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Management of the peripartum period in a mast cell patient

I’ve been getting a lot of questions about pregnancy and delivery in mast cell patients. I had an interesting case a couple of years ago that I thought people might find illuminating. I contacted the patient and she had no problem with me sharing her case.

The case involved a pregnant mast cell patient experiencing both cardiovascular and mast cell driven complications of the pregnancy with significant risk of preterm delivery. I worked with the patient and her care team to develop a plan to minimize the risk of mast cell activation and anaphylaxis both before and after delivery. Mom delivered by Cesarean and had no complications during or after delivery. Baby also suffered no complications associated with birth.

This is some of the material I provided to her team.


Mast cell disease is a group of proliferative and non-proliferative conditions that is hallmarked by severe allergic reactions and anaphylaxis to triggers by non-IgE pathways. Due to the the diverse role of mast cells in many processes, including allergy, immune defense, wound healing and reproduction, mast cell degranulation and activation is an ever present threat.


Mast cell patients are recommended to premedicate prior to any procedure, including non-invasive procedures, to suppress mast cell activation.

24 hours before:
50mg prednisone

1-2 hours before:
50mg prednisone
50mg diphenhydramine
150mg ranitidine
10mg montelukast

An IV protocol used by some patients in place of the oral meds at 1-2 hours:
50mg diphenhydramine
40mg famotidine
40mg methylprednisolone

Following procedures/medical events/anaphylaxis, some patients do best with a taper of antihistamines and steroids to suppress rebound reactions and biphasic anaphylaxis in the following days. An example of this regimen is:

Antihistamine support:
-50mg diphenhydramine IV every 4 hours for first 24 hours
-50mg diphenhydramine IV every 6 hours for next 48 hours
-50mg diphenhydramine IV prn thereafter

Corticosteroid coverage:
Corticosteroids play an integral role in modulating mast cell activation. In the days following procedures/medical events/anaphylaxis, some patients do best with a steroid taper. Please note that the reason for the taper is NOT to prevent adrenal insufficiency, but to provide adequate steroid coverage to suppress mast cell reactions at a time when a non-mast cell patient would safely tolerate an abrupt cessation of steroids.

There is no defined protocol, but many patients use a Medrol dosepak or seven day prednisone taper following anaphylaxis and do well with this protocol following other procedures/events.

Cardiovascular concerns:

In cardiac patients with mast cell disease, Kounis Syndrome (allergic angina/MI) is a risk. In this condition, patients experience angina/MI as the result of a histamine driven process. Mast cell rescue medications (diphenhydramine, famotidine, methylprednisolone) should be given along with appropriate management of cardiovascular symptoms (nitroglycerin, calcium channel blockers). Epinephrine can be used if appropriate.

Beta blockers are a hard contraindication for mast cell patients as they interfere with the action of epinephrine. Use of beta blockers is commonly cited as a risk factor for fatal anaphylaxis. ACE inhibitors are often not recommended due to interaction with the angiotensin/renin system in which mast cells actively participate.

Pain management:

Most opiates are not recommended for mast cell patients due to induction of mast cell degranulation. Fentanyl and hydromorphone are the ones most often used successfully and are the drugs of choice for acute pain management.

Literature findings:

Ciach K, et al. Pregnancy and delivery with mastocytosis treated at the Polish Center of the European Competence Network on Mastocytosis (ECNM). PLoS One 2016; 11(1): e0146924

  • Five women delivered via cesarean. In one patient, the cesarean was performed specifically because of concerns about vaginal delivery in a mastocytosis patient. In the other four cases, cesarean was performed because of preeclampsia; improper positioning of the fetus; lack of labor progression; and large size of the fetus’ head relative to the size of the uterus. In all of these cases, spinal anesthesia was used with no complications.
  • Twelve women delivered vaginally without complications. In two patients, an epidural was used for pain management. In three patients, medication (oxytocin) was used to induce uterine contraction.
  • Four patients experienced pregnancy complications in the second trimester. The complications were pregnancy induced hypertension and swelling of the extremities; deep thrombosis (blood clot formation); toxoplasmosis, an infection; preterm labor without delivery; and vaginal bleeding in the first trimester.
  • Four patients delivered early, at 26 weeks, 36 weeks, and 37 weeks. The woman who delivered at 26 weeks had preeclampsia and her baby died less than a month after delivery due to extreme prematurity. Twelve patients delivered full term. Three babies had low birth weight upon delivery.
  • Mastocytosis patients are at higher risk of complications that involve clotting. Mast cell patients often experience coagulation irregularities, such as blood clot formation.
  • There have been three cases reported in literature of mastocytosis patients who developed preeclampsia that required preterm delivery.
    In order to suppress mast cell reactions and anaphylaxis, patients were premedicated before delivery with antihistamines and corticosteroids. Another study on pregnancy in mastocytosis reported that even with premedication, some patients still experienced mast cell activation during or after labor.
  • Epinephrine, antihistamines and glucocorticoids (steroids) should be readily available during and after labor

Matito A, et al. Clinical impact of pregnancy in mastocytosis: A study of the Spanish network on Mastocytosis (REMA) in 45 cases. Int Arch Allergy Immunol 2011; 156: 104-111.

  • 22% (10) of patients delivered via caesarean. 78% (35) delivered vaginally.
    Nine patients required labor induction. Oxytocin was used in eight cases and dinoprostone was used in one case.
  • Premedication for mast cell activation with antihistamines and glucocorticoids was only given to 38% (17) of patients.
  • 82% (37) of patients received anesthesia. 32 patients received epidurals; 3 received local anesthesia; and 2 received general anesthesia.
  • 11% of patients had mast cell activation symptoms, including flushing and itching, during or just following labor.

Dewachter P, et al. Perioperative management of patients with mastocytosis. Anesthesiology 2014, 12): 753-759.

  • Mastocytosis symptoms can improve, worsen, or remain unchanged during pregnancy.
  • Anesthesia management of mastocytosis patients has not been well described, with 13 CM patients and 33 SM patients mentioned in literature since 2000.
  • In one instance, IV epinephrine was necessary following labor to manage low blood pressure and difficulty breathing in an SM patient.
  • Early use of epidural anesthesia is recommended for mastocytosis patients to manage pain as pain triggers mast cell degranulation.
  • Patients should continue their regular medications to manage mast cell disease until the day of surgery.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 77

90. What causes pain in mast cell disease?

  • Most mast cell patients experience some kind of pain. Because mast cells are involved in pain sensation and inflammation, mast cell patients are at risk of pain by different mechanisms throughout their body.
  • Mast cells are involved in nerve pain. Mast cells often live very close to nerves, sometimes so close they are touching. When nerve cells feel pain, they release mediators to activate mast cells. The mast cells then activate other nearby nerve cells. The result of this is that the brain gets a pain signal from lots of nerves, not just the nerves that initially felt the pain, so the pain you feel is worse.
  • Mast cells participate in inflammation. One of the big things they do is send signals to other immune cells to come to the site of inflammation. These cells release mediators that can cause pain or make it worse. Nerve cells nearby will send a stronger pain signal again in response to these immune cells causing inflammation.
  • Mast cells are involved in hyperalgesia, when your nerves are very sensitive and send a stronger than normal pain response to things that shouldn’t normally be very painful. For this reason, many mast cell patients have a heightened pain response, even to things that aren’t normally very painful.
  • Mast cells are associated with a number of chronic pain conditions.
  • Visceral pain is when you feel pain in your internal organs, like your GI tract or your liver. Visceral pain is often not localized so it can be hard to tell what is actually hurting. Mast cell patients often report visceral pain.
  • Pelvic pain is linked to mast cell activation and can cause serious symptoms, including painful sex. Pelvic floor dysfunction is sometimes seen in mast cell patients. Interstitial cystitis, chronic inflammation of the bladder, is also driven by mast cells, although it’s not exactly clear how.
  • Mast cells are major players in GI pain. Mast cell degranulation activates the nerves inside the GI tract, which can cause abdominal pain. This causes pain in a number of GI diseases aside from mast cell disease.
  • Many mast cell patients have connective tissue disease like Ehlers Danlos Syndrome. This can cause the organs to not be supported properly, causing them to move around, activating a pain response.
  • Mast cells can cause bone pain in multiple ways. In systemic mastocytosis, production of so many mast cells in the bone marrow can cause pressure inside the bone that causes pain. Mast cell mediators can cause dysregulation of the system that degrades old parts of the bone and replaces it with new, stronger bone. This can cause the bones to be too thick or too thin. Mast cell patients may have bone disorders as a result and should be especially watchful for Mast cell mediators like histamine can also irritate the cells on the outside of the bone, causing pain.
  • Mast cell activation can cause headaches and migraines. Mast cell mediators can affect how much blood is getting to the head and brain, which can cause pain. Many mast cell patients have POTS, which can also cause the same problem.
  • Systemic mastocytosis patients can have dense infiltration of their organs by mast cells. This infiltration punches holes in the tissue, leading to inflammation and pain.
  • Cutaneous mastocytosis patients have similar issues with infiltration of the skin.
  • Infiltration is NOT necessary for mast cell activation to cause pain.
  • Mast cell patients have to be cautious in how they treat their pain as many medications for pain management can cause mast cell degranulation.
  • NSAIDs can be used in patients that tolerate them.
  • Acetaminophen and tramadol are considered mast cell friendly.
  • Gabapentin and pregabalin are sometimes used for neurologic pain in mast cell patients.
  • If opiates are needed, fentanyl and hydromorphone are preferred. Morphine is a massive mast cell degranulator and should be avoided.
  • Certain numbing medications can trigger mast cells, like ester caine anesthetics.
  • Cyclobenzamide is a muscle relaxer commonly used in mast cell patients.


For more information, please visit the following posts:

Mast cells in nerve pain

The Provider Primer Series: Medications that impact mast cell degranulation and anaphylaxis

Premedication and surgical concerns in mast cell patients

The Sex Series – Part Six: Male pelvic floor and mast cells

The Sex Series – Part Eight: Female pelvic floor dysfunction

The Sex Series – Part Nine: Female pelvic floor dysfunction



I have a sunburn. Today, I embarked upon that most quintessential New England autumn venture: apple picking. It was supposed to be about 70 degrees with a breeze and some clouds. Instead it was almost 90 degrees with a little breeze and a sun beaming directly down upon us. I always wear sunblock on my face and cover a lot of my skin, even in the summer, so it wasn’t too bad.

The sunburn is on my chest and shoulders. It’s not serious. It won’t blister. It looks red and angry and kind of hurts. Not a lot of pain, but there. Persistent. Stinging.

I have been sick a long time. And that means have been in pain a long time, too. There are lots of different pains and I know them all. I know the loose instability of stretching a joint too far. I know the burning of flushing skin and the stinging that remains after the flush is gone. The abdominal neuropathy that spreads like lightning across my midsection, electric fractals emanating from a central point. The hard swelling of my colon when fluid is trapped in the tissue. The way it feels like broken glass when my GI tract reluctantly moves things through its lower portions. The white hot fire of something passing over an open wound. The acid throbbing of vasculitis. The beating against the back of my skull of a terrible headache. The pressure of food that will not move as my stomach swells around it.

I have needed pain medication of one kind of another for several years. I have lived a very privileged life and I have been very lucky to have a medical team that has been largely the same for several years. My doctors know me pretty well. And because they have seen me screaming in pain and seen the damage that caused the pain, they are willing to help me manage my pain. It is a never ending process of adjusting medications and behaviors and foods but I have options that many people do not. I am lucky. Very lucky.

Drug addiction is a hell I wish on no one and one that has affected me personally in many ways. Heroin abuse is often a complication of opiate abuse: it renders a similar high but is cheaper and easier to get (as I understand it – I do not have personal experience with heroin). Sometimes people who are prescribed opiates for legitimate reasons become addicted and are forced to buy pills illegally or resort to other products, like heroin. Often, people with addiction come to heroin or pills another way, without ever having had a medical reason for using them.

Last year, the CDC made broad recommendations regarding prescriptions for opiates, probably the most well known drug class of pain killers. I had anticipated their recommendations with dread and I was not disappointed. In brief, their recommendations were that every other avenue for pain management be thoroughly exhausted before use of opiates, which would almost certainly render pain relief. The quantities to be prescribed were small and the courses short, irrespective of whether or not this was appropriate to the pain condition or realistic in any way.

Patients would all be drug tested frequently so that we could prove over and over again that we are not drug addicts. Our medication would not be filled without us proving over and over again that we are not drug addicts.

And for those patients like me who have debilitating, chronic pain, there were provisions for trialing removal of pain meds so that they could determine whether or not we actually needed them and if it was possible to reduce the dose at all. Most alarmingly, in my state, they adopted guidelines that could people like me to be evaluated by a doctor who knows nothing about me or my rare disease in order to determine whether or not I really needed these drugs. I am not an addict. I take my medication as directly. I fully comply with any and all guidelines and am happy to pee in a cup every time they instruct me to. But I am still afraid. I am afraid that I will do everything right and still end up in severe pain with no drugs to manage it because government agencies are conflating the epidemic of drug addiction with the necessary pain management of chronic pain patients. And that fear is getting larger and larger as time passes.

This past week, a large pharmacy chain in the US announced that they would only dispense seven days of opiates for “new” patients. There is already a lot of debate about what exactly this means but I guarantee it means more trouble and stress and fear for people like me. I cannot imagine a system in which a pharmacist can know my personal health and pain situation better than my provider of many years. What if the pharmacy decides I’m a new patient and just won’t give me more than seven days? What happens then? There are no answers yet on what will happen, but I don’t need to specifics to know that the people who will be most affected are people like me.

There are many practical reasons why this particular practice is a terrible idea. For one, it requires patients to be seen again to get a new prescription after seven days. For a pain situation in which a patient might need pain meds for a month, this would translate to four office visits instead of one. That’s four copays. That’s four trips with associated expenses. And that’s four copays at the pharmacy. That’s four office visits that already overextended provider’s office now needs to find time for. And when they can’t find the time, those patients may be left without any pain medications until the next appointment.

But these are not the reasons that literally keep me up at night so that I am writing this post at 12:50am despite being absolutely exhausted. What keeps me up is that no matter what, no matter what the intentions are for all these restrictions, and who they are supposed to affect, me and people like me will suffer. We already know what it is like to be treated like a junkie. We already know that we have to convince every provider we interact with that we use pain medication responsibly as directed at appropriate doses for our pain condition. We already know that we’re never totally convinced that those providers believe that.

But most of all, we know pain. And we know that in the current climate of increasing restrictions on pain management, we will have more pain than we used to. Pain that could be treated effectively if there was not such a stigma upon using opiates for chronic pain when everything else has failed. Pain we remember and are afraid of.

Pain is such an abstract quality to those who don’t live with it. People who don’t have it often do not empathize with those of us who do. We are often painted as lazy or attention seeking. Some day, those people will know about pain, and they will feel guilty then. But it will be too late at that point. People like me can’t wait for that day.

Pain is a monster with many faces that haunts every moment of your life. It eats our sore muscles and swollen joints and ruined organs and twisted bones. It eats and eats and eats until there is nothing left that suggests a person lived in this vessel. That there was once a life here, and dreams, and aspirations. That beautiful things lived here before they were destroyed.

Pain is not something you can overcome as a society by pretending the people who have it will be able to figure out another way to manage it when you rob them of their best tools. Chronic pain kills people. We know this fact. It is not disputed. Pain causes inflammation that can cause strokes, heart attacks, cancer. It causes despair and loneliness. It causes suicide.

I am afraid that we will not be remembered as the generation that overcame opiates. I am afraid that we will be remembered as the generation that pain destroyed. If we are remembered at all.



United States of Meth

Last week, I tested positive for methamphetamine.

I was on the red line train on my way to work, looking through my emails to pass time. There was a note from my health care system that a test result had been added to my patient profile. I clicked over and was horrified to discover that my urine had tested positive for meth. I burst into tears and called the office of the ordering physician in sheer panic.

Fear raises my blood pressure and elevated blood pressure decreases my hearing so I walked through Cambridge for a few blocks trying to will myself to hear the admin on the other end. I did several really stupid and unhelpful things to try and improve my hearing (including switching my phone to the ear I haven’t heard out of in six years and then covering that same ear) before finding a doorway to duck into down a quiet side street.

I think blubbering is too strong of a word to describe me here but I don’t know what word means one step down from blubbering so I’m going to call it “light blubbering.” I was light blubbering while telling the admin that I saw the positive test on my profile and that I wanted to know how to get it straightened out. She asked if I wanted to leave a message for my doctor.

I did, but wasn’t really sure how to phrase this. Finally I said (while light blubbering), “What should I say?”

The admin seemed equally perplexed and finally said, “I don’t know… maybe ‘I don’t use meth’?”

So that’s the message I left.

In July of 2013, I went to the ER with severe obstructive bowel pain. The kind of pain that feels like I am being repeatedly kicked in the stomach while at the same time my GI tract is being twisted.  It was two months after I had had my ostomy placed. My incisions weren’t even completely healed. I was having a bad reaction to pain and called the services for my surgeon and mast cell specialist on the way over. I arrived at the emergency department of the hospital where I had just had surgery and where I was seen several times a month. All of my records were there.

There were notes that if I presented in the emergency room degranulating/having anaphylaxis, to administer IV Benadryl, IV Pepcid and IV Solu-Medrol, and if I was in pain, to administer hydromorphone, one of the drugs of choice for mast cell patients with serious pain. I was puking from the reaction to the pain, tachycardic and flushing in waves a deep red like some sort of underwater creature that changes colors to tell other animals what it is feeling. Like a delicate jellyfish that communicates its intentions while vomiting and screaming every time I threw up because the tensing pulled on my incisions.

I guess my jellyfish routine sucked because in a very short period of time, I was embarrassed by several medical professionals in quick succession as a direct result of explaining that fentanyl and hydromorphone are the drugs of choice for mast cell patients. When they were collectively done treating me like garbage, the nurse ripped the IV out of my arm and I left without pain management. If you ever want to see a provider determine that you are worthless, lying, drug seeking scum, just tell anyone in an emergency department that you can only take fentanyl or hydromorphone for opiates. This is so true that there are memes about it.

Last month, the admin at one of my doctor’s offices told me that a new state law requires that certain patients provide urine samples to be tested for drugs of abuse. That’s fine. No problem. I have done this voluntarily in the past and I have nothing to hide. I went to the office, peed, and turned in my little cup to the nurse. I was not at all concerned that I would test positive for drugs of abuse because I don’t take drugs that aren’t prescribed to me. Then I tested positive for meth and just about had a heart attack on the red line train.

I think most people know that there is an ever worsening addiction epidemic in these united states. When I worked in pharmacy, I interfaced regularly with people struggling with addiction. People would come in with prescriptions from stolen prescription pads, or call in their own prescriptions pretending to be their doctor, or add a zero to the end of the quantity on a real prescription. I worked in a 24 hour pharmacy the week my state started imposing limits on the amount of pseudoephedrine that could be bought by a person to mitigate the ballooning meth problem. I was present when robbery for oxycontin became a looming threat in all pharmacies. I went to a high school that has had a huge number of former students die from overdose or complications of drug abuse. I am very aware that there are people who seek drugs for illicit use. (Disclaimer: I am not disparaging people with addiction. Some of the people closest to my heart are in recovery.)

Working in pharmacy, I also saw a lot of people who were in a tremendous amount of pain and who suffered because of others who abused drugs, especially prescription drugs. A few years later, I would also learn how embarrassing and difficult it is to be a chronic pain patient. The nurse who ripped out my IV and threw me out of the emergency department was a symptom of this larger system that sees everyone who needs pain management as an addict or as too lazy to work other options. Every single time I have to admit that I am in pain (even if I don’t need medication for it), I am forced to assess how likely it is that they think I’m spinning a larger tale to end with a prescription request.

The legislation that requires urine tests from pain patients reinforces the idea that if you have chronic pain and you don’t have cancer that you aren’t trying hard enough to find other ways to manage it or that you are selling/abusing/doing something illegal with your meds. I have spent years getting to a point where I can function at a moderate level much of the time. I exercise almost every day, either walking a few miles, swimming, or doing 60-90 minutes of advanced yoga at home. I have used massage, meditation/visualization, acupuncture, reflexology, and supplements like turmeric, magnesium and vitamin D to bring my pain level down. I have tried diets (some of which helped, most of which didn’t). I have tried showering in cold water to decrease inflammation. I take lots of meds to reduce inflammation and pain associated with my disease. I have been in pain a long time. I have tried pretty much everything. It’s not always possible to manage pain without use of pain medication.

While investigating false positive urine tests, I came across a lot of stories. There has been a story circulating on Facebook for a while about a woman who tested positive for meth during her labor and delivery. This ushered in a nightmare situation where a woman who didn’t use illicit drugs was separated from her baby while CPS determined whether or not she could bring the baby home.

I also found some other stories. A few were about newly implemented guidelines for when pharmacy personnel should suspect drug abuse. These guidelines include such things as going to a new pharmacy (though pharmacies will not tell you over the phone if they have controlled substances on hand); changing pharmacies (because no one ever moves); and paying cash (because insurance never rejects valid claims). There were some more ridiculous rules of thumb for how to identify a drug seeker. I fit at least half of them.

I spent most of the day after seeing this positive test result combing through literature on medications that can cause false positive results for drugs of abuse. Ranitidine can cause a false positive for methamphetamine. Even knowing this, I was still terrified. Even though I know I don’t use meth, I was still terrified. Even though I felt sure this would get straightened out, I could not stop worrying about it.

I called the office again the following morning because I had not heard back yet. The admin asked if I wanted another doctor to call me so I wouldn’t have to wait as long. “No! No,” I said, the second ‘no’ in a more forced-relaxed tone of voice. You know how you know something sounds bad but you just need to slip it in anyway and you can’t scare anyone because if you do (insert catastrophe)? This was one of those times. Is my voice the appropriate amount of nonchalant? Is this the voice of a meth user? “I have a really complicated medical history so it’s easier if I just talk to providers who know me,” I finally said, the words wavering a little more than I wanted. “I’ll just wait.”

The office NP (who is lovely and knows me) called later that day. She told me that no one called me because they knew it was a false positive. I exhaled two days’ worth of anxiety as she chatted cheerily. She hung up and everything was fine and I needed a nap to recover.

I have actual nightmares about medications and treatments that help keep me stable being taken away because my doctor retires or moves away or just doesn’t want to give it to me anymore. This terror is reality for most rare disease patients and probably plenty of patients who don’t have rare diseases. All of us, even those with solid care teams, are at the mercy of these providers and their personalities and these systems that see us as numbers and statistics that can’t really be in pain for so long.

I would like to say that I think things are improving or will improve for people like me but the truth is that I doubt that will ever be the case. Not every person who needs pain management is drug seeking but you would never know that in these united states.

Symptoms, mediators and mechanisms: A general review (Part 1 of 2)

Skin symptoms    
Symptom Mediators Mechanism
Flushing Histamine (H1), PGD2 Increased vasodilation and permeability of blood vessels

Blood is closer to the skin and redness is seen

Itching Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria Histamine (H1), PAF, heparin, bradykinin Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of skin

Angioedema Histamine (H1), heparin, bradykinin, PAF Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of tissue


Respiratory symptoms    
Symptom Mediators Mechanism
Nasal congestion Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Sneezing Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Airway constriction/ difficulty breathing Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Increased mucus production

Smooth muscle constriction


Cardiovascular symptoms    
Symptom Mediators Mechanism
Low blood pressure Histamine (H1), PAF,  PGD2, bradykinin Decreased force of heart contraction

Increased vasodilation and permeability of blood vessels

Impact on norepinephrine signaling

Change in heart rate

Presyncope/syncope (fainting) Histamine (H1), histamine (H3), PAF, bradykinin Increased vasodilation and permeability of blood vessels

Decrease in blood pressure

Dysfunctional release of neurotransmitters

High blood pressure Chymase,  9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

Tightening and decreased permeability of blood vessels

Tachycardia Histamine (H2), PGD2 Increasing heart rate

Increasing force of heart contraction

Impact on norepinephrine signaling

Arrhythmias Chymase, PAF, renin Impact on renin-angiotensin pathway

Impact on norepinephrine signaling


Gastrointestinal symptoms    
Symptom Mediators Mechanism
Diarrhea Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Gas Histamine (H1), histamine (H2), bradykinin Smooth muscle constriction

Increased gastric acid secretion

Abdominal pain Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Nausea/vomiting Histamine (H3), serotonin Dysfunctional release of neurotransmitters
Constipation Histamine (H2), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters


The Sex Series – Part Nine: Female pelvic floor dysfunction (2 of 2)

Muscular dysfunction in the pelvic floor starts when something happens that causes an injury or large scale inflammation to the pelvic floor.  This causes a large scale release of calcium, which causes the muscle to become too tight (hypertrophic).  As a result of this tightness, metabolism in the tissues increases and substances like histamine, serotonin and prostaglandins are released.  These mediators trigger neurologic pain perception.   The pain causes tightness, which causes more pain, and the cycle continues.

Hypertrophic muscles become musculodystrophic as fibrosis occurs.  The muscle becomes atrophied and is replaced by less extensible connective tissue.  As a result, the muscles aren’t as flexible as they should be. This also means that they cannot relax normally.  This activates trigger points in the pelvic floor and increases tone and spasm in pelvic structures, including the bladder, uterus, and rectum.

Treatment for pelvic floor dysfunction of women is very well described in literature.  It relies largely upon patient education and compliance with various exercises to retrain the muscles to relax completely at will.  Trigger-point pressure, both internal and external, can be applied by the patient or partner to help the muscles relax.  Vaginal or anal dilators, vaginal cones and bladder training can also be effective. Physical therapy including myofascial release and biofeedback are also important to treatment.

While initial treatment of PFD can be complex and time-consuming, the results are very good.  One study followed a cohort for ten years. 71% of women in this cohort reported major reduction or elimination of pain level following physical therapy and exercises done at home. After ten years, 89% of women reported major reduction or elimination of pain.  Many patients continued their home exercises during that time.



Bortolami A, et al. Relationship between female pelvic floor dysfunction and sexual function: an observational study. J Sex Med 2015; 12: 1233-1241.

Hartmann D, Sarton J. Chronic pelvic floor dysfunction. Best Practice & Research Clinical Obstetrics and Gynaecology 2014, 28: 977-990.

Espuña-Pons M, et al. Pelvic floor symptoms and severity of pelvic organ prolapse in women seeking care for pelvic floor problems. European Journal of Obstetrics and Gynecology and Reproductive Biology 2014, 177: 141-145.

Ramalindam K, Monga A. Obesity and pelvic floor dysfunction. Best Practice and Research Clinical Obstetrics and Gynaecology 2015, 29: 541-547.

Graziottin A, et al. Mast cells in chronic inflammation, pelvic pain and depression in women. Gynecol Endocrinol 2014; 30 (7): 472-477.

Ahangari A. Prevalence of chronic pelvic pain among women: an updated review. Pain Physician 2014; 17: e141-147.

The Sex Series – Part Eight: Female pelvic floor dysfunction (1 of 2)

Chronic pelvic pain (CPP) in women is staggeringly common, with incidence ranging from 5.7-26.6%, depending on the study. CPP is marked by intermittent or constant pain in the lower abdomen or pelvis, lasts at least six months, and is not associated directly with menstruation, pregnancy or intercourse. Mast cells are known to be involved in the inflammatory processes of these conditions and are therefore linked to CPP.

It can be caused a wide variety of conditions that affect organs or structures in the pelvis, including endometriosis, inflammatory bowel diseases affecting the lower tract, interstitial cystitis, ovarian cysts and hypermobility type Ehlers Danlos Syndrome (HEDS).  Over half of women with CPP report chronic bladder pain, for which interstitial cystitis is a common cause.  Interstitial cystitis is widely accepted to be a mast cell mediated disease.

Despite the frequency of CPP, many exploratory surgeries to identify the cause find nothing (28-55%). Chronic pain from these conditions alters the way the sensory nerves in the pelvic cavity send signals to the spinal cord.  This in turn disrupts interpretation of pain and sensation by the nerves, creating more visceral pelvic pain.

Pelvic floor dysfunction (PFD) affects about 26% of women with CPP.  This dysfunction can cause embarrassing and disabling symptoms, including urinary and fecal incontinence. Pelvic organ prolapse occurs when organs such as the bladder move out of the correct position and impinge on other structures, such as the vagina. Pelvic organ prolapse can be called by pelvic floor dysfunction and it can cause pelvic floor dysfunction.

Sexual dysfunction affects 15-65% of PFD patients. PDF interferes with correct function of a number of muscles, including the levator ani, which hold urogenital structures in place and allow them stretch and contract during penetration and orgasm.  Patients with pelvic organ prolapse often feel a bulge pushing against the vaginal wall that interferes with vaginal penetration.  Vulvodynia, vestibulodynia, vaginismus and painful intercourse are commonly seen in PFD.

In PDF patients, muscles in the pelvic floor can be hypotonic (not tight enough), hypertonic (too tight), or have normal tone. Hypotonic dysfunction is more likely to cause incontinence, bladder symptoms and pelvic organ prolapse.  Hypertonic dysfunction is associated much more with pain and sexual dysfunction. Reduction of the high tone is necessary to reduce pain.


Bortolami A, et al. Relationship between female pelvic floor dysfunction and sexual function: an observational study. J Sex Med 2015; 12: 1233-1241.

Hartmann D, Sarton J. Chronic pelvic floor dysfunction. Best Practice & Research Clinical Obstetrics and Gynaecology 2014, 28: 977-990.

Espuña-Pons M, et al. Pelvic floor symptoms and severity of pelvic organ prolapse in women seeking care for pelvic floor problems. European Journal of Obstetrics and Gynecology and Reproductive Biology 2014, 177: 141-145.

Ramalindam K, Monga A. Obesity and pelvic floor dysfunction. Best Practice and Research Clinical Obstetrics and Gynaecology 2015, 29: 541-547.

Graziottin A, et al. Mast cells in chronic inflammation, pelvic pain and depression in women. Gynecol Endocrinol 2014; 30 (7): 472-477.

Ahangari A. Prevalence of chronic pelvic pain among women: an updated review. Pain Physician 2014; 17: e141-147.

The Sex Series – Part Six: Male pelvic dysfunction and mast cells

Chronic pelvic pain syndrome (CPPS) affects about 15% of male patients and 90% of patients with chronic prostatitis. Patients with these conditions experience pain in the pelvis, abdomen and genitalia, as well as urinary tract symptoms without evidence of infection. Pain can be intermittent or constant, and can interfere with daily activities including sitting, standing, urination and defecation.

CPPS also causes sexual symptoms. Painful ejaculation, erectile dysfunction, and other types of ejaculation dysfunction are all common in this patient group.  In one study, 40% of patients with CPPS were found to have erectile dysfunction.  In another, 72% of patients reported either erectile dysfunction or difficulty with ejaculation.

Pelvic floor dysfunction is a component of CPPS. Many of these patients have abnormally tense pelvic floor muscles, which can cause muscle spasm and obstruct bloodflow. CPPS patients are more likely than healthy controls to have vascular dysfunction associated with nitric oxide level. In a group of 146 patients with CPPS and verified pelvic floor spasm, 56% experienced painful ejaculation.  Visceral and myofascial pain and spasm of the muscles in the pelvic floor contribute to CPPS.  While pelvic floor dysfunction has been well researched for female patients, there are far fewer studies on pelvic floor dysfunction in men.  Biofeedback and pelvic floor physical therapy can resolve issues with erectile dysfunction and other sexual issues.

IL-17, expressed by special T cells called Th17 cells, is required to develop CPPS-like conditions in animal models. IL-17 triggers mast cell degranulation and secretion of many inflammatory molecules.  A number of mast cell mediators are elevated in patients with CPPS. IL-1b, TNF, IL-6 and IL-8 are higher in seminal fluid of these patients.  CCL2 and CCL3 expression is also increased. In the prostate of animals with a CPPS model, TNF, IL-17a, IFN-γ and IL-1b are all increased.

Tryptase has been found to induce pelvic pain. Levels of tryptase and carboxypeptidase A3 are higher in CPPS patients than in healthy controls.  Tryptase binds to a receptor called PAR2.  When tryptase binds to this PAR2 receptor, it is thought that it makes nerves oversensitive. If the PAR2 receptor is blocked, pelvic pain is mitigated.  In animal models where they cannot make tryptase-like products, pelvic pain does not develop in CPPS.

Nerve growth factor (NGF) is a mast cell mediator that has been implicated in CPPS. It is elevated in seminal plasma of CPPS patients and directly correlates with pain level. It is thought that NGF makes the peripheral nerves oversensitive and causes more nerve cells than usual to be present. NGF and tryptase were elevated in prostate secretions of most CPPS patients in a small patient group. Of note, NGF release occurs and increases weeks after initial symptoms.

In animal models, injecting cetirizine (H1 antihistamine) into the peritoneal cavity decreased pain by about 13.8%; ranitidine (H2 antihistamine), 6.1%; cromolyn, 31.4%. A combination of all three decreased pain by 69.3%. When cromolyn and cetirizine were used together, larger pain relief was achieved than when used individually, but this was not seen when using ranitidine and cromolyn together.  These data suggest that H2 signaling is not a major contributor in chronic pelvic pain in male patients.

Pelvic floor dysfunction is also common in heritable connective tissue diseases and is often present in hypermobile patients.


Done JD, et al. Role of mast cells in male chronic pelvic pain. Journal of Urology 2012: 187, 1473-1482.

Roman K, et al. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome. Pain 2014: 155 (7), 1328-1338.

Cohen D, et al. The role of pelvic floor muscles in male sexual dysfunction and pelvic pain. Sex Med Rev 2016; 4, 53-62.

Murphy SF, et al. IL17 mediates pelvic pain in experimental autoimmune prostatitis (EAP). PLoS ONE 2015, 10(5) : e0125623.


Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Four)

The relationship between Ehlers Danlos Syndrome and dysautonomia, the dysfunction of autonomic nervous system, is currently being elucidated.  There is a correlation between hypermobility and autonomic symptoms. One study found that in patients with autonomic dysfunction, 18% had EDS, compared to the control group, in which only 4% had EDS.

Ehlers Danlos Syndrome alters collagen structure throughout the body. In HEDS, this usually affects the skin less than in other types of EDS.  In the cardiovascular system, this contributes to vascular laxity, which allows excessive dilation of the blood vessels, causing orthostatic intolerance. Importantly, you do not see the spontaneous rupture of blood vessels seen in VEDS.

In HEDS, connective tissue defects in the GI tract lead to dysfunctional peristalsis (contraction of GI tract to move food through it), excessive stretching or swelling, dysregulation of intestinal permeability and damage to the epithelial cells of the GI tract. Without proper connective tissue support, the bladder can become distended or impinge on other structures, as in cystocele.  HEDS frequently causes weakness in the pelvic floor and can lead to prolapse of pelvic organs.

Pain and fatigue are often attributed to dysautonomia in EDS patients, but it could also be caused by HEDS. Peripheral neuropathy is prevalent in HEDS and can drive pain in this population.  Many HEDS patients have sensory pain, such as tingling, pins and needles, numbness, radiating or burning pain. If the autonomic nervous system is responsible for the pain signals, it could provide a link between dysautonomia and pain. Chronic pain and inflammation can change the structure and behavior of the nervous system, making it easier to transmit pain signals.  Orthostatic intolerance can activate the sympathetic nervous system, part of the autonomic nervous system, contributing to these types of symptoms.

By contrast, many HEDS patients are known to frequently have anxiety, palpitations, dizziness, shortness of breath and high affective distress.  Rather than being from HEDS directly, these are likely from dysautonomia.


de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.


I have always been fascinated by both the human body and the diseases that affect it. When I was about ten years old, my parents bought me a medical dictionary. I read it cover to cover. I wrote little stories about people with Legionnaire’s Disease and Tetrology of Fallot, describing the symptoms and treatments in vivid detail.

It was in this dictionary that I first read about phantom pain. It always made a weird sort of sense to me. Bodies are creatures of habit, just like us. Of course your body expects to have all of the parts it started with. Of course your brain would assume it was merely misinterpreting signals when suddenly a limb was missing. The alternative was too awful to consider.

It never occurred to me that the body could experience phantom pain from a part of the body that was never supposed to exist. As soon as my epidural line was pulled five days post-op, I started having severe sporadic pain where my stoma used to be. It was distinct from the other pains – the burning in the lower colon, the sharpness in the rectum, the soreness near the incisions.

This was something different. It felt like when my body tried to pass stool through the stoma, but couldn’t because of an obstruction. It was the same exact same sensation. My body remembers the route of a path that should never have been there to begin with.

I lived 29 years without an ostomy. In the two years that I had it, I believed it was the best solution for me, and for most of that time, I believed that I would always have it. The only way to survive was a radical acceptance of this defect. I told myself that this was the best option for my body and I made myself believe it. I believed it so much that even my body was convinced.

I still have a wound where my stoma was. It is closing slowly. Mostly the pain is manageable; I know it will never really go away. Several times a day, I feel my body mimic the pressure of an obstruction behind the stoma, the twisting and lines of pain spiderwebbing into my lower back. The pain isn’t real, but my brain won’t believe it.

Phantom pain is notoriously resistant to pain medication. One of the better options is the use of psychological “tricks” to convince your body that it is still intact. I am thinking about how to do this. But I don’t know which version of my GI tract my brain thinks is real.