Subcutaneous Methylnaltrexone For Treatment Of Opioid-Induced Constipation In Cancer Versus Noncancer Patients: An Analysis Of Efficacy And Safety Variables From Two StudiesⅢ
Sep 12, 2023
Results
Patients
In the pooled population, a total of 178 patients received methylnaltrexone and 185 patients received placebo; 65.2% (n=116) of patients in the methylnaltrexone group and 61.6% (n=114) of patients in the placebo group had cancer. Demographics and baseline characteristics are shown in Table 1.
Patients with cancer were taking higher median daily doses of opioid morphine equivalents (methylnaltrexone: 180 mg/d; placebo: 188 mg/d) at baseline compared with those without cancer (methylnaltrexone: 120 mg/d; placebo: 80 mg/d). Almost all (98.6%) patients were using laxatives at baseline, with similar laxative use between groups. There were no notable differences in current and worst pain scores between study populations at baseline.
Effect on Laxation In patients with and without cancer, methylnaltrexone induced a significantly greater RFL response within 4 hours after the first dose of treatment compared with placebo (P < 0.0001; Figure 1). Significant differences in RFL after ≥2 of the first 4 doses of the study drug were also observed (Figure 1B). The probability of having an RFL within 4 and 24 hours after the first dose of study medication was significantly greater following methylnaltrexone treatment in both cancer and noncancer patients compared with placebo (Figure 2).
The median times to laxation within 24 hours after the first dose of study medication were 0.96 hours and 22.53 hours in cancer patients who received methylnaltrexone and placebo, respectively (P < 0.0001), and 1.25 hours and >24 hours in noncancer patients who received methylnaltrexone and placebo, respectively (P=0.0002).
These data indicate that most cancer and noncancer patients who received methylnaltrexone and responded to treatment did so within the first hour after the first dose of the study drug. The mean weekly number of laxations within 24 hours after dosing was similar in methylnaltrexone-treated patients with and without cancer by week 2 of the study and was higher in both cancer and noncancer patients who received methylnaltrexone versus placebo (Figure 3). Among cancer and noncancer groups, significantly higher proportions of patients receiving methylnaltrexone versus placebo achieved ≥3 RFL per week in both weeks 1 and 2 of the study (Figure 4).
Rescue Medication Use and Pain Scores
Smaller proportions of methylnaltrexone-treated patients in both cancer and noncancer groups required the use of rescue laxatives compared with cancer and noncancer patients receiving a placebo. However, these differences did not reach significance (Figure 5). There were no significant changes in current pain scores from baseline to day 7 post-dose among patients treated with methylnaltrexone or placebo in both cancer (P = 0.7043) and noncancer groups (P = 0.6075). Among patients with cancer, current pain scores were 3.6 at baseline and 2.9 at day 7 post-dose for those receiving methylnaltrexone and 3.5 at baseline and 3.2 at day 7 post-dose for those receiving placebo.
Baseline and day 7 post-dose current pain scores for patients without cancer were 4.4 and 3.6, respectively, among those receiving methylnaltrexone and 4.0 and 3.5, respectively, among those receiving placebo. Similarly, worst pain scores were not significantly different from baseline to day 7 post-dose in cancer (P = 0.9200) and noncancer (P = 0.7800) patients treated with methylnaltrexone or placebo. Among patients with cancer, the worst pain scores were 5.1 at baseline and 4.0 at day 7 post-dose for those receiving methylnaltrexone and 5.2 at baseline and 4.3 at day 7 post-dose for those receiving placebo. For those without cancer, the worst pain scores at baseline and day 7 postdose were 5.6 and 4.7, respectively, for methylnaltrexone and 5.4 and 4.4, for placebo.
Adverse Events
Overall, slightly higher proportions of cancer patients (methylnaltrexone group: 87.9% [n = 102]; placebo group: 79.8% [n = 91]) versus noncancer patients (methylnaltrexone group: 69.8% [n = 44]; placebo group: 70.4% [n = 50]) experienced TEAEs. Table 2 shows TEAEs occurring in >5% of patients in any treatment group. The most frequently occurring TEAEs in cancer patients who received methylnaltrexone or placebo included abdominal pain (24.1% [n = 28] and 9.6% [n = 11], respectively), disease progression (8.6% [n = 10] and 14.0% [n = 16], respectively), and nausea (14.7% [n = 17] and 14.0% [n = 16], respectively). Similar TEAEs were reported in the non-cancer cohort.
The most frequently occurring TEAEs reported in noncancer patients receiving methylnaltrexone or placebo included abdominal pain (17.5% [n = 11] and 11.3% [n = 8], respectively), nausea (4.8% [n = 3] and 9.9% [n=7], respectively), and diarrhea (4.8% [n = 3] and 8.5% [n = 6], respectively). Serious AEs were reported more commonly in methylnaltrexone-treated patients with cancer (17.2% [n = 20]) compared with those without cancer (7.9% [n = 5]). Serious AEs of disease progression (methylnaltrexone, 7.8% [n = 9]; placebo, 11.4% [n = 13]) and malignant neoplasm progression (methylnaltrexone, 5.2% [n = 6]; placebo, 10.5% [n = 12]) were reported in cancer patients.
Other serious AEs occurring in ≥2 cancer patients were fall (methylnaltrexone, 0%; placebo, 1.8% [n = 2]), spinal cord compression (methylnaltrexone, 0%; placebo, 1.8% [n = 2]), and dyspnea (methylnaltrexone, 0%; placebo, 1.8% [n = 2]). Serious AEs occurring in ≥2 noncancer patients were aggravated congestive cardiac failure (methylnaltrexone, 1.6% [n = 1]; placebo, 1.4% [n = 1]) and concomitant disease progression (methylnaltrexone, 3.2% [n = 2]; placebo, 1.4% [n = 1]).
Discussion
Nearly two-thirds of patients included in this pooled post hoc analysis had cancer. Baseline characteristics were similar between cancer and noncancer patients, with the exception that cancer patients were receiving a higher dose of opioid morphine equivalents at baseline. Despite this, along with several nonopioid-related factors that could contribute to constipation in cancer patients (e.g., cancer-related physiologic dysfunction, concomitant medications, dehydration, immobility, diet, or metabolic causes),11 the percentage of patients achieving a laxation response was similar in cancer and non-cancer patients and significantly greater than placebo. Methylnaltrexone induced laxation within 4 hours after administration of the first dose in the majority of patients with and without cancer, versus less than 20% of patients who received placebo.
Similar results were obtained within 4 hours after at least 2 of the first 4 doses of methylnaltrexone. The laxation effect of methylnaltrexone was achieved rapidly within 1 hour among the majority of patient responders. Overall, the time to RFL was significantly reduced after treatment with methylnaltrexone compared with placebo.
The mean number of weekly laxations within 24 hours of study drug administration by week 2 was significantly higher with methylnaltrexone versus placebo. Among both cancer and noncancer groups, significantly higher proportions of patients receiving methylnaltrexone versus placebo achieved ≥3 RFL per week in both weeks 1 and 2.
These results show that methylnaltrexone effectively reduces OIC in cancer patients, despite the likelihood that nonopioid-related factors contributed to constipation in this population and support the use of SC methylnaltrexone in patients with active cancer taking opioids for cancer-related pain.
The laxation response associated with methylnaltrexone decreased the need for rescue laxatives in both patients with and without cancer. Importantly, there were no significant changes from baseline to day 7 post-dose in current or worst pain scores for cancer and noncancer patients receiving methylnaltrexone or placebo. These results demonstrate that methylnaltrexone therapy allowed patients to continue their opioid treatment without experiencing an increase in pain while reducing their constipation.
Consistent with prior studies in patients with advanced
illnesses, this study showed that methylnaltrexone was well
tolerated in cancer and noncancer patients.13,29–31 Adverse
events and serious AEs occurred more frequently in cancer
patients, likely as a result of their underlying disease and
treatment. Although AEs such as abdominal pain and nausea
occurred more frequently with methylnaltrexone, this may
have been due to the increased laxation response observed
with treatment.33 The AE profile of methylnaltrexone does
not suggest symptoms associated with opioid withdrawal,
confirming the drug’s selective effect on peripheral μopioid receptors.30,31,33
Serious AEs of disease progression and malignant neoplasm progression were reported in cancer patients during these studies. It is important to note that these patients were taking higher doses of opioids at baseline than noncancer patients, and that, in advanced cancer patients, peripheral μopioid receptors may play a role in disease progression.24,25,34 Indeed, cellular, animal, and human data suggest that targeting these receptors may have the potential as anticancer therapy.17,24,25,35
Based on this evidence, Janku et al examined the potential effects of methylnaltrexone on survival.24 Findings revealed significantly longer overall survival times for cancer patients treated with methylnaltrexone versus placebo, and even greater benefits were observed in those patients who had a laxation response to methylnaltrexone. No treatment-related differences in overall survival were observed in noncancer patients.
Collectively, these findings may suggest a direct effect of methylnaltrexone on cellular tumor targets related to peripheral μ-opioid receptors24 that could result in the slowing of disease progression. It is unclear if other factors related to OIC relief such as indirect effects on gut function and immunosuppression may be involved in mitigating cancer progression.21,22,24,36,37 Moreover, constipation may be a risk factor for reduced survival as it relates to patients’ global quality of life,21 performance status, including decreased appetite and anorexia-cachexia syndrome,21,22 as well as increased intestinal permeability.38
Data from the current post hoc analysis cannot provide conclusions regarding the effect of opioids on cancer and survival, but they do indicate that methylnaltrexone was safe and effective in an advanced cancer population and that no differences in laxation response to methylnaltrexone were observed between cancer and noncancer patients. These preliminary results provide a basis for a better understanding of the clinical effects of methylnaltrexone in cancer patients who are receiving opioids and help to support future studies of methylnaltrexone as a potential treatment for cancer.
This post hoc analysis has some limitations. The two studies pooled in this analysis were not initially designed to compare outcomes for cancer versus noncancer patients. In addition, the trials were of short duration given the patients’ advanced illnesses. The effect of methylnaltrexone over a 10-week open-label extension was found to be generally consistent with that of a 2-week randomized controlled trial, though again patients were not stratified by cancer/noncancer.29 Given the advanced-illness diagnoses in this population, these patients were inherently very ill; AEs observed during the study could be attributable to underlying disease.
Conclusions
Treatment with methylnaltrexone resulted in significantly higher proportions of both cancer and noncancer patients with OIC achieving laxation responses within 4 hours of administration compared with placebo. Additionally, among those achieving a laxation response, laxation occurred significantly faster with methylnaltrexone than with placebo and was associated with a reduced need for rescue laxatives and no significant changes in pain.
Methylnaltrexone was also generally well tolerated in all patient groups. These results show that methylnaltrexone effectively reduces OIC in cancer patients as well as noncancer patients, despite the several nonopioid-related factors that may contribute to constipation in the prior population, and support the approval and use of SC methylnaltrexone for OIC in patients with active cancer taking opioids for cancer-related pain.
Natural Herbal Medicine For Relieving Constipation-Cistanche
Cistanche is a genus of parasitic plants that belongs to the family Orobanchaceae. These plants are known for their medicinal properties and have been used in Traditional Chinese Medicine (TCM) for centuries. Cistanche species are predominantly found in arid and desert regions of China, Mongolia, and other parts of Central Asia. Cistanche plants are characterized by their fleshy, yellowish stems and are highly valued for their potential health benefits. In TCM, Cistanche is believed to have tonic properties and is commonly used to nourish the kidney, enhance vitality, and support sexual function. It is also used to address issues related to aging, fatigue, and overall well-being. While Cistanche has a long history of use in traditional medicine, scientific research on its efficacy and safety is ongoing and limited. However, it is known to contain various bioactive compounds such as phenylethanoid glycosides, iridoids, lignans, and polysaccharides, which may contribute to its medicinal effects.
Wecistanche's cistanche powder, cistanche tablets, cistanche capsules, and other products are developed using desert cistanche as raw materials, all of which have a good effect on relieving constipation. The specific mechanism is as follows: Cistanche is believed to have potential benefits for relieving constipation based on its traditional use and certain compounds it contains. While scientific research specifically on Cistanche's effect on constipation is limited, it is thought to have multiple mechanisms that may contribute to its potential to relieve constipation. Laxative Effect: Cistanche has long been used in Traditional Chinese Medicine as a remedy for constipation. It is believed to have a mild laxative effect, which can help promote bowel movements and induce constipation. This effect may be attributed to various compounds found in Cistanche, such as phenylethanoid glycosides and polysaccharides. Moistening the Intestines: Based on traditional use, Cistanche is considered to have moisturizing properties, specifically targeting the Intestines. Promoting hydration and lubrication of the Intestines may help soften tools and facilitate easier passage, thereby relieving constipation. Anti-inflammatory Effect: Constipation can sometimes be associated with inflammation in the digestive tract. Cistanche contains certain compounds, including phenylethanoid glycosides and lignans, that are believed to have anti-inflammatory properties. By reducing inflammation in the intestines, it may help improve bowel movement regularity and relieve constipation.
