Painful Diabetic Neuropathy ( PDN ) : An Update for Clinicians

Neuropathy is one of the most common complications in both type I and type II diabetes mellitus. It can present in various forms, either focal or symmetrical. The most common form is a chronic, symmetrical, length dependent axonal sensorimotor polyneuropathy. This disease can also affect the autonomic nervous system and plays an important role in other subsequent complications. Some patients are asymptomatic, but many patients have sensory symptoms, either negative or positive ones. These symptoms may fl uctuate over time. Some of them also have pain associated with neuropathy, so called painful diabetic neuropathy (PDN). As Jambart et al noted about Middle Eastern patients: “The odds of painful DPN were highest among patients with peripheral vascular disease, diabetic retinopathy and diabetic nephropathy.”

Diabetes mellitus is also the most common cause of distal symmetric polyneuropathy. 4Therefore, it is the most common cause of neuropathic pain. 5The prevalence of neuropathic pain in the diabetic population varies enormously according to different studies which estimate a range between 3% and 50% of patients. 3,6 recent survey in the United Kingdom revealed the prevalence of 26.4% and 80% of patients reporting moderate to severe pain. 7aving PDN has a signifi cant negative effect on the quality of life, especially the physical aspect, and a signifi cantly worse trajectory of quality of life outcomes over time and long-term increased total costs. 7,8

PDN pain syndrome
The diagnosis of PDN is a clinical one, which relies on the patient's description of pain.The symptoms are distal, symmetrical, often associated with nocturnal exacerbations, and commonly described as prickling, deep aching, sharp, like an electric shock, and burning with hyperalgesia and frequently allodynia upon examination. 1,9The symptoms are usually associated with the clinical signs of peripheral neuropathy, although occasionally in acute painful diabetic peripheral neuropathy (DPN), the symptoms may occur in the absence of signs.
Common painful symptoms also include sharp or lancinating pain attacks, allodynia, cramping and gnawing. 10,11These symptoms are commonly used in rating scales and standard pain questionnaires to assess frequency and severity of painful symptoms, and treatment response.Moreover, since each type of pain is believed to be caused by a different pathophysiological mechanism, therefore, each neuropathic pain medication might have a different effect on sensory symptoms. 12espite the advances in neurophysiologic studies, diagnosis cannot be made without taking a full history and giving a physical examination.Incorporating standard pain questionnaires in clinical evaluation will also aid earlier diagnosis and better management in these patients. 11n our study, 13 we used the DN4 questionnaire, which has been validated as a reliable screening tool for neuropathic pain in diabetic patients. 14The questionnaires can be used to screen and differentiate between neuropathic and non-neuropathic pain. 15Almost all patients had more than one type of pain which adds more complexity to the clinical evaluation. 13This may imply that the mechanism of pain is most likely due to small nerve fi bers, rather than large fi ber dysfunction.Previous clinical and electrophysiological studies also confi rmed that the neuropathic pain in diabetic polyneuropathy is not associated with the degree of involvement of large diameter sensory fi bers or the severity of the diabetes. 16,17nterestingly, when looking at sharp pain, the duration of diabetes was not associated with painful symptoms. 13This was due to the natural history of small fi ber neuropathy which can occur in the pre-diabetes stage. 18Although the pain of PDN may resolve completely over time in some patients, in those in whom painful neuropathic symptoms had persisted over 5 years, no signifi cant improvement in pain intensity was observed. 19

Impact of PDN upon quality of life
The presence of PDN signifi cantly affected patients' quality of life, especially physical function.Moreover, it was associated with a signifi cantly worse trajectory of quality of life outcomes over time and long-term increased total costs, when comparing to patients with non-painful diabetic polyneuropathy.The presence and severity of neuropathic pain were associated with greater impairments in a number of important Health Related Quality of Life (HRQoL) domains. 8,16,20,21Regarding the SF-36 subcategories, pain symptoms had more effect on physical function and role-physical, than social function and emotional well-being. 133][24] When comparing to other diabetic populations and other diseases, PDN patients had a poorer physical function than those with other chronic neurological illnesses or the general diabetic population. 25Their QOL was similar to that of diabetic foot ulcer patients, which indicated severe disability.
A recent American Academy of Neurology evidence-based review has used Visual Analog Scale (VAS) as a primary measure and physical function and QOL, e.g.SF-36 as guidelines for effi cacious assessment, in order to formulate recommendations for pharmacological treatment of painful diabetic polyneuropathy. 26owever, in clinical trial situations, Quantitative Sensory Testing (QST) is still necessary for a more objective measurement of outcome, as well as HRQoL. 21,27

Treatment of PDN
Regarding the symptomatic treatment of this condition, Thai and international guidelines recommend the use of tricyclic antidepressants (TCA) e.g.amitriptyline, nortriptyline and calcium channel ligands (e.g.gabapentin, pregabalin) as fi rst line treatments. 5,9,26,28The second and third line medications are selective norepinephrine serotonin reuptake inhibitors (SNRIs) e.g.venlafaxine and duloxetine and opioids (e.g.tramadol, oxycodone and morphine).However, using strong opioids in this indication should be reserved for severe and refractory cases under pain specialist supervision.Capsaicin cream and percutaneous electrical nerve stimulation can also be used as adjunctive treatments, with less systemic side effects. 5,26 n comparing the effi cacy of each medication according to number needed to treat (NNT) for 50% pain reduction, TCA and opioid are slightly more effective than other groups.They are followed by calcium channel ligands and SNRIs. 29The medication selection should also consider other factors, such as type of pain, pharmacokinetics, co-existing symptoms or diseases, side effects and price.Recommended medications and dosage of neuropathic pain medication were summarized in Table 1.
Despite the improvement in treatment modalities for chronic pain in recent years, patients with PDN continue to be inadequately treated.The different profi les of pain quality and spatial characteristics suggest that assessing patterns of pain symptoms might contribute to the identifi cation of distinct pathophysiologic mechanisms, subgroups of patients and the development of mechanism -based treatment approaches. 31,32This will eventually improve the outcome and qualities of life in these patients.

Conclusion
Neuropathy is one of the most common complications in both type I and type II diabetes patients.The most common form is the chronic, symmetrical, length dependent, axonal sensorimotor polyneuropathy which affects either large or small sensory nerve fi bers, or autonomic nerve fi bers.Many patients suffer from neuropathic pain due to this condition, so called painful diabetic neuropathy.Generally, various types of pain can occur in the same patient in moderate to severe degree.Symptomatic treatment and pain control are the main therapeutic strategies.Many national and international organizations have recommended tricyclic antidepressants and calcium channel ligands as fi rst line treatment options.This will eventually prevent other related complications and should improve the patient's quality of life.