Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00163553 |
| Other study ID # |
01833 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
September 9, 2005 |
| Last updated |
January 29, 2009 |
| Start date |
December 2004 |
Study information
| Verified date |
January 2009 |
| Source |
Austin Health |
| Contact |
Dean A Cowie, MBBS, FANZCA |
| Phone |
61-3-9496-3227 |
| Email |
dean.cowie[@]austin.org.au |
| Is FDA regulated |
No |
| Health authority |
Australia: Department of Health and Ageing Therapeutic Goods Administration |
| Study type |
Interventional
|
Clinical Trial 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.
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
space.5 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 surgery.8 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 used.14 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
pethidine.14 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
agents.18
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 pethidine.19 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
mcg/kg 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 mg/ml
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 ml/h 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 mcg/kg) as a
rescue medication up to every 2 hours. At the same time, the epidural infusion will be
increased by 10 ml/h to a maximum of 40 ml/h. 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 PMI/SUR) 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 (yes/no)
- Spinal instrumentation (yes/no)
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 0.8 and a significance level of 0.05, 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 Student's 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 < 0.05 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.
