The Pelvic Pain PuzzleHow Pain from the Pelvis is Processed

Angie Stoehr, MD FACOG

Pelvic and Sexual Pain Specialist

I have no relevant financial disclosures.

Pelvic Specific Pain PhenomenaPatient Case #1

23 yo G1P1, 1 year s/p cesarean for failure to progress. She presents

with complaint of 3 months of right hip pain. She recently went to

another provider who found a painful nodule in the lateral edge of

her cesarean scar. This was thought to be a fibroma, and was injected

with steroids. The pain in her hip worsened after the injection.

Pelvic Specific Pain PhenomenaPatient case #2

28 yr old G3P3, history of 3 prior SVDs with a complaint of 6 years

left lower quadrant pain and new onset pain with intercourse. She

has seen three other physicians for this. She has had two ultrasounds

of the pelvis which were read as normal. Her pain is described as

shooting, stabbing, aching pressure, which is worse during menses

and mid-cycle. She also notes that her pain worsened about 2 years

ago, which coincided with her divorce. Over the last two months, she

has become intimate with a new partner, and notices pain with

penetration. It feels like he “hits something”. This reproduces the pain

in her left lower quadrant.

Overview of the Pain Pathway

Pain receptors in pelvis

Spinal cord

Lower midbrain “gateways”

Midbrain limbic system +insular cortex

Cortex

Body response

What Triggers a Pain Signal

❏ Neuropathic pain signals: from nerves themselves❏ Cesarean scar burning- Patient case #1?

❏ Diabetic tingling

❏ Herpes Zoster pain

❏ Nociceptive pain signals: sensory neuron picking up possible

threat❏ Patient case #2?

Different Types of Nociception

❏ Visceral nociception❏ Coming from internal organs

❏ Stretch, inflammation, lack of blood flow

❏ Often referred pain

❏ MI

❏ Cholecystitis

❏ Appendicitis

❏ Difficult for patient to localize

❏ Difficult for patient to describe

❏ Often accompanied by autonomic stimulation- nausea, sweating, elevated

heart rate

❏ Patient case #2?

Different Types of Nociception

❏ Somatic nociception❏ Coming from skin, muscle, bone, joint

❏ Heat, crushing, cutting, burning, stretch, lack of blood flow, inflammation

❏ Easily localized by patient

❏ Easily described by patient

What Triggers a Nociceptive Signal

❏ Actual tissue damage❏ Suspected tissue damage

RUBBER BAND EXPERIMENT

The Importance of Context

❏ Actual tissue damage❏ Car accident

❏ Surgery

❏ Suspected tissue damage❏ Bodily context mimics actual tissue damage

❏ Increased stress hormones

❏ Cortisol

❏ Anxiety, negative emotions

❏ Immune system activation

❏ Inflammation

❏ Patient case #2!!

Cortisol

InflammationAnxiety

PAIN

Suspected Tissue Damage- Stress

❏ Alters pain receptor activation thresholds

❏ Interferes with pain down-regulatory mechanisms

❏ Epigenetic changes in DNA methylation

❏ Specific pelvic syndromes affected by stress❏ IC/BPS

❏ Cortisol predictive of symptoms

❏ IBS

❏ Stress reaction in relation to pain❏ Innervation of the gut

❏ Microbiome

The Gut Microbiome

❏ Gut microbiome functions❏ Breakdown of plant based food

❏ Aids in digestion

❏ Gut lining barrier function and development

❏ Dysfunction highly related to inflammation

❏ Immune system development

❏ Estrogen metabolism

❏ Affects and is affected by❏ Inflammation/Immune system activation

❏ Stress

❏ Antibiotics

❏ DIET

Suspected Tissue Damage-Anxiety/Depression

❏ Inter-connectivity

❏ Pain causes depression

❏ Depression increases pain signalling

❏ Known studied effects❏ Low back pain

❏ Knee pain

❏ Pelvic pain

❏ Chronic regional pain syndrome

Suspected tissue damage- Inflammation

❏ Immune system activation❏ Food sensitivity

❏ Gluten sensitivity

❏ Celiac, Crohn’s, Eczema

❏ Exposure to inflammatory organisms

❏ Microbiome

❏ Inflammatory markers❏ Mast cells

❏ Lymphocytes

❏ Cytokines, neurokines

Suspected tissue damage- Inflammation

❏ Vulvodynia/Vestibulodynia❏ Instigated by C. albicans

❏ Immune activation when vulvar cells exposed to yeast

❏ Endometriosis❏ Blood vessel growth

❏ Innervation

❏ IBS❏ Immune markers in lining of gut

❏ Can be instigated by viral gastroenteritis

❏ IC/BPS❏ Mimics UTI symptoms

Pelvic Specific Pain Phenomena

❏ Viscerovisceral Convergence❏ Hypogastric plexuses

❏ Convergence at spinal cord

❏ Lack of topography in the thalamus

❏ Viscerosomatic Convergence❏ Visceral signals and somatic signals overlaid at spinal cord

❏ Dorsal root ganglion of spinal cord

❏ Small portion of signals from visceral nerves

❏ Majority of signals from somatosensory nerves

❏ Referred pain may be remote

❏ Viscerosomatic reflex

Copyright When It Hurts, Dr A Stoehr, Published April 2018

The brain doesn’t know where the pain is coming from. It guesses!

Lower Midbrain “Gateways”

❏ Periaqueductal Gray ❏ Ascending and descending pain modulation

❏ Stress induced analgesia

❏ Pain anticipation

❏ Pain distraction, DNIC

❏ Cardiovascular control

❏ Vagus nerve

❏ Heart rate/blood pressure

❏ Thalamus ❏ Major pain relay station

❏ Initial localization

❏ Thalamic stroke- resistant chronic pain

Midbrain Limbic System and Insular Cortex

❏ Contextual processing❏ Insular cortex, amygdala, cingulate cortex, hippocampus,

and hypothalamus.

❏ Rollercoaster vs bear

❏ Related functions❏ Learned fear

❏ Fight or flight

❏ Pain related anxiety/depression

❏ Sexual satisfaction

❏ Aggression

❏ Daydreaming

❏ Basic emotions

❏ Addiction, compulsion

❏ Self-awareness

Cortical Processing of Pain

❏ Networks❏ Frontoparietal (anticipation of intensity)

❏ Supplementary motor area, primary somatosensory cortex, and secondary

somatosensory cortex

❏ Increased nerve response❏ Allodynia- normal stimuli

❏ Hyperalgesia- painful stimuli

❏ Change in motor cortex ❏ Excitability of cortical nerves

❏ Altered brain morphology with chronic pain

❏ Reorganization of intracortical circuits

❏ Cognitive resources reallocated to pain processing

Pearls

❏ The pain your patient feels is real

❏ Context is everything

❏ The microbiome is powerful

❏ The fact that she can’t describe or localize the pain doesn’t mean

she’s crazy

❏ Most pelvic pain patients aren’t med seeking

❏ There are ways to interfere with these processes to alleviate

pain!

Pelvic Specific Pain PhenomenaPatient Case #1

23 yo G1P1, 1 year s/p cesarean for failure to progress. She presents with complaint of 3

months of right hip pain. She recently went to another provider who found a painful

nodule in the lateral edge of her cesarean scar. This was thought to be a fibroma, and was

injected with steroids. The pain in her hip worsened after the injection.

Diagnosis: ilioinguinal nerve neuropathy

Pelvic Specific Pain PhenomenaPatient case #2

28 yr old G3P3, history of 3 prior SVDs with a complaint of 6 years left lower quadrant

pain and new onset pain with intercourse. She has seen three other physicians for this.

She has had two ultrasounds of the pelvis which were read as normal. Her pain is worse

during menses and mid-cycle. She also notes that her pain worsened about 2 years ago,

which coincided with her divorce. Over the last two months, she has become intimate

with a new partner, and notices pain with penetration. It feels like he “hits something”.

This reproduces the pain in her left lower quadrant.

Diagnosis: Interstitial cystitis, hypertonic pelvic floor dysfunction

References

● Aredo J, Heyrana K, Karp B, Shah J, Stratton P. Relating chronic pelvic pain and endometriosis to signs of sensitization and

myofascial pain and dysfunction. Seminars in Reproductive Medicine. 2017;35(1):88-97.

● Uesaka T, Young HM, Pachnis V, Enomoto H. Development of the intrinsic and extrinsic innervation of the gut. Dev Biol.

2016;417(2):158-67.

● Lee Y, Park K. Irritable bowel syndrome: Emerging paradigm in pathophysiology. World J Gastroenterology.

2014;20(10):2456-2469.

● O’Mahoney SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan, metabolism and the brain-gut-microbiome

axis. Behav Brain Res. 2015;15(277):32-48.

● Garland EL. Pain processing in the human nervous system: a selective review of nociceptive and biobehavioral pathways.

Prim Care. 2012;39(3):561-571.

● Regauer S, Eberz B, Beham-Schmid C. Mast cell infiltrates in vulvodynia represent secondary and idiopathic mast cell

hyperplasias. APMIS. 2015;123(5):452-456.

● Akopians AL, Rapkin AJ. Vulvodynia: the role of inflammation in the etiology of localized provoked pain of the vulvar vestibule

(vestibulodynia). Semin Reprod Med. 2015;33(4):239-245.

● Leclair CM, Leeborg NJ, Jacobson-Dunlop E, Goetsch MF, Morgan TK. CD4-positive T-cell recruitment in primary-provoked

localized vulvodynia: potential insights into disease triggers. J Low Genit Tract Dis. 2014;18(2):195-201.

● Falsetta ML, Foster DC, Woeller CF, Pollock SJ, Bonham AD, Haidaris CG, Stodgell CJ, Phipps RP. Identification of novel

mechanisms involved in generating localized vulvodynia pain. Am J Obstet Gynecol. 2015;213(1):38.e1-38.e12.

● Schrepf A, O’Donnell MA, Luo Y, Bradley CS, Kreder KJ, Lutgendorf SK. Inflammation and symptom change in interstitial

cystitis/bladder pain syndrome: a multidisciplinary approach to the study of chronic pelvic pain research network study.

Urology. 2016;90:56-61.

References cont...

● Schrepf A, O’Donnell MA, Luo Y, Bradley CS, Kreder KJ, Lutgendorf S, MAPP Network. Inflammation and inflammatory

control in interstitial cystitis/bladder pain syndrome: associations with painful symptoms. Pain. 2014;155(9):1755-1761.

● MAPP Research Network. The multidisciplinary approach to the study of chronic pelvic pain (MAPP) research network:

yielding new insights into challenging urologic pain syndromes. National Institute of Diabetes and Digestive and Kidney

Diseases. 2016:1-6

● Piche T. Tight Junctions and IBS--the link between epithelial permeability, low-grade inflammation, and symptom generation?

Neurogastroenterol Motil. 2014;26(3):296-302.

● Verdu EF, Collins SM. Irritable bowel syndrome and probiotics: from rationale to clinical use. Curr Opin Gastroenterol.

2005;21:697-701.

● Ahn SH, Edwards AK, Singh SS, Young SL, Lessey BA, Tayade C. IL-17 contributes to the pathogenesis of endometriosis by

triggering proinflammatory cytokines and angiogenic growth factors. J Immunol. 2015;195:2591-2600.

● Rajilić-Stojanović M, Jonkers DM, Salonen A, Hanevik K, Raes J, Jalanka J, de Vos WM, Manichanh C, Golic N, Enck P,

Philipou E, Iraqi FA, Clarke G, Spiller RC, Penders JP. Intestinal microbiota and diet in IBS: causes, consequences, or

epiphenomena? Am J Gastroenterol. 2015;110:278-287.

● Hyland NP, Quigley EMM, Brint E. Microbiota-host interactions in irritable bowel syndrome: epithelial barrier, immune

regulation and brain-gut interactions. World J Gastroenterol. 2014;20(27):8859-8866.

● Thomas S, Izard J, Walsh E, Batich K, Chongsathidkiet P, Clarke G, Sela DA, Muller AJ, Mullin JM, Albert K, Gilligan JP,

DiGuilio K, Dilbarova R, Alexander W, Prendergast GC. The host microbiome regulates and maintains human health: a primer

and perspective for non-microbiologists. Cancer Res. 2017;77(8):1783-1812.

● Monda V, Villano I, Messina A, Valenzano A, Esposito T, Moscatelli F, Viggiano A, Cibelli G, Chieffi S, Monda M, Messina G.

Exercise modifies the gut microbiota with positive health effects. Oxidative Medicine and Cellular Longevity. 2017; art

3831972:1-8.

References cont...

● Amaral FA, Sachs D, Costa VV, Fagundes CT, Cisalpino D, Cunha TM, Ferreira SH, Cunha FQ, Silva TA, Nicoli JR, Vieira

LQ, Souza DG, Teixeira MM. Commensal microbiota is fundamental for the development of inflammatory pain. PNAS.

2008;105(6):2193-2197.

● Braundmeier-Fleming A, Russell NT, Yang W, Nas MY, Yaggie RE, Berry M, Bachrach L, Flury SC, Marko DS, Bushell CB,

Welge ME, White BA, Schaeffer AJ, Klumpp DJ. Stool-based biomarkers of interstitial cystitis/bladder pain syndrome.

Scientific Reports. 2016;6:26083.

● Hindiyeh N, Aurora SK. What the gut can teach us about migraine. Curr Pain Headache Rep. 2015;19(7):33.

● Moloney RD, Johnson AC, O’Mahoney SM, Dinan TG, Greenwood-Van Meerveld B, Cryan JF. Stress and the microbiota-gut-

brain axis in visceral pain: relevance to irritable bowel syndrome. CNS Neurosci Ther. 2016;22(2):102-117.

● Palm NW, de Zoete MR, Flavell RA. Immune-microbiota interactions in health and disease. Clin Immunol. 2015;159(2):122-

127.

● Laschke MW, Menger MD. The gut microbiota: a puppet master in the pathogenesis of endometriosis? Am J Obstet Gynecol.

2016; 215(1):68.e1-4.

● Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen-gut microbiome axis: physiological and clinical implications.

Maturitas.2017;103:45-53.

● MacDermott RP. Treatment of irritable bowel syndrome in outpatients with inflammatory bowel disease using a food and

beverage intolerance, food and beverage avoidance diet. Inflamm Bowel Dis. 2007;13(1):91-96.

● Janicki T. Chronic pelvic pain as a form of complex regional pain syndrome. Clinical Obstetrics and Gynecology.

2003;46(4):797-803.

● Neugebauer V. Amygdala pain mechanisms. Handb Exp Pharmacol. 2015;227:261-284.

● Hampson JP, Reed BD, Clauw DJ, Bhavsar R, Gracely RH, Haefner HK, Harris, RE. Augmented central pain processing in

vulvodynia. J Pain. 2013;14(6):579-589.

References cont...

● Mercier C, Léonard G. Interactions between pain and the motor cortex: Insights from research on phantom limb pain and

complex regional pain syndrome. Physiother Can. 2011;63(3):305-314.

● Kim W, Kim SK. Neural circuitry remodeling and structural plasticity in the cortex during chronic pain. Korean J Physiol

Pharmacol. 2016;20(1):1-8.

● Mathur VA, Khan SA, Keaser ML, Hubbard CS, Goyal M, Seminowicz DA. Altered cognition-related brain activity and

interactions with acute pain in migraine. NeuroImage: Clinical. 2015;7:347-358.

● Huang L, Kutch JJ, Ellingson BM, Martucci KT, Harris RE, Clauw DJ, Mackey S, Mayer EA, Schaeffer AJ, Apkarian AV,

Farmer MA, MAPP. Brain white matter changes associated with urological chronic pelvic pain syndrome: multisite

neuroimaging from a MAPP case-control study. Pain. 2016;157:2782-2791.

● Lackner JM, Brasel AM, Quigley BM, Keefer L, Krasner SS, Powell C, Katz LA, Sitrin MD. The ties that bind: perceived social

support, stress, and IBS in severely affected patients. Neurogastroenterol Motil. 2010;22(8):893-900.

● Lackner JM, Gudleski GD, Firth R, Keefer LA, Brenner DM, Guy K, Simonetti C, Radziwon C, Quinton S, Krasner SS, Katz L,

Garbarino G, Iacobucci G, Sitrin MD. Negative aspects of close relationships are more strongly associated than supportive

personal relationships with illness burden of irritable bowel syndrome. J Psychosom Res. 2013;74(6):493-500.

● Rakhila H, Girard K, Leboeuf M, Lemyre M, Akoum A. Macrophage migration inhibitory factor is involved in ectopic

endometrial tissue growth and peritoneal-endometrial tissue interaction in vivo: a plausible link to endometriosis involvement.

PLoS ONE. 2014;9(10):e110434.

● Green AL, Wang S, Owen SL, Xie K, Bittar RG, Stein JF, Paterson DJ, Aziz TZ. Stimulating the human midbrain to reveal the

link between pain and blood pressure. Pain. 2006;124(3):349-359.

● Yarushkina NI, Filaretova LP. Role of periaqueductal gray matter of the midbrain in regulation of somatic pain sensitivity during

stress: participation of corticotropin-releasing Factor and Glucocorticoid Hormones. Usp Fiziol Nauk. 2015;46(3):3-16.

● Linnman C, Moulton EA, Barmettler G, Becerra L, Borsook D. Neuroimaging of the periaqueductal gray: state of the field.

Neuroimage. 2012;60(1):505-522.

References cont...

● Wu D, Wang S, Stein JF, Aziz TZ, Green AL. Reciprocal interactions between the human thalamus and periaqueductal gray may be

important for pain perception. Exp Brain Res. 2014;232(2):527-534.

● Yen CT, Lu PL. Thalamus and pain. Acta Anesthesiolica Taiwanica. 2013;51:73-80.

● Leonard BE. Pain, depression and inflammation: are interconnected causative factors involved? Mod Trends Pharmacopsychiatry.

2015;30:20-35.

● Graziottin A, Skaper SD, Fusco M. Mast cells in chronic inflammation, pelvic pain and depression in women. Gynecol Endocrinol.

2014;30(7):472-477.

● Koh JS, Ko HJ, Wang SM, Cho KJ, Kim JC, Lee SJ, Pae CU. Depression and somatic symptoms may influence on chronic

prostatitis/chronic pelvic pain syndrome: a preliminary study. Psychiatry Investig. 2014;11(4):495-498.

● Hong S, Zheng G, Wiley J. Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral

nervous system. Gastroenterology. 2015;148(1):148-157.

● Pierce AN, Christianson JA. Stress and chronic pelvic pain. Prog Mol Biol Transl Sci. 2015;131:509-539.

● Zheng G, Hong S, Hayes JM, Wiley J. Chronic stress and peripheral pain: evidence for distinct, region-specific changes in visceral

and somatosensory pain regulatory pathways. Exp Neurol. 2015;273:301-311.