Expert: William J. Walker, Pharm.D. - 2/2/2005

Question
Dosage: Nexium, 40 mg. daily.  After starting Nexium in March of 2004 on a daily basis, I have developed constant esophageal pain and also angios.

Diagnosis: GERD and a hiatal hernia.  Tests have been endoscopy, Upper GI, CT scan with an IV contrast and last test was a Bravo to measure acid.  

Vitamins:  Strict organic food diet plus enzymes to assist in digesting my food as I have few or no enzymes.  Also, I take numerous other vitamins from Perque and Standard Process.   

I am desperately searching for an answer as I am
otherwise very healthy.  

Thank you.

Answer
If I am astute enough to deduce that your question here is to determine whether or not it is your esomeprazole that is causing your esophageal pain then it is important to ask you a couple of questions regarding your stated history.

What do you mean by angios?    Do you mean to say that you developed esophageal varices?    Or blood vessels that are enlarged,  weakened,  and potentially bleeding?

How do you know that you have little or no enzymes?   Was that diagnosed?    How?   And by whom?

For the meantime I will attempt to define the adverse outcome profile of this (and similar) agent.

In general, esomeprazole has been well-tolerated in clinical trials (n > 10,000). Greater than 2900 patients have been evaluated in 6—12 month long studies. The types of adverse events are similar with short or long-term use, and have been comparable to placebo rates. The safety profile of esomeprazole is similar to omeprazole.

The most frequently (>=1%) reported adverse events with esomeprazole use were gastrointestinal (GI) in nature, including abdominal pain (3.8%), constipation, diarrhea (4.3%), flatulence (1.8%), nausea/vomiting (3.8%), and xerostomia (dry mouth). Other notable GI events that occurred in < 1% of patients, but were judged by investigators to be possibly or probably related to esomeprazole include: anorexia, bowel irregularity, dyspepsia, dysphagia, eructation, esophageal disorder, GI hemorrhage, melena, tongue edema, and ulcerative stomatitis.

Headache occurred in up to 5.5% of patients using esomeprazole. Other notable, but rare (< 1%) central nervous system adverse events possibly or probably related to esomeprazole include: confusion, depression, dizziness, nervousness, insomnia, and migraine.

Post-marketing spontaneous reports have included anaphylactic shock or anaphylactoid reactions. Hypersensitivity reactions occurring in < 1% of patients judged by investigators during pre-approval trials as possibly or probably related to esomeprazole included: angioedema, dermatitis, pruritus, rash (unspecified), maculopapular rash, and urticaria. Rare cases of severe generalized skin reactions including toxic epidermal necrolysis (TEN) (some fatal), Stevens-Johnson syndrome and erythema multiforme have occurred. Exfoliative dermatitis has been reported with omeprazole, and could potentially occur with esomeprazole based on the similarity in dermatological reactions reported to date.

Elevated hepatic enzymes (ALT, AST and alkaline phosphatase) and hyperbilirubinemia have been rarely (< 1%) reported, both with esomeprazole and omeprazole. Overt liver disease (some cases fatal) has been reported with omeprazole, but not esomeprazole. Pancreatitis has also been reported in post-marketing experience.

Rare cardiovascular system adverse reactions with esomeprazole include chest pain, flushing, hypertension, and tachycardia. A reduction in potassium levels was noted in <= 1% of patients, but an association with hypokalemia was not made.

As with omeprazole, rare hematologic abnormalities have been reported with esomeprazole including anemia, leukocytosis, leukopenia, and thrombocytopenia. In a study of healthy volunteers, it was shown that omeprazole caused a significant reduction in cyanocobalamin absorption (vitamin B12 deficiency). Although clinical data in esomeprazole is lacking, it may be prudent to monitor patients for signs of pernicious anemia. Neurological manifestations of pernicious anemia can occur in the absence of hematologic changes.

Animal and human data have demonstrated a proliferation of enterochromaffin-like cells due to hypergastrinemia, which may be associated with the development of malignant gastric carcinoma during long-term administration of proton pump inhibitors (PPIs). In over 1,000 patients treated with esomeprazole for up to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose, but no patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa. In esomeprazole clinical trials, there were dose-related increases in mean fasting gastrin levels which reached plateaus at 2 to 3 months and returned to baseline 4 weeks after drug discontinuation. According the the manufacturer of esomeprazole, < 1% of patients were reported to have hypergastrinemia or GI dysplasia. Historically, omeprazole has been given for as long as 5 years without concern for the development of gastric neoplasia. The overall risk of carcinoid tumors during therapy with PPIs is low based on cumulative safety experience; monitoring of serum gastrin levels during PPI therapy is generally not necessary.

As you can see there are very rare reports of gastrointestinal complaints that have been associated with proton pump inhibitors including esophageal problems and vascular diatheses.   These problems,  as evaluated by investigators,   were felt to be caused by the drug but that causality was never subjected to rigorous statistical analysis.    What remains as a diagnostic challenge is to separate out events and/or symptoms that are a direct result of the disease and those that are resulting from the treatment itself.    GERD and erosive esophagitis are the obvious sources of most complaints of esophageal pain.   Varices and upper GI bleeding are also directly associated with the same conditions.   Hiatal hernia is included of course.    Typically a practitioner's sleuthing skills enable some clinical guesswork to stand up well to scientific method.   So that timing of events tell more of the nature of the issue in question.   If your symptoms,  for instance,  did not occur until after drug treatment was started and simultaneous to the diagnostic proof of problem resolution then it is highly suggestive that the drug is the cause.  In other words,  if your original complaint had been medically cleared up and resolved by virtue of drug therapy only to develop into the current problem later it is probably the case.   Otherwise I would have to say that it would be difficult at best to rule out a progression of your hiatal hernia condition.   At the very least your present complaints warrant further diagnostic investigation.   I cannot tell by your statement whether the vast battery of tests you were subjected to took place before or after you developed this pain.   Either way it is important to have the matter fully investigated.

I do know that taking PPI agents with too little water can result in the dose lodging in the esophagus.   Especially the capsular forms.   The gelatin adheres to the lining and the capsule then dissolves directly in the esophagus.   This can result in pain and irritation.

Finally,   it cannot be totally ruled out that your plethora of vitamins and supplements are causing this problem.   Between the potential for individual products and/or constituents to cause GI side effects and the potential for a raise in gastric pH to result in drug interactions there is much to consider there.   Not to mention the effect that all of these things have on your primary condition of hiatal hernia.

In terms of my own opinion I would lean more towards the notion that your hiatal hernia has not responded well to the treatment.   Either from a lack of response or an inadequate dosage.   As many as 50% have failed on PPI in non-erosive type reflux disease.   Some of these require dosing two to four times a day.

In patients with atypical/extra-esophageal manifestations of GERD, PPIs have improved the rate of symptom resolution. However, even in responders there is still a need for at least double dose PPI to control patients' symptoms. Additionally, duration of treatment with PPIs in these patients may require three to six months to demonstrate symptom improvement. Furthermore, a subset of patients with atypical/extra-esophageal manifestations of GERD demonstrates the need for a very high dose of PPIs for symptom control.

I would consider discussing this in great detail with your physician.   Present all of the possibilities and then request his/her opinion.    Some options here would be to increase your dosage,   change to another PPI,   add another agent (H2 antagonist, sucralfate),  or perhaps even surgery to repair the hiatal hernia.   Of course if this does in fact turn out to be a drug induced problem then it would be wise to stay away from all PPIs.   It is therefore prudent that you have this thoroughly worked up.