Rebound Acid Reflux with PPIs May Induce Dependence

Popular antacids known as proton pump inhibitors, or PPIs, may cause or aggravate the very acid-reflux symptoms they're used to treat, according to a new study.

After two months of taking esomeprazole (Nexium), 44 percent of healthy volunteers who started with no symptoms developed significant heartburn, acid reflux or dyspepsia, compared with 15 percent who took a harmless placebo, the scientists reported in the July issue of Gastroenterology.

Worse, this apparent "rebound" acid secretion could lead to dependence on the drugs, according to the research team led by Dr. Peter Bytzer of Copenhagen University in Denmark.

PPIs are among the most commonly prescribed drugs worldwide, with doctors in the United States writing 113.4 million prescriptions for the drugs last year, according to the health care information company IMS Health. The class includes drugs such as Prilosec, Nexium and Prevacid.

Many primary care doctors put patients with symptoms of chronic heartburn on a trial course of a PPI, a class of drugs that includes such well-known trade names as Prevacid, Aciphex and Prilosec, in addition to Nexium.

However, the researchers noted that up to one-third of these patients keep taking the drug after the symptoms are gone. Physicians in some studies have reported problems getting patients to withdraw from the drug or reduce the dosage they take.

"Thus, patients with ambiguous symptoms that are not truly acid related may be prescribed a PPI empirically, but may find it difficult to withdraw from therapy because of the development of true acid-related symptoms," the researchers said.

The hypothesis, though controversial, has been that PPIs perpetuate symptoms and necessitate their continued long-term use.

The theory behind this is that lowered stomach acid levels caused by the action of the drugs causes the body to compensate by secreting even more acid into the stomach, the researchers said.

Bytzer's results supported this theory. Symptoms in the PPI group continued, even in the final week of the study, after gastric acid suppression had normalized.

Steps to Limit Antacid Dependency

In an accompanying editorial, Dr. Kenneth McColl and Dr. Derek Gillen of the University of Glasgow in Scotland said the findings should challenge current "liberal" prescribing habits.

Among their recommendations:

Restrict PPI use to patients who are most likely to benefit from them, such as those with symptoms accompanied by endoscopic evidence of acid damage.

Limit the PPI trial period to one or two weeks to reduce the chance of inducing hyperacidity and associated symptoms.

Adopt a "step-up" approach rather than "step-down" from medications to lifestyle alterations and milder medications such as antacids or alginates.

Inform patients about rebound acid hypersecretion and its potential effects as part of the discussion about side effects and safety.

To prove that the "acid rebound" symptoms were not simply a relapse of symptoms from underlying disease, Dr. Bytzer's group conducted a double-blind, placebo-controlled trial in 120 healthy volunteers without any prior acid-related disease, symptoms, or treatment.

These participants were randomly selected to receive either 12 weeks of placebo pills or eight weeks of the PPI esomeprazole followed by four weeks of placebo.

None of the symptoms reported on the Gastrointestinal Symptom Rating Scale questionnaire patients filled out each week was different between groups through week eight.

But after the PPI group discontinued therapy in week nine, their dyspepsia and reflux syndrome scores on the gastrointestinal-specific scale climbed in comparison with the placebo group.

For weeks nine through 12, the esomeprazole group reported more of the form of indigestion known as dyspepsia, as well as acid reflux. The typically mild to moderately severe reflux symptoms showed up within the first two weeks after discontinuation of esomeprazole for the majority of patients.

PPI dependency May Dog Some Patients

The researchers acknowledged that the symptoms seen in these healthy individuals could differ from those in symptomatic patients.

"On the other hand, rebound acid hypersecretion could be even more relevant in patients with reflux disease or other acid-related disorders," they said, if those patients find it difficult to quit PPIs because of rapid recurrence of symptoms aggravated or even provoked by rebound acid hypersecretion.
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Life Without Vicodin Will Be OK, Doctors Say

For 22-year-old Jacob Rosenberg, life without his daily dose of Vicodin wouldn't be much of a life at all.


"Before I began taking narcotics two years ago, I would spend my days in bed," said Rosenberg, who has suffered from fibromyalgia and rheumatoid arthritis for five years, and chronic pain for 10. "I was in college and I wasn't capable of doing anything – go to classes or go out."

"But since I've been on Vicodin my pain is 80 percent diminished," said Rosenberg. "It gives me the ability to be a normal person."

Rosenberg is one of millions of Americans who fill prescriptions each year for an acetaminophen-based narcotic – or combination drugs – such as Vicodin or Percocet, the two most popularly prescribed drugs in the country.


But patients like Rosenberg are worried that the solution to their pain may soon be unavailable to them after an expert advisory panel for the U.S. Food and Drug Administration voted earlier this week to ban combination drugs.

The panel's vote came after days of deliberation over ways to reduce the liver damage risk associated with acetaminophens. The panel also voted to keep over-the-counter combination pills containing acetaminophen on the shelves and lower the maximum dosage of these pills.

The panel voted 36 to 1 to recommend a "black box" warning for prescription medications that combine acetaminophen with another drug.

"It's completely unfair to take these drugs away from us," said Rosenberg. "Without them you can't act like a normal person."

Experts Say Hope Is Not Lost Without Combination Drugs

But medical professionals disagree, and say that those suffering from chronic pain will not be left without medication should the FDA decide to heed the advice of the panel.

"There are a lot more drugs out there than are being used," said Dr. Charles Kim, a pain management specialist at Mount Sinai School of Medicine in New York.

"I would tell patients who are panicking over [this vote] to relax, it doesn't mean they're going to take pain medication off the market completely but just that they're thinking about changing certain prescribing patterns to increase safety," said Kim.

More FDA regulation on prescription combination agents as well as more labeling of over-the-counter acetaminophens could help reduce the number of unintended overdoses, according to Dr. Eugene Viscusi, the director of pain management at Thomas Jefferson University in Philadelphia.

Because nearly 42,000 people visit emergency departments each year with acetaminophen overdoses, half of which are accidental, eliminating drugs that aren't clearly labeled to have acetaminophen in them could decrease this number significantly, said Viscusi.

"The problem is not just with prescription narcotics," said Viscusi, "It's their use in combination with over-the-counter drugs."

Eliminating combination drugs would result in patients being able to treat their pain with two different pills, rather than just one. While some may see this as an inconvenience, Viscusi said he's hopeful it might lead to increased awareness about what patients are actually ingesting.

"This would be the best thing," said Viscusi. "If you're taking the acetaminophen separately from your opioid then you know exactly what you're taking."

And as for patients who say nothing else will ease their pain but the acetaminophen-based narcotics, Viscusi says there are other drugs that can help them.

"There will be other drugs, it just may require a little adjustment in thinking for those doctors who consistently prescribe Vicodin and Percocet," said Viscusi.

Other Drug Alternatives

Percocet, for example, could be given to patients by prescribing them Oxycodone – which does not include acetaminophen – and then instructing the consumer to take Tylenol as well.

Still, Viscusi is advocating for better labeling on over-the-counter drugs in addition the ban of combination agents as well as more education for consumers and medical professionals alike.

Kim agrees with Viscusi and said that with more training and education, doctors will realize the Vicodin and Percocet are not the only options for pain management.

"Many doctors don't readily have the experience or knowledge of prescribing other agents that either reduce the amount of acetaminophen or take it out completely, such as Norco, Roxicodone, OxyIR, OxyFast or hydromorphone," said Kim.

"These can be safely and effectively used on patients with quality of life-dependent needs who many not be candidates for the acetaminophen, yet need the adequate pain relief to function in their daily lives," he added.

But those who would likely be directly affected by an FDA ban on combination drugs – patients of chronic pain – are still worried.

"This will hurt a huge amount of people who look to those medications to help manage the pain so they can be a productive part of society," said Penney Cowan, the executive director of The American Chronic Pain Association, who has been suffering from chronic pain herself for more than 30 years.

"It will narrow the field even more when it comes to treatment for pain," said Cowan. "There is going to be a point where there just won't be any other options."

"The problem with pain is that we don't see it, and we can't measure it," said Cowan. "People don't understand just how much pain we are in."
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FDA Approves Drug for Dogs' Cancer

Having raised and bred show dogs, Lisa Peterson knew there was something wrong with her 9-year-old Norwegian elkhound Basia when she put her up on the table to groom her -- and noticed something unusual in the dog's mammary chain.

"It was a lump that was getting bigger; it was suspicious," she said.

Peterson took Basia to her veterinarian, who scheduled exploratory surgery. But on the day of the operation, it was already too late. Basia had cancer, and the tumor was already too big to be operated on. And she had to be put down.

Peterson's experience is not unusual when it comes to a type of tumor known as canine cutaneous mast cell tumors, which account for roughly one-fifth of all skin tumors in dogs. And they often are deadly.

But now a new drug -- the first to be approved by the U.S. Food and Drug Administration to treat cancer in dogs -- may soon change that outcome for some pet owners.

Palladia, manufactured by Pfizer Animal Health, has elicited optimism from veterinarians and pet owners alike.

"It is a real breakthrough for a cancer drug to be made specifically for animals," said Lawrence McGill, a veterinary pathologist at ARUP Laboratories in Salt Lake City, Utah.

"Hopefully, this is the start of many products coming forward so that we can help pets with cancer. I strongly suspect that veterinary medicine will continue to utilize human anti-cancer drugs where appropriate, but new drugs directed towards improving the health and welfare of dogs, cats and other pets will be greatly utilized and appreciated," he said.

Dog Cancer Drug Shows Attitude Shift

The fast-growing nature of canine cutaneous mast cell tumors makes them particularly dangerous, veterinary experts say.

"Unfortunately, this tumor can double in size overnight," said Gregory K. Ogilvie, a veterinary oncologist in Southern California.

This type of cancer can be lethal for other reasons as well.

"The tumor is unlike any other in that it releases chemicals in the bloodstream that can cause swelling, inflammation, bruising bleeding, stomach ulcers and therefore anemia and significant abdominal pain," Ogilvie said.

For these reasons, many owners view the new option as a godsend. Peterson noted that the approval of the drug shows "companies catering to consumers' needs to care for their pets at a high level," as well as a shift in many people's attitudes toward dogs.

"I think it shows that in our culture, dogs are really considered valued family members," said Peterson.

Assuming pet insurance will cover the cost of the drug, Peterson said, "It's going to be win-win for the pet owner who needs to care for their animal should they get cancer."

Insurance and cost remain a concern, but it is too soon to tell whether it should be.

Ogilvie said he and other veterinarians spoke with Pfizer officials who were trying to determine a fair price for the drug.

"From the veterinary community, the hope is it will be affordable for the average client for many months, if not years of therapy, and the company has assured us that it will be," he said.

Rick Goulart, a spokesman for Pfizer Animal Health, confirmed that a price has not been set. He said that the drug was currently available, but only through veterinary oncologists, who are attempting to figure out the best protocol for administering the drug. Because of this testing, the drug is provided to the oncologists without cost.

"The drug is made available to this specialist, who through the end of the year will be able to advance their experience with it," he said. "Veterinarians who now have access to the product are gaining experience with Palladia as they determine what protocols are right for bringing a pet owner in to get [a dog] treated for mast cell tumors."

Palladia will be available for sale through veterinarians in 2010.

Optimism For The Future

Like other cancer drugs, Palladia has unpleasant side effects that can include impaired mobility, diarrhea, loss of appetite and weight loss. However, it differs from many conventional cancer therapies in pets.

"This is a therapy that has capitalized on decades of basic research to understand how cancer survives thin the body and how to beat it," said Ogilvie.

The drug attacks the tumors' communications systems and ability to spread through the body.

Perhaps its most important for pet owners is that it is an oral medication that can be administered at home.

"Most cancer therapies have to be administered by a high-technology system and oftentimes in the hospital," said Ogilvie. "This oral therapy removes our patients from the clinic and places them on the couch with their families and therefore allows their families to provide this therapy ... in [a] loving environment.

"It really adds the personal touch that our clients can provide in their home along with the greatest advancement in molecular therapeutics and veterinary medicine."
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Did the Drugs Make Him Do It? The Zoloft Defense

It all began with the Prozac defense. Then came the Ambien defense. And now the Zoloft defense.

The side effects of certain psychoactive drugs have for years emerged in court cases as the supposed hidden culprits in various crimes, from vehicular homicide to physical assault.

Now, the most recent example of this legal move is being played out in the First District Court in Hempstead in Long Island, N.Y.

According to court documents, 38-year-old Brandon Hampson of Lynbrook, N.Y., is charged with assault against his then-girlfriend, Lisa Essling, 28, of Amlverne, N.Y. on Aug. 25, 2006. Police claim that Hampson tackled Essling to the ground before punching and kicking her in her head, face and back. Hampson is charged with third-degree assault, a misdemeanor crime. The charge is accompanied by four other counts that suggest violent behavior from Hampson.

Eric Bernstein, who is defending Hampson in the case, said that he believes the fact that his client had been taking the anti-depression drug Zoloft, but had been off the medication prior to the incident, strongly suggests that withdrawal from the antidepressant could explain his behavior.

"Our defense is that ... withdrawal from the drug was a contributing factor -- if not directly responsible -- for the event," Bernstein said. "Clearly this is not a joke or gimmick-type defense. This is very serious, very legitimate and is going to get a lot of traction. You're going to be seeing more of this, because it's real."

There are signs that the defense could face an uphill battle. Hampson was convicted of assault against a former girlfriend in 1995; Bernstein would not comment on whether he was taking Zoloft at or near the time of that episode.

Eric Phillips, the prosecuting attorney in the case, said no evidence exists to suggest that Hampson had been taking Zoloft at or near the time of the 1995 assault -- which, if true, could affect how a jury perceives the likelihood that side effects from the drug could be involved in the more recent incident.

Zoloft Data Shows No Increased Violence Risk, Company Says

"We are confident in our prosecution of the defendant in that we will -- and the victim will -- prevail in our case," Phillips said.

Meanwhile, Pfizer, the manufacturer of Zoloft, said in a statement Wednesday that no evidence exists to suggest that their drug would have violence-inducing side effects that could lead to such an episode.

"Zoloft is a safe and effective medication that has been used to treat millions of patients with depression and anxiety disorders," the statement reads. "We continuously monitor the postmarketing safety of our medicines and evaluate all available data to ascertain any signal of increased risk.

"Pfizer's evaluation of Zoloft data never has revealed any signal of an increased risk of violence related to either use or discontinuation of use (withdrawal) of Zoloft."

The case is not the first to throw the popular antidepressant into the legal limelight. One high-profile South Carolina case in February 2005 focused on a teenager who was found guilty of shooting his grandparents to death when he was 12 years old and was subsequently sentenced to 30 years in prison.

In one January 2004 case, defense attorneys argued that in 2002, 27-year-old Christopher Bernaiche of Southgate, Mich., was acting under the influence of Prozac when he got into a fight at a bar -- and then returned with a gun, killing two and injuring three others.

And while it is not an antidepressant like Zoloft or Prozac, Ambien has also entered the realm of the legal system as a defense against reckless driving charges. The drug made national headlines on May 5, 2006, when Rhode Island Rep. Patrick Kennedy smashed his Ford Mustang into a barrier near Capitol Hill. He later released a statement saying that he had been disoriented by two prescription medications he had taken, one of which was Ambien.

As for the so-called Zoloft defense, "There are a lot of cases that have attempted this before," Bernstein said -- though he added that such cases have often been complicated by a jury's unwillingness to accept the argument that violent behavior could be explained away by the effects of a drug.

Questions Surround Antidepressant Side Effects

Yet, there have been instances in the past where such arguments with regard to the class of antidepressants known as selective serotonin reuptake inhibitors, or SSRIs, have been successful. In February 2000, 28-year-old Christopher DeAngelo was acquitted of a bank robbery charge by a Connecticut judge on the grounds that DeAngelo's judgment was impaired by the antidepressant Prozac and the anxiety medication Xanax.

Whether such a defense is scientifically feasible is still a matter of debate in the medical community. While the U.S. Food and Drug Administration has made additions to labeling on SSRIs to warn of the possibility of suicidal behaviors in children using the drugs, they have not included warnings with regard to other behavioral tendencies, such as aggression.

Bernstein argued that Health Canada -- the Canadian counterpart to the FDA -- since May 2004 has required labeling for SSRIs to warn both adults and children of "severe agitation-type adverse events coupled with self-harm or harm to others" including "hostility" and "aggression."

Dr. Stefan Kruszewski, a Harrisburg, Pa., psychiatrist and expert witness for the defense, said he could only speak generally about SSRIs and not about the Hampson case specifically.

"In a case-by-case basis, all you can do is look at the evidence," he said.

But he said that biologically speaking, the idea that antidepressants could result in unwanted behavioral changes, including violence, is definitely plausible.

"To say that these drugs are incapable of inducing violence is just silly to me," he said.

Dr. John Abramson, clinical instructor at Harvard Medical School in Boston and author of "Overdosed America," agreed.

"Whether or not in this particular case this woman was harmed as a result of side effects of coming off the medication, there are always risks of medications," said Abramson, who is not involved with the Hampson case.

Abramson said that while the verdict should be left up to the courtroom, such cases should draw doctors' attention to the possible side effects of SSRIs.

"There isn't a medicine that's powerful enough to be helpful that isn't powerful enough to cause side effects," said Abramson. "We forget that. We hope that medicines are going to be magic pills and they're not."
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FDA Group Issues Cautions on Acetaminophen Overdose

When Antonio Benedi of Springfield, Va., felt a case of the flu coming on one weekend in February 1993, he did what millions of others do -- he reached for a common over-the-counter pain medication.
"I was taking Tylenol like I was supposed to, by the label," he said.

A few days later the then 37-year-old Benedi was in a coma and in desperate need of a liver transplant.

Benedi, like hundreds of Americans each year, experienced acute liver failure as a result of taking acetaminophen, the most commonly used painkiller in the country today. Many of these cases are due to either intentional or unintentional overdose. Past research also suggests that combining the medication with alcoholic beverages increases the risk of liver damage.

But Benedi, who was formerly a special assistant to President George H.W. Bush, said that while he did take the medicine on a mostly empty stomach, he neither overdosed on acetaminophen, nor had an alcoholic beverage while he was taking the drug. He said he did occasionally enjoy a glass of wine, but never while taking acetaminophen.

"It's not the mixing of the two; I never misused anything," he said. "I took Tylenol as recommended for three days. By Monday night, my liver was failing. By the time I reached the hospital I was near death."

Today, Benedi, now 53, is still living with the transplanted liver he received 16 years ago. Three years ago he required a kidney transplant as well -- a result of the damage that his organs sustained from the anti-rejection drugs he had to take after his liver transplant. And now this transplanted kidney may be failing as well.

On Wednesday, a U.S. Food and Drug Administration working group released a report urging stronger warnings and stricter dose limits for drugs that, like Tylenol, contain acetaminophen -- and hence may pose an increased risk of liver injury to those who use them improperly.

Among other things, the recommendations call for moving the maximum adult daily dose for acetaminophen to no more than 3,250 milligrams from the current max of 4,000 milligrams per day. The recommendations would also limit the strength of immediate release versions of the drug and place greater controls on the use of acetaminophen in liquid formulations for children.

Limit Doses of Tylenol or Acetaminophen
McNeil Consumer Healthcare, a Johnson & Johnson subsidiary and the manufacturer of Tylenol, said in a statement Thursday that they fear the recommendations could have the effect of steering consumers away from an appropriate and safe drug.

"While we share the FDA's mutual goal of preventing and decreasing the misuse and overdose of acetaminophen, we have concerns that some of the FDA recommendations could discourage appropriate use and are not necessary to addressing the root causes of acetaminophen overdose," the statement reads.

Still, emergency room doctors are no strangers to acetaminophen overdoses. Dr. Richard O'Brien, a spokesman for the Dallas-headquartered American College of Emergency Physicians, said that such cases are very common is his emergency department -- and not all are intentional overdoses in which patients have tried to commit suicide.

"I do see an occasional overdose where people don't read the label of multiple products," he said. "The combination products where they're taking the equivalent of three times the dose, multiple times a day... acetaminophen is a liver toxin, and I have seen people die of liver failure from it."

Liver transplant specialists agreed. "People are frequently pushing the toxic dose limits by taking too much directly and by unknowingly consuming in other products in parallel," noted Dr. Dan Salomon, transplant biologist at the Scripps Research Institute in La Jolla, Calif.

Dr. Jeffrey Punch, chief of the Division of Transplantation at the University of Michigan Transplant Center in Ann Arbor, Mich., said he has seen patients in need of a liver after problems linked to acetaminophen, "especially patients that take over-the-counter acetaminophen as well as a narcotic drug like Vicodin that also includes large amounts of acetaminophen.

"It is made worse if they take too much acetaminophen along with alcohol and/or while fasting," he added.

Lingering Concerns Over Acetaminophen Overdose

The report is not the first time that concerns over the potential for acetaminophen overdose have surfaced. In 2002, Dr. Peter Lurie of the consumer advocacy group Public Citizen appeared before the FDA's Nonprescription Drugs Advisory Committee to relay concerns about unintentional overdoses associated with acetaminophen. In November 2005, a study in the journal Hepatology found that the majority of acute liver failure cases in the U.S. were due to acetaminophen poisoning. And more recent research has suggested that these cases may be on the rise.

Worse, O'Brien said, is that because many who take the medicine are already sick, they could be experiencing the side effects of acetaminophen poisoning without knowing it.

"That's the problem because some of the symptoms are like the flu: nausea, vomiting, and abdominal pain," he said. "It's usually fatal over a day or two."

But Punch said that even the new recommendations may not have a great impact on public health.

"I support the measures, but I don't think the change in maximum dosage will have much effect," he said.

Protecting Yourself From Acetaminophen Overdose

Punch said that if there is a take-home message for consumers, it would be the importance of paying attention to dosage recommendations for acetaminophen.

"It is found in cold medicines, in prescription pain relievers, and in [over-the-counter] pain relievers," he said. "People think that OTC drugs are benign, but they can be just as dangerous as prescription drugs if not taken correctly."

As for Benedi, a jury later found in his favor in an $8 million decision against Johnson & Johnson.

"I went through hell, and so did my family, watching me almost die," he said. "People should really be aware of the dangers of taking Tylenol when not eating properly and if they are used to having a beer or two over the weekends."
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