Effective Management and Treatment of Diabetic Peripheral Neuropathic Pain (DPNP)

Effective Management and Treatment of Diabetic Peripheral Neuropathic Pain (DPNP) Diagnosis and management in general practice Dr Marie-France Kong Co...
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Effective Management and Treatment of Diabetic Peripheral Neuropathic Pain (DPNP) Diagnosis and management in general practice Dr Marie-France Kong Consultant Physician & Diabetologist University Hospitals of Leicester NHS Trust

UKCYB00560 March 2010

Diabetes Worldwide Epidemic: Trends

500 450 400 350 300 Millions with 250 diabetes 200 150 100 50 0


285 177 135 30 1985





YEAR 1.King H et al Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998 Sep;21(9):1414-31. 2. WHO Fact Sheet; The cost of Diabetes. http://www.who.int/hpr/gs.fs.diabetes.shtml 2000. 3. International Diabetes Federation, Diabetes Atlas, www.diabetesatlas.org UKCYB00560 March 2010

Diabetes in the UK Nation












Northern Ireland






Diabetes UK (2004) Diabetes in the UK, A report from Diabetes UK, October 2004. Diabetes UK (2009) Diabetes in the UK 2009: Key Statistics on Diabetes, September 2009.

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Major Complications of Diabetes Microvascular Peripheral Nervous System (Neuropathy)


A Leading Cause of Death

Heart and Coronary Circulation (Coronary heart disease)

Kidney (Nephropathy)

Eyes (Retinopathy)

Brain and Cerebral Circulation (Cerebrovascular disease)

Diabetes Lower Limbs (Peripheral vascular disease)

Diabetic Foot (Ulceration and amputation)

Reduced Life Expectancy

Diabetic Foot (Ulceration and amputation)

Amos AF, et al. Diabet Med. 1997;14(Suppl 5):S7-S85. Meltzer S, et al. CMAJ. 1998;20(Suppl 8):S1S29. UKCYB00560 March 2010

Multiple Factors Contribute to Risk of Diabetic Neuropathy •

Longer duration of disease

Poor glycaemic control



Male gender



Boulton, A.J.M., et al., Diabetic Somatic Neuropathies, 2004, Diabetes Care, 27(6):1458-1486 UKCYB00560 March 2010

Patho-physiology and Clinical Pathogenesis of Diabetic Neuropathy Hyperglycaemia, hyperlipidemia, hyperinsulinaemia, growth factor deficiency

Oxidative stress and autoimmunity

Microvascular complications

Progressive demyelination and axonal loss

Sensory loss Loss of sensitivity to light touch, pinprick and temperature

Sensory gain More sensitive to light touch, pinprick and temperature

Vinik AI. Am J Med. 1999;107(2B):17S-26S. Dyck PJ, et al. Neurology. 1976;26:466-71. Attal N, et al. Acta NeurolScand Suppl. 1999;173:12-24.

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Distal Symmetric Polyneuropathy is the most common form of neuropathy 100

Prevalence of neuropathy in the Rochester diabetic neuropathy study, 1986

90 Patients (%)

80 70 60

60.4 47.3

50 40


30 20 10


0 All neuropathy

Distal polyneuropathy

Carpal tunnel syndrome

Autonomic neuropathy

Adapted from Eastman, R.C., Neuropathy in Diabetes in Diabetes in America , pp. 339-348, 2nd Ed., 1995, NIH Publication No. 95-1468 UKCYB00560 March 2010

Prevalence of DPNP in Type 2 Diabetes1 26% of Type 2 patients had DPNP associated with decreased quality of life


80% of these patients report moderate to severe pain

Type 2 Diabetics

1. Davies M, et al. Diabetes Care. 2006;29:1518—22.

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DPNP – Under Reported and Undertreated1 In a Study of 350 with diabetes and 344 matched patients without diabetes, 56 had painful neuropathy 12.5% had never reported their symptoms to their physician

39.3% had never received any treatment for their pain

1. Daousi C, et al. Diabetic Med. 2004;21:976—82 UKCYB00560 March 2010


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Diagnosing DPNP in primary care 1. Establish diagnosis of diabetes or impaired glucose tolerance (IGT) 2. Establish presence of painful neuropathy – Validated questionnaires (LANSS/NPQ/BPI-DPN/Pain detect) – Handheld screening devices (10-g monofilament, 128-Hz tuning fork, pinprick) 3. Assess pain characteristics – Distal, symmetrical, numbness, tingling vs. burning, aching, throbbing pain – Spontaneous pain (continuous or intermittent) vs. stimulusevoked pain 4. Rule out non-diabetic causes for neuropathy and/or pain – Metastatic disease / Infection / Toxic substances

Argoff CE, et al. Mayo Clin Proc. 2006;81(4, suppl):S3-S11. LANSS = Leeds Assessment of Neuropathic Symptoms and Signs. BPI-DPN: Brief Pain Inventory for Diabetic Peripheral Neuropathy.

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Outcome of Sensitization1–3 Hyperalgesia: Exaggerated and prolonged painful response to noxious stimulus Allodynia: Pain from normally innocuous stimuli; reduced threshold for eliciting pain HYPERALGESIA


10 8 6 Injury


4 Allodynia 2 0 Innocuous


1. Woolf CJ, Salter MW. Science. 2000;288:1765–1768. 2. Basbaum AI, Jessell TM. Principles of Neural Science. 4th ed. New York, NY: McGraw-Hill;2000:479. 3. Cervero F, Laird JMA. Pain. 1996;68:13–23. Copyright © 1996, by permission from The International Association for the Study of Pain. UKCYB00560 March 2010

Symptoms of Neuropathic Pain Stabbing sensation Pins and needles sensation

Electric shock-like sensation Numb sensation

Throbbing sensation

Shooting sensation

Burning sensation

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DPNP Can Negatively Impact Patients’ Quality of Life1,2

The majority of patients experience pain on a constant, daily basis1

“Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage3”

mood sleep energy mobility work social activities enjoyment of life

1. Galer BS, et al. Diabetes Res Clin Pract. 2000;47:123–128; 2. Benbow SJ, et al. QJM. 1998;91:733–737; 3. Ad Hoc Committee of the IASP Task Force on Taxonomy. Pain Terms Pain 1994;n/a: 208-13

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TYPICAL CASE • 79 y old lady with type 2 DM, hypertension, microalbuminuria • On metformin 1g bd • HbA1c 7.1% • Referred Jan 2008 c/o pins and needles in feet • Cannot sleep at night • On gabapentin • Smokes 2-3 cigs/day UKCYB00560 March 2010

• TFTs, Vitamin B12, folate levels checked • Vit B12 level 195 ng/l (220-700) • LFTs normal • Seen by SpR - Advised to increase gabapentin or switch to pregabalin if side-effects • Tighten BP control • ?Vit B12 injections UKCYB00560 March 2010

• • • • • •

Jan 2009 Still c/o pain in feet Unsteady on feet Amitriptyline has been added in Some benefit Trial of Versatis patch

• April 2010 – Try duloxetine. Stop amitriptyline. Can continue gabapentin + Versatis patch UKCYB00560 March 2010


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Neuropathic Pain Injury

Brain Peripheral nerve damage

Multiple mechanisms

“Maladaptive pain is an expression of the pathological operation of the nervous system: it is pain as disease.”

Woolf CJ. Ann Intern Med. 2004;140:441–451. UKCYB00560 March 2010

Spinal Cord Atrophy in Diabetic Peripheral Neuropathy • Significant reduction in spinal cord xsectional area at time of clinical DPNP. • This shows that the spinal cord is a potential pharmaceutical target.

Selvarajah D, et al. Diabetes Care. 2006;29:2664–2669. UKCYB00560 March 2010

Pharmacological Treatment of Neuropathic Pain Tricyclic antidepressants* Serotonin-norepinephrine reuptake inhibitors Selective serotonin reuptake inhibitors* Opioids Tramadol Cannabinoids*

Descending Inhibitory Pathways (NE/5HT, enkephalins)

Peripheral Sensitization Na+ Carbamazepine* Oxcarbazepine* Tricyclic antidepressants* Topiramate* Lamotrigine* Lidocaine

Spinal Cord

Central Sensitization Ca++


Gabapentin Levetiracetam* Oxcarbazepine* Lamotrigine* Pregabalin

Ketamine* Dextromethorphan* Methadone* Memantine*

*Not Licensed for the treatment of DPNP Adapted from Beydoun, et al. J Pain Symptom Manage. 2003;25(suppl 5):S18-30. UKCYB00560 March 2010

Serotonin and Noradrenaline: role in neuropathic pain •

• •

Neuropathic pain is associated with increased excitation and decreased inhibition of ascending pain pathways

Ascending Monoamine Pathway Descending Pain Modulatory Pathway

Descending pathways modulate ascending signals NA and 5-HT: – Key neurotransmitters in descending inhibitory pain pathways – Increased availability may promote pain inhibition centrally

Ascending Pain Pathway

Peripheral Pain Fibre

Fields HL, et al. In: Wall PD et al., eds. Textbook of Pain, 4th ed. 1999:310. UKCYB00560 March 2010


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QOF and DPNP management

The QOF does not reward points specifically for DPNP But helps to address risk factors: Macrovascular: Cholesterol, BP, smoking cessation, obesity, HbA1C and IHD are all monitored & treated Microvascular: Regular retinopathy, neuropathy and nephropathy screening form part of QOF Quality and Outcomes Framework guidance for GMS contract 2009/10, March 2009 UKCYB00560 March 2010

The multi-disciplinary approach • A holistic approach, addressing biological (physical), psychological and social aspects • Includes CBT (cognitive behavioural therapy), pain management programs, exercise etc. • These approaches are mentioned for completeness; only pharmacological treatments are the subject of this presentation

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Pharmacological Options • When any treatments are considered there are a number of factors to consider • The S.T.E.P.S approach can be used to evaluate pharmaceutical options • Guidelines are also useful UKCYB00560 March 2010

S.T.E.P.S • Safety – Profile of the drug in terms of risk of serious or life threatening consequences.

• Tolerance – More variable, often patient dependent.

• Efficacy – Does it work?

• Price – Cost effectiveness, not just drug price

• Simplicity – Consider dosing, titration, route of administration, etc. Shaughnessy, AF, American Family Physician, December 15, 2003 - http://www.aafp.org/afp/2003/1215/p2342.html UKCYB00560 March 2010

Neuropathic Pain: Approach to Treatment Diagnosis Treat underlying condition

Symptomatic treatment

Prevention (if possible)

Improve physical functioning

Reduce pain

Reduce psychological distress

Improve overall quality of life

Adapted from Turk DC. Clin J Pain. 2000;16:279-280. UKCYB00560 March 2010

DPNP - Pharmacological Management ♦ Agents licensed in the UK1-6: – – – – –

Duloxetine Gabapentin Pregabalin Capsaicin cream Paracetamol, aspirin, ibuprofen (broad licence for neuralgia)

♦ Unlicensed agents6-7: – – – – – –

NSAIDs Tricyclic antidepressants – e.g., amitriptyline Anticonvulsants – e.g., carbamazepine, phenytoin, topiramate Opioid analgesics Tramadol Other antidepressants – e.g., venlafaxine

1.Cymbalta SPC . 2.Neurontin SPC. 3.Lyrica SPC. 4.Axsain SPC. 5.Anadin Ibuprofen SPC. 6. British National Formulary.58, September 2009. Section 6.1.5; Page 389 7. Boulton AJM, et al. Diabetes Care. 2004;27:1458–1486.

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Pharmacological options overview • Simple analgesia: – Paracetamol - no evidence in DPNP;

• NSAIDS: – no evidence of efficacy in neuropathic pain;

• Topical preparations: – Capsaicin (licensed), lidocaine (unlicensed)

• Opiates

British National Formulary 58, September 2009. Section 6.1.5; Page 389 British National Formulary 58, September 2009. Section 4.7.3; Page 246-247

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Clinical Data: Review of Two Licensed Treatments

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Pregabalin for DPNP1

Least-squares Mean Pain Score

Pregabalin 300 mg/day and 600 mg/day improved SF-MPQ and sleep interference, and pregabalin improved some domains of the SF-36 7 6 5 **


* *


Placebo (n=97) Pregabalin 75 mg (n=77) Pregabalin 300 mg (n=81) Pregabalin 600 mg (n=81)

2 1 0



1. Lesser H, et al. Neurology. 2004;63:2104—10.

2 Weeks


** *p=0.0001 **p

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