Prof. Arun Aggarwal Pain Management Centre , Royal Prince Alfred Hospital SYDNEY, AUSTRALIA

1. Long and Short-Term Effectiveness of Sub-anaesthetic KETAMINE in Chronic Refractory Non-Malignant Pain Management Prof. Arun Aggarwal Pain Management Centre , Royal Prince Alfred Hospital SYDNEY, AUSTRALIA

2. Professor Aggarwal is on medical advisory boards, received sponsorship or honoraria from the following companies: • BioCSL • Hospira • iNova • Mundipharma • Pfizer • UCB DISCLOSURES

3. Ketamine is a non-competitive antagonist of N-Methyl-D- Aspartate (NMDA) receptor • Acts on: • Kainate • Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid • Gamma-aminobutyric acid (GABA) receptors • Inhibition of voltage gated Na(+) and K (+) channels and • Serotonin, dopamine re-uptake • Antagonizing NMDA receptors • Improves opioid receptors sensitivity • Reduces opioid tolerance • Suppresses opioid-induced hyperalgesia KETAMINE

4. 1963 • First synthesized by a Belgian chemist, C.L. Stevens • 1966 • Patented by Parke Davis • 1970 • Ketamine was approved by the FDA • First used on American soldiers during the Vietnam War • Ketamine has been used in clinical practice for over 35 years for management of chronic pain, however there is limited data available on its clinical effect • In extremely small doses, ketamine can block opioid-induced hyperalgesia and reduce neuropathic pain KETAMINE

5. During normal nerve stimulation, impulses reaches the axon terminal and Na+ and voltage dependent Ca+ gates are opened. The surge of free Ca+ acts as a messenger and the contents are emptied by exocytosis into the synaptic cleft. • The Ca+ is removed and Glutamate, an excitatory amino acid neurotransmitter diffuses across the synaptic cleft and binds to specific post-synaptic protein receptors • When the gates are left open to long, it allows more Ca+ into the cell, triggering the release of more glutamate. The neurons become overstimulated resulting in death, excitotoxicity. NMDA RECEPTOR NMDA-receptor antagonists, such as ketamine, bind to the glutamate receptor site and suppress central sensitization and protects the neurons from excitotoxicity

6. WIND-UP

7. Determine whether ketamine provides long and short-term benefits: • Reduce pain levels • Reduce opioid requirements • Retrospective chart review of 52 patients with chronic pain attending the RPAH Pain Clinic between 2007 and 2011 • The assessment was based on the evaluation of a questionnaire performed over a telephone conversation STUDY

8. DATA COLLECTED • Age • Gender • Diagnosis • Pain location • Duration of chronic pain • Pre and post admission and current pain medications • Hospital stay duration • Ketamine dose and side effects • Opioids withdrawal symptoms • VAS pre and post admission and current • Clonidine dose used to treat opioid withdrawal symptoms • Benzodiazepine dose used to treat Ketamine side effects

9. SAMPLE SIZE & AGE

10. 85% of patients were on at least 1 co-analgesic • 38% of patients were on at least 3 co-analgesics • The top 3 co-analgesics were: • TCA’s • COX-2 inhibitors • Paracetamol • 52 patients who received Ketamine infusions • 45 were using high opioid doses without relief • 7 were receiving high doses of anti-neuropathic medications for neuropathic pain without relief CO-ANALGESIC USAGE

11. 50ml Syringe Ketamine 200mg +/- Lignocaine 2000mg (2x10x10% xylocaine) Day 1 2ml/hr ie 8mg/hr or 192mg/day Day 2 2.5ml/hr Day 3 3ml/hr Day 4 Double Ketamine (400mg) and reduce back to 2ml/hr AV. DAILY KETAMINE DOSE

12. HOSPITAL LENGTH of STAY

14. Frequency VAS SCORES BEFORE / AFTER KETAMINE VAS before Ketamine (mean 6.38) VAS after Ketamine (mean 4.60)

15. VAS Before-After DIFFERENCE IN VAS SCORES (BEFORE / AFTER KETAMINE Patients 1-52

16. Frequency DIFFERENCE IN VAS SCORES (BEFORE / AFTER KETAMINE) 42/56 Improved VAS Difference

17. Significant reduction in mean pain intensity by VAS: • 6.38 before ketamine • 4.60 after ketamine • (p < 0.005) VAS SCORES (BEFORE / AFTER KETAMINE)

18. Frequency EQUIVALENT MORPHINE DOSE (BEFORE / AFTER KETAMINE) Equivalent Morphine (mg)

19. There was significant reduction in opioid dose at the end of ketamine infusion with the mean morphine equivalent dose: • 216 mg/day before ketamine • 89 mg/day after ketamine • (p < 0.005) EQUIVALENT MORPHINE DOSE BEFORE / AFTER KETAMINE

20. KETAMINE SIDE EFFECTS

21. OPIOID WITHDRAWAL SYMPTOMS

22. Prospective study to evaluate long-term efficacy of sub-lingual ketamine lozenges in reducing opioid dose after a 3-7 day ketamine infusion on another 48 patients • Oral or sub-lingual ketamine formulations are not currently commercially available in Australia. They have to be manufactured in hospital or compounding pharmacies • Studies have shown that the bioavailability of sub-lingual formulation is superior, 40% compared to 20% for the oral formulation • Dose 50mg bd increasing if required to 100mg tds FOLLOW-UP STUDY

23. KETAMINE INFUSION VS KETAMINE INFUSION + LOZENGES

24. EFFECT OF KETAMINE INFUSION LOZENGES NO LOZENGES

25. EFFECT OF LOZENGES AFTER DISCHARGE

26. 52yo Registered Nurse • Right TN Dx 1997 • Lacinating pain in 2nd and 3rd division • Responded well to Tegretol and Epilim • Developed drug induced hepatitis • Microvascular Decompression 1998 • Pain free for next 4-5 years (normal facial sensation) • Dec 2003, pain recurred • Commenced on Gabapentin – no response • 2ndmicrovascular decompression Aug 2004 • No evidence of vascular compression, nerve “pinched” • Pain free for 3 months then recurred Mrs CH

27. R facial pain in all divisions of V nerve • Sharp, shooting, knife-like lasting for seconds • Aggravated by touching face, chewing, talking, smiling, blinking, blowing nose, applying make up • Increased sensitivity to touch over face • Canberra hospital in Dec 2004 • 5 day Lignocaine infusion revealed pain but recurred once infusion ceased • Subsequently tried: • Endone, MS Contin, Baclofen, Mexilitine • Stereotactic Radiotherapy in March 2005 • Considered palliative rhizolysis or radiofrequency abalation • Permanent sensory loss and pain relief for 2-3 years only • Gabapentin 600 mg and Lamotrigine 150 mg 6 times a day Mrs CH

28. Initial Consultation 2006 • Admitted to RPAH in February 2006 • Ketamine and Lignocaine infusion • Improved pain within 24 hours • Reduced Gabapentin and Lamotrigine within 3 days • 50% to 3 times a day • Discharged home pain free • Ketamine lozenges 25 mg three times a day Mrs CH

29. March 2006 (4 weeks post) • Remained pain free • Able to touch face, rub cream, blow nose (unable to do for over 2 years) • Ceased Gabapentin and reduced Lamotrigine to 100mg tds • Feels less drowsy and has more energy • 3 months later ceased Lamotrigine • Able to wear make-up and no pain with wind blowing on face • December 2006 – (nearly 12 months post infusion) • Leading a completely normal life, without pain worry • Ketamine 25 mg three times a day only • Ceased Ketamine lozenges Jan 2008 • Remained pain free, off all medications Mrs CH

30. June 2011 • 3 month recurrence of right facial sharp, stabbing pain on touch and wind • Anxiety +++ about pain increasing in severity • Considered Trileptal, but drug induced hepatitis to Tegretol • Duloxetine 30 mg daily • Pain free again • June 2013 • Remains pain free on Duloxetine 30mg daily Mrs CH

31. Oct 2012 • Recurrence of pain, not responding to increasing Duloxetine to 60mg daily and adding Trileptal • 2nd Ketamine and Lignocaine infusion • Pain free after Day 3 • Discharged on Ketamine lozenges 25mg three times a day • After 6 weeks, reduced Ketamine to 25mg daily • Ceased Duloxetine and Trileptal • Able to touch face once again and no sharp stabbing pain • March 2013 • Pain recurred • Ketamine increased slowly to 50mg twice a day • Trileptal recommenced at 150mg twice a day • Pain well controlled – Last review Apr 15 Mrs CH

32. The ketamine infusion was tolerated well with only 1 patient prematurely ceasing the infusion • 46% of patients experienced light-headness or dizziness, but did not need to discontinue the infusion • Overall reduction in opioid use after Ketamine infusion was 30% • When Ketamine lozenges were given after the infusion, 31% were able to completely cease opioids compared to 6% without lozenges • Reduction in pain (VAS) in 42/56 patients with only 5 patients noticing no change in the VAS by the end of the infusion CONCLUSION

33. Provides strong evidence that a 3-7 day intravenous ketamine infusion has the potential to: • Reduce VAS and • Equivalent morphine doses in the short and long-term, even in chronic pain patients who have responded poorly to treatment in the past. • When Ketamine lozenges are given after the infusion, long-term benefits are sustained with reduced opioid use and pain control CONCLUSION

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