Epidemiology
Estimates of the prevalence of pDPN vary widely in the region due to a paucity of data. Moreover, current prevalence rates may be underestimated as patients often do not approach their physicians with symptoms of neuropathic pain and many remain undiagnosed.(8) The worldwide prevalence of pDPN among patients with DM is estimated to be around 30%, however in the Middle East and North Africa this ranges from 22.5-65% (Figure 1). (1, 10, 13)

Of note, most data have been gathered from patients in secondary and tertiary care centers and studies in primary care are required to establish the true prevalence of pDPN.

Figure 2: Intense pain, sleep disturbance, and mood disorders significantly reduce the quality of life and functionality of patients with pDPN


Burden
As pDPN can have significant adverse effects on quality of life, early recognition of neuropathic symptoms is crucial. Severe pain may significantly interfere with a patient's ability to exercise or walk, limit general activities of daily living, and alter sleep patterns as symptoms are often most intense at night(5, 14, 15). Indeed, one study reported that patients with pDPN who suffered from severe pain were willing to trade nearly a full day of their lives in order to avoid 1 additional hour of pain.(15) In addition, they also reported feeling approximately (21) years older than their actual age.(15) The combination of intense pain, sleep disturbance, poor mobility, and inability to perform general activities of daily living imposes a heavy toll on patients, which are strongly associated with mood disorders such as depression and anxiety (Figure 2).(16) Whilst a previous study of 200 Emirati subjects with diabetes demonstrated an above average QoL score, this was significantly reduced in those with at least one complication affecting the 'foot', heart, eye or kidney.(17)

Etiology and risk factors
The exact etiology of pDPN is unknown and may be attributable to a combination of chronic hyperglycemia and cardiovascular risk factors such as dyslipidaemia and hypertension.(18)

The Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, showed that intensive glycemic control can delay the development and progression of diabetic neuropathy in patients with type 1 DM (T1DM).(19, 20) However, patients with type 2 DM (T2DM) do not seem to benefit from intensive glycemic control as per a Cochrane meta-analysis and several large clinical trials.(4, 21, 22) Lipid levels, blood pressure, inflammation, insulin resistance, oxidative stress, vitamin D deficiency, height, cigarette smoking, and alcohol consumption have all been related to pDPN in various studies.(2, 10, 22-24)

Epidemiological analyses suggest that the following are significant risk factors for pDPN(25):
• long-standing diabetes of >10 years' duration
• age >65 years
• body mass index (BMI) >30
• female sex

Pathophysiology
The exact mechanisms underlying pDPN remain unclear, but both the peripheral and central nervous system are thought to be involved. Painful sensations can arise from damage to the A and C nerve fibers. Lesions of the peripheral nerves can increase their excitability, a phenomenon known as peripheral sensitization. This occurs via increased or altered sodium channel expression and function, which is associated with spontaneous painful discharges and reduced thresholds for activation leading to neuropathic pain.(26) Increased calcium channel expression also encourages the release of excitatory neurotransmitters such as glutamate and substance P, and can increase the excitability of neurons in the spinal cord (central sensitization)(Figure 3).(23, 27)

Efferent nerve fibers that descend from the brain to the dorsal horn of the spinal cord have a powerful inhibitory effect on pain signals sent via the afferent fibres; their function is reliant on neurotransmitters such as y-aminobutyric acid (GABA), serotonin, and noradrenalin. Dysfunction of these pathways can also result in central sensitization.(27)

Figure 3. Pain pathways in patients with diabetic peripheral neuropathy



Clinical presentation
Patients with pDPN tend to describe their symptoms using similar terms and most describe either numbness or a tingling, electric shock-like, burning, shooting or stabbing pain in their feet or lower legs due to the involvement of the small sensory nerve fibers (Table 1).(5, 28, 29)

Table 1. Common Arabic, English and French terms used to describe symptoms of neuropathic pain by patients with pDPN.


A classic 'stocking - glove' distribution of pain is expected with symptoms initially occurring in the toes, feet and lower limbs and in advanced cases progressing to the fingers and hands.(4) Many patients report that their symptoms are worse at night.(5, 28, 29)

Practice points: Typical symptoms of pDPN Symptoms vary among patients but typically include at least one of the following: • Numbness • Tingling sensation • Shooting/Stabbing pain • Burning sensation

Other characteristics
• Worse at night
• Stocking - glove distribution: Starts in the feet, progresses up the lower limbs.

Table 2: Conditions to be ruled out when considering a pDPN diagnosis


Diagnosis and evaluation
A comprehensive physical examination should be performed when a patient with diabetes presents with neuropathic pain. A careful clinical history should be undertaken as the differential diagnoses are many and varied, and diagnosis may be challenging (Table 2).

The first step in assessing a patient is to determine whether there is any evidence of neuropathic pain. Neuropathic pain can be distinguished from nociceptive pain by using a screening tool and performing a thorough clinical examination (Table 3).

Table 3: Tests to be performed before diagnosing pDPN

SCREENING TOOLS

It is recommended that all patients with metabolic syndrome/impaired glucose tolerance and Type 1/2 diabetes should be screened for neuropathic pain at least annually. A number of different screening tools are available that can aid with differentiating neuropathic and nociceptive pain including the Neuropathic Pain Questionnaire, the Leeds Assessment of Neuropathic Pain and Symptoms scale and the McGill Pain Questionnaire.(18, 25)

The Doleur Neuropathique en 4 Questions (DN4) scale is recommended as it has a sensitivity and specificity of 82.9% and 89.9%, respectively, and validated translations are available in 15 languages, including English, Arabic and French (see: Appendix).(25, 29, 30) It is a 10-item questionnaire - 7 items are based on symptoms and 3 on a simple and easy to perform clinical examination. A score ?4 is suggestive of neuropathic pain (Figure 4).(25)

Figure 4: English translation of the Doleur Neuropathique en 4 Questions (DN4) scale recommended for distinguishing nociceptive and neuropathic pain (29)

CLINICAL ASSESSMENTS

Patients with pDPN present initially with pain in the feet and physicians are thus advised to remove a patient's shoes and socks to undertake a thorough clinical examination of the patient's feet. Tests include not only the three tests performed as part of the DN4 (testing for touch, pinprick, and allodynia), but also a more careful analysis of the patient's description of their pain. Traditionally, a monofilament has been used for assessing neuropathy; however, this is only useful for evaluating advanced neuropathy and for identifying patients at high risk of foot ulceration. It should therefore not be used to identify neuropathy as it will often be normal despite significant small fiber neuropathy.

The 3L (listen, look, locate) approach is recommended for identifying signs and symptoms of neuropathic pain(27):

• Listen to the patient's verbal description of their pain and note any mention of non-painful symptoms that are experienced in the same area as the pain.
• Look for any sensory abnormalities such as pain felt upon touching the sensitive area and note any unusually warm or cold regions and differences in color or texture relative to a non-painful adjacent site.
• Locate the region of pain and document its position using a pain drawing, which can be created by the patient or the physician. Make a note of any abnormal sensations on the drawing.

Practice points: Recommendations for Clinical Assessment • Apply the DN4 screening tool to identify neuropathic vs nociceptive pain • Remove the patient's shoes and socks and examine his/her feet • Employ the 3L approach: Listen to the vocal description of pain, locate the region of pain, and look for somatosensory deficits with the help of simple bedside tests

Increasing patient awareness is important for encouraging patients to self-report painful symptoms. Patients may not volunteer this information and it is recommended that physicians ensure that all at-risk patients are aware of the possibility of developing pDPN and of the symptoms they should look out for. It is also important to note that approximately 10-15% of patients with diabetes who experience neuropathic symptoms will have a neuropathy from another cause that may be treatable.

Practice points: 'Red flags' indicating that referral to a neurologist is required • Asymmetrical pain • Predominance of motor vs sensory neuropathy • Rapid progression • Acute onset • Prominent autonomic symptoms

Contemporary Management
There is currently no cure for pDPN and treatment is challenging as many patients do not experience sufficient pain relief.(28, 31) In this context, combination pain relief regimens may be more effective than the traditional approach of trialing and discontinuing a single agent if this fails to provide sufficient relief.(31)

Treatment goals are focused on preventing the development or progression of DPN through an improvement in glycaemic control and vascular risk factors and educating patients as to how best to address their symptoms, employing pharmacologic and/or non-pharmacologic agents to help manage neuropathic pain to improve the patient's QoL.(5)

Practice points: Treatment Goals • A clinically meaningful reduction in pain(32): ...o 30-50% reduction in pain on a visual analog scale or ...o 2-point reduction on a 10-point Likert scale • Manage sleep • Educate patients .. o Provide information on pDPN ...o Provide guidance on self-care

First- and second-line recommendations for treatment published in guidelines for the Middle East and North Africa are consistent with those used globally and are summarized in Table 4. Most recent guidelines for treating neuropathic pain - including the International Association for the Study of Pain Neuropathic Pain Special Interest Group (NeuPSIG) - recommend the use of anticonvulsant GABA analogs (pregabalin or gabapentin), serotonin-norepinephrine reuptake inhibitors (SNRIs e.g., duloxetine), or tricyclic antidepressants (TCAs) as first-line therapy. Other options include opioid analgesics (Table 5).(31, 32) Other therapies such as topical nitrate, vitamin D and alpha lipoic acid, (33, 34) as well as non-pharmacological therapy such as acupuncture, and transcutaneous electrical nerve stimulation may also have a place in treating patients with pDPN. Vitamin B is frequently used in pDPN management in the MENA region, however, there are limited data in randomized trials testing the efficacy of vitamin B for treating peripheral neuropathy and meta-analyses have reported inconclusive evidence for its role in therapy.(35)

Table 4: Global first- and second-line recommendations for the treatment of neuropathic pain associated with diabetic peripheral neuropathy (31, 32)

Practice points: Pharmacologic therapy of pDPN • Use GABA analogs (pregabalin or gabapentin), tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) first-line • Consider combining pregabalin or gabapentin with SNRIs or TCAs • Opioid analgesics can be given for second-line use

Patient counseling
Patients should be given clear, specific information on how to use their medications as well as counseling on expectation of the response to therapy, as an expected response may be 50% at best whilst a 30% reduction in pain is considered clinically meaningful. Patients may be disappointed if they expect complete resolution of their painful symptoms.

Physicians should clarify that the agents prescribed are used for a specific purpose and that many have multiple indications: TCAs for example are prescribed for their effect on neuropathic pain not because of their antidepressant effects and this should be made clear to patients. In addition, patients should also be educated about the side effects of different medications especially when prescribed in high doses and both benefits and disadvantages should be openly discussed with the patient, to ensure compliance.

It is also important to follow-up on treatment to ensure that the prescribed medication is having the intended effect; if not, the dose should be increased or an alternative be prescribed. A simple 11-point pain scale can be useful for distinguishing 'before' and 'after' pain scores to help determine the effectiveness of the prescribed treatment.

Table 5: Summary characteristics of treatments recommended for neuropathic pain associated with diabetic peripheral neuropathy.29, 31, 32, 34, 36 EU: European Union; ME: Middle East;
US: United States

DISCUSSION

pDPN is increasingly common in the Middle East and North Africa but is underdiagnosed. Physicians in the region are encouraged to familiarize themselves with the latest guidelines for diagnosing and managing the condition. The use of screening tools such as the DN4 should be combined with a comprehensive physical examination to identify patients suffering from pDPN and DPN. The 3L (listen, look, locate) approach to clinical assessment is recommended. Physicians should educate their patients on identifying pDPN to avoid unnecessary suffering with loss of sleep and a reduced QoL.

Once neuropathy has been diagnosed, causes other than pDPN should be excluded. Affected patients can be managed according to international treatment recommendations for pDPN. Anticonvulsants (such as pregabalin and gabapentin), SNRIs and TCAs are recommended for first-line treatment. Patients should be closely followed-up and those with inadequate pain relief should be offered an alternative first-line agent that has a different mechanism of action, or combination therapy. Second-line agents should be reserved for patients who suffer more severe pain and who are unable to obtain adequate relief from first-line agents either alone or in combination.

Treatment Algorithm

Acknowledgements
Dr Sid Ahmed Kherraf of Pfizer Inc. coordinated the expert panel meeting. Editorial and writing support was provided by Ms Lianne Cowie and Mr Andy Lee of MIMS (Hong Kong) Limited and was funded by Pfizer. Pfizer provided an unrestricted educational grant but did not write or control the scientific content of the manuscript.

APPENDICES

Appendix A - English DN4 questionnaire (29)



Appendix B - French DN4 questionnaire (29)



Appendix C - Arabic DN4 questionnaire (30)

REFERENCES

1. Halawa MR, Karawagh A, Zeidan A, Mahmoud AE, Sakr M, Hegazy A. Prevalence of painful diabetic peripheral neuropathy among patients suffering from diabetes mellitus in Saudi Arabia. Curr Med Res Opin. 2010 Feb;26(2):337-43.
2. 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 Apr;28(4):956-62.
3. Alamdari A, Mozafari R, Tafakhori A, Faghihi-Kashani S, Hafezi-Nejad N, Sheikhbahaei S, et al. An inverse association between serum vitamin D levels with the presence and severity of impaired nerve conduction velocity and large fiber peripheral neuropathy in diabetic subjects. Neurol Sci. 2015 Jul;36(7):1121-6.
4. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012 Jun 13(6):CD007543.
5. Kuritzky L, Samraj GP, Argoff CE. Current treatments in the management of diabetic peripheral neuropathic pain. Pain Med. 2009;63:62-73.
6. Schumacher C, Glosner SE. Assessment of pain and impact of care among patients with painful diabetic peripheral neuropathy. J Am Pharm Assoc (2003). 2014 Jan-Feb;54(1):14-8.
7. Boulton AJ, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet Med. 1998 Jun;15(6):508-14.
8. Boulton AJ. Management of diabetic peripheral neuropathy. Clinical diabetes. 2005;23:9-15.
9. Herman WH, Kennedy L. Underdiagnosis of peripheral neuropathy in type 2 diabetes. Diabetes Care. 2005 Jun;28(6):1480-1.
10. Jambart S, Ammache Z, Haddad F, Younes A, Hassoun A, Abdalla K, et al. Prevalence of painful diabetic peripheral neuropathy among patients with diabetes mellitus in the Middle East region. J Int Med Res. 2011;39(2):366-77.
11. Zabetian A, Keli HM, Echouffo-Tcheugui JB, Narayan KM, Ali MK. Diabetes in the Middle East and North Africa. Diabetes Res Clin Pract. 2013 Aug;101(2):106-22.
12. Petropoulos IN, Javed S, Azmi S, Khan AN, Malik RA. Diabetic neuropathy and painful diabetic neuropathy in the Middle East and North Africa (MENA) region: Much work needs to be done. Journal of Taibah University Medical Sciences. 2016;11(4):284-94.
13. Aouiche S, Ouerdane K, Frioui M, Boudiba A. Painful Diabetic Neuropathy: Frequency, Risk Factors, and Severity in a Cohort of 400 Diabetic Patients in Algeria. Médecine des Maladies Métabolique. 2014;8(2):211-5.
14. Quattrini C, Tesfaye S. Understanding the impact of painful diabetic neuropathy. Diabetes Metab Res Rev. 2003 Jan-Feb;19 Suppl 1:S2-8.
15. Stacey BR, daCosta DiBonaventura M, Martin S. Assessing the Relationship between Pain Intensity and Quality of Life in Subjects with Painful Diabetic Peripheral Neuropathy. Poster Presentation #130 at the 29th Annual Scientific Meeting of the American Pain Society; Baltimore, MD, USA; May 6-8, 2010.
16. Tesfaye S, Boulton AJ, Dickenson AH. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care. 2013 Sep;36(9):2456-65.
17. Bani-Issa W. Evaluation of the health-related quality of life of Emirati people with diabetes: integration of sociodemographic and disease-related variables. East Mediterr Health J. 2011 Nov;17(11):825-30.
18. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86.
19. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care. 2010 May;33(5):1090-6.
20. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008 Feb 7;358(6):580-91.
21. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010 Aug 7;376(9739):419-30.
22. Davis TM, Yeap BB, Davis WA, Bruce DG. Lipid-lowering therapy and peripheral sensory neuropathy in type 2 diabetes: the Fremantle Diabetes Study. Diabetologia. 2008 Apr;51(4):562-6.
23. Celikbilek A, Gocmen AY, Tanik N, Borekci E, Adam M, Celikbilek M, et al. Decreased serum vitamin D levels are associated with diabetic peripheral neuropathy in a rural area of Turkey. Acta Neurol Belg. 2015 Mar;115(1):47-52.
24. Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AA, Feldman EL. Elevated triglycerides correlate with progression of diabetic neuropathy. Diabetes. 2009 Jul;58(7):1634-40.
25. Chetty S, Baalbergen E, Bhigjee AI, Kamerman P, Ouma J, Raath R, et al. Clinical practice guidelines for management of neuropathic pain: expert panel recommendations for South Africa. S Afr Med J. 2012 Mar 08;102(5):312-25.
26. Lauria G, Ziegler D, Malik R, Merkies IS, Waxman SG, Faber CG. The role of sodium channels in painful diabetic and idiopathic neuropathy. Curr Diab Rep. 2014 Oct;14(10):538.
27. Gilron I, Watson CP, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMAJ. 2006 Aug 1;175(3):265-75.
28. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010 Aug;9(8):807-19.
29. Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain. 2005 Mar;114(1-2):29-36.
30. Harifi G, Ouilki I, El Bouchti I, Ouazar MA, Belkhou A, Younsi R, et al. Validity and reliability of the Arabic adapted version of the DN4 questionnaire (Douleur Neuropathique 4 Questions) for differential diagnosis of pain syndromes with a neuropathic or somatic component. Pain Pract. 2011 Mar-Apr;11(2):139-47.
31. Javed S, Alam U, Malik RA. Burning through the pain: treatments for diabetic neuropathy. Diabetes Obes Metab. 2015 Dec;17(12):1115-25.
32. Ziegler D, Fonseca V. From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J Diabetes Complications. 2015 Jan-Feb;29(1):146-56.
33. Basit A, Basit KA, Fawwad A, Shaheen F, Fatima N, Petropoulos IN, et al. Vitamin D for the treatment of painful diabetic neuropathy. BMJ Open Diabetes Res Care. 2016;4(1):e000148.
34. Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJ. Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279.
35. Ang CD, Alviar MJ, Dans AL, Bautista-Velez GG, Villaruz-Sulit MV, Tan JJ, et al. Vitamin B for treating peripheral neuropathy. Cochrane Database Syst Rev. 2008 Jul 16(3):CD004573.
36. Bohlega S, Alsaadi T, Amir A, Hosny H, Karawagh AM, Moulin D, et al. Guidelines for the pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the Middle East region. J Int Med Res. 2010 Mar-Apr;38(2):295-317.