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Bowel Dysfunction and Management

Prokinetic Agents

Chronic constipation is a common problem after SCI, with a prevalence of up to 80% of affected individuals (Krogh et al. 2002). The presence of constipation in patients with SCI with slow transit times has been well-documented (Geders et al. 1995).

Five studies exploring the use of cisapride for neurogenic bowel management have been removed from this review as the drug is no longer available.

Discussion

Prokinetic agents are presumed to promote transit through the GI tract, thereby decreasing the length of time needed for stool to pass through the intestines and increasing the amount of stool available for evacuation. Since constipation in patients with both acute and chronic SCI is considered primarily a consequence of prolonged colonic transit time, stimulating intestinal motility would appear to be a reasonable therapeutic approach. Segal et al. (1987) investigated the use of metoclopramide (a potent dopamine receptor antagonist with prokinetic properties) for enhancing gastric emptying in individuals with SCI. They found that impaired gastric emptying in patients with SCI can be significantly improved using metoclopramide. Improvement in constipation and increased frequency of bowel movement were also seen with the use of prucalopride – a novel, highly selective serotonin receptor agonist with enterokinetic properties that facilitates cholinergic and excitatory non-adrenergic, non-cholinergic neurotransmission (Krogh et al. 2002). Korsten et al. (2005) found that neostigmine (a reversible cholinesterase inhibitor) or the combination of neostigmine and glycopyrrolate administered intravenously improved stool expulsion over normal saline. Rosman et al. (2008) reported similar findings for the use of neostigmine and glycopyrrolate in combination over placebo. Finally, a study by Cardenas et al. (2007) reported an increase in the number of days with bowel movements in approximately one-fifth of the subjects given sustained-release fampridine (selective potassium channel blocker).

Conclusion

Prucalopride: There is level 1b evidence (from one RCT: Krogh et al. 2002) that prucalopride increases stool frequency, improves stool consistency and decreases gastrointestinal GI transit time; higher doses (2mg/day) were associated with moderate/severe abdominal pain.

Metoclopramide: There is level 2 evidence (from one prospective controlled trial; N=20) (Segal et al. 1987) that intravenous administration of metoclopramide decreases time of gastric emptying.

Neostigmine: There is level 1b evidence (from one RCT: Korsten et al. 2005) that neostigmine, administered with or without glycopyrrolate, leads to a greater expulsion of stool. There is level 1 evidence that neostigmine with glycopyrrolate decreases total bowel evacuation times and improves bowel evacuation.

Fampridine: There is level 1b evidence (from one RCT: Cardenas et al. 2007) that fampridine can increase the number of days with bowel movements.

In very small studies prucalopride, metoclopramide, neostigmine, and fampridine have been found to improve constipation in individuals with SCI. Prucalopride is not currently available the United States but is available in Canada and Europe. More research is required on prokinetic agents prior to their regular use in neurogenic bowel dysfunction.

Author Year; Country

Score

Research Design

Total Sample Size

 Methods Outcome
Rosman et al. 2008;

USA

PEDro = 8

Crossover RCT

N = 7

 Population: 7 SCI participants with defecatory problems (mean (SD) age: 46.9 (3.4) yrs, range 30 – 56 yrs); 4 cervical, 3 thoracic.

Treatment: injections of neostigmine (2 mg) and glycopyrrolate (0.4 mg) for 1 week, wash-out period for 1 week, and placebo for 1 week, in random order

Outcome Measures: Total bowel evacuation time; time to first flatus; time to beginning of stool flow; time to end of stool flow.
  1. Compared with placebo, neostigmine/glycopyrrolate significantly reduced the total bowel evacuation time (mean (SD)) from 98.1 (7.2) min to 74.8 (5.8) min
  2. Neostigmine/glycopyrrolate significantly reduced the mean (SD) time to first flatus from 56.9 (5.4) min to 21.8 (4.5) min
  3. Neostigmine/glycopyrrolate significantly reduced the mean (SD) time to beginning of stool flow from 69.8 (2.8) to 42.3 (6.4) min, and time to end of stool flow from 80.3 (4.0) to 53.3 (8.3) min.
Krogh et al. 2002; Denmark

PEDro = 7

Double blind RCT

N=22

 Population: mean (SD) age: 34.7 (2.5) yrs (placebo), 36.5 (3.9) yrs (1mg group), 44.3 (3.1) yrs (2mg group). No information on level of injury was reported.

Treatment: Participants randomized with double blind design to treatment with prucalopride 1mg or placebo, taken once daily for 4 wks. A 2nd group of participants was randomized to prucalopride 2mg or placebo for 4wks

Outcome measures: constipation; urinary habit; constipation severity and symptoms; colonic transit times
  1. Compared with baseline, constipation severity decreased with prucalopride. The VAS score for treatment efficacy showed a clear dose response (medians 4, 52, and 73 for placebo, 1 and 2 mg, respectively).
  2. Self-report diary showed an improvement in average weekly frequency of all bowel movements over 4 wks within the 2 mg group (median 0.6).
  3. 3 participants (2 mg group) reported moderate/severe abdominal pain and 2 discontinued treatment. Adverse events (AEs) were reported by 6/7 in the placebo group, and by 7/8 and 6/8 in the 1 and 2mg groups. The most common AEs were gastrointestinal (flatulence, abdominal pain and diarrhea).
Korsten et al. 2005; USA

PEDro = 6

RCT

N=13

 Population: Level of injury: C4-T12 (5  tetraplegics, 8 paraplegics; 12/13 motor complete, 5/13 sensory incomplete); Age: mean (range) 46 (25-69)yrs; Duration of injury: mean (range) 14 (1-31)yrs

Treatment: On different days, participants received, in a randomized, double-blinded design, one of three intravenous infusions (normal saline, 2 mg neostigmine, or 2 mg neostigmine and 0.4 mg glycopyrrolate)

Outcome Measures: time to bowel evacuation using barium paste
  1. Neostigmine and the combination of neostigmine and glycopyrrolate both caused a similar expulsion of the stool, which was greater than with normal saline (median score 3 vs. 4 vs. 0, respectively)
  2. Mean time to expulsion was 11.5 min (range 5-20 min) after neostigmine and 13.5 min (range 4-23 min) after the combination
  3. There was no correlation between the level of SCI and likelihood of bowel evacuation with any of the infusions
Cardenas et al. 2007; USA

PEDro = 6

RCT

N=91

 Population: 91 participants with motor-incomplete SCI randomized to three groups:

(I) Fampridine, sustained release, 25 mg bid: Level of injury: 23 cervical, 7 thoracic; AIS grade: 14 C, 16 D; 22M:8F; Age: mean (range) 44 (23-66)yrs; Duration of injury: mean (range) 8.3 (1-30)yrs

(II) 40 mg bid: Level of injury: 24 cervical, 6 thoracic; AIS grade: 12 C, 18 D 26M:,4F; Age: mean (range) 42 (21-67)yrs; Duration of injury: 10.8 years, range 1-35;

(III) Placebo: Level of injury: 26 cervical, 5 thoracic; AIS grade: 18 C, 13 D; 24M:7F; Age: mean (range) 38 (19-61)yrs; Duration of injury: mean (range) 8.3 (1-37)yrs

Treatment: Drug treatment (Fampridine orally 25mg bid or 40mg bid) or placebo for 8 weeks

Outcome Measures: Number of days with bowel movement, Subject Global Impression (SGI), Ashworth
  1. A significantly larger number of participants in the 25 mg bid (6/30 participants) and 40 mg bid (7/30 participants) groups had an increase in the number of days with bowel movements compared to participants in the placebo group. Number of days increase not reported.
  2. In total 78% of participants completed the study. More (13/30) discontinued from Group II than Group I (4/30) and Group III (3/31). The most frequent AEs were hypertonia, generalized spasm, insomnia, dizziness, asthenia, pain, constipation, and headache. One subject in Group II suffered a seizure.
  3. SGI changed significantly in favor of Group I (mean=4.5). Group II had a mean of 3.6 and Group III had a mean of 3.9.
  4. Subgroup analysis of participants with baseline Ashworth scores >1 showed significant improvement in spasticity in Group I versus Group III (Ashworth mean score: Group I= 1.0; Group 2= 1.1; Group III= 1.2).
Segal et al. 1987;

USA

Prospective Controlled Trial

N=28

 Population: 11 participants with tetraplegia, 9 participants with paraplegia (all complete SCI), 8 able-bodied controls; Age range: 20-55yrs

Treatment: participants ingested a liquid meal, then within 2 weeks, ingested 2nd liquid meal while metoclopramide (10mg) was administered intravenously; gastric emptying (GE) was evaluated after each liquid meal

Outcome Measures: half time of gastric emptying, gastric emptying patterns in the early and later phases
  1. The mean GE half time for a liquid meal decreased in the participants with tetraplegia from 104.8 min to 18.8 min after treatment with metoclopramide
  2. The pretreatment mean GE of 111.5 min decreased to 29.1 min among the participants with paraplegia.
Kim et al. 2016

South Korea

Pre-post

N=25

 Population: N=25 (22M, 3F)

Mean (SD) age 50.9 (17.3) years

Mean (SD) time since SCI 5.3 (6.0) months

19 traumatic, 6 non-traumatic

Cervical AIS-A/B/C/D: 2/2/3/7

Thoracic AIS-A/B/C/D: 3/3/1/4

Treatment: Poncirus fructus extract 800mg before breakfast & lunch for 14 days

Outcome Measures: Bristol Stool Form Scale, constipation score, stool retention score, colon transit time, adverse events
  1. Significant decrease in mean (SD) constipation score (4.60±3.35 to 3.48±2.42)
  2. Significant increase in mean (SD) Bristol score (3.52±1.33 to 4.32±1.44)
  3. Significant decrease in mean (SD) CTT total, (57.4±20.7 to 41.2±25.5h), in right colon (14.4±16.2 to 10.1±12.1h), and in left colon (21.8±12.3 to 14.8±11.8h)
  4. Significant decrease in stool retention score total (7.25±1.60 to 6.46±1.53), in right colon (2.45±0.61 to 1.90±0.64) and in rectosigmoid colon (1.90±0.85 to 1.40±0.88)
  5. Adverse events: 2 reported loose stool, and 7 reported diarrhea (2 with causes unrelated to treatment)
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