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    Very informative blog and thanks for sharing with others also. Like to share some tips to avoid exercise injuries. Make sure you are having regular check ups and warm up and stretch before exercises. Make sure you are hydrating before, during, and after your workout and dress properly for your workout.
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  • Because of the inherent subjective nature of pain, and the fact that the word “pain” itself connotes multiple meanings, the International Association for the Study of Pain (IASP) has established a standardized definition of pain. The definition makes several important points: Pain is an unpleasant emotional experience as well as an unpleasant sensory experience. This distinction between the sensory aspects of pain and its emotional (or affective) component has had a significant influence on both research and the treatment of chronic pain. Also emphasized by the IASP in defining pain is that pain is always subjective. If patients regard their experience as pain and if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. IASP Task Force on Taxonomy. In: Merskey H, Bogduk N, eds. Classification of Chronic Pain . 2nd ed. Seattle, Wash: IASP Press; 1994:209-214.
  • Nociceptive, or inflammatory, pain is pain resulting from activity in neural pathways caused by potentially tissue-damaging stimuli. 1 Examples include postoperative pain, arthritis, mechanical low back pain, sickle cell crisis, and sports or exercise injuries. Neuropathic pain is pain caused by a primary lesion or dysfunction in the peripheral and/or central nervous systems. 2 Examples of peripheral neuropathic pain syndromes include HIV sensory neuropathy, postherpetic neuralgia (PHN), and diabetic neuropathy. Examples of central neuropathic pain include central poststroke pain, spinal cord injury pain, trigeminal neuralgia, and multiple sclerosis pain. As indicated by the “mixed type” area on the slide, chronic pain can be of mixed etiology with both nociceptive and neuropathic characteristics. Two types of neuropathic pain—PHN and diabetic neuropathy—will be emphasized within this module. These types of pain are being stressed because the great majority of randomized controlled trials of treatments for neuropathic pain have examined these two disorders, and because our understanding of the mechanisms of neuropathic pain is largely derived from those studies. 1. Portenoy RK, Kanner RM. Definition and Assessment of Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice . Philadelphia, Pa: FA Davis Company; 1996:4. 2. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain . Minneapolis, Minn: The McGraw-Hill Companies Inc; 2000:8-9.
  • Abstract Background: Recent consensus guidelines recommend pregabalin as a first-tier treatment for painful diabetic peripheral neuropathy (DPN). We evaluated the efficacy of pregabalin 600 mg/d (300 mg dosed BID) versus placebo for relieving DPN-associated neuropathic pain, and assessed its safety using objective measures of nerve conduction (NC). Methods: In this randomized, double-blind, placebo-controlled trial, the primary efficacy measure was endpoint mean pain score (MPS) from daily pain diaries (11-point scale). NC velocity and sensory and motor amplitudes were assessed at baseline, endpoint, and end of follow-up (2 weeks post-treatment). At each timepoint, the median-motor, median-sensory, ulnar-sensory, and peroneal-motor nerves were evaluated. Secondary efficacy measures included weekly MPS and proportion of responders (patients achieving ¡Ý50% reduction in MPS from baseline to endpoint). After 1-weeks' dosage escalation, pregabalin-treated patients received 300 mg BID for 12 weeks.
  • Results: Eighty-two patients received pregabalin and 85 placebo. Mean durations were 10 years for diabetes and ~5 years for painful DPN. Pregabalin-treated patients had lower MPS than controls (mean difference, -1.28; p <.001).
  • Results: Eighty-two patients received pregabalin and 85 placebo. Mean durations were 10 years for diabetes and ~5 years for painful DPN. Pregabalin-treated patients had lower MPS than controls (mean difference, -1.28; p <.001).
  • Results: Eighty-two patients received pregabalin and 85 placebo. Mean durations were 10 years for diabetes and ~5 years for painful DPN. Pregabalin-treated patients had lower MPS than controls (mean difference, -1.28; p <.001).
  • Conclusion: Pregabalin 600 mg/d (300 mg BID) effectively reduced pain, was well tolerated, and had no statistically significant or clinically meaningful effect on NC in patients with painful DPN. Trial registration: ClinicalTrials.gov NCT00159679 Received: 28 February 2008 Accepted: 16 September 2008
  • OBJECTIVE: To evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS: Data were pooled across seven double-blind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks.
  • RESULTS: Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs.. placebo, all P < or = 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P < or = 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (> or =30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.
  • RESULTS: Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs.. placebo, all P < or = 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P < or = 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (> or =30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.
  • RESULTS: Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs.. placebo, all P < or = 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P < or = 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (> or =30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.
  • CONCLUSIONS: Treatment with pregabalin across its effective dosing range is associated with significant, dose-related improvement in pain in patients with DPN.
  • A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8-week trial (with subsequent open-label phase) evaluated the effectiveness of pregabalin in alleviating pain associated with diabetic peripheral neuropathy (DPN). For enrollment, patients must have had at baseline: 1- to 5-year history of DPN pain; pain score > or =40 mm (Short-Form McGill Pain Questionnaire [SF-MPQ] visual analogue scale); average daily pain score of > or =4 (11-point numerical pain rating scale [0 = no pain, 10 = worst possible pain]). One hundred forty-six (146) patients were randomized to receive placebo (n = 70) or pregabalin 300 mg/day (n = 76). Primary efficacy measure was endpoint mean pain score from daily patient diaries (11-point numerical pain rating scale). Secondary measures included SF-MPQ scores; sleep interference scores; Patient and Clinical Global Impression of Change (PGIC and CGIC); Short Form-36 (SF-36) Health Survey scores; and Profile of Mood States (POMS) scores. Safety assessment included incidence and intensity of adverse events, physical and neurological examinations, and laboratory evaluations. Pregabalin produced significant improvements versus placebo for mean pain scores (P < 0.0001); mean sleep interference scores SF-36 Bodily Pain subscale (P < 0.0001); total SF-MPQ score (P < 0.01); SF-36 Bodily Pain subscale (P < 0.03); PGIC (P = 0.001); and Total Mood Disturbance and Tension-Anxiety components of POMS (P < 0.03). Pain relief and improved sleep began during week 1 and remained significant throughout the study (P < 0.01). Pregabalin was well tolerated despite a greater incidence of dizziness and somnolence than placebo. Most adverse events were mild to moderate and did not result in withdrawal. Pregabalin was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.
  • A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8-week trial (with subsequent open-label phase) evaluated the effectiveness of pregabalin in alleviating pain associated with diabetic peripheral neuropathy (DPN). For enrollment, patients must have had at baseline: 1- to 5-year history of DPN pain; pain score > or =40 mm (Short-Form McGill Pain Questionnaire [SF-MPQ] visual analogue scale); average daily pain score of > or =4 (11-point numerical pain rating scale [0 = no pain, 10 = worst possible pain]). One hundred forty-six (146) patients were randomized to receive placebo (n = 70) or pregabalin 300 mg/day (n = 76). Primary efficacy measure was endpoint mean pain score from daily patient diaries (11-point numerical pain rating scale). Secondary measures included SF-MPQ scores; sleep interference scores; Patient and Clinical Global Impression of Change (PGIC and CGIC); Short Form-36 (SF-36) Health Survey scores; and Profile of Mood States (POMS) scores. Safety assessment included incidence and intensity of adverse events, physical and neurological examinations, and laboratory evaluations. Pregabalin produced significant improvements versus placebo for mean pain scores (P < 0.0001); mean sleep interference scores SF-36 Bodily Pain subscale (P < 0.0001); total SF-MPQ score (P < 0.01); SF-36 Bodily Pain subscale (P < 0.03); PGIC (P = 0.001); and Total Mood Disturbance and Tension-Anxiety components of POMS (P < 0.03). Pain relief and improved sleep began during week 1 and remained significant throughout the study (P < 0.01). Pregabalin was well tolerated despite a greater incidence of dizziness and somnolence than placebo. Most adverse events were mild to moderate and did not result in withdrawal. Pregabalin was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.
  • A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8-week trial (with subsequent open-label phase) evaluated the effectiveness of pregabalin in alleviating pain associated with diabetic peripheral neuropathy (DPN). For enrollment, patients must have had at baseline: 1- to 5-year history of DPN pain; pain score > or =40 mm (Short-Form McGill Pain Questionnaire [SF-MPQ] visual analogue scale); average daily pain score of > or =4 (11-point numerical pain rating scale [0 = no pain, 10 = worst possible pain]). One hundred forty-six (146) patients were randomized to receive placebo (n = 70) or pregabalin 300 mg/day (n = 76). Primary efficacy measure was endpoint mean pain score from daily patient diaries (11-point numerical pain rating scale). Secondary measures included SF-MPQ scores; sleep interference scores; Patient and Clinical Global Impression of Change (PGIC and CGIC); Short Form-36 (SF-36) Health Survey scores; and Profile of Mood States (POMS) scores. Safety assessment included incidence and intensity of adverse events, physical and neurological examinations, and laboratory evaluations. Pregabalin produced significant improvements versus placebo for mean pain scores (P < 0.0001); mean sleep interference scores SF-36 Bodily Pain subscale (P < 0.0001); total SF-MPQ score (P < 0.01); SF-36 Bodily Pain subscale (P < 0.03); PGIC (P = 0.001); and Total Mood Disturbance and Tension-Anxiety components of POMS (P < 0.03). Pain relief and improved sleep began during week 1 and remained significant throughout the study (P < 0.01). Pregabalin was well tolerated despite a greater incidence of dizziness and somnolence than placebo. Most adverse events were mild to moderate and did not result in withdrawal. Pregabalin was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.
  • Acta Neurol Taiwan. 2005 Jun;14(2):48-54. Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials. Sun Y , Lai MS , Lu CJ . Source Department of Neurology, En Chu Kong Hospital, No. 399, Fuhsin Road, San-shia, Taipei, Taiwan. sunyu@ms4.hinet.net Abstract The clinical effectiveness of vitamin B12 and its active coenzyme form on diabetic neuropathy is uncertain. Therefore, we searched the English- and non-English-language literature on this topic by using MEDLINE (Ovid, PubMed), the Cochrane Controlled Trials Register, and related papers. We identified seven randomized controlled trials from June 1954 to July 2004 and reviewed them for the clinical effectiveness of vitamin B12 according to the following parameters: Measurement scales of somatic and autonomic symptoms or signs; vibrometer-detected thresholds of vibration perception; and, electrophysiologic measures such as nerve conduction velocities and evoked potentials. Three studies involved the use of vitamin B complex (including B12) as the active drug, and four used methylcobalamin. Two studies were of fairly good quality (Jadad score = 3/5), and five were of poor quality (Jadad score < or = 2/5). Both the vitamin B12 combination and pure methylcobalamin had beneficial effects on somatic symptoms, such as pain and paresthesia. In three studies, methylcobalamin therapy improved autonomic symptoms. Effects on vibration perception and electrophysiological measures were not consistent. With both the vitamin B12 combination and pure methylcobalamin, symptomatic relief was greater than changes in electrophysiological results. However, more high-quality, double-blind randomized controlled trials are needed to confirm the effects of vitamin B12 on diabetic neuropathy.
  • Zhonghua Nei Ke Za Zhi. 1999 Jan;38(1):14-7. [Effect of mecobalamin on diabetic neuropathies. Beijing Methycobal Clinical Trial Collaborative Group]. [Article in Chinese] Li G . Source Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029. Abstract OBJECTIVE: To investigate the effect of mecobalamin on diabetic neuropathies. METHODS: One hundred and eight patients with non-insulin dependent diabetes mellitus were involved in a randomized positive-control clinical trial. 62 cases were treated with mecobalamin 500 microg intramuscularly three times a week for four weeks then followed by 500 microg orally three times a day for additional eight weeks. 46 cases were treated with vitamin B(12) in the same way and served as controls. RESULTS: Twelve weeks after the treatment, spontaneous pain and numbness of limbs were improved by 73% and 75% in the mecobalamin group, which were much higher than those in the controls (36% and 45% respectively). Hypoesthesia, hotness, coldness, oral dryness and dysuria showed better response in the mecobalamin group than in the controls (55% vs 25%, 52% vs 18%, 59% vs 30%, 53% vs 19%, 63% vs 20% respectively). Mecobalamin also benefited nerve reflection and conduction velocity to a certain extent. No obvious side effects were found. CONCLUSION: Mecobalamin might be worthy of use as a safe agent in the treatment of diabetic neuropathies.
  • http://www.endfatigue.com/tools-support/Nitroglycerine-Spray-For-Diabetic-Neuropathy.html

Management+of+Diabetic+Neuropathy Management+of+Diabetic+Neuropathy Presentation Transcript

  • Diabetic Neuropathy
  • IASP Definition of Pain
    • “ Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”
  • Nociceptive vs Neuropathic Pain Mixed Type Caused by a combination of both primary injury and secondary effects Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system Postoperative pain Mechanical low back pain Sickle cell crisis Arthritis Postherpetic neuralgia Neuropathic low back pain CRPS* Sports/exercise injuries *Complex regional pain syndrome Central post- stroke pain Trigeminal neuralgia Distal polyneuropathy (eg, diabetic, HIV)
  • Diabetic Neuropathy can be defined as:
    • “ The presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after other causes have been excluded”
  • Features of Diabetic Neuropathy
    • Common complication affecting up to 50% patients with DM
    • Diagnosed in the presence of 2 abnormal symptoms or signs
    • Frequently asymptomatic & mostly untreatable
    • Requires careful examination/assessment to detect (NDS, NSS)
    • Affects quality of life (pain, depression)
    • Patients with DN are 15 times more likely to have LL amputation
    • Foot problems are the commonest reason for in-patient admission
    • Death most frequently due to cardiovascular disease
  • What causes Diabetic Neuropathies?
    • Metabolic factors - such as high blood glucose, long duration of diabetes, abnormal blood fat levels, and possibly low levels of insulin
    • Neurovascular factors , leading to damage to the blood vessels that carry oxygen and nutrients to nerves
    • Autoimmune factors that cause inflammation in nerves
    • Mechanical injury to nerves
    • Lifestyle factors , such as smoking or alcohol use
  • Burden of Diabetes Neuropathy
    • Cost to the Patient: pain
    • loss of function
    • depression
    • loss of independence
    • loss of earnings
    • Cost to the Health Care Service: GP, community/OP/IP services
    • Cost to society: Number of patients growing of Diabetes (Diabetic Capital of World)
    • Workforce
    • Welfare system
    • Increasing prevalence across all age groups
  • Etiology & Pathophysiology
    • Alterations in nerve blood flow
    • Schwann cell (SC) dysfunction: Primary demyelination, secondary segmental demyelination due to impairment of axonal control of myelination, remyelination, SC proliferation, atrophy of denervated bands of SC, basal lamina hypertrophy.
    • Neuronal degeneration & progressive impairment of regeneration (esp. thin myelinated fibres)
    • Neuronal damage caused by hyperglycaemia (activation of the polyol p’way, synthesis of AGE products, excess activation of PKC-driven p’ways, microangiopathy of the vasa nervorum)
    • Oxidative stress
  • Types of Diabetic Neuropathy
    • Sensorimotor: Acute reversible (hyperglycaemic neuropathy)
    • Persistent Symmetrical*
    • Focal & Multifocal
    • Autonomic: Gustatory sweating
    • Postural hypotension
    • Gastroparesis
    • Diabetic diarrhoea
    • Neuropathic bladder
    • ED
    • Neuropathic oedema
    • Charcot arthropathy
  • Risk Factors
    • Modifiable: Glycaemic control
    • Dyslipidemia
    • Hypertension
    • BMI
    • Smoking
    • Excessive alcohol
    • Prevention/delaying the onset of DM
    • Non-modifiable: Age of onset of diabetes
    • Duration of DM
    • Genetic factors
    • Presence of other complications of DM
  • Management of Diabetic Neuropathy
  • Goals of Neuropathic Pain Management Treat/prevent recurrence of pain-causing condition Reduce pain Improve physical/psychologic function Improve quality of life
  • Diabetic Neuropathy- Pain Assessment Scales
  • Neuropathic Pain: Nonpharmacologic Treatment Options
    • Cognitive-behavioral strategies
      • Meditation
      • Imagery
      • Biofeedback
      • Relaxation therapy
    • Physical rehabilitation
    • Acupuncture
    • Transcutaneous electrical nerve stimulation
  • DIABETIC NEUROPATHY MANAGEMENT - ALGORITHM
  • APPROACHES TO THE MANAGEMENT OF NEUROPATHIC PAIN Monotherapy Combinations Additional Measures First-line TCA Low-dose TCA+ AE Paracetamol Acupuncture Physiotherapy Anti-epileptic (AE) Second-line Alternative antidepressant Opioid with TCA or AE Opioid Capsaicin Third-line Alternative opioids Intrathecal drug delivery Neuromodulation
  • Management of Diabetic Peripheral Neuropathy Managing Neuropathic Pain: New Approaches For Today's Clinical Practice Charles E. Argoff, MD, www.medscape.com Parameters Significance Tight glucose control Can reverse the changes but only if the neuropathy and diabetes is 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 Citalopram FDA not approved, no more efficacious than placebo in several controlled trials. Antiepileptic drugs (AED’s) e.g. Gabapentin & Pregabalin Emerging as first line treatment for painful neuropathy. Methylcobalamin Exerts neuroprotective effects, regenerates myelin sheath
  • Latest Guidelines on Neuropathy Management Neurology® 2011;76:1–1
  • Summary of Recommendations
  • Guidelines – At a Glance
    • Pregabalin is established as effective and should be offered for relief of PDN (Level A).
    • Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B).
    • Other treatments have less robust evidence or the evidence is negative.
    • Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.
    Neurology® 2011;76:1–1
  • Pregabalin in the management of DPNP
  • How does Pregabalin work??? Pregabalin binds with high affinity to the alpha2-delta site ( voltage-gated calcium channels) in Neurons Reduces the calcium-dependent release of several neurotransmitters (Glutamate , Substance P) Increases neuronal GABA levels Reduces neuropathic pain & also exerts anticonvulsive and anxiolytic effects
  • Pregabalin
    • FDA approved indications –
      • Management of neuropathic pain associated with diabetic peripheral neuropathy
      • Management of postherpetic neuralgia
      • Adjunctive therapy for adult patients with partial onset seizures
      • Management of fibromyalgia
  • Pregabalin – From Clinical Experience
    • Accepted First line therapy in the management of DPN.
    • More than 140 clinical studies and 20 studies exclusively in DPN support the use of Pregabalin in Neuropathy management.
    • Daily dosages of Pregabalin (150mg / 300 mg) in divided dosages; B.I.D or T.I.D) reduces at least 50% of pain score in DPN patients.
  • Pregabalin from the clinical trials…
    • More than 2000 patients on Pregabalin therapy actually had a relief from the DPN.
    • The dosage schedule for the all the trials was 150 mg (B.I.D) as initial dose and 600 mg (B.I.D) as the maximum dose per day.
    • Pregabalin offered superior profile in terms of efficacy & safety when compared with the placebo as well as other comparative drugs.
    Thus, Pregabalin 150 mg – 600 mg/day in divided dosages is the effective dose for the treatment of Diabetic Peripheral Neuropathy…
  • Pregabalin 600 mg dose…
    • Trial Method - 12 weeks randomized, double-blind, placebo-controlled trial.
    • Interventions – 82 patients received Pregabalin 300 mg BID & 85 patients were on Placebo.
    • Outcomes –
      • Primary – Change in mean pain score (MPS) from daily pain diaries (11-point scale).
      • Secondary - Weekly MPS and proportion of responders
    • Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
  • Results – Weekly least-squares mean pain scores Improvement in the Pregabalin group was evident at week 1 and this improvement was maintained at every weekly time point through week 13 Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
  • Results – Responder rate 49% patients in Pregabalin group responded to ≥50% reduction in mean pain score from baseline to endpoint as compared to 23% in placebo group. Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
  • Results - Global improvement On both the clinician-rated and the patient-rated instruments, there was a response favoring Pregabalin compared with placebo CGIC – Clinical Global Impression of Change scales PGIC – Patient Global Impression of Change scales Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
  • Conclusion
    • Pregabalin 600 mg/d (300 mg BID) effectively reduced pain & was well tolerated.
    Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
  • Pregabalin across all dosage range…
    • Trial method – Data pooled across seven double blind, randomized, placebo-controlled trials using Pregabalin
    • Intervention – Pregabalin 150, 300, and 600 mg/day administered TID or BID.
    • Treatment duration – 5 to 13 weeks
    ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008
  • Results – Change in least-squares mean pain score Significant reductions in end point least-squares mean pain score were observed for all three dosages of Pregabalin i.e.150, 300, and 600 mg/day ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008
  • Results - Proportion of patients meeting improvement from baseline in mean pain score Significant improvements from baseline was observed for all three dosages of Pregabalin i.e.150, 300, and 600 mg/day ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008
  • Results – Survival curve analysis The median time to onset of a sustained (≥ 30% at end point) 1-point improvement was 4 days in patients treated with Pregabalin 600 mg/day, 5 days in patients treated with Pregabalin 300 mg/day, 13 days in patients treated with Pregabalin 150 mg/day, and 60 days in patients receiving placebo. ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008
  • Conclusion…
    • Treatment with Pregabalin across its effective dosing range i.e. 150 – 600 mg/day (B.I.D or T.I.D) is associated with significant, dose-related improvement in pain in patients with DPN.
    ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008
  • Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial.
    • Trial method – Randomized, double-blind, placebo- controlled, parallel-group, multicenter trial
    • Intervention –146 patients were randomized to receive placebo (n = 70) or Pregabalin 300 mg/day (n = 76).
    • Treatment duration – 8 weeks
    • Outcomes- Mean pain score from daily patient diaries (11-point numerical pain rating scale).
    Rosenstock J, Tuchman M, LaMoreaux L, Sharma U et.al, Pain. 2004 Aug;110(3):628-38.
  • Results – Effect on Mean Weekly Pain scores in DPN Pregabalin produced significant improvements for mean pain scores; mean sleep interference scores; and Total Mood Disturbance versus placebo Rosenstock J, Tuchman M, LaMoreaux L, Sharma U et.al, Pain. 2004 Aug;110(3):628-38.
  • Conclusion…
    • Pregabalin was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.
    Rosenstock J, Tuchman M, LaMoreaux L, Sharma U et.al, Pain. 2004 Aug;110(3):628-38.
  • Along with that, Pregabalin Sustained Release…
    • Increased patient compliance – Reduces the pill burden in polypharmacy.
    • Round the clock pain management – 24 hour steady therapeutic concentration.
    • Lesser dose escalation and dose titration – Higher responder rate.
    • Improved quality of life – No breakthrough events during night, no morning tingling sensation.
    • Improved work efficiency during the production hours of day – Lesser or negligible events of drowsiness during the day hours.
  • Overall…
    • Pregabalin is safe and efficacious in the management of Diabetic Peripheral Neuropathy.
    • From various clinical trials Pregabalin improved mean pain score & also improved mood, sleep disturbance, and quality of life.
    • The effective dosage range of Pregabalin established from the clinical trials is 150 mg to 600 mg per day in divided dosages.
    • Pregabalin SR enhances patient compliance
  • Pregabalin better than Gabapentin…. Feature Pregabalin Gabapentin T max 1 h., Pregebalin SR (3-4 hr) 3.5 h. Absorption Fast Slow Oral Bioavailability > 90 % independent of dose 35% - 57 % dependent of dose Plasma concentrations Predictable & Linear Unpredictable & non-linear Potency based on Plasma conc . 2.5 times more potent - Drug-Drug interactions No Known drug-drug interactions Oral antacids reduce bioavailability by 20 – 30 % Dosage (starting dose) 2 times a day ( 75 to 150 mg/day ), Pregebalin SR (150, 300 mg / day) 3 times a day ( 300 to 900 mg/day ) Overall Pharmacokinetic More stable Less stable At high dosage Fast absorption Less absorption Onset of action 1 – 2 days ≥ 9 days Dose increases Non – linear Linear and predictable Protein binding Varied Predictable levels
  • Antidepressants in DPNP
    • USP DI Volume I: Drug Information for the Healthcare Professional . 27th ed. Greenwood Village, CO: Thomson Micromedex; 2007.
  •  
    • Compared with placebo, Amitriptyline reduced pain to a similar extent whether patients were not depressed or were depressed
  •  
  • Tricyclic antidepressants
    • Advantages
      • Well documented efficacy in treatment of PHN and DPN.
      • Recommended as first-line agents for all neuropathic pain by many practitioners
    • Disadvantages
      • Unacceptable side effects like
        • Anticholinergic effects: Dry mouth, constipation, blurred vision, urinary retention, dizziness, tachycardia, memory impairment
        • Sedation
        • Alpha-1-adrenergic effects: Orthostatic hypotension / syncope
        • Cardiac conduction delays/heart block: Arrhythmias, Q-T prolongation
        • Other side effects: Weight gain, excessive perspiration, sexual dysfunction
  • SNRI – AN OVERVIEW
    • Neurotransmitter synthesis
    • Neurotransmitter storage
    • Vesicle transport
    • Vesicle fusion and Neuro-
    • transmitter release
    • Autoreceptor binding
    • Receptor binding
    Duloxetine MOA DULOXETINE ACTS HERE NEUROTRANSMITTER REUPTAKE
  • Duloxetine
    • Pharmacokinetics:
    • Well-absorbed after oral doses
    • Peak plasma levels occur in 6 hours
    • An elimination half-life is 16 hours
    • Preferred in elderly patients and those with cardiac disease
    • Use cautiously in patients with any hepatic insufficiency & in renally impaired patients. (should be initiated at a lower dose & then increased gradually.)
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  • Advantages of Duloxetine Over Gabapentin
    • At monotherapy with Duloxetine results in a 30 to 50% reduction in pain, a multi-drug regime may be helpful.
    • Duloxetine - Has anti - depressant & central pain inhibitory actions. It is used as OD or BD. Higher dose is even taken OD.
    • Proven beneficial in neuropathic pain . Dose should by OD or BD.
  • Serotonin Reuptake Inhibitors
    • Advantages:
      • selective and are better tolerated than TCAs, with fewer associated side effects and toxicities.
    • Disadvantages:
      • FDA not approved
      • Except Duloxetine which is a SNRI all the other agents in this group are believed to be less efficacious in the treatment of neuropathic pain and are not regarded as first-line agents
      • Though the SNRI duloxetine has recently received FDA approval for use in DPNP it has poor efficacy in the treatment of PHN
  • Methylcobalamin in Management of Diabetic Neuropathy
    • Despite of symptomatic treatment with Drugs there are still some treatment gaps which needs to be addressed –
    • Regeneration of Myelin Sheath of Neuron
    • Long-term neuropathy management
    • Methylcobalamin is the active form of vitamin B12 acting as a cofactor for methionine synthase
    Methylcobalamine Vitamin B12 deficiency Demyelination (destruction or loss of the myelin sheath) which damages the neurons Helps in the formation of myelin (component of myelin sheath). Promotes nerve regeneration & improves transmission. Methylcobalamin
  • Methylcobalamine from Clinical Evidences…
    • 7 randomized controlled trials from June 1954 to July 2004 was evaluated & reviewed
      • Both the vitamin B12 combination and pure methylcobalamin had beneficial effects on somatic symptoms, such as pain and paresthesia.
      • methylcobalamin therapy improved autonomic symptoms.
      • Leads to symptomatic relief
    Acta Neurol Taiwan. 2005 Jun;14(2):48-54.
  • Effect of mecobalamin on diabetic neuropathies. Beijing Methycobal Clinical Trial Collaborative Group
    • Methylcobalamine after twelve weeks after the treatment –
      • 73% improvement in spontaneous pain
      • 75% improvement in numbness of limbs
    • Hypoesthesia, hotness, coldness, oral dryness and dysuria showed better response than the controls group
    • Also benefited nerve reflection and conduction velocity
    Mecobalamin might be worthy of use as a safe agent in the treatment of diabetic neuropathies Zhonghua Nei Ke Za Zhi. 1999 Jan;38(1):14-7.
    • Improves symptoms related to Neuropathy such as 1
      • Paraesthesia
      • Burning pain
    • Increases synthesis of Lecithin, major component of myelin sheath
    • Regenerates myelin sheath and thus protects nerve axons and peripheral nerves
    • Excellent tolerability and no known toxicity.
    Role of Methylcobalamine in Neuropathy Acta Neurol Taiwan. 2005 Jun;14(2):48-54.
  • Nitroglycerine Spray in Management of DPNP
  • Nitroglycerin – Place in therapy
    • Vasodilation due to nitric oxide, a derivative of glyceryl-trinitrate, may explain its analgesic effects, while stimulation of angiogenesis in the blood vessels supplying the nerves could explain the temporal increase in the analgesic effects
  • Glyceryl trinitrate spray in the management of painful diabetic neuropathy: a randomized double blind placebo controlled cross-over study.
    • Trial method – Randomized, double-blind, placebo- controlled, cross-over trial
    • Intervention – 48 patients were randomized to receive placebo (group A) or GTN (group B).
    • Treatment duration – 10 weeks
    • Outcomes- Patients of group B observed significant improvement in all pain scores compared to group A (p<0.001). The numbers needed to treat (NNT) calculated on VAS as pain parameters came out to be 4. The drug was well tolerated by all the patients except palpitation and headache for some days in five patients.
    • Conclusion- GTN spray, a well tolerated drug, provides significant improvement in painful diabetic neuropathy.
    Diabetes Res Clin Pract. 2007 Aug;77(2):161-7
  • Summarizing…
    • Neuropathy is a multifactorial problem.
    • Neuropathy - The most common complication and greatest source of morbidity and mortality in diabetes patients.
    • Despite advances in the understanding of the metabolic causes of neuropathy, treatments have been limited by side effects and lack of efficacy.
    • The unmet needs of DPN has to be addressed and needs to be managed with either the new convincing formulations of existing molecules or with the newer agents to have a control.
  • THANK YOU