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Opioids and the Gastroenterologist: A Painful Issue

Wendell K. Clarkston, MDProfessor of MedicineGI Program DirectorUMKC School of Medicine

No financial relationships to disclose

Disclosures:

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• Introduction• Pathophysiology and Clinical Effects of Opioids• Opioids for Sedation for GI Procedures• Foreign Body Ingestion of Opioids• Opioid Withdrawal• Opioid Use in Chronic GI Diseases• Narcotic Bowel Syndrome• Opioid Induced Constipation and Ileus

Outline

• Karl Marx 1844: “Religion is the Opium of the People”• 2018: “Opium is the Religion of the People?”• “Pain as the Fifth Vital Sign”, JCAHO• Introduction, prescription, and marketing of Opioids for

non-cancer pain• “The Opium Epidemic”- rising use and wave of deaths• 90% of patients with moderate to severe pain are treated

with opioids, 20% presenting are prescribed opioids, 4% of patients are on opioids for at least 3 months

Issues Regarding Opioids

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Economic Cost of the Opioid Epidemic in Missouri 2016 (HIDI HealthStats)

• Opioid receptors are G protein-coupled receptors that regulate functions including pain, reward mood, stress, GI and respiratory functions

• Reduce intracellular cAMP by inhibiting adenylate cyclase• Reduce neuronal excitability by hyperpolarization due to

increased K permeability and inhibition of calcium channels• Overall effect is inhibitory on the neuron, reducing

acetylcholine release

Pathophysiology and Clinical Effects of

Opioids

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• 3 types of opioid receptors: Mu, Delta, Kappa• Located in the CNS and peripheral nervous system• Mu receptors are the principal mediators of analgesic

action, as well as major GI side effects.• Kappa receptors also mediate analgesia and bowel effects• Delta receptors have some analgesic effects and inhibition

of motility and secretion

Pathophysiology and Clinical Effects of

Opioids

Opioid Receptors

Mu Delta Kappa

Location Myenteric, submucosal plexus, CNS, spinal cord

Myenteric plexus, CNS

Myenteric plexus, Afferent neurons

Endogenous ligand B-endorphin Enkephalin Dynorphin

Pharmacologic agonist

Morphine, trimebutine, loperamideEluxadoline

Pharmacologic antagonist

Naloxone, naltrexone Eluxadoline, alvimopan

-PAMORA Alvimopan, methylnaltrexone, Naloxegol, naldemidine

GI Effects * Delayed transit, visceral nociception

Delayed transit

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• Pure agonists: Codeine, hydrocodone, morphine, hydromorphone, fentanyl, oxycodone, oxymorphone, levorphanol, methadone, meperidine

• Agonist-antagonists: Buprenorphine (partial), butorphanol, dezocine, nalbuphine, pentazocine

• Pure antagonists: Alvimopan, methylnaltrexone, naloxone, naltrexone, nalmafene

Classification of Opioids for Pain

Management

* GI Effects of Opioids

Site Pharmacologic Effect Clinical Effect

Esophagus/LES Simultaneous contracts and inhibits

LES relaxation

Dysphagia, “achalasia”

Gastroduodenum Inhibits gastric emptying, increased

SB motility then quiescence,

increased pyloric tone

Anorexia, nausea, vomiting,

gastroparesis, postoperative ileus

GB and Biliary

Tract

Contraction, sphincter of Oddi spasm,

decreased secretion

Biliary pain, delayed digestion

Small Bowel Increased tone/segmentation,

increased transit time, increased

absorption, decreased secretion

Indigestion, bloating, distension,

constipation, postoperative ileus

Colon Same as small bowel Bloating, distension, spasms, cramps,

pain, constipation, hard and dry stools

Anorectum Decreased rectal sensitivity, increased

internal sphincter tone

Incomplete evacuation, straining,

constipation

Opioids in Gastroenterology….Camilleri M et al. Clin Gastroenterol Hepatol 2017;15:1338-1349

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• Mixed mu opioid receptor agonist and delta receptor antagonist

• Reduces bowel transit and decreased pain with low risk of mu receptor agonist side effects

• Approved in 2015 for diarrhea predominant IBS• Can cause pancreatitis/SOD: Limit to patients with a

gallbladder and without prior pancreatitis

Eluxadoline

• Bind to mu receptors in the CNS• Analgesia/ supplement to sedation/ synergistic• Cough and gag suppressant• Suppresses autonomic response• Treatment of injection site and post-procedure pain

Periprocedural Use of Opioids

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• Euphoria, delirium, acute tolerance, hyperalgesia• Nausea, vomiting, urinary retention, constipation, ileus• Increased intracranial pressure• Cardiorespiratory depression and hypotension• Chest and skeletal muscle rigidity• Pruritus• Greater length of hospital stay• Potential for abuse• Risk factors for sedation: elderly, comorbid conditions, those

receiving adjunctive therapy, those with delayed effects

Potential Adverse Reactions to Opioids

• Synthetic derivative of morphine, 50-100 times more potent• Rapid onset of action in 1-2 minutes, often combined with

benzodiapepines. Duration of action 30-60 minutes• Initial dose 50-100 mcg, 25ug supplemental every 2-5 min.

Reduce dose by 50% in the elderly• Respiratory depression is the main risk- may persist beyond

analgesic effect• Antidote is naloxone, .2-.4 mg IV every 2-3 min, monitor 2 hrs

AGA Institute Review of Endoscopic Sedation. Gastroenterology 2007;133:675-701

Fentanyl

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• Internal concealment• Narcotics wrapped in balloons or condoms• CT scan can be helpful in detection• Rupture and leakage can be fatal• Endoscopic removal is not recommended• Surgical removal is recommended if packets

obstruct or fail to progress

ASGE Guidelines on Foreign Bodies 2011

Foreign body ingestion/ body packing of narcotics

• Withdrawal occurs with a patient dependent on opioids suddenly reduces or stops them

• Locus coeruleus at the base of the brain triggers withdrawal: Lacrimation, rhinorrhea, piloerection, myalgia, diarrhea, nausea and vomiting, cramping, pupillary dilation, photophobia, insomnia, autonomic hyperactivity, yawning

• COWS (Clinical Opioid Withdrawal Scale) measures severity

• Treatments: Gradual Cessation, Methadone, buprenorphine, probuphine, clonidine, Naltrexone, Naloxone, loperamide, promethazine Shah M, Huecker MR, StatPearls 2018

Symptoms and Treatment of Opioid

Withdrawal

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• Inflammatory bowel disease• Chronic pancreatitis• Chronic diarrhea/ functional bowel disease

• Don’t Feed the Bears or the Bears will be back for more!

Opioid use in chronic GI diseases

• 93,668 patients in Truven Marketscan Database 2007-2015• 18.2 % received chronic opioid therapy• Annual prevalence increased to a peak of 12.2% in 2012• Increased in males and older patients• In those followed longitudinally, 30.5% remained on narcotics

for 2 years, and 5.3% for four years• Sustained opioid use in young patients with IBD is increasingly

common

Inflammatory bowel diseases 2018 Sep 15;24 (10) 2093-2103

Opioid Use in Adolescents and Young

Adults with IBD

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• Development or worsening of abdominal pain linked to chronic or escalating doses of opioids (occurs in 6% of opioid users)

• Proposed mechanisms: Neuroimmune response of spinal glial cells, bimodal influences at opioid transmembrane receptors, leading to tolerance for inhibitory effects, with sensitization of excitatory receptors, progressing to paradoxical hyperalgesia.

• Treatment: Accurate diagnosis, therapeutic relationship, eventual complete detoxification from opioids.

• Recidivism rate is about 50%.Szigethy E, et al. Curr Gastroenterol Rep 2014 16:410

Narcotic Bowel Syndrome

• Frequent or recurring abdominal pain managed with high dose or chronic

opioid therapy

• Pain that is not explained by an alternative GI diagnosis

• Escalating pain with continued or increasing doses of opioids

• Substantial deterioration or incomplete resolution with increasing opioids

• Substantial worsening of pain as the opioid concentration wanes post

dosing and improvement immediately after dosing

• Progression in the duration, frequency, and intensity of abdominal pain

over time

Farmer AD et al. Narcotic Bowel Syndrome. Lancet Gastroenterol Hepatol 2017’2:361-68.

Narcotic Bowel Syndrome: Rome IV Dx Criteria

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• Minimally invasive surgery• Supportive care• Pain management• Limitation of opioids• Electrolyte replacement• Bowel rest/ decompression with NG tube• Nutritional support• ? PAMORAs: Methylnaltrexone, Alvimopan

Prevention and Treatment of Postoperative Ileus

Colonic Pseudo-obstruction (Ogilvie’s

Syndrome)- Predisposing Factors

• Postsurgical• Trauma• Age• Sepsis• Neurologic Disorders• Hypothyroidism• Renal insufficiency

• Viral Infections (HSV, Varicella)• Cardiac or Respiratory Disorders• Electrolyte imbalances (K, Ca, Mg)• Medications (narcotics, TCADs,

phenothiazides, antiparkinsondrugs, anesthetics)

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• Multiple retrospective and prospective observational trials support the effectiveness of neostigmine

• One RCT exists: Ponec et al. (N Engl J Med 1999;341:137-41) Randomized 21 patients who had failed conservative therapy to neostigmine vs placebo.

• 10/11 (91%) who received neostigmine responded in a median time of 4 minutes

• 2/10 later required decompression• Symptomatic bradycardia requiring atropine occurred in 2

patientsElsner J et al. The Annals of Pharmacology 2012;46:430-5

Neostigmine for Acute Colonic Pseudo-obstruction

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• Mu opioids increase fluid absorption and inhibit colonic motility

• OIC is defined as a change in bowel habits after opioid therapy, characterized by any of the following: Reduced frequency (< 3 BM/wk), straining, sense of incomplete evacuation, and harder stool frequency

• BFI (bowel function index) can be used to determine severity of OIC and response to treatment (BFI>30)

Opioid Induced Constipation (OIC)

• OTC Laxatives• Tapentadol (mu receptor agonist and norepinephrine

reuptake inhibitor)• Oxycodone/ naloxone• Lubiprostone (except in patients on methadone)• PAMORA (peripherally acting mu opioid receptor

antagonists)- methylnaltrexone, naloxegol, alvimopan, naldemidine

Treatment of OIC

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• A quarternary N-methyl derivative of naltrexone- does not cross to the brain

• Multiple studies show efficacy of 12 mg subq daily or 450 mg po daily

• Abdominal pain, nausea, vomiting, and hyperhidrosis were the primary side effects

Treatment of OIC: Methylnaltrexone

• A pegylated derivative of naloxone- does not cross the blood brain barrier

• Large 12 week phase II and III studies efficacy• The most common side effects were abdominal pain,

diarrhea, nausea, headache, and flatulence. • FDA approved, at 25 mg po daily

Treatment of OIC: Naloxegol

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• PAMORA• Approved for management of postoperative ileus in

patients after bowel resection at 12 mg po bid for 7 days• Metanalysis shows that alvimopan significantly reduces the

time to first passage of stool postoperatively• Possibly associated with increased risk of acute MI• Limited use and hospitals must register

Treatment of Post-Op Ileus/ ? OIC:

Alvimopan

• PAMORA

• Placebo controlled trial in 97 patients with OIC and cancer• Dose .2 mg po daily showed efficacy• Quality of life measurements improved significantly

Katami et al. Annals of Oncology 29:1461-67.

Treatment of OIC: Naldemidine

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Meta-Analysis: RCTs for OIC

Drug N RCTs Relative effect

Mechanism of Action FDA Approved

Lubiprostone 1284 3 .90 Chloride channel activator

Y

Alvimopan 1579 4 .68 PAMORA Y

Methylnaltrexone 1622 6 .75 PAMORA Y

Naloxegol 1522 3 .77 PAMORA Y

Naldemidine 1524 4 .65 PAMORA Y

Naloxone 838 5 .63 Nonselective ORA Y

Prucalopride 196 1 .88 5HT4 Agonist N

Axelopran 201 1 .60 Multiple ORA N

Nee et al. Clin Gastroenterol Hepatol 2018:16:1569-1584

• Opioid use in the United States remains a major health issue, and may cause serious GI side effects, including narcotic bowel syndrome, Opiate Induced Constipation, and postoperative ileus/ colonic pseudo-obstruction

• Gastroenterology Professionals should understand opioid physiology, and the clinical use of opioid agonists and antagonists

• Gastroenterology Professionals should remain aware of the high risk of addiction with prescription of narcotic medications for chronic GI diseases and functional pain, and limit narcotic use in their practice

Conclusions