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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 DISCLOSURES Professor Aggarwal is on medical advisory boards, received sponsorship or honoraria from the following companies: • • • • • • BioCSL Hospira iNova Mundipharma Pfizer UCB KETAMINE • Ketamine is a non-competitive antagonist of N-Methyl-DAspartate (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 • 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 NMDA RECEPTOR • 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 antagonists, such as ketamine, bind to the glutamate receptor site and suppress central sensitization and protects the neurons from excitotoxicity WIND-UP STUDY • Determine whether ketamine provides long and shortterm 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 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 SAMPLE SIZE & AGE Gender Size Percentage Male 32 62% Female 20 38% TOTAL SAMPLE 52 100% Average Age Age Range Male 48 Years 9 months 23-87 Years Female 49 Years 9 months 24-78 Years TOTAL SAMPLE 49 Years 2 months Gender CO-ANALGESIC USAGE • 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 • 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 AV. DAILY KETAMINE DOSE Description Average daily ketamine infusion dose (mg) Lowest 201 Highest 526 Sample Average 228 50ml Syringe Ketamine 200mg +/- Lignocaine 2000mg (2x10x10% xylocaine) Day 1 Day 2 Day 3 Day 4 2ml/hr ie 8mg/hr or 192mg/day 2.5ml/hr 3ml/hr Double Ketamine (400mg) and reduce back to 2ml/hr HOSPITAL LENGTH of STAY Gender Average stay (days) Range (days) Male 6.1 3–8 Female 6.7 3 – 10 TOTAL SAMPLE 6.3 3 - 10 Post herpetic neuralgia 3% Other Chronic Neuropathic Pain Syndrome 3% Fibromyalgia 2% Other Other, including Metabolic Bone 9% Disease, Phantom pain, Retinopathy, Pancreatitis, Visceral, MS, Mastocytosis, TMJD & Vulvodynia (each 1%) Peripheral neuropathy secondary to diabetes 4% Radiculopathy 4% Idiopathic 5% Chronic Lumbar Spinal Pain 41% Trigiminal Neuralgia 8% Migraine 8% CRPS 13% PAIN LOCATION VAS SCORES BEFORE / AFTER KETAMINE 15 12 Frequency 11 10 10 9 9 7 7 6 5 5 5 5 4 3 3 5 5 3 2 0 2 2 9 10 0 1 2 3 4 5 6 7 8 9 10 VAS before Ketamine (mean 6.38) 1 2 3 4 5 6 7 8 VAS after Ketamine (mean 4.60) DIFFERENCE IN VAS SCORES (BEFORE / AFTER KETAMINE 12 Before After VAS Before-After 10 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Patients 1-52 DIFFERENCE IN VAS SCORES (BEFORE / AFTER KETAMINE) 42/56 Improved 18 16 16 Frequency 14 12 11 10 8 8 7 6 4 2 1 0 -4 3 2 0 0 -3 -2 -1 1 0 1 2 VAS Difference 3 4 5 2 6 1 7 VAS SCORES (BEFORE / AFTER KETAMINE) • Significant reduction in mean pain intensity by VAS: • 6.38 before ketamine • 4.60 after ketamine • (p < 0.005) EQUIVALENT MORPHINE DOSE (BEFORE / AFTER KETAMINE) 50 40 40 Frequency 47 32 30 30 20 20 11 10 10 5 2 1 0 200 400 600 800 1000 1200 1400 3 0 1600 2 0 200 400 Equivalent Morphine (mg) 600 800 1000 1200 1400 1600 EQUIVALENT MORPHINE DOSE BEFORE / AFTER KETAMINE • 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) KETAMINE SIDE EFFECTS 100% 90% 80% 70% 60% 50% 46% 40% 25% 30% 20% 10% 0% 12% 12% 2% 2% 8% OPIOID WITHDRAWAL SYMPTOMS Yawning Nausea / vomiting Diarrhoea Chills Insomnia Anxiety Restlessness Muscle aches Ataxia Dysarthria Suicidal thoughts Abdominal Cramps Dialated Pupils Agitation Tachycardia 2% 15% 6% 6% 6% 10% 15% 8% 2% 0% 2% 6% 6% 10% 2% 0% 20% 40% 60% 80% 100% FOLLOW-UP STUDY • Prospective study to evaluate long-term efficacy of sublingual 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 KETAMINE INFUSION VS KETAMINE INFUSION + LOZENGES Ketamine infusion & Lozenges after discharge 16% Ketamine Infusion only 84% EFFECT OF KETAMINE INFUSION No change in opioid or analgesic use 61% Complete cessation of opioids 6% Increase in opioid use 11% Reduction in opioid use 22% NO LOZENGES No change in opioid or analgesic use 61% Complete cessation of opioids 31% Increase in opioid use 0% Reduction in opioid use 8% LOZENGES EFFECT OF LOZENGES AFTER DISCHARGE 70% 61% 61% Patients treated with Ketamine Lozenges after discharge 60% Pateints treated with KI only 50% 40% 30% 31% 22% 20% 10% 0% 6% 11% 8% 0% Complete cessation No change in Reduction in opioid Increase in opioid of opioids opioid or analgesic use use use Mrs CH 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 2nd microvascular decompression Aug 2004 No evidence of vascular compression, nerve “pinched” Pain free for 3 months then recurred Mrs CH 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 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 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 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 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 CONCLUSION • 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 • 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 REFERENCES • Chong C, Schug S, Page-Sharp M, Jenkins B, Ilett K. Development of a Sublingual Formulation of Ketamine for Use in Neuropathic Pain. Preliminary Findings from a Three-Way Randomized Crossover Study. Clin Drug Invest 2009; 29(5):317-324 • Hocking G, Cousins M. Ketamine in Chronic Pain Management: An Evidence-Based Review. Anesth Analg 2003; 97:1730-9 • Akers J. The renaissance of ketamine. Australas Anaesth 2000; 25–35 • Backonja M, Arndt G, Gombar KA, Check B, Zimmermann M. Response of chronic neuropathic pain syndromes to ketamine: A preliminary study. Pain 1994;56:51–7 • Hocking G, Cousins M. Ketamine in Chronic Pain Management: An Evidence-Based Review. Anesth Analg 2003; 97:1730-9