Randomized Controlled Study of Ketamine Administration for Postoperative Pain Management in Patients Undergoing Knee Arthroplasty,
Phase: NA
Conditions: Knee Arthroplasty, Postoperative Pain, Pain Management, Analgesia, Opioid Use, Ketamine
Sponsor: State Budgetary Healthcare Institution, National Medical Surgical Center N.A. N.I. Pirogov, Ministry of Health of Russia

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Randomized Controlled Study of Ketamine Administration for Postoperative
Pain Management in Patients Undergoing Knee Arthroplasty
NCT Number: NCT07059429
Document Type: Study Protocol
Document Date: May 21, 2025
Principal Investigator:
Ivan Shcheparev, MD, PhD
Principal Investigator
N.I. Pirogov National Medical and Surgical Center
Institution:
N.I. Pirogov National Medical and Surgical Center
Moscow, Russia
Contact Information:
is22@list.ru
+7 (901) 908-90-88

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1. Background and Rationale
Ketamine is a widely used NMDA receptor antagonist with strong analgesic
properties. International studies demonstrate its efficacy and safety for perioperative
and postoperative pain management, particularly as part of multimodal analgesia after
major surgery. Subanesthetic doses (0.06–0.3 mg/kg/h) are associated with significant
opioid-sparing effects and lower rates of postoperative nausea, vomiting, and
neuropsychiatric complications. In Russia, ketamine is not currently labeled for
postoperative analgesia, highlighting the need for high-quality evidence in this
context.
2. Objectives
Primary Objective:

To evaluate whether intravenous ketamine infusion reduces opioid consumption
within the first 24 hours after knee arthroplasty compared to standard analgesia.
Secondary Objectives:

To compare pain intensity at multiple time points within 24 hours postoperatively.

To assess the incidence and severity of neuropsychiatric adverse events and
postoperative nausea/vomiting.

To determine the total number of ketamine boluses and cumulative dose
administered in the ketamine group.
3. Study Design
Type: Prospective, randomized, controlled, single-center study.
Study Period: July 2025 – January 2026.
Setting: N.I. Pirogov National Medical and Surgical Center.
This study was preceded by a pilot phase (n=42, conducted separately) to inform
sample size calculations and protocol refinement.

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4. Study Population
Inclusion Criteria:

Age >18 and <90 years.

Undergoing knee arthroplasty.
Exclusion Criteria:

Age <18 or >90 years.

Spinal anesthesia intraoperatively.

Epidural analgesia postoperatively.

Sciatic nerve, genicular nerve, or lumbar plexus block perioperatively.

Known allergy to ketamine or NSAIDs.

Contraindications to ketamine as specified in the product instructions.

More than 24 hours elapsed since the end of surgery.

Ineffectiveness of analgesia provided by the study protocol.
5. Interventions
Intervention Group (Ketamine + Standard Analgesia):

Ketoprofen 100 mg twice daily (dose adjustments allowed).

Paracetamol 1000 mg every 8 hours (adjustments allowed).

Continuous ketamine infusion via PCA: 0.15 mg/kg/h, 1 mg bolus, 5 min lockout,
max 500 mg/24 h, administered via a dedicated peripheral line.

Morphine 10 mg IM as needed for breakthrough pain.
Control Group (Standard Analgesia Only):

Ketoprofen 100 mg twice daily (dose adjustments allowed).

Paracetamol 1000 mg every 8 hours (adjustments allowed).

Morphine 10 mg IM as needed for breakthrough pain.
Regional Anesthesia:
Repeat femoral nerve block under ultrasound guidance (ropivacaine 0.5% up to 10 ml)

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in cases of severe femoral nerve pain postoperatively. Patients requiring repeated
block will be analyzed separately.
6. Outcomes
Primary Outcome:
1.
Total opioid analgesic consumption (converted to morphine equivalents, mg)
within the first 24 hours after surgery.
Secondary Outcomes:
1.
Pain intensity by NRS at 0, 2, 4, 6, 10, 14, 18, and 24 hours after surgery.
2.
Incidence and severity of neuropsychiatric adverse events (graded by CTCAE).
3.
Incidence of postoperative nausea and vomiting.
4.
Total number of ketamine boluses and cumulative ketamine dose (intervention
group).
7. Sample Size Calculation
A preliminary pilot study involving 42 patients was conducted separately to assess the
variability of key parameters, including pain intensity measured by the Numeric
Rating Scale (NRS) and opioid analgesic consumption. This pilot phase was
completed prior to the initiation of the main study and served to inform protocol
refinement and sample size estimation. Based on the pilot data, the standard deviation
of the primary endpoint (total morphine equivalents consumed in the first 24 hours
postoperatively) and the minimal clinically important difference between groups were
calculated. Using these pilot-derived parameters, a formal sample size calculation was
performed with a statistical power of 80% and a significance level of p < 0.05. An
additional 10% margin was added to account for potential dropouts and study
withdrawals, yielding an initial target of 68 patients (34 per group). However, the
sample size was subsequently increased to 100 patients (50 per group) to further
strengthen statistical validity and enable subgroup analyses, particularly for patients
requiring repeated femoral nerve blocks. Patients undergoing knee arthroplasty who
met the eligibility criteria were enrolled in the main study between July 2025 and
January 2026. The pilot phase cohort (n=42) was conducted as a separate preliminary

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investigation and is not included in the main study enrollment of 100 participants
reported herein.
8. Statistical Analysis
A pilot study with 42 patients was initially conducted to assess the variability of key
parameters such as NRS pain scores and opioid analgesic consumption. The collected
data allowed for the calculation of standard deviations and the minimal clinically
significant difference between groups, which were then used to determine the required
sample size (power 80%, alpha 0.05). An additional 10% was added for potential loss
to follow-up, resulting in a sample size of 68 patients (34 per group).
Data Analysis:
Categorical variables will be compared using the chi-squared test or Fisher’s exact
test, as appropriate. Continuous variables will be tested for normality using the
Shapiro–Wilk test. For normally distributed variables, independent samples t-tests
will be used; for non-normally distributed variables, the Mann–Whitney U test will be
applied. Correlation analyses will use Pearson or Spearman correlation coefficients,
depending on data distribution. Statistical significance will be set at p < 0.05.
Multivariable Analysis:
A multivariate binary logistic regression will be performed with the occurrence of at
least one neuropsychiatric adverse event (yes/no) as the dependent variable.
Independent variables included in the model will be:

Ketamine dose at the onset of adverse event (mg)

Total ketamine dose over 24 hours (mg)

NRS pain scores at three time intervals (0–2 hours, 3–10 hours, 11–24 hours)

Sex (male/female)

Age (years)

Body weight (kg)

Height (cm)

Analgesia effectiveness (0 = effective, 1 = ineffective)

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All continuous variables will be included without prior categorization. Categorical
variables will be binary coded. The model will be assessed by β coefficients, odds
ratios (OR) with 95% confidence intervals, and p-values. Model quality will be
evaluated using the Hosmer–Lemeshow test. Results will be considered statistically
significant at p < 0.05.
All analyses will be performed using IBM SPSS Statistics version 27.0.
9. Ethics
The study protocol was approved by the Local Ethics Committee of the N.I. Pirogov
National Medical and Surgical Center (approval number: [Protocol №4, 21-May-
2025]). Informed consent will be obtained from all participants prior to enrollment.
10. References
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