Approach to painful diabetic peripheral neuropathy

Shraddha B Lumpatki; Karakkattu V Kavitha; Manas V Manohar; Ambika G Unnikrishnan

doi:10.4103/cdrp.cdrp_4_22

REVIEW ARTICLE

Year : 2022 | Volume : 1 | Issue : 2 | Page : 99-113

Approach to painful diabetic peripheral neuropathy

Shraddha B Lumpatki¹, Karakkattu V Kavitha², Manas V Manohar³, Ambika G Unnikrishnan¹
¹ Department of Diabetology and Endocrinology, Chellaram Diabetes Institute, Pune, Maharashtra, India
² Department of Podiatry, Chellaram Diabetes Institute, Pune, Maharashtra, India
³ Department of Anaesthesia and Pain Management, Chellaram Diabetes Institute, Pune, Maharashtra, India

Date of Submission	01-Apr-2022
Date of Decision	05-May-2022
Date of Acceptance	05-May-2022
Date of Web Publication	16-Jul-2022

Correspondence Address:
Ambika G Unnikrishnan
Department of Diabetology and Endocrinology, Chellaram Diabetes Institute, Lalani Quantum, NH-4, Bavdhan (Budruk), Pune - 411 021, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cdrp.cdrp_4_22

Abstract

Painful diabetic peripheral neuropathy (PDPN) is a commonly encountered problem by a physician and poses a major treatment challenge. Although poor glycemic control is considered to be a main cause for the development of peripheral neuropathy, the overall etiopathogenesis remains unclear and needs further research. There are various tools to assess the status of nerves, but PDPN being a subjective factor is often measured in terms of pain scores or pain scale looking at the intensity and the phenotype of pain. PDPN affects the individual's quality of life and daily living and often disturbs the sleep and mental health. The management of PDPN includes achieving good glycemic control, following foot care practices, including the use of appropriate footwear and treatment for pain relief. The treatment of choice varies from topical application to the pain relieving patches and use of drugs such as anticonvulsants, antidepressants, and opioids which have shown some beneficial effect. Interventional and regional anesthesia have also been tried for the treatment of PDPN. Surgical decompression has shown a favorable effect on pain relief. There are unmet needs in the therapeutic management of PDPN, as available drugs give acceptable pain relief in very few patients, and fear of side effects may limit full-dose treatment. Till date, no medicine is available to reverse neuropathy.

Keywords: Complications, diabetes mellitus, neuropathic pain, neuropathy, painful neuropathy

How to cite this article:
Lumpatki SB, Kavitha KV, Manohar MV, Unnikrishnan AG. Approach to painful diabetic peripheral neuropathy. Chron Diabetes Res Pract 2022;1:99-113

How to cite this URL:
Lumpatki SB, Kavitha KV, Manohar MV, Unnikrishnan AG. Approach to painful diabetic peripheral neuropathy. Chron Diabetes Res Pract [serial online] 2022 [cited 2023 Mar 29];1:99-113. Available from: https://cdrpj.org//text.asp?2022/1/2/99/351236

Introduction

Painful limb is a commonly faced challenge and needs to be distinguished between musculoskeletal, vascular, and neurological cause. The focus of this article is limited to neuropathic pain associated with diabetes. Neuropathic pain occurs as a result of direct damage to the somatosensory nerves, worldwide the most common cause of it is diabetic peripheral neuropathy (DPN).^[1] Nearly 50% of individuals with long-standing diabetes suffer from peripheral neuropathy (PN) and about 7%–10% of newly diagnosed individuals with diabetes have neuropathy.^[2] The prevalence of painful diabetic peripheral neuropathy (PDPN) among individuals with diabetes mellitus (DM) is roughly about 10%–20% and in those with DPN is about 40%–50%.^[3],[4],[5] A study from Belgium reported the prevalence of PDPN as 14% among individual with diabetes, with higher number of cases being reported in subjects with type 2 diabetes than type 1.^[6] In another study, up to 25% of individuals having prediabetes had PN, and among them, up to 21% had neuropathic pain in a less severe form.^[7]

Risk Factors

Apart from the well-known risk factors of DPN, i.e., obesity, older age, cigarette smoking, duration of diabetes, and poor glycemic control (elevated HbA1c), the risk factors specific for PDPN include genotypic variants of voltage-gated sodium channels (NAV 1.7 mutations), nephropathy, and Vitamin D deficiency.^{[8],[9],[10],[11],[12],[13]} Studies have suggested changes in central nervous system (CNS) as conferring additional risk for PDPN.^{[14],[15],[16],[17]} However, these remains as association, without any hints of causation.

Pathophysiology of Diabetic Peripheral Neuropathy

Chronic hyperglycemia activates collateral pathways of glucose utilization in peripheral nerves [Figure 1].^[18] End products of these pathways cause oxidative stress, release of inflammatory cytokines, and mitochondrial dysfunction. This leads to microvascular changes, nerve ischemia, and structural and functional alteration in peripheral nerve contributing to the onset and progression of DPN – painful or painless.

Figure 1: Pathophysiology of DPN and PDPN. PDPN: Painful diabetic peripheral neuropathy, DPN: Diabetic peripheral neuropathy

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To understand the pathogenesis, it is important to revisit the pain pathway as shown in [Figure 2]. Learning that, it is easy to understand the following theories and hypothesis related to the pathogenesis of PDPN.

Figure 2: Revisiting the pain pathway. Any noxious stimulus releases inflammatory chemicals at the site which triggers the depolarization of nociceptors thus generating action potential. This action potential is carried by afferent nerves via DRG to dorsal
horn of spinal cord, where nociceptive sensations are relayed in spinal cord to spinothalamic tract by release of glutamate and substance P. These chemicals transmit pain information through spinothalamic tract to thalamus then to cortex where pain is
interpreted and perceived. The afferent nerves and DRG are PNS, and Dorsal Horn onward, i.e., Spinal cord and brain are CNS. The afferent nerves A-delta (myelinated) and small unmyelinated C-fibers are mainly responsible for carrying nociceptive sensations.
Superficial sharp pricking pain is transmitted by A delta fibers and deep seated aching, burning, itching pain associated with hyperalgesia and allodynia is transmitted by Small unmyelinated C fibers. A alpha- carries limb proprioception, A-beta carries limb
proprioception, pressure and vibration. DRG: Dorsal root ganglion, CNS: Central nervous system, PNS: Peripheral nervous system

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Microvascular blood flow

Increased blood flow due to structural and functional abnormalities in vasa-nervosum and arteriovenous shunting in epineural blood vessels causing elevated nerve epineural oxygen saturation has been considered to have a role in the pathogenesis of PDPN. Serum markers of angiogenesis (vascular endothelial growth factor) and endothelial dysfunction (soluble intercellular adhesion molecule-1) were found to be elevated in painful DPN and symptomatic DPN, respectively.^[19],[20] Together, the aforesaid factors suggest that vascular abnormalities could contribute to diabetic neuropathy.

Insulin signaling pathway defects

Insulin contributes to proper neuronal function by increasing expression of neuromodulator proteins and peptides such as calcitonin gene-related peptide. Insulin deficiency is closely linked to mitochondrial dysfunction, altered neurochemical synthesis, reduced capacity of regeneration, growth, and repair, thus triggering neuronal dysfunction. There is a growing evidence that insulin deficiency in relatively euglycemic individuals can trigger DPN.^{[21],[22],[23]} Animal studies have shown an improvement in sensory and motor nerve conduction defects with a prevention of axonal atrophy with intrathecal delivery of insulin for 4 weeks, which was not observed with subcutaneous insulin.^[24] Local intraplantar (hindpaw) insulin delivery in experimental rats have shown to reverse loss of intraepidermal nerve fiber density and a slight decrease in DPN symptoms.^[25]

Neuromas and ectopic signals causing hyperexcitability

Initial low levels of oxidative stress due to hyperglycemia affects small nerve fibers; with increase in oxidative stress, there is an escalation in the stages of DPN.^{[26],[27],[28]} Damaged nerves regenerate by sprouting in all directions called neuromas which then cause pressure damage to the adjacent undamaged nerves^[29] and generate ectopic signals which affects the surrounding unaffected nerves and cell bodies of dorsal root ganglion (DRG) which is responsible for hyperexcited responses along with increased sensitivity to a given stimulus also called as peripheral sensitization.^[30] These increased signals alter the gate (described below in gate control theory) and are perceived as pain.

Role of dorsal root ganglion

DRG was once thought to be only a conduit between peripheral nervous system (PNS) and CNS. However, currently, DRG is considered to be a part of PNS and has a role in peripheral sensitization through expression of voltage-gated sodium channels and voltage-independent potassium channels.^[31] Voltage-gated calcium channels (Cav 3.2) have a role in allodynia.^[32]

Sympathetic modulation

Normally, A-delta and C-fibers are not directly connected to sympathetic nervous system, but nerve damage in periphery causes sympathetic sprouting in DRG and there occurs epinephrine-mediated transmission from one axon to another, which causes sympathetic sensory coupling and sympathetically mediated pain.^[33],[34]

Gate control theory

Transmission of impulse from PNS and CNS is gated at dorsal horn. A-delta and C-fibers (associated with pain stimulus) open the gate and A-beta (associated with touch/vibration/pressure) closes the gate. The final outcome depends on the input impulses that are generated in high numbers.^[35]

Central inhibition

Transmission of pain signals at the dorsal horn is controlled by brainstem nuclei via the descending modulatory pathway. These may dampen or increase the pain signal. The inhibitory effect is caused by projecting serotonin or opioid, thus decreasing pain sensation. Exogenous opioids imitate endogenous opioids and antidepressants (especially selective serotonin reuptake inhibitors [SSRIs]) increasing availability of these neurotransmitters in the dorsal horn. In contrast, anxiety and fear influence this inhibitory mechanism; thus, cognitive behavioral therapy is helpful in pain management.^[36]

Definition, Classification, and Clinical Manifestation

PDPN is defined as “pain as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes”.;^[37],[38] DPN has a varied range of presentation and it is classified depending on the pattern, fibers involved, and pain character. The classification system of typical (distal sensorimotor polyneuropathy [DSPN]) versus atypical (all other forms of DPN) as described by Thomas and Boulton is universally acceptable.^[39],[40] Characteristics of both are described in [Table 1].^{[2],[37],[39],[41],[42],[43],[44],[45],[46],[47],[48]} When classifying on the basis of pain symptoms, DPN can have positive or negative symptoms, can be acute or chronic and can have different pain character as described in NPSI questionnaire [Figure 3].

Figure 3: Characteristics of painful and nonpainful DPN. *Allodynia: Feeling of pain even on application of nonpainful stimulus.
**Hyperalgesia: Increased sensitivity to painful stimulus. DPN: Diabetic peripheral neuropathy

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;

Table 1: Typical and atypical diabetic peripheral neuropathy

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Acute Painful Neuritis

Sudden tight glucose control in long-standing diabetes leads to small fiber neuropathy (SFN) manifesting in severe pain and paresthesia occurring in 6 months of rapid glucose control also called as treatment-induced neuropathy (insulin neuritis).^[49] Pain is generally more in the feet than the hands, symmetric in nature and length dependent, but few may report generalized pain, especially in type 1 diabetes. It is also associated with worsening of preexisting retinopathy and autonomic dysfunction, especially in type 1 diabetes. Pain is self-limiting and improves with slower glucose control.

Acute neuritis or polyneuropathy can occur following poor glycemic control with ketoacidosis, although it is a rare phenomenon but responds to good glycemic control.

Sometimes, there may be continuous unremitting burning pain as if walking on a hot sand with exacerbations at night with significant allodynia and hyperalgesia leading to hopelessness and depression. In worse cases, appetite is lost, which is associated with significant weight loss termed as diabetic neuropathic cachexia.^[50] Motor function remains intact, while mild sensory loss is noted, more for thermal than vibration. It is self-limiting and needs symptomatic treatment. Other causes of neuropathy with weight loss such as amyloidosis, heavy metal toxicity, Fabry's disease, and HIV should be excluded.

Chronic Painful Diabetic Neuropathy

It refers to painful neuropathy, which is going on for more than 6 months. DSPN, sensory and sensorimotor, is the most common presentation of chronic diabetic neuropathy, which can be painful or painless.^[2] It has length-dependent glove stocking pattern of involvement, i.e., pain reaches upto the knee first before fingers/hands are involved, in severe cases trunk is involved [Table 1]. Others forms of chronic painful diabetic neuropathy (CPDN) includes diabetic mononeuropathies or multiple mononeuropathies. The most common mononeuropathies are median neuropathy at the wrist and ulnar neuropathy at the elbow.^[51] In cranial mononeuropathies, third-nerve (oculomotor) palsy is the most common, followed by fourth (trochlear), seventh (facial), and sixth (abducens). Diabetic third-nerve palsies are characteristically pupil sparing.^[52] Multiple neuropathies refer to the involvement of two or more nerves. These nerves are involved sequentially or irregularly one after another. Another type of CPDN includes diabetic radiculoplexopathy, which typically presents with severe pain in the lower back, hip, and thigh in a unilateral manner. Atrophy and weakness of muscles (proximal more than distal) are apparent within a few days to weeks. Weakness usually progresses over several weeks to month and later there is slow recovery. Pain subsides before the motor symptoms improve, but there may be residual weakness, sensory loss, and pain.^[53] There may be coexisting DSPN in half of these individuals. Individuals with severe pain in acute stage have been treated with glucocorticoids, intravenous (IV) immunoglobulin, and cyclophosphamide therapy.^[54] PDPN is also associated with autonomic features such as postural hypotension, bowel/bladder incontinence, erectile dysfunction, abnormal sweating, and dryness of the skin. In the feet, excessive dryness leads to fissures, which can act as a portal of entry for the bacterial infection.^[53]

Diagnosis

History

Limb pain needs to be differentiated between neuropathic and non-neuropathic, neuropathic pain is associated with nerve distribution territory or dermatome, whereas non-neuropathic pain does not. Furthermore, non-diabetic causes [Table 2] should be ruled out wherever suspected. Pain in DPN is bilateral and symmetrical. It involves toes/ forefoot or entire foot ascending upward and worsens at night. Involvement of hands and trunk is seen in severe cases, sometimes causing disturbed sleep and tiredness during the daytime.^[40] Three highly sensitive symptoms indicating DPN are tingling, numbness, and increased pain on touch.^[55]

Table 2: Differentials of painful diabetic peripheral neuropathy

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Examination

Before neurological examination, foot inspection should be carried out, looking for skin abnormalities, ulcers, cracks (fissures), callosities, nail abnormalities, infections, deformities (clawing of toes, hammer toe, Charcot foot, etc.) and identifying high-risk areas of ulceration, muscle wasting, and range of motion at joints.^[56] Vascular examination involves palpation of dorsalis pedis and posterior tibial arteries, assessing for temperature differences between the limbs, loss of hair, and assessment of ankle brachial index.

Neurological examination involves detailed assessment of various systems. In motor system examination, one should look for atrophy of small muscles of the feet, strength of dorsiflexors, and plantar flexors of the feet, toe, and fingers and to check for ankle reflexes, if it is reduced or absent.^[57] Large fiber sensory assessment includes vibration, position, light touch, and pressure sensations. Vibration assessment (A-alpha, A-beta fiber) is done using a 128-Hz tuning fork/biothesiometer. Biothesiometer has greater accuracy; if the vibration is not felt at >25 volts, it is termed to be abnormal.^[58] Position sense (A-beta fiber) of the great toe should be assessed by plantar flexion and dorsiflexion at metatarsophalangeal joint and interphalangeal joint with closed eyes. Light touch and pressure (A-beta fiber) is assessed with a 10-g Semmes–Weinstein monofilament; a 3-point check is considered to be effective than 10-point check.^[59] Test is abnormal if the patient does not perceive the touch and absence of protective sensation increases the risk of ulcer development.^[60] Small fiber sensory test includes pinprick and thermal sensation; pinprick (C fibers) is assessed using an instrument called “Neurotip,” which has a high specificity (88%) in ruling SFN.^[61] Temperature (A-delta fibers) assessment is done using glass tubes filled with hot and cold water or a simple tool called “Tip Therm.” It has high sensitivity (98%) especially for warm detection.^[61] Allodynia (denotes small fiber affliction) or pain on simple touch sensation is assessed using brush or cotton wisp, if the sensation is not perceived distally then the examination should be carried out proximally till the sensation is perceived to identify the area of involvement.^[60]

There are grades of certainties when diagnosing PN: possible, probable, and definite. When there are only symptoms or signs - it is a possible DPN, if symptoms and signs both are present- it is a probable DPN and if both symptoms and signs are present with confirmed diagnostic testing - it is a definite DPN.^{[37],[62],[63]} It is not always possible to conduct Nerve Conduction Studies (NCS) in clinical practice or it may be negative if small nerve fibers are involved hence for practical purposes probable neuropathic pain is enough for the diagnosis i.e., the presence of abnormal pin prick or decreased thermal perception and inability to detect vibration along with symptoms gives the diagnosis of DPN. As per the recommendation of American Diabetes Association (ADA), all the subjects with type 2 diabetes should be screened for DPN at the diagnosis and for type 1 diabetes after 5 years of diagnosis and annual screening thereafter.^[64]

Scores and scales

Scores for identifying the pain of neuropathic origin are Douleur Neuropathique 4 (DN4) questionnaires, Leeds Assessment Neuropathic Symptoms and Signs scale, Neuropathic Pain Questionnaire, and IDentification Pain (ID Pain).^{[65],[66],[67],[68]} Scores to assess the severity of neuropathic pain and its interference with daily life or for the assessment of quality of life are Modified Brief Pain Inventory and the Patients Global Impression of Change scale (PGICS). The scoring systems are mainly used for research purposes. In clinical practice, Visual Analog Scale (VAS) or 11-point Numerical Rating Scale (11-point NRS) are used to grade the pain intensity. Among all the scores, DN4 questionnaire has a good sensitivity and specificity in identifying neuropathic pain, it can be used in routine clinical practice. It is a 10-point questionnaire with 7 sensory descriptors (burning, painful cold, electric shock like, tingling, pins and needles, numbness, and itching) and 3 clinical signs (touch hypoesthesia, pin prick hypoesthesia, pain provoked, or increased on brushing). Positive response to each carries 1 point and negative response 0 point. Scores ≥4/10 indicate neuropathic pain. For guiding the treatment, the NPSI Questionnaire is useful. In NPSI, symptoms are categorized as : a) spontaneous superficial pain-burning; b) spontaneous deep pain-squeezing, pressure like; c) Paroxysmal painful attacks-electric shock like or stabbing; d) evoked pain-pain provoked or increased by brushing, pressure, cold in the painful area and e) abnormal sensation (paresthesia/dysesthesia)-tingling or pins and needles.^[69] The PGICS measures responses from very much improved to very much worse.^[70] VAS and 11-point NRS are the linear scales where the patients can mark from no hurt to the worst possible hurt.^[71]

Laboratory test and imaging

DPN is a clinical diagnosis, radiological and laboratory testing is rarely needed. It should be carried out wherever applicable according to the differentials.^[72] The differentials for clinical diagnosis have been mentioned in [Table 2]. Glycosylated Hemoglobin (HbA1c) should be tested to know the status of glycaemic control. Furthermore, it is important to obtain a fundus examination to look for associated diabetic retinopathy, normal fundus examination will not rule out DPN, but the presence of retinopathy will support the diagnosis.

Objective tests

Nerve conduction studies

This test is a highly sensitive and specific in the diagnosis of large fiber neuropathy, but it does not diagnose SFN, which can develop early in the course of disease. The typical finding in DSPN is reduced or absent sensory nerve action potential from predominant axonal loss mainly in the legs. With disease progression, compound motor action potentials are also reduced and abnormalities may be observed in hands too, thus reflecting length-dependent degeneration of large myelinated nerve fiber. Nerve conduction velocities are normal or only mildly delayed, if it is <70% of lower normal limit, or if the conduction block is present, there is superimposed peripheral nerve demyelination.

Electromyography

It is performed to distinguish neuropathic from myopathic processes, especially when there is motor involvement. It is performed in distal muscles in entrapment neuropathy, in proximal muscles in amyotrophy, and in paraspinal and limb muscles in suspected radiculopathy.

Bedside quantitative sensory testing

This is used to detect both small and large fiber affection. It has seven components, i.e., thermal non- painful perception, touch sensation (dynamic and static mechanical detection), mechanical pain sensitivity, wind up, dynamic mechanical allodynia, pressure pain sensitivity, and vibration perception.^[73]

Intraepidermal nerve fiber density

It is an invasive procedure (involves skin biopsy) that is not done routinely in a clinical practice. It is more sensitive than NCS or sural nerve biopsy in diagnosing SFN.^[74]

Treatment

There are three major approaches to the treatment of PDPN. The only approach which slows down the progression of DPN and the associated pain is tight glycemic control. The other two are pathogenesis-based treatment and symptomatic pain management.

Glycemic control

Reduction in HbA1c can improve SNF function, nerve conduction, and vibration threshold abnormalities.^[75] The HbA1c goal is <7% for most DPN patients, but the risk of hypoglycemia and complications should be taken into account before tight glucose control.^[75] In Type 1 diabetes, studies have shown the role of intensive glucose control in both primary and secondary prevention of PDPN. In type 2 diabetes, poor glycemic control is certainly a risk factor for PDPN, but intensive glycemic control has shown only modest but statistically significant benefit for secondary prevention of PDPN.^[75] The reasons for this probably could be dyslipidemia, obesity, and cardiovascular complications associated with type 2 diabetes, which by themselves are independent risk factors for PDPN. In DCCT Trial, tight glucose control using daily basal, 3-4 bolus injections, or insulin pump has shown a superior result with 64% decrease in neuropathy over a period of 5 years as compared with twice daily combination of intermediate acting and rapid acting insulin.^[76] A study showed that treatment with insulin-sensitizing drugs in Type 2 DM has got less incidence of DPN compared to insulin-providing treatment.^[77]

Treatment based on pathogenetic mechanism

Pancreatic transplantation: It has shown reversal of neuropathy and improvement in neurophysiological parameters.^{[78],[79],[80]} However, such benefits take around 10 years after transplantation.^[81] Due to complexity of procedure, the lesser invasive option of islet cell transplantation has been suggested in type 1 diabetes and it has shown a marked improvement in neurophysiology^[82]
α-Lipoic acid: It is an antioxidant licensed to treat symptomatic DSPN.^[1] Clinical improvement is seen with IV 600 mg/day over 3 weeks in a meta-analysis with 4 randomized control trials (RCTs).^[83] However, another RCT showed no improvement in neuropathy.^[84] Hence, efficacy is uncertain
Benfotiamine (B1)/Methylcobalamine (B12)/Pyridoxine (B6): BEDIP study with B1 200 mg once daily for 3 weeks and BENDIP with B1 300 mg and 600 mg once daily for 6 weeks showed subjective pain relief.^[85] B1 with B6/B12 combination for 12 weeks improved nerve conduction and vibration perception in peroneal nerve^[86]
Aldose reductase inhibitors: Epalrestat (50 mg thrice daily) treatment is associated with improvement in nerve conduction as well as symptoms however side effects such as hepatic dysfunction and gastrointestinal adverse effects have to be considered^[87]
Angiotensin-converting enzyme inhibitor: In a large RCT (DEMAND Study), delapril was shown to significantly reduce the progression of neuropathy compared to placebo
Control of dyslipidemia and hypertriglyceridemia: Lipid-lowering agents like HMG Co-A reductase inhibitors have neuroprotective effects. Lowering triglycerides with diet and exercise have shown to increase IENFD in subjects with impaired glucose tolerance^[62] and fenofibrate was shown to reduce amputations in the FIELD study.^[88],[89]

Symptomatic pain management

There are three treatment options that are approved by the FDA for the treatment of painful PDPN i.e., duloxetine, pregabalin, and tapentadol ER extended release. In painful DPN, monotherapy is not a rule and 100% pain relief is not always a reachable goal. Even 30% reduction in pain intensity from baseline is considered meaningful.^[90] Various medications that have shown significant pain relief with tolerable side effects are used in practice [Table 3].^{[91],[92],[93],[94]} It is important for clinicians to gain an overview about mechanism of pain and possible treatment options [Figure 4].

Figure 4: Pain targets

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Table 3: Pharmacological treatment of diabetic peripheral neuropathy-dosage

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First-line agents

GABA analogs

For clinical use pregabalin is preferred over gabapentin which is a FDA approved because of higher quality studies available on effects, predictable pharmacokinetics, shorter titration period, and improves numerous quality of life measures. Gabapentin nonetheless has few drug interactions, less expensive and improves mental health and vitals. Prominent side effects includes somnolence, dizziness, peripheral edema, headache, xerostomia, and constipation.^[95] These drugs do not generally have addiction potential, but both pregabalin and gabapentin should be avoided in people with a history of substance abuse disorder; both agents can have side effects if used concomitantly with other psychoactive agents.^[96]

Serotonin norepinephrine reuptake inhibitor

Duloxetine is FDA approved drug. Major side effect is nausea. Other less common but serious side effects are hepatotoxicity, orthostatic hypotension, falls and syncope, serotonin syndrome, abnormal bleeding, severe skin reactions, mania, angle closure glaucoma, hyponatremia, seizures, urinary hesitancy, and retention.^[97]

Tricyclic antidepressants

This includes amitriptyline, nortriptyline, and desipramine. Major side effects are dry mouth, urinary retention, orthostasis, insomnia, fatigue, headache, and dizziness. Anticholinergic side effects can be lowered by slow titration or using secondary amines. These agents should be used with caution in patients with ischemic heart disease and ventricular conduction abnormalities. All patients above 40 years should get an electrocardiogram done before starting on these agents.^[98]

Second-line agents

Opioid-like drugs

Tramadol and tapentadol (ER) are the agents used to treat PDPN. Major side effects are constipation, nausea, drowsiness. These agents are used only as second-line drugs in people whose pain is severe not controlled with first-line agents and requiring opioids daily round-the-clock.^[99] Serotonin norepinephrine reuptake inhibitor (SNRIs) such as venlafaxine can be used as a second-line agent. Major side effects are nausea; however, the drug can also cause cardiac conduction abnormality and hypertension.^[100],[101] These are obvious factors limiting the drug use. Venlafaxine causes withdrawal symptoms when stopped immediately; hence, it is advised to taper down the medicine slowly.

Topical medications

Five percent lidocaine-acts by stabilizing neuronal membrane via inhibiting fast voltage-gated sodium channels.^[102] In general, one patch is applied daily with a maximum limit of 3 patches per day. Capsaicin 0.075%-acts by Transient receptor potential cation channel subfamily V member 1 (TRPV1) desensitization and also by depleting substance P.^[103],[104] It is applied 4 times daily. Isosorbide dinitrate spray-acts by dilatation of endoneurial blood vessels; the dose is 30 mg daily applied at the bottom of the feet.^[103]

Third-line agents

Selective serotonin reuptake inhibitor

Citalopram and paroxetine are the agents used from this class. Dose ranges from 10 to 40 mg daily.^[105],[106]

Opioids

Oxycodone and morphine sulfate are the agents used. Dose range for oxycodone is 10–40 mg twice daily (maximum dose is 120 mg) and for morphine sulfate is 15–30 mg, 12-24 hourly. Major side effects are constipation, nausea, and sedation.^[98]

Valproate, topiramate, carbamazepine, oxcarbazepine, lamotrigine and lacosamide are not recommended for treatment of PDPN.^[107],[108]

As a conclusion to this section, pregabalin, gabapentin, duloxetine and amitriptyline have level A evidence for first-line treatment of PDPN.^{[107],[109],[110],[111],[112],[113]} SNRIs such as venlafaxine, opioid-like medication-tramadol and tapentadol (ER) also have level A evidence for second-line treatment of PDPN.^{[107],[109],[111],[112],[113],[114],[115]} Topical treatment like lidocaine patch 5% or Capsaicin 0.075% cream have Level B evidence for second-line treatment of PDPN.^{[103],[107],[112],[116],[117]} Finally, SSRIs like citalopram, paroxetine, ecitalopram and opioids-oxycodone controlled release may be used ideally, only as next line therapies.^{[107],[109],[111],[112],[118]}

Additional Evidence From Clinical Trials

This section will help in choosing the agents based on the evidence from clinical trial. Trial conducted by Wernicke and colleague suggests that the appropriate dose of duloxetine is 60 mg once a day. In a meta-analysis, comparing duloxetine and pregabalin, pregabalin showed a marginal improvement over duloxetine, Duloxetine and amitriptyline also had a comparable efficacy.^{[119],[120],[121]} In a trial by Max et al., amitriptyline and desipramine showed comparable pain relief.^[122] In various studies, amitriptyline was compared with pregabalin, duloxetine and gabapentin taken together these studies showed pregabalin to be superior and duloxetine and gabapentin having comparable efficacy.^{[121],[123],[124]} Algorithm used in clinical practice for the management of PDPN is shown in [Figure 5]. Consensus guidelines by Argoff et al., recommends duloxetine as the first choice followed by pregabalin, tricyclic antidepressant (TCAs), and oxycodone (CR).^[125] The American Association of Neurology (AAN) guidelines recommend use of pregabalin as the first-line therapy with level A recommendation. Gabapentin, amitriptyline, venlafaxine, duloxetine, sodium valproate are the second-line agents with level B recommendation. Use of dextromethorphan, oxycodone, morphine sulfate, and tramadol has got level B recommendation and to be used after failure of response to anticonvulsants and antidepressants. The AAN guidelines recommend against the use of oxcarbazepine, lamotrigine, and lacosamide (level B).^[126] Preference to medications depends on the comorbidities and contraindications [Table 4] as per the Toronto Consensus Panel on Diabetic Neuropathy.^[127] There are some additional benefits with individual agent along with pain relief. For example- duloxetine and TCAs may be chosen for PDPN with depression, duloxetine and pregabalin for generalised anxiety disorder and duloxetine, Pregabalin, TCAs and opioids for PDPN with insomnia.^[128] The dose of appropriate and effective medication chosen should be titrated according to the efficacy and side effects. Lack of efficacy should be stated only after 2–4 weeks of trial using adequate dosage.^[129] A practical approach to the management of DPN is summarized in [Figure 5].^[130]

Figure 5: Practical approach to the management of DPN. DPN: Diabetic peripheral neuropathy

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Table 4: Selected contraindications to pharmacotherapy in painful diabetic peripheral neuropathy

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Combination therapies

Combination versus Monotherapy of pregaBalin and dulOxetine in Diabetic Neuropathy study (COMBO-DN) is one such study, where the responses to treatment in subgroups based on sensory profiles were prospectively assessed with initial monotherapy and then combination therapy of duloxetine and pregabalin.^[131] The data suggest that if there is insufficient pain relief after 8 weeks treatment of 60 mg/d of duloxetine, patients might benefit from combination treatment by adding 300 mg/d of pregabalin especially if they have high intensity pressing pain and evoked pain. However, it is possible that maximizing therapy with duloxetine to 120 mg/d might be helpful in patients having paresthesia and dysesthesia. In contrast, patients who are started on pregabalin initially with 300 mg/d, adding 60 mg/d duloxetine in case of nonresponse led to numerically higher decrease in NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/d. Furthermore, it was suggested that this combination therapy works better in mild–moderate pain; in severe pain, maximizing monotherapy has greater benefit (but this finding was not statistically significant). Several other studies have relied on clustering of clinical features for selecting phenotypes responding to drugs, but no clear evidence has emerged.^{[132],[133],[134]}

Surgical decompression

It has been tried in refractory cases. It is evident from autopsies of diabetic neuropathy patients that the nerves affected were 50% larger in cross-sectional area with significant edema and thus vulnerable to compression at anatomical tunnels such as carpal tunnel and tarsal tunnel. This can cause pain, which could also be a glove stocking distribution type. This compression initiates a cascade of pathology causing subperineural and endoneural oedema which leads to impaired blood nerve barrier. Thus causing connective tissue changes leading to perineural thickening and a cascade of demyelination and degeneration. Hence, decompression surgeries have shown effect on not just pain relief but significant prevention of foot ulcers and amputation. However, this procedure has limited benefit except in some specific situations; moreover, patients often do not wish for an invasive therapy.^[135]

Nonpharmacological treatment

There are several nonpharmacological approaches such as foot care, lifestyle interventions (weight loss, alcohol, and smoking cessation), exercise or balance training, physical therapy, and cognitive-behavioral therapy.

Electrical nerve stimulation-transcutaneous and percutaneous : it can be started anytime as an adjunct to pharmacological treatment and may reduce the need for oral nonopioid analgesic medication.^[136],[137]

Spinal cord stimulation

It is one of the emerging options. A randomized control trial showed that 10-kHz spinal cord stimulation relieves pain without exacerbating underlying paresthesia and thus can be considered in cases of inadequate pain relief.^[138] DRG stimulation/neuromodulation has also shown a promising result in refractory PDPN.^[139]

Monochromatic infrared energy (MIRE)

It was approved by the FDA in 1994 to increase circulation and reduce pain.^[140] Symptomatic reversal of DPN was reported with the use of noninvasive MIRE device.^[141] An RCT showed 50% improvement in sensation in subjects who had not progressed to profound sensory loss and decreased symptoms among those with loss of protective sensation after 6–12 active treatments.^[142]

There are other pharmacological options which are under trial: (a) Xenon402 (Nav1.7 blocker),^[143] a peripherally acting Na(v)1.7 sodium channel blocker (b) EMA401 (a novel AT2R antagonist),^[144] an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia, which is being explored in a randomised, double-blind, placebo-controlled phase 2 clinical trial and (c) Ziconotide (N Type calcium channel inhibitor),^[145] an FDA-approved treatment for reducing allodynia, though intrathecal route of administration limits its use.

{Figure 2}

Any lower limb pain in an individual with diabetes should be differentiated between neuropathic and nonneuropathic pain. Probable diagnosis of PDPN is made if both symptoms and signs are present in the same dermatomal distribution. Examination by bedside QST and/or NCS confirm the diagnosis. Better glucose control and use of pregabalin or duloxetine can help relieve the symptoms. Gabapentin and amitriptyline may also be used as first-line agents. Opioid-like drugs and topical treatments are used as second-line agents. Nonpharmacological measures include foot care and lifestyle management. Other therapies like electrical nerve and spinal cord/DRG stimulation have shown some benefits in pain relief. There is a need for further research to better understand the pathogenesis and the management to halt the progression or reverse the neuropathy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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