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

2. Session Objectives Become familiar with: – The MOA of ketamine as an analgesic – The common dosing regimens for subcutaneous ketamine infusions – The most common adverse effects Be able to explain the evidence behind SC ketamine infusions in palliative care Be able to describe monitoring parameters for a patient receiving SC ketamine infusion for pain control

3. 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

4. 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

5. 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

6. Background Adverse effects of ketamine: – Increased muscle tone – Tachycardia – Hypertension – Diplopia – Nystagmus – Neuropsychiatric Dysphoria Hallucinations Nightmares – Sedation – Confusion – Disorientation – Delirium – Dizziness 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

7. Hardy et al. DesignMulti-site, dose-escalation, double-blind, randomized, placebo- controlled phase III trial PopulationInclusion: > 18 y.o. palliative patients Refractory chronic pain secondary to cancer BPI > 3 Exclusion: Received ketamine within 6 months for pain Radiotherapy to pain site within 2 weeks Any other procedures/therapies likely to affect pain Baseline: N 185; age ~63; ~56% male; 300/410 mg morphine equivalent; average BPI score 5.3; median performance status 60% InterventionKetamine SC with dose titration over 5 days (100, 300, 500 mg) + opioids vs. placebo + opioids Primary Outcome Improvement in pain at end of 5-day study period J Clin Oncol. 2012 Sep 10;30(29):3611-7

8. Hardy et al. Results KetaminePlaceboOutcome Improvement in pain (5 days) 27%31%NSS Worst pain score5.306.01SS Average pain score3.113.49NSS Least pain score--NSS Breakthrough dosing 2 (1-4) 3 (1-4) NSS Adverse events172103SS - 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

9. 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

10. Jackson et al. DesignProspective, multicenter, un-blinded, open-label audit PopulationInclusion: Refractory cancer-associated pain on opioids and other co- analgesics > moderate pain (> 3/10) Exclusion: Inability to assess response due to significant confusion, dementia Anticipated prognosis < 2 weeks Raised intra-cranial pressure, severe cardiac disease, poorly controlled HTN, hx of hemorrhagic stroke Baseline: N 39; median age ~56; mean parenteral morphine 231 mg daily; InterventionContinuous SC ketamine infusion (100, 300, 500 mg) x 3 – 5 days and regular therapy Primary Outcome Pain relief J Pain Symptom Manage. 2001;22(4):834-42

11. 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

12. Jackson et al. Limitations Study design lower on hierarchy (#3) – Potential for confounders and bias No comparator group to conclude if results are statistically significant J Pain Symptom Manage. 2001;22(4):834-42

13. 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

14. 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

15. 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.

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

17. 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

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

19. CNS Chemoreceptor Increased ICP Haloperidolsedation, extrapyramidal symptoms (EPS) Prochlorperazinesedation, anticholinergic effects, EPS, hypotension with IM/IV Methotrimeprazinesedation, EPS Metoclopramidediarrhea, abdominal cramps, headache, hyperprolactinemia, drowsiness, fatigue, EPS Dexamethasonemood changes, increased appetite, GI irritation, fluid retention, weight gain LorazepamSedation, dizziness

20. Gastrointestinal Gastric irritation/GERD Gastric stasis Obstruction Metoclopramidediarrhea, abdominal cramps, headache, hyperprolactinemia, drowsiness, fatigue, EPS Domperidonediarrhea, abdominal cramps, headache, hyperprolactinemia, drowsiness, fatigue PPIdiarrhea, flatulence, abdominal pain Ranitidinerash, diarrhea, constipation Dexamethasonemood changes, increased appetite, GI irritation, fluid retention, weight gain

21. Psychological LorazepamSedation, dizziness, cognitive impairment Vestibular Dimenhydrinatesedation, anticholinergic effects, confusion Scopolamineconfusion, dry mouth, constipation

22. 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

23. 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

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

25. Questions?