2 nd Cancer Pain Symposium Opiate Related Side Effects: Focus on Constipation

1. 2nd Cancer Pain SymposiumOpiate Related Side Effects: Focus on Constipation Lydia Mis, PharmD, BCOP Clinical Oncology Pharmacist June 6, 2008 Duke University Hospital School of Nursing

2. Objectives • List the common toxicities associated with opioid analgesic use • Understand the mechanisms associated with opioid toxicity • Describe pharmacologic and non-pharmacologic means by which to treat and prevent opioid associated toxicities

3. Opioid Induced Nausea Pathophysiology Implications Tolerance to the nauseating effects may occur Slow titration to a therapeutic dose may decrease likelihood of developing nausea • Circulating blood opiates activate receptors in the chemoreceptor trigger zone located outside of the blood brain barrier • This transmits a signal to the vomiting center, located in the medulla of the brain

4. Opiate Induced Nausea • Prevention • Make antiemetics available with opioid prescription and slowly titrate up on doses • Assessment of alternate causes • Constipation, CNS pathology, chemotherapy, radiation therapy, GI obstruction • Treatment • Consider non-opiates adjuncts as alternatives • Antiemetic therapy

5. Opioid Induced Nausea • Nausea persistent for > 1 week • Reassess cause and severity of nausea • Change opioid (rotation) • Refractory nausea • Persists after above has been tried • Reassess cause and severity of nausea • Consider neuroaxial analgesia or neuroablative techniques to potentially reduce opiate dose NCCN Practice Guidelines in Oncology - v.1.2007 Adult Cancer Pain

6. Opioid Induced Sedation • Preventive measures • Initiate opioids at lowest possible doses tailored for patient opioid history and clinical status • If dose needs to be increased, do so by 25-50% • Counsel pts -  dose →  sedation x 24-72 hrs • Persistent sedation > 1 week after initiation of opioids • Evaluate for other causes of sedation • CNS pathology, other sedating medications, hypercalcemia, dehydration, sepsis, hypoxia

7. Opioid Induced Sedation • Persistent sedation > 1 wk after start • Consider ∆ of opioid or ↓dose to lowest possible • Consider adjuvant analgesics • Consider lower dose more frequently to ↓peaks • Consider CNS stimulants • Caffeine, methylphenidate, dextroamphetamine, modafinil • Refractory sedation • Reassess cause and severity & consider neuroaxial analgesia or neuroablative techniques NCCN Adult Cancer Pain v.1.2007

8. Opioid Induced Delirium • Assess for other causes of delirium • Hypercalcemia, CNS pathology, brain metastasis, other psychoactive medications • Consider change opiate or adjuvant analgesic to decrease dose • Consider neuroleptic agent • Antipsychotics: haloperidol, risperidone, etc NCCN Practice Guidelines in Oncology Adult Cancer Pain v.1.2007

9. Opioid Induced Motor and Cognitive Dysfunction • Stable dose of opioids > 2 weeks are not likely to interfere with psychomotor and cognitive function • Monitor closely during analgesic administration and titration • Patients should not drive during initial titration and should be counseled not to drive x 48 hours after dose increase NCCN Practice Guidelines in Oncology Adult Cancer Pain v.1.2007

10. Opioid Toxicity Syndrome • Use of extremely high doses of opioids (> 100 mg/hr morphine or equivalent) • Hyperalgesia, myoclonic jerks, AMS •  Dose of opioid  pain not analgesia • Associated with dehydration, renal impairment, debilitated patients with advanced disease • Treatment: opioid rotation and NMDA antagonists (methadone or ketamine) NCCN Practice Guidelines Adult Cancer Pain v1.2007 J Clin Oncol 2007;25(28):4497-4498

11. Opioid Induced Respiratory Depression • Use reversal agents sparingly • If respiratory problems or acute MS ∆ • Naloxone Intravenous Administration • 0.4 mg diluted in 10 mls NS • Give 1 ml (0.04mg) Q 30-60 seconds until improvement in symptoms is noted x 10 minutes • Note: half-life of opioid >>> half-life of naloxone • If no response, consider alternative causes of respiratory depression NCCN Adult Cancer Pain v.1.2007

12. Opioid Induced Constipation • WD is a 44 yo female admitted to the inpatient 9300 service with abdominal pain • Metastatic gastric cancer (liver, bone) with delays in chemotherapy d/t increased abdominal pain unresponsive to current pain regimen of OxyContin 40 mg TID and prn oxycodone

13. Opioid Induced Constipation • Other meds on admission included • Protonix, ativan, cipro/augmentin, ritalin, zofran, neurontin • Senna 1 tab BID, colace, lactulose, fleets • Patient states maintaining hydration & urination, no BM x 7 days PTA • CT abdomen ordered • Chemistries notable for Ca2+ 12.3

14. Opioid Induced Constipation

15. Opioid Induced Constipation

16. Opioid Induced Constipation • Patient CT Scan/KUB suggestive of severe hypercalcemia or opioid induced constipation • Aggressively managed with enemas, oral laxatives, stool softeners, osmotic agents, IV hydration and zometa • Discharged home on same opioid dose and aggressive bowel regimen with instructions

17. Opioid Induced Constipation Cause Prevention Hydration/fluids, exercise Stool softener Sorbitol, lactulose, docusate, miralax, SMOG enemas Stimulant laxatives Bisacodyl, senna Saline laxatives MOM, fleets, mag citrate Prokinetic agents Metoclopramide • Dehydration, electrolyte abnormalities • Opioid analgesics – directly acting on opioid receptors in the gut • Ondansetron & other agents causing constipation • Chemotherapy agents known to affect nerve conduction in the gut

18. Opioid Induced Constipation Evaluation Treatment Sorbitol/lactulose 30 ml Q3h x 3 then prn Bisacodyl 10-15 mg PO or 10 mg PR daily Docusate 200 mg BID or Miralax 17 gm po BID Senna-S 2 tab po BID “Fiber + Opiate = Brick” • Patient history • Listen for bowel sounds • R/O obstruction - Scans • Rectal exam – Impaction? • R/O organic causes • Hypercalcemia, treatment related constipation, hydration, hypothyroidism • Peritoneal carcinomatosis • Abdominal adenopathy NCCN v.1.2007, J Pain Symptom Manage 2008;35(1):103-113

19. Opioid Induced Constipation • Methylnaltrexone (naloxone derivative) • New kid on the block for treatment and prevention of opioid induced constipation • Peripherally-acting mu-opioid receptor antagonist for use in patients with advanced illness receiving palliative care • Does not reverse analgesia • Contraindicated if patient has bowel obstruction • Typically dosed 8-12 mg (wt based) SQ every other day (up to Q 24 hours) http://www.wyeth.com/hcp/relistor/landing, accessed 5/08

20. Opioid Induced Constipation • Causes intense laxation within 30 minutes of dose • Close proximity to proper facilities needed • DC for severe or persistent diarrhea or if need for systemic opioids are eliminated