Introduction
The optimal management of opioid therapy–induced adverse effects is still an unmet need. Constipation is a considerable issue for cancer patients, particularly those with a progressive disease [
1]. An accurate analysis of the appropriateness of current therapies requires involvement of the various healthcare professionals who provide care to patients on opioid therapy.
An early multidisciplinary approach may support clinicians in the management of opioid-induced constipation (OIC), minimise the risks of neglecting it and increase the adherence of patients to the proposed pain therapy.
A panel of Italian clinicians from different areas of expertise (anaesthesiology and pain therapy, oncology, haematology, palliative care, gastroenterology) convened to draw up an expert opinion on OIC, aiming at constituting a first step towards a shared pathway among the various clinical disciplines and hopefully to involve nursing professionals and caregivers.
A terminology issue?
The definition of OIC is currently based on four parameters [
2]:
-
reduced bowel movement frequency;
-
development or worsening of straining to pass bowel movements;
-
a sense of incomplete rectal evacuation;
-
harder stool consistency.
The term opioid-induced bowel dysfunction (OIBD) is preferred over OIC as it implies a broader definition involving the entire gastrointestinal apparatus and refers to a wider range of parameters, including pain, fatigue, stress, flatulence and duration of constipation (which should be not less than 7 days, according to the Bowel Function Index, BFI) [
3].
OIBD is often poorly detected or underestimated and, as a consequence, addressed later in comparison to other adverse effects of opioid therapy. In clinical practice, the available guidelines are not always adequately considered and are sometimes incorrectly applied [
4].
Cancer versus non-cancer chronic pain
The issue of OIBD cannot be solely associated with the underlying disease, since opioids are used by a wide variety of patients, not only for cancer pain treatment. It is understandable that its psychophysical impact is greater in cancer patients, especially in those receiving palliative care, but the condition of patients under chronic opioid therapy for musculoskeletal pain or neuralgias should not be ignored.
OIBD prevention or symptomatic treatment?
The onset rate of OIBD ranges between 2 and 40% [
14,
15], suggesting the high probability for patients under opioid therapy to develop constipation.
OIBD therapy includes several lines of treatment, defined in the most recent recommendations and guidelines [
12,
16].
The main characteristic of OIBD is a delayed colonic transit. Opiates interfere with the release of acetylcholine at the level of inhibitory neurons of the myenteric plexus, resulting in an increase in the circular muscle cells tone. The measurement of opioid potency relative to morphine is based on this model of inhibition [
17].
This consideration suggests that the prescription of opioid therapy should be associated from the outset with prevention of constipation and close monitoring of therapeutic efficacy every 3 days, at least in the initial phase of treatment. However, pre-existing conditions must be always considered.
A key issue is preventing faecaloma. An increased intake of fibre may not be able to stimulate motor activity and paradoxically would favour the formation of faecalomas. Osmotic laxatives are often considered as the first choice to soften faeces, but they are associated with several side effects including flatulence and nausea. Saline laxatives may trigger electrolytic disorders, and disaccharides can cause abdominal distension and flatulence [
18].
Among osmotic laxatives, macrogol can be definitely recommended as a preventive therapy, as it is not associated with relevant side effects, except inappetence and nausea when administered at high dosages [
19].
An algorithm proposed in 2005 suggested [
20]:
2.
macrogol plus a stimulant laxative (senna or bisacodyl);
3.
association of three or more laxatives in case of non-responsiveness.
Should PAMORA be recommended as soon as possible?
The dose-dependent effect of opioids on bowel transit is a discussed topic [
24,
25]. The sensitization of enteric mu-opioid receptors is already noticeable at low doses of opiates. Indeed, some guidelines recommend increasing the dose of laxatives in parallel with the dosage of opioids [
4].
It is widely accepted that the use of two or more laxatives combining a softening and a stimulating action may cause unpleasant side effects, from abdominal pain and flatulence to nausea and vomiting. Consequently, patients may require switching to two or more laxatives or the administration of other drugs against such effects, further worsening their condition.
If preventive treatments have proven to be ineffective, opioids should be rotated and, if no favourable results are achieved, a specific pharmacological therapy should be initiated. The drugs should be characterised by rapid onset of action, manageability and ease of use by the patient [
16]. Because the predominant actions of opioids on the gastrointestinal tract are mediated by mu receptors, the administration of specific peripherally acting mu-opioid receptor antagonists (PAMORAs) is advisable. Methylnaltrexone and alvimopan were the early drugs in this group but they were not approved for oral use in OIBD [
3,
26]. Naloxegol (Moventig®, Kyowa Kirin), the latest PAMORA, has been recently approved as the first oral drug for OIBD [
27].
An objective criterion should be established to determine when to initiate the pharmacological administration of PAMORAs. A timely start would not harm the patient and would be consistent with the terminological use of the OIBD acronym. This approach deviates from the current indications [
28].
The pivotal trials of naloxegol showed that the response rate achieved with naloxegol 25 mg was 14–15% higher compared to placebo, whereas in the subpopulation with inadequate laxative response (LIR), the response rate difference between naloxegol 25 mg and placebo exceeded 20% and the number of patients to be treated due to non-response was halved [
16,
29].
Therefore, a possible algorithm is shown:
-
Macrogol (125 ml) in the preventive phase, with reassessment every 3 days;
-
at the onset of constipation, macrogol at incremental doses (125 ml twice daily up to 250 ml twice daily), with assessment every 3 days, for 1 week;
-
in case of no response after 1 week, at the maximum dosage of macrogol, the concurrent administration of stimulants, such as bisacodyl 10 mg/day [
30] or senna 24–48 mg/day [
31]. The efficacy of sennosides may vary depending on the composition of the microbiota and the amount absorbed. Bisacodyl is preferred, because it is not assimilated into the enterohepatic system and is not activated by the intestinal enzymes [
30];
-
after a further week, in case of no response and after an enema rescue therapy, start PAMORA therapy.
If a patient is constipated and had not preventively received macrogol, it should be prescribed at the maximum dosage along with opioid rotation [
32].
Based on the previously reported timeframe, from the onset of constipation, 14 days of intervention with macrogol and stimulants should occur before starting with the PAMORA agent.
Naloxegol starting dose
In two pivotal trials in which patients were receiving oral morphine, two doses of naloxegol, 25 mg and 12.5 mg, were compared [
29,
33]. Efficacy with the 25-mg dosage was achieved in both trials, while in one trial, the 12.5-mg dose was ineffective [
29]. It is therefore advisable that naloxegol should be initiated at a dose of 25 mg, possibly providing a subsequent de-escalation when needed or in case of impaired renal function.
Expectations from naloxegol therapy
When should the therapeutic response to naloxegol be considered satisfactory? A clinician should not necessarily aim for a complete resolution of constipation, as well as to meet the challenging target of total pain relief following the intake of strong analgesics. Guidelines suggest that patient’s personal opinion should be considered when assessing the benefits of the therapies.
Cyclic or long-term therapy?
The Board unanimously agree that the naloxegol dose of 25 mg/day should be maintained, even if the patient reports an evacuation frequency higher than three bowel movements per week. A time-limited discontinuation could provide an indication of therapeutic efficacy in a responsive or ultra-responsive patient.
How to manage opioid therapy?
Alongside naloxegol therapy, a patient with OIBD should have already undergone opioid switching. The selection of the opioid is based on the clinician’s judgement and not on therapeutic protocols, which have never been definitely established [
43]. Early or preventive opioid switching is probably unnecessary and should only be considered for refractory or resistant patients.
The Board highlight the feasibility of using naloxegol in case of opioid switching to oxycodone plus naloxone (Targin®, Mundipharma Pharmaceuticals), or in case the patient experiences OIBD while already under this opioid. The association of naloxegol with oxycodone plus naloxone is generally not contraindicated [
44]. An increase of the dose of naloxegol to 50 mg is not supported. Alternatively, in the absence of data, the Board suggest discontinuing naloxegol whenever oxycodone plus naloxone is prescribed in the opioid switch. It must be considered that the effects of equivalent doses of oxycodone and oxycodone plus naloxone do not always overlap, and cases of overdose or insufficient analgesia resulting from switches from one formulation to the other have been reported [
45].
In summary:
-
in case of oxycodone plus naloxone, naloxegol should be discontinued or not prescribed;
-
in case of a switch from oxycodone plus naloxone to only oxycodone, naloxegol should be associated if OIBD occurs.
Conclusions
OIBD is an important and common problem in the context of pain medicine and palliative care. The treatment of OIBD should be managed by a multidisciplinary team, and it is advisable to involve general practitioners, because patients on opioid therapy very often receive both hospital and home care. Anyway, the awareness and perception of this problem is still poor among health providers, despite the publication in recent years of guidelines and consensus conferences. We are aware that all the statements included in this text are expression of the opinions and personal experiences of a multidisciplinary Italian Board, which was constituted with the aim to offer a pragmatic and feasible approach to a heavy problem that affects many suffering and frail patients. Clinical research and practice jointly advance towards optimising the care of painful patients treated with opioids. PAMORAs are a valid and scientifically supported therapeutic aid for the treatment of OIBD. Among them, naloxegol is a promising drug, for which an increasingly widespread use is expected. The following would be desirable:
-
studies on the duration of naloxegol therapy and on the effects of its discontinuation;
-
studies on the efficacy of naloxegol after a dose reduction to 12.5 mg/day;
-
studies on the association of naloxegol with laxatives in non-responsive patients, as suggested by the EFIC Scandinavian guidelines [
7];
-
pharmacoeconomics studies to assess the cost-benefit ratio associated with the strategy of anticipating the drug treatment with PAMORAs.
Acknowledgments
The Authors would like to thank Brunilde Iovene, an independent medical writer, who provided editorial assistance during manuscript preparation on behalf of Springer Healthcare Communications. They would also like to thank Carmen Innes, an independent medical writer on behalf of Springer Healthcare Communications, who styled the manuscript for submission. These services were funded by Kyowa Kirin Srl. No other funding or sponsorship was received. All named authors have met the ICMJE criteria for authorship of this manuscript, taken responsibility for the integrity of the work as a whole and given final approval for the version to be published.
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