Systematic review of modulators of benzodiazepine receptors in irritable bowel syndrome: Is there hope?

Table 1 A summary of the pathophysiological mechanisms of irritable bowel syndrome

Mechanism	Description
Visceral hypersensitivity	↓ Threshold of visceral perception, hyperalgesia; ↑ Viscerosomatic referral areas
Modulation of CNS	Altered activation in reaction to rectosigmoid stimuli; fail to inhibit pain perception; activation of pain facilitatory pathways
Stress	Changes in visceral perception and neuro-endocrine responses to stressor
Infection	↑ Incidence after bacterial, viral, parasitic infections
Inflammation	Increased inflammatory cytokines; decreased anti-inflammatory cytokines
Serotonin	Influencing gut motility, sensation and secretion; altered serotonin signaling in IBS
Genetic factors	Familial clustering

CNS: Central nervous system; IBS: Irritable bowel syndrome.

Table 2 Common therapeutic modalities

Therapeutic approach	Mechanism	Example of drugs	Therapeutic issues
Cholinergic system	Muscarinic receptor antagonists	Hyoscine, cimetropium, zamifenacin, solifenacin	Limited value, limited side effects, no interaction
Serotonin system	5-HT receptor antagonists	Alosetron, tegaserod, renzapride	Safe on cardiovascular system, anxiolytic, psychological side effects, adverse effects
Antidepressants (SSRIs, TCAs, SNRIs)	Neurotransmitter reuptake inhibitor	Paroxetine, desipramine, venlafaxine	Limited use, serious side effects, limited efficacy
Adrenergic agents	α, β3 adrenergic agents	Clonidine, solabegron	Limited use, side effects, limited efficacy
Corticoid system	CRF antagonists	Α-Helical CRH9-41	Limited use, under investigation
Cholecystokinin		Loxiglumide, dexloxiglumide	Limited use, under investigation
Neurotrophins	Enhance neuron survival and development	NT3	Expensive, under investigation, limited use
Sleeping process	Sleep regulator	Melatonin	Limited use
BZD receptor modulators		Gabapentin, dextofisopam, pregabalin	Side effects, limited use, under investigation
Guanylate cyclase-c agonists	Activates guanylate cyclase-c receptor in enterocytes	Linaclotide	Limited use, well toleration, minimal side effects, under investigation
Opioid system	Modulating visceral nociception	Asimadoline, naloxone, naltrexone	Limited central side effects, good efficacy
Neurokinin antagonists	Affect colonic motility	Ezlopitant, nepadutant	Under investigation

SSRIs: Selective serotonin reuptake inhibitors; TCAs: Tricyclic antidepressants; SNRIs: Serotonin norepinephrine reuptake inhibitors; NT3: Neurotrophine-3; BZD: Benzodiazepine; 5-HT: 5-hydroxytryptamine; CRF: Corticotrophin-releasing factor.