Painful Diabetic Polyneuropathy

Dimitris Papadopoulos MD Fellow Of Interventional Pain Practice (FIPP)

Updated 19 May, 2011


Diabetic polyneuropathy is one of the most common types of neuropathy. There are approximately 250 million people worldwide suffering from diabetes mellitus and 20-30 million of them suffer from neuropathy. Diabetic polyneuropathy is closely correlated with the diabetic chronicity and blood glucose control. Close blood glucose control determines the prevention of painful diabetic polyneuropathy to a significant extent.

Diabetic Polyneuropathy is the result of the direct glucose effect on nerve cells. Nerve impairment is accompanied by microvascular dysfunction that affects the nerve vascular network. This is due to oxidation, which is caused by hyperglycaemia and other disorders of homeostasis and metabolism. This is the reason why neuropathy and neuropathic pain occur more frequently in patients with chronic and well-controlled diabetes who have at the same time other cardiovascular risk factors, such as hypertension, hyperlipidaemia and dyslipidaemia (high triglycerides and low HDL/ High Density Lipoproteins) that are responsible for causing microvascular complications of diabetes.



The initial symptoms observed are reduced sensibility, burning sensation (occurring particularly at night and aggravating with contact) and tingling sensation in lower extremities  (pins-and-needles). There may also be acute paroxysmal pain attacks. Symptoms may be accompanied by trophic changes and poor wound healing due to microangiopathy. It is also likely to have allodynia and hyperpathia.

The clinical examination should include full neurologic examination of sensory and motor functions and reflex evaluation.


Specific laboratory workup, as well as nerve conduction tests and electromyography can supplement the diagnostic control.


Further examinations should be conducted to rule out other causes of polyneuropathy in case the patient reports one of the following symptoms: acute onset, asymmetry of symptoms, great deal of pain, marked motor symptoms or rapid progression of motor symptoms. Painful diabetic polyneuropathy has to be differentiated from other types of polyneuropathy with the use of specific tests. The differential diagnosis from polyneuropathy of toxic aetiology is of particular high importance because it is a reversible condition.



Proper and effective treatment of diabetes mellitus with close blood glucose control, plays a major role in preventing and delaying the onset of symptoms in painful polyneuropathy. Once symptoms begin, they rarely subside on their own and there is need for specific pharmacotherapy to cope with the neuropathic pain.

The therapeutic target is to:

  • Reduce peripheral sensitization
  • Reduce ectopic activity
  • Reduce central sensitization
  • Increase central pain inhibition

The drugs used belong to the following categories:

  • Antidepressants
  • Antiepileptics
  • Opioids


Comparative studies on pharmacotherapies for painful diabetic polyneuropathy have demonstrated that tricyclic antidepressants are the most effective drugs. However, their administration in high and effective doses is limited due to adverse events often occurring. There are also specific contraindications which do not allow their use.

Published studies have shown that   serotonine/ noradrenaline reuptake inhibitors (SNRI”S) duloxetine (Cymbalta) and venlafaxine (Efexor) are effective in treating pain in painful diabetic polyneuropathy.  Duloxetine is administered in the dose of 60 mg a day or 120 mg twice a day. According to the results of three studies, 45-55% of patients who received duloxetine reported more than 50% improvement in pain intensity compared to the comparator drug.

In the dosage of 120 mg, the number needed to treat (NNT) for more than 50% pain improvement was 4,9 patients (NNT 4,9), whereas in the 60 mg dosage the number to treat for  more than 50% pain improvement was 5,2 patients (NNT 5,2).


Several antiepileptic drugs have been studied for painful diabetic polyneuropathy. Treatment with gabapentin (Neurontin) has shown only small differences compared to amitryptiline (antidepressant). In the Pregabalin (Lyrica) group, 39-46% of patients reported over 50% pain improvement with the dosage from 300 to 600 mg. Carbamazepine (Tegretol) is less effective than Pregabalin (Lyrica). Duloxetine (Cymbalta), pregabalin (Lyrica) and gabapentin (Neurontin) seem to have similar efficacy in painful diabetic polyneuropathy.

According to the published international treatment guidelines for painful diabetic polyneuropathy, the following are recommended:

1.   First- line drug
•    Duloxetine (Cymbalta)
If there is contraindication for Duloxetine (Cymbalta), the treatment should start with amitriptyline (Saroten).

2.   Second-line drug (in case first-line drug fails)
•    Amitriptyline (Saroten).
•    Pregabalin (Lyrica)
•    Combination of the two

3.   Third-line drug
•    Tramadol (Tramal, Oxxalgan)
•    Lidocaine patch

In refractory cases, intravenous lidocaine can be tried.


Should the conservative treatment fail or serious intolerable adverse events occur from pharmacotherapy, Spinal Cord Stimulation (SCS) is indicated. As long as the patient reports more than 50% pain relief during the trial period, the final implantation of the neurostimulation system is performed. There are 4 studies showing satisfactory results for SCS in painful diabetic polyneuropathy and the method is recommended in case the conservative treatment fails.