Opioids and the Gastroenterologist: A Painful Issue

Transcription

1 Opioids and the Gastroenterologist: A Painful Issue Wendell K. Clarkston, MD Professor of Medicine GI Program Director UMKC School of Medicine Disclosures: No financial relationships to disclose 1

2 Outline 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 Issues Regarding Opioids 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 2

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4 Economic Cost of the Opioid Epidemic in Missouri 2016 (HIDI HealthStats) Pathophysiology and Clinical Effects of Opioids 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 4

5 Pathophysiology and Clinical Effects of Opioids 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 Opioid Receptors Location Mu Delta Kappa Myenteric, submucosal plexus, CNS, spinal cord Myenteric plexus, CNS Myenteric plexus, Afferent neurons Endogenous ligand B-endorphin Enkephalin Dynorphin Pharmacologic agonist Morphine, trimebutine, loperamide Eluxadoline Pharmacologic antagonist -PAMORA Naloxone, naltrexone Alvimopan, methylnaltrexone, Naloxegol, naldemidine Eluxadoline, alvimopan GI Effects * Delayed transit, visceral nociception Delayed transit 5

6 Classification of Opioids for Pain Management 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 * GI Effects of Opioids Site Pharmacologic Effect Clinical Effect Esophagus/LES Gastroduodenum GB and Biliary Tract Simultaneous contracts and inhibits LES relaxation Inhibits gastric emptying, increased SB motility then quiescence, increased pyloric tone Contraction, sphincter of Oddi spasm, decreased secretion Dysphagia, achalasia Anorexia, nausea, vomiting, gastroparesis, postoperative ileus 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:

7 Eluxadoline 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 Periprocedural Use of Opioids 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 7

8 Potential Adverse Reactions to Opioids 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 Fentanyl Synthetic derivative of morphine, times more potent Rapid onset of action in 1-2 minutes, often combined with benzodiapepines. Duration of action minutes Initial dose 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:

9 Foreign body ingestion/ body packing of narcotics 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 Symptoms and Treatment of Opioid Withdrawal 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

10 Opioid use in chronic GI diseases 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 Adolescents and Young Adults with IBD 93,668 patients in Truven Marketscan Database % 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)

11 Narcotic Bowel Syndrome 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 :410 Narcotic Bowel Syndrome: Rome IV Dx Criteria 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 :

12 Prevention and Treatment of Postoperative Ileus Minimally invasive surgery Supportive care Pain management Limitation of opioids Electrolyte replacement Bowel rest/ decompression with NG tube Nutritional support? PAMORAs: Methylnaltrexone, Alvimopan 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, antiparkinson drugs, anesthetics) 12

13 Neostigmine for Acute Colonic Pseudoobstruction 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 patients Elsner J et al. The Annals of Pharmacology 2012;46:

14 Opioid Induced Constipation (OIC) 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) Treatment of 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 14

15 Treatment of OIC: Methylnaltrexone 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: Naloxegol 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 15

16 Treatment of Post-Op Ileus/? OIC: Alvimopan 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 OIC: Naldemidine 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:

17 Meta-Analysis: RCTs for OIC Drug N RCTs Relative effect Mechanism of Action Lubiprostone Chloride channel activator Alvimopan PAMORA Y Methylnaltrexone PAMORA Y FDA Approved Y Naloxegol PAMORA Y Naldemidine PAMORA Y Naloxone Nonselective ORA Y Prucalopride HT4 Agonist N Axelopran Multiple ORA N Nee et al. Clin Gastroenterol Hepatol 2018:16: Conclusions 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 17