The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 19

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

28. Why are so many mast cell patients anemic?
• Anemia occurs when a person has too few red blood cells or not enough hemoglobin. Red blood cells are essentially envelopes that serve specifically to hold hemoglobin. Hemoglobin is a molecule made with iron that picks up oxygen. When you have either too few red blood cells or they don’t have enough hemoglobin, not enough oxygen gets to all the parts of the body that need it.
Patients with chronic illness of many kinds often have anemia. This is called anemia of chronic inflammation or anemia of inflammatory response.
• This type of anemia occurs because of the overactivity of a hormone called hepcidin. This hormone tells cells in the GI tract to hold onto any iron they find. This means they do not pass the iron along to the blood so it can make hemoglobin. Since the body isn’t making enough hemoglobin, the body doesn’t get enough oxygen.
• Mast cell patients often have anemia of chronic inflammation so they may be anemic regardless of how much iron they have in their diet. However, increased supplementation sometimes helps.
• There are several forms of iron that can be taken by mouth. IV iron is also an option. Some people have luck cooking in cast iron pans or using the “Lucky Iron Fish” to get even more iron into their diet in hopes that they can take up a little bit more.
Having enough iron available also decreases mast cell activation. Mast cells make smaller amounts of inflammatory molecules when the body has sufficient iron.
• Mast cell patients may also selectively malabsorb iron in their GI tracts. This means that even if they are absorbing enough of other nutrients, they may not absorb enough iron properly due to inflammation. This sometimes improves with antihistamines.
• Mast cell patients usually take histamine H2 blockers. This decreases the strength of stomach acid which can affect absorption of nutrients like iron. Taking PPIs can do the same thing.
• Malabsorption of other nutrients, like copper, can contribute to anemia.
• Insufficient amounts of B12 or folate can cause also contribute to anemia.

For more detailed reading, please visit these posts:
Anemia of chronic inflammation
MCAS: Anemia and deficiencies
Effect of anemia on mast cells

The MastAttack 107: The Layperson’s Guide to Mast Cell Diseases, Part 17

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

25. How do I know what I will react to?
There is no way to definitively know what things will make you react. It is difficult to predict. There are some general guidelines many of us use to figure out what may be a problem but the only way to really know is to try something.
• Please note that because mast cell reactions are not known to be triggered by the same mechanisms as traditional allergies, you cannot exclude an entire class of drugs because you react to one in the way that you do for traditional allergies. This is particularly worth noting for opiates: reaction to morphine, for example, does not exclude fentanyl or hydromorphone.
• Mast cell reactions are not inherently triggered by IgE the way that “true” allergies are. This means that blood tests for IgE allergies will not identify triggers accurately for most mast cell patients. (Although some mast cell patients do have some IgE allergies.)
• Additionally, skin testing is wildly inaccurate in mast cell patients because of how reactive our skin is.
Stopping antihistamines is dangerous for mast cell patients.
Allergy testing is not accurate for mast cell patients.
• There are several ways that various things can cause mast cell reactions. Generally, they do it in one of the following ways: they cause mast cells to empty the chemicals in their pockets into the body (degranulation); they cause mast cells to release chemicals in another way; they already contain significant amounts of histamine; or the interfere with the mechanisms for controlling mast cell activation.
There are a number of medications that can cause mast cell degranulation or histamine release. Please note that not all of these medications are problematic for every patient. Only a provider managing your case can determine if these are safe for you or not. The major medications that may cause degranulation or histamine are listed below. This list is not exhaustive.

-Alcohol: Widely used to sterilize body area, surfaces, or tools; also used when preparing many medications that are not soluble in water
-Amphoterecin: Antifungal
-Aspirin: NSAID, for pain, inflammation, to block prostaglandins, to prevent clot formation
-Atracurium, mivacurium, rocuronium: Muscle relaxant
-Caine anesthetics (esters): Anesthetics, to numb
-Codeine, morphine, meperidine: Opiates, for pain or cough
-Colistin: Antibiotic
-Dextran: Volume expander, used in surgical or emergency situations to improve blood pressure
-Dextromethorphan: Cough suppressant
-Miconazole: Antifungal
-Nefopam: For pain
-NSAIDs (non steroidal anti-inflammatory drugs): For pain, inflammation, blocking production of prostaglandin
-Polymyxin B: Antibiotic
-Radioopaque contrast: To visualize structures in medical scanning procedures
-Reserpine: High blood pressure medication and antipsychotic
-Succinylcholine: Paralytic used for surgical procedures
-Thiopental: Anesthesia induction for surgical procedures
-Vancomycin (especially IV): Antibiotic

• There are a number of medications that are known to interfere with the mechanisms for controlling mast cell activation. Adrenaline is naturally made by the body to help control mast cell activation and other activities. When you interfere with the ability of adrenaline to act, it can potentially trigger mast cell activation. Drug classes that do this include beta blockers and alpha adrenergic blockers. This is particularly an issue if there is a history of anaphylaxis because these medications can interfere with Epipens.
Many foods either contain histamine or can trigger mast cell release of histamine. As with medication, you cannot exclude an entire family of foods because you react to one in the way that you do for traditional allergies.
• There are many lists of foods to avoid. They often conflict with each other. There is not yet a definitive list available. Despite this, there are some general rules of thumb that are agreed upon on what to avoid.
• Products that are fermented, contain alcohol, are overly ripe or leftover from previous days (especially meats), or contain dyes or preservatives are generally excluded.
• Beyond this, recommendations vary a lot more. Many diets recommend excluding yeast, citrus fruits, and nightshade vegetables.
Many activities inherently activate mast cells. Being too hot, standing or sitting in direct sunlight, exercise, sexual activities, menstruation, infection, and any type of physical trauma, even minor, can trigger mast cell activation as part of normal mast cell function.
Premedication is recommended for any medical procedure, even minor, as they can trigger mast cell activation.
• Patients may find that premedication prior to other activating activities is helpful for suppressing reactions.
Ultimately, the only way to know what is activating is through trial and error. Patients should consult their care team about what to trial, when, and how to make it as safe as possible.

For more detailed reading, please visit these posts:

Food allergy series: Mast cell reactions and the low histamine diet

The Provider Primer Series: Introduction to Mast Cells

The Provider Primer Series: Medications that impact degranulation and anaphylaxis

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 10

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

17. Does mast cell disease impact mood, anxiety, and depression?
Yes. This has been described in literature for over 30 years. In 1986, a paper described a series of patients with systemic mastocytosis who had severe psychiatric symptoms as a result of their disease. It was called “mixed organic brain syndrome”.
Depression, anger, bipolar disorder, attention deficit disorders, anxiety, irritating, and panic disorders have all been associated with mast cell disease.
• One study found that in a group of patients with cutaneous mastocytosis and systemic mastocytosis, 75% of the patients had symptoms of depression. In another study, 60% had symptoms of depression or anxiety.
• Many patients have been diagnosed with a psychiatric condition before learning that they have mast cell disease. For many mast cell patients, managing their diseases lessens the severity of their psychiatric symptoms. Antihistamines have been reported many times to improve these symptoms.
• Mast cells are often sitting right next to nerve cells throughout the body. Mast cells are found in large numbers in the brain. Chemicals released by mast cells can cause psychiatric symptoms.
• Some of the chemicals released by mast cells are specifically intended to talk to nerve cells. Histamine is one such chemical. When histamine is not released in the right amounts at the right times, it can affect how other chemicals are released. Some of these chemicals are also for cells to talk to nerves, like serotonin and dopamine. Mast cells can also release serotonin.

18. Are medications for depression, anxiety or other psychiatric conditions used in mast cell patients?
Yes. As with every medication, only you and your care team can decide if a medication is safe for you. No medication is universally safe or always dangerous.
Benzodiazepines are usually well tolerated in mast cell patients. Benzodiazepines actually interact with mast cells and can make them release fewer chemicals. (Be aware that the IV forms of these medications sometimes have alcohol in them).
SSRIs are sometimes taken by mast cell patients. Mast cell patients should be cautious because they can increase serotonin levels and mast cells can also release serotonin.
• Tricyclic antidepressants are more commonly used in mast cell patients. Tricyclic antidepressants actually work as antihistamines, too.
• Other drugs that can manage psychiatric symptoms, like mirtazapine, olanzapine, and quetiapine, also have antihistamine properties.
For more detailed reading, please visit these posts:

 

Neuropsychiatric features of mast cell disease: Part 1 of 2

Neuropsychiatric features of mast cell disease: Part 2 of 2

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 9

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

15. How is mast cell disease treated?
• There are a number of medications to treat mast cell disease. Mast cells release so many chemicals, some in a large quantity. We are not able to totally stop mast cells from releasing the chemicals so we need to use many medications to block their effects on the body.
The baseline regimen for mast cell patients include antihistamines and mast cell stabilizers. Specifically, patients are usually prescribed two antihistamines that work two different ways. These are called H1 antihistamines and H2 antihistamines. The H in these meds stand for histamine. There are many antihistamine options. Antihistamines stop the histamine from working in the body. Even still, many patients experience histamine driven symptoms
Mast cell stabilizers work by making mast cells less likely to release chemicals. There are fewer options for mast cell stabilizers. Cromolyn is a very common mast cell stabilizer. Ketotifen is both a mast cell stabilizer and an antihistamine. Ketotifen that you can take as a pill is not approved in the US because there was not a market for it so it was never submitted to the FDA. However, patients can get ketotifen in pill form through compounding pharmacies in the US.
• Other types of medication commonly used for mast cell disease that block the effect of mast cell chemicals include leukotriene inhibitors and PAF blockers.
Some medications can stop mast cells from making specific chemicals. These include COX inhibitors, lipoxygenase inhibitors, and corticosteroids like prednisone.
Many patients are deficient in some vitamins or minerals because they don’t absorb them well in the GI tract. Vitamin D and iron are commonly low. Patients often take supplements to replace these deficiencies.
• Chemo drugs are sometimes used to treat severe mast cell disease. These drugs can kill mast cells and/or decrease the amount of chemicals released.
• IV fluids are reported by patients to help with symptoms such as fatigue and swelling.
• There are many other medications that can be used to treat other symptoms.

16. Do I have to take medication if I feel okay?
Mast cell patients are usually recommended to take baseline medications like antihistamines and mast cell stabilizers even if they feel okay. This is for two main reasons: mast cells can damage your body even if you don’t feel it; and if you do not take baseline medications, you will have less protection from a severe reaction and anaphylaxis.
• Many patients have other medications prescribed to be taken as needed. These medications are given when symptoms are bad and do not necessarily have to be taken daily.
• Please speak with your provider to clarify what meds are taken as needed and what meds are taken every day.
For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

Beta blockers and epinephrine

Beta blockers (often styled β-blockers) are medications used primarily for their impact on blood pressure and heart rhythm. Given their low cost and relative safety, beta blockers are very commonly prescribed for a number of other conditions as well, including anxiety. They work by blocking beta adrenergic receptors found throughout the body and specifically interfere with the action of norepinephrine and epinephrine.

The use of beta blockers in patients with risk of anaphylaxis requires some special consideration. This is because beta blockers directly block many of the places where epinephrine works to mitigate anaphylaxis. This means that using epinephrine to treat the anaphylaxis may be ineffective. This particular topic has been heavily researched and has not always yielded uniform findings.

The largest and most robust study included over 5000 patients with a history of systemic allergic reactions. This study found that patient use of beta blockers increased the risk of severe anaphylaxis. Use of ACE inhibitors, another drug class that impacts blood pressure, also increased the risk of severe anaphylaxis but to a smaller extent.

However, the risk of severe anaphylaxis was most increased in patients who took both beta blockers and ACE inhibitors together. Both beta blockers and ACE inhibitors were found to both decrease the threshold for mast cell activation and to prime mast cells (make them more easily activated).

Ongoing treatment with beta blockers has been found to be a risk factor for fatal anaphylaxis in some studies. It has also been found to be a risk factor for biphasic anaphylaxis, a type of anaphylaxis in which you have a second anaphylactic episode in the hours that follow successfully treated anaphylaxis.

Patients who must take beta blockers may be given a glucagon autoinjector for use prior to using injectable epinephrine. The reason for this is glucagon is the antidote to beta blocker overdose. When epinephrine binds to the beta receptor, it results in the cells making a molecule called cAMP. cAMP is a very important molecule for cells and it sends signals within the cell to regulate bodily processes. When a patient takes beta blockers, epinephrine can’t tell the cell to make cAMP. Glucagon is able to tell the cell to make cAMP even if the beta receptor is blocked. This action effectively counteracts the beta blocker.

Mast cell patients are usually recommended to use other medications to manage blood pressure and arrhythmias, including calcium channel blockers or renin inhibitors.

 

References:

Simons FER, et al. (2015) 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organization Journal, 8(32).

Nassiri M, et al. (2015) Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming. J Allergy Clin Immunol, 135: 491-499.

Shephard G. (2006) Treatment of poisoning caused by β-adrenergic and calcium-channel blockers. American Journal of Health-System Pharmacy, 63(19): 1828-1835.

Tole J, Lieberman P. (2007) Biphasic anaphylaxis: review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin N Am, 27(2): 309-326.

Kolch UW, et al. (2016) Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research, x: 1-10.

Reitter M, et al. (2014) Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and management analysis. Allergy, 69: 954-959.

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

A number of medications can induce mast cell degranulation and histamine release. Other medications increase the risk of anaphylaxis and can increase the severity of anaphylaxis.

Medication reaction profile is very individual and not all mast cell patients react to the medications listed below. Additionally, there may be a need for some mast cell patients to take  medications listed below if the benefit outweighs the risk.

Medications that are reported to induce mast cell degranulation and histamine release
Alcohol[i] Amphoterecin B[ii] Aspirin[i] Atracurium[iii]
Caine anesthetics (esters)[iv] Codeine[v] Colistin (polymyxin E)[vi] Dextran[iii]
Dextromethorphan[iii] Gelatine[iii] Iodine based radiographic dye[vii] Meperidine[viii]
Miconazole[ix] Mivacurium[iii] Morphine[iv] Nefopam[iii]
NSAIDs[x] Phentolamine[xi] Polymyxin B[v] Reserpine[xii]
Rocuronium[iv] Succinylcholine[iv][xiii] Thiopental[iv] Tolazoline[v]
Vancomycin[xiv] (especially when given intravenously)

 

Patients on beta blockers are more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. Beta blockers also impede treatment of anaphylaxis by interfering with the action of epinephrine[xvi]. Patients at risk for anaphylaxis who are on beta blockers should get a glucagon pen to use prior to epinephrine[xv].

Beta adrenergic blockers[xvi] (Note: List is not exhaustive)
Acebutolol Atenolol Betaxolol Bisoprolol
Bucindolol Butaxamine Cartelol Carvedilol
Celiprolol Esmolol Metoprolol Nadolol
Nebivolol Oxprenolol Penbutolol Pindolol
Propranolol Sotalol Timolol

 

Alpha blockers impede treatment of anaphylaxis by interfering with the action of epinephrine[xvii].

Alpha-1 adrenergic blockers[xvii] (Note: List is not exhaustive)
Alfuzosin Amitryptiline Amoxapine Atiprosin
Carvedilol Chlorpromazine Clomipramine Clozapine
Dapiprazole Dihydroergotamine Doxazosin Doxepin
Ergotamine Etoperidone Fluphenazine Hydroxyzine
Imipramine Labetalol Loxapine Mianserin
Nefazodone Olanzapine Phentolamine Prazosin
Quetiapine Risperidone Silodosin Tamsulosin
Thimipramine Thioridazine Trazodone

 

Alpha-2 adrenergic blockers[xvii] (Note: List is not exhaustive)
Buspirone Chlorpromazine Clozapine Esmirtazapine
Fluophenazine Idazoxan Loxapine Lurasidone
Mianserin Mirtazapine Olanzapine Phentolamine
Risperidone Thioridazine Yohimbe

Patients on angiotensin-converting enzyme (ACE) inhibitors are also more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. The exact reason for this is unclear but ACE inhibitors impede appropriate bradykinin metabolism which may contribute to anaphylaxis[xvi].

Angiotensin converting enzyme (ACE) inhibitors[xvi] (Note: List is not exhaustive)
Benazopril Captopril Enalapril Fosinopril
Lisinopril Moexipril Perindopril Quinapril
Ramipril Trandolopril

Special notes:

Aspirin use in mast cell patients to suppress prostaglandin production is becoming increasingly common[xviii]. In some situations, other NSAIDs are also used.

Fentanyl, sufentanil, remifentanil and alfentanil are the preferred opioids for mast cell patientsiv. Hydromorphone releases minimal histamine and is also used in mast cell patients.[xix]

References:

[i] Valent P. (2014). Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clinical & Experimental Allergy, 44, 914-920.

[ii] Lange M, et al. (2012). Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci, 8(3), 533-541.

[iii] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[iv] Eggleston ST, Lush LW. (1996). Understanding allergic reactions to local anesthetics. Ann Pharmacother, 30(7-8), 851-857.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Kwa A, et al. (2014). Polymyxin B: similarities to and differences from colistin (polymyxin E). Expert Review of Anti-infective Therapy, 5(5), 811-821.

[vii] Kun T, Jakubowski L. (2012). Pol J Radiol, 77(3), 19-24.

[viii] Blunk JA, et al. (2004). Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analq, 98(2), 364-370.

[ix] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[x] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xi] Powell JR, Shamel LB. (1979). Interaction of imidazoline alpha-adrenergic receptor antagonists with histamine receptors. J Cardiovasc Pharmacol, 1(6), 633-640.

[xii] Muroi N, et al. (1991). Effect of reserpine on histamine metabolism in the muse brain. J Pharmacol Exp Ther, 256(3), 967-972.

[xiii] Sadleir PH, et al. (2013). Anaphylaxis to neuromuscular blocking drugs : incidence and cross-reactivity in Western Australia from 2002 to 2011. Br J Anaesth, 110(6), 981-987.

[xiv] Sanchez-Borges M, et al. (2013). Hypersensitivity reactions to non beta-lactam antimicrobial agents, a statement of the WAO special committee on drug allergy. World Allergy Organization Journal, 6(18), doi:10.1186/1939-4551-6-18

[xv] Thomas M, Crawford I. (2005). Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers. Emerg Med J, 22(4), 272-273.

[xvi] Lieberman P, Simons FER. (2015). Anaphylaxis and cardiovascular disease: therapeutic dilemmas. Clinical & Experimental Allergy, 45, 1288-1295.

[xvii] Higuchi H, et al.(2014). Hemodynamic changes by drug interaction of adrenaline with chlorpromazine. Anesth Prog, 61(4), 150-154.

[xviii] Cardet JC, et al. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep, 13(1), 10-18.

[xix] Guedes AG, et al. (2007). Comparison of plasma histamine levels after intravenous administration of hydromorphone and morphine in dogs. J Vet Pharmacol Ther, 30(6), 516-522.

Gastroparesis: Treatment (part 2)

Initial management of gastroparesis often focuses on treating dehydration and electrolyte and nutritional deficits.  One study found that 64% of gastroparesis patients were not consuming enough daily calories to support the needs of their bodies, which can worsen symptoms.  Vitamins A, B6, C, and K, as well as iron, potassium and zinc are frequently deficient in this population.  Small meals low in fat and fiber are recommended for gastroparesis patients.  Liquids or blended solids often empty normally from the stomach.

For cases in which oral diet is unable to provide sufficient calories and nutrition, placement of a feeding tube may be necessary.  Jejunal feeding tubes are often used successfully.  Prior to surgical placement of a feeding tube, a nasojejunal tube should be used successfully.  PEG-J or Jet-PEG tubes allow venting of gastric secretions to reduce vomiting and nausea while providing a feeding route.

TPN (total parental nutrition) is given intravenously, but carries risks, including central line infections.  For patients in whom oral feeding is not feasible, a feeding tube is often considered the safer option.

Metoclopramide, a dopamine D2 receptor antagonist, is approved for treatment of gastroparesis.  However, treatment beyond 12 weeks should be considered only if the improvement on this medication is significant enough to outweigh risks.  Metoclopramide can cause dystonia and tardive dyskinesia.  Benzodiazepines and antihistamines are sometimes used to treat these side effects.  Domperidone is also a dopamine D2 receptor antagonist, but has lower incidence of side effects.  It is not approved in the US, but can be obtained via special FDA approval for US patients.

Medications to increase gastric motor activity, like erythromycin, are often used in gastoparesis patients.  When taken orally, erythromycin often becomes less effective after several weeks of relief.  Proton pump inhibitors and H2 antihistamines may provide some relief as gastroparesis is often associated with and irritating to GERD.

Medications for management of nausea and vomiting are mainstays for many gastroparesis patients, with phenothiazines or antihistamines often used for this purpose.  5-HT3 receptor antagonists like ondansetron are also widely used.  The neurokinin receptor-1 antagonist aprepitant is sometimes used after failing other antiemetics.  Scopolamine patches and dronabinol are also options.  Tricyclic antidepressants can be used to manage nausea, vomiting and abdominal pain, with nortriptyline and desipramine often preferred over amitriptyline, which can cause delayed emptying.  Mirtazapine has been reported as successful in a case study.

Abdominal pain associated with gastroparesis can be difficult to manage because opiates can induce gastroparesis.  Gabapentin, tramadol, tapentadol, pregabalin and nortriptyline are non-opiate options for pain management.

For some patients, more invasive treatment is indicated.  Some patients with gastroparesis have increased tone in the pyloric canal, which can contribute to delayed gastric emptying.  Injection of botulinum toxin (Botox) into the pyloric sphincter is sometimes tried.  In double-blind studies, use of Botox increases gastric emptying but does not improve symptom profiles.

There are surgical options to manage gastroparesis, with varying results.  Gastric electrical stimulation is considered for patients with long term symptoms that have not improved despite treatment.  These devices are implanted and provide low grade electrical stimulation to the stomach and increase motility.  In diabetic gastoparesis patients, this method improved quality of life and decreased symptoms.  Patients who acquired gastroparesis following surgery, or whose gastroparesis is idiopathic, were less likely to improve using GES.  Pyloroplasty and gastrectomy (partial or complete) have been trialed in some patients, but there is not a clear trend in the data.

Acupuncture has been shown to benefit gastroparesis patients in a number of studies, including one blinded, randomized study. Symptom severity was improved in those receiving acupuncture and gastric emptying time was decreased.  Autogenic retraining using the program developed by NASA for space motion sickness has shown some benefit.  Autogenic retraining was found to be more successful in patients with intact autonomic function.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

All the favors in pharmacy land

For most of my adult life, I have had the feeling that I didn’t have any money. I worked full time in college, and two full time jobs in grad school. I worked full time for a biotech company after I graduated, while also working side jobs. I certainly worked a lot for not having money.

At some point, I sat down and went through all my finances in detail. I looked at years of bank statements, credit card statements and student loan agreements. I tallied how much I spent on gas, on car repairs, on food, on fun. But none of those were the issue. I had one expense that was more than all of those put together: medical bills.

I literally just sighed as I typed that sentence. And you know what? I bet all the sick kids reading this sighed along with me. I don’t even get mad about it anymore. I am just resigned. Sigh.

I accepted a temporary position at my current company about two years ago. After six months as a contractor, I accepted a full time position. My contractor insurance was garbage and I needed comprehensive coverage badly. I eagerly flipped through the insurance information packets, basking in the golden glow of great medical coverage. It was overwhelming and wonderful. It was also a little sad that I was barely 30 years old and so excited about copayments and yearly out-of-pocket maximum costs that only had three zeros at the end.

I signed up for PPO insurance, which for our non-American readers means I can pick which doctors I see without being referred by my primary care physician (PCP, usually called general practitioner in other countries). There are caveats to PPO plans, but it is overall less restrictive and therefore desirable for me, as I often need specialist appointments on short notice.

In the US, it is not unusual for your medical insurance (doctor visits, hospital stays, medical supplies) to be managed by a different and completely separate company from your prescription coverage. So when I picked my PPO insurance, I also had to pick a large prescription carrier that forced upon the unwitting masses the bane of my existence: mail-order prescriptions.

I worked in pharmacy for about ten years. In that time, prescription insurance companies directly caused most of the issues that made my job frustrating and difficult. The prescription carrier I got along with my (amazing, approves everything) PPO is well known for rejecting claims for stupid reasons. But I needed a PPO and this was the corresponding prescription insurance. I didn’t have a choice.

So I got my new prescription insurance card and used it to fill my monthly medications at my local pharmacy. That went okay for a couple of months. Then I got a notification that my insurance would only pay for three fills of a maintenance medication (one that is taken all the time as part of your baseline care). Any fills after that would have to be filled with a mail order pharmacy.

Because I need a million strange things, I called my health insurance case manager. She sympathized but had nothing to do with pharmacy benefits. I told her that I had called the prescription company and asked for a case manager. They wouldn’t give me one. She couldn’t do anything.

The mail order pharmacy got new prescriptions for my meds from my doctors. They filled them and shipped them out to me. I opened the first huge box of meds and immediately knew something was wrong. I take ondansetron (zofran) 8mg three times a day every day. I have done this for years. I have tried to decrease and it always goes very badly. I have a prior authorization done every year to approve for 270 tablets/90 days for four total fills to coverage three a day dosing for the entire year. The pharmacy received a prescription that said that.

Except the person filling the prescription looked at it and thought, nobody takes three of these a day every day. Surely this is a mistake! And bless their hearts, they did me the huge favor of correcting that prescription from 270 with 3 refills to 27 with 30 refills. That’s much better.

So I had nine days of zofran. I called them and told them what happened. I was on the phone for two hours. They told me it was all set and they were sending the rest. Three days later, a package arrived. It had one bottle of 27 ondansetron.

I’m not going to bore you with the sordid details because I bet you all know where this is going. You know, right? Yup. Nine phone calls and every single one of them went exactly the same way except by the ninth, I was crying in frustration. I was out of my medication and every time I called, they told me it was all set and they fixed the error. And then nine more tablets would show up and we would start all over again.

This is a repeating cycle. The mail-order pharmacy is forever filling my 270 tablet (insurance approval obtained) prescription for 27 tablets.

So, mail order pharmacies are difficult. I don’t think that is surprising anyone here. But at the same time as this was going on in what I assume was a distant state where everyone is brainwashed to reassure me that they are fixing my problem right before they throw my precious bottles of ondansetron into a bottomless pit, I started having some problems closer to home.

I still got some prescriptions filled at my local pharmacy (this is entirely at the discretion of the pharmacy insurance.) There were only three I got filled locally regularly – prednisone, fluticasone nasal spray, and Epipens. Last October, I was counting out my prednisone 1mg tablets to put into my pill organizer when I realized there were a bunch of 5mg tablets mixed in with the 1mg tablets. I had been sick for three weeks and wondering why I felt decent one day and miserable the next. That would be because I was dispensed two strengths of a medication for which 1mg differences matter a lot. So that sucked. I called the pharmacist and she apologized and filled my script with 1mg tablets instead of both and I got on with my life. I understand that mistakes get made sometimes. It’s fine.

Then in December, this same pharmacy lost a prescription from my PCP. In May, they lost a prescription for prednisone for premedication before surgery. I had called the previous week to make sure it was there and sent my mother to pick it up on the Monday before my Wednesday surgery. It was gone. So that was quite a circus getting that straightened out the day before major surgery. The district pharmacy supervisor called me and we had a long conversation about my weird diseases and surgery and she apologized and I needed to go have surgery so I just let it go.

Two weeks ago, I called to get my Epipens filled. I had a new prescription that was on file from March. Guess what, guys? GUESS WHAT. That prescription was gone, too.

At this point, I just hung up the phone because I was about to start screaming. I called the district pharmacy supervisor on Monday and she went by the pharmacy to pull the original prescription book from the day it was sent over in March. It was there. It was filled, returned to stock and never put on hold. This was three prescriptions, all from different offices, in under a year, with a dispensing error right off the top.

While I was dealing with the Epipen situation, I ordered refills for all of my mail order meds and GUESS HOW MANY ONDANSETRON CAME IN MY ORDER. JUST. GUESS.

I called the poor nurse at my PCP’s office who does all my prior authorizations and I literally sobbed over how sick I was of fighting for things like meds to not vomit up everything I eat. This woman is a saint and she tag teams my insurance company with me to get things taken care of. To demonstrate my gratitude, I hereby bestow upon her the internet moniker of Nurse Amazing.

In the last two weeks, Nurse Amazing and I made over a dozen phone calls between us and had the same conversation over a dozen times. After one particularly hopeless day, she asked if my IV meds were covered under my medical benefit. They are. “If we have to, maybe we can just call in enough IV Zofran to get you through.” HOW DO I LIVE IN A WORLD WHERE IT IS EASIER TO GET IV MEDS THAN NON-CONTROL SUBSTANCE TABLETS WITH NO POTENTIAL FOR ABUSE? HOW IS THE WORLD LIKE THIS?

The Universe cut me a break this time. I finally got the rest of my ondansetron delivered Saturday.

While Nurse Amazing was on the phone with my insurance, she noticed my Enbrel prescription was about to expire so she gave them a new one over the phone. “She hasn’t taken this since last year,” the agent told the nurse so apparently they are also throwing away any record of my monthly order for this (refrigerated, requires signature and scheduled delivery) medication. My Enbrel arrived expediently with no paperwork of any kind. Just a labelled box of prefilled syringes, an ice pack and nothing else.

I just went to pick up my Epipens. The pharmacist did not apologize and did not look the least bit like she gave a shit that I have spent over 65 hours in the last three weeks trying to fill my medications at SIX pharmacies as required by insurance (for those keeping score: retail pharmacy, mail order pharmacy, specialty mail order pharmacy for Enbrel, a second retail pharmacy that stocks one of my harder to source meds, compounding pharmacy for ketotifen, IV pharmacy for IV push meds/infusions). And you know what? It’s one thing to make consecutive mistakes, and it’s another thing to make consecutive mistakes and act like I am an asshole for expecting my medications to be filled and tracked correctly.

“This copay is high but I can only charge you half because of what happened,” she said. Where ‘what happened’ meant they lost the prescription for my lifesaving epinephrine autoinjectors.

“I would appreciate it if you would waive the copay in light of all the time spent getting this straightened out,” I said in my most exhausted voice both because I am so exhausted and also because it was either exhaustion or screaming vulgarities.

“Fine,” she said. You know that voice people use when they think they’re doing you a favor, like they’re giving you something that you shouldn’t expect? It was that voice. “Fine.” In that voice. I signed, took my Epipens and left.

On my way home, I remembered that I got shorted needles by my IV pharmacy (which has never made a mistake with my meds or supplies.) I stopped by the other pharmacy in walking distance because I just did not want to go back to the one where the pharmacist was doing me favors.

In Massachusetts, you can buy syringes without a prescription if you’re over 18. I walked up to the counter with my license out and prepared myself for the inevitable condescension that usually accompanies buying syringes without a prescription.

The technician came right over. “I need twenty syringes, inch long needle, any gauge you want,” I said.

“Okay,” she said, smiling. “Any specific volume?”

“It doesn’t really matter. My infusion pharmacy just didn’t send me enough for this week.”

“Well, that’s not okay,” she said and you know what? SHE ACTUALLY MEANT IT. “I’ll bring over a few and you can pick.”

She brought over a few types and I picked the one I wanted and she rang me out.

As a demonstration of my appreciation for her smile and sympathy, she shall hereafter be known as Technician Amazing throughout all the lands. I have a dream that one day she will be successively promoted to the position of Supreme Pharmacy Ruler and she will decree that it shall be illegal to provide any less than 270 tablets of ondansetron when the prescription says 270 tablets of ondansetron.

Probably won’t happen like that. But it’s okay to dream.

Mast cell medications: Everything but antihistamines

The following medications listed are available in oral, intramuscular or intravenous formulation. Not all medications are available in the US or Europe. Topical and inhaled medications are not included in these lists.

Mast cell stabilizers interfere structures on the cell membrane required for degranulation and thus prevent the release of granule contents, including histamine.

Mast cell stabilizers
Cromolyn sodium/ Cromoglicic acid/ Nedocromil
Ketotifen
Omalizumab*
Quercetin
*mechanism unclear

 

Beta-2 adrenergic agonists cause smooth muscles to relax, which allow airways to open. These are used almost exclusively in asthma and pulmonary disease, which a secondary use in controlling uterine contractions in labor.

Beta-2 adrenergic agonists
Albuterol
Terbutaline

 

Leukotriene receptor antagonists work by interfering with the function of leukotrienes by blocking the CysLT1 receptor. Leukotrienes are heavily involved in airway reactivity and inflammation.

Leukotriene receptor antagonists
Montelukast
Pranlukast
Zafirlukast

 

5-lipoxygenase inhibitors prevent leukotrienes from being made.

5-lipoxygenase inhibitor
Curcumin
St. John’s Wort
Zileuton

 

Corticosteroids interfere with the activity of mast cells and production of mast cell mediators.

Mast cell stabilizers
Budesonide*
Dexamethasone
Hydrocortisone
Prednisone
Prednisolone
*taken orally, with effects local to the GI tract

 

Proton pump inhibitors reduce the production of gastric acid and treat heartburn, nausea and reflux. This can also be achieved by H2 antihistamines and for this reason, the two classes are often confused. The following medications, which are taken often by mast cell patients, have no known antihistamine effect. They can safely be taken with H2 antihistamines and help many mast cell patients, but it is important to clarify that they are NOT antihistamines.

Proton pump inhibitors
Dexlansoprazole
Esomeprazole
Ilaprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole

Mast cell medications: Antihistamines by receptor activity

The following medications listed are available in oral or intravenous formulation. Not all medications are available in the US or Europe. Topical and inhaled medications are not included in these lists.

H1 antihistamines interfere with the action of histamine at the H1 receptor. This can help with many symptoms, including flushing, itching, hives, burning skin, nasal congestion, sneezing, constriction of airway, shortness of breath, GI cramping, diarrhea, gas, abdominal pain, tachycardia, blood pressure variability or dizziness. What symptoms are best alleviated varies with the medication; they do not all address all symptoms equally.

First generation Second and third generation Atypical antipsychotics
Alimemazine Acrivastine Aripiprazole
Azatadine Astemizole Asenapine
Benztropine Azelastine Clozapine
Bepotastine Bepotastine Iloperidone
Brompheniramine Bilastine Olanzapine
Buclizine Cetirizine Paliperidone
Captodiame Clemastine Quetiapine
Carbinoxamine Clemizole Risperdone
Chlorcyclizine Clobenztropine Ziprasidone
Chloropyramine Desloratadine Zotepine
Chlorpheniramine Ebastine
Chlorphenoxamine Emedastine
Cinnarizine Epinastine Typical antipsychotics
Clemastine Fexofenadine Chlorpromazine
Cyclizine Ketotifen Flupenthixol
Cyproheptadine Latrepirdine Fluphenazine
Dexbrompheniramine Levocabastine Perphenazine
Dexchlorpheniramine Levocetirizine Prochlorperazine
Dimenhydrinate Loratadine Thioridazine
Diphenhydramine Mebhydrolin Thiothixene
Diphenylpyraline Mizolastine
Doxylamine Rupatadine
Embramine Setastine Tetracyclic antidepressants
Etodroxizine Talastine Amoxapine
Ethylbenztropine Terfenadine Loxapine
Etymemazine Maprotiline
Flunarizine Mianserin
Histapyrrodine Tricyclic antidepressants Mirtazapine
Homochlorcyclizine Amitriptyline Oxaprotiline
Hydroxyethylpromethazine Butriptyline
Hydroxyzine Clomipramine
Isopromethazine Desipramine
Meclizine Dosulepin
Mequitazine Doxepin
Methdilazine Imipramine
Moxastine Iprindole
Orphenadrine Lofepramine
Oxatomide Nortriptyline
Oxomemazine Proptriptyline
Phenindamine Trimipramine
Pheniramine
Phenyltoloxamine
Pimethixene
Prometheazine
Propiomazine
Talastine
Thonzylamine
Tolpropamine
Tripelennamine
Triprolidine

 

H2 antihistamines interfere with the action of histamine at the H2 receptor. This helps mostly with symptoms affecting the GI tract, such as abdominal pain, nausea, and diarrhea. To a lesser extent, H2 antihistamines can decrease vasodilation.

H2 antagonists
Cimetidine
Famotidine
Lafutidine
Nizatidine
Ranitidine
Roxatidine

 

There are few H3 antihistamines and for this reason, their exact effects are largely unknown.  However, in research, H3 antihistamines modulate nerve pain and may normalize the release of several neurotransmitters, including serotonin.

The only medication with known H3 activity available for patient use as an antihistamine anywhere in the world is betahistine. It is anti-vertigo drug used mostly in treatment of Meniere’s disease and other balance disorders. Betahistine actually increases release of histamine and for this reason has been associated with the risk of severe allergic events while taking it.

A 2014 paper described for the first time the H3 reverse agonist/ selective antagonist effects of two antiarrhythmic drugs, amiodarone and lorcainide. This is a very new finding and has not been investigated yet in humans; however, this behavior would explain some of the neurologic effects of these two medications.

H3 antihistamines
Amiodarone*
Betahistine
Lorcainide*

 

Thioperamide has shown promise in research as an H3 and H4 antihistamine, but is not available for patient use.

I have seen blurbs on forums and the internet in which people state that amphetamines are H3 antagonists and doxepin is an H4 antihistamine. I cannot find any evidence that this is the case. Amphetamines interact with the transport of histamine in a very complex way, and that can theoretically interfere with the ability of cells to use histamine. However, this is not the same as a true antihistamine, and the effect of amphetamines on histamine has been difficult to quantify.