Opioid-induced constipation can occur with a patient’s first dose of opioid medication and is typically a chronic problem for the duration of opioid therapy.² Reports suggesting that some routes of delivery are less associated with constipation than others are overstated.³ Unlike most of the other side effects associated with opioid use, patients do not develop pharmacological tolerance and the constipation persists. A vicious cycle can develop in which patients taking opioids for pain develop OIC, resulting in more pain and causing them to take more opioids, which further increases constipation. Ultimately, OIC may prompt patients to refuse higher doses of opioids or discontinue opioid therapy, making OIC treatment a critical component of care (Figure 1). This newsletter reviews the epidemiology and pathophysiology of OIC and discusses recent developments in its treatment.

Figure 1. Opioid-induced constipation: issues for patients.

Back to top

Opioids are one of the most commonly prescribed medication classes in the United States,⁴ with opioid pain medication used in the care of more than 50% of cancer patients.⁵ Other examples of advanced illness for which patients may receive palliative care using opioids include heart disease, human immunodeficiency virus/AIDS, amyotrophic lateral sclerosis, chronic obstructive pulmonary disease, chronic liver disease, chronic renal disease, and Alzheimer’s disease/dementia. According to experts, constipation occurs in practically all patients receiving opioid therapy in the palliative care setting.⁶ Some patients may also experience other complications that can cause constipation, such as structural abnormalities, metabolic or neurologic disturbances, compromised diets, dehydration, and/or inactivity.

Back to top

There are 3 subtypes of opioid receptors located throughout the central and peripheral nervous systems: mu (μ), delta (δ), and kappa (κ). Opioid receptors are stimulated by both endogenous opioid agonists (eg, endorphins and enkephalins), which act at all 3 receptor subtypes, and exogenous opioid agonists (eg, codeine and morphine), which differ in their relative affinities for the μ, δ, and κ opioid receptors.^7-9 Mu receptors are located in the central and peripheral nervous systems and are especially dense along the intestinal wall.^7,10 Stimulation of the μ receptors, either through central communication with the sympathetic and parasympathetic components of the autonomic nervous system or peripherally, at the level of the gastrointestinal tract, affects a number of gastrointestinal functions. These include increased segmental contraction with decreased forward peristalsis, increased intestinal fluid absorption, reduction of intestinal secretions, increased ileocecal and anal sphincter tones, and impaired defecation reflex, ultimately resulting in OIC.^1,11

Back to top

Many clinicians believe they can manage OIC using a regimen of conventional laxatives, which is often not the case.¹ Others view OIC as an unmanageable, universal adverse effect of opioid therapy and assume that it is necessary to decrease or eliminate opioids if OIC becomes clinically problematic, potentially resulting in insufficient analgesia for the patient. However, relatively recent advances in treatment may make it possible to manage OIC without compromising analgesia. The goal of treatment should be to prevent symptoms rather than to manage established OIC. Because OIC is an almost inevitable consequence of opioid use, measures to prevent constipation should begin when opioids are first prescribed.⁷

Until recently, OIC and idiopathic constipation were both treated symptomatically with traditional laxatives that did not target the underlying pathophysiology of the condition. However, traditional laxatives often provide less than optimal relief of OIC symptoms because they do not address its opioid-mediated cause.¹² For example, in a study of patients with OIC receiving standard laxative treatment, more than half were dissatisfied with the outcome.¹³

When laxatives are insufficient, an alternative approach to OIC is to selectively block peripheral opioid receptors without compromising the effect of opioids on the central receptors that mediate analgesia. For example, methylnaltrexone bromide, a peripheral μ-opioid receptor antagonist, reverses peripheral opioid effects (eg, delay of gastrointestinal transit) without affecting analgesia or evoking symptoms of withdrawal, by selectively displacing opioids from the μ-opioid receptors outside the central nervous system. Methylnaltrexone bromide is a quaternary N-methyl derivative of naltrexone, a systemic opioid antagonist. It is the addition of the methyl group that increases the structure’s polarity, which decreases its lipid solubility and prevents it from crossing the blood-brain barrier (Figure 2).

Figure 2. Chemical structures of morphine, naltrexone, and methylnaltrexone. Images from the National Center for Biotechnology Information. PubChem Substance Database; SIDs= 148818, 170471, 685076; Source=ChemIDplus, http://pubchem.ncbi.nlm.nih.gov. Accessed August 2, 2011.

In 2008, based on the success of 2 randomized, placebo-controlled clinical trials, subcutaneous methylnaltrexone bromide received an indication from the Food and Drug Administration for treating OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. The first study was a randomized, double-blind, placebo-controlled, multicenter clinical trial that studied the efficacy of methylnaltrexone bromide in 154 adult patients with advanced disease and OIC. The investigators reported that 62% of patients who were administered 0.15 mg/kg methylnaltrexone bromide experienced laxation (ie, a rescue-free bowel movement) within 4 hours, compared to 14% of patients in the control group (P<0.0001). Approximately half of the patients who responded to methylnaltrexone bromide experienced laxation within 30 minutes of drug administration.¹⁴ In the second study, investigators compared methylnaltrexone bromide with a placebo in 133 adult subjects with advanced illness and OIC. They reported that, within 4 hours of the first methylnaltrexone bromide dose, 48% of patients experienced laxation, compared to 15% of patients in the placebo group (P<0.001). Patients treated with methylnaltrexone bromide also had significantly higher rates of laxation within 4 hours of at least 2 of the first 4 doses (52%) than did patients in the placebo group (9%; P<0.001).¹⁵ Overall, in both studies, 30% of all patients who responded to methylnaltrexone bromide reported laxation within 30 minutes of administration. Both studies also reported mild adverse effects, the most common of which were abdominal pain, flatulence, nausea, dizziness, and diarrhea (Figure 3).

Figure 3. Laxation response within 4 hours of the first dose. *P<0.0001 vs placebo.

Back to top

While opioids are effective analgesics for patients with advanced illness receiving palliative care, OIC is a common, predictable complication of opioid therapy that has been difficult to manage optimally. The past 2 decades have seen significant advancement in understanding about the way in which opioids act on μ receptors to promote analgesia in the central nervous system, as well as their impact on peripheral receptors, such as those in the gastrointestinal tract.  Opioid-induced constipation treatment has evolved from the use of conventional laxatives to a targeted therapeutic approach, when laxatives are insufficient, in which peripheral opioid-receptors are selectively blocked to address the direct physiological effects of opioids on the gut, while maintaining the desired analgesic action on the central nervous system. Although OIC may seem like a minor complication when considered in the context of advanced illness, it can have a significant impact on quality of life and healthcare costs. Unlike idiopathic constipation, which is managed with conventional laxatives, OIC can be treated with precision by addressing its underlying pathophysiology and without compromising analgesia when laxatives are insufficient.

Back to top

About the author

Charles F von Gunten, MD, PhD, FACP, FAAHPM Charles F von Gunten, MD, PhD, FACP, FAAHPM is the Provost, The Institute for Palliative Medicine at San Diego Hospice, a teaching and research affiliate of the University of California, San Diego School of Medicine, University of San Diego and San Diego State University. He is founding Medical Director of the Doris A. Howell Service, a palliative care consultation service at UCSD Health Center and Editor-in-Chief of the Journal of Palliative Medicine. Dr von Gunten has been particularly interested in the integration of hospice and palliative care into academic medicine. He received an established investigator award from the National Cancer Institute and has published and spoken widely on the subjects of hospice, palliative medicine, and pain and symptom control.

About the author

Charles F von Gunten, MD, PhD, FACP, FAAHPM Charles F von Gunten, MD, PhD, FACP, FAAHPM is the Provost, The Institute for Palliative Medicine at San Diego Hospice, a teaching and research affiliate of the University of California, San Diego School of Medicine, University of San Diego and San Diego State University. He is founding Medical Director of the Doris A. Howell Service, a palliative care consultation service at UCSD Health Center and Editor-in-Chief of the Journal of Palliative Medicine. Dr von Gunten has been particularly interested in the integration of hospice and palliative care into academic medicine. He received an established investigator award from the National Cancer Institute and has published and spoken widely on the subjects of hospice, palliative medicine, and pain and symptom control.

About the author

Charles F von Gunten, MD, PhD, FACP, FAAHPM Charles F von Gunten, MD, PhD, FACP, FAAHPM is the Provost, The Institute for Palliative Medicine at San Diego Hospice, a teaching and research affiliate of the University of California, San Diego School of Medicine, University of San Diego and San Diego State University. He is founding Medical Director of the Doris A. Howell Service, a palliative care consultation service at UCSD Health Center and Editor-in-Chief of the Journal of Palliative Medicine. Dr von Gunten has been particularly interested in the integration of hospice and palliative care into academic medicine. He received an established investigator award from the National Cancer Institute and has published and spoken widely on the subjects of hospice, palliative medicine, and pain and symptom control.