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Treatment of diabetic neuropathy ARMAN TAHERI MD ANESTHETIST & PAIN SPECIALIST ASSISTNT PROFESSOR OF TUMS [email protected] 6/11/2010 ARMAN TAHERI MD 1 Treatment of diabetic neuropathy • • 6/11/2010 • ARMAN TAHERI MD ANESTHETIST & PAIN SPECIALIST ASSISTNT PROFESSOR OF TUMS • [email protected] ARMAN TAHERI MD 2 DCCT, UKPDS, and other studies: the central role of hyperglycemia in the pathogenesis of diabetic microvascular complications such as retinopathy, nephropathy, and neuropathy. The Diabetes Control and Complications Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 1995; 122:561 Both the incidence and severity of diabetic microvasculopathy are modulated by individual genotypes. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995; 38:869 Although the molecular basis of how hyperglycemia causes tissue injury is still being defined, two proposed mechanisms, both linked to what has been termed "oxidative stress," are the downstream impact of accumulation of sorbitol and advanced glycosylation end products. 6/11/2010 ARMAN TAHERI MD 3 In the USA:the most common cause of painful neuropathy is glucose intolerance.. Neuropathy can be one of the earliest manifestations of DM. DNP can even precede the development of serum abnormalities. 2 h glu. tolerance testing= more sensitive method of detecting DM causes several types of neuralgia: small fibers are the most common form. Diabetic small fiber neuropathy: burning feet. Diabetic autonomic features: impaired thermoregulation & sweet production. Neuropaty and vascular insufficiency: main risk factors for foot ulceration and amputation. In DPN: Both myelinated and unmyelinated fibers degeneration. Demyelination Endoneural vascular resistance, autoimmune inflammation→→→nerve damage. Proximal motor neuropathies(intraneural vasculitis)=diabetic amyotrophy Autonomic neuropathies, nerve ischemia (acute painful DPN),hypoglycemic neuropathy, treatment induced neuropathy, distal motor neuropathy, Multineuropathy multiplex=multifocal neuropathies=local loss of function in several peripheral nerrves. 6/11/2010 ARMAN TAHERI MD 4 • Peripheral and autonomic neuropathies are a major cause of morbidity in patients with diabetes mellitus. There are three main elements in the treatment regimen: • Glycemic control • Foot care • Treatment of pain 6/11/2010 ARMAN TAHERI MD 5 GLYCEMIC CONTROL The most important treatment for the prevention of diabetic neuropathy is optimal glucose control. In the Diabetes Control and Complications Trial (DCCT), the occurrence of diabetic neuropathy was reduced by 60 percent over a 10-year period with rigorous blood glucose control in patients with type 1 diabetes. Similar findings were noted in the Stockholm Diabetes Intervention Study [. Reichard, P, Berglund, B, Britz, A, et al. Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years. J Intern Med 1991; 230:101 The effect of hyperglycemia on disease progression appears to be dosedependent: in the Oslo Diabetes study each 1 percent rise in hemoglobin A1c (HbA1c) values was associated with a 1.3 m/sec slowing of nerve conduction at eight years. Amthor, KF, Dahl-Jorgensen, K, Berg, TJ, et al. The effect of 8 years of strict glycaemic control on peripheral nerve function in IDDM patients: The Oslo Study. Diabetologia 1994; 37:579. 6/11/2010 ARMAN TAHERI MD 6 Established neuropathy Several small, mostly uncontrolled studies suggest that neuropathic symptoms may improve with intensive antidiabetic therapy. Boulton, AJ, Drury, J, Clarke, B, Ward, JD. Continuous subcutaneous insulin infusion in the management of painful diabetic neuropathy. Diabetes Care 1982; 5:386 In the DCCT, after follow-up for five years, patients with possible or definite clinical neuropathy at baseline, treated with intensive glycemic control, had an increase in nerve conduction velocity . Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995; 38:869 The American Diabetes Association in 2005 recommended that the first step in the management of patients with symptomatic diabetic polyneuropathy should be to aim for stable and optimal glycemic control .ARMAN Boulton, AJ, Vinik, AI, Arezzo, JC, et al. Diabetic neuropathies: a statement by the American 6/11/2010 TAHERI MD 7 Diabetes Association. Diabetes Care 2005; 28:956 FOOT CARE • We combine good glucose control with foot care. • Patients need to inspect their feet for the presence of dry or cracking skin, fissures, plantar callus formation, and signs of early infection between the toes and around the toe nails daily. • Regular foot examinations by the physician to detect early neuropathy are also an essential component of the treatment of diabetic patients. • Once a patient has diabetic neuropathy, foot care is even more important to prevent ulceration, infection, and amputation. 6/11/2010 ARMAN TAHERI MD 8 PAINFUL DIABETIC NEUROPATHY Only a small fraction of patients with DPN have painful symptoms. Patients with painful DPN should be treated with a systematic, stepwise approach. Boulton, AJ, Vinik, AI, Arezzo, JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005; 28:956. Before initiating therapy, it is important to confirm that the pain is due to neuropathy. 6/11/2010 ARMAN TAHERI MD 9 Diagnosis The onset of severe pain in the feet and lower limbs can be very distressing and disabling. A disc lesion ? if the pain has developed : to recent trauma or its onset is abrupt & is more often unilateral than pain related to peripheral neuropathy. (EMG&NCV) • peripheral vascular disease? The physical examination may be helpful (pulse touch) • Several clues that the patient has neuropathic pain are the location of pain (feet more than calves), the quality of the pain, and the timing of pain (present at rest, improves with walking). • It is also important to confirm that the pain is due to diabetic polyneuropathy, and nondiabetic etiologies should be excluded. 6/11/2010 ARMAN TAHERI MD 10 Spontaneous resolution • Once the diagnosis of painful DPN is established, reasured that the condition is usually self-limited. In a prospective study of 29 patients, for example, pain remitted in 16 within 12 months. Young, RJ, Ewing, DJ. Clarke, BF. Chronic and remitting painful diabetic polyneuropathy: correlations with clinical features and subsequent changes in neurophysiology. Diabetes Care 1988; 11:34 • Remission was more likely if :the sudden onset of symptoms after metabolic change (either an episode of diabetic ketoacidosis or occasionally an improvement in glycemic control), when the duration of diabetes was relatively short, or when marked weight loss preceded the onset of pain . Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995; 38:869 • The mechanisms responsible for the resolution of pain are not understood. Proposed mechanisms:1.altered perception of pain, 2.further deterioration of the nerve so that it no longer responds to stimulation (so that the patient is at even greater risk from trauma), 3. improvement in nerve function. 6/11/2010 ARMAN TAHERI MD 11 PAIN CONTROL • Duloxetine and pregabalin are the only drugs formally approved by the European Medicines Agency and by the US Food and Drug Administration (FDA) for the treatment of painful diabetic polyneuropathy. • Smaller clinical trials confirm the efficacy of several other drugs or classes of drugs, including tricyclic agents, gabapentin, capsacin, mexilentine, opioids, and antioxidants. • While none of these compounds are approved by the US FDA for the treatment of painful DPN, they are commonly used in clinical practice for that purpose. • A panel of pain specialists published consensus guidelines in 2006 for the treatment of painful DPN . The following observations were made regarding agents with clinical trial evidence of effectiveness in the treatment of painful diabetic polyneuropathy : 6/11/2010 ARMAN TAHERI MD 12 . Argoff, CE, Backonja, MM, Belgrade, MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc 2006; 81:S12 PAIN CONTROL • First-tier agents, supported by evidence from two or more randomized clinical trials, were tricyclics as a class, duloxetine, pregabalin, and controlled-release oxycodone • Second tier agents, supported by evidence from one randomized clinical trial, were carbamazepine, gabapentin, lamotrigine, tramadol, and extended-release venlafaxine • Topical therapies, supported by evidence from one randomized clinical trial or evidence from studies of other painful neuropathies, included capsaicin and lidocaine • We typically begin treatment of painful diabetic polyneuropathy (DPN) with a tricyclic agent, duloxetine, gabapentin, or pregabalin . 6/11/2010 ARMAN TAHERI MD 13 PAIN CONTROL • Tricyclic drugs Many tricyclic antidepressant drugs (but not selective serotonin reuptake inhibitors) have been found in doubleblind, randomized controlled trials to improve symptoms in patients with painful DPN, and a systematic review found that tricyclic antidepressants were more effective for short-term pain relief than traditional or newer generation As an example, a placebo-controlled, double-blind, randomized, cross-over trial anticonvulsants . compared amitriptyline, desipramine and fluoxetine with placebo. Both tricyclic drugs •were Kvinesdal, B, Molin, J, Froland, Gram, LF.to Imipramine treatment of painfulthe diabetic neuropathy. JAMA 1984; equally effective and A, superior fluoxetine or placebo; benefit was noted 251:1727. within two continued toofincrease weeks.ofDesipramine had somewhat • Wong, MC,weeks Chung, and JW, Wong, TK. Effects treatmentsatforsix symptoms painful diabetic neuropathy: systematic review. BMJ 2007; 335:87 fewer side effects than amitriptyline, particularly dry mouth . The average effective dose, titrated over six weeks to achieve control of symptoms, was 111 mg/day for 105:Altering mg/day forthe amitriptyline, 40 mg/day for There was no •desipramine, Tricyclics centraland perception offluoxetine. pain &sooner correlation between effect relief of pain, dosage, plasma drug suggesting therapeutic (within sixorweeks) andconcentrations, at lower doses than that the clinical response and tolerability of side effects are the best guides to dose is typical when these drugs are given for the treatment of titration. depression. Max, MB, Lynch, SA, Muir, J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326:1250. 6/11/2010 ARMAN TAHERI MD 14 PAIN CONTROL • We use either amitriptyline or desipramine in patients with severe pain. This class of drugs can be added to pregabalin or anticonvulsants but not to duloxetine. The starting dose of desipramine is 25 mg, taken at bedtime. The dose can be increased to a maximum of 200 mg/day over a few weeks. • We frequently substitute nortriptyline for amitriptyline if anticholinergic side effects are a problem. • Amitriptyline and nortriptyline are both contraindicated in patients with cardiac disease. In these patients, we consult with the patient's cardiologist and give either doxepin, the least cardiotoxic tricyclic antidepressant, or antidepressant drugs unrelated to the tricyclic family such as trazodone or paroxetine . • • Davis, JL, Lewis, SB, Gerich, JE, et al. Peripheral diabetic neuropathy treated with amitriptyline and fluphenazine. JAMA 1977; 238:2291. Sindrup, SH, Gram, LF, Brosen, K, et al. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 1990; 42:135. • Common side-effects of tricyclic antidepressants include dry mouth and somnolence. We recommend initiating tricyclic therapy with a dose at bedtime. Urinary retention may occur, especially in men with enlarged prostates. 6/11/2010 ARMAN TAHERI MD 15 PAIN CONTROL Duloxetine : • A dual serotonin and norepinephrine reuptake inhibitor. • In three 12-week randomized, blinded, controlled trials involving 1102 subjects. Pain improvement occurred significantly more frequently with duloxetine 60 or 120 mg daily than with placebo (47 and 48 percent, versus 29 percent with placebo). Pain improvement was noted as early as the first week of treatment and continued for the duration of the studies. Duloxetine showed rapid onset of action and sustained benefit, and it was also effective in relieving pain at night. The 120 mg daily dose was not as well tolerated as 60 mg daily, although both were beneficial. Lunn, MP, Hughes, RA, Wiffen, PJ. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev 2009; :CD007115 6/11/2010 ARMAN TAHERI MD 16 PAIN CONTROL • While duloxetine was more effective than placebo, all three trials were of relatively short duration, and the long-term effectiveness and safety of duloxetine is uncertain. In addition, there are no trials comparing the effectiveness of duloxetine with other drugs for the treatment of DPN. Furthermore, in clinical trials evaluating painful DPN, duloxetine treatment resulted in modest increases in fasting plasma glucose . Duloxetine (Cymbalta) for diabetic neuropathic pain. Med Lett Drugs Ther 2005; 47:67. • The most common reported side effects : Nausea, somnolence, dizziness, decreased appetite, and constipation. Hot flashes and erectile dysfunction (infrequently). • Because nausea is common: to take the drug on a full stomach. Duloxetine should not be taken with other serotonin or norepinephrine uptake inhibitors but can be combined with anticonvulsant therapy. 6/11/2010 ARMAN TAHERI MD 17 PAIN CONTROL Anticonvulsants: • Both newer (gabapentin, pregabalin) and older (carbamazepine) anticonvulsants are useful for treating painful DPN 6/11/2010 ARMAN TAHERI MD 18 PAIN CONTROL Gabapentin • In three randomized, double-blind studies gabapentin significantly reduced pain and sleep interference and improved mood and quality of life. The major side effects were dizziness and confusion. • A randomized study that compared gabapentin with amitriptyline found no difference between the two drugs with regard to pain relief. Gabapentin is more expensive than amitriptyline, but it may be better tolerated at the doses required to treat neuropathy. We typically use gabapentin 300 to 600 mg three times daily; the drug can be titrated slowly to high doses of up to 900 mg four times daily.Backonja, M, Beydoun, A, Edwards, KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. A • randomized controlled trial. JAMA 1998; 280:1831. Morello, CM, Leckband, SG, Stoner, CP, et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med 1999; 159:1931 6/11/2010 ARMAN TAHERI MD 19 PAIN CONTROL Pregabalin : Alpha2-delta ligand that is structurally related to gabapentin but without known activity at GABA or benzodiazepine receptors. Presynaptic inhibitor of the release of excitatory neurotransmitters (glutamate, substance P, and calcitonin gene-related peptide (CGRP) ). • • Dooley, DJ, Mieske, CA, Borosky, SA. Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett 2000; 280:107. Fehrenbacher, JC, Taylor, CP, Vasko, MR. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 2003; 105:133. 6/11/2010 ARMAN TAHERI MD 20 PAIN CONTROL • The effectiveness of pregabalin for the treatment of painful DPN was evaluated in a pooled analysis of seven randomized clinical trials, of 5 to 13 weeks duration, with a total of 1510 patients in the intention-to-treat population. The following observations were reported: • Freeman, R, Durso-Decruz, E, Emir, B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care 2008; 31:1448. I) Compared with placebo, pregabalin treatment at total daily doses of 150, 300, and 600 mg : statistically significant reduction in the mean pain score, the primary end point of all included studies. The median time to a sustained one point improvement in pain score for pregabalin (at 150 mg, 300 mg, and 600 mg) and placebo was 4, 5, 13, and 60 days, respectively. II) With higher doses, there was a clear dose-related increase in effectiveness, and an increase in the incidence of most adverse events. III) The most common adverse events: dizziness, somnolence, and peripheral edema. The incidence of clinically meaningful weight gain (defined as a ≥7 percent weight increase from baseline to end point) was significantly higher for patients assigned to pregabalin than for those assigned to placebo (2.0 to 3.9 percent versus 0.7 percent). 6/11/2010 ARMAN TAHERI MD 21 PAIN CONTROL Pregabalin: • Blurred vision (more common with pregabalin than with placebo) . There are no trials comparing pregabalin with other drugs for the treatment of painful diabetic peripheral neuropathy. Pfizer Lyrica will undergo phase IV vision, nerve impairment studies. The Pink Sheet 2005; 67:7. • Pregabalin is started at 50 mg twice a day (total 100 mg/day) and is then slowly increased to 150 mg two times a day (total 300 mg/day, the maximum dose approved by the FDA for diabetes-associated neuropathic pain) over a week or more. It can also be administered 100 mg three times a day. • Pregabalin can cause sedation and confusion. • (habit forming ) 6/11/2010 ARMAN TAHERI MD 22 PAIN CONTROL Other anticonvulsants Lamotrigine (200 to 400 mg/day) has been reported to attenuate the pain of DPN, and carbamazepine may also have benefit. • • Eisenberg, E, Lurie, Y, Braker, C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001; 57:505. Rull, JA, Quibrera, R, Gonzalez-Millan, H, Lozano, CO. Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol): double blind crossover trial. Diabetologia 1969; 5:215. • Common side effects of carbamazepine : dizziness, nausea, and skin rash, and in rare cases, leukopenia; • Monthly monitoring of blood counts for three months after starting carbamazepine treatment is suggested. The evidence regarding benefit of topiramate for painful DPN is equivocal. • • Raskin, P, Donofrio, PD, Rosenthal, NR, et al. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology 2004; 63:865. Thienel, U, Neto, W, Schwabe, SK, Vijapurkar, U. Topiramate Diabetic Neuropathic Pain Study Group. Topiramate in painful diabetic polyneuropathy: findings from three double-blind placebo-controlled trials. Acta Neurol Scand 2004; 110:221 6/11/2010 ARMAN TAHERI MD 23 PAIN CONTROL Capsaicin cream : Many hot peppers . Analgesia through local depletion of substance P. Available in a cream for topical application. In randomized trials in patients with DPN, capsaicin has been associated with modest, but statistically significant improvement in symptoms, the ability to do daily tasks, and in physician global assessment compared with placebo. • • Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Capsaicin Study Group. Diabetes Care 1992; 15:159. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. The Capsaicin Study Group. Arch Intern Med 1991; 151:2225. • We add topical capsaicin if neuropathic pain persists with maximal medical treatment. Our experience agrees with the literature indicating that two-thirds of diabetic patients with painful neuropathy respond to this combination . • . Feldman, EL, Stevens, MJ, Greene, DA. Treatment of diabetic neuropathy. In: Advances in Endocrinology and Metabolism, Mazzaferri, EL, Bar, RS, Kreisberg, RA (Eds), Mosby Year Book, Chicago 1994, p.393. • Capsaicin (0.075 percent) is applied topically four times daily over painful areas. Local burning and skin irritation can occur, but this becomes less of a problem with continued use 6/11/2010 ARMAN TAHERI MD 24 PAIN CONTROL Anesthetic drugs : Pain despite the above regimen: mexiletine ; A medium dose of 450 mg/day appears to be effective while causing few side effects. • Dejgard, A, Petersen, P. Kastrup, J. Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet 1988; 1:9. Stracke, H, Meyer, UE, Schumacher, HE. Federlin, K. Mexiletine in the treatment of diabetic neuropathy. Diabetes Care 1992; 15:1550. • An open-label trial found that application of up to four lidocaine patches (5 percent) for up to 18 hours per day significantly improved pain and quality of life ratings in 56 patients with painful DPN. Barbano, RL, Herrmann, DN, Hart-Gouleau, S, et al. Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy. Arch Neurol 2004; 61:914. 6/11/2010 ARMAN TAHERI MD 25 PAIN CONTROL • Alpha-lipoic acid The pathogenesis of DPN : increased oxidative stress. Antioxidants : to diminish oxidative stress, improve the underlying pathophysiology of neuropathy, and reduce pain. • Alpha-lipoic acid (ALA), a potent antioxidant, has been associated with benefit for symptomatic DPN in several prospective, placebo-controlled studies • In the SYDNEY 1 trial, daily intravenous ALA for three weeks was associated with reduced pain, paresthesia, and numbness . Ametov, AS, Barinov, A, Dyck, PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 2003; 26:770. • In the SYDNEY 2 trial, 181 patients with diabetes and symptomatic distal symmetric polyneuropathy were randomly assigned to one of three doses of orally administered ALA (600, 1200, or 1800 mg daily) or to placebo for five weeks [49Ziegler, D, Ametov, A, Barinov, A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 2006; 29:2365.]. The following observations were reported: • All three doses of oral ALA treatment: a statistically significant reduction in the primary outcome measure, the neuropathy total symptom score (a summation of stabbing pain, burning pain, paresthesia, and asleep numbness), compared with placebo . The benefit of ALA did not differ by dose. 6/11/2010 ARMAN TAHERI MD 26 • • • • • • • • • • • What is Alpha Lipoic Acid? Other names: lipoic acid, thioctic acid, ALA Alpha lipoic acid is a fatty acid found naturally inside every cell in the body. to produce the energy for our body's normal functions. Alpha lipoic acid converts glucose (blood sugar) into energy. Alpha lipoic acid is also an antioxidant, a substance that neutralizes potentially harmful chemicals called free radicals. to recycle antioxidants (vitamin C and glutathione ) Glutathione is an important antioxidant that helps the body eliminate potentially harmful substances. Alpha lipoic acid increases the formation of glutathione. Alpha lipoic acid is made by the body and can be found in very small amounts in foods such as spinach, broccoli, peas, Brewer's yeast, brussel sprouts, rice bran, and organ meats. Alpha lipoic acid supplements are available in capsule form at health food stores, some drugstores, and online. For maximum absorption, the supplements should be taken on an empty stomach. Why People Use Alpha Lipoic Acid Peripheral Neuropathy Peripheral neuropathy can be caused by injury, nutritional deficiencies, chemotherapy or by conditions such as diabetes, Lyme disease, alcoholism, shingles, thyroid disease, and kidney failure. Symptoms can include pain, burning, numbness, tingling, weakness, and itching. Alpha lipoic acid is thought to work as an antioxidant in both water and fatty tissue, enabling it to enter all parts of the nerve cell and protect it from damage. Preliminary studies suggest that alpha lipoic acid may help. In one of the largest studies on the use of alpha lipoic acid, 181 people took 600 mg, 1200 mg or 1800 mg of alpha lipoic acid a day or a placebo. After 5 weeks, alpha lipoic acid improved symptoms. The dose that was best tolerated while still providing benefit was 600 mg once daily. 6/11/2010 ARMAN TAHERI MD 27 PAIN CONTROL • • • • Alpha-lipoic acid Side Effects Side effects of alpha lipoic acid may include headache, tingling or a "pins and needles" sensation, skin rash, or muscle cramps. a few reports in Japan of a rare condition insulin autoimmune syndrome in people using alpha lipoic acid. The condition causes hypoglycemia and antibodies directed against the body's own insulin without previous insulin therapy. The safety of alpha lipoic acid in pregnant , children, or people with kidney or liver disease is unknown. Possible Drug Interactions: Alpha lipoic acid may improve blood sugar control, so people with diabetes who are taking medication to lower blood sugar, such as metformin (Glucophage), glyburide (DiaBeta, Glynase), should only take alpha lipoic acid under the supervision of a qualified health professional and have their blood sugar levels carefully monitored. Animal studies : alpha lipoic acid may alter thyroid hormone levels, so it could theoretically have the same effect in humans. People taking thyroid medications such as levothyroxine should be monitored by their healthcare provider 6/11/2010 ARMAN TAHERI MD 28 PAIN CONTROL • A clinically meaningful response, defined as ≥50 percent reduction in neuropathic symptoms, was observed in 50 to 62 percent of patients treated with ALA versus 26 percent with placebo, a difference that was statistically significant. • The optimal dose of ALA was 600 mg once daily, as higher doses were limited by increasing adverse events (nausea, vomiting, vertigo) without increasing efficacy. • The strength of these findings is limited by the short duration of this trial. There are no long-term studies that assess the affect of alpha-lipoic acid on progression of neuropathy. • However, based upon these data, we suggest treatment with oral ALA 600 mg once daily for patients with symptomatic painful diabetic polyneuropathy who are refractory to or intolerant of antidepressants (eg, amitriptyline, duloxetine) or anticonvulsants (eg, gabapentin, pregabalin) that have been established as beneficial for this condition. 6/11/2010 ARMAN TAHERI MD 29 PAIN CONTROL Opioids: Tramadol (Ultram) . A randomized, double-blind study found that tramadol, at an average dose of 210 mg/day, was more effective than placebo for relieving pain, without any important effects on sleep . The most frequent adverse effects were nausea, constipation, headache, and somnolence. Harati, Y, Gooch, C, Swenson, M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50:1842. • CR oxycodone at a daily dose of 10 to 60 mg : effective and safe for the treatment of painful DPN, (two randomized clinical trials) . • In the larger of these trials : 159 patients, oxycodone CR at an average dose of 37 mg daily (range 10 to 99 mg daily) → more pain relief than placebo . Gimbel, JS, Richards, P, Portenoy, RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003; 60:927 • Methadone :to treat refractory painful neuropathy , although no clinical trial data exist to support its effectivenessHays, L, Reid, C, Doran, M, Geary, K. Use of methadone for the 6/11/2010 ARMAN TAHERI MD treatment of diabetic neuropathy. Diabetes Care 2005; 28:485. 30 PAIN CONTROL Combination therapy Treatment of neuropathic pain with combinations of drugs from different medication classes is modestly more effective than monotherapy. • In a single-center randomized trial of 44 patients with neuropathic pain (a majority with diabetic polyneuropathy), gabapentin + morphine was more effective than either agent alone for reducing the mean intensity of pain during week four of treatment at the maximum tolerated daily dose (mean, gabapentin 1705 mg and morphine 34 mg in combination) . Gilron, I, Bailey, JM, Tu, D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005; 352:1324 • Constipation, sedation, and dry mouth (the most frequent side effects of the combination therapy). • A similar single center randomized trial of 47 patients (most with DPN) found that the combination of nortriptyline with gabapentin was more effective than either agent alone for reducing the mean intensity of daily pain during week four of treatment at the maximum tolerated daily dose (mean, nortriptyline 50 mg and gabapentin 2180 mg in combination) . Gilron, I, Bailey, JM, Tu, D, et al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009; 374:1252 • In both reports, the benefit of combination treatment was small but statistically significant. 6/11/2010 ARMAN TAHERI MD 31 PAIN CONTROL Transcutaneous electrical nerve stimulation (TENS) pain despite combination drug therapy. • Although data are limited, a 2010 guideline from the American Academy of Neurology concluded that TENS is probably effective for reducing pain from diabetic polyneuropathy, based upon the following evidence: Dubinsky, RM, Miyasaki, J. Assessment: efficacy of transcutaneous electric nerve stimulation in the treatment of pain in neurologic disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010; 74:173 • One trial assigned 31 patients with chronic painful DPN to either TENS or sham treatment to the legs for 30 minutes daily for four weeks . Symptomatic improvement (of at least one grade on a unique zero to five scale) occurred in 15 of 18 patients (83 percent) with TENS treatment, compared with five of 13 patients (38 percent) who received sham treatment (odds ratio 6, 95% CI 1.1-33.4) . Kumar, D, Marshall, HJ. Diabetic peripheral neuropathy: amelioration of pain with transcutaneous electrostimulation. Diabetes Care 1997; 20:1702 • Another trial evaluated 19 patients with mild to moderate symptomatic diabetic polyneuropathy . Compared with sham treatment, active treatment with TENS led to a statistically significant reduction in total symptom score at six and twelve weeks. In addition, TENS therapy was associated with a statistically significant but modest improvement in pain on the visual analog scale at six weeks Forst, T, Nguyen, M, Forst, S, et al. Impact of low frequency transcutaneous electrical nerve stimulation on symptomatic diabetic neuropathy using the new Salutaris device. Diabetes Nutr Metab 2004; 17:163 6/11/2010 ARMAN TAHERI MD 32 PAIN CONTROL • Acetyl-L-carnitine : (ALC), has been evaluated in patients with DPN. • • two randomized controlled trials of identical design, an intention to treat analysis of 1257 patients with DPN found that ALC 1000 mg (but not 500 mg) three times daily compared with placebo was associated with significant improvement in pain scores in one of the studies and in the combined cohort . The benefit of ALC requires confirmation, particularly since significant improvement was not seen in both trials or at the lower dose of ALC. Quatraro, A, Roca, P, Donzella, C, et al. Acetyl-L- carnitine for symptomatic diabetic neuropathy. Diabetologia 1995; 38:123. Sima, AA, Calvani, M, Mehra, M, Amato, A. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebocontrolled trials. Diabetes Care 2005; 28:89. 6/11/2010 ARMAN TAHERI MD 33 PAIN CONTROL • Isosorbide — A placebo-controlled pilot study of isosorbide nitrate topical spray in 22 diabetic patients reported a significant reduction in overall neuropathic pain and burning sensation in the treatment group . Yuen, KC, Baker, NR, Rayman, G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double-blind placebocontrolled cross-over study. Diabetes Care 2002; 25:1699 6/11/2010 ARMAN TAHERI MD . 34 PAIN CONTROL • Nonsteroidal antiinflammatory drugs (NSAIDs) are effective in patients with musculoskeletal or joint abnormalities secondary to long-standing neuropathy; the joint deformities may actually be the primary source of pain. Both ibuprofen (600 mg four times daily) and sulindac (200 mg twice daily) can lead to substantial pain relief in patients with diabetic neuropathy . Cohen, KL, Harris, S. Efficacy and safety of nonsteroidal anti-inflammatory drugs in the therapy of diabetic neuropathy. Arch Intern Med 1987; 147:1442 • Theoretically: NSAIDs may impair nerve circulation and worsen nerve injury due to inhibition of prostacyclin synthesis. Cautious use of this class of drugs is warranted until this possibility is fully evaluated 6/11/2010 ARMAN TAHERI MD 35 PAIN CONTROL • Venlafaxine : In a randomized controlled trial, in 244 patients with painful DPN . At six weeks, treatment with venlafaxine at higher (150 to 225 mg daily) but not lower (75 mg daily) doses was associated with significant benefit in the primary outcome measures of pain intensity and pain relief compared with placebo. The strength of this finding is limited by the short duration of this trial. • Nausea and somnolence were the most common side effects of venlafaxine, and blood pressure and cardiac rhythm changes occurred more often with venlafaxine treatment than with placebo. Rowbotham, MC, Goli, V, Kunz, NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 2004; 110:697 6/11/2010 ARMAN TAHERI MD 36 Recommendations • Our treatment recommendations for symptomatic diabetic polyneuropathy are similar to the algorithm outlined by the American Diabetes Association (ADA), which recommends treatment in sequential steps ordered as follows • Exclude nondiabetic etiologies • Stabilize glycemic control (insulin not always required in type 2 diabetes) • Antidepressant drugs (eg, amitriptyline, other tricyclics, duloxetine) • Anticonvulsants (eg, gabapentin, pregabalin) • Alpha-lipoic acid • Opioid or opioid-like drugs (eg, tramadol or controlled release oxycodone) • Consider pain clinic referral • The drug treatment options and suggested doses. • The ADA statement notes that nonpharmacologic, topical, or physical therapies might be useful at any stage. These measures include acupuncture, capsaicin, glyceryl trinitrate spray or patches, and other therapies. Boulton, AJ, Vinik, AI, Arezzo, JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005; 28:956 6/11/2010 ARMAN TAHERI MD 37 NONGLYCEMIC MEASURES : • Angiotensin converting enzyme inhibitors, multifactorial risk factor reduction, and aldose reductase inhibitors are potential strategies for treating diabetic neuropathy. Angiotensin converting enzyme (ACE) inhibitors Treatment of hypertension Prevention of progression of nephropathy in patients with diabetes. Inhibiting the production of angiotensin II, thereby lowering systemic and intraglomerular pressures. May be beneficial in diabetic retinopathy and neuropathy. The effect of the ACE inhibitor trandolapril on DPN was assessed in 41 normotensive diabetic patients who were randomly assigned to trandolapril or placebo . The patients receiving trandolapril had a small but significant improvement in several measures of peroneal and sural nerve physiology. Malik, RA, Williamson, S, Abbott, C, et al. Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial. Lancet 1998; 352:1978 6/11/2010 ARMAN TAHERI MD 38 Multifactorial risk factor reduction : The potential efficacy of intensive combined therapy in patients with type 2 diabetes and microalbuminuria was examined in the Steno type 2 trial . In this prospective study, 160 patients were randomly assigned to standard or multifactorial intensive therapy. The intensive regimen consisted of behavioral therapy (including advice concerning diet, exercise, and smoking cessation) and pharmacologic intervention (consisting of the administration of multiple agents to attain several aggressive therapeutic goals) . Diabetic autonomic and peripheral neuropathy were present at baseline in 28 and 34 percent, respectively. • At a mean follow-up of 7.8 years, there was a significantly lower rate of progression of autonomic neuropathy in the intensive therapy group (30 versus 54 percent, relative risk 0.37), but no slowing of progression of peripheral neuropathy . Gaede, P, Vedel, P, Larsen, N, et al. Multifactorial intervention and cardiovascular diseae in patients with type 2 diabetes. N Engl J Med 2003; 348:383. 6/11/2010 ARMAN TAHERI MD 39 Aldose reductase inhibitors • In addition to lowering blood glucose concentrations,. • sorbitol accumulation might play a role in diabetic neuropathy, use of an aldose reductase inhibitor to prevent sorbitol formation might be beneficial. • In the available studies of this unapproved class of medications, aldose reductase inhibitors have produced inconsistent benefits in diabetic neuropathy. 6/11/2010 ARMAN TAHERI MD 40 Surgical decompression Surgical decompression of multiple peripheral nerves (the Dellon procedure) is an alternative, controversial method for treating DPN. The purported rationale for surgical decompression is based on the notion that the metabolic stress of diabetes renders peripheral nerves susceptible to compressive injury at sites of potential nerve entrapment , and that compressive injury of multiple peripheral nerves is what leads to symptoms in most patients . However, there are no adequately designed trials to support the use of surgical decompression of multiple peripheral nerves as a treatment for symptomatic DPN. Therefore, this treatment is not recommended 6/11/2010 ARMAN TAHERI MD 41 THANK YOU 6/11/2010 ARMAN TAHERI MD 42 PAIN CLINIC, SHARIATI HOSPITAL, 17 ,Second ave. North Amirabad st. TEHRAN,IRAN 6/11/2010 ARMAN TAHERI MD 43