Sunday, February 24, 2013

Enemas and IBD


Enemas:  The Back Story


An enema is the introduction of liquid into the rectum from the direction opposite that of digestion – i.e. through a tube inserted into the anus.  Enemas (or Cylsters, for ye olde word for enemas) have been around for hundreds of years.  They were popular forms of “treatment” in the pre-scientific medical world, and were popular in Victorian times as everything from a cure for cholera to a disciplinary measure.  Enemas have consisted of everything from soapy water to tobacco (while a nice story, there isn’t much evidence to this being the origin of “blowing smoke up one’s ass”).(1)  Compulsive enema use for sexual gratification (klismaphilia) is even a recognized paraphilia in the DSM IV-TR. (2) 

The enema is touted as a miracle cure as part of several dubious, unproven, and sometimes dangerous regimes.  It is also used in modern medicine for science-based treatment and procedure preparation.  What does the evidence tell us about some popular enema uses, and what are their impacts on individuals with IBD.*

Coffee Enemas


Coffee enemas were popularized as part of the Gerson Therapy, developed in the 1940’s by a German-born doctor practicing in the United States as part of a treatment for headaches.  The treatment was expanded to include everything from arthritis to cancer, and is still perpetuated on many sites online.  The American 
Cancer Society summarizes the treatment very well:
Available scientific evidence does not support claims that Gerson therapy is effective in treating cancer, and the principles behind it are not widely accepted by the scientific and medical communities. It is not approved for use in the United States. Gerson therapy can be dangerous. Coffee enemas have been associated with serious infections, dehydration, constipation, colitis (inflammation of the colon), electrolyte imbalances, and even death.(3)

Coffee enemas cause inflammation of the colorectal area, and have been a cause of everything from acute colitis (something those with IBD should be keenly aware of) to rectal burns.(4,5)  There have been multiple deaths related to septicemia and electrolyte imbalances from this practice also.  There are no clinically sound trials showing any benefits to this treatment for any condition, and the exacerbation of IBD symptoms is likely given the known side effects.  As such, there is never any reason for those with IBD to engage in coffee enemas based on the current research.

Colonic Cleansing


Colonic hydrotherapy uses enemas and enema-like treatment to combat “autointoxication”, a poisoning of the body by intestinal waste.  It generally involved irrigating the bowels in a clinic using large amounts of water pumped in through the rectum (there are other forms that are laxative based, but this covers the enema-based ones).  The water may or may not contain other compounds, depending on the setting.  There are two problems with this, there is no evidence (or viable mechanism of action) for autointoxication and the enemas themselves can have side effects.  Colon irrigation has limited medical uses that will be covered in a future article, but the application is short term and to address post-surgical issues (there is some evidence of efficacy for neurogenic bowel dysfunction treatment as well).

A 2009 systemic review of the available studies on colonic cleansing concluded:
there are no methodologically rigorous controlled trials of colonic cleansing to support the practice for general health promotion. Conversely, there are multiple case reports and case series that describe the adverse effects of colonic cleansing. The practice of colonic cleansing to improve or promote general health is not supported in the published literature and cannot be recommended at this time.(7)

The adverse events associated with this form of enema include hypokalemia (potassium imbalance), rectal perforation, and amebiasis (an intestinal infection that killed at least 6 people in once colon cleansing clinic case).(8,9,10)  The risk of infection and electrolyte imbalance and lack of efficacy would contraindicate use by those with IBD, who may be on immunosuppresants and already have electrolyte imbalance risks due to chronic diarrhea and malabsorption. 

Sodium Phosphate Enemas


The most common use of enemas is the over-the-counter purchase of products for self-administration and treatment of motility issues.  Simply put, people use the enema products they can purchase at the grocery store to self-treat constipation and similar concerns (or to address the not proven “autointoxication” noted above).  They can also be used medically in procedure prep and post-procedure treatment.
While commonly believed to be an effective treatment for constipation, the clinical evidence is lacking.  There have been no comprehensive studies showing that these enemas are effective for the treatment of constipation.(11)

A comprehensive review of the risks associated with these enemas found that electrolyte imbalance and hypernatraemia were the two most common side effects.  12 deaths associated with the use of these were found, but the individuals identified were polarized as very old or very young.  There is a risk of perforation of the bowel as well, but the cases identified were due to product misuse and not the treatment itself.  While not risk free, the number of adverse events associated with these products is minimal given their prevalence and widespread usage.  Individuals suffering from reduced bowel motility (e.g. Hirschsprung's) should avoid the enemas because of increased risk of potassium imbalance. (12)

Bottom Line


·         There is no clinical evidence supporting the efficacy of sodium phosphate enemas, coffee enemas, or colon cleansing for the treatment of IBD.
·         The risks vary from minimal (sodium phosphate enemas) to high (coffee enemas) for adverse side effects.
·         Those with IBD should avoid self-directed enema treatment.  Doctor prescribed treatments of coffee enemas are not supported by the evidence, and colonic cleansing (through irrigation or sodium phosphate enemas) should be restricted to pre and post-op cleansing routines.
*The use of enemas for preparation and as a medical delivery mechanism will be covered in a separate article
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1.       Multiple.  Transactions of the Medical and Physical Society of Calcutta.Volume the Seventh.  1835.
2.       Denko, Joanne D. "Klismaphilia: Enema as a sexual preference." American journal of psychotherapy.  1973.
4.       Lee, Chang Jung, et al. "Coffee enema induced acute colitis." Korean Jorunal of Gastroenterology 2008.
5.       Sashiyama, Hiroshi, et al. "Rectal burn caused by hot-water coffee enema."Gastrointestinal endoscopy.  2008.
6.       Eisele, John W., and Donald T. Reay. "Deaths related to coffee enemas."JAMA: The Journal of the American Medical Association 1980.
7.       Acosta, Ruben D., and Brooks D. Cash. "Clinical effects of colonic cleansing for general health promotion: a systematic review." The American journal of gastroenterology, 2009.
8.       Dunning, Marcelle F., and Fred Plum. "Potassium depletion by enemas." The American journal of medicine.  1956.
9.       Biering-Sørensen, F., et al. "Rectum perforation during transanal irrigation: a case story." Spinal cord 2008.
10.   Istre, Gregory R., et al. "An outbreak of amebiasis spread by colonic irrigation at a chiropractic clinic." New England Journal of Medicine. 1992.
11.   Davies, Caroline. "The use of phosphate enemas in the treatment of constipation." Nursing times.  2004.
12.   Mendoza, J., et al. "Systematic review: the adverse effects of sodium phosphate enema." Alimentary pharmacology & therapeutics.  2007.

Sunday, February 17, 2013

Colonoscopy Preparation


The Ins and Outs (and Outs and Outs and Outs) of Colonoscopy Preparation


Preparing for a colonoscopy is generally worse than the procedure itself (at least for 78% of patients [1]).  For most, the procedure is performed under sedation* in the United States.  In Europe and Asia, sedation-free colonoscopies are the standard (and are an option in the US).(2)  Because of the sedation, most US-based patients don’t remember a thing about the scope itself, and the only residuals (aside from the sedative effect) are a bit of bloating and a little gas release.  For those with IBD, the prep itself is what is most dreaded.

The prep involves some form of fasting, coupled with a bowel cleansing routine that involves frequent and urgent trips to the bathroom.  Depending on the timing of the procedure itself, it lasts for anywhere between 12 and 18 hours.  Of the various bowel cleansing methods, none are pleasant but there is some variability in how well they are tolerated and how well they work at cleansing. 

The most common preparation put forth is Polyethylene Glycol (or PEG).  PEG is used in everything from paintballs to electronics manufacturing, and has been the drug of choice for colon prep for a couple of decades.  Originally, PEG preps contained sulfate compounds (that were not well tolerated), and required large volumes (4 Liters) of liquid be consumed the night before the procedure.  The taste and volume led to nausea and non-compliance with the prep, but advancements have been made in the past few years to address these concerns.*

The original PEG preparations (GoLYTLELY™, CoLyte™) were fairly poor tasting.  The first enhancement to PEG was to remove the sodium sulfate.  This resulted in high volumes of slightly less salty (and therefore less pleasant) preparation material.  The new versions, called PEG-SF, included NuLYTELY™ and TriLyte™), had similar performance to PEG and largely replaced the original formulations (though they are still used where electrolyte imbalances are a high risk).

The next generation PEG formulations were low-volume PEG.  These halved the amount of liquid that needed to be taken to 2 Liters, generally through the use of Bisacodyl and/or Magnesium Citrate or Ascorbic Acid (Moviprep™ and MiraLax™).  The taste wasn’t any better, but there was less of the prep to consume.  Research showed no clinical difference between the low volume and high volume PEG preps.
Following the introduction of low volume PEG, another enhancement was split-dosage preparation.  Split dosing involved taking half of the dose the night before, and the second half closer to the time of the procedure.   Originally frowned upon because risks associated with anesthesia and non-evacuated gastric contents, these have now been accepted and show higher patient compliance with equal or better prep quality. (3,4)

For a few years, it appeared that pill-based preps, based on Sodium Phosphate, would overtake the PEG-based preparations.  They involved swallowing many large pills with water (Visicol™, OsmoPrep™), but had good tolerance due to the lack of needing to consume liters of salty muck.  Sodium Phophate had been previously used in over-the-counter prep Fleet PhoshoSoda, a drinkable prep.  Unfortunately, in 2008 the FDA gave them the kiss-of-death black box labeling due to potential kidney damage, and they are now very limited in their use.(5)

A new version of low-volume PEG, PEG-CS (polyethylene glycol-citrate-simethicone) with bisacodyl, that is sulfate free has shown promise in clinical trials as being even better prep than standard low volume prep, but has yet to make a major market impact.(6)

Clear liquid diets are still the standard prior to prep.  There have been some low-residue diets like NutraPrep that have been proposed as adjuncts to the clear liquid.  Ultimately, the clear liquid diets help keep dyes that would affect contrast out of the colon and are a necessary part of the early preparation process.  Unfortunately, they are not an effective substitute for the cleansing PEG. 
Hopefully, the bar will continue to be lowered in terms of the volume needed to be consumed for prep, and the flavors will improve.  Remember, a good prep not only provides the best diagnostic result, but avoids retesting and potentially hazardous situations.

Bottom Line


·         Low-volume PEG are the best tolerated and current standard preps
·         Sodium Phosphate pill-based preps are contraindicated

* The original guidance told patients to try mixing the PEG with Gatorade or similar drinks to cut the flavor.  The practical impact was similar to using cologne in lieu of a shower – it didn’t so much cover up the unpleasantness as mix it with something palatable.
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(1)    Nicholson, Fiona B., and Melvyn G. Korman. "Acceptance of flexible sigmoidoscopy and colonoscopy for screening and surveillance in colorectal cancer prevention." Journal of medical screening. 2005.
(3)    Kilgore, Todd W., et al. "Bowel preparation with split-dose polyethylene glycol before colonoscopy: a meta-analysis of randomized controlled trials."Gastrointestinal endoscopy 2011.
(4)    Wexner, Steven D., et al. "A consensus document on bowel preparation before colonoscopy: prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES)." Diseases of the colon & rectum 2006.
(6)    Friedman, L. S., Commentary: low-volume bowel preparation for colonoscopy. Alimentary Pharmacology & Therapeutics, 2012.

Sunday, February 10, 2013

IBD Drug Costs


Are pharmaceutical companies evil?


A dose of Humira can cost as much as $750 without insurance.  The yearly cost of drugs like Humira, Cimzia, and Remicade are approximately $20,000 per person without aid.  This cost is staggering – how can a drug company justify charging so much money for a necessary drug?  The short, simplistic answer is that drug companies are for-profit entities.  They are beholden to shareholders to make money, and they need to continue making money to survive.  Like all business entities, pharmaceutical companies are bureaucracies and are not necessarily models of efficiency.  Some of the money goes to waste in the system, and some does go to line the pockets of executives.  Like all things in life, however, the reality isn’t that simple. (1)

The Cost of a New Drug


The cost to develop a new drug ranges anywhere from $4 billion to $12 billion US dollars. (2)  This number represents not only the raw research that goes into a particular drug, but all of the dead-end pathways followed by scientists on their path to development.  Basic testing is performed using computer models and then animal models.  Very few actual drugs make it to the clinical trial phase.  Clinical trials are broken up into three areas:

Phase 1 Trials.  These are small scale trials on healthy individuals to determine the safety of a drug.
Phase 2 Trials.  The second phase of trials are to determine the efficacy of a drug and to further evaluate the safety.  They are generally done on a medium scale of several hundred people.
Phase 3 Trials.  The final phase of trials are on several thousand individuals and further evaluate safety and efficacy, in addition to dosing and side effect confirmation.

Despite spending billions to get to clinical trials, the failure rate on them is very high.  94% of all drugs that reach clinical trials fail before coming to market – this includes 82% of phase 2 trials and 50% of phase 3 trials.  The 94% number also excludes drugs taken off the market post-trial.  This failure rate is also why we should be skeptical of promising results in animal studies (or pre-animal studies) ever reaching the market.

A second cost factor is the life of the drug.  The pharmaceutical company that developed a drug generally has 20 year of patent protection on exclusivity for making that drug.  In realistic terms, that is down to approximately 12 years from the time to drug is available on the market, leaving just that long to recoup R&D expenditures.(4)  Once a drug goes off-patent, generic manufacturers generally undercut the price (they don’t have to do the R&D or marketing, and their costs are limited to manufacturing costs) and it loses its profitability.

The third cost is direct cost of drug production.  This is paying for all of the raw materials, putting them together, transporting them to the drug store, and the associated sales and marketing budgets.  The costs are exacerbated by regulatory agencies around the world that impose strict controls and oversight overhead on manufacturing.

The drug companies use their highly successful drugs to support other orphan drugs that are not profitable and cannot be due to high manufacturing costs or a limited market.  If a drug company develops a drug to treat a rare disease -- let’s say Berdon Syndrome, a disease where microcolon is one of the symptoms.  Since there are only 230 known cases, each would have to theoretically share the R&D costs for the drug, resulting in a $52 million per person drug charge.  Drug companies subsidize drugs and research on these conditions through profits on more prevalent conditions.  Unfortunately, very rare conditions rarely have any R&D dollars put against them by drug companies due to the low upside profit potential.

Outside the direct development costs, drug development has many hidden costs.  The first and largest hidden cost is piracy.  Several large nations with poor intellectual property protection have been known to state-subsidize drug production and ignore patents, in gross violation of international treaties.  While good for their citizens (and the political contributors that run the state-sponsored companies), the rest of the world must shoulder an even greater share of the cost of drug development in increases costs. 

Another hidden cost (at least to US consumers) is socialized medicine elsewhere in the world.   Countries with state-run healthcare systems can dictate rates to the drug companies, who are stuck making a decision of whether to do business with that country and lose money on a particular drug (which requires further price increases for US consumers) or forego doing business there.  The business is generally not restricted to one drug – a company may be forced to discount a new drug to be permitted to sell a more prevalent and popular drug within that country.

How do we apply these numbers to Crohn’s and Ulcerative Colitis?  Let’s go back to the prevalence numbers:
·         5 out of every 1,000 people in the US have IBD.  This amounts to approximately 1.5 million cases.  Worldwide, this would be approximately 35 million cases. *
·         For a given drug, let’s say Humira or Remicade, there may be 10% of affected individuals that qualify for (medically) and take that drug, so we are down to approximately 3.5 million potential users.  Of these, approximately 50% will be living in countries that either never approved the drug or have a high enough piracy rate to make selling the drug not worthwhile, bringing the number to 1.75 million.
·         The 1.75 million individuals may take the drug for 12 years before generics come into play.  Realistically, the time is more likely to be 6 years if you include the time to get patients to adopt a new drug, then the drop-off when competitors come on the market with similar but more effective drugs.  At 6 years, this is 72 doses for a product like Humira.
·         1.75 million people x 72 doses = 126 million doses of the drug sold.  This doesn’t include losses due to bad batches, theft, or spoilage.
·         Due to international bargaining, only half of those doses are sold at a reasonable cost – the rest are provided at a greatly reduced cost closer to the actual per-dose manufacturing cost.
·         $12 billion / 63 million lifetime doses sold = 190 dollars per dose to recoup R&D costs.

The numbers above are very rough example of drug costing.  For Remicade, even if it were free to manufacture and deliver (it’s not – it’s actually very expensive), it would need to cost $190 per dose above those numbers just to recoup R&D costs.

The description above is a gross oversimplification of the system.  There are other factors at play – drug manufacturers find new indications for a drug to combat multiple conditions, or off-label uses increase prescriptions.  Drug companies spend money wining and dining doctors to encourage prescriptions, and recently in the US have jumped on the direct-to-consumer marketing bandwagon.  On the other hand, the big drug companies all offer discount programs on the most expensive drugs, and insurance companies and big pharmacies (like Walmart) collectively bargain for good prices.  Drug companies are made up of doctors who are trying to help people by doing breakthrough research, but also of business people who need to maintain an ongoing concern to be able to develop future drugs. 

There is certainly unethical behavior that goes on in the pharma industry – check out the class action suits regarding skewed trials and coverups on safety issues to see the dark underbelly.  That said, even with the profiteering and corruption, there is still a high baseline cost to delivering novel new drugs, a cost that unfortunately the patients must bear.

Bottom Line


·         Developing new pharmaceutical is an expensive proposition.  The more limited the market, the more the cost per-dosage to recoup R&D spend.

* NOTE:  The prevalence worldwide is not equal to the US prevalence, and many places don’t have access to modern medical treatments.  This number is not meant to handle those issues, just to provide a conservative basis for calculating ROI.
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Sunday, February 3, 2013

Rare Forms of IBD

Crohn's and Ulcerative Colitis Aren't the Only Inflammatory Bowel Diseases



Crohn’s Disease and Ulcerative Colitis are the two best known types of inflammatory bowel disease (IBD) and get most of the attention, but there are other forms of IBD that are rarer but can be just as serious.  To give props to a few (not all) of the less common forms of IBD:

Ischemic Colitis.  The lack of bloodflow to the large intestine can cause inflammation, and in the extreme tissue death.  Ischemic colitis is generally acute, and can be brought on by everything from intense exercise to cocaine usage to vasoconstricting drugs.  Treatment is generally bowel rest and fluids, and most cases resolve on their own.  With extreme cases, tissue death occurs and requires immediate surgical intervention to prevent life threatening complications.

Ischemic Colitis can also become a chronic condition.  Similar to Crohn’s and UC, chronic ischemic colitis can case structuring and the associated complications.  Chronic ischemic colitis requires medical management and monitoring to prevent an acute emergency event. (1)

Behçet's disease.  Behçet's, first identified by Turkish dermatologist Hulusi Behçet, is a condition causing systemic vasculitis.  Behçet's is an autoimmune disease that primarily targets the mucus membranes, and oral lesions similar to those that appear with other forms of IBD are one of the more common symptoms.  While Behçet's can (and does) effect other systems not commonly impacted by other IBD diagnoses such as the genitals, lungs, and eyes. 

Behçet's overlaps with other forms of IBD in a second location – the ileocecal valve.  Behçet's can cause inflammation and damage to the valve area, which causes a mimicking of the symptoms of UC and Crohn’s.  Though Behçet's targets the blood vessels, it has shown to be responsive to treatment using the same anti TNF-alpha treatments that are used with other forms of IBD.  It is generally a diagnosis of exclusion – ruling out the more common forms of IBD and looking at extra-intestinal manifestations. (2)

Diversion Colitis.  Diversion colitis is an abnormal inflammation in a part of the colon that has been removed from function, generally by a colostomy or ileostomy.  While this can happen with surgical intervention to treat Crohn’s or UC, diversion colitis occurs in patients that have had surgical interventions not related to underlying IBD (e.g. from trauma or unrelated medical issues such as cancer).

Because it occurs following surgical intervention, diversion colitis is generally found through symptoms of abdominal pain or unusual rectal discharge.  Follow-up colonoscopy can also identify inflammation, polyps, granuloma formation, and other signs of IBD.  Diversion colitis is treated with enemas or systemic IBD drugs, or surgery to remove the effected portions. (3)

Collagenous and Lymphocitic Colitis (CLC).  CLC is a late onset disease, generally occurring in individuals that have not previously had IBD and manifest diarrheal symptoms in their 70s and 80s.  It is characterized by lymphocytes in the mucosal layer or inflammation of the collagenous areas.  The primary symptom, as noted, is uncontrolled diarrhea.  Though the origin is unknown, CLC is potentially another autoimmune disorder, and has some comorbidity with diseases like rheumatoid arthritis.

CLC is treated similar to other IBDs, with corticosteroids being the initial treatment option.  5-ASA treatments have been used, and anti TNF-alpha drugs may show potential promise. (4)

Unfortunately for those with rare diseases, the medical literature and treatment options tend to be more limited.  Drug companies are not eager to pursue additional indications for their drugs because the cost to do so will never be recouped for less common drugs, and doctors are not likely to see them (even busy GI doctors), so they are harder to diagnose.  That said, they are as damaging and as serious as the more common Crohn’s and UC versions of inflammatory bowel disease. 

Other autoimmune disorders are co-morbid with Crohn’s and Ulcerative Colitis, or may have intestinal manifestations not directly diagnosed as such (e.g. Lupus, Rheumatoid Arthritis, Sjogren's).  There are also even more rare IBD disorders, and there are other diseases that can mimic IBD symptoms such as irritable bowel syndrome, colon cancer, and celiac disease.  These disorders, and how they are differentially diagnosed from IBD, will be covered in future posts. 

Bottom Line


·         Crohn’s and Ulcerative Colitis are not the only forms of IBD out there, though they represent the lion’s share of diagnosed cases.
·         Less prevalent forms of IBD generally have similar treatments, but receive less press, fewer research dollars, and are less frequently seen (and understood) by doctors.

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1.       Sreenarasimhaiah, Jayaprakash.  Diagnosis and management of ischemic colitis.  Current Gastroenterology Reports, 2005.
2.       Lee, S. K., et al. Differential diagnosis of intestinal Behçet’s disease and Crohn’s disease by colonoscopic findings. Endoscopy, 2009.
3.       Ma, C. K., C. Gottlieb, and P. A. Haas. Diversion colitis: a clinicopathologic study of 21 cases. Human pathology.  1990.
4.       Zins, B. J., W. J. Sandborn, and W. J. Tremaine. Collagenous and lymphocytic colitis: subject review and therapeutic alternatives. The American journal of gastroenterology, 1995.