INTRODUCTION:

Constipation is characterized by infrequent bowel movements, typically fewer than three times per week, accompanied by the passage of hard stools. It is commonly associated with lower abdominal distention, bloating, and discomfort.

Several risk factors contribute to constipation, including female gender, advanced age, physical inactivity, low fiber diet, low caloric intake, lower socioeconomic status, limited educational attainment, and the use of multiple medications¹. Medication that causes constipation is opioids, especially in patients with cancer. Constipation induced by opioid therapy stands out as one of the most prevalent and troublesome side effects. Opioid usage has seen a significant rise in the United States, with approximately 235 million prescriptions in 2012^2-4. The Southeast Asian population has witnessed a surge in opioid misuse, particularly with substances like heroin, which has extended beyond cases related to underlying diseases like cancer. This trend has led to a notable increase in opioid use disorder and withdrawal issues in the region⁵. Addressing the complexities of opioid misuse in patients with cancer is crucial for developing targeted interventions and support systems to mitigate the impact on individuals' health and well-being. Moreover, an estimated 75% of individuals diagnosed with cancer necessitate opioid therapy to manage severe pain associated with cancer⁶. OIC is characterized by changes in bowel habits or defecation patterns as a result of opioid treatment. It encompasses symptoms like a decreased frequency of bowel movements, specifically fewer than three per week, a sensation of incomplete evacuation, increased straining, or the presence of harder stool consistency, as defined by the ROME IV criteria^7-8.

The first line of medication for constipation is oral laxatives and stool softeners. Conventional laxatives or stool softeners exhibit limited efficacy as they fail to address the underlying mechanism of opioids. In cancer patients with opioid use, laxatives with a combination of stool softeners may be inadequate. Therapeutic opioids are attached to the peripheral µ-opioid receptor in the gastrointenstinal (GI) tract^9-14. Moreover, the activation of the mu-opioid receptor (µ-opioid receptor) has been implicated in promoting cancer progression. The use of opioids has been linked to a shorter overall survival in individuals with cancer^14-16. The main way opioid analgesics cause opioid-induced constipation (OIC) is by inhibiting mu-opioid receptors (MORs) in the gastrointestinal (GI) tract. When these peripheral MORs are inhibited, it leads to an increased absorption of fluids from the intestines, a reduction in fluid secretion, and a disruption in the normal peristaltic movements of the GI tract. This combination of effects results in a slowed transit time of the intestinal contents, which can contribute to the development of constipation. By slowing down the movement of the intestines and altering fluid dynamics, opioids create conditions that favor the accumulation and hardening of stool, making bowel movements more difficult and infrequent. These physiological changes highlight why opioid use is closely associated with significant gastrointestinal side effects, particularly constipation, which is a common and often distressing complication for patients undergoing opioid therapy.^13,18-20. While standard laxative treatments may provide relief for some patients, they fail to address the root cause of opioid-induced constipation, which is the inhibition of mu-opioid receptors (MORs) in the gastrointestinal (GI) tract. These receptors play a key role in regulating bowel function, and their inhibition by opioids leads to the slowed peristalsis and altered fluid absorption that cause constipation. Therefore, although laxatives can help alleviate symptoms by softening stool or stimulating bowel movements, they do not counteract the underlying receptor-level effects of opioids within the GI tract, leaving the primary issue unresolved.^13,21-22. In 2008, the Food and Drug Administration (FDA) approved methylnaltrexone, an opioid receptor antagonist, as a treatment for opioid-induced constipation (OIC). This approval represented a significant development in managing OIC, particularly for those who require opioid therapy for pain relief in advanced illnesses. Methylnaltrexone is recognized for its safety and effectiveness, offering relief from constipation without interfering with the pain-relieving effects of opioids. However, while methylnaltrexone has been widely accepted for its general use in OIC, its specific efficacy in the cancer patient population has not been fully established. This leaves some questions unanswered regarding its optimal application in this group, highlighting the need for further research to better understand its role in treating OIC among cancer patients. As such, healthcare providers must carefully consider the available evidence when choosing the most appropriate treatment for OIC in various patient populations.^23-24. Methylnaltrexone decreases opioid effect peripherally by antagonizing opioid receptors without impairing its analgesic effect²⁴. Methylnaltrexone is a selective mu-opioid receptor antagonist. It acts peripherally, targeting opioid receptors outside the central nervous system and designed to remain confined within the peripheral system and not cross the blood-brain barrier. Thus, decreasing constipation without decreasing analgesic effect^18-19,25-26.

MATERIALS AND METHODS:

Review Registration:

This review was reviewed and registered in the International Prospective Registered for Systematic Review (PROSPERO) with registration ID CRD42023469292.

Search Strategy and Inclusion Criteria:

We searched literature using Pubmed, WileyOnline, CENTRAL (Cochrane Central Register of Controlled Trials), Google scholar, and Science Direct for RCT and Observational Studies. The search strategy was primarily designed for the Pubmed database from January 2013 to September 2023. We conducted a literature search using Boolean logic as a free-text term: ((Methylnaltrexone) AND ((Opioid-induced Constipation) OR (OIC) OR (Constipation)) AND ((Cancer) OR (Malignancy))). The filter is set for all types of articles except for review articles and meta-analysis articles. The English language articles were included in this study, otherwise were excluded. Studies evaluating the efficacy of methylnaltrexone for opioid-induced constipation (OIC) in cancer patients were considered eligible for inclusion. There were no restrictions on the subject age, sex, and cancer types in this study. Results of the searches were combined using Google Drive for each database, and the duplications were removed. Two researchers (KMNP and PISLD) independently evaluated each article. This study followed the PRISMA guidelines.

Definition:

Opioid-induced constipation (OIC) is defined as having used fewer than 3 laxatives in the past week or experiencing no bowel movements within 48 hours. The patients received an opioid and laxative regimen for active cancer with/without metastases. Rescue-free bowel movement (RFBM) and Rescue-free laxation (RFL) are defined as the absence of laxative, suppository, or enema use within 4 hours after the initial administration of methylnaltrexone or placebo. The influence of treatment on opioid analgesics was gauged by evaluating alterations in pain from baseline, employing a scale that ranged from 0 (no pain) to 10 (worst pain). Pain scores were recorded within 4 hours after administering a single dose to each study group. These measurements were used to evaluate the effects of the treatment.

Risk of Bias and Quality Assessment:

The risk of bias for the studies included in the review was evaluated using two specific tools: the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) and the Risk of Bias 2 (RoB2) tool. The selection of the appropriate tool was guided by the study design, with RoBANS being used for nonrandomized studies and RoB2 for randomized studies. This approach ensured a tailored assessment of bias, accounting for the unique aspects of each study design to provide a comprehensive evaluation of the potential risks. RoB2 was used to assess the Randomized-controlled Trial Study, and RoBANS was used to assess the Cohort Study. RoB2 included five domains rated low, unclear, and high-risk. Meanwhile, RoBANS included six domains rated. The studies' quality was evaluated utilizing the CASP (Critical Appraisal Skills Programme) checklist. It consists of an 11-item checklist to assess the validity, importance, and applicability of included studies. The quality of the studies was classified as Good, Fair, and Poor. Any disagreement will be discussed with third parties (NPGRS, DAS, and IKM).

Data Extractions:

Data extraction was performed by four reviewers (KMNP, PISLD, NLPYD, and NNGKD), divided based on study design, encompassing RCTs and Cohort studies. Each reviewer read the full-text article and at the same time extracted data on Google Sheets based on data availability. The following data were extracted: study characteristics (author, year of study, country, study design, population, total patients, age, male gender, intervention, control, follow-up, and outcomes. The study outcomes were extracted: the efficacy, the adverse events (AEs), the severe adverse events (SAEs), and pain score changes. The pain score changes were extracted from the qualitative data. Meanwhile, the efficacy, the adverse events (AEs), and the severe adverse events (SAEs) were extracted from the quantitative data included in the meta-analysis.

Statistical Analysis:

Statistical analysis was carried out using R Statistic 4.2.3. and Review Manager version 5.4. The assessment of statistical heterogeneity employed the chi-square and I² tests, with a significance threshold set at p < 0.1. The random effect model was used in this study to evaluate size effects. The findings were expressed as odds ratios (OR) accompanied by 95% confidence intervals (95% CI) and p-values. The Randomized Controlled Trial studies were analyzed using Review Manager for dichotomous data (Methylnaltrexone vs. Placebo) and performed using a forest plot. The observational cohort studies were analyzed using R statistic for proportional meta-analysis, and the results were performed using forest plots.

RESULT:

Study Selection:

A total of 393 articles were screened from databases of PubMed, CENTRAL, Science Direct, and Google Scholar for the last 10 years. There were 34 articles obtained after duplications were removed and then assessed for eligibility. There are 27 articles excluded due to incomplete and not relevant to the outcome. Seven articles were included for systematic review. From the seven articles, there were six articles included in the meta-analysis (Figure 1).

Characteristic of Studies:

Seven studies included in the systematic review consist of 4 RCT studies and 3 Cohort studies. This study included 1377 cancer patients with OIC, there were 1044 cancer patients included in the primary outcome of the meta-analysis. From those studies, the most intervention given to the patient is methylnaltrexone 0.15mg/kg and four-hour follow-up after the first dose of methylnaltrexone (Table 1).

Risk of Bias Assessment:

All of the 7 studies included in the systematic review were low risk of bias, both RCT and cohort studies using different risk of bias tools. There were 2 cohort studies that had an unclear bias in the confounding variables domain^27-28. Also, the 3 cohort studies did not blind the outcome assessment (Figure 2)^27-29.

Figure 1. PRISMA flowchart

The Efficacy of Methylnaltrexone:

The efficacy of methylnaltrexone was analyzed in six studies that consisted of four randomized controlled trials and two cohort studies. In RCTs, the efficacy was compared between methylnaltrexone and placebo. The random effect model result showed a significant difference in 4-hour laxations after the first dose (OR 8.96, 95%CI 3.68 - 21.81, p<0.00001) compared to control group (Figure 3). Cohort studies using proportional analysis found that the pooled rate was 71% (n= 2 studies, 95%CI 0.54 - 0.88) (Figure 4).

Figure 2. Risk of Bias RCT (a) and Cohort study (b)

Figure 3. The Comparative Efficacy of Methylnaltrexone Versus Placebo in Cancer Patients (RCTs)

Figure 4. The Comparative Efficacy of Methylnaltrexone Versus Placebo in Cancer Patients (Cohorts)

Table 1. Characteristics of studies

No.	Author, Year	Country	Study Design	Total Patients	Population	Age (Years)	Male (%)	Intervention Group	Control Group	Follow-up	Outcome
1	Mori et al., 2016^[27]	USA	Prospective cohort	12	Cancer patient ≥ 18 years old with ≥ 3 months of life expectancy	52	41.7	Methylnaltrexone single dose SC	-	4 hours,24 hours, 48 hours	RFL 4 hours and 24 hours, with or without laxatives 48 hours, overall pain score, opioid withdrawal, laxation assessment, constipation assessment, and patient satisfication with methylnaltrexone pada 4, 24, 48 hours after administration.
2	Nelson et al., 2019²⁸	USA	Retrospective cohort	333	1-95 years old cancer patient with methylnaltrexone therapy	55	37.53	Methylnaltrexone 12 mg SC, Child dose 1.6-12 mg	-	24 hours, 72 hours, 1 week after administration	Post methylnaltrexone complication
3	Rodrigues et al., 2013^[29]	Canada	Retrospective cohort	15	4-17 years old cancer patient with methylnaltrexone therapy	14	33.33	Methylnaltrexone 0.15 ± 0.02 mg/kg/dose (3-12 mg/dose)	-	4 hours and 24 hours	Bowel movement in 4 hours, AEs after 24 hours,
4	Nalamachu et al., 2015^[30]	USA	RCT	203	Cancer patients≥ 18 years old with 1-6 months of life expectancy	-	49.1	Methylnaltrexone 0.15 mg/kg and 0.30 mg/kg	Placebo	4hours	RFBM 4 hour, AEs, and SAEs.
5	Chamberlain et al., 2023^[31]	USA	RCT	355	Cancer patients≥ 18 years old with 1-6 months of life expectancy	63.5	53.2	Methylnaltrexone 0.15 mg/kg and 0.30 mg/kg	Placebo	4hours and 24 hours	RFL 4 hours and 24 hours, Cumulative RFL, Time to first RFL, Pain scale changes, and AEs
6	Chamberlain et al., 2021^[32]	USA	RCT	230	Cancer patient ≥ 18 years old with ≥1 month of life expectancy	63.8	53	Methylnaltrexone 0.15 mg/kg	Placebo	4hours and 24 hours	RFL 4 hours and 24 hours, AEs, and Pain scale changes
7	Janku et al., 2016^[33]	USA	RCT	229	Adult cancer patients with OIC refractory from laxatives and treated in palliative care	-	54.1	Methylnaltrexone 0.15 mg/kg and 0.30mg/kg	Placebo	4 hours	Laxation in 4 hours, Mortality rate

Severe Adverse Events (SAE) of Methylnaltrexone:

The severe adverse events were compared in four studies with two RCTs and two Cohort studies. In the RCTs between methylnaltrexone and the placebo group, No significant difference was observed (OR 1.06, 95% CI 0.21 - 5.44, p = 0.94) compared to control group (Figure 7). Meanwhile, in cohort studies, a pooled rate of 0% of severe adverse events in methylnaltrexone groups (n = 2 studies, 95% CI 0.00-0.02) (Figure 8). In RCT studies, severe adverse events were falls, spinal cord compression, dyspnea, and malignant neoplasm progression. These SAEs were deemed unrelated to the drug and were primarily observed in patients whose primary diagnosis was cancer. Meanwhile, cohort studies reported extra-systole and cardiovascular collapse as SAEs.

Pain Score Changes of Methylnaltrexone:

Studies from Chamberlain et al. found no significant difference in the pain scale compared to the pain scale baseline between methylnaltrexone and the placebo group. Pain scales were compared from the worst current pain scale and the mean pain scale from a 4-hour examination after the first dose. There were decreasing pain scales in both treatment groups. Before the first treatment, the methylnaltrexone group had a mean (SD) pain scale of 3.4(2.6) and placebo group pain scale of 3.4(2.5). After the first dose, in the methylnaltrexone group, there was a decreasing pain scale (-0.4 from the current pain and -0.5 from the worst pain). Meanwhile, in the placebo group, there were decreasing pain scale of -0.2 and -0.4, respectively^31-32.

DISCUSSION:

Effective cancer pain management is a crucial aspect of patient care, significantly impacting the individual's overall quality of life, as evidenced by various studies. The presence of cancer-related pain has been linked to heightened levels of anxiety, depression, decreased general health, cancer fatigue, alterations in physical abilities, and psychological disturbances^33-34. The severity of stress experienced by patients is closely tied to the stage of cancer, with higher-stage cancers associated with increased stress levels. Unfortunately, a considerable portion of patients, only 44%, report having a good quality of life, while the majority falls into the categories of low or average quality of life (3% and 53%, respectively)^35-36. Addressing cancer pain becomes paramount for enhancing the patient's quality of life, and improving patient knowledge is recognized as a key factor in achieving better outcomes³⁷. A range of drug modalities is available for managing cancer pain, including intravenous and transdermal fentanyl, morphine, tramadol, tapentadol, and methylnaltrexone ^38-41. Additionally, palliative radiotherapy has shown effectiveness in controlling cancer pain⁴². This comprehensive approach to cancer pain management aims to alleviate suffering and enhance the overall well-being of patients undergoing cancer treatment. Besides that, opioid use also could alter bowel movement due to inhibition in µ-opioid receptors, especially central-acting opioids. Bowel movement disturbance could cause opioid-induced constipation. Opioid-induced constipation has been associated with alterations in Aquaporin-3 (AQP3) expression, contributing to the constipating effects observed. A recent animal study conducted on mice revealed that Polyethylene Glycol 4000 (PEG-4000) demonstrated efficacy in reducing AQP3 expression. This reduction in AQP3 expression was linked to an increase in the water percentage within the colon of mice⁴³. These findings suggest a potential avenue for addressing opioid-induced constipation by modulating AQP3 expression, and PEG-4000 emerges as a promising candidate for further exploration in this context.

Opioid-induced constipation is common in cancer patients. A recent laxative drug for opioid-induced constipation was found ineffective and has many adverse effects. The adverse events recorded was opioid withdrawal and pain. Methylnaltrexone is a novel drug exhibiting selective antagonism of peripheral opioid receptors, suggesting its potential efficacy in the treatment of OIC. In a prior study conducted by Thomas et al., it was observed that 48% of patients achieved RFL after the initial administration of methylnaltrexone, contrasting with 15% in the placebo group. The study also revealed a significant increase in the number of patients experiencing rescue-free laxation (RFL) after receiving two or more of the initial four doses of methylnaltrexone compared to those in the placebo group, with a p-value of less than 0.001. Additionally, findings from Thomas et al. showed consistent RFL following each dose over a 13-day period, further supported by a p-value of less than 0.005. In a separate phase 2 trial involving patients with opioid-induced constipation (OIC), methylnaltrexone demonstrated its potential to effectively alleviate constipation caused by opioids without compromising pain relief or triggering opioid withdrawal symptoms. These results underscore the drug's therapeutic benefits in managing OIC while maintaining the overall efficacy of opioid therapy.⁴⁴ In the study conducted by Bull et al., it was observed that 62.9% of patients in the study group successfully achieved a resolved bowel movement (RFBM) within 4 hours after receiving two or more of the initial four doses during the first week of treatment. This finding highlights the rapid and effective response to the treatment, indicating that a significant proportion of patients experienced relief from constipation shortly after the initial dosing period. This result, with a 95% confidence interval ranging from 53.5% to 71.7%, was significantly higher compared to the placebo group, where only 9.6% of patients achieved RFBM within the same timeframe. The confidence interval for the placebo group was 4.9% to 16.6%, and the difference between the two groups was statistically significant, with a p-value of less than 0.0001. This significant disparity highlights the effectiveness of the treatment in resolving bowel function compared to the placebo. The initiation of RFBM after the first dose was remarkably swift in the methylnaltrexone group, with a median time of 0.8 hours, in contrast to 23.6 hours in the placebo group (p<0.0001). This study also found that the efficacy during a 10-week open-label study was consistent with two-week RCT results⁴⁵.

The response of methylnaltrexone was rapid within 4 hours after the drug was administered, and most had laxation within 1 hour. Approximately half of the patients exhibited no response to the initial dose, and this phenomenon was attributed to the antagonist-agonist ratio. In a distinct placebo-controlled trial conducted by In a 2005 study by Thomas et al., it was revealed that subcutaneous injections of methylnaltrexone at a dose of 0.15mg were as effective as those at 0.3mg. Both doses exhibited comparable effectiveness in the treatment. Advanced illness patients with OIC may have other causes such as low oral intake, imbalance in metabolic, immobility, neurologic disorders, and other drug adverse effects⁴⁶.

In the randomized controlled trial conducted by Bull et al., the predominant AEs in the methylnaltrexone group were abdominal pain (33.6%) and nausea (11.2%). SAEs were reported in 21.1% of patients in the placebo group, while 12.1% of patients in the methylnaltrexone group experienced SAEs. Importantly, none of these SAEs were considered related to the study drug. Additionally, in the open-label study, the most common adverse events observed in more than 10% of patients included peripheral edema, diarrhea, abdominal discomfort, nausea, and dyspnea. These findings highlight the prevalence of these side effects across both treatment and placebo groups, though none were directly linked to methylnaltrexone. AEs considered by researchers relate to the drug research occurring in 25.5% of patients in open-label studies; The adverse events most commonly reported in the patient population, each with an incidence of 5% or greater, included abdominal pain, diarrhea, and flatulence. Specifically, abdominal pain was observed in 15.4% of patients, making it the most frequently encountered issue. Diarrhea was reported by 7.4% of the patients, while flatulence was experienced by 3.4% of the population. These figures highlight the prevalence of these particular side effects among patients, underscoring the need for careful monitoring and management of these adverse events during treatment. Consistent with earlier studies in palliative care and noncancer pain, abdominal pain was the predominant adverse event among patients receiving methylnaltrexone, and its intensity was predominantly mild to moderate. Methylnaltrexone also did not disrupt opioid analgesia. As a naltrexone derivative with a positive charge, methylnaltrexone does not exert an impact on the central nervous system in humans due to its inability to penetrate the BBB^18,24,26,45.

Thomas et al. extensively documented the variations in pain scores associated with methylnaltrexone. The outcomes revealed that methylnaltrexone did not induce an escalation in pain or initiate opioid withdrawal. These findings provide support for the proposition that methylnaltrexone exerts its effects peripherally. Lipman et al.'s investigation also delineates minimal alterations in pain scores and opioid withdrawal. Additionally, a separate study demonstrated that there were no statistically significant differences in current pain scores from baseline to day 7 following treatment with either methylnaltrexone or placebo. This indicates that neither treatment led to notable changes in pain levels over the course of the study period, suggesting that methylnaltrexone does not impact pain control while addressing opioid-induced constipation. This lack of significant difference was observed in both cancer and non-cancer patient groups. Specifically, in the cancer patient group, the baseline pain scores were recorded at 3.6 for those who received methylnaltrexone and at 3.5 for those who were given placebo. By day 7 post-dose, the pain scores for the methylnaltrexone group decreased to 2.9, while those for the placebo group slightly increased to 3.2. Despite these changes, the statistical analysis revealed p-values of 0.7043 for the cancer group and 0.6075 for the non-cancer group. These findings indicate that there were no significant differences in pain scores between the methylnaltrexone and placebo treatments in either patient group. This suggests that methylnaltrexone, while effective for managing constipation, does not alter pain levels, maintaining comparable outcomes to placebo in terms of pain management, indicating that the treatment did not result in a meaningful change in pain levels over the study period.³² Enhancing the management of cancer pain involves considering alternative approaches that do not interfere with drug metabolism. Hypnosis and foot massage are among these alternatives, providing relaxation for patients. These non-pharmacological interventions have shown promise in reducing pain levels and improving overall patient comfort ⁴⁷. Integrating such complementary therapies into the comprehensive care plan for individuals with cancer pain can contribute to a more holistic and patient-centered approach to pain management.

CONCLUSION:

This systematic review and meta-analysis offer robust evidence that methylnaltrexone significantly improves laxation within 4 hours after the initial dose, in contrast to a placebo. The analysis confirms that methylnaltrexone is highly effective in inducing bowel movements quickly, demonstrating a clear benefit over placebo treatments. This highlights its potential as a valuable option for patients suffering from opioid-induced constipation. The analysis highlights that methylnaltrexone effectively induces bowel movements more quickly than placebo, underscoring its efficacy as a treatment for opioid-induced constipation. These findings support the use of methylnaltrexone as a viable option for patients who require rapid relief from constipation related to opioid use. Importantly, methylnaltrexone does not impact the analgesic mechanism of action, thereby ensuring it does not interfere with the primary treatment for cancer pain in patients experiencing OIC.

CONFLICT OF INTEREST:

None declared.

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Received on 03.01.2024 Revised on 15.06.2024

Accepted on 18.09.2024 Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):24-32.

DOI: 10.52711/0974-360X.2025.00004

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