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


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 Seven: Mast cell activation and anal penetration

So far in this series, we have talked a lot about vaginally penetrating sex.  But that’s not the only way to have sex so for now, let’s move on.

Anally penetrating sex can be safe, painless and pleasurable for many people.  It is enjoyed by many partners of various sexual orientations.  The anus is an inherently different environment than the vagina and as such, preparation for and participation in anally penetrating sex is a bit different.

An obvious difference is that the anus does not self-lubricate in preparation for sex.  Use of external lubricant is HUGELY important.  Silicone based lubes are often used for anally penetrating sex because it is slicker and is not broken down as quickly by your body as water based lubricants. When selecting a lubricant, be sure to research whether components can irritate the anus and rectum.  In particular, many spermicides are very irritating to rectal tissue. Of course, in the same way that a person can react to lubricant in the vagina, you can react to lubricant in the rectum and anus.  Contact dermatitis or other types of allergic reaction can occur.

Though “vigorous anal penetration” is often considered a risk factor for anal or rectal injury, the actual incidence of these injuries is low and mostly occurs in sexual assault situations.  Injury to the sphincter musculature is unusual.  Large patient groups of gay men who engage in anal sex have been surveyed regarding issues or injuries associated with receiving anal penetration over a long period of time.  Some patients reported infrequent or “slight” incontinence, attributed by medical professionals to the inability of the anal sphincter to close as tightly in the immediate time after penetration.  However, in other studies, no patients have reported this issue.  The most frequent problem, as also seen in vaginal intercourse, is the transmission of sexually transmitted infections.  This can be mitigated by using condoms.

Anal penetration should not hurt.  The person receiving and giving should take steps to relax the anal sphincter, use adequate lubrication, and be sensitive to any pain.  Painful penetration can indicate a problem and should be taken seriously by both partners. Regardless of how an injury was acquired, anal sex can irritate any condition that affects the rectum or anus.

Hemorrhoids are blood vessels that become distended.  They can occur internally or externally, and are often painless.  The first indication of hemorrhoid is often bright red blood on toilet paper.  If a blood clot forms in the hemorrhoid, it can become very painful and swollen.  It is not entirely understood how hemorrhoids form, but straining to stool, increased pressure in the abdominal cavity, obesity and pelvic floor dysfunction are often linked to formation.

Mast cells are increased in hemorrhoid associated tissue and may affect hemorrhoid formation and resolution through release of mediators like tryptase, chymase and platelet activating factor. One study found that the number of mast cells in acute and chronic hemorrhoids is not different, indicating that mast cells can be associated throughout the lifecycle.

Fissures are tears in the anal or rectal tissue.  Fissures can be very painful, especially during and after defecation.  Fissures also cause bright red blood on the toilet paper or stool.  Patients who have fissures often have increased resting pressure when tested with anorectal manometry, meaning their muscles are more tense than usual.  Fissures can also be mast cell activating, as mast cells are active in wound healing.  Tears in the rectum and anus do not heal as quickly as those in the vagina.

Rectal itching is not unusual in allergy/mast cell patients.  Mast cells are natively present in the rectum and can degranulate in response to stimuli just like mast cells anywhere else.  Mediators released can also cause pain.  Care should be taken to reduce friction as much as possible to try to prevent degranulation from pressure.  Itching and pain can also be signs of reacting to condoms or lubricants used.

Pelvic floor dysfunction can also make anal sex painful, as the rectum and anus may not be properly supported by connective tissue.  Patients with pelvic floor dysfunction or connective tissue defects should be cautious to observe any pain or discomfort when receiving anal penetration. Pelvic floor dysfunction, and the other conditions mentioned above, can be irritated by anal penetration.

As described earlier in the series, it is possible to have an allergic reaction to semen, either due to the presence of allergens or to the composition of the semen itself. If semen enters the body during anally penetrating sex, it is possible to have an allergic reaction.  Condoms can prevent these reactions, and are also recommended to decrease risk of infection due to contact with GI flora.



Chond PS, Bartolo DCC. Hemorrhoids and fissure in ano. Gastroenterol Clin N Am 2008, 37: 627-644.

Cawich SO, et al. Complete anal sphincter complex disruption from intercourse: A case report and literature review. International Journal of Surgery Case Reports 2012: 3, 565-568.

Zamvar V, et al. Severe anal pain caused by food allergy?: A case report. European e-Journal of Clinical Nutrition and Metabolism 2010, 5: e144-e145.

Taweevisit M, et al. Increased mast cell density in haemorrhoid venous blood vessels suggests a role in pathogenesis. Singapore Med J 2008; 49 (12): 977-979.

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.