Motility Disorders Irritable Bowel Syndrme
(sleep, diet and sexual functioning) were significantly improved by ketotifen, but not by placebo.63
Sedation or drowsiness are recognized
adverse effects of the drug, and may have unblinded the study and influenced patient reported outcomes. Ketotifen treatment did not affect the release of tryptase from rectal mucosal biopsies. These data underscore the need for further research.
5-Aminosalicylic Acid (5-ASA) Compounds Mesalazine reduces total immunocytes, mast cells, and mucosal levels of interleukin 1b (IL-1b) (pg/ml), histamine (ng/ml) and tryptase (ng/ml) in patients with IBS. This was associated with improved wellbeing and satisfaction with treatment. The sample size was too small to demonstrate significance in symptoms of bowel function and pain.64
Corticosteroids
Prednisone was not effective in relief of symptoms of IBS.65 is effective for lymphocytic and collagenous colitis;66
Budesonide given the potential
role of immune activation in IBS and the overlap of IBS and lymphocytic colitis, clinical trials are awaited.
Medications Targeting Visceral Sensation In clinical practice, antidepressants are still the most widely used agents to attempt to reduce visceral sensitivity in IBS. We have previously commented67
that the several meta-analyses published to date included trials with very different eligibility and quality criteria, and came to different overall conclusions68–70
based on inclusion of small trials that had
very large effects that do not appear to be generalizable, such as the highly significant effects of amitryptiline 10mg/day.71
superior to placebo in pediatric patients with IBS.75 More recent
literature continues to provide no evidence of efficacy with drugs such as paroxetine, imipramine or citalopram.72–74
In addition, amitryptiline is not Therefore, effective
treatments for the pain component of lower FGID and IBS remain elusive.
In pharmacodynamic trials, the peripheral κ opioid agonist, asimadoline, reduced pain sensation at relatively low levels of colonic distension76 without effects on colonic compliance, motility or transit. A clinical trial suggested adequate relief, especially in patients with IBS-D and at least moderate pain during the run-in period.77
Intermittent, on-demand use
of asimadoline during attacks of IBS pain was not efficacious to relieve the pain.78
Gabapentin, a 3-alkylated analog of g-amino butyric acid (GABA), reduces central sensitization in human experimental hyperalgesia. A study in 40 IBS-D patients of five-day treatment with gabapentin, 300mg/day, followed by 600mg/day, showed that there was attenuation
1.
Brandt LJ, Chey WD, Foxx-Orenstein AE, et al., Am J Gastroenterol, 2009;10:S1–S35.
2. Camilleri M, Chang L, Gastroenterology, 2008;135:1877–91. 3.
4. 5. 6. 7.
De Maeyer JH, Lefebvre RA, Schuurkes JA, Neurogastroenterol Motil, 2008;20:99–112.
Morganroth J, Brozovich FV, McDonald JT, Jacobs RA, Am J Cardiol, 1991;67:774–6.
Bouras EP, Camilleri M, Burton DD, et al., Gastroenterology, 2001;120:354–60.
Camilleri M, Kerstens R, Rykx A, Vandeplassche L, N Engl J Med, 2008;358:2344–54.
Quigley EM, Vandeplassche L, Kerstens R, Ausma J, Aliment Pharmacol Ther, 2009;29:315–28.
36 8. 9.
Michael Camilleri, MD, is a consultant in the Division of Gastroenterology and Hepatology, Department of Internal Medicine at Mayo Clinic in Rochester, Minnesota. He holds the academic rank of Professor of Medicine and Physiology and is the Atherton and Winifred W Bean Professor. He was named as Distinguished Investigator at Mayo Clinic Rochester in 2008. Dr Camilleri attended the University of Malta Medical School. He completed a residency at St Luke’s University Hospital in Malta and a clinical residency,
fellowship and research in internal medicine and gastroenterology at Hammersmith Hospital, University of London, United Kingdom, receiving a masters degree in physiology. In addition, he completed a research and a clinical fellowship at Mayo Graduate School. He was elected Fellow of the Royal College of Physicians of London and Edinburgh and is a Fellow of the American College of Physicians (ACP), the American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA).
Summary and Conclusions
There are several promising novel treatments of lower FGIDs. The peripheral targets of medical therapy often address the bowel dysfunction of lower FGIDs and this is often associated with pain relief.
The new 5-HT4 agonists are more specific and continue to show cardiovascular safety. Secretory agents have high specificity; those with low bioavailability (e.g. linaclotide) have high safety margins. Patients need more specific agents to relieve the abdominal pain in IBS, and this is endorsed by the US Food and Drug Administration (FDA) proposed interim end-points for IBS drugs.83
The potential risks of agents
“borrowed” from other indications (like hyperlipidemia, inflammatory bowel disease or somatic pain) are known. With a greater understanding of pathophysiologic mechanisms in IBS,84
relevant targets for medical
therapy, a healthy pipeline of medications that appear safe, and clarity on trial end-points, there is reason to be optimistic that new medications will relieve patients with IBS and lower FGIDs. n
of rectal sensitivity to distension and increased rectal compliance.79 Pregabalin has been tested in IBS patients in a pharmacodynamic study,80
but no clinical trials are reported to date.
New Centrally Acting Agents in IBS The benzodiazepine receptor modulator dextofisopam binds to 2,3-benzodiazepine receptors located in subcortical and hypothalamic regions. In animal models, tofisopam reduced stimulation-induced colonic motility and visceral sensitivity.81
In a 12-week, phase II study of
The most prominent effects, observed within the first four weeks, included improved consistency and frequency of bowel movements. The drug appeared to be well tolerated.
IBS-D or IBS-alternating patients, there were more months with adequate relief in the dextofisopam group compared with the placebo group.82
Tack J, van Outryve M, Beyens G, Kerstens R, Gut, 2009;58:357–65.
Camilleri M, Kerstens R, Beyens G, Robinson P, Gastroenterology, 2009;136(Suppl 1):240.
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11. Dennis D, Palme M, Irwin I, Druzgala P, Teichman S, Gastroenterology, 2004;126:A641.
12. Camilleri M, Vazquez-Roque MI, Burton D, et al., Neurogastroenterol Motil, 2007;19:30–8.
13. Johnson AC, Tyler KR, Palme M, Greenwood-Van Meerveld B, Gastroenterology, 2009;136(Suppl 1):158.
14. Palme M, Milner PG, Ellis DJ, Marmon T, Canafax DM,
Gastroenterology, 2010;138(Suppl 1):S128–9.
15. Smith JA, Beattie DT, Marquess D, et al., Naunyn Schmiedebergs Arch Pharmacol, 2008;378:125–37.
16. Beattie DT, Armstrong SR, Shaw JP, et al., Naunyn Schmiedebergs Arch Pharmacol, 2008;378:139–47.
17. Camilleri M, Manini M, McKinzie S, et al., Neurogastroenterol Motil, 2008;20(Suppl 2):6.
18. Goldberg MR, Li Y-P, Pitzer K, et al., Gastroenterology, 2008;133:A547.
19. Hirata T, Funatsu T, Keto Y, et al., Inflammopharmacol, 2007;15:5–9.
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US GASTROENTEROLOGY & HEPATOLOGY REVIEW
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