PRODUCT

MONOGRAPH

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CONTENTS

S.NO. PARTICULARS PAGE NO.

1 Neuropathic pain, general introduction, prevalence and causes 3-4

2 Neuropathic pain Pathophysiology 5

3 Pathogenesis of Diabetic Neuropathy 6

4 Management Of Neuropathic pain 7-8

5 Rationale of combination 9

6 Mechanism of Action of all ingredients 10

7 Competitors of Axinerve NP 11

8 Attached LBL 12

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INTRODUCTION
Neuropathic Pain is one of the most common types of pain, but it is often under-
recognized and undertreated.
The international Association for the Study of Pain (IASP) defines NP as “pains
resulting from disease or damage of the peripheral or central nervous systems and
from dysfunction of the nervous system.
The Exact prevalence of neuropathic pain is not known. It has been shown that the
about 26% of patients with type 2 diabetes can experience neuropathy. Cancer
patients indicate a prevalence of 19–39. About 1% and 37% of chronic low back
pain patients may have a neuropathic component related to it. Pain continues after
healing of rash in 8% of Herpes Zoster patients. Stroke, Multiple sclerosis, and
spinal cord injury result in neuropathic pain in 8%, 7% and 67% of patients
respectively. Depression, anxiety, and sleep disorders were significantly more
prevalent in patients with neuropathic pain compared to without such pain.
Even with high prevalence in chronic conditions, the overall numbers of NP
conditions tends to be small. One of the reasons is the lack of identification,
diagnosis, and treatment. There is no standard approach between health care
providers for NP.

Diabetic Neuropathy
A global epidemic of diabetes mellitus has emerged and India leads the world with
largest number of diabetic subjects earning the dubious distinction of being termed
the “Diabetes capital of the world.
Global Scenario

Diabetes has become one of the largest global health-care problems of the 21st
century. The number of people with diabetes worldwide is predicted to double
between 2000 and 2030, reaching a pandemic level of 366 million people. Diabetic
polyneuropathy (DPN), which has a lifetime prevalence of approximately 50%, is
the most common diabetic complication. DPN is a leading cause for disability due
to foot ulceration and amputation, gait disturbance, and fall-related injury.
Approximately 20 to 30% of patients with DPN suffer from neuropathic pain.

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Indian Scenario

The overall prevalence of neuropathy in a study with type 2 diabetic subjects is

19.1%. According to recent study, the prevalence of neuropathy in India was 8.4%
and this figure is significantly higher.

Neuropathic pain: Causes

Neuropathic pain is due to myriad of disorders. Most of neuropathic conditions are
not isolated to pure pain fibers and can coexist with inflammatory, visceral and/or
nociceptive pain as well as neuropathic dysfunction like autonomic nervous system
involvement in diabetes.

The Major Categories of Neuropathic Pain

Toxic Chemo-radiation therapy in the treatment of cancer, medication like

Isoniazid and thallium, exposure to chemical like lead, copper and
arsenic.
Metabolic
Diabetes, Beriberi (Vitamin B1), Alcohol induced neuropathy.
Trauma
Phantom Limb syndromes and/or complex regional pain syndromes.
Compressive
Carpal tunnel syndrome and compartment syndromes.

Autoimmune
Chronic inflammatory demyelinating polyneuropathy and vasculitic
neuropathy.
Infectious Post Herpetic neuralgia, Lyme Disease (Spirochetes), Chagas
disease (trypanosomes), Leprosy (mycobacterium), HIV, Guillain-
Barre Syndrome post- infectious

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Neuropathic Pain: Pathophysiology
Ectopic nerve activity/Peripheral Sensitization This mechanism is responsible
for pain sensed in the absence of external stimuli. Spontaneous nerve activity has
been shown in both the injured nerve as well as uninjured neighboring nerves. This
spontaneous activity is thought to be related to an increase in voltage gated sodium
channel expression. This increased expression allows for decreased activation
thresholds and increased membrane excitability.
Central Sensitization Regular discharge from peripheral nerves causes release of
excitatory neuropeptides and amino acids in the dorsal horn. This leads to
phosphorylation of NMDA and AMPA receptors and expression of voltage gated
sodium channels (similar to ectopic nerve activity).
Inflammatory reaction Inflammation results in activation of microglia in the
nerve as well as the dorsal root ganglion. A pro-inflammatory milieu is created
including cytokines, chemokines, substance P, TNF alpha, etc. These factors
facilitate neuropathic pain by further enhancing neuroexcitability.

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 Pathogenesis of Diabetic Neuropathy
The etiology and pathogenesis of diabetic neuropathy is multifaceted and attributed
to the effects of hyperglycemia, accumulation of advanced glycation end products
(AGEs) oxidative stress, and altered transport of nutrients within the nerve axons.

Diabetes Mellitus

Hyperglycemia

Advanced glycation Polyol pathway Free radical generation Phosphokinase C

end products activity and oxidative stress activity

Vascular and neural dysfunction

leading to complication

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Management of Neuropathic Pain
The aim of treatment is pain relief and functional rehabilitation, which are assessed
with repeated requests to rate pain intensity. Reduction of pain by atleast 30% is
clinically relevant.

Many agents have been utilized and studied for treatment. Several controlled
studies have demonstrated that painful DPN can be relieved by antidepressants,
anticonvulsants, tramadol, opioids and topical application of capsaicin and recent
meta-analysis support those findings.
Anticonvulsants and tricyclic antidepressants have emerged as mainstay of
therapy. Tricyclic antidepressants have long been used to treat all forms of
neuropathic pain.

Algorithm for treatment of diabetic peripheral

Neuropathic pain. (TCAs = tricyclic antidepressants.)

Patient with diabetes mellitus and symmetric peripheral pain

Initial evaluation
Establish realistic goals for treatment
Optimize glycemic control, lipid levels, and blood pressure
Rule out other causes of neuropathy*

TCAs+
Nortriptyline (Pamelor; 25 to 50 mg at bedtime)
or
Amitriptyline (25 to 150 mg at bedtime)

Anticonvulsants
Gabapentin (Neurontin; 300 mg at bedtime)
or

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 Gabapentin (300 to 1,200 mg three times per day)
or
Pregabalin (Lyrica; 50 to 200 mg three times per day)
or
Carbamazepine+

(Tegretol; 200 to 600 mg twice per day)

Serotonin-norepinephrine reuptake inhibitors

Duloxetine (Cymbalta; 60 to 120 mg per day)

Or

Venlafaxine, extended release (Effexor XR; 150 to 225 mg per day)

Opiates
Oxycodone, controlled release
(Oxycontin; 10 to 40 mg twice per day)

Or

Tramadol (Ultram; 50 to 400 mg per day)

Consider combination therapy with opiates
Consider referral to pain specialist

Only 20 to 40% reduction in pain intensity is achieved with current drugs. To

address this shortcoming, combination of drugs acting through different
mechanisms may produce improved pain relief. Thus a need exists for safe, better-
tolerated, effective agents for painful DPN.

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 Rationale of combining Nortriptyline with Pregabalin and Methylcobalamin
Combination
Current drugs reduce neuropathic pain and improve quality of life; however, as
single agents they are limited by incomplete efficacy and dose limiting adverse
effects. Therapeutic benefits may include greater efficacy, lower doses and fewer
adverse effects.
Because of the failure of the existing painkillers to provide adequate relief, there is
a constant search for newer options- for treating pain of diabetic neuropathy.
Pregabalin and Nortriptyline are both the gold standards in treating neuropathic
pain syndromes.
A variety of medications (oral and Topical) are available for treating neuropathic
pain, and guidelines have been published for its treatment, including two that have
focused specifically on Neuropathic pain. Both of these guidelines recommend
pregabalin, Gabapentin and tricyclic antidepressants as first- line therapy.

Nortriptyline is the first line therapy for the treatment of neuropathic pain

Synergize the effect of Pregabalin in treating Diabetic peripheral
neuropathic Pain.

Combining Pregabalin with Tricyclic antidepressant demonstrates larger
pain reduction effects in spinal cord injury.

Remarkable reduction in pain intensity in PHN (Post Herpetic Neuralgia)
as compared to pregabalin alone

Adding Tricyclic antidepressant to pregabalin improve global status, pain
and other symptoms in patient with fibromyalgia with an incomplete
response to pregabalin treatment.

Better safety and tolerability profile of Nortriptyline as compared to
amitriptyline in elderly have been reported in Cochrane studies.

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Mechanism of Action of all active ingredients
Nortriptyline
Nortriptyline and Pregabalin are both the gold standards in treating neuropathic
pain syndromes.
Nortriptyline blocks the reuptake of noradrenaline and serotonin and resulting
increased availability of these neurotransmitters at the synapse which may inhibit
nociception by actions at spinal cord, brain stem or thalamic sites.
With Nortriptyline pain relief may also be the result of opiate like actions on
central neurons.
Nortriptyline relieves pain by ameliorating insomnia & depression.
Pregabalin
Pregabalin binds subunits of voltage activated ca2+ channels leading to decrease
ca2+ influx into nerve terminals and reduce the release of neurotransmitters
including glutamate and NE.
Methylcobalamin
Methylcobalamin works by functioning in the production of a material called
myelin, which covers and protects nerve fibers and thereby promotes myelination.

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 Competitors For Axinerve NP

Brand Name Company MRP

GB 29 Total Corona 195

Finenerve-NT Akumentis 179

Nortipan M Medley 170

Dubinor Glenmark 130

Nervijen-NP Jenburkt 129

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Front Back

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