Table 1.
Recent clinical studies on PAMORAs and the secretory drug lubiprostone with key findings
| Study | Patients/doses | Constipation-related end points | Constipation-related results | Of note |
|---|---|---|---|---|
| Alvimopan | ||||
| Webster et al,42 2008 RCT DB PC 8 wks |
522 patients with noncancer pain and opioid-induced bowel dysfunction were randomized to alvimopan 0.5 mg BID, 1 mg alvimopan QD, 1 mg alvimopan BID, or placebo | Weekly SBM over baseline symptoms | Significantly more mean weekly SBMs over initial 3 wks of treatment with alvimopan 0.5 mg BID, alvimopan 1 mg QD, and alvimopan 1 mg BID vs placebo along with symptomatic improvement | The best benefit-to-risk profile occurred with alvimopan 0.5 mg BID |
| Lubiprostone | ||||
| Cryer,43 2014 R DB PC RCT 12 wks |
836 noncancer pain patients with OIC randomized to lubiprostone 24 μg or placebo BID | SBM over baseline symptoms | SBM frequency vs baseline was significantly higher at wk 8 (P=0.005) and overall (P=0.004) in lubiprostone vs placebo patients. Lubiprostone patients had improved symptoms and patients rated it more effective than placebo for 11 of the 12 wks (P<0.05) | |
| Spierings et al,44 2015 PC DB studies 9 months |
439 noncancer chronic pain patients with OIC received lubiprostone 24 μg BID | Rescue medication use, weekly SBM frequency symptoms | Rescue medication use decreased from the first to ninth month (33.0%–18.6%) and mean weekly SBM increased significantly over baseline at all months (P<0.001, range 4.9–5.3 vs 1.4 at baseline) | |
| Methylnaltrexone | ||||
| Iyer et al,452011 RCT 4 wk |
469 noncancer pain patients with OIC were randomized to MN once a day, every other day, or placebo | Constipation symptoms self-reported by patients based on questionnaire | In the MN daily group, significant improvements occurred for rectal symptoms, stool symptoms, and global scores vs placebo. In the MN every other day group, significant improvements over placebo occurred in stool symptoms and global scores | |
| Michna et al,46 2011 RCT DB 4 wk |
460 noncancer pain patients with OIC randomized to MN <12 mg QD or every other day (alternating with placebo) | Bowel movement count, time of bowel movement, straining, sense of complete evacuation, Bristol Stool Form Scales, QoL | 34.2% of MN patients had RFBM within 4 hours of first dose vs 9.9% placebo group (P<0.001). NNT −4. MN patients had shorter time to first RFBM and greater increase in number of RFBMs per week (P<0.001 and P<0.05, respectively) | |
| Nalamachu et al,47 2015 Responder analysis of two RCTs |
Two Phase III RCTs (n=288) in post hoc analysis of responder population Patients were treated with 0.15 mg/kg or 0.30 mg/kg MN or placebo | RFBM within 4 hours of first dose | >50% of MN patients (both doses) had a RFBM within 4 hours of dosing compared with 14.6% of placebo patients (P<0.0001) | Largest differences between MN and placebo occurred in patients taking doses of 0.30 mg/kg and who had a noncancer primary diagnosis (70.0% vs 12.8%, P<0.001) |
| Viscusi et al,48 2016 RCT + OLE |
134 placebo-treated patients median 150 mg/d MEQ with <3 RFBM weekly taking ≥50 mg/d MEQ; randomized to 12 mg/d of MN or placebo for 4 wks (RCT) then OLE for 8 wks with MN 12 mg/d as needed | RFBM within 4 hours of dose; ≥3 RFBM per week; an increase of at least one RFBM per week over baseline | 9.7% (placebo) and 45.9% (MN) patients experienced an RFBM within 4 hours of first dose during RCT. 70% of placebo patients who crossed over to MN had ≥3 RFBM a week and an increase of at least one RFBM over baseline | Results in the OLE were durable >8 wks |
| Naloxegol | ||||
| Chey et al,1 2014 Two identical Phase III RCT DB studies 12 wk ITT |
Outpatients with noncancer pain and OIC (n=4,652 and 5,700) Once daily dose of 12.5 mg or 25 mg naloxegol or placebo | ≥3 SBM per week and increase of ≥1 SBM for weeks ≥9 of the 12 wk study and for ≥3 wks of the last 4 wks | The naloxegol 25 mg group was significantly more likely than placebo to meet end points (in one of the studies 44.4% vs 29.4%, P=0.001). Pain scores and daily opioid doses were similar among groups. AEs were highest in the 25 mg naloxegol group | The time to first postdose SBM was significantly shorter with either dose of naloxegol than placebo (in study 4) or with 25 mg only compared with placebo (study 5), P<0.01 both studies |
| Tack et al,49 2015 Pooled data from two DB RCTs 12 wk |
720 noncancer pain patients with laxative-refractory OIC randomized to be treated daily with 25 mg naloxegol, 12.5 mg naloxegol, or placebo | Time to first postdose laxation, SBMs, OIC symptoms | Response rates highest in 25 mg naloxegol patients (P<0.001) and 12.5 mg (P=0.005) vs placebo. Median times to first postdose SBM were 7.6 hours, 19.2 hours, and 41.1 hours for naloxegol 25 mg, 12.5 mg, and placebo, respectively | |
| Oxycodone/naloxone | ||||
| Blagden et al,50 2014 Pooled analysis from extensions of two Phase III trials | Pooled data from 474 patients with moderate to severe chronic pain taking OXN PR or OXY PR | Analgesia and bowel function using BPI and BFI, respectively; laxative use | At start of extension, mean BFI scores were 44.3 for OXY PR and 29.8 for OXN PR groups; 1 wk later scores were similar (26.5 and 27.5, respectively) with durable results | <10% of patients took laxatives regularly |
| Koopmans et al,51 2014 Pooled analysis from RCTs | (Pooled data from 75) LROIC patients treated with OXN PR (20–120 mg/d) for 4 wks or 12 wks | Analgesia and bowel function using BPI and BFI, respectively; laxative use | Significant improvements in bowel function with OXN PR (BFI score reduction 21.2). Number of patients with normal BFI score increased from 9.5% at baseline to 43.1% at day 15 of OXN PR | During study, 36% of patients stopped using laxatives (P<0.001) |
| Lowenstein et al,52 2009 RCT DB DD PG MC study 4 wk |
265 OIC patients with moderate to severe chronic noncancer pain taking 60–80 mg/d OXN PR or OXY PR | BFI and laxative use | OXN PR had significantly better BFI scores at 4 wks (P<0.0001) vs OXY PR patients. OXN PR patients had a median of 3.0 CSBM per wk at 4 wks compared with OXY PR patients at 1.0. OXN PR patients took less laxative | |
| Meissner et al,53 2009 RCT DB 4 wk study then 2 wks oxycodone only |
202 chronic pain patients (97.5% with noncancer pain) on stable oral oxycodone therapy (40–80 mg/d) randomized to receive 10 mg/d, 20 mg/d, or 40 mg/d naloxone or placebo (loose dose combination therapy) | BFI | Naloxone 20 mg and 40 mg significantly improved bowel function through end of maintenance phase vs placebo (P<0.05) | Analgesic efficacy was not diminished by naloxone. The study recommended a 2:1 dose ratio of oxycodone to naloxone |
| Poelaert et al,54 2015 NI Ob 12 wk |
68 LROIC with severe chronic pain (91% noncancer pain) treated for 90 days with OXN PR or OXY PR (median dose 20 mg/d) | Laxative use, QoL | OXN PR patients used significantly less laxatives (P<0.001) and had significantly improved QoL scores vs OXY PR patients | Response rate to OXN PR was 95% |
| Sanders et al,55 2015 R DB Ascending dose 6 wk |
40 noncancer pain patients with OIC randomized into four groups in ascending dose design (2.5 mg, 5 mg, 10 mg, and 20 mg sustained-release naloxone) vs placebo given once a day for 3 wks then BID for 4–6 wks | SBM change over baseline | Significant SBM improvements occurred at doses of 5 mg, 10 mg, and 20 mg sustained-release naloxone with mean changes in SBM over baseline ranging from 2.21 mg, 2.37 mg, 4.11 mg, and 5.19 mg for 2.5 mg, 5 mg, 10 mg, and 20 mg, respectively, vs 1.38 for placebo | The highest incidence of TEAE occurred in the placebo group |
| Simpson et al,56 2008 R DB MC trial 12 wk |
322 noncancer pain patients taking 20–50 mg/d oxycodone randomized to oral oxycodone PR or oral oxycodone/naloxone PR | BFI | Oxycodone/naloxone significantly improved BFI scores after 4 wks | Analgesic efficacy was similar in both groups |
| Ueberall and Mueller-Schwefe,57 2015 R OL study with blinded end points 12 wk |
453 patients with low back pain randomized to OXN, OXY, or morphine | Patients without an AE-related discontinuation with a combined end point of ≥50% improvement in pain intensity, disability, and QoL and a ≤50% worsening of bowel function | 22.2% of OXN vs 9.3% of OXY and 6.3% of morphine patients met the end point with significant differences between OXN and OXY (P<0.001) and OXN and morphine (P<0.001) but no significant difference between OXY and morphine. TEAEs occurred in 45 OXN, 69 OXY, and 75 morphine patients and overall were 51% GI in nature | |
Note: Studies are presented and grouped by agent and then in alphabetical order by first author.
Abbreviations: AE, adverse event(s); BFI, Bowel Function Index; BID, twice daily; BPI, brief pain inventory; CSBM, complete spontaneous bowel movement; DB, double-blind; DD, double-dummy; ITT, intention-to-treat; LROIC, laxative-refractory OIC patients; MC, multicenter; MEQ, morphine equivalent; MN, methylnaltrexone; NI, noninterventional; NNT, number needed to treat; Ob, observational; OIC, opioid-induced constipation; OL, open-label; OLE, open-label extension; OXN, oxycodone/naloxone fixed-dose combination product; OXN PR, oxycodone/naloxone fixed-dose combination product in prolonged-release formulation; OXY, oxycodone; PC, placebo-controlled; PG, parallel group; PR, prolonged release; QD, once daily; QoL, quality of life; R, randomized; RCT, randomized controlled trial; RFBM, rescue-free bowel movement, defined as a bowel movement not occurring within 24 hours of rescue laxative use; SBM, spontaneous bowel movement; TEAE, treatment-emergent adverse event(s); wk, week.