Transcript Ketamine - 2 nd International Conference and Exhibition on Pain

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:
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BioCSL
Hospira
iNova
Mundipharma
Pfizer
UCB
KETAMINE
• Ketamine is a non-competitive antagonist of N-Methyl-DAspartate (NMDA) receptor
• Acts on:
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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
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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
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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
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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