Neuropathy Clinical Reprint 2013 Final 03

v o l u m e 12 n u m b e r 4FALL 2013

Practical Information for Primary Care

Status of Painful Diabetic Peripheral Neuropathy in the Arab World :A Call to Action

Monira Al-Arouj, MD; Samir H. Assaad-Khalil, MD, PhD; Ebtesam M Ba-Essa, FRCP; Megahed Abu El-Magd, MD; Mohamed Fahmy, MD, PhD., Martha Funnell, PhD; Sherif Hafez, MD, FACP; Mahmoud Ibrahim, MD; Abdulrazzaq Al-Madani, MD; Abdullah Ben Nakhi, MD; Gamela Nasr, MD ; Abraham Thomas , MD, FACP

[Middle East Edition]

177 Volume 12, Number 4, 2013 • ClINICAl DIAbeTeS (mIDDle eAST eDITIoN)

L O C A L A R T I C L E S

Status of Painful Diabetic Peripheral Neuropathy in the Arab World :A Call to Action

Monira Al-Arouj, MD1; Samir H. Assaad-Khalil, MD, PhD2; Ebtesam M Ba-Essa, FRCP3; Megahed Abu El-Magd, MD4; Mohamed Fahmy, MD, PhD5., Martha Funnell, PhD6; Sherif Hafez, MD, FACP7; Mahmoud Ibrahim, MD8; Abdulrazzaq Al-Madani, MD9; Abdullah Ben Nakhi, MD1; Gamela Nasr, MD10 ; Abraham Thomas , MD, FACP11

1Dasman Diabetes Institute, Kuwait; 2Department of Internal Medicine, Unit of Diabetes & Metabolism, Faculty of Medicine, Alexandria University, Egypt; 3Dammam Medical Complex, Dammam, Saudi Arabia; 4Department of Internal Medicine & Endocrinology, Faculty of Medicine, Mansura University, Mansura, Egypt; 5Department of Internal Medicine & Endocrinology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 6Department of Medical Education, University

of Michigan Medical School, Michigan, USA; 7Department of Internal Medicine & Diabetes, Faculty of Medicine, Cairo University, Cairo, Egypt; 8EDC Center for Diabetes Education, McDonough, GA , USA; 9Dubai Hospital, Dubai, United

Arab Emirates; 10Department of Cardiology, Suez Canal University, Egypt; 11Division Head Endocrinology, Diabetes, Bone & Mineral Disorders, Whitehouse Chair in Endocrinology, Henry Ford Hospital, Detroit MI, USA.

AbstractDiabetes is one of the most challeng-ing health problems with its incidence and prevalence rising in almost every country in the world. However, the prevalence in the Arab region has been the highest. The prevalence of painful diabetic peripheral neuropa-thy (DPN) among type 1 or type 2 diabetic adults in the Arab countries is very high.

Because of the high prevalence and associated impact on the quality of life, disability, and economic impact of painful DPN, it was recommended that diabetic patients should be periodically screened, using a simple instrument such as the DN4, and receive appropriate treatment as soon as symptoms and signs appear.

Educational programs concerning painful DPN should target key phy-sician leaders and educators so they can be trained to train the others. These programs should be designed to enables these key doctors to deliver the same educational content to the primary health care providers including, but not limited to fam-ily physicians, nurses and diabetes educators.

Also campaigns to target lay people should be developed, using the suitable tools adapted for each com-munity, to increase public awareness of the diabetic neuropathic pain problem and possible ways of pre-vention with a special focus on the need for glycemic control

Keywords: Painful Neuropathy, Arab World.Corresponding Author Details:Mahmoud Ibrahim, MD Director EDC, Center for Diabetes Education, McDonough, GA, USA. [email protected] Diabetes in the Arab countriesDiabetes is undoubtedly one of the most challenging health problems, where its incidence and prevalence are rising approximately in every country of the world. However, the prevalence seen in the Arab region has been the highest 1. Current data shows that almost 20.5 mil-lion people from 20 Arab countries are diabetics, and 13.7 million are in the pre-diabetes stage. This high prevalence of diabetes is reflected by the finding that five of the top 10 countries with the greatest diabetes prevalence in subjects 20-79 years old were actually from the Arab

region1. Population-based diabetes studies have shown that the preva-lence of diabetes in these countries was 23.9% in Kuwait, 23.4% in Saudi Arabia, 23.3% in Qatar and 22.4% in Bahrain1. The age-specific prevalence of diabetes shows that in developed countries, most people with diabetes are above the age of retirement, while in Arab countries; approximately 73% of people with diabetics are younger than sixty. This younger age could significantly increase disability due to diabetes in a younger and more likely to be working population, making the impact even greater1.

Despite the emphasis on glycemic control, evidence of improvement in A1C control over time remains scant. in Egypt Only 16.5% of patients had A1C < 7% and 28.5% of them had very poor glycemic control as represented by an A1C > 9%.2

A screening campaign of 197,681 participants in an eastern province of Saudi Arabia, demonstrated an estimated prevalence of diabetes of 15.7%. However, only 33.8% of patients with diabetes achieved their glycemic control targets (fasting blood glucose less than 130 mg/dl or

178Volume 12, Number 4, 2013 • ClINICAl DIAbeTeS (mIDDle eAST eDITIoN)


random capillary blood glucose less than 180 mg/dl). Multiple logistic regression analysis showed that higher age, current smoking and lower level of physical activity were significantly associated with uncon-trolled diabetes.3 Another study in Saudi Arabia revealed that only 27% of people with type 2 Diabetes reached their glycemic target (A1C < 7%).4

Painful Diabetic Peripheral NeuropathyThe neuropathies developing in patients with diabetes are known to be heterogeneous by their symptoms, pattern of neurologic involvement, and course. An internationally agreed definition of Diabetic Painful Neuropathy DPN for clinical prac-tice is: the presence of symptoms and/or signs of peripheral nerve dysfunc-tion in patients with diabetes after a careful clinical examination of the lower extremities and the exclusion of other causes. However, not all patients with peripheral nerve dys-function have a neuropathy caused by diabetes. Confirmation can be established with quantitative electro-physiology, sensory, and autonomic function testing 5-6-7.

How should the severity of a patient's polyneuropathy be assessed? The severity of a patient's polyneuropathy is obviously the sum of the patient's symptoms, neurological signs, test abnormalities, dysfunctions and other adverse outcomes. Numerous classifications have been proposed in the recent years, which have been based mainly on one originally proposed by Thomas.8

Separate definitions for typical Diabetic sensorimotor polyneu-ropathy DPN (DSPN) and atypical DPNs were proposed by Tesfaye and Boulton, et al. DSPN is a symmetri-cal, length-dependent sensorimotor polyneuropathy attributable to meta-bolic and microvascular alterations as a result of chronic hyperglycemia exposure (diabetes) and cardiovas-cular risk covariates accompanied by

an abnormality of nerve conduction tests, which is frequently subclinical. Coexisting retinopathy and nephrop-athy strengthen the diagnosis after exclusion of other causes of senso-rimotor polyneuropathy. 5

For epidemiologic surveys or con-trolled clinical trials of DSPN, it is advocated to use appropriate nerve conduction (NC) testing as an early and confirmed diagnosis of the occur-rence of DSPN. On the other hand, atypical DPNs have been less well characterized and studied. Composite scores of neuropathy symptoms, signs, neurophysiologic test abnor-malities, and other dysfunctions and impairments may provide an indica-tion of its severity 9-10

An alternative approach for esti-mating the severity is to define this severity by grades. Dyck described the stages of severity ranging from Grade 0 where there is no abnormal-ity in the NC up to Grade 2b where the NC abnormality is accompanied by a moderate degree of weakness (i.e. 50%) of ankle dorsiflexion with or without neuropathy symptoms. 11

However, definitions of typical DPN are: 1- Possible DSPN where you can find the presence of symptoms or signs of DSPN including decreased sensation, positive neuropathic sensory symptoms predominantly in the toes, feet, and/or legs; or signs such as a symmetric decrease in distal sensation or unequivocally decreased or absent ankle reflexes. 2-Probable DSPN which is a combination of symptoms and signs of neuropathy, including any two or more neu-ropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes. 3-Confirmed DSPN is the pres-ence of an abnormality of NC and symptom(s) and/or sign(s) of neu-ropathy. If NC is normal, a validated measure of small fiber neuropathy (SFN) may be used. To assess for the severity of DSPN, you need to sum the scores of neurologic signs, symptoms or nerve test scores, scores

of function of acts of daily living or of predetermined tasks or of disabil-ity. 4- Subclinical DSPN it is the lack of signs or symptoms of neuropathy with abnormal NC(s) or a validated measure of SFN. It is recommended that definitions 1, 2, or 3 be used for clinical practice and definitions 3 or 4 be used for research studies. 12-13-14

Atypical DPNsBefore further classification of these polyneuropathies, setting the mini-mal criteria for diagnosis, estimating the severity of neuropathy, and further studies characterizing the epidemiology and mechanisms are needed. 14

PAINFUL DPN is pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes, which was adapted from a definition recently proposed by the International Association for the Study of Pain. 12 Its prevalence in the diabetic population is difficult to estimate as definitions have varied enormously among studies; however, it is roughly estimated that between 3 and 25% of patients might experi-ence neuropathic pain (NP) with limited data on the natural history. 13 In practice, the diagnosis of painful DPN is a clinical one, which relies on the patient’s description of pain. The symptoms are distal, symmetrical, often associated with nocturnal exacerbations, and com-monly described as prickling, deep aching, sharp, like an electric shock, and burning with hyperalgesia and frequently allodynia upon examina-tion. 13 The symptoms are usually associated with the clinical signs of peripheral neuropathy, although occasionally in acute painful DPN, the symptoms may occur in the absence of the typical signs. A num-ber of simple numeric rating scales can be used to assess the frequency and severity of painful symptoms. 14 After exclusion of other causes of neuropathic pain NP. The severity of pain can be reliably assessed by the old and validated visual analog



scale, or the widely used numerical rating scale, e.g. the 11-point Likert scale ranging from (0 _ no pain, 10 _ worst possible pain). Quality of life (QoL) improvement should also be assessed, preferably using a validated neuropathy-specific scale such as Neuro-QOL or the Norfolk Quality of Life Scale. 15 Outcomes must be measured using patient-reported improvement in scales for pain and QoL as measured on validated instruments. External observers can play no part in the assessment of the subject’s responses to the new thera-pies for NP; thus, measures such as the “physician’s global impression of response” are not valid.

Painful neuropathy in the Arab countries In a step to determine the preva-lence of painful DPN in the Arab countries, the main objective of a recent study done by Jambart and his colleagues was to determine the prev-alence of painful DPN among type 1 or type 2 diabetic adults attend-ing outpatient clinics in the Middle East Region, specifically Egypt, Lebanon, Jordan and the Gulf States of Kuwait and the United Arab Emirates (n = 4097.) Overall,

53.7% of 3989 patients with DN4 data met the criteria for painful DPN (Douleur Neuropathique-4 [DN4] scores ≥4). The symptom ranged from itching (23.1%) to burning sen-sation (59.3%) including hypothesia, painful cold, electric shock, tingling and numbness (Figure 1). Significant predictors of painful DPN included longer duration (≥10 years) of dia-betes (odds ratio [OR] 2.43), age ≥65 years (OR 2.13), age 50 – 64 years (OR 1.75), presence of type 1 versus type 2 diabetes (OR 1.59), body mass index ≥30 kg/m2 (OR 1.35) and female gender (OR 1.27). Living in one of the Gulf States was associ-ated with the lowest odds of having painful DPN (OR 0.44). The odds of painful DPN were highest among patients with peripheral vascular dis-ease (OR 4.98), diabetic retinopathy (OR 3.90) and diabetic nephropathy (OR 3.23) (Figure 2.) Because of the high prevalence, associated suffering, disability and economic burden of painful DPN, it was recommended that diabetic patients should be periodically screened, using a simple instrument such as the DN4, and receive appropriate treatment as early as the symptoms and signs start to appear. 16

Treatment of Painful Diabetic Neuropathic PainThere are many available treat-ment options; however, a rational approach to treating the patient with painful DPN requires an understanding of the evidence for each intervention. Pharmacological management of painful DPN almost exclusively consists of symptomatic therapies improving symptoms without an effect on underlying causes or natural history 17. The antioxidant lipoic acid administered intravenously is the only pathogenic treatment that has efficacy confirmed from several randomized controlled trials and in a meta-analysis18. Again Level A evidence supports the use of tricyclic antidepres-sants (e.g., amitriptyline) 21, the anticonvulsants gabapentin and pregabalin, and the serotonin and norepinephrine reuptake inhibitor duloxetine 17-20-22-23. On the other hand there are also randomized controlled trials (RCT) supporting the use of opiates, such as oxycodone and tramadol in painful DPN 17-20. However in another study, there was no evidence to support the use of the cannabinoids 24. Thus, it is recommended that first line therapy



for painful DPN could be a tricyclic antidepressant, duloxetine, prega-balin, or gabapentin, after careful consideration of individual patient comorbidities and the cost of the drug 17-20-22. Combinations of the first-line therapies could be an option, if significant pain persists , after initiation of first-line monotherapy 17-20. If these changes and combined therapy do not control the pain, , opi-oids, like tramadol and oxycodone, may be considered in combination with first-line therapies as part of the treatment plan 17-20. Preliminary evidence shows promise for topical treatment, using a 5% lignocaine plaster applied to the most painful area 25, although larger RCTs are required. Non-pharmacological treatments, such as spinal cord stimu-lation, might be useful in refractory painful DPN, 19 however, insufficient evidence exists for any other non- pharmacological therapies.

Old and New drugsAlthough several novel analgesic drugs have recently been introduced into clinical practice, the pharma-

cologic treatment of chronic DPN remains a challenge for the physi-cian. Individual tolerability remains a major aspect in any treatment decision. Advanced knowledge in the neurobiology of neuropathic pain and an increasing perception of the commercial value of analgesic agents have led to a real need for research develops to novel pharmaceutical approaches. According to a recent review 26, at least 50 new molecular entities have reached the clinical stage of development, including glutamate antagonists, cytokine inhibitors, vanilloid-receptor agonists, cat-echolamine modulators, ion-channel blockers, anticonvulsants, opioids, cannabinoids, COX inhibitors, acetylcholine modulators, adenos-ine receptor agonists, and several miscellaneous drugs. Eight drugs are presently in phase III trials. Strategies that may show promise over existing treatments include topical therapies, analgesic combinations, and, in the future, gene- related therapies 26.

Whether the efficacy and safety differ between the newer and older

compounds has not been systemati-cally addressed in comparative trials, although clinical experience indi-cates that the rates of adverse events (AEs) of the newer compounds may be lower than those of the older ones, such as tricyclic antidepressants. Almost no information is available from controlled trials on long-term analgesic efficacy. Only few stud-ies have used drug combinations, indicating that the latter may result in enhanced efficacy. 26There are many unanswered ques-tions and areas relating to painful DPN that warrant further investiga-tion, including population-based prevalence and natural history stud-ies, trials using active comparators rather than placebo, assessment of combination therapies in addition to placebo, and longer-term studies of the efficacy and durability of treat-ments of painful DPN 26

Recently a multidisciplinary panel , including key physicians and researchers concerned with neu-ropathic pain in the Middle East area along with an international

Figure 1 & 2 reproduced with permission of the JIMR



panel, met together to review the most recent data in an attempt to form a consensus for evidence based guidelines to treat DPN (mainly peripheral painful DPN) in patients from the Middle East. This expert panel recommended pregabalin, gabapentin and second-ary amine tricyclic antidepressants (nortriptyline and desipramine) as first-line treatments for peripheral DPN. Serotonin–norepinephrine reuptake inhibitor antidepressants, tramadol and controlled-release opioid analgesics were preferred by the same panel to serve as second line treatments. They also addressed the need to increase diagnostic awareness of DPN , use validated screening questionnaires, and undertakes more research on treatment in the Middle East region27

The Role of Diabetes Education and the Diabetes EducatorThe provision of comprehensive diabetes self-management educa-tion as well as specific information about neuropathy and foot-care is recommended as part of the on-going clinical care of diabetes.28,29 All patients with diabetes need general education about long-term complica-tions and foot care. Patients who have high risk foot conditions, such as neuropathy, need to understand their personal risk factors and specific strategies to prevent further damage.28,30,31Education about appropriate foot care is particularly important for patients who are at high risk. 30 and has been shown to positively influence foot care behavior in the short-term. 31 Patients with neu-ropathy and other high-risk foot conditions need to understand the implications of decreased sensa-tion, the importance of appropriate footwear and daily foot inspection, how to effectively care for their feet and when to seek care.28

Foot care education has the poten-tial to prevent further damage and the ulcerations that can lead to amputations, other morbidities and

mortality. While all health care pro-fessionals who provide diabetes care need to provide this information, the diabetes educator can play a key role in providing effective education. The role of the educator is particularly important in busy practices where foot care education can become secondary to medical management. As part of initial education, the diabetes educator can:• Provideinformationabout

potential complications, includ-ing neuropathy and prevention strategies, such as blood glucose management.

• Teachpatientstoidentifysymp-toms that could be linked to neuropathy and when to report them to the provider, stressing the importance of early detection to prevent further damage. Because many symptoms are vague and may not be recognized by patients as linked to diabetes or nerve damage, this is a particularly important role for the educator.

• Teachpatientsinitialfootcare strategies, such as remov-ing shoes and socks at all diabetes-related visits to facilitate examination and reminding providers of the need for an annual comprehensive exam. In addition, home care, such as appropriate daily care and foot-wear are initial education topics the educator can address.

As part of continuing education, the diabetes educator can:• Reviewpreventionstrategiesfor

complications and symptoms to report to physicians.

• Conductfootinspectionsandtoscreen for neuropathy (checking pulses, reflexes and sensation with a monofilament) using standard screening instruments . http://www.med.umich.edu/mdrtc/profs/survey.html#mnsi

After the diagnosis of neuropathy, the diabetes educator can:• Assistpatienttocopewiththe

bad news of a complication.

Offer reassurance that amputa-tions are not an inevitable result. 32

• Provideinformationaboutmedi-cations available for pain relief and other strategies to ease pain (e.g. keeping bed covers away from painful feet).

• Emphasizethecriticalimpor-tance of foot care and provide personalized strategies to prevent trauma. Stress the importance of protecting the feet, inspecting for injury and seeking prompt treatment for any issues.

• Workwiththepatienttocreatea daily plan for foot care that accommodates the patient’s physical findings, schedule, lifestyle and culture.

RecommendationsIn the Arab countries, the high prevalence of the Diabetic Painful Neuropathy is actually leading to significant morbidity and disability, which could also create an economic burden. Accordingly, there is a great need to tackle this problem , even though DPN may not be life threaten-ing issue, such as the macrovascular complications of diabetes. Yet DPN negatively impacts the quality of life.

The recommendations included hereunder provide guidance on appropriate care and measures that can be modified according to suit the needs of each country.

A) The Establishment of Painful Neuropathy Leaders:

Programs should be targeting key doctors concerned with painful neuropathy in a way to train the trainers. These programs should be designed in a way to enables these key doctors to deliver the same materials and messages to the primary health care provid-ers in their area, including, but not limited to family physicians , nurses, and diabetes educators.

B) Lay people targeted campaigns should be designed using the suitable tools



for each community aiming to increase public awareness of the neuropathic pain problem and the possible ways of prevention with a special focus on the glycemic control.For a more in depth and recent review of diabetic neuropathy33

Disclosure:Authors of this article have no relevant financial relationships to

disclose.This article is a part of an edu-cational activity supported & sponsored without restriction by Pfizer.

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Neuropathy Clinical Reprint 2013 Final 03