessening the pain of PDN.
•  Based on Class I evidence, isosorbide dinitrate spray is probably
effective for the treatment of PDN.
Recommendation:
•  Capsaicin and isosorbide dinitrate spray should be considered for
the treatment of PDN (Level B).
Conclusions:
•  Based on Class III studies, there is insufficient evidence to
determine if IV lidocaine is effective in lessening the pain of PDN.
•  Based on Class III evidence, the Lidoderm patch is possibly
effective in lessening the pain of PDN.
Recommendation:
•  The Lidoderm patch may be considered for the treatment of PDN
(Level C).
Conclusions:
•  Based on a Class I study, electrical stimulation is probably
effective in lessening the pain of PDN and improving QOL.
•  Based on single Class I studies, electromagnetic field treatment,
low-intensity laser treatment, and Reiki therapy are probably not
effective for the treatment of PDN.
Recommendations:
•  Percutaneous electrical nerve stimulation should be considered for
the treatment of PDN (Level B).
•  Electromagnetic field treatment, low-intensity laser treatment, and
Reiki therapy should probably not be considered for the treatment
of PDN (Level B).