Ignite Creation Date:
2024-05-05 @ 11:53 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00163553
Status:
UNKNOWN
Last Update Posted:
2009-01-30
First Post:
2005-09-09
Brief Title:
Neuraxial Pethidine After Lumbar Surgery Trial
Sponsor:
Austin Health
Organization:
Austin Health
Study Overview
Official Title:
Neuraxial Pethidine After Lumbar Surgery Trial
Status:
UNKNOWN
Status Verified Date:
2009-01
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The hypothesis is that epidural pethidine is an effective form of pain relief following lumbar spinal surgery resulting in significantly lower usage of concomitantly administered intravenous patient-controlled analgesia PCA pethidine
Detailed Description:
Rationale Lumbar laminectomy is commonly performed to alleviate local or nerve root pain in the lower back and legs Post-operative pain relief may consist of oral or parenteral medication with an increasing body of research focussing on the use of epidural analgesics and anaesthetics see references It is the current practice of surgeons at this hospital to use an epidural infusion of pethidine in some patients
Epidural medication has sometimes been administered at the conclusion of an operation as a single dose in the form of a spray1 2 3 paste 4 or been sponged onto the exposed epidural space5 Agents used in this manner have included morphine tramadol buprenorphine and methylprednisolone In one such study Bourke6 found that a single dose of epidural morphine 3 mg reduced pain scores and analgesic requirements for 24 hours when compared to the same dose given intramuscularly suggesting that direct epidural administration is superior to parenteral administration
As an alternative analgesics have been infused post-operatively via and epidural catheter placed at the end of surgery under direct vision Cohen7 compared an epidural infusion of morphine and bupivacaine to PCA morphine in 54 patients and found no difference in outcome between groups Other studies which have been uncontrolled or unblinded have demonstrated the efficacy of epidural narcotic administration morphine fentanyl and hydromorphone following lumbar laminectomy surgery8 9 10 11 12 Thus there is some evidence supporting the use of this form of analgesia despite a report of an incidence of technical failure in surgically-positioned epidural catheters 13
To date no published study has investigated the use of epidural pethidine following lumbar laminectomy Pethidine has some theoretical advantage over other agents used14 As an opioid with intermediate lipid solubility it is less likely to leave the epidural space than fentanyl The low lipid solubility of morphine increases its likelihood of causing central respiratory depression as it crosses the dura to the site of action at a slower rate than pethidine14 Pethidine also has an intrinsic local anaesthetic activity
An early study showed that patients receiving a single dose of epidural pethidine at the end of major surgery had a longer period before further analgesics were required than patients receiving equipotent doses of morphine or pethidine Blake15 compared patient-controlled epidural pethidine PCEA with intravenous patient-controlled analgesia PCA pethidine following abdominal aortic surgery where all patients also received epidural bupivicaine The PCEA group had lower pain scores despite having lower plasma pethidine concentrations confirming the central action of epidural pethidine In a similar study Chen16 compared epidural and PCA pethidine in 37 patients following gastrectomy Pain and satisfaction scores were similar but the epidural group had lower plasma concentrations of pethidine and norpethidine
The current proposed study will compare the efficacy of a continuous infusion of epidural pethidine through a surgically-placed catheter to PCA pethidine in patients who have undergone a lumbar laminectomy Both strategies are considered usual practice for this institution PCA pethidine has been used for postoperative analgesia following a variety of surgeries Compared to PCA morphine and fentanyl it has been shown to associated with similar patient satisfaction17 Pethidine also caused less vomiting and pruritis than other agents18
One potential consideration with the use of pethidine is its metabolite norpethidine Norpethidine is an excitatory neurotoxin that has been shown to cause seizures in animals It is renally excreted and hence may accumulate in patients with renal failure There are case reports of patients experiencing seizures during the use of PCA pethidine19 20 21 In each of these cases the patients had received high doses long-term therapy or both The average reported dose administered in the 24 hours prior to the seizure was 1900 mg By contrast the mean 24-hour dose in the Woodhouse study18 was 410 mg and none of the 135 patients in those studies18 17 exhibited any excitatory side effects
Hypothesis The hypothesis is that epidural pethidine is an effective form of pain relief following lumbar spinal surgery resulting in significantly lower usage of concomitantly administered intravenous PCA pethidine
Methods A double-blind randomised controlled trial comparing a continuous epidural pethidine infusion to a placebo normal saline epidural infusion following lumbar laminectomy surgery Both groups will receive intravenous PCA pethidine analgesia as well as routine analgesic adjuvants paracetamol diazepam The follow-up period will be 48 hours
Inclusion criteria
Adults undergoing lumbar spinal surgery
Exclusion criteria
Lack of informed patient consent
Acute or chronic renal failure
Known allergy or intolerance to pethidine or tramadol
Chronic respiratory insufficiency
Epidural contraindicated coagulopathy systemic infection
All consenting patients will be randomised to one of two groups the epidural pethidine group group P or the placebo group group N All patients will receive fentanyl 2 - 3 mcgkg intra-operatively as part of a balanced anaesthesia Otherwise the anaesthesia will not be controlled At the conclusion of surgery all patients will have an epidural catheter placed under direct vision by the consultant surgeon In the recovery room all patients will have a patient-controlled analgesia PCA machine attached to the side arm of the intravenous infusion line All participants will receive written as well as standard verbal instruction on the use of the PCA The 30 ml PCA syringe will contain pethidine 10 mgml saline Patients will be given standard instructions on the use of the PCA machine The PCA machine will be set to deliver a one millilitre bolus with a five minute lockout and a maximum dose of 20 ml 200 mg over four hours In addition an infusion will be connected to the epidural catheter containing either pethidine 250 mg in 250 ml saline group P or saline 250 ml group N The infusion will be commenced at 10 -20 mlh according to the preference of the attending anaesthetist This will generally depend on the age and weight of the patient
Patients will in the high-dependency area of the neurosurgical ward and will be reviewed frequently in the usual manner of patients receiving parenteral narcotics Patients who develop pain will be encouraged to use the PCA Any patient expressing dissatisfaction in their pain relief will be offered an injection of intramuscular morphine 50 mcgkg as a rescue medication up to every 2 hours At the same time the epidural infusion will be increased by 10 mlh to a maximum of 40 mlh All patients will be visited by blinded study personnel at 1 4 24 and 48 hours for collection of data and also twice daily by the hospital acute pain service At the end of 48 hours the epidural catheter will be removed and patients will be treated according to usual hospital pain management practices
In the event of a severe adverse reaction or uncontrollable pain the patient will be excluded from further participation in the study and will be unblinded Pain management will be in accordance with the wishes of the acute pain team and treating unit Data from these patients will be analysed according to intention to treat criteria
Primary end-point
Cumulative 24-hour pethidine consumption
Patient data
Age
Gender
Body mass index
Current medications
Preoperative opioid analgesic use none low high - high dose being 300 mg codeine or dextropropoxyphene daily or oral morphine or parenteral opioid use
Compensable status HNC TAC WCV or PMISUR 22
Surgical data
Anatomical extent of surgery number of spinal levels
Highest anatomical surgical level
Experience level of primary surgeon trainee or consultant
Anatomical level of epidural tip identified from postoperative X-Ray when taken as routine care only
Dural tear at the time of surgery yesno
Spinal instrumentation yesno
Other end-points all at 1 4 24 and 48 hours unless stated
Cumulative pethidine dose
Cumulative morphine dose
VAS scores for pain at rest and during movement
Sedation score 1 - 4 16
VAS scores for nausea pruritis
Other adverse events agitation tremor hallucinations seizure
Patient satisfaction scale for pain control during study 48 hours very dissatisfied dissatisfied neutral satisfied very satisfied 17
Plasma pethidine and norpethidine levels 24 hours
Physiotherapy assessment of ability to deep breathe cough unable poor adequate good
Length of inpatient stay
Statistical considerations The study will be powered to detect a difference in cumulative 24-hour pethidine consumption Based on a baseline 24-hour consumption of 410 mg 18 with a standard deviation of 100 16 a power of 08 and a significance level of 005 the sample size required to detect a 20 difference in pethidine consumption is 24 subjects per group This difference would be considered clinically significant A total of 60 patients will be enrolled to allow for loss of data due to participant drop-out
The analysis will be on an intention-to-treat basis The unpaired Students t-test and the Mann-Whitney U-test will be used to analyse univariate parametric and non-parametric data respectively Serial measurements will be analysed by using repeated measures analysis of variance any significant overall differences between groups will be investigated with t-tests at individual time intervals The Chi-squared test will be used to compare categorical data A p value 005 is considered significant The number and reason for participants not completing the study will be reported
Adverse event reporting Information concerning adverse events is to be collected as end-points for the study This includes pain scores sedation scores respiratory depression nausea pruritis agitation tremor hallucinations and seizures
All other adverse events whether resulting from the use of study medication or procedural errors or apparently independent of the study will be recorded
A serious adverse event is defined as one which causes patient death is life threatening prolongs hospital stay or results in a persistent or significant disability or incapacity TGA An independent physician will be appointed to review all serious adverse events This review will occur within 24 hours of the adverse event occurring The monitoring physician may suspend the study if warranted on the basis of the occurrence of adverse events All serious adverse events will be reported to the Drug Trial Subcommittee of the Human Research Ethics Committee as soon as possible
Epidural medication has sometimes been administered at the conclusion of an operation as a single dose in the form of a spray1 2 3 paste 4 or been sponged onto the exposed epidural space5 Agents used in this manner have included morphine tramadol buprenorphine and methylprednisolone In one such study Bourke6 found that a single dose of epidural morphine 3 mg reduced pain scores and analgesic requirements for 24 hours when compared to the same dose given intramuscularly suggesting that direct epidural administration is superior to parenteral administration
As an alternative analgesics have been infused post-operatively via and epidural catheter placed at the end of surgery under direct vision Cohen7 compared an epidural infusion of morphine and bupivacaine to PCA morphine in 54 patients and found no difference in outcome between groups Other studies which have been uncontrolled or unblinded have demonstrated the efficacy of epidural narcotic administration morphine fentanyl and hydromorphone following lumbar laminectomy surgery8 9 10 11 12 Thus there is some evidence supporting the use of this form of analgesia despite a report of an incidence of technical failure in surgically-positioned epidural catheters 13
To date no published study has investigated the use of epidural pethidine following lumbar laminectomy Pethidine has some theoretical advantage over other agents used14 As an opioid with intermediate lipid solubility it is less likely to leave the epidural space than fentanyl The low lipid solubility of morphine increases its likelihood of causing central respiratory depression as it crosses the dura to the site of action at a slower rate than pethidine14 Pethidine also has an intrinsic local anaesthetic activity
An early study showed that patients receiving a single dose of epidural pethidine at the end of major surgery had a longer period before further analgesics were required than patients receiving equipotent doses of morphine or pethidine Blake15 compared patient-controlled epidural pethidine PCEA with intravenous patient-controlled analgesia PCA pethidine following abdominal aortic surgery where all patients also received epidural bupivicaine The PCEA group had lower pain scores despite having lower plasma pethidine concentrations confirming the central action of epidural pethidine In a similar study Chen16 compared epidural and PCA pethidine in 37 patients following gastrectomy Pain and satisfaction scores were similar but the epidural group had lower plasma concentrations of pethidine and norpethidine
The current proposed study will compare the efficacy of a continuous infusion of epidural pethidine through a surgically-placed catheter to PCA pethidine in patients who have undergone a lumbar laminectomy Both strategies are considered usual practice for this institution PCA pethidine has been used for postoperative analgesia following a variety of surgeries Compared to PCA morphine and fentanyl it has been shown to associated with similar patient satisfaction17 Pethidine also caused less vomiting and pruritis than other agents18
One potential consideration with the use of pethidine is its metabolite norpethidine Norpethidine is an excitatory neurotoxin that has been shown to cause seizures in animals It is renally excreted and hence may accumulate in patients with renal failure There are case reports of patients experiencing seizures during the use of PCA pethidine19 20 21 In each of these cases the patients had received high doses long-term therapy or both The average reported dose administered in the 24 hours prior to the seizure was 1900 mg By contrast the mean 24-hour dose in the Woodhouse study18 was 410 mg and none of the 135 patients in those studies18 17 exhibited any excitatory side effects
Hypothesis The hypothesis is that epidural pethidine is an effective form of pain relief following lumbar spinal surgery resulting in significantly lower usage of concomitantly administered intravenous PCA pethidine
Methods A double-blind randomised controlled trial comparing a continuous epidural pethidine infusion to a placebo normal saline epidural infusion following lumbar laminectomy surgery Both groups will receive intravenous PCA pethidine analgesia as well as routine analgesic adjuvants paracetamol diazepam The follow-up period will be 48 hours
Inclusion criteria
Adults undergoing lumbar spinal surgery
Exclusion criteria
Lack of informed patient consent
Acute or chronic renal failure
Known allergy or intolerance to pethidine or tramadol
Chronic respiratory insufficiency
Epidural contraindicated coagulopathy systemic infection
All consenting patients will be randomised to one of two groups the epidural pethidine group group P or the placebo group group N All patients will receive fentanyl 2 - 3 mcgkg intra-operatively as part of a balanced anaesthesia Otherwise the anaesthesia will not be controlled At the conclusion of surgery all patients will have an epidural catheter placed under direct vision by the consultant surgeon In the recovery room all patients will have a patient-controlled analgesia PCA machine attached to the side arm of the intravenous infusion line All participants will receive written as well as standard verbal instruction on the use of the PCA The 30 ml PCA syringe will contain pethidine 10 mgml saline Patients will be given standard instructions on the use of the PCA machine The PCA machine will be set to deliver a one millilitre bolus with a five minute lockout and a maximum dose of 20 ml 200 mg over four hours In addition an infusion will be connected to the epidural catheter containing either pethidine 250 mg in 250 ml saline group P or saline 250 ml group N The infusion will be commenced at 10 -20 mlh according to the preference of the attending anaesthetist This will generally depend on the age and weight of the patient
Patients will in the high-dependency area of the neurosurgical ward and will be reviewed frequently in the usual manner of patients receiving parenteral narcotics Patients who develop pain will be encouraged to use the PCA Any patient expressing dissatisfaction in their pain relief will be offered an injection of intramuscular morphine 50 mcgkg as a rescue medication up to every 2 hours At the same time the epidural infusion will be increased by 10 mlh to a maximum of 40 mlh All patients will be visited by blinded study personnel at 1 4 24 and 48 hours for collection of data and also twice daily by the hospital acute pain service At the end of 48 hours the epidural catheter will be removed and patients will be treated according to usual hospital pain management practices
In the event of a severe adverse reaction or uncontrollable pain the patient will be excluded from further participation in the study and will be unblinded Pain management will be in accordance with the wishes of the acute pain team and treating unit Data from these patients will be analysed according to intention to treat criteria
Primary end-point
Cumulative 24-hour pethidine consumption
Patient data
Age
Gender
Body mass index
Current medications
Preoperative opioid analgesic use none low high - high dose being 300 mg codeine or dextropropoxyphene daily or oral morphine or parenteral opioid use
Compensable status HNC TAC WCV or PMISUR 22
Surgical data
Anatomical extent of surgery number of spinal levels
Highest anatomical surgical level
Experience level of primary surgeon trainee or consultant
Anatomical level of epidural tip identified from postoperative X-Ray when taken as routine care only
Dural tear at the time of surgery yesno
Spinal instrumentation yesno
Other end-points all at 1 4 24 and 48 hours unless stated
Cumulative pethidine dose
Cumulative morphine dose
VAS scores for pain at rest and during movement
Sedation score 1 - 4 16
VAS scores for nausea pruritis
Other adverse events agitation tremor hallucinations seizure
Patient satisfaction scale for pain control during study 48 hours very dissatisfied dissatisfied neutral satisfied very satisfied 17
Plasma pethidine and norpethidine levels 24 hours
Physiotherapy assessment of ability to deep breathe cough unable poor adequate good
Length of inpatient stay
Statistical considerations The study will be powered to detect a difference in cumulative 24-hour pethidine consumption Based on a baseline 24-hour consumption of 410 mg 18 with a standard deviation of 100 16 a power of 08 and a significance level of 005 the sample size required to detect a 20 difference in pethidine consumption is 24 subjects per group This difference would be considered clinically significant A total of 60 patients will be enrolled to allow for loss of data due to participant drop-out
The analysis will be on an intention-to-treat basis The unpaired Students t-test and the Mann-Whitney U-test will be used to analyse univariate parametric and non-parametric data respectively Serial measurements will be analysed by using repeated measures analysis of variance any significant overall differences between groups will be investigated with t-tests at individual time intervals The Chi-squared test will be used to compare categorical data A p value 005 is considered significant The number and reason for participants not completing the study will be reported
Adverse event reporting Information concerning adverse events is to be collected as end-points for the study This includes pain scores sedation scores respiratory depression nausea pruritis agitation tremor hallucinations and seizures
All other adverse events whether resulting from the use of study medication or procedural errors or apparently independent of the study will be recorded
A serious adverse event is defined as one which causes patient death is life threatening prolongs hospital stay or results in a persistent or significant disability or incapacity TGA An independent physician will be appointed to review all serious adverse events This review will occur within 24 hours of the adverse event occurring The monitoring physician may suspend the study if warranted on the basis of the occurrence of adverse events All serious adverse events will be reported to the Drug Trial Subcommittee of the Human Research Ethics Committee as soon as possible
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None