Naldemedine compared to placebo for opioid‐induced bowel dysfunction for people with cancer 

Patient or population: people with cancer irrespective of whether receiving palliative care and with opioid‐induced bowel dysfunction

Settings: not stated

Intervention: naldemedine

Comparison: placebo

Laxation response: risk of spontaneous rescue‐free bowel movements^ain the short term^b

—

—

—

Not reported

Laxation response: risk of spontaneous rescue‐free bowel movements^ain the medium term^c

RR 2.00 (1.59 to 2.52) NNTB 3 (3 to 4)

418 (2 studies)

⊕⊕⊕⊝

Moderate^d

Laxation response: patient assessment of change in bowel status at the end of trial

—

—

—

Not reported

Symptoms of opioid withdrawal^ein the

medium term^c

Naldemedine 0.1 mg: MD ‐0.10 (‐0.56 to 0.36); naldemedine  0.2 mg: MD 0.30 (‐0.21 to 0.81); naldemedine  0.4 mg: MD 0.20 (‐0.36 to 0.76)^d

112 in comparison with naldemedine 0.1 mg and 0.4 mg, 114 in comparison with 0.2mg (1 study)

⊕⊝⊝⊝
Very low^f,g

Serious adverse events^h

RR 3.34 (0.85 to 13.15)

418 (2 studies)

⊕⊕⊝⊝
Low^d,i

Adverse events

RR 1.49 (1.19 to 1.87)

418 (2 studies)

⊕⊕⊕⊝

Moderate^d

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

RR: risk ratio; NNTB: number needed to treat for an additional beneficial outcome; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Low dose naldemedine compared to higher‐dose for opioid‐induced bowel dysfunction for people with cancer 

Patient or population: people with cancer irrespective of whether they are receiving palliative care and with opioid‐induced bowel dysfunction

Setting: not stated

Intervention: Naldemedine 0.1 mg daily

Comparison: Naldemedine 0.4 mg daily

Laxation response: risk of spontaneous rescue‐free bowel movements in the short term^a

—

—

—

Not reported

Laxation response: risk of spontaneous rescue‐free bowel movements in the medium term^b,c

RR 0.69 (0.53 to 0.89)

111 (1 study)

⊕⊕⊝⊝

Low^d,e

Laxation response: patient assessment of change bowel status at end of trial

—

—

—

Not reported

Symptoms of opioid withdrawal^fin the medium term^b

MD 

‐0.30 [‐0.85, 0.25]

112 (1 study)

⊕⊕⊝⊝

Low^d,e

Serious adverse events^g

RR 0.25 (0.03, 2.17)

112 (1 study)

⊕⊕⊝⊝

Low^d.e

Adverse events

RR 0.84 (0.67,1.06)

112 (1 study)

⊕⊕⊝⊝

Low^d,e

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; ; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Naloxone compared with placebo for people with cancer and receiving palliative care with opioid‐induced bowel dysfunction

Patient or population: people with cancer and receiving palliative care with opioid‐induced bowel dysfunction

Settings: community

Intervention: naloxone

Comparison: placebo

Laxation response: risk of spontaneous rescue‐free bowel movements in the short term^a

—

—

—

Not reported

Laxation response: risk of spontaneous rescue‐free bowel movements in the medium term^b

—

—

—

Not reported

Laxation response: patient assessment of change in bowel status at the end of trial

—

—

—

Not reported

Symptoms of opioid withdrawal in the medium term

—

17 (1 study) 

—

Full data not provided 

Serious adverse events

—

17 (1 study)

⊕⊝⊝⊝

Very low^c,d

No serious adverse events were reported

Adverse events

—

—

—

Not reported

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Naloxone + oxycodone prolonged release tablets compared with oxycodone prolonged‐released tablets for people with cancer and opioid‐induced bowel dysfunction

Patient or population: people with cancer irrespective of whether they were receiving palliative care opioid‐induced bowel dysfunction

Settings: community

Intervention: naloxone + oxycodone prolonged‐release tablets (OXN PR)

Comparison: oxycodone prolonged‐released tablets (OXY PR)

Laxation response: risk of spontaneous rescue‐free bowel movements in the short term^a

—

—

—

Not reported

Laxation response: risk of spontaneous rescue‐free bowel movements in the medium term^b

—

—

—

Not reported

Laxation response: Patient assessment of change in bowel status^cat the end of trial

Study 1: Mean change ‐ 11.14 (‐19.03, ‐3.24)

Study 2: Little to no change p value = 0.264

212 (2 studies)

⊕⊕⊝⊝

Low^d,e 

Full data not provided in either study

Symptoms of opioid withdrawal^fin the medium term^b

MD ‐0.63 (‐2.44, 1.18)

133 (1 study)

⊕⊕⊝⊝

Low^d,e

—

Serious adverse events^g

RR 0.68 (0.44 to 1.06)

362 (3 studies)

⊕⊝⊝⊝

Very low^d,e,h

—

Adverse events

RR 1.01 (0.87 to 1.18)

362 (3 studies)

⊕⊕⊝⊝

Low^d,e

—

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio; ; MD: mean difference

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Methylnaltrexone compared to placebo for opioid‐induced bowel dysfunction in people receiving palliative care irrespective of whether they had cancer

Patient or population: people receiving palliative care irrespective of whether they had cancer with opioid‐induced bowel dysfunction

Setting: hospital and community

Intervention: methylnaltrexone

Comparison: placebo

Laxation response: risk of spontaneous rescue‐free bowel movements^ain the short term^b

RR 2.97 (2.13 to 4.13) NNTB 3 (2 to 3)

287 (2 studies)

⊕⊕⊝⊝

Low^c,d

Laxation response: risk of spontaneous rescue‐free bowel movements^ain the medium term^e

RR 8.15 (4.76 to 13.95) NNTB 2 (2 to 2)

305
(2 studies)

⊕⊕⊕⊝

Moderate^c,f

Laxation response: patient assessment of change in bowel status^gat the end of trial

RR 2.32 (1.64 to 3.27)*

287 (2 studies)

⊕⊕⊝⊝

Low^c,d

Proportion reporting improvement

Symptoms of opioid withdrawal^hin the medium term

MD ‐0.20 (‐0.80 to 0.40)

133 (1 study)

⊕⊕⊝⊝

Low^c,d

Serious adverse eventsⁱ

RR 0.59 (0.38 to 0.93)

364
(2 studies)

⊕⊕⊝⊝

Low^c,d

Adverse events

RR 1.17

(CI 1.05 to 1.30)

518
(3 studies)

⊕⊕⊝⊝

Low^c,j

Heterogeneity was substantial (74%). We did not undertake a sensitivity analyses as none of our predefined criteria for undertaking one were matched.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; MD: mean difference; RR: risk ratio; NNTB: number needed to treat for an additional beneficial outcome

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Methylnaltrexone 1 mg compared to methylnaltrexone 5 mg or greater for opioid‐induced bowel dysfunction in people receiving palliative care irrespective of whether they had cancer

Patient or population: people receiving palliative care irrespective of whether they had cancer with opioid‐induced bowel dysfunction

Setting: hospital and community

Intervention 1: lower‐dose methylnaltrexone (study 1: 3 doses, 1 week, 1 mg; study 2: 1 dose, 0.15 mg/kg)

Intervention 2: higher‐dose methylnaltrexone (study 1: 3 doses, 1 week, 5‐20 mg; study 2: 1 dose, 0.30 mg/kg)

Laxation response: risk of spontaneous rescue‐free bowel movements^ain the short term^b

Study 1: RR 0.21 (0.03 to 1.41)

Study 2: 

RR 1.06 (0.77 to 1.46)

135 (2 studies) Study 1: n = 33

Study 2: n = 102

⊕⊕⊝⊝

Low^c,d

Study data not combined as methylnaltrexone dosing differed substantially per study.

Laxation response: risk of spontaneous rescue‐free bowel movements^a,in the medium term^e

 RR 2.91 (0.82 to 10.39)

26 (1 study)

⊕⊝⊝⊝

Very low^c,f

Laxation response: patient assessment of change in bowel status^gat the end of trial

RR 0.98 (0.71 to 1.35)

102 (1 study)

⊕⊕⊝⊝

Low^c,d

Symptoms of opioid withdrawal in the medium term

MD ‐0.25 (‐0.84 to 0.34)

102 (1 study)

⊕⊕⊝⊝

Low^c,d

Data not combined as methylnaltrexone dosing differed.

Serious adverse events

—

—

—

In one trial, 15 serious adverse events occurred during the randomised trial phase but it does not report what arm the events occurred in. 

Adverse events

Study 1: RR 1.00 (1.00 to 1.00)

Study 2: RR 0.90 (0.73 to 1.13)

135 (2 studies)

Study 1: n = 33

Study 2: n = 102

⊕⊕⊝⊝

Low^c,d

Study data not combined as methylnaltrexone dosing differed substantially per study

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; MD: mean difference; RR: risk ratio.

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.