Therapeutic Retention Enemas: An Underutilized Modality for UC

Mark Davis, ND

The use of therapeutic enemas has a robust tradition in the history of naturopathic medicine. In addition, my own grandfather, a medical doctor, had a habit of administering a cleansing enema to any of his 8 children who displayed any sign of acute illness, which, in the words of my brother, “if nothing else, probably cut down on malingering.” Despite these facts, I made it into my 30s and through my entire professional training as a naturopathic doctor without having given, received, or even witnessed an enema of any type.

This article focuses on the use of enemas in ulcerative colitis (UC) – an autoimmune inflammatory bowel disease (IBD). Two-thirds of UC patients have distal disease, confined to the left side of the colon. Therapeutic retention enemas are highly indicated for this population, but may also be utilized for patients with more extensive disease, up to and including pancolitis.

Rectally-administered therapies are underutilized in IBD, due in part to physician perception of patient unwillingness to use them, and embarrassment in discussing rectal modalities1; however, in my practice I’ve prescribed and administered hundreds of enemas and found them to be extremely helpful in the treatment of UC, especially left-sided UC and ulcerative proctitis, the latter of which is notoriously stubborn to medical management.

Enemas, in General

An enema, meaning “to send in,” is also known as a clyster, meaning “to wash out.” These 2 etymologies reflect the 2 basic types of enemas: retention enemas are used to deliver a medicinal substance to the colorectum for topical action or absorption via the mucosa, while cleansing enemas are used to wash out the contents of the colon.

Retention enemas are the topic of this article. They can be delivered in a small volume, for example half-ounce (15 mL) vitamin E or colostrum enemas, 60 mL mesalamine enemas, or 100 mL butyrate enemas, or in even larger volumes, such as 500+ mL calendula tea enemas. Retention enemas are generally considered safe for patients with IBD; however, incorrect insertion method has on rare occasion been associated with rectal perforation.2

Cleansing enemas can be small-volume, eg, 4.5 oz hyperosmostic sodium phosphate or lubricant oil enemas, or large-volume, as in the case of water cleansing enemas ranging from 500 to 1500 mL in volume.

There’s a bit of an art to judging what volume is appropriate for a given patient, and the tolerable volume might change depending on the severity of the patient’s disease state, time of day, most recent meal, and other factors. Patients with UC often experience frequent, loose, and urgent stool, so retaining even small-to-moderate volumes can be challenging. Helping them to find the best time of day and time to administer in relation to eating, as well as managing urgency and frequency with oral interventions – ranging from curcumin and activated charcoal to loperamide, cholestyramine, and prednisone – can assist them in retaining therapeutic enemas for long enough to realize benefit from them.

Vitamin E

Vitamin E, an antioxidant and anti-inflammatory, acts as a vulnerary nutrient when applied topically. In an open-label trial, 14 patients with mild-to-moderately active distal UC self-administered about half an ounce of d-α-tocopherol (8000 IU) QD for 12 weeks.3 At 4 weeks 21% were in remission, and at 12 weeks 64% were in remission. The erythrocyte sedimentation rate (ESR) dropped 80% during this time. Since this trial was published, I have used vitamin E retention enemas with my patients with distal colonic IBD, either alone or in combination with other rectal therapies. Several patients have experienced discernible improvement over time, which we attribute to the vitamin E enemas.

Summary:
Small-volume, liquid vitamin E retention enemas (8000 IU), when used for 2-12+ weeks, may contribute to remission in patients with distal UC.

Colostrum

Colostrum is an immunoglobulin-rich, post-partum, pre-milk mammary gland secretion that is crucial for the health of newborn mammals. Humans have used bovine colostrum orally for many conditions. In a randomized, double-blinded trial, 14 patients with mild-to-moderately active distal UC self-administered half an ounce of liquid colostrum or a control solution rectally BID for 4 weeks.4 At the end of this time period there was a significant improvement in histological scores in the colostrum group, and at 6 months only 13% of the colostrum group required steroids (vs 50% of the placebo enema group). I have used liquid colostrum enemas in my practice, but not for long enough to comment yet on their efficacy.

Summary:
Small-volume, liquid colostrum retention enemas (half-ounce), when used daily for 4 weeks, appear to significantly improve colon mucosal healing and decrease steroid dependence in patients with distal UC.

Calendula

Calendula is one of our best vulnerary herbs. A randomized controlled trial looked at the ability of calendula tea retention enemas to promote colon mucosal healing in dogs with acetic acid-induced UC.5 Although they did not carefully report details of benefit in the calendula vs placebo groups, the authors reported “significant mucosal healing” 1 month after the subjects received 7 days of calendula tea enemas. Since reading that report, I have used large-volume (half-liter or more) calendula tea retention enemas daily with quite a few patients with distal and proximal colonic IBD, some of whom have reported discernible decreases in rectal discharge of blood and/or mucus, as well as decreases in abdominal pain using this intervention.

Summary:
Large-volume calendula tea enemas may benefit some patients with active UC.

Butyrate

Butyric acid is a short-chain fatty acid generated by colonic bacteria. It is used in enema form to down-regulate inflammation and oxidative stress in the colon, which can be achieved even proximal to the sigmoid using only a 60 mL (100 mM butyrate) enema preparation.6 This decrease in inflammation may promote the tolerance of commensal microbes that is critically lacking in IBD.7

Early open-label and single-blind trials using butyrate enemas reported significant benefit in distal colitis8,9; however, later randomized controlled trials only reported significant benefit over placebo in some subgroups10 or for secondary endpoints,11 or found no benefit compared to placebo.12 I have not yet found butyrate enemas to offer significant benefit for my patients with UC, but I have only used them a few times, and other colleagues have reported meaningful benefit.

Summary:
There is conflicting data for small-volume butyrate enemas in the treatment of active distal colitis. Patients who have had IBD for <6 months and who have high compliance rates for this therapy may be the most likely to achieve benefits,10 including decreased bleeding and urgency.11

Probiotics

Oral and rectal probiotics can help induce and maintain remission in patients with UC.13,14 In my experience, individual response to any given probiotic is highly idiosyncratic, so trial and error is my preferred approach to probiotic selection in IBD. That being said, several probiotic enema trials deserve mention, if nothing else to illustrate the point that probiotic enemas can be a useful intervention for UC patients.

In 1 trial, 5-aminosalicylic acid (5-ASA), alone or with oral Lactobacillus casei, failed to alter colon microflora; however, those interventions along with additional L casei enemas significantly altered colonic flora and Toll-like receptor expression and interleukin levels.15

Another group administered either Lactobacillus reuteri enemas (10 billion CFU per rectum QHS) or placebo enema for 8 weeks to 40 children with active distal UC.16 At 8 weeks, there was significant clinical and histological improvement in the probiotic group, vs no significant change in the placebo group. Clinical remission was reached in 31% of the probiotic enema group and in none of the placebo group.16

Many American clinicians are not familiar with the probiotic E coli Nissle 1917 (aka Mutaflor), which has been used in Europe for IBD and other conditions for almost 100 years. This is because the US Food and Drug Administration does not permit Mutaflor to be imported. Oral preparations compare favorably to mesalamine in achieving and maintaining remission when used in adults17 and children18 with active UC. Mutaflor enemas trend towards greater efficacy than placebo enemas for patients with moderately-active distal UC, with benefit increasing with increased volumes up to 40 mL.19

Bifidobacterium enemas have been given to successfully resolve necrotizing enterocolitis.20 This is not an autoimmune colitis like UC; however, it does demonstrate the ability of Bifidobacteria to safely and effectively alter colon flora to reduce dangerous inflammation.

I routinely prescribe Lactobacillus spp and Bifidobacterium spp probiotics enemas at doses of 10-500 billion CFU for patients with distal UC, and have found them to assist in inducing and maintaining remission.

Summary:
Probiotic enemas may help induce and maintain remission in patients with distal UC. Discovering the best species, dose, and frequency of administration for an individual patient will likely involve some individualized experimentation.

Fecal Microbiota Transplantation

Fecal slurry preparations, known as fecal transplant or fecal microbiota transplantation (FMT), have been used orally as “yellow dragon soup” to resolve intractable diarrhea since the 4th century in China.21 Autologous and exogenous fecal-derived microbes have been administered via enema for UC and other conditions at least since 1910 in the United States.22 Whole-stool fecal slurry enemas have been used for infectious colitis since at least 1958.23 They have also been used by naturopathic doctors for IBD and other conditions in the United States since at least the 1970s,24 and are now used widely in North America for Clostridium difficile (C diff) infections not responding to standard therapies.25,26 When compared with colonoscopic and naso-duodenal delivery, FMT retention enemas have comparable or superior efficacy at resolving C diff infections.

A systematic review of case series of FMT for IBD, in general, reported a 76% response rate and 63% remission rate following FMT.27 A more recent and thorough systematic review and meta-analysis of FMT for IBD reported that 45% of IBD patients achieved clinical remission following FMT.28 A subgroup analysis of cohort studies demonstrated clinical remission in 22% of patients with UC.28

In an open-label trial, 10 children and young adults with mild-to-moderately active UC were given FMT retention enemas (average 165 mL) for 5 consecutive days.29 Of the 9 patients who were able to retain the enemas, 78% showed a clinical response at 1 week, 33% achieved remission at 1 week, and 67% retained their clinical response at 1 month.

Seventy-five active UC patients were randomized to receive weekly either an enema of 50 mL of FMT or a 50 mL water enema (control group) for 6 weeks.30 At 7 weeks, 24% of those in the FMT group were in remission vs only 5% of those in the placebo group. Stool donated by 1 particular donor led to remission in 39% of recipients, while stool from other donors led to remission in only 10% of the participants, suggesting statistical evidence for donor dependence. Participants with UC for less than 1 year were also significantly more likely to respond. There was no difference in adverse events between the FMT and control groups.30

In my practice, I’ve counseled hundreds of adults and children with IBD on the use of home FMT retention enemas. My observations are similar to those in the literature: following an initial series of one 4.5 oz FMT retention enema per day for 10 more-or-less-consecutive days, I see about a quarter of my patients with UC achieve remission, another half discernibly improve, and the last quarter experience no apparent benefit.

Summary:
FMT retention enemas cannot be prepared or administered by clinicians in North America for any patient other than those with C diff infections not responding to standard therapies31; however, many patients with UC turn to their clinicians for guidance around best practice for home FMT, and for stool donor screening. FMT retention enemas, used daily or weekly for 5 to 10 or more times, are significantly likely to lead to a clinical response, and have a 25% or greater chance of inducing remission within 6 to 10 administrations.

5-Aminosalicylic Acid (5-ASA)

Mesalamine is the prescription 5-ASA (a salicylate derivative) most commonly used in IBD. It acts locally in the gut as a cyclooxygenase (COX)-inhibitor and antioxidant.32 Mesalamine preparations induce intolerance or hypersensitivity reactions in about 8% of patients with UC, and may rarely aggravate UC.33

Mesalamine enemas, used nightly for 12-34 weeks, appear to induce remission in the majority of patients with left-sided UC who are unresponsive or intolerant of other therapies.34 Mesalamine enema is equivalent or superior to oral mesalamine at inducing remission in patients with active left-sided UC, and oral and rectal mesalamine combined appears to be more effective than either individually.35 Mesalamine enema is equivalent (and non-significantly superior) to oral mesalamine at maintaining UC patients in remission.36 Mesalamine enemas may be safer in pregnancy and may have fewer side effects than oral preparations.37

Clinicians may think of mesalamine enema for the two-thirds of IBD patients whose disease is limited to the left side of the colon, but it also offers benefit for patients with disease that extends beyond the splenic flexure.38 The use of suppositories, rectal foams, or liquid enemas is based on the extent of the disease.

Efficacy of enemas does not appear to increase with doses over 1 mg.39 The most common mesalamine enema includes potassium metabisulfite as an inactive ingredient, but there is a sulfite-free version available for patients sensitive to sulfites.

Mesalamine enemas are significantly superior to corticosteroid enemas at inducing and retaining remission40; however, corticosteroid enemas may be indicated if other interventions including mesalamine enemas fail or if individual circumstances warrant.

Summary:
Mesalamine enemas, when used for >3 months at 1 mg per rectum QHS by patients who tolerate 5-ASA derivatives, are likely to induce and help maintain remission for many of the two-thirds of UC patients whose disease is mild or moderate and confined to the left side.

Corticosteroids

Before corticosteroids were available, a first attack of UC was fatal about one-third of the time; now that number approaches 0.41 Corticosteroids induce partial or complete remission from IBD about 75% of the time,42 but potential side effects – including osteoporosis,43 osteonecrosis,44 and sleep and mood disturbances45 – limit its use. Corticosteroids are not helpful in maintaining long-term remission once it has been achieved, especially when used for longer than 3 months after induction of remission.46 In addition, as many as 9% of people with IBD may have a steroid allergy.47

In North America, the corticosteroids most commonly used for IBD are prednisone, hydrocortisone, and budesonide. The latter 2 are commonly used as enema preparations. Budesonide is a synthetic corticosteroid with low systemic availability due to high first-pass hepatic metabolism, so it has a greatly diminished side-effect profile.48 As many as one-half of IBD patients who don’t respond to mesalamine enemas may respond favorably to budesonide or hydrocortisone enemas,49 and twice-daily budesonide enemas lead to significantly more complete mucosal healing than once-daily enemas.50

Markers of bone formation fall rapidly within 5 days of starting oral corticosteroids; however, no decrease in bone formation markers occur within 2 weeks of starting prednisolone or hydrocortisone enemas.51

Patients tend to prefer foam over liquid enema preparations, though both are equally effective at inducing remission.52

Summary:
Corticosteroid enemas used for 6 to 8 weeks may induce remission in 50% or more of patients with left-sided UC not responding to 5-ASA enemas. Budesonide (2 mg per rectum BID) is the delivery method most likely to deliver the best outcome.

Other Therapies

There are other types of therapeutic retention enemas described in the literature for use in UC that I have not had the opportunity or additional training to appropriately use.

Historically, Chinese medicine did not use enemas as a delivery method for botanicals or other therapeutic substances53; however, in the past couple of decades, several authors have reported on the use of Chinese medicine herbal enemas to treat UC with varying degrees of efficacy.54-57 This treatment paradigm and the language of choice of these articles leave this author unable to appropriately assess the use of these therapies.

Alicaforsen, a prescription ICAM-1 inhibitor, given as an enema, is superior to placebo and equivalent to mesalamine enemas at inducing remission in patients with UC for up to 10 weeks, and is significantly superior to placebo and mesalamine at maintaining remission at 30 weeks in patients with moderately-to-severely active distal disease.58 Alicaforsen is approved as an orphan drug in Europe, but is not available in the United States.

A turmeric extract, standardized to 72% curcumin and given as a retention enema (140 mg of NCB-02 in 20 mL of water) QHS for 8 weeks, produced a trend towards more remission compared to placebo enema in patients with mild-to-moderate distal UC. Patients who completed all 8 weeks of therapy experienced significantly more remission (71%) than those in the placebo group (31%).59

Epidermal growth factor, a cytokine found in saliva, urine, and breast milk, given as 100 mL retention enemas (delivering 5 µg of epidermal growth factor) once nightly for 14 days, was able to induce remission in 10/12 patients with mild-to-moderate left-sided UC, whereas a placebo enema consisting of the same delivery medium led to remission in only 1/12.60 Unfortunately, no other groups have replicated these astounding results.

Nicotine retention enemas (3-6 mg nicotine for 4 weeks) may contribute to clinical improvement in patients with UC who don’t improve with corticosteroid or mesalamine enemas, albeit with some mild and transient adverse effects.61 However, they have not been found to induce remission more frequently than placebo enemas in broader UC patient groups.62 Nicotine is contraindicated for patients with CD.

Sodium hyaluronate (a mucosal hydrant and healer) enemas, given for 4 weeks, appear to be safe and may contribute to clinical response and mucosal healing in patients with distal UC.63

Rectal ozone may contribute to more rapid healing in patients with distal UC.64

Conclusion:
One-quarter of 1% of people in the United States have ulcerative colitis.65 For many of them with distal or more extensive colitis, retention enemas may be an excellent and underexamined method to deliver therapeutic liquids, including anti-inflammatory, vulnerary, and microbiota-altering substances. Knowing the value and advantages of these substances when delivered via enema may help clinicians and patients overcome the discomfort felt when talking about rectally-administered therapies.


Mark Davis Mark Davis, ND, specializes in naturopathic gastroenterology at the Bright Medicine Clinic in Portland, Oregon. Dr Davis is one of a handful of physicians in the North America with clinical expertise in fecal microbiota transplantation (FMT), which he offers via retention enema and capsule. Dr Davis sits on the board of directors of the Fecal Transplant Foundation, and he is the chairperson of the Fecal Microbiota Transplantation committee for the C diff Foundation. He received his ND degree with honors in research from the National College of Natural Medicine. His website is brightmedicineclinic.com.

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