Exploring Pharmacological Treatments For Chronic Idiopathic Constipation In Adults: A Look Back To The FutureⅡ
Sep 05, 2023
3. Commercially Available Drugs with Evidence of Efficacy on CIC
3.1. Magnesium Salts
Pharmaceutical preparations containing magnesium (magnesium nitrate, magnesium sulfate, magnesium oxide, magnesium hydroxide, and magnesium citrate) have been in use in Eastern and Western countries since at least the 8th century [13]. However, the use of magnesium salts was more based on anecdotal than on actual scientific evidence [14]. Some small pediatric studies showed that magnesium hydroxide was as effective as macrogol in relieving symptoms in children [15,16], but no data were available on adult CIC patients. More recently, due to its safety, availability, and substantially low cost (at least compared to other laxatives), there has been renewed interest in magnesium salts.
Two randomized clinical trials on the effects of magnesium oxide in adult CIC patients have recently appeared in the literature. In a double-blind randomized controlled trial patients received magnesium oxide (0.5 g t.i.d.) or a placebo for 28 days; the first group had a significant improvement in overall constipation scores compared to the placebo (70.6% vs. 25%, p = 0.015), a significant overall increase in spontaneous bowel movements (SBM, 6.07 ± 2.26 vs. 2.86 ± 2.42, p = 0.002) and an improvement in the quality of life, as well as in colonic transit time [17]. In a second randomized, placebo-controlled, double-blind trial, patients received magnesium oxide (1.5 g per os), senna (1 g) or a placebo for 28 days. Analysis of the study data revealed that an overall improvement in symptoms was documented in 68.3% of patients who received magnesium oxide, 69.2% of those who received senna, and 11.7% of those who received the placebo (p < 0.0001) [18].
Compared to the placebo, SBM increased significantly in patients taking magnesium and senna (p < 0.001), and the same was documented for complete SBM (p < 0.01). Furthermore, significant improvements in the quality of life were recorded for senna (p < 0.05) and magnesium (p < 0.001) compared to the placebo. No significant adverse events were reported for both laxatives. Interestingly, despite the long history of treating CIC with natural mineral waters rich in magnesium sulfate [19], no controlled studies on this topic were available until recently. Some recent studies, however, have demonstrated the benefits of this treatment in constipated subjects. In a randomized, double-blind, placebo-controlled trial 244 constipated women (Rome III criteria) were randomized to drink 1.5 L of natural low-mineral water (controls), 0.5 L of magnesium sulfate-rich natural mineral water (Hépar) plus 1 L of natural low-mineral water, or 1 L of Hépar plus 0.5 L of natural low-mineral water daily for four weeks [20].
Information was obtained on the number and type of stools (according to the Bristol scale), abdominal pain, adverse events, and rescue medications. Analysis of the results showed that after the first week, no changes in bowel parameters occurred. After two weeks, constipation improved in about 20% of the controls, in about 31% of the Hépar 0.5 L group, and about 38% in the Hépar 1 L group; both Hépar groups showed significant differences compared to the controls. The Hépar 1 L group also showed a significant decrease in fecal consistency and the use of rescue drugs compared to the controls. The safety of this approach was rated as very good by the investigators, and no serious adverse events were reported [20]. These results were confirmed by a subsequent investigation carried out by the same group in 226 patients, randomized to drink 1.5 L of natural low-mineral water (controls), or 1 L Hépar plus 0.5 L of natural low-mineral water over two weeks [21].
Again, no safety concerns were raised and the response time for symptom improvement was one week. Another randomized, double-blind, placebo-controlled study of 100 patients with CIC (Rome III criteria) evaluated the effects of magnesium sulfate-rich mineral water (Ensinger Schiller Quelle), 1 L per day, compared to the same amount of carbonated tap water (as placebo) over six weeks [22]. The primary endpoint was the change in the frequency of evacuations/week between baseline and the end of the study, while the secondary endpoint was the change in the frequency of evacuations/week between baseline and three weeks.
Analysis of the results showed that after six weeks of treatment, no significant differences were appreciated between the two groups; however, at three weeks significant differences were found in the active treatment group compared to placebo (2.02 ± 2.22 vs. 0.88 ± 1.67 defecations/week, p = 0.005), suggesting that the effect of this mineral water was time-limited. Another randomized, double-blind, placebo-controlled study examined the effects of another mineral water rich in magnesium sulfate (Donat) on 106 CIC patients (Rome III criteria) over six weeks [23].
Patients were randomized into four arms, two drinking 300 mL/day of Donat or low-mineral sparkling water (placebo), and two drinking either 500 mL/day of Donat or a placebo as above. Data analysis showed no significant benefit of Donat in the 300 mL arm, which was closed after the interim analysis, whereas in the 500 mL arm, patients drinking Donat displayed significant improvements at the end of the study period compared to the placebo in the number of complete spontaneous bowel movements (p = 0.036), stool consistency (p < 0.01), and subjectively perceived constipation symptoms (p = 0.005).
The treatment was considered safe overall by the investigators. To date, the use of magnesium oxide in the treatment of patients with CIC is only mentioned in Japanese guidelines, with a “strong” recommendation [13,24]. Other magnesium salts are mentioned in other guidelines but with a “weak” recommendation due to the low level of evidence for these combinations [13].
3.2. Colchicine
Colchicine is a natural alkaloid with a long historical use in medicine for the treatment of inflammatory diseases, such as gout; its effects on gastrointestinal transit acceleration have been documented for centuries [25]. A recent systematic review confirmed that colchicine increases the rate of gastrointestinal adverse events, especially diarrhea [26]. The latter fact, well-known among physicians, stimulated the interest of researchers as a potentially useful effect in patients with CIC.
Thus, after a preliminary report on its efficacy in three severely constipated Parkinsonian patients [27], colchicine was tested in a small uncontrolled/pilot study to treat CIC patients refractory to conventional medical therapy. Verne and colleagues treated seven of these patients with colchicine, 0.6 mg per os t.i.d. for two months, documenting a significant increase in SBM compared to baseline (6.4 ± 0.7 vs. 1.7 ± 0.5, p < 0.05) [28]. Subsequently, two randomized, placebo-controlled trials were conducted on severely constipated patients who did not respond to medical treatment. In the first study, 16 patients were randomized to receive 0.6 mg colchicine t.i.d. or a placebo for a month [29].
Compared to the placebo and baseline, colchicine significantly increased the number of weekly bowel movements (2.7 ± 1.8 vs. 9.9 ± 5.3, p < 0.0001) and accelerated colonic transit (63.1 ± 12.9 vs. 29.1 ± 19.1 h, p < 0.0001). In the second study, 60 patients (30 in each group) were randomized to receive colchicine (1 mg q.i.d.) or a placebo for two months [30]. At the end of the study period, the symptom score (Knowles–Eccersley–Scot score) was significantly reduced for colchicine compared to the placebo (11.7 ± 4 vs. 18.7 ± 4, p = 0.0001).
3.3. Misoprostol
An analog of prostaglandin E1, misoprostol is sometimes used in gastroenterology as a preventive agent against the adverse effects of non-steroidal anti-inflammatory drugs [31]. Due to its effects on accelerating gastrointestinal transit [32,33], misoprostol often causes diarrhea, especially at higher doses, and this effect has been exploited as a possible treatment for CIC [34]. Two small studies were carried out in patients with severe symptoms and refractory to other treatments. The first was a three-week double-blind, randomized, crossover study of nine patients [35]. Compared to the placebo, misoprostol (1200 mcg/day) significantly increased the number of weekly evacuations (6.5 ± 1.3 vs. 2.5 ± 0.11, p = 0.001), total weekly stool weight (976.5 ± 289 g vs. 434.6 ± 190.5 g, p = 0.001), and large bowel transit time (66 ± 10.2 h vs. 109.4 ± 8 h, p = 0.0005).
The second open-label study lasted four weeks and was conducted in 18 CIC patients with refractory symptoms, who were administered misoprostol (600–2400 mcg/day) as an adjunctive therapy [36]. As six patients dropped out of the study due to adverse events (cramps and abdominal discomfort), data were obtained from the remaining 12; in these patients, a significant reduction in the mean interval between the frequency of defecations compared to baseline was reported (4.8 vs. 11.2 days, p = 0.0004). In a small subgroup of patients (N = 4) in this study, the effect of a single dose (400 mcg/day) of the drug on post-prandial colonic motor activity was evaluated and compared with results obtained in five healthy controls.
Misoprostol significantly increased the colonic motor response to the meal in the whole colon, with a greater response in the left than in the right segments of the large bowel. Despite the potential usefulness of misoprostol for the treatment of constipated subjects, due to its abortive effects [37] and the fact that most patients were women, this drug has not been further exploited in other randomized controlled trials for the treatment of CIC.
3.4. Antibiotics
Although there is recent evidence that the gut microbiome may be abnormal and play an important clinical role in CIC patients [38–40], the effects of its imbalance caused by various factors (including antibiotic therapies [41]) have only been explored in a limited number of studies. In a small uncontrolled study, eight women with CIC resistant to dietary fibers were given ispaghula for a fortnight, followed by oral vancomycin (250 mg t.i.d.) for two further weeks while continuing to receive the fiber supplement [42].
Daily bowel symptoms (diary) and stools were collected during the two study periods. Whole gut transit time and the oro–caecal transit time (breath hydrogen test) after a standard meal were measured at the end of each period together with gastrointestinal symptoms (visual analog scale). Administration of vancomycin significantly increased the frequency and improved the consistency of stools, ease of defecation, and the amount of stool the patients felt they were producing. However, objective measures of stool weight and whole or oro–caecal intestinal transit time showed no significant differences.
In a controlled pilot study, 30 patients with CIC unresponsive to dietary fibers were randomized to receive oral lincomycin (500 mg) and fibers or placebo plus fibers for 10 days, followed by a 10-day period in which they only received fibers [43]. In the lincomycin group, the frequency of weekly defecations increased from 2.6 to 4.4 (p < 0.02), while it remained unchanged (2.9) in the placebo group. Another pilot study, randomized and placebo-controlled, investigated the effect of rifaximin (400 mg t.i.d.) on the colonic transit and methane production of 23 CIC patients [44].
After 14 days of treatment, rifaximin-treated patients had a significantly reduced colonic transit compared to the placebo, while the weekly stool frequency (diary) and form (Bristol stool scale) tended to improve, and methane production was reduced. Two studies conducted by the same group showed that eradication of Helicobacter pylori in patients with associated CIC can improve constipation symptoms. In a short-term study, 166 patients underwent eradication (vonoprazan plus amoxicillin/clarithromycin or amoxicillin/metronidazole, or amoxicillin/sitafloxacin) and constipation-related symptoms were assessed with the gastrointestinal symptom rating scale score [45].
In patients with successful eradication, scores were significantly improved two months after eradication, compared to baseline (8.00 ± 2.8 vs. 6.16 ± 3, p < 0.01), while scores in patients with failed eradication were similar before and after eradication. The same group carried out another such study over a long-term period (2 and 12 months) [46]. Two hundred and seventy-eight Helicobacter pylori-positive patients underwent eradication as in the first study.
Constipation-related scores, measured as above, showed that successfully eradicated patients improved significantly compared to baseline two months (7.91 ± 3.15 vs. 6.07 ± 2.75, p < 0.01) and one year after treatment (6.85 ± 3.46, p = 0.04). In patients with improved scores two months after treatment, an improvement one year after treatment was observed. In contrast, patients without an improvement after two months did not show an improvement after one year.
3.5. Pyridostigmine
Acetylcholinesterase inhibitors, such as neostigmine and pyridostigmine, delay the degradation of acetylcholine at the synaptic cleft. This increase in acetylcholine has been shown to increase gut motility, which has led to their use in dysmotility of the gastrointestinal tract [47], including CIC. In an uncontrolled pilot study, 10 CIC patients with autonomic neuropathy were treated with a placebo for a fortnight and then given pyridostigmine up to the maximum tolerated dose (180 to 540 mg/day) for six weeks [48]. Analysis of the results showed that the drug was well-tolerated in most patients, but symptoms (severity scores of constipation) improved in only 40% of patients, and colonic transit was accelerated in only 30% of cases. In another small uncontrolled study, six patients with CIC were initially given 10 mg b.i.d. of pyridostigmine, increased to 30 mg b.i.d. for several weeks if the initial dose was ineffective [49].
Only one constipated patient showed transient benefits from the treatment. In a further randomized controlled investigation, 30 CIC constipated patients with diabetes mellitus (18 type 1, 12 type 2) were given either a placebo or pyridostigmine (60 mg t.i.d. at baseline and increased by 60 mg every third day up to the maximum tolerated dose or 120 mg t.i.d., maintaining this dose for a week) [50].
Patients were evaluated clinically and by gastrointestinal and colonic transit scintigraphy at baseline and on the last three and seven days of treatment. Analysis of the results showed that pyridostigmine significantly improved daily stool frequency (0.95 ± 0.2 vs. 1.5 ± 0.2, p = 0.02), consistency (Bristol scale, 2.5 ± 0.3 vs. 3.4 ± 0.2, p < 0.005), and ease of stool transit (3.5 ± 0.2 vs. 3.8 ± 0.5, p < 0.04). In addition, the drug significantly accelerated colonic transit after 24 h (1.96 ± 0.18 vs. 2.45 ± 0.20, p < 0.01), but showed no significant effects compared to the placebo about gastric or small bowel transit.
A more recent double-blind study compared the effects of pyridostigmine and bisacodyl in CIC patients refractory to conventional treatments. For this purpose, 68 of these patients (34 per group) were randomly assigned to pyridostigmine (60 mg t.i.d.) or bisacodyl (5 mg t.i.d.) for four weeks [51]. Compared to baseline, the number of weekly defecations improved significantly in both the pyridostigmine group (1.55 ± 1.28 vs. 5.96 ± 1.84, p = 0.005) and the bisacodyl group (2.26 ± 1.48 vs. 5.16 ± 1.95, p = 0.005).
3.6. Trimebutine
Trimebutine maleate is a spasmolytic drug that acts on the gastrointestinal tract through an agonist effect on peripheral mu, kappa, and delta opioid receptors, the release of gastrointestinal peptides (motilin), and modulation of the release of other peptides (gastrin, glucagon, and vasoactive intestinal peptide) [52].
The drug is effective in stimulating colonic motility in experimental animals [53]. The effects of trimebutine in patients with CIC were analyzed in a double-blind crossover study of 24 patients. Fecal frequency, colonic transit time, and electromyographic activity of the large intestine were evaluated at baseline and after receiving trimebutine (200 mg per day) or a placebo for one month [54].
Compared to the placebo, (a) stool frequency did not differ after trimebutine treatment, although both significantly increased stool frequency, suggesting a placebo effect on this variable; (b) colonic transit time decreased significantly (from 105 ± 19 to 60 ± 11 h) only in patients with delayed transit; (c) trimebutine, again in patients with delayed transit, significantly increased the number of post-prandial propagating burst (from 2.1 +/− 0.3 bursts/h to 3.5 +/− 0.6 bursts/h), events associated with the colonic transport of contents and defecatory stimuli [55].
Natural Herbal Medicine For Relieving Constipation-Cistanche
Cistanche is a genus of parasitic plants that belongs to the family Orobanchaceae. These plants are known for their medicinal properties and have been used in Traditional Chinese Medicine (TCM) for centuries. Cistanche species are predominantly found in arid and desert regions of China, Mongolia, and other parts of Central Asia. Cistanche plants are characterized by their fleshy, yellowish stems and are highly valued for their potential health benefits. In TCM, Cistanche is believed to have tonic properties and is commonly used to nourish the kidney, enhance vitality, and support sexual function. It is also used to address issues related to aging, fatigue, and overall well-being. While Cistanche has a long history of use in traditional medicine, scientific research on its efficacy and safety is ongoing and limited. However, it is known to contain various bioactive compounds such as phenylethanoid glycosides, iridoids, lignans, and polysaccharides, which may contribute to its medicinal effects.
Wecistanche's cistanche powder, cistanche tablets, cistanche capsules, and other products are developed using desert cistanche as raw materials, all of which have a good effect on relieving constipation. The specific mechanism is as follows: Cistanche is believed to have potential benefits for relieving constipation based on its traditional use and certain compounds it contains. While scientific research specifically on Cistanche's effect on constipation is limited, it is thought to have multiple mechanisms that may contribute to its potential to relieve constipation. Laxative Effect: Cistanche has long been used in Traditional Chinese Medicine as a remedy for constipation. It is believed to have a mild laxative effect, which can help promote bowel movements and induce constipation. This effect may be attributed to various compounds found in Cistanche, such as phenylethanoid glycosides and polysaccharides. Moistening the Intestines: Based on traditional use, Cistanche is considered to have moisturizing properties, specifically targeting the Intestines. Promoting hydration and lubrication of the Intestines may help soften tools and facilitate easier passage, thereby relieving constipation. Anti-inflammatory Effect: Constipation can sometimes be associated with inflammation in the digestive tract. Cistanche contains certain compounds, including phenylethanoid glycosides and lignans, that are believed to have anti-inflammatory properties. By reducing inflammation in the intestines, it may help improve bowel movement regularity and relieve constipation.
