A Prospective, Randomized, Controlled Trial of Methylene Blue Injection for Costal Cartilage Harvest Postoperative Analgesia

Abstract

Background

In plastic surgery, costal cartilage is an excellent support material. However, postoperative pain from costal cartilage harvesting can impact patient recovery and satisfaction with the surgery. Recent reports have shown that methylene blue (MB) is an effective local analgesic in postoperative management.

Objectives

We aimed to evaluate the safety and effectiveness of MB for pain relief in patients undergoing costal cartilage harvesting.

Methods

A total of 106 patients undergoing costal cartilage harvesting surgery were selected from the plastic surgery department between December 2022 and March 2024. They were randomly divided into 2 groups: the MB group and the ropivacaine group, with 53 patients in each group. Pain levels were assessed with a numerical rating scale, the Insomnia Severity Index (ISI), arm elevation angle, and postoperative satisfaction scales at 1 day, 3 days, 5 days, 1 week, 1 month, and 3 months postoperatively.

Results

Patients receiving MB exhibited a significant decrease in pain scores from 5 days to 1 month of treatment compared to the ropivacaine group. Additionally, in the MB group there was an improvement in ISI scores from 5 days to 1 month compared to the ropivacaine group. Furthermore, during the 3-month follow-up, the MB group had significant increases in satisfaction scores compared to the control group. Arm elevation angle in the MB group was significantly higher compared to the ropivacaine group at 5 days, 1week, and 1month. No serious adverse events were reported, with only 2 patients experiencing an allergic rash.

Conclusions

Methylene blue demonstrated significant pain reduction with minimal adverse effects.

Level of Evidence: 3 (Therapeutic)

In plastic surgery, ear deformities and nose deformities caused by congenital malformations or trauma are common. These surgeries often necessitate the use of scaffold materials for reconstruction. Autologous rib cartilage, with its high toughness, malleability, and excellent mechanical strength, is widely chosen for these reconstructive procedures.^1,2 However, due to its deep tissue location, harvesting rib cartilage inevitably causes significant trauma to surrounding tissues, leading to severe postoperative pain. This intense pain greatly affects the psychological well-being of patients undergoing repair and cosmetic procedures, severely limiting a positive postoperative experience. Given the prevalence of this problem, new and improved pain treatment options are desperately needed.

Currently, standard postoperative pain management methods include patient-controlled intravenous analgesia (PCIA), oral analgesics, and local anesthesia infiltration around the donor site. However, these methods have not been successful in providing lasting and efficient relief. Recent reports have identified methylene blue (MB) as an effective local analgesic for postoperative pain management.³ MB is a guanylyl cyclase inhibitor capable of suppressing the production of superoxide radicals. It has been demonstrated to serve as an antioxidative and anti-inflammatory agent in the treatment of a variety of conditions. Of particular note, MB has recently been reported as an effective treatment for various painful syndromes, including postoperative pain, discogenic pain, and neuropathic pain.^3,4 Its analgesic mechanism operates through the destruction of nerve endings, and it may also facilitate anti-inflammatory effects by inhibiting the nitric oxide inflammatory pathway with induced guanylate cyclase.⁵

The aforementioned research suggests that MB injection is a promising option for managing postoperative pain following rib cartilage harvest surgery. However, the ability of this method to provide safe, effective, and long-term analgesia remains uncertain. Therefore, this prospective randomized study was designed to evaluate the efficacy and safety of MB in providing postoperative analgesia following costal cartilage harvest surgeries.

METHODS

Participants

The study cohort consisted of 106 participants who required rib cartilage extraction for rhinoplasty procedures. These individuals were enrolled between December 2021 and March 2024 in the Department of Plastic Surgery. Participants were excluded if they had the following conditions: long-term use of analgesics, a local anesthesia allergy, mental disorders, inadequate cognitive abilities, presence of depression, or were undergoing treatment for depression with antidepressants or anxiolytic drugs. Follow-up assessments were conducted up to 3 months postsurgery. All enrolled patients provided signed informed consent before undergoing injection, and the study protocol received approval from the Ethics Committees of Xijing Hospital (approval no. KY20200611-G-1). Patients were randomized to receive either methylene blue (MB) injections or ropivacaine treatments immediately after the single rib cartilage harvest surgery. The allocation scheme was derived from a table of random numbers. The study employed a 1:1 randomization of MB injection and ropivacaine.

MB Injection

In all experimental groups, the surgical harvest of costal cartilage was performed by the same surgeon. We utilized a 3-cm incision to obtain a 5-cm segment of costal cartilage, with the incision made directly above the cartilage. Treatment with methylene blue (MB) injection or ropivacaine was meticulously carried out according to the designated intervention, specified within a sealed envelope to maintain the integrity of the randomization schedule. Both the patients and the surgeons conducting the postoperative follow-up examinations were kept unaware of the specific injectable, ensuring proper blinding. Due to the distinctive blue coloration of MB, the surgeons who performed the injection were excluded from the patient follow-up to prevent unblinding. For the intervention, 2 mL of 1% MB solution (20 mg, Ji Chuan Pharmaceutical Ltd., Jiangsu, China) or 2 mL of ropivacaine solution (10 mg, Rui Yang Pharmaceutical Ltd., Shandong, China) were administered into the intercostal nerves and muscles immediately after removal of the costal cartilage. Posttreatment, patients were shielded from any interaction with individuals who had knowledge of the randomization details to preserve the study's double-blind design.

Follow-up and Outcome Measures

Follow-up assessments were conducted at time intervals postoperatively: 1 day, 3 days, 5 days, 1 week, 1 month, and 3 months. To minimize the risk of investigator bias, these evaluations were carried out by a clinician or researcher who was blinded to the patient group allocations. The primary aim of the study was to evaluate and compare the effectiveness of pain relief across the 2 groups. The main outcomes were quantitatively measured by changes in pain intensity, utilizing a numerical rating scale (NRS) for pain self-assessment. Additional parameters included patient satisfaction, sleep quality, upper limb mobility, and any complications arising from the treatment.

Numerical Rating Scale

The severity of patient pain was quantified with a numerical rating scale. This scale facilitated assessment of pain intensity in the 2 study groups. NRS scores ranging from 0 (no pain) to 10 (worst pain imaginable)were recorded in the 2 groups and provided a detailed metric for capturing subtle variations in the patients’ pain experiences.

Sleep Quality

The Insomnia Severity Index (ISI), a validated 7-item self-report instrument, was employed to gauge the severity of insomnia symptoms. This questionnaire, designed to evaluate the nature and impact of insomnia over a retrospective 2-week period, culminated in a composite score ranging from 0 to 28, with lower scores denoting improvement in the symptoms of insomnia.

Arm Elevation Angle Assessment

Arm elevation angle assessment was performed to detect the recovery of motor function in patients. Patients were positioned in an upright seated posture, with arms being elevated anteriorly in line with the body to gauge the angle of arm elevation achievable without pain. The angle was measured with the arms naturally hanging along the midaxillary line as the baseline reference of 0 degrees and reaching an angle parallel to the shoulders, considered as 90 degrees.

Postoperative Satisfaction

We evaluated patients’ pain satisfaction with treatment outcomes with a 5-point Likert scale, including very satisfied (5 points), satisfied (4 points), average (3 points), dissatisfied (2 points), and very dissatisfied (1 point).

Emergency Preparedness

Any event with the potential to be life threatening or capable of resulting in disability or deformity served as grounds for terminating the study immediately. Regarding complications related to MB injections, there was a risk of neurologic deficits or acute allergic reactions. Any participant in the MB injection group experiencing symptoms such as numbness, dysesthesia, or radiating leg pain and weakness in the lower extremity was to undergo comprehensive neurological evaluation, including magnetic resonance imaging and electromyography. Furthermore, any participant in the MB injection group presenting with symptoms of generalized pruritic eczema or shock would be treated with a desensitization protocol involving corticosteroids, and emergency administration of adrenocortical hormones would be readily available for resuscitation purposes.

Sample Size

Due to the lack of benchmarks for the efficacy of local MB injections in patients undergoing rib cartilage harvest, a pilot study was carried out before commencement of the main research. This step was taken in adherence to the ethical standards set forth in the Declaration of Helsinki and was sanctioned by the Ethics Committee. The assignment scheme was generated from a table of random numbers. The random assignments were stratified in each study group. Results from the pilot study revealed that the treatment was 50% effective in the ropivacaine group (5 out of 10 patients) and 90% effective in the MB group (9 out of 10 patients). With a 2-tailed alpha set at 0.05 and aiming for a statistical power of 90%, it was calculated that a minimum of 96 patients would need to be evenly distributed among the randomized groups to detect a primary outcome reliably. Considering a 10% loss to follow-up, the sample size was at least 106 in total, and 53 in each group (Figure 1).

Statistical Analysis

Quantitative variables were summarized as mean ± SD, and comparisons between groups were conducted with a suite of statistical tests. The chi-square test and Levene's test for equality of variances were deployed to evaluate the homogeneity of variances, and Fisher’s exact test and the independent samples t test were utilized to ascertain differences between the groups as appropriate. The conformity of the measurement data to a normal distribution was verified with the Kolmogorov-Smirnov test. For data adhering to a normal distribution, analysis was performed with the independent t test as well as the repeated measures analysis of variance (ANOVA). The threshold for statistical significance was set at P < .05. All statistical analyses were executed with SPSS software (version 22; SPSS Inc., Chicago, IL).

RESULTS

Preoperative Patient Characteristics

The demographic profiles of the patients, including gender, age, height, weight, body mass index (BMI), numerical rating scale score, and Insomnia Severity Index (ISI) score, were meticulously documented before surgery. The baseline characteristics were similar in the 2 groups. At the 3-month follow-up, a total of 100 patients were enrolled in 2 groups, the MB group with 51 patients and ropivacaine group with 49 patients. There were 38 females and 13 males in the MB group, and the ropivacaine group consisted of 36 females and 13 males. The mean age for patients in the MB group was 33.12 ± 6.15, and in the ropivacaine group it was 34.42 ± 5.51. Comparative analysis revealed no statistically significant disparities in these parameters between the 2 cohorts (Table 1).

Numerical Rating Scale Pain Scores

When compared with the ropivacaine cohort, the NRS scores at 5 days, 1week, 2 weeks, and 1month were significantly reduced in the MB group. Notably, the NRS scores were observed to be at their nadir in the ropivacaine group on day 1, subsequently exhibiting a marked increase after day 5 (Figure 2).

The Insomnia Severity Index

Before the operation, there was no discernible difference in the baseline Insomnia Severity Index (ISI) scores between the 2 groups. The ISI scores displayed a notable increase in both groups at the 1-day mark. Subsequently, the scores in the ropivacaine group showed a gradual increase, whereas those in the MB group did not exhibit any significant change. Moreover, at each subsequent observation time point, 5 days, 1 week, 1 month, and 3 months postsurgery, the ISI scores of the MB group were substantially lower than those of ropivacaine group, with the differences reaching statistical significance (P < .05) (Figure 3).

Postoperative Satisfaction

Patient satisfaction with treatment outcomes was measured with a 5-point Likert scale. In MB groups, patients expressed satisfaction of 4.21 ± 0.41 points with the treatment. In ropivacaine group, patients expressed satisfaction of 2.11 ± 0.38 points with the treatment. Notably, patients in the MB group reported significantly higher satisfaction levels at 3 months postsurgery compared to those in the ropivacaine group (P < .05) (Table 2).

Arm Elevation Angle Assessment

Before the operation, there was no significant difference in arm elevation angle scores between the 2 groups. On the first day postsurgery, although the arm elevation angle was slightly higher in the MB group compared to the ropivacaine group, there was no statistically significant difference. Interestingly, at 5 days and 1 week postsurgery, the arm elevation angle in the ropivacaine group was significantly lower than the first day postsurgery. However, at 5 days, 1week, and 1 month postsurgery, the arm elevation angle in the MB group was significantly higher compared to the ropivacaine group, with the differences reaching statistical significance (P < .01) (Table 3).

Adverse Complications

During the follow-up period, there were no adverse complications reported in either group, such as vascular puncture, hypotension, bradycardia, pleural puncture, pneumothorax, or poisoning from ropivacaine or methylene blue. There were only 2 patients who had a postoperative rash, which was successfully alleviated with an intravenous infusion of a steroid sodium chloride solution. Additionally, all surgical incisions healed well, with no instances of necrosis or infection observed. Some patients exhibited blue staining at the incision site, and the blue discoloration of the skin vanished within a week because the substance was metabolized through the urine. Patients experienced a light green change in their urine, which gradually faded over time postsurgery. The urine typically returns to its normal color after about a week.

DISCUSSION

Pain is an adverse sensory and emotional experience linked with actual or potential tissue damage. The occurrence of postoperative pain can lead to several complications, such as atelectasis and pulmonary infections, which can negatively impact early mobility and extend the recovery period after surgery.⁶ Effectively managing postsurgical pain is crucial for improving respiratory function, reducing the risk of developing chronic pain conditions, encouraging early movement, aiding the prompt return of bowel function, minimizing postsurgical morbidity, and enhancing postoperative rehabilitation efforts.⁷ MB has been employed in the treatment of various painful conditions, including postoperative, discogenic, and neuropathic pain. Our article aims to explore the efficacy and safety of MB for local postsurgical anesthesia in comparison to long-acting anesthetics like ropivacaine in patients undergoing rib cartilage harvesting in plastic surgery.

Pain is a distressing physical and emotional experience that can significantly affect patient treatment outcomes and satisfaction with postoperative care.⁸ Excellent pain management following surgery is not only desired but essential. In extreme cases, pain may lead to complications such as pulmonary atelectasis and infections. Additionally, the tachycardia and elevated arterial systolic pressure stemming from postoperative pain can increase bleeding, exacerbate sensations of chest tightness and pain, prolong the duration of drainage tube placement, and ultimately delay recovery and affect the overall surgical outcome.⁹ Superior postoperative analgesia is vital to facilitate swift patient recovery and prevent postoperative complications.

Current analgesic methods employed after surgery include oral medications, intravenous pain relievers, and local infiltration with anesthetics.¹⁰ However, oral analgesics often provide inadequate relief. Although postoperative analgesia pumps that deliver medication slowly address this issue, they have their drawbacks.¹¹ High doses of opioids may lead to adverse effects, including nausea, vomiting, and drowsiness.¹² Local anesthesia is simple and effective, yet the short half-life of common local anesthetic agents is a limitation. Ropivacaine is a regional anesthetic commonly utilized for its prolonged duration of action, minimal side effects, and extensive range of efficacy. Reports suggest that intercostal nerve blocks with ropivacaine can effectively alleviate pain in patients undergoing thoracic surgery.¹³ However, for pain following rib cartilage harvesting, the duration of relief provided by local infiltration of ropivacaine remains relatively short. The analgesic effects of ropivacaine as a long-acting local anesthetic last for up to 72 hours. Selecting an optimal analgesic strategy is of the utmost importance.

Since its initial synthesis in 1876, methylene blue has found myriad applications in diverse medical fields. Notably, as a neurolytic agent, methylene blue has shown remarkable efficacy in treating conditions such as pruritus ani and alleviating the pain associated with acute fractures.¹⁴ The analgesic timeline associated with methylene blue suggests neurolysis as a plausible mechanism, seemingly acting as a long-term inhibitor of peripheral axons by denaturing extracellular nociceptive nerve terminals.¹⁵ This leads to a breakdown of pain nerve conduction due to neural destruction. Typically, peripheral nerve damage results in acute axonal degeneration within 30 minutes. This degenerative process progresses with cellular membrane swelling and, within 24 hours, leads to the disruption of myelin sheaths within the peripheral nervous system. Additionally, anti-inflammatory properties of methylene blue have been posited, particularly through the inhibition of the nitric oxide inflammatory pathway through an interaction with induced guanylate cyclase.¹⁶ Previous studies have consistently confirmed the long-term analgesic effects of methylene blue. Our research, extending over a 3-month follow-up period, reveals that the analgesic efficacy of methylene blue did not demonstrate any significant decline over this duration. Consequently, in our experiments, methylene blue has proven to be a long-term and effective analgesic for postoperative pain following rib cartilage extraction.

Following the removal of rib cartilage, we can directly visualize the ribs and the plane beneath, which allows for precise local injections. During the removal process, the intercostal muscles are widely dissected and damaged, leading to severe local irritation from the tissue destruction, which also contributes to postoperative pain.¹⁷ The pain after rib cartilage removal is caused by the intercostal nerves and local muscle pain. Therefore, the blockade of the intercostal nerves and their surrounding muscle planes is widely employed in procedures such as thoracotomies, breast surgeries, and treatment of rib fractures to mitigate anterolateral chest wall pain.¹⁸ We opted to administer methylene blue (MB) locally in the block of the anterior serratus muscle and intercostal muscles, which can be performed for patients undergoing costal cartilage harvest. This technique facilitates analgesia by blocking the lateral cutaneous branch of the intercostal nerve.

Although methylene blue (MB) has generally been considered safe, there have been multiple reports concerning its cytotoxic and neurotoxic effects.¹⁹ These adverse effects include hemolytic anemia, phototoxicity, and apoptosis in the central nervous system.²⁰ Notably, neurotoxic side effects have been predominantly reported in cases following MB injections. For instance, lumbar intrathecal administration of MB has led to paraplegia and spinal cord necrosis. Epidural administration of MB has also resulted in paraplegia and inflammation of both the spinal cord and nerve roots in cats, as well as quadriplegia associated with spinal inflammation in a human patient.²¹ Intravenous administration of MB has been linked to toxic encephalopathy–like symptoms, including confusion, aphasia, and disorientation. Interestingly, a vast majority of previous studies have emphasized the neuroprotective effects of MB, making its safety a point of interest. However, complications and adverse reactions associated with postoperative local injections of MB for postsurgical pain have been infrequently reported. Our research confirms this, with only a single patient experiencing local pruritus, which significantly subsided after administration of a corticosteroid infusion. No other significant neurological reaction or local skin discomfort was observed among the patients. Some studies have raised concerns about skin necrosis as a potential complication of MB injection.^22,23 However, our follow-up on skin incision healing after costal cartilage removal revealed no adverse effects on wound healing due to MB. Therefore, we believe that local injection of MB to manage postsurgical pain is both safe and effective. However, the product information for MB does not provide guidance on this method of local injection. We have only conducted clinical experiments with this drug, and a significant number of cytotoxicity studies and large-scale multicenter clinical trials are needed to evaluate its safety and efficacy for standardized clinical use.

Our study employed a large sample size design and included long-term follow-up of patients following methylene blue (MB) injection. However, this study still had some limitations. In the application of MB in other clinical subspecialties, no significant clinical side effects or toxic reactions have been reported. Drawing inspiration from other clinical subspecialties’ application of MB, we only conducted clinical observational studies in this experiment. Future research should include validation studies at the cellular level. In addition, we conducted a 3-month follow-up on the postoperative pain of patients after injection, and although injection of MB can significantly reduce early postoperative pain, pain perception also exists. There have been no reported cases of long-term sensory changes in our patients. However, we did not conduct further follow-up on long-term pain perception. Long-term follow-up is scientifically rigorous, and further exploration of the effects of MB on deep and superficial sensory changes would be meaningful.

CONCLUSIONS

In summary, methylene blue can effectively alleviate pain following costal cartilage removal, enabling patients to navigate the perioperative period with increased comfort. Local infusion with MB can significantly reduce pain intensity, all while incurring minimal to no serious adverse side effects.

Acknowledgments

Drs Z Zhang and Zhu contributed equally to this work as co-first authors.

Disclosures

The authors declare that they have no known competing financial interests or personal relationships that influenced the work reported in this paper.

Funding

This work was supported by grants from the National Natural Science Foundation of China under Grant 82102355, and the Air Force Medical University clinical research project 2014LC2214.

REFERENCES

Author notes