**5. Conclusions**

comprise abdominal pain (28% of the treated patients), flatulence (13%), nausea (11%), dizzi‐ ness (7%) and diarrhoea (5%) [16]. However, the administration of MNTX may be associated with an increased risk of gastrointestinal perforation in patients with diseases that decrease gut wall integrity (cancer, peptic ulceration and Ogilvie's syndrome) or on concomitant medications (NSAIDs, bevacizumab). GI perforation occur at different possible locations (duodenum, small and large bowel). A possible contributing factor might be the prokinetic effect of MNTX. It is not known if dose and duration of the treatment with MNTX relate to this complication [95]. As MNTX does not cross the blood–brain barrier, there is no attenua‐ tion of analgesia nor is there an opioid withdrawal syndrome [17]. The use of MNTX is con‐ traindicated in patients with mechanical bowel obstruction, in acute abdominal conditions and in case of allergy to the drug. MNTX may be used in palliative care patients with OIBD not amenable to the treatment with oral laxatives. Several clinical studies have demonstrat‐ ed the effectiveness of MNTX in patients with advanced diseases and with OIBD [16,17,95,96,98–100]. Peripherally active opioid receptor antagonists in the treatment of OIBD are effective and safe in [101-4]. Long–term efficacy and safety of opioid antagonists is not yet clearly established, in part due to a limited number of randomized studies [105-6].].

The Expert Working Group of the Polish Association for Palliative Medicine developed a three step ladder for the management of OIC (Fig. 1) [43]. This updated version of the ladder takes into account new therapies directed at the underlying mechanism of OIBD [107].

Drug(s) of step II:

 Rectal suppositories PAMORA\*

(Methylnaltrexone – sc)

*Constipation persists or intensifies*

constipation [43,107]

192 Dyspepsia - Advances in Understanding and Management

 Drug(s) of step I (oral): Osmotic agents: lactulose or macrogol Stimulants: antranoids or poliphenolics Oxycodone/naloxone

3

2

1

Fig. 1. The three-step ladder of the management of opioid–induced

 Invasive procedures of step III: Rectal enema Manual evacuation\*\*

*Constipation persists or intensifies*

At the first step traditional oral laxatives and/or PR oxycodone/PR naloxone may be considered. PR oxycodone/PR naloxone targets the source of OIBD (prevention and treatment) as PR naloxone blocks opioid receptors in the gut and PR oxycodone provides effective analgesia. PR oxycodone/PR naloxone may be considered in cancer pain patients who are at high risk of OIBD development such as those with GI tumors, patients who require combined treatment with opioids and other drugs disturbing normal bowel function, e.g. advanced cancer patients. At the second step subcutaneous administration of MNTX may be considered

\* PAMORA–peripherally acting mu–opioid receptor antagonists (methylnaltrexone) indicated for patients who do not respond to traditional oral laxatives without bowel obstruction and acute abdominal illness; \*\* This procedure should be used only when other measures fail and the faecal impaction causes significant pain and distress for the patient. It should be proceeded by a sedative and analgesics (local and systemic) administration that provide effective relief of

severe pain and distress associated with manual stool evacuation; sc – subcutaneous

**Figure 1.** The three-step ladder of the management of opioid–induced constipation [43,107]

20

OIBD in patients diagnosed with chronic diseases is a challenging problem that health care providers often underestimate. This is particularly important in patients regularly receiving opioids for pain or other indications. Thanks to newly introduced drugs that target the cause of OIBD, a more effective therapy is available. The experience with MNTX and PR oxycodone/PR naloxone in patients suffering from OIBD is promising. Further clinical stud‐ ies are needed to develop more effective guidelines for the management of OIBD and to es‐ tablish more precisely the role of opioid receptor antagonists. The role of opioid receptor antagonists as potential antiemetic and prokinetic agents should be further explored as sug‐ gested by experimental studies in animals. The cost-benefit from new therapies must be carefully considered; overall resources may actually be saved from reduced use of tradition‐ al laxatives. The most important advantage of targeted therapies is to decrease patient suf‐ fering from OIBD, substantial reduce the need to perform invasive rectal procedures and most importantly, improve quality of life.

### **Author details**

Wojciech Leppert\*

Address all correspondence to: wojciechleppert@wp.pl

Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland

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