Disclosures: Understanding Central Sensitization Syndromes: What is the diagnosis? Definitions:

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1 Understanding Central Sensitization Syndromes: Fibromyalgia, Chronic Pelvic Pain, and Painful Bladder Syndrome Molly Heublein, MD Assistant Clinical Professor of Medicine UCSF Women s Health Center of Excellence None Disclosures: What is the diagnosis? A painful disorder, more common in women, worsened with hormonal fluctuations and stress, characterized by nervous system hypersensitivity leading to allodynia and/or hyperalgesia. No specific lab test or pathognomonic exam finding confirms this condition. Definitions: Hyperalgesia: a normally painful stimulus is more painful than is typical Allodynia: A normally nonpainful stimulus is registered as painful For our purposes today I will use some overlapping terms Central sensitization=central pain Interstitial cystitis (IC)= Bladder pain syndrome/painful bladder syndrome (BPS)

2 Objectives for today: Discuss pain processing and central pain Chronic Overlapping Pain Conditions Review fibromyalgia as a classic central sensitization disorder Discuss overlap of fibromyalgia with chronic pelvic pain and painful bladder syndrome Consider best practices to address patients suffering from these conditions These conditions all display: Diffuse or localize hyperalgesia and/or allodynia Aggregate data suggest underlying problem with pain or sensory amplification rather than a structural or inflammatory condition 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 9 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.

3 Types of pain Clinical Case: Cause of pain: Responds to: Classic examples: Peripheral (nociceptive) Mechanical damage or inflammation NSAIDS, opiods, local proceedures Acute pain due to injury, OA, RA, cancer pain Neuropathic Damage or entrapment of peripheral nerves Peripheral and central therapies. Entrapment responds to surgery or injection Diabetic neuropathy, radicular back pain, postherpetic neuralgia 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

4 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 Cause of pain: Responds to: Classic examples: Types of pain Peripheral (nociceptive) Mechanical damage or inflammation NSAIDS, opiods, local proceedures Neuropathic Damage or entrapment of peripheral nerves Peripheral and central therapies. Entrapment responds to surgery or injection The bio-medical Diabetic model neuropathy, of pain Acute pain due to injury, OA, RA, cancer does pain not hold radicular up back specific pain, postherpetic neuralgia pathologic findings are not seen in most patients with chronic pelvic pain, painful bladder syndrome, or fibromyalgia Cause of pain: Types of pain Peripheral (nociceptive) Mechanical damage or inflammation Neuropathic Damage or entrapment of peripheral nerves Centralized Central disturbance in pain processing (hyperalgesia/allody nia) Types of pain are not exclusive, most patients have overlapping pain generators Responds to: NSAIDS, opiods, local proceedures 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) May, 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

5 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 on 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

6 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 Neurotransmitters 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 Elevated levels of endogenous opioids

7 fmri data 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: doi: /art Brain Connections and Pain pain network, including the insular cortex, anterior cingulate cortex, somatosensory cortices, and thalamus important for pronocioceptive experience, whereas the Default Mode Network (resting/internal thoughts) has been linked to pain modulation through descending inhibitory pathways fmri, EEG, and proton magnetic resonance spectroscopy have shown increased connectivity in patients with chronic pain 27 women w fibromyalgia blinded cross over design showed decreased pain and neural connectivity treated w pregabalin Harris et al. Pregabalin Rectifies Aberrant Brain Chemistry, Connectivity, and Functional Response in Chronic Pain Patients. Anesthesiology 2013;119(6):

8 Diffuse Noxious Inhibitory Control (DNIC) In healthy humans and laboratory animals, application of an intense painful stimulus for 2 to 5 minutes produces generalized whole-body analgesia. Thought to be mediated through descending opoid, and sertotin-noradrenergic pathways This analgesia has been consistently observed to be attenuated or absent in groups of FM patients as compared to healthy controls

9 Back to patient care. Bell shaped curve of pain experience, multifactorial changes in pain processing People can have a turned up, amplified gain on pain sensation. You may find objective findings that could typically cause pain, without pain (in patients who have a pain volume at the low level) or no findings in patients who have a lot of pain (volume on high) Think of this as a spectrum, rather than a discrete yesno Fibromyalgia-ness (Wolfe) Chronic Overlapping Pain Conditions In patients w FM: 12% had BPS In patients with CPP, 40% had BPS Maixner. Overlapping Chronic Pain Conditions: Implications for Diagnosis and Classification The Journal of PainVolume 17, Issue 9, Supplement, September 2016, Pages T93-T107 Not to scale. % data from: Hoeritzauer. Chapter 38 - Urologic symptoms and functional neurologic disorders. Handbook of Clinical Neurology. Volume 139, 2016, Pages

10 Prevalence of Fibromyalgia by Age Prevalence of Fibromyalgia in other Central Sensitivity Syndromes Marcus et al. Fibromyalgia, A Practical Clinical Guide. New York Springer- Verlag 2011, XII 200. Muhammad Yunus. The Prevalence of Fibromyalgia in Other Chronic Pain Conditions. Pain Research and Treatment. Volume 2012 (2012), Article ID 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

11 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. 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 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 Mar 1; 93(5):

12 Painful Bladder Syndrome (BPS) Red Flags: Weight loss, gross hematuria, mass on US, postcoital bleeding, postmenopausal symptoms 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 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

13 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 order 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! Don t Ignore the Peripheral Pain Give your patients a clear diagnosis- give a name to their symptoms Stop the testing/referrals

14 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 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 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. 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 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.

15 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 muskuloskeletal 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, postherpetic, and spinal cord), epilepsy Binds to alpha2-delta protein, an auxiliary subunit of voltagegated 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 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, orthostatic hypotension are common side effects Hauser, et al. Review of Pharmacologic Therapies in Fibromyalgia. Arthritis Res Ther. 2014; 16(1): 201.

16 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 Resources for patients Fibroguide: Free online CBT program for patients with fibromyalgia: 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: 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): Clauw D. Fibromyalgia and Related Conditions. Mayo Clinic Proceedings. 90(5) May,

17 References Clauw D. Fibromyalgia and Related Conditions. Mayo Clinic Proceedings. 90(5) May, 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 Gracely, R. H et al. (2002), Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis & Rheumatism, 46: doi: /art Hanno et al. Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome: AUA Guideline Amendment. Journal of Urology. 193 (5): 2015 May Harris et al. Pregabalin Rectifies Aberrant Brain Chemistry, Connectivity, and Functional Response in Chronic Pain Patients. Anesthesiology 2013;119(6): 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 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 pages Smith, et al. Fibromyalgia an Afferent Processing Disorder Leading to a Complex Pain Generalized Syndrome. Pain Physician 2011; 14:E Speer et al. Chronic Pelvic Pain in Women. American Family Physician Mar 1; 93(5): Muhammad Yunus. The Prevalence of Fibromyalgia in Other Chronic Pain Conditions. Pain Research and Treatment. Volume 2012 (2012), Article ID 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