ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12606000201572

Ethics application status

Not yet submitted

Date submitted

27/02/2006

Date registered

29/05/2006

Date last updated

29/05/2006

Type of registration

Prospectively registered

Titles & IDs

Public title

The effect of rate of administration of tramadol on incidence of post operative nausea and vomiting after any surgical operation for which significant postoperative pain is expected

Scientific title

The effect of rate of administration of tramadol on the incidence of post operative nausea and vomiting after any surgical operation for which significant postoperative pain is expected

Universal Trial Number (UTN)

Trial acronym

Nil

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Post operative nausea and vomiting

Condition category

Condition code

Surgery

Pain management

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

‘Fast’ group – will receive 2.5 mg/kg tramadol (made to 10 ml with addition of saline) intravenously over 2 minutes and 10 ml saline via a syringe driver over 30 minutes.
‘Slow’ group – will receive 10 ml saline over 2 minutes and 2.5 mg/kg tramadol (made to 10 ml with addition of saline) intravenously via a syringe driver over 30 minutes.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

‘Placebo’ group – will receive 10 ml saline over 2 minutes and 10 ml saline via syringe driver over 30 minutes.

Control group

Placebo

Outcomes

Primary outcome [1]

Comparative peak change from baseline in nausea visual analogue score (VAS) scores between fast, slow and placebo tramadol administration groups

Timepoint [1]

Over 3 hours after administration of tramadol/placebo

Secondary outcome [1]

Comparative vomiting frequencies, morphine PCA usage, pain scores, duration spent in PACU and patient satisfaction scores between fast, slow and placebo tramadol administration groups over three hours.

Timepoint [1]

Measured at time points 0, 0.25, 0.5, 1, 2 and 3 hours after the administration of tramadol or placebo.

Eligibility

Key inclusion criteria

English spoken as first language, or fluent as a second language• Scheduled to have elective non-abdominal surgery under general anaesthesia (including general, orthopaedic, plastic, ENT, urologic, dental or vascular surgery) • Requiring general anaesthesia• Significant post-operative pain requiring opioid therapy expected.

Minimum age

18 Years

Maximum age

50 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Inadequate English comprehension• History of allergy or sensitivity to tramadol or morphine• History of previous episode of significant post operative nausea and vomiting• History of significant motion sickness• Epilepsy• Administration of tramadol within previous 36 hours• American Society of Anaesthesiologists’ (ASA) physical status IV or V, reflecting serious cardiorespiratory co-morbidity.• Currently taking selective serotonin receptor inhibitor, tricyclic antidepressant or monoamine oxidase inhibitor drugs• Currently taking prophylactic antiemetics• Pregnancy.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

opaque envelopes

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Computer generated list

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 4

Type of endpoint/s

Pharmacodynamics

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/07/2006

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

150

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

Australian and New Zealand College of Anaesthetists Project Grant

Address [1]

Country [1]

Primary sponsor type

Other Collaborative groups

Name

ANZCA (australaian and New Zealand College of Anaesthetists)

Address

Country

Australia

Secondary sponsor category [1]

Hospital

Name [1]

Melbourne Health

Address [1]

Country [1]

Australia

Ethics approval

Ethics application status

Not yet submitted

Ethics committee name [1]

Melbourne Health Ethics Committee

Ethics committee address [1]

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

Ethics approval number [1]

Summary

Brief summary

Research Aim

The manufacturer’s current recommendation for the rate of administration of tramadol is over 2-3 minutes. In spite of this, many clinicians administer tramadol as a slow infusion as they believe that this reduces the incidence of some side effects including nausea and vomiting. The aim of this research is to determine whether there is a different incidence of nausea and vomiting when tramadol is administered slowly or rapidly. 

Study Outline

Patients greater than or equal to 18 years of age presenting for significant non-abdominal surgery at the Royal Melbourne Hospital will be studied. These patients are at significant risk of post-operative pain and often require continuing post-operative analgesia.
After informed consent, patients will undergo their respective surgical operations under a standardised general anaesthetic. All patients will receive intravenous morphine for intra-operative analgesia and morphine patient-controlled analgesia (PCA) for post-operative analgesia.
Patients will be randomised to receive tramadol or placebo, immediately postoperatively, in the post-anaesthetic care unit (PACU) in one of the following ways:
1)Intravenous tramadol (2.5 mg/kg) fast (conventional therapy over 120 seconds as per manufacturer’s product information) 
2)Intravenous tramadol (2.5 mg/kg) slowly (over 30 minutes)
3)Placebo (no tramadol)
Postoperatively, when the patient is fully awake and able to speak, they will be asked to rate their pain on a 100mm visual analogue scale (0 = No pain to 100mm = Worst imaginable pain). Patients will only receive tramadol or placebo in one of the above ways if they rate their pain as greater than 30mm on a 100mm visual analogue scale. Otherwise they will be excluded from the trial. At this point in the PACU, they will receive their trial drug (tramadol or placebo) as planned.
Patients will be reviewed at 0 (before administration of tramadol/ placebo), 0.25, 0.5, 1, 2 and 3 hours after the administration of tramadol or placebo is commenced. Recordings for nausea, using a visual analogue scale (0 = No nausea to 100mm = Worst imaginable nausea), and episodes of vomiting will be the main clinical outcomes measured. Additionally, PCA usage, pain scores and patient satisfaction will be recorded.

4. Study Endpoints
Primary End Point: Comparative peak change from baseline in nausea visual analogue score (VAS) scores between fast, slow and placebo tramadol administration groups.
Secondary End Points: Comparative vomiting frequencies, morphine PCA usage, pain scores, duration spent in PACU and patient satisfaction scores between fast, slow and placebo tramadol administration groups.

Research Plan
This trial will be conducted in the operating theatres and surgical wards of the Royal Melbourne Hospital. Ethics committee approval will be obtained prior to the commencement of the trial.
Patients presenting for the trial who meet the eligibility criteria will be approached and written informed consent will be obtained. This will occur in the pre-admission clinic or day of surgery admission area of the Royal Melbourne Hospital.
Eligibility
Inclusion Criteria
•	Males and females aged 18-50 years 
•	English spoken as first language, or fluent as a second language
•	Scheduled to have elective non-abdominal surgery under general anaesthesia (including general, orthopaedic, plastic, ENT, urologic, dental or vascular surgery) 
•	Requiring general anaesthesia
•	Significant post-operative pain requiring opioid therapy expected
Exclusion Criteria
•	Inadequate English comprehension
•	History of allergy or sensitivity to tramadol or morphine
•	History of previous episode of significant post operative nausea and vomiting
•	History of significant motion sickness
•	Epilepsy
•	Administration of tramadol within previous 36 hours
•	American Society of Anaesthesiologists’ (ASA) physical status IV or V, reflecting serious cardiorespiratory co-morbidity.
•	Currently taking selective serotonin receptor inhibitor, tricyclic antidepressant or monoamine oxidase inhibitor drugs
•	Currently taking prophylactic antiemetics
•	Pregnancy
Randomisation and Blinding
A three-arm prospective randomised double-blind controlled trial will be undertaken.
All eligible patients will be randomised preoperatively to one of three groups by using sealed opaque envelopes containing the information regarding whether the patient is to receive tramadol ‘fast’ or ‘slow’ or receive placebo. Envelopes will not be opened until after consent is obtained. Randomisation will be performed using a computer-generated list. All patients will be blinded to which group they are in and all will receive a loading dose of 2.5 mg/kg of tramadol (or placebo) intravenously as this has been shown to be the optimum amount required for maximal efficacy with minimal side effects. The study drugs will be prepared by a research nurse/ pain nurse and labelled ‘Fast’ or ‘Slow’. One or both of theses study drugs will be placebo but the identity will be unknown to the patient, PACU nurse looking after that patient and investigator (Dr Sud Agarwal, Dr Malcolm Hogg or AMS Medical Student) who will be collecting data from that patient. The PACU nurse will administer the drugs blind to the identity of the drugs. The identity of the ‘Fast’ and ‘Slow’ study drugs will be recorded by the research nurse/ pain nurse and will not be made available to the investigators.
‘Fast’ group – will receive 2.5 mg/kg tramadol (made to 10 ml with addition of saline) intravenously over 2 minutes and 10 ml saline via a syringe driver over 30 minutes.
‘Slow’ group – will receive 10 ml saline over 2 minutes and 2.5 mg/kg tramadol (made to 10 ml with addition of saline) intravenously via a syringe driver over 30 minutes.
‘Placebo’ group – will receive 10 ml saline over 2 minutes and 10 ml saline via syringe driver over 30 minutes.
Postoperative assessment regarding nausea, pain, vomiting frequency, patient satisfaction and morphine PCA usage will be performed by a second blinded second investigator.
Sample Size Calculation
The sample size of 150 patients is calculated based on reported peak nausea visual analogue scores in response to 2.5 mg/kg of intravenous tramadol:
? = 0.05
? = 0.2
? = 0.3 (a 3 out of 10 difference on a ten point Visual Analogue Score)
? = 0.5 (Standard Deviation)15
Calculates sample size required in each group as 44 for p<0.05. Sample sizes of 50 for each group have been chosen to allow for patients dropping out or being excluded after recruitment. This sample size was calculated using the UCLA statistical sample size calculator.
Nausea Score Estimation
Nausea after the administration of tramadol will be obtained at described time intervals (t = 0, 0.25, 0.5, 1, 2 and 3 hours) using a 100-mm visual analogue scale. All participants will be asked to make a mark on a continuous scale to indicate the level of nausea experienced.
Procedure
Operative Period
All patients will be given a standardised general anaesthetic for their surgical procedure with patient and equipment monitoring implemented as per the Australian and New Zealand College of Anaesthetists’ guidelines. A standard and widely practiced anaesthetic technique will be utilised. This will include midazolam, fentanyl, propofol (and atracurium for relaxant general anaesthesia) for induction followed by maintenance with sevoflurane in 50% oxygen in nitrogen. All patients who had relaxant general anaesthesia will receive neostigmine and glycopyrrolate reversal. Inhaled anaesthetic concentration will be at the discretion of the attending anaesthetist. Morphine, paracetamol or NSAIDs may be utilised for intraoperative analgesia. Wound infiltration with local anaesthetics by surgeons at any time of the procedure is permissible, but the use of tramadol or any antiemetics are not permitted intraoperatively or postoperatively unless it is being administered as part of this trial or as rescue anti-emesis.
Post-operative Period
In the PACU immediately following the end of their operation, all patients will receive tramadol or placebo as per the directions for the group they have been randomised to (see above under Randomisation and Blinding).
Patients in all groups will be asked to describe their nausea, pain, dizziness and patient satisfaction score on four separate 100-mm visual analogue scales (VAS) at 0, 0.25, 0.5, 1, 2 and 3 hours after commencement of administration of tramadol. In addition, PCA usage and any episodes of vomiting will be recorded for all patients within the three hour period.
‘Rescue Analgesia’
Any patient who continues to have inadequate analgesia even after receiving paracetamol, NSAIDs and morphine via PCA will be reviewed by the pain registrar on call at that time and will be given morphine intravenous boluses until their pain is relieved.
‘Rescue Anti-emesis'
Any patient who continues to experience significant nausea (greater than 70 mm on VAS) or who vomits will be reviewed by the pain registrar on call at that time and will be offered antiemetics: 10-20 mg metoclopramide and/ or 0.02 mg/kg droperidol and/ or 4-8 mg dexamethasone and/or ondansetron 4-8 mg until their nausea/ vomiting is relieved.
Data Collection
Pre-operative: age, sex, height, weight, ASA physical status, operation, smoking status, menstrual status (if applicable), history of motion sickness, history of PONV. These (along with duration of anaesthesia) include all the factors cited by Apfel as prospective predictors which allow PONV risk scoring16.
Intra-operative: IV morphine total dose, fentanyl/ paracetamol/ NSAID/ alpha-2 agonist usage, estimated average sevoflurane expired end-tidal concentration, estimated average inspired oxygen concentration, use of local anaesthetic wound infiltration, any surgical complications, total surgical time, duration of anaesthesia.
Post-operatively: (in theatre PACU and hospital wards): analgesic requirements (IV and oral opioids, paracetamol, NSAIDS), pain scores, requirement for any ‘rescue analgesia’, nausea VAS, pain VAS, dizziness VAS, patient satisfaction VAS, total morphine PCA usage, requirement for any ‘rescue anti-emesis’, number of episodes (if any) of vomiting and duration of stay in PACU. Nausea, pain, dizziness and satisfaction data will be collected by a second blinded investigator who will ask all patients to mark a standard 100 mm VAS. 
Any clinically significant event during the course of the study period (3 h) (such as seizures, rash etc) will be recorded.
A Log will be kept including the number of eligible patients, refusals, recruited and randomised patients, dropouts and completed participants.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Sud Agarwal

Address

Royal Melbourne Hospital
Parkville
Melbourne VIC 3052

Country

Australia

Phone

+61 3 93427000

Fax

[email protected] and [email protected] (Please use both is permissible)

Contact person for scientific queries

Name

Sud Agarwal and Malcolm Hogg

Address

Royal Melbourne Hospital
Parkville
Melbourne VIC 3052

Country

Australia

Phone

+61 3 93427000

Fax

[email protected] and [email protected] (Please use both is permissible)

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

Trial Review

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Documents added automatically