Clinical Therapeutics/Volume ], Number ], 2018

Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy

Zohaib Iqbal, MRCP1; Shazli Azmi, MRCP, PhD2; Rahul Yadav, MRCP, MD3; Maryam Ferdousi, PhD2; Mohit Kumar, MRCP4; Daniel J. Cuthbertson, FRCP, PhD5; Jonathan Lim, MRCP5; Rayaz A. Malik, FRCP, PhD2,6;andUazmanAlam,MRCP,PhD5,7,8 1Department of Endocrinology, Pennine Acute Hospitals NHS Trust, Greater Manchester, United Kingdom; 2Institute of Cardiovascular Science, University of Manchester and the Manchester Royal Infirmary, Central Manchester Hospital Foundation Trust, Manchester, United Kingdom; 3Department of Endocrinology, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, United Kingdom; 4Department of Endocrinology, Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, United Kingdom; 5Diabetes and Endocrinology Research, Department of Eye and Vision Sciences and Pain Research Institute, Institute of Ageing and Chronic Disease, University of Liverpool and Aintree University Hospital NHS Foundation Trust, Liverpool, United Kingdom; 6Weill Cornell Medicine–Qatar, Doha, Qatar; 7Department of Diabetes and Endocrinology, Royal Liverpool and Broadgreen University NHS Hospital Trust, Liverpool, United Kingdom; and 8Division of Endocrinology, Diabetes and Gastroenterology, University of Manchester, Manchester, United Kingdom

ABSTRACT there is no licensed pathogenetic treatment for diabetic Purpose: Diabetic peripheral neuropathy (DPN) is neuropathy. Management of painful DPN remains chal- the commonest cause of neuropathy worldwide, and lenging due to difficulties in personalizing therapy and its prevalence increases with the duration of diabetes. ascertaining the best dosing strategy, choice of initial It affects approximately half of patients with diabetes. pharmacotherapy, consideration of combination therapy, DPN is symmetric and predominantly sensory, starting and deciding on defining treatment for poor analgesic distally and gradually spreading proximally in a glove- responders. Duloxetine and pregabalin remain first-line and-stocking distribution. It causes substantial morbid- therapy for neuropathic pain in DPN in all 5 of the major ity and is associated with increased mortality. The published guidelines by the American Association of unrelenting nature of pain in this condition can Clinical Endocrinologists, American Academy of Neurol- negatively affect a patient's sleep, mood, and function- ogy, European Federation of Neurological Societies, Na- ality and result in a poor quality of life. The purpose of tional Institute of Clinical Excellence (United Kingdom), this review was to critically review the current liter- and the American Diabetes Association, and their use has ature on the diagnosis and treatment of DPN, with a been approved by the US Food and Drug Administration. focus on the treatment of neuropathic pain in DPN. Implications: Clinical recognition of DPN is imper- Methods: A comprehensive literature review was ative for allowing timely symptom management to undertaken, incorporating article searches in electronic reduce the morbidity associated with this condition. databases (EMBASE, PubMed, OVID) and reference (Clin Ther. 2018;]:]]]–]]]) & 2018 Elsevier HS Jour- lists of relevant articles with the authors' expertise in nals, Inc. All rights reserved. DPN. This review considers seminal and novel re- Key words: diabetes, diagnosis, epidemiology, neu- search in epidemiology; diagnosis, especially in relation ropathy, pharmacotherapy. to novel surrogate end points; and the treatment of neuropathic pain in DPN. We also consider potential Accepted for publication April 2, 2018. new pharmacotherapies for painful DPN. https://doi.org/10.1016/j.clinthera.2018.04.001 Findings: DPN is often misdiagnosed and inad- 0149-2918/$ - see front matter equately treated. Other than improving glycemic control, & 2018 Elsevier HS Journals, Inc. All rights reserved.

] 2018 1 Clinical Therapeutics

INTRODUCTION Epidemiology Diabetes has reached epidemic proportions world- Epidemiologic studies of diabetic neuropathy have wide, with International Diabetes Federation estimates provided heterogeneous results, owing to different pa- suggesting a prevalence of 425 million people world- tient populations, definitions of neuropathy used, and wide in 2017, rising to 628 million by 2045.1 This rise methods of assessments. Prediabetes is also associated will be accompanied by an increase in the prevalence with neuropathy.11 In the San Luis Valley cohort,12 the of the complications of diabetes.2 DPN is the most prevalence of peripheral neuropathy in patients with common cause of neuropathy worldwide, and is diabetes was 25.8%, as compared to 11.2% in subjects estimated to affect around half of people with with impaired glucose tolerance (IGT) and 3.9% in diabetes.3,4 It causes considerable morbidity, impairs control subjects. The MonItoring trends and quality of life, and increases mortality.5,6 Indeed, determinants in CArdiovascular/Cooperative Research approximately one fourth of the US health care in the Region of Augsburg (MONICA/KORA)13 expenditure on diabetes is spent on DPN.7 investigators found the prevalence of neuropathic pain Diabetic neuropathy refers to a collection of clin- to be 13.3% in patients with diabetes versus 8.7%, ically diverse disorders affecting the nervous system, 4.2%, and 1.2% in subjects withIGT,impairedfasting with differing anatomic features, clinical courses, and glucose, and controls, respectively. PROMISE phenotypes. The common underlying pathophysiology (Prospective Metabolism and Islet Cell Evaluation)14 is a consequence of hyperglycemia and microangiop- followed up patients longitudinally who were at risk for athy.8 The commonest form is distal symmetric developing diabetes. At 3 years, the prevalence of sensorimotor polyneuropathy9; however, most body neuropathy (as assessed using the Michigan systems can be affected through involvement of the Neuropathy Screening Instrument) was 50% in autonomic nerves. Despite the considerable, health patients who developed diabetes, 49% in those with care–related economic burden and effect on quality prediabetes, and 29% in controls.15 of life in DPN, treatment options are limited and In a Spanish study, the reported prevalence of DPN prevention remains the key goal.10 The purpose of this in primary care was 21% compared to 27% in- review was to critically review the current literature on hospital.16 The Rochester Neuropathy Study evaluated the diagnosis and treatment of DPN, with a focus on data from 380 participants16; DPN, diagnosed using a the treatment of neuropathic pain in DPN. multifaceted approach, including the neuropathy symptom score, neuropathy disability score, and nerve conduction studies, was found in 66% and 59% of MATERIALS AND METHODS patients with type 1 and 2 diabetes, respectively. A comprehensive literature review was undertaken, Importantly, approximately 10% of participants had incorporating article searches in electronic databases a nondiabetic etiology of the neuropathy.16 (EMBASE, PubMed, OVID) and reference lists of A large-scale, multicenter study (N ¼ 6500) re- relevant articles with the authors' expertise in DPN. vealed DPN (based on questionnaire and examina- Articles published from inception of databases to tion) in 28.5%.4 A community-based study in December 2017 were identified. Data from articles ~15,000 patients with diabetes showed that 34% of that were felt not relevant by authors with the patients had symptoms of painful neuropathy, with an guidance of the senior reviewers (R.A.M., U.A.) were increased risk in patients with type 2 diabetes, women, excluded from the review. and people of South Asian origin.17 The prevalence of DPN is considered to be low in RESULTS patients with early type 1 diabetes; however, among Databases searches were undertaken and 188 papers participants in the Diabetes Control and Complica- were cited in the final manuscript. Authors excluded tions Trial (DCCT), the prevalences of abnormal studies that were not considered relevant to the aims neurologic exam results were almost 20% in those of this article. Further appraisal of selected articles on conventional treatment and almost 10% in those were undertaken and any relevant explanatory data on intensive treatment, after ~5 years of follow-up.18 from said articles were included in the present review In the EURODIAB IDDM complications study,19 as descriptive prose. which evaluated over 3000 patients across 16

2 Volume ] Number ] Z. Iqbal et al. countries, there was a 28% baseline neuropathy type 1 diabetes.30 The Pittsburgh Epidemiology of prevalence, which rose by 23.5% after 7 years. The Diabetes Complications Study suggested that duration risk factors for the development of neuropathy of diabetes, HbA1c, smoking status, and high-density included age, duration of diabetes, poor glycemic lipoprotein cholesterol are associated with control, elevated low-density lipoprotein cholesterol neuropathy.31,32 The Wisconsin Epidemiologic Study and triglycerides, hypertension, obesity, and of Diabetic Retinopathy reported a 20% decrease in 19 smoking. The EDIC (Epidemiology of Diabetes the prevalence of DPN for a 2% decrease in HbA1c 33 Interventions and Complications) study, following over 4 years of follow-up. In DCCT, HbA1c values up patients up for 13 years after the initial 6.5 years were 7.4% in the intensive group and 9.1% in the of the DCCT,8 showed an initial 64% reduction in the conventional group, and the risk reduction for incident risk for DPN in those on intensive compared to DPN with intensive glucose control was 64% after 6.5 conventional treatment during the DCCT period and years of follow-up.8 By the 5th year of the EDIC study, a 30% risk reduction was maintained in the follow-up despite HbA1c values in the 2 groups being similar EDIC study period.8 (8.1% vs 8.2%), the prevalences of DPN and cardiac More recently, the prevalence of DPN in youth with a autonomic neuropathy remained significantly lower in shorter duration of diabetes has been reevaluated. In patients who had been on intensive therapy compared SEARCH (the Search for Diabetes in Youth Study),20 a to standard therapy during DCCT.34 This phenomenon cohort of young people (aged o20 years) who had a has been termed metabolic memory. duration of diabetes of over 5 years were evaluated using In type 2 diabetes, the evidence for the role of the Michigan Neuropathy Screening Instrument.21 Data improved glycemic control in slowing the progression – from 1374 patients with type 1 diabetes and 258 with of neuropathy in patients is limited.35 37 ACCORD type 2 diabetes were studied, revealing prevalence rates of (Action to Control Cardiovascular Risk in DPN of 7% and 22%, respectively,21 suggesting an Diabetes )36 showed a significant reduction in loss of excessive burden of DPN even in adolescents. sensation to light touch, which was only 1 of 4 neuropathy end points after a follow-up of 5 years. Pathogenetic Treatments It should be noted that the intensive glucose-lowering Numerous pathogenetic treatments that target the regimen was associated with increased mortality underlying molecular and cellular mechanisms involved (hazard ratio ¼ 1.22; 95% CI, 1.01–1.46; P ¼ 0.04), in DPN, including aldose reductase inhibitors, benfoti- suggesting harm associated with tight glycemic control,6 amine, and protein kinase C inhibitors, have undergone and self-reported DPN conferred a higher risk for clinical trials over the past 4 decades.10 All have failed in mortality in the intensive glycemic control group than 38 Phase III clinical trials, and none have been approved by in those with a higher HbA1c and those on aspirin. the US Food and Drug Administration (FDA) as disease- modifying treatments for DPN.22,23 Multiple reasons Lipids have been cited for this failure. In part, the end points There is an association between plasma triglycerides/ selected, including composite clinical scores and quanti- remnant lipoproteins and the risk for DPN.19 In animal tative sensory testing (QST), which relies on patients' models, treatment with specific fatty acids, such as responses, are deemed to be subjective24 and prone to docosahexaenoic acid, have been shown to exhibit a high variability, and even objective measures such as protective effect and potentially even can reverse DPN.39 neurophysiology have been shown to have high It has been suggested that cholesterol-lowering treatments – interobserver variability.25 28 It is now also evident that (statins and ezetimibe)40,41 and triglyceride-lowering treat- the rate of DPN progression is slower than predicted,23 in ments (fibrates)40 may reduce the progression and severity part due to concomitant use of routine therapies such as of DPN. Well-planned randomized trials are needed to angiotensin-converting enzyme inhibitors,29 and therefore evaluate the impact of intensive plasma lipid normaliza- trials need to be of longer duration. tion on DPN.

Glycemic Control Diet and Lifestyle Interventions Glycemic control has been shown to prevent or In patients with IGT, lifestyle intervention could delay the progression of neuropathy in patients with arrest the underlying process that leads to neuropathy.

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The Diabetes Prevention Program study42 diabetes, there were improvements in body mass demonstrated that lifestyle changes and treatment index, systemic inflammation, metabolic parameters, with metformin reduced the prevalence of diabetes and small nerve fibers, as measured by corneal in those with IGT. Lifestyle intervention may also be confocal microscopy (CCM).47 effective in preventing DPN, as shown in the IGT Micronutrient deficiencies after bariatric surgery Causes Neuropathy study,43 in which diet and are associated with an acute neuropathy,48,49 and exercise counselling in subjects with IGT resulted in longer longitudinal studies that accurately phenotype increased intraepidermal nerve fiber density (IENFD) neuropathy are required to delineate potential risk and an improvement in neuropathic pain. factors for this condition.

Diagnosis of DPN Weight Loss The American Diabetes Association's position state- Experimental studies have shown that incretin- ment on diabetic neuropathy (2017) advises that the based therapies have valuable effects on diabetic early recognition of neuropathy and initiation of complications, independent of their glucose-lowering appropriate management are essential to the manage- abilities, mainly mediated by their antiinflammatory ment of patients with diabetes.50 Alternative etiologies 44 and antioxidative stress properties. However, in a of neuropathy should be actively diagnosed and treated. pilot study in patients with type 2 diabetes and mild to These include chronic inflammatory demyelinating moderate DPN, 18 months of treatment with polyneuropathy, B12 deficiency, hypothyroidism, and exenatide, compared with glargine, had no effect on uremia, which may concomitantly occur in diabetes.51 45 neuropathy. The tests frequently used to diagnose DPN have been In a meta-analysis of data from 10 studies, there listed in Table I, along with their advantages & was greater remission and lower risks for micro- disadvantages and type of nerve fiber they assess. vascular and macrovascular disease and mortality in the bariatric surgery group as compared to a non- Screening surgical treatment group in patients with type 2 Patients with type 2 diabetes mellitus should be diabetes after at least 5 years of follow-up.46 In a screened annually from diagnosis, and those with type study of bariatric surgery in patients with and without 1 diabetes, after 5 years of diagnosis.50 People with

Table I. A summary of the common tests used to assess neuropathy.

Test Advantage Disadvantage Type of Nerve

NCS Sensitive, specific, and Must be done by trained Large fiber reproducible and easily professional. standardized gold standard technique Only assesses large fiber damage. NDS Good predictor for risk for Does not detect sub-clinical large Large and small ulceration fiber damage. fiber QST Reproducible and reliable Subjective Large and small fiber Skin biopsy Gold Standard, reliable and Invasive procedure. Needs Small fiber reproducible specialized laboratory service. CCM Rapid, reproducible, non-invasive. Must be done by trained Small fiber Can detect small fiber damage and professional. track progression.

CCM ¼ corneal confocal microscopy; NCS ¼ nerve conduction studies; NDS ¼ neuropathy disability score; QST ¼ quantitative sensory testing.

4 Volume ] Number ] Z. Iqbal et al. prediabetes should also undergo an assessment for and the 10g monofilament. The exact pathophysio- neuropathy if symptoms are present.50 logic mechanisms of DPN remain to be elucidated, and treatments targeted at the natural history and Assessment pathophysiologic mechanisms of DPN are urgently The assessment of patients for DPN should include required. a careful and focused history. Symptomology of neuropathy will differ according to the type of nerve Diagnostic Definition fiber involvement. Patients with large fiber dysfunc- The Toronto Diabetic Neuropathy Expert group57 tion may experience numbness, tingling, or poor classifies DPN as: balance. Small fiber neuropathy (SFN) may present with neuropathic pain described as burning, stabbing, 1. Confirmed DPN—abnormal nerve conduction and or electric shocks. Pain is the trigger for patients to a symptom or sign of neuropathy; seek medical care in 25% of patients diagnosed with 2. Probable DPN—2 or more of the following signs or DPN.13,52 symptoms: neuropathic symptoms, decreased distal fl Many patients may be asymptomatic, and thus sensation, or decreased/absent ankle re exes; or — examination is key to the diagnosis. A bedside test 3. Possible DPN any of the following symptoms: decreased sensation, positive neuropathic sensory should be employed for both small and large fiber symptoms (eg "asleep numbness," prickling/stab- neuropathy, such as the neuropathy disability score bing, burning, or aching pain), predominantly in (NDS), which is a validated reliable and reproducible the toes, feet, or legs; OR signs, including symmet- screening tool that can also assess the severity of ric decrease of distal sensation or decreased/absent neuropathy. The NDS consists of testing sensory ankle reflexes. modalities, which include pain sensation (pinprick), temperature perception (using hot and cold rods), and vibration (128-Hz tuning fork), all scored as either The ADA's position statement does not recommend normal (0) or reduced/absent (1). Abbott et al53 the use of neurophysiology for the diagnosis of typical showed that a neuropathy disability score of 46/10 DPN, and this testing modality should be reserved for was an independent risk factor for new foot ulcers. All patients in whom atypical features are present or the patients should undergo annual 10-g monofilament diagnosis is unclear. and pedal pulse evaluation to assess the risk for foot ulcers.50 The key is that the 10-g monofilament should Neuropathy Symptoms not be used to diagnose or exclude DPN as it detects Questionnaires are a subjective method to assess only advanced neuropathy. Indeed, in a recent and quantify the severity of neuropathic symptoms systematic review it was shown to have a very poor and pain. The McGill Pain Questionnaire58 is widely diagnostic utility, with a sensitivity of 88% but a used to evaluate neuropathic pain. Other specificity of only 55%, when nerve conduction was questionnaires specifically developed for neuropathic used to diagnose DPN.54 The alternative 1-g pain quantification are the Brief Pain Inventory,59 monofilament may, however, be better for detecting Neuropathic Pain Questionnaire,60 Neuropathic Pain earlier neuropathy.55 The assessment of SNF remains Symptom Inventory,61 and the Doleur Neuropathique a particular challenge, especially in diabetic 4.62 The Neuropathic Symptom Profile has been neuropathy.56 validated to detect and stage the severity of DPN is common, and the diagnosis of DPN begins neuropathy.63 The Brief Pain Inventory, Neuropathic with a careful history and examination of sensory and Pain Questionnaire, Neuropathic Pain Symptom motor symptoms and signs. The quality and severity Inventory and NSP are all validated self- of neuropathic pain, if present, should be assessed administered questionnaires. using a validated method that is reproducible, such as the Michigan Neuropathy Screening Instrument. Ex- Quantitative Sensory Testing amination within a clinic setting should include QST, which includes a thermal threshold assess- inspection of the feet and evaluation of reflexes and ment for cold sensation (A-δ fibers) and warm sensa- sensory responses to vibration, light touch, pinprick, tion (c fibers), assesses small fiber dysfunction and

] 2018 5 Clinical Therapeutics therefore can detect early neuropathy, but is highly Novel Surrogate Imaging Markers of DPN subjective. However, QST is a sensitive method of Corneal Confocal Microscopy detecting SFN, particularly in those patients with Over the past 2 decades, the significance of evalu- normal nerve conduction study results,64 and may ating corneal nerve morphology as a surrogate marker be used where no definitive quantitative structural for peripheral neuropathies has been established. assessment of small nerve fibers (skin biopsy or CCM) CCM has been suggested as a surrogate end point can be undertaken. for the assessment of DPN, as it allows direct visual- Also, vibration perception threshold, assessed using ization of peripheral nerves and is a rapid, non- a biothesiometer, correlates with the severity of DPN, invasive, and objective technique,72,73 with high and a vibration perception threshold of 425 V is a sensitivity and specificity to diagnose early nerve fiber strong predictor of foot ulceration.65 damage23 and repair.74 Several studies have shown that CCM is highly correlated with IENFD loss23 and Nerve Conduction Studies is comparable to the diagnostic ability of skin Nerve conduction studies (NCSs) are commonly biopsy.75,76 A number of parameters are used to used to assess the severity of DPN and are considered quantify the corneal sub-basal nerve plexus and to be sensitive and specific for DPN.66 Interestingly, include corneal nerve fiber length, corneal nerve Dyck et al24 compared NCS to individual physicians' branch density, and corneal nerve fiber density. clinical diagnosis of DPN and found that clinician's CCM has been extensively used to identify small diagnoses were excessively variable and frequently nerve fiber damage in a range of peripheral neuro- inaccurate, with an overestimation of DPN. Vinik pathies, including DPN,77,78 HIV neuropathy,79 et al67 conducted a study in 205 patients with both chemotherapy-induced peripheral neuropathy,80 type 1 and 2 diabetes and mild DPN and showed that CIDP,81 Fabry disease,82 and idiopathic SFN.83 sural nerve conductivity correlated well with the CCM can detect subclinical small nerve fiber severity of DPN. However, NCSs evaluate only large damage in patients with IGT84 and has been shown myelinated nerve fibers and cannot detect an early to predict the development of DPN85 and the end SFN as commonly seen in prediabetes and short- points of foot ulceration and Charcot foot.86 CCM duration diabetes. The ADA's position statement may be an ideal technique to monitor the progression does not advocate the routine use of NCS, and it of DPN, as it is noninvasive and hence reiterative.87 should be reserved for patients with atypical features in whom the diagnosis is unclear.50 Optical Coherence Tomography Skin Biopsy Optical coherence tomography is a noninvasive, Skin biopsy enables direct visualization of thinly reproducible ophthalmic imaging technique that was myelinated and nonmyelinated nerve fibers that are recently introduced as a surrogate end point for the the earliest to be affected in DPN. Skin biopsy can be assessment of retinal nerve fiber loss in neurologic used to diagnose SFN.68 The European Federation for conditions.88,89 Retinal nerve fiber layer (RNFL) Neurological Societies' guidance recommends a punch thinning is reported in patients with DPN associated skin biopsy at the distal leg or proximal thigh for the with the severity of neuropathy, particularly in pa- diagnosis of SFN.69 The assessments of intraepidermal tients with a higher risk for foot ulceration.90 Previous nerve fibers and IENFD are currently advocated in studies have suggested that RNFL loss in patients with clinical practice in the United States43 and are diabetes may be independent of diabetic retinopathy recommended as an end point in clinical trials.23 and represents a distinct type of neuropathy.91,92 Pittenger et al70 showed a reduction in IENFD in Measuring RNFL thickness has also been suggested patients with SFN, with a sensitivity between 74% as a potentially useful means to assess and monitor and 87.5%, and that IENFD was inversely correlated axonal loss in patients with DPN, as RNFL thinning with QST. An inverse correlation has also been shown was greater in patients with DPN compared to those between IENFD and the duration of diabetes, without DPN over the course of 4 years.93 However, neurologic impairment score, and results of sensory larger-scale, longitudinal prognostic and interven- evaluation.70,71 tional studies using optical coherence tomography as

6 Volume ] Number ] Z. Iqbal et al. a surrogate marker are required before routine use of paroxysms and deep aching pain was found in those this modality can be recommended. with IN.100 We have also demonstrated preclinical The use of optical coherence tomography as a evidence on the physiology and pharmacology of rate- possible diagnostic modality is still in its infancy and dependent depression of the spinal H-reflex as a requires longitudinal studies alongside established marker for spinal disinhibition in painful diabetic biomarkers, such as electrophysiology and skin bi- neuropathy,101 and recently translated the use of opsy. CCM has a wealth of research, particularly in rate-dependent depression as a biomarker of spinally DPN. However, the availability of CCM as a diag- mediated pain to a personalized-medicine approach in nostic modality is limited due to a lack of expertise the treatment of painful DPN.102 In this section, we in its use as a surrogate marker in peripheral consider the current pharmacologic treatments for neuropathies. alleviating pain in DPN, the most frequently used of which are highlighted in Table II. Symptomatic Treatment of DPN Neuropathic pain is a debilitating feature of DPN Antidepressants resulting in significant morbidity.94 Current guidelines Neurologic pathways implicated in mood disorders advocate the use of therapies targeting the symptoms of share neurotransmitters with pathways associated painful DPN, particularly as there is a lack of treatments with pain processing.103 It is therefore not surprising targeting the pathogenetic mechanisms. Although that there is a dual utility in alleviating neuropathic measures such as tight glycemic control may prevent pain. the progression of diabetic neuropathy, there is no evidence that improved glycemic control improves pain Tricyclic Antidepressants in DPN. Moderate improvements in pain are considered The precise mechanism of action of TCAs in to be ~30% to 50% pain relief, whereas 450% pain analgesic efficacy is unclear, but they are thought to relief is considered a good outcome.95 A recent indirectly modulate the opioid system in the brain via systematic review concluded that duloxetine, serotonergic and norepinephrine neuromodulation, – venlafaxine, pregabalin, oxcarbazepine, tricyclic among other properties.104 106 TCAs require up-titra- antidepressants (TCAs), atypical opioids, and tion to effective doses, often over a period of 6 to 8 botulinum toxin were more effective than placebo for weeks before reasonable effects are noted; hence, relieving neuropathic pain, but quality of life was poorly compliance may sometimes be compromised.107 A reported. Studies were however short term and drugs meta-analysis by Rudroju et al108 concluded that had substantial discontinuation rates of ~10%.96 amitriptyline was the least effective but a well- The limited benefit of any one agent alone reflects tolerated agent compared to other antidepressant the complex etiologic basis of neuropathic pain. Thus, agents used to treat painful DPN. In a joint report there is an increasing recognition that "one size does on painful DPN from the American Academy of not fit all," and rather than having an agnostic Neurology, the American Association of approach (ie, blindly trying different therapies until Neuromuscular and Electrodiagnostic Medicine, and one works), we should consider better clinical pheno- the American Academy of Physical Medicine and typing and targeted therapies.97 However, superficial Rehabilitation, published in 2011, it was concluded clinical phenotyping in relation to symptomatology that amitriptyline has the greatest efficacy among the has not been shown to improve the response to TCAs.109 Despite studies showing the efficacy of therapy.98 More detailed phenotyping using QST imipramine,110 it was also concluded that there is has shown that patients with an irritable nociceptor currently insufficient evidence for the routine use of (IN) phenotype (n ¼ 31) compared to a non-IN imipramine. phenotype (n ¼ 52) had a significantly greater TCAs remain as the first- or second-line recom- response to oxcarbazepine and a reduced overall mendations in all 5 international guidelines on pain number needed to treat (NNT) (6.9 vs 3.9).99 In a management in DPN, with most citing amitriptyline as smaller-scale study, the relative efficacy of 5% the drug of choice among the TCAs (Table III). The lignocaine was assessed in 15 patients with IN and 2017 position statement from the ADA stated that, 25 patients with non-IN, a greater effect on pain although effective for the treatment of neuropathic

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Table II. Commonly used therapies for painful diabetic peripheral neuropathy.

Common Initial Maintenance Adverse Drug Class Agent Dose Dose Reactions Common Drug Interactions

Anticonvulsants Pregabalin 25–75 mg 300–600 mg Dizziness Respiratory depression when TID daily Somnolence combined with opioids. Additive Headache effects on cognition and motor Weight gain function may occur when combined Nausea with benzodiazepines, alcohol, or Vomiting opioids. Dry mouth Gabapentin 100–300 900– 3600 Dizziness mg TID mg daily Somnolence Ataxia Fatigue Antidepressants Duloxetine 20–30 mg 60–120 mg Somnolence Avoid concurrent use with irreversible once once daily Dizziness MAOIs due to increased risk for daily serotonin syndrome. Headache Combination with tramadol may Nausea lower seizure threshold. Dry mouth Avoid use with ciprofloxacin. Reduced appetite Venlafaxine 37.5 mg 75–225 mg Nausea Avoid use with MAOIs due to once once daily Dizziness increased risk for serotonin daily syndrome. Constipation Avoid use with linezolid (a weak MAOI). Dry mouth Concurrent use with other SNRIs, Weight loss SSRIs or serotonin receptor Constipation agonists (eg, triptans) increases risk for serotonin syndrome. Potential use is advised with caution. Amitriptyline 10–25 mg 25–100 mg Abdominal Avoid MAOIs due to risk for serotonin once once daily pain syndrome. daily Fatigue Concurrent use with drugs prolonging QT interval may predispose to ventricular arrhythmias. Headache Concurrent use with tramadol may precipitate development of the serotonin syndrome and should be done with caution. Dizziness Concurrent use with anticholinergic Insomnia drugs may potentiate their effects, Orthostatic thus increasing the risk for paralytic hypotension ileus.

(continued)

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Table II. (continued).

Common Initial Maintenance Adverse Drug Class Agent Dose Dose Reactions Common Drug Interactions

Anorexia Nausea Urinary retention Constipation Blurred vision Mydriasis Weight gain Xerostomia Somnolence Opioids Tramadol 50 mg 200– 400 mg Constipation Concurrent use with MAOIs and QID QID linezolid increases risk for serotonin syndrome. Somnolence Combination therapy with SSRIs, Nausea SNRIs, TCAs, or antipsychotics can Headache lower seizure threshold, leading to Dizziness convulsions. Combination use with caution is advised. Tapentadol 50–100 600 mg daily Same as Concurrent use with SSRIs or SNRIs (immedi- mg 4–6 above may increase risk for serotonin ate times syndrome. Use with caution is release) per day advised. Can take Concurrent use with MAOIs can result 700 mg in hypertensive crisis. on first Use with enzyme inducers such as day rifampicin or St John's wort may reduce efficacy.

MAOIs ¼ monoamine oxidase inhibitors; SNRIs ¼ serotonin norepinephrine re-uptake inhibitors; SSRIs ¼ selective serotonin re-uptake inhibitors; TCAs ¼ tricyclic antidepressants.

pain, TCAs should be used with caution given randomized, controlled trial and showed some effi- their higher-risk profile, particularly in elderly cacy.114 These drugs primarily exert their effect via populations.50 inhibiting serotonin and norepinephrine reuptake, resulting in the excitation of inhibitory descending Serotonin–Norepinephrine Reuptake Inhibitors pathways with alleviation of neuropathic pain.115 Two serotonin–norepinephrine reuptake inhibitors Duloxetine at both 40 mg and 60 mg has shown are used in painful DPN, duloxetine and, to a lesser efficacy in treating painful DPN.116 A Cochrane extent, venlafaxine, which does not have FDA appro- review including 8 trials (n ¼ 2728) showed that 60 val for use in the treatment of painful DPN. A third mg of duloxetine daily was more efficacious compared serotonin–norepinephrine reuptake inhibitor is des- with placebo, with a 50% pain reduction by 12 weeks venlafaxine, which was evaluated in a single (NNT ¼ 5; 95% CI, 4–9).117 Tanenberg et al118

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Table III. Current guidelines for painful diabetic peripheral neuropathy.

Line of Treatment EFNS (2010)111 AAN (2011)109 NICE (2013)112 AACE (2015)113 ADA (2017)50

1st line Amitriptyline Pregabalin Amitriptyline Amitriptyline Duloxetine Duloxetine Duloxetine SNRI Pregabalin Pregabalin Pregabalin Pregabalin Venlafaxine Gabapentin Gabapentin Sodium valproate Clonidine Gabapentin 2nd line Tramadol Amitriptyline Amitriptyline Tramadol TCA Opioids Duloxetine Duloxetine Tapentadol Gabapentin Sodium Valproate Pregabalin Topiramate Venlafaxine Gabapentin Oxcarbazepine Gabapentin Lidocaine 5% Tramadol Capsaicin Opioids Capsaicin 3rd line Capsaicin Tramadol

AACE ¼ American Association of Clinical Endocrinologists; AAN ¼ American Academy of Neurology; ADA ¼ American Diabetes Association; EFNS ¼ European Federation of Neurological Societies; NICE ¼ National Institute of Clinical Excellence (UK); SNRI ¼ serotonin norepinephrine reuptake inhibitor; TCA ¼ tricyclic antidepressant. showed that duloxetine was noninferior to pregabalin venlafaxine must be slowly weaned to reduce the in treating painful DPN in patients exhibiting an potential for adverse events,124 and it has not been inadequate response to gabapentin. Duloxetine has a approved by the FDA for use in treating neuropathic superior safety profile compared to amitriptyline, pain. owing to the comparably lower rates of anticholinergic side effects. However, one study Anticonvulsants found a 20% and 14% respective prevalence of Similarities in the mechanisms of neuropathic pain somnolence and constipation in a cohort of patients and epilepsy led to the use of anticonvulsant medi- treated with 60 mg of duloxetine daily.119 A post hoc cations in the treatment of painful DPN.125 analysis of 3 pooled, double-blind, placebo-controlled Carbamazepine has been used efficaciously in the trials evaluating the use of duloxetine in older patients management of trigeminal neuralgia for many years; (aged 465 years) advocated the tolerability and however, a Cochrane Collaboration review found that efficacy of this drug in the older population.120 it had limited utility in the treatment of painful Venlafaxine showed efficacy in treating painful DPN,126 and it is not recommend for painful DPN. DPN in a double-blind placebo controlled trial in Similarly, in a recent Cochrane review, oxcarbazepine which pain-intensity visual analog scale (VAS) scores showed little evidence for efficacy in painful diabetic were used as the primary outcome measure.121 A neuropathy.127 Cochrane Collaboration systematic review122 of venlafaxine for the treatment of neuropathic pain α2δ Ligands reported an NNT of 3.1 (95% CI, 2.2–5.1), which Gabapentin is a lipophilic analogue of γ-amino- 123 is comparable to that of amitriptyline. Venlafaxine butyric acid that binds to the α2δ1 subunit of the has shown superiority to duloxetine in some studies; voltage-gated calcium channel on the presynaptic however, there is a lack of larger-scale trials showing membranes and reduces excitability of chiefly gluta- this effect.124 Additionally, it is important to note that minergic neurones.128

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Backonja et al129 investigated its use in neuropathic efficacy and tolerability between high-dose monother- pain in a double-blind, placebo-controlled trial of apy and standard-dose combination therapy with patients randomized to either gabapentin or placebo. both pregabalin and duloxetine.139 This Significant improvement in pain scores were seen 8 multinational, randomized, double-blind, parallel- weeks after the start of treatment.129 Asystematic group trial was conducted in patients with painful review of 35 studies (n ¼ 727) in patients with DPN resistant to standard-dose monotherapy. After unselected neuropathic pain concluded that randomization and elimination of noneligible patients, gabapentin was an effective agent in alleviating pain; 173 received high-dose monotherapy with either however, its effectiveness may be reduced if duloxetine 120 mg daily or pregabalin 600 mg daily, administered at low doses.130 Rudroju et al108 and 170 patients received combination therapy with compared the efficacy and tolerability of 6 agents used duloxetine 60 mg daily and pregabalin 300 mg in the management of painful DPN in a meta-analysis daily.139 A 2-point reduction in the Brief Pain of data from 21 trials and concluded that gabapentin Inventory score was the primary outcome measure; provided a good balance between tolerability and no significant difference was shown when comparing efficacy for the treatment of painful DPN. the standard-dose combination therapy to the high- Pregabalin, another analogue of γ-aminobutyric dose monotherapy therapy in those who did not acid has higher potency and has been approved achieve adequate pain relief on standard-dose by the FDA for use in treating painful DPN duloxetine or pregabalin.139 based on several robust randomized, controlled trials In a secondary analysis, duloxetine 60 mg was that have shown its efficacy in the treatment of found to be more efficacious compared with pregaba- – painful DPN.131 133 Snedecor et al134 undertook a lin 300 mg/day in the initial 8-week run in phase. To comparative meta-analysis of data from studies of a date, this is the only head to head trial of duloxetine number of agents in the treatment of painful DPN and and pregabalin. A further exploratory post hoc anal- found pregabalin to be the most efficacious in ysis of data from Combination vs. Monotherapy of reducing pain VAS scores. pregaBalin and duloxetine in Diabetic Neuropathy Somnolence is listed as a common side effect of (COMBO-DN) showed that high-dose monotherapy pregabalin, as studies in healthy volunteers have was favorable in patients with severe pain, whereas shown that it enhances slow-wave sleep. A placebo- combination therapy was more beneficial in patients controlled trial evaluated the efficacy of pregabalin, with moderate and mild pain.140 Also, patients who amitriptyline, and duloxetine in pain relief and the received duloxetine (60 mg/d) as initial therapy had a effects on sleep.135 Duloxetine increased sleep better response to combined duloxetine and fragmentation, while pregabalin promoted sleep.135 pregabalin for evoked or severe tightness and a These findings are in agreement with those from greater benefit with high-dose duloxetine (120 mg/d) previous studies showing that pregabalin improves for paresthesia–dysaesthesia.140,141 subjective sleep and quality of life in patients with painful DPN.136,137 Side effects include edema and Other Anticonvulsants mood disturbance, and it is important to warn The use of topiramate has been evaluated in several patients not to abruptly discontinue its use, as this placebo-controlled trials, with differing results. Raskin has been linked to the development of seizures, et al142 randomized 323 subjects to topiramate versus cerebral edema, and encephalopathy.138 Both placebo and found a significant 30% reduction in pain gabapentin and pregabalin are commonly prescribed VAS scores with topiramate.142 A recent smaller study as first-line agents for treating painful DPN, and this is from Iran143 showed that gabapentin and topiramate indeed a reflection of the current recommendations. equally reduced pain scores.143 However, a Cochrane Collaboration review of data from 3 placebo- COMBO-DN Study controlled, parallel-group trials showed that The only 2 medications with both FDA and Euro- topiramate lacks evidence of efficacy in painful DPN.144 pean Medicines Agency approval for use in the treat- Lamotrigine is chemically unrelated to other anti- ment of painful DPN are pregabalin and duloxetine. epileptic agents. It is thought to exert its antiepileptic The COMBO-DN study was designed to compare the effect via sodium channels. Lamotrigine has been

] 2018 11 Clinical Therapeutics assessed in painful DPN. Eisenberg et al145 observed a use of modified-release tapentadol for the treatment of significant reduction in the numeric pain scale in 83% neuropathic pain.151 of patients randomized to lamotrigine compared to 73% receiving placebo, but this study was relatively Opioid Agonists small-scale (n ¼ 59). In an analysis of data from 2 There is increasing concern for opioid dependency, randomized trials, lamotrigine (300 and 400 mg daily) especially during long-term use, despite the efficacy of showed inconsistent effects in DPN, and while it was opioids in treating neuropathic pain.152 A Cochrane well tolerated,146 it cannot be advocated for use in Collaboration review153 evaluated the use of painful DPN.147 oxycodone modified release, morphine, levorphanol, A double-blind, placebo-controlled trial of lacosa- and methadone in the treatment of neuropathic pain mide found it to be efficacious compared to placebo; and found that, in studies lasting 12 weeks or less, however, the cohort receiving 600 mg daily had a opioids exhibited a significant analgesic effect much higher withdrawal rate due to adverse reactions, compared to placebo, but the results were subject to such as nausea, tremor, headache, and fatigue.148 The bias due to relatively small sample sizes and short efficacy of lacosamide over placebo was also marginal, duration of studies.153 Additional data are needed to and it is therefore currently not recommended for use characterize long-term efficacy and the safety profile in painful DPN.147 of opioids in neuropathic pain.

Opioid Analgesia Topical Medications Partial µ-Receptor Agonists Topical treatments for painful DPN may be partic- Tramadol is a centrally acting synthetic opioid that ularly useful for patients not tolerating conventional is a nonselective agonist with affinity at the µ-, δ-, and systemic therapies, as there is a reduced prevalence of κ-opioid receptors, with preferential affinity for the µ- adverse effects.154 Furthermore, the risk for drug– receptor, and also inhibits norepinephrine and sero- drug interactions is also significantly reduced, making tonin reuptake.149 A Cochrane Collaboration review topical therapies more attractive for a growing found that the efficacy of tramadol in neuropathic number of patients with multiple comorbidities and pain was determined in small-scale, largely inadequate polypharmacy. studies with a potential risk for bias.149 Although data Capsaicin is a naturally occurring alkaloid found in from 3 of these trials were further analyzed in a meta- red chili peppers. It works by selectively agonizing analysis and showed an NNT for 50% pain reduction the transient receptor potential vanilloid 1 (TRPV1) of 4.4 (95% CI, 2.9–8.9),149 it still concluded that receptor, which is expressed on small nerve fibers. there were insufficient data of adequate quality to Downstream signals from the TRPV1 receptor result provide convincing evidence that tramadol is effective in the release of substance P and its subsequent in relieving neuropathic pain.149 Anecdotally, depletion, which causes a reduction of painful stimuli tramadol may be used to treat breakthrough pain in conveyed to the CNS.155,156 The Capsaicin Study combination with other neuropathic pain agents, Group conducted a double-blind, placebo-controlled although its use in combination with TCAs and trial (n = 277) of 0.0075% topical capsaicin and serotonin–norepinephrine reuptake inhibitors is found a significant reduction in pain, as measured by cautioned due to the increased risk for serotonin physicians' global evaluation and a VAS scale.157 syndrome, with increased risks for confusion, Capsaicin is currently recommended as third-line seizures, labile blood pressure, and, in extreme cases, therapy in the United Kingdom's National Institute coma and death. of Clinical Excellence guidelines and second-line by Tapentadol is similar to tramadol in its mechanism the American Academy of Neurology for the of action. Schwartz et al150 conducted a 12-week treatment of neuropathic pain. Its use is severely open-label study in 396 patients with DPN, which limited by the frequency of application (4 times demonstrated a 30% pain reduction in 65% of daily) and burning pain frequently induced on patients and a 50% pain reduction in 34.9% of application. Of concern, capsaicin has been shown patients.150 A subsequent 12-week study confirmed to lead to a reduction in thermal nociception and total these earlier data, and in 2012 the FDA approved the denervation, with a putative increased risk for diabetic

12 Volume ] Number ] Z. Iqbal et al. foot ulceration, and is not recommended in the Gordon of the Royal Canadian Army Medical Corps treatment of painful DPN.158 used IV procaine to successfully provide analgesia to Furthermore, currently not included in any pub- burn patients as early as 1943.163 Viola et al164 was the lished guidance for painful DPN is the 8% capsaicin first group to evaluate the effectiveness of IV lidocaine patch, which was initially tested in patients with infusion, in a double-blind, placebo-controlled trial in postherpetic neuralgia. A recent review reported its patients with intractable painful DPN refractory to efficacy in a number of neuropathies of varying standard treatment. A randomized, placebo-controlled etiology and included data from a 12-week double- trial of IV lidocaine infusion in 15 patients showed a blind trial in patients with painful DPN, in whom it significant analgesic effect, which persisted for up to 28 improved both pain and sleep quality significantly; yet days.164 There were no significant side effects of this the review, despite including a study on the use of treatment, although this cohort was small. The efficacy capsaicin in skin biopsies, failed to report on the of lidocaine seems to be due to several independent outcomes.159 modes of action targeting neuropathic pain. Lidocaine Lidocaine plaster 5% applied for 18 h/d has been modifies sodium channel expression, reducing peripheral shown to effectively provide relief in painful DPN and nociceptive sensitization,165 and it also has anti- has been extensively used in postherpetic neuralgia. A inflammatory properties similar to those of systematic review of data from 38 studies found a conventional anti-inflammatory drugs.166 Inflammatory significant pain reduction using the 5% lidocaine cytokines are thought to play a role in secondary patch that was comparable to those with amitripty- hyperalgesia and the sensitization of the CNS to line, capsaicin, gabapentin, and pregabalin.154 The inappropriate pain signals.167 lidocaine patch was also found to be associated with fewer and less clinically significant side effects Emerging Therapies for Painful DPN compared to systemic agents.154 A meta-analysis Virtually no new novel analgesics have been app- reported that the 5% lidocaine patch was as roved by the FDA for the treatment of neuropathic efficacious as pregabalin in treating painful DPN.134 pain over the past 20 years. There are several emerging Topical isosorbide dinitrate has been evaluated in treatments that may potentially shift the pharmacologic the treatment of painful DPN. Impaired nitric oxide paradigm in the treatment of neuropathic pain synthesis has been found to play a role in DPN (Table IV). Such targets include suppression of pathogenesis. The vasodilatory response to nitrogly- glutaminergic neurotransmission,168 N-methyl- 169 cerin directly releases nitric oxide, suggesting a poten- D-aspartate receptor antagonism, angiotensin II tial role for its use in patients with DPN.160 Alterations receptor type 2 antagonism, and presynaptic modula- of neuronal nitric oxide synthase in the dorsal root tion of cannabinoids170 and humanized anti–nerve ganglion cells and in the spinal cord may contribute growth factor monoclonal antibodies.171 to spinal sensory processing, as well as to the Dextromethorphan is an N-methyl-D-aspartate re- development of neuronal plasticity phenomena in the ceptor antagonist that has been evaluated in Phase III dorsal horn of the spinal cord, as previously described clinical trials for the treatment of painful DPN. In in experimental studies.160 Yuen et al161 found addition, it also has properties of serotonin reuptake significant reductions in pain and intensity in a inhibition. Administered as monotherapy, dextrome- double-blind trial recruiting 22 patients. Later, thorphan has limited bioavailability due to rapid Rayman et al162 described a case series of 18 patients catabolism by hepatic cytochrome P-450 2D6. It must treated with glyceryl-trinitrate patches with localized therefore be administered with a potent P-450 2D6 pain showing a reduction in pain scores. Topical inhibitor such as quinidine. Shaibani et al172 evaluated lidocaine and glyceryl-trinitrate patches may be used 2 doses of dextromethorphan/quinidine, 45/30 mg in combination to provide 24-hour pain cover with and 30/30 mg, in a double-blind, placebo-controlled alternating 12-hour applications of each therapy. trial (n ¼ 379) and showed that dextromethorphan/ quinidine was significantly more efficacious compared Intravenous Lidocaine with placebo, with a reasonable safety profile. IV lidocaine has been used in the treatment of pain Desvenlafaxine is the most potent metabolite of the produced by nerve injury for many years. Major parent compound venlafaxine and has been evaluated

] 2018 13 Clinical Therapeutics

Table IV. Emerging therapies for the treatment of painful diabetic peripheral neuropathy.

Drug Drug Class Developer

Dextromethorphan/quinidine Glutamate antagonist Avanir, New York, New York combination EMA401 Angiotensin II type 2 receptor Novartis, East Hanover, New Jersey antagonist Capsaicin, dermal patch (NGX- Vanilloid-receptor agonist NeurogesX, San Mateo, California 4010) Desvenlafaxine SR SNRI Wyeth, Madison, New Jersey Lacosamide (SPM-927) Amino acid anticonvulsant Schwarz Pharma, Mequon, Wisconsin Lamotrigine once daily Anticonvulsant GlaxoSmithKline, Research Triangle Park, North Carolina Oravescent fentanyl Opioid agonist Cephalon, Frazer, Pennsylvania Tramadol ER Mu-opioid antagonist and SNRI TheraQuest Biosciences, Blue Bell, Pennsylvania GW-406381 COX-2 inhibitor GlaxoSmithKline Cibinetide (ARA290) Peptide of erythropoietin Araim, Tarrytown, New York Innate repair receptor and TRPV1 antagonist

COX ¼ cyclooxygenase; ER ¼ extended release; SNRI ¼ serotonin–norepinephrine reuptake inhibitor; SR ¼ sustained release; TRPV1 ¼ transient receptor potential vanilloid 1. in patients with painful DPN.114,173 In a Phase III significantly increased small nerve fiber abundances multicenter, randomized placebo-controlled trial (n = in the cornea and skin, with improved neuropathic 412), graduated doses of 200 and 400 mg/d desvenla- pain in patients with DPN178 and sarcoid faxine were found to be effective in relieving pain and neuropathy.179 improving activity.114 Tanezumab is a fully humanized anti–nerve growth EMA401 is an angiotensin II type 2 receptor factor monoclonal antibody. However, this class of antagonist that was evaluated in a multicenter, drugs has a long and checkered history, with the FDA randomized, placebo-controlled trial in 183 patients placing a clinical hold on clinical studies of anti–nerve with postherpetic neuralgia over 28 days and showed growth factor monoclonal antibody in late 2010, benefit.174 Anand et al175 showed angiotensin 2 because of reports of serious joint-related adverse immunostaining in 75% of small- to medium- events and sympathetic nerve damage tolerability diameter human dorsal root ganglia neurons and concerns. However, the FDA lifted its hold in March that this was the major ligand for angiotensin II type 2015, and in 2017 granted fast-track status as a 2 receptor.175 Angiotensin 2–mediated angiotensin II nonopioid pain medication,180 particularly for hip type 2 receptor signaling was reversed by EMA401, and knee osteoarthritis.181 In the only reported establishing a mechanism for its action in neuropathic study in DPN, 20 mg of SC tanezumab was pain.175 administered on day 1 and week 8 and showed a Cibinetide (ARA290), a nonhematopoietic peptide reduction in DPN pain but no improvement in of erythropoietin, interacts selectively with the innate patients' global assessment of pain.182 repair receptor–mediating tissue protection176 and Vitamin D deficiency is associated with paresthesia also antagonizes the transient receptor potential and parasympathetic dysfunction183,184 and is highly vanilloid 1 receptor,177 mediating disease-modifying prevalent in diabetic populations.185 Shebab et al186 and analgesic effects, respectively. It has shown showed that vitamin D deficiency is a risk factor for

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] 2018 15 Clinical Therapeutics

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