Opioid Use and Gut Dysbiosis in Cancer Pain Patients

Abstract

Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.

Keywords: PAMORAs; analgesia; constipation; gut dysbiosis; gut–brain axis; microbiota; neuroinflammation; opioids; tolerance.

Figure 1

Mechanisms of opioid-mediated modifications of the gut microbiota. Opioids ensure analgesia and cause constipation through their activity on mu-opioid receptors respectively in the central and enteric nervous system. Leaky-gut has been recognized as the main mechanism of bacterial translocation, which activates enteric glia, leading to the massive release of pro-inflammatory mediators. The resulting altered gut microbiota has been implicated in most of the challenging conditions related to chronic opioid use, such as tolerance, addiction, and reward. The bidirectional relationship between the gut microbiota and the brain play a key role in the well-known gut–brain axis.