Candy Bridget, Jones Louise, Vickerstaff Victoria, Larkin Philip J, Stone Patrick
Marie Curie Palliative Care Research Department, UCL Division of Psychiatry, 6th Floor, Maple House, 149 Tottenham Court Road, London, UK, W1T 7NF.
Cochrane Database Syst Rev. 2018 Jun 5;6(6):CD006332. doi: 10.1002/14651858.CD006332.pub3.
Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care.
To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care.
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data.
We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced.
Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE.
We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence.Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42).
AUTHORS' CONCLUSIONS: In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.
阿片类药物引起的肠道功能障碍（OIBD）的特征为便秘、排便不尽、腹胀和胃反流。它是癌症疼痛治疗和姑息治疗中的主要不良事件之一，会导致发病率增加和生活质量下降。这是两项Cochrane系统评价的更新。其中一项于2011年第1期发表，关于泻药和甲基纳曲酮用于姑息治疗患者便秘的管理；该评价于2015年更新，排除了甲基纳曲酮。另一项于2008年第4期发表，关于μ-阿片受体拮抗剂（MOA）用于OIBD。在本次更新的评价中，我们仅纳入了关于MOA（包括甲基纳曲酮）用于癌症患者和接受姑息治疗患者的OIBD的试验。
评估MOA用于癌症患者和接受姑息治疗患者的OIBD的有效性和安全性。
我们检索了Cochrane对照试验中心注册库、MEDLINE、Embase、CINAHL和Web of Science至2017年8月。我们还检索了临床试验注册库和监管网站。我们联系了MOA的制造商以获取更多数据。
我们纳入了随机对照试验（RCT），这些试验评估了MOA用于癌症患者和处于姑息阶段患者的OIBD的有效性和安全性，无论他们患何种终末期疾病。
两位评价作者评估偏倚风险并提取数据。合并试验数据的适宜性取决于各试验间足够的同质性。我们的主要结局为排便、对疼痛缓解的影响和不良事件。对疼痛缓解的影响是主要结局，因为MOA的一个可能的不良作用是减少阿片类药物的疼痛缓解效果。我们使用GRADE评估这些结局的证据。
我们为本次更新识别了4项新试验，使本评价纳入的试验总数达到8项。共有1022名癌症患者（无论疾病分期）或处于任何疾病姑息治疗阶段的男性和女性在这些试验中被随机分组。评估的MOA为口服纳地美定和纳洛酮（单独或与羟考酮联合使用），以及皮下注射甲基纳曲酮。试验将MOA与安慰剂或不同剂量的活性干预措施或与其他药物联合使用进行比较。纳地美定试验以及两项纳洛酮与羟考酮联合使用的试验纳入了无论疾病分期的癌症患者。单独使用纳洛酮的试验纳入了晚期癌症患者。4项关于甲基纳曲酮的试验在姑息治疗中进行，其中大多数参与者患有癌症。所有试验都容易出现偏倚；4项试验处于高风险，因为它们每组的样本量少于50名参与者。在225名参与者中进行的纳地美定与安慰剂对比试验中，干预组在两周治疗期间有更多的自发排便（风险比（RR）1.93，95%置信区间（CI）1.36至2.74；中等质量证据）。与高剂量相比，低剂量导致的自发排便较少（0.1毫克与0.2毫克：RR 0.73，95%CI 0.55至0.95；；0.1毫克与0.4毫克：RR 0.69，95%CI 0.53至0.89；中等质量证据）。有中等质量证据表明纳地美定对阿片类药物戒断无影响。有5例严重不良事件。所有均发生在服用纳地美定的患者中（低质量证据）。纳地美定组其他（非严重）不良事件的发生率有所增加（RR 1.36，95%CI 1.04至1.79，中等质量证据）。最常见的不良事件是腹泻。单独使用纳洛酮或与羟考酮（一种阿片类药物）联合使用与仅使用羟考酮相比的试验未评估给药前两周的排便反应。有极低质量证据表明单独使用纳洛酮，以及中等质量证据表明羟考酮/纳洛酮对镇痛无影响。有低质量证据表明羟考酮/纳洛酮不会增加严重不良事件的风险，中等质量证据表明它不会增加不良事件的风险。在对287名参与者的两项试验的合并分析中，我们发现与安慰剂相比，甲基纳曲酮在24小时内诱导更多排便（RR 2.77，95%CI 1.91至4.04，I² = 0%；中等质量证据）。在合并分析中，我们发现甲基纳曲酮在两周内诱导更多的排便反应（RR 9.98，95%CI 4.96至20.09，I² = 0%；中等质量证据）。在甲基纳曲酮组中，首次给药后24小时内无补救排便反应的参与者比例为59.1%，安慰剂组为19.1%。有中等质量证据表明阿片类药物戒断率未受影响。甲基纳曲酮未增加严重不良事件的可能性；干预组的严重不良事件较少（RR 0.59，95%CI 0.38至0.93；I² = 0%；中等质量证据）。经历不良事件的参与者比例无差异（RR 1.17，95%CI 0.94至1.45；I² = 74%；低质量证据）。甲基纳曲酮增加了腹痛和肠胃胀气的可能性。两项试验比较了不同剂量甲基纳曲酮的给药方案，高剂量与低剂量相比。对于早期排便，有低质量证据表明不同剂量在镇痛和不良事件方面无明显差异。两项试验均在首次给药后24小时内测量排便反应（试验一：RR 0.82，95%CI 0.41至1.66；试验二：RR 1.07，95%CI 0.81至1.42）。
在本次更新中，关于纳地美定的结论是新的。有中等质量证据表明，口服纳地美定可在两周内改善癌症和OIBD患者的肠道功能，但会增加不良事件的风险。关于纳洛酮和甲基纳曲酮的结论没有变化。纳洛酮试验未评估24小时或两周内的排便情况。有中等质量证据表明甲基纳曲酮可在短期内和两周内改善接受姑息治疗患者的肠道功能，低质量证据表明它不会增加不良事件。需要更多试验，包括对不良事件的更多评估。目前的试验均未评估对儿童的影响。
