1. Special K What Evidence for Infusions is “Bursting” at the Seams? Sukhjinder Sidhu Interior Health Pharmacy Resident October 10, 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 at RIH, 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 MOA of ketamine: – Inhibition of NMDA receptors where it blocks excitatory nerve activity – Agonist activity at opioid mu receptors – Inhibition of glutamate receptors facilitating GABA – Inhibition of synaptic re-uptake of monoamines – Modulates central sensitization and hyperalgesia Onset of action is 15-30 minutes within initiation of SC infusion http://www.yacpalliativecare.co.uk/documents/download25.pdf J Pain Symptom Manage; 2011 Mar;41(3):640-49 All Gwent Palliative Medicine Consultants Group July 2010

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 Contraindications – Absolute Intracranial HTN Seizures Neurological impairment – Relative HTN Cardiac failure Previous CVA J Pain Symptom Manage; 2011 Mar;41(3):640-49 All Gwent Palliative Medicine Consultants Group July 2010

7. 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

8. Clinical Question In an adult palliative patient with uncontrolled pain on optimal doses of opioids, are subcutaneous ketamine infusions as adjuvants to opioids more effective for pain relief and improve quality of life without increasing the risk of adverse events compared to opioids alone?

9. Literature Search DATABASE Google Scholar, PubMed, Embase, Cochrane SEARCH TERMS Ketamine Pain, intractable; pain; palliative Analgesia Cancer; neoplasms NOT pediatric NOT surgery RESULTS 4 RCTs 1 Cochrane Review 3 Reviews 2 Non-RCTs 5 Case Studies 1 Chart Audit 1 Site Specific Guideline/Protocol FOR REVIEW 2 RCTs 1 Case Series

10. Salas et al. DesignProspective, randomized, double-blind, placebo-controlled PopulationInclusion: > 18 y.o with cancer pain refractory to standard opiates NPIS > 4/10 after 24 hrs of continuous IV morphine Histological diagnosis of cancer (locally advanced/metastatic) Hospitalization in a specific palliative care unit Exclusion: CI to use of ketamine WHO performance status > 3 Sleepiness score > 16 on Epworth Slumber Scale Baseline: N 20; age ~ 60; pain 5.8/10; Epworth Slumber Scale 9/11 InterventionKetamine (0.5 mg/kg/day, then 1 mg/kg/day after 24 hrs) + morphine IV vs. saline + morphine IV Primary Outcome Change of pain level between baseline and 2 hours after baseline using NPIS J Palliat Med. 2012 Feb;15(3):287-93

11. Salas et al. Results Δ from baseline at 2 hrs Δ from baseline at 24 hrs Δ from baseline at 48 hrs Patients with ↓ pain Ketamine36.4%30.0%50.0% Placebo22.2%33.3%25.0% Self-reported pain Ketamine--1.95 + 2.82-1.65 + 3.27 Placebo--0.22 + 2.72-0.38 + 2.72 Nausea, Tiredness, Depression, Anxiety, Drowsiness, Lack of appetite, Well-being, SOB, Sleepiness -NSS Side effects--NSS J Palliat Med. 2012 Feb; 15(3):287-93

12. Salas et al. Limitations Sample size small – Moderate efficacy may have been missed due to low statistical power Short study period of 48 hours Ketamine doses were lower than standard used at RIH – 23 – 43 mg vs. 100 – 500 mg – Too low to detect a difference? Daily morphine doses could be increased daily by 50% if necessary No assessment of other comorbidities J Palliat Med. 2012 Feb; 15(3):287-93

13. 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

14. 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

15. 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

16. Summary Salas et al.Hardy et al. Pain reliefNSS Worst pain score - SS Increase quality of lifeNSS? Adverse eventsNSSSS

17. 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

18. 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

19. 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

20. Conclusion Inconclusive evidence as to the effects of ketamine on pain and quality of life – Higher quality studies are required – Palliative, especially end-of-life, difficult to conduct studies No studies stratified using PPS – Unknown if certain functional capacity will benefit It would be appropriate to trial burst ketamine infusion in palliative patients with severe pain refractory to opioids as a last ditch effort – Case by case – not all refractory patients will find benefit – Ensure all pain and adjuvant therapies have been optimized – Important to reiterate to patient the current evidence – Ensure healthcare team objectively evaluates outcomes Important to not provide false hope

21. Practical Question When initiating ketamine infusion opioids should be decreased by 25-50% for safety as ketamine decreases opioid tolerance… But practically, can you accomplish this in patients with uncontrolled severe pain?

22. 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 Drug interactions as CYP3A4 substrate

23. 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.