Download - Unmet needs in Peripheral Neuropathy

APOLLO HOSPITALS, JUBILEE HILLS,HYDERABAD

DR SUDHIR KUMAR MD DM

CONSULTANT NEUROLOGIST

WHAT ARE THE CHALLENGES IN INDIA WHEN IT COMES TO “NERVE CARE”?

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MAJOR UNMET NEEDS AND ISSUES IN PERIPHERAL NEUROPATHY

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PDN: Painful Diabetic neuropathy

DAG :Di-AcylGlycerol

LDL :Low-Density Lipoprotein

PKC: Protein Kinase C.

Rayaz .AM et al, Pathophysiology and Treatment of Painful Diabetic Neuropathy ,Current Pain and Headache

Reports 2008, 12:192–197

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Pathophysiology of PDN

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• Peripheral neuropathies are frequent, although their clinical relevance tends to be underestimated in comparison with CNS diseases considered to be more severe and epidemiologically more relevant: both these assumptions should be carefully weighed against the available data.

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• The frequency of peripheral neuropathies increases with age, thus having a negative impact on a part of the population potentially already affected by other neurological or systemic diseases. This might produce a sum of negative effects, worsening the quality of life of the patients.

3• Several peripheral neuropathies occur in the context of systemic

diseases or medical conditions requiring drug administration.

Unmet Needs & Issues

Expert Opin Pharmacother. 2016;17(3):381-94.

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• Many patients are not aware of their diagnosis, are not given the diagnosis or being treated, or the diagnosis is delayed. Time from symptom onset to actual diagnosis is very high making it difficult to reverse the actual nerve damage

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• Idiopathic neuropathy, that is neuropathy for which a cause is not identified, is common, accounting in referral series for 25% of all neuropathy patients and 50% or more of patients with small fibre neuropathy.

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• Treatment of the underlying disease may improve disease-related neuropathies. However, severe peripheral neuropathies requiring intense and sometimes urgent treatment are isolated diseases of the peripheral nervous system and need specific treatment.



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• No effective preventive/causal treatment is available for several peripheral neuropathies with high incidence, while symptomatic treatment of neuropathic pain related to peripheral neuropathies is more effective.

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• Preclinical studies are based on animal models that only partially recapitulate the full clinical features of the human disease. Refinement of these models will be a critical step in the future investigation of more effective treatments of peripheral neuropathies.

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• An effective multidisciplinary, coordinated approach including not only neurologists but also specialists of the related medical conditions is needed in order to design more relevant clinical trials on the treatment of peripheral neuropathies



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Indian Scenario

Prevalence of DPN in India

Indian J Med Res. 2011;133:369-380

Author Year Study City Prevalence (%)

High prevalence

of DPN ranging from 9-

64%1 – High Prevalence

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The cases had a mean age of 47.6 ± 10.2 years (59% males)

duration of symptoms of 5.9 ± 8.2 months prior to presentation.

Overall prevalence of DPN was 29.2% [95% CI 22.8-35.7].

PN among matched control was 10.7% (95% CI 3.5-17.8).

Prevalence of DPN showed an increasing trend with age.

J Postgrad Med. 2014 Jul-Sep;60(3):270-5.

1 – High Prevalence

Indian Scenario


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The interrelationship between neuropathic pain, sleep, and anxiety/depression

Pain

Functionalimpairment

Anxiety anddepression

Sleepdisturbance

Nicholson B et al. Comorbidities in chronic neuropathic pain, Pain Med 2004;5(Suppl 1):S9-27.

2 – Negative Symptoms

Indian Scenario


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Most experimental studies in humans and animals show that sleep deprivation produces hyperalgesic changes1

Concurrent management of disturbed sleep and pain in patients with chronic pain is advisable:1

Pain enhances arousal and disrupts sleep

Sleep deprivation and sleep disruption increase pain sensitivity and vulnerability to pain

A vicious circle with sleep disorder and chronic pain maintaining and augmenting each other may result

Sleep disruption contributes to pain

1. Lautenbacher S et al. Sleep deprivation and pain perception ,Sleep Med Rev 2006;10:357-69.


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Pain intensity increases with increasing sleep disturbance in patients with neuropathic pain

Pre

sen

t p

ain

in

ten

sity

p=0.0001

603 patients with neuropathic pain of multiple etiologiesMOS = Medical Outcomes StudyRejas J et al. Psychometric properties of the MOS (Medical Outcomes Study) Sleep Scale in patients with neuropathic pain Euro J Pain 2007;11:329-40.

Worse sleep

0 10 20 30 40 50 60

No pain

Mild

Discomforting

Distressing

Horrible

Excruciating

Mean MOS Sleep Scale 9-item index score

53.7

51.8

47.1

40.5

38.8

34.1


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Neuropathic Pain is Prevalent Across a Range of Different Conditions

HIV = human immunodeficiency virus1. Sadosky A et al. Pain Pract 2008; 8(1):45-56; 2. Davis MP, Walsh D. Am J Hosp Palliat Care 2004; 21(2):137-42; 3. So YT et al. Arch Neurol 1988; 45(9):945-8; 4. Schifitto G et al. Neurology 2002; 58(12):1764-8; 5. Morgello S et al. Arch Neurol 2004; 61(4):546-51; 6. Stevens PE et al. Pain 1995; 61(1):61-8; 7. Smith WC et al. Pain 1999; 83(1):91-5; 8. Freynhagen R et al. Curr Med Res Opin 2006; 22(10):1911-20; 9. Andersen G et al. Pain 1995; 61(2):187-93; 10. Siddall PJ et al. Pain. 2003; 103(3):249-57; 11. Rae-Grant AD et al. Mult Scler 1999; 5(3):179-83.

11–26%1

~33%2

35–53%3–5

20–43% of mastectomy patients6,7

Up to 37%8

Diabetes

Cancer

HIV

Post-surgical

Postherpeticneuralgia

Chronic low back pain

8%9

75%10

~55%11

Stroke

Spinal cord injury

Multiple sclerosis

7–27% of patients with herpes zoster1

Condition% affected by peripheral

neuropathic pain% affected by central

neuropathic pain

3 – Systemic Disease

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DPN – The inevitable

J Diabetes Invest 2014; 5: 714–721

• Progressive• Almost all patient

develops DPN over a time period

N = 2006 Indian patients with diabetes

4 – Time to diagnosis

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Delay in diagnosis of Neuropathy

Symptom onset to diagnosis

J Peripher Nerv Syst. 2012 May;17 Suppl 2:1-3.

4 – Time to diagnosis

Less than 30% weregiven a diagnosis in

1 year and some patients had

symptoms for over 15 years before they

were diagnosed

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1. Is it focal ( involving a particular nerve only) or multifocal (involving many nerves

• In a single or multiple places, or symmetric ( equal on either portion of the body)

2. If symmetric

• a. Proximal – predominantly motor ( GBS ) except lead neuropathy ,which is distal

• b. Distal – motor or sensory or mixed ( toxic, diabetic, metabolic)

Issues in Diagnosis of PN

http://www.apiindia.org/pdf/medicine_update_2010/neurology_07.pdf

4 – Diagnosis

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1• PN can be mimicked by myelopathy, synringomyelia, or tabes dorsalis,

and tumors of spinal cord.

2• Not but not the least , but most confusing pictures will be given in

hysterical conversion reactions.

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• Early lesions mimic pure sensory neuropathy but , careful examination will reveal subtle motor neuropathy, which is a common feature in diabetic PN. Unless it is observed it is often missed.

4• Symptoms of distal motor weakness are more reliable than our

examinations.

Diagnostic Cascade - PITFALLS

http://www.apiindia.org/pdf/medicine_update_2010/neurology_07.pdf

4 – Diagnosis

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Diagnosing Neuropathic Pain Is Challenging

Harden N, Cohen M. J Pain Symptom Manage 2003; 25(5 Suppl):S12-7; Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):1959-64.

Diagnostic challenges

Multiple, complex

mechanisms

Diverse symptoms

Difficulties in communicating and

understanding symptoms

Recognition of comorbidities

Unmet Need 4 – Diagnosis

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IASP Definition of Pain

IASP : International Association for the Study of Pain

“Pain is an unpleasant sensory and emotional experience

associated with actual or potential tissue damage or described in

terms of such damage.”

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Pathophysiological Classification of Pain

Freynhagen R, Baron R. Curr Pain Headache Rep 2009; 13(3):185-90; Jensen TS et al. Pain 2011; 152(10):2204-5; Julius D et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Ross E. Expert Opin Pharmacother 2001; 2(1):1529-30; Webster LR. Am J Manag Care 2008; 14(5 Suppl 1):S116-22; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.

Multiple types of pain coexist in many

conditions(mixed pain)Nociceptive pain

- Somatic- Visceral

Neuropathic pain- Peripheral

- Central

Central sensitization/dysfunctional pain

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The International Association for the Study of Pain (IASP) defines neuropathic pain as

“pain arising as a direct consequence of a lesion or disease or dysfunction affecting the nervous system.”

Two types

Peripheral Neuropathic pain: Lesion in Peripheral Nervous system

Central Neuropathic pain: Lesion in Central Nervous system

What is Neuropathic pain?

http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions


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Simplified Pathophysiology of Neuropathic Pain

1. Gilron I et al. Neuropathic pain: a practical guide for the clinician, CMAJ 2006;175:265-75.2- Ralf Baron, et al, Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment.. Lancet Neurol 2010; 9: 807–19

NeP

Peripheral mechanisms

Abnormaldischarges

Central mechanisms

Peripheral neuronhyperexcitability1

Loss ofinhibitory controls1,2

Central mechanisms

Central neuron hyperexcitability (central sensitization)1 NeP = Neuropathic pain

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Classification

Neuropathic PainPain caused by a lesion or disease of the

somatosensory nervous system

Peripheral Neuropathic PainPain caused by a lesion or disease of

the peripheral somatosensory nervous system

Central Neuropathic PainPain caused by a lesion or disease of

the central somatosensory nervous system

International Association for the Study of Pain. IASP Taxonomy, Changes in the 2011 List. Available at: http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions


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Patients with neuropathic pain may use these pain descriptors

“Numbness”1

“Shooting”1 “Burning”1

“Electric shock-

like”1

“Tingling”1

1. Baron R ,et al , Assessment and diagnosis of neuropathic pain. Curr Opin Support Palliat Care 2008;2:1-81

Be alert for common verbaldescriptors of neuropathic pain1

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The 3L Approach to Diagnosis

Patient verbal descriptors of pain, questions and answers

Nervous system lesion or abnormality

Sensory abnormalities (skin and joints)

Listen1

Look1Locate2

1. Gilron I et al. Neuropathic pain: a practical guide for the clinician ,CMAJ 2006;175:265-75.2. Haanpää ML et al. Assessment of Neuropathic Pain in Primary Care , Am J Med 2009;122(10 Suppl):S13-21.

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• 25% – Dyck et al. (1981)

• 23% – Barohn (1998)

• 19% – Verghese et al. (2001)

Idiopathic or cryptogenic neuropathy

• 90% – Periquet et al. (1999)

• 50% – Venkataramana et al. (2005)

• 50% – De Sousa et al. (2006)

Percent idiopathic of small fiber neuropathy

Patients with idiopathic neuropathy, despite intensive evaluation

J Peripher Nerv Syst. 2012 May;17 Suppl 2:1-3.

5 – Idiopathic Neuropathy

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Generally accepted that intensive diabetes therapy aimed at near normoglycemia should be first step in the treatment of any form of DN.

Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial- (10,000 patients) -new cases of neuropathy significantly reduced intensive group

ADVANCE trial –( 11,000 patients)- (5y) not significantly affected by intensive control

Diabetes Control and Complication Trial (DCCT; 1995) – (5y) intensive management reduces neuropathy by 64%. Benefit persisted for 8 years after DCCT

Effect of Normoglycemia on DPN

6 – Underlying Disease

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Parameters Significance

Tight glucose control in DPNP Can reverse the changes but only if the neuropathy and diabetes are recent in onset.

Tricyclic antidepressants (TCA’s) e.g. Amitriptyline, Nortriptyline Effective but suffer from multiple side effects that are dosage dependent

Serotonin reuptake inhibitor (SSRI’s) e.g. Fluoxetine, Paroxetine, Sertraline and CitalopramFDA not approved, no more efficacious than placebo in several controlled trials.

Antiepileptic drugs (AED’s) e.g. Gabapentin & PregabalinEmerging as first line treatment for painful neuropathy.

Methylcobalamin Exerts neuroprotective effects, regenerates myelin sheath

Management of Peripheral Neuropathy & other associated Syndromes

7 – No effective preventive/causal treatment

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•Class – Serotonin-Norepinephrine reuptake inhibitor (SNRI’s)

Duloxetine

•Class – Anticonvulsant drug / Antiepileptic drugs (AED’s)

Pregabalin

•Class – Long-acting opioid

Tapentadol ER

USFDA Approved Drugs for DPN The only 3 drugs approved by the FDA for diabetic peripheral neuropathy –


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Frequent need for two or more drugs to control chronic pain

Frequent need for at least one drug therapy for psychologic non-pain suffering

Frequent need for at least one drug therapy for side effects of core therapies

Need for a sound pharmacodynamic/pharmacokinetic basis for the use of more than one drug from a particular class

Need for critical review of the use of three or more drugs for any single indication

Need to beware of additive and synergistic effects and drug interactions

Issues in the Use of Combination Therapy


J Pain Symptom Manage. 2003 May;25(5 Suppl):S12-7.

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Most treatments today are centered on pain reduction and improvement in function

These medicines used for neuropathic pain help ONLY “calm down” the nervous system

and reduce the pain, but does not address the root cause i.e. degeneration of neurons

due to oxidative stress

No therapy used to regenerate the damaged nerves

Lack of response and unwanted side-effectsof conventional pharmacological treatments

force many suffers of painful diabetic neuropathy to explore alternative dietary

supplements

GAPS

GAPS with Current Therapy


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Despite peripheral neuropathies being common diseases, in most cases only symptomatic agents are approved for their treatment

In case of rare neuropathies, new expensive drugs have been approved on the basis of rather weak although positive results

One of the main reasons for this largely unsatisfactory situation is the incomplete knowledge of the pathogenic mechanisms leading to peripheral nerve damage, which prevents rationale-based preclinical studies and effective translation into the clinical practice

Need for Better Pre-Clinical Models

8 – Animal Models


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Under this perspective, refinement of the available preclinical models is a critical step

Diabetic neuropathy stands as a clear example, since none of the available models (e.g. acute streptozotocin-induced, spontaneous occurring in fatty animals, genetically determined diabetes) is really able to recapitulate the pathologic, neurophysiologic, and clinical features of the human disease.

Similar, inconsistencies exists in CIPN animal modelling, with highly different results obtained in short-term, high dose studies (where neuropathic pain is a common feature) versus longer studies using lower doses that more closely resemble the clinical use of anticancer chemotherapy drugs.

Inflammatory neuropathies have been reproduced in animals without a definite demonstration of more effective mimicking of the human disease using pure or complex antigens.


8 – Animal Models


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Recognition of these limitations will improve preclinical research in the future and it is likely that effective treatments will also be

discovered for the peripheral neuropathies, still ‘orphans’ at

this moment.


8 – Animal Models


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Since several peripheral neuropathies occur in the context of more systemic medical conditions, collaboration among researchers and clinicians belonging to different fields is mandatory in order to allow a ‘positive contamination’ and a more fruitful exchange of knowledge and experience, eventually improving the approach to this complex and still unsolved problem.

Multidisciplinary Approach

9 – Multidisciplinary Approach


SOLUTION TO CURRENT UNMET NEEDS

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Making a Differential Diagnosis

1. Gilron I et al. Neuropathic pain: a practical guide for the clinician, CMAJ 2006;175:265-75.

2. Baron R, Tölle TR. Assessment and diagnosis of neuropathic pain, Curr Opin Support Palliat Care 2008;2:1-8.3. Haanpää ML et al. Assessment of Neuropathic Pain in Primary Care Am J Med 2009;122(10 Suppl):S13-21.

Yes

No

Probablenociceptive pain

Can you detect sensoryabnormalities using

simple bedside tests?1-3

Are verbal descriptorssuggestive of neuropathic pain?1

YesNo

Neuropathic pain syndromelikely: initiate treatment3

Yes

NoCan you identify the

responsible nervous systemlesion/dysfunction?3

Consider specialist referral, andif neuropathic pain is still

suspected consider treatment in the interim period3

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Management of Neuropathic Pain

Treatment of underlying conditions

Diagnosis

Improvedsleep

quality

Improved overall

quality of life

Improved physical

functioning

Improved psychological

state

Reduced pain

Haanpää ML et al. Am J Med 2009; 122(10 Suppl):S13-21; Horowitz SH. Curr Opin Anaesthesiol 2006; 19(5):573-8; Johnson L. Br J Nurs 2004; 13(18):1092-7;Meyer-Rosberg K et al. Eur J Pain 2001; 5(4):379-89; Nicholson B et al. Pain Med 2004; 5(Suppl 1):S9-27.

The earlier a diagnosis is made, the more opportunities there are to improve patient outcomes

Pharmacological and non-pharmacological

treatment of neuropathic pain

Treatment ofcomorbidities

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2o goals

Goals in the Treatment of Neuropathic Pain

*Note: pain reduction of 30–50% can be expected with maximal doses in most patients Argoff CE et al. Mayo Clin Proc 2006; 81(Suppl 4):S12-25; Lindsay TJ et al. Am Fam Physician 2010; 82(2):151-8.

1o goal:

>50% pain relief*

… but be realistic!

Sleep Mood

FunctionQuality of life

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Download - Unmet needs in Peripheral Neuropathy

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