• constipation
• pharmacology
• clinical trials

We read with interest the recent systematic review and network meta-analysis on the efficacy of pharmacological treatment of opioid-induced constipation (OIC).1 The authors reviewed 27 randomised controlled trials (RCTs) involving 9149 patients and concluded that naloxone was the best drug in patients with OIC, followed by naldemedine. We believe that several factors impacted the appraisal of relative efficacy and deserve discussion especially in network meta-analyses with no head-to-head drug trials.

1. Distribution and potential for opioid withdrawal: Naloxone is a lipophilic, non-selective and competitive opioid receptor antagonist. The oral formulation of naloxone has a bioavailability of ~2%; however, it is widely distributed, has a narrow therapeutic index and the oral doses required to treat OIC can increase the risk of opioid withdrawal symptoms. On the other hand, peripherally acting mu-opioid receptor antagonists such as naldemedine and naloxegol are extensively absorbed and excreted, do not cross the blood–brain barrier and are less likely to antagonise the analgesic effect of the opioid.

2. The oral formulation of naloxone used in most OIC trials is in fixed ratio combination with oxycodone (oxycodone PR/naloxone PR (OXN)). However, the doses of naloxone ranged from 2.5 mg daily to 40 mg daily, and the fixed dose ratio of opioid:naloxone ranged from fixed 2:1 ratio2 3, to a varying ratio of 1:1 to 8:1.4–6 OXN is available for prescription in a fixed 2:1 dose ratio, and therefore, it would be interesting to restrict the analysis to clinically available doses. In contrast, RCTs for naldemedine or naloxegol tested narrower dose ranges that included the doses approved for marketing: 0.1, 0.2 or 0.4 mg orally daily for naldemedine,7 8 or 12.5 and 25 mg orally daily for naloxegol.9 10 The heterogeneity in dose ranges tested variability may have biased the assessment of the drugs’ efficacy, and hence the interpretation of the results of the network meta-analysis.

3. Variation in trial design and primary or secondary outcome endpoints: Naloxone trials used variable endpoints: three trials assessed bowel function index (BFI),2 3 5 one trial constipation assessment scale (CAS)4 and one trial ‘change in weekly number of spontaneous bowel movements (SBMs)'.6 In contrast, the phase III trials for naldemedine7 and naloxegol9 used the same, US Food and Drug Administration (FDA)-approved primary endpoint for constipation (three or more SBMs/week and an increase of one or more SBM over baseline for ≥9 of 12 and ≥3 of the final four treatment weeks). This FDA endpoint appears more difficult to achieve compared with BFI or CAS. Furthermore, the naloxone trial by Lowenstein et al 3 may have been confounded by rescue medication since it is unclear whether bisacodyl use was excluded in the primary outcome measure.

   The network meta-analysis excluded a phase II RCT by Webster et al 10 on naloxegol which included 208 patients since the trial did not have a dichotomous outcome, and this exclusion, potentially impacted naloxegol’s efficacy relative to other drugs.

4. Network meta-analysis to appraise relative efficacy of drugs should require a similar disease burden or a ‘level-playing field’. For OIC, this may be baseline BFI on first-line laxative therapy, and the median dose of opioids expressed as the oral morphine equivalents (OMEs). Patients with OIC included in the larger naloxone trials (Simpson et al, Lowenstein et al and Meissner et al) were on lower OMEs than patients included in the naldemedine and naloxegol trials, as documented in table 1. Indeed sensitivity analysis would be appropriate to determine if median OME dose affected the appraisal of relative efficacy of the opioid antagonists.

In summary, we recommend further analyses to ascertain the best drug(s) for OIC.