1, treatment of chronic constipation
First, medication.
(a) serotonin 4 receptor agonists
1.Procarbril: It is the first serotonin 4 receptor agonist with high selectivity and affinity. The main mechanisms are as follows: ① activating intestinal intermediate neurons and increasing intestinal high-amplitude propulsion peristalsis; ② Improve visceral sensitivity. The short-term efficacy of procardipine in the treatment of chronic constipation has been confirmed by phase III clinical trials, and its efficacy has nothing to do with constipation types. The long-term efficacy of this drug is still controversial. Studies have shown that the curative effect of procarbapril can be maintained for a long time. However, another study shows that its long-term efficacy is not better than placebo, and the reason for this result is not clear. The most common adverse reaction of procaine is diarrhea, and the incidence of headache, abdominal pain and vomiting is low, and most of them are mild and temporary. Unlike cisapride and tegaserod, prucalopride has no interaction with potassium channels of human ether-a-go-go related gene (hERG), but has low affinity with serotonin 1 and serotonin 2B, so no cardiovascular adverse events caused by prucalopride have been found.
The constipation guidelines of the World Gastroenterology Organization (WGO) list procardipine as Grade I evidence and Grade A advice. Because 85% of constipation patients in previous studies were adult women, the drug is only approved for adult female constipation patients who are ineffective in laxative treatment in China and Europe. Recent phase III clinical trials show that procaine can also effectively treat chronic constipation in adult men.
2. Other new serotonin 4 receptor agonists under study: ①Velusetrag, also known as TD-5 108, has an affinity for serotonin 4 receptor at least 400 times that of other serotonin receptor subtypes. Single dose of Velusetrag can significantly accelerate the transmission of small intestine and colon, and multiple doses can accelerate gastric emptying. A phase II clinical trial showed that Velusetrag could significantly increase the number of spontaneous defecation without cardiovascular adverse reactions. ② Naripril, also known as ATI-7505, has little interaction with AEKG channel and 5- hydroxytryptamine 3 receptor, is not metabolized by cytochrome P450 enzyme, and has little probability of interaction with other drugs. Nalobili can accelerate intestinal transmission, reduce the viscosity of feces, and significantly increase the number of spontaneous defecation in constipation patients. Common adverse reactions include headache, diarrhea, nausea and vomiting. ③YKP 108 1 1 and TD-8954, the former can accelerate intestinal transmission and improve constipation symptoms of patients with chronic constipation; The effectiveness and safety of the latter in promoting sports need further study and confirmation.
(II) Chloride ion channel activator
Rubiprostone is a bicyclic fatty acid derived from prostaglandin, and its mechanism may be as follows: ① activating type 2 chloride channel, allowing a large amount of liquid to enter the intestinal cavity; (2) Increasing gastric mucus secretion in basic state is beneficial to food emptying; ③ Activating ATP-sensitive potassium channels and regulating the pacing potential of interstitial cells of colon Cajal. Rubiprostone can safely and effectively treat chronic disease constipation (CIC), constipation irritable bowel syndrome (IBS), opioid-induced constipation (OIC) and Parkinson's disease complicated with constipation, and its common adverse reactions are nausea and diarrhea. The US Food and Drug Administration has approved rubiprostone for treating CIC, female constipation IBS and 0IC. WGO listed Rubiprostone as Grade I evidence and Grade A suggestion. However, rubiprostone has not been used for clinical treatment in China.
(3) guanylate cyclase C(GC-C) agonist
1. linalool peptide: The mechanism is as follows: ① activating GC-C, promoting intestinal fluid secretion and accelerating intestinal transport; ② Reduce visceral hypersensitivity; ③ Maintenance of intestinal mucosal barrier, anti-inflammation and regulation of intestinal mucosal cell regeneration and apoptosis. Linalool peptide can improve constipation, abdominal pain, abdominal discomfort and other symptoms in patients with constipation IBS and CIC, and improve their quality of life. Linalool mainly acts on the digestive tract, with low oral bioavailability and few systemic adverse reactions. The common adverse reaction is diarrhea. At present, FDA and European Medical Organization (EMA) have approved it to treat constipation IBS and CIC. WGO classified it as second-level evidence and B-level suggestion.
2. Pulika Nateptide: It is a GCC agonist under study, which can increase the number of spontaneous defecation in patients with constipation, with good safety and tolerance.
(d) Ileal bile acid transport inhibitor
Elobixibat, also known as A3309, is a highly selective ileal bile acid transport inhibitor, which can regulate the intestinal and liver circulation of bile salts, promote the synthesis of bile salts and discharge them into the intestinal cavity, thus promoting intestinal secretion and motivation. Elobixibat can accelerate the intestinal transmission of constipation patients and improve constipation symptoms. Elobixibat has low oral bioavailability and few systemic adverse reactions. The common adverse reactions are abdominal cramps and diarrhea. The efficacy and safety of Elobixibat need to be further confirmed by large-scale research.
(5) Opioid μ receptor inhibitors
Opioid drugs can activate intestinal opioid μ receptor while exerting analgesic effect, thus inhibiting intestinal peristalsis and intestinal fluid secretion, leading to constipation. Traditional laxatives are not effective for OIC, so peripheral opioid μ receptor inhibitors (such as methylnaltrexone, ivemopan and naloxone) can be used to treat OIC. Studies have shown that methylnaltrexone and ivemopan can increase the frequency of defecation in patients with OIC. FDA and EMA have approved the use of methylnaltrexone to treat patients with terminal diseases (such as incurable malignant tumors or other terminal diseases) that are ineffective for laxatives. Avimopan has been approved by FDA for the treatment of postoperative intestinal obstruction, but it is only used for hospitalized patients because it may increase the risk of myocardial infarction. Naloxitol can also improve the constipation symptoms of patients with refractory OIC and maintain the analgesic effect of opioids. Unlike methylnaltrexone, naloxone can be administered orally. The FDA and EMA have approved naloxone for the treatment of OIC.
Second, non-drug therapy.
biofeedback
Biofeedback is a psychotherapy technique developed on the basis of behavioral therapy, which may play a role by improving the dysfunction of bidirectional brain-gut axis in patients with uncoordinated defecation. A recent long-term follow-up study shows that biofeedback can effectively improve constipation symptoms of patients with uncoordinated defecation. 20 15 American and European Neurogastroenterology and Dynamics Societies recommend biofeedback for short-term and long-term treatment of incongruous defecation (Grade I evidence, Grade A recommendation), but it is not recommended for constipation patients without defecation disorder.
(b) nerve stimulation
SNS was first used to treat urinary incontinence and urinary retention, and has been gradually used to treat intractable constipation since 1990s. Its therapeutic mechanism is still unclear. Different from the previous view (it may act through afferent and efferent nerves), a systematic review study analyzed from two aspects of "clinical symptoms and physiological effects" and concluded that SNS may act by affecting pelvic floor afferent nerves or central nervous system. In addition, SNS can relax the rectal wall and improve rectal sensitivity.
The effect of SNS on chronic constipation is still controversial. A long-term follow-up study shows that SNS can improve the symptoms and quality of life of patients with chronic constipation, especially for non-obstructive constipation (OOC). Different from the above research results, a recent observation study included 44 patients with chronic constipation who received temporary SNS treatment, of which 15 patients received permanent SNS implantation, but only 5 patients were relieved after long-term follow-up; In this study, the success rate of slow transit colonoscopy (STC) is similar to OOC. At present, European experts believe that the evidence of SNS in the treatment of fecal incontinence and constipation is not sufficient, and further research is needed to confirm it. When the constipation symptoms (excluding organic obstruction) of STC and/or OOC patients last for more than 1 year, and other treatments are ineffective, SNS (evidence level 4, not recommended) can be considered.
(3) Electrical stimulation of colon and rectum
1. Colonic electrical stimulation: A recent exploratory study showed that the symptoms of chronic constipation were improved in two STC patients who failed to respond to general treatment.
2. Rectal electrical stimulation: Compared with SNS and colon electrical stimulation, implanted electrodes in rectum are relatively noninvasive. One study included 147 patients with functional defecation disorder who did not respond to biofeedback therapy. The results showed that the effective rates of rectal electrical stimulation were 50.8% and 64.8% for patients with rectal hyposensitivity and non-rectal hyposensitivity, respectively. This method can be used as a new choice for the treatment of refractory chronic constipation with ineffective biofeedback.
(d) body surface electrical stimulation
1. Tibial nerve stimulation: Tibial nerve is a branch of sciatic nerve, which contains nerve fibers of lumbar 4 and 5 and sacrum 1 ~ 3. These nerve fibers come from the same spinal cord segment as those innervating pelvic floor and rectum. Percutaneous tibial nerve stimulation (PTNS) has been used to treat fecal incontinence, overactive bladder and chronic pelvic pain. An exploratory study included 18 STC patients (including 17 women with an average age of 47) who did not respond to biofeedback therapy. The results show that PTNS can improve constipation symptoms and improve the quality of life of patients.
Compared with PTNS, percutaneous tibial nerve stimulation (TTNS) does not require acupuncture, is relatively non-invasive and can be used by patients at home. A study involving 12 female patients with chronic constipation found that after TTNS treatment, 26% patients' constipation-related quality of life and symptom scores were significantly improved, and 2 of them felt that their constipation symptoms were completely improved.
2. Transabdominal electrical stimulation (TES); TES uses four surface electrodes, two of which are placed next to the 9th and 10 thoracic vertebrae to the 2nd lumbar vertebrae, and the other two are placed under the ribs on both sides of the anterior abdominal wall. As early as 2004, Australian scholars conducted exploratory research and TES on 8 children with refractory STC. The results showed that TES could increase the number of spontaneous defecation in five children. Subsequently, the team conducted a randomized controlled study and a long-term follow-up study in turn. The results show that TES can improve the constipation symptoms of STC children. The researchers adjusted the treatment scheme of STC children who did not respond to TES treatment in the past to family portable TES treatment (that is, the treatment time was increased from 20 minutes three times a week to 1 time a day and 1 hour each time), but the constipation symptoms of some children could still be improved. Regarding the evaluation of the efficacy of TES in the treatment of adult STC, an experimental study involving 1 1 adult STC patients showed that after TES treatment, constipation symptoms of 7 patients were improved; TES may provide a new choice for the treatment of chronic constipation. However, the existing research sample size is small and the research quality level is low. In the future, it is still necessary to design a well-designed large sample study to further verify its efficacy and explore possible treatment mechanisms.
3. Han's transcutaneous acupoint electrical stimulation (HANS): In recent years, Han has combined transcutaneous nerve electrical stimulation with acupuncture and acupoint selection, and placed skin surface electrodes on acupoints for electrical stimulation. Because this method is non-invasive, it has been gradually applied to the treatment of various gastrointestinal functions and dynamic diseases. Studies have shown that Hans can improve constipation symptoms. Its mechanism may be related to regulating vagus nerve excitability, changing gastrointestinal hormone level, or repairing interstitial cells and intestinal neurons damaged by Cajal. HANS is safe and simple, which is more suitable for family individualized treatment. However, its long-term efficacy still needs to be verified by large sample and multi-center research.
4. Electroacupuncture therapy: Acupuncture is a general definition, including hand acupuncture, electroacupuncture therapy, warming acupuncture and acupoint injection. In recent years, most clinical studies to evaluate the curative effect of acupuncture on chronic constipation involve electroacupuncture therapy. The curative effect of electroacupuncture treatment may be related to the depth or frequency of stimulation, acupoints, constipation types and combined drug treatment. Although some studies have shown that electroacupuncture therapy can alleviate the symptoms of chronic constipation, most related studies have small sample size and low quality, and its efficacy needs to be further verified by well-designed multicenter randomized controlled studies.
2. How to prevent routine constipation
1. Avoid eating too little or food is too fine, lack of residue, and reduce the stimulation to colon movement. Eat more laxative foods, such as bananas, cabbage, bean sprouts, apples, hawthorn and so on.
2. Avoid disturbing defecation habits: constipation is prone to occur due to mental factors, changes in life patterns, and excessive fatigue during long-distance travel.
3. Avoid abuse of laxatives: abuse of laxatives will weaken the sensitivity of the intestine, form dependence on some laxatives, and cause constipation.
4. Arrange life and work reasonably, so as to combine work and rest. Appropriate cultural and sports activities, especially abdominal muscle exercise, are conducive to the improvement of gastrointestinal function, which is more important for sedentary and highly focused mental workers.
5. Develop good defecation habits, defecate regularly every day, form conditioned reflex, and establish good defecation rules. Don't ignore when defecating, defecate in time. The environment and posture of defecation should be as convenient as possible, so as not to inhibit defecation and destroy defecation habits.
6. It is suggested that patients drink at least 6 cups of 250 ml water every day, exercise moderately, and develop the habit of defecation regularly (twice a day, each time 15 minutes). After waking up and eating, the action potential activity of the colon is enhanced, pushing the feces to the distal end of the colon, so morning and after eating are the easiest time to defecate.
7. Timely treatment of anal fissure, perianal infection, adnexitis and other diseases, laxatives should be used with caution, and strong stimulation methods such as intestinal lavage should not be used.
8. Help to absorb nutrition: If you ingest probiotics every day, you can not only inhibit the production of harmful intestinal flora, but also provide a good growth environment for beneficial intestinal bacteria and create a healthy intestine. There is also Bacillus subtilis contained in "Mommy Love", which has a good effect on lactose decomposition and can help children digest and absorb milk or milk powder. And the beneficial bacteria in Mommy Love can promote the absorption of nutrients such as protein contained in milk powder and milk. It contains nutrients necessary for metabolism and vitamins B 1, B2 and B6 necessary for growth and development, which can help children grow and develop well.
9. It is recommended to take probiotics to improve the balance of intestinal flora. Mommy loves probiotics best. Probiotics can improve intestinal health, reduce constipation, maintain intestinal barrier function and enhance autoimmune function.