Focus on Asthma and COPD
A Peer-Reviewed Newsletter – Issue 2
August 2015

Current Treatment Options for Opioid-Induced Constipation

Kevin R. Murphy, MD

Joyce S. Willens, PhD, RN, BC

College of Nursing, Villanova University

800 East Lancaster Avenue
Villanova, PA 19085
Phone: (610) 519-6832
Fax: (610) 519-7650
Email: joyce.willens@villanova.edu

Key Points

  • Opioid-induced constipation is reported by 40% to 80% of patients undergoing opioid pharmacotherapy for chronic noncancer pain and may impact overall health and quality of life.
  • Conservative treatment options include lifestyle and behavioral modifications.
  • Laxatives may provide symptomatic relief, but are often of limited benefit in patients with opioid-induced constipation (OIC) and have side effects.
  • The recent availability of prescription therapies that target the underlying pathophysiology of OIC provides additional treatment options for this patient population.

Introduction

Opioid-induced constipation (OIC) is reported in 40% to 80% of patients receiving opioids for chronic noncancer pain.1,2 Although there is no generally accepted definition of OIC, an expert panel proposed a definition that could provide consistency in the criteria used to diagnose the condition.3 OIC was defined as “a change, when initiating opioid therapy, from baseline bowel habits, defecation patterns, and what individuals would consider as abnormal that is characterized by any of the following: (1) a reduced frequency of spontaneous bowel movements (SBMs); (2) development or worsening of straining to pass bowel movements (BMs); (3) a sense of incomplete rectal evacuations; or (4) harder stool consistency.”3 Application of this definition in the initial evaluation of patients presenting with symptoms of constipation will enable the healthcare provider to accurately diagnose OIC and assess its severity.

The presence of OIC has implications beyond the discomfort associated with an inability to perform regular BMs. If not properly treated, OIC can result in deleterious complications (eg, overflow diarrhea [leakage of watery stool] and stool incontinence resulting from fecal impaction, bowel obstruction, inadequate drug absorption),4,5 together with increased healthcare costs and use.6 The majority of patients receiving opioids on a daily basis for noncancer pain reported at least a moderately negative effect of constipation on quality of life and activities of daily living.1 In a large multinational survey, nearly one half of patients reported that constipation moderately or completely interfered with opioid medications in the control of chronic pain.7 The negative impact of OIC can result in interruption or discontinuation of opioid medications despite the need for analgesia.8

Healthcare providers need to be more aware of the frequency and severity of clinical consequences of OIC, as well as the clinical benefits and potential limitations of the various treatment options for this condition. This article provides an overview of current treatment approaches for OIC in patients with chronic noncancer pain.

Treatment Options for OIC

The available treatment options for OIC range from conservative, noninvasive approaches to targeted prescription pharmacotherapy. A variety of nonpharmacologic and targeted pharmacologic approaches are recommended by guidelines as appropriate therapies for the treatment of OIC (Figure 1).9

Figure 1. General guidance for the treatment of patients with OIC and chronic noncancer pain10

OIC=opioid-induced constipation; PAMORA=peripherally acting μ-opioid receptor antagonist; PEG=polyethylene glycol.

Management of OIC With Lifestyle and Behavioral Options

Lifestyle and behavioral modifications, including increased intake of fluids and dietary fiber and increased physical activity, are often initially recommended for the treatment of patients with OIC.5,10 The clinical benefits and potential limitations of these approaches are summarized in Table 1. Although there is no definitive evidence from clinical trials for the effectiveness of lifestyle or behavioral options in the treatment of OIC, they may provide some benefit as a first-line or adjunctive approach.

Management of OIC With Conventional Laxatives

Patients who do not respond to lifestyle modifications may achieve symptomatic relief from laxative therapies. Conventional laxatives, including bulk-forming, osmotic, stimulant, and surfactant laxatives, relieve constipation by increasing the presence of fluid in the bowel, softening the stool, inhibiting reabsorption of fluid, and increasing bowel contractions.11 Most laxatives are available as over-the-counter preparations, and lactulose is available by prescription in the United States.

An overview of the clinical utility of representative types of laxatives for the treatment of constipation is presented in Table 2. First-line laxative treatment of OIC often involves the use of a stimulant in combination with a stool softener.11 Effective relief may require rectally administered agents or supplementation with saline laxatives.12 However, laxatives do not directly target the symptoms of OIC, which result from actions at the μ-opioid receptor. Some of the adverse effects (eg, nausea, vomiting, abdominal pain) associated with laxative use are also associated with OIC, and some types of laxatives may actually worsen OIC.10,13 Therefore, laxatives should be used judiciously in patients with OIC, coupled with appropriate patient monitoring.

Table 1. Lifestyle and Behavioral Modifications for the Treatment of OIC4,5,10,22-26
Modification Clinical Benefits Potential Limitations
Increased intake of dietary fiber
  • Increased retention of water in colon
  • Stool bulk increased
  • Stimulation of peristalsis
  • Decrease in transit time
  • Difficult to ingest if not taken with enough fluid
  • May increase gas, bloating
  • Risk for bowel obstruction if stenoses present
Increased intake of fluids
  • Acts as natural stool softener
  • Frequency of SBMs increased
  • May enhance effects of dietary fiber
  • Ineffective if patient is not initially dehydrated
Increased physical exercise
  • Frequency of CBMs/wk increased
  • Decreased frequency of BMs requiring straining
  • Frequency of hard stools decreased
  • May assist in establishing regular bowel routine if undertaken following breakfast when propulsive movements are strongest
  • Usefulness may be compromised by severity of chronic pain
  • May be ineffective in elderly patients in long-term care setting
Biofeedback therapy*
  • Defecation effort (eg, anal relaxation, rectal pressure) improved
  • Improved colonic transit time
  • Frequency of BMs and CBMs/wk increased
  • Laxative use discontinued by some patients
  • Decreased need for digital assistance with defecation
  • No improvement in hard stools or straining vs standard therapy (ie, diet, exercise, and laxatives)
  • Bowel satisfaction score not improved vs standard therapy

BM=bowel movement; CBM=complete bowel movement; OIC=opioid-induced constipation; SBM=spontaneous bowel movement.

*Benefits demonstrated in patients with dyssynergic defecation; utility in OIC unknown.

Table 2. Laxative Therapies for the Treatment of OIC10, 27-35
Laxative Class Generic Name (Trade Name) Clinical Benefits Potential Limitations
Bulk-forming agent Psyllium fiber (Metamucil®)
  • Often recommended in patients with mild to moderate symptoms of constipation
  • Increased frequency of BMs/wk
  • Increased stool weight and improved stool consistency
  • Decreased pain on defecation
  • Colonic transit time and rectal motor function unchanged
  • Increased stool bulk may distend the colon, resulting in worsening of abdominal pain, and may contribute to bowel obstruction
Osmotic agent Lactulose liquid (Constulose®)
  • Increased water content of stools
  • Stool softener
  • Increased frequency of BMs/d
  • More frequent days with BM
  • Flatulence, intestinal cramps
  • Risk of diarrhea and electrolyte imbalances with excessive dosing
  • Nausea and vomiting
  • Treatment may be more acceptable if mixed with other liquids (eg, fruit juice, water, or milk)
  • Elderly, debilitated patients may require periodic monitoring of serum electrolytes
Lactulose powder (Kristalose®)
  • Increased water content of stools
  • Stool softener
  • Increased frequency of BMs/d
  • More frequent days with BM
  • Flatulence, intestinal cramps
  • Risk of diarrhea and electrolyte imbalances with excessive dosing
  • Nausea and vomiting
  • Elderly, debilitated patients may require periodic monitoring of serum electrolytes
Polyethylene glycol 3350 (MiraLAX®)
  • Frequency of BMs/d increased in
    1‒3 days
  • Less straining during BM
  • Decreased use of suppositories/microenemas
  • Rectal bleeding, diarrhea, nausea, vomiting, abdominal pain, bloating, cramping
Stimulant Bisacodyl tablet (Dulcolax®)
  • Increased colonic peristalsis
  • Improved frequency of BMs/d with 3-day regimen
  • Improved stool consistency
  • Effectiveness and safety similar in geriatric and younger patients
  • Stomach discomfort, faintness, and cramps
Surfactant Docusate sodium (Dulcolax® liquid gel; DulcoEase® soft gel)
  • Hydrates and softens dry, hard stools
  • Produces BM within 6‒12 hours
  • Stomach pain, nausea, vomiting, rectal bleeding

BM=bowel movement; OIC=opioid-induced constipation.

Management of OIC With Targeted Prescription Therapies

Targeted therapies may be helpful in the many patients who do not respond adequately to lifestyle/behavioral modifications and laxative therapies.10 Peripherally acting μ-opioid receptor antagonists (PAMORAs)—including methylnaltrexone and naloxegol—target the underlying cause of symptoms in patients with OIC while preserving opioid analgesia. In contrast, lubiprostone, a chloride channel activator, counteracts the antisecretory bowel effects of opioids by increasing fluid transport into the intestine.11 The clinical benefits and potential limitations of these agents are summarized in Table 3.

Table 3. Targeted Prescription Therapies for the Treatment of OIC14-18,20
Drug Class Generic Name (Trade Name) Clinical Benefits Potential Limitations
PAMORA Methylnaltrexone (Relistor®)
  • ≥3 SBMs/wk in more patients with OIC and chronic noncancer pain during 4-week regimen compared with placebo
  • ~50% of patients experienced SBM before second dose
  • Higher rate of laxation in majority of patients with OIC and advanced illness receiving palliative care
  • Durable laxation response over 3‒4 months of treatment
  • No meaningful changes in daily opioid dose or pain scores compared with placebo
  • Abdominal pain, diarrhea, and nausea (patients with OIC and chronic noncancer pain)
  • Abdominal pain, flatulence, nausea, dizziness, and diarrhea (patients with advanced illness)
  • Monitor for maintenance of pain relief and symptoms of opioid withdrawal*
Naloxegol (Movantik™)
  • Improvement in percentage of patients with ≥3 SBMs/wk over 12 weeks, including those using laxatives (eg, stool softeners, stimulants, polyethylene glycol)
  • Improved time to first postdose SBM
  • Increased mean number of d/wk with an average of 1‒3 SBMs/d
  • Overall safety and effectiveness similar in geriatric vs younger patients
  • No meaningful changes in daily opioid dose or pain scores compared with placebo
  • Abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache
  • Patients receiving methadone may experience a greater frequency of GI side effects
  • Monitor for symptoms of opioid withdrawal*
  • Use with strong CYP3A4 inhibitors not recommended
Secretagogue Lubiprostone (Amitiza®)
  • Improves intestinal fluid secretion and passage of stools
  • Increased proportion of patients with ≥1 SBM improvement from baseline
  • Improvement from baseline in SBMs/wk
  • Nausea, diarrhea
  • Effectiveness not established in patients with OIC receiving diphenylheptane opioids (eg, methadone)
  • Unknown whether patients aged ≥65 y respond differently than younger patients

GI=gastrointestinal; OIC=opioid-induced constipation; PAMORA=peripherally acting μ-opioid receptor antagonist; SBM=spontaneous bowel movement.

*May include abdominal pain, anxiety, chills, diarrhea, hot flush, hyperhidrosis, irritability, nausea, tremor, and yawning

Although methylnaltrexone (Relistor®) was approved for the treatment of OIC in adult patients with chronic noncancer pain in 2014, it has been available since 2008 for use in adult patients with OIC undergoing palliative care who do not respond adequately to laxatives.14 In a 4-week, double-blind, randomized, placebo-controlled, phase 3 clinical trial, more patients with chronic noncancer pain and OIC treated with subcutaneous methylnaltrexone (34.2% vs 9.9%; P<0.001) experienced rescue-free bowel movements (RFBMs), defined as bowel movements in the absence of rescue laxatives (eg, bisacodyl tablets), within 4 hours of the first dose of study medication compared with placebo.15 Methylnaltrexone produced a significant change from baseline in the frequency of RFBMs when dosed daily (QD; 3.1 vs placebo, 1.5 RFBM per week, P<0.001) or on alternative days (2.1 vs placebo, 1.5 RFBM per week, P<0.01).15

Treatment-emergent adverse events (AEs) were mostly mild to moderate in intensity, and the rates were similar following subcutaneous treatment with methylnaltrexone QD (49.3%) and every other day (45.3%) compared with placebo (38.3%).15 The incidence of gastrointestinal (GI) AEs, including abdominal pain, diarrhea, and nausea, was higher in both of the methylnaltrexone groups compared with placebo.15 Patients in both methylnaltrexone groups exhibited higher rates of study discontinuation (QD, 6.7%; every other day, 8.8%) compared with placebo (2.5%).15 Overall, there were no changes in opioid analgesia during the 4-week treatment period, consistent with the peripheral actions of methylnaltrexone.15

Naloxegol (Movantik™), an orally administered PAMORA, was approved in 2014 for use in adult patients with OIC and chronic noncancer pain.16 In 2 multicenter, double-blind, randomized, placebo-controlled, phase 3 clinical trials, patients reported higher response rates, defined as ≥3 SBMs per week and an increase from baseline of ≥1 SBM for ≥9 of 12 weeks and for ≥3 of the final 4 weeks of treatment, when administered the 25-mg dose in both studies (P=0.001 and P=0.02, respectively) and the 12.5-mg dose (P=0.02) in the first study compared with placebo.17 Significantly higher response rates were also observed in patients in both studies who had an inadequate response to laxatives when administered naloxegol 25 mg (P=0.002 and P=0.01, respectively) and when treated with naloxegol 12.5 mg in the first study (P=0.03) compared with placebo.17 Compared with placebo, patients achieved shorter times to the first SBM and had a greater mean number of days per week with ≥1 SBM after treatment with naloxegol 25 mg (both studies, P<0.001) and with naloxegol 12.5 mg in the first study (P<0.001).17

Patients treated with naloxegol 25 mg (61.2% and 69.0%) and naloxegol 12.5 mg (49.3% and 59.6%) reported higher overall rates of AEs compared with placebo (46.9% and 58.9%).17 The most common GI AEs reported with naloxegol included abdominal pain, diarrhea, nausea, and vomiting; these events occurred early after the first dose of study medication, were mostly mild to moderate in intensity, and occurred at higher frequency with an increasing dose of naloxegol.17 Consistent with the peripheral actions of naloxegol, mean daily opioid doses remained stable, and there were no clinically meaningful changes in pain scores or signs of opioid withdrawal.17

Another available prescription therapy for the treatment of patients with OIC is lubiprostone (Amitiza®).18 Lubiprostone is an orally administered secretagogue that causes local activation of chloride channels and enhances intestinal secretion and GI motility.19 In a double-blind, randomized, placebo-controlled, phase 3 clinical trial, patients treated with lubiprostone 24 μg twice daily reported an improvement from baseline in SBMs at week 8 (3.3 vs 2.4 SBMs per week; P=0.005) and overall (2.2 vs 1.6 SBMs per week; P=0.004) compared with placebo.20 When treated with lubiprostone, a higher percentage of patients achieved their first SBM within 24 hours (38.8% vs 27.8%; P=0.018) after the first dose compared with placebo.20

Gastrointestinal AEs that occurred more frequently with lubiprostone than with placebo included nausea (16.8% vs 5.8%; P<0.001), diarrhea (9.6% vs 2.9%; P=0.007), and abdominal discomfort (8.2% vs 2.4%, P=0.014).20 Lubiprostone did not cause meaningful changes in patient self-assessed pain interference, pain severity, or worst pain.20

Conclusions

Opioid-induced constipation is a distressing and commonly reported consequence of opioid treatment that negatively impacts quality of life and long-term management of chronic pain. Although lifestyle modifications, behavioral approaches, and laxatives are first-line treatment options and are generally well tolerated, evidence is lacking to support their effectiveness in treating OIC.

The use of targeted pharmacologic therapies may provide more rapid and consistent relief from the symptoms of OIC relative to lifestyle and behavioral approaches or the use of conventional laxatives. Furthermore, achievement of BMs with agents designed to specifically affect the physiologic mechanisms that modulate GI secretion and motility may reduce the need for other strategies for normalizing bowel function. Although a once-daily BM may be desired by most patients,21 each individual may differ on the details of what constitutes a “normal” BM pattern for them.11 Therefore, careful patient monitoring is necessary to ensure that the patient is experiencing a therapeutic laxation effect within the continuum of “normal,” without experiencing other untoward GI side effects or compromised pain relief.

Methylnaltrexone, naloxegol, and lubiprostone, recently approved pharmacologic agents with proven clinical efficacy, provide alternative treatment options for patients with OIC and noncancer pain. The availability of newer mechanism-based pharmacologic agents provides an additional resource for nurses and nurse practitioners to better manage patients with OIC and chronic pain.

Acknowledgements

This article was supported by AstraZeneca Pharmaceuticals LP (Wilmington, DE). Editorial support was provided by Craig Albright, PhD, and Diane DeHaven-Hudkins, PhD, from Complete Healthcare Communications, Inc. (Chadds Ford, PA), and was funded by AstraZeneca Pharmaceuticals LP.

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