Disclosures: Understanding Central None Sensitization Syndromes: - - PDF document

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Understanding Central Sensitization Syndromes:

Fibromyalgia, Chronic Pelvic Pain, and Painful Bladder Syndrome

Molly Heublein, MD molly.heublein@ucsf.edu Assistant Clinical Professor of Medicine UCSF Women’s Health Center of Excellence

Disclosures:

 None

What is the diagnosis?

A painful disorder, more common in women, worsened with hormonal fluctuations and stress, characterized by allodynia and/or

• hyperalgesia. No pathognomonic exam

finding, lab test, or imaging study confirms this condition.

Migraine

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Migraine

Chronic Fatigue Syndrome Irritable Bowel Syndrome Primary Dysmenorrhea

Migraine

Fibromyalgia Chronic Pelvic Pain

Chronic Fatigue Syndrome Irritable Bowel Syndrome Painful bladder syndrome Primary Dysmenorrhea Myofacial pain syndrome

Migraine

Fibromyalgia Chronic Pelvic Pain

Chronic Fatigue Syndrome Irritable Bowel Syndrome

Tempomandibular joint disorder Vulvodynia

Painful bladder syndrome Primary Dysmenorrhea

Multiple Chemical Sensitivity Syndrome

Myofacial pain syndrome

Central Sensitization Syndromes

Migraine

Fibromyalgia Chronic Pelvic Pain

Chronic Fatigue Syndrome Irritable Bowel Syndrome

Tempomandibular joint disorder Vulvodynia

Painful bladder syndrome Primary Dysmenorrhea

Multiple Chemical Sensitivity Syndrome

Myofacial pain syndrome

Functional dyspepsia

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Central Sensitization Syndromes

Migraine

Fibromyalgia Chronic Pelvic Pain

Chronic Fatigue Syndrome Irritable Bowel Syndrome

Tempomandibular joint disorder Vulvodynia

Painful bladder syndrome Primary Dysmenorrhea

Multiple Chemical Sensitivity Syndrome

Myofacial pain syndrome

Mechanical low back pain Functional dyspepsia

Objectives for today:

 Discuss pain processing and central pain  Discuss overlap of fibromyalgia with chronic pelvic pain

and painful bladder syndrome

 Review fibromyalgia as a classic central sensitization

disorder

 Consider best practices to address patients suffering

from these conditions

Chronic Overlapping Pain Conditions Clinical Case:

35 yo woman comes to pcp office c/o anxiety and dysuria.

 Hx of IBS diagnosed at age 22, and chronic pelvic pain

diagnosed at age 29. She follows strict diets and takes some medications to help manage both, but does still experience frequent symptoms of nausea, abd bloating, and internal pelvic burning or pulling pain.

 In the past 2 mo she has noted recurrent episodes of what

she thought were UTIs but did not respond completely to

• antibiotics. She continues to have dysuria, urinary

frequency, and bladder pain.

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Types of pain

Peripheral (nociceptive) Neuropathic Cause of pain: Mechanical damage or inflammation Damage or entrapment

• f peripheral nerves

Responds to: NSAIDS, opioids, local procedures Peripheral and central

• therapies. Entrapment

responds to surgery or injection Classic examples: Acute pain due to injury, OA, RA, cancer pain Diabetic neuropathy, radicular back pain, postherpetic neuralgia

Clinical Case:

35 yo woman comes to pcp office c/o anxiety and dysuria.

 Hx of IBS diagnosed at age 22, and chronic pelvic pain

diagnosed at age 29. She follows strict diets and takes some medications to help manage both, but does still experience frequent symptoms of nausea, abd bloating, and internal pelvic burning or pulling pain.

 In the past 2 mo she has noted recurrent episodes of what

she thought were UTIs but did not respond completely to

• antibiotics. She continues to have dysuria, urinary

frequency, and bladder pain.

Clinical Case

Our patient has undergone:

• EGD and Colo X2 over the years
• modified barium swallow
• multiple Uas, STI screens
• pelvic ultrasound
• CT abdomen Pelvis

Clinical Case

Our patient has undergone:

• EGD and Colo X2 over the years
• modified barium swallow
• multiple urinalyses
• sexually transmitted infection screens
• pelvic ultrasound
• CT abdomen Pelvis

ALL REPORTED NORMAL

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Types of pain

Peripheral (nociceptive) Neuropathic Cause of pain: Mechanical damage or inflammation Damage or entrapment

• f peripheral nerves

Responds to: NSAIDS, opioids, local procedures Peripheral and central

• therapies. Entrapment

responds to surgery or injection Classic examples: Acute pain due to injury, OA, RA, cancer pain Diabetic neuropathy, radicular back pain, postherpetic neuralgia

The bio-medical model of pain does not hold up specific pathologic findings are not seen in most patients with chronic pelvic pain, painful bladder syndrome, or fibromyalgia

What did you do last time you saw a patient like this?

• A. Refer her to a psychiatrist, this is probably a somatoform

disorder.

• B. Tell her there is nothing wrong with her and she should feel

better soon.

• C. Explain the idea of central pain, discourage more advanced

testing, and help establish a treatment plan.

• D. Say “there is nothing wrong with your bladder/GI tract/etc,

let me refer you to this other specialist who can evaluate you more for muscle/uterus/etc problems”

What did you do last time you saw a patient like this?

• A. Refer her to a psychiatrist, this is probably a somatoform

disorder.

• B. Tell her there is nothing wrong with her and she should feel

better soon.

• C. Explain the idea of central pain, discourage more advanced

testing, and help establish a treatment plan.

• D. Say “there is nothing wrong with your bladder/GI tract/etc,

let me refer you to this other specialist who can evaluate you more for muscle/uterus/etc problems”

Types of pain

Peripheral (nociceptive) Neuropathic Centralized Cause of pain: Mechanical damage

• r inflammation

Damage or entrapment

• f peripheral nerves

Central disturbance in pain processing (hyperalgesia/allody nia) Responds to: NSAIDS, opioids, local procedures Peripheral and central

• therapies. Entrapment

responds to surgery or injection Centrally acting drugs Classic examples: Acute pain due to injury, OA, RA, cancer pain Diabetic neuropathy, radicular back pain, postherpetic neuralgia Fibromyalgia, irritable bowel syndrome, tension headache, IC, chronic pelvic pain

Adapted from: Clauw D. Fibromyalgia and Related Conditions. Mayo Clinic Proceedings. 90(5). 2015 May, 680-692.

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Types of pain are not exclusive, most patients have overlapping pain generators

• Hoffman. Central and Peripheral Pain Generators in Women with Chronic Pelvic

Pain: Patient Centered Assessment and Treatment. Current Rheumatology

• Reviews. Volume 11 , Issue 2 , 2015

In patients with central sensitization many studies have shown changes in sensory processing:

 Lower pain thresholds to pressure/heat/cold/electrical

stimuli based on subjective reporting (both magnitude and duration of pain sensation)

 Lower thresholds to auditory and visual stimuli as noxious

• n subjective reporting

 Changes in localized brain metabolism and

interconnectivity

 Increased levels of activating cytokines and decreased

levels of cytokines in descending inhibitory pathways

 Reduction in activity of inhibitory pain relieving pathways

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Responses to painful stimuli vary dramatically in the population

Genetic basis

 Catechol-O-methyltransfease (COMT) is one of several

enzymes that breaks down catecholamines

 This study looked at 202 healthy women, and assessed

genetic variation in COMT genes, baseline response to pain, and risk of developing TMJ dysfunction

 Low pain sensitivity was associated with higher COMT

activity levels and reduced risk of developing TMJ Dysfunction

Luda Diatchenko et al; Genetic basis for individual variations in pain perception and the development of a chronic pain condition, Human Molecular Genetics, Volume 14, Issue 1, 1 January 2005, Pages 135–143.

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Neurotransmitters

 COMT activity is important for breakdown of dopamine,

norepinephrine, epinephrine

 Higher levels of substance P in the CSF  Elevations in CNS glutamate levels in fibromyalgia,

measured both in the CSF and directly in the brain using proton spectroscopy (H-MRS) are also found in individuals with fibromyalgia

Experience of Pain

16 FM patients and 16 matched controls were exposed to painful pressures during fMRI scanning.

• increased neural activations in the primary and

secondary somatosensory cortex, the insula, and the anterior cingulate with painful stimuli.

• regions of activation were similar for the patients and

controls, but the control group needed almost double the pressure to develop the same level of pain

Gracely, et al. (2002), Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis & Rheumatism, 46: 1333–1343. doi:10.1002/art.10225

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Brain Connections and Pain

 fMRI, EEG, and proton magnetic resonance

spectroscopy have shown increased connectivity in patients with chronic pain  the Default Mode Network (resting/internal thoughts) is

more linked to pain processing sites in the brain

 Hypothesized that patients with chronic pain may not be

able to disengage from internal stimuli

Greater Connectivity between anterior insula and medial prefrontal cortex in women with chronic pelvic pain compared to controls

As-Sanie, Sawsan et al. “Functional Connectivity Is Associated with Altered Brain Chemistry in Women with Endometriosis-Associated Chronic Pelvic Pain.” The journal of pain: official journal of the American Pain Society 17.1 (2016): 1–13. PMC. Web. 7 Dec. 2017.

Connectivity and Relief

 27 women w fibromyalgia blinded cross over design

treated w pregabalin

 Studied with proton magnetic resonance spectroscopy,

functional magnetic resonance imaging, and functional connectivity magnetic resonance imaging showed that pregabalin treatment reduced brain insula glutamate levels and decreased connectivity of pronocioceptive brain areas to the default mode network

 These factors were associated with the clinical pain

relief on pregabalin

Harris et al. Pregabalin Rectifies Aberrant Brain Chemistry, Connectivity, and Functional Response in Chronic Pain Patients. Anesthesiology 2013;119(6):1453-1464.

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Diffuse Noxious Inhibitory Control (DNIC)

 In healthy humans and laboratory animals, application

• f an intense painful stimulus for 2 to 5 minutes

produces generalized whole-body analgesia.

 Thought to be mediated through descending opioid,

and serotonin-noradrenergic pathways

 This analgesia has been consistently observed to be

attenuated or absent in groups of FM patients as compared to healthy controls

• Maixner. Overlapping Chronic Pain Conditions: Implications for Diagnosis and Classification The Journal of PainVolume 17, Issue 9,

Supplement, September 2016, Pages T93-T107

Back to patient care….

 Bell shaped curve of pain experience, multifactorial

changes in pain processing

 People can have a turned up, amplified gain sensation  You may find objective findings that could typically

cause pain, without pain (in patients who have a pain volume at the low level)

 Think of this as a spectrum, rather than a discrete yes-

no Fibromyalgia-ness (Wolfe)

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Pain Experience vs Pathology

Sawsan As-Sanie et al. Increased Pressure Pain Sensitivity in Women With Chronic Pelvic Pain. Obstet Gynecol. 2013 Nov; 122(5): 1047–1055. Mean Pressure Pain Thresholds (kg/cm2) at the Nondominant Thumbnail in Patient Subgroups Compared With Various Comparison Groups P= 0.001 P=0.19

Chronic Overlapping Pain Conditions

In patients w FM: 12% had BPS In patients with CPP, 40% had BPS

Not to scale. % data from: Hoeritzauer. Chapter 38 - Urologic symptoms and functional neurologic disorders. Handbook

• f Clinical Neurology. Volume 139, 2016, Pages 469-481.

Prevalence of other pain conditions with chronic pelvic pain

Sawsan As-Sanie et al. Increased Pressure Pain Sensitivity in Women With Chronic Pelvic Pain. Obstet Gynecol. 2013 Nov; 122(5): 1047–1055.

Clinical Case:

35 yo woman comes to pcp office c/o anxiety and dysuria

 Hx of IBS diagnosed at age 22, and chronic pelvic pain

diagnosed at age 29. She follows strict diets and takes some medications to help manage both, but does still experience frequent symptoms of nausea, abd bloating, and internal pelvic burning or pulling pain.

 In the past 2 mo she has noted recurrent episodes of what

she thought were UTIs but did not respond completely to

• antibiotics. She continues to have dysuria, urinary

frequency, and bladder pain.

 On more questioning, she also c/o back pain, chest pain,

fatigue, and mental slowing.

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How do we diagnose fibromyalgia?

• A. 11/18 positive tender points
• B. LP with high substance P
• C. Refer to a rheumatologist for diagnosis
• D. Widespread pain index >6, Symptoms severity score

>4

How do we diagnose fibromyalgia?

• A. 11/18 positive tender points
• B. LP with high substance P
• C. Refer to a rheumatologist for diagnosis
• D. Widespread pain index >6, Symptoms severity score

>4

Fibromyalgia Diagnosis

ACR 2010 updated guidelines: A patient satisfies diagnostic criteria for fibromyalgia if the following 3 conditions are met:

 Widespread pain index (WPI) ≥7 and symptom severity (SS)

scale score ≥5 or WPI 3 - 6 and SS scale score ≥9.

 Symptoms have been present at a similar level for at least 3

months.

 The patient does not have a disorder that would otherwise

explain the pain.

Wolfe, et al. American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Symptom

• Severity. F Arthritis Care & Research; Vol. 62, No. 5, May 2010, pp 600–610

Widespread Pain Index (WPI): note the number areas in which the patient has had pain over the last week. In how many areas has the patient had pain? Score will be between 0 and 19.


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Symptoms Severity (SS) scale score:


Fatigue
 Waking unrefreshed
 Cognitive symptoms
For the each of the 3 symptoms above, indicate the level of severity over the past week using the following scale:
0 = no problem
1 = slight or mild problems, generally mild or intermittent
2 = moderate, considerable problems, often present and/or at a moderate level
3 = severe: pervasive, continuous, life- disturbing problems

Considering somatic symptoms in general, indicate whether the patient has:*
0 = no symptoms
1 = few symptoms
2 = a moderate number of symptoms
3 = a great deal of symptoms




The SS scale score is the sum of the severity of the 3 symptoms (fatigue, waking unrefreshed, cognitive symptoms) plus the extent (severity) of somatic symptoms in general. The final score is between 0 and 12.

Somatic Symptoms Fibromyalgia Diagnosis

 ACR 2010 updated guidelines:

A patient satisfies diagnostic criteria for fibromyalgia if the following 3 conditions are met:

 Widespread pain index (WPI) ≥7 and symptom severity (SS)

scale score ≥5 or WPI 3 - 6 and SS scale score ≥9.

 Symptoms have been present at a similar level for at least 3

months.

 The patient does not have a disorder that would otherwise

explain the pain.

American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Symptom Severity. F Wolfe, et

• al. Arthritis Care & Research; Vol. 62, No. 5, May 2010, pp 600–610

Chronic Pelvic Pain Syndrome (CPP)

 Persistent, non-cyclical pain localized to the pelvis,

lasting longer than 6 months

 No other specific etiology is discovered

Speer et al. “Chronic Pelvic Pain in Women”. American Family

• Physician. 2016 Mar 1; 93(5):380-387

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Red Flags: Weight loss, gross hematuria, mass

• n US, postcoital

bleeding, postmenopausal symptoms

Painful Bladder Syndrome (BPS)

 An unpleasant sensation perceived to be related to the

urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration in the absence of infection or other identifiable causes

Hanno et al. Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome: AUA Guideline Amendment. Journal of Urology. 193 (5): 2015 May. 1545-1553.

Clinical Workup

 History… does it feel like centralized pain?

 Significant pain and fatigue  Diffuse symptoms that don’t “make sense” in a typical

medical paradigm

 Multiple negative evaluations  Multiple specialists without clear diagnoses  Depression possible but physical symptoms out of

proportion to severity of mental illness

 Diagnoses of other central pain syndromes

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Clinical Workup

 History… does it feel like centralized pain?  Physical exam… basically normal

 Focus on specific areas of pain any signs of

inflammatory/degenerative arthritis, masses, localized tenderness

 Any signs of anatomically consistent neuropathy  Signs of something that would explain fatigue (pallor,

goiter, obesity, etc)

Clinical Workup

 History… does it feel like centralized pain?  Physical exam… basically normal  Testing? CBC, TSH, ESR or CRP

 Consider specific testing ie CK for myalgias, LFTs for abd

pain, UA for urinary symptoms, STI screening for pelvic pain, imaging for localized symptoms

 Consider ferritin, vitamin D (placebo benefits?)  Think carefully about ANA/autoimmune markers- don’t

• rder unless you really suspect

Make the diagnosis!

 Ok to do the million dollar work up if you’re not sure….

But only do it once!

 Give your patients a clear diagnosis- give a name

to their symptoms

 Stop the testing/referrals

Don’t Ignore the Peripheral Pain

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First step is educating patients

 “you have a real disease, and I believe that you hurt”  “you will need to live with this for the long term, but we

can help you manage it”

 “It will wax and wane, but you will not be left disfigured/in

the hospital/in a wheelchair because of this”

 “We understand what is happening in this condition, the

way your brain is processing sensations has the volume turned up”

What is the best first line treatment for central pain conditions?

• A. Pregabalin
• B. Exercise and cognitive behavioral therapy
• C. Opioid analgesics
• D. NSAIDS and Acetaminophen

What is the best first line treatment for central pain conditions?

• A. Pregabalin
• B. Exercise and cognitive behavioral therapy
• C. Opioid analgesics
• D. NSAIDS and Acetaminophen

Treatment of Central Pain Conditions

Non-Pharmacologic treatment is first line:

• Exercise
• Graded exercise therapy prescription, start low and go

slow

• This has the most significant benefit seen in trials
• Cognitive Behavioral Therapy
• Complementary treatments: acupuncture, meditation,

massage, yoga

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Graded Exercise Therapy Here is the principle: Think of exercise as if it were a medicine and you are trying to find the right dose. Too low a dose leaves you feeling worse, and too high a dose causes you to crash afterward and feel worse. Choose a length of time that you are willing to do sustained gentle aerobic exercise daily (e.g. walking for 15 mins once a day everyday) Continue at this level for two weeks. At the end of two weeks ask yourself: “How do I feel after engaging in this level of exercise for two weeks?” If you feel the same or better then increase the length of time by 10% (e.g. in this example you would add 1.5 minutes for a new total of 16.5 minutes) and continue at this new level for another two weeks. If you feel worse then reduce the length of time by 25% (e.g. in this example you would reduce by about 4 minutes to a new total of 11 minutes) After two weeks at the new level ask yourself the question again and proceed accordingly. Continue until you no longer receive any benefit from increasing the length of time. If you are too fatigued to begin with aerobic exercise then you can begin with gentle stretching and range-of-motion exercises, using the same principle of gradation.

Pharmacologic treatment for central pain

 Important to set expectations of (limited) benefit  “Rational polypharmacy” may be appropriate  Pain in these conditions does tend to flair and wane, so

monitoring benefit is sometimes difficult

Serotonin Norepinephrine Reuptake Inhibitors

Milnacipran (Savella)

• FDA approved for fibromyalgia, has not been shown to help with depression

Duloxetine (Cymbalta)

• FDA approved for fibromyalgia, chronic diabetic neuropathic pain, chronic

musculoskeletal pain (OA or low back pain) and depression/anxiety (Venlafaxine has less norepinephrine effects and so likely has less effect on chronic pain) Convenient daily dosing, easy to get to therapeutic doses Nausea and constipation were the most common events . Risks of suicidality, hepatotoxicity, abnl bleeding, elevated bp, serotonin syndrome, urinary hesitancy, seizures

Pregabalin

Approved for fibromyalgia, neuropathic pain (diabetic, post-herpetic, and spinal cord), epilepsy Binds to alpha2-delta protein, an auxiliary subunit of voltage-gated calcium channels, probably reducing release of several neurotransmitters which can reduce of abnormal neuronal excitability Dizziness was most common side effect. General warnings for suicidality, unsafe in pregnancy, rare hypersensitivity rxn, angioedema, peripheral edema, sedation, gynecomastia Gabapentin has a similar mechanism of action but has not been extensively studied/fda approved for central pain conditions

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Tricyclic Antidepressants (TCAs)

Amitriptyline/ Nortriptyline - Off label treatment for fibromyalgia Reduce reuptake of serotonin/ norepinephrine, but also antagonize NMDA, specific serotonin subtype, and histamine receptors (among others) Daily qhs dosing, may also help with sleep disturbances Fatigue, dry mouth, constipation, blurred vision,

• rthostatic hypotension are common side effects

Hauser, et al. Review of Pharmacologic Therapies in Fibromyalgia. Arthritis Res Ther. 2014; 16(1): 201.

Others with less evidence (off label)

 Gabapentin (Neurontin)  Tizanidine (zanaflex)  Cyclobenzaprine (flexeril)  Baclofen  Pramipexol (requip)  Tramadol (ultram)  Modafanil (provigil)  Low dose Naltrexone

In Summary

 Central pain conditions are common, especially in

women

 Recent pain research can help give us and our patients

better understanding of these conditions and allow us to better treat patients’ pain

 Important to give patients a specific diagnosis and

treatment plan

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Resources for patients

 Fibroguide: Free online CBT program for patients with

fibromyalgia: http://fibroguide.med.umich.edu/fibroguide.html

 Suggest a book for patients to self education- for

example Managing Pain Before it Manages You by Margaret Caudill

 Recommend relaxation apps such as headspace,

kardia anti-stress breath pacer, or calm

To learn more:

 Free podcast lectures on pain management:

https://www.painweek.org/podcasts.html

 Suggested reviews:

 Yunus MB. Editorial review: an update on central

sensitivity syndromes and the issues of nosology and

• psychobiology. Curr Rheumatol Rev. 2015;11(2):70-85.

 Clauw D. Fibromyalgia and Related Conditions.

Mayo Clinic Proceedings. 90(5). 2015 May, 680-692.

References

 Clauw D. Fibromyalgia and Related Conditions. Mayo Clinic Proceedings. 90(5). 2015 May, 680-692.  Diatchenko L et al; Genetic basis for individual variations in pain perception and the development of a chronic pain condition, Human Molecular Genetics, Volume 14, Issue 1, 1 January 2005, Pages 135–143.  Gracely, R. H et al. (2002), Functional magnetic resonance imaging evidence of augmented pain processing in

• fibromyalgia. Arthritis & Rheumatism, 46: 1333–1343. doi:10.1002/art.10225

 Hanno et al. Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome: AUA Guideline

• Amendment. Journal of Urology. 193 (5): 2015 May. 1545-1553.

 Harris et al. Pregabalin Rectifies Aberrant Brain Chemistry, Connectivity, and Functional Response in Chronic Pain Patients. Anesthesiology 2013;119(6):1453-1464  Hauser, et al. Review of Pharmacologic Therapies in Fibromyalgia. Arthritis Res Ther. 2014; 16(1): 201. 

• Hoeritzauer. Chapter 38 - Urologic symptoms and functional neurologic disorders. Handbook of Clinical
• Neurology. Volume 139, 2016, Pages 469-481.



• Hoffman. Central and Peripheral Pain Generators in Women with Chronic Pelvic Pain: Patient Centered

Assessment and Treatment. Current Rheumatology Reviews. Volume 11 , Issue 2 , 2015

References, cont



• Maixner. Overlapping Chronic Pain Conditions: Implications for Diagnosis and Classification The

Journal of PainVolume 17, Issue 9, Supplement, September 2016, Pages T93-T107  Marcus et al. Fibromyalgia, A Practical Clinical Guide. New York Springer-Verlag 2011, XII 200.  Sluka et al; Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience. V338, 3 December 2016. pages 114-129.  Smith, et al. Fibromyalgia an Afferent Processing Disorder Leading to a Complex Pain Generalized

• Syndrome. Pain Physician 2011; 14:E216-245.

 Speer et al. “Chronic Pelvic Pain in Women”. American Family Physician. 2016 Mar 1; 93(5):380-387  Muhammad Yunus. The Prevalence of Fibromyalgia in Other Chronic Pain Conditions. Pain Research and Treatment. Volume 2012 (2012), Article ID 584573  Wolfe, et al. American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Symptom Severity. F Arthritis Care & Research; Vol. 62, No. 5, May 2010, pp 600–610