Attrition of methylnaltrexone treatment-emergent adverse events in patients with chronic noncancer pain and opioid-induced constipation: a post hoc pooled analysis of two clinical trials

Introduction

Opioids, despite their potential drawbacks, remain an analgesic mainstay for patients with a number of chronic refractory pain conditions, including appropriate patients with chronic noncancer pain. The use of opioids, even over the short-term, may be associated with gastrointestinal side effects, such as nausea, abdominal pain, vomiting, and constipation.^1–4 Of these, constipation has been ranked by patients as the most bothersome,² and can have a demonstrably negative impact on quality of life.^5,6 Opioid-induced constipation (OIC) occurs in as many as 80% of patients treated with opioids,⁷ frequently leading to dose reduction or discontinuation of therapy.^1,2,4,8,9 Moreover, whereas other gastrointestinal side effects associated with opioids tend to dissipate over time, OIC is generally not subject to the development of tolerance and, therefore, presents a patient management challenge requiring ongoing assessment, monitoring, and treatment.¹ Preventative measures and common constipation remedies, including lifestyle changes and over-the-counter or prescription laxatives, only provide limited relief from OIC.^8,10,11

Methylnaltrexone (Relistor^®, Salix Pharmaceuticals, a division of Bausch Health US, LLC, Bridgewater, NJ) is a peripherally acting μ-opioid receptor antagonist that reverses opioid-induced effects in the gastrointestinal tract, such as delayed gastric emptying and prolonged oral-cecal transit time.^12,13 Pain relief with opioid therapy, however, is maintained during methylnaltrexone treatment because the high polarity and low lipid solubility of the molecule inhibits its passage through the blood-brain barrier, thereby preserving centrally mediated opioid analgesia.^14,15 Methylnaltrexone is available in subcutaneous and oral formulations, both of which are approved for the treatment of OIC in adults with chronic noncancer pain.¹⁶ Subcutaneous methylnaltrexone is also indicated for the treatment of OIC in patients with advanced illness or pain caused by active cancer.^16–18

In clinical trials, the majority of treatment-emergent adverse events (TEAEs) that occurred during methylnaltrexone treatment were gastrointestinal in nature (e.g., abdominal pain, diarrhea, nausea).^15,19–21 As many of these events are also common during laxation, it is plausible that gastrointestinal TEAEs reported in patients who received methylnaltrexone, most of whom had not had an adequate response to their laxative regimens before entering the studies, are of short duration and may be linked to successful relief of OIC. To test this hypothesis, the frequency of TEAEs after multiple doses of methylnaltrexone in two randomized, placebo-controlled clinical trials were evaluated. Relationships between TEAE frequency and methylnaltrexone efficacy, measured by opioid withdrawal symptom frequency, changes in pain intensity, and rescue-free bowel movements (RFBMs) within 4 hours of the first study drug dose, were also evaluated.

Methods

Results

A total of 1263 patients who received at least one dose of study medication were included in the pooled analysis: 900 had been randomized to methylnaltrexone (subcutaneous, n = 298; oral, n = 602) and 363 had been randomized to placebo. Patients in the subcutaneous methylnaltrexone treatment group were evenly divided between those who received 12 mg once daily (n = 150) and 12 mg every other day (n = 148). Among those in the oral methylnaltrexone treatment group, 201, 202, and 200 patients were randomized to treatment with methylnaltrexone 150 mg, 300 mg, and 450 mg once daily, respectively. Among all patients, 88% completed the double-blind phase. The discontinuation rate ranged from 10.0% to 18.8% depending on the methylnaltrexone dose and route of administration. The most common reasons for discontinuation were TEAEs, patient request, and protocol violations. Patients who discontinued due to TEAEs most commonly reported gastrointestinal complaints, such as abdominal pain, nausea, and vomiting (Table 1).

Demographic and baseline characteristics were generally well balanced among treatment groups (P>0.05 for all methylnaltrexone vs placebo, Table 2). Patients in the oral methylnaltrexone treatment group reported modestly lower rates of baseline laxative use and a slightly greater mean number of RFBMs per week compared with patients who received subcutaneous methylnaltrexone. Baseline median daily morphine-equivalent doses and baseline mean pain scores were comparable among treatment groups.

Opioid withdrawal and maintenance of analgesia

In all treatment groups, slight decreases in SOWS total scores were observed between baseline and the day 1 postdose assessment, with the least decline occurring in the subcutaneous methylnaltrexone treatment group (Figure 1A). The difference in decrease from baseline in SOWS total scores between treatment groups was statistically significant for the comparison of the combined methylnaltrexone treatment group versus placebo at day 1 (least-squares means, −3.6 and −2.6, respectively; P = 0.01), but was not statistically significant at weeks 2 or 4. Similar results were observed for SOWS total scores without cramping (Figure 1B).

Figure 1. Effect of study treatment on SOWS (A) total score and (B) total score without cramping.

Data are presented as means ± standard deviations.*P < 0.05 for the comparison of change from baseline in least-squares mean values in the all methylnaltrexone vs placebo treatment groups.

BL = baseline; MNTX = methylnaltrexone; PBO = placebo; SC = subcutaneous; SOWS = Subjective Opioid Withdrawal Scale.

The OOWS total scores increased slightly from baseline to the day 1 postdose assessment in all methylnaltrexone treatment groups, whereas the placebo score remained unchanged (Figure 2A). The difference in changes from baseline values between the combined methylnaltrexone treatment group and placebo was statistically significant at day 1 (least-squares means, 0.13 and −0.02, respectively; P=0.001), but not at weeks 2 or 4. When cramping was omitted from the OOWS total score, the observed increases from baseline score in the methylnaltrexone treatment group lessened but remained significantly different from placebo at day 1 (Figure 2B).

Figure 2. Effect of study treatment on OOWS (A) total score and (B) total score without cramping.

Data are presented as means ± standard deviations. *P = 0.001; ^†P < 0.05; for the comparison of change from baseline in least-squares mean values in the all methylnaltrexone vs placebo treatment groups.

BL = baseline; MNTX = methylnaltrexone; OOWS = Objective Opioid Withdrawal Scale; PBO = placebo; SC = subcutaneous.

Pain intensity scores did not change significantly from baseline for any treatment group throughout the study (Figure 3). Least-squares mean changes in pain intensity score ranged from −0.02 to −0.12.

Figure 3. Pain scores during treatment with methylnaltrexone or placebo.

Data are presented as means ± standard deviations. MNTX = methylnaltrexone; PBO = placebo; SC = subcutaneous.

Discussion

In this pooled analysis of patients with chronic, noncancer pain and OIC, rates of TEAEs decreased considerably between the first and second dosing days following treatment with methylnaltrexone and were comparable to placebo after the second dose. Abdominal pain, nausea, hyperhidrosis, and diarrhea were the most frequently reported TEAEs in the methylnaltrexone treatment group at day 1 and also demonstrated the most pronounced decreases in frequency after the second dose. The presence of abdominal pain was predominantly reported as mild or moderate in intensity, and very few patients discontinued due to abdominal pain. An association was detected between the presence of the gastrointestinal symptoms of abdominal pain, upper abdominal pain, nausea, and diarrhea on day 1 and the occurrence of an RFBM within 4 hours of the first methylnaltrexone dose. Together, these data demonstrate the rapid attrition of early-onset TEAEs occurring with methylnaltrexone treatment for OIC, and suggest that gastrointestinal symptoms may be due, in part, to resumption of bowel function/constipation relief.

A similar decrease in abdominal pain frequency from the first to second dose of methylnaltrexone was reported in a prior post hoc analysis using data from two randomized, placebo-controlled clinical trials of subcutaneous methylnaltrexone in patients with advanced illness whose laxative therapy response was insufficient (N=288).²³ In that study, abdominal pain was reported by 23% of patients following the first methylnaltrexone dose, by 13% of patients following the second dose, and by less than 10% of patients following the fifth dose, a rate similar to the frequency of abdominal pain reported by the placebo group (9.8%). The investigators also observed a relationship between abdominal pain and laxation response. In total, 80% of patients in the methylnaltrexone treatment group who experienced abdominal pain on study day 1 had an RFBM within 4 hours of the first study drug dose, whereas 47.2% of patients without abdominal pain on day 1 demonstrated an RFBM response. These data support the hypothesis that, in patients with OIC despite ongoing laxative use, the process of being rapidly induced to a bowel movement is initially accompanied by abdominal pain with the first dose, but once laxation has occurred, subsequent doses are generally not accompanied by such pain.

In the current study, safety and efficacy assessments were generally comparable between the subcutaneous and oral methylnaltrexone formulations, although the frequency of TEAEs after the first dose of study drug and the decrease in TEAE rates from day 1 to treatment day 2 were greater among patients treated with subcutaneous methylnaltrexone. There are intrinsic and study-design related factors that could contribute to this observed difference between formulations. First, patients who received subcutaneous methylnaltrexone had a greater response rate (i.e., RFBM within 4 hours of first study drug dose) compared with patients who received oral methylnaltrexone. It has been postulated that the greater initial response rate is due to a faster onset of effect with the subcutaneous formulation, which, unlike the oral formulation, does not require time for absorption.²⁰ If the hypothesis that the frequencies of the observed gastrointestinal symptoms are partially due to OIC relief is correct, then a greater rate of RFBM response within 4 hours would naturally be linked to a greater frequency of early-onset gastrointestinal TEAEs consistent with laxation, such as abdominal pain and cramping. Second, the study of oral methylnaltrexone investigated three doses, the lower doses being one third (150 mg) and two thirds (300 mg) of the recommended methylnaltrexone dose (450 mg). As oral methylnaltrexone efficacy has been shown to be dose dependent,²⁰ the inclusion of lower doses in this analysis may have influenced RFBM response and the frequency of any associated TEAEs. However, when the patients receiving the methylnaltrexone doses that are approved for OIC treatment (subcutaneous methylnaltrexone 12 mg/day or oral methylnaltrexone 450 mg/day) were analyzed separately, more patients who were responders than nonresponders reported having abdominal pain on day 1, indicating that treatment with the approved doses may have an effect on efficacy. In addition, when discontinuation rates were assessed for each dose and regimen, overall discontinuation rates and discontinuation rates due to TEAEs were consistent between the approved doses (subcutaneous methylnaltrexone 12 mg/day and oral methylnaltrexone 450 mg/day) and the other studied doses (subcutaneous methylnaltrexone 12 mg every other day and oral methylnaltrexone 150 or 300 mg/day), further supporting the safety profile of the approved doses.

Pooled data from the two included clinical trials indicate that methylnaltrexone does not induce symptoms of opioid withdrawal. Scores for SOWS and OOWS showed slight changes after the initial study drug dose but returned to baseline levels by the subsequent assessment and were stable thereafter. Early changes in SOWS and OOWS scores could be partially attributable to changes in gastrointestinal TEAE frequency, as several items in both assessments address gastrointestinal symptoms.²² Interestingly, the initial decrease from baseline in SOWS was greatest in the placebo group. The clinical significance of a decrease from baseline in SOWS score is not clear, as it insinuates that a patient had symptoms of opioid withdrawal prior to receiving methylnaltrexone that were lessened by treatment. As pain intensity scores were consistent throughout the 12-week study durations and compromised analgesia typically precedes symptoms of opioid withdrawal in patients with chronic pain,^24,25 the clinical significance of the SOWS and OOWS score changes observed in this study are even more questionable. Further studies evaluating and validating the use of the OOWS and SOWS in patients taking opioids for chronic nonmalignant pain without an opioid addiction are needed. However, data from this analysis affirm that neither subcutaneous nor oral methylnaltrexone negatively influences opioid-mediated analgesia. Lack of opioid withdrawal symptoms and maintenance of analgesia are consistent with methylnaltrexone’s pharmacologic profile and lack of effect on centrally mediated analgesia.^14,15

There are limitations that need to be considered when interpreting the findings from this analysis. The designs of the two studies were similar, but not identical, which adds potential confounding factors to the analysis. As mentioned above, the oral methylnaltrexone formulation needs time to be absorbed prior to producing any effects not required by the subcutaneous formulation, which could influence the timing of treatment effects. In addition, individual subcutaneous and oral dose groups were combined for the purposes of this analysis, and oral methylnaltrexone efficacy has been shown to be dose dependent.²⁰ However, in the individual published studies, the total numbers of TEAEs did not vary appreciably among dose groups^19,20 thus any influence on the TEAE attrition assessment is likely to be minimal. The observation period of both studies was limited: opioid withdrawal symptoms were only reported during the 4-week, double-blind treatment period, and pain intensity over 12 weeks. Longer-term data regarding the impact of methylnaltrexone on these parameters is available from a 48-week, open-label study, in which no indications of opioid withdrawal, loss of opioid-mediated analgesia, or alteration in median morphine equivalent dose were observed during methylnaltrexone treatment.²¹

Conclusion

The attrition of TEAEs after the first dose of methylnaltrexone and the association between gastrointestinal TEAEs and laxation response support the hypothesis that early-onset TEAEs experienced with methylnaltrexone treatment, particularly gastrointestinal TEAEs, are at least partially due to laxation. Treatment with methylnaltrexone was additionally shown to relieve OIC without inducing withdrawal symptoms or compromising analgesia. For patients with chronic pain and OIC, methylnaltrexone offers a well-tolerated and effective treatment option for constipation relief.

Data availability