Current and Evolving Standards of Care For Patients with Southern Pain Society 2020

Miroslav Backonja, MD Department of Anesthesiology and Pain Medicine Department of Neurology University of Washington – Seattle

Objectives

• Definition of neuropathic pain (NP) and its implications • Application of new assessment approaches to NP and their implications for treatment • An example of pain to demonstrate challenges in assessing and treating NP • Standards and practice of NP treatment • Developments in treatment of NP

Neuropathic Pain

Pain caused by a lesion or disease of the somatosensory nervous system.

Treede et al. Neurology 2008 Jensen et al Pain 2011 https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698

1 Neuropathic Pain

Pain caused by a lesion or disease of the somatosensory nervous system. Central Sensitization

Treede et al. Neurology 2008 Jensen et al Pain 2011 Peripheral Sensitization https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698

Neuropathic Pain – Implications of definition

- It is necessary to perform neurological somatosensory exam across the range of fiber types, including small fibers (e.g. such as test for cold and hot) to establish the diagnosis of neuropathic pain

- NP is a positive and confirmatory diagnosis, not diagnosis of exclusion

-In NP, history and neurological sensory exam reveal a mix of positive phenomena (e.g. allodynia) and negative (e.g. deficits) phenomena across the range of sensory modalities

Question for the audience:

• By raising your hands, please indicate as Yes: Are you sufficiently well trained to perform neurological sensory examination across all modalities which would allow you to make with confidence diagnosis of neuropathic pain and its severity?

2 Pain Mechanisms as the Basis for the Multi-Modal Neuropathic Pain Therapy

Perception Endogenous Modulation Cognitive behavioral approaches Norepinephrine Serotonin Endogenous Endocannabinoids

Descending Inhibition TCAs: SNRIs: : ,

Transduction Synaptic Transmission TRPV1: a-2-d Ca++ : GBP,PGB NMDAr: Periph. Transmission Opioids: morphine, tramadol Na+: , TCA Ca++: ziconotide

Revised after: Beydoun A, Backonja M. J Pain Symptom Manage.2003.

Third mechanistic pain term

Nociplastic pain (2016) Pain that arises from altered despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain. • Note: Patients can have a combination of nociceptive and nociplastic pain

• Commentary: Nociplatic pain is now interchangeably used to mean central sensitization or what is also called centralized pain, all of which is frequently confused and differentiated from central neuropathic pain

Interpreting NP in context of total patient In patients with , NP is more then likely that NP is one of a few types of pain; most often associated is myofascial pain

3 Comparison of NP Symptoms Discrimination Tools

Bennett M et al, Pain 2007

Types of Pain in PHN

Implication When examining patient where working diagnosis is Neuropathic Pain, anticipate a mix of positive and negativesigns.

Baron et al Lancet Neuro 2010 Fosterpointer et al Pain 2018

Stratifying patients with peripheral neuropathic pain

based on sensory profiles J. Vollert et al.·158 (2017) 1446–1455

4 Controlled Pain Modulation - CPM

• Utilizes principles of descending modulation • Rating of one stimulus is affected by another noxious stimulus • Example of CPM predicting response of response to Duloxetine among patients with Painful Diabetic Neuropathy

Yarnitsky et al 2010, 2012, 2013

The effect of in peripheral neuropathic pain depends on pain phenotype D.T. Demant et al. / PAIN 155 (2014) 2263–2273

Patients with peripheral neuropathic pain: polyneuropathy, surgical or traumatic nerve injury, or PHN 83 patients: 31 irritable nocicipetor by QST and 52 nonirritable nociceptor phenotype NNT - > 50% pain relief: 6.9 (95% CI 4.2-22) in the total sample, 3.9 (2.3-12) in the irritable, and 13 (5.3-100) in the nonirritable nociceptor phenotype

Case Study: VAMC in Madison WI Little NP Tool that Could

Setting: Primary Care Clinics (residents, fellows, NP’s, PA’s) Challenge: too many opioids, too many frustrated patients and providers Opportunity: intervention to improve pain assessment • MA notices pain rating > 4/10 on intake => administer ID Pain • IDPain > 2/6 => flag to provider that pain is probably Neuropathic • Provider performs standardized sensory exam => confirm DX • Order labs: BS, HgbA1c, TFTs, B12, folate • Consider further work-up as indicated • Prescribe: GBP, TCA*,

Outcome: Improved care, less frustration

5 Case Study: VAMC in Madison WI Little NP Tool that Could Setting: Primary Care Clinics (residents, fellows, NP’s, PA’s) Challenge: too many opioids, too many frustrated patients and providers Opportunity: intervention to improve pain assessment • MA notices pain rating > 4/10 on intake => administer IDPain • IDPain > 2/6 => flag to provider that pain is probablyNeuropathic • Provider performs standardized sensory exam => confirmDX • Order labs: BS, HgbA1c, TFTs, B12, folate • Consider further work-up as indicated • Prescribe: GBP, TCA*,

Outcome: Improved care, less frustration

Beyond Nervous System: Immune, MSK, GI, endocrene …. Beyond Physiology: gender, genetics, environment ….

Integrative Pain Medicine, including care of patients with NP, guides us to look at the whole patient in their environment

Types of Therapies for Neuropathic Pain

Disease modifying * None available at the present

Symptomatic * Pharmacological neuromodulation • topical • systemic • intrathecal * Electrical neuromodulation and neuroablation * Behavioral therapies and interventions

6 Principles of Pharmacotherapy

• Assessment of pain and associated symptoms – implications for treatment planning: • Constant ongoing pain => scheduled meds • Pain flares => non- approaches • Associated comorbidities => specific therapies

Painful Diabetic Neuropathy

Age 20 years or older: 30.2 million people (12.2%) of the U.S. population have diabetes, report 2017

http://www.cdc.gov/diabetes/pubs/statsreport17/national-diabetes-report-web.pdf

60-70% has neuropathy 15-31 % have neuropathic pain symptoms (PDN)

PDN estimated at > 2,500,000

National Diabetes Statistics Report

Pathophysiology Diabetic Neuropathy (DN) Hyperglycemia - central to all pathogenic process Impaired structure - axons, myelin and other supporting elements Impaired repair and regenerative mechanisms Hypoxia - microvascular insufficiency

Pathogenesis of pain in DN (PDN) Increase of alpha-adrenoceptors mRNA in DRG’s Impaired Na+ channel function (e.g. Nav1.7) Spinal mechanisms - loss of inhibition Supraspinal factors - not well studied, probably important

Said G Nat Clin Pract Neurol 2007 Tefsay et al, Diab Met Res Rev 2012 Urban et al, Exp Neuro 2012

7 Diabetic (DPN): A Heterogeneous Disorder

Symptoms depend on types of nerve fibers involved

Sensory fibers => Altered sensory function Pain, numbness, loss of proprioception

Autonomic fibers => Loss of function Digestive, urogenital, cardiovascular, sudomotor

Motor fibers => Muscle weakness

Types of Diabetic Neuropathy and its Distribution with Associated Neuropathic Pain

1. radiculitis 2. entrapment 3. plexopathy 4. distal polyneuropathy 5. mononeuritis multiplex

Therapies Proven in Randomized Clinical Trials to be Effective in Relieving Pain of DPN

Centrally-acting Treatments Peripherally-acting Treatments Antidepressants Topical TCAs, Duloxetine* (SNRI) Capsaicin* Lidocaine , * Vasodilators Isosorbide dinitrate analgesics Complementary Alternative * Medicine Spinal cord stimulation Alpha (PO, IV)

* Therapies currently FDA-approved in the US for the treatment of pain of DPN

8 Is there a way to predict those patients likely to respond to a drug?

Conditioned Pain Modulation (CPM): - Activates descending inhibition - Patients with NP have impaired CPM - Example: patients with DPN who have impaired CPM preferentially respond to duloxetine

Yarnitsky et al Pain 2012

Finnerup N et al Lancet Neurol 2015

Finnerup N et al Lancet Neurol 2015 Strong recommendations for use

First Line Therapy

Gabapentin 1200–3600 mg, in three divideddoses

Gabapentin ER 1200–3600 mg, in two divideddoses

Pregabalin 300–600 mg, in two divideddoses

Duloxetine 60–120 mg, once a day

TCAs 25–150 mg, once a day

9 Finnerup N et al Lancet Neurol 2015 Weak recommendations for use

Second line therapy

Capsaicin 8% patches* 1-4 patches to the painful area for 30-60 min every 3 mo

Lidocaine patches* 1-3 patches to the region of pain once a day, up to 12h

Tramadol 200–400 mg, in two (tramadol ER) or three divideddoses

Third line therapy

Strong opioids Individual titration

*peripheral neuropathic pain

Finnerup N et al Lancet Neurol 2015

Panel: Drugs or drug classes with inconclusive recommendations for use or recommendations against use based on the GRADE classification

Inconclusive recommendations Weak recommendations against use • Combination therapy • • Capsaicin cream • • • topical • Strong recommendations against use • • • NMDA antagonists • • Oxcarbazepine • SSRI antidepressants • Tapentadol • •

Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS)

Barohn et al JAMANeuro 2020 Primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of 50% from baseline to week 12) and quit (participants who discontinued medication) rates No clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine

10 • Authors' conclusions There was insufficient evidence to support or refute the suggestion that has any efficacy in any neuropathic pain condition.

Authors' conclusions • The potential benefits of -based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes

• Authors' conclusions Multiple, good-quality studies demonstrate superior eicacy of two-drug combinations. However, the number of available studies for any one specific combination, as well as other study factors (e.g. limited trial size and duration), preclude the recommendation of any one specific drug combination for neuropathic pain.

11 Combination Therapy

Combination therapy (preferred over term polypharmacy) is commonly practiced, so, Guiding Principles are desired: • Attempt is made to match mechanism of action (MOA) with pain type • Priority is given to drugs that treat more then one morbidity • Avoid prescribing 2 or more drugs with same MOA • Balance effects and side effects • Star low and go slow since titration is necessary • Assess effects and side effects as you adjust doses

Recent Experience from Controlled Randomized Trials for NP Therapies Summary from available data • 40-50% of patients obtain >30% pain relief • multiple failed trails vs. failed drugs • very little was learned from those trials, about the drugs or about the disease

Past performance doesn‘t predict future performance, but past failures certainly make us are very concerned if not certain that future failures are likely

Review of RCTs with Novel Mechanisms of Action Sources

• Web in general: Results 1 - 10 of about 57,400/84,200 for: neuropathic pain and emerging and future treatments

• Clinicaltrials.gov: 982 studies: neuropathic pain • Published reviews: • Abbadie C, et al. Brain Res Rev. 2009 60(1):125-34 • Stuart RM, Winfree CJ. Neurosurg Clin N Am. 2009 Jan;20(1):111-20

12 And not such a happy story:

ClinicalTrials.gov Identifier:NCT03297294

Recruitment Status : Terminated (for safety reasons) First Posted : September 29, 2017 Last Update Posted : May 2, 2019

Experimental Drugs for Neuropathic Pain Kinga Sałata,*, Beata Gryzłob and Katarzyna Kuligc Current Neuropharmacology, 2018, 16, 1193-1209

Experimental Drugs for Neuropathic Pain Kinga Sałata,*, Beata Gryzłob and Katarzyna Kuligc Current Neuropharmacology, 2018, 16, 1193-1209

13 Experimental Drugs for Neuropathic Pain Kinga Sałata,*, Beata Gryzłob and Katarzyna Kuligc Current Neuropharmacology, 2018, 16, 1193-1209

Though drug development for NP might change ….

14 Conclusions

Goals of neuropathic are achieved utilizing specific assessments, treatment planning and monitoring, following principles of multidisciplinary and multimodal therapy.

Currently available therapies provide only partial pain relief in subset of patients, while majority of patients do not obtain much pain relief.

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