Cleveland Clinic Foundation, Department of Gastroenterology and Hepatology, Cleveland, OH
The authors declare that they have nothing to disclose.
Reprints: Bret A. Lashner, MD, Cleveland Clinic Foundation, Department of Gastroenterology and Hepatology, 9500 Euclid Avenue, Mail Code A31, Cleveland, OH 44195 (e-mail: firstname.lastname@example.org).
A large number of patients with Crohn’s disease require medication for pain management at some point in their disease process. Narcotic analgesics are commonly used pain medications in inflammatory bowel disease (IBD); however, their use is controversial.1 Although chronic opioid use produces a paradoxical visceral hyperalgesia, the inflammatory effects are less understood.2,3 Both endogenous and exogenous opioid compounds have a range of effects on the physiology of cell growth and immunity in autoimmune disorders, independent of their role in nociception. In this issue of the Journal of Clinical Gastroenterology, Smith et al4 hypothesize that modifying endogenous opioids decreases inflammation in children with moderate to severe Crohn’s disease.
OPIOIDS AFFECT CELL PROLIFERATION
Opioid compounds interact with 3 major G-protein-coupled receptors: μ, κ, and δ receptors.5 Although cells of the nervous system express these opioid receptors in high density, they are also expressed at lower levels by immunomodulating cells including neutrophils, monocytes, macrophages and lymphocytes. Both endogenous and exogenous opioids affect immunity and cell growth through alterations in the expression of cytokines and cytokine receptors.6
Enkephalin peptides, a class of endogenous opioids, are located throughout the gastrointestinal tract7 and have also been linked to cell growth. [Met5]-enkephalin, renamed opioid growth factor (OGF) for its unique role in cell proliferation, interacts with a unique receptor, opioid growth factor receptor (OGFR), to inhibit DNA synthesis. This system is tonically active and inhibitory; thus, its blockade increases cell proliferation. The effect of OGF was seen first in experiments in which endogenous opioids were injected as against opioid antagonists into Sprague-Dawley rats and cerebellar cell growth was examined. By looking for intracellular uptake of radioactive thymidine, Zagon and McLaughlin8 showed that injection with methionine-enkephalin (OGF) resulted in a decreased proportion of cells incorporating radioactive thymidine. In addition, injection with high-dose naltrexone (50 mg/kg) was associated with an increased proportion of cells incorporating radioactive thymidine, whereas injection with low-dose naltrexone (1 mg/kg) resulted in a decreased proportion of labeled cells as well.8 Thus, opioid activation of the OGF-OGFR axis results in decreased cell proliferation, whereas blockade of this axis results in increased cell proliferation. And antagonism of this axis is dosage dependent: cell proliferation is dependent on the duration of opioid receptor blockade. Zagon and colleagues hypothesized that low-dose naltrexone actually elevates endogenous opioid levels and increases the number of opioid receptors to result in supersensitivity to endogenous opioids, resulting in a decrease in cell proliferation. The inhibitory function of OGF and its induction with low-dose naltrexone have been replicated in other tissues including the heart, the vasculature, the corneal epithelium, and astrocytes.9–12
OPIOIDS AFFECT IMMUNE CELL PROLIFERATION
In extension, enkaphalin and opioid receptors are ubiquitous, and there is evidence of their involvement in immunity. [Met5]-enkephalin or OGF has been shown to have effects on natural killer cells.13 Zagon’s group showed that T lymphocytes and B lymphocytes are modulated by OGF as well. Immunohistochemical studies demonstrate that spleen-derived mouse lymphocytes have immunoreactivity for OGF enkephalin and OGFR, lymphocyte numbers and associated cytokines are suppressed with the addition of OGF,14,15 and opioid receptors modulate macrophage phagocytosis.16 As stimulation of the OGF-OGFR axis modifies immune cell proliferation, induction of this system may have a therapeutic role in modulating autoimmune disorders such as Crohn’s disease.
Naltrexone, a long-acting opioid inhibitor, blocks all opioid receptors, including the interaction between OGF and OGFR. Dose-dependent responses have been observed.8 High doses of naltrexone result in continuous inhibition of OGF-OGFR binding and thus in increased DNA synthesis and cell proliferation. In contrast, low doses of naltrexone result in short-term blockade of OGF-OGFR, stimulating a biofeedback mechanism that increases OGF-OGFR binding, and then decreases DNA synthesis and cell proliferation. Thus, by this mechanism, low-dose naltrexone may have an immunomodulatory and anti-inflammatory role in autoimmune diseases such as Crohn’s disease.
NALTREXONE SEEMS SAFE AND EFFECTIVE IN ADULTS AND IN PEDIATRIC PATIENTS WITH IBD
In this edition of the Journal of Clinical Gastroenterology is included a pilot prospective clinical trial conducted by Smith et al4 in children younger than 18 years of age with moderate to severe Crohn’s disease. Pediatric patients pose a unique challenge in Crohn’s disease because of additional theoretical risks including growth failure, malnutrition, opportunistic infections, and hepatosplenic lymphoma. In this study, 12 children were randomized to receive low-dose naltrexone (0.1 mg/kg), 4.5 mg maximum, orally for 16 weeks or placebo for 8 weeks followed by low-dose naltrexone for 8 weeks. Endpoints were safety and tolerability and a 10-point decline in pediatric Crohn’s disease activity index (PCDAI). The children were permitted to remain on their maintenance Crohn’s medication throughout the study if they included aminosalicylates or thiopurines. Side effects associated with naltrexone were few. Unusual dreams occurred more often in the naltrexone group, but this finding was not significant with this sample size. Hepatotoxicity has been noted with high doses of naltrexone, but no laboratory abnormalities occurred in these patients. Clinical activity scores comparing pretreatment PCDAI scores (34.2±3.3) with scores after 8 weeks on naltrexone therapy (21.7±3.9) showed significant improvement. Twenty-five percent achieved clinical remission and 67% had a significant response to therapy, which is higher than what would be expected for a spontaneous response. This study suggests that naltrexone is safe in pediatric patients with Crohn’s disease. Taking this study in combination with the prior adult studies that reported improvement in clinical activity scores in 85% of adults treated, we can conclude that naltrexone may indeed be a safe and effective option for treatment for Crohn’s disease in adults and children.
NARCOTICS MAY WORSEN INFLAMMATION AND INCREASE MORTALITY, INFECTION, AND READMISSION
Prospective data from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool registry suggest that opioids are associated with higher morbidity and mortality in Crohn’s disease.17,18 These data also indicate that patients receiving narcotic analgesics are also at greater risk for developing serious infections, perhaps because some of the signs and symptoms of infection are masked by these agents. In addition, patients with IBD admitted for pain control are twice as likely to be readmitted within 30 days as compared with those admitted for other issues. Sixty-four percent of patients who were readmitted versus 52% who were not readmitted were discharged on an oral narcotic during the index admission, although this was not statistically significant (P=0.06), suggesting the ill effects of opioid use.19
In conclusion, although the etiology of Crohn’s disease is unknown, it is clear that it involves the multifactorial variables of genes, the environment, and immunology. Traditionally, treatment for Crohn’s disease aims to reduce the inflammatory response. It is clear that opioids and opioid antagonists affect inflammation; thus, as naltrexone shows promising evidence to decrease inflammation in pediatric Crohn’s disease patients, narcotics should not be a part of the medication regimen in IBD, even to control diarrhea.
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