Diabetic Neuropathy: An approach to the clinical management

1
Diabetic NeuropathyAn 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 ofPeripheral 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 (Charcots 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 Hgb9.0.
• 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 (plt0.001)
• 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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PreventionThe 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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PreventionThe Diabetes Control and Complications
Trial NEJM 1993

• Two cohorts
• Primary prevention cohort (n726) type 1 for
  1-5yrs, without retinopathy and urinary albumin
  lt40mg/24hrs
• Secondary prevention cohort (n715) type 1 for
  1-15 yrs, with mild to moderate retinopathy and
  urinary albuminlt200mg/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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PreventionThe 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 lt180mg/dl
• a weekly 3AM glucose gt65
• a monthly Hgb A1c lt6.05
• Conventional therapy consisted on 1 to 2
  injections a day

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PreventionThe 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, p0.006) and the secondary
  prevention cohort by 57 (7 vs 16, plt0.001)
• Risks severe hypoglycemic episodes were 3x
  greater in the intensive therapy group.

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DCCT
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PreventionKumamoto StudyDiabetes 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 (plt0.05)
• 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 ngt46

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Tricyclic AntidepressantsMax 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 AntidepressantsMcQuay et al.
Pain. 1996

• Meta-analysis of RCTs from 1950-1994
• 13 trials reviewed for Diabetic Neuropathy
• main outcome was 50 decrease in pain
• n13 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 AntidepressantsMcQuay 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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SSRIsSindrup 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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SSRIsSindrup 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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SSRIsSindrup et al. Pain. 1990

• Results
• Median VAS (max 500)
• 141 placebo vs 85 paroxetine (p0.0039)
• 141 placebo vs 37 imipramine (plt 0.00005)
• Median neuropathy score ( max 12)
• 5.75 placebo vs 3.75 paroxetine (p0.0121)
• 5.75 placebo vs 1.97 imipramine (p0.0002)

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SSRIsSindrup et al. Pain. 1990

• Results showed significant improvement with
  paroxetine over placebo BUT Imipramine was
  significantly better than paroxetine on both
  scales (p0.0007 and p0.0071)
• drug levels did not correlate with response
• only took 4 to 5 days to reach maximal effect

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SSRIs and TricyclicsMax 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 TricyclicsMax 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 TricyclicsMax 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 TricyclicsMax 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 (p0.03)

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AnticonvulsantsMcQuay 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 gt11, CrCllt60ml/min
• only stable dose of SSRI allowed others DCd
• 7 day screening phase followed by 8 week double
  blinded phase
• first 4 wks titration, last 4wks stable dose

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GabapentinBackonja 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. clinicians global impression of change

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GabapentinBackonja 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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GabapentinBackonja 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
  (plt0.001) versus 6.5 to 5.1 on placebo
• Well tolerated only 7 pts withdrew from side
  effects (dizziness and somnolence)

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GabapentinBackonja 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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MexilitineStracke 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,
  MIlt3mos, arrhythmias Crgt1.5mg/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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MexilitineStracke 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 (p0.06), BUT by
  subgroup analysis mexilitine was effective for
  stabbing, heat, burning and formication ( p0.02,
  p0.01, p0.01, and p0.04)
• formication- parathesia sensation of small
  insects creeping under the skin

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MexilitineStracke 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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MexilitineStracke 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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MexilitineOskarsson 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 (p0.029
  and p0.046)

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Tramadol (Ultram)Harati et al. Neurology 1998

• Multicenter, RCT
• 131 pts with glyc Hgb lt14, moderate pain
• excluded severe depression, CrCllt30ml/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 DCd 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 (n65)
• 63 followed up, 43 completed study
• 9 withdrew due to side effects
• 9 withdrew from treatment ineffectiveness
• Placebo (n66)
• 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 (plt0.001)
• Average dose of tramadol 210 mg/day
• On the pain relief scale
• tramadol averaged 2.1 (moderate relief)
• placebo averaged 0.9 (slight relief) (plt0.001)

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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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CapsaicinDonofrio et al. Archives of Int Med
1991

• Multicenter, double-blind, vehicle-controlled
• 227 pts with glyc Hgblt11, 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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CapsaicinDonofrio et al. Archives of Int Med
1991

• 227 patients randomized
• Capsaicin n138
• 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 n139
• 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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CapsaicinDonofrio et al. Archives of Int Med
1991

• Capsaicin had a greater number of improved pts at
  2, 4, 6, and 8 weeks (plt0.05) 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 (p0.014)
• At 8 weeks Capsaicin decreased pain by 40 from
  baseline versus 28 in placebo (p0.014)

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CapsaicinDonofrio 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 (lt2 weeks) the results were not
  significant (p0.06)

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CapsaicinDonofrio 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 gt50 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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