Diabetic Peripheral Neuropathy: Current Concepts and Treatment

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www . DCMS online . org Northeast Florida Medicine Spring 2005 23 Diabetes and Neuropathy Diabetic Peripheral Neuropathy: Current Concepts and Treatment By Timothy L.

Sternberg, DMD, MD Director, Center for Pain Management University of Florida/Shands Jacksonville Painful diabetic peripheral neuropathy (PDN) is a significant cause of pain and distress in patients with diabetes mellitus (DM). 1 It affects patients with both Type 1 and 2 DM. Poor blood glucose control is a prominent risk factor.

The overall incidence is 20-24%. 2 The prevalence increases as the disease progresses, with approximately 50% of patients developing PDN 25 years after initial diagnosis of DM. 3 PDN is a type of neuropathic pain (i.e., caused by damage or dysfunction of the nervous system).

It is typically a distal symmetrical neuropathy; the longest axons displaying symptoms first, with pain manifesting initially in the feet, then distal lower extremities, and eventually the hands. 4 The pain is characterized by typical neuropathic descriptors (burning, tingling, aching dysesthesias), usually accompanied by some sensory loss, and is typically worse at night. 5 Over 50% of patients report substantial compromise of activities of daily living including mobility, work, sleep, recreation and social activities.

4 The pathophysiology of neuropathic pain involves increased afferent ... more. less.

nociceptor depolarization, decreased central nervous system inhibition, or altered processing with amplification of nociceptive transmission (central sensitization or cwind-up d). 6 The diabetically involved neuronal hyperexcitability may be due to injury and subsequent up-regulation of sodium channels in the dorsal root ganglion. 1, 7, 8 Diagnosis Diagnosis is usually readily established with the history and physical examination. The history is usually of slowly progressive distal painful burning dysesthesias (unpleasant abnormal sensations) with some degree of hypesthesia (decreased sensation to normal stimuli) in a stocking 3glove type distribution. Physical exam confirms a degree of peripheral sensory loss, allodynia (pain to a normally non-painful stimulus), or hyperalgesia (increased pain to a normally painful stimulus). Nerve conduction/electromyographic studies may reveal the typical changes consistent with bilateral symmetrical axonal neuropathy such as low or absent sensory action potentials with normal distal latencies. 9 Nerve biopsy is only indicated to differentiate PDN from another pathologic process that may be amenable to more specific treatment. Treatment The mainstay of treatment for PDN is pharmacologic. If initial evaluation indicates poor glycemic control, oral hypoglycemic medications and/or insulin should be titrated to achieve consistently controlled blood glucose levels. The majority of analgesic pharmacotherapeutic options involve medicines initially developed to treat another neurologic conditions, with most working in the central nervous system. 10 Medications that have the most evidence for efficacy are tricyclic antidepressants (TCAs) 11, 12, 13 and anticonvulsants. 14, 15 Other medications that have shown some degree of efficacy in the treatment of PDN are multiple other medications, including capsaicin cream, 16 levodopa, 17 tramadol, 18, 19 opioids, 20, 21 serotonin specific reuptake inhibitors (SSRIs), 22 serotonin-norepinephrine reuptake inhibitors (SNRIs), 23 and antiarrhythmics. 24 Only two medications, duloxetine (Cymbalta®), a recently developed SNRI, and pregabalin (Lyrica®), an anticonvulsant, are FDA approved for PDN treatment. As in other medical conditions for which multiple options are available, the number of medications proposed seems inversely proportional to any one being particularly successful. None relieve the pain completely. A practical goal of treatment is a moderate degree of pain relief with a medical regimen having acceptable side effects at a cost and dosing regimen for which the patient is likely to be compliant. 24 Spring 2005 Northeast Florida Medicine www . DCMS online . org TCAs have a long and proven record in treating PDN. They are generally efficacious, inexpensive, and have an easy dosing regimen. Amitriptyline, desipramine, clomipramine, imipramine have all been used success- fully. 10 The limiting factor is the multitude of side effects, (e.g., tachycardia, orthostatic hypotension, dry mouth, somnolence, urinary retention, and altered sexual function) which are associated with this class of drugs. Sedative side effects can be used to advantage by dosing these medications at night, a time when the pain of PDN is particularly annoying. Amitriptyline or nortriptyline, 25 mg at bedtime (10 mg for the elderly), is moderately efficacious, tolerated well, and is a practical starting regimen. The newer antidepressants, including the SSRIs and SNRIs, are not any more efficacious than the TCAs though generally have a better side effect profile. SSRIs, such as fluoxetine (Prozac®) 25 and paroxetine (Paxil®) 22 are generally less effective than the TCAs. SNRIs, such as venlafaxine (Effexor®), seem to be as effective as TCAs. 23 The newest antidepressant used for PDN is the recently released SNRI duloxetine (Cymbalta®), the first FDA-approved medication for the treatment of this condition. At a dose of 60 mg/day, approximately half of the patients report a 50% reduction in pain. 26 Though this has not been compared to TCAs in a head-to- head trial, the response rate seems comparable. Side effects are generally tolerable and include nausea, dry mouth, constipation, and insomnia. The high cost of this drug, compared to generic TCAs, may be worth it in patients at particular risk for morbidity from the cardiac or anti-cholinergic side effects of TCAs. Anticonvulsants also have a proven tract record in PDN. Carbamazepine, phenytoin, lamotrigine, and others have been successfully used, 10 though gabapentin (Neurontin®) seems to be the preferred drug of this class used currently. Gabapentin is relatively easy to use; there is little organic toxicity, obviating the need to monitor blood levels, hematologic or chemical profiles. It has a wide therapeutic window, with doses ranging from 100 mg at bedtime to 1200 mg three times a day. Side effects of gabapentin, such as sedation and dizziness, are tolerable and are generally accommodated by the patient after several weeks of use. A practical regimen is to start the patient at 300 mg at bedtime, increase to twice per day after three days, and increase to three times a day after three more days. If the clinical response is still insufficient, the dose can be titrated to 600 mg three times per day over 2-3 weeks. Should there be no clinical response at the latter dose, it would be advisable to choose another drug rather than continue to escalate the dose. If there is a good initial clinical response, but this eventually fades, the dose can then be titrated up further. Older generic anticonvulsants (e.g. carbamazepine and phenytoin) have associated toxicities necessitating laboratory monitoring, and the newer agents seem to offer no particular advantage over gabapentin. The newest anticonvulsant related medication is pregabalin (Lyrica®), recently approved by the FDA for the management of PDN and postherpetic neuralgia (PHN), and is under consideration for adjunctive treatment of partial seizures. Early studies have shown a rapid and meaningful pain reduction in both PDN and PHN. 27 The antiarrhythmic mexilitine is effective at reducing the nocturnal pain and sleep disruption, 24 although this drug requires laboratory monitoring. The topical agent capsaicin, 0.075%, applied multiple times per day, is effective 16 but particularly difficult for patients to use. An alkaloid found in chili pepper, capsaicin works by initially releasing, then depleting, the pain neurotransmitter Substance P. This causes an intense burning sensation that may persist for several weeks into treatment. As a consequence, initial enthusiasm generated when this drug was released has been tempered by a high degree of patient noncompliance. The analgesic tramadol (Ultram®, Ultracette®) is effective for neuropathic pain including PDN. 18 Initially started at 25-50 mg twice daily, it can be titrated up to 100 mg every six hours. The principal side effects of nausea and somnolence can be mitigated by slow titration. It is a non-controlled medicine with essentially no abuse potential. Opioids, once thought to be ineffective in relieving neuropathic pain, in fact are effective, just less so than their efficacy in relieving somatic nociceptive pain. Because the pain of PDN is continuous, time-released formulations of oxycodone (Oxycontin®), morphine (MS Contin® and generic), or a long acting opioid such as methadone, are generally used. Practical starting doses are Oxycontin 10 mg twice daily, MS Contin 15 mg twice daily, or methadone 5-10 mg three times daily. Well-known difficulties with opioids include not only the relatively www . DCMS online . org Northeast Florida Medicine Spring 2005 25 predictable tolerance and dependence, but also the necessity of closely monitoring and documenting drug usage patterns. Physical modalities such as transcutaneous electrical nerve stimulation (TENS) have been tried with modest success. 28 Acupuncture has also been reported to be beneficial by practitioners of that modality. Invasive therapy has a limited role in PDN. Surgical decompression of peripheral nerves has slowed progression of the neuropathic process. 29 Surgical sympathectomy, spinal cord stimulation, and central neuraxial blockade have all been reported to be useful, but not rigorously tested. When superficial tactile allodynia is a prominent feature of the patient 9s presentation, this author has found that a diagnostic lumbar paravertebral sympathetic block can be useful in assessing the degree of sympathetically mediated pain. When sympathetically mediated pain is a prominent feature, as evidenced by over 50% pain reduction with the sympathetic block, a percutaneous radiofrequency rhizotomy of the sympathetic chain can follow for a more long-lasting effect. Current investigations include use of aldose reductase inhibitors, alpha-lipoic acid, gamma-linolenic acid, and nerve growth factor. Where they may fit into future therapy remains to be determined. Conclusion Painful peripheral neuropathy is common in patients with diabetes mellitus, and its prevalence increases with disease duration and poor glycemic control. Initial attention should be directed at controlling blood glucose levels. First line therapy for PDN would need to include a TCA or SNRI and an anticonvulsant. The recently released duloxetine (Cymbalta) and pregabalin (Lyrica), an antidepressant and anticonvulsant respectively, are the only two FDA medications specifically approved for treatment of PDN. Further analgesia can be obtained with tramadol or a long-acting opioid. For those failing therapy with combined antidepressant/anticonvulsant/opioid, third-line therapies can be sequentially tried. REFERENCES 1.Backonja MM, Serra J. Pharmacologic management part1: better-studied neuropathic pain diseases. Pain Med 2004; 5:S1:S28-47. 2.Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 2002; 18:350-4. 3.Pirart J. Diabetes mellitus and its degenerative complications: A prospective study of 4,4000 patients observed between 1947 and 1973. Diabetes Care 1978; 1:168-88. 4.Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: Epidemiology, pain description, and quality of life. Diabetes Res Clin Pract 2000; 47:123-8 5.Nicholson B, Verma S. Co morbidities in chronic neuropathic pain. Pain Medicine 2004; 5:S1: S9-27. 6.Dworkin RH, Backonha M, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003; 60:1524-34. 7.Schmeichel AM, Schmelzer JD, Low PA. Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. Diabetes 2003; 52:165-71 8.Craner MJ, Klein JP, Renganathan M, Black JA, Waxman SG. Changes of sodium channel expression in experimental painful diabeti c neuropathy. Ann Neurol 2002; 52:786-92. 9.Abrams BM, Waldman HJ, et al. Diagnostic tools available for pain management. In: Raj PP, editor. Pain Medicine: A Comprehens ive Review. 2 nd Edition. St. Louis: Mosby; 2003:182-200. 10.Backonja M-M, Serra J. Pharmacologic Management Part 1: Better-Studied Neuropathic Pain Diseases. Pain Medicine 2004; 5:S28-S47. 11.Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA 1984; 251:1727-30. 12.Max MB, Kishore-Kumar R, Schafer SC, Meister B, Bracely RH, Smaller B, Dubner R. Efficacy of desipramine in painful diabetic neuropathy: A Placebo-controlled tria. Pain 1991;45:3-9. 13.Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ, Smaller B, Dubner R. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 1987; 37:589-96. 14.Serpell MG. Neuropathic Pain Study Group. Gabapentin in neuropathic pain syndromes: A randomized, double-blind, placebo- controlled tria. Pain 2002; 99:557-66. 15.Wilton TD. Tegretol in the treatment of diabetic neuropathy. S Afr Ned H 1974; 48:869-72. 16.The Capsaicin Study Group. Treatment of painful diabetic neuropathy with topical capsaicin: A multicenter, double-blind, veh icle- controlled study. Arch Intern Med 1991; 151:2225-9. 17.Ertas M, Sagduyu A, Arac N, Uladag B, Ertedin C. Use of levodopa to relieve pain from painful symmetrical diabetic polyneuro pathy. Pain 1998;75:257-9. 26 Spring 2005 Northeast Florida Medicine www . DCMS online . org 18.Harati Y, Gooch C. Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neu ropathy. Neurology 1998; 50:1842-6. 19. Sindrup SH, Andersen G, Madsen C, Smith T, Bronsen K, Jensen TS. Tramadol relieves pain and allodynia in polyneuropath: A r andomized, double-blind, controlled trial. Pain 1999; 83:85-90. 20.Gimbel JS, Richards P, Portenoy RK. Controlled-reliease oxycodone for pain in diabetic neuropathy: A randomized controlled t iral. Neurology 2003; 60:927-34. 21.Watson CPN, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: A rand omized controlled trial in painful diabetic neuropathy. Pain 2003; 105:71-8. 22.Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in t he treatment of diabetic neuropathy symptoms. Pain 1990; 42:135-44. 23.Sindrup SH, Bach FW, Madsen C, Gram LF, Jensen TS. Venlafaxine verses imipramine in painful diabetic polyneuropathy: A rando mized, controlled trial. Neurology 2003; 60:1284-9. 24.Oskarsson P, Ljunggren J-G, Lins P-E, Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. The Mexiletine Study Group. Diabetes Care 1997; 20:1594-7. 25.Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in di abetic neuropathy. N Engl J Med 1992; 3261250-6 26.Eli Lilly and Company. Cymbalta package insert. 2004 27.Pfizer, Inc. News release. Dec 31 2004. 28.Kumar D and Marshall HJ: Diabetic peripheral neuropathy: Amelioration of pain with transcutaneous electrostimulation. Diabetes Care 20: 1702-1705, 1997. 29.Aszmann OC, Kress KM, Dellon AL: Results of decompression of peripheral nerves in diabetics: a prospective, blinded study. Plast Reconstr Surg 106(4):816-22, 2000 Say goodbye to that beeper 4 n ow your after-hour calls can be managed by our own Nurse Practitioners and Physician Assistants through PHYSICIAN CALL SERVICE, INC. We are experienced, licensed medical professionals who give your patients prompt, caring, personalized service. 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