Journal of the Peripheral Nervous System 17(Supplement):22–27 (2012)

REVIEW

Treatments for diabetic neuropathy Vera Bril Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada

Abstract Diabetic neuropathy comprises disorders of peripheral nerve in diabetes patients after exclusion of other disorders and can be focal or diffuse. The focal diabetic neuropathies tend to resolve spontaneously and are treated by reassurance, physiotherapy and analgesia for painful symptoms. Diabetic sensorimotor polyneuropathy (DSP) is the most frequent form of diabetic neuropathy and effective disease-modifying treatment is not available beyond the interventions of optimal glycemic control, and possibly lifestyle and risk factor modification. In contrast, a recent evidence-based guideline shows that effective treatments for painful DSP include: pregabalin, amitriptyline, duloxetine, venlafaxine, gabapentin, opioids, nitrate sprays, capsaicin, and transcutaneous electrical nerve stimulation. The choice of treatment is guided by the clinical status of the individual patient.

Key words: evidence, diabetes, neuropathy, pain, treatment

Introduction

nerve entrapments such as carpal tunnel syndrome are more prevalent in those with diabetes than the nondiabetic population (Perkins et al., 2002), likely due to underlying intraneural pathologic mechanisms, but the treatment can be the same as in non-diabetic subjects although the outcomes of intervention may not be as good. Most of the other non-compressive mononeuropathies resolve spontaneously with time, and no specific intervention is available to enhance recovery from neuropathy. It may be that these mononeuropathies are due to microvasculitis in the nerve (Llewelyn et al., 1998; Tracy et al., 2009). Immunotherapy in DLSPRN has not proven to be effective to date in rigorous studies (Chan et al., 1996) and is not advised currently. Reassurance, physiotherapy, and treatment for neuropathic pain should be offered and is discussed below. The clinical presentation of diabetic cachexia is unmistakable, and treatment is improved glycemic control, pain control, and attention to adequate hydration and nutrition. This disorder is also typically self-limited. Diabetic pandysautonomia is treated symptomatically according to the involved organ systems after the exclusion of other pathologies causing those particular dysfunctions. Management of different autonomic dysfunctions generally requires

Diabetic neuropathy comprises disorders of peripheral nerve in people with diabetes mellitus after exclusion of other causes and can be classified broadly as symmetrical or asymmetrical (Dyck, 1987). Asymmetrical neuropathies include upper limb mononeuropathies (carpal tunnel syndrome, cubital tunnel syndrome, and brachial plexopathy), cranial nerve palsies (third and sixth), lower limb mononeuropathies (peroneal nerve palsy), diabetic lumbosacral plexoradiculoneuropathy (DLSPRN), and truncal radiculopathy. Symmetrical neuropathies include the most frequent: diabetic sensorimotor polyneuropathy (DSP), but also diabetic cachexia with small fiber neuropathy, diabetic pandysautonomia, and hypoglycemic neuropathy. Evaluation of the asymmetrical neuropathies requires exclusion of alternate diagnoses such as intracerebral aneurysms for cranial neuropathies 3 and 6, and spinal stenosis for DLSPRN. Peripheral

Address correspondence to: Vera Bril, MD, University Health Network, University of Toronto, 5EC-309, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. Tel: +(1)416340-3315; Fax: +(1)416-340-4189; E-mail: [email protected] © 2012 Peripheral Nerve Society

22

Bril

Journal of the Peripheral Nervous System 17(Supplement):22–27 (2012)

shown in Fig. 3 (Albers et al., 2010). This work showed conclusively that in patients with type 1 diabetes, intensified glycemic control minimizes DSP and stops progression, although regression of established DSP does not occur. For type 2 diabetes patients, the evidence for intensified glycemic control is less certain. The UK Prospective Diabetes Study (UKPDS) showed us minimal changes at 15 years with ‘‘better’’ control with an improvement in VPT compared to the conventional group starting at 8 years (UKPDS Group, 1998). DSP was assessed minimally in this study. No change in ankle reflexes or erectile dysfunction was observed between the two treatment arms after 15 years. In the Kumomoto study, neuropathy advanced less in type 2 diabetes patients in the intensified group (target A1C 7%) as measured by median nerve conduction studies and vibration perception thresholds (Ohkubo et al., 1995) and the effects on median nerve conduction studies separated more after 8 years of intensified control (Shichiri et al., 2000). Recently, concern about rigorous control in type 2 diabetes patients has been expressed, as 20% increased mortality from all causes was observed in the intensive treatment group in the ACCORD study (ACCORD Study Group et al., 2011) and the study was terminated early as a consequence of this unexpected finding in this group. So, the benefits of strict glycemic control in type 2 diabetes patients are less convincing. There is increasing evidence that other risk factors such as hypertension, high body mass index, hyperlipidemia, and smoking predispose to development of DSP (Tesfaye et al., 2005), so control of those risk factors may be an effective intervention for neuropathy in diabetes patients. With respect to other pathophysiological mechanisms in diabetes nerve, clinical trials of various interventions have essentially failed. The potential reasons for failure of these clinical trials include: the intervention does not work, the climate is changing with more patients having good glucose control or good risk factor control, the diabetes treatment is better during the trial for all patients, the endpoints are insufficiently sensitive or specific, the studies are too short with too few subjects, or the neuropathy is too advanced (Dyck et al., 2007). It is clear that peripheral nerves in diabetes have impaired axonal regeneration (Zochodne, 2007; Zochodne et al., 2007), and it may be that this defect prevents any recovery once axonal neuropathy is established. Still, it is also important to recall that ‘‘absence of evidence is not evidence of absence’’ (Altman and Bland, 1995) and that more suitably designed clinical trials might show disease modification in DSP. Interventions may need

collaboration with specialist physicians in those areas.

Diabetic Sensorimotor Polyneuropathy The most common form of diabetic neuropathy is DSP. Other diagnoses that need to be excluded, as treatment for these neuropathies needs to be considered, are as follows: chronic inflammatory demyelinating polyneuropathy, vitamin B12 deficiency, paraproteinemia, and other types of polyneuropathy such as familial, toxic, neoplastic, hypothyroid, uremic, and ethanol induced. The symptoms of DSP are positive such as paresthesiae and pain in the distal lower extremities, often described as burning, hyperaesthesia, and allodynia, or negative such as numbness, loss of sensation, insensitivity to temperature changes, unsteadiness ambulating with falls, Charcot joints, and unsuspected foot trauma leading to infections, ulceration, and amputation. It is important to appreciate that one-fourth of patients with DSP have significant persistent depression that may require intervention (Vileikyte et al., 2009). In a survey of patients with painful diabetic neuropathy (PDN), 60% of medical visits were related to this problem and 86% of patients had activity limitations (Gore et al., 2006). DSP is prevalent among those with diabetes reaching 27.6% in one study (Ziegler et al., 2009). Further, 13% of patients with impaired glucose tolerance, a prediabetes state, had polyneuropathy suggesting that the prediabetic state is also associated with development of neuropathy (Papanas et al., 2011).

Treatment of DSP Disease modification The treatment of DSP can be considered in two spheres: disease modification and symptomatic (pain) control. Currently, most clinical trials are for the treatment ofPDN rather than disease modification. Many of the disease modification studies have failed to show efficacy. Figure 1 shows the presumed pathogenesis of DSP and interventions tried for the treatment (Cameron et al., 2001; Obrosova, 2009). The evidence for disease modification with intensified glycemic control is from the Diabetes Control and Complications Trial (DCCT) (Fig. 2) that showed primary and secondary risk reduction in type 1 patients with intensified control compared with conventional treatment (Diabetes Control and Complications Trial Research Group, 1993). The treatment effect persists indicating a memory effect as 23

Bril

Journal of the Peripheral Nervous System 17(Supplement):22–27 (2012)

Figure 1. Current understanding of pathophysiology of diabetic sensorimotor polyneuropathy.

regimens such as tai chi chuan, which may also be helpful (Hung et al., 2009). Careful attention to footwear and avoidance of inadvertent injury are also beneficial to the patient with impaired sensitivity in the foot.

Symptom control for PDN The main treatment for DSP with PDN is treatment of painful symptoms. There is no evidence that PDN responds to improved glycemic control or exercise. Abnormal nociceptive input along thinly myelinated Aδ and unmyelinated C fibers is transmitted along central pathways to the thalamus and cerebral cortex. The perception of pain is not explained simply by injury to peripheral nerve fibers, but modulation of the nociceptive input by spinal cord and cerebral mechanisms plays a major role in perception of pain. The context (beliefs, expectation, and placebo effect), cognitive set (increased vigilance, attention, and distraction), injury (nerves with peripheral and central sensitization), mood (depression and anxiety), and chemical structural changes (neural degeneration, neurotransmitter changes, and maladaptive plasticity) all play important roles in the degree of pain perceived by the patients. Some measure of pain should be used consistently in the clinic to follow patients; for example, the 11 point Likert scale from 0 for no pain to 10 for maximal pain possible. In addition to pain management, other factors such as sleep disturbances, limitation of physical activities, mood disorders, and reduced quality of life need to be considered in comprehensive care of the patient in distress with PDN.

Figure 2. Reduction of neuropathy with intensified glycemic control in type I diabetes patients. Prevalence of diabetic neuropathy by clinical examination, autonomic system testing and nerve conduction studies in type 1 diabetes patients after 5 years of intensified glycemic control compared with conventional control observed in the Diabetes Control and Complications Trial study (Diabetes Control and Complications Trial Research Group, 1993).

to be as long as 5 years (as in the DCCT) or 8 years (as in the UKPDS) to show any change in peripheral nerve function in diabetes. Alternatively, interventions aimed specifically at nerve regeneration may need to be employed. Patients with DSP should be provided foot care which helps reduce amputation rates (Yesil et al., 2009), physiotherapy training for gait and balance to improve mobility (Allet et al., 2009), and other exercise 24

Bril

Journal of the Peripheral Nervous System 17(Supplement):22–27 (2012)

(a)

(b)

Figure 3. Prevalence of neuropathy observed in long-term follow-up of the Diabetes Control and Complications Trial (DCCT) cohort. Prevalence of diabetic neuropathy remains reduced in patients who were in the intensified glycemic control arm of the DCCT study (Albers et al., 2010).

Patient expectations need to be managed carefully: the treatments available for PDN do not relieve pain completely in the majority of patients, and most have significant adverse effects that the patient must be advised to expect. Farrar et al. showed that 30% and 50% reduction in pain correspond to the patients’ global impression of change of much improved, and very much improved, respectively (Farrar et al., 2001). Therefore, the target for reduction in pain should have a magnitude of at least 30%. Furthermore, most patients consider pain levels of 1 to 3 on the Likert visual analog scale as mild and may not wish to consider any intervention due to the potential for adverse effects with treatment. Finally, the physician–patient therapeutic relationship plays a major role in reducing pain as shown in 550 placebo treated patients from a series of clinical trials of pregabalin. About 20% of the placebo treated patients had ≥50% pain relief and almost 40% had ≥30% pain relief throughout the course of the studies (Freeman et al., 2008). So, utilization of the ‘‘placebo’’ effect may be advantageous in the clinic. Table 1 provides a summary of evidence-based treatments for PDN from a recently published practice guideline based on a strict systematic review of the literature (Bril et al., 2011). Although this guideline

Table 1. AAN, AANEM, and AAPM&R evidence-based guidelines for the treatment of painful diabetic neuropathy (Bril et al., 2011). Level

Recommended

Not recommended

A B

Pregabalin 300–600 mg/day Gabapentin 900–3600 mg/day Valproate 500–1200 mg/day Venlafaxine 75–225 mg/day Duloxetine 60–120 mg/day Amitriptyline 25–100 mg/day Dextromethorphan 400 mg/day Morphine sulphate titrated to 120 mg/day Tramadol 210 mg/day Oxycodone, mean 37 mg/day, maximum 120 mg/day Capsaicin, 0.075% QID Isosorbide dinitrate spray Electrical stimulation, percutaneous nerve stimulation × 3–4 weeks

Oxcarbazepine Lamotrigine Lacosamide Clonidine Pentoxifylline Mexiletine Magnetic field stimulation Low-intensity laser treatment Reiki therapy – – – –

AAN, American Academy of Neurology; AANEM, American Association of Neuromuscular and Electrodiagnostic Medicine; AAPMR, American Academy of Physical Medicine and Rehabilitation

25

Bril

Journal of the Peripheral Nervous System 17(Supplement):22–27 (2012)

intensive glucose lowering on cardiovascular outcomes. N Engl J Med 364:818–828. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, Waberski BH, Lachin JM, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2010). Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care 33:1090–1096. Allet L, Armand S, de Bie RA, Golay A, Monnin D, Aminian K, Staal JB, de Bruin ED (2009). The gait and balance of patients with diabetes can be improved: a randomised controlled trial. Diabetologia 53:458–466. Altman DG, Bland JM (1995). Absence of evidence is not evidence of absence. BMJ 311:485. Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, European Federation of Neurological Societies (2010). EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 17:1113–e88. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, Feldman E, Iverson DJ, Perkins B, Russell JW, Zochodne DW, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Academy of Physical Medicine and Rehabilitation (2011). Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 76:1758–1765. Cameron NE, Eaton SE, Cotter MA, Tesfaye S (2001). Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 44:1973–1988. Chan YC, Lo YL, Chan ESY. Immunotherapy for diabetic amyotrophy. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006521. DOI: 10.1002/14651858.CD00 6521.pub2. Diabetes Control and Complications Trial Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977–986. Dyck PJ (1987). Diabetic neuropathy. In: Diabetic Neuropathy., Dyck PJ, Thomas PK, Asbury AK, Winegrad AI, Porte D (Eds). W.B. Saunders Co, Philadelphia, pp 223–237. Dyck PJ, Norell JE, Tritschler H, Schuette K, Samigullin R, Ziegler D, Bastyr EJ III, Litchy WJ, O’Brien PC (2007). Challenges in design of multicenter trials: end points assessed longitudinally for change and monotonicity. Diabetes Care 30:2619–2625. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM (2001). Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94:149–158. Freeman R, Durso-DeCruz E, Emir B (2008). 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 31:1448–1454.

provides the evidence base for the use of different treatments, physicians need to tailor the intervention for individual patients considering the specific clinical context. For example, a patient with severe PDN and no other medical issues could be offered pregabalin. However, if a patient has severe PDN and also significant peripheral edema, then pregabalin would not be the first choice as one of the common side effects of pregabalin is peripheral edema. If a patient has depression associated with PDN, then an antidepressant such as duloxetine or venlafaxine should be considered as initial treatment as both depression and painful symptoms can be treated by the same medication. Some patients have severe PDN with other major systemic disorders making use of any oral agent problematic, as all have the potential for major adverse effects. In this type of patient, topical therapy or transcutaneous electrical nerve stimulation may be considered before any oral medication. As reported by the European Federation of Neurological Society guidelines, treatment response can vary for different neuropathic pain disorders (Attal et al., 2010), and the PDN guidelines should be read with that in mind. The PDN review process revealed major issues to consider when treating patients with PDN (Bril et al., 2011). PDN is a chronic disorder, but it is unknown how long to treat the patient or when to withdraw treatment as all the studies are short term. It is possible to calculate numbers needed to treat but not numbers needed to harm for each intervention because reporting of side effects in published articles is insufficient. The effect sizes of interventions relative to placebo are not large, standardized metrics for pain relief and side effects are not used and cost effectiveness of different treatments is not considered. Class I comparison studies of different interventions are not available and the mechanisms of pain relief for many interventions are not understood. Pain is not completely relieved in most patients, only a proportion of patients respond to any intervention, and strong evidence for combination treatments is lacking. It is evident that much work needs to be done to clarify important issues around the management of PDN although effective treatment options are available.

Disclosure The author declares no conflict of interest.

References ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewald WT (2011). Long-term effects of

26

Bril

Journal of the Peripheral Nervous System 17(Supplement):22–27 (2012)

Tracy JA, Engelstad JK, Dyck PJB (2009). Microvasculitis in diabetic lumbosacral radiculoplexus neuropathy. J Clin Neuromuscul Dis 11:44–48. UKPDS Group (1998). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837–853. Vileikyte L, Peyrot M, Gonzalez JS, Rubin RR, Garrow AP, Stickings D, Waterman C, Ulbrecht JS, Cavanagh PR, Boulton AJ (2009). Predictors of depressive symptoms in persons with diabetic peripheral neuropathy: a longitudinal study. Diabetologia 52:1265–1273. Yesil S, Akinci B, Bayraktar F, Havitcioglu H, Karabay O, Yapar N, Demirdover C, Yener S, Yalcin M, Comlekci A, Eraslan S (2009). Reduction of major amputations after starting a multidisciplinary diabetic foot care team: single centre experience from Turkey. Exp Clin Endocrinol Diabetes 117:345–349. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group (2009). Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. Pain Med 10:393–400. Zochodne DW (2007). Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms. Muscle Nerve 36:144–166. Zochodne DW, Guo GF, Magnowski B, Bangash M (2007). Regenerative failure of diabetic nerves bridging transection injuries. Diabetes Metab Res Rev 23:490–496.

Gore M, Brandenburg NA, Hoffman DL, Tai KS, Stacey B (2006). Burden of illness in painful diabetic peripheral neuropathy: the patients’ perspectives. J Pain 7:892–900. Hung JW, Liou CW, Wang PW, Yeh SH, Lin LW, Lo SK, Tsai FM (2009). Effect of 12-week tai chi chuan exercise on peripheral nerve modulation in patients with type 2 diabetes mellitus. J Rehabil Med 41:924–929. Llewelyn JG, Thomas PK, King RHM (1998). Epineurial microvasculitis in proximal diabetic neuropathy. J Neurol 245:159–165. Obrosova IG (2009). Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics 6:638–647. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M (1995). Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulindependent diabetes mellitus: a randomized prospective 6year study. Diabetes Res Clin Pract 28:103–117. Papanas N, Vinik AI, Ziegler D (2011). Neuropathy in prediabetes: does the clock start ticking early? Nat Rev Endocrinol 7:682–690. Perkins BA, Olaleye D, Bril V (2002). Carpal tunnel syndrome in patients with diabetic polyneuropathy. Diabetes Care 25:565–569. Shichiri M, Kishikawa H, Ohkubo Y, Wake N (2000). Longterm results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 23(Suppl. 2):B21–B29. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH, EURODIAB Prospective Complications Study Group (2005). Vascular risk factors and diabetic neuropathy. N Engl J Med 352:341–350.

27