Mechanistic overview of how opioid analgesics promote constipation

Opioids are highly effective analgesic drugs. Although on-target side-effects including dependence, tolerance and respiratory depression limit their use, they remain the mainstay clinically important analgesics. Opioid use is also associated with severe intractable constipation. This significantly impacts patient quality of life and daily activities, resulting in noncompliance to analgesic regimens. Receptors specific for opioids are expressed by neurons of the enteric nervous system (ENS). These neurons are located within the gut wall and coordinate essential gastrointestinal (GI) functions. Opioids inhibit enteric neurons, suppressing GI movement and secretory activity. Unlike the other side-effects of opioids, constipation is resistant to tolerance and therefore persists with prolonged treatment. In this chapter, we describe the innervation of the GI tract, the expression and function of opioids and their receptors in the ENS and provide an overview of the mechanisms that lead to opioid-induced constipation (OIC). Potential approaches to treat or manage OIC are summarized.