Efficacy of Intrathecal Oxytocin to Speed Recovery After Hip Surgery

This is a single-center, NIH funded clinical study at Wake Forest Baptist Medical Center. The investigators anticipate that intrathecal oxytocin will speed recovery from pain after major surgery (hip arthroplasty). For this study, the investigators will use a randomized, controlled and blinded study of intrathecal oxytocin in patients scheduled for hip arthroplasty, with primary outcome being the slope of change in pain over the first 60 days following surgery, using growth curve modeling and a ln(time) function.

• Oxytocin (Drug), also known as Pitocin: spinal injection of oxytocin
• Placebo (Drug), also known as Saline: spinal injection of placebo

Primary outcomes

• Comparison of Adjusted Trajectory Model for Pain Between Oxytocin and Placebo--Intercept [The first day after hospital discharge]: Daily pain intensity report for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for oxytocin and placebo group separately. The daily pain intensity was the WORST pain (not the average pain) in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain. Values represent an intercept of modeled worst daily pain on the first day after hospital discharge across all participants, extracted from the mixed effect model. The intercept is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.
• Comparison of Adjusted Trajectory Model for Pain Between Oxytocin and Placebo--Slope [Postoperative Day 1 through Postoperative Day 60]: Daily pain intensity report for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for oxytocin and placebo group separately. The daily pain intensity was the WORST pain in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain. Slope is defined as change in pain . Values represent the slope of modeled worst daily pain (0-10 scale as described above) divided by the natural log of time (days) across all participants, extracted from the mixed effect model. The slope is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.

Secondary outcomes

• Comparison of Adjusted Trajectory Model for Daily Steps Between Oxytocin and Placebo--Intercept [The first day after hospital discharge]: Daily steps for each subject were fitted using growth curve model with parameters of intercept (modeled initial steps) and slope of change in natural log of time, adjusted for prognostic predictors for oxytocin and placebo group separately. This is considered as the modeled change in activity listed in the protocol. Values represent an intercept of modeled daily steps on the first day after hospital discharge across all participants, extracted from the mixed effect model. The intercept is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.
• Comparison of Adjusted Trajectory Model for Daily Steps Between Oxytocin and Placebo--Slope [Postoperative Day 1 through Postoperative Day 60]: Daily steps for each subject were fitted using growth curve model with parameters of intercept (modeled initial steps) and slope of change in natural log of time, adjusted for prognostic predictors for oxytocin and placebo group separately. This is considered as the modeled change in activity listed in the protocol. Values represent the slope of daily steps divided by the natural log of time (days) across all participants, extracted from the mixed effect model. The slope is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.
• Comparison of Adjusted Trajectory Model for World Health Organization Disability Assessment Score 2.0 Value Between Oxytocin and Placebo--Intercept [Modeled WHODAS 2.0 one week after hospital discharge]: Weekly World Health Organization Disability Assessment Score 2.0 (WHODAS 2.0) value for each subject was fitted using growth curve model with parameters of intercept (modeled initial score) and slope of change in natural log of time, adjusted for prognostic predictors for oxytocin and placebo group separately. Scale is 12 to 36 with higher scores meaning greater disability. Values represent an intercept of modeled WHODAS 2.0 score one week after hospital discharge across all participants, extracted from the mixed effect model. The intercept is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.
• Comparison of Adjusted Trajectory Model for World Health Organization Disability Assessment Score 2.0 Value Between Oxytocin and Placebo--Slope [Postoperative Day 7 through Postoperative Day 56]: Weekly World Health Organization Disability Assessment Score 2.0 (WHODAS 2.0) value for each subject was fitted using growth curve model with parameters of intercept (modeled initial score) and slope of change in natural log of time, adjusted for prognostic predictors for oxytocin and placebo group separately. Scale is 12 to 36 with higher scores meaning greater disability. Values represent the slope of WHODAS 2.0 score divided by the natural log of time (days) across all participants, extracted from the mixed effect model. The slope is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.
• Comparison of Adjusted Trajectory Model for Probability of Taking Opioids Daily Between Oxytocin and Placebo--Intercept [The first day after hospital discharge]: Daily probability of taking opioids for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for oxytocin and placebo group separately. Values represent an intercept of modeled probability of taking opioid, on a 0-1 probability scale, on the first day after hospital discharge across all participants, extracted from the mixed effect model. The intercept is a number representative of all participants in the Arm and is an estimate with standard deviation based on the model.
• Comparison of Adjusted Trajectory Model for Probability of Taking Opioids Daily Between Oxytocin and Placebo--Slope [Postoperative Day 1 through Postoperative Day 60]: Daily probability of taking opioids for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for oxytocin and placebo group separately. Values represent the slope of daily probability of taking opioids divided by the natural log of time (days) across all participants, extracted from the mixed effect model. The slope is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model
• Iowa Gambling Task [Preoperative, 2 months after surgery]: This is a computer based card game which assesses risk taking and impulsivity in which a score of -100 to 100 is calculated. Lower numbers indicate greater impulsiivity
• Wisconsin Card Sort Task [Preoperative, 2 months after surgery]: This is a physical card sorting game which measures attention to shifts in implicit rules as the game progresses. Perseverative errors are the number of sequential errors when rules of the game shift and reflect dysfunction of attention. This score ranges from 0 to 64 with larger numbers reflecting more dysfunction of attention.
• Tampa Scale of Kinesiophobia [Preoperative, 2 months after surgery]: This 17-question scale assesses the degree of fear of pain from joint movement and is commonly used in orthopedic injury or surgery studies. The scale ranges from 17 to 68 with 17 indicating no fear of movement and 68 indicating severe fear.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* Scheduled for unilateral, primary total hip replacement
* American Society of Anesthesiologists physical status 1-3

Exclusion Criteria:

* Pregnancy
* Currently Workman's Comp litigation related to hip replacement
* Taking greater than 100 milligrams of morphine (or equivalent)
* Suffering from a psychotic disorder or a recent psychiatric hospitalization

Participant flow

Outcome results

• Comparison of Adjusted Trajectory Model for Pain Between Oxytocin and Placebo--Intercept (Primary), Number, score on a scale: Oxytocin 8.5 (5.8 to 11.2); Placebo 8.6 (5.9 to 11.3) (p 0.75)
• Comparison of Adjusted Trajectory Model for Pain Between Oxytocin and Placebo--Slope (Primary), Number, Score on a scale: Oxytocin -1.9 (-2.2 to -1.6); Placebo -2 (-2.3 to -1.7) (p 0.057)
• Comparison of Adjusted Trajectory Model for Daily Steps Between Oxytocin and Placebo--Intercept (Secondary), Number, Daily Steps: Oxytocin 144 (-2436 to 3527); Placebo 546 (-3241 to 4332) (p 0.41)
• Comparison of Adjusted Trajectory Model for Daily Steps Between Oxytocin and Placebo--Slope (Secondary), Number, Daily steps: Oxytocin 562 (-130 to 1248); Placebo 218 (-472 to 907) (p <0.001)
• Comparison of Adjusted Trajectory Model for World Health Organization Disability Assessment Score 2.0 Value Between Oxytocin and Placebo--Intercept (Secondary), Number, score on a scale: Oxytocin 23.2 (9.5 to 41.2); Placebo 29.1 (13.5 to 44.8) (p 0.002)
• Comparison of Adjusted Trajectory Model for World Health Organization Disability Assessment Score 2.0 Value Between Oxytocin and Placebo--Slope (Secondary), Number, Score on a scale/ln(days): Oxytocin -7.1 (-11 to -3.2); Placebo -5.6 (-9.5 to -1.7) (p 0.001)
• Comparison of Adjusted Trajectory Model for Probability of Taking Opioids Daily Between Oxytocin and Placebo--Intercept (Secondary), Number, Probability of taking opioids: Oxytocin 0.9995 (0.9985 to 1.0005); Placebo 0.9998 (0.9989 to 1.0007) (p 0.537)
• Comparison of Adjusted Trajectory Model for Probability of Taking Opioids Daily Between Oxytocin and Placebo--Slope (Secondary), Number, Probability of taking opioids/ln(days): Oxytocin -0.953 (-0.959 to -0.947); Placebo -0.787 (-0.799 to -0.775) (p 0.010)
• Iowa Gambling Task (Secondary), Mean, units on a scale: Oxytocin 13 +/- 30; Placebo 21 +/- 31 (p .55)
• Wisconsin Card Sort Task (Secondary), Mean, units on a scale: Oxytocin 6.3 +/- 4.2; Placebo 6.8 +/- 4.9 (p 0.46)
• Tampa Scale of Kinesiophobia (Secondary), Mean, units on a scale: Oxytocin 37 +/- 4.8; Placebo 38 +/- 4.6 (p 0.38)

Adverse events

Time frame: Deaths and Serious adverse events were evaluated from baseline through month 6. Non-serious adverse events were evaluated from baseline through month 2.

Limitations and caveats: The trial was terminated early because of depletion of funding. Power analysis was based on 120 subjects and only 90 were studied before termination of funding .

• Study Protocol (PDF, 2016-12-13)
• Statistical Analysis Plan (PDF, 2022-01-03)
• Informed Consent Form (PDF, 2020-09-30)

• James C Eisenach, MD, Principal investigator, Wake Forest University Health Sciences