1. Emmeline Tran, PharmD, BCPS Medical University of South Carolina PGY2 Internal Medicine Resident

2.  Develop a therapeutic plan for the treatment of refractory pain using intravenous lidocaine or ketamine

3. BiologicalSocial Psychological  Pain  Complex  Subjective Institute of Medicine. 2011.

4.  34 year old male  Past medical history ▪ Sickle cell disease ▪ Chronic pain  Pain medications ▪ ibuprofen 800 mg PO TID ▪ gabapentin 800 mg PO TID ▪ hydromorphone PCA ▪ Total daily dose = 300 mg

5. Step 3:strong opioids ± non-opioidsStep 2: mild opioids ± non-opioids Step 1: non- opioids Can Fam Physician. 2010 Jun;56(6):514-7, e202-5.

6. Step 4:?Step 3: strong opioids ± non- opioids Step 2: mild opioids ± non-opioids Step 1: non- opioids Can Fam Physician. 2010 Jun;56(6):514-7, e202-5.

7.  Adjunctive agent  High degree of opioid tolerance  Neuropathic pain Pain Physician. 2013 May-Jun;16(3):231-49.

8.  Mechanism of Action primary afferent neuron dorsal root thalamus cortex transmission modulation perception Pain Physician. 2013 May-Jun;16(3):231-49.

9.  Mechanism of Action primary afferent neuron dorsal root thalamus cortex transmission modulation perception Pain Physician. 2013 May-Jun;16(3):231-49.

10.  Mechanism of Action  Non-selective sodium channel blocker sodium channel potassium channel intracellular fluid extracellular fluid sodium potassium Pain Physician. 2013 May-Jun;16(3):231-49.

11. extracellular fluid intracellular fluid  Mechanism of Action  Non-selective sodium channel blocker sodium potassium sodium channel potassium channel Pain Physician. 2013 May-Jun;16(3):231-49.

12. Lidocaine IV Dosing Challenge: 100 mg over 30 minutes Infusion: 0.5 to 2 mg/kg/hour Increase by up to 20% per hour (max 2 mg/kg/hour) Onset of action 10 to 30 minutes Half-life Initial: 7 to 30 minutes Terminal: 1.5 to 2 hours Metabolism CYP1A2, CYP3A4 Excretion Primarily in the urine LexiComp. Accessed February 29, 2016. Micromedex. Accessed February 29, 2016. Pain Physician. 2013 May-Jun;16(3):231-49.

13. Side Effects Neurological Tremor Insomnia Cardiovascular Arrhythmias Hemodynamic instability Gastrointestinal Metallic taste Tremor Other Hypersensitivity reactions/anaphylaxis LexiComp. Accessed February 29, 2016. Micromedex. Accessed February 29, 2016. Pain Physician. 2013 May-Jun;16(3):231-49.

14.  Clinical Pearls  No formal renal or hepatic dose adjustments, use caution  Telemetry is not necessary for patients with no previous cardiac conditions ▪ Cardiac arrhythmias and hemodynamic instability are possible, but not found in trials when used in pain management LexiComp. Accessed February 29, 2016. Micromedex. Accessed February 29, 2016. J Palliat Med. 2015 Apr;18(4):373-7.

15.  Adjunctive agent  High degree of opioid tolerance  Opioid-induced hyperalgesia  Neuropathic pain Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83. Pain Physician. 2007 May;10(3):493-500. Biomed Pharmacother. 2006 Aug;60(7):341-8.

16.  Mechanism of Action primary afferent neuron dorsal root thalamus cortex transmission modulation perception Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83.

17.  Mechanism of Action primary afferent neuron dorsal root thalamus cortex transmission modulation perception Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83.

18. intracellular fluid  Mechanism of Action  N-methyl-D-aspartate (NMDA) antagonist NDMA receptor NMDA receptor extracellular fluid calcium Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83.

19. intracellular fluid  Mechanism of Action  N-methyl-D-aspartate (NMDA) antagonist NDMA receptor NMDA receptor extracellular fluid calcium Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83.

20. POIV Dosing 10 to 15 mg PO every 6 hours Dose escalations: 10 mg daily or 25% every 6 hours Do not increase more often than every 24 hours Bolus: 5 to 10 mg IV Repeat x 1, 15 minutes after if needed Continuous infusion: 2 to 3 mcg/kg/min Increase by 1 mcg/kg/min (max of 6 mcg/kg/min) Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83. Pain Physician. 2007 May;10(3):493-500. Biomed Pharmacother. 2006 Aug;60(7):341-8.

21.  Clinical Pearls  IV: PO conversion = 1:1 ▪ IV product is used orally  No consensus on a uniform ketamine protocol or dose  Reduce the long acting opioid dose by ~25 to 50% Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83. Pain Physician. 2007 May;10(3):493-500. Biomed Pharmacother. 2006 Aug;60(7):341-8.

22.  Clinical Pearls  No formal renal or hepatic dose adjustments, use caution  Elderly patients may warrant dose reductions Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83. Pain Physician. 2007 May;10(3):493-500. Biomed Pharmacother. 2006 Aug;60(7):341-8.

23. POIV Onset of action 15 to 20 minutes Half-life 2.5 to 3 hours2 to 3 hours Metabolism CYP2B6, CYP2C9, CYP3A4 Excretion Primarily in the urine Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83. Pain Physician. 2007 May;10(3):493-500. Biomed Pharmacother. 2006 Aug;60(7):341-8. LexiComp. Accessed February 29, 2016. Micromedex. Accessed February 29, 2016.

24.  Clinical Pearls  Not well-studied for breakthrough pain ▪ Give one-tenth to one-sixth of oral dose or 5 to 10 mg IV for breakthrough pain  Discontinuation can be done safely without concerns for withdrawal Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83. Pain Physician. 2007 May;10(3):493-500. Biomed Pharmacother. 2006 Aug;60(7):341-8.

25. Side Effects Neurological Hallucinations Delirium Drowsiness Alterations in body image and mood Floating sensations Vivid dreams Respiratory Respiratory depression (rare) Cardiovascular Hypertension Tachyarrhythmias Gastrointestinal Nausea, vomiting Anorexia Hypersalivation Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83. Pain Physician. 2007 May;10(3):493-500. Biomed Pharmacother. 2006 Aug;60(7):341-8.

26.  Clinical Pearls  Most common side effects are psychomimetic ▪ Test dose of 5 mg IV or 20 mg PO ▪ Use benzodiazepine or butyrophenone to help prevent or manage  Cardiovascular side effects and respiratory depression are rare Pain Physician. 2013 May-Jun;16(3):231-49. J Palliat Med. 2012 Apr;15(4):474-83. Pain Physician. 2007 May;10(3):493-500. Biomed Pharmacother. 2006 Aug;60(7):341-8.

27.  34 year old male  Past medical history ▪ Sickle cell disease ▪ Chronic pain  Pain medications ▪ ibuprofen 800 mg PO TID ▪ gabapentin 800 mg PO TID ▪ hydromorphone PCA ▪ Total daily dose = 300 mg Which of the following would you try next? a. Lidocaine IV b. Ketamine PO c. Ketamine IV d. None of the above

28.  34 year old male  Past medical history ▪ Sickle cell disease ▪ Chronic pain  Pain medications ▪ ibuprofen 800 mg PO TID ▪ gabapentin 800 mg PO TID ▪ hydromorphone PCA ▪ Total daily dose = 300 mg Which of the following would you try next? a. Lidocaine IV b. Ketamine PO c. Ketamine IV d. None of the above

29.  Pain is difficult to treat  Utilize medications with unique mechanisms of action in the treatment of refractory pain

30.  Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington (DC): National Academies Press (US); 2011.  Kosharskyy B, Almonte W, Shaparin N, Pappagallo M, Smith H. Intravenous infusions in chronic pain management. Pain Physician. 2013 May-Jun;16(3):231-49.  Okon T. Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician. 2007 May;10(3):493-500.  Prommer EE. Ketamine for pain: an update of uses in palliative care. J Palliat Med. 2012 Apr;15(4):474-83.

31.  Caused by exposure to opioids  State of nociceptive sensitization  Characterized by a paradoxical response  Receiving opioids causes increased sensitivity to certain painful stimuli Pain Physician. 2011 Mar-Apr;14(2):145-61.

32.  Mechanism of action  Abnormal activation of NMDA receptors Pain Physician. 2011 Mar-Apr;14(2):145-61. intracellular fluid NDMA receptor NMDA receptor extracellular fluid calcium