DIABETIC NEUROPATHY: CLINICAL MANAGEMENT - PART 8 pdf

affects, which are predictable. Although drowsiness and lethargy are common, the anti- cholinergic side affects, particularly dry mouth, are most troublesome. Selective Serotonin-Reuptake Inhibitors The selective serotonin-reuptake inhibitors inhibit presynaptic reuptake of serotonin but not norepinephrine. Studies suggest that treatment with paroxetine (44) and citalo- pram (45) both at 40 mg per day, are efficacious in relieving neuropathic pain. Anticonvulsants Anticonvulsants have been used in the management of neuropathic pain for many years (8). Limited evidence exists for the efficacy of phenytoin and carbamazepine in painful neuropathy. Carbamazepine proved to be successful in the management of trigeminal neuralgia and following this was used in painful neuropathy. Of the few small clinical trials in diabetic neuropathy, the one by Rull et al. (46) did report quite a number of adverse events. It is the frequency of adverse events, particularly central (somnolence, dizziness), together with a lack of clinical trial data that limits the use of this agent. GABAPENTIN Gabapentin is now widely used for the relief of neuropathic pain and is specifically licensed for this indication in certain European countries. It is structurally related to the neurotransmitter γ-aminobutyric acid (GABA) and was first introduced as an anticon- vulsant for complex partial seizures. In a large controlled trial of Gabapentin in sympto- matic diabetic neuropathy, significant pain relief together with reduced sleep disturbance was reported using dosages of 900–3600 mg daily (47). In a recent review of all the tri- als of Gabapentin for neuropathic pain, it was concluded that dosages of 1800–3600 mg per day of this agent were effective: the side effect profile also seems superior to that of the tricyclic drugs (48). PREGABALIN Pregabalin, which is structurally related to Gabapentin, has recently been confirmed to be useful in painful diabetic neuropathy in a randomized controlled trial (49). Treatment of Painful Diabetic Neuropathy 359 Table 5 Commonly Used Pharmacological Therapies for Painful Diabetic Neuropathy Drug class Drug Daily dose (mg) Side-effects References Tricyclics Amitriptyline 25–150 ++++ 42,43 Imipramine 25–150 ++++ 42,43 Desipramine 25–150 ++++ 42 SSRIs Citalopram 40 +++ 45 Paroxitene 40 +++ 44 Anticonvulsants Carbamazepine 200–800 +++ 46 Gabapentin 900–3600 ++ 47,48 Pregabalin 150–600 ++ 49 Opioids Tramadol 50–400 +++ 53,54 Oxycodone-CR 10–60 ++++ 55,56 In contrast to Gabapentin, which is usually given three times daily, Pregabalin is effec- tive when given twice daily. This agent was recently licensed for the indication of neuropathic pain by the FDA. OTHER ANTICONVULSANTS In recent years, controlled trial evidence has also been published for a number of other anticonvulsant treatments including oxcarbazepine, sodium valproate, topiramate, and lamotrigine (8,50–52). Opioids The weak opioid-like centrally acting agent tramadol has been shown to be useful in the management of patients with painful neuropathy in a randomized controlled trial (53). A follow-up study to the original trial suggested that symptomatic relief could be maintained for at least 6 months’ usage (54). More recently, two randomized trials have confirmed the efficacy of controlled-relief oxycodone for neuropathic pain in diabetes (55,56). It is advised that opioids such as oxycodone-CR should be considered as add- on therapies for patients failing to respond to nonopioid medications. Other Pharmacological Treatments Mexiletine is a Class 1B antiarrhythmic agent and is a structural analog of lignocaine. Its efficacy in neuropathic pain has been confirmed in controlled trials (57). However, in this review of seven controlled trials of mexiletine, it was suggested that it only provided a modest analgesic effect (57). Regular EKG monitoring is essential and its short-term use should be reserved for patients who have failed to respond to other agents. The 5-hydroxytryptamine and norepinephrine reuptake inhibitor duloxetine was licensed by the FDA for usage in neuropathic pain in late 2004. This is an interesting agent as it has analgesic and antidepressant effects, but at the time of writing, evidence for the efficacy of this agent was only available in abstract form (41). Preliminary studies using two inhibitors of N-methyl- D-Aspartate (NMDA) receptors provide preliminary evidence for efficacy of these agents. A small study of the NMDA receptor antagonist dextromethorphan (58) and a larger study of memantine (59) suggest that this class of drugs might prove to be useful in treating neuropathic pain in the future. Table 6 lists the number needed to treat for some of the more commonly used agents described in this section. Topical and Nonpharmacological Treatments of Painful Neuropathy Topical Agents C APSAICIN Capsaicin, which is the “hot” ingredient of red chilli pepper, depletes tissue of sub- stance P and reduces chemically-induced pain. There have been a number of controlled studies of topically-applied capsaicin cream (0.075%) in the treatment of painful diabetic neuropathy. Although a meta-analysis (60) did suggest overall efficacy from a number of trials, the most recent trial failed to demonstrate any pain relief with capsaicin (61). A potential problem with all trials of capsaicin is the difficulty in ensuring that it is truly blinded, as topical capsaicin itself gives rise to transient local hyperalgesia (usually a mild burning sensation) in many patients. 360 Boulton TOPICAL NITRATE A controlled study suggested that the local application to the feet of isosorbide dini- trate spray was effective in relieving overall pain and a burning discomfort of painful neuropathy (62). More recently, the use of nitrate patches has also been shown to be useful (63). However, both of these studies were small and single center and a multi- center trial is now indicated for this agent. LIDOCAINE A preliminary study of topically-applied 5% lidocaine by a patch demonstrated improve- ments in pain and QoL outcomes during a 3-week treatment period (64). However, as this was not a controlled trial, a properly designed study is required before this can be recommended. Psychological Support/Counselling It is vital to provide all patients with a full explanation of their condition, to allay the fear and misconception often that they have some underlying malignancy, and informing them that the natural history might well be that the pain resolves in due course and that specific treatments are available for the pain in the short term, can be extremely helpful (23). Further evidence emphasizing the importance of comfort and support to improve painful symptomatology was provided in some preliminary observations of Kaye et al. (65) who also demonstrated that disappointment and failure of health care can result in intensification of painful symptomatology. Acupuncture Several uncontrolled studies report significant benefits of acupuncture in the relief of painful symptomatology. In the most recent of these, a 10-week uncontrolled study of up to six courses of traditional Chinese acupuncture, resulted in 77% of patients expe- riencing significant pain relief and during a follow-up of up to 1 year, the majority of patients were able to stop or significantly reduce their other pain medication (66). Although, controlled trials are needed to confirm the benefits of acupuncture which Treatment of Painful Diabetic Neuropathy 361 Table 6 Number Needed to Treat Successfully and Number Needed to Induce a Harmful Effect Drug NNT (CI) NNH (CI) Carbamazepine 3.3 (2–9.4) 1.9 (1.4–2.8) Gabapentin 3.7 (2.4–8.3) 2.7 (2.2–3.4) Mexiletine 10 (3–∞) 5–10 Phenytoin 2.1 (1.5–3.6) 9.5 (4.9–130) Pregabalin 3.3 (2.3–5.9) 3.7 TCAs 2.4 (2–3) 2.7 (2.1–3.9) Topiramate 3 (2.3–4.5) 9 Tramadol 3.4 (2.3–6.4) 7.8 NNT, numbers needed to treat to achieve pain relief in 1 patient; NNH, numbers needed to treat to harm in 1 patient; CI, 95% confidence interval. appears to be free of side-effects, these are difficult to design because of the problems encountered with finding the correct site for “sham” acupuncture. Other Physical Therapies Many other physical therapies have been proposed, but most are supported by small single-center studies, thus, indicating the need for proper multicenter-controlled trials. The efficacy of pulsed-dose electrical stimulation through stocking electrodes in the treatment of painful diabetic neuropathy that was previously supported in an open- labelled study was not confirmed to be efficacious in a recent randomized cross-over trial (67). A number of other physical therapies have been proposed and do have support from small-controlled trials: these include low-intensity laser therapy (68), monochromatic infrared light treatment (69), percutaneous electrical nerve stimulation (70), and static magnetic field therapy (71). For patients with the most severe painful neuropathy in unresponsive to conventional therapy, the use of electrical spinal cord stimulation was proposed in a small case series (72). However, although this cannot be generally rec- ommended except in very resistant cases as it is invasive, expensive, and unproven in controlled studies, a recent follow-up of patients suggested that long-term symptomatic relief can be achieved (73). CONCLUSION The treatment of painful diabetic distal polyneuropathy remains a daunting challenge to the physicians. Major problems in this area remain the paucity of large multicenter conclusive trials, the frequency of side-effects, and particularly the lack of controlled trials using comparator therapies rather than a placebo. Before embarking on a pharma- cological therapy, the importance of a thorough history and examination together with an understanding approach, and a serious attempt to stabilize glycemic control cannot be overemphasized. Finally, it must be remembered that all patients with distal sensory polyneuropathy are at potential risk of foot ulceration and should receive preventative foot care education as outlined in Chapter 28 of this volume. REFERENCES 1. Rollo J. Cases of Diabetes Mellitus. 2nd ed. Dilly, London, 1798, pp. 17–62. 2. Boulton AJM, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient manage- ment of diabetic peripheral neuropathy. 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Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med 2005;25:393–398. Treatment of Painful Diabetic Neuropathy 365 22 Focal and Multifocal Diabetic Neuropathy Gérard Said, MD SUMMARY Diabetic neuropathy is currently the most common neuropathy in the world, and it is associated with a wide range of clinical manifestations. The vast majority of patients with clinical diabetic neuropathy have a distal symmetrical form of the disorder that progresses following a fiberlength- dependent pattern, with sensory and autonomic manifestations predominating. Occasionally, patients with diabetes can develop focal and multifocal neuropathies that include cranial nerve involvement and limb and truncal neuropathies. This neuropathic pattern tends to occur after 50 years of age, and mostly in patients with long-standing diabetes mellitus. Length-dependent diabetic polyneuropathy does not show any trend towards improvement, and either relentlessly progresses or remains relatively stable over a number of years. Conversely, the focal diabetic neuropathies, which are often associated with inflammatory vasculopathy on nerve biopsies, remain self-limited, sometimes after a relapsing course. Other causes of neuropathies must be excluded in diabetic patients with focal neuropathies, and treatable causes must always be sought in diabetic patients with disabling motor deficit. Key Words: Proximal diabetic neuropathy; diabetic ophthalmoplegia; thoracic neuropathy; inflammatory diabetic neuropathy; nerve biopsy. INTRODUCTION Diabetic neuropathy is the most common neuropathy in industrialized countries, with a remarkable range of clinical manifestations. More than 80% of the patients with clinical diabetic neuropathy have a distal sy mmetrical form, with predominant or isolated sensory and autonomic manifestations (1,2). In the others, and usually in association with symptomatic or latent distal symmetrical sensory polyneuropathy, patients with diabetes might develop a focal neuropathy that includes cranial nerve involvement, limb and truncal neuropathies, and proximal diabetic neuropathy (PDN) of the lower limbs. In this group of neuropathies the disorder tends to occur both in men and women more than 50 years of age, most with longstanding type 1 and type 2 diabetes. The long-term prognosis of focal neuropathy is good in most cases, but sequelae occur. The occurrence of focal neuropathy in patients with diabetes requires first to exclude a nerve lesion owing to a superimposed cause by appropriate investi- gations. Then, to consider the occurrence of nondiabetic neuropathies more common From: Contemporary Diabetes: Diabetic Neuropathy: Clinical Management, Second Edition Edited by: A. Veves and R. Malik © Humana Press Inc., Totowa, NJ 367 in patients with diabetes, before concluding that the patient is suffering from a focal diabetic neuropathy and discussing which treatment, if any, is needed in addition to control of diabetes. CRANIAL DIABETIC NEUROPATHY Oculomotor nerve palsies are the most common if not the only cranial neuropathy observed in patients with diabetes. Historical Background Ogle in 1866, was the first author to mention the occurrence of diabetic ophthalmo- plegia (3). In 1905, Dieulafoy published a series of 58 personal cases, in which most of the clinical characteristics of diabetic ophthalmoplegia were described (4). In 1935, Waite and Beetham (5) performed the first epidemiological study on the subject in which they compared the occurrence of oculomotor palsy in 2002 diabetic patients with 457 patients without diabetes. A series of other clinical reports have refined our knowledge on the subject but pathological studies remain scanty with only a few autopsy cases studied (6–8) and the pathophysiology of oculomotor palsies in patients with diabetes remains a matter of discussion. Epidemiology Such as focal neuropathy observed in other sites of the body, diabetic ophthalmople- gia is uncommon in diabetic patients. In 1933, Gray (9) observed two patients with oph- thalmoplegia among 500 diabetic patients examined and Waite and Beetham (5,10) estimated the incidence of oculomotor palsy among patients with diabetes to be 0.8–1.8%. It is interesting to note that in this study, the frequency of oculomotor palsy was 0.8% in patients of less than 45 years of age, against 2.1% after 45 years. Frequency of involvement of the different oculomotor nerves: the sixth and the third cranial nerves are most commonly affected. In a series of 58 cases of diabetic ophthal- moplegia, Dieulafoy (4) reported 35 cases of sixth nerve palsy, 12 cases of third nerve palsy, five cases of fourth nerve palsy, and six cases of external ophthalmoplegia. The sixth cranial nerve was more often affected than the third one in two series (5,11). Conversely, in other series the third nerve is predominantly affected as the 14 patients reported by Weinstein and Dolger (12), included seven cases of third nerve palsy, six of sixth nerve involvement, and one with simultaneous involvement of both nerves. In an analysis of 811 cases of oculomotor palsies, diabetes accounted for 2.6% of third nerve palsy, 1.9% of sixth nerve palsy, and 0.6% of fourth nerve palsy (13). Finally, in Zorrilla and Kozak’s series of 24 cases, 17 patients had an involvement of the third nerve, including two bilaterally, and seven cases of sixth nerve palsy, but no fourth nerve involvement (14). Clinical Manifestations In virtually all cases diabetic ophthalmoplegia occurs in patients with diabetes with more than 50 years of age, both in type 1 and type 2 diabetes. Rare cases have been reported in younger patients or even in children (15). The onset is rapid, within a day or two. In many cases, the patient experiences pains a few hours to a few days before notic- ing diplopia. Pain thus preceded the onset of diplopia in 14 out of the 25 patients 368 Said reported by Green et al. (16) and in 18 out of the 22 episodes of oculomotor palsy that occurred in the 20 patients reported by Goldstein and Cogan (17). Pain seems common when the third cranial nerve is affected than when the sixth nerve is involved (14). Pain is usually aching behind or above the eye, and sometimes more diffuse, but always homolateral to the oculomotor palsy. Pain is often attributed to the involvement of the first and second divisions of the trigeminal nerve within the cavernous sinus (14), whereas others suggest a role for activation of pain-sensitive endings within the sheath of the third nerve as it traverses the cavernous sinus (8,18). Pain does not persist after the onset of diplopia. Oculomotor dysfunction is often incomplete when the third nerve is involved, one or two muscles might only be paralyzed. In their series of 22 episodes of ophthalmoplegia observed in 20 patients, Goldstein and Cogan (17) mentioned 12 episodes of complete dysfunction, three episodes of nearly complete dysfunction, and three of partial paraly- sis. Ptosis is marked, the eye is deviated outward when the internal rectus muscle is affected; the patient is unable to move the eye medially, upward, or downward. Pupillary innervation is often spared, as in 75% of the cases in (17), whereas massive pupillar paralysis was observed in only two out of 20 patients. In another study (16) pupillary function was spared in 68% of cases, whereas Rucker (13) observed pupillary dysfunction in three out of 21 cases of third nerve palsy. Sparing of pupillary function permits differentiation of third nerve palsy of diabetic origin from third nerve palsy, resulting from compression of the nerve by an aneurysm of the posterior communicat- ing artery in which pupillary dilatation is very common. The centrofascicular lesion found by Asbury and coworkers (8) at an autopsy of a patient with third nerve palsy accounts for sparing of pupillary function because of the relative sparing of pupillomo- tor fibers, which are peripherally placed in the third nerve (18). However, it has been suggested recently that isolated third nerve lesions in patients with diabetes, with or without pupillary sparing, could result from mesencephalic infarcts (19). In any case, brain magnetic resonance imaging should be performed to exclude a tumor, an aneurysm, or a hematoma. Spontaneous complete recovery invariably occurs within an average 2–3 months, independently of the quality of control of hyperglycemia. Aberrant regeneration and synkinesis, which are so common after facial nerve palsy of different origin, do not disturb recovery of diabetic ophthalmoplegia. Pathology Two serial section studies performed in patients with third cranial nerve palsy demonstrated a centrofascicular lesion of the nerve in its intracavernous portion (7,8). In the latter report, the axons were relatively spared on silver-stained sections. The myelin destructive lesion was 6–7 mm in length and the fibers placed at the periphery of the nerve trunk were relatively spared, which accounted for the pupillary sparing. The authors found no occluded vessel either intraneurally or in the nutrient vessels supply- ing the third nerve. In both reports the authors agreed that the observed centrofascicu- lar lesions of the third nerve were most likely ischemic in origin. However, it must be noted that nerve ischemia usually induce axonal nerve lesions, and not demyelinative ones. An inflammatory process of the type observed in biopsy specimens of the femoral nerve with partial ischemic lesions should also be considered. Focal and Multifocal Diabetic Neuropathy 369 [...]... 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