Review Article Open Access
Diabetic Peripheral Neuropathy: Current Concepts and Future Perspectives
Ashok K Saxena*, Shivika Nath and Ruchi Kapoor
Department of Anesthesiology and Pain Management UCMS, University of Delhi and GTBH 110095, India
*Corresponding author: Ashok K Saxena, Department of Anesthesiology and Pain Management, UCMS, University of Delhi and GTBH 110095, India, Tel: +09869300703, E-mail: @,
Received: May 12, 2015; Accepted: December 03, 2015; Published: December 25, 2015
Citation: Saxena AK, Nath S, Kapoor R (2015) Diabetic Peripheral Neuropathy: Current Concepts and Future Perspectives. J Endocrinol Diab 2(5): 1-18.
Abstract Top
Background: Peripheral Diabetic Neuropathy (PDN) is the clinical condition and one of the most common complications of diabetes affecting approximately 50% of people. Out of it, 16% to 33% of the patients manifest Neuropathic Pain (NP) associated with PDN. Neuropathic Pain in PDN arises due to nerve fiber injury both at the central and peripheral level and the pain is so severe that these patients have higher health care costs due to hospitalizations that are more frequent and thus, it affects their quality of life. Management of PDN includes both preventions of hyperglycemia and cardiovascular risk factors known to exacerbate neuropathy and the treatment of neuropathic pain. This review article focuses on current aspect and future perspective of epidemiology, basic understanding and recent advances of the mechanisms and therapeutics of PDN.

Methods: All relevant data, RCTs, meta-analysis, review article and case reports (1976-2014) with relevance to PDN were accessed and incorporated in this review article.

Results: In the results we describe here the treatment protocol of neuropathic pain including PDN according to (NeuPSIG) The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines, Canadian pain society (CNS), European Federation of Neurological Societies guidelines (EFNS), American Academy of Neurology (AAN), American Association of Neuromuscular and Electrodiagnostic Medicine guidelines (AANEM). NeuPSIG guidelines recommend the use of TCAs, duloxetine, Venlafaxine, gabapentin, pregabalin and topical lidocaine as first line therapy. Tramadol and opioids as a second line and certain antidepressant medications (eg., bupropion, citalopram and paroxetine), certain antiepileptic medications (eg., carbamazepine, lamotrigine, oxcarbazepine, topiramate, and valproic acid), topical low-concentration capsaicin, dextromethorphan, memantine, and mexiletine as third line therapy. According to Canadian Pain Society, the analgesic agents for Neuropathic Pain including PDN are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin) as a first line. Second-line treatments recommended are serotonin-noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Fourth-line treatments include cannabinoids, methadone, and anticonvulsants (lamotrigine, topiramate and valproic acid), but this line of medications has lesser evidence of efficacy. EFNS Guidelines recommended TCA, gabapentin, pregabalin and SNRI [selective serotonin norepinephrine reuptake inhibitors (duloxetine, venlafaxine)] as first-line treatment in Painful Peripheral Neuropathy (PPN) particularly in PDN. Tramadol is recommended as second line except for patients with exacerbations of pain (for the tramadol/ acetaminophen combination) or those with predominant coexisting non-neuropathic pain. Third-line therapy includes strong opioids. According to AAN, AANEM, and AAPM&R evidence-based guidelines for the treatment of painful diabetic neuropathy, they classified the therapy into recommended and non-recommended drugs where recommended drugs include pregabalin, gabapentin, valproate, Venlafaxine, duloxetine, amitriptyline, Dextromethorphan, morphine sulfate, tramadol, oxycodone, capsaicin, isosorbide dinitrate spray and electrical stimulation.

Conclusion: In conclusion, PDN, being the most important underlying causes for neuropathic pain, remains a challenging condition to manage. It requires increased level of awareness and special communication between patients and pain specialist to the extent that all decisions about which therapy to start with and when to switch over to the next option with an alternative mechanism of action are especially needed.
Introduction
Neuropathic pain is defined by International Association for Study of Pain (IASP) as pain arising as a direct consequence of lesion or disease of the system either somatosensory system either at peripheral or central level [1]. Diabetic neuropathy and Postherpetic neuralgia are major causes of neuropathic pain. It has been seen that neuropathy is a common complication of diabetes, affecting up to 50% of patients [2-6]. A consensus statement produced by an international meeting on the diagnosis and management of diabetic neuropathy defined it as "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes."[7]. Although, there are many types of neuropathy with a variety of clinical presentations. This article focuses on one type of neuropathy, Peripheral Diabetic Neuropathy (PDN). In this review, we will focus on current aspect, future perspective, epidemiology, basic understanding and recent advances in mechanisms and management of diabetic neuropathy.
Epidemiology
Peripheral Diabetic Neuropathy (PDN), the most common complication of diabetes, is defined as a symmetrical, lengthdependent distal sensorimotor polyneuropathy, a consequence of metabolic and microvascular alterations. PDN is the clinical condition [8] and approximately 50% patients will have pain as a symptom of neuropathy [9]. This pain is very severe and usually exacerbated by activity and relieved with rest and very different from musculoskeletal pain or vascular insufficiency. Because of the severity of pain, the quality of life of patients affected and increases health care cost [10,11].

The prevalence of DPN in the United States is approximately 50% of patients with type 1 and type 2 diabetes [2] and 16% to 33% of people with diabetes of >25years develop PDN [4], thus it is a common clinical problem. One study conducted in Finland found a prevalence of neuropathy up to 8.3% in newly diagnosed type 2 diabetes [12]. Discussing the pathophysiology, hyperglycemia is highly correlated with the development and progression of all neuropathies, including PDN [13,14]. The Diabetes Control and Complications Trial (DCCT) showed that tight glycemic control will reduce the incidence of neuropathy by 60 % [15] However, even in patients with long-term excellent glycemic control (A1C < 8%), the lifetime incidence of PDN remains 20% [16].

Other risk factors thought to be associated with diabetic neuropathy are hyperlipidemia, hypertension, cigarette smoking, consumption of alcohol, and weight. However, there has been no absolute evidence regarding the association of attributing these risk factors in reducing diabetic neuropathy or any other longterm complications. Although prevention of these risk factors may reduce an incidence of coronary artery disease, peripheral vascular disease, and stroke.
Pathophysiology
Neuropathic Pain is a complex, chronic pain state that usually is accompanied by tissue injury. It is common in clinical practice and presents a challenge to patients and clinicians alike. With neuropathic pain, the nerve fibers are damaged, may become dysfunctional or injured. Neuropathic Pain is the result of disease or injury to the peripheral or central nervous system (spinal or supraspinal nervous system) and the lesion may occur at any point. These damaged nerve fibers include a change in nerve function- both at the site of the injury and areas around the injury [17] and they send incorrect signals to other pain centers. The impact of a nerve fiber injury includes a change in nerve function—both at the site of the injury and areas around the injury [17]. Clinical manifestations of Neuropathic Pain typically include positive sensory phenomena such as spontaneous pain, paraesthesias, allodynia, and hyperalgesia [18]. Features that differentiate Neuropathic Pain from other types of pain include pain and sensory symptoms lasting beyond the healing period.

The theories regarding the pathophysiology of Neuropathic Pain are multiple. Before going into details, a short review regarding pain circuit is needed. There are two types of pain circuits: facilitatory and inhibitory circuits' facilitatory circuit responsible for pain sensation, and is particularly mediated by glutamate (excitatory neurotransmitter) mediated receptors. The inhibitory circuits cause pain suppression mainly mediated by GABA (gamma amino butyric acid), which is an inhibitory neurotransmitter. The mechanism underlying neuropathic pain, however, is not as clear. Several animal studies have shown that many mechanisms may be involved. First order neurons may increase their firing if they are partially damaged due to increase in the number of sodium channels and thus enhanced depolarization leads to spontaneous pain and movement-related pain. Impairment of Inhibitory circuits at the level of the dorsal horn or brain stem allows uninhibited transmission of pain impulses. In addition, there are several changes in the central processing of pain where there is increased the sensitivity of spinal neurons and decrease in activation thresholds resulting in central sensitization phenomenon operating in patients of diabetic neuropathy. Raja, et al. [19] in an interesting study described that blockade of α -adrenergic receptor function with intravenous infusion of the antagonist phentolamine also leads to pain relief. Thus, there also can be the affiliation of the sympathetic nervous system towards neuropathic pain.

The exact mechanism of nerve damage in diabetic neuropathy is still unclear, metabolic and vascular/hypoxic factors appear to be involved [20]. Advance Glycosylation End Products (AGEP) may damage capillaries; inhibit axonal transport leading to axonal degeneration. Increase production of sorbitol due to activation of polyol pathway causes structural nerve damage. Also, increased endoneurial vascular resistance to hyperglycemic blood can lead to nerve ischemia.
Classification
In the present review article, our emphasis is primarily on painful diabetic neuropathy, which is a polyneuropathy, and here we will classify based on the above only. There are two types of PDN (a) acute sensory neuropathy and (b) chronic sensorimotor neuropathy. Acute sensory neuropathy is usually associated with hyperglycemia and resolves with normal glucose levels. It is without associated signs. Chronic sensorimotor neuropathy causes long-term pain. In next Para, we have described the chronic distal sensory and sensorimotor polyneuropathy.
Symptoms and Signs of Distal Sensory and Sensorimotor polyneuropathy
Thomas, et al has described the commonest variety of neuropathy in diabetic patients, distal sensory neuropathy where insidious onset is common [22]. Initially small and large fibers may be affected in varying degrees, but later typically, both are affected. This is a length-dependent process, and a distal part of the longest nerves affected earliest. Thus, the earliest symptoms typically involve the toes and then ascend. The arms are involved later, less often and less severely, also in a distal-toproximal pattern. Early arm involvement warrants consideration of entrapment neuropathies. If severe, the midline abdomen and the head may be involved. The most common symptoms are numbness, tingling, and pain. Commonly patients present
Table 1: Classification of Diabetic Neuropathy.
Florian P Thomas, the spectrum of neuropathy, Associate Professor of Neurology, Molecular Virology, and Molecular Microbiology and Immunology Saint Louis VA Medical Center, Saint Louis University School of Medicine Saint Louis, MO 63110 ThomasFP@slu.edu) [24].
Table 2: AAN, AANEM, and AAPM&R evidence-based guidelines for the treatment of painful diabetic neuropathy (Bril, et al. [99]).

Level

Recommended

Not Recommended

A

Pregabalin 300–600 mg/ day

Oxcarbazepine

B

Gabapentin (900–3600 mg/ day)

Lamotrigine

 

Valproate 500–1200 mg/ day

Lacosamide

 

Venlafaxine 75–225 mg/ day

Clonidine

 

Duloxetine 60–120 mg/ day

Pentoxifylline

 

Amitriptyline 25–100 mg/ day

Mexiletine

 

Dextromethorphan 400 mg/ day

Magnetic field Stimulation

 

Morphine sulphate titrated to 120 mg/ da

Low-intensity laser treatment

 

Tramadol 210 mg/ day

Reiki therapy

 

Oxycodone, mean 37 mg/ day, maximum 120 mg/ day

-

 

Capsaicin, 0.075% QID

-

 

Isosorbide dinitrate spray

-

 

Electrical stimulation percutaneous nerve stimulation × 3–4 weeks

-

AAN: American Academy of Neurology; AANEM: American Association of Neuromuscular and Electrodiagnostic Medicine; AAPMR: American Academy of Physical Medicine and Rehabilitation
Table 3: AAN, AANEM, and AAPM&R evidence-based guidelines for the treatment of painful diabetic neuropathy (Bril, et al. [99]).

Cognitive behavioral therapy

Elderly patients with neuropathic pain

Relaxation Techniques

Chronic Pain

Acupuncture

Spinal Cord Injury

Mirror Therapy

 

Phantom Pain Complex Regional Pain Syndrome (CRPS)

Stroke

 

Graded Motor Imagery

Stroke

Visual Illusion

Spinal Cord Injury

AAN: American Academy of Neurology; AANEM: American Association of Neuromuscular and Electrodiagnostic Medicine; AAPMR: American Academy of Physical Medicine and Rehabilitation
with foot pain, which can be deep, aching, stabbing tingling, burning, "like water running over the skin, or electric shocklike, or increase the sensitivity of pain even on light touching (allodynia-like). The pain get worse at night and disturb sleep and sometimes it is associated with numbness, and patients may describe this sensation like "wearing gloves or socks". Gait ataxia may be reported with increased number of falls. Distal weakness is less common and occurs in later stages. Examination generally demonstrates distal generalized sensory loss, with reduced or absent ankle jerks with the loss of pinprick sensation [23].
Diagnosis
The diagnosis of PDN is based on symptoms and physical examination, including blood pressure recording, heart rate, muscle strength, reflexes and sensitivity to position changes, vibration, temperature, or light touch, and foot examination. If the patient seems to be positive for peripheral neuropathy, then there is the need for more frequent foot examination where nylon monofilament similar to a hairbrush or von frey hairs is used to assess protective sensation (mechanical nociceptive threshold test). Temperature perception and sense of vibration also need to be assessed. Other tests that can be used to assess the extent of nerve damage include nerve conduction studies or electromyography and sural nerve biopsy.
Nerve conduction velocity/ Electromyography
Since diabetic neuropathy is usually both axonal and demyelinating [25], it leads to chronic neuropathy, and here lower limbs are affected foremost. Thus, Nerve Conduction Velocity (NCV) is highly sensitive to detect a sensory abnormality, which demonstrates conduction slowing and decrease in amplitude. However, sensory responses disappear in more severe cases. Motor NCS may demonstrate slowing and decrease in amplitude in advance cases, even in the absence of neuropathic signs and symptoms.

EMG may be normal in mild or asymptomatic subjects, but demonstrates denervation in more severe cases and worse distally [22,26].

A sural nerve biopsy finding shows loss of myelinated and unmyelinated axons. Demyelination is also seen by fiber teasing and reduplication of the basal lamina [20] leading to the thickness of walls of small neural blood vessels, particularly endoneurial capillaries.

However, other etiologies of painful peripheral neuropathy should also be ruled out. Patients with diabetic neuropathy are also at risk of other types of neuropathy including B12 deficiency, chronic inflammatory demyelinating neuropathy, hypothyroidism, RLS ("Restless leg syndrome"), PLMS ("Periodic limb movement in sleep") and uremia and thus need to be evaluated for the above, including thyroid function tests, ANA (antinuclear antibody), rheumatoid factor, ESR, immunofixation electrophoresis, CBC and iron studies. However, recent reports suggest some of these patients have impaired glucose tolerance [27]. In addition, HIV, HCV also to be ruled out if suspected.
Management
Prevention: It includes strict optimization of blood sugar levels, cessation of smoking, reduction in alcohol intake, control of hyperlipidemia and hypertension. It has been seen that daily intake of aspirin, graded motor imagery [28-30], antioxidant and herbal therapy also have a role in the prevention of PDN.

Treatment: Diverse pharmacological treatments of NP have become available, and interpreting the data on their efficacy and safety involves substantial complexities and ambiguities. Here we will describe the NEUPSIG (The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain) pharmacological guidelines [31], for the management of Neuropathic Pain including painful diabetic neuropathy. According to Dworkin RH, et al. [31] Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel α2- δ2 ligands (i.e., gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. On the other hand, Opioids and tramadol were recommended as second-line treatments and in exceptional cases, it can be considered for first-line use. Third line medications include certain antidepressant medications (e.g., bupropion, citalopram, and paroxetine), certain antiepileptic medications (eg., carbamazepine, lamotrigine, oxcarbazepine, topiramate, and valproic acid).

Several recent clinical trials have examined the role of botulinum toxin, [30,31] 8% concentration capsaicin patch [32,33], lacosamide [34-38], selective serotonin reuptake inhibitors [39-42], and combination therapies [43-46] in various Neuropathic Pain conditions.

These consensus guidelines are not applicable on pediatric patients, patients with trigeminal neuralgia (for which separate treatment recommendations are available, [47-50] or conditions that are not clearly NP (e.g., fibromyalgia and irritable bowel syndrome). The guidelines Emphasize on combination therapy because single drug therapy may not provide adequate pain relief to the patients of neuropathic pain.
First Line Therapy
Antidepressants with both norepinephrine and serotonin Reuptake Inhibitors
A large number of placebo-controlled RCTs have found tricyclic antidepressants (TCAs) to be efficacious for several different types of NP [51]. TCAs were introduced in the late 1950s and it is the most studied class of a drugs in the treatment of PDN. This group of drug also treats depression, common comorbidity in patients with chronic pain, but their analgesic efficacy has also been studied. Amitriptyline was the first TCA to be studied in 1977 [52]. It was a serotonin and noradrenaline reuptake inhibitors, it also blocks alpha

Adrenergic, H1- histamine, muscarinic cholinergic, and N-methyl-D-aspartate receptors [53]. Amitriptyline has been a first-line treatment for Neuropathic Pain for many years. Other TCAs include Imipramine which is also a serotonin and noradrenaline reuptake inhibitor and it block a- adrenergic, H1- histamine, muscarinic cholinergic, and N-Methyl-D-aspartate receptors [52]. Imipramine has been studied in six placebocontrolled trials [54–57] and efficacy has not been proven.

TCAs act centrally to reduce the perception of pain. TCAs generally have the lowest NNT (number 1needed to treat) of the medications used to treat PDN. On the basis of trials conducted to evaluate the efficacy of TCAs in patients of PDN, ~30% of patients obtain 50% pain relief. They are also inexpensive and convenient to give due to single daily dosing. However, anticholinergic adverse effects are common and include dry mouth, orthostatic hypotension, constipation, and urinary retention. Low doses initially, titrated dosing or using a secondary amine TCA (Nortriptyline and desipramine are a metabolite of amitriptyline.) reduces these adverse effects. Cardiac toxicity is a concern with TCAs thus according to NeuPSIG guidelines it is recommended to prescribe TCAs with caution in patients with an ischemic cardiac disease or ventricular conduction abnormalities, limiting the dosages to less than 100 mg/d and when possible, electrocardiogram to be done for patients older than 40 years. It takes about 6 to 8 weeks of the timeperiod for an adequate pain relief with TCA.
Duloxetine and venlafaxine
These are selective serotonin-norepinephrine reuptake inhibitors (SSNRIs that have been studied in peripheral NP (a third SSNRI, milnacipran, has been studied only in fibromyalgia). Duloxetine has shown consistent efficacy in painful DPN [58] with 1-year effectiveness in an open-label trial [59]. In a recent Post Hoc Analysis by Tanenberg, et al. [60] it was concluded that in patients with DPN inadequately treated with gabapentin without the concomitant use of antidepressants, switching to duloxetine instead of pregabalin might provide better pain reduction. Teninberg, et al. [60] also emphasize that in nonrespondents to gabapentin who were concomitantly using Antidepressants, switching to duloxetine and Pregabalin may provide similar pain reduction. Duloxetine has not been studied in other types of neuropathies, thus, its efficacy is not known. Duloxetine has been effective in treating depression, and anxiety disorder with 60mg of daily dosing. The most common adverse effect of duloxetine is nausea, which seems to be reduced by administering 30 mg once daily for 1 week before increasing it to 60 mg once daily. Duloxetine has no effect on ECG and blood pressure [61] and a recent review concluded that aminotransferase monitoring is unnecessary [62]. Duloxetine along with pregabalin are approved by USFDA for the treatment of PDN [60].

Venlafaxine has shown efficacy in painful DPN and painful polyneuropathies of all origins [58]. It requires 2 to 4 weeks to titrate effective dosage (i.e., 150-225 mg/d). It is available in short- and long-acting preparations. Cardiac conduction abnormalities have been reported with this drug in a small number of patients [63] and it can increase blood pressure, therefore, venlafaxine should be prescribed with caution in patients with cardiac disease. In addition, Venlafaxine should not be abruptly stopped but need to be tapered because of the risk of withdrawal syndrome [64].
Calcium channel α2 - δ2 ligands (Gabapentin and Pregabalin)
Gabapentin and pregabalin each bind to voltage-gated calcium channels at the δ2-δ2 subunit and inhibit neurotransmitter release. Several clinical trials have proven its efficacy in NP as compared to placebo [58,50]. However there is no specific clinical trial has been done in patients of PDN. Gabapentin and pregabalin have few drug interactions, but both can produce dose-dependent dizziness and sedation, which can be reduced by starting with lower dosages and titrating cautiously. Dosage reduction is required in patients with renal insufficiency and dosage calculation is done using creatinine clearance for both medications. Gabapentin pharmacokinetics is nonlinear (due to saturable absorption), and thus dosing requires careful titration. Treatment should be initiated at low dosages with gradual increases until pain relief, or 3600 mg/d in 3 divided doses is reached. An adequate trial of treatment with gabapentin can require 2 months or more for effective trial. Gabapentin has similar efficacy to Pregabalin. However, pregabalin has linear pharmacokinetics, and dosing is simpler. The drug is given at 150 mg/d in 2 or3 divided doses, which is then titrated up to 300 mg/d after 1 or 2 weeks.

For patients who tolerate 300 mg/d, but pain relief is not adequate, the dosage can be further titrated to 600 mg/d. These higher dosages are not effective and are associated with greater adverse effects. Pregabalin may provide analgesia more quickly than gabapentin because the initial dosage of 150 mg/d has been found to be efficacious in some trials and the total time required to titrate to a full dosage is less [65]. This drug has fewer adverse effects including rhabdomyolysis, acute renal failure, central nervous system effects, hyperthermia, and secondary angle glaucoma and it should not be ignored. Thus, patients on pregabalin need to be carefully monitored for myopathy. It is advised to avoid this drug in patients with hypertension and congestive heart failure. In the United States, pregabalin is a Schedule V drug.
Topical Lidocaine
The 5% lidocaine patch has been proven to be very effective and have excellent tolerability in RCTs involving patients with different types of peripheral NP [58,50]., However, individual role in DPN has not yet been studied. As a topical treatment without any significant systemic absorption, the local reactions are more common as compared to systemic side effects and decreased drug interactions attribute to safer choice in older patients or patients with complex NP (Table 2). Lidocaine gel (5%), which is less expensive than the lidocaine patch, has also shown efficacy in allodynia [58,50]. Topical lidocaine is most appropriate in welllocalized NP, and it is unlikely to be effective in patients with central NP, thus attempts to predict the category of patients likely to be benefited from lidocaine are still unsuccessful [66,67].
Second Line Therapy
In Certain circumstances tramadol and opioid analgesics have shown efficacy in several high-quality RCTs involving patients with different types of NP, but there is no RCTs has been done in patients of PDN. With this class of drugs, long-term safety and efficacy are the matter of concern in relation to the first-line medications. The NeuPSIG guidelines recommend that tramadol and opioids should typically be reserved for patients who have not responded to first-line medications. However, in acute NP, NP due to cancer, episodic exacerbations of severe NP these medications are recommended as first-line treatments, as well as when titrating one of the first line medications to provide prompt pain relief.
Tramadol
Tramadol, which has shown efficacy in several NP conditions, but no RCTs, has studied its efficacy in patients of DPN. It is a weak opioid μ-receptor agonist that also inhibits reuptake of serotonin and norepinephrine. Like strong opioid analgesics, it provides relatively rapid pain relief, although it may be somewhat less efficacious than strong μ-agonists (e.g., morphine and oxycodone) [50]. The risk of abuse with tramadol seems considerably less than that with opioid analgesics [58] but the adverse effect of tramadol is similar to that of opioids. However, tramadol also lowers the seizure threshold and has some interactions with certain medications e.g., SSNRIs and Selective Serotonin Reuptake Inhibitors (SSRIs) leading to serotonin syndrome, a potentially fatal reaction. Although the risk of serotonin syndrome is quite rare but should be the matter of concern. Dosing of tramadol is typically started with 50 mg once or twice daily and then increased gradually as needed to a maximum of 400 mg/ d; older patients and those with renal or hepatic dysfunction should be maintained with lower dosages as they are more prone to drug accumulation.
Opioids
Several RCTs [58,68] has shown that opioid analgesics provide greater pain relief than placebo in different types of NP as found with TCA and gabapentin [69]. However, one study [70] studied the efficacy of morphine and had shown a small effect in reduction of neuropathic pain. RCTs to see the role of opioids in patients of DPN has not been done. Concerns including risks of hypogonadism, immunologic changes, and opioid misuse or abuse, and long-term safety, opioids are not recommended for routine first-line use and should generally be reserved for patients who do not respond to the first-line medications. Constipation, nausea, and sedation are the most common side effects of opioids. Thus initiating treatment with low dosages and titrating gradually can reduce nausea and sedation. Long term opioids therapy causes physical dependence thus its dosages need to be tapered in patients on long-term therapy of opioids and also instruct patients not to stop it abruptly. The opioidprescribing guidelines recommend the use of lowest effective dosage and monitoring for signs of inappropriate use [71-73]. Use of extended-release formulations is recommended for opioids and has been shown to be efficacious in NP trials.
Third-line Medications
Several additional medications have shown efficacy for the treatment of NP in either a single RCT or inconsistently across multiple RCTs. The NeuPSIG guidelines recommend that these medications should generally be reserved for patients who cannot tolerate or who do not respond adequately to first- and second-line medications. These medications include certain antidepressant medications (eg., bupropion, citalopram, and paroxetine), certain antiepileptic medications (eg., carbamazepine, lamotrigine, oxcarbazepine, topiramate, and valproic acid), topical lowconcentration capsaicin, dextromethorphan, memantine, and mexiletine [58].
Lamotrigine
Its efficacy in PDN has been studied in two trials, one openlabel [74] and one parallel placebo controlled [75] and it is less effective and has side effects.
Sodium valproate
Two studies evaluated its efficacy [76,77] and the drug was found to be efficacious in PDN and associated with lesser side effects.
Topiramate
One class II study [78] evaluated its efficacy in patients of PDN and reported small effect compared to placebo and an NNT of 6.6% for >30% pain reduction. It acts peripherally as a sodium channel blocker and at the GABA receptor and has several side effects such as cognitive slowing, dizziness, and risk of kidney stones. In one study group of patients' topiramate was discontinued due to side effects.
Mexiletine
It is an oral analog of lidocaine and is a class IB antiarrhythmic agent and it acts peripherally as an ion channel blocker to suppress pain. It has been evaluated in five studies [79-83] in patients of PDN and found to be effective in relieving pain. It has a faster onset of action but associated with side effects such as toxic epidermal agranulocytosis and hepatotoxicity. It is contraindicated in patients with second and third degree AV block. Patients on mexiletine therapy should be monitored for CBC, platelet count, ECG and liver enzymes tests.
Carbamazepine
Carbamazepine drug typically reserved and indicated in the management of trigeminal neuralgia. It acts by blocking the sodium channels on the A-delta nerve fibers and has a good efficacy but associated with several side effects including aplastic anemia. In one study Chakrabarti AK, et al [84] studied its efficacy in patients of PDN and was not found to be effective in relieving pain. Gomez-Perez FJ, et al. [85] evaluated the efficacy of carbamazepine in PDN and results were found to be negative. Recently Grosskopf, et al, done a placebo-controlled trial and evaluated efficacy of oxcarbazepine [86] (having a benign side effect profile), in patients of PDN and it was not found to be efficacious. In another trial, Dogra et al also showed similar results in patients of PDN [87]. However, Beydoun et al showed 50% pain reduction in patients of PDN compared with placebo [88].
Central NP
Relatively few RCTs have been conducted in patients with NP caused by lesions in the central nervous system. No study has been conducted as regards to the efficacy of cannabinoids in PDN. In some trials, cannabinoids appear to be efficacious in multiple sclerosis associated NP, but the use of cannabinoids is limited due to poor availability and risks of abuse leading to psychosis, especially in high-risk individuals [58,89,90]. Patients with central NP who do not respond adequately to these medications can be treated with the first and second-line medications that have established efficacy in peripheral NP.
Miscellaneous Drugs
In this section, we briefly discuss several recent RCTs for a certain miscellaneous group of drugs that should be considered in future efforts for the treatment guidelines. These studies have been selected because they involve novel treatments.

Botulinum toxin: Efficacy of botulinum toxin in the treatment of cervical dystonia and various types of spasticity is well established, but its role in PDN has been suggested by Finnerup NB, et al. [51] On the basis of this research and observations, a double-blind trial was conducted in which 29 patients with PHN or posttraumatic or postoperative NP and mechanical allodynia. They were randomized to intradermal injection of botulinum toxin type A or matching placebo within the area of allodynia [91]. Pain intensity decreased during 24 weeks' time period and brush-evoked allodynia were significantly reduced at 4 and 12 weeks after treatment in patients who received botulinum toxin vs. placebo.

8% Concentration capsaicin patch: It is an alkaloid derived from chilies. It has the peripheral action by decreasing the neurotransmitter substance P from sensory nerves. It is applied topically and is not absorbed in the systemic circulation. Topical low-concentration capsaicin is currently considered as a thirdline treatment of NP. But the role of capsaicin patch has not been established in patients of PDN. A high-concentration capsaicin patch has been studied in multiple RCTs in patients with PHN and painful HIV neuropathy [92] and results of 2 phase 3 trials in PHN showed that a single application of the high-concentration patch vs a low-concentration control patch was efficacious in reducing pain from the second week after the capsaicin application throughout a subsequent 8-week period [32,33].

The high-concentration capsaicin patch help in reducing the dosage of existing pharmacological agents, if applied to the patients of neuropathic pain. Its single application provides pain relief for 2-3 months .and thus reducing the dose requirement of other pharmacological agents. However, the long-term benefits and safety of repeated applications of this treatment are unknown, because skin biopsy studies have shown transient epidermal denervation by Capsaicin [93] and failure of heat sensation [94].

Lacosamide: Lacosamide is a new antiepileptic medication that has activity at voltage-gated sodium channels. In addition to epilepsy, lacosamide has been studied extensively in painful DPN. Rauck RL, et al. [34] in single phase 2 trial evaluated the efficacy of lacosamide in PDN and it has been proven to be effective. Shaibani A, et al. [35] in a parallel group phase 3 trial, found evidence of lacosamide in relieving pain in patients of PDN. Wymer, et al [36] also found similar results in PDN. Also, in an RCT evidence of efficacy of lacosamide in PDN was seen [37]. Later on in a trial by Hidvegi T, et al. [38] concluded the statistical significance of the result in patients of PDN was marginal (P =.0507), Despite its approval for adjunctive treatment of partial onset seizures, lacosamide was not approved for the treatment of painful DPN by either the food and drug administration or the european medicines agency. It will be difficult to define recommendations for lacosamide for the treatment of NP. In the United States, lacosamide is a Schedule V drug.
Selective serotonin re-uptake inhibitors
As previously mentioned, SSRIs have been considered thirdline medications for patients with NP including PDN. This is because the evidence of the analgesic efficacy of this class of antidepressants in patients of PDN has been inconsistent. In one older study by Sindrup SH, et al. [39] showed evidence of moderate effect of paroxetine in PDN. In another trial, Paroxetine was not found to be effective in patients of PDN [40] In a trial by Sindrup SH, et al. [40] evaluated the efficacy of citalopram [95] in PDN and showed a moderate effect. No efficacy for fluoxetine [41] compared with placebo in several clinical trials was seen in this group of patients.

A recent crossover RCT showed escitalopram benefited patients with PDN, compared with placebo, a benefit that appeared to be independent of antidepressant effects. However, the authors concluded that escitalopram "appears to have a clinically relevant effect in only a few patients and … can probably not be recommended as first or second line treatment in neuropathic pain" p281 [42]. In recent years after their introduction, SSRIs began to replace TCAs in psychiatry as first-line medications for the treatment of depression, due to safety against overdose, with lesser side effects and lack of need of titration. Hence, careful re-evaluation is needed for the role and efficacy of SSRIs in the patients of NP.

Doxepin: Doxepin, which is similar in function to amitriptyline and imipramine, has not been evaluated in the treatment of PDN.

Clonidine: Its efficacy has been evaluated in some studies and has shown no benefit in relieving pain in PDN.

NSAIDs: NSAIDs have also been used in PDN; however, it has been associated with renal dysfunction and hence should be used with caution.

Carisbamate: Recently Smith T, et al. [96] evaluated the efficacy of this newly developed therapeutic agent in patients of PDN and post-herpetic neuralgia. 3 RCTs were done, I and 2 RCTs were placebo controlled and evaluated efficacy over 4 weeks' period. Third RCTs evaluated the efficacy in these patients over a period of 15 weeks. Carisbamate was given in a dosage of 400mg/ day in 1 and 2 trials and 800mg/ day, 1200 mg/day given in 3 RCT. This drug however, is well tolerated but did not demonstrate efficacy in Neuropathic Pain across these studies.
Combination Therapies
Most of the studies have demonstrated the effects of individual medications in specific conditions. However, as indicated earlier, no medication is universally effective. Hence, in clinical practice 2 or more medications are often used in combination to possibly achieve either an additive beneficial effect or a reduction in the adverse effects associated with the use of single medications particularly if they act at different sites in pain signaling pathways or modulate different neurotransmitter systems. In one of the first RCTs of combination therapy for NP, the combination of gabapentin and extended-release morphine combination required lower dosages of both medications and resulted in better pain relief as compared to single medication when administered to the patients [97]. In another RCT by Hanna M, et al. [43] concluded consistent results when given the combination of extended release oxycodone or matching placebo in the combination with existing gabapentin treatment in patients of PDN.

Recent RCTs have examined the combination of nortriptyline and gabapentin [44] and was found to be superior to either of these 2 medications administered alone in patients of DPN. Baron R, et al. [45] studied the combinations of pregabalin and topical 5% lidocaine and results showed efficacy in patients of PDN. Sodium valproate and glyceryl trinitrate spray combination has been studied in one study [46] and have shown that combination therapies may have a role in the treatment of NP but the relevant data in support of it in patients of PDN has not been studied till now.

Keeping in view of all above RCTs on combination therapy, additional studies are needed to develop guidelines on it and benefit of polypharmacy.

Adding to the management guidelines of neuropathic pain, according to Canadian pain society guidelines [47] on pharmacological management of chronic Neuropathic Pain including PDN, Moulin DE et al recommended analgesic agents for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments, recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Fourth-line treatments include cannabinoids, methadone and anticonvulsants (lamotrigine, topiramate and valproic acid), but this line of medications has lesser evidence of efficacy. Treatment must be individualized for each patient based on efficacy, side-effects and drug availability and cost. Further studies are suggested to compare the efficacy of individual medications, combinations of medications and longterm outcomes.

According to EFNS guidelines on the pharmacological treatment of Neuropathic Pain including Painful Diabetic Neuropathy: 2010 revision [98]. Attal, et al. [98] recommended TCA, gabapentin, pregabalin and SNRI (duloxetine, venlafaxine) as first-line treatment in NP particularly in PDN. Tramadol is recommended as the second line except for patients with exacerbations of pain (for the tramadol/acetaminophen combination) or those with predominant coexisting nonneuropathic pain. Third-line therapy includes strong opioids however its long-term safety and efficacy is a topic of concern.

According to AAN, AANEM guidelines, the management of Neuropathic Pain including PDN is tabulated below [99].

American Academy of Neurology (AAN); American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM); American Academy of Physical Medicine and Rehabilitation (AAPMR).
Non-Pharmacological Management
Laser therapy
The laser is another physical therapy agent that can be used in the treatment of neuropathic pain. However, its efficacy is still not being studied in patients of PDN. Very low level of laser has been shown effective in patients with neuropathic pain [100]. It decreases pain and inflammation, in addition to improving functional ability. In rats, it has been studied that it decreases the level of (HIF 1-a) hypoxia-induced factor, which is a modulator in inflammation and released after chronic constrictive nerve injury [101]. However, other studies of the effectiveness of laser therapy in neuropathic pain are also done in rats [102,103]. But, there is not enough evidence to suggest that it is effective in neuropathic pain in diabetic patients.
Interventional pain management
Sympathetic blocks (lumbar sympathetic blocks and thoracic paravertebral blocks)
The sympathetic nervous system has been implicated in pain associated with painful diabetic neuropathy. But, therapeutic intervention targeted at the sympathetic nervous system has not been established. In a case report Jianguo, et al. [104] tested the hypothesis that sympathetic nerve blocks significantly reduce pain in a patient with painful diabetic neuropathy who has failed multiple pharmacological treatments. The diagnosis of small fiber sensory neuropathy was based on clinical presentations and confirmed by skin biopsies. A series of 9 lumbar sympathetic blocks over a 26-month period provided sustained pain relief in his legs. Additional thoracic paravertebral blocks were given to control pain in the trunk which is occasionally be seen in severe diabetic neuropathy cases due to extensive involvement of the intercostal nerves. These blocks provided sustained and significant pain relief and improvement in the quality of life. They thus provided the first clinical evidence of the significant role of sympathetic nervous system in painful diabetic neuropathy and sympathetic blocks can be an effective management modality of painful diabetic neuropathy.
Spinal Cord Stimulation (SCS)
It is an invasive treatment for chronic pain based on electrical stimulation of the dorsal columns of the spinal cord. Mechanisms being not known, believed to involve spinal and supraspinal effects. It is a proven effective therapy for various types of mixed neuropathic conditions but the effectiveness of SCS treatment for PDN is not well established. However, recently Slangen, et al. [105] suggested that Spinal Cord Stimulation (SCS) may have positive effects in resolving neuropathic pain in DPN. There was also one randomized control trial by De Vos, et al. [106], which investigated the effectiveness of SCS in patients with PDN. Sixty patients with PDN in the lower extremities refractory to conventional medical therapy were taken and followed for 6 months. They were randomized 2:1 to best conventional medical practice with (SCS group) or without (control group), and both groups were assessed at regular intervals. At each follow-up visit, the EuroQoL 5D, the Short Form Mcgill Pain Questionnaire (SF-MPQ) and a Visual Analogue Scale (VAS, ranging 0–100) were used to measure pain intensity. The results have showed the patients in the SCS group unlike those in the control group, experienced reduced pain and improved health and quality of life after 6 months of treatment. In patients with refractory painful diabetic neuropathy spinal cord stimulation therapy is quite effective and significantly reduced pain and improved quality of life.
Electrical stimulation
Pulsed-dose electrical stimulation is evaluated as an analgesic modality in patients with painful diabetic neuropathy. Using a knitted silver-plated nylon/Dacron stocking electrode, patients were given electrical stimulation over the period of 1 month and using a 10 cm visual analog scale, the pain was measured. Pain measurements were found to be significantly reduced at the end of the 4-week therapy and at 1 month after complete discontinuation of therapy than at the initiation of therapy. The results of this study show that nocturnal doses of pulsed-electrical stimulation may be effective in reducing subjective, burning, diabetic Neuropathic Pain in a group of patients with grossly intact protective sensation and relatively good distal vascular perfusion. To the authors' knowledge, this is the first analytic report of pulsed-dose electrical nerve stimulation delivered through a stocking electrode for treatment of symptomatic diabetic neuropathy in the medical literature [107].
Neurostimulation techniques (never been explored in cases of PDN)
Transcranial Magnetic Stimulation (TMS) and Cortical Electrical Stimulation (CES), Spinal Cord Stimulation (SCS) and Deep Brain Stimulation (DBS) have also been found to be effective in the treatment of neuropathic pain, but the role in PDN is still not been established. Lefaucheur, et al. [107,108] investigated 60 patients with chronic unilateral Neuropathic Pain caused by one of the following lesions: thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus lesion, or trigeminal nerve lesion. Transcranial magnetic stimulation was applied 3 weeks apart in two sessions, with a frequency of 10 Hz. The pain level of patients was assessed with Visual Analog Scale (VAS). Thirty-nine patients reported a decrease in pain depending on the localization and cause of pain.

Capel, et al. [109] have done a randomized, placebocontrolled study and evaluated the effects of CES in 27 patients with spinal cord injury. The pain was assessed with VAS and McGill Pain Questionnaire, but other functional related factors like depression, anxiety, analgesic usage were also monitored. In this study, patients receiving CES reported the decrease in pain intensity.

Another randomized placebo-controlled study was done by Tan, et al. [110] using CES in 38 spinal cord injury patients who suffered from chronic neuropathic and musculoskeletal pain for at least 3 months. The patients in CES group have reported a decrease in pain intensity immediately, and this decrease did not change over time. However, the result was not statistically significant. Despite several studies being done on neurostimulation, definitive result in patients of Neuropathic Pain is very small.
TENS
It is one of the best modalities in neuropathic pain. In a study, Jin DM, et al. [111]. evaluated the role of TENS and has shown evidence of efficacy in the treatment of Neuropathic Pain due to PDN The mechanism being TENS acts centrally, it activates μ-opioid receptors in spinal cord and brainstem when applied in low frequency while high-frequency TENS produces its effect via δ-opioid receptors. European Federation of Neurological Societies (EFNS) has published a guideline about the use of therapeutic electrical neurostimulation techniques in chronic Neuropathic Pain [112]. The guideline suggests that the effectiveness of TENS depends on the intensity, frequency, duration and the number of sessions. In this guidelines, they also suggested that acupuncturetype TENS (0-4 Hz) has been found more acceptable when compared to high-frequency TENS due to increased sensation of numbness but sufficient evidence is not there. Also, Several clinical trials evaluate the role of TENS in Neuropathic Pain and was found to be effective [113-115]. As a result, TENS can be effective in the treatment of painful peripheral neuropathy. However, we cannot comment on TENS efficacy appropriately due to inadequate study designs and short follow-up durations. There is need for more randomized, double blind studies done with larger patient groups, particularly in patients of PDN.
Other physical therapy modalities
Include pain modulators like hot and cold packs, ultrasound, short wave diathermy, low-frequency currents (diadynamic currents, interferential currents) and techniques like high voltage galvanic stimulation (Table 3).

Hot and cold applications: Hot and cold applications can be used together as in contrast baths. Sometimes fluidotherapy or whirlpool can also be chosen for this purpose. In all these superficial heat agents should not be applied because of the risk of an increase in pain. The modalities have been found to be effective in chronic pain, but there is a definite need of studies which support their effectiveness [116].

Ultrasound and short wave diathermy: Ultrasound and short wave diathermy which are deep heating agents like are not recommended in the treatment of neuropathic pain. They are helpful especially in joint contractures, and adhesions. It increases the flexibility of collagen fibers and circulation of connective tissues which help functional restoration. It may provide to decrease neuropathic pain.

Massage: Massage is also not recommended. In AIDS patients with neuropathic pain, massage therapy has been applied but there have been no significant changes on pain intensity [117]. There is another study that has investigated the role of massage in spinal cord injury patients. While the study claims that massage appears as one of the effective ways of therapy, it does not specify the type of pain [118].

Rehabilitation: It is s also an essential part of treatment in Neuropathic Pain (Table 3). The main aims of rehabilitation are to decrease pain and improve dysfunction, increase quality of life, and to decrease intake of medications. One of the major parts of rehabilitation methods are therapeutic exercise, however, there is no sufficient evidence supporting it. There are several therapeutic exercises have already been used in the rehabilitation program such as conditioning, strengthening and stretching exercises. Kuphal, et al. [119] developed a Neuropathic Pain model in rats by making injury to their sciatic nerve and showed that 25 days of exercises in water and swimming decreased pain, reduced edema, and inflammation. The purposes of behavioral therapy are to treat emotional and mental dysfunction, relieving the patient from anxiety or depression, psychosocial treatment approaches, cognitive behavioral methods have showed that psychosocial support increases the efficacy of treatment. We should include psychosocial management programs to our standard therapy regimens in neuropathic pain. The use of CBT is gradually increasing in neuropathic pain. Especially in elderly patients, relaxation techniques, the accurate planning of activity-rest cycles, cognitive reconstruction, and meditation can be used [120]. Cha, et al. [121] investigated the healing effect of acupuncture in neuropathic pain induced in rats and found out that acupuncture is effective in the treatment of neuropathic pain.

Rapson, et al. [122] applied electro acupuncture in 36 Spinal Cord Injury (SCI) patients with neuropathic pain 5 times a week for 30 minutes and suggested that pain intensity decreased after therapy and there were not any side effects.

Mirror therapy and graded motor imagery: Mirror therapy and graded motor imagery are rehabilitation procedures developed with the hope of correcting phantom limb and chronic low back pain, which is due to primary somato sensory cortical changes.

Mirror therapy is one of the rehabilitation methods that are widely used in patients suffering from neuropathic pain. In mirror therapy, the patient puts his affected limb into mirror box and keeps the unaffected side in front of the mirror. Unaffected limb in front of the mirror makes simple movements, patient imagines doing same movements with the affected limb. Although it may increase the pain but the patient tries to tolerate it. This method has been used in this method has been used in patients with stroke, phantom limb pain and Complex Regional Pain Syndrome (CRPS) [123]. In a randomized controlled study with 22 patients with amputated limbs, 4 weeks of mirror therapy were compared with covered mirror therapy (sham mirror therapy) and mental imagery [124]. There was a significant decrease in VAS in mirror therapy group compared with the others.

Graded Motor Imagery (GMI) is a comprehensive program, which activates cortical motor networks and improves cortical organization in three steps: laterality training, imagined hand movements, and mirror visual feedback [28]. Moseley, et al. [29] has done one study in CRPS type 1 patients which received GMI for 6 weeks, 2 weeks in each step, and compared with conventional physical therapy and medication. The study was done in 51 patients and showed the significant decrease in pain in GMI group compared with other groups. However, Johnson, et al. [30] failed to show the effectiveness of GMI in CRPS patients. There is definitely a need for more evidence regarding the role of both mirror therapy and GMI in neuropathic pain.
New recent potential therapies
Now in clinical trials: Two treatments that might be useful in opposing some of the pathogenic factors that are thought to lead to neuropathy are now in clinical trials.

α-lipoic-acid: This free radical scavenger antioxidant has been shown to be efficacious in the management of painful neuropathies when administered parenterally [126] Infusion of the anti-oxidant a-lipoic acid at a dose of 600 mg i.v. per day over a 3-week period has been found to be useful in reducing neuropathic pain 53. A meta-analysis including 1258 patients from four prospective trials showed that treatment with a-lipoic acid (600 mg/day) for 3 weeks was associated with a significant improvement in neuropathic pain, as well as neuropathic deficits [127]. Oral treatment with a-lipoic acid for 5 weeks improved neuropathic symptoms and deficits in patients with DPN [128].

Protein kinase C inhibition: Elevated protein kinase C activities thought to play a significant role in the etiology of diabetic microvascular complications. Studies have been conducted using a protein kinase C- β inhibitor (LY333531) [129]. A preliminary study suggested the possibility of this agent improving positive symptoms of allodynia and prickling pain. Large, phase III, multicenter clinical trials are in progress [130].

Below is the table 4 describing the latest compounds acting on pathogenic factors of diabetic neuropathies that have undergone trials for eliciting the treatments of the same.
Discussion
Despite being common, DPN continues to be under diagnosed and undertreated and thus management of the patients with DPN must depend on individual requirements and on the presence of other comorbidities. Pharmacological treatment of DPN includes tricyclic compounds, serotonin-noradrenalin reuptake inhibitors, the anti-oxidant-lipoic acid, anticonvulsants, opiates, membrane stabilizers, topical capsaicin and so on.

Although poor blood glucose control in diabetic patients is an important risk factor for the Development of Peripheral Neuropathy (DPN). Furthermore, traditional cardiovascular risk factors for macrovascular disease also leads to an increased risk of DPN. Recently several studies in experimental diabetes examining the pathogenesis of DPN have identified a number of metabolic abnormalities (as described in figure 1) including polyol pathway hyperactivity, increased advanced glycation end-point formation, alterations in the protein kinase C beta pathway through diacylglycerol and oxidative stress. There is now strong evidence suggesting nerve ischemia as the cause of DPN. Various Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia as the leading cause neuropathic pain. These endoneurial microvascular changes strongly correlate with clinical severity and the degree of nerve-fiber ischemia. Thus, with regard to this several clinical trials have been done to evaluate the efficacy of compounds in the treatment of diabetic peripheral neuropathy in animals and
Table 4: Compounds that have undergone trials for the treatment of diabetic peripheral neuropathies (adapted from Reference [131]). ACE: Angiotensin-Converting Enzyme; BDNF: Brain-Derived Neurotrophic Factor.

Abnormality

Compound

Aim of Treatment

Status of randomized clinical trials

Polyol pathway­

 

Aldose reductase inhibitors

Sorbinil

Tolrestat

 

Ponalrestat

 

Zopolrestat

 

Zenarestat

 

Lidorestat

 

Fidarestat

 

Ranirestat

 

Epalrestat

 

Nerve sorbitol¯

Withdrawn (adverse events)

Withdrawn (adverse events)

 

Inefective

 

Withdrawn (marginal efects)

 

Withdrawn (adverse events)

 

Withdrawn (adverse events)

 

Efective in phase II trials

 

Efective in phase II trial

 

Marketed in Japan

myo-Inositol­

 

myo-Inositol

 

Nerve myo-inositol­

 

Equivocal

 

g-Linolenic acid synthesis¯

g-Linolenic acid

 

 

Essential fatty acids metabolism­

 

 

Withdrawn (effective: deficits)

 

Oxidative stress­

 

a-Lipoic acid

Oxygen free radicals¯

 

Effective in randomized clinical

trials (studies ongoing)

 

 

Vitamin E

 

Oxygen free radicals¯

 

Effective in one randomized

clinical trial

Nerve hypoxia­

Vasodilators

 

Nerve blood flow­

 

 

 

ACE inhibitors

 

Prostaglandin analogs

 

PhVEGF165 gene transfer

Angiogenesis­

 

Effective in phase II trial

 

Effective in phase II trial

Phase III trial ongoing

Protein kinase C­

 

Protein kinase Cb inhibitor

(ruboxistaurin)

 

Nerve blood flow­

 

Phase III trial ongoing

C-peptide¯

C-peptide

 

 

Nerve blood flow­

 

Effective in phase II trials

 

Neurotrophism¯

 

Nerve growth factor

 

Nerve regeneration,

growth­

 

Ineffective

 

 

BDNF

Nerve regeneration,

growth­

 

Ineffective

Long-chain fatty acid

metabolism

Acetyl-L-carnitine

Long-chain fatty acid

accumulation¯

 

Ineffective

Table 5: Usual Effective dosages & Titration Schemes for the treatment of PDN [134].
References
  1. Trede RD, Jensen TJ, Campbell JN, et al. Neuropathic pain; redefinition and a grading system for clinical and research purpose.Neurology.2008; 70(18): 1630-1635.
  2. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population based cohort: The Rochester Diabetic Neuropathy Study. Neurology.1993; 43(4): 817-824.
  3. 3.Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993; 36(2): 150–154.
  4. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (author's translation).Diabeta Metab.1977; 3(2): 97-107.
  5. Kumar S, Ashe HA, Parnell LN, Fernando DJ, Tsigos C, Young RJ, et al.The prevalence of foot ulceration and its correlates in type 2 diabetic patients: a population-based study. Diabet Med 1994; 11(5): 480–484.
  6. Cabezas Cerrato J. The prevalence of clinical diabetic polyneuropathy in Spain: a study in primary care and hospital clinic groups. Neuropathy Spanish Study Group of the Spanish Diabetes Society (SDS). Diabetologia.1998; 41(11): 1263–1269.
  7. Boulton AJ, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet Med. 1998; 15(6): 508-514.
  8. Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010; 33(10): 2285-93. doi: 10.2337/ dc10-1303.
  9. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005; 28(4): 956–962.
  10. DiBonaventura MD, Cappelleri JC, Joshi AV. Association between pain severity and health care resource use, health status, productivity and related costs in painful diabetic peripheral neuropathy patients. Pain Med. 2011; 12(5): 799-807. Doi: 10.1111/ j.1526-4637.2011.01103.x. 
  11. Ritzwoller DP, Ellis JL, Korner EJ, Hartsfield CL, Sadosky A. Comorbidities, healthcare service utilization and costs for patients identified with painful DPN in a managed-care setting. Curr Med Res Opin. 2009; 25(6): 1319-1328.  doi: 10.1185/ 03007990902864749.
  12. Partanen J, Niskanen L, Lehtinen J, Mer-vaala E, Siitonen O, Uusitupa M. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995; 333(2): 89-94.
  13. Adler AI, Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Smith DG. Risk factors for diabetic peripheral sensory neuropathy: results of the Seattle Prospective Diabetic Foot Study. Diabetes Care. 1997; 20(7): 1162-1167.
  14. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with dia-betes. N Engl J Med 1994; 331(13): 854-860.
  15. Writing Team for the DCCT/EDIC Research Group: Effect of intensive therapy on the microvascular complications of type 1 dia-betes mellitus. JAMA. 2002; 287(19): 2563–2569.
  16. Martin CL, Albers J, Herman WH, Cleary P, Waberski B, Greene DA, et al. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care. 2006; 29(2): 340–344.
  17. Backonja MM, Argoff CE. Neuropathic Pain-Definition and Implications for Research and Therapy. J Neuropathic Pain Sympt Palliation. 2005; 1(2): 11-17.
  18. Backonja MM. Defining Neuropathic Pain. Anesth Analg. 2003; 97(3): 785-790.
  19. Raja SN, Treede RD, Davis KD, Campbell JN. Systemic Alpha-Adrenergic Blockade with Phentolamine; a Diagnostic test for Sympathetically Maintained Pain. Anesthesiology. 1991; 74(4): 691-698.
  20. Vinik AI. Diagnosis and management of diabetic neuropathy. Clin Geriatr Med.1999; 15(2): 293-320.
  21. Vera Bril. Treatments for diabetic neuropathy. Journal of the Peripheral Nervous System. 2012; 17: 22-27.
  22. Thomas PK. Classification, differential diagnosis and staging of diabetic peripheral neuropathy. Diabetes. 1997; 46(Suppl. 2): S54-57.
  23. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005; 28(4): 956–962.
  24. Florian P. Thomas, Associate Professor of Neurology, Molecular Virology, and Molecular Microbiology and Immunology Saint Louis VA Medical Center Saint Louis University School of Medicine, Saint Louis, MO 63110.
  25. Donofrio PD, Albers JW. AAEM mini monograph #34: polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve. 1990; 13(10): 889-903.
  26. Dumitru. Electrodiagnostic Medicine, Hanley & Belfus, Philadelphia. 1995; p. 821-4.
  27. Novella SP, Inzuchhi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve. 2001; 24(9): 1229-12231.
  28. Priganc VW, Stralka SW. Graded motor imagery. J Hand Ther. 2011; 24: 164-168.
  29. Moseley GL. Graded motor imagery for pathologic pain: a randomized controlled trial. Neurology. 2006; 67(12): 2129-2134.
  30. Johnson S, Hall J, Barnett S, Draper M, Derbyshire G, Haynes L, et al. Using graded motor imagery for complex regional pain syndrome in clinical practice: failure to improve pain. Eur J Pain. 2012; 16(4): 550-561.  doi: 10.1002/ j.1532-2149.2011.00064.x.
  31. Dworkin RH, O'Connor AB, Audette J, Baron R, Gourlay GK, Haanpää ML, et al. Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update. Mayo Clin Proc. 2010; 85: S3-14. doi: 10.4065/mcp.2009.0649.
  32. Backonja M, Wallace MS, Blonsky ER, Cutler BJ, Malan P Jr, Rauck R, et al. NGX-4010, a high concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol. 2008; 7(12): 1106-1112. Doi: 10.1016/ S1474-4422(08)70228-X.
  33. Qutenza (NGX-4010):  Full prescribing information.  http://www.neurogesx.com/ngx_4010. Accessed January 12, 2010.
  34. Rauck RL, Shaibani A, Biton V, Simpson J, Koch B. Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study. Clin J Pain. 2007; 23(2): 150-158.
  35. Shaibani A, Fares S, Selam JL, Arslanian A, Simpson J, Sen D, et al. Lacosamide in painful diabet-ic neuropathy: an 18-week double-blind placebo-controlled trial. J Pain. 2009; 10(8): 818-82. doi: 10.1016/ j.jpain.2009.01.322.
  36. Wymer JP, Simpson J, Sen D, Bongardt S, Lacosamide SP742 Study Group. Efficacy and safety of lacosamide in diabetic neuropathic pain: an 18-week double-blind placebo-controlled trial of fixed-dose regimens. Clin J Pain. 2009; 25(5): 376-85. doi: 10.1097/ AJP.0b013e318196d2b6.
  37. UCB, Inc. Clinical study summary (CS template, StudyNo.SP874. http://www.clinicalstudyresults S) .org/documents/company-study_8251_0.pdf. Accessed January 12, 2010.
  38. Hidvégi T, Bretschneider B, Thierfelder S, Sommerville K, Bongardt S. Long-term efficacy of lacosamide in subjects with diabetic neuropathic pain: results of a double-blind, randomized withdrawal trial. Presented at: 27th annual meeting of the American Pain Society; Tampa, FL; 2008; May 8-10.
  39. Sindrup SH, Gram LF, Brøsen K, Eshøj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990; 42(2): 135-144.
  40. Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen, Gram LF. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992; 52(5): 547-552.
  41. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992; 326(19): 1250-1256.
  42. Otto M, Bach FW, Jensen TS, Brøsen K, Sindrup SH. Escitalopram in painful polyneuropathy: a randomized, placebo-controlled, cross-over trial. Pain. 2008; 139(2): 275-283. doi: 10.1016/ j.pain.2008.04.012.
  43. Hanna M, O'Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008; 12(6): 804-813. doi: 10.1016/  j.ejpain.2007.12.010.
  44. Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009; 374(9697): 1252-1261. doi: 10.1016/ S0140-6736(09)61081-3. 
  45. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M. Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post herpetic neuralgia and diabetic polyneuropathy. Curr Med Res Opin. 2009; 25(7): 1677-1687.  doi: 10.1185/ 03007990903048078.
  46. Medicines Agency. CHMP assessment report for Qutenza. http://www.emea.europa.eu/humandocs/PDFs/EPAR/Qutenza/H-909-en6. pdf. Accessed January
  47.  Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, et al. Pharmacological management of chronic neuropathic pain—consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag. 2007; 12(1): 13-21.
  48. Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, et al. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol. 2008;  15(10): 1013-1028. doi: 10.1111/ j.1468-1331.2008.02185.x.
  49. Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008; 71(15): 1183-1190. doi: 10.1212/ 01.wnl.0000326598.83183.04.
  50. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for Neuropathic Pain treatment: an evidence based proposal. Pain. 2005; 118(3): 289-305.
  51. Tugnoli V, Capone JG, Eleopra R, Quatrale R, Sensi M, Gastaldo E, et al. Botulinum toxin type A re-duces capsaicin-evoked pain and neurogenic vasodilatation in human skin. Pain. 2007; 130(1-2): 76-83.
  52. Davis JL, Lewis SB, Gerich JE, Kaplan RA, Schultz TA, Wallin JD. Peripheral diabetic neu-ropathy treated with amitriptyline and fluphenazine. JAMA. 1977; 238(21): 2291–2292.
  53. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol. 2005; 96(6): 399–409.
  54. Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA. 1984; 251(13): 1727-1730.
  55. Young RJ, Clarke BF. Pain relief in diabetic neuropathy: the effectiveness of imipramine and related drugs. Diabet Med. 1985; 2(5): 363-366.
  56. Sindrup SH, Ejlertsen B, Froland A, Sindrup EH, Brosen K, Gram LF. Imipramine treatment in diabetic neuropathy: relief of subjective symptoms without changes in peripheral and autonomic nerve function. Eur J Clin Pharmacol 1989: 37; 151-153.
  57. Sindrup SH, Bach FW, Madsen C, Gram LF, Jensen TS. Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology. 2003; 60(8): 1284-1289.
  58. Dworkin RH, O'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007; 132(3): 237-251.
  59. Raskin J, Smith TR, Wong K, Pritchett YL, D'Souza DN, Iyengar S, Wernicke JF, et al. Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain. J Palliat Med. 2006; 9(1): 29-40.
  60. Tanenberg RJ, Clemow DB, Giaconia JM, Risser RC. Duloxetine compared with pregabalin for diabetic peripheral Neuropathic Pain management in patients with suboptimal pain response to Gabapentin and treated with or without Antidepressants: A post Hoc Analysis. Pain Pract. 2014; 14(7): 640-648. doi: 10.1111/ papr.12121.
  61. Wernicke J, Lledó A, Raskin J, Kajdasz DK, Wang F. An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo controlled studies. Drug Saf. 2007; 30(5): 437-455.
  62. McIntyre RS, Panjwani ZD, Nguyen HT, Woldeyohannes HO, Alsuwaidan M, Soczynska JK, et al. The hepatic safety profile of duloxetine: a review. Expert Opin Drug Metab Toxicol. 2008; 4(3): 281-285.  doi: 10.1517/ 17425255.4.3.281.
  63. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double blind, placebo controlled study. Pain. 2004; 110(3): 697-706.
  64. Fava M, Mulroy R, Alpert J, Nierenberg AA, Rosenbaum JF. Emergence of adverse events following discontinuation of treatment with extended release venlafaxine. Am J Psychiatry. 1997; 154(12): 1760-1762.
  65. Stacey BR, Barrett JA, Whalen E, Phillips KF, Rowbotham MC. Pregabalin for postherpetic neuralgia: placebo controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain. 2008; 9(11): 1006-1017. doi: 10.1016/ j.jpain.2008.05.014.
  66. Wasner G, Kleiner A, Binder A, Schattschneider J, Baron R. Posther petic neuralgia: topical lidocaine is effective in nociceptor -deprived skin. J Neurol. 2005; 252(6): 677-686.
  67. Herrmann DN, Pannoni V, Barbano RL, Pennella-Vaughan J, Dworkin RH. Skin biopsy and quantitative sensory testing do not predict response to the lidocaine patch in painful neuropathies. Muscle Nerve. 2006; 33(1): 42-48.
  68. Wu CL, Agarwal S, Tella PK, Klick B, Clark MR, Haythornthwaite JA, et al. Morphine versus mexiletine for treatment of post amputation pain. Anesthesiology. 2008; 109(2): 289-296. doi: 10.1097/ ALN.0b013e31817f4523.
  69. Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002; 59(7): 1015-1021.
  70. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005; 352(1): 1324-1334.
  71. British Pain Society. Recommendations for the appropriate use of opioids for persistent non-cancer pain. London, England: British Pain Society, 2005. http://www.britishpainsociety.org/opioids_doc_2004.pdf. Accessed January 12, 2010.
  72. Højsted J, Sjögren P. Addiction to opioids in chronic pain patients: a literature review. Eur J Pain. 2007; 11(5): 490-518.
  73. Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009; 10(2): 113-130. doi: 10.1016/ j.jpain.2008.10.008.
  74. Eisenberg E, Alon N, Ishay A, Daoud D, Yarnitsky D. Lamotrigine in the treatment of painful diabetic neuropathy. Eur J Neurol.1998; 5(2): 167–173.
  75. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology. 2001; 57(3): 505-509.
  76. Kochar DK, Jain N, Agarwal RP, Srivastava T, Agarwal P, Gupta S. Sodium valproate in the management of painful neuropathy in type 2 diabetes: a randomized placebo con-trolled study. Acta Neurol Scand. 2002; 106(5): 248 -252.
  77. Kochar DK, Rawat N, Agrawal RP, Vyas A, Beniwal R, Kochar SK, et al. Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study. QJM. 2004; 97(1): 33-38.
  78. Raskin P, Donofrio PD, Rosenthal NR, Hewitt DJ, Jordan DM, Xiang J, et al. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology. 2004; 63(5): 865-873.
  79. Oskarsson P, Ljunggren JG, Lins PE. Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. Diabetes Care. 1997; 20(10): 1594-1597.
  80. Stracke H, Meyer UE, Schumacher HE, Federlin K. Mexiletine in the treatment of diabetic neuropathy. Diabetes Care.1992; 15(11): 1550-1555.
  81. Stracke H, Meyer U, Schumacher H, Arm-brecht U, Beroniade S, Buch KD, et al. Mexiletine in treatment of painful diabetic neuropathy. Med Klin (Munich). 1994; 89(3): 124-131.
  82. Dejgard A, Petersen P, Kastrup J. Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet. 1988; 1(8575-8576): 9-11.
  83.  Wright JM, Oki JC, Graves L. Mexiletine in the symptomatic treatment of diabetic peripheral neuropathy. Ann Pharmacother. 1997; 31(1): 29-34.
  84. Chakrabarti AK, Samantaray SK. Diabetic peripheral neuropathy: nerve conduction studies before, during and after carbamazepine therapy. Aust N Z J Med. 1976; 6(6): 565-568.
  85. Gomez-Perez FJ, Choza R, Rios JM, Reza A, Huerta E, Aguilar CA, et al. Nortriptyline -fluphenazine vs. carbamazepine in the symptomatic treatment of diabetic neuropathy. Arch Med Res. 1996; 27(4): 525-529.
  86. Grosskopf J, Mazzola J, Wan Y, Hopwood M. A randomized, placebo-controlled study of oxcarbazepine in painful diabetic neuropathy. Acta Neurol Scand. 2006; 114(3): 177-180.
  87. Dogra S, Beydoun S, Mazzola J, Hopwood M, Wan Y. Oxcarbazepine in painful diabetic neuropathy: a random-ized, placebo-controlled study. Eur J Pain 2005; 9(5): 543-554.
  88. Beydoun A, Shaibani A, Hopwood M, Wan Y. Oxcarbazepine in painful diabetic neuropathy: results of a dose ranging study. Acta Neurol Scand. 2006; 113(6): 395-404.
  89. O'Connor AB, Schwid SR, Markman J, Hermann D, Dworkin RH. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain. 2008; 137(1): 96-111.
  90. Rice ASC. Should cannabinoids be used as analgesics for neuropathic pain? Nat Clin Pract Neurol. 2008; 4(12): 654-655. doi: 10.1038/ ncpneuro0949.
  91. Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol. 2008; 64(3): 274-283. Doi: 10.1002/ ana.21427.
  92. European Medicines Agency. CHMP assessment report for Qutenza. http://www.emea.europa.eu/humandocs/PDFs/EPAR/Qutenza/H-909-en6. pdf. Accessed January 12, 2010.
  93. Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004; 127(pt 7): 1606-1615.
  94. Magerl W, Fuchs PN, Meyer RA, Treede RD. Roles of capsaicin-in-sensitive nociceptors in cutaneous pain and secondary hyperalgesia. Brain. 2001; 124(pt 9): 1754-1764.
  95. Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen T, Gram LF.. Dejgaard A, Brøsen K, Aaes-Jørgensen, Gram LF. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992; 52(5): 547-552.
  96. Smith T, DiBernardo A, Shi Y, Todd MJ, Brashear HR, Ford LM, et al. Efficacy and safety of carisbamate in patients with diabetic neuropathy or postherpetic neuralgia: results from 3 randomized, double-blind placebo-controlled trials,  Pain Pract. 2014; 14(4): 332-42. doi: 10.1111/ papr.12080.
  97. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005; 352(13): 1324-1334.
  98. Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. EFNS guidelines on pharmacological treatment of Neuropathic Pain revision. European Journal of Neurology. 2010; 17(9): 1113-e88. doi: 10.1111/ j.1468-1331.2010.02999.x.
  99. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, et al. Evidence based guideline: Treatment of painful diabetic neuropathy.Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011; 76(20): 1758-1765.  doi: 10.1212/ WNL.0b013e3182166ebe. 
  100. Giuliani A, Fernandez M, Farinelli M, Baratto L, Capra R, Rovetta G, et al. Very low level laser therapy attenuates edema and pain in experimental models. Int J Tissue React. 2004; 26(1-2): 29-37.
  101. Hsieh YL, Chou LW, Chang PL, Yang CC, Kao MJ, Hong CZ, et al. Low level laser Therapy alleviates Neuropathic Painand promotes function recovery in rats with chronic constriction injury: possible involvements in hypoxia-inducible factor 1α (HIF-1 α). J Comp Neurol. 2012; 520(13): 2903-2916. doi: 10.1002/ cne.23072.
  102. Baratto L, Calzà L, Capra R, Gallamini M, Giardino L, Giuliani A, et al. Ultra low level laser therapy. Lasers Med Sci. 2011; 26(1):     103-112. doi: 10.1007/ s10103-010-0837-2.
  103. Lim J, Chae W, Lee S, Jeong S, Youn D, Chang-S, et al. Effect of GaAlAs Laser and Acupuncture Therapy at BL40 on Neuropathic Pain in Rats. Journal of Acupuncture and Meridian Studies 2011; 4: 267.
  104. Jianguo Cheng, Anuj Daftari, lan Zhou. Case report on Sympathetic blocks provided sustained pain relief in a patient with refractory painful diabetic neuropathy. Case report in Anaesthesiology, 2012; Article ID 285328,5 pages.
  105. Slangen R, Schaper NC, Faber CG, Joosten EA, Dirksen CD, van Dongen RT, et al. Spinal cord stimulation and pain relief in painful diabetic peripheral neuropathy. Diabetes care. 2014; 37(11): 3016-3024. doi: 10.2337/ dc14-0684.
  106. de Vos CC, Meier K, Zaalberg PB, Nijhuis HJ, Duyvendak W, Vesper J, et al. Spinal cord stimulation in patients with painful diabetic neuropathy: A multicentre randomized clinical trial. Pain. 2014; 155(11): 2426–2431. doi: 10.1016/ j.pain.2014.08.031. 
  107. Armstrong DG, Lavery LA, Fleischi JG, Gilham KA. Is electrical stimulation effective in reducing Neuropathic Painin patients with diabetes? J foot ankle surgery. 1997; 36(4): 260-263.
  108. Lefaucheur JP, Drouot X, Menard-Lefaucheur I, Zerah F, Bendib B, Cesaro P, et al. Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatry. 2004; 75(4): 612-616.
  109. Capel ID, Dorrell HM, Spencer EP, Davis MW. The amelioration of the suffering associated with spinal cord injury with subperception transcranial electrical stimulation. Spinal Cord 2003; 41: 109-117.
  110. Tan G, Rintala DH, Thornby JI, Yang J, Wade W, Vasilev Cl. Using cranial electrotherapy stimulation to treat pain associated with spinal cord injury. J Rehabil Res Dev. 2006; 43(4): 461-474.
  111. Jin DM, Xu Y, Geng DF, Yan TB. Effect of transcutaneous electrical nerve stimulation on symptomatic diabetic peripheral neuropathy: a meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2010; 89(1): 10-15.  doi: 10.1016/ j.diabres.2010.03.021.
  112. Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P, Jensen TS, Lefaucheur JP, et al. EFNS guidelines on neuro stimulation therapy for neuropathic pain. Eur J Neurol. 2007; 14(9): 952-970.
  113. McQuay HJ, Moore RA, Eccleston C, Morley S, Williams AC. Systematic review of outpatient services for chronic pain control. Health Technol Assess. 1997; 1(6): i-iv.
  114. Akyuz G, Kayhan O, Babacan A, Gener FA. Transcutaneous electrical nerve stimulation (TENS) in the treatment of postoperative pain and preventionof paralytic ileus. Clinical Rehabilitation. 1993; 7: 218-222.
  115. Bloodworth DM, Nguyen BN, Garver W, Moss F, Pedroza C, Tran T, et al. Comparison of stochastic vs. conventional transcutaneous electrical stimulation for pain modulation in patients with electromyographically documented radiculopathy. Am J Phys Med Rehabil. 2004; 83(8): 584-591.
  116. Akyüz G, Özkök Ö. Evidence based rehabilitation in chronic pain syndromes. Agri. 2012; 24(3): 97-103. doi: 10.5505/ agri.2012.46320.
  117. Ownby KK. Effects of ice massage on Neuropathic Pain in persons with AIDS. J Assoc Nurses AIDS Care. 2006; 17(5): 15-22.
  118. Nayak S, Matheis RJ, Agostinelli S, Shifleft SC. The use of complementary and alternative therapies for chronic pain following spinal cord injury: a pilot survey. J Spinal Cord Med. 2001; 24(1): 54-62.
  119. Kuphal KE, Fibuch EE, Taylor BK. Extended swimming exercise reduces inflammatory and peripheral Neuropathic Painin rodents. J Pain. 2007; 8(12): 989-997.
  120. Ferrell BR. Patient education and nondrug interventions. Pain In The Elderly, Seattle, USA: IASP Press; 1996.
  121. Cha MH, Choi JS, Bai SJ, Shim I, Lee HJ, Choi SM, et al. Antiallodynic effects of acupuncture in neuropathic rats. Yonsei Med J. 2006; 47(3): 359-366.
  122. Rapson LM, Wells N, Pepper J, Majid N, Boon H. Acupuncture as a promising treatment for below-level central neuropathic pain: a retrospective study. J Spinal Cord Med. 2003; 26(1): 21-26.
  123. Lee MM, Cho HY, Song CH. The mirror therapy program enhances upper-limb motor recovery and motor function in acute stroke patients. Am JPhys Med Rehabil. 2012; 91(8): 689-696, quiz 697-700. doi: 10.1097/PHM.0b013e31824fa86d.
  124. Chan BL, Witt R, Charrow AP, Magee A, Howard R, Pasquina PF,  et al. Mirror therapy for phantom limb pain. N Engl Med. 2007; 357: 2206-2207.
  125. Gulseren Akyuz and Ozge Kenis. Physical Therapy Modalities and Rehabilitation Techniques in the Treatment of Neuropathic Pain. Int J phy med rehabil. 2014; 93(3): 253-9. doi: 10.1097/ PHM.0000000000000037.
  126. Hamza MA, White PF, Craig WF, Ghoname ES, Ahmed HE, Proctor TJ, et al. Percutaneous electrical nerve stimulation: a novel analgesic therapy for diabetic neuropathic pain. Diabetes Care. 2000; 23(3): 365-370.
  127. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabetic Med. 2004; 21(2): 114–121.
  128. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, et al. Oral treatment with a lipoic acid improves symptomatic diabetic polyneuropathy-The SYDNEY 2 trial. Diabetes Care. 2006; 29(11): 2365-2370.
  129. Litchy W, Dyck P, Tesfaye S. For the MBBQ Study Group: Diabetic peripheral neuropathy (DPN) assessed by neurological examination and composite scores is improved with LY333531 treatment (Abstract). Diabetes. 2002;45: A197.
  130. Weintraub MI, Wolfe GI, Barohn RA, Cole SP, Parry GJ, Hayat G, et al. Static magnetic field therapy for symptomatic diabetic neuropathy; a randomized, double-blind, placebo controlled trial. Arch Phys Med Rehabil. 2003; 84(5): 736-46.
  131. Ziegler D. Treatment of diabetic neuropathy and neuropathic pain: how far have we come? Diabetes Care. 2008; 31(Suppl 2): S255–S261. doi: 10.2337/ dc08-s263.
  132. Rudofsky G Jr, Reismann P, Witte S, Humpert PM, Isermann B, Chavakis T, et al. Asp299Gly and Thr399Ile Genotypes of the TLR4 Gene Are Associated with a Reduced Prevalence of Diabetic Neuropathy in Patients with Type 2 Diabetes. Diabetes Care. 2004; 27(1): 179-183.
  133. Gandhi RA, Marques JL, Selvarajah D, Emery CJ, Tesfaye S. Painful diabetic neuropathy is associated with greater autonomic dysfunction than painless diabetic neuropathy. Diabetes Care. 2010; 33(7): 1585-1590. doi: 10.2337/dc09-2314.
  134. Mary Margaret Huizinga, Amanda Peltier. Painful Diabetic Neuropathy: a management centered review.  Clinical Diabetes. 2007; 25: 1.
  135. VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel: Duloxetine (Cymbalta) in painful diabetic neuropathy and fibromyalgia [article online]. Available from http://www.pbm.va.gov/monograph/6upaeDulox-etine.pdf.
 
Listing : ICMJE   

Creative Commons License Open Access by Symbiosis is licensed under a Creative Commons Attribution 3.0 Unported License