1. 2 nd Cancer Pain Symposium Opiate 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  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 Implications  Tolerance to the nauseating effects may occur  Slow titration to a therapeutic dose may decrease likelihood of developing nausea

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 Ca 2+ 12.3

14. Opioid Induced Constipation

16.  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  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 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

18. Opioid Induced Constipation Evaluation  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 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” 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