Methods to Reduce and Treat Opioid Induced Adverse Events. Raymond Sinatra, MD, PhD

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1 Methods to Reduce and Treat Opioid Induced Adverse Events Raymond Sinatra, MD, PhD

2 Opioid Analgesics Annoying Side Effects Life Threatening Side Effects Improved Pain Control

3 Opioid Induced Adverse Events Acute Pain Nausea Vomiting Confusion Excessive Sedation OBD- Ileus Pruritus Chronic Pain Nausea Confusion Sedation OBD- Constipation Physical Dependence Psychological Dependence

4 Opioid Side Effects May Contribute To Under-Management of Pain Incidence (%) Nausea 1,2,3 24%-54% Vomiting 2,3 15%-39% Constipation 3 10% 1. Chelly et al. Anesth Analg. 2004;98: ; 2. Sucato et al. Spine. 2005; 30: ; 3. Smith et al. Am J Surg. 2004; 187:

5 Patients Rank Vomiting as the Most Undesirable Outcome, Even More Undesirable Than Pain Patient Ranking Rank Postoperative Anesthesia Outcomes 1 Vomiting 2 Gagging on endotracheal tube 3 Incisional pain 4 Nausea 5 Recall without pain 6 Residual weakness 7 Shivering 8 Sore throat 9 Somnolence N=101; F-test <0.01. Adapted from Macario A. Anesth Analg. 1999;89: ,

6 Patient Concerns Over Side Effects Are Greater Than Fear of Pain 100.0% Post-Operative Recovery Period: Patient Concerns Patients (%) 77.5% 55.0% 32.5% 49% 27% 10.0% Nausea & Vomiting 13% Pain Impaired Alertness (N=220) Eberhart et al. Br J Anaesth. 2004;92:

7 Multimodal Approach to Pain Management Neural Blockade Lidoderm Patch Exparel Anti-inflammatory Agents NSAIDS, APAP Cox-2 Inhibitor Nontraditional techniques Accupuncture TENS Physical Therapy Relaxation Therapeutic Massage Opioid Foundation Interventional Techniques Facet block Spinal Stimulation Neurolysis Anti-neuropathics Gabapentin Pregabalin Ketamine Cymbalta TCA s Kehlet H, Mogensen T. Br J Surg. 1999;86: ; Basse L, et al. Dis Colon Rectum. 2004;45: ; Abraham NS, et al. Br J Surg. 2004;91:

8 Opioid Induced Nausea and Vomiting

9 Prevalence of PONV Overall Up to 30% for all surgeries and patient populations 1 3 Outpatient About 40% of patients treated at outpatient surgery centers 4 Breakthrough More than 30% of patients receiving prophylactic antiemetics 3 1.! Kovac AL. Drugs. 2000;59: ! Habib AS, Gan TJ. Can J Anesth. 2004;51: ! Apfel CC et al. N Engl J Med. 2004;350: ! Carroll NV et al. Anesth Analg. 1995;80:

10 Global Risk Factors for PONV Patient Primary Predictors: Female sex, history of PONV or motion sickness, nonsmoker, use of postoperative opioids 1 Additional Risk Factors: Younger age (in adults), 2 4 history of migraine, 5 preoperative anxiety, coexisting medical conditions, presence of pain 4 Surgery Type of Procedure: Plastic, orthopedic, ophthalmologic, ENT, gynecologic (non-d&c), laparoscopic 6 Length of Procedure: Longer duration 2 Anesthesia General anesthesia 2 Use of Opioids, Use of N2O 1.! Apfel CC et al. Anesthesiology. 1999;91: , 2.Sinclair DR et al. Anesthesiology. 1999;91: ! Apfel CC et al. Int Anesthesiol Clin. 2003;41: Kovac AL. Drugs. 2000;59: ! Stadler M et al. Anesthesiology. 2003;98: ! Carroll NV et al. Anesth Analg. 1995;80:

11 Patients With PONV, % Nearly 80% of PONV Occurs Within 48 Hours 78% 22% 20 <48 Hours Postdischarge Only >48 Hours 5 Days Postdischarge Only (45/58) (13/58) Nearly 65% of patients did not experience PONV symptoms until after leaving the recovery room. Only 12% of patients experienced PONV symptoms solely in the recovery room. Carroll NV et al. Anesth Analg. 1995;80:

12 Impact of Multiple Patient-Related Risk Factors* 80 Risk of PONV Increased Based on Number of Primary Risk Factors Present Patients With PONV, % % 61% 79% 0 10% 21% No Risk Factors 2 Risk Factors 4 Risk Factors Primary Risk Factors: Female sex History of PONV or motion sickness Nonsmoking General anesthesia and use of postoperative opioids *!Validated in 2,722 adult patients receiving inhalational anesthesia.! Apfel CC et al. Anesthesiology. 1999;91:

13 Key Neurotransmitters in the Substance P Serotonin! Emetic! Reflex! Center 1 3 Acetylcholine Dopamine Histamine Opioid receptors are also located in the chemoreceptor trigger zone (CTZ); opioids are a risk factor for PONV. 1. Nelson TP. J Perianesthesia Nurs. 2002;17: Cameron D, Gan TJ. Anesthesiology Clin N Am. 2003;21: Harrison S, Geppetti P. Int J Biochem Cell Biol. 2001;33:

14 Overview: Mediators and Management of N & V Chemotherapy, Opioids, Anesthetics Cerebellum Olfactory, Visual, and Noxious input Somato- Sensory Cortex Vomiting Reflex Brain Stem Vagal Motor Nucleus Antihistamines, NSAIDS 5 HT and NK-1 Antagonists Vomiting Center Metoclopramide Hollow Viscus & Peritoneum CTZ NTS 5-HT Antagonists Stomach & Small Intestine Surgery, Chemotherapy, Infection, Distention, Obstruction Anti-Dopaminergics Naloxone, NK-1 Inhibitors Canabinoids 5 HT and NK-1 Antagonists Antihistamines, Scopolamine Vestibular Nuclei Benzodiazepines Limbic Cortex Fear, Anxiety, Memory ENT Surgery Motion, N 2 0

15 Targeting Emetic Neurotransmitters Acetylcholine: Anticholinergic agents (eg, atropine, scopolamine) are among the oldest first-generation antiemetic agents. Inhibit muscarinic and cholinergic receptors in cerebral cortex and pons Histamine: Antihistamines (eg, dimenhydrinate, diphenhydramine, hydroxyzine) centrally block both H 1 receptors and acetylcholine. Main site of action is the vomiting center and vestibular pathways Particularly useful for PONV associated with middle ear surgery involving components of the vestibular nerve Kovac AL. Drugs. 2000;59:

16 Serotonin and 5-HT 3 Receptor Pathway First recognized with high-dose metoclopramide 1 More than 80% of 5-HT is localized in the gut. 2 At least 7 different subtypes of 5-HT receptors have been identified. 3 The 5-HT 3 receptor is highly specific for nausea and vomiting. 4 5-HT 3 receptors are located peripherally and centrally. 2 1.! Scuderi PE. Int Anesthesiol Clin. 2003;41: Endo T et al. Toxicology. 2000;153: ! Cameron D, Gan TJ. Anesthesiology Clin N Am. 2003;21: Nelson TP. J Perianesthesia Nurs. 2002;17: ! Saito R et al. J Pharmacol Sci. 2003;91: Hornby PJ. Am J Med. 2001;111:106S 112S. 7.! Stahl SM. J Clin Psychiatry. 2003;64:

17 Substance P and NK 1 Receptor Pathway Substance P/NK 1 receptors are highly concentrated in brainstem vomiting center. Area postrema Nucleus tractus solitarius Dorsal motor nucleus of the vagus nerve Primary mechanism of substance P/NK 1 receptor pathway appears to be central. Saito R et al. J Pharmacol Sci. 2003;91:87 94.

18 2 Clinical Trials of Aprepitant vs. Ondansetron 2 Multicenter, randomized, double-blind, active comparator-controlled, parallelgroup clinical studies 1658 patients undergoing open abdominal surgery requiring at least an overnight stay. Patients were randomized to receive 40- mg aprepitant, 125-mg aprepitant, or 4-mg ondansetron. Emend package insert June 2006

19 2 Clinical Trials of Ondansetron 40 mg given IV immediately prior to induction Aprepitant 125 mg or 40 mg given orally 1 to 3 hours prior to induction with 50 ml of water. A comparison between the 125-mg dose and the 40-mg dose did not demonstrate any additional clinical benefit. Emend package insert June 2006

20 Emend package insert June 2006 *p<0.001

21 Emend package insert June 2006 *p<0.001

22 Antiemetic Dosing Antihistamines and Anticholinergics Diphenhydramine (Benadryl) 25 to 50 mg orally Meclizine (Antivert) 12.5 to 25 mg orally every six to eight hours Scopolamine Patch (apply every 2 days) Antipsychotics and related agents Haloperidol (Haldol) 0.5 to 2 mg orally 2-4 times per day Prochlorperazine (Compazine) 5 to 10 mg oral or IV every 6-8 hrs or 25 mg rectally (less sedating than promethazine) Promethazine (Phenergan) 12.5 to 25 mg orally, IV, or rectally every 4-6 hours (Dopamine-blocking properties less than prochlorperazine) Prokinetic agents Metoclopramide (Reglan) 5 to 10 mg orally or IV four times per day Serotonin antagonists Ondansetron (Zofran) 4 mg orally or IV two to four times per day Granisetron (Kytril) 1 mg orally or IV twice per day NK-1 Antagonists

23 Opioid Induced Bowel Dysfunction

24 Opioid-Induced Bowel Dysfunction (OBD) Severe constipation observed in patients treated acutely and chronically with opioid analgesics May lead to physical and functional deterioration May be dose dependent, but can occur with low opioid doses Variable onset and intensity between patients Unlike other opioid-induced side effects which resolve over time, tolerance to OBD is not observed with continued opioid therapy Papagallo M. Am J Surg 2001; Kurz A, Sessler DI Drugs 63:

25 Post Operative Ileus (POI) A severe form of constipation that includes the following symptoms: Acute abdominal distention/bloating following surgery Visceral pain Nausea/vomiting Inability to pass stools Inability to tolerate a solid diet Kehlet H, Holte K. Am J Surg (5A Suppl):3S 10S. Holte K, Kehlet H. Drugs :

26 Pathogenesis of POI Neurogenic: sympathetic hyperactivity Inflammatory: cellular and humoral factors including endogenous opioid peptides Due to surgical manipulation Hormonal: corticotrophin releasing factor Pharmacologic::primarily, opioid analgesics

27 Management Approaches for POI Current Treatments Emerging Therapies Supportive care NG intubation Fluid restriction Early oral/enteral feeding Epidural analgesia as part of multimodal therapy Peripherally selective opioid antagonists Pharmacologic Options Traditional laxatives Opioid-sparing approaches Surgical Options Laparoscopy vs. open surgery Holte K, Kehlet H. Br J Surg. 2000;87: ; Holte K, Kehlet H. Drugs. 2002;62:

28 Block propulsive peristalsis Increase intestinal fluid absorption OPIOIDS Inhibit intestinal ion and fluid secretion Most common and debilitating symptom of OBD Defined as less than 3 bowel movements per week Occurs in 33% of cancer patients, and 40% of non cancer patients on chronic opioid therapy Can be more distressing than pain in some patients) Papagallo M Am J Surg 182: 11-18, 2001, Panchal SJ, et al. Int. J. Clin. Pract. 2007; 61(7): Holzer P. Neurosci. Lett. 2004; 361:

29 Duration of Adverse Events after Analgesic Therapy in Cancer Patients Schug et al. J Pain Symptom Manage :

30 OBD: Impact on Analgesia The benefit of opioid analgesia in nonmalignant and cancer pain is often limited by the development of OBD 1,2 A survey by Palmer et al. demonstrated that patients might prefer inadequate pain relief over adequate pain management with associated OBD 3 Would effective treatment of OBD lead to increased opioid consumption and improved pain relief? 1 Pappagallo, Am J Surg, 182(suppl) (2001) 11S-18S; 2 Walsh, J Pain Symptom Manage, 5 (1990) ; 3 Palmer et al., # th Annual Scientific meeting of the American Pain Society, 2001, Phoenix, AZ.

31 Strategies to Reduce Bowel Dysfunction with Chronic Opioid Treatment Limit opioid exposure employ multimodal or balanced analgesic regimens Anticipate and aggressively treat OBD with stool softeners and laxatives Consider prophylactic bowel regimen Consider opioid rotation Selectively block opioid effects in the GI tract (IV and orally administered antagonists (in development) Holzer P. Neurosci Lett. 2004; 361:

32 Constipation: First-Line Treatments Laxative agents Stimulating agents Stool softeners Surfactants Osmotic agents Bulk-forming agents Diphenylmethanes Anthraquinones Salt Carbohydrates Bisacodyl Sodium picosulfate Dantron Senna Magnesium sulfate, citrate, or hydroxide Docusate sodium Lactulose Sorbitol Mannitol Fiber Methylcellulose Psyllium Polycarbophil Tamayo AC, Diaz-Zuluaga PA. Support Care Cancer. 2004;12: ; Lembo A, Camilleri M. N Engl J Med. 2003;349:

33 Case for Opioid Rotation Incidence of constipation significantly lower in patients taking fentanyl for chronic pain than in those taking morphine P< Fentanyl (n= 250) Morphine (n = 238) Allan L, et al. BMJ. 2001;322:1-7.

34 Naloxone: A central and peripheral Opioid-Receptor Antagonist May reduce some side effects associated with epidural opioids Readily crosses the BBB 1, 2 Can cause symptoms of systemic withdrawal 1, 2 Reversal of opioid-mediated analgesia1, 3, 4 Has been advocated but has not been approved for POI 1 1 Narcan Prescribing Information; 2 Kurz A, Sessler D. Drugs. 2003; 63: ; 3 Liu M, Wittbrodt E. J Pain Symptom Manage. 2002; 23: Thomas MC et al. Am J Health-Syst Pharm. 2003;60:

35 Peripheral Opioid Antagonists Quaternary Opioid Compounds that do not enter the CNS Methylnaltrexone Alvimopan

36 Peripherally Selective Opioid-Receptor Antagonists: Implications for Management Fewer opioid-related side effects at higher opioid doses No reversal of opioid analgesia Decreased nausea and vomiting Decreased time to upper/lower GI function Decreased rate of POI Decreased rate of NG tube insertion Decreased time to ready for discharge But questions remain: appropriate patient selection (used prophylactically); costeffectiveness

37 Alvimopan: A New Orally Administered mu-opioid Receptor Antagonist Unique clinical pharmacologic profile Limited oral bioavailability (6% in humans) Primary site of activity is at opioid receptors in the myenteric plexus High binding affinity for gut, µ-opioid receptor (K i <1 nmol/l) Zimmerman DM, et al. J Med Chem. 1994; 37: ; Schmidt WK. Am J Surg (Suppl): 27S-38S; Holzer P. Neurosci Lett. 2004; 361: ; Kurz A, Sessler D. Drugs. 2003; 63:

38 Alvimopan as Treatment for Opioid- Induced Bowel Dysfunction Proportion of patients reporting a bowel movement within 8 hours of study drug adminstration significantly greater in alvimopan-treated patients Placebo 0.5 mg (n = 54) 1.0 mg (n = 58) (n = 56) Overall (21 d) Week 1 Week 2 Week 3 *p < 0.01 vs. placebo, **p < vs. placebo Paulson DM, et al. J. Pain. 2005; 6(3): Treatment period

39 Alvimopan as Treatment for Opioid-Induced Bowel Dysfunction Time to first bowel movement sooner in patients on 0.5 and 1 mg alvimopan compared to those on placebo N=148, p < Paulson DM, et al. J. Pain. 2005; 6(3):

40 Methylnaltrexone (Relistor): A Peripherally Selective mu-receptor Antagonist Addition of CH 3 (methyl) group to naltrexone, limits BBB penetration Does not reverse opioid-mediated analgesia or initiate withdrawal IV, SC, and oral preparations Recently approved for the treatment of OBD in patients treated with opioids for chronic pain Yuan CS. J Support Oncol. 2004; 2: Yuan CS, et al. Clin Pharmacol Ther. 1996; 59: Yuan CS, et al. JAMA. 2000; 283: Yuan CS, et al. Pharmacol Ther. 2000; 67:

41 Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation Patients randomized to MNTX experiencing laxation within 4 and 24 hours significantly greater than those randomized to placebo Placebo MNTX 0.30 mg/kg MNTX 0.15 mg/kg % Patients hours 24 hours Time of Evaluation *P< vs. placebo; +P< vs. placebo (Chi-square); ++P< vs. placebo (Chi-square) Thomas J, et al. J Clin Oncol. ASCO Meeting Proceedings. 2005;23(16S):abstract 8003.

42 Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation Time to laxation significantly better for methylnaltrexone-treated group compared to placebo group within first 5 hours mg/kg 0.30 mg/kg Placebo p < % Time (h) Yuan CS, Israel RJ. Expert Opin. Investig. Drugs. 2006; 15(5): ; Thomas J, et al ASCO annual meeting, oral presentation.

43 Methylnaltrexone in Cancer Patients with Opioid-Induced Constipation Subcutaneous methylnaltrexone rapidly induces laxation in cancer patients with opioid-induced constipation in 2-week study Placebo (n=42) MNTX 0.15 mg/kg (n=37) hours at least 2 of first 4 doses within 4 hr *p = ; **p < Karver SB, et al. J. Clin. Oncol. ASCO Annual Meeting Proceedings. 2007; 25(18S): abstract 9081.

44 Opioid-Induced Pruritis Unpleasant and common adverse effect of opioid treatment Appearance more likely during epidural or intrathecal analgesia vs. systemic analgesia Caused by activation of opioid receptors in cervical and trigeminal centers Also caused by opioid-mediated release of histamine Momeni M, et al. Drugs. 2006;66(18): ; Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. Minneapolis, MN. McGraw-Hill; 2004:53-70.

45 Opioid-Induced Pruritis Pharmacologic Treatment Options Antihistamines Sedative Hypnotics SSRI Diphenhydramine (25-50 mg PO/IV q 6h) Hydroxyzine (Atarax) (25 mg PO q 6h) Cetirizine (Zyrtec)10 mg orally 1X per day Fexofenadine (Allegra) 60 mg orally 2X per day Loratadine (Claritin) 10 mg orally 1X per day Lorazepam (1 mg SL/PO/IV q 6h) Droperidol (15 µg-50 µg droperidol per mg of morphine) Paroxetine NALOXONE? IV, intravenous; PO, by mouth; SL, sublingual; SSRI, selective serotonin reuptake inhibitor. Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. Minneapolis, MN. McGraw-Hill; 2004:53-70.

46 Opioid Induced Respiratory Depression

47 Opioid Induced Respiratory A serious to life threatening complication observed with acute administration of IV, Oral, and Neuraxial opioids Less commonly observed with chronic opioid exposure Related to opioid binding and depression of neurons in the brainstem respiratory center. Worsened by co-administration of sedative hypnotics and CNS depressants Cepeda MS, Farrar JT : Side effects of opioids during short-term administration: effect of age, gender, and race., Clin Pharmacol Ther Aug;74(2):

48 Opioid Induced Respiratory Depression Clinical depression of CO2 induced hyperventilation is commonly observed, Bradypnea and respiratory arrest are observed in 1/1000 patients Symptoms are more common in elderly and debilitated patients and COPD patients Compared with patients aged between 16 and 45 years, those aged between 61 and 70 years had 2.8 times the risk of development of respiratory depression. Patients aged 71 to 80 years had 5.4 times the risk; and those over 80 years had 8.7 times the risk. Cepeda MS, Farrar JT : Side effects of opioids during short-term administration: effect of age, gender, and race., Clin Pharmacol Ther Aug;74(2):

49 Respiratory Depression Treatment Generally symptoms can be controlled by removal of opioids, other sedative hypnotics and treatment with supplemental oxygen Mild symptoms may be controlled with Nalbuphine 10-20mgs or Naloxone 1/2-1 amp (200mcg) Severe overdose may be reversed with Naloxone 1-2 amps ( mcg) Respiratory arrest often requires intubation and mechanical ventilation to reduce pco2 and reverse respiratory acidosis

50 CNS Effects

51 CNS Effects: Opioid induced sedation is mediated by activation of Kappa opioid receptors Excessive sedation is commonly observed in elderly and debilitated patients (effects are transient, although some patients remain symptomatic) The reported incidence of sedation is between 20 and 60 percent. 3 It commonly presents with initiation of opioid therapy or with dose increases. 7 Pharmacologic management of sedation through the use of psychostimulants may be considered, although data supporting their use are lacking in clinical trials. 1,29 In addition, potential side effects of psychostimulants warrant judicious prescribing in this setting. Cepeda MS, Farrar JT : Side effects of opioids during short-term administration: effect of age, gender, and race., Clin Pharmacol Ther Aug;74(2):

52 CNS Effects:Confusion/Agitation Opioid induced confusion is mediated by activation of Kappa and Sigma (PCP) opioid receptors Like sedation, confusion is commonly observed in elderly and debilitated patients, and often presents with initiation of opioid therapy or with dose increases. 7 Treatment of cognitive impairment involves the use of antipsychotics. A recent Cochrane review found that Haloperidol and chlorpromazine (Thorazine) were most effective in treating delirium, Benzodiazepines have been used with antipsychotics when severe agitation is present. 3 Although they could enhance sedative effects and perhaps worsen cognition. Cepeda MS, Farrar JT : Side effects of opioids during short-term administration: effect of age, gender, and race., Clin Pharmacol Ther Aug;74(2):

53 Medications for Treating Opioid-Induced CNS symptoms Delirium or reduced cognition Haloperidol (Haldol) 0.5 to 2 mg orally twice per day (Often first choice; inexpensive; minimal sedation and cardiovascular effects) Quetiapine (Seroquel) 25 to 50 mg orally twice per day (More sedating than haloperidol) Risperidone (Risperdal) 0.25 to 1 mg orally twice per day (Expensive) Donepezil (Ari-cept) limited evidence supporting its use Sedation Dextroamphetamine (Dexedrine) 2.5 to 5 mg orally twice per day (Judicious use advised; adverse effects include tremor, delirium, decreased appetite, and hallucinations) Methylphenidate (Ritalin) 2.5 to 5 mg orally twice per day (Administer in the

54 Pain Management-Related Opioid Addiction Is Rare Despite Common Perceptions Concerns about addiction are a common reason for under-use of opioids 1 Opioid addiction rarely develops after receiving opioids for analgesia without prior history of substance abuse Long-term opioid use for non-cancer pain resulted in only 6 cases (2.6%) of possible drug abuse 2 There were no cases of de novo addiction Addiction is primarily associated with pre-existing aberrant drug use behaviors 3 1. Weissman et al. Wis Med J. 1991;90:671-5; 2. Portenoy et al. Clin J Pain. 2007;23: ; 3. Fleming et al. J Pain. 2007;8:

55 Opioid-Induced Urinary Retention Opioid effects on urinary bladder not well studied, but source of morbidity Overall incidence with IV opioids is 23% Epidural and intrathecal analgesia associated with higher incidence (42%-80% for intrathecal morphine) May be treated with IV naloxone Relieved by catheterization Ruan X. Pain Physician. 2007; 10: ; Dolin SJ, Cashman JN. Br J Anaesth. 2005;95: ; Rosow CE. Clin Pharmacol Ther. 2007;82:48-53; Momeni M, et al. Drugs. 2006;66:

56 Opioid-Induced Urinary Retention Methylnaltrexone Methylnaltrexone reverses remifentanil-induced bladder dysfunction without reversing central opioid effects 1,000 Placebo 1,000 Methylnaltrexone Amount Voided, ml Baseline R Placebo Baseline R MNTX R, remifentanil; MNTX, methylnalrexone. Rosow CE. Clin Pharmacol Ther. 2007;82:48-53.

57 Evidence Based Recommendations for Managing Opioid Adverse Events Opioid rotation and multimodal analgesia may be used for managing opioid-induced adverse effects. B No antiemetic has been shown to be superior to another in this setting, cost can be used to determine the treatment for opioid-induced nausea. C Monotherapy with stool softeners for constipation is not recommended. Transdermal fentanyl (Duragesic) is an option for pain control in patients with constipation from oral opioids. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. C B

58 Thank You! any Questions?