Innovative Solutions for Diabetic Neuropathy Pain Nilesh Patel Advanced Pain Management Npatel@Apmhealth.Com 941-744-6960

Innovative Solutions for Diabetic Neuropathy Pain

Nilesh Patel Advanced Pain Management [email protected] 941-744-6960 March 16, 2018. 3:45-5:00. Chula Vista Resort. 2501 River Rd. Wisconsin Dells, WI 53965

Disclosures

• No paid relationship with ANY industry • Not on any paid medical advisory boards • Speaker Bureau for Electro Core (Vagal Stimulator) • I am employed by Advanced Pain Management and they have Research Funded by Boston Scientific, Nevro, Abbott, Semnur; Registry Enrollment with VertiFlex for Lumbar Stenosis

Objectives:

• Understand the most current literature pertaining to pathophysiology and treatment of diabetic neuropathy • Understand the innovations in dealing with Pain from Diabetic Neuropathy (PDN) ADA specified...

• “With the ADA Standards of Care, we do not recommend opiates for pain management. Would you be able to present on the safer approaches to pain management for people with neuropathy? You can still touch on the topic of opioids, as we do recognize that they are effective for pain, but we want to make sure the information is presented as they are not the first line of defense for treating diabetic neuropathy… • ..and also ensure our audience has a strong understanding of prevention of neuropathy as well as those other treatment options”

Heidi Dietrich Associate Manager – Midwest Division 1/3/18

CDC 2016 article quote

• “Several guidelines agree that first- and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs….”

• Broadly, ADA agrees with the CDC

Wallen M, Gillies D. Intra-articular steroids and splints/rest for children with juvenile idiopathic arthritis and adults with rheumatoid arthritis. Cochrane Database Syst Rev 2006:(1):CD002824. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006;2:CD005328. Buchbinder R, Green S, Youd JM. Corticosteroid injections for shoulder pain. Cochrane Database Syst Rev 2003;1:CD004016. Food and Drug Administration. Epidural corticosteroid injection: drug safety communication. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2014

Agency for HealthCare Research and Quality

Prevent Complications: • Intensive glycemic control is more effective than standard control for prevention of amputation • Home monitoring of foot skin temperature, therapeutic footwear, and integrated interventions are effective for preventing incidence and/or recurrence of foot ulcers.

Recent CDC estimates of diabetes in the US: 29.1 million people with diabetes = 9.3% of the population Another 86 million people are pre-diabetic (>1 in 3 people) Costs: $245 billion(Direct medical costs = $176 & Indirect costs = $69 billion)

Estimates of painful diabetic neuropathy (PDN) prevalence: 20% to 26% of those with diabetes have PDN ~5.8 to 7.6 million people in the US with PDN

CDC National Diabetes Statistics Report, 2014 Davies M et al. Diabetes Care 2006 Schmader KE. Clin J Pain 2002 7

Painful Diabetic Neuropathy: Why Bother?

Painful neuropathy leads to: • Impaired ability to perform daily activities • Decrease in quality of life such as general activity, mood, mobility, self-care, recreational and social activities

• Abbott CA et al. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care. 2011 Oct;34(10):2220-4. doi: 10.2337/dc11-1108. PMID: 21852677. • CL M et al. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. . Diabetes Care. 2006;2006(29):340-40. • Kosinski MR, Schein JR, Vallow SM, Ascher S, Harte C, Shikiar R, et al. An observational study of health-related quality of life and pain outcomes in chronic low back pain patients treated with fentanyl transdermal system. Current Medical Research and Opinion. 2005;21(6):849–862. doi: 10.1185/030079905X46377. • Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: Epidemiology, pain description, and quality of life. Diabetes Research and Clinical Practice. 2000;47(2):123–128. doi: 10.1016/S0168-8227(99)00112-6.

Sad Reality about lack of effectiveness (PDN medications)

Most patients STOP MEDS with 12 months due to inefficacy and/or side effects Most patients do not switch to a different medication

Yang M et al. Pain Medicine 2015 Questions

Q1. What is the NNT for Gabapentanoids (Gabapentin, and Pregabalin)

• 1 • 2-5 • 4-6 • >6

Questions

Q2. The most effective group of medications for neuropathic pain, based on NNT

• Tricyclic antidepressants (e.g. amitriptyline) • Gabapantenoids (e.g. Pregabalin and gabapentin) • Opiates (e.g. Oxycodone, hydrocodone, morphine) • SSRI/SNRI (e.g. Venlafaxine and Duloxetine)

Questions Q3. The CDC and State Board guidelines suggest the following • Lowest possible opiate dose not to exceed 90mg morphine equivalent • Prescription on Naloxone if patient at high risk for overdose and deaths • Checking PDMP on patients at initiation of opiate therapy and at least once every three months • All of the above Questions

Q4. Spinal stimulation effectiveness for neuropathic pain, which of the following are true statements?

• For focal neuropathic pain (e.g. foot pain) dorsal root ganglion stimulation is the most optimal option • For peripheral sensory motor neuropathic pain High Frequency stimulation has been shown to decrease pain, improve function and decrease opiate use at 24 onth follow up • For lumbar post laminectomy and CRPS the long term data supports use • All of the above

Questions

Q5. Lumbar epidural steroids are effective for which of the following conditions

• Diabetic Neuropathic pain • Lumbar stenosis with claudication pain when used, as part of a multimodal therapy • Axial non radicular pain due to lumbar spondylosis • Post-surgical pain in a patient who has undergone thyroidectomy

Neuropathic Pain

To better understand the application of these medications, we must first understand:

1. Neurophysiology of Pain 2. Neuro-Modulatory Systems 3. Classes of Medications, Sites of Actions

Then we will tackle clinical use:

1. Effectiveness Data 2. How to use these clinically But how do these medications provide pain relief?

That requires understanding of some very basic normal physiology and abnormal physiology .

Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60. Obata . Analgesic Mechanisms of Antidepressants for Neuropathic Pain Int J Mol Sci. 2017 Nov 21;18(11).

But how do these medications provide pain relief?

That requires understanding of some very basic normal physiology and abnormal physiology .

• Signal transduction to conduction to Synaptic transmission • Ascending and Descending modulation

Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60. Obata . Analgesic Mechanisms of Antidepressants for Neuropathic Pain Int J Mol Sci. 2017 Nov 21;18(11).

But how do these 3 medications provide pain relief?

That requires understanding of some 2 1 very basic normal physiology and abnormal physiology.

• Signal transduction to conduction to Synaptic transmission • Ascending and Descending modulation • 1st 2nd 3rd order

That requires understanding of some 2 1 very basic normal physiology and abnormal physiology.

• Signal transduction to conduction to Synaptic transmission • Ascending and Descending modulation • 1st 2nd 3rd order –HAND OFF=OPPORTUNITY TO MANAGE TRAFFIC : AMPLIFY? SUPPRESS?

Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60. Obata . Analgesic Mechanisms of Antidepressants for Neuropathic Pain Int J Mol Sci. 2017 Nov 21;18(11).

But how do these medications provide pain relief?

That requires understanding of some very basic normal physiology and abnormal physiology .

• Signal transduction to conduction to Synaptic transmission • Ascending and Descending modulation • 1st 2nd 3rd order • Lateral and Medial Systems

Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60. Obata . Analgesic Mechanisms of Antidepressants for Neuropathic Pain Int J Mol Sci. 2017 Nov 21;18(11).

But how do these medications provide pain relief?

That requires understanding of some very basic normal physiology and abnormal physiology .

Lateral system, neurons are projected to the somatosensory cortex; Records pain intensity and the site of transmission;

Medial system projects to the anterior cingulate cortex and insular cortex . Thus pain‐associated anxiety and fear

Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60. Obata . Analgesic Mechanisms of Antidepressants for Neuropathic Pain Int J Mol Sci. 2017 Nov 21;18(11). Primary afferent nociceptors convey noxious information to projection neurons within the dorsal horn. A subset of these projection neurons transmits information to the somatosensory cortex via the thalamus, providing information about the location and intensity of the painful stimulus. Other projection neurons engage the cingulate and insular cortices via connections in the brainstem (parabrachial nucleus) and amygdala, contributing to the affective component of the pain experience. This ascending information also accesses neurons of the rostral ventral medulla and midbrain periaqueductal gray to engage descending feedback systems that regulate the output from the spinal cord.

• Let us summarize these events as pain comes from Viscera, Joints, Lower Back etc.

• The information reaching the brain needs amplification initially

• But once we determine context and that it is NOT a matter of life and death matter you can focus elsewhere.

Iimamura M et al. mpact of nervous system hyperalgesia on pain, disability, and quality of life in patients with knee osteoarthritis: a controlled analysis. Arthritis Rheum 2008; 59: 1424-31. Wylde V et al. Somatosensory abnormalities in knee OA. Rheumatology (Oxford) 2012; 51: 535-43.

Under normal conditions: Eudynia

1. Normally pain is carried by A-delta and c-fibers Under normal conditions: Eudynia 1. Normally pain is carried by small fibers: A delta and c fibers 2. Touch and proprioception are carried by the larger A beta fibers

Abnormal Pain sensation : Maldynia “Central Hypersensitization” due to….

1. Glutamate/NMDA receptor-mediated sensitization 2. Dis-inhibition: Interneurons and Descending inhibitory pathways 3. Microglial activation: Morphine Hyperalgesia 4. Immune Activation

At 1st order nerve terminals (in the spinal cord dorsal horn) activation of the calcium channels release excitatory neurotransmitters, such as glutamate and substance P, act on 2nd order postsynaptic receptors.

This step is regulated by both local inhibitory interneurons and descending projection neurons from the brainstem to the spinal cord, which is a pharmacologically important target site. Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60. Major inhibitory neurotransmitters include, norepinephrine, Seratonin, glycine, opioid peptides, and γ‐aminobutyric acid (GABA)

• Norepinephrine acts on α2‐adrenergic receptors. • Serotonin act son several types of receptors, including 5‐HT2a receptors • Opioid peptides act on the post synaptic μ receptors

Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60.

Major inhibitory neurotransmitters include, norepinephrine, Seratonin, glycine, opioid peptides, and γ‐aminobutyric acid (GABA)

So anything that increases serotonin and Norepinephrine will dampen the signals.

Likewise opioid peptides act at μ opioid receptor plays an important role in the analgesic action of morphine Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60.

WHY NORTRIPTYLINE and SEROTONIN? DESCENDING INHIBITORY CONTROL SYSTEMS Norepinephrine is a principal neurotransmitter facilitating the “descending inhibitory systems” Norepinephrine is released from the projection neurons descending from the brainstem to the spinal cord and acts on α2‐adrenergic receptors. Serotonin is also released from these descending projection neurons and is thought to act on several types of receptors, including 5‐HT2a receptors. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005454 61 RCT, 2005 Cochran Review:

TCA of NNT 3.6 for “moderate pain relief”

Venlafaxine (3 RCT): AVG NNT of 3.1 Diabetic neuropathy: NNT 1.3

NNH: Aamitriptyline 6 to 28 Venlafaxine: 9.2 to 16.2

Norepinephrine is a principal neurotransmitter facilitating the “descending inhibitory systems” Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005454

TCA SNRI SNRI SSRI SSRI

1. Increasing noradrenaline in the spinal cord by reuptake inhibition directly inhibits neuropathic pain through α₂-adrenergic receptors. 2. Increasing noradrenaline acts on the locus coeruleus and improves the function of an impaired descending noradrenergic inhibitory system. Serotonin and dopamine may reinforce the noradrenergic effects to inhibit neuropathic pain.

Obata H. Analgesic Mechanisms of Antidepressants for Neuropathic Pain. Int J Mol Sci. 2017; 18: 2483

Major inhibitory neurotransmitters include opioid peptides, norepinephrine, opioid peptides glycine, and γ‐aminobutyric acid (GABA). Opioid receptors are G proteine receptors that are categorized into three subtypes (μ, δ, and κ receptors). μ opioid receptor plays an important role in the analgesic action of morphine. Opioids act not only on the central end of the primary sensory neuron, but also on the brain, brainstem, and spinal cord.

Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60. Main actions of Opioids at the dorsal horn

μ opioid receptor stimulation in the spinal cord is a very efficacious mechanism to block synaptic transmission, limiting the number of nociceptive stimuli that reach thalamus and eventually the cortex where conscious perception of pain occurs

70% of μ opioid receptor are presynaptic and 30% post synaptic

The activation of presynaptic μ receptors (on 1st order C and Aδ fibers) causes the inhibition of calcium ion channel, preventing the release of excitatory neurotransmitters.

The activation of postsynaptic μ receptors (on 2nd order neurons) causes potassium ion channels activation with consequent efflux of potassium ions and hyperpolarization of the projecting cell.

Golan DE, Tashjan AH, Armstrong EJ. Principles of Pharmacology. The Pharmaphysiologic Basis of Drug Therapy, 2nd Edition. Baltimore: Wolters Kluwer Health, 2008).

Main actions of Opioids

70% of μ opioid receptor are presynaptic and 30% post synaptic

The activation of presynaptic μ receptors (on 1st order C and Aδ fibers) causes the inhibition of calcium ion channel, preventing the release of neurotransmitters.

The activation of postsynaptic μ receptors (on 2nd order neurons) causes potassium ion channels activation with consequent efflux of potassium ions and hyperpolarization of the projecting cells

Major inhibitory neurotransmitters include opioid peptides, norepinephrine, opioid peptides glycine, and γ‐aminobutyric acid (GABA). Gabapentin and pregabalin are GABA analogs that have structural similarity to GABA. bind to the voltage‐dependent calcium channel auxiliary subunit α2δ, with a high affinity. These α2δ ligands exert an analgesic effect by suppressing the presynaptic calcium influx and inhibiting the release of excitatory neurotransmitters. Both agents have been found to be effective for the treatment of the numbness and pain associated with PHN and DPN

Nishikawa N, Nomoto M. Management of neuropathic pain. J Gen Fam Med. 2017 Apr; 18(2): 56–60. Major inhibitory neurotransmitters include opioid peptides, norepinephrine, opioid peptides glycine, and γ‐aminobutyric acid (GABA).

Tramadol and Tapentadol are a centrally-acting analgesic with broad activity achieved by combining two established analgesic principles (μ-opioid receptor agonist and noradrenaline reuptake inhibition) in a single molecule. These molecules offer a better balance between efficacy and tolerability than classical opioids and they cause less respiratory depression than traditional opiates

Pergolizzi J, Alon E, Baron R, Bonezzi C, Dobrogowski J, Gálvez R, et al. Tapentadol in the management of chronic low back pain: a novel approach to a complex condition? J Pain Res. 2011;4:203–10

Not only are these safer, but they are appropriate for acute and chronic settings: Use of antagonist shift the curve to the left, showing that the greater effect of Topentadol in acute setting is from Opiates agonist as opposed to NE reuptake inhibition which dominates the action in chronic setting.

Schröder et al. Differential contribution of opioid and noradrenergic mechanisms to the antinociceptive and antihypersensitive efficacy of tapentadol in rat models of nociceptive and neuropathic pain. European Journal of Pain, 14; 8: 814–821,

Topentadol

Acute Pain: More Opiate Analgesia Chronic Pain: More NE mediated analgesia

Anticonvulsants

Valproic Acid Morphine Sodium Channel Blockers

Duloxetin

NMDA-Receptor Antagonists Opioids Topicals

Imipramine

Tramadol Antidepressants Lamotrigine

Baclofen Oxycodone

Peripheral neuropathic pain drugs: NNT

Tricyclic antidepr. 397 Valproate 83 NNT to achieve pain relief >50%

Lamotrigine/Phenytoin/Carbazpn 109 Opioids 149 150 Tramadol Gabapentin/pregabalin 1057 SNRI 420

Mexiletine 120

NMDA antagonists 466 Capsaicin 389 SSRI 81

Topiramate 214

0 2 4 6 8 10 12 NNT Finnerup et al. Lancet 2015

Peripheral neuropathic pain drugs: NNT

Tricyclic Antidepresants . 397 NNT to achieve pain relief >50%

150 Tramadol Gabapentin/pregabalin 1057 SNRIs Duloxetin, Venlafaxin, 420

0 2 4 6 8 10 12 NNT Finnerup et al. Lancet 2015 Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Gabapentin and Pregabalin: NNT 7

NNT Gabapentin is 7.2 NNT Pregabaline is 7.7

NNH:13.9 NNT 7.7

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Gabapentin and Pregabalin: NNT 7 Neither undergo metabolism by phase I or phase II enzymes and are excreted unmodified by the kidneys. Thus safe in polypharmacy and where C P450 metabolism

Gabapentinoids have been proven to be efficacious in several neuropathic conditions such as post-herpetic neuralgia, painful diabetic neuropathy, painful polyneuropathy, and low back pain.

Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49:661–669. doi: 10.2165/11536200-000000000-00000. Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Gabapentin and Pregabalin: NNT 7 Adverse Effects: • Pregabalin is dizziness, followed by somnolence, dry mouth, edema, and blurred vision, with treatment discontinuation due to somnolence occurring in 4% of patients.

• Gabapentin, dizziness and somnolence occur in more than 20% of patients and are the most commonly reported adverse effects; other adverse effects include confusion and peripheral edema.

• For both drugs, adverse effects are dose-dependent and reversible

Anti epileptics: Dose and AEs

Membrane stabilizers Starting Target dose/day Side effects for pain control dose/day

Carbamazepine 200 600-1200 Sedation, ataxia, diplopia leukopenia, Na+ Tegretol  Valproate Depakote 400-500 1000-3000 weight , plt, liver failure

Pregabalin Lyrica  75 300-600 weight 

Gabapentin Neurontin 100-300 1800-3600 weight , headache, twitching

Lamotrigine Lamictal 50 300-500 rash, Stevens-Johnson sdme

Levetiracitam Keppra 1000 3000 recurring infections

OxcarbazepineTrileptal 300 600-2400 Na+

Tiagabine Gabitril 4 32-56 nervousness, flu-like symptoms

TopiramateTopamax 25-50 200-400 weight , renal calculi

Zonisamide Zonegran 100 600 weight , renal calculi

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Tricyclic Antidepressants NNT 3.6

NNH:11.8 NNT 3.6 The most effective TCAs for pain are Desipramine and Amitriptyline and their metabolites Nortriptyline and Imipramine. TCAs have been proven to be efficacious in several neuropathic conditions, including painful polyneuropathy, post-herpetic neuralgia, peripheral nerve injury, and painful diabetic neuropathy. Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Tricyclic Antidepressants NNT 3.6

The most effective TCAs for pain are Desipramine and Amitriptyline and their metabolites Nortriptyline and Imipramine. TCAs have been proven to be efficacious in several neuropathic conditions, including painful polyneuropathy, post-herpetic neuralgia, peripheral nerve injury, and painful diabetic neuropathy.

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Tricyclic Antidepressants NNT 3.6 Adverse Effects: • Anticholinergic effects are a major concern • Dry mouth, orthostatic hypotension, constipation, and urinary retention • Cardiotoxicity • Weight Gain

• Limits the dosage to less than 100 mg/day

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Duloxetine and Venlafaxine NNT 6.4 Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Duloxetine and Venlafaxine NNT 6.4

• Duloxetine has shown consistent efficacy in painful diabetic neuropathy and low back pain

• Dosing of duloxetine: 30-60 mg 1-2 times daily

• Nausea is the most common adverse effect of duloxetine (Decreased by lowering the dosage to 30 mg once daily for 1 week then to 60 mg daily)

Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ. 2014;348:g1799. doi: 10.1136/bmj.g1799. King JB, Schauerhamer MB, Bellows BK. A review of the clinical utility of duloxetine in the treatment of diabetic peripheral neuropathic pain. Ther Clin Risk Manag. 2015;11:1163–1175.

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Recommendations

Strong Opioids NNT 4.3

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Tramadol (sufficient data in 2015), Topentadol

Norepinephrine binds to α2-adrenergic receptors, localized on presynaptic (nociceptors) and postsynaptic (spinothalamic) neurons, thus inhibiting synaptic transmission with mechanisms identical to those described for μ receptors: blockade of presynaptic calcium ion channels and activation of postsynaptic potassium ion channels.

Tramadol and Tapentadol allows norepinephrine to accumulate in the spinal cord synapses and are μ agonists

• Hartrick CT, Rozek RJ. Tapentadol in pain management: a μ-opioid receptor agonist and noradrenaline reuptake inhibitor. CNS Drugs. 2011 May;25(5):359–70. • Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012 Jul 11;7:CD008943 Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Tramadol (sufficient data in 2015), Topentadol

Because of simultaneous stimulation of μt + α2 : • Consistent reduction of adverse events (N, V, C) • Better control of mixed pain, very frequent in several clinical conditions, such as low back pain, in which neuropathic and nociceptive components co-exist • Better response to norepinephrine and opioids • Potentially fewer overdose and deaths

Studies involving 5% Topical Lidocaine for Painful Diabetic Neuropathy

Baron R et al. The 5% Lidocaine-Medicated Plaster: Its Inclusion in International Treatment Guidelines for Treating Localized Neuropathic Pain, and Clinical Evidence Supporting its Use. Pain Ther. 2016; 5: 149–169.

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Tramadol, Topentadol and Topical Lidocaine

Lidocaine can penetrate no deeper than 8–10 mm, thus indicated in well-localized neuropathic pain. Minimal Absorption.

Efficacy has been documented in different types of localized neuropathic pain: post-herpetic neuralgia, painful diabetic neuropathy, post-surgical and post-traumatic pain related to incision of the skin .

The most common adverse effects of lidocaine are mild local reactions due to its topical application. Expensive, approved for PHN

Baron R, Allegri M, Correa-Illanes G, et al. The 5% lidocaine-medicated plaster: its inclusion in international treatment guidelines for treating localized neuropathic pain, and clinical evidence supporting its use. Pain Ther. 2016;5:149–169. doi: 10.1007/s40122-016-0060-3. Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 First.. Second.. Third Line

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 First.. Second.. Third Line

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 First.. Second.. Third Line Peripheral neuropathic pain drugs: NNT

Tricyclic Antidepresants . NNT 3.6 and NNH 11.8

Oxycodone 10-120/MS 90-240mg NNT 4.3 and NNH 11.7 in 12 RCT neuropathic for dose of 180MEDD

Tramadol up to 400mg NNT 4.7 and NNH 12.6

Gabapentin/pregabalin NNT 7.7 and NNH 13.9

NNT 3.6 SNRIs Duloxetin, Venlafaxin, NNH 6.3

0 2 4 6 8 10 12 NNT Finnerup et al. Lancet 2015 NNT to achieve pain relief >50%

AHCPR on Pharmacologic Rx

- Although tricyclic antidepressants have long been recommended as a secondary treatment option for chronic low back pain, Duloxetin .appears to be more effective than tricyclic antidepressants, as well as being associated with a more favorable safety profile, which could impact the selection of drugs within the antidepressant class.

- Antiseizure medications, such as gabapentin and pregabalin are being prescribed more for radicular low back pain than other back pain, despite the lack of evidence showing that they are effective.

- NSAIDS Small benefits

- Benzodiazepines and acetaminophen ineffective

Chou R. Noninvasive Treatments for Low Back Pain Comparative Effectiveness Reviews, No. 169. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Feb.

Single drugs have high NNTs, thus combination therapy common

50% Rx 1 + Rx 2

Rx 2

Rx 1 Pain Pain Relief

Cochrane Database 2012. Combination pharmacotherapy for the treatment of neuropathic pain in adults. ttp://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008943.pub2/abstract;jsessionid=3C710E6B636E8E4C2569572E18449875.f03t01?systemMessage=Please+be+advised+that+we+experience d+an+unexpected+issue+that+occurred+on+Saturday+and+Sunday+January+20th+and+21st+that+caused+the+site+to+be+down+for+an+extended+period+of+time+and+affected+the+ability+of+us ers+to+access+content+on+Wiley+Online+Library.+This+issue+has+now+been+fully+resolved.++We+apologize+for+any+inconvenience+this+may+have+caused+and+are+working+to+ensure+that +we+can+alert+you+immediately+of+any+unplanned+periods+of+downtime+or+disruption+in+the+future. e.g. Gabapentin and Nortriptyline Combination therapy…

50% Rx 1 + Rx 2

Rx 2

Rx 1 Pain Pain Relief

.Combined gabapentin and nortriptyline is more efficacious than either drug given alone for neuropathic pain, therefore these Canadian authors recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Gilron I et al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2009 Oct 10;374(9697):1252-61. doi: 10.1016/S0140-6736(09)61081-3. Epub 2009 Sep 30.

Ample RCTs data for Combination therapy

50% Rx 1 + Rx 2

Opioid + TCA: Pain Pain Relief Opioid + AED: AED + TCA: 0%

Chapparo LE et al. Cochrane Database 2012. Combination pharmacotherapy for the treatment of neuropathic pain in adults. ttp://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008943.pub2/abstract;jsessionid=3C710E6B636E8E4C2569572E18449875.f03t01?systemMessage=Please+be+advised+that+we+experience d+an+unexpected+issue+that+occurred+on+Saturday+and+Sunday+January+20th+and+21st+that+caused+the+site+to+be+down+for+an+extended+period+of+time+and+affected+the+ability+of+us ers+to+access+content+on+Wiley+Online+Library.+This+issue+has+now+been+fully+resolved.++We+apologize+for+any+inconvenience+this+may+have+caused+and+are+working+to+ensure+that +we+can+alert+you+immediately+of+any+unplanned+periods+of+downtime+or+disruption+in+the+future.

“Central Hypersensitization” due to….

Microglial and Immune Activation : What can be done about this? LBP: Combination therapy show improvement in pain, and function TOPENTADOL= Opiate AGONIST + NE increase PEA= Mast Cell Stabilizer plus Micgrolia

Palmitoylethanolamide (PEA), a member of the N-acylethanolamine family, produced by most mammalian cells and which is particularly abundant in brain tissues. PEA exerts its effects on cellular targets involved in the generation and maintenance of pain [15] by down-modulating mast cell activation and controlling microglial cell behaviors

LBPCombination CombinationNewer therapy therapy RCTs show data show forimprovement improvement Combination in in pain,therapy pain, and and function function as well reduction in dose of Topentadol

CombinationNewerPost therapy RCTslumbar show data Laminectomy forimprovement Combination Syndrome: in pain,therapy and function (Combination therapy TPD + PGB then PEA added)

Paladini A et al. Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome. Pain Res Treat. 2017; 2017, Aug 10. doi: 10.1155/2017/1486010 CombinationNewerPost therapy RCTslumbar show data Laminectomy forimprovement Combination Syndrome: in pain,therapy and function (Combination therapy TPD + PGB then PEA added)

Paladini A et al. Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome. Pain Res Treat. 2017; 2017, Aug 10. doi: 10.1155/2017/1486010

CombinationNewerPost therapy RCTslumbar show data Laminectomy forimprovement Combination Syndrome: in pain,therapy and function (Combination therapy TPD + PGB then PEA added)

Paladini A et al. Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome. Pain Res Treat. 2017; 2017, Aug 10. doi: 10.1155/2017/1486010

CombinationNewerPost therapy RCTslumbar show data Laminectomy forimprovement Combination Syndrome: in pain,therapy and function (Combination therapy TPD + PGB then PEA added)

Paladini A et al. Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome. Pain Res Treat. 2017; 2017, Aug 10. doi: 10.1155/2017/1486010 Studies involving 5% Topical Lidocaine for Painful Diabetic Neuropathy

Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Tramadol, Topentadol and Topical Lidocaine

Lidocaine can penetrate no deeper than 8–10 mm, thus indicated in well-localized neuropathic pain. Minimal Absorption.

The most common adverse effects of lidocaine are mild local reactions due to its topical application.

FDA Approved for PDN

Drugs approved for pain in diabetic neuropathy: • Duloxetine • Pregabalin • Tapentadol

Dy SM et al. Preventing Complications and Treating Symptoms of Diabetic Peripheral Neuropathy. Comparative Effectiveness Review No. 187. (Prepared by the Johns Hopkins University Evidence- based Practice Center under Contract No. 290-2015-00006-I.) AHRQ Publication No. 17-EHC005- EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2017. Agency for HealthCare Research and Quality

• SNRI (Duloxetine, Venlafaxine): Moderate • AEDs (Pregabalin, Gabapentin, Oxcarbazepine): Low • TCAs (Amitriptyline, Nortriptyline): Low • Atypical opioids, botulinum; alpha-lipoic acid • Spinal cord stimulation are more effective than placebo but with low SOE.

Currently used Therapies

1. Anticonvulsants: Gabapentin, Pregabalin (66.6%) 2. Antidepressants: Amitriptyline, duloxetine, Nortriptyline, Venlafaxine, Desipramine (17.4%) 3. Opioids and Atypical Opiates: Tramadol, Tapentadol oxycodone, morphine (12.7%) 4. Topical Agents: lidocaine, capsaicin (3.3%) 5. Mindfulness, CBT, Modalities: Unknown 6. Conventional low frequency spinal cord stimulation Dy SM et al. Preventing Complications and Treating Symptoms of Diabetic Peripheral Neuropathy. Comparative Effectiveness Review No. 187. (Prepared by the Johns Hopkins University Evidence- based Practice Center under Contract No. 290-2015-00006-I.) AHRQ Publication No. 17-EHC005- EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2017.

AHCPR: Pregabalin

AHCPR: Tramadol and Topentadol

Sad Reality about effectiveness and use of PDN medications

Most patients STOP MEDS with I 12 months deu to inefficacy and/or side effects Most patients do not switch to a different medication

Yang M et al. Pain Medicine 2015 AHCPR: Spinal Stimulation (Failed conventional Rx, Multicenter RCT; N=96, >6 mo f/u European studies)

Dy SM et al. Preventing Complications and Treating Symptoms of Diabetic Peripheral Neuropathy. Comparative Effectiveness Review No. 187. (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No. 290-2015-00006-I.) AHRQ Publication No. 17- EHC005-EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2017. de Vos CC et al. Spinal cord stimulation in patients with painful diabetic neuropathy: a multicentre randomized clinical trial. Pain. 2014 Nov;155(11):2426-31. doi: 10.1016/j.pain.2014.08.031. PMID: 25180016.

Slangen R et al. Spinal cord stimulation and pain relief in painful diabetic peripheral neuropathy: a prospective two-center randomized controlled trial. Diabetes Care. 2014 Nov;37(11):3016-24. doi: 10.2337/dc14-0684. PMID: 25216508.

Conventional Spinal Stimulation versus Conventional Medical Practice • N= 60: RCT 20 CMP and 40 CMP plus SCS. • Netherlands, Denmark, Belgium & Germany from 11/08 and 10/12. Refractory diabetic neuropathic pain >5/10 >1 year 6 month post in the Netherlands, Denmark, Belgium and Germany

Duartes RV et al. Quality of life increases in patients with painful diabetic neuropathy following treatment with spinal cord stimulation. Qual Life Res (2016) 25:1771–1777

Duartes RV et al. Quality of life increases in patients with painful diabetic neuropathy following treatment with spinal cord stimulation. Qual Life Res (2016) 25:1771–1777 Conventional Spinal Stimulation versus Conventional Medical Practice

Duartes RV et al. Quality of life increases in patients with painful diabetic neuropathy following treatment with spinal cord stimulation. Qual Life Res (2016) 25:1771–1777

Conventional Spinal Stimulation versus Conventional Medical Practice

• N= 60: RCT 20 CMP and 40 CMP plus SCS. • Netherlands, Denmark, Belgium & Germany from 11/08 and 10/12. Refractory diabetic neuropathic pain >5/10 >1 year 6 month post in the Netherlands, Denmark, Belgium and Germany 1. Because “over 50 % pain relief after 3 years of SCS therapy was reported by five out of six patients with PDN in a non-randomised studies (Daousi 2005), …long- term follow-up of the cohort of this RCT is required to verify if these results are corroborated in patients with PDN” 2. Since then the technology has improved dramatically Duartes RV et al. Quality of life increases in patients with painful diabetic neuropathy following treatment with spinal cord stimulation. Qual Life Res (2016) 25:1771–1777

Daousi, C., Benbow, S. J., & MacFarlane, I. A. (2005). Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabetic Medicine, 22(4), 393–398.

PDN Study HF 10: Pain Relief (N=25 3 mo follow up at NANS 2018; 18 LE 7 UE:

• Major inclusion criteria

– Clinical diagnosis of peripheral polyneuropathy (PPN) of the upper or the lower limb(s)

– Refractory to conservative therapy for> 3 months

– Mean upper or lower limb VAS ≥5 out 10 cm

• Major exclusion criteria

– Mononeuropathy or neuropathies of the trunk

– Failed prior SCS trials for chronic intractable pain PDN Study HF 10: Pain Relief (N=25 3 mo follow up at NANS 2018; 18 LE 7 UE:

All Implanted Subjects (N=18) Implanted PDN Subjects (N=7) 10.0 10.0 8.0 8.0 7.5 8.0

6.0 6.0

4.0 4.0 2.9 VAS (cm) VAS 2.2 (cm) VAS 2.1 1.9 2.3 2.3 2.1 1.9 2.0 0.9 2.0 1.1

0.0 0.0 BL EOT 1 Wk 1 Mo 3 Mo 6 Mo BL EOT 1 Wk 1 Mo 3 Mo 6 Mo

100% 100% 100% 100% 83% 83% 86% 86% 86% 78% 76% 80% 80% 71%

60% 60%

40% 40%

20% 20%

Responder Responder Rate (%) Responder Responder Rate (%) 0% 0% BL EOT 1 Wk 1 Mo 3 Mo 6 Mo BL EOT 1 Wk 1 Mo 3 Mo 6 Mo 88

Videos • N:\Marketing\Patient Testimonials\2018\angela- diabetes\angela--diabetic-neuropathy.mp4 • https://www.youtube.com/watch?v=kqEgH QHAMqM&sns=em • https://www.youtube.com/watch?v=FRpC WB_Eh4Y • https://youtu.be/Zy1hTemOf8k • https://www.youtube.com/watch?v=tvPuuH KL6W8&sns=em

Current Multi-Center US PDN HF-10 SCS Study Recruiting. No cost to patient [email protected]

Inclusion: • Diagnosis of diabetic neuropathy (PDN) of the lower limbs. • Minimum of 12 mo conservative Rx including failed trial of Pregabalin (just need to have tried Lyrica) • Average VAS > 5 average over 7 days at the time of enrollment. • Pain Meds stable for at least 30 days prior to enrollment. Exclusion: • Diagnosis of lower limb mono-neuropathy, lower limb amputation, gangrenous ulcers of lower limbs (>/=3cm). • Hgb A1C > 9%. • BMI >40. • MEDD greater than 120mg. • Failed prior SCS Trial or Explanted Permanent Implant. • Existing drug pump or implanted device. Answers Q1. What is the NNT for Gabapentanoids (Gabapentin, and Pregabalin)

• 1 • 2-5 • 4-6 • >6

Answer d.

- Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73

Answers

Q2. The most effective group of medications for neuropathic pain, based on NNT

• Answer a.

- Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta- analysis. Lancet Neurol. 2015;14:2:162-73

Answers

Q3. The CDC and State Board guidelines suggest the following • Lowest possible opiate dose not to exceed 90mg morphine equivalent • Prescription on Naloxone if patient at high risk for overdose and deaths • Checking PDMP on patients at initiation of opiate therapy and at least once every three months • All of the above

• Answer d.

- Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65:1–49. http://www.cdc.gov/media/modules/dpk/2016/dpk-pod/rr6501e1er-ebook.pdf - Wisconsin Medical Examining Board Opioid Prescribing Guideline – November 16, 2016 https://dsps.wi.gov/Documents/BoardCouncils/MED/MEDGuidelinesV4.pdf Answers

Q4. Spinal stimulation effectiveness for neuropathic pain, which of the following are true statements? • • For focal neuropathic pain (e.g. foot pain) dorsal root ganglion stimulation is the most optimal option • For peripheral sensory motor neuropathic pain High Frequency stimulation has been shown to decrease pain, improve function and decrease opiate use at 24 onth follow up • For lumbar post laminectomy and CRPS the long term data supports use • All of the above

• Answer d.

-Liem L, Russo M, Huygen FJ, et al. One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain. Neuromodulation. 2015;18:41–48 -Kapural L et al. Comparison of 10-kHz High-Frequency and Traditional Low-Frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: 24-Month Results From a Multicenter, Randomized, Controlled Pivotal Trial. Neurosurgery 0: 1-10, 2016 - Verrills P, Sinclair C, Barnard A. A review of spinal cord stimulation systems for chronic pain. J Pain Res. 2016 Jul 1;9:481-92. doi: 10.2147/JPR.S108884. eCollection 2016. (Review)

Answers

Q5. Lumbar epidural steroids are effective for which of the following conditions

• Answer: b.

-Manchikanti L et al. Efficacy of epidural injections in the treatment of lumbar central spinal stenosis: a systematic review. Anest Pain Med 2015: 5; e23139. doi: 10.5812/aapm.23139. eCollection 2015 Feb

Answers Q1. What is the NNT for Gabapentanoids (Gabapentin, and Pregabalin)

• 1 • 2-5 • 4-6 • >6

Answer d.

- Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73 Answers

Q2. The most effective group of medications for neuropathic pain, based on NNT

• Answer a.

- Finnerup NB et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta- analysis. Lancet Neurol. 2015;14:2:162-73

Answers

• Answer d.

Answers

• Answer d.

Q5. Lumbar epidural steroids are effective for which of the following conditions

• Answer: b.