Nebulized Sub-dissociative Dose Ketamine for Treating Pain
Condition: Pain
Study type: Interventional
Phase: Phase 4

Summary: 
      The investigators previous research study comparing the efficacy of intravenous ketamine to
      morphine showed ketamine to provide equivalent relief of moderate to severe acute pain in
      emergency department patients. A second study by the investigators showed that increasing the
      time of administration of the ketamine, from a push injection to a drip infusion, will
      minimize the adverse effects experienced by recipients of ketamine.

      The investigators now aim to see if nebulized subdissociative-dose ketamine administered as a
      single agent in a dose of 1.5 mg/kg via Breath-Actuated Nebulizers (BAN) over 5-15 minutes
      will provide a better pain relief in comparison to 1 mg/kg and 0.75 mg/kg doses or if the
      lower doses are equally as effective.
    

Detailed description: 
      STUDY DESIGN

      Subjects: Patients 18 years of age and older presenting to the ED with acute and chronic
      painful conditions such as traumatic and non-traumatic abdominal, flank, back, or
      musculoskeletal pain as well as exacerbation of chronic abdominal, musculoskeletal and
      neuropathic pain with a score of 5 or more on a standard 11- point (0 to 10) numeric rating
      scale and requiring sub-dissociative dose ketamine analgesia, as determined by the treating
      attending physician. Patients' screening and enrollment will be performed by study
      investigators and research assistants. All patients will be enrolled at various times of the
      day when study investigators will be available for patient enrollment and an ED pharmacist
      will be available for medication preparation

      Eligibility Criteria: Patients 18 years of age and older presenting to the ED with acute and
      chronic painful conditions such as traumatic and non-traumatic abdominal, flank, back, or
      musculoskeletal pain as well as exacerbation of chronic abdominal, musculoskeletal and
      neuropathic pain with a score of 5 or more on a standard 11- point (0 to 10) numeric rating
      scale.

      Exclusion Criteria: Altered mental status, allergy to ketamine, pregnant patients, weight
      greater than 150 kg, unstable vital signs (systolic blood pressure <90 or>180 mm Hg, pulse
      rate <50 or >150 beats/min, and respiration rate <10 or >30 breaths/min), inability to
      provide consent, and past medical history of alcohol or drug abuse, or schizophrenia.

      Design: This is a prospective, randomized, double-blind trial comparing analgesic efficacy
      and safety of nebulized SDK administered at three different doses to patients presenting to
      the ED of Maimonides Medical Center with acute and chronic painful conditions. Upon meeting
      the eligibility criteria, patients will be randomized into one of three study arms based on
      the dosing of the SDK: 0.75 mg/kg, 1 mg/kg, and 1.5 mg/kg.

      Data Collection Procedures: Each patient will be approached by a study investigator for
      acquisition of written informed consent and Health Insurance Portability and Accountability
      Act authorization after being evaluated by the treating emergency physician and determined to
      meet study eligibility criteria. When English will not be the participant's primary language,
      a staff interpreter or licensed telephone interpreter would be used. Baseline pain score will
      be determined with an 11-point numeric rating scale (0 to 10), described to the patient as
      "no pain" being 0 and "the worst pain imaginable" being 10. A study investigator will record
      the patient's body weight and baseline vital signs. The on-duty ED pharmacist will prepare a
      breath-actuated nebulizer with doses of 0.75 mg/kg, 1 mg/kg, and 1.5 mg/kg according to the
      predetermined randomization list, which will be created in SPSS (version 24; IBM Corp,
      Armonk, NY) with block randomization of every 10 participants. The medication will be
      delivered to the treating nurse in a blinded fashion and will be administered via
      breath-initiated nebulization with a minimum time of 5 min and maximum time of 15 min up to
      three doses.

      Study investigators will record pain scores, vital signs, and adverse effects at 15, 30, 60,
      90, and 120 minutes. If patients reported a pain numeric rating scale score of 5 or greater
      and requested additional pain relief, a second (equivalent to the first dose) of SDK via BAN
      will be administered to the patient in a blinded fashion. In situations when nebulized SDK
      will fail to achieve acceptable (by patient) pain relief or patient will refuse to continue
      nebulized SDK treatment, morphine at 0.1 mg/kg will be administered as a rescue analgesic.

      All data will be recorded on data collection sheets, including patients' sex, demographics,
      medical history, and vital signs and entered into SPSS (version 24.0; IBM Corp) by the
      research manager. Development of the randomization list, confirmation of written consent
      acquisition for all participants, and statistical analyses will be conducted by the research
      manager and statistician, who would work independent of any data collection.

      Patients will be closely monitored for any change in vital sings and for adverse effects
      during the entire study period (up to 2 h) by study investigators. Common adverse effects
      that are associated with sub-dissociative dose ketamine are felling of unreality, dizziness,
      nausea, vomiting, and sedation.

      Data Analysis: Data analyses will include frequency distributions, paired t-test to assess a
      difference in pain scores within each group, and independent-sample t-test to assess
      differences in pain scores between the 3 groups at the various intervals.

      Mixed-model linear regression will be used to compare changes in pain numeric rating scale
      across time points. This will compensate for participants lost to follow-up and allow all
      patients' data to be analyzed on an intention-to-treat principle.

      For categorical outcomes (eg, complete resolution of pain), a X2 or Fisher's exact test will
      be used to compare outcomes at 30 minutes. Percentage differences and 95% confidence
      intervals between the treatment groups will be calculated for all time points with P<.05 to
      denote statistical significance. Based on the validation of a verbally administered rating
      scale of acute pain in the ED and the comparison of verbal and visual pain scales, we will
      use a primary outcome consisting of a minimal clinically meaningful difference of 1.3 between
      three groups at the 30-minute pain assessment.28,29

      Sample Size: Assuming an SD of 3.0, a power analysis determined that a repeated-measures
      ANOVA with a sample size of 34 patients per group ( 102 total) will provide at least 80%
      power to detect a difference of at least 1.3 at 30 minutes (as well as at any other interval
      post-baseline), with an alpha=.05. To account for possible missing data the total sample size
      will be 120 patients (40 per group).A pre-planned interim data analysis will occur upon
      reaching a total of total of 60 patients ( 20) patients per group.

      Expected Outcomes: The primary outcome will include a comparative reduction of pain scores on
      numeric rating pain scale (NRS) between recipients of nebulized SDK at three different doses
      at 30 minutes post-analgesic administration. The secondary outcomes will include a need for
      second or third dose, a need for rescue analgesia at either 30 or 60 minutes and adverse
      events in each group. With respect to unique adverse effects of SDK, we will use Side Effect
      Rating Scale for Dissociative Anesthetics (SERSDA) and Richmond Agitation Sedation Scale
      (RASS) (ref) SERSDA Scale includes fatigue, dizziness, nausea, headache, feeling of
      unreality, changes in hearing, mood change, general discomfort, and hallucinations with
      severity of each graded by patients on a five-point scale, with "0" representing the absence
      of any adverse effects and "4" representing a severely bothersome side effect. RASS evaluates
      the severity of agitation and/or sedation in accordance to the nine-point scale with scores
      ranging from "-4" (deeply sedated) to "0" (alert and calm) to "+4" (combative).
    

Intervention name(s): Ketamine 0.75 mg/kg; Ketamine 1.0 mg/kg; Ketamine 1.5 mg/kg
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Patients with moderate to severe pain will receive Ketamine at a dose of 0.75mg/kg; Patients with moderate to severe pain will receive Ketamine at a dose of 1.0 mg/kg; Patients with moderate to severe pain will receive Ketamine at a dose of 1.5 mg/kg
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment