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

Sukhjinder SidhuInterior Health Pharmacy Resident

October 16, 2013

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.pdfJ Pain Symptom Manage; 2011 Mar;41(3):640-49

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

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

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.pdfJ Pain Symptom Manage; 2011 Mar;41(3):640-49

Niesters M et al. Br J Clin Pharmacol. 2013 Feb; n/a-n/a

Hardy et al.Design Multi-site, dose-escalation, double-blind, randomized, placebo-

controlled phase III trialPopulation Inclusion:

• > 18 y.o. palliative patients• Refractory chronic pain secondary to cancer• BPI > 3Exclusion:• Received ketamine within 6 months for pain • Radiotherapy to pain site within 2 weeks• Any other procedures/therapies likely to affect painBaseline:N 185; age ~63; ~56% male; 300/410 mg morphine equivalent; average BPI score 5.3; median performance status 60%

Intervention Ketamine 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

Hardy et al. ResultsKetamine Placebo Outcome

Improvement in pain (5 days)

27% 31% NSS

Worst pain score 5.30 6.01 SS

Average pain score 3.11 3.49 NSS

Least pain score - - NSS

Breakthrough dosing

2 (1-4)

3(1-4)

NSS

Adverse events 172 103 SS

- 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

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

Jackson et al.Design Prospective, multicenter, un-blinded, open-label audit

Population Inclusion:• 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 strokeBaseline:N 39; median age ~56; mean parenteral morphine 231 mg daily;

Intervention Continuous 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

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

ConclusionDay 1• 100 mg/50 mL NS SC infusion, run over 24 hours at 2 mL/hourDay 2• If ineffective: increase to 300 mg/50 mL NS SC infusion, run

over 24 hours at 2 mL/hourDay 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

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

ReferencesHardy 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.

A Case of Nausea

Sukhjinder SidhuInterior Health Pharmacy Resident

October 16, 2013

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

Identify Causes

http://www.medicalook.com/diseases_images/nausea.jpg

Medications – opioids, chemoBiochemical – uremia, hypercalcemiaToxins – sepsis, tumor factorsIncreased intracranial pressure

Gastric irritation/GERDGastric stasisConstipationObstructionAbdominal cramps

Movement

Sights, smells, memories

CNS• Chemoreceptor•

• Increased ICP

Haloperidol sedation, extrapyramidal symptoms (EPS)Prochlorperazine sedation, anticholinergic effects, EPS,

hypotension with IM/IVMethotrimeprazine sedation, EPSMetoclopramide diarrhea, abdominal cramps, headache,

hyperprolactinemia, drowsiness, fatigue, EPS

Dexamethasone mood changes, increased appetite, GI irritation, fluid retention, weight gain

Lorazepam Sedation, dizziness

Gastrointestinal• Gastric irritation/GERD

•

• Gastric stasis

• Obstruction

Metoclopramide diarrhea, abdominal cramps, headache, hyperprolactinemia, drowsiness, fatigue, EPS

Domperidone diarrhea, abdominal cramps, headache, hyperprolactinemia, drowsiness, fatigue

PPI diarrhea, flatulence, abdominal painRanitidine rash, diarrhea, constipation

Dexamethasone mood changes, increased appetite, GI irritation, fluid retention, weight gain

PsychologicalLorazepam Sedation, dizziness, cognitive impairment

VestibularDimenhydrinate sedation, anticholinergic effects, confusionScopolamine confusion, dry mouth, constipation

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

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

Avoid Combinations

• Dimenhydrinate and scopolamine patch as same mechanism of action

• Metoclopramide plus– Haloperidol– Methotrimeprazine– Prochlorperazine

Increased risk of EPS

Questions?