Gabapentin in the Treatment of Peripheral neuropathy Gabator 300/400 mg capsule

Introduction to Neuropathy Neuropathic pain develops as a result of damage or dysfunction of the nerves of the Peripheral or Central nervous system. Common examples include painful diabetic neuropathy, post-herpetic neuralgia and trigeminal neuralgia Peripheral Neuropathic Pain Nerves of peripheral nervous system are damaged Central Neuropathic pain Nerves of Central nervous system are damaged NICE clinical guideline 96, Neuropathic pain :The pharmacological management of neuropathic pain in adults in non-specialist settings Issue date: March 2010 2

Classification of Neuropathic Pain Mononeuropathy Involvement of a single nerve Multiple mononeuropathy Two or more nerves individually affected. Polyneuropathy Generalized involvement of peripheral nerves Neurophathies may also be categorized based on a functional classification (motor, sensory, autonomic, or mixed) or the type of onset (acute - hours or days, subacute - weeks or months, or chronic - months or years).  The most common form of neuropathy is (symmetrical) peripheral polyneuropathy, which mainly affects the feet and legs on both sides of the body. http://www.medicalnewstoday.com/articles/147963.php

Causes of Neuropathic Pain Exposure to drugs, alcohol, toxins Neuropathic Pain Surgical procedures/ Amputation Traumatic Nerve injury/ compression Metabolic disturbance Viral infection Neuropathic pain is a disease, like myocardial infarction is a disease. Myocardial infarction may be caused by smoking, or hypertension, or diabetes. Multiple different things contribute to the cause of myocardial infarction, but myocardial infarction is the disease. Similarly, neuropathic pain is a disease, and this slide shows many of the different conditions that can result in neuropathic pain. But the pain is nonprotective. It is something that persists and behaves separately as a disease itself. Cancer related (disease or treatment Vascular related neurodegenerative Nutritional deficiency

Nociceptive vs Neuropathic Pain

Pain Pathways in CNS Brain

Prevalence Of Neuropathy in Eastern Cape. South Africa (2011) Neuropathy is a common general complaint in community There is a need for focused attention on women and the elderly. South Afr J Anaesth Analg 2011;17(5), 329-337

Targets for controlling Neuropathic pain Restore inhibitory neurotransmission: GABA Block peripheral sensitization: Sodium channel Block central sensitization Modulate calcium channels http://www.medscape.org/viewarticle/453496_1 Taylor BK, Curr Pain Headache Rep; 2001;5;151-161

Pharmacologic Treatment for Neuropathic pain CATEGORY EXAMPLES Topical Agents Lidocaine patch 5%, capsaicin Opioids Oxycodone, Tramadol, Fentanyl, Morphine, Hydrocodone Antidepressants Tricyclic Antidepressants Amitryptiline, Nortryptiline, Desipramine, Imipramine, Doxepin Selective Noredrinaline reuptake inhibitors Duloxetine, Venlafaxine Anticonvulsants Carbamazepine, Valproate, Lamotrigine, Topiramate, Gabapentin, Pregabalin http://www.medscape.org/viewarticle/530441_1http://www.medscape.org/viewarticle/530441_1

Glutamate & substance P GABATOR Class: Antiepileptic Mechanism of action Gabapentin binds to alpha – 2 – delta subunit of voltage-sensitive calcium channels and decreases the release of glutamate and Substance-P neurotransmitters Gabapentin enters the body through a carrier protein mechanism. Glutamate & substance P GABAPENTIN

Approved Indication Gabapentin is used primarily for the treatment of seizures, neuropathic pain FDA approval Neuropathic pain associated with postherpetic neuralgia Adjunctive therapy for partial seizures Adult Adolescent (12 Years & Above) Pediatric (3-12 years) http://www.rxlist.com/neurontin-drug/indications-dosage.htm

Guidelines & Recommendations Level A drug In the treatment of PHN Level B drug In the treatment of DPNP American Academy of Neurology1,2 Level A drug In trigeminal neuralgia, chronic radiculopathy European Federation Neurological Societies Task Force3 First line treatment option In management of chronic neuropathic pain Canadian Pain Society4 First-line treatment In peripheral neuropathic pain Expert panel recommendations for the middle East region5 Elderly adults with partial-onset seizures ILAE treatment guidelines6 Adopted from: http://www.aan.com/professionals/practice/pdfs/pn_guideline_physicians.pdf Adopted from http://www.aan.com/practice/guideline/uploads/480.pdf Eur J Neurol. 2010 Sep;17(9):1113-e88. Pain Res Manag. 2007 Spring; 12(1): 13–21. J Int Med Res. 2010 Mar-Apr;38(2):295-317. Epilepsia. 2006 Jul;47(7):1094-120.

Pharmacokinetics Absorption Bioavailability: 60%, Increased with high fat meal Peak plasma time: 2-4 hr Distribution Protein Binding: less than 3% Metabolism Not metabolized Excretion Kidney: 76% to 81% Feces: 10% to 23% Half-life: 5-7 hr http://www.rxlist.com/neurontin-drug/side-effects-interactions.htm

Indication and Dosage Partial seizure; Adjunct Start with 300 mg 3 times daily - 900 to 1800 mg given in 3 divided doses, dosages up to 2400 mg have been well tolerated Post-herpetic neuralgia 300 mg/day – 1800 mg/day http://www.rxlist.com/neurontin-drug/side-effects-interactions.htm

Dosing: Special Population Dosage in Renal Failure Dosage in Hepatic Insufficiency No dose adjustment is required Dosage in Geriatric Patients Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients Severity RENAL FUNCTION CREATININE CLEARANCE  (ML/MIN) TOTAL DAILY DOSE RANGE (MG/DAY) DOSE REGIMEN (MG) MILD > 30-59 400-1400 200 BID 300 BID 400 BID 500 BID 700 BID MODERATE > 15-29 200-700 200 QD 300 QD 400 QD 500 QD 700 QD SEVERE 15 100-300 100 QD 125 QD 150QD http://www.rxlist.com/neurontin-drug/side-effects-interactions.htm

Adverse Reactions & Contraindications Fatigue Weight Increase Back Pain Peripheral Edema Dizziness Somnolence Nausea Chills & Fever If known hypersensitivity to the product or any of its components http://www.rxlist.com/neurontin-drug/side-effects-interactions.htm

Drug Interactions Drug Interaction Comments Antacid Reduced the bioavailability of gabapentin Gabapentin be taken at least 2 hours following Antacid administration Naproxen Coadministration of naproxen sodium capsules with Gabapentin appears to increase the amount of gabapentin absorbed by 12% to 15%.  Hydrocodone Coadministration of Gabapentin decreases hydrocodone Cmax and AUC values in a dose-dependent manner relative to administration of hydrocodone alone Hydrocodone increases gabapentin AUC values by 14% Cimetidine The mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10% in presence of cimetidine Cimetidine appeared to alter the renal excretion of gabapentin  http://www.rxlist.com/neurontin-drug/side-effects-interactions.htm

Gabapentin in Neuropathy Safety, tolerability, and efficacy of gabapentin in neuropathic pain: Results of a post-marketing surveillance study in 1214 Filipino patients Ester S BITANGA MD, *Alejandro C BAROQUE MD, **Alberto S SANTOSOCAMPO MD, **Almar Y GUEVARRA RN, **Margaret B QUERIJERO MD, ***Carlos L CHUA MD Philippine Neurological Association, *Santo Tomas University Hospital, **Medical Affairs Division, Pfizer Philippine, ***University of Philippine-Philippine General Hospital Abstract A post-marketing surveillance study of gabapentin usage in Filipino patients with neuropathic pain was conducted. Safety, tolerability and analgesic efficacy were assessed after a minimum of two weeks of gabapentin treatment, with starting and final doses determined by the prescribing physician. Of the 1,214 patients who entered the study, 95.7% completed the minimum two weeks duration of therapy. The mean age was 54 years, and the most common neuropathic pain diagnoses were painful diabetic neuropathy (30.4%), nonspecific neuropathies (20.2%), trigeminal neuralgia (12.8%), central pain after stroke (8.8%), and post-herpetic neuralgia (8.4%). Ninety-two percent of patients were maintained within a dose range of 300mg/day to 1200mg/day. The incidence of adverse events was 6%, and consisted mostly of somnolence and dizziness, with 76% of patients reporting “very good” to “excellent” tolerability. There were 34 documented dropouts (2.9%), of which only seven (0.6%) were thought to be related to an adverse event from gabapentin. Visual analog scale pain scores declined significantly from a mean of 67.8 + 20 mm at baseline, to 16.1 + 15mm after treatment (p< 0.05). In conclusion, gabapentin at 300mg/d to 1200mg/d is well tolerated and efficacious among Filipino patients with various neuropathic pain syndromes. Gabapentin showed significant reduction in pain and other related symptoms in all types of neuropathic pain Neurol J Southeast Asia 2002; 7 : 25 – 34

Gabapentin on QoL Pain. 2002 Oct;99(3):557-66. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Serpell MG; Neuropathic pain study group. Source University Department of Anaesthesia and Pain Management, Gartnavel General Hospital, 30 Shelly Court, G12 0YN, Scotland, Glasgow, UK. mgserpell@altavista.net Abstract A double-blind, randomised, placebo-controlled 8-week study was conducted to evaluate the efficacy and safety of gabapentin in the treatment of neuropathic pain, using doses up to 2400 mg/day. The study used a novel design that was symptom- rather than syndrome-based; an approach that aimed to reflect the realities of clinical practice. Participants had a wide range of neuropathic pain syndromes, with at least two of the following symptoms: allodynia, burning pain, shooting pain, or hyperalgesia. Patients were randomised to gabapentin (n=153) or placebo (n=152). Gabapentin was given in three divided doses, initially titrated to 900 mg/day over 3 days, followed by two further increases, to a maximum of 2400 mg/day if required by the end of week 5. The primary outcome measure was changed in average daily pain diary score (baseline versus final week). Over the 8 week study, this score decreased (i.e. improved) by 1.5 (21%) in gabapentin treated patients and by 1.0 (14%) in placebo treated patients (P=0.048, rank-based analysis of covariance). Significant differences were shown in favour of gabapentin (P<0.05) for the Clinician and Patient Global Impression of Change, and some domains of the Short Form-McGill Pain Questionnaire. Improvements were also shown in patient-reported outcomes in quality of life, as seen by significant differences in favour of gabapentin in several domains of the Short-Form-36 Health Survey. Gabapentin was well tolerated and the majority of patients completed the study (79 versus 73% for placebo). The most common adverse events were mild to moderate dizziness and somnolence, most of which were transient and occurred during the titration phase. This study shows that gabapentin reduces pain and improves some quality-of-life measures in patients with a wide range of neuropathic pain syndromes. Comment in Gabapentin improves overall quality of life (QoL) in patients with neuropathic pain Pain. 2002 Oct;99(3):557-66.

Place in Therapy Gabapentin Broad spectrum of action Improves QoL Over all symptom control No Drug interactions Benign side effect profile

Salient Features Effective in spectrum of neuropathic pain Improves various aspects of Neuropathic pain Improves co-morbid conditions associated with pain Improves overall quality of life No significant drug interactions Recommended & approved by various regulatory bodies An effective choice in employed patients

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