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Intravenous Ketamine for Pain Control During First Trimester Surgical Abortion

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03751423
Recruitment Status : Recruiting
First Posted : November 23, 2018
Last Update Posted : February 13, 2020
Sponsor:
Information provided by (Responsible Party):
Dr. Marie Eve Sophie Bussiere-Cote, Queen's University

Tracking Information
First Submitted Date  ICMJE November 20, 2018
First Posted Date  ICMJE November 23, 2018
Last Update Posted Date February 13, 2020
Actual Study Start Date  ICMJE June 10, 2019
Estimated Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2018)
VAS Pain Score - Immediate Post-Procedure [ Time Frame: Immediate Post-Procedure ]
The primary outcome measure is mean difference in immediate post-operative pain measured by the visual analogue pain scale (VAS). The VAS is a validated tool for research in operative pain management. Using this scale, participants rate their current pain on a scale from 0 to 10 by drawing an "x" on the horizontal line. This line is 10cm long and the participant's pain level is measured using a ruler to the millimeter mark and translated to a score out of 100mm. If the "x" falls between millimeter marks on the ruler the reader will round up to the nearest mark.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 20, 2018)
  • VAS Pain Score - Prior to Discharge [ Time Frame: Prior to discharge from recovery room on day of procedure (typically within 1h post-procedure) ]
    This secondary outcome will post-operative pain prior to discharge measured by the visual analogue pain scale (VAS). The VAS is a validated tool for research in operative pain management. Using this scale, participants rate their current pain on a scale from 0 to 10 by drawing an "x" on the horizontal line. This line is 10cm long and the participant's pain level is measured using a ruler to the millimeter mark and translated to a score out of 100mm. If the "x" falls between millimeter marks on the ruler the reader will round up to the nearest mark.
  • Length of Stay in Recovery [ Time Frame: Day of Procedure ]
    Length of stay in recovery in minutes from transfer from the procedure room till discharge.
  • Satisfaction with Pain Control - Prior to Discharge [ Time Frame: Prior to discharge from recovery room on day of procedure (typically within 1h post-procedure) ]
    Satisfaction with pain control will be assessed using a 5-point Likert scale. 1 is the worst score and 5 is the best.
  • Medication Side Effects [ Time Frame: Prior to discharge from recovery room on day of procedure (typically within 1h post-procedure) ]
    Medication side effects from administration till discharge as reported by the care providers and nurses.
  • Provider Assessment of Intra-Operative Pain Management [ Time Frame: Intra-Operative ]
    Provider assessment of intra-operative pain will be reported using a 5-point Likert scale. 1 is the worst score and 5 is the best.
  • Wong-Baker Faces Pain Score - Immediate Post-Procedure [ Time Frame: Immediate Post-Procedure ]
    Pain score will immediate post-procedure will also be reported using the Wong-Baker Faces Pain Rating Scale.
  • Wong-Baker Faces Pain Score - Prior to Discharge [ Time Frame: Prior to discharge from recovery room on day of procedure (typically within 1h post-procedure) ]
    Pain score will prior to discharge will also be reported using the Wong-Baker Faces Pain Rating Scale.
  • Pain Control After Discharge [ Time Frame: 2-4 weeks post-procedure ]
    Pain control after discharge will be assessed via telephone questionnaire using a 5-point Likert scale. 1 is the worst score and 5 is the best.
  • Satisfaction with Pain Control After Discharge [ Time Frame: 2-4 weeks post-procedure ]
    Satisfaction with pain control after discharge will be assessed via telephone questionnaire using a 5-point Likert scale.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Intravenous Ketamine for Pain Control During First Trimester Surgical Abortion
Official Title  ICMJE Intravenous Ketamine for Pain Control During First Trimester Surgical Abortion
Brief Summary

A therapeutic abortion is one of the most common procedures performed in Canada, with approximately 100,000 occurring annually. 95% of induced abortions are done surgically, with just over two thirds of these procedures taking place in the first trimester.

This study will be a randomized, controlled, double-blinded, single-centre superiority trial with three parallel groups; oral morphine vs intravenous fentanyl vs intravenous ketamine. The primary outcome will be immediate post-operative pain following a first trimester therapeutic abortion as assessed using the visual analogue scale. Randomization will be performed as block randomization with a 1:1:1 allocation ratio. In total, 123 participants will be recruited and randomized, with 41 being assigned to each treatment arm. This study will be conducted at the Women's Clinic at Kingston General Hospital in Kingston, Ontario, Canada. Women from Kingston and the surrounding areas are referred to this clinic and can self-refer for therapeutic abortion.

The investogators hope that this research will move us towards a better form of pain control for our participants undergoing first trimester surgical abortion, without increasing length of stay, side effects, or adverse events. This, in turn, will hopefully improve access to optimal pain control to participants undergoing first trimester surgical abortion in an outpatient setting.

Detailed Description

Rationale:

At present, the gold standard for pain control during first trimester abortion is the combination of a paracervical block with moderate intravenous (IV) sedation. Paracervical blocks are routinely done with lidocaine, with or without epinephrine or vasopressin. Moderate sedation is commonly achieved using fentanyl 50-100ug IV and midazolam 1-2mg IV. The issue with the use of IV opioids for sedation is the need for continuous cardio-respiratory monitoring, due to the risk of cardio-respiratory depression or collapse. This therefore limits the ability of some centers to provide the best form of pain control for their participants undergoing first trimester surgical abortion. For instance, our center currently uses a paracervical block plus a combination of oral medications (morphine and lorazepam), which has been found to be inferior to a paracervical block plus IV sedation. All participants without contraindications to NSAIDs are pre-medicated with naproxen as recommended.2 The investigators also have access to nitrous oxide/oxygen 50:50 (Entonox) to use as an adjunct, however this has not been found to significantly improve procedural or post-operative pain.

In the past, ketamine was used for pain control during first trimester abortion. Ketamine is a dissociative agent and does not carry the same risk of cardio-respiratory depression as intravenous opioids. Ketamine was felt to be ideal for first trimester surgical abortion -as the medication has uterotonic properties, which could result in less blood loss. Doses of 0.5mg/kg IV were typically used. However, the use of ketamine for first trimester surgical abortion decreased dramatically after the 1970-1980's due to reports of adverse events including emergence phenomena (nightmares), nausea, and vomiting. In fact, only one study published during this time did not find negative emergence phenomena in participants exposed to ketamine. More recently, a systematic review concluded that ketamine was an inferior agent when compared to propofol for pain control during first trimester surgical abortion. However, propofol, a general anesthetic requiring continuous cardio-respiratory monitoring, should not be placed in the same anesthetic category as ketamine. Furthermore, propofol is only available in a limited number of settings offering first trimester surgical abortion.

Over the last 10 to 15 years, ketamine has become an increasingly commonly used dissociative agent for procedural sedation in the emergency department. The benefits of its use include the simultaneous provision of both sedation and analgesia, while maintaining airway reflexes and respiratory drive. Intravenous ketamine use in the emergency department has been shown to yield high success rates (94% to 100%). In addition, of all the drugs commonly used in this setting, ketamine has one of the highest safety profiles and lowest rates of complications.

The investigators are interested in re-visiting whether ketamine would be an appropriate choice of anesthetic for first trimester surgical abortion. If ketamine is found to be superior to IV fentanyl, it would potentially increase access to optimal pain control in settings where continuous cardio-respiratory monitoring is not available. Furthermore, in the current era of opioid misuse, it is important that providers look for alternative forms of pain management when appropriate. In fact, the Society for Family Planning recently put out a call to action for more research on alternative options to control pain short of moderate or deep sedation.

Study Setting:

This study will be conducted at the Women's Clinic at Kingston General Hospital in Kingston, Ontario, Canada. Women from Kingston and the surrounding areas are referred to this clinic and can self-refer for therapeutic abortion.

Study Drugs:

  • PO Morphine
  • IV Fentanyl
  • IV Ketamine
  • PO Placebo
  • IV Placebo

Administration of Study Drugs:

Once written informed consent is received the care provider will determine opiate sensitization stratum and write orders for the appropriate amount of oral morphine to be dispensed to the participant.

The next sequential randomization envelope for the appropriate stratum will then be retrieved. Within the randomization envelope there will be two envelopes, one for nursing staff and one for the anesthetist. Drug dispensing will be done in two stages.

Nursing staff will open their envelope to determine from which drawer they are to dispense the oral morphine dose ordered by the care provider (A, B or C). Two will be placebo and one will be oral morphine, but nursing staff will be blinded to group assignment.

The anesthetist will open her envelope prior to the procedure to determine group assignment. She will be responsible for the mixing and administration of all IV medications and will not be blinded to group assignment. All other study staff, clinical staff and the participant will remain blinded to group assignment.

Nursing staff will be responsible for dispensing and administering all other standard medications including dimenhydrinate, naproxen, lorazepam and misoprostol.

For all participants the anesthetist will prepare IV medications according to participant group assignment, ketamine, fentanyl or normal saline only. The syringes will be labelled with the participant's name and hospital identification number. The syringes will be used for IV drug administration during the procedure. Naloxone and/or midazolam will be administered as needed at the discretion of the anesthetist.

Standard Script:

Prior to starting the procedure, the physician administrating sedation during the procedure will inquire into some of the participant's favorite places and/or ideas, as this will be used to individualize guided imagery for each participant during the procedure. An example of such guided imagery during the procedure may include the physician asking the participant to feel the sand on her feet at her favorite beach, to hear the waves landing on the shore, and to feel the warmth of the sun on her skin. In addition to guided imagery performed during the procedure, the voices in the room will be minimized only to necessary communication in a calm gentle tone, and soothing music will be played quietly in the background. The guided imagery and room setup will be used for all participants, regardless of the study drug that they receive.

Consent Process:

Once the participant registers at the Women's Clinic, she will be asked by the nurse at intake if she would be interested in participating in the research study. If she is agreeable, the surgeon will proceed with the consent process.

If the participant consents to participate in the study, the surgeon will administer a questionnaire to obtain a thorough medical history, collect information on participant demographics and determine whether the participant is opiate naïve or opiate sensitized.

Randomization:

Participants will be randomized to one of three treatment arms following receipt of written informed consent.

Allocation Sequence Generation:

The allocation sequence will be generated by an epidemiologist in the Department of Obstetrics and Gynecology at Queen's University. Randomization will be blocked and stratified. Stratification will be based on the participant's current opiate usage to ensure that participants who are opiate sensitized are evenly distributed between the groups. Unique allocation sequences will be generated for each stratum. Random block sizes of 3 and 6 will be used for each of the sequences. For both sequences, participants will be allocated in a 1:1:1 ratio, with equal chance of being assigned to all three groups. An appropriate statistical program will be used to generate the two allocation sequences.

Randomization Process:

Randomization will be done with consecutively numbered opaque envelopes. Research staff will assemble these envelopes based on the two allocation sequences. The envelopes will be clearly labelled with the stratum (opiate sensitized or naïve). Within each envelope there will be two envelopes, one for nursing staff and one for the anesthetist. A sheet within the envelope for the nursing staff will indicate from which drawer they are to dispense the oral morphine (A, B, C). This will be done to ensure that nursing staff remains blinded to group assignment. A sheet inside the envelope for the anesthetist will indicate arm allocation (PO morphine, IV ketamine, IV fentanyl). The envelopes and sheets will be identical, except for the number and strata label on the outside and text on the sheet inside, to minimize the chance of accidental unblinding.

Upon receipt of written informed consent, the care provider will determine whether the participant is opiate sensitized or naïve and write an order for an oral morphine dose. The participant will be randomized by selecting the next envelope in the sequence of the appropriate stratum based on the consecutive numbering. Nursing staff will open their labeled envelope to determine from where to dispense the oral morphine. The anesthetist will open her envelope to determine the participant's group allocation and dispense the appropriate IV medications. Both envelopes will then be sealed and place in the participants chart. The envelopes will only be opened in the case of emergency unblinding or by study staff for data entry at a later date.

The Procedure:

The participant will undergo her procedure with the pain control regimen based on the randomization. The anesthetist will maintain a drug administration log throughout the procedure, including the use of any reversal agents. The total amounts of drugs mixed, used and wasted will be recorded in this log. Only the anesthetist will have access to this log in order to maintain blinding. It will be sealed and kept in the participants chart after the procedure is complete. It will only be opened if emergency unblinding is required or by research staff for data entry at a later date.

Once the procedure is complete, the nurse and/or surgeon will administer the immediate post-operative pain assessment. The surgeon will record their assessment of intra-operative pain management and their guess as to group assignment. Any adverse events or medication side effects during the procedure will be recorded by the clinical team (nurses and surgeons).

The Recovery Room:

In the recovery room, the clinical team (nurses and surgeons) will record any side effects or adverse events. Length of stay in recovery will be recorded in minutes by the nursing staff. The participant will be administered a final pain assessment by nursing staff prior to discharge. The participant will also be given a self-administered questionnaire with questions about participant satisfaction, likelihood of using the same pain regimen at a future procedure, and their guess regarding their group assignment.

Follow-Up:

The participant will be contacted by a member of the research team within 2-4 weeks of the procedure. This will be done by telephone. The participant will be asked a series of questions relating to satisfaction, complications that may have arisen following discharge, the likelihood of using the same pain regimen at a future procedure, and their guess regarding their group assignment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This study will be a randomized, controlled, double-blinded, single-centre superiority trial with three parallel groups.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description:
For the three treatment arms, the nurses, the study participants, and the abortion provider will be blinded to study arm assignment and will remain blinded throughout the course of the study. As such, all study personnel who will be administering questionnaires will be appropriately blinded to minimize bias. The provider of the IV medications will not be blinded. This decision was made in order to ensure participant safety in titrating medication doses, and to avoid the need to unblind all members if a reversal agent is required. The provider of the anesthetic will not disclose which study arm the participant belongs to and will not be involved in administering questionnaires or data analysis.
Primary Purpose: Supportive Care
Condition  ICMJE Abortion in First Trimester
Intervention  ICMJE
  • Drug: PO Morphine
    10-20mg oral morphine depending on such factors as weight (100-200mcg/kg), previous opiate exposure (opiate naïve vs opiate sensitized), and participant's previous experiences with opiate medications for painful procedures. Dosing will be determined at the discretion of the surgical provider in clinic that day, as per standard of care.
    Other Name: Morphine Sulphate
  • Drug: IV Fentanyl
    0.5-1mcg/kg IV fentanyl over 2 minutes repeated every 5 minutes as needed until appropriate analgesia is reached.
    Other Name: Fentanyl Citrate Injection
  • Drug: IV Ketamine
    200-500mcg/kg IV over 2 minutes repeated every 5 minutes as needed until appropriate analgesia is reached
    Other Name: Ketamine Hydrochloride Injection
  • Drug: PO Placebo
    A standard placebo pill, the same size, shape and colour of the oral morphine. The placebo will be administered to the participants randomized to the IV ketamine and IV fentanyl during pre-op in the same manner the oral morphine would be administered.
    Other Name: Oral Placebo Pill
  • Drug: IV Placebo
    This normal saline will be administered to the participants randomized to the oral morphine group during the procedure in the same manner that IV fentanyl or IV ketamine would be administered.
    Other Name: Normal Saline
Study Arms  ICMJE
  • Active Comparator: PO Morphine & IV Placebo
    One third of study participants will be randomized to this local standard of care arm.
    Interventions:
    • Drug: PO Morphine
    • Drug: IV Placebo
  • Active Comparator: IV Fentanyl & PO Placebo
    One third of study participants will be randomized to this current gold standard of care arm.
    Interventions:
    • Drug: IV Fentanyl
    • Drug: PO Placebo
  • Experimental: IV Ketamine & PO Placebo
    One third of study participants will be randomized to this experimental arm.
    Interventions:
    • Drug: IV Ketamine
    • Drug: PO Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 20, 2018)
123
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2020
Estimated Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Confirmed first trimester pregnancy with an ultrasound showing a viable intrauterine pregnancy with a gestational age of less than 12 weeks since the last menstrual period
  2. Unwanted pregnancy and consented to undergo a first trimester surgical abortion

Exclusion Criteria:

  1. Age <18 years at the time of study enrollment
  2. Known allergy or sensitivity to any of the medications used in the study
  3. Any serious medical comorbidity that would make IV sedation contraindicated in an outpatient setting (ex. Heart disease, lung disease)
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jessica Pudwell, MPH 613-549-6666 ext 3937 jessica.pudwell@queensu.ca
Contact: Heather Ramshaw, BSc 613-548-1372 ramshawh@queensu.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03751423
Other Study ID Numbers  ICMJE OBGY-KET-18
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Dr. Marie Eve Sophie Bussiere-Cote, Queen's University
Study Sponsor  ICMJE Dr. Marie Eve Sophie Bussiere-Cote
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sophie Bussiere-Cote, MD Queen's University
Principal Investigator: Ashley Waddington, MD, MPA Queen's University
PRS Account Queen's University
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP