Enteral Naloxone for Opioid-Induced Constipation

At a recent pharmacy committee meeting, we discussed the potential use of enteral naloxone for ICU patients with opioid-induced constipation.

Background:

  • Opioids bind to mu receptors within the gastrointestinal tract. Activation of the bowel opioid receptors slow gastric transit time, decreases gastric secretions, and reduces intestinal muscle tone leading to enhanced fluid absorption and subsequently dry and hard stools.
  • Naloxone (Narcan®) solution for oral/enteral use
    • Mechanism of action:
      • Pure opioid antagonist that competes and displaces opioid at opioid receptor sites
    • FDA-approved indication: Antidote; opioid antagonist
    • Mechanism of action:
      • As an antidote – pure opioid antagonist that competes and displaces opioids at opioid receptor sites
      • As an oral agent – Enteral administration of naloxone blocks opioid action at the intestinal receptor level but has low systemic bioavailability (if dosed properly) due to marked hepatic first-pass metabolism. As a result, oral naloxone only binds strong enough for a pharmacologic response at opioid receptors in the gastrointestinal tract without reducing the central effect of the opioid and precipitating systemic withdrawal.

Potential alternatives:

  • Methylnaltrexone (Relistor®) SQ 12mg/0.6mL (much more expensive)
  • Rectal treatments: Bisacodyl (Dulcolax®), Enema
  • Oral constipation medications:
    • Polyethylene glycol (Miralax®)
    • Bisacodyl (Dulcolax®)
    • Senna (Senokot®)

Administration:

  • Dose recommendations: 10 – 20 mcg/kg dose PO q8h (max dose: 400mcg) for 5 – 7 days, then re-evaluate therapy
  • Oral/enteral dose should be not administered intravenously to prevent systemic effect and withdrawal in patients

My take: Enteral naloxone (IV solution) may be helpful for opioid-induced constipation but caution is needed to assure it is administered enterally and at proper dose.

Some of the research studies:

  1. Tofil N, Benner K, Faro S, Winkler M. The Use of Enteral Naloxone to Treat Opioid-Induced Constipation in a Pediatric Intensive Care Unit. Pediatr Crit Care Med. 2006;7(3):254-272.
  2. Akkawi R, Eksborg S, Andersson A, et al. Effect of Oral Naloxone Hydrochloride on Gastrointestinal Transit in Premature Infants Treated with Morphine. Acta Paediatrica.2008;98:442-447
  3. Liu M, Wittbrodt E. Low-Dose Oral Naloxone Reverses Opioid-Induced Constipation and Analgesia. J Pain Symptom Manage. 2002;23(1):48-53
  4. Friedman J, Dello Buono F. Opioid antagonist in the Treatment of Opioid-Induced Constipation and Pruritus. Ann Pharmcother. 2001;35:85-91
  5. Meissner W, Schmidt U, Hartmann M, et al. Oral Naloxone Reverses Opioid-Associated Constipation. Pain. 2000;84:105-109

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Smoking, Alcohol and Obesity Increase Risk of Malignancies + Staff Morale (Humor)

S-M Wang et al. The American Journal of Gastroenterology: September 2021 – Volume 116 – Issue 9 – p 1844-1852. Open Access: Population Attributable Risks of Subtypes of Esophageal and Gastric Cancers in the United States

This study examined population risks for esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric noncardia adenocarcinoma (GNCA).

“We prospectively examined the associations for risk factors and these cancers in 490,605 people in the National Institutes of Health-the American Association of Retired Persons Diet and Health cohort Diet and Health Study cohort from 1995 to 2011.”

Key findings:

My take: Tobacco, Obesity and Alcohol are associated with increased risk for a large proportion of esophageal and gastric cancers in the United States

Related article: VK Rustgi et al. Gastroenterol 2021; 161: 171-184. Open Access: Bariatric Surgery Reduces Cancer Risk in Adults With Nonalcoholic Fatty Liver Disease and Severe Obesity

Key findings:

  • The IPTW (inverse probability of treatment weighting)-adjusted risk of any cancer and obesity-related cancer was reduced by 18% (hazard ratio, 0.82; 95% CI, 0.76–0.89) and 25% (hazard ratio, 0.65; 95% CI, 0.56–0.75), respectively, in patients with versus without bariatric surgery.
  • In cancer-specific models, bariatric surgery was associated with significant risk reductions for colorectal, pancreatic, endometrial, thyroid cancers, hepatocellular carcinoma, and multiple myeloma.

Link: Improving Morale (53 seconds)

What To Do with Perianastomotic Ulcerations

C Madre et al. JPGN 2021; 73: 333-337. A European Survey on Digestive Perianastomotic Ulcerations, a Rare Crohn-like Disorder Occurring in Children and Young Adults

This survey study with 51 children described the etiology and treatment of perianastomic ulcerations (PAU).

Key findings:

  • Most common initial etiologies: necrotizing enterocolitis (n = 20) or Hirschsprung disease (n = 11)
  • Median onset of symptoms: 39 [22–106] months after surgery
  • Clinical features: Anemia was the most prevalent symptom followed by diarrhea, abdominal pain, bloating, and failure to thrive. Hypoalbuminemia, elevated CRP, and fecal calprotectin were common
  • Deep ulcerations were found in 59% of patients usually proximally to the anastomosis (68%)
  • Treatments:  treatments reported to be the most effective included exclusive enteral nutrition (31/35, 88%), redo anastomosis (18/22, 82%), and alternate antibiotic treatment (37/64, 58%). The authors note that despite similarity to Crohn’s disease, there was a lack of response to immunosuppressors and anti-TNF therapies
From JPGN twitter feed. Figure 2 in article showing examples of ileocolonic ulcerations

Related article: H Barraclough et al. JPGN 2021; 73: 329-332. Anastomotic Ulcers: A Tertiary Centre Experience of Endoscopic Management Techniques This study summarized a tertiary care center experience with 9 patients (2 with IBD). Frequent treatment included aminosalicylates, and endoscopic treatments (APC, endoclips).

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Not The Onion: Cow Potty Training

AP: No bull: Scientists potty train cows to use ‘MooLoo’

An excerpt:

Turns out cows can be potty trained as easily as toddlers… 11 out of 16 cows learned to use the “MooLoo” when they had to go…And it took only 15 days to train the young calves.

[Results were] published Monday in the journal Current Biology...Massive amounts of urine waste is a serious environmental issue,…A single cow can produce about 8 gallons (30 liters) of urine a day… toilet training animals makes it easier to manage waste products and reduce greenhouse gas emissions

The researchers mimicked a toddler’s training, putting the cows in the special pen, waiting until they urinated and then giving them a reward: a sweet liquid of mostly molasses… If the cows urinated outside the MooLoo after the initial training, they got a squirt of cold water…

The biggest environmental problem for livestock, though, is the heat-trapping gas methane they emit in belches and flatulence, a significant source of global warming. The cows can’t be trained not to belch or fart, Matthews said: “They would blow up.”

And below from The Onion:

From The Onion

Celiac Disease and Lack of Response to Hepatitis B Immunization

A Aneja et al. JPGN Reports February 2021 – Volume 2 – Issue 1 – p e046: Open Access: Clinical Characteristics of Children With Celiac Disease Not Responding to Hepatitis B Vaccination in India

Methods: The study population from consisted of 3 groups—50 newly diagnosed CD children (group 1), 50 previously diagnosed CD children who were on gluten free diet (GFD) >3 months (group 2), and 100 age and gender matched healthy controls (group 3).

Key findings:

  • Positive anti-HBs response was found in 46% in newly diagnosed CD children, 60% in CD children on GFD, and 83% in healthy controls (P < 0.001)
  • Ongoing gluten intake has significant impact on protective immune response to Hepatitis B vaccine
  • 44 out of 45 (97.77%) nonresponders from CD group seroconverted after a single booster dose

My take: Check Hep B immune response in patients with celiac disease.

Related blog post: Improving Care Process in Celiac Disease

AGA Clinical Practice: Colorectal Dysplasia in Inflammatory Bowel Diseases

SK Murthy et al. Gastroenterol 2021: DOI:https://doi.org/10.1053/j.gastro.2021.05.063. Full Text: AGA Clinical Practice Update on Endoscopic Surveillance and Management of Colorectal Dysplasia in Inflammatory Bowel Diseases: Expert Review

Some of the recommendations:

Best Practice Advice 1: Precancerous colorectal lesions in inflammatory bowel disease should be described as either polypoid (≥2.5 mm tall), nonpolypoid (<2.5 mm), or invisible (detected on nontargeted biopsy), using a modified Paris Classification. The older terms dysplasia-associated lesion or massadenoma-like mass, and flat dysplasia (when referring to dysplasia detected in nontargeted biopsies) should be abandoned.

Best Practice Advice 3: Initial colonoscopy screening for dysplasia should be performed at 8–10 years after disease diagnosis in all people with colonic inflammatory bowel disease, and immediately on diagnosis of primary sclerosing cholangitis. Staging biopsies should be taken from multiple colonic segments to assess histologic disease activity and extent and to help guide future surveillance intervals.

Best Practice Advice 8: Extensive nontargeted biopsies (roughly 4 adequately spaced biopsies every 10 cm) should be taken from flat colorectal mucosa in areas previously affected by colitis when white light endoscopy is used without dye spray chromoendoscopy or virtual chromoendoscopy. Additional biopsies should be taken from areas of prior dysplasia or poor mucosal visibility. Nontargeted biopsies are not routinely required if dye spray chromoendoscopy or virtual chromoendoscopy is performed using a high-defintion endoscope, but should be considered if there is a history of dysplasia or primary sclerosing cholangitis.

Improving Surveillance and Screening Colonoscopy

R Keswani et al. Gastroenterol 2021; 161: 701-711. Full text (open access) AGA Clinical Practice Update on Strategies to Improve Quality of Screening and Surveillance Colonoscopy: Expert Review

While these guidelines are geared towards adult gastroenterologists for colorectal cancer screening, some advice is universally applicable

  • tracking quality metrics: good prep, cecal intubation rate, and adverse events
  • good bowel preparation instructions
  • detailed endoscopy reports
  • appropriate followup: All patients with advanced adenomas should have repeat colonoscopy in 3 years. Average-risk patients with normal screening colonoscopies or those with only small distal hyperplastic polyps should not undergo repeat examinations before 10 years

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Vedolizumab Exposure in Newborns

M Juulsgard et al. AP&T 2021: https://doi.org/10.1111/apt.16593. Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study

Key findings:

  • In 50 vedolizumab-exposed pregnancies, we observed 43 (86%) live births, seven (14%) miscarriages, no congenital malformations and low risk of adverse pregnancy outcomes
  • The mean time to vedolizumab clearance in infants was 3.8 months (95% CI, 3.1-4.4)
  • No infant had detectable levels of vedolizumab at 6 months of age
  • Developmental milestones at 12 months were normal or above average
  • Neither vedolizumab exposure in the third trimester (RR 0.54, 95% CI, 0.28-1.03) nor combination therapy with thiopurines (RR 1.29, 95% CI, 0.60-2.77) seemed to increase the risk of infections in the offspring

My take: Given the good safety profile of vedolizumab, this small study provides additional reassurance regarding use of vedolizumab during pregnancy.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

ImproveCareNow Work in Progress

P Kandavel et al. JPGN 2021; 73: 345-351. Reduced Systemic Corticosteroid Use among Pediatric Patients With Inflammatory Bowel Disease in a Large Learning Health System

In this study of 27,321 patients enrolled in the ImproveCareNow (ICN) learning health system, key findings:

  • Corticosteroid use decreased from 28% (2007) to 12% (2018)
  • Black patients received corticosteroids more commonly than white patients. This disparity improved as corticosteroid use decreased in both groups
  • Anti-tumor necrosis factor-alpha medication use <120 days after diagnosis was associated with a reduction in corticosteroid use
  • As corticosteroid use decreased, steroid-sparing therapy use increased and height and weight z scores improved, particularly among children with Crohn disease
  • 27 centers (31%) had a significant reduction in steroid use, 5 (6%) had a significant increase, and 45 (52%) had variability in steroid use. 9 centers (11%) had <2 years of data.

My take: These findings are expected but nice to see. Patients in the ICN are using less steroids and growing better. Given the variation in care among centers, there is more work needed.

From JPGN twitter feed

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How Good is Your Prep?

There are a lot of articles that have been published regarding bowel preparations prior to colonoscopy, especially in adults. One of the key advances has been split-prep dosing, which is not utilized much in the pediatric age group.

Nevertheless, a recent pediatric study (S Kumar et al. JPGN 2021; 73: 325-328. Inadequate Bowel Preparation in Pediatric Colonoscopy—Prospective Study of Potential Causes) shows that inadequate bowel preparation in their prospective cohort (n=334) was less prevalent than that noted from typical adult data. Their bowel preparation assessmetn was based on Boston Bowel Preparation Scale (BBPS).

Key finding: Inadequate bowel preparation (IBP) was noted in 12.8% (41/321); there were no age, gender, obesity, race, or insurance type associated with IBP. (IBP was defined by BBPS <5)

Their preparation instructions:

  • If <25 kg, “119 g of PEG 3350 mixed in 32 oz of sport drink” and then “additional 32 oz of a sports drink without PEG 3350”
  • If 26-49 kg, “238 g of PEG 3350 mixed with 64 ounces of fluids” and then “additional 64 oz of a sports drink without PEG 3350”
  • If >50 kg, “238 g of PEG 3350 mixed with 64 ounces of fluids” and then “64 ounces of a sports drink and four bisacodyl tablets”

My take: If you are seeing a high rate of IBP, the prep instructions in this study could be replicated (given their good results), split preps could be given for teens, and better instructions (visual aids) could be needed.

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Splatter Paint Studio (on the beltline)

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.