Sucralfate

Leading Article

Drugs 27: 194-209 (1984) 00 12-6667/84/0003-0209/$08.00/0 © ADIS Press Limited All rights reserved.

Sucralfate A Review of its Pharmacodynamic Properties and Therapeutic Use in Peptic Ulcer Disease

R.N. Brogden, R.C. Heel, T.M. Speight and G.s. Avery ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: S. Balik, Long Island Jewish-Hillside Medical Center, New York, USA; M.I.S. Lallgmall, Department of Therapeutics, University of Nottingham, United Kingdom; G. McHardy, Medical Center of New Orleans, New Orleans, USA; I .N. Maries, Gastrointestinal Clinic, University of Cape Town, Cape Town, South Africa; T. Miyake, Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan; D.W. Piper, Royal North Shore Hospital of Sydney, St Leonards, New South Wales, Australia; C.T Ric/Ulf'tuoII, Gastroenterology Section, Veterans Administration Medical Center, Dallas, USA.

Contents

Summary ... ... .. .... ......... .. ... .. ... ..... .... ... ..... .. .... ... .. ........ .... ..... ..... .... .............. ...... ...... ....... ... ..... ..... .. 195 I. Pharmacodynamic Studies ... ....... ......... ....... ...... ......... ....... .... .. .... .. ... ....... ........ ... .... .. .. .... ....... 196

1.1 Affinity for Gastric and Duodenal Ulcers ..... ....... .... .. ........ ...... ... ...... ......... ........ .... ... ... 196 1.2 Effect on Pepsin .... .. ...... .. .... .. .................................... .. .. .... .. .. .. .... .. ........ ...... .. .. .. ......... .. ... 197 1.3 Effect on Gastric Juice .. .......... ........ .. .. .. ........ .... .. ............ .. .... .. .... ...... .. .. .... .. ...... ...... .. ...... 197 1.4 Effect on Bile Salts .......... .. ..... ..... .. .. ...... ....... .... .. .. ... .. .. .... .. ...... .. ...... .. .... ... .. .... .. ............. .. 198 1.5 Effect on Gastric Emptying ................ .. .............. .... .. .. .... .. .. .... .............. .. .... ...... .... .... .. .... 198 1.6 Prevention of Experimental Gastric and Duodenal Mucosal Damage ........ ............ .. 198 1.7 Effect on Transmucosal Electric Potential Difference ........ .. .... .. .... .... .. .. .... .. ............ ... 199 1.8 Mechanism of Action ...... .. ...... .. .... .. .. .... .. .. .... .. .. .... .. ..... .. .. ... ................ .................. .. .. .... . 199 1.9 Toxicity Studies .......... .. ........ .. ..... ... .. .. .. ...... ........... .. .. ... ..... .. ...................... .. .... ...... .. ........ 200

2. Pharmacokinetic Studies ......... ....... ...... ... ... .... ..... ... .... .... ......... ...... ........ ...... .......... ........ .. .. .... 200 3. Therapeutic Trials .... ..... ....... .. ............. .......... ... .. .. .. ... .. .... ... .... ......... .... ........ ............... .... ..... .. . 200

3.1 Treatment of Duodenal Ulcer. .... ...... ........ .... .... ...... ............ ..... ..... .... .. ..... ... .. ... ..... ... ...... 201 3.1.1 Sucralfate Compared with Placebo ......... .... ........ ...... ...... .. .. ............ ..... .... ..... .. .... .. 20 I 3.1.2 Sucralfate Compared with Cimetidine ...... ....... ... .. .. .. ............ .......... ..... .... ......... ... 201 3.1.3 Sucralfate Compared with Antacid Therapy ... .... .. .. ...... ...... ... .... ............ .. .. .... ... .. . 20 I

3.2 Treatment of Gastric Ulcer ......................... .. .... ... .. ..... .. ... .. .... .... .... ... .. .. .......... .... ......... .. 20 I 3.3 Prevention of Ulcer Recurrence .... .. .... ...... .... .. .. .. .. .... .. .... .. ........... .. .. .. .. .. ... .. .... .. .. ......... . 202 3.4 Sucralfate in Duodenal Ulcers 'Refractory' to H2-Receptor Antagonists and in

Chronic Gastritis ..... ... .. ... .. .. .... .. ..... ....... .... ...... .. ....... .... .. ............ ...... .. ....... .. .... ............. ... 205 3.5 Reflux Oesophagitis and Gastritis ................................. .... .. .... .. .... .. ...... .. .. .. ................ .. 205

Sucralfate: A Review

Summary

195

4. Side Effects ............................................................................................................................. 205 5. Drug Interactions ................................................................................................................... 205 6. Dosage and Administration .................................................................................................. 206 7. The Role of Sucralfate in Peptic Ulcer Disease ................................................................. 206

Synopsis: Sucra/fate l is a basic aluminium salt of sulphated sucrose which is advocated for use in peptic ulcer disease. It is minimally absorbed after oral administration and is believed to act primarily at the ulcer site by protecting the ulcer from the effects of pepsin. acid and possibly bile salts.

Controlled therapeutic trials have demonstrated that sucra/fate Jg 4 times daily is effective in increasing the rate of healing of duodenal and gastric ulcer over a period of 4 to 8 weeks. Trials comparing sucra/fate and cimetidine have not found any significant difference in efficacy between the drugs in small numbers of patients. A dosage of 2g daily given prophylactically decreases the rate of recurrence of duodenal ulcers. but the efficacy of sucra/fate in preventing relapse of gastric ulcers has yet to be clearly demonstrated.

Sucra/fate is particularly well tolerated. Constipation. the most common side effect. occurs in 2% of patients.

Thus. sucra/fate offers an effective and well tolerated alternative for the management of peptic ulcer disease.

Pharmacodynamic Studies: Animal studies have demonstrated a white paste-like substance that adheres selectively to ulcerated tissue after oral administration of sucralfate. The greater affinity of sucralfate for ulcer tissue than for healthy tissue has been confirmed in humans with gastric or duodenal ulcer who have undergone gastric resection or endoscopic biopsy.

Sucralfate decreases pepsin activity in vivo in rats and humans, and in diffusion cell experiments sucra1fate-coated albumin was protected from peptic activity for over 3 hours. In other in vitro experiments sucralfate has been shown to adsorb bile salts, to decrease acid diffusion and have acid-buffering properties. However, sucra1fate is minimally antacid.

Sucralfate decreases the frequency of ulcerous lesions in animals, caused by a variety of ulcerogenic substances and experimental techniques. In healthy subjects, aspirin-induced gastric mucosal damage was completely prevented in 8 of 12 subjects by prior administration of sucralfate Ig. The ability of sucra1fate to limit gastric mucosal damage is also suggested by a rise in transmucosal electric potential difference following its administration in patients with gastric ulcer.

Pharmacokinetic Studies: Sucralfate is minimally absorbed after oral administration, with only 0.5 to 2.2% of a dose being recovered in the urine over a 4-day period after ingestion of 14C-Iabelled sucralfate. In animal distribution studies, 85 to 95% of a dose was located in the gastrointestinal tract.

Therapeutic Trials: Sucralfate has been compared with placebo and with cimetidine in patients with duodenal or gastric ulcer. Controlled trials have reported endoscopically confirmed healing of duodenal ulceration in 67 to 92% of patients treated with sucralfate 4g daily for 4 weeks and in 25 to 64% treated with placebo. The consumption of antacids has varied considerably between studies and may have contributed to the high placebo response rates in some studies.

I 'Antepsin' (Ayerst, Farmos, Medipolar); 'Carafate' (Marion); 'Iselpin' (Ayerst); 'Sulcrate' (Nordic); 'Ulcermin' (Jaba); 'Ulcerlmin' (Chugai); 'U1cogant' (Merck); 'Ulsanic' (Chugai, Du Pont).

Sucralfate: A Review 196

Comparisons of sucralfate 4g and cimetidine 1 to 1.2g daily have generally been reasonably well designed, but have usually involved too few patients to be expected to detect any possible significant difference in efficacy between the drugs. Healing rates with sucralfate and cimetidine have been 66 to 80% and 73 to 75%, respectively, at 4 weeks.

Placebo-controlled studies in gastric ulcer have usually been less well designed than those in duodenal ulcer, although sucralfate 4 to 4.5g daily has been more effective than placebo in patients assessed endoscopically. In gastric, as in duodenal, ulcer, comparisons with cimetidine have included relatively small numbers of patients, and healing rates with both drugs have been similar after 6 or 8 weeks of treatment.

Sucralfate Ig twice daily administered prophylactically decreases the frequency of recurrence of duodenal ulcer relative to placebo over a period of 6 months. There was a tendency for 2g daily to be more effective than 19 daily in preventing duodenal ulcer relapse, but too few patients were included in each study group to permit any firm conclusion. Preliminary studies of sucralfate in the prevention of gastric ulcer recurrence are inconclusive. Further studies with different dosages of sucralfate in adequate numbers of patients are necessary to establish the efficacy of the drug in preventing recurrence of gastric ulcer and to determine the optimum dosage.

Side Effects: Few side effects are associated with administration of sucralfate 4g daily in the treatment of duodenal or gastric ulcer. Constipation is the most frequently reported complaint, which occurs in about 2% of patients. As sucralfate is a phosphate binder in patients with uraemia, it has potential to induce hypophosphataemia.

Dosage and Administration: The recommended adult dosage of sucralfate in the treatment of duodenal or gastric ulcer is Ig 3 times daily on an empty stomach, 1 hour before meals or 2 hours after meals, and 19 at bedtime. Treatment should be continued until the ulcer is healed, or if endoscopic reassessment is not possible, for up to 8 weeks.

1. PharmacodY1UJmic Studies 1.1 Affinity for Gastric and Duodenal Ulcers

Sucralfate is a basic aluminium salt of sulphated sucrose (fig. 1) structurally related to heparin, but without its anticoagulant properties (McGraw et al., 1981). Its development followed laboratory studies of amylopectin, a synthetic polysaccharide, which yielded inconclusive results in clinical trials of ulcer healing (Baron et al., 1977; Cocking, 1972; Landecker et al., 1976; Sun, 1973; Sun and Ryan, 1970; Zimmon et al., 1969) and caused colitis-like lesions in animals (Marcus and Watt, 1974). Sucralfate does not produce colitis-like lesions (Nagashima, 1981c).

Sucralfate is inherently viscous at acid pH and apparently forms a paste which preferentially adheres to the ulcer. The paste appears to act as a physical barrier to the diffusion of acid, pepsin and bile salts, and to form complexes with protein at the ulcer surface which resist peptic hydrolysis.

In vitro, the addition ofO.lN hydrochloric acid to sucralfate powder results in a sticky paste-like substance which adheres tightly to the bottom of a glass plate. In contrast, dried aluminium hydroxide gel forms a fine non-adherent dispersion (Nagashima and Yoshida, 1979). As paste formation depends on total mEq of available acid, rather than on acid concentration, sufficient acid is available in the empty human stomach to permit paste formation in vivo following a single 19 dose of sucralfate (Nagashima and Yoshida, 1979).

Animal studies have demonstrated that after sucralfate administration a white paste-like substance adheres selectively to ulcerous and eroded areas of the stomach (Nagashima and Hirano, 1980; Steiner et al., 1982), probably due to electrostatic attrac-


tion (Nagashima, 1981a; Nagashima and Yoshida, 1979), and that the binding is sustained longer after administration of 14C-sucralfate than the soluble potassium salt of sucrose sulphate (Nagashima et aI., 1980b). The extent of binding of sucralfate to gastric ulcers is increased by pretreatment with cimetidine 25 and 250 mg/kg (Lacz et al., 1983).

The relative affinity of sucralfate for tissue from gastric and duodenal ulcers has been demonstrated in humans (Nakazawa et al., 1981; Sasaki et aI., 1983). In 6 patients with gastric ulcer who had received sucralfate 6g daily for 3 to 5 days, ulcer tissue samples obtained at gastric resection 2 to 16 hours after the last dose contained higher mean concentrations of aluminium and sucrose sulphate than non-ulcerated tissue (fig. 2). Mean concentration of sucrose sulphate was about twice that of aluminium (Nakazawa et aI., 1981). Similar results were obtained by Sasaki et a1. (1983) in 17 patients with duodenal ulcer who were given a single dose

b [R is S03 (A12 (OHls)]

Fig. 1. Structural formula and primary structure of sucralfate.

Secondary polymerism is not depicted.

197

of sucralfate Ig. Biopsy specimens of ulcerated tissue contained higher concentrations of aluminium than non-ulcerated tissue 3 and 6 hours after ingestion of sucralfate. A higher affinity of sucralfate for recently healed duodenal ulcer than for adjacent healthy mucosa was found in 21 patients whose ulcer had healed within the previous month (Sasaki et aI., 1983).

1.2 Effect on Pepsin

One of the principal mechanisms by which sucralfate is considered to promote healing of peptic ulceration is the inhibition of peptic hydrolysis of mucosal protein. Experimental data suggest that the interaction of sucralfate polyanions with substrate proteins inhibits pepsin activity by preventing binding of pepsin to ulcer protein, thus interrupting the first step in peptic hydrolysis (Nagashima, 1981 a; Samloff, 1983).

In vitro diffusion cell apparatus experiments demonstrated that albumin coated with sucralfate was protected from peptic activity for more than 3 hours (Nagashima, 1981b), whereas sucrose octasulphate was less effective in protecting albumin.

Sucralfate has also been shown to decrease pepsin activity in vitro in human and rat gastric fluid (Borella et aI., 1979), and in vivo in pylorus-ligated rats (unpublished data on file, Marion laboratories), and in 20 patients with gastric or duodenal ulcer in whom a 32% decrease in luminal pepsin activity was observed 20 to 30 minutes after ingestion of sucralfate Ig (Masuda et aI., 1970).

1.3 Effect on Gastric Juice

Studies in animals and in humans indicate that sucralfate has little or no antacid activity in vitro or in vivo.

Although dosages 3 to 36 times the recommended human dose produced a significant increase in the pH of rat stomach contents, these increases were small compared with those produced by antacids (Borella et al., 1979).

In 5 healthy volunteers, sucralfate Ig did not alter the pH of gastric contents up to 60 minutes


after a high protein test meal. In 6 subjects, sucralfate O.5g did not increase the pH of fasting gastric contents, whereas 4 'Maalox' tablets produced a significant increase in pH (McGraw et a1., 1981).

In vitro cell diffusion studies suggest that the viscous layer of sucralfate which forms at acid pH has acid-buffering capacity and forms a barrier to diffusion of acid as well as pepsin (Nagashima, 1981 b) [see section 1.2].

Sucralfate Ig 4 times daily did not alter the bacterial flora of gastric juice or its mutagenicity to Salmonella TAlOO in 20 patients with peptic ulceration, whereas cimetidine 400mg twice daily increased bacterial content and mutagenicity of gastric juice in another group of 30 patients (Morris et a1., unpublished data).

0.5

0.4

N

E u t7 w CD

~ 0.2 <a <> ::> II)

'0 E

0.1 '"

sulphate

Fig. 2. Concentrations of aluminium and sucrose sulphate in ulcerated IZI and non-ulcerated. gastric mucosa of 6 patients with gastric ulcer who underwent gastric resection 2 to 16 hours after a 1.5g dose of sucralfate (data from Nakazawa et aI., 1981).

198

1.4 Effect on Bile Salts

In vitro, sucralfate adsorbs 20 to 45% of glycocholic acid present at neutral pH (Caspary, 1981a). Adsorption is about 3 times greater below pH 4 and comparable with that achieved with cholestyramine (Bruugsgard et a1., 1981). However, the extent of 'true' bile salt binding by sucralfate was considered by Schenkein et ai. (1983) to be too low to alter intraluminal bile salt concentration.

1.5 Effect on Gastric Emptying

The demonstration of prolongation of gastric emptying after sucralfate administration in rats (Borella et a1., 1979) has been confirmed in man. Thus, in 12 volunteers, sucralfate Ig significantly prolonged the emptying of an isotope-labelled liquid meal comprising protein, carbohydrate and fat. Such an effect could prolong the retention of sucralfate in the stomach (Hurwitz et a1., 1982).

1.6 Prevention of Experimental Gastric and Duodenal Mucosal Damage

Sucralfate has been shown to decrease the frequency of ulcerous lesions in animals, caused by a variety of ulcerogenic substances and techniques, and in humans administered aspirin.

A dose-related decrease in erosion index, and a reduction in gastric mucosal permeability to 1251_ albumin and prevention of a decrease in transmucosal potential difference was noted by Nagashima et a1. (1983) in rats with gastric mucosal damage induced by ethyl alcohol. Sucralfate 50 mgjkg decreased erosion index by 60%, whilst dosages of 200 mg/kg or more produced a 90% or greater inhibition oflesions. Sucralfate, 200mg administered before and at 3 and 6 hours after commencing a 24-hour infusion of pentagastrin and bethanecol, prevented duodenal ulceration in the rat (Smolow et aI., 1983). Ulceration produced by the same secretagogues was prevented by a combination of sucralfate 20mg plus ranitidine 5 mgjkg 4 times daily, whereas the same doses of each drug were ineffective when given alone (Zimmerman et al., 1982).


A decrease in ethyl alcohol-induced mucosal necrosis and haemorrhagic area was achieved with sucralfate 125mg (Hollander et aI., 1983; Tarnawski et aI., 1983), and ulcer index in rats was reduced by sucralfate following administration of acetic acid, taurocholic acid, cysteamine, indomethacin, prednisone or reserpine (Borella et aI., 1979; Harrington et aI. , 1981; Hirano and Takagaki, 1974; Miyoshi et aI. , 1968). However, the protection afforded by sucralfate 125mg was decreased when the prostaglandin synthetase inhibitor indomethacin 20 mg/kg was also given I hour before 2ml of 100% ethyl alcohol (Hollander et aI., 1983). These findings suggest sucralfate protects against alcohol-induced necrosis of the gastric mucosa through local prostaglandin synthesis and release.

In a placebo-controlled study in healthy subjects, sucralfate Ig 4-hourly administered 30 minutes before aspirin 900mg completely protected 8 of 12 subjects from endoscopically confirmed erosion of the gastric mucosa (Tesler and Lim, 1981). Partial protection was achieved in a further 3 subjects, but they were considered failures in terms of the study protocol. Sucralfate did not decrease plasma salicylate concentrations. On the basis of gastric deoxyribonucleic acid loss, a single dose of sucralfate 2g was more effective than placebo in decreasing gastric mucosal damage caused by taurocholic acid in 8 patients with superficial gastritis (Corinaldesi et aI. , 1982).

1.7 Effect on Transmucosal Electric Potential Difference

The measurement of transmucosal electric p0-

tential difference is a simple nonspecific method for detecting functional damage to the gastric mucosa. Mackel and Hausding (1981) recorded an increase in potential difference after ingestion of sucralfate 500mg in 6 patients with gastric ulcer, which was interpreted as a positive protective influence. In a controlled study, Caspary (198Ib) noted that a single dose of sucralfate Ig diminished the decrease in gastric potential difference in response to glycocholic acid compared with that after

199

glycocholic acid alone. These findings confirm work in animals, which found that concurrent administration of sucralfate and a mucosal damaging agent, ethyl alcohol, taurocholic acid or glycocholic acid, limited the decrease in potential difference compared with that seen when these agents were administered alone (Bighley and Giesing, 1981 ; Harrington et aI., 1981).

1.8 Mechanism of Action

Since sucralfate is minimally absorbed (see section 2), the demonstrated beneficial effect of sucralfate (section 3) is believed to occur because the drug acts either in the gastric or duodenal lumen or at the ulcer site. The possible mechanisms of action include decreased peptic activity and inhibition of peptic hydrolysis of mucosal protein, protection of the ulcer from acid and adsorption of bile salts, and through an effect on local prostaglandin synthesis (section 1.6).

Studies in man have shown sucralfate to be present in greater concentrations in ulcerated than in non-ulcerated tissue (section 1.1; fig. 2), and that luminal peptic activity is decreased by therapeutic doses of sucralfate in patients with gastric or duo-

rig. 3. Recurrence rates of peptic ulceration in 95 patients whose initial ulcer healed during treatment with sucralfate Gl or cimet

idine. [data after Marks et aI., 1983]. 86 patients were followed for 1 year or until relapse. Differences between the groups were significant only at 3 months.


denal ulcers (section 1.2). In vitro studies suggest that sucralfate forms complexes with proteins, inhibiting protein hydrolysis, and it is presumed that sucralfate binds to proteins in human ulcer tissue, thus preventing further damage. It has also been demonstrated in vitro that sucralfate forms a barrier to acid diffusion and has acid-buffering capacity. However, it is not known if this effect occurs in patients with ulcers, but it is clear that sucralfate is not an antacid at usual therapeutic dosages. In vitro studies also indicate that sucralfate adsorbs bile acids, but the relevance of this effect to the successful treatment of peptic ulceration is uncertain (Richardson, 1982).

1.9 Toxicity Studies

Acute toxicity studies in various rodent species could not determine a median lethal dose (LDso) for sucralfate, due to a lack of toxicity (Eberstein; Hirano et ai., unpublished data on file, Marion Laboratories). Sucralfate showed no significant effects in blood coagulation, whole blood clotting and prothrombin time in dogs and rabbits (unpublished data on file, Marion Laboratories). Alterations in the cardiovascular status of dogs and rabbits have not been observed, and no central nervous system effects have been seen in animals (unpublished data on file, Marion Laboratories).

2. Pharmacokinetic Studies

On the basis of urinary recovery of radioactivity after oral administration of 14C-labelled sucralfate, the drug is minimally absorbed. Plasma concentration of aluminium after administration of sucralfate 4g daily for up to 10 weeks to 17 patients with gastric or duodenal ulceration was not significantly different from that in a control group who had not ingested aluminium-containing compounds (Kinoshita et ai., 1982). In patients with uraemia, however, there is appreciable systemic absorption of aluminium (Leung et ai., 1983). In 6 healthy male subjects, the total urinary excretion of radioactivity was 0.5 to 2.2% over a 4-day period after a single Ig dose of labelled drug (Giesing

200

et ai., 1982). Maximum urinary excretion occurred during the first 4 hours after administration. These data confirm absorption studies showing 3 to 5% absorption after oral administration in animals, and distribution studies indicating that 85 to 95% of the administered dose was located in the gastrointestinal tract (unpublished data on file, Marion Laboratories).

3. Therapeutic Trials

Sucralfate has been compared with placebo and cimetidine in reasonably designed trials employing endoscopic evaluation.

Patient numbers have been adequate in the comparisons with placebo (section 3.1.1), but have been too small in studies comparing sucralfate and cimetidine (sections 3.1.2 and 3.2) to detect any possible small differences in efficacy between the drugs. Although the placebo-controlled trials have

Table I. Summary of results of double-blind therapeutic trials comparing sucralfate 4g daily and placebo in patients with endo

scopically confirmed duodenal ulcer

Reference

Fixa and Komarkova (1973)

Hollander (1983)

McHardy (1981)

Moshal et ai. (1980)

Roufail (1979)d

Sung et al. (1983)

No. of patients evaluated

124

55

216

59

54

65

Duration (weeks)

4

4

4

6-12

4

4

Endoscopic healing rate (%)

sucralfate placebo

80 60

92 58 828 538

75 64

60b 24b

77e 44e

67 578

73 25

a Results incorporating patients excluded for reasons other than compliance.

b Results at 6 weeks.

c Results at 12 weeks.

d This study formed part of the multicentre trial subsequently

reported by McHardy (1981). e Healing rates not significantly different.


all been double-blind, those comparing sucralfate and cimetidine have generally been single-blind with the endoscopist unaware of each patient's treatment. Patients have been randomly allocated to treatment groups in all studies, and in nearly all instances the groups have been shown to be comparable with respect to age, sex distribution, duration of disease and presence of relapse, and in several studies, other factors which could affect the outcome. However, comparability of groups between centres of multicentre trials was not established.

Symptomatic improvement has been recorded in most studies, but as none have reported details of pretreatment severity of symptoms, its relationship to drug therapy is uncertain.

Study protocol has varied with respect to allowable antacid usage, which may have influenced the outcome in some of the placebo-controlled studies by increasing the proportion of apparent placebo responders.

3.1 Treatment of Duodenal Ulcer

3.1.1 Sucra/fate Compared with Placebo Sucralfate, administered either 1 hour before or

2 hours after meals and at bedtime, has been shown to be more effective than placebo in promoting ulcer healing in all trials except the study of Roufail (1979) [table I]. After 4 weeks of treatment, healing rates ranged from 67 to 92% with sucralfate and from 25 to 64% with placebo (Fixa and Komarkova, 1973; Hollander, 1983; McHardy, 1981; Roufail, 1979; Sung et aI., 1983). A 6-week evaluation period was chosen by Moshal et al. (1980) who reported healing rates of 60% and 24% with sucralfate and placebo, respectively.

The rather high healing rates in placebo-treated patients studied by McHardy (1981) and Roufail (1979) may reflect the substantial consumption of liquid antacid permitted by the protocol of this multicentre trial.

3.1.2 Sucra/fate Compared with Cimetidine Sucralfate 4g daily has been compared with ci

metidine 1 to 1.2g daily in patients with endo-

201

scopically confirmed duodenal ulcer. After 4 weeks' treatment, healing rates with su

cralfate have ranged from 66 to 80% whilst the corresponding values with cimetidine were 71 to 76% (table III).

Only the study of Martin et al. (1982) was double-blind. In none of the other studies was any attempt made to disguise the tablets or to use the 'double-dummy' technique employed by Martin and his colleagues. Antacid use was minimal in all of these studies.

The rate of ulcer healing with sucralfate and cimetidine has been similar in all studies, with no statistically significant difference having been demonstrated. The lack of difference may indicate that the drugs are in fact equally effective, but it may also be due to the small numbers of patients studied (table II).

3.1.3 Sucra/fate Compared with Antacid Therapy In an open randomised trial, sucralfate 4g daily

was more effective than antacid (aluminium-magnesium hydroxide plus magnesium carbonate) IOml 7 times daily in 40 patients with endoscopically confirmed duodenal ulcer. After 6 weeks of treatment, the ulcer was healed in 78% and 48% of patients treated with sucralfate and antacid, respectively (Laitinen et aI., 1983a).

3.2 Treatment of Gastric Ulcer

The efficacy of sucralfate in gastric ulcer has generally been less well studied than in duodenal ulcer (section 3.1). Sucralfate 2.8 to 4g daily has been found to be more effective than placebo in patients assessed endoscopically. Although doubleblind, these studies have lacked data on essential design features such as comparability of groups (Fixa and Komarkova, 1973), initial ulcer size (Fixa and Komarkova, 1973; Yamagata et aI., 1974), or patient compliance (Fixa and Komarkova, 1973; Mayberry et aI., 1978; Yamagata et aI., 1974). Healing rate in these studies has ranged from 50 to 85% with sucralfate and from 17 to 71 % with placebo.


Table II. Summary of the design of therapeutic trials comparing sucralfate with cimetidine in patients with duodenal ulcer (see table

III for study results)

Reference Double- Single- 'Blind' No. of Comparability Compliance Definition

blind blind endoscopy patients of groups checks of healing

Hentschel et a!. (1983) + + O· + + +

Marks et a!. (1980, 1981) + + O· + + +

Martin et a!. (1982) + O· + + +

Pop et a!. (1983) + + O· + + +

a Too few patients to detect any possible small differences between effective drugs. Key: + = adequate, specifically stated; 0 = inadequate.

Table III. Summary of results of controlled therapeutic trials comparing sucralfate (S) and cimetidine (C) in patients with duodenal ulcer (see table II for study design)

Reference No. of patients Daily dose· Endoscopic healing rate (%)

evaluated (g) 8 weeks 12 weeks 4 weeks 6 weeks

Hentschel et al. (1983) 72 S4 66 91 C1 73 84

Marks et a!. (1981) 57 S4 83 100 C1 71 86

Martin at al. (1982) 59 S4 80 90 C 1.2b 76 86

Pop et a!. (1983) 63 S4 71 97 C1 75 97

a Sucralfate given in 4 doses of 19; cimetidine given in 3 doses of 200mg and 400mg at night unless otherwise indicated. b Cimetidine given in 4 doses of 300mg.

The comparisons with cimetidine have usually been well designed in most respects (table IV), although too few patients have been included to detect any small differences in efficacy which may exist between the drugs; healing rates with both drugs were similar after 6 or 8 weeks of treatment. As has been found with other drugs, such as ranitidine (Brogden et at., 1982), the rate of healing of gastric ulcers with sucralfate is slower than that of duodenal ulcers. After 4 weeks of treatment with sucralfate, 36 to 50% of gastric ulcers (table V) and 67 to 92% of duodenal ulcers (table I) have been healed. As in duodenal ulcer studies, only 1 trial

comparing sucralfate and cimetidine (Martin et al., 1983a,b) has been double-blind.

3.3 Prevention of Ulcer Recurrence

A recently reported study by Marks et at. (1983) indicates that relapse of duodenal and gastric ulcer occurs in about 30% and 50% of patients, respectively, over a 6-month period. 12 months after initial therapy with either sucralfate or cimetidine there was a recurrence of ulceration in about 70% of patients, although the mean duration of remission was longer in patients treated with sucralfate


(7.3 months) than in those treated initially with cimetidine (4.6 months).

Initial studies indicate that prophylactic administration of sucralfate 1 or 2g daily decreases the rate of duodenal ulcer recurrence (table VI) relative to placebo over a period of 6 months (Classen et al., 1983) or 12 months (Marks and Girdwood,

203

1983; Moshal et aI., 1983). A low relapse rate (11%) over a 6-month period during administration of sucralfate 3g daily was noted by Libeskind (1983) in patients whose duodenal ulcer was initially healed with cimetidine. There was a tendency for sucralfate 2g daily to be more effective than Ig daily in preventing recurrence of duodenal ulcer (Marks

Table IV. Summary of the design of therapeutic trials comparing sucralfate and cimetidine in patients with gastric ulcer (see table

V for study results)

Reference Patient Double- Single-seleetion blind blind criteria

Laitinen et al. + + (1983)

Marks et al. ±b 0 + (1980)

Martin et al. ±c + (1983a,b)

Pop et al. (1983) + +

'Blind' No. of endoscopy patients

+ 0·

+ 0·

OS

+ OS

Comparability Initial of groups ulcer size

comparability

+ 0

+ +

+ +

+ +

a Too few patients to deteet any possible small differences between effective drugs.

b No age limits, exclusion criteria incomplete.

c No mention of biopsy to exclude malignancy. Key: + = adequate, specifically stated; ± = limited, uncertain, incomplete; 0 = inadequate.

Compliance Possible checks influence of

antacids

0 0

+ +

+ +

+ +

Table V. Summary of results of therapeutic trials comparing sucralfate (S) and cimetidine (C) in patients with gastric ulcer (see table IV for study design)

Reference No. of Daily dose· Endoscopic healing rate (%)

patients (g) 4 weeks 6 weeks 8 weeks 12 weeks

Laitinen et al. (1983) 69 S 4b 47 80 C1 48 73

Marks et al. (1980) 55 S4 63 74

C1 75 89

Martin et al. (1983a,b)d 34 S4 53 76 C 1.2c 53 82

Pop et al. (1983) 58 S4 36 71

C1 60 83

a Sucralfate 19 administered 0.5 to 1 hour before, or 2 to 3 hours after, meals and at night. Cimetidine administered with meals (200mg) and at night (400mg) unless otherwise stated.

b Timing of administration in relation to meals not stated.

c Cimetidine 300mg administered 4 times daily.

d Martin et al. (1983a) reported on 25 of the 34 patients reported by Martin et al. (1983b).


Table VI. Summary of comparative studies of sucralfate (S) in the prevention of ulcer recurrence

Reference No. of Dosage patients (mg/day)

Comparisons with placebo

Classen et al. (1983) 126 S2OO0 Placebo

55 S2OO0

Placebo

Marks and Girdwood (1983) 35 S 1000

S2OO0 Placebo

258 S 1000

S2OO0 Placebo

Moshal et al. (1983) 32 S 2500b

Placebo

Comparison with cimetidine (C)

Libeskind (1983) 64 S3000c

C 600C Placebo

30 S3000

C600 Placebo

a Statistically significantly different from placebo.

Recurrence

rate

14/66 (21%)a

30/60 (50%)

11/30 (37%)

11/25 (40%)

3/14 ~ 1/9

(17%)8

7/12 (58%)

5/9 ~ (47%)a 2/6 9/10 (90%)

44%a

82%

2/18 (11%)a

8/24 (33%)a

13/22 (59%) 2/10 (20"/ojd

3/11 (27%)

4/9 (44%)

Duration

of study (months)

6

6

6

12

12

6

6

Type of

ulcer

Duodenal

Gastric

Duodenal

Duodenal

Duodenal

Duodenal

Gastric

b Sucralfate administered as 500mg 3 times daily and 1000mg at night. C Sucralfate administered as 1000mg 3 times dally. d Too few patients for statistical analysis. e Only 25 of the original 35 patients completed 12 months in the study at the time of reporting.

and Girdwood, 1983), but the number of patients who received each treatment was too small to permit meaningful analysis. Thus, further studies in adequate numbers of patients employing different dosages of sucralfate are required to determine the optimum dosage regimen for the prevention of duodenal ulcer recurrence.

Preliminary studies of sucralfate in the prevention of gastric ulcer recurrence are inconclusive. Classen et al. (1983) found similar rates of recurrence after 6 months' administration of sucralfate 2g daily or placebo. The similar recurrence rate in patients treated with sucralfate 3g daily or cimetidine 600mg daily suggests that the higher dosage of sucralfate may be needed in gastric ulcer (Libeskind, 1983), but the small number of patients

studied by Libeskind (1983) precludes firm conclusions.

Miyake et al. (1980) found a difference of borderline significance (p = 0.065) in the recurrence rate of gastric ulcers in patients treated for 6 months with thrice daily doses of an antacid (2g aluminium hydroxide gel, 0.5g magnesium oxide) alone or combined with sucralfate 4g daily. The relapse rates of 17% (antacid alone) and 7% (antacid plus sucralfate) were lower than generally observed. 12 months after withdrawal of treatment, the cumulative rate of recurrence was 22% and 34% in patients initially treated with sucralfate plus antacid and antacid alone, respectively (p = 0.065). However, when patients whose prestudy ulcer took longer than 8 weeks to heal were compared, ulcer


recurrence was significantly lower in sucralfate patients (37%) than in control patients (81%). Interpretation of the results is complicated by the lack of placebo control; only the endoscopist responsible for evaluating the endoscopic photographs was unaware of the treatment allocation.

3.4 Sucralfate in Duodenal Ulcers 'Refractory' to HrReceptor Antagonists and in Chronic Gastritis

In 16 of 20 patients, sucralfate 3g daily for 6 weeks resulted in endoscopically confirmed healing of a duodenal ulcer which had not decreased in size during 8 weeks of treatment with cimetidine Ig daily (13 patients) or ranitidine 300mg daily (7 patients) [Guslandi et al., 1983]. However, the open nature of this study limits the clinical relevance of these findings.

3.5 Reflux Oesophagitis and Gastritis

In a double-blind trial, sucralfate 2g 4 times daily was compared with alginate plus antacid in 40 patients with symptomatic, endoscopically confirmed reflux oesophagitis (Laitinen et al., 1983b). After 6 weeks' treatment, complete endoscopic healing was present in 54% of patients treated with sucralfate and in 44% receiving alginate plus antacid.

No significant difference between sucralfate 3g daily and carbenoxolone 150mg daily in promoting endoscopic healing was noted in 20 outpatients with endoscopic and histological evidence of chronic superficial gastritis. However, sucralfate provided greater symptomatic relief (Guslandi et al., 1981). Similarly, in 16 patients with bile reflux gastritis, sucralfate 4g daily was apparently more effective than placebo on the basis of the patients' subjective assessment, but this difference was not apparent on repeat endoscopy (Kairaluoma et al., 1983).

4. Side Effects

Sucralfate has been very well tolerated by patients receiving usually 4g daily over periods of

205

4 to 12 weeks. Reports of serious adverse effects have been rare to date, a perforated duodenal ulcer having been reported during sucralfate therapy (Caccese et aI., 1982), and side effects have rarely necessitated withdrawal of treatment.

Sucralfate has been used in the treatment of peptic ulcer for several years in Japan, and in a report by Ishimori (1981), data accumulated over a 4-year period in 2298 patients indicated a 3.5% incidence of side effects. In a review of 91 studies published between 1967 and 1980, side effects occurred in 3.6% of 2306 patients (Ishimori, 1981). As many patients in these studies received concomitant therapy with other antiulcer drugs, a separate analysis of 1149 patients treated only with sucralfate revealed an overall side effect incidence of 3.1 %. Constipation accounted for 2.1 %, dry mouth 0.3% and nausea 0.3% whilst other effects such as abdominal discomfort or fullness, dizziness, and skin eruption each occurred in 0.1 % of patients (Ishimori, 1981).

In studies that have compared sucralfate and placebo in the treatment of peptic ulceration (e.g. Hollander, 1981; McHardy, 1981; Sung et al., 1983), the side effects have been similar in nature and frequency in both groups. In the multicentre study reported by McHardy (1981), side effects occurred in 12.9% of patients treated with sucralfate and in 12.1 % of the placebo group. The most common complaint in the sucralfate group was constipation, which occurred in 3 of 116 patients (2.6%).

Laboratory investigations performed routinely during therapeutic trials have revealed no coagulation or other abnormalities considered to be directly associated with sucralfate. However, plasma aluminium concentrations are increased in patients with severely impaired renal function (Leung et al., 1983), and plasma phosphate is decreased in such patients (Sherman et aI., 1983).

5. Drug Interactions

As sucralfate adsorbs bile salts in animals (section 1.4) and decreases pepsin activity in humans (section 1.2), its ability to influence the absorption


of concomitantly administered drugs has been studied.

In dogs, concomitant administration of sucralfate and phenytoin decreased the relative bioavailability of phenytoin to 62%, but bioavailability was not affected when the drugs were given 2 hours apart. Sucralfate did not affect the absorption of commercially available digoxin, quinidine, propranolol or aminophylline when administered concomitantly, or of tetracycline given 2 hours after sucralfate (Lacz et aI., 1982). Minor changes in the proportion of the dose of digoxin eliminated occurred in healthy subjects given sucralfate simultaneously. These changes were minimised by administering the drugs 2 hours apart (Giesing et al., 1983).

A possible clinically important interaction between sucralfate and warfarin has been reported in 1 patient receiving stable dosages of warfarin (Smg alternating with 7.Smg daily) and an unstated dose of sucralfate. After temporary discontinuation of warfarin because of upper gastrointestinal haemorrhage, the drug was restarted at the previous dosage and sucralfate added to the therapeutic regimen. During a week of sucralfate administration, plasma warfarin concentrations were 0.5 to 0.6 mgf L compared with 1.5 to 1.6 mg/L over a 2-month period prior to sucralfate therapy. Over a 9-day period after sucralfate withdrawal, plasma warfarin concentration increased to 1.6 mgfL and prothrombin time subsequently increased to pre-sucralfate levels (Mungall et aI., 1983). Thus, caution is advisable when sucralfate and warfarin are administered concomitantly, and particularly after sucralfate withdrawal if warfarin dosage has been adjusted to maintain prothrombin times.

6. Dosage and Administration

The recommended adult dosage of sucralfate in the treatment of duodenal or benign gastric ulcer is Ig 3 times daily on an empty stomach, 1 hour before or 2 hours after meals, and Ig at bedtime. Treatment should be continued until the ulcer is healed, or for up to 8 weeks if endoscopic reassessment is not possible. If there is no objective

206

improvement of gastric ulcer after 6 weeks' treatment with sucralfate, alternative treatment should be considered.

The presence of malignant gastric neoplasm should be excluded before treating symptoms of gastric ulceration with sucralfate.

In patients with advanced renal failure, the absorption of aluminium after sucralfate administration was similar to that after a dosage of aluminium hydroxide containing an equal amount of elemental aluminium (Leung et aI., 1983), and serum phosphate concentrations may be decreased in such patients (Sherman et aI., 1983). Thus, caution should be exercised when administering sucralfate in patients with impaired renal function.

7. The Role of Sucralfate in Peptic Ulcer Disease

As might be expected at this stage of its development, the extent of published therapeutic experience with sucralfate is considerably less than that with cimetidine, but controlled studies indicate that sucralfate is effective in accelerating the healing of duodenal ulcers. Sucralfate has been less well studied in gastric ulcer, although it has generally been found to be more effective than a placebo. Although sucralfate has not been found to be statistically significantly different from cimetidine in the treatment of either duodenal or gastric ulcer, the small numbers of patients studied precludes a firm conclusion that these drugs are equally effective.

Preliminary studies show that sucralfate 2g daily is effective in decreasing the recurrence of duodenal ulcer. However, the optimum maintenance dosage in duodenal ulcer has not been defined, and the efficacy of sucralfate in preventing recurrence of gastric ulcer has yet to be clearly demonstrated.

Sucralfate is minimally absorbed and has a limited potential to cause systemic side effects in patients with normal renal function. However, sucralfate is an effective phosphate binder in patients with uraemia (Leung et al., 1983; Sherman et aI., 1983) and thus has the potential to induce hypophosphataemia in such patients with ulcer disease.


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Authors' address: R.N. Brogden, ADIS Drug Information Services, P.O. Box 34-030, Birkenhead, Auckland 10 (New Zealand).

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