Diabetic polyneuropathy is a major complication of diabetes mellitus and is the most common form of neuropathy in the developed world. It is not a single entity; it encompasses several neuropathic syndromes, by far the most common of which is diabetic peripheral neuropathy (DPN) (Fig. 1) . The increasing worldwide prevalence of diabetes is having a major impact on the burden of associated complications including DPN. Although estimates of the prevalence of DPN vary substantially, depending on diagnostic criteria and the intensity of investigation, most studies suggest that about 30–50% of all diabetic people are affected. There is now little doubt that poor blood glucose control is an important risk factor for the development of DPN . Furthermore, recent research has shown traditional cardiovascular risk factors for macrovascular disease to be associated with an increased risk of DPN .
Approximately, one third of all diabetic patients with DPN present with diabetic peripheral neuropathic pain (DPNP).
Diabetic peripheral neuropathic pain
Pain is the most distressing symptom of DPN and the main reason for seeking medical attention . Affected patients often have a progressive build-up of unpleasant sensory symptoms including tingling (paraesthesiae); burning pain; shooting pains (like ‘electric shock’) down the legs; lancinating (also likened to ‘stabbing or knife like’ pains); contact pain often with day-time clothes and bedclothes (allodynia); pain on walking often described as ‘walking barefoot on marbles’, or ‘walking barefoot on hot sand’; sensations of heat or cold in the feet; persistent achy feeling in the feet and cramp-like sensations in the legs . With advanced disease the pain can extend above the feet and may involve the whole of the legs, and when this is the case there is often upper limb involvement also.
DPNP is characteristically more severe at night, and often prevents sleep . Some patients may be in a constant state of tiredness because of sleep deprivation . Others are unable to maintain full employment. Severe painful neuropathy can occasionally cause a marked reduction in exercise threshold so as to interfere with daily activities. This is particularly the case when there is an associated disabling, severe postural hypotension due to autonomic involvement. Thus DPNP has a major negative impact on quality of life with associated depression and anxiety .
Although the epidemiology and risk factors for DPN have been extensively studied [2,3,6,7] there are only very few studies looking at the prevalence of DPNP specifically, and report a prevalence rate of 10–26% reflecting differing criteria used to define neuropathic pain [8–11]. In a study of newly diagnosed type 2 diabetic individuals, 6% reported pain at diagnosis (vs. 3% of controls), and this had increased to 20% 10 years later . In one population-based study involving 350 diabetic patients (and 344 age-matched and sex-matched controls), the prevalence of DPNP, as assessed by structured questionnaire and examination, was estimated at 16%. It was notable that, of these patients, 12.5% had never reported symptoms to their doctor and 39% had never received treatment for their pain . In a more recent cross-sectional study in which DPNP was assessed by survey of symptoms, neurological history and examination, 26% of patients with type 2 diabetes were shown to have DPNP. Of these, 80% reported moderate-to-severe pain and this was associated with curtailment of quality of life . In the EURODIAB prospective study nearly a quarter developed neuropathic symptoms over a 7-year period . Thus a significant number of our diabetic patients suffer from neuropathic pain. Unfortunately, unlike in DPN where the risk factors are reasonably well defined, the risk factors for DPNP are not known, although data from the EURODIAB cohort suggest that female sex is an independent-risk factor .
Acute painful neuropathies
DPNP may present acutely within the context of very poor glycaemic control, typically in type 1 individuals (acute painful neuropathy of poor glycaemic control)  or after initiation of treatment (acute painful neuropathy of rapid glycaemic control) . These acute syndromes are relatively rare compared with the chronic painful neuropathy associated with DPN. In these acute painful neuropathies there is a very rapid build-up of unpleasant sensory symptoms within weeks leading to persistent lower limb burning pain, paraesthesiae and allodynia, with a nocturnal exacerbation and depression [12,13]. There may also be marked precipitous weight loss . Sensory loss is often mild or absent, and there are no motor signs [12,13]. Fortunately, in acute painful neuropathies there is complete resolution of symptoms within year .
Mechanisms of neuropathic pain in diabetes
The exact pathophysiological mechanisms of neuropathic pain in diabetes remain unknown although several mechanisms including neurostructural correlates for painful neuropathy been postulated (Table 1) . More recently, in-vivo studies have shown an increase in sural nerve epineurial blood flow in individuals with DPNP compared with those with painless DPN . The study thus suggests that haemodynamic factors may have important role in the pathogenesis of neuropathic pain and may offer further insight into potential treatments for this distressing condition. Another recent study measured foot skin vasodilator responses to acetylcholine and sodium nitroprusside as well as vasoconstrictor responses to sympathetic stimulation, and found an impairment of cutaneous endothelium-related vasodilatation and C-fibre mediated vasoconstriction in DPNP . Sorensen et al. examined intraepidermal nerve fibres (IENFs) to evaluate the role of small nerve fibres in the genesis of neuropathic pain . They found more severe loss of IENF is associated with the presence of neuropathic pain in individuals with early neuropathy.
Recent studies are also increasingly showing the damaging insult of diabetes to be at all levels of the nervous system, from the level of the peripheral nerve to the brain. There is now MRI evidence for the involvement of the spinal cord in DPN  and this appears to be early . Lesions in the spinal cord may result in pain syndromes similar to those seen after spinal cord injury or demyelination . In some patients with painful neuropathy, there may be little in the way of abnormalities on clinical examination or electrophysiological parameters, but there may be evidence of marked abnormalities in somatosensory evoked potentials within the spinal cord . Recently, studies using magnetic resonance (MR) spectroscopy have also demonstrated the presence thalamic neuronal dysfunction in painless  but not DPNP , suggesting that a functioning thalamus, which is the gateway to all sensory information, is required in order to perceive pain . It is thus increasingly clear that the impact of diabetes on the nervous system is far more generalized than previously thought. This has opened a whole new area for further research and modern imaging techniques are currently investigating the full extent of involvement of the central nervous system in both DPN and DPNP.
Advances in pain imaging
Recent advances in neuroimaging methods have led to better understanding and refinement of how pain is represented in the cerebral cortex. Early descriptions of pain pathways in humans consisted of relatively simple connections from primary nociceptors to spinal cord and to thalamus, finally terminating in the cerebral cortex. Functional MRI (fMRI) and positron emission tomography studies have subsequently modified this ‘hard-wired circuits’ view to a more plastic and integrative model, revealing that pain is so much more than sensation.
Studies based on fMRI have investigated changes in brain activity in response to various experimental stimuli inducing pain. This has led to the characterization of a network of brain areas that consistently activate in response to pain, forming a ‘pain matrix’ . These cortical and subcortical brain networks (regions) comprise the primary and secondary somatosensory cortices, the insular cortex, the anterior cingulate cortex, the thalamus and the prefrontal cortex. These regions are primarily responsible for discriminating location and intensity of painful stimuli together with affective pain processing. Disruption of the cortical and subcortical brain regions that form the pain matrix, and the pathways between them, are thought to have implications for the pathogenesis and persistence of neuropathic pain. These studies, however, have been performed mainly in healthy volunteers following acute pain stimulation, and changes in the brain associated with chronic pain in the context of diabetes need to be investigated.
We have recently looked at the fMRI to acute, lower limb heat pain in healthy volunteers, nonneuropathic diabetic and neuropathic individuals with and without painful symptoms . There was significantly lower fMRI response to acute heat pain stimulation in the diabetic cohort compared with healthy volunteers. There was no difference between nonneuropathic diabetic and healthy volunteers but those with DPNP showed significantly greater response than those with painless DPN. The neuroanatomical areas that showed a greater response in the DPNP group include the primary somatosensory cortex, lateral frontal and cerebellar regions .
Recent advances in the management of diabetic peripheral neuropathic pain
The assessment and management of neuropathic pain continues to pose considerable challenge to clinicians [5,16]. A careful history and peripheral neurological/vascular examination of the patient is essential in order to exclude other possible causes of leg pain such as peripheral vascular disease, prolapsed intervertebral discs, spinal-canal stenosis etc. Unilateral leg pain should arouse a suspicion that the pain may be due to lumbar–sacral nerve root compression. These patients may well need to be investigated with a lumbar–sacral MRI. The quality and severity should be assessed preferably using a suitable pain rating scale [e.g. visual analogue scale (VAS) or numeric rating scale (NRS)], so that response to treatment may be evaluated. Most importantly, an empathic approach with a multidisciplinary team support is crucial as the psychological impact of DPNP is considerable [4,5,16].
Although there is strong evidence for importance of tight glucose control in delaying and possibly preventing the onset of DPN, the same cannot be said for DPNP. However, despite the lack of well designed, controlled studies looking at the impact of intensive glycaemic control in patients with DPNP, there is a general consensus that good blood glucose control should be the first step in the treatment of any form of diabetic polyneuropathy. Traditional markers of large vessel disease including hypertension, obesity, hyperlipidaemia and smoking also appear to be independent risk factors for DPN  and therefore need also to be effectively managed by life style change and drug therapy.
Pharmacological treatment of diabetic peripheral neuropathy
Table 2 shows the range of pharmacological treatments for painful diabetic neuropathy.
Only two (duloxetine and pregabalin) are formally approved for the treatment of DPNP by the FDA. Pain reduction of over 50% is considered clinically significant.
Several randomized controlled trials have demonstrated the efficacy of tricyclic compounds (TCAs) in DPNP [28–30]. However, TCAs also have many side effects including anticholinergic effects such as dry mouth, sweating, sedation, and dizziness. As there is nocturnal exacerbation of painful symptoms treatment is ideally started with a small dose (10–25 mg) of either amitripyline or imipramine at night and this will assist with sleep. The dose is then gradually titrated depending on adverse events and efficacy. In addition, recent data from a retrospective study including 58 956 person years follow-up on TCA therapy, indicate an increased risk of sudden cardiac death associated with TCA doses in excess of 100 mg/day . There is thus a good rationale for not prescribing TCAs to diabetic patients with cardiovascular disease. Also in those with autonomic neuropathy care should be taken not to exacerbate symptoms of postural hypotension with TCAs.
Selective serotonin noradrenaline reuptake inhibitors
Selective serotonin noradrenaline reuptake inhibitors (SNRIs) such as duloxetine relieve pain by increasing synaptic availability of 5-HT and noradrenaline in the descending pathways that are inhibitory to pain impulses. The efficacy of duloxetine in painful DPN has been investigated in three identical trials [31–33] and pooled data from these shows that the 60 mg/day and 120 mg/day doses are effective in relieving painful symptoms, starting within a week. Efficacy was maintained throughout the treatment period of 12 weeks, and 45–55% of patients achieved at least 50% pain reduction.
The number needed to treat (NNT) to achieve at least 50% pain reduction (clinically meaningful pain reduction) was 4.9 for 120 mg/day, and 5.2 for the 60 mg/day. A particular advantage of duloxetine was that there was no weight gain during prolonged treatment of upto a year.
Venlafaxine 75 mg/day and 150–225 mg/day were compared with placebo, in 244 diabetic patients with DPNP, in a 6-week trial. There was significant pain relief in the higher dose-group but not in the lower dose . Side effects included somnolence, nausea, hypertension and rather worryingly seven patients treated with venlafaxine developed clinically significant ECG changes . This is a major concern as many diabetic patients have coexistent cardiac disease.
Gabapentin and pregabalin bind to the α-2-δ subunit of the calcium channel reducing calcium flux, and thus resulting in reduced neurotransmitter release in the hyperexcited neurone.
Gabapentin, titrated from 900 mg/day to 3600 mg/day over 4 weeks followed with another 4 weeks at the maximum dose, has been compared with placebo . 59.5% in the treatment arm, 67% of whom received the highest dose of gabapentin, achieved at least 50% reduction in pain compared with 32.9% with placebo.
Evidence for the efficacy of pregabalin in DPNP is even better as there have been several clinical trials in DPNP that demonstrated its efficacy compared with placebo . One study looked at a combined analysis of six controlled trials of 5–12 weeks duration, and found 39 and 46% of patients with DPNP treated with pregabalin 300 mg/day and 600 mg/day, respectively, achieved at least 50% pain relief . Data from seven clinical trials involving pregabalin showed an NNT of 4.04 for the 600 mg/day and 5.99 for the 300 mg/day [37•]. Only the 600 mg/day dosage showed efficacy when administered BID [37•]. The median time to onset of a sustained (≥30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day and 5 days in patients treated with pregabalin at 300 mg/day [37•].
The opiate derivative tramadol has been found effective in relieving neuropathic pain . Another opiod, oxycodone slow release has also been shown effective in the management of neuropathic pain .
Although clinicians are rather conservative in the use of opioid agonists, prescribing them mainly as an add-on to other therapy, there is little clinical evidence to support this approach. In one crossover study, low-dose combination therapy with gabapentin and morphine was significantly more effective than either monotherapy at a higher dose . However, combination treatment was associated with a higher frequency of adverse effects than monotherapy . Recently, prolonged-release oxycodone was also found to enhance the effects of existing gabapentin therapy in patients with DPNP .
Topical capsaicin works by depleting substance ‘P’ from nerve terminals, and there may be worsening of neuropathic symptoms for the first 2–4 weeks of application. Topical capsaicin (0.075%) applied sparingly 3–4 times per day to the affected area has also been found to relieve neuropathic pain .
Lacosamide is a promising anticonvulsant for the treatment of painful DPN. In a phase-2 study lacosamide was found to be beneficial in relieving DPNP but phase 3 studies are now required .
A meta-analysis including 1258 patients from four prospective trials showed that treatment with α-lipoic acid (600 mg/day intravenously) for 3 weeks was associated with significant and clinically meaningful improvement in positive neuropathic symptoms (pain, burning, paraesthesia and numbness), as well as neuropathic deficits . Oral treatment with α-lipoic acid for 5 weeks improved neuropathic symptoms and deficits in patients with DPN . An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio , but a confirmatory larger trial may be required.
Figure 2 compares the NNTs for the various drugs in painful neuropathy including DPNP . The size of circles corresponds to the total number of patients used in trials. TCAs have the lowest NNTs . However, some of the clinical trials were crossover, and that is likely to lower the NNT . TCAs also have increased risk of adverse side effects, including sedation; dry mouth, sweating, dizziness, as well as contraindications for use in heart disease, epilepsy and glaucoma . The largest number of patients in trials involved pregabalin, duloxetine, and gabapentin, and these compounds appear to have similar intermediate efficacy (Fig. 2). Nausea is more common for duloxetine [31–33] whereas dizziness and somnolence are more common for pregabalin and gabapentin [35,36,37•].
A recent consensus meeting carefully evaluated the trial evidence for the various pharmacological treatments for painful DPN and suggested a treatment algorithm  (Fig. 3). The panel compared the relative efficacy and safety of treatments for painful DPN, based on the available NNT for neuropathic pain (including painful DPN) and NNH data, and recommended that a TCA, SNRI or an α-2-δ agonist should be considered for first-line treatment of painful DPN (Fig. 3). On the basis of trial data, duloxetine the preferred SNRI and pregabalin would be the preferred α-2-δ agonist. Initial selection of appropriate treatment may depend on assessment of comorbidities and contraindications as well as cost. In diabetic patients with a history of heart disease, elderly patients on other concomitant medications such as diuretics and antihypertesives, patients with comorbid arthostatic hypotention etc., TCAs have relative contraindication. In those with liver disease duloxetine should not be prescribed and in those with oedema pregabalin or gabapentin should be avoided. If pain is inadequately controlled, depending on contraindications, a different first-line agent may be considered.
Combination of 1st line therapies may be considered if there is pain, despite a change in first-line monotherapy (Fig. 3). If pain is inadequately controlled opiods such as tramadol and oxycodone may be added in a combination treatment.
Lack of response and unwanted side effects of conventional drug treatments forces many sufferers to try alternative therapies such as acupuncture , near-infrared phototherapy , low intensity light amplification by stimulated emission of radiation (LASER) therapy , magnetic field therapies  and transcutaneous electrical stimulation (TENS) , frequency modulated electromagnetic neural stimulation (FREMS) therapy [51,52], high frequency external muscle stimulation  and as a last resort, implantation of electrical spinal cord stimulator .
Electrical spinal cord stimulation
Neuropathic pain can sometimes be extremely severe, interfering significantly with patients' sleep and daily activities. Unfortunately, some patients are not helped by conventional pharmacological treatment. Such patients pose a major challenge for they are severely distressed and sometimes wheelchair bound. The last option for such patients is electrical spinal cord stimulation that has been found to relieve both background and peak neuropathic pain . This form of treatment is particularly advantageous, as the patient may not require any other pain relieving medications, with all their side effects. Clearly, as the procedure is invasive it is reserved as a last option and is available in specialist centres. A recent follow-up of patients fitted with electrical spinal cord stimulators found that stimulators continued to be effective 10 years after implantation .
Another recent prospective, open-label study looked at 11 diabetic patients with chronic pain in their lower limbs and with no response to conventional treatment . Nine individuals had significant pain relief with the electrical stimulator 6 months after implantation and eight patients were able to significantly reduce their pain medication. For six of them, the stimulator was the sole treatment for their neuropathic pain .
DPNP is a significant clinical problem affecting 10–20% of all diabetic patients. Despite this it continues to be underdiagnosed and undertreated, and this unsatisfactory scenario must change. The minimum requirements for diagnosis of DPNP are assessment of symptoms and neurological examination, with shoes and sock removed. Bilateral sensory impairment is almost always present. First-line therapies for DPNP are a TCA, SNRI (such as duloxetine) or anticonvulsants (such as pregabalin or gabapentin), taking into account patient comorbidities and cost. Combination therapy may be useful but further research is required. For intractable painful neuropathy that doesnot respond to any pharmacological and simple nonpharmacological treatments consider implantable electrical spinal cord stimulator. Studies are required on direct head-to-head comparative trials and long-term efficacy of drugs, as most trials have lasted less than 16 weeks.
There is also a need for further controlled trials to investigate nonpharmacological treatments.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 149–150).
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