Clinical trial NCT03751423: Intravenous Ketamine for Pain Control During First Trimester Surgical Abortion
Official title: Intravenous Ketamine for Pain Control During First Trimester Surgical Abortion
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE3
Conditions: Abortion in First Trimester
Keywords: procedural sedation
ketamine
fentanyl
morphine
Lead sponsor: Queen's University
Sponsor class: OTHER
First posted: 2018-11-23
Enrollment: 123
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will be a randomized, controlled, double-blinded, single-centre superiority trial with three parallel groups.
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility criteria: 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)

Primary outcomes:
measure: VAS Pain Score - Immediate Post-Procedure
timeFrame: Immediate Post-Procedure
Secondary outcomes:
measure: VAS Pain Score - Prior to Discharge
timeFrame: Prior to discharge from recovery room on day of procedure (typically within 1h post-procedure)
measure: Length of Stay in Recovery
timeFrame: Day of Procedure
measure: Satisfaction with Pain Control - Prior to Discharge
timeFrame: Prior to discharge from recovery room on day of procedure (typically within 1h post-procedure)
measure: Medication Side Effects
timeFrame: Prior to discharge from recovery room on day of procedure (typically within 1h post-procedure)
measure: Provider Assessment of Intra-Operative Pain Management
timeFrame: Intra-Operative
measure: Wong-Baker Faces Pain Score - Immediate Post-Procedure
timeFrame: Immediate Post-Procedure
measure: Wong-Baker Faces Pain Score - Prior to Discharge
timeFrame: Prior to discharge from recovery room on day of procedure (typically within 1h post-procedure)
measure: Pain Control After Discharge
timeFrame: 2-4 weeks post-procedure
measure: Satisfaction with Pain Control After Discharge
timeFrame: 2-4 weeks post-procedure
Other outcomes:
Locations:
city: Kingston
country: Canada
facility: Queen's University
state: Ontario
Study officials:
affiliation: Queen's University
name: Sophie Bussiere-Cote, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Queen's University
name: Ashley Waddington, MD, MPA
role: PRINCIPAL_INVESTIGATOR
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