(451) Efficacy and safety of methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain: a placebo crossover analysis

Viscusi, Eugene R.; Barrett, Andrew C.; Paterson, Craig; Forbes, William

doi:10.1016/j.jpain.2014.01.362

Cited by 8 publications

(20 citation statements)

References 23 publications

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“…Viscusi et al [35] showed that approximately a range of 53 --70% methylnaltrexone patients compared to 35 --41% placebo patients had ‡ 3 RFBMs/week and 1 RFBM increase over baseline; however, the treatment phase was open label in this crossover trial and methylnaltrexone dosing was flexible (pro re nata). Still, these results can be confirmed roughly by Michna et al and Thomas et al [36,50] ( Table 3).…”

Section: Methylnaltrexonementioning

confidence: 86%

“…However, authors used different terms in their inclusion criteria and for outcome analysis. For example, the expression rescue-free bowel movement (RFBM) was chosen in two studies [35,36] and was defined by BMs that occurred without using any laxatives in the prior 24 h. Though, the expression spontaneous bowel movement (SBM) was more common [11,12,31,32,[37][38][39][40][41]. Interestingly, SBM was defined exactly the same as RFBM by authors who gave a definition for SBM [11,12,31,32,[37][38][39].…”

Section: Bm Measuresmentioning

confidence: 99%

“…In the present work OOMs for methylnaltrexone were examined in seven studies with overall 1760 participants ( Table 2) [35,36,[46][47][48][49][50]. Viscusi et al [35] showed that approximately a range of 53 --70% methylnaltrexone patients compared to 35 --41% placebo patients had ‡ 3 RFBMs/week and 1 RFBM increase over baseline; however, the treatment phase was open label in this crossover trial and methylnaltrexone dosing was flexible (pro re nata).…”

Section: Methylnaltrexonementioning

confidence: 99%

“…Two authors report that methylnaltrexone is not related to serious adverse events (SAEs) in their studies [35,49]. Michna et al [36] reported extrasystoles in one female that seemed to be related to study medication.…”

Section: Serious Aesmentioning

confidence: 99%

“…Still, irregular AEs with a very low incidence such as dizziness [48,50,52] or urinary tract infection [35,52] were not listed.…”

Section: Safetymentioning

confidence: 99%

See 4 more Smart Citations

Advances in pharmacotherapy for opioid-induced constipation – a systematic review

Siemens¹,

Gaertner²,

Becker³

2014

Expert Opinion on Pharmacotherapy

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Section: Methylnaltrexonementioning

confidence: 86%

Section: Bm Measuresmentioning

confidence: 99%

Section: Methylnaltrexonementioning

confidence: 99%

Section: Serious Aesmentioning

confidence: 99%

“…Still, irregular AEs with a very low incidence such as dizziness [48,50,52] or urinary tract infection [35,52] were not listed.…”

Section: Safetymentioning

confidence: 99%

See 3 more Smart Citations

Advances in pharmacotherapy for opioid-induced constipation – a systematic review

Siemens¹,

Gaertner²,

Becker³

2014

Expert Opinion on Pharmacotherapy

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Phase 1, Randomized, Double‐Blind, Placebo‐Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers

Fukumura

Yokota

Baba

et al. 2017

Clinical Pharm in Drug Dev

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Naldemedine (S-297995) is a peripherally acting μ-opioid receptor antagonist for the treatment of opioid-induced constipation, a common side effect of opioid therapy. We determined the safety, tolerability, and pharmacokinetic profiles of oral naldemedine in healthy volunteers in 2 randomized, double-blind, placebo-controlled, phase 1 studies. In the single ascending dose study, subjects received a single dose of naldemedine (0.1-100 mg; n = 42) or placebo (n = 14). In the multiple ascending dose study, subjects received once-daily naldemedine (3-30 mg; n = 27) or placebo (n = 9) for 10 days. On day 1 of the single ascending dose studies and day 10 of the multiple ascending dose studies, respectively, the maximum plasma concentration levels of naldemedine were 1.98 to 2510 ng/mL and 73.8 to 700 ng/mL, peaked at 0.5 hours and 0.5 to 0.75 hours, and the fraction excreted in urine was 15.9% to 20.5% and 19.7% to 19.1%. There were no major safety or tolerability concerns even at naldemedine doses 150 to 500 times the therapeutic dose of 0.2 mg. The incidence of adverse events was not dose dependent. Gastrointestinal adverse events occurred more frequently with naldemedine vs placebo, and all of these were considered treatment related. Overall, naldemedine was rapidly absorbed, and no safety or tolerability issues were noted at the doses evaluated.Keywords naldemedine, opioid-induced constipation, peripherally acting μ-opioid receptor antagonist, pharmacokinetics, safety Opioid-induced constipation (OIC) is a frequent and debilitating side effect of opioid analgesics, which are widely used to manage moderate to severe chronic pain. Unlike other side effects of opioids, OIC is generally not self-limiting. 1,2 OIC is characterized by reduced frequency of bowel movements, development or worsening of straining, a sense of incomplete evacuation, and hard stools after the initiation of opioid therapy. 3,4 Opioids act on the μ-, δ-, and κ-opioid receptors distributed widely in the central and peripheral nervous systems. Although the role of δ-and κ-opioid receptors in causing gastrointestinal adverse events (AEs) is less clear, the importance of μ-opioid receptors is better understood. The stimulation of μ-opioid receptors, which are expressed throughout the gastrointestinal tract, alters neural activity in the submucosal and myenteric plexuses of the enteric nervous system. These alterations can lead to impairment of gastrointestinal fluid secretion and motility, along with increased fluid absorption, resulting in OIC. 4,5 Laxatives are often used as first-line treatment for OIC, but many patients do not achieve satisfactory relief of constipation. 4,6 A targeted pharmacological treatment for OIC is peripherally acting μ-opioid receptor antagonists (PAMORAs). PAMORAs aim to reverse OIC by blocking the action of opioids at peripheral μ-opioid receptors in the gastrointestinal tract without affecting analgesia. 4 Naldemedine This is an open access article under the terms of the Creative Commons Attribution-NonCommerc...

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Periarticular injection and continuous femoral nerve block versus continuous femoral nerve block alone on postoperative opioid consumption and pain control following total knee arthroplasty: Randomized controlled trial

Dimaculangan

Chen

Borzio

et al. 2019

Journal of Clinical Orthopaedics and Trauma

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Continuous femoral nerve block (CFNB) has been used to prevent the breakthrough pain after total knee arthroplasty (TKA). Multimodal drug injection (PMDI) has also been shown to decrease opioid consumption and pain. We investigated whether the use of PMDI further improves analgesic and rehabilitation outcomes when used in conjunction with CFNB. This is a prospective randomized controlled study of 44 patients undergoing primary TKA. The treatment group (n = 23) received a PMDI of combined ropivacaine, epinephrine, ketorolac and morphine, and the controlled group (n = 21) received saline at wound closure. Total opioid consumption, pain scores, knee range of motion (ROM) outcomes, length of stay, and patient satisfaction were measured and compared. The total consumption of morphine is similar between the two groups (52.6 AE 40.6 vs. 41.5 AE 32.9, p = 0.325). The mean morphine consumption of the treatment group was significantly lower than the control at 4 h after surgery (4.2 AE 5.5 vs. 11.3 AE 8.1, p = 0.002) but comparable on POD1, POD2, and POD3. The mean pain scores were significantly higher in the treatment group than the control group at POD2 (at rest: 47.3 AE 29.1 vs. 23.8 AE 20.6, p = 0.004; after PT: 57.7 AE 25.4 vs. 35.2 AE 26.8, p = 0.007) and POD3 (at rest: 30.9 AE 30.3 vs. 14.8 AE 20.9, p = 0.045; after PT: 50.2 AE 30.6 vs. 29.0 AE 32.1, p = 0.035), and not significantly different at 4 h after surgery or at POD1. Mean maximal knee flexion ROM in degrees during active and active assisted mobilization showed no significant difference between the control and the treatment groups on POD2 and POD3. The mean length of stay of the treatment group is significantly longer than the control group (5.1 AE 2.1 vs. 3.8 AE 1.6, p = 0.032). At discharge, no significant difference exists between the two groups for mean patient satisfaction. The addition of PMDI led to a decrease in opioid consumption in the immediate postoperative period but with no significant difference in the total consumption within the first three days postoperatively. This finding provides an opportunity for appropriate preoperative treatment and education for both patients and caregivers.

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(451) Efficacy and safety of methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain: a placebo crossover analysis

Cited by 8 publications

References 23 publications

Advances in pharmacotherapy for opioid-induced constipation – a systematic review

Advances in pharmacotherapy for opioid-induced constipation – a systematic review

Phase 1, Randomized, Double‐Blind, Placebo‐Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers

Periarticular injection and continuous femoral nerve block versus continuous femoral nerve block alone on postoperative opioid consumption and pain control following total knee arthroplasty: Randomized controlled trial

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