Diabetic Neuropathy An approach to the clinical management
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Diabetic Neuropathy: An approach to the clinical management William L. Watkins, MD Internal Medicine Resident Grand Rounds February 16, 1999
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Case Presentation HPI: HJ is a 51yo bm with a PMH of Type 2 Diabetes Mellitus who presents to walk in clinic to establish a new physician with complaints of polydipsia, polyuria, and burning and tingling of the legs. PMH: Type 2 Diabetes and Hypertension PSH: Appendectomy, Hemmorrhoidectomy SH: tobacco 1/2 ppd, denies ETOH
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Case Presentation Allergies: NKDA MEDS: Procardia XL, Prilosec, Neurontin 300mg tid Insulin 70/30 30u in AM, 15u in PM
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Case Presentation PE: Temp 98.4, HR 100, BP 128/90, Wt. 132# Thin black male, with an unremarkable exam Ext: no edema, ulcerations, or deformities Neuro: strength: 5/5 all extremities reflexes: absent Achilles bilaterally sensation: diminished to light touch below ankle
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Case Presentation Labs: fingerstick glucose 250 Hgb A1c 15.7% Assessment: Uncontrolled diabetes with signs of neuropathy Plan: Optimize glycemic control, refer to diabetes education, evaluate for other late complications such as retinopathy (optho) and nephropathy (microalbumin) and...
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Case Presentation What do I do for the burning and tingling in his legs? Do I continue or change his Neurontin?
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Objectives 1. Review the basic principles and epidemiology of diabetic neuropathy. 2. Review the clinical trials supporting the prevention of neuropathy with tight glycemic control. 3. Discuss the medications used to treat painful diabetic neuropathy. 4. Discuss the prevention of foot complications which commonly occur with neuropathy.
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Diabetic Neuropathy The most common of all the late complications of diabetes mellitus Cause of much suffering in patients with painful neuropathy Can lead to foot ulcerations, charcot neuroarthropathy, and amputations without proper foot care.
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Definition according to the San Antonio Conference on Diabetic Neuropathy 1988 “Diabetic neuropathy is a descriptive term meaning a demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes mellitus without other causes for peripheral neuropathy. The neuropathic disorder includes manifestations in the somatic and/or autonomic parts of the peripheral nervous system.”
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Classification of Diabetic Neuropathy Mononeuropathy: involvement of a single nerve characteristically results in foot drop, wrist drop, or cranial nerve III, IV, or VI paralysis Radiculopathy: a sensory syndrome of pain over multiple spinal nerves, mimics zoster pain Diabetic amyotrophy: a rare disorder resulting in atrophy and weakness of the pelvic girdle musculature
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Classification of Diabetic Neuropathy Autonomic neuropathy: involvement of the involuntary nervous system. Can involve: The gastrointestinal tract: gastroparesis, constipation, diarrhea The cardiovascular system: orthostatic hypotension, tachycardia, alteration of heartrate control The genitourinary system: impotence, urinary retention, incontinence Other: abnormality in perspiration, excessive sweating or dryness
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Classification of Diabetic Neuropathy Peripheral sensorimotor polyneuropathy: the most common of the diabetic neuropathies accounting for 80% of neuropathy in diabetic patients.
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Signs and symptoms of Peripheral Sensorimotor Polyneuropathy Distal, bilateral,symmetrical, stocking-glove distribution. Symptoms range from numbness (“deadness”) to severe pain. Burning, alteration of temperature sensation, parathesias, shooting, or stabbing pains are common. May worsen at night. Minor motor involvement causing weakness.
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Physical Exam Clues to the Diagnosis Decrease or absent reflexes (Achilles) Loss or diminished vibratory sensation (128Hz tuning fork), pin prick, light touch, or pressure perception Muscle atrophy Foot complications, ulcerations, blisters, deformities (Charcot’s joint)
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Electrophysiologic Studies Most sensitive, reliable, and reproducible measurement of nerve function which correlate with findings on biopsy NCV demonstrate demyelination and axonal degeneration in the form of decreased amplitudes of the compound muscle action potential and sensory action potential. The earliest finding is distal slowing of conduction with preservation of proximal NCV. EMG reveals denervation and reinnervation
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Differential Diagnosis Up to 10% have other etiologies Metabolic etiologies: B12/ folate deficiency, hypothyroidism,uremia Toxic etiologies: ETOH, heavy metals, medications Inflammatory etiologies: vasculitis, sarcoid, SLE, syphilis, leprosy Other: paraneoplastic, leukemia, amyloid
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Pathophysiology Not clearly understood Polyol theory: Glycosolated end- products theory
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Incidence The largest prospective study followed 4400 patients from 1947 to 1973. (Pirart. Diabetes Care 1978) 7.5% at baseline already had neuropathy 50% showed evidence of neuropathy at the end of the 25 years. Criteria used was loss of Achilles and/or patellar reflexes combined with a clear decrease in vibratory sensation
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Incidence (Partanen,NEJM 1995) A more recent study followed 133, newly diagnosed, type 2 diabetics for 10 years compared with non-diabetic controls. Primary Care Physicians managed the diabetes, the mean glyc Hgb=9.0%. Definite Polyneuropathy: abnormal NCV in both the peroneal and sural nerves with clinical symptoms (bilateral pain or parathesias with absence of achilles reflex or decrease in vibratory sense) Probable Polyneuropathy: abnormal NCV in both without clinical symptoms or abnormal NCV in 1 nerve with clinical symptoms
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Incidence (Partanen,NEJM 1995) At baseline, 3.8% of the type 2 patients had definite polyneuropathy and 4.5% had probable polyneuropathy vs 2.1% of the nondiabetic controls At 10 yrs, 20% of the type 2 patients had definite polyneuropathy and 20% had probable polyneuropathy vs 5.8% of the controls (p<0.001) The incidence can approach 40% in ten years depending on the use of NCV
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Management Prevention of neuropathy through tight glycemic control, goal is to achieve “normal” levels Control of neuropathic pain Simple analgesics (acetaminophen, NSAIDS) Tricyclic antidepressants SSRIs Anticonvulsants Mexilitine Tramadol Capsaicin Prevention of foot complications
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Prevention The Diabetes Control and Complications Trial NEJM 1993 The DCCT evaluated the effects of intensive therapy in reducing chronic microvascular and neurologic complications in type 1 diabetic patients. Large, multicenter, randomized controlled trial 1441 pts., mean age 27, 53% men, 96% white Excluded HTN, hypercholesterolemia, severe medical conditions, severe diabetic complications
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Prevention The Diabetes Control and Complications Trial NEJM 1993 Two cohorts: Primary prevention cohort (n=726): type 1 for 1-5yrs, without retinopathy and urinary albumin <40mg/24hrs Secondary prevention cohort (n=715): type 1 for 1-15 yrs, with mild to moderate retinopathy and urinary albumin<200mg/24hrs Randomized among the cohorts: 711 received intensive therapy, 730 received conventional therapy Principle outcome was retinopathy, but renal, neurologic, and cardiovascular outcomes were measured
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Prevention The Diabetes Control and Complications Trial NEJM 1993 The intensive therapy consisted of three or more injections of insulin a day or an external pump Blood glucose measured 4 times a day Goal of intensive therapy: preprandial glucose of 70-120 mg/dl postprandial glucose <180mg/dl a weekly 3AM glucose >65 a monthly Hgb A1c <6.05% Conventional therapy consisted on 1 to 2 injections a day
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Prevention The Diabetes Control and Complications Trial NEJM 1993 99% completed the study, 95% exams completed Clinical neuropathy: an abnormal neurologic exam plus abnormal NCV or autonomic testing Results: In the patients in the primary prevention cohort who did not have neuropathy at baseline, intensive therapy reduced the appearance of clinical neuropathy at 5 years by 69% (3% vs 10%, p=0.006) and the secondary prevention cohort by 57% (7% vs 16%, p<0.001) Risks: severe hypoglycemic episodes were 3x greater in the intensive therapy group.
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Prevention Kumamoto Study Diabetes Research and Clinical Practice 1995 Similar to the DCCT but involved type 2 patients 110 Japanese pts randomly assigned to multiple injection therapy vs conventional 1-2 injections The neurologic endpoints were NCV, vibratory thresholds, and autonomic neuropathy Results: median NCV (both sensory and motor) significantly increased (improved) after 6 years in the multiple injection therapy pts (p<0.05) This study supported the use of aggressive therapy in type 2 patients to prevent neuropathy
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Management of Neuropathic Pain Symptomatic control of neuropathic pain Simple analgesics (acetaminophen, NSAIDS) Tricyclic antidepressants SSRIs Anticonvulsants Mexilitine Tramadol Topical Capsaicin
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Tricyclic Antidepressants Traditional medications used to manage diabetic neuropathic pain. Very few RCTs, unable to find n>46
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Tricyclic Antidepressants Max etal. Neurology. 1987 Small, randomized, double blind, crossover study Two-week drug free baseline followed by two 6-week treatment periods, no washout period control was benztropine 1mg with a lactose placebo (with diazepam 5mg to 1st 18 days) Evaluated by diary recording choosing between 13 words with different ratings 29 pts completed the study, 8 pts did not complete the study (5 withdrew, 1 no diary, 1 noncompliant)
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Tricyclic Antidepressants Max etal. Neurology. 1987 Of the 29 pts, 17 were men, median age 57, diabetes for 11 years, 3 diet controlled 23 of 29 had less pain with amitriptyline vs placebo, 1 of 29 less pain with placebo, 5 unchanged Mean dose of amitriptyline 90mg amitriptyline relieved pain in both depressed and non-depressed
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Meta-Analysis of Antidepressants McQuay et al. Pain. 1996 Meta-analysis of RCTs from 1950-1994 13 trials reviewed for Diabetic Neuropathy main outcome was 50% decrease in pain n=13 to 46 for each study, duration 4-6 weeks amitriptyline(1), desipramine(2), nortriptyline(1), imipramine(4), fluoxetine(1), paroxetine(1), clomipramine(1), citalopram(1), mianserine(1)
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Meta-Analysis of Antidepressants McQuay et al. Pain. 1996 Only 6 of 13 showed significant benefit, but when combined the odds ratio for all antidepressants was 3.6 with NNT= 3 Combined NNT for the 8 tricyclics was 3.2 NNT for imipramine was 3.7, desipramine was 3.2 paroxetine was 5, fluoxetine was 15.3 placebo response varied from 0 to 75% effective
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SSRIs Sindrup et al. Pain. 1990 Paroxetine (40mg) vs Placebo vs Imipramine (dose adjusted) 2-week by 2-week by 2-week, double blinded, randomized crossover design 29pts., Type 1 with one year history of pain 3 withdrew during imipramine titration 7 others did not complete the double blinding due to side effects, noncompliance, analgesics
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SSRIs Sindrup et al. Pain. 1990 19 pts completed the study 1 additional pt. completed paroxetine placebo Evaluated by 100mm Visual Analog Scale (for 5 items) and neuropathy score by one MD observer
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SSRIs Sindrup et al. Pain. 1990 Results: Median VAS (max 500) 141 placebo vs 85 paroxetine (p=0.0039) 141 placebo vs 37 imipramine (p< 0.00005) Median neuropathy score ( max 12) 5.75 placebo vs 3.75 paroxetine (p=0.0121) 5.75 placebo vs 1.97 imipramine (p=0.0002)
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SSRIs Sindrup et al. Pain. 1990 Results showed significant improvement with paroxetine over placebo BUT Imipramine was significantly better than paroxetine on both scales (p=0.0007 and p=0.0071) drug levels did not correlate with response only took 4 to 5 days to reach maximal effect
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SSRIs and Tricyclics Max et al. NEJM 1992 Amitriptyline vs Desipramine and Fluoxetine vs Placebo 2 randomized, 2 crossover studies each of 6-weeks with a 2-week washout in between Evaluated by daily entry of 13 words with different intensity ratings and by a Global pain relief scale complete, a lot, moderate, slight, none or worse
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SSRIs and Tricyclics Max et al. NEJM 1992 29 pts randomly assigned to ami/desip and 5 non-randomly assigned (fluoxetine filled) An additional 20 pts joined after completing the fluoxetine study 28 pts randomly assigned to fluoxetine study and 17 non-randomly assigned (contraindications to amitriptyline), an additional 9 pts joined after completing ami/desip study
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SSRIs and Tricyclics Max et al. NEJM 1992 38 pts completed ami/desip study 16 pts withdrew due to side effects 46 pts completed fluoxetine/placebo 8 pts withdrew Amitriptyline mean dose 105mg Desipramine mean dose 111mg Fluoxetine dose 40mg
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SSRIs and Tricyclics Max et al. NEJM 1992 Results: Decrease in pain score (+/- .06) placebo = 0.22 and fluoxetine = 0.27 amitriptyline = 0.38 and desipramine = 0.31 No significant difference among amitriptyline vs desipramine No significant difference among fluoxetine vs placebo except in subset of depressed pts (p=0.03)
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Anticonvulsants McQuay et al. BMJ. 1995 Meta-analysis of RCTs for chronic pain 3 studies from 1966-1994 focused on diabetic neuropathy Two studies (1st phenytoin, 2nd carbamazepine) showed 30-50% more pts improving after 2 weeks c/w placebo 3rd study with phenytoin did not show significant improvement
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Gabapentin (Neurontin) Backonja et al. JAMA. 1998 (ParkeDavis) Large, multicenter, RCT (7/96-3/97) Type 1 and 2 diabetics with neuropathy for 1-5 yrs, at least 40 of 100 on VAS scale excluded glyc Hgb >11%, CrCl<60ml/min only stable dose of SSRI allowed others DC’d 7 day screening phase followed by 8 week double blinded phase first 4 wks titration, last 4wks stable dose
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Gabapentin Backonja et al. JAMA. 1998 (ParkeDavis) 232 pts screened, 165 pts eligible and randomized; 84 gabapentin, 81 placebo primary endpoint: 11 point Likert scale (0, no pain; 10 worst) secondary endpoints: McGill pain questionnaire, weekly sleep interference score, pts global impression of change. clinician’s global impression of change
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Gabapentin Backonja et al. JAMA. 1998 (ParkeDavis) 56pts (67%) received 1200 mg tid (3600mg) 70/84 (83%) gabapentin completed study 7 (8%) withdrew from adverse effects 65/81 (80%) placebo completed study 5 (6%) withdrew form adverse effects Differences were significant at the end point for the mean pain score, mean sleep interference score, total pain, visual analog score, and the present pain intensity score
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Gabapentin Backonja et al. JAMA. 1998 (ParkeDavis) ~60% (47/79) had much/mod improvement on the pts global impression of change scale versus 33% (25/76) in the placebo group Mean daily pain score in the gabapentin group decreased from 6.4 at baseline to 3.9 at 8 weeks (p<0.001) versus 6.5 to 5.1 on placebo Well tolerated only 7 pts withdrew from side effects (dizziness and somnolence)
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Gabapentin Backonja et al. JAMA. 1998 (ParkeDavis) 6.4 to 3.9 vs 6.5 to 5.1 for ~$396/mo (NCBH) for 3600 mg/day in 300mg tabs
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Mexilitine Stracke et al. Diabetes Care 1992 Multicenter, RCT 100 patients with score of at least 25% VAS 95 pts qualified excluded other neuropathies, ETOH abuse, CHF, MI<3mos, arrhythmias Cr>1.5mg/dl, cirrhosis, hepatitis 1 week prior all DN meds stopped acetaminophen up to 2500mg/day allowed 1st 3-weeks dose titrated 75 to 225mg tid Last 3-weeks dose remained fixed
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Mexilitine Stracke et al. Diabetes Care 1992 Endpoints: McGill pain questionnaire, visual analog score, and acetaminophen use Mexilitine did not have significant benefit regarding the overall criteria (p=0.06), BUT by subgroup analysis mexilitine was effective for stabbing, heat, burning and formication ( p=0.02, p=0.01, p=0.01, and p=0.04) formication- parathesia sensation of small insects creeping under the skin
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Mexilitine Stracke et al. Diabetes Care 1992 Acetaminophen consumption did not differ mexilitine at 225mg/day was not significant 450mg/day favorable effects in subgroups, 675mg/day minor improvement over 450mg Side effects more common in high doses GI upset, CNS symptoms No effect on ECG intervals
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Mexilitine Stracke et al. Diabetes Care 1992 Mexilitine trended toward global improvement but not significant EXCEPT in stabbing, heat, burning, and formication versus placebo Greater improvement if two or more symptoms were involved
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Mexilitine Oskarsson et al. Diabetes Care 1997 Similar study which compared three doses of mexilitine 250mg, 450mg, and 675mg 126 pts, 95 to mexilitine, 31 to placebo Three week study, 1st wk dose increased No significant reduction in daytime pain or global assessment of efficacy In the 675mg group, Significant reduction in nighttime pain and sleep disturbances (p=0.029 and p=0.046)
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Tramadol (Ultram) Harati et al. Neurology 1998 Multicenter, RCT 131 pts with glyc Hgb <14%, moderate pain excluded severe depression, CrCl<30ml/min, Hx of narcotic or ETOH abuse, or evidence of ulcerations, amputations, and joint deformities Screening phase followed by a 42 day double-blind treatment phase tricyclics and anticonvulsants DC’d 21days prior and no other analgesics permitted
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Tramadol (Ultram) Harati et al. Neurology 1998 Dose titrated from 50mg/day to 200mg/day by day 10, maximal dose of 400mg/day by day 28, and the dose remained fixed for the last for the last 14 days Endpoint: 5 point Likert Scale (0, none; 4,worse) Evaluated day 1, 14, 28, and 42 Pain relief rating scale relative to end of the washout period ( -1 worse; 0 none; ...4 complete)
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Tramadol (Ultram) Harati et al. Neurology 1998 131 patients randomized Tramadol (n=65) 63 followed up, 43 completed study 9 withdrew due to side effects 9 withdrew from treatment ineffectiveness Placebo (n=66) 64 followed up, 39 completed study 1 withdrew from side effects 22 withdrew from treatment ineffectiveness
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Tramadol (Ultram) Harati et al. Neurology 1998 Baseline on pain intensity scale (0- 4) tramadol 2.5 vs placebo 2.6 After 42 days tramadol 1.4 vs placebo 2.2 (p<0.001) Average dose of tramadol 210 mg/day On the pain relief scale: tramadol averaged 2.1 (moderate relief) placebo averaged 0.9 (slight relief) (p<0.001)
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Tramadol (Ultram) Harati et al. Neurology 1998 Secondary endpoints showed significant improvement in the quality of life and improved social and physical functioning. No difference in sleep Adverse effects: nausea (23%), constipation (21.5%), headache (16.9%), and somnolence (16.9%)
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Capsaicin Donofrio et al. Archives of Int Med 1991 Multicenter, double-blind, vehicle-controlled 227 pts with glyc Hgb<11%, mod-severe pain No alterations in diabetic neuropathy medications Pain assessed by a physician global evaluation (6 point scale) and a visual analog scale Capsaicin 0.075% topically QID aspirin, acetaminophen, and ibuprofen allowed as needed for burning from the cream
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Capsaicin Donofrio et al. Archives of Int Med 1991 227 patients randomized Capsaicin n=138 121 (88%) completed the first two-week visit 38 pts failed to complete the study at 8 weeks 18 from adverse effects, 7 poor compliance Placebo n=139 131 (94%) completed the first two-week visit 20 pts failed to complete the study at 8 weeks 5 from adverse effects, 6 poor compliance
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Capsaicin Donofrio et al. Archives of Int Med 1991 Capsaicin had a greater number of improved pts at 2, 4, 6, and 8 weeks (p<0.05) by the physician global evaluation Also, pts improved over the first 6-weeks by the visual analog scale and continued to be significant at 8 weeks (p=0.014) At 8 weeks Capsaicin decreased pain by 40% from baseline versus 28% in placebo (p=0.014)
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Capsaicin Donofrio et al. Archives of Int Med 1991 Based on intention to treat analysis, the measurements pooled from the pts who completed the first visit (2 weeks) were still significant, BUT when including pts who withdrew prior to the first visit (<2 weeks) the results were not significant (p=0.06)
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Capsaicin Donofrio et al. Archives of Int Med 1991 Side effects more common in Capsaicin group. 108 pts vs 41 pts in the placebo. Included burning, cough, irritation, and rash were the most common 10% in capsaicin group and 16% in placebo added or increased other DN meds despite study protocol
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Alternative Therapies Electrical Spinal Cord Stimulation 10 pts who failed conventional treatment had a thoracolumbar epidural electrode placed random order of placebo stimulator versus electrical stimulator evaluated by a visual analog scale and exercise tolerance by treadmill. 8/10 had statistically significant relief
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Alternative Therapies Acupuncture 46 pts treated with six courses of acupuncture over 10 weeks 77% showed significant improvement.
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Possible Future Therapies Aldose reductase inhibitors: inhibit aldose reductase, the rate limiting step in the formation of sorbitol in the polyol pathway used in some countries for many years
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Possible Future Therapies A meta-analysis evaluated tolrestat, a newer and better tolerated ARI 3 RCTS, total 738 pts endpoint based on NCV, not clinical symptoms after 24 to 52 weeks, pts had a reduced risk for developing nerve function loss vs placebo, BUT when stratified according to baseline NCV there was NO statistically significant difference. Recommend more studies.
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Possible Future Therapies Nerve Growth Factors: Apfel et al. Published first RCT in 1998 250 pts, subcutaneous recombinant human nerve growth factor 3xweek for 6 months Significant improvement in three endpoints the sensory component of the neurological exam two quantitative sensory tests subjects impression of improvement NGFs may be effective, current studies ongoing
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Prevention of Foot Complications Patients should be instructed to: Keep their feet clean and dry at all times Never walk barefoot Avoid high impact exercise (esp w/deformities) check water temperature wear properly fitting shoes (athletic shoes or special orthotic footwear if necessary inspect their feet daily for calluses, infections, abrasions, or blisters
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Prevention of Foot Complications At each office visit the physician should: inspect the feet, this reinforces the importance of foot care to patients manage any ulcer, infections, or deformities aggressively have a low threshold for referral to a podiatrist
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Prevention of Foot Complications Foot care is important. An article in Diabetes Care presented the following: A study of 239 diabetics with foot ulcers 62% were classified as neuropathic vs 38% ischemic by clinical exam. 60% of the ischemic group also had neuropathy Diabetics have an age adjusted rate of amputations 15 times that of non-diabetics Three year survival after amputation was 50% Estimated >50% of amputations can be prevented
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Summary Diabetic neuropathy is common up to 40-50% over a 10-25 year span The DCCT proved tight control can prevent neuropathy by 57-69% at 5yrs Once a patient develops neuropathy, there are few treatments proven to be effective Foot care is essential in preventing neuropathic complications
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Neurology. 1987. Of the 29 pts, 17 were men, median age 57, diabetes for 11 years, .... Neurology 1
Neurology. 1987. Of the 29 pts, 17 were men, median age 57, diabetes for 11 years, .... Neurology 1998. Dose titrated from 50mg/day to 200mg/day by day 10, ...
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