Multiple Sclerosis and PainBrett R. Stacey, MD

Medical Director, UW Center for Pain Relief

Professor, Anesthesiology and Pain Medicine

Disclosures

Official:

• Will discuss off label medication uses

• CONFLICTS:• Funded research and consulting: Teva.

• Consulting: Kineta

• Research: Pfizer, Vertex, Axsome

The Obvious: I am not a neurologist

OTHER Conflicts• I am a clinician, not a basic scientist

• My preference it to see patients with neuropathic pain and/or CRPS

• I will express some opinions

Jean-Martin Charcot

First describes Multiple Sclerosis in 1868

• PubMed for “Pain Multiple Sclerosis” from 1868: first paper on the topic in English in 1969

My neurology rotation as an intern: “aside from trigeminal neuralgia and painful spasticity, MS isn’t a

painful disease”

Charcot JM (1868). "Histologie de la sclérose en plaques". Gazette des hopitaux, Paris (in French). 41: 554–55Kuroiwa, Y. and H. Shibasaki (1968). "Painful tonic seizure in multiple sclerosis treatment with diphenylhydantoin and carbamazepine." Folia PsychiatrNeurol Jpn 22(2): 107-119.Albert, M. L. (1969). "Treatment of pain in multiple sclerosis--preliminary report." N Engl J Med 280(25): 1395.

N O W

• A focus on quality of life, patient experience, and new treatments have dramatically increased awareness of pain in MS.

• A search at: https://clinicaltrials.gov/

for Multiple Sclerosis and Pain reveals:

• I anticipate our understanding of pain in MS and treatment options will expand dramatically in the next few years

Pain

“An unpleasant sensory and emotional experienceassociated with actual or potential tissue damage, ordescribed in terms of such damage.”

International Association for the Study of Pain (IASP)

Chronic Pain: ongoing pain with no clear endpoint that impacts quality of life

Pain is connected to the Body

https://well.blogs.nytimes.com/2008/04/22/pain-as-an-art-form/

But Pain Is an Experience of the Brain

Beyond the ongoing pain

• Less Active → deconditioned, obese, injury-prone

• Altered Mood: irritable, depressed, anxious, angry

• Poor Sleep

• Loss of Energy

• Loss of Libido

• Work/Vocational Issues

• Legal Issues

Still more

• Financial Concerns

• Family Stress

• Decreased Self Esteem

• Frequent use of the health care system, with decreased satisfaction

• Use of Medications

• Fear of Injury

• Misconceptions

• Meaning, faith, Quality of Life

Pain in Multiple Sclerosis

Meta-analysis and review (2013): pain in 55-70%:

• headache (43%; 95% CI 33–52%)

• neuropathic extremity pain (26%; 95% CI 7–53%)

• back pain (20%; 95% CI 13–28%)

• painful spasms (15%; 95% CI 8.5–23%)

• Lhermitte sign (16%; 95% CI 10–25%), and

• trigeminal neuralgia (TN) (3.8%; 95% CI 2–6%)

A recent multi-site Italian study looking carefully for neuropathic pain in 1249 patients:

• 34% with pain, of those:• 67% with “nociceptive pain”, primarily MSK• 43% neuropathic, 7.6% TN

Foley, P. L., et al. (2013). "Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis." Pain 154(5): 632-642.Solaro, C., et al. (2018). "Identifying neuropathic pain in patients with multiple sclerosis: a cross-sectional multicenter study using highly specific criteria." J Neurol265(4): 828-835. http://menace-theoriste.fr/scepticisme-du-xviie-au-xixe-siecle/swtor_skeptical/

Pain in Multiple Sclerosis

• Heterogeneous

• Fluctuates

• Neuropathic pain is a subset

• Can be unrelated to Multiple Sclerosis diagnosis

• Treatments not studied very extensively

Pain in MS vs Other conditions

Multiple Sclerosis• Depression, anxiety,

distress predict pain

• More pain = poorer function

• Trigeminal neuralgia not infrequent

• Dramatically waxes and wanes

• Disease modification

Everything else• Depression, anxiety,

distress predict pain

• More pain = poorer function

• Trigeminal neuralgia is rare

• Major fluctuations unusual

• Disease modification = aspirational goal

What is Neuropathic Pain?

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

International Association for the Study of Pain 2011: www.iasp-

pain.org/resources/painDefinition

• In English: Pain originating from demonstrable damage or disease of the nerves, spinal cord, or brain. Not originating in the bones, muscles, organs.

History and Symptoms Common to Neuropathic Pain

• Pain described as burning, tingling, electric, numb, or shooting, unusual

• Sensitive to cold, heat, or touch

• Changes in appearance

• Patient may guard and protect painful area

• Possible reports of neuro deficits

• History of injury, disease associated with nerve injury

• Impaired motor control or guarding

• History of other neuropathic pain

• May worsen at night

• Occasionally, neglect: “it doesn’t feel like my arm”

Assessing the Pain

• Number scale: 0 to 10, none to worst imaginable

• Ask about ALL the pain

• Also: impacts on function, mood, work, recreation, health, family, sleep, sex, etc

• Ask the patient: “what do you think is causing this pain?” “what do you think needs to be done?”

• Review history: prior pain? past treatments? other health issues? physical/emotional/sexual abuse? substance abuse? prior mental health issues? Family history? Pre-pain physical condition?

• Physical examination- complete = not limited to neuro exam

• Testing

Anesthesiology 2010;112:810-33; Breivik H, Br J Anaesth. 2008;101(1):17-24

Assess and graph core patient-reported outcomes of chronic pain management over time

Displays relationships between chronic pain treatments and patient outcomes

Identifies high-risk situations

The UW PainTracker™

Physical Examination

• Appearance• Guarding, loss of range of motion• Atrophic changes

• Loss: Sensory, motor, reflex

• Positive Sensory Findings:• Allodynia: painful response to normally

nonpainful stimuli--light touch, cold, vibration

• Hyperalgesia: increased response to painful stimuli

• Hyperpathia: repeated stimulus becomes more painful

• MSK: general screen for the entire body, more detailed of painful region

“Mixed” pain

• Neuropathic pain may coexist with other pain types

• Nociceptive or musculoskeletal pain may need different treatment than neuropathic component

• Therefore, it is not uncommon to need combination treatment to optimize outcome

Treatment

Effectively treating pain often tied to improving mood,

coping, sleep, and function while reducing distress.

Balancing Treatment: the sum is greater than the parts

Mental Health:CBT, Self Management, Mindfulness, Acceptance, Control

Rehabilitation:Improve functionOvercome deconditioningIndependent exercisePacing

Medical:Disease managementMedication InterventionCoordinationReinforcement

Background: Previous experiences, genetics, OVERALL HEALTH, insurance, work, disability, money, family, leisure, meaning

Integrative Medicine

Mechanism based treatment

Rasmussen PV, et al Eur J Neurol 2004; Chen H, et al Mayo Clin Proc 2004; Edwards RR et al Anesthesiology2006.;

Freynhagen R. et al Pain. 135(1-2):65-74, 2008 Mar; Mackey S, et al. J Pain 13(1):58-63, 2012 Jan

Rational, sounds good, and it is the future, BUT… we aren’t there yet

MS Specific Medication Trials for PAIN

Few

No 1st line evidence

Medication Options for Neuropathic Pain

Best Evidence:

• Antidepressants:• TCAs : Nortriptyline,

Desipramine (Amitriptyline, etc)

• SNRIs: Duloxetine, Venlafaxine

• Gabapentin, Pregabalin

• Carbamazepine for TGN

• Opioids + Tramadol*

• Topical Lidocaine Patch

Second-line:

• Opioids and Tramadol*

Others:

• Other Antiepileptics

• Other Antidepressants

• Capsaicin (PHN)

• ETC: alpha 2 agonists, antiarrthymics, etc

Smith, BH, et al. Br J Anaesth. 111(1):73-9, 2013 Dworkin RH, et al. Mayo Clin Proc. 85(3 Suppl):S3-14, 2010Attal N et al, Eur J Neurol. 17(9):1113-e88, 2010 Moulin DE, et al. Pain Res Manag 12(1):13-21, 2007 Chetty S, et al. SAMJ 102(5):312-25, 2012 Finnerup NB, et al. Lancet Neurol 14(2):162-173, 2015

Other treatments not well represented

• Mental health: cognitive behavioral approaches, mindfulness, hypnosis

• Physical activity/exercise: physical therapy, stretching, aerobic exercise, Yoga, Pilates, Tai Chi

• Diet, weight loss, sleep

• Alternative medicine approaches

• Interventions/Procedures

• Disease and comorbidity management

• New, developing medications

Medications that are used, but……………

• NSAIDs: for neuropathic pain: • Absent from ANY neuropathic guideline• Commonly used in the US and Europe in clinical practice

• Despite being a wide-spread treatment for pain, there is a paucity of neuropathic NSAID clinical trial data, though suggestive animal data2

Pain. 2009 Jun;143(3):169-71

• Minimal evidence for many chronic pain conditions

• SSRIs: widely used, minimal positive data• Absent from ANY neuropathic guideline

Max, MM, et al. NEJM 326.19 (1992): 1250-1256.

Cochrane Database of Systematic Reviews. (3):CD005454, 2005.

Tricyclics

The Good

• Many trials for many conditions

• Recognized as first-line txfor neuropathic pain, headache, evidence in MSK

• Sleep

• Cheap

• Nortriptyline/Desipraminemay be better tolerated

The Bad

• Many contraindications

• Excessive death

• Often underdosed (dose 50-150 mg)

• Often prescribed despite problems

• Check ECG/QT/interactions

• Anticholinergic effects

Attal N et al Eur J Neurol 2006Salerno et al Arch Int Med 2002Watson et al Neurology 1998Shimbo et al Am J Med 2000

Swenson JR et al Can J Psychiatry. 2006Berger A et al Eur J Clin Pharmacol 2006Gore M et al Pain Pract 2006 Berger et al Clin JPain. 2007

Duloxetine• Selective serotonin norepinephrine reuptake

inhibitor (SSNRI)1

• Approved for “neuropathic pain associated with diabetic peripheral neuropathy” 2,3,4

• Also FDA approved for chronic MSK pain, fibromyalgia, GAD, depression

• Nothing better than duloxetine for low back pain

• Two DBPCRTs in MS (Brown, T. R. and A. Slee (2015). Int J MS Care 17(2): 83-89. Vollmer, T. L., et al. (2014). Pain Pract 14(8): 732-744.)

• Dosing: start 20-30 with food, effective dose most commonly 60 mg

1. Cymbalta package insert; 2. Goldstein et al. Pain. 2005;116:109-118; 3. Wernicke JF et al. Neurology. 2006;67:1411-1420; 4. Raskin J et al. Pain Med. 2005;6:346-356. 3. Chou R, Deyo R, Friedly J, Skelly A, Hashimoto R, Weimer M, Fu R, Dana T, Kraegel P, Griffin J, Grusing S. NonpharmacologicTherapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice GuidelineNonpharmacologic Therapies for Low Back Pain. Annals of internal medicine. 2017 Apr 4;166(7):493-505

Gabapentin

• 1994: available, unknown mechanism, not for pain

• 1996: Case series in neuropathic pain suggestive of efficacy1

• 1998: largest drug studies ever completed for neuropathic pain published 2,3

• Absorption decreases as dose increases

• Effective doses: 1200-2400 mg/day, max dose 3600 mg/day

• Doesn’t work for MSK pain without sensitization

1. Stacey, BR, et al. RAPM. 21.2 (1996): 65.

2. Rowbotham M et al. JAMA. 1998;280:1837-1842. (225 subjects)

3. Backonja M et al. JAMA. 1998;280:1831-1836. (165 subjects)4. Gorson KC et al. J Neurol Neurosurg Psychiatry 1999;66:251-252 (40 subjects, dose 900 mg)

Pregabalin

• Compared to gabapentin: • More potent, faster onset

• Linear absorption (90% at all doses)1,2

• Increased bioavailability2

• BID or TID dosing2

• Begins working in 1 day3

• Reduces allodynia3

• Potentially effective in treatment resistant patients4

• May be opioid sparing5

1. Wesche D, Bockbrades H. Poster. APS 2005, Boston, Mass. 2. Lyrica Package Insert 3. Stacey BR, et al. J Pain 9.11 (2008): 1006-1017, 2008 Nov. 4. Stacey BR et al, Pain Medicine 9(8), 1202-1208. 5. Gore M. Sadosky A. Tai KS. Stacey B. Clin Ther 29(8):1655-70, 2007 Aug.

Stacey BR et al, Pain Medicine 9(8), 1202-1208, 2008 Nov

Low dose naltrexone

• Toll-like receptor 4 or TLR4 antagonist, other mechanisms possibly including opioid growth factor• Macrophages and microglia

• Anti-inflammatory effect

• Studies in Fibromyalgia, Crohn’s Disease and MS

• Multiple Sclerosis:• Small studies with variable results: improvements in pain

and QOL

• Dose usually 4.5 mg/day or less

Younger, J., et al. (2014). Clinical rheumatology 33(4): 451-459. Patten, D. K., et al. (2018). Pharmacotherapy 38(3): 382-389 Sharafaddinzadeh, N., et al. (2010). Mult Scler 16(8): 964-969. Ludwig, M. D., et al. (2016). Mult Scler J Exp Transl Clin 2: 2055217316672242.

.

Trigeminal Neuralgia• 5-10% of Multiple Sclerosis patients, can be presenting

problem• Medications: carbamazepine, oxcarbazepine,

misoprotolol• Surgery: lower success rate than non-MS TN

• Radiosurgery• Decompression• Other neuro-destructive approaches

• Important to distinguish from neuropathy: Head and/or facial pain in the distribution of one or more branches of the trigeminal nerve caused by another disorder and indicative of neural damage.

Zakrzewska, J. M., et al. (2018). "A Systematic Review of the Management of Trigeminal Neuralgia in Patients with Multiple Sclerosis." World Neurosurg 111: 291-306.

Cannabis, Cannabinoids

• Much suggestive evidence in MS

• Mostly non-standardized dosing/delivery• Nabiximols (Sativex®) is a sublingual spray 2.7 mg THC

and 2.5 mg CBD per dose approved in the UK and other countries for treatment of various aspects of MS

• Review of reviews: “Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.”

Nielsen, S., et al. (2018). "The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews." Curr Neurol Neurosci Rep 18(2): 8.

Combination pharmacotherapy

2012 Cochrane Review: “Multiple, good-quality studies demonstrate superior efficacy of two-drug combinations…(limited data)…preclude the recommendation of any one specific drug combination for neuropathic pain”

More recent studies:

• Pregaballin + imipramine in painful polyneuropathy= better pain control, more side effects in a DBPCRT, crossover design vs either agent

• Pregabalin, duloxetine, or combo in pDPN: trends, but not clear superiority

• Morphine, nortriptyline, combo: superior efficacy with combo

Chaparro, LE, et al. "Combination pharmacotherapy for the treatment of neuropathic pain in adults." The Cochrane Library (2012).Holbech, JV, et al. "Imipramine and pregabalin combination for painful polyneuropathy: a randomized controlled trial." Pain 156.5 (2015): 958-966. Tesfaye, S, et al. "Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”–a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain." PAIN® 154.12 (2013): 2616-2625.Gilron, I, et al. “Combination of morphine with nortriptyline for neuropathic pain.” Pain. 2015 Aug;156(8):1440-8.

Who is an interventional candidate?

Green light:• Localized pain: one body

region, one nerve, one area

• Pain consistent/persistent

• History, physical, and diagnostic testing consistent

• Distress, mood, medical illness under control

• Reasonable effort at initial conservative treatment• Medications• Rehabilitation = physical

therapy

• Reasonable expectations

LESS good candidate:• Diffuse/widespread pain

• Poorly managed anxiety, depression, substance use

• Pain with minimal stimulation

• Unrealistic expectations

• Unwilling to be active in their care

• Pain that fluctuates/migrates

• Others:• High dose opioids?• Smoking?• Severe deconditioning• Increased risk of

complications

Summary

Pain in Multiple Sclerosis:

• Common

• Varied

• Can wax and wane or be stable/persistent

• Impacts QOL

• Focal or unimodal treatment for focused/persistent pain in patient otherwise doing well

• Comprehensive treatment: pain, mood, sleep, function, coping for difficult cases

Thank You!

Questions?