Abstract
Background
Postoperative pain management in orthopedic surgeries, particularly after lower limb fractures, remains a challenge. Systemic opioids are commonly used but pose risks of addiction and adverse effects. This study investigates the potential of inhalational oxytocin as an adjunct for pain control.
Objective
To evaluate the effectiveness of twice-daily inhalational oxytocin administered three days before and two days after surgery in reducing postoperative opioid consumption.
Methods
A prospective randomized controlled trial was conducted with 36 patients undergoing lower limb fracture surgery. Participants were randomly assigned to two groups:
• Group I (control): Received an inhalational placebo.
• Group II (oxytocin): Received inhalational oxytocin.
Pain scores were assessed using the Visual Analog Scale (VAS), total postoperative morphine consumption, and the time to first analgesic request. Hemodynamic parameters and adverse events were also recorded.
Results
Patients in the oxytocin group demonstrated a delayed first analgesic request (12.89 hours vs. 8.05 hours in the control group, p = 0.001) and significantly lower total morphine consumption (3.22 mg vs. 7.39 mg, p = 0.001). VAS scores were significantly lower at 2, 4, and 6 hours postoperatively in the oxytocin group ( p = 0.015, 0.006, 0.001, respectively). No significant differences were observed in mean arterial pressure, heart rate, intraoperative fluid requirements, or adverse events between groups.
Conclusion
Inhalational oxytocin effectively reduced postoperative pain and opioid requirements without affecting hemodynamic stability or causing adverse events. These findings suggest its potential as a safe adjunct in postoperative pain management.
1
Introduction
Traffic accident is the most prevalent etiology of fractures, with femoral bone fractures being the most common type Orthopedic procedures are associated with severe acute pain and lasting chronic pain. , Implementing an improved pain management strategy is a an important aspect of postoperative care in orthopedic surgeries. Umanaged pain can lead to an inability to engage in physiotherapy, joint stiffness, , delayed wound healing, hemodynamic instability, progression to chronic pain, elevated costs, extended hospital stays, and elevated morbidity and mortality. Consequently, postoperative analgesia for femoral fractures is crucial for facilitating early mobilization, preventing complications, and restoring function. Doctors often prescribe opioids to relieve pain after orthopedic surgery because their effects last longer than in other types of surgery. However, patients need multiple doses, which can lead to addiction.
In addition to the pain resulting from the fracture, patients can experience postoperative complications such as incision pain, limb edema, and restricted mobility, which adversely impact their quality of life. Despite the increasing focus on postoperative pain and the numerous proposed strategies to alleviate it, the outcomes remain unsatisfactory. Up to seventy percent of patients are dissatisfied with the analgesic efficacy post-surgery, and an additional twenty-five to fifty-five percent from acute pain to chronic postoperative pain.
Opioids constitute a class of drugs utilized in pain treatment and management; nonetheless, opioid receptors distribution in and outside the nervous system results in a wide array of adverse effects from opioid analgesics, such as euphoria, dysphoria, respiratory depression, constipation, sedation, endocrine suppression, cardiovascular disorders (such as bradycardia), convulsions, nausea, vomiting, and pruritus. Moreover, prolonged administration of opioid analgesics may cause tolerance and, in certain patients, opioid-induced hyperalgesia and/or allodynia.
Opioids exhibiting serotonergic action, including oxycodone, tramadol, fentanyl, dextromethorphan, methadone, codeine, meperidine, and buprenorphine, may induce serotonin syndrome when administered concurrently with other serotonergic agents. Consequently, coadministration with other serotonergic drugs must be approached with caution or completely avoided.
Numerous investigations indicate that polypeptides, including oxytocin, reach trigeminal nerve, cerebrospinal fluid, and brain tissue following intranasal administration. Specifically, our and other groups, utilizing a radiolabeling technique in rodent models, have demonstrated that intranasally administered radiolabeled oxytocin accumulates in respiratory and olfactory epithelium, trigeminal ganglion, olfactory bulb, and various brain areas including hypothalamus, thalamus, midbrain, and pons.
Moreover, new research involving rodents and non-human primates offer direct proof that intranasal administration of labeled oxytocin reaches brain tissue by olfactory and/or trigeminal routes, accumulating in target regions such as amygdala and hippocampus. , The intranasal administration of exogenous polypeptides, like oxytocin, has demonstrated functionally significant increases in cerebrospinal fluid concentrations. ,
Intranasal oxytocin has been examined by multiple research groups for the alleviation of migraine and various other pain types. Analgesic impacts of intranasally administered oxytocin have been demonstrated for pain following mild traumatic brain injury, wound pain, chronic low back pain, and chronic pelvic pain. The neuronal activity modulation in trigeminal nerve, limbic and cortical brain regions, together with ascending and descending pain pathways in the spinal cord, has been proposed as potential mechanisms for the pain-modulating impacts of oxytocin. A present investigation utilizing functional magnetic resonance imaging in chronic low back pain patients indicates that the striatum is essential in the pain-modulating impacts of oxytocin. Besides chronic back pain, oxytocin serves an analgesic function in migraine. Garcia-Boll and colleagues have recently shown that oxytocin decreases neuronal firing in the trigeminocervical complex induced by meningeal electrical stimulation, a well-established electrophysiological model of migraine. Additional potential mechanisms for migraine relief involve the inhibition of Calcitonin gene-related peptide release, which is significant in migraine. Intranasal administration of oxytocin has demonstrated a reduction in headache frequency among patients with chronic and high-frequency episodic migraines.
This study proposes that inhaling oxytocin twice daily, three days before surgery and two days after, effectively reduces opioid consumption
2
Aim of the work
This investigation aimed to detect value of inhalational oxytocin in decreasing opioid consumption after lower limb fracture.
2.1
The primary outcome
Total postoperative morphine requirement in the first 72 postoperative hours.
2.2
The secondary outcomes
- 1.
Time to the first request of morphine rescue analgesia.
- 2.
visual analogue scale score 2, 4, 6, 12, 24, 48, 72 hours postoperative.
- 3.
Perioperative hemodynamics (MAP – HR).
- 4.
Postoperative side effect as nausea, vomiting.
3
Patients & methods
This prospective randomized controlled investigation was carried out over a duration of six months at Mansoura University Hospital. Following approval from the Institutional Research Board at the Faculty of Medicine, Mansoura University, patients were interviewed, and written informed consent was acquired from 36 patients scheduled for lower limb fracture surgery Fig. 1 .
Reporting Guideline: This randomized controlled trial was designed and reported in accordance with the Consolidated Standards of Reporting Trials ( CONSORT ) guidelines. A CONSORT flow diagram outlining the patient enrollment, allocation, follow-up, and analysis is included ( Fig. 2 ).
3.1
Inclusion criteria
- •
Age from eighteen to forty-five years old.
- •
ASA of class I and II.
- •
Both sexes.
3.2
Exclusion criteria
- •
Patient refusal.
- •
Uncontrolled psychiatric diseases.
- •
Known intolerance to the study drugs.
- •
Unstable cardiovascular condition.
3.3
Sample size calculation
Sample size estimation was based on pain score changes among patients with oxytocin and control group retrieved from earlier research. Utilizing the G power program version 3.1.9.7 to estimate the sample size based on an effect size of 1.13, an α error of 0.05, a 2-tailed test, and a power of 90.0 percent, the total estimated sample size was at least 18 patients in each group.
3.4
Randomization
36 eligible patients were randomly assigned utilizing a computer-generated randomization table, with group assignments concealed in sealed opaque envelopes, into two identical groups:
- •
Group I (control) (number=18): Patients received inhalational placebo twice daily for 3 days before the operation and continued for 3 days after surgery.
- •
Group II (oxytocin) (number=18): Patients received inhalational oxytocin twice daily for 3 days before the operation until the day of the operation and continued for 3 days after surgery.
3.5
Anesthetic management
Patients were assessed pre-operatively by:
- •
History.
- •
Physical examination.
- •
Basic laboratory tests plus investigations required for any morbid condition.
Patients were on inhalational drugs twice daily three days before surgery. On the patient’s arrival at PACU, under standard monitoring (Electrocardiogram, pulse oximetry, non-invasive blood pressure measurement), two 18 G or 20 G peripheral venous cannulae were secured, and 7 mL/kg of Ringer’s solution was infused. The VAS scale was explained to all patients.
3.6
Spinal anesthesia
Before spinal anesthesia, Ringer’s solution was continued for all patients in both groups in a sitting position. A median or paramedian approach was used. A dural puncture was performed at the L3–4 or the L4–5 interspace utilizing a 25-G needle by one anesthesiologist who was blinded to group assignments. A 2.5 ml of bupivacaine 0.5 % plus 20 μg fentanyl was then injected intrathecally after a free flow of cerebrospinal fluid was observed.
The anesthetist documented the patient’s height, weight, age, medical history, puncture level, block level, number of punctures, and vital signs (heart rate, blood pressure, electrocardiogram, oxygen saturation) prior to the block performance and subsequently every five minutes for forty-five minutes post-block.
3.7
Intraoperative assessment
Intravenous fluids were identical in the two groups 10 mL/kg/h, based on the intraoperative hemorrhage level.
Intraoperative sedation was provided with 0.01 to 0.03 mg per kilogram intravenous midazolam for anxious patients.
3.8
Postoperative management
At the end of the procedure, following admission to recovery, prior to discharge from recovery, and 6, 12 hours, and day one, all patients received ketorolac and paracetamol 500 mg every 8 hours and continued on inhalational drugs twice daily for three days postoperatively. Pain intensity at rest, movement, and on coughing was evaluated utilizing a 10-point visual analogue scale score at zero, two, four, eight, sixteen, and twenty-four hours post-operatively. When the patients experienced pain (visual analogue scale score more than four millimeters), a bolus dose of intravenous morphine 0.02 mg per kilogram was administered and could be repeated every fifteen minutes until a visual analogue scale score of not more than three millimeters was reached Figs. 3 and 4 .
The duration of analgesia for the initial rescue analgesic requirement was documented.
The total dose of analgesic utilized was recorded.
4
Result
The current investigation was randomized and controlled, and conducted on 2 groups; group 1 (control) who receive inhalational placebo twice daily 3day before operation and continue for 3days after surgery and group 2 (oxytocin) who receive inhalational oxytocin twice daily 3day before operation until day of operation and continue for 3days after surgery
A statistically insignificant distinction has been detected among investigated groups regarding age, sex and diagnosis of disease. Mean age of control group is 48.61±12.60 years versus 52.33±17.62 years for oxytocin group. As regards sex distribution; 38.9 % of control group versus 50 % of oxytocin group are males as shown in Table 1 .
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