Managing Diabetic Peripheral Neuropathic Pain (DPNP)
Because of the prevalence of overweight (BMI 25-29.9) and obesity (30-39.9) in the United States, the incidence of diabetes is increasing.1 By the year 2010, the World Health Organization (WHO) estimates that there will be 220 million people with this disease worldwide.2 These statistics demonstrate the need to educate the physician not only about diabetes prevention and management, but also the treatment of its many complications, including peripheral neuropathy. Nearly a quarter of diabetics suffer from diabetic peripheral neuropathy now and up to 50% of all diabetics develop peripheral neuropathy after 25 years of having their disease.3 The annual incidence rate is 2%.4 Patients with diabetic peripheral neuropathy manifest painful symptoms, which are commonly characterized as burning, aching, tingling, cold, lancinating, allodynia, and/or numbness. Numerous therapeutic agents are available but there is no single therapeutic agent available that is without adverse effects and is completely effective for the general diabetic population.
There are several proposed mechanisms that alter the neural structure and predispose a patient for the development of peripheral neuropathy. These include advance glycation end products (AGEs), protein kinase C (PKC), oxidative stress, and the Polyol pathway, all of which ultimately lead to the damage of nerves. Understanding more about these individual pathophysiologic changes is important for two reasons. First, these mechanisms serve as a basis for the pharmacological action of various medications such as PKC inhibitors, which are now in clinical trials. In contrast, most of the currently recommended pharmacologic agents target the aberrant or ectopic neural signaling which are consequences of the neural damages. Second, hyperglycemia has been suggested as a catalyst for the neural tissue’s conversion from normal physiologic behavior to the pathologic state pain-producing state. Therefore, there is an emphasis on good glucose control for the prevention of pain and the progression of diabetic peripheral neuropathy.
Beyond the mechanisms of neural destruction, the types of nerves damaged translate into the pattern of clinical symptoms and signs that the patient may report and exhibit. Small nerve fiber damage produces abnormalities in the sensation of temperature, light touch, pin prick, and pain typically experienced in the early stages of DPN.5 Later, large nerve fiber damage produces diminished vibration sensation, position sense, muscle strength, sharp-dull discrimination, and two-point discrimination.5
|Advanced glycation end products (AGES)||Formed during the Maillard reaction, advanced glycation end products (AGEs)6 act on specific receptors (RAGEs), inducing monocytes and endothelial cells to increase the production of cytokines and adhesion molecules.7 AGEs can form cross-links in matrix structural proteins induce mutagenesis of bacterias, physiologically increase in number as patient ages, and in pathologic states like diabetes and renal failure.6|
|Protein Kinase C (PKC)||A family of 12 isoenzymes, PKC is activated by phosphorylation and is involved in intracellular signaling and binding to the second messenger diacylglycerol.4 Conditions with increased levels of glucose have found increased levels of PKC and diacyclglycerol in retinal, aortic, and renal tissue but decreased in neural tissues.4 However, PKC inhibitors studies suggest improvement in Na+-K+ ATPase activity, which contributes to the diminished NCV in diabetes.4|
|Oxidative Stress||Radicals are generated from glucose metabolism to produce ATP. 4 Radicals, such as superoxide anion, are capable of profound tissue damage as well as diacyclglycerol synthesis, which activates PKC.4|
|Polyol Pathway||This is generally a physiologic catabolic pathway supplied by intracellular glucose. It becomes pathologic when excessive glucose increases the reduction and regeneration of glutathione requiring NADPH. This results in an imbalance NADHPH/NAD ratio that causes depletion of glutathione, increases AGEs, and activates PKC and diacylglycerol4. The first redox reaction of this pathway produces sorbitol. Accumulation of this compound was once thought to be destructive to nerves; however, a study was conducted showing insignificant levels of sorbitol in diabetic patients.4|
|Diabetes Mellitus (DM)|| |
|Impaired Glucose Tolerance (IGT)|| |
During the clinical encounter, there are several points that must be considered for patients with suspected diabetic peripheral neuropathy. First, some patients may not reveal symptoms immediately, but these can be detected through proper inquiry. There are also patients who are asymptomatic, but manifest signs during the physical exam. To elicit these signs, there are several tests that can be performed such as checking for pinprick sensation, temperature sensation, vibration perception with a 128-hz tuning fork, pressure sensation using a 10-g microfilament at the distal halluces, and the ankle reflexes.8 Having more than one abnormality noted gives a >87% sensitivity in detecting diabetic peripheral neuropathy.8 These simple measures are not only sensitive for the detection of diabetic peripheral neuropathy, but help to predict further complications associated with diabetes. The combined loss of the 10-g monofilament pressure sensation and reduced vibration perception predicts the real risk for developing foot ulcers.8