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1-15 January 2010  
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Home - Market - Article

Surviving IBS

Difficult to diagnose and treated more as an embarrassing secret or worse, a psychiatric disorder, Irritable Bowel Syndrome (IBS) accounts for 25-50 percent of gastroenterology consultations. Notwithstanding two drug recalls on safety issues, pharmaceutical companies have not given up on the IBS pie while alternative treatments like probiotics are fighting for their share too. Viveka Roychowdhury analyses

As a child, Heather Van Vorous used to get stomach pains severe enough to pass out. But it was after six years of hearing her pediatrician telling her to 'stop whining' that her condition was finally diagnosed as Irritable Bowel Syndrome (IBS). Today, her book, 'The First Year: IBS', is a survivor's guide for other people with IBS.

Event though the term IBS was first used as early as 1950 in The Rocky Mountain Medical Journal, to describe patients with diarrhea, abdominal pain, constipation with no recognizable infective cause, such cases were thought to be psychosomatic, or mental disorders. This approach further discouraged patients coming forward with gastrointestinal (GI) related problems and even today, it is estimated that upto 70-80 percent of IBS cases remain improperly undiagnosed thanks to overlapping symptoms. To further complicate matters, symptoms are typically intermittent but may be continuous and according to the Rome II criteria, symptoms need to manifest at least for 12 weeks (either intermittently or continuously) in a period of one year to be diagnosed as IBS.

According to Shashank Sandu, Director, Sandu Pharma, "The annual direct and indirect medical costs of IBS management in the US have been reported to be as high as $ 8 billion and $ 25 billion respectively. These costs place IBS among the 10 most expensive GI diseases in the US. Yet only six percent of the direct costs are attributed to medication (compare this to Gastro Esophageal Reflux Disease (GERD), for which drug costs are estimated at 63 percent of total direct costs), making IBS a relatively under-penetrated market. Given its 12 percent prevalence and assuming 50 percent penetration, seven (30-day) prescriptions per year and pricing in line with Novartis' tegaserod, IBS could represent a market on par with the current GERD ($15 billion) and depression ($14 billion) markets." Though no such pharmacoeconomic data is available in the Indian context, it would be safe to say that the need for such medications and consequently the size of the market would be similar.

Lengthy diagnosis

"The current approach to IBS patients is based on a positive diagnosis of the symptom complex, exclusion of underlying organic disease, and institution of a therapeutic trial"

- Dr. Amit Maydeo
Consultant gastroenterologist
Fortis Hiranandani Hospital,
Navi Mumbai

"Given its 12 percent prevalence and assuming 50 percent penetration, seven (30-day) prescriptions per year and pricing in line with Novartis' tegaserod,
IBS could represent a market on par with the current GERD ($15 billion) and depression ($14 billion) markets"

- Shashank Sandu
Director
Sandu Pharma

"The brain-gut axis is an extremely important aspect in IBS. There is visceral hypersensitivity in IBS, ie. a mild stimulus of pain is often perceived as severe in patients with IBS. An impaired inhibition of pain also contibutes to visceral hypersensitivity in IBS. This means the standard pain medication won't work alone"

- Dr. Devendra Desai
Consultant Gastroenterologist
P D Hinduja National Hospital
& Medical Research Centre, Mumbai

"You can control the symptoms (of IBS), but you can't eliminate the
syndrome, because there is no underlying disease that you are treating"

- Dr Vivek Raj
Director and Senior Consultant Department of Gastroenterology and Hepatology, Max Super Specialty Hospital (MSSH), New Delhi

Enumerating the patient centric issues specific to IBS, Dr Devendra Desai, Consultant Gastroenterologist, P D Hinduja National Hospital & Medical Research Centre, Mumbai says, "These challenges are met by identifying the patient's symptoms and applying the diagnostic criteria. Identifying alarm symptoms and signs such as weight loss, blood in stool and anemia along with basic blood, ultrasound and endoscopic examination. The treatment is tailored to the individual patient. Establishing doctor- patient relationship is an important aspect."

Adding to the list, Dr Amit Maydeo, Consultant Gastroenterologist, Fortis Hiranandani Hospital, Navi Mumbai lists drug compliance, desire to undergo investigations, associated psychological issues. He emphasizes that it is very important to have a strong rapport between the doctor and the patients as all the above mentioned problems can be tackled once this rapport is established. The current approach to IBS patients is based on a positive diagnosis of the symptom complex, exclusion of underlying organic disease, and institution of a therapeutic trial, he explains.

Dr Vivek Raj, Director and Senior Consultant, Department of Gastroenterology and Hepatology, Max Super Specialty Hospital (MSSH), New Delhi also points out that a definitive positive diagnosis of IBS becomes slightly more complicated in Indian populations, (when compared to the US or UK) due to the relative increased prevalence of GI infections like giardiasis and amoebiasis. Because the physician has to rule out underlying organic pathologies, patients may feel that they are being investigated unnecessarily and this leads to a feeling of frustration as they may need to try out different treatment regimens to see which one works for them, explains Raj. You can control the symptoms, but you can't eliminate the syndrome, because there is no underlying disease that you are treating, he says, presenting in a nutshell the dilemma posed by IBS.

Lines of treatment

Raj says that often the first line of treatment is fibre supplementation. Depending on the dominant symptom, there are three different sub-types of IBS: IBS-C (constipation), IBS-D (diarrhoea), or IBS-A (altering diarrhoea and constipation episodes). Though the incidence of IBS steadily increased over the years, there were no drugs which specifically addressed IBS and clinicians had no other choice but to treat the symptoms. Hence antispasmodics and anticholinergics were prescribed for patients complaining of abdominal pain and bloating, antidiarrheals for diarrhoea, laxatives for constipation, and in cases where the doctor felt stress was the underlying cause, antidepressants were used.

In fact, it was only in the 1990s that publications like The Journal of Clinical Gastroenterology started carrying studies suggesting the role of what is called the 'brain-gut axis'. As Desai explains, "The brain-gut axis is an extremely important aspect in IBS. There is visceral (gut) hypersensitivity in IBS, ie. a mild stimulus of pain is often perceived as severe in patients with IBS. An impaired inhibition of pain also contibutes to visceral hypersensitivity in IBS. This means the standard pain medication won't work alone."

Elaborating, Maydeo points out, "Numerous neurotransmitters are found in the brain and gut that regulate GI activities, including 5-hydroxytryptamine (5-HT, serotonin) and its 5-HT3 and 5-HT4 receptors." The emergence of 5HT modulators, at the start of the new millennium, gave fresh hope to both physicians as well as IBS patients as these were the first drugs specifically treating IBS.

The market therefore was quite hopeful when in February 2000, the US FDA gave marketing approval to GSK's Lotronex, (Alosetron hydrochloride). A potent and selective 5-HT3 antagonist, Lotronex was meant to be prescribed only for women with diarrhea, but had to be withdrawn from the market by November 2000, because of serious, life-threatening, gastrointestinal side effects. A Frost & Sullivan Market Insight, published in August 2003 points out that Lotronex had already generated revenues close to $36 million in these nine months, fully deserving The Indian Journal of Pharmacology's (2001; 33: 49) decision to include Alosetron hydrochloride in its Molecules of the Millennium listing.

The degree of unmet medical need in IBS can be gauged by the fact that patient and clinician pressure (in the form of emails and representations) brought Lotronex back on the market, albeit in a restricted manner. In June 2002, it was approved again by the FDA as a supplemental New Drug Application (sNDA) that allowed restricted marketing only to women with severe IBS-D who are unresponsive to other therapies, points out Sandu.

Novartis' Zelnorm (tegaserod maleate), which targets another neurotransmitter-receptor, as a 5HT4 agonist) got US FDA approval in August 2002 (well ahead of its expected 2005 approval) for the short-term treatment of women with constipation-predominant IBS. Between its launch in November 2002 and the end of the year, Zelnorm grossed $14 million in sales, according to the same Frost & Sullivan Market Insight report. In a company press release detailing second quarter results in 2006, Zelnorm/Zelmac's worth was put at $ 263 million. The release also mentioned that it had 'maintained strong growth as use in the US reached an all-time high of 270,000 total prescriptions in May 2006, a 28 percent increase over May 2005.'

But notwithstanding these impressive sales, a retrospective analysis of clinical trial data by the US FDA indicated a possible link between Zelnorm and incidents of heart attacks and stroke. According to the data review, 0.11 percent of patients taking Zelnorm experienced unusual cardiovascular events, compared with 0.01percent of patients treated with a placebo. Zelnorm too was withdrawn from the market in 2007.

Good bacteria to the rescue?
In November this year, international gastroenterology and microbiology experts were invited by Institut Rosell-Lallemand to share and discuss with representatives from the pharma and healthcare industry the latest research on probiotics in IBS, ahead of the UEGW/ Gastro 2009 conference. According to Bérengère Feuz, Gastro-enterology International Product Manager - Human Nutrition, Institut Rosell-Lallemand, Canada, one of the main conclusions at the seminar was that today, a few probiotic strains are now documented for their overall effects on IBS symptoms, supported by state of the art clinical trials.

Of all alternative therapies for IBS, probiotics are to date the best documented ones and as an illustration, she mentions a recent meta-analysis of 14 randomized, controlled clinical trials of various probiotics for IBS Dr Lynne McFarland published in 2008. It was concluded that "probiotic use was associated with improvement in global IBS symptoms compared to placebo (…) Probiotics were also associated with less abdominal pain compared to placebo." The authors concluded that, due to the methodological limitations of contributing studies, these results should however be interpreted with caution and that probiotics warrant further studies as a potential therapy for IBS.

Feed-back from the practice was also in strong favor of probiotics in IBS. Feuz quote another expert at the seminar, Professor Philippe Marteau, a leading gastroenterologist from Paris Hospital, who explained that, in the past 15 years, studies have accumulated and there are now serious randomized double blind placebo controlled studies with probiotics in IBS, so in his opinion there is a good level of clinical proof.

He explained that probiotics are like any other active ingredient, there are some studies out there, either positive or negative, and doctors and consumers should make an effort to look at the data, make their own mind about a product when they have all the right information. As with antibiotics, he reckons that under the probiotics umbrella stand a large number of products, all different, and that it is necessary to gather information on each of them, starting with the most studied ones.

Only a few probiotics are clinically documented for IBS, such as Lactobacillus plantarum 299v, and these products should be recommended to patients who are already in favor of this idea. Indeed, according to Marteau and many physicians, a patient opinion about a treatment is crucial to its success, and they reckon that the patient should always be at the center of the therapeutic strategy.

Going back to the scientific studies, Feuz mentions that the probiotic strain L. plantarum 299v, which was first used in Sweden fifteen years ago is one of the most documented probiotic strain in IBS patients. Niedzielin et al. have shown that, in a placebo-controlled randomized study, intestinal discomfort was improved by up to 95 percent in patients (compared to 15 percent with placebo), while abdominal pain and bloating were also significantly decreased. L. plantarum 299v modes of action, on the other hand have been extensively studied (close to 20 scientific papers are available about this strain). Since 2007 the clinically documented probiotic strain L. plantarum 299v is present in India through two distribution agreements. Aristo Pharmaceuticals markets the probiotic under the Darolac IBS trademark, while Ranbaxy distributes the probiotic among gastroenterologists and other gastro specialists under trade name Leviosa299v.

Commenting on the mechanism thought to be behind the beneficial action of IBS, Raj says that increasing intake of curds (and probiotic supplements) would on one level, lead to a more balanced diet as well improve gut immunity and motility. Some research reports show that an enrichment of intestinal flora with Lactobacillus reduced amounts of E.coli and Salmonella species. Probiotics are also thought to exert antibacterial activity through the direct secretion of proteases directed against the bacterial toxins to through their ability to adhere to epithelial cells and thus exclude pathogens.

Alternate avenues

"Probiotics appear like a more holistic approach, they will not only reduce the symptoms like a traditional drug will do but will also treat the cause, without the side effects that can be experienced with several of the drugs usually prescribed to treat IBS"

- Bérengère Feuz
Gastro-enterology International Product Manager - Human Nutrition
Institut Rosell-Lallemand,
Canada

So today, though the IBS patient has limited access to newer drugs, they come with riskier safety profiles and are strictly for short term use. IBS is however a chronic condition. Also most of these drugs tend to target women with IBS, while the condition is also prevalent in men. The patient has no option but to look at alternative treatments. Desai says that besides prescription drugs, psychotherapy and hypnotherapy are known to help in IBS while Maydeo lists Ayurveda, yoga meditation, physical exercises as some of the available alternatives.

Similarly, Maydeo laments that fact that there has been a significant increase in the incidence of IBS over the years as there has been a significant change in the lifestyles of people. As he points out, today, people do not take adequate food on time and have no time for physical activities such as walking or yogic exercises.

Desai elaborates on the role of diet and lifestyle changes in IBS, saying, "Some IBS patients have abnormal colonic fermentation and produce excessive amount of hydrogen. Diet that excludes a range of non-absorbable carbohydrates may be beneficial. Soluble fibers which are fermented should be avoided in these patients. Sometimes exclusion diet which exclude the offending agents are helpful. Common offenders are cereals (often wheat), citrus fruits, dairy products, onion, tea, coffee and nuts. It is important that during this process the patient should not become nutritionally deficient."

Maydeo is of the opinion that probiotics play a very important role in controlling IBS. "I would say adults should discontinue taking milk and increase the consumption of yoghurt or buttermilk as they are rich in probiotics and soothing on the digestive system," he opines.

Probiotics have in fact been the subject of considerable global research. According to Bérengère Feuz, Gastro-enterology International Product Manager - Human Nutrition, Institut Rosell-Lallemand, Canada, "Increasingly, scientific and clinical results advocate the potential of specific probiotic strains and formulations as a more global approach to improving overall gut function and reducing IBS symptoms in patients. Probiotics appear like a more holistic approach, they will not only reduce the symptoms like a traditional drug will do but will also treat the cause, without the side effects that can be experienced with several of the drugs usually prescribed to treat IBS."

Besides probiotics, Ayurveda's holistic approach too appears to benefit IBS patients by providing symptomatic relief. As Sandu points out, IBS is a chronic relapsing disorder and although its prevalence in a community seems to be stable, there is a continuing substantial turnover of patients. Each year about 30 percent of patients will lose their symptoms, and 10 percent will gain new symptoms. In follow-up studies of 1 to 10 years 50-70 percent become virtually asymptomatic, and about one third will experience persistent symptoms. For example, for long term use, Ayurvedic formulations like bael fruit (Aegle marmelos) is considered to be a good natural remedy for IBS. Listing a few of the brands from the Sandu stable, he lists Bilagyl, Sandu Kutajarishta and Berbenteron Compound for IBS-D and Sarak Churna in IBS-C.

Patient support

Treatment of IBS needs a mix of pharmacological treatment and supportive measures, say Sandu. Patient awareness programmes can meet some of the treatment challenges posed by IBS by increasing awareness and de-stigmatising the disease condition. In the US and European countries, these awareness campaigns are the norm as the patients still remember the Lotronex and Zelnorm market withdrawals and awareness campaigns are aimed at overcoming the fears of side effects and educating the patient on the proper use of newer IBS-specific medication and lifestyle changes which could lessen the symptoms.

Sandu cites examples of organizations like the Indian Society of Gastroenterology and individual gastroenterology consultants running awareness campaigns in India. Similarly, he relates how a community meeting about diagnosing and living with IBS was held in Bhubaneswar on World Digestive Health Day (May 29) where for the first time in India, patient educational literature about IBS (in Hindi and Oriya) was distributed. Along the same line, a continuing medical training course with a special focus on IBS was held at the Department of Gastroenterology at Calicut Medical College.

Possible future therapies

Sandu opines that as the IBS market is large and under-penetrated, it is attractive for novel, safe and efficacious therapies. He points to the response of patient advocacy groups to the withdrawal of alosetron in 2000 and the subsequent reinstatement of this drug underscores the level of unmet medical need in this area. In the near future, he predicts that we will likely see second-generation agents in these classes and several other compounds and classes of compounds for IBS.

Pharma companies are presently tinkering with some promising candidates, which will hopefully have better safety profiles. The search is also on for biomarkers for IBS that could help stratify patients on the basis of pathophysiology and lead to novel drug candidates. Till these pass the US FDA's stringent benchmarks and hit the market, patients with IBS have no choice but to 'learn to live with the disease', as Raj puts it.

viveka.r@expressindia.com

 



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