Methylnaltrexone for opioid-induced constipation: review and meta-analyses for objective plus subjective efficacy and safety outcomes

Figures & data

Figure 1 Methylnaltrexone randomized controlled trials for opioid-induced constipation treatment: study flow diagram.

Table 1 Characteristics of included studies

Author (year), existing source	Drug, dosage, and treatment period*	OIC patient’s condition	Sample size (% female)	Dropouts n (%), comments
Bull et al^Citation38 (2015), full-text	Sc MNTX; IG: 38 kg to <62 kg: 8 mg; ≥62 kg: 12 mg, qod; 2 weeks	Advanced illness (mostly cancer patients)	O: 230 (49%)	PBO: 26 (23%) IG: 27 (23%)
Anissian et al^Citation42 (2012), full-text	Sc MNTX; IG: 12 mg, qd; 4 or 7 days	Orthopedic surgical procedure	O: 37 (67%)	PBO: 3 (20%) IG: 3 (17%)
Rauck et al^Citation37,Citation41 (2012), abstract	Oral MNTX; IGs: 150, 300, or 450 mg, qd; 4 weeks	Chronic noncancer pain	O: 804 (N/S)	PBO: no dropouts reported IGs: no dropouts reported
Michna et al^Citation36 (2011), full-text	Sc MNTX; IG 1: 12 mg, qd, IG2: 12 mg, qod; 4 weeks	Chronic nonmalignant pain	O: 469 (59%)	PBO: 16 (10%), IG1: 28 (19%), IG2: 28 (19%)
Slatkin et al^Citation39 (2009), full-text	Sc MNTX; IG1: 0.15 mg/kg, IG2: 0.3 mg/kg; single injection; 1 day	Advanced illness (mostly cancer patients)	O: 154 (46%)	Dropouts: 2 (1%); 1 noncompliant, 1 died
Portenoy et al^Citation26 (2008), full-text	Sc MNTX; IG1: 1 mg, IG2: 5 mg, IG3: 12.5 mg, IG4: 20 mg; qod; 1 week	Advanced illness (mostly cancer patients)	O: 33 (55%)	IG1: 3 (30%), IG2: 2 (29%), IG3: 3 (30%), IG4: 3 (50%); Note: no PBO
Thomas et al^Citation40 (2008), full-text	Sc MNTX; IG: 0.15 mg/kg, qod; 2 weeks; note: 0.30 mg/kg when <3 BMs/week after 8 days	Advanced illness (mostly cancer patients)	O: 133 (57%)	PBO: 17 (24%), IG: 10 (16%); Note: different doses in IG

Notes:

* Refers to the blinded phase of the RCTs (not to the open-label phase or the follow-up). Adapted from Advances in pharmacotherapy for opioid-induced constipation – a systematic review, Siemens W, Gaertner J, Becker G, Expert Opin Pharmacother, 2015;16(4):515–532,⁶ with the permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com).

Abbreviations: BM, bowel movement; IG, intervention group; MNTX, methylnaltrexone; n, number of patients; N/S, not specified; O, overall; OIC, opioid-induced constipation; PBO, placebo; qd, every day (Latin: quaque die); qod, every other day (Latin: quaque altera die); RCT, randomized controlled trial; Sc, subcutaneous.

Figure 2 Methylnaltrexone versus placebo: rescue-free bowel movement within 4 hours after the first dose.

Table 2 Objective outcome measures assessing OIC

Author (year)	Category	Results
Bull et al^Citation38 (2015)	BM frequency	–
	BM within 4 hours	RFBM: after ≥2 of the first 4 doses: MNTX: 62.9% vs PBO: 9.6% (P<0.0001)
		RFBM after the first dose: MNTX: 69.8% vs PBO: 17.5% (P<0.0001)
		RFBM after ≥4 of the maximum 7 doses: MNTX 62.2% vs PBO: 4.9% (P<0.0001)
	Time to first BM	RFBM after first dose: median time for MNTX: 0.8 hours vs PBO: 23.6 hours (P<0.0001)
Anissian et al^Citation42 (2012)	BM frequency	–
	BM within 4 hours	First dose: laxation IG. PBO, 4 hours: 38.9% vs 6.7%, P=0.046
		Note: laxation within 2 hours: 33.3% vs 0%, P=0.021
	Time to first BM	IG < PBO, median time to laxation: 15.8 vs 50.9 hours, P=0.0197
Rauck et al^Citation37,Citation41 (2012)	BM frequency	≥3 RFBMs/week with an increase of ≥1 RFBM/week over baseline for ≥3 of first 4 weeks: 150 mg: 41.3% (ns), 300 mg: 47.8% (P=0.03), 450 mg: 50.5% (P=0.008); P-values based on comparison with PBO: 36.8%
		RFBM/week mean change from baseline: 150 mg: 1.88 (ns), 300 mg: 2.39 (P=0.009), 450 mg: 2.40 (P=0.009); P-values based on comparison with PBO: 1.71
	BM within 4 hours	All doses, RFBM: 150 mg: 21.1% (P=0.31), 300 mg: 24.6% (P=0.004), 450 mg: 27.4% (P<0.0001); P-values based on comparison with PBO: 18.1%
	Time to first BM	–
Michna et al^Citation36 (2011)	BM frequency	≥3 RFBMs/week: IG1: 58.7%, IG2: 45.3%, PBO: 38.3%
		Baseline RFBM ~1: mean change: IG1: 3.1, IG2: 2.2, PBO: 1.5, both IGs P<0.01 vs PBO
	BM within 4 hours	First dose (RFBM): IG1: 33.3%, IG2: 35.1%, PBO: 9.9%; both IGs P<0.001 vs PBO
		All doses (RFBM): IG1: 28.9%, IG2: 30.2%, PBO: 9.3%; both IGs P<0.001 vs PBO
	Time to first BM	IG1 and IG2 shorter compared with PBO, P<0.001
Slatkin et al^Citation39 (2009)	BM frequency	–
	BM within 4 hours	Single dose (RFBM): MNTX 0.15 mg/kg: 61.7% (95% CI, 47.8% to 75.6%)
		MNTX 0.3 mg/kg: 58.2% (95% CI, 45.1% to 71.2%)
		PBO: 13.5% (95% CI, 4.2% to 22.7%); IGs vs PBO P<0.0001
	Time to first BM	Median time to RFBM: IG1: 1.1 hours, IG2: 0.8 hours, PBO >24 hours, both IGs vs PBO P<0.0001
* Portenoy et al^Citation26 (2008)	BM frequency	–
	BM within 4 hours	First dose: MNTX 1 mg: 1/10 (10%); MNTX 5 mg: 3/7 (43%); MNTX 12.5 mg: 6/10 (60%), MNTX 20 mg: 2/6 (33%); MNTX ≥5 mg: 11/23 (48%)
	Time to first BM	Median time to laxation was >48 hours for the 1 mg dose group and 1.72, 0.48, and 6.75 hours in the 5, 12.5, and 20 mg dose groups
Thomas et al^Citation40 (2008)	BM frequency	≥3 RFBMs/week: MNTX: 68%, PBO: 45%, P=0.009
	BM within 4 hours	First dose: MNTX: 48%, PBO: 15%, P<0.001
		After one or more doses: MNTX: 79%, PBO: 46%
		After ≥2 of the first 4 doses: MNTX: 52%, PBO: 8%, P<0.001
	Time to first BM	First dose, median: MNTX: 6.3 hours, PBO: >48 hours, P<0.001

Notes:

* Dose-ranging study; no placebo. Adapted from Advances in pharmacotherapy for opioid-induced constipation – a systematic review, Siemens W, Gaertner J, Becker G. Expert Opin Pharmacother, 2015;16(4):515–532,⁶ with the permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com).

Abbreviations: BM, bowel movement; IG, intervention group; MNTX, methylnaltrexone; ns, not (statistically) significant; OIC, opioid-induced constipation; PBO, placebo; RFBM, rescue-free bowel movement; CI, confidence interval.

Table 3 Patient-reported outcomes assessing OIC

Author (year)	Results
Bull et al^Citation38 (2015)	–
Anissian et al^Citation42 (2012)	Global Satisfaction With Treatment Scale (very satisfied, satisfied, or minimally satisfied):
	After 4 hours: MNTX: 83.3%, PBO: 60.0%
	Day 7: MNTX: 83.3%, PBO: 53.3%
	Dissatisfaction (minimally dissatisfied, dissatisfied, or very dissatisfied):
	Day 7: MNTX: 0%, PBO: 26.7%
Rauck et al^Citation37,Citation41 (2012)	–
Michna et al^Citation36 (2011)	Straining Scale (0 [none] to 4 [very severe]) → Percentage of RFBMs rated as “none” or “mild”:
	Week 1: MNTX qd: 28.1%, MNTX qod: 28.5%, PBO: 14.0%, IGs vs PBO P<0.02
	Week 2: MNTX qd: 26.9%, MNTX qod: 26.8%, PBO: 15.2%, IGs vs PBO P<0.02
	Week 3: MNTX qd: 29.0%, MNTX qod: N/S, PBO: 14.4%, MNTX qd vs PBO P=0.002
	Week 4: N/S
	Sensation of complete evacuation (yes/no) → Percentage of RFBMs rated as “yes” Week 1–3: N/S
	Week 4: MNTX qd: 27.4%, MNTX qod: N/S, PBO 19.9%, P<0.04
Slatkin et al^Citation39 (2009)	GCIC → Improvement (slightly better, somewhat better, much better):
	After 24 hours: MNTX 0.15 mg/kg: 58.7%, MNTX 0.30 mg/kg: 58.8%, PBO: 21.6%
* Portenoy et al^Citation26 (2008)	Constipation severity (none, mild, moderate, severe, very severe) → moderate to very severe:
	Baseline: 28/33 (85%)
	After 1 week: 4/11 (36%)
	Difficulty passing stool (no difficulty, slight, moderate, considerable, great)
	≥5 mg groups improved compared with 1 mg group (nqd)
	Patient satisfaction with study medication (1 [very satisfied] to 7 [very dissatisfied])
	No trends observable (nqd)
Thomas et al^Citation40 (2008)	Stool difficulty 1–5 (ranging from no difficulty to great difficulty)
	More MNTX than PBO patients had reductions in stool difficulty (nqd)
	GCIC
	Better (slightly better, somewhat better, much better):
	Day 7: MNTX: 36/49 (73.5%), PBO: 20/57 (35.1%)
	Day 14: MNTX: 36/53 (67.9%), PBO: 25/56 (44.6%)
	Worse (much better, somewhat better and slightly better):
	Day 7: MNTX: 0/49 (0%), PBO: 2/57 (3.5%)
	Day 14: MNTX: 2/53 (3.8%), PBO: 2/56 (3.6%)

Notes:

* Cave: dose-ranging study; no placebo.

Abbreviations: GCIC, Global Clinical Impression of Change; IG, intervention group; MNTX, methylnaltrexone (group); N/S, not specified; nqd, no quantitative data provided; OIC, opioid-induced constipation; PBO, placebo; qd, every day (Latin: quaque die); qod, every other day (Latin: quaque altera die); RFBM, rescue-free bowel movement.

Table 4 Global burden measures assessing OIC

Author (year)	Results
Bull et al^Citation38 (2015)	–
Anissian et al^Citation42 (2012)	–
Rauck et al^Citation37,Citation41 (2012)	–
Michna et al^Citation36 (2011)	PAC-QOL (0–4; smaller values indicate a better status)
	Improvement for week 4:
	MNTX qd: −0.74 (33%), PBO: −0.39 (18%), P<0.001;
	MNTX qod: −0.59 (27%), P=0.014 from baseline but ns compared with PBO
Slatkin et al^Citation39 (2009)	Constipation distress (1 [none]; 2 [a little bit]; 3 [somewhat]; 4 [quite a bit]; 5 [very much])
	Improvement (change by at least one category toward none):
	After 4 hours: MNTX 0.15 mg/kg: 64.4%, MNTX 0.30 mg/kg 63.5%, PBO: 34.0%
* Portenoy et al^Citation26 (2008)	Constipation distress (none, a little bit, somewhat, quite a bit, or very much)
	Baseline: 28/33 (85%) with somewhat, quite a bit, or very much distress
	After 1 week: 4/11 (36%) with somewhat, quite a bit, or very much distress
Thomas et al^Citation40 (2008)	Constipation-related distress (rated on a scale from “none” to “very much”)
	More MNTX than PBO patients had reductions in distress (nqd)

Notes:

* Cave: dose-ranging study; no placebo.

Abbreviations: MNTX, methylnaltrexone; nqd, no quantitative data provided; ns, not statistically significant; OIC, opioid-induced constipation; PAC-QOL, Patient Assessment of Constipation–Quality of Life; PBO, placebo; qd, every day (Latin: quaque die); qod, every other day (Latin: quaque altera die).

Figure 3 Methylnaltrexone versus placebo: abdominal pain.

Figure 4 Subgroup analysis for cancer vs noncancer patients: abdominal pain.

Figure 5 Random-effects model: subgroup analysis for cancer vs noncancer patients: abdominal pain.

Figure 6 Methylnaltrexone versus placebo: nausea.

Figure 7 Methylnaltrexone versus placebo: diarrhea.

Figure 8 Risk of bias summary.

Note: + refers to low risk of bias; ? refers to unclear risk of bias; – refers to high risk of bias.

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