Pharmacological prevention and treatment of opioid-induced constipation in cancer patients: A systematic review and meta-analysis.

BACKGROUND: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients. METHODS: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed. RESULTS: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates. CONCLUSIONS: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made.

Effects of Electroacupuncture for Opioid-Induced Constipation in Patients With Cancer in China: A Randomized Clinical Trial.

Importance: Opioid-induced constipation (OIC) is prevalent among patients treated with opioids for cancer pain. Safe and effective therapies for OIC in patients with cancer remain an unmet need. Objective: To determine the efficacy of electroacupuncture (EA) for OIC in patients with cancer. Design, Setting, and Participants: This randomized clinical trial was conducted at 6 tertiary hospitals in China among 100 adult patients with cancer who were screened for OIC and enrolled between May 1, 2019, and December 11, 2021. Interventions: Patients were randomized to receive 24 sessions of EA or sham electroacupuncture (SA) over 8 weeks and then were followed up for 8 weeks after treatment. Main Outcomes and Measures: The primary outcome was the proportion of overall responders, defined as patients who had at least 3 spontaneous bowel movements (SBMs) per week and an increase of at least 1 SBM from baseline in the same week for at least 6 of the 8 weeks of the treatment period. All statistical analyses were based on the intention-to-treat principle. Results: A total of 100 patients (mean [SD] age, 64.4 [10.5] years; 56 men [56.0%]) underwent randomization; 50 were randomly assigned to each group. Among them, 44 of 50 patients (88.0%) in the EA group and 42 of 50 patients (84.0%) in the SA group received at least 20 (≥83.3%) sessions of treatment. The proportion of overall responders at week 8 was 40.1% (95% CI, 26.1%-54.1%) in the EA group and 9.0% (95% CI, 0.5%-17.4%) in the SA group (difference between groups, 31.1 percentage points [95% CI, 14.8-47.6 percentage points]; P < .001). Compared with SA, EA provided greater relief for most OIC symptoms and improved quality of life among patients with OIC. Electroacupuncture had no effects on cancer pain and its opioid treatment dosage. Electroacupuncture-related adverse events were rare, and, if any, all were mild and transient. Conclusions and Relevance: This randomized clinical trial found that 8-week EA treatment could increase weekly SBMs with a good safety profile and improve quality of life for the treatment of OIC. Electroacupuncture thus provided an alternative option for OIC in adult patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03797586.

Involvement of the Peripheral µ-Opioid Receptor in Tramadol-Induced Constipation in Rodents.

Tramadol is a weak opioid that produces analgesic effect via both the µ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

Delphi consensus on strategies in the management of opioid-induced constipation in cancer patients.

BACKGROUND: Opioid-induced constipation (OIC) is a frequent and bothersome adverse event related with opioid therapy in cancer patients. Despite the high prevalence, medical management of OIC is often uncertain. The current project aimed to investigate expert opinion on OIC management and provide practical recommendations to improve the clinical approach of OIC in cancer patient. METHODS: A modified Delphi method was conducted involving 46 different physicians experts in OIC. Using a structured questionnaire of 67 items this project intended to seek consensus on aspects related to diagnosis, treatment, and quality of life of cancer patients suffering with OIC. RESULTS: After two rounds, a consensus was reached in 91% of the items proposed, all in agreement. Agreement was obtained on OIC definition (95.7%). Objective and patient-reported outcomes included in that definition should be assessed routinely in clinical practice. Responsive to symptom changes and easy-to-use assessment tools were recommended (87.2%). Successful diagnosis of OIC requires increase clinicians awareness of OIC and proactivity to discuss symptoms with their patients (100%). Successful management of OIC requires individualization of the treatment (100%), regular revaluation once is established, and keeping it for the duration of opioid treatment (91.5%). Oral Peripherally Acting µ-Opioid Receptor Agonists (PAMORAs), were considered good alternatives for the treatment of OIC in cancer patients (97.9%). This drugs and laxatives can be co-prescribed if OIC coexist with functional constipation. CONCLUSIONS: The panelists, based on their expert clinical practice, presented a set of recommendations for the management of OIC in cancer patients.

Naloxegol rescue with methylnaltrexone highly effective.

Opioid-induced constipation (OIC) is common and can significantly affect quality of life. Naloxegol and methylnaltrexone are peripherally acting µ-opioid receptor antagonists (PAMORAs) which are effective for the management of OIC. We report on a case in the palliative care setting where a patient with established OIC had an inadequate response to naloxegol but an effective and immediate response to methylnaltrexone at the dose recommended for her weight. This is the first reported case of two PAMORAs used concomitantly.

Multidisciplinary intervention incorporating pharmacists in management of opioid-naïve patients with moderate to severe cancer pain.

OBJECTIVE: This study aims to investigate the impact of intervention of multidisciplinary team incorporating pharmacists for management of opioid-naïve patients with moderate to severe cancer pain. METHODS: A retrospective cohort study was conducted to compare pre- and post-multidisciplinary intervention groups in opioid-naïve patients with moderate to severe cancer pain. Primary outcome was the proportions of appropriate pain assessment and opioid titration. Secondary outcomes were pain intensity (PI), length of hospital stay, opioid escalation index percentage (OEI%) and incidences of opioid-related adverse events. RESULTS: A total of 400 patients were included in the study (pre-intervention, n = 200; post-intervention, n = 200). Continuous improvement in pain assessment and titration was recorded after intervention. Though no substantial differences existed between groups in PI on the day of discharge, post-intervention group was associated with reduced length of hospital stay as well as decreased proportion of subjects with OEI% >5%. As for safety, significant decreases in constipation and vomiting were seen. CONCLUSION: Findings suggest that interventions of multidisciplinary team incorporating pharmacists could improve cancer pain management for opioid-naïve patients. Pharmacists should be considered as an important member of a multidisciplinary team in good pain management.

More opioids, more constipation? Evaluation of longitudinal total oral opioid consumption and self-reported constipation in patients with cancer.

PURPOSE: Opioid-induced constipation (OIC) is a distressing physical symptom for patients with cancer taking opioids. Total opioid consumption may contribute to developing worsening OIC-related symptoms. We completed a retrospective analysis examining the association of total daily opioid consumption on self-reported constipation in patients with cancer. METHODS: In over 5 clinic visits, we collected self-reported constipation scores and 24-h oral morphine equivalents (OME). We examined the association between OME and the presence of constipation (i.e., score > 3) and the relationship of OME between patients with or without constipation. RESULTS: Of 297 patients with cancer, we observed 57.8% with constipation and 42.4% without constipation at the first clinic visit. Age was similar in both groups (54.2 ± 14.5 vs. 56.4 ± 14.8 years [mean ± SD]) and the majority of patients were women (63.7% vs. 61.1%). The most common cancer type in patients with constipation was non-colorectal gastrointestinal (n = 25, 14.6%), while in patients without constipation was colorectal gastrointestinal (n = 25; 19.8%). Across visits, we observed weak or no association between OME and self-reported constipation (r = 0.01-0.27). At the first visit, higher mean OME was seen in patients who self-reported constipation (133.4 vs 76; p < 0.05). Age, sex, metastatic disease, and stimulant laxative use were not associated with constipation. CONCLUSIONS: We observed weak to no association between OME and constipation in patients with cancer. These results suggest a lack of a clear association between total opioid consumption and self-reported constipation.

Strong opioids and non-cancer chronic pain in Catalonia. An analysis of the family physicians prescription patterns. / Opioides fuertes y dolor crónico no oncológico en Cataluña. Análisis del patrón de prescripción por parte de los médicos de familia.

OBJECTIVE: To identify family doctor prescription patterns for strong opioids for chronic, non-cancer-related pain. MATERIALS AND METHODS: Design A descriptive study based on a self-administered email questionnaire. LOCATION: All primary health care centres in Catalonia. PARTICIPANTS: 3,602 family doctors, all members of the Catalan Society of Family and Community Medicine. INTERVENTIONS: Email survey of Catalan family doctors. MAIN MEASUREMENTS: Demographic data, number of patients treated with potent opioids for chronic non-cancer pain, type of opioid used and indications, prescribing patterns and relationship with the Pain Management Unit. RESULTS: A total of 551 answers were obtained from 3,602 questionnaires sent (response rate of 15.3%), in which 480 physicians (87%) prescribed strong opioids for musculoskeletal pain, 268 (48.6%) prescribed ultra-rapid fentanyl and 434 (78.7%) reduced benzodiazepines dosage when prescribing potent opioids. The most common adverse effects were constipation and nausea. The main problems related with opioid prescription were improper use (341, 71%) and patient and/or practitioner reluctance (87, 18.1%). The assessment of the relationship with Pain Management Units was 2±1 (on a 1 to 5 scale), with communication (271, 52.2%) and accessibility (141, 27.1%) being the areas most in need of improvement. CONCLUSIONS: Opioid prescribing patterns generally follow clinical guidelines (e.g. reduction of benzodiazepine use or dose titration). However, there are some areas of improvement, such as sparse use of laxatives or use of ultra-rapid opioids for unapproved indications and in patients with no background opioid therapy. Family doctors perceive patient reluctance to adhere to the prescribed treatment, and call for specific training and better relationships with Pain Management Units.

Opioid-Induced Constipation in Oncological Patients: New Strategies of Management.

OPINION STATEMENT: Cancer-associated pain has traditionally been treated with opioid analgesics, often in escalating doses. Opioid-induced constipation (OIC) is a common problem associated with chronic use of opioid analgesics. Typical treatment strategies to alleviate constipation are based on dietary changes, exercise, and laxatives. However, laxatives have a nonspecific action and do not target underlying mechanisms of OIC. This article will review prevalent, clinical presentation and recommendations for the treatment of OIC. An independent literature search was carried out by the authors. We reviewed the literature for randomized controlled trials that studied the efficacy of laxatives, naloxone, and naloxegol in treating OIC. Newer strategies addressing the causal pathophysiology of OIC are needed for a more effective assessment and management of OIC. Finally, traditional recommended therapies are appraised and compared with the latest pharmacological developments. Future research should address whether naloxegol is more efficacious by its comparison directly with first-line treatments, including laxatives.

Relationship Between Constipation and Medication.

Constipation is very common and can be caused by adverse drug reactions as a result of many drugs. While the adverse effects of several medications such as opioids and anticholinergic agents are well established and well known, other commonly prescribed drugs, such as hypnotics, are less well understood. This review presents the results of an analysis of the relationship between constipation and drugs.

Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and network meta-analysis.

OBJECTIVE: Opioids are increasingly prescribed in the West and have deleterious GI consequences. Pharmacological therapies to treat opioid-induced constipation (OIC) are available, but their relative efficacy is unclear. We performed a systematic review and network meta-analysis to address this deficit in current knowledge. DESIGN: We searched MEDLINE, EMBASE, EMBASE Classic and the Cochrane central register of controlled trials through to December 2017 to identify randomised controlled trials (RCTs) of pharmacological therapies in the treatment of adults with OIC. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of pharmacological therapies was reported as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested and ranked treatments according to their P-score. RESULTS: Twenty-seven eligible RCTs of pharmacological therapies, containing 9149 patients, were identified. In our primary analysis, using failure to achieve an average of ≥3 bowel movements (BMs) per week with an increase of ≥1 BM per week over baseline or an average of ≥3 BMs per week, to define non-response, the network meta-analysis ranked naloxone first in terms of efficacy (RR=0.65; 95% CI 0.52 to 0.80, P-score=0.84), and it was also the safest drug. When non-response to therapy was defined using failure to achieve an average of ≥3 BMs per week, with an increase of ≥1 BM per week over baseline, naldemedinewas ranked first (RR=0.66; 95% CI 0.56 to 0.77, P score=0.91) and alvimopan second (RR=0.74; 95% CI 0.57 to 0.94, P-score=0.71). CONCLUSION: In network meta-analysis, naloxone and naldemedine appear to be the most efficacious treatments for OIC. Naloxone was the safest of these agents.