Special K What Evidence for Infusions is “Bursting” at the Seams?

1. Special KWhat Evidence for Infusions is “Bursting” at the Seams? Sukhjinder Sidhu Interior Health Pharmacy Resident October 16, 2013

2. Background • Rationale for ketamine use: • At subanesthetic doses, a synergistic effect between ketamine and opioids has been observed in patients who are already receiving high doses of opioids • Currently it is used in palliative cancer pain that has failed to respond fully to opioids http://www.yacpalliativecare.co.uk/documents/download25.pdf J Pain Symptom Manage; 2011 Mar;41(3):640-49

3. Background • How it works: • Inhibits NMDA receptor, like methadone producing an analgesic effect • Acts on opioid receptors, like morphine resulting in opioid-sparing effects • Onset of action is 15-30 minutes within initiation of SC infusion

4. Background • Subcutaneous dosing regimens: • 1 – 2.5 mg/kg/24 hr, then increase by 50 – 100 mg/24 hr (max 3.6 g/24 hr) • Burst: J Pain Symptom Manage; 2011 Mar;41(3):640-49

5. Background • Adverse effects of ketamine: • Neuropsychiatric • Dysphoria • Hallucinations • Nightmares • Sedation • Confusion • Disorientation • Delirium • Dizziness • Increased muscle tone • Tachycardia • Hypertension • Diplopia • Nystagmus http://www.yacpalliativecare.co.uk/documents/download25.pdf J Pain Symptom Manage; 2011 Mar;41(3):640-49 Niesters M et al. Br J Clin Pharmacol. 2013 Feb; n/a-n/a

6. Hardy et al. J Clin Oncol. 2012 Sep 10;30(29):3611-7

7. Hardy et al. Results • - Most common adverse events = lightheadedness, hypoxia, and somnolence • - Serious adverse event included bradyarrhythmia and cardiac arrest • - Pyschotoxicity risk increased each day with ketamine use, becoming significant after day 3 (OR 2.53; 95% CI 1.11 to 5.78; p = 0.027). J Clin Oncol. 2012 Sep 10;30(29):3611-7

8. Hardy et al. Limitations • Short study period • No data on long-term benefits/risks of ketamine use • Did not assess control of other comorbidities • Small population studied J Clin Oncol. 2012 Sep 10;30(29):3611-7

9. Jackson et al. J Pain Symptom Manage. 2001;22(4):834-42

10. Jackson et al. Results • Overall response 67% • 15/17 somatic • 14/23 neuropathic • After cessation of ketamine, of those that responded, 24/29 maintained good pain control (8 weeks) • 12 reported adverse psychomimetic effects; risk increasing with dose • 6 “spaced out” feeling • 3 hallucinations • 2 drowsiness • 1 dizziness J Pain Symptom Manage. 2001;22(4):834-42

11. Conclusion Day 1 • 100 mg/50 mL NS SC infusion, run over 24 hours at 2 mL/hour Day 2 • If ineffective: increase to 300 mg/50 mL NS SC infusion, run over 24 hours at 2 mL/hour Day 3 • If ineffective: increase to 500 mg in 50 or 100 mL NS SC infusion, run over 24 hours • Contact pharmacy to determine rate and concentration Day 4 & 5 • Maintain 500 mg SC infusion, then discontinue

12. Monitoring Plan • Pain, BP, HR, RR • Day 1: baseline; 30 min, 1 hour, 4 hour • If relative CI or on long-acting opioids: Q4H until dose titration complete • All others: daily • Dysphoria, hallucinations, delirium • Baseline and on-going while on therapy • If ketamine works, be prepared to titrate down other opioids

13. References Hardy J, Quinn S, Fazekas B, Plummer J, Eckermann S, Agar M, et al. Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Toxicity of Subcutaneous Ketamine in the Management of Cancer Pain. J Clin Oncol. 2012 Sep 10;30(29):3611–7. Jackson K, Ashby M, Martin P, Pisasale M, Brumley D, Hayes B. “Burst” Ketamine for Refractory Cancer Pain: An Open-Label Audit of 39 Patients. J Pain Symptom Manage. 2001;22(4):834–42. Ketamine use in chronic pain. Available from: www.yacpalliativecare.co.uk/documents/downloads25.pdf Niesters M, Martini C, Dahan A. Ketamine for Chronic Pain: Risks and Benefits: Ketamine risks and benefits. Br J Clin Pharmacol. 2013 Feb;n/a–n/a. Pain management – ketamine infusions for adult patients with acute and chronic non malignant pain. Available from: www.seslhd.health.nsw.gov.au Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A. Ketamine*. J Pain Symptom Manage. 2011 Mar;41(3):640–9. Salas S, Frasca M, Planchet-Barraud B, Burucoa B, Pascal M, Lapiana J-M, et al. Ketamine Analgesic Effect by Continuous Intravenous Infusion in Refractory Cancer Pain: Considerations about the Clinical Research in Palliative Care. J Palliat Med. 2012 Feb;15(3):287-93.

14. A Case of Nausea Sukhjinder Sidhu Interior Health Pharmacy Resident October 16, 2013

15. Meet AK • Nausea & vomiting worsening over past 1 to 2 weeks • Previous treatments: • haloperidol • dimenhydrinate 50 mg • metoclopramide • ondansetron • Medications have yet to provide much benefit

16. Identify Causes Medications – opioids, chemo Biochemical – uremia, hypercalcemia Toxins – sepsis, tumor factors Increased intracranial pressure Sights, smells, memories Gastric irritation/GERD Gastric stasis Constipation Obstruction Abdominal cramps Movement http://www.medicalook.com/diseases_images/nausea.jpg

17. CNS • Chemoreceptor • Increased ICP

18. Gastrointestinal • Gastric irritation/GERD • Gastric stasis • Obstruction

19. Psychological Vestibular

20. Still Not Effective? • Increase the dose of current medication • Add on new medication • Switch to infusion • Olanzapine • most evidence for chemotherapy induced N&V • Octreotide • increases gut motility and decreases gut secretion • useful for obstructions

21. Back to AK • Continue with scopolamine patch Q3 days • Added on dexamethasone 8 mg SC QAM • If some improvements, may increase dexamethasone to 8 mg SC BID or 16 mg PO daily • If ineffective at day 2, addition of haloperidol 0.5 – 1 mg SC Q8H to start

22. Avoid Combinations • Dimenhydrinate and scopolamine patch as same mechanism of action • Metoclopramide plus • Haloperidol • Methotrimeprazine • Prochlorperazine Increased risk of EPS

23. Questions?