Opioid-Induced Constipation: New and Emerging Therapies—Update 2016
Two identical efficacy and safety studies were performed (Study 1 and Study 2). The primary endpoint was defined as ≥ 3 SBMs per week and a change from baseline of ≥ 1 SBM per week for at least 9 out of the 12 study weeks, and 3 out of the past 4 weeks.26 There was a statistically significant difference in response for the 25 mg naloxegol treatment group versus placebo for the primary endpoint in Study 1 and Study 2. Statistical significance for the 12.5 mg treatment group versus placebo was observed in Study 1 but not in Study 2.26
One secondary endpoint in both studies was response in laxative users with OIC symptoms. In this subgroup, 42% and 50%, respectively, reported using laxatives on a daily basis. A statistically significantly higher percentage of patients in both studies responded with naloxegol 25 mg versus placebo. This was also seen with naloxegol 12.5 mg in Study 1, but it was not tested in Study 2.
Time to first bowel movement was 6 to 20 hours in naloxegol-treated patients compared to 36 hours in the placebo group. The most common adverse events were abdominal pain (12% to 21%), diarrhea (6% to 9%), nausea, and flatulence.28 Contraindications for naloxegol include known, suspected, or at increased risk of GI obstruction; concomitant administration of strong cytochrome P (CYP) 450 3A4 inhibitors; and serious or severe hypersensitivity reaction to naloxegol or any of its ingredients.26
Prior to initiation of naloxegol, it is recommended to discontinue all maintenance laxative therapy, which can be resumed after 3 days if there is a suboptimal response to naloxegol. Standard dosing of naloxegol is 25 mg by mouth once daily 1 hour before or 2 hours following the first meal of the day. In patients unable to tolerate this dose, a 12.5 mg dose of naloxegol is recommended. Renal adjustment of the starting dose is suggested in patients with a creatinine clearance < 60 mL/min.25 Serious adverse reactions that may occur include opioid withdrawal. Opioid withdrawal, considered in this trial to be at least 3 symptoms potentially related to opioid withdrawal, occurred in 1% of patients on naloxegol 12.5 mg compared to 3% on naloxegol 25 mg; less than 1% of patients on placebo experienced opioid withdrawal.
The FDA recently approved a supplemental New Drug Application (sNDA) for naloxegol tablets. The sNDA proposed changes including: information regarding the administration of crushed tablets mixed in water given orally or via nasogastric (NG) tube, the addition of severe abdominal pain and/or severe diarrhea to the Warnings and Precautions and Adverse Reactions sections, and a clarification to the effects of race on pharmacokinetics.25
The updated labeling for Movantik now states that for patients who are unable to swallow the tablet whole, the pill can be crushed to a powder, mixed with 4 oz (120 mL) of water, and consumed immediately. The glass should be refilled with 4 oz (120 mL) of water, stirred and the contents consumed. Also, naloxegol can be administered via a NG tube with specific instructions listed under Dosage and Administration.25
In April 2013, the FDA approved lubiprostone (Amitiza) as the first oral treatment for OIC in adults with CNCP. Lubiprostone had previously been approved for the management of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C).27
Lubiprostone works by activating type 2 chlorine channals (ClC-2) in epithelial cells lining the intestinal tract. Once ClC-2 are activated, the chloride concentration in the intestinal lumen increases. As chloride moves into the intestinal lumen, sodium ions and fluids then passively follow.27,28 By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, easing the passage of stool.27
The efficacy of Amitiza in the treatment of OIC was assessed in 3 studies. The proportion of lubiprostone-treated patients (24 mcg twice daily) in the studies who qualified as “overall responder” was 27.1%, 24.3%, and 15.3% compared with 18.9%, 15.4%, and 13.0% of the placebo-treated patients.27
A study by Marciniak et al, concluded that both lubiprostone and senna improved constipation-related symptoms and quality of life in patients with OIC, with no significant differences between groups.29
A recent meta-analysis concluded that the limited data existing for lubiprostone means that more trials are required before a definitive recommendation can be made on its use in OIC.30
The most common adverse reactions associated with this agent include nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence, as well as dyspnea within an hour of the first dose. This symptom generally resolves within 3 hours, but may recur with repeat dosing. Patients who experience dyspnea should inform their HCP. Some patients have discontinued therapy because of dyspnea.27 The dosage should be reduced in patients with moderate or severe hepatic impairment. The drug’s efficacy in patients taking methadone has not been established.
A combination of prolonged-release (PR) oxycodone and naloxone (Targiniq; Purdue Pharmaceuticals) was approved by the FDA in 2014 for the treatment of patients with severe pain.31 One aim of this formulation is to counteract OIC through the local antagonist effect of naloxone in the gut wall, while maintaining analgesia due to the low bioavailability of oral naloxone.
Three large, 12-week, randomized, double-blind, phase 3 trials in patients with moderate to severe, chronic, non-malignant pain, plus a prospectively planned pooled analysis of 2 of these studies, demonstrated that PR oxycodone/naloxone (OXN)improved bowel function, as measured by the BFI, compared with PR oxycodone alone. Additionally, OXN relieved pain more effectively than placebo and no less effectively than PR oxycodone after 12 weeks.32
More recently, a study of 68 laxative-refractory OIC patients with severe chronic pain were treated for 91 days with OXN (median daily dose, 20 mg). Treatment with OXN resulted in a significant and clinically relevant decrease of pain of 2.1 units (P < 0.001; 95% CI, 1.66-2.54) and of BFI by 48.5 units (P < 0.001; 95% CI, 44.4-52.7) compared with PR oxycodone treatment alone; use of laxatives was also significantly reduced (P < 0.001). Approximately 95% of patients were responders, and quality of life (as measured by using the EQ-5D) improved significantly. Adverse events were opioid related, and OXN treatment was well tolerated.33
In addition to lowering the rate of OIC, a small study of 37 patients found that treatment with OXN had an “overall positive effect on patients, consisting mainly of decreasing the severity of the constipation problems, increasing health-related quality of life, and decreasing the use of healthcare resources.”34 In addition, the author reported patients had fewer problems with OIC after the initiation of OXN according to the BFI score.