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2. disease

LITERATURE REVIEW
Deglycyrrhizinated Licorice (DGL) for
Gastrointestinal Ulcers: How Can Something So Good
Be So Poorly Proven?
By Tina Kaczor, ND, FABNO
Licorice root has been widely used as herbal medicine dating back
to at least 500 BC.1 Traditional applications across diverse cultures
include as both a demulcent and an anti-inflammatory, often used to
soothe respiratory or gastrointestinal (GI) symptoms. Modern botanical applications of the herb continue this tradition, with recommendations including the treatment of gastric ulcers, bronchitis, cough,
and dyspepsia.2 While licorice is indispensable in these and many
other herbal applications, it comes with a slight but measurable risk
of side effects when used as a whole-root extract.
One of the constituents in licorice root is glycyrrhizin, a triterpene
glycoside that has been shown to have aldosterone-like effects.3 High
doses or chronic consumption of glycyrrhizin from licorice root can
create side effects that mimic a hypermineralcorticoid state. Clinically,
this presents as electrolyte imbalances, hypertension, and possible
cardiac abnormalities. While side effects are not common and risk
is further minimized with monitoring of the patient and knowledge
of proper dosing, removal of the glycyrrhizin compound eliminates
the risk altogether. Today, deglycyrrhizinated licorice (DGL), which is
specifically marketed for GI complaints, is a popular over-the-counter
supplement.
While DGL is popular for relieving gastric irritations, clinical trial
support is weak. DGL exemplifies a widely accepted natural agent that
“works” when assessed empirically but has yet to meet criteria for
inclusion in an evidence-based, conventional medical paradigm.
Modern History
Modern medical history of licorice root begins in 1946, with the first
article about “licorice juice” for gastric ulcers, published by Dutch
physician F. E. Revers.4 Two years later he published a report on the
use of licorice juice in the treatment of duodenal ulcers.5 While efficacy was demonstrated, side effects of edema, headaches, and cardiac
complaints were also observed in these early applications of crude
licorice extract. In 1950, J. G. Borst and colleagues proposed that the
side effects were due to retention of sodium and water along with
increased excretion of potassium and suggested the constituent glycyrrhizin (glycyrrhizinic acid) was to blame.6 By 1952, Revers had tried
an extract of licorice with glycyrrhizic acid removed in a patient with
peptic ulcer.7 He reported that removal of glycyrrhizin from the licorice extract resulted in the eradication of observed side effects. Reintroduction of whole root consumption in the same patient confirmed
the hypermineralcorticoid side effects were indeed due to glycyrrhizin.
Support for the Beneficial Effects of DGL
Much of the in vitro data on licorice root is on glycyrrhizin, with
less information available on the other constituents of licorice. For
example, glycyrrhizin and its derivatives have been shown to effectively kill H. pylori strains, including those that are clarithromycin- or
metronidazole-resistant. 8 Various flavonoids found in DGL have also
been shown to be bactericidal toward H. pylori, and may account for
some of the anti-ulcer activity preserved with the removal of glycyrrhizin. 9 In addition, DGL has demonstrated the ability to increase
mucin, possibly by increasing the number of mucous secreting cells
in the stomach.10
Perhaps the most suggestive evidence supporting DGL’s healing
effect of GI mucosa is demonstrated through protection from aspirininduced GI bleeding. Rats given a large dose of DGL (2,000 mg/kg
orally) demonstrated a reduction in aspirin-induced gastric lesions
when the DGL was coadministered but not when it was given before
aspirin ingestion. In this same study, DGL delivered intraperitoneally
showed reductions of the gastric lesion scores, implying there may be
a systemic component to the therapeutic effect. One human, placebocontrolled crossover study demonstrated that fecal blood loss induced
by aspirin (375 mg three times daily) was significantly reduced with
coadministration of DGL (175 mg/dose aspirin).11
DGL: Clinical Evidence to Date
Four different licorice medicaments are used in clinical studies on
ulcerative diseases, and differentiation among them is essential to an
accurate review of the literature. The four include crude extracts of
the whole plant, DGL combined with other agents (ie, Caved-S), DGL
alone, and drug analogs of glycyrrhizin derivatives (eg, carbenoxolone, enoxolone). Many reviews, references, and marketing materials
on DGL report on these four forms interchangeably. A closer look
at this indiscriminate use of clinical trial data shows that they are
not equivalents, and extrapolation of studies using agents containing
glycyrrhizin or glycyrrhizin-like compounds are not relevant when
compiling trial data on DGL.
Crude extracts of licorice are a traditional use of the plant and led
to the initial interest of Revers and others in proving its therapeutic
use for ulcers. Since the crude extract contains glycyrrhizin, and glycyrrhizin has been shown to heal ulcerative lesions as a single agent,
the efficacy of licorice crude extract can be assumed to be at least
partly due to the glycyrrhizin content. DGL by definition is lacking
glycyrrhizin; therefore its efficacy in ulcerative complaints must be
proven independently from data on crude extracts.
Carbenoxolone (Biogastrone™), a synthetic analogue of the
biologically active metabolite of glycyrrhizin, β-glycyrrhetinic acid,
is an approved drug in the United Kingdom and Europe for ulcers
and aphthous stomatitis. Carbenoxolone and the newer analogue,
enoxolone, both have a well-documented risk of inducing symptoms
of a hypermineralcorticoid state. The induction of side effects with a
©2009 Natural Medicine Journal 1(3), November 2009 | Page 1
glycyrrhetinic acid analogue is to be expected, as glycyrrhizin and its
metabolites have long been identified as the agents inducing these
side effects.5 As synthetic analogues of the very constituent that was
removed from DGL, there should be no extrapolation of clinical trial
data derived from carbenoxolone or enoxolone as support or repudiation of DGL’s efficacy in ulcerative complaints.
That leaves clinical trials with DGL as a single agent or DGL in
combination with other compounds as the only relevant trials in an
assessment of the clinical evidence. While trials of DGL as a single
agent are ideal, the majority of published trials are on a combination
product, Caved-S, in which DGL comprises 42% of the weight of each
capsule. The components of Caved-S are DGL (380 mg), bismuth
subnitrate (100 mg), aluminium hydroxide gel (100 mg), magnesium
subcarbonate (200 mg), sodium bicarbonate (100 mg), frangula bark
(30 mg), per tablet. It is essential to note that the term DGL is often
used synonymously with Caved-S in the primary publications as well
as in current reviews and marketing materials. For this reason, the
form of the intervention used is included in the table summarizing
the available trial data. (Table 1)
There have been no new clinical trials on the use of DGL for ulcers
in more than 20 years. The trials that have been published on Caved-S
and DGL, as a whole, have been criticized for their lack of rigorous
design. Most trials were small (the largest trial evaluated 96 patients).
Not all trials were blinded, and many did not include a placebo control
group, or the placebo was not adequately matched to the intervention
group. Further, the natural course of ulcerative disease is one of exacerbation and remission, leading to a significant number of results in
which participants experienced improvements regardless of the intervention. This makes a statistically significant improvement in the rate
of healing difficult to obtain in trials with small numbers of patients.
A comparison of the results derived from these trials provides
conflicting results without trend or obvious conclusions able to be
drawn. A cursory look at the summary of clinical trials (Table 1) shows
no standard dosage, delivery, trial duration, or methodology used in
the majority of trials. How efficacy was assessed varied between the
trials as well with questionnaires, clinical observation, barium radiography, or endoscopic assessments used.
Despite these many shortcomings, the results of some trials are
intriguing enough to merit deeper exploration. The most impressive
trial demonstrating benefit, published in 1973, enrolled 40 patients
with more than six relapses of duodenal ulcer in the prior 12 months.
The study clinic was also a surgical clinic, and all patients had been
referred to the clinic for consideration of duodenal resection from
a community physician. All patients had symptoms of unrelenting
vomiting and/or pain on enrollment. Since these patients were
severely ill, no placebo was offered; instead two levels of moderate
and intense intervention with Caved-S was used. The moderate intervention included 8 tablets 8 times daily for 8 weeks, and intense intervention was 12 tablets 8 times daily for 16 weeks. While none of the
patients required surgical intervention in the ensuing year, the cohort
consuming the higher dosage for longer duration had significantly
fewer symptomatic events during that year as well. Both groups used
a dosage of Caved-S significantly higher than most trials, with a total
DGL consumption of 4,560 mg/day in the high-dose group.12
In another trial by W. Larkworthy and colleagues, the intervention closely matched the above intervention of over 4 g daily, except it
used DGL as a single agent and there was a mastication group to see
if chewing conferred any benefit.13 This trial, which assessed patients
endoscopically, did not show statistical difference in the healing of
ulcers between the intervention and placebo groups. This may be due
to the suggestion of five meals per day for all study participants. This
frequency of eating increased the salivation of all participants, which
has been independently proven to have an anti-ulcer effect.14 Further
trials assessing the efficacy of these high doses are warranted to definitively answer the question of statistically significant effects of DGL.
As an aside, Larkworthy and colleagues suggest that further trials
must include endoscopic assessment, as symptoms do not always
correlate with healing of ulcers. This suggests that licorice’s painrelieving abilities should be assessed separately from its ability to
visibly increase the rate of healing in future trials.
Why is there such a lack of trials in the past 20 years? With the
advent of H2 blockers in the late 1970s and early 1980s, the medical
management of ulcers changed dramatically, followed by the even
more dramatic shift toward use of antibiotics after the widespread
acceptance of the role of H. pylori in ulcer etiology in most patients
in the 1990s. DGL was no longer being studied for up-front application in the healing of ulcers, but as maintenance therapy alone or
with H2 blockage agents. Caved-S was demonstrated to be equivalent to cimetidine in the prevention of relapse in a two-year follow up
study undertaken by A. G. Morgan and colleagues.15 Another study
in 1987 showed DGL decreased the rate of relapse in patients taking
ranitidine for gastric ulcers.16 The introduction and widespread usage
of the proton pump inhibitors (such as omeprazole) further clouds
the issue. This drug class has a more powerful acid suppression effect
than the older class of H2 blockers, and there is no data on the use
of DGL with proton pump inhibitors. Nevertheless, cumulatively the
data suggest DGL may have a role in protecting the erosion of mucosa
and decreasing relapse; therefore it deserves continued consideration
for adjunctive management in these patients.
Conclusion
Deglycyrrhizinated licorice (DGL) is specifically used to promote the
healing of ulcers and reduce ulcer-related symptoms. While it appears
to be efficacious in this regard, the only clinical trials published using
DGL as a treatment are poorly designed and/or were conducted
more than 20 years ago. Well-designed, larger clinical trials may be
helpful to delineate optimal dosage of DGL, as well as to determine
which patient populations can derive the most benefit. Meanwhile,
the incentive for the continued use of DGL will remain the anecdotal
relief of symptoms—a strong impetus for both the clinician and the
patient experiencing pain.
Tina Kaczor, ND, FABNO, is a naturopathic
physician board certified in naturopathic
oncology. She received her naturopathic doctorate
from National College of Natural Medicine, and
completed her residency in naturopathic oncology
at Cancer Treatment Centers of America in Tulsa,
Okla. Dr. Kaczor received undergraduate degrees
from the State University of New York at Buffalo.
She is the current president of the Oncology
Association of Naturopathic Physicians and secretary of the American
Board of Naturopathic Oncology. She is adjunct faculty at National
College of Natural Medicine as well as the Helfgott Research Institute
in Portland, Ore. She has been published in several peer-reviewed journals and is the Medical Editor of the Natural Medicine Journal.
1
Shibata S. A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi. 2000;120(10):849-862.
2
Blumenthal M. The ABC Clinical Guide to Herbs. Austin, TX: American
Botanical Council; 2003:282-287.
3
Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza
sp. and its bioactive compounds. Phytother Res. 2008;(6):709-724.
4
Revers FE. Does succus of licorice have a healing effect on the stomach ulcer?
therapy. Ned Tijdschr Geneeskd. 1946;90:135-137.
©2009 Natural Medicine Journal 1(3), November 2009 | Page 2
5
Revers FE. The treatment of gastric ulcer and duodenal ulcer with licorice
succus. therapy. Ned Tijdschr Geneeskd. 1948:92;2968-2973.
11
Rees WD, Rhodes J, Wright JE, Stamford LF, Bennett A. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol. 1979;14(5):605-607.
6
Borst JG, Blomhert G, Molhuysen JA, Gerbrandy J, Turner KP, de Vries LA.
Excretion of water and electrolytes during a 24-hour period and under influence of licorice extract. Acta Clin Belg. 1950;5(4):405-409.
12
Tewari SN, Wilson AK. Deglycyrrhizinated liquorice in duodenal ulcer. Practitioner. 1973;210(260):820-823.
7
Revers FE. Licorice juice without glycyrrhizinic acid in peptic ulcer therapy.
Ned Tijdschr Geneeskd. 1952;96(38):2338-2341.
13
Larkworthy W, Holgate PF, McIllmurray MB, Langman MJ. Deglycyrrhizinised liquorice in duodenal ulcer. Br Med J. 1977;2(6095):1123.
8
Krausse R, Bielenberg J, Blaschek W, Ullmann U. In vitro anti-Helicobacter
pylori activity of Extractum liquiritiae, glycyrrhizin and its metabolites. J
Antimicrob Chemother. 2004;54(1):243-6.
14
Malhotra SL, Saigal ON, Mody GD. Role of saliva in the aetiology of peptic
ulcer. Br Med J. 1965;1(5444):1220-1222.
9
Fukai T, Marumo A, Kaitou K, Kanda T, Terada S, Nomura T. Anti-Helicobacter pylori flavonoids from licorice extract. Life Sci. 2002;71(12):14491463.
15
Morgan AG, Pacsoo C, McAdam WA. Maintenance therapy: a two year
comparison between Caved-S and cimetidine treatment in the prevention of
symptomatic gastric ulcer recurrence. Gut. 1985;26(6):599-602.
10
van Marle J, Aarsen PN, Lind A, van Weeren-Kramer J. Deglycyrrhizinised
liquorice (DGL) and the renewal of rat stomach epithelium. Eur J Pharmacol.
1981;72(2-3):219-225.
16
Morgan AG, Pacsoo C, Taylor P, McAdam WAF. Does Caved-S decrease
the gastric ulcer relapse rate during maintenance treatment with ranitidine?
Aliment Pharmacol Ther. 1987:1(6); 633-638.
Table 1 Chronological Listing of Clinical Trials on DGL And Ulcers
Journal
Citation
Gut. 1968;
9(1):48-51
Form of
DGL used
Caved-S
Dosage Used Duration
of Trial
2 tablets,
8 weeks,
chewed 3
with
times daily
4-week
after meals
crossover
Gut. 1969;
10(4):299302
DGL
380mg/
capsule
2 capsules,
3 times daily
after meals
4 weeks
Gut. 1971;
12(6):449451
Caved-S
2 tablets,
chewed 3
times daily
after meals
4 weeks
Br Med J.
1971;
3(5773):
501-503
DGL,
380 mg/
capsule
2 capsules,
3 times daily
after meals
6 weeks
Summary of Design
Summary of Outcome
Authors’ Conclusions
Double-blind randomized controlled trial (RCT)
of 6 gastric and 48 duodenal ulcer patients.
Crossover was done in all gastric ulcer patients
and 15/48 patients with duodenal ulcers. All
patients were classified as “good,” “improved,”
or “not improved” based on reported pain
levels. Radiological imaging was also used
before and after intervention. Usage of antacid
was recorded in all patients.
Double-blind RCT of 33 patients with radiographic evidence of gastric ulcerations greater
than 10 mm2. Healing of ulcers was assessed
through radiography.
Double-blind, placebo-controlled study of
47 patients with active duodenal ulcer for
a minimum of 6 months. Inclusion included
baseline radiographic evidence of deformed
duodenal bulb or ulcer niche as well as
abdominal pain. Assessment was through
symptom questionnaire. Intervention consisted
of 4 weeks of treatment.
Multicenter RCT in the United Kingdom. 90
men with recurrent duodenal ulcers. Symptoms
assessed through patient reports and practitioner observation, fortnightly. Frequency of
alkali medication for symptom relief was also
tracked. Serum pepsinogen measured in both
groups.
Double-blind RCT with control group receiving
carbenoxolone. 37 patients with radiographically
confirmed gastric ulcers greater than 10mm2.
All patients received antacid for 1 week prior
to study participation. Assessments were done
radiographically.
All patients with gastric ulcers achieved
symptomatic and radiographic improvements. There was less use of antacid in
the Caved-S group and a trend toward
improvements in observed symptoms in the
duodenal ulcer intervention group. Followup imaging of duodenal ulcer patients
suggests a spasmolytic effect of DGL at
the level of the duodenal bulb.
The group receiving DGL had an average
reduction in ulcer size of 76%, versus
34% for the placebo group. No side effects
were reported.
There was no significant difference in
symptom reports between the two groups.
Electrolytes, complete blood count,
blood urea nitrogen, and urinalysis were
unchanged in both groups. No side effects
were reported.
“Duodenal ulcer patients showed
marked improvements, with radiographical improvements in a few
cases.” All gastric ulcer patients
showed healing of ulcers. There
appears to be a spasmolytic effect
of DGL in patients with duodenal
ulcers.
No measurable difference in subjective pain reports. No difference in the
amount of alkali medication consumed
for symptomatic relief. No difference
in practitioner reported observations of
patient’s relief of symptoms. No change in
serum pepsinogen levels.
Br J Clin
DGL
2 capsules,
4 weeks
The group receiving carbenoxolone had
Pract.
380 mg/
3 times daily
100% of ulcers either reduce in size or
1972;
capsule
after meals
heal completely. This compared to an
26(12):56385% response in patients receiving DGL.
566
There was no difference in the amount
of antacids needed by the two groups
throughout the trial.
Practitioner. Caved-S
8 tablets, 8
One year Double-blind trial using two different doses
None of the patients required surgical
1973;
times daily for
of Caved-S in 40 duodenal ulcer patients with intervention during the year of follow-up.
210(260):
8 weeks, or
unremitting pain and greater than 6 relapses
Most of the patients receiving 8 tablets
820-823
12 tablets, 8
in 12 months. Relapse was defined through the daily did have a relapse of symptoms
times daily for
presence of pain, and relapse-free defined by
within the year. Patients receiving 12
16 weeks
its absence. All patients had been referred for tablets daily did not suffer relapse. This
surgical intervention.
difference was statistically significant.
Gut. 1973;
DGL, 380
2 capsules,
8 weeks, Double-blind, placebo-controlled trial of 68
There was no statistical difference in the
14(9):711- mg/capsule taken orally 3 with
patients with radiographically confirmed
healing of the intervention group versus
715
times daily
4 week gastric ulcer(s). Assessment was done through placebo.
crossradiographic follow-up.
over
DGL represents a therapeutic alternative to carbenoxolone without the
risk of mineral corticoid side effects.
There is no advantage to the addition
of DGL in symptom management in
patients with duodenal ulcers.
There is no measurable advantage of
DGL over placebo.
The difference between carbenoxolone and DGL is statistically not
significant. As it has no side effects,
DGL represents a safe alternative to
carbenoxolone.
Higher doses of Caved-S confer a
greater protection from relapse of
duodenal ulcer symptoms. Caved-S
demonstrated efficacy even in
patients with severe, relapsing
duodenal ulcers who were referred
for surgical intervention.
The location of the ulcer in the
stomach, as well as the initial size,
influences the healing time. With
these considerations, previous
studies showing efficacy may have
had placebo groups unmatched to
interventional groups.
©2009 Natural Medicine Journal 1(3), November 2009 | Page 3
Br Med J.
1977;
2(6095):
1123
DGL
450 mg/
capsule
(Ulcedal)
or 450mg/
block chew­
ing gum
Br Med J.
DGL
1978;
(Ulcedal)
1(6106):148 450 mg/
capsule
Gut. 1978;
19(9):779782
DGL
(Ulcedal)
450 mg/
capsule
2 capsules,
8 weeks
5 times daily
or 2 blocks,
chewed for
30 minutes
5 times daily
between meals
5 capsules
2 years
daily
Controlled trial of 34 patients with duodenal
ulcers. DGL consumed as capsules or chewing
gum versus placebo of either capsules or
chewing gum of inert substance. Endoscopy
was used to assess efficacy.
There was no difference in healing of
ulcers between the intervention group vs.
placebo.
The results do not support the
concept of DGL usage in duodenal
ulcer. Saliva introduced through
chewing did not confer any benefit
to healing either. Since symptoms
do not correlate with healing, trials
should be endoscopically controlled.
Double-blind, placebo-controlled trial of 33
Relapse rates were 45% and 59% for the Although the results did not reach
patients with healed gastric ulcerations.
DGL and placebo groups respectively. This statistical significance, the need for
Assessment was through gastroscopy and
was not statistically significant.
prophylaxis in this patient populabarium imaging every 6 months. Patients were
tion lends itself to the use of DGL
followed for up to 2 years.
given the trend of less recurrence
combined with a low toxicity profile.
2 capsules, 4 4 weeks Double-blind RCT of 96 patients with
Median percentage change in the ulcer area This trial was designed to show a
times daily
endoscopy-verified gastric ulcers. Assessment was comparable in both groups. Symptom statistically significant benefit of
was through repeat endoscopy and radiological improvement was also comparable in the
DGL if there was a doubling of the
assessment. Ulcer healing was defined as
two groups. Endoscopic and radiographic
assumed placebo-healing rate of
re-epithelialization of lesion on visualization
results had little concordance.
30%. It did not show this; therefore
through gastroscopy. Radiographical healing
there is no justification for continued
was defined as disappearance of the ulcer
use of DGL.
crater on repeat imaging.
Only clinical trials published in English with the full text available in electronic or hard copy are included above.
NMJ OCT09 LR
©2009 Natural Medicine Journal 1(3), November 2009 | Page 4