Diabetic Peripheral Neuropathy Charles E. Argoff, MD
Disclosure Consultant/Independent Contractor: Boehringer Ingelheim, Grünenthal Pharmaceuticals, Depomed, Jazz Pharmaceuticals, plc, Insys Pharmaceuticals, Shinogi Pharmaceuticals Grant/Research Support: Endo Pharmaceuticals, Forest Laboratories, Lilly USA LLC, NeurogesX, Pfizer Inc. Honoraria: Boehringer Ingelheim,, Depomed Endo Pharmaceuticals, Forest Laboratories, Janssen, Jazz, King, Lilly USA LLC, NeurogesX, Nuvo Research, Pfizer Inc. Sanofi-Aventis, US, LLC Speakers Bureau: Endo Pharmaceuticals, Forest Laboratories, Janssen Pharmaceuticals, Inc. Lilly USA LLC, Pfizer Inc., NeurogesX
Learning Objectives Recognize neuropathic pain conditions (distinguish from nociceptive pain) and the consequences of under-treatment (knowledge) Apply on evidence-based strategies to provide appropriate primary interventions that can ameliorate chronic pain associated with DPN distal to the knee (competence, performance) List secondary strategies to further mitigate neuropathic pain in DPN (competence, performance) Describe the recommendations for monitoring and modifying pain treatments (knowledge, competence)
Lecture Overview Etiology Morbidity Treatments Summary
Epidemiology Diabetic polyneuropathy (DPN) is the most common complication and greatest source of morbidity in people with diabetes. According to the CDC, 60-70% of patients with diabetes (6.1 million) develop DPN.1 – 16.2% of type 2 diabetic patients present with DPN.2 – However, only 1 in 4 patients are diagnosed.3
Diabetes is the most common cause of polyneuropathy in the U.S. 1: 2011 National Diabetes Fact Sheet, CDC 2: Daousi et al 2004 Diabet Med 3: Diabetes Information Library
Epidemiology People whose diabetes is not well controlled have the highest risk of developing DPN Other risk factors are unclear –Some people have diabetes for more than 20 years without complications, while others who are considered “prediabetic” already show signs of DPN
Morbidity DPN has a major impact on quality of life. – Decreased activity – Significantly increased morbidity – Increased medication usage and burden on healthcare system – Estimated to cost up to $13.7 billion dollars and contributes to 27% of direct medical costs in the U.S.4
Progression of DPN is associated with serious health problems including amputation. – Type 2 diabetes is the most common cause of atraumatic limb loss in the U.S.1 1: 2011 Diabetes Fact Sheet. CDC. 4: Gordois et al 2003 Diabetes Care
Pain Pain is common in DPN, although not all patients with DPN experience pain7 –Often described as burning, pins and needles, tingling, shooting, deep aching, jabbing, stabbing, or cold –Can be provoked or worsened with activity –Can disrupt sleep –Allodynia may occur
7: Kuritzky 2010 J Fam Pract
Etiology DPN is considered a microvascular complication of type 2 diabetes –Nerve dysfunction is secondary to disease of the microvasculature (vasa nervorum) –Similar to retinopathy and nephropathy
Etiology Exact pathogenesis of DPN is unknown Possible causes:6 – Nerve hypoxia/ischemia – Oxidative stress – Metabolic etiologies
• Accumulation of fructose or sorbitol • L-carnitine deficiency • Nerve growth factor deficiency • Myoinositol deficiency • Impaired fatty acid and prostaglandin metabolism • Excessive glycogen accumulation
5: Tesfaye et al 1992 Diabetologia 6: Harati 1997 Neurol Clin
7 Diagnosing DPN
Most common form: distal symmetrical polyneuropathy –Sensory or sensorimotor –Large fibers and/or small fibers are involved. •Sensory symptoms normally precede motor, and smallfiber dysfunction occurs prior to large-fiber
–Stocking-glove pattern 7: Kuritzky 2010 J Fam Pract
Diagnosing DPN Large-fiber neuropathy –Painless paresthesias and impairment of vibration8 –Can also include proprioceptive dysfunction, altered touch and pressure sensation, and loss of ankle reflex8 –Abnormal nerve conduction studies8 –Associated with cardiovascular risk factors9 • Male sex, obesity, elevated cholesterol, smoking 8: Bansal et al 2006 Postgrad Med J 9: Elliot et al 2009 Diabetes Care
Diagnosing DPN Small-fiber neuropathy8 –Patients experience burning pain –Loss of pain and temperature sensations –Normal nerve conduction studies –Epidermal nerve fiber analysis emerging as diagnostic tool –Quantitative sensory testing (QST) 8 Bansal et al 2006 Postgrad Med J
Assessment In patients with DPN, diabetes may co-occur with other causes of neuropathy –In one study, 53% of type 2 diabetes patients had one or more additional causes of neuropathy10 • Alcohol abuse • Neurotoxic medication • Vitamin deficiency • Renal failure 10: Gorson et al 2006 J Neurol Neurosurg Psychiatry
Assessment Tools Monofilament testing 128-Hz tuning fork
Monofilament Testing 5.07 Semmes-Weinstein (10-g) nylon monofilament test11 Test the monofilament on the patient’s hand so he/she knows what to anticipate Apply the monofilament perpendicular to the skin’s surface and use sufficient force to cause the filament to bend or buckle Duration should be approximately 1 second per site Avoid ulcers, calluses, scars, and necrotic tissue
11: National Diabetes Education Program
128-Hz Tuning Fork Set the prongs into motion, and place bottom of tuning fork on bony prominence of dorsal great toe Determine whether vibration sense is normal, impaired, or absent – Normal = patient feels vibration while it is vibrating – Impaired = patient feels vibration initially but stops feeling it prior to cessation of vibration of the tuning fork – Absent = no vibration felt
12: Meijer et al 2005 Diabetes Care
Further Testing Nerve conduction studies –Sensitive and specific for large-fiber dysfunction –NCS in DPN typically demonstrate demyelination and loss of axons –As mentioned earlier, NCS are normal in pure smallfiber neuropathy
7 Diagnostic Tips
Inquire about activities of daily living, sleep, depression, or obstacles to successful exercise Use a 128-Hz tuning fork to assess vibratory sensation, and a 5.07 Semmes-Weinstein monofilament to assess pressure sensation Kanji et al. JAMA 2010 Watch patients ambulate at each visit Investigate other causal or contributing factors 7 Kuritzky 2010 J Fam Pract
Assessment of Pain Use of validated pain rating scales can be helpful to assess both the presence and quality of pain Examples include –Leeds Assessment of Neuropathic Symptoms and Signs13 –Neuropathic Pain Scale14 –Neuropathic Pain Questionnaire15 –Brief Pain Inventory for Diabetic Peripheral Neuropathy16 13: Bennet et al 2001 Pain 14: Galer et al 1997 Neurology 1:5 Krause et al 2003 Pain 16: Zelman et al 2005 J Pain Symptom Manage
Treatment of DPN Glycemic control –There is a linear relationship between A1c levels and DPN7
Other risk factors –Educate patient about risks of obesity, smoking, hypertension, and hyperlipidemia • Tight regulation of blood pressure is as effective as glucose control at reducing microvascular aggregates17
7: Kuritzky et al 2010 J Fam Pract 17: UK Prospective Diabetes Study (UKPDS) Group 1998 Lancet
Treatment of DPN Two goals of therapy: – Treatment of symptoms – Treatment of underlying pathogenic mechanisms
Neuropathic pain is a heterogeneous condition, and treatment must be individualized – Outcomes of randomized controlled trials may not apply to a particular patient
Potential Treatments of Underlying Pathogenic Mechanisms Many have been studied, but none is currently FDA-approved for treating DPN Agents with promising results in clinical trials: – Alpha-lipoic acid – Acetyl-L-carnitine
Agents with disappointing results:
– Nerve growth factor – Vasodilators – Aldose reductase inhibitors – Angiotensin-converting enzyme (ACE) inhibitors – Vitamin E
Alpha-Lipoic Acid Not approved by FDA for treatment of DPN Clinical trials have shown reduction in symptom severity – SYDNEY 2: 181 patients treated with oral ALA 600 mg daily for 5 weeks 20 • Significant reduction in total symptom score compared to placebo • Higher doses (1200 or 1800 mg) provided similar rates of symptom relief • Adverse effects similar to placebo • No change in nerve conduction studies
– Meta-analysis of 4 trials (1258 patients) showed over 50% improvement in total symptom score compared to placebo after 3 weeks18 18 Ziegler et al 2004 Diabet Med.. 20 Ziegler et al 2006 Diabetes Care
Acetyl-L-Carnitine Not approved by FDA for treatment of DPN Deficient in the nerve fibers of patients with type 2 diabetes 2 clinical trials (1257 patients)21 – 1000 mg 3 times daily for 52 weeks – Showed an increase in sural nerve fibers and regeneration of nerve fiber clusters – Increased vibration perception and reduced pain, especially in those with high A1C levels (>8.5%) – No change in nerve conduction studies 21: Sima et al 2005 Diabetes Care
Treating the Symptoms of DPN Important to understand full scope of patient pain7 – Is depression or sleeplessness involved? – Tailoring treatment plan for pain relief and other symptoms will provide increased relief
Meaningful reduction of pain – Patients with chronic pain state that a 30% reduction in pain is meaningful22 – >50% reduction in pain is significant improvement22 7: Kuritzky 2010 J Fam Pract. 22: Argoff et al 2006 Mayo Clinic Proc
Treating the Symptoms of DPN Only 2 agents are approved by the FDA for treatment of painful DPN: – Duloxetine – Pregabalin
Other agents effective for DPN pain: – Tricyclic antidepressants – Gabapentin – Topical lidocaine – Certain opioids – Topiramate and other anticonvulsants 22: Argoff et al 2006 Mayo Clin Proc
Duloxetine Serotonin and norepinephrine reuptake inhibitor (SNRI) Shown to reduce pain by 50% in almost half of patients23 Not effective against numbness or tingling associated with DPN 23: Goldstein et al 2005 Pain
Pregabalin Alpha2-Delta Agonist/Calcium Channel Modulator Shown to reduce pain by >50% in 39% of patients (compared to 15% with placebo)24 Also improved sleeplessness associated with DPN
24: Richter et al 2005 J Pain
7 Symptom Treatment Options 1st Line Calcium channel alpha2-delta ligands – Gabapentina – Pregabalin
Serotonin-norepinephrine re-uptake inhibitors – Duloxetinea – Venlafaxine ER
Topical lidocaine
– 5% lidocaine patch
Tricyclic antidepressants – Secondary amines • Nortriptyline • Desipramine
– Tertiary amines
• Amitriptyline • Imipramine
aApproved by FDA for use in treatment of DPN
7 Symptom Treatment Options 1st Line Calcium channel alpha2-delta ligands – Gabapentin – Pregabalina
Serotonin-norepinephrine re-uptake inhibitors – Duloxetinea – Venlafaxine ER
Topical lidocaine
– 5% lidocaine patch
Tricyclic antidepressants – Secondary amines
2nd Line Opioid agonists – – – – –
Morphine Oxycodone CR Methadone Levorphanol Hydromorphone
Tramadol
• Nortriptyline • Desipramine
– Tertiary amines
• Amitriptyline • Imipramine aApproved by FDA for use in treatment of DPN
7 Symptom Treatment Options 1st Line Calcium channel alpha2-delta ligands – Gabapentin – Pregabalin
Serotonin-norepinephrine re-uptake inhibitors – Duloxetine – Venlafaxine ER
Topical lidocaine
– 5% lidocaine patch
2nd Line Opioid agonists – Morphine – Oxycodone CR – Methadone – Levorphanol – Hydromorphone Tramadol
3rd Line •
– – – – – –
• Nortriptyline • Desipramine
– Tertiary amines
• Amitriptyline • Imipramine
Carbamazepine Lamotrigine Oxcarbazepine Phenytoin Topiramate Valproic acid
•
Anti-depressants
•
Antiarrhythmic
•
Capsaicinoid
Tricyclic antidepressants – Secondary amines
Anticonvulsants
– Bupropion – Citalopram – Paroxetine – Mexiletine
– Topical capsaicin
aApproved by FDA for use in treatment of DPN
Dosing Suggestions for 1st Line Treatments7 Drug
Start Dose
Titration
Max Dose
Trial Duration
Nortriptyline, desipramine a
25 mg at bedtime
Increase by 25 mg daily every 3-7 days as tolerated
150 mg daily; if blood level of medication and metabolite is below 100 ng/mL (mg/mL), continue with caution
6-8 weeks with at least 2 weeks at maximum tolerated dose
Duloxetine
30 mg once daily
Increase to 60 mg once daily after one week
60 mg twice daily
4 weeks
Venlafaxine
3.75 mg once or twice daily
Increase by 75 mg each week
225 mg daily
4-6 weeks
Gabapentin a
100-300 mg at bedtime or 100-300 mg three times daily
Increase by 100-300 mg three times daily every 17 days as tolerated
3600 mg daily (1200 mg three times daily); reduce if impaired renal function
3-8 weeks for titration plus 2 weeks at maximum dosage
Pregabalin a
50 mg three times daily or 75 mg twice daily
Increase to 300 mg daily after 3-7 days, then by 150 mg/d every 3-7 days as tolerated
600 mg daily (200 mg three times daily or 300 mg twice daily); reduce if impaired renal function
4 weeks
Topical lidocaine 5% lidocaine patch
Maximum of 3 patches daily for a maximum of 12h
None needed
Maximum of 3 patches daily for a maximum of 12-18h
3 weeks
aConsider lower starting dosages and slower titration in geriatric patients.
Dosing Suggestions for 2nd Line Treatments7 Drug
Start Dose
Titration
Max Dose
Trial Duration
Morphine, oxycodone, methadone, levorphanol a,b
10-15 mg morphine every 4 h or as needed (equianalgesic dosages should be used for other opioid analgesics)
After 1-2 weeks, convert total daily dosage to longacting opioid analgesic and continue short-acting medication as needed
No maximum dosage with careful titration; consider evaluation by pain specialist at relatively high dosages (eg, 120-180 mg morphine daily; equianalgesic dosages should be used for other opioid analgesics)
4-6 weeks
Tramadolc
50 mg once or twice daily
Increase by 50-100 mg daily in divided doses every 3-7 days as tolerated
400 mg daily (100 mg four times daily); in patients older than 75 use 300 mg daily
4 weeks
aConsider lower starting dosages and slower titration in geriatric patients. bFirst-line only in certain circumstances
cConsider lower starting dosages and slower titration in geriatric patients; dosages given are for short-acting formulation.
Approach to Pharmacotherapy of DPN Pain 1. Select a first-line agent 2. If this medication confers no benefit at an adequate dose, or side effects are intolerable, switch to another first-line agent 3. If the first-line agent is only partially effective, add another first- or second-line agent 4. If first- and second-line agents are not adequate, consider adding a thirdline medication or referring to a Pain Management specialist  Patients may require a combination of several medications  In general, agents taken in combination should represent distinct pharmacologic classes
7 When to Avoid Medications
Medical Comorbidities
Glaucoma
Duloxetine,a tricyclic antidepressants
Cardiac disease
Tricyclic antidepressants
Hypertension
Duloxetine, tricyclic antidepressants
Renal insufficiency
Duloxetine,b gabapentin,c oxycodone CR,c pregabalin,c tramadold
Hepatic insufficiency
Duloxetine, oxycodone CR, tramadol
Respiratory depression
Oxycodone CR, tramadol
Falls or balance issues
Pregabalin, tricyclic antidepressants
Erectile dysfunction
Duloxetine, oxycodone CR, pregabalin, tricyclic antidepressants
Orthostatic hypotension
Duloxetine, oxycodone CR, tricyclic antidepressants aContraindicated in uncontrolled narrow-angle glaucoma
bAvoid if creatinine clearance <30 mL/min
cReduce dose if creatinine clearance <60 mL/min
dReduce dose if creatinine clearance <30 mL/min
7 When to Avoid Medications Psychiatric Comorbidities
Other Issues
Depression
Oxycodone CR, pregabalin
Anxiety
Gabapentin, oxycodone CR, tramadol
Potential for suicide
Duloxetine, gabapentin, oxycodone CR, pregabalin, tramadol, tricyclic antidepressants
Abuse potential
Oxycodone CR, tramadol
Drug Interactions
Duloxetine, tricyclic antidepressants
Weight gain
Pregabalin, tricyclic antidepressants
Edema
Gabapentin, pregabalin
aContraindicated in uncontrolled narrow-angle glaucoma
bAvoid if creatinine clearance <30 mL/min
cReduce dose if creatinine clearance <60 mL/min
dReduce dose if creatinine clearance <30 mL/min
Recommendations for Monitoring Symptomatic Therapy22 At each visit, it is important to ask the following questions to evaluate patient care: – Has the pain improved, stayed the same, or become worse? • To what degree? • Has anything changed that might have affected this? • Do you feel an impact on your physical and social functioning?
– Has the quality or type of pain changed? – Have you experienced any side effects? • What impact do they have? • How have you managed them?
– Are you satisfied with the treatment? • If not, what are your concerns?
22 Argoff et al 2006 Mayo Clin Proc
Summary DPN is a complicated syndrome Diagnosis of DPN requires careful history and physical examination, aided by the use of diagnostic tools – 128-Hz tuning fork – Monofilament testing Success in pain alleviation is considered to be a reduction of 30-50% and generally requires combination therapy – Duloxetine and pregabalin are currently the only drugs approved by the FDA for DPN pain – However, adjuvant analgesics are the mainstay of therapy – The tricyclic antidepressant and anticonvulsant groups are supported by the most extensive evidence – The selection of an adjuvant analgesic is often based on patient comorbidities and tolerability
• Frequent follow-up is needed to optimize therapy
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