Low Dose Peri-operative IV Ketamine for Chronic Post-surgery Pain Prevention

• Sponsor: Imperial College Healthcare NHS Trust (Other)
• Overall Status: Completed
• CT.gov ID: NCT01296347
• Collaborator: National Institute for Health Research, United Kingdom (Other)
• Enrollment: 77
• Location: 1
• Arms: 2
• Duration (Months): 51
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

This study will test the null hypothesis that low-dose ketamine given peri-operatively will have no effect on the development of chronic post-surgical pain, in patients undergoing thoracotomy or video assisted thoracic surgery (VATS) procedures

A double-blind, randomised placebo-controlled trial will be used to test the null hypothesis. Potential participants due to undergo either thoracotomy or video assisted thoracic surgery (VATS) will be identified by the collaborating thoracic surgeons in the out-patient department. Patients will be sent information about the study by post, prior to admission for surgery. If they are willing to participate, written consent will be sought on the ward preoperatively, where they will complete baseline measures of pain.

Patients will be randomised to receive an intravenous infusion of placebo (saline) or ketamine running at 0.1mg/kg/hour, starting 10 minutes prior to the surgical incision and continuing for the first three postoperative days (96 hours in total). Prior to starting the infusion a loading dose of ketamine (0.1 mg per kg) will be administered.

Condition or Disease	Intervention/Treatment	Phase
Chronic Postoperative Pain	Drug: Ketamine	Phase 4

Detailed Description

This study will test the null hypothesis that low-dose ketamine given peri-operatively will have no effect on the development of chronic post-surgical pain, in patients undergoing thoracotomy or video assisted thoracic surgery (VATS) procedures

A double-blind, randomised placebo-controlled trial will be used to test the null hypothesis. Potential participants due to undergo either thoracotomy or video assisted thoracic surgery (VATS) will be identified by the collaborating thoracic surgeons in the out-patient department. Patients will be sent information about the study by post, prior to admission for surgery. If they are willing to participate, written consent will be sought on the ward preoperatively, where they will complete baseline measures of pain.

Patients will be randomised to receive an intravenous infusion of placebo (saline) or ketamine running at 0.1mg/kg/hour, starting 10 minutes prior to the surgical incision and continuing for the first three postoperative days (96 hours in total). Prior to starting the infusion a loading dose of ketamine (0.1 mg per kg) will be administered. All staff, including the anaesthetist, surgical team, ward nurses and the principal investigator will be blind to the treatment given throughout the study. The key to the randomisation will be revealed at the end of the study.

Patients will be asked to complete a numeric pain score (NPS) and standard pain questionnaires which includes the Brief Pain Inventory [BPI], short form Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS]) prior to surgery, then at 6 weeks, 3, 6 and 12 months after surgery. The surgical area will also be examined at 6 weeks, 6 and 12 months for signs of neuropathic or nerve pain. Whilst in hospital patients will be asked to score their pain daily, on a numeric pain scale of 0 to 10. Consumption of morphine and side-effects will be recorded.

Patients will receive standard post-operative analgesia.

A sample size calculation based on a previous study, to detect a reduction in pain of 2 points the 10 point numeric pain scale at the 6 week assessment, with α = 5%, 1 - β = 90% and a bilateral hypothesis, would require a sample size of 36 per group, 72 patients in total. This will require a total study population of 144 patients, as both video assisted thoracic surgery (VATS) and thoracotomy patients will be studied.

A two samples t-test will be used to compare the numeric pain scores between the ketamine and placebo groups at each time point. If these data are not normally distributed then the Mann Whitney test will be used. The scores from the Brief Pain Inventory (BPI) and short form Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) will be analysed in the same manner. The Chi Squared test will be used to compare dichotomous data, such as the incidence of side-effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 77 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: A Double-blind, Randomised Placebo-controlled Trial to Determine Whether Low-dose Intravenous Ketamine Peri-operatively Can Prevent Chronic Post-surgical Pain, in Patients Undergoing Thoracotomy or Video Assisted Thoracic Surgery (VATS)
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Saline Patients will receive a placebo infusion of 0.9% sodium chloride, which will start 10 minutes prior to the start of the operation and continue for 96 hours.
Experimental: ketamine Patients will receive intravenous ketamine, starting 10 minutes prior to surgery and will continue for 96 hours	Drug: Ketamine; Intravenous infusion of ketamine starting 10 minutes prior to surgery and running for 96 hours, which will be administered at a rate of 0.1mg/kg/hour. A loading dose of 0.1mg/kg will be administered prior to the start of the infusion; Other Names: Ketalar

Outcome Measures

Primary Outcome Measures

1. Pain Score on Moving at 6 Weeks [6 weeks after surgery]

   Measures in pain include: Numeric pain score of 0 to 10. Zero denotes 'no pain'; 10 denotes 'pain as bad as you can imagine'

Secondary Outcome Measures

1. Analgesic Consumption (Opioid) [6 weeks, 3 month, 6 month]

   Analgesia consumption will be measured post-operatively and at 6 weeks

2. Sensory Testing [6 weeks, 6 months, 12 months]

   Hypoaesthesia: light touch of the blunt end of a paintbrush was felt less precisely, than in healthy tissue. Hyperalgesia: the pain induced by a sterile neurotip, applied perpendicular to the skin is felt abnormally strongly, in comparison to the contralateral side. Static allodynia: the application of a Von Frey hair number 14. (8g) was unpleasant, in comparison to the contralateral side. Dynamic allodynia: three successive gentle strokes of an 8 mm-wide paintbrush over a 40 mm distance, is unpleasant, in comparison to the contralateral side.

3. Incidence of Side-effects, Nausea [108 hours]

   The presence of nausea recorded at the above time points

4. Incidence of Side Effect, Vomiting [108 hours]

   The presence of vomiting recorded at the above time points

5. Incidence of Side Effect, Lightheaded [108 hours]

   The presence of lightheaded recorded at the above time points

6. Incidence of Side Effect, Vivid Dreams [108 hours]

   The presence of vivid dreams recorded at the above time points

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• All adult patients (18 years and above) who are undergoing either thoracotomy or video assisted thoracic surgery (VATS).

• Participants must be able to understand English.

Exclusion Criteria:

• Patient refusal

• History of previous chronic thoracic pain

• Neuropathic pain (whatever the site), existing at time of recruitment

• Pre-operative analgesic treatments which include the following medications: strong opioids (step 3 analgesics), tricyclic antidepressants, venlafaxine, gabapentin, pregabalin, duloxetine, clonazepam or carbamazepine.

• Allergy to bupivacaine, morphine, paracetamol, tramadol, dihydrocodeine or ketamine.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Imperial College Healthcare NHS Trust	London		United Kingdom	W2 1NY

Sponsors and Collaborators

• Imperial College Healthcare NHS Trust
• National Institute for Health Research, United Kingdom

Investigators

• Principal Investigator: Gillian M Chumbley, BSc, PhD, Imperial Healthcare NHS Trust

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gillian Chumbley, Consultant Nurse, Imperial College Healthcare NHS Trust
• ClinicalTrials.gov Identifier: NCT01296347
• Other Study ID Numbers: Chumbley1
• First Posted: Feb 15, 2011
• Last Update Posted: Sep 4, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Gillian Chumbley, Consultant Nurse, Imperial College Healthcare NHS Trust: Ketamine; Thoracotomy; VATS; Pain
• Additional relevant MeSH terms: Pain, Postoperative; Ketamine

Study Results

Participant Flow

Arm/Group Title	Saline	Ketamine
Arm/Group Description	Patients will receive a placebo infusion of 0.9% sodium chloride, which will start 10 minutes prior to the start of the operation and continue for 96 hours.	Patients will receive intravenous ketamine, starting 10 minutes prior to surgery and will continue for 96 hours Ketamine: Intravenous infusion of ketamine starting 10 minutes prior to surgery and running for 96 hours, which will be administered at a rate of 0.1mg/kg/hour. A loading dose of 0.1mg/kg will be administered prior to the start of the infusion
Period Title: Allocation
STARTED	38	39
COMPLETED	35	35
NOT COMPLETED	3	4
Period Title: Allocation
STARTED	35	35
COMPLETED	35	34
NOT COMPLETED	0	1
Period Title: Allocation
STARTED	35	34
COMPLETED	34	33
NOT COMPLETED	1	1
Period Title: Allocation
STARTED	34	33
COMPLETED	32	31
NOT COMPLETED	2	2
Period Title: Allocation
STARTED	32	31
COMPLETED	28	28
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	Saline	Ketamine	Total
Arm/Group Description	Patients will receive a placebo infusion of 0.9% sodium chloride, which will start 10 minutes prior to the start of the operation and continue for 96 hours.	Patients will receive intravenous ketamine, starting 10 minutes prior to surgery and will continue for 96 hours Ketamine: Intravenous infusion of ketamine starting 10 minutes prior to surgery and running for 96 hours, which will be administered at a rate of 0.1mg/kg/hour. A loading dose of 0.1mg/kg will be administered prior to the start of the infusion	Total of all reporting groups
Overall Participants	35	35	70
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	68	61	64.5
Sex: Female, Male (Count of Participants)
Female	23 65.7%	15 42.9%	38 54.3%
Male	12 34.3%	20 57.1%	32 45.7%
Region of Enrollment (participants) [Number]
United Kingdom	35 100%	35 100%	70 100%

Outcome Measures

1. Primary Outcome

Title	Pain Score on Moving at 6 Weeks
Description	Measures in pain include: Numeric pain score of 0 to 10. Zero denotes 'no pain'; 10 denotes 'pain as bad as you can imagine'
Time Frame	6 weeks after surgery

Outcome Measure Data

Analysis Population Description

Ketamine group one participant did not have data

Arm/Group Title	Saline	Ketamine
Arm/Group Description	Patients received a placebo infusion of 0.9% sodium chloride, which started 10 minutes prior to the start of the operation and continued for 96 hours.	Patients received intravenous ketamine, starting 10 minutes prior to surgery and continued for 96 hours
Measure Participants	35	34
Median (Inter-Quartile Range) [units on a scale]	0	1.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Ketamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Analgesic Consumption (Opioid)
Description	Analgesia consumption will be measured post-operatively and at 6 weeks
Time Frame	6 weeks, 3 month, 6 month

Outcome Measure Data

Analysis Population Description

Participant who experienced pain.

Arm/Group Title	Saline	Ketamine
Arm/Group Description	Patients received a placebo infusion of 0.9% sodium chloride, which started 10 minutes prior to the start of the operation and continue for 96 hours.	Patients received intravenous ketamine, started 10 minutes prior to surgery and continued for 96 hours
Measure Participants	18	18
6 weeks	9	0
3 months	21	17
6 months	34	9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Ketamine
	Comments	6 weeks
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Saline, Ketamine
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Saline, Ketamine
	Comments	6 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Sensory Testing
Description	Hypoaesthesia: light touch of the blunt end of a paintbrush was felt less precisely, than in healthy tissue. Hyperalgesia: the pain induced by a sterile neurotip, applied perpendicular to the skin is felt abnormally strongly, in comparison to the contralateral side. Static allodynia: the application of a Von Frey hair number 14. (8g) was unpleasant, in comparison to the contralateral side. Dynamic allodynia: three successive gentle strokes of an 8 mm-wide paintbrush over a 40 mm distance, is unpleasant, in comparison to the contralateral side.
Time Frame	6 weeks, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Incidence of Side-effects, Nausea
Description	The presence of nausea recorded at the above time points
Time Frame	108 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Saline	Ketamine
Arm/Group Description	Patients received a placebo infusion of 0.9% sodium chloride, which started 10 minutes prior to the start of the operation and continue for 96 hours.	Patients received intravenous ketamine, starting 10 minutes prior to surgery and continued for 96 hours
Measure Participants	35	35
Count of Participants [Participants]	14 40%	17 48.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Ketamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Incidence of Side Effect, Vomiting
Description	The presence of vomiting recorded at the above time points
Time Frame	108 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Saline	Ketamine
Arm/Group Description	Patients received a placebo infusion of 0.9% sodium chloride, which started 10 minutes prior to the started of the operation and continue for 96 hours.	Patients received intravenous ketamine, started 10 minutes prior to surgery and continued for 96 hours
Measure Participants	35	35
Count of Participants [Participants]	8 22.9%	8 22.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Ketamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Incidence of Side Effect, Lightheaded
Description	The presence of lightheaded recorded at the above time points
Time Frame	108 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Saline	Ketamine
Arm/Group Description	Patients received a placebo infusion of 0.9% sodium chloride, which started 10 minutes prior to the started of the operation and continue for 96 hours.	Patients received intravenous ketamine, started 10 minutes prior to surgery and continued for 96 hours
Measure Participants	35	35
Count of Participants [Participants]	5 14.3%	14 40%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Ketamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Incidence of Side Effect, Vivid Dreams
Description	The presence of vivid dreams recorded at the above time points
Time Frame	108 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Saline	Ketamine
Arm/Group Description	Patients received a placebo infusion of 0.9% sodium chloride, which started 10 minutes prior to the started of the operation and continue for 96 hours.	Patients received intravenous ketamine, started 10 minutes prior to surgery and continued for 96 hours
Measure Participants	35	35
Count of Participants [Participants]	2 5.7%	13 37.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Saline, Ketamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	For 108 hours the ketamine or placebo infusion was running and whilst the patient remained in hospital after surgery
Arm/Group Title	Saline		Ketamine
Arm/Group Description	Patients will receive a placebo infusion of 0.9% sodium chloride, which will start 10 minutes prior to the start of the operation and continue for 96 hours.		Patients will receive intravenous ketamine, starting 10 minutes prior to surgery and will continue for 96 hours Ketamine: Intravenous infusion of ketamine starting 10 minutes prior to surgery and running for 96 hours, which will be administered at a rate of 0.1mg/kg/hour. A loading dose of 0.1mg/kg will be administered prior to the start of the infusion
All Cause Mortality
	Saline		Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/39 (0%)
Serious Adverse Events
	Saline		Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/38 (21.1%)		9/39 (23.1%)
Cardiac disorders
cardiac arrest	1/38 (2.6%)	1	0/39 (0%)	0
Hypotension	0/38 (0%)	0	1/39 (2.6%)	1
Eye disorders
Hallucination, visual	2/38 (5.3%)	2	2/39 (5.1%)	2
Psychiatric disorders
Confusion postoperative	0/38 (0%)	0	0/39 (0%)	0
Agitation postoperative	1/38 (2.6%)	1	0/39 (0%)	0
Renal and urinary disorders
Renal failure	1/38 (2.6%)	1	0/39 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory tract infection	3/38 (7.9%)	3	1/39 (2.6%)	1
Bronchial obstruction	0/38 (0%)	0	1/39 (2.6%)	1
Respiratory distress	0/38 (0%)	0	1/39 (2.6%)	1
Lung hypoinflation	0/38 (0%)	0	1/39 (2.6%)	1
Pulmonary embolism	0/38 (0%)	0	1/39 (2.6%)	1
Vocal cord paralysis	0/38 (0%)	0	1/39 (2.6%)	1
Other (Not Including Serious) Adverse Events
	Saline		Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/38 (89.5%)		39/39 (100%)
Gastrointestinal disorders
Nausea	14/38 (36.8%)	14	17/39 (43.6%)	17
Vomiting	8/38 (21.1%)	8	8/39 (20.5%)	8
Nervous system disorders
Dizziness	5/38 (13.2%)	8	14/39 (35.9%)	21
Vivid dreams	2/38 (5.3%)	2	13/39 (33.3%)	13
Skin and subcutaneous tissue disorders
Pruritus	13/38 (34.2%)	13	12/39 (30.8%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.