Category: 8. Health

The Public Health Ministry on Monday issued a warning against purchasing ultrasonic scalers online for self-use to remove plaque and tartar, cautioning that improper use could damage teeth and lead to infections.

Anukool Pruksanusak, spokesman for the ministry, issued the warning after ultrasonic scalers gained popularity on social media, with advertisements claiming that users could save money by cleaning their teeth at home instead of visiting a dentist.

Anukool stressed that only qualified dentists are trained to use ultrasonic scalers safely and effectively, as their use requires experience, manual skill, sensory precision, and a thorough understanding of oral anatomy. Without these, improper use can cause harm rather than benefit.

A research team in Japan has outlined a newly developed model for predicting the likelihood of intracranial aneurysms recanalising after coil embolisation treatments. Detailing their work in the Journal of Stroke and Cerebrovascular Diseases, researchers propose a “practical, externally validated” scoring system based on four significant risk factors for recanalisation: rupture status, aneurysm volume, Raymond-Roy occlusion classification (RROC), and volume embolisation ratio of the first coil (FVER).

Via a single-centre, retrospective analysis including patients with cerebral saccular aneurysms who underwent initial coil embolisation at their hospital between 2012 and 2023, Ken Aoki, Hiroyasu Nagashima and Yuichi Murayama—all based at the Jikei University School of Medicine in Tokyo, Japan—attempted to provide clarity on the known postoperative recanalisation risks associated with the procedure. Prior analyses have revealed recanalisation rates close to 25% in addition to retreatment rates of roughly 10–20% in these cases.

The researchers excluded cases in which there was less than one year of follow-up, retreatment, or utilisation of bioactive coils, and their key outcomes of interest were postoperative RROC scores in addition to a number of aneurysm characteristics. Univariate and multivariate Cox proportional hazard models were used to identify independent recanalisation predictors, with a simplified risk score being constructed using least absolute shrinkage and selection operator (LASSO) logistic regression and β-coefficients from multivariable analysis. Both internal and external validation of the scoring system were performed.

Some 79 patients were ultimately analysed, with 21 experiencing recanalisation (26.6%) and eight undergoing retreatment during the follow-up period. Based on multivariate analyses, the researchers identified aneurysm rupture, aneurysm size >7mm, neck size >5mm, aneurysm volume >155mm³, immediate postoperative absence of complete aneurysm occlusion (RROC without Class I), FVER <8%, and first coil percentage (FCP) <26%, as potential recanalisation predictors. They also found that, while balloon assistance was more prevalent in recanalised versus non-recanalised patients, this difference did not reach statistical significance.

The researchers subsequently settled on four independent predictors of post-coiling recanalisation: aneurysm rupture, aneurysm size ≥7mm, RROC without Class I, and FVER <8%. An integer-based risk scoring system—ranging from zero to seven in value—was constructed based on these variables.

“In the cohort analysed in this study, the model demonstrated strong discrimination with a C-statistic of 0.87,” the authors note. “Internal validation using 1,000 bootstrap replications yielded a bias-corrected C-statistic of 0.89. External validation was conducted using an independent cohort of 468 patients, of whom 35 (7.5%) experienced recanalisation. The model retained good discriminative ability in this external dataset with a C-statistic of 0.81.”

They go on to detail that calibrations within the external validation cohort revealed a “slight overestimation” of recanalisation risk in patients with higher scores, while the Hosmer-Lemeshow test indicated a statistically significant ‘poor fit’ (p=0.0007) for the model. Risk stratification based on total scores demonstrated “clinically relevant separation”, as recanalisation occurred in 1.8% of patients with low scores (0–2), 13.5% with intermediate scores (3–4), and 41.5% with high scores (5–7), confirming—in the researchers’ view—the utility of their scoring system for individualised risk assessments.

While several prior studies have proposed alternative models for predicting post-coiling aneurysm recurrence, the present approach is distinct from these efforts in that it places greater emphasis on “clinical practicality”, and ultimately offers a “simple” solution to inform risk-based follow-up planning and support clinical decision-making.

“Aneurysm volume had the highest individual AUC [area under the curve] but, due to measurement variability, aneurysm size was used instead,” the authors explain. “FVER was chosen over FCP as it can be computed immediately post-embolisation without procedural dependency. The score reflects effect sizes from the multivariable model, while accounting for predictor collinearity. When applied to our cohort, our model demonstrated superior discriminative power (AUC, 0.89) compared to [other] models.”

The researchers feel that key limitations of their study include its single-centre, retrospective nature and relatively small number of recanalisation events in both cohorts—and, while their model appears able to effectively distinguish between low- and high-risk patients, its predictive probabilities “did not fully align with observed outcomes in the external population”.

“This discrepancy may reflect differences in patient characteristics, procedural techniques or follow-up imaging schedules between cohorts,” they add. “Nevertheless, risk stratification remained clinically meaningful across all score categories. Based on the observed threshold, we propose that patients with a score ≥3 be considered for shorter-interval imaging follow-up due to increased recanalisation risk.”

Concluding their paper, the authors posit that further multicentre validations across diverse populations are necessary to fully establish the scoring system’s generalisability, and—while they included morphological and procedural variables—haemodynamic factors like wall shear stress were not evaluated and should be incorporated into future prediction models utilising larger, prospective datasets.

Introduction

Glaucoma is defined as a progressive optic neuropathy that will ultimately lead to considerable visual field loss and eventually cause blindness.¹ Glaucoma’s prevalence estimated to reach 111.8 million people worldwide in 2040, with around 8.39% of blindness cases caused by glaucoma worldwide.^2,3

Slowing disease progression and preserving the visual field and, by extension, patient quality of life are the key goals for glaucoma management. Reduction of intraocular pressure (IOP) is the only proven method to treat glaucoma, where it can be decreased utilizing medical therapy, eye drops and oral medication, laser therapy, surgery, or a combination of therapies.⁴

Surgical procedures have advanced over the past 40 years from full-thickness techniques to guarded filtration procedures, and options vary from trabeculectomy, deep sclerectomy, tube shunts, and suprachoroidal derivation (SCD).^1–4

Trabeculectomy is not frequently used as the first-line procedure; it is primarily performed in eyes that are resistant to medical and laser interventions and in advanced cases. When comparing trabeculectomy with nonpenetrating surgeries (deep sclerectomy, viscocanalostomy, and canaloplasty), a meta-analysis reported that while trabeculectomy was more effective in reducing intraocular pressure, it carried an increased risk of complications such as fibrosis, infections or hypotony.⁵ Moreover, the use of postoperative medication was still needed frequently to maintain adequate IOP control.^6–8 This has led researchers to look for methods to mitigate such complications.

One such technique under study is trabeculectomy with suprachoroidal derivation (SCD). It is a relatively new surgical technique developed by Rodolfo A. Perez et al and introduced in the literature in 2013.⁹ Two filtration mechanisms are used to decrease IOP. First, the classical route is created by trabeculectomy, where aqueous humor is drained from the anterior chamber via the subconjunctival fistula, and the second route utilizes the suprachoroidal space to filter aqueous through the uveoscleral mechanism.

Theoretically, these two mechanisms will provide superior IOP control and maintain aqueous drainage through the suprachoroidal space in the event of bleb failure over time.

In the literature, there is scarce of data regarding the outcome of trabeculectomy with suprachoroidal derivation procedure, only one case series including 41 eyes was published by Perez-Grossmann et al in 2019.

In this study, we retrospectively evaluated the outcomes of suprachoroidal derivation procedure in patients with uncontrolled IOP in a tertiary hospital in Saudi Arabia. The primary outcomes were the assessment of the procedure’s efficacy and, more importantly, its safety during the procedure and postoperatively. This article considers the largest case series evaluating the outcome of this new technique.

Methods

This study is approved by the local ethics committee at Prince Sultan Military Medical City. Records of the patients who underwent suprachoroidal derivation surgery between the years 2012 and 2018 were accessed, and relevant patient data were retrospectively reviewed. Inclusion criteria: patients with moderate or severe glaucoma whose high IOP is uncontrolled using topical and oral anti-glaucoma medications who underwent trabeculectomy with suprachoroidal derivation. Exclusion criteria included: 1) patients with a history of glaucoma surgery, including trabeculectomy or glaucoma drainage devices, and 2) a history of uveitis. Given the retrospective nature of the study, patient consent to review their medical records was waived. However, strict patient confidentiality was maintained and complied in accordance with the Declaration of Helsinki.

Surgical Procedure

Topical and subconjunctival anesthesia is applied with Proparacaine and Lidocaine 2%, respectively. A 6 mm fornix-based conjunctival fornix-based incision is made in the superior or superior temporal quadrant, with a 2 mm relaxing incision in each end performed for better visualization. Tenon’s capsule is dissected, followed by episcleral vessel cauterization. With a 3 mm Crescent knife, a 5x5x5mm limbus-based scleral flap with 50% thickness that reaches the clear cornea is made. A second rectangular 4x3x4mm limbus-based scleral flap of 30% scleral thickness is built below the first one. A microsponge is used to apply Mitomycin-c (0.4mg/mL) for 3 minutes in a central area of 7 mm, and then copious saline solution is used to irrigate the area. Using Vannas scissors, the inner flap was divided into three sections measuring 1 mm each, and then the central flap was removed. To reach the suprachoroidal space, a 2-mm Crescent knife was used to make a 3-mm incision of the 20% remaining scleral thickness, Figure 1. With a blunt spatula, the suprachoroidal space was carefully dissected, and with a Kelly punch, a 0.9 mm incision was made in the posterior lop of the remaining sclera, Figure 2. The lateral scleral flaps were inserted in the suprachoroidal space, allowing the aqueous to flow from the anterior chamber to the suprachoroidal space, Figure 3. A side port knife was used to create a 1-mm penetrating incision at the limbus, and then a Kelly punch was used to take a 0.9 mm bite. Vannus scissors were used to create basal iridectomy, which allowed the anterior chamber to communicate with the scleral channel. The channel was covered with the first scleral flap to create a tunnel, and it was sutured with one stitch in each corner and two stitches in each of the three sides of the flap using Nylon 10/0 to get a watertight seal. The scleral flap was used to cover the newly formed channel. A single stitch was used in each corner, followed by a double stitch to seal the three sides of the flap. Finally, using a 10–0 nylon, the conjunctiva was sutured to the limbus.

Figure 2 Shows 0.9mm incision made in the posterior lop of the remaining sclera by the Kelly punch.

Figure 3 Shows the lateral scleral flaps inserted in the suprachoroidal space, allowing the aqueous to flow from the anterior chamber to the suprachoroidal space.

Postoperatively, all patients received Prednisolone Acetate 1% drops every 4 hours daily with slow tapering over a period of 8 weeks, also all patients received moxifloxacin drops every 6 hours for 2 weeks.

Outcomes

Relevant outcomes were recorded before and after surgery and at each consecutive visit for all patients. Outcomes included best corrected visual acuity using the Snellen chart, intraocular pressure measured by the Goldman applanation tonometer, and dilated fundus exam. All examinations were performed by ophthalmologists and confirmed by a single doctor who performed the surgeries.

Visual acuity was converted into LogMar for all patients. For eyes with irregular corneas that could affect the readings, the Goldman applanation tonometer was substituted for tonometry (Tono-Pen; Reichert Technologies).

The number of topical medications used was recorded before and after surgery and in subsequent follow-up visits. The need for adding medication and bleb needling was documented based on IOP elevation and clinical judgment. Lens status was documented as phakic or pseudophakic eyes. Types of glaucoma were separated into categories recorded as primary open angle, primary closed angle, pseudoexfoliation, neovascular and other secondary angle closure, Table 1.

Table 1 Frequencies of Types of Glaucoma

We define surgical success as IOP control to between 6–21 mmHg postoperatively with no medication use three months postoperatively. Qualitative success is defined as the need to use one medication to maintain IOP control. Failure is defined as use of two or more antiglaucoma medications post operatively to control IOP or failure to control IOP post operatively.

Statistical Analysis

Analysis was performed by a trained statistician using SPSS version 27. Mean and standard deviation are used to present continuous baseline data, and frequency and percentages are used to report categorical data. A repeated measures t-test was used to compare mean differences, and a p-value < 0.05 was considered statistically significant.

Results

Data Screening

After the data cleaning, a total of 59 patients (71 eyes) who underwent trabeculectomy with suprachoroidal derivation by a single surgeon were included in this analysis. A summary of group statistics and results of statistical testing are found in Tables 2 and 3.

Table 2 Summary of Group Statistics

Table 3 Summary of Statistical Testing Results

The sample consisted of 71 eyes, 62% males and 38% females, with a mean age of 67.94 years (SD = 9.047). The minimum age was 51, whereas the maximum was 88. The median follow-up period was 23 months. Out of the 71 cases, 28 cases (39%) were combined with phacoemulsification.

Visual acuity was assessed before and after surgery, and no statistically significant difference was observed (M = 0.559, SD = 0.642) to post-op (M = 0.555, SD = 0.676), t(70) = 0.115, p = 0.909. The surgery was not related to any change in VA following surgery. Intraocular pressure change was found to be statistically significantly reduced after surgical intervention. A repeated measures t-test found IOP from before surgery (M = 18.77, SD = 7.194) to post-surgery (M = 13.69, SD = 4.842), t(70) = 4.889, p = 0.0001, IOP in patients reduced from pre-surgery to post-surgery significantly. A Paired t-test was conducted to examine the change in the number of medications before and after surgery. Results showed that there was a statistically significant change in the number of medications from pre-surgery (M = 3.28, SD = 1.185) to post-surgery (M = 1.11, SD = 1.358), t(70) = 11.729, p = 0.0005.

A secondary analysis was performed to assess the relationship between suprachoroidal derivation surgery and three variables: gender, lens status, and type of glaucoma. Results showed that there was a significant gender difference between males (M = 7.159, SD = 9.096) and females (M = 1.704, SD = 7.124) (t(69) = −2.654, p = 0.010) on IOP changes. Results showed that males demonstrated higher IOP reduction than females.

An independent samples t-test was carried out to assess the difference in IOP change based on lens type. Results showed that there was no significant difference in IOP changes based on lens type: pseudophakic (M = 3.902, SD = 9.102) and phakic (M = 6.7, SD = 8.15), t(69) = −1.336, p = 0.186.

An independent samples t-test was conducted to assess the difference in IOP change based on the type of glaucoma. Results revealed that there was no significant difference in IOP change based on the type of glaucoma (F(7, 63) = 0.388, p = 0.906) as summarized in Table 4.

Table 4 Differences in Changes in IOP Based on the Type of Glaucoma

A final analysis was performed to ascertain the success of suprachoroidal derivation in glaucoma patients in terms of intraocular pressure (IOP) and the number of medications postoperatively at three months. Table 5 illustrates the proportion of participants who achieved complete success, qualified success, or failure. The proportion of patients who achieved complete success after surgery (47.9%), followed by qualified success (29.6%), and failure at (22.5%). Patients maintained these outcomes 23 months after surgery.

Table 5 Proportion of Patients’ Success of Surgery

Discussion

Compared to the published literature,^9,10 this study is the largest cohort study in terms of the sample size of 71 patients undergoing the novel technique of trabeculectomy with suprachoroidal derivation. This technique has an advantage over the standard trabeculectomy technique by employing two separate pathways to maintain aqueous drainage: the subconjunctival space through the trabeculectomy fistula and the suprachoroidal space utilizing the uveoscleral outflow. Theoretically, this should help maintain aqueous outflow through the secondary suprachoroidal space if the filtering bleb fails due to vascularization or fibrosis.

The success rate of glaucoma filtration surgery rests upon the wound healing process and the stability of the bleb over time.^10–13 Complications during wound healing increase the risk of IOP elevation and progression of optic disc damage and, ultimately, visual field loss and reduced visual acuity.^12–14 Failure of trabeculectomy in the past denotes a higher risk of failure in subsequent surgeries in the same eye, including drainage devices.¹⁵ Using mitomycin-C increases the rate of success but also increases the risk of future complications.¹⁶

The reasoning behind utilizing the suprachoroidal space is related twofold. First, the process of bleb scarring is hypothesized to be related to exposure to aqueous rich with inflammatory mediators; this leads to a fibrotic response when in contact with tenon tissue. Second, the choroidal resorptive function and the negative difference in hydrostatic pressure and the natural counterpressure of the suprachoroidal space are documented in the literature as having a predilection against hypotony while simultaneously allowing for aqueous drainage. Thus, from a technical and a practical perspective, the suprachoroidal space is an attractive option for assisting in aqueous outflow.

Perez-Grossmann et al, in 2019, studied the effects of the suprachoroidal derivation technique on 41 eyes (31 completed the 24-month follow-up) and found no statistically significant demographic difference between pre- and post-follow-up patients. Mean IOP showed a reduction of 11.29 ± 9.32 mmHg from baseline, a 48.60% statistically significant reduction (p<0.001). Moreover, glaucoma medication usage was reduced from baseline in 80.65% of the sample (p<0.001), with 96.77% of patients achieving an IOP <15 mmHg at the last follow-up.¹⁰ Both findings are consistent with our findings in the study where mean IOP was reduced by 5.08 ± 2.35 mmHg (p<0.0001) and post-op number of medication reduced by 2.17 ± 0.17 (p<0.0001) with an average follow-up of 17 months.

Contrary to their findings, however, we did find a significant difference between male and female IOP of 5.04 ± 1.98 mmHg (P<0.0001). This could be due to the increased number of male patients included in this study compared to females or could be due to a disparity in IOP measurement between the genders prior to the surgical intervention; neither interpretation can be discerned as the cause of this variability with certainty.

It is important to note that among the 71 patients included in this study, no intraoperative complications were reported. This is a central point, given the concern over the dreaded suprachoroidal hemorrhage or detachment complications that could be associated with filtration surgeries. However, the complication distribution post-op included hypotony (2 patients; one needing AC reformation 1st-day post-op), microleak (3 patients), and hyphema that resolved one week after surgery. The overall postoperative complications due to this technique were 10% resolving within the first week of surgery. No long-term complications were observed in this sample.

Compared to the standard trabeculectomy technique as reviewed in 2023 by Wagner et al, and taking the complete success rate as a measure, the complete success rate was 69%,¹⁷ which is higher than the complete success rate presented in the sample included in this study (47.9%) but lower than the success rate reported by Grossman et al (80.65%).¹⁰ This begs the question of to what extent the suprachoroidal derivation contributes to the success rate or lack thereof compared to trabeculectomy alone; the answer is difficult to ascertain from the current data. Moreover, Wagner et al report a low complication rate and cited that experienced surgeons could be the cause of the lower complication rate in the standard trabeculectomy cohort. Thus, the surgeon factor can be applied to our study and can explain the reduced complication rate; however, no comparative study investigated the complication rate between the standard trabeculectomy and trabeculectomy with suprachoroidal derivation performed by experienced surgeons to ascertain if a significant difference exists between the two techniques in terms of complications.

Limitations of this study are threefold: first, the retrospective design makes the findings prone to confounding factors uncorrected for by control processes such as randomization. This is a design limitation and can only be overcome by conducting a prospective design. Moreover, the relationship between IOP control change and the surgical technique begs the question of whether the results are due to the trabeculectomy alone or to the trabeculectomy with suprachoroidal derivation; a control group is necessary to ascertain the difference. Finally, the relatively low complication rate could be due to the surgeon factor, given the complexity of the procedure. Thus, the low complications reported in this study could not be generalized to the surgical technique itself with a reasonable degree of certainty. To overcome this, long-term follow-ups of patients undergoing suprachoroidal derivation by multiple surgeons who are performing this technique are warranted.

Conclusion

This is the largest study on suprachoroidal derivation surgery to date. The surgical technique provides a safe and effective route for aqueous outflow in combination with standard filtration surgery. It is set to mitigate the adverse effects of bleb failure by providing a secondary route for aqueous outflow while assisting in the reduction of IOP during the bleb’s lifetime. The safety profile of this technique in this sample is comparable to trabeculectomy alone. However, the dreaded suprachoroidal hemorrhage is always a possibility, although there is no literature to support its increased risk using this technique.

Further cohort studies will add more information about the suprachoroidal derivation technique in terms of efficacy or safety. Thus, the next step is conducting randomized clinical trials comparing this novel technique to trabeculectomy. This will resolve the ambiguity regarding its true impact on IOP control long-term and complication profile.

Clinical Significance

Trabeculectomy alone has a myriad of potential points of failure in the short and long term. This modification including the suprachoroidal space has the potential to mitigate these potential failures and maintains a secondary route of aqueous drainage preventing IOP spikes and preventing the damaging effects on the optic nerve in the case of a failing bleb. In this article, trabeculectomy with suprachoroidal derivation showed as a novel surgical technique for glaucoma a good success rate with comparable complication rate to standard trabeculectomy.

Abbreviations

IOP, intraocular pressure; SCD, Suprachoroidal derivation; Mm, Millimeter; M, Mean; SD, Standard Deviation; P, p-value; T, t-statistic; F, f-statistic.

Data Sharing Statement

The data that support the findings of this study are available through the corresponding author. Restrictions apply to the sharing of these data requiring the approval of the research center at PSMMC upon request.

Ethics Approval and Patient Consent to Participate

Ethical approval and patient consent were obtained through the IRB committee in our center.

Patient Consent for Publication

Not applicable given the design of the study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

No funding was received for this study.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311(18):1901–1911. doi:10.1001/jama.2014.3192

2. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081–2090. PMID: 24974815. doi:10.1016/j.ophtha.2014.05.013

3. Vision Loss Expert Group of the Global Burden of Disease Study; GBD 2019 blindness and vision impairment collaborators. Global estimates on the number of people blind or visually impaired by glaucoma: a meta-analysis from 2000 to 2020. Eye. 2024;38(11):2036–2046. PMID: 38565601; PMCID: PMC11269708. doi:10.1038/s41433-024-02995-5

4. Burr J, Azuara‐Blanco A, Avenell A, Tuulonen A. Medical versus surgical interventions for open angle glaucoma | Cochrane Library. 2012. Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004399.pub3/full. Accessed August 7, 2024.

5. Rulli E, Biagioli E, Riva I, et al. Efficacy and safety of trabeculectomy vs nonpenetrating surgical procedures: a systematic review and meta-analysis. JAMA Ophthalmol. 2013;131(12):1573–1582. doi:10.1001/jamaophthalmol.2013.5059

6. Jampel HD, Musch DC, Gillespie BW, et al. Perioperative complications of trabeculectomy in the collaborative initial glaucoma treatment study (CIGTS). Am J Ophthalmol. 2005;140(1):16–22. doi:10.1016/j.ajo.2005.02.013

7. Gedde SJ, Schiffman JC, Feuer WJ, et al. Three-year follow-up of the tube versus trabeculectomy study. Am J Ophthalmol. 2009;148(5):670–684. doi:10.1016/j.ajo.2009.06.018

8. Olayanju JA, Hassan MB, Hodge DO, Khanna CL. Trabeculectomy-related complications in Olmsted County, Minnesota, 1985 through 2010. JAMA Ophthalmol. 2015;133(5):574–580. doi:10.1001/jamaophthalmol.2015.57

9. Grossmann RA, Grigera DE, Wenger A. Novel surgical technique in refractory open angle glaucoma: case report. Pan Am J Ophthalmol. 2013;12(2):54–56.

10. Perez-Grossmann RA, Grigera DE, Wenger A. Trabeculectomy with suprachoroidal derivation in eyes with uncontrolled glaucoma: a case series with a 24-month follow-up. Ophthalmol Ther. 2019;8(2):323–331. doi:10.1007/s40123-019-0179-5

11. Van Bergen T, Van de Velde S, Vandewalle E, Moons L, Stalmans I. Improving patient outcomes following glaucoma surgery: state of the art and future perspectives. Clin Ophthalmol. 2014;8:857–867. doi:10.2147/OPTH.S48745

12. Skuta GL, Parrish RK. Wound healing in glaucoma filtering surgery. Surv Ophthalmol. 1987;32(3):149–170. doi:10.1016/0039-6257(87)90091-9

13. Zada M, Pattamatta U, White A. Modulation of fibroblasts in conjunctival wound healing. Ophthalmology. 2018;125(2):179–192. doi:10.1016/j.ophtha.2017.08.028

14. Schlunck G, Meyer-ter-Vehn T, Klink T, Grehn F. Conjunctival fibrosis following filtering glaucoma surgery. Ex Eye Res. 2016;142:76–82. doi:10.1016/j.exer.2015.03.021

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17. Wagner FM, Schuster AK, Kianusch K, Stingl J, Pfeiffer N, Hoffmann EM. Long-term success after trabeculectomy in open-angle glaucoma: results of a retrospective cohort study. BMJ Open. 2023;13(2):e068403. doi:10.1136/bmjopen-2022-068403

Introduction

Opioids have long served as fundamental elements in general anesthesia practice. The clinical application of opioids has evolved from initial morphine to pethidine and subsequently to the fentanyl family. However, opioid-related adverse effects and complications, such as respiratory depression, nausea and vomiting, persist. Recent studies indicate that opioids may not only interfere with immune processes but also induce postoperative hyperalgesia and tolerance.^1–3 Opioid dependence has become a global public health concern. The prescription opioid crisis has resulted in profound social, medical, and economic consequences that persist today.⁴ Given these risks, OFA has gained increasing attention and research interest as an alternative strategy in recent years.

OFA refers to a technique that completely avoids any opioids during the perioperative period while achieving adequate analgesia and anesthesia management through multimodal analgesic strategies.⁵ In 1993, Friedberg first introduced an opioid-free combination of ketamine and propofol.⁶ OFA can reduce the incidence of postoperative nausea and vomiting while providing adequate analgesia without interfering with postoperative recovery.⁷ In clinical practice, various non-opioid intravenous analgesics are widely used, including non-steroidal anti-inflammatory drugs (NSAIDs), α2-adrenergic receptor agonists, N-methyl-D-aspartate (NMDA) receptor antagonists, gabapentinoids, sodium channel blockers, corticosteroids, and magnesium sulfate. Unlike opioids, which act primarily through central mu-opioid receptor agonism—posing risks such as respiratory depression and dependence—key non-opioid agents exert their effects through distinct mechanisms. Local anesthetics block sodium channels to inhibit nerve conduction; NSAIDs and acetaminophen inhibit cyclooxygenase enzymes to reduce inflammatory pain; ketamine antagonizes NMDA receptors, modulating central sensitization; and dexmedetomidine activates alpha-2 adrenergic receptors to produce both analgesia and sedation. This multimodal strategy enables effective pain control while minimizing opioid-related adverse effects.

Perioperative pain management is a critical component of surgical practice, directly affecting patient satisfaction, length of hospital stays, surgical costs, readmission rates, and complication incidence. OFA can optimize anesthesia management by reducing doses of hypnotic agents, maintaining hemodynamic stability, and improving perioperative clinical outcomes. These strategies align well with the evolution of enhanced recovery after surgery (ERAS) protocols, jointly promoting optimization and innovation in perioperative management.

OFA has gained increasing relevance in modern clinical practice, particularly for patients with opioid use disorder or those undergoing chronic opioid therapy. These populations often exhibit altered opioid receptor sensitivity and a heightened risk of opioid-induced hyperalgesia, tolerance, and dependency.⁸ OFA offers a multimodal approach that minimizes these risks and supports safer perioperative care. Recent studies support its use in reducing postoperative opioid requirements and improving recovery outcomes in high-risk patients.⁹

Bibliometrics refers to the quantitative analysis of academic literature, using statistical and network-based methods to examine publication patterns, research hotspots, and collaboration structures. In the context of OFA, bibliometric analysis offers an objective lens to trace the field’s development—particularly its response to the opioid crisis and advancements in anesthetic techniques. This approach enables the identification of knowledge gaps, emerging research trends, and influential contributors, thereby providing a data-driven foundation for understanding OFA’s rapid growth and informing future clinical and research priorities.

Methods

Data Collection and Retrieval Strategy

This study conducted a retrospective bibliometric analysis of OFA literature published between 1980 and 2024. Data were extracted from the Web of Science Core Collection (WOSCC) using the following search strategy: (((TS= (opioid-free anesthesia)) OR TS= (opioid free anesthesia)) OR TS= (opioid-free anaesthesia)) OR TS= (opioid free anaesthesia)). The search strategy was developed and finalized in December 2024. To avoid the influence of ongoing database updates and ensure reproducibility, we completed all literature retrieval and data downloads on December 31, 2024. This date represents the definitive cut-off point for data inclusion in this study.

Inclusion and Exclusion Criteria

This study systematically searched for original research articles and reviews on OFA published between January 1980 and December 2024. All searches were completed by December 30, 2024, to avoid bias from database updates. Two researchers independently performed literature screening, including initial screening (based on title and abstract), full-text evaluation (for uncertain records), and final determination of included studies. The initial screening showed 95% agreement between the two researchers. A third researcher participated in the discussion for disputed records until a consensus was reached. Exclusion criteria included letters, meeting abstracts, book reviews, and other non-research publication types.

Data Analysis and Visualization

This study systematically extracted metadata from the search results, including publication year, journal name, country/region, research institution, author information, keywords, and references. Data analysis was comprehensively processed using multiple bibliometric software tools. First, Bibliometrix in R was used for fundamental bibliometric analysis, including journal source statistics of citations and references. Core journal identification based on Bradford’s law, construction of international collaboration networks, and highly cited literature analysis were performed. To thoroughly demonstrate research collaboration networks and knowledge evolution pathways, Citespace was employed to generate country collaboration networks, author and institutional collaboration networks, and reference and keyword burst detection maps. In the network maps, node size corresponds to publication quantity, while node centrality reflects its importance level. This study employed VOSviewer for keyword co-occurrence analysis to further reveal research hotspots. The analysis selected the “All Keywords” mode, merged synonyms, and ultimately presented results through network visualization and density visualization modes. All analyses were based on the final search dataset completed on December 30, 2024, to ensure result reproducibility.

Results

Publication Output and Citation Impact

Eight hundred sixty-one publications on OFA were included from 1980 to 2024 (Figure 1A), showing a clear temporal growth trend with particularly significant increases in the last decade. This growth trend stems from multiple interacting factors: primarily the opioid abuse crisis in the United States and associated societal issues (including addiction and overdose deaths) that prompted strict opioid prescription regulations worldwide; secondly, the rapid development of clinical alternatives, including innovations in regional anesthesia techniques, development of novel non-opioid analgesics, and clinical application of target-specific drugs; furthermore, international clinical guidelines recommending perioperative opioid reduction have further propelled research advancements in this field. Bibliometric analysis reveals substantially enhanced research impact in the recent five years, with total citations exceeding 1,000, including 2,219 citations in 2024 alone (Figure 1B), fully demonstrating the growing academic importance and attention of OFA research.

Journal Analysis

Journal distribution analysis of OFA research (Figure 2A) shows BRITISH JOURNAL OF ANAESTHESIA ranked first with 39 publications (4.53%). Bradford’s law analysis (Figure 2B) identified a core zone comprising 18 journals (Table 1) collectively publishing 289 articles (33.57%), where ANESTHESIOLOGY, with an impact factor of 9.3 emerged as the highest-IF journal in the core zone, and 66.67% (12/18) of core journals belonged to JCR Q1 category. Cited journal analysis (Figure 2C) indicates ANESTHESIOLOGY, ANESTHESIA AND ANALGESIA, and BRITISH JOURNAL OF ANAESTHESIA formed the top three most-cited journal clusters.

Figure 2 Bibliometric analysis of sources in the field of opioid-free anesthesia. (A) The top 10 most relevant sources. (B) Core sources by Bradford’s Law. (C) The top 10 most local cited sources.

Table 1 Top 18 Journals of the Most Publications Related to Opioid-Free Anesthesia

Countries and Institutions Analysis

Country analysis of OFA research reveals significant geographical disparities (Figure 3A). The United States leads globally with 291 publications and 7,896 citations, likely attributable to the Centers for Disease Control and Prevention’s opioid prescription restrictions and promotion of alternative analgesic strategies. Although China ranks second with 84 publications, its 843 citations suggest room for improvement in international influence. In contrast, England’s modest output (68 publications) achieved 2,722 citations, highlighting the high-quality nature of its research. International collaboration analysis (Figure 3B) shows active participation from Chinese, British, and Italian authors. The country collaboration network (Figure 4A) includes 65 nations with 233 links, featuring strong partnerships between England, Germany, Australia, and Japan. Institutional analysis (Table 2) shows that the United States institutions claimed 6 top 10 positions, France 2, Egypt, and Germany 1 each, led by the University of Texas System (33 publications). The institutional network (Figure 4B) comprises 278 institutions with 335 links, showing relatively loose collaboration (density=0.008) with small-group clustering. Notably, Assistance Publique Hopitaux Paris emerges as the most central hub (centrality=0.14), reflecting its academic leadership in this field.

Figure 3 Bibliometric analysis of countries in the field of opioid-free anesthesia. (A)The top 10 countries by number of publications and citations. (B) Top 10 corresponding author’s countries.

Figure 4 Cooperation network among (A) countries, (B) institutions, and (C) authors.

Table 2 Top 10 Institutions According to the Total Number of Publications

Authors Analysis

Analysis of prolific authors (Table 3) reveals Juan P. Cata as the most productive scholar in this field with 10 publications. This researcher has specialized in OFA studies since 2014. According to Price’s Law, we defined authors with ≥3 publications as prolific, identifying 18 core researchers meeting this criterion. Collaboration network analysis (Figure 4C) shows Juan P. Cata, Changhong Miao, and Wankun Chen have formed a relatively stable research team. Still, the network contains numerous isolated nodes and lacks effective connectivity between research groups, reflecting significant deficiencies in academic collaboration among researchers. This fragmented collaboration pattern may hinder cross-team knowledge exchange.

Table 3 Top 10 Most Productive Authors According to the Total Number of Publications

Research Directions and Hotspot Analysis

The two most-cited pivotal studies in OFA research demonstrate (Figure 5A) that the top-cited study by Ziemann-Gimmel et al (2014, Br J Anaesth) demonstrated that opioid-free total intravenous anesthesia in bariatric surgery significantly reduced the relative risk of postoperative nausea and vomiting (PONV) by 46.4% (absolute risk reduction 17.3%); The second most-cited systematic review by Frauenknecht et al (2019, Anesthesia) further confirmed that while no significant difference existed in postoperative pain scores, OFA significantly reduced PONV risk. These two high-impact studies collectively established the clinical advantage of OFA in PONV reduction, providing evidence-based guidance for anesthetic protocol selection.

The evolution of OFA research demonstrates distinct developmental phases (Figure 5B and C). Early studies by the Biki B team primarily investigated the relationship between anesthetic techniques and oncological outcomes, revealing that opioids may suppress immune function and consequently affect cancer recurrence, highlighting the potential value of regional anesthesia in oncologic surgery. These groundbreaking studies provided crucial theoretical foundations for OFA applications in oncologic surgery. Subsequent research by the Bakan M team through prospective randomized controlled trials confirmed that dexmedetomidine-based OFA protocols significantly reduced early postoperative opioid requirements and PONV incidence, though without demonstrating superior analgesic efficacy compared to traditional opioid-containing regimens. In the most recent phase, the Salomé A team conducted evidence-based, comprehensive evaluations of OFA’s clinical benefits and limitations. This evolutionary trajectory reflects the scientific pathway from basic research to clinical validation and demonstrates the sustained contributions from diverse research teams.

Figure 5 Bibliometric analysis of documents and references in the field of opioid-free anesthesia. (A) Most local cited documents, (B) Most local cited references and (C) Top 25 References with the Strongest Citation Bursts.

Keyword Analysis

Keyword co-occurrence analysis (Figure 6A) revealed four core themes in OFA research. The red cluster primarily focuses on OFA, containing 22 keywords, including opioid-free anesthesia (182), dexmedetomidine (125), and ketamine (66). The green cluster concentrates on anesthesia with 22 keywords like analgesia (194), morphine (86), and fentanyl (56). The blue cluster features perioperative management, highlighting 20 keywords such as surgery (180), postoperative pain (158), and opioids (135). The yellow cluster represents analgesia, covering 16 keywords, including pain (192), anesthesia (167), and management (94). These thematic clusters maintain relative independence while exhibiting intrinsic connections, forming a comprehensive research framework.

Temporal keyword analysis (Figure 6B) demonstrates distinct evolutionary characteristics in OFA research: Early-stage research (dark nodes) primarily focused on basic anesthetic protocols (morphine, fentanyl); Mid-term studies gradually shifted toward perioperative management optimization (surgery, postoperative pain); Recent studies (light nodes) have emphasized clinical outcome improvement (OFA, ERAS, enhanced recovery). Burst detection analysis (Figure 6C) further identifies three persistently active research directions: Prevention and management strategies for PONV, Technical optimization of opioid-free analgesia, And evaluation frameworks for patient quality of life. These findings provide clear directional guidance for future research in this field.

Figure 6 Bibliometric analysis of the keywords in the field of opioid-free anesthesia. (A) Co-occurrence analysis of keywords in the field of opioid-free anesthesia, (B) Timeline distribution of keywords in the field of opioid-free anesthesia, (C) Top 25 Keywords with the Strongest Citation Bursts.

Discussion

General Information

This study systematically elucidates the global development trends of OFA research from 1980 to 2024 through bibliometric analysis. The results demonstrate a significant temporal growth pattern, with particularly exponential increases in publications over the past decade and 2,219 citations recorded in 2024 alone, reflecting sustained academic attention to OFA research. Geographically, the United States dominates with 291 publications and 7,896 citations, demonstrating its leadership in policy guidance and scientific innovation. China shows comparable output but significantly fewer citations. England demonstrates quality-over-quantity with 2,722 citations from 68 publications. International collaborations show fragmented cluster patterns.

Knowledge Structure

The evolution of research hotspots demonstrates distinct phases: initial focus on basic anesthetic protocols, transitional emphasis on perioperative management optimization, and recent prioritization of clinical outcome enhancement. Keyword analysis identified four core themes: OFA pharmacological agents/regimens, perioperative management, and analgesic strategies, with PONV prevention/management, personalized OFA, and quality-of-life assessment representing the most active current frontiers.

Balanced anesthesia effectively controls surgical nociception and postoperative pain through combined pharmacological agents targeting distinct sites in the nociceptive system. The current practice of balanced anesthesia typically relies on opioid medications. However, accumulating evidence suggests opioids are suboptimal analgesics, mainly when used as monotherapy. Strictly speaking, “analgesia” is more precisely defined as “antinociception” – a complex physiological phenomenon involving multiple mechanisms and pathways that cannot be achieved solely through opioid receptor modulation. Opioid analgesic efficacy varies by pain type, demonstrating potency against visceral and inflammatory pain but limited effectiveness for Aδ fiber-mediated dynamic pain and central sensitization-associated neuropathic pain. This differential efficacy underscores the clinical necessity for mechanism-based multimodal analgesic strategies.³⁵

OFA can effectively meet analgesic requirements for mild-to-moderate pain. OFA delivers sufficient analgesia for mild-pain surgeries (inguinal herniorrhaphy, varicose vein ligation, and laparoscopic procedures). Furthermore, OFA demonstrates comparable efficacy in moderate-pain surgeries such as knee/distal leg procedures, shoulder/back operations, hysterectomies, and maxillofacial surgeries.³⁶ However, OFA exhibits limitations in high-pain surgeries (thoracotomy, laparotomy, total joint arthroplasties, and major vascular procedures). Thus, multimodal analgesia combining non-opioid agents with opioids or enhanced analgesic protocols is recommended for optimized pain control and patient comfort.³⁷ Substantial evidence confirms multimodal analgesia significantly reduces postoperative opioid requirements while improving pain management.^38,39

Common multimodal analgesic agents include acetaminophen, NSAIDs, α2-adrenergic agonists, (NMDA) receptor antagonists, gabapentinoids, and local anesthetics. By suppressing noradrenergic neurotransmission, α2-adrenergic agonists effectively modulate central nervous system hyperexcitability. Choi et al demonstrated that although α2-adrenergic agonists provide weaker direct analgesia than opioids, they reduce opioid requirements by 30–50%.⁴⁰ Research evidence indicates that incorporating dexmedetomidine into OFA protocols significantly improves postoperative pain scores, reduces opioid consumption, and decreases the incidence of PONV. However, these studies also identified extended extubation times, prolonged PACU stays, and increased bradycardia rates in OFA patients.^41,42

Grounded in multimodal analgesia principles, opioid-free patient-controlled intravenous analgesia (OF-PCIA) has emerged as a significant pain management strategy. This approach achieves postoperative analgesia through synergistic combinations of two or more non-opioid analgesics. Studies confirm the feasibility of purely OF-PCIA in selected cases, effectively controlling surgical inflammation while reducing adverse effects like respiratory depression, nausea, vomiting, and hyperalgesia. Furthermore, this method decreases postoperative opioid dependence and may mitigate risks of tumor recurrence and metastasis.⁴³ Particularly for elderly, frail, or critically ill patients, OF-PCIA demonstrates less impact on consciousness and respiratory function, offering superior safety compared to conventional opioid-based PCIA. A clinical trial in thyroidectomy patients confirmed that the dexmedetomidine-flurbiprofen combination significantly enhances post-anesthesia pain control, reduces emergence agitation, mitigates cognitive impairment, and improves immune function/wound healing.⁴⁴ In total joint arthroplasty analgesia, studies reveal that NSAIDs-gabapentin PCIA regimens achieve comparable pain scores to opioid-only analgesia while significantly reducing opioid consumption and postoperative pulmonary complications.⁴⁵ Furthermore, evidence indicates NSAIDs-ketamine combinations produce synergistic analgesia via multiple mechanisms: elevating pain thresholds, modulating pain perception, and suppressing inflammatory responses, thereby alleviating hyperalgesia.⁴⁶ Notably, NSAIDs-tramadol coadministration counteracts tramadol-induced constipation and enhances cellular immunity by stimulating macrophage release of proinflammatory cytokines.⁴⁷ Concurrently, OF-PCIA demonstrates significant clinical advantages in ambulatory and ERAS settings.⁴⁸ However, OF-PCIA presents certain limitations in clinical practice. Compared to opioids, non-opioid analgesics have a relatively narrow therapeutic window and are prone to ceiling effects. Yet, with advancements in multimodal analgesia and nerve block techniques, OF-PCIA combined with regional anesthesia now adequately serves some severe postoperative pain cases.

Cancer is an inflammatory disease that often involves some degree of immune suppression. Studies have documented opioid-mediated immunosuppression that promotes tumor dissemination.⁴⁹ This raises concerns about opioids potentially influencing cancer recurrence and tumor progression. Opioids have been shown to modulate the activity of various immune cells, including NK cells. Rodent studies indicate chronic high-dose opioid exposure may inhibit tumor progression, whereas acute/low-dose perioperative opioids could promote tumor growth.⁵⁰ Existing studies have associated opioids with poorer oncological outcomes.^51,52 Compared to traditional opioids, OFA protocols typically combine α2-agonists, lidocaine, regional techniques, and ketamine, which synergistically mitigate surgical stress and maintain immune-inflammatory homeostasis.^53,54 However, randomized controlled trial data remain scarce for cancer surgery populations. Significant knowledge gaps persist regarding OFA in cancer surgery, with marked methodological heterogeneity in existing studies precluding definitive conclusions about its impact on early postoperative outcomes.⁵⁵ Although preliminary findings suggest potential advantages of OFA in perioperative immediate outcomes, higher-quality clinical trials are needed to validate its superiority in cancer surgery patients.

Despite the growing interest in OFA, current protocols face several limitations that restrict their universal applicability. A key concern is the ceiling effect of many non-opioid analgesics, such as NSAIDs and acetaminophen, which limits their efficacy in managing moderate-to-severe postoperative pain. Additionally, agents like dexmedetomidine and ketamine may cause hemodynamic instability or delayed emergence. To address these challenges, future research should explore novel multimodal drug combinations that synergistically enhance analgesia without increasing adverse effects. Promising strategies include pairing α2-agonists with NMDA antagonists or integrating anti-inflammatory agents with regional anesthesia techniques. Personalized OFA regimens based on surgical type and patient comorbidities may also improve safety and effectiveness in diverse clinical settings.^28,42

The Frontiers

PONV

Our bibliometric analysis identified PONV as one of the most frequently cited and persistently active research hotspots in the field of OFA. This reflects not only the academic interest but also the growing clinical relevance of PONV in perioperative care. The consistent emergence of this theme across high-impact studies suggests a strong translational potential, with implications for refining anesthesia protocols and enhancing guideline recommendations—particularly within ERAS pathways.

PONV has long been recognized as a critical outcome measure in ERAS protocols. Recent studies show that while OFA demonstrates comparable pain control and opioid consumption to conventional anesthesia, it significantly reduces PONV incidence, albeit with higher bradycardia rates in OFA patients.^8,30,33 Frauenknecht et al compared opioid-based versus OFA regarding immediate postoperative pain and PONV. Analysis of 23 RCTs demonstrated that intraoperative opioids failed to improve 2-hour resting pain scores compared to OFA but were significantly associated with increased PONV rates.³² Notably, for cancer patients with potential chemotherapy-induced nausea preoperatively, anesthetic strategies reducing both opioid use and PONV are particularly valuable. However, the specific effect of OFA on PONV reduction remains unconfirmed in the oncologic population.

Personalized OFA

Although evidence supports OFA’s efficacy and clinical feasibility, the lack of high-quality data on optimal non-opioid combinations and personalized dosing precludes definitive recommendations for universal OFA adoption. Current evidence suggests implementing multidimensional preoperative screening (genetic testing, standardized questionnaires, and advanced imaging) to identify high-risk patients for opioid-related complications. This personalized risk assessment strategy facilitates optimized anesthesia selection and enhances perioperative safety.

Patients with preexisting respiratory depression risk factors, particularly obese patients with obstructive sleep apnea, should avoid medications that may exacerbate respiratory depression. Given the substantially increased risk of opioid-related adverse events in obese patients, evidence has accumulated supporting OFA use in this population. A systematic review and meta-analysis confirmed that opioid-sparing strategies significantly reduce opioid-induced respiratory depression incidence.⁵⁶ α2-adrenergic agonists like clonidine and dexmedetomidine may provide safer analgesic alternatives for obese patients.

Studies reveal that 10% of cardiothoracic surgery patients continue opioid use at 90 days postoperatively, suggesting opioid-based anesthesia may promote chronic opioid consumption.⁵⁷ This prevalence may be higher in reality due to underreported opioid-related complications in cardiac surgery populations. Research shows cardiac surgery patients receiving dexmedetomidine-based OFA require significantly fewer postoperative IV opioids than conventional opioid anesthesia. OFA patients experience reduced cough-associated pain and lower atrial fibrillation rates.⁵⁸

Future research should prioritize the development of more targeted OFA with improved receptor specificity while optimizing surgery-tailored OFA protocols based on procedural invasiveness and patient risk profiles. International multicenter collaborations will be essential to overcome sample size limitations and standardize outcome measures. Particular emphasis should be placed on investigating OFA’s long-term immunological impacts, especially its potential to modulate cancer-related immunity and influence recurrence risks through well-designed longitudinal studies with oncology-specific endpoints.

Strengths and Limitations

The rapid advancement of computer science has driven a transition from traditional laboratory-based research to digital and networked paradigms, significantly increasing attention to bibliometric analysis. Bibliometrics is valuable for assessing research outputs, identifying disciplinary trends, and enhancing study quality. This study’s significance lies in conducting the first systematic bibliometric analysis of OFA while providing valuable references and insights to guide future research directions for scientists and clinicians. However, several limitations should be acknowledged. First, the relatively small sample size of OFA studies and our exclusive use of the Web of Science Core Collection may have resulted in incomplete literature coverage. The exclusive use of the Web of Science may introduce selection bias, as it predominantly indexes high-impact journals, potentially overlooking relevant studies from other sources. Additionally, excluding non-English publications limits geographic representation and may omit regionally significant findings, particularly from non-Western research communities. As a retrospective study, there is an inevitable time lag between data collection and publication. Although data were retrieved on December 31, 2024, the conclusions remain consistent with the current trajectory of the field. Given the rapid development of OFA research, periodic updates will be essential to ensure continued relevance. While bibliometric analysis reveals macro-level research trends, it cannot replace systematic reviews when evaluating clinical efficacy. Future work may combine our findings with meta-analyses to bridge knowledge mapping and evidence synthesis.

Conclusions

This bibliometric analysis highlights the rapid development of OFA research, driven by the opioid crisis and innovations in alternative analgesia. Over the past decade, the field has shown exponential growth, with major focuses including OFA protocol development, perioperative optimization, PONV prevention, and integration into ERAS pathways. However, clinical adoption remains variable, and high-quality evidence on long-term outcomes—such as chronic pain, opioid dependence, and cancer prognosis—is still lacking. These limitations, along with the exclusive use of a single database and heterogeneity in included studies, may affect the generalizability of our findings. Future research should prioritize the development of individualized, evidence-based OFA protocols and assess their efficacy through multicenter randomized controlled trials in cancer surgery populations, as well as comparative trials with conventional opioid-based regimens. Such studies will be essential to bridge current knowledge gaps, support clinical translation, and improve patient outcomes across diverse surgical contexts.

Abbreviations

OFA, opioid-free anesthesia; NSAIDs, non-steroidal anti-inflammatory drugs; NMDA, N-methyl-D-aspartate; ERAS, enhanced recovery after surgery; OF-PCIA, opioid-free patient-controlled intravenous analgesia.

Funding

This research received no external funding.

Disclosure

The authors declare no conflicts of interest in this work.

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As the aging population grows, could your supplement routine help combat muscle and bone decline? This new review highlights which emerging options hold real promise, and where science still needs to catch up.

Review: Beyond Calcium and Vitamin D: Exploring Creatine, β-Hydroxy-β-methylbutyrate, Prebiotics and Probiotics in Osteosarcopenia. Image Credit: Evgeniy Lee / Shutterstock

In a recent review article published in the journal Nutrients, researchers investigated the effectiveness of emerging nutritional supplements, including prebiotics, probiotics, and creatine, in improving muscle and bone health in older individuals with osteosarcopenia.

They concluded that novel supplements have the potential to play a significant role in nutritional interventions aimed at improving bone and muscle composition and enhancing physical function in older adults. However, further research is needed to determine their efficacy and identify which populations benefit most. The review also highlights that agents affecting bile acid metabolism are an emerging area of interest within the gut–bone–muscle axis.

Growing burden of osteosarcopenia

Osteosarcopenia is a growing health concern among older adults, defined by the combined presence of osteoporosis (weakened bone structure and low bone density) and sarcopenia (muscle loss with age).

As the global elderly population is expected to reach 1.5 billion by 2050, the prevalence of osteosarcopenia is likely to increase, making it an urgent public health issue.

Osteoporosis increases the risk of fractures, particularly in older adults who are also more prone to falls. Sarcopenia contributes to loss of muscle strength and physical function, and there is currently no approved medication to treat it.

When these two conditions occur together, they amplify each other’s adverse effects, increasing the risks of death, falls, and disability.

The biological mechanisms behind osteosarcopenia are complex. Shared risk factors such as impaired protein metabolism, hormonal changes, oxidative stress, and chronic inflammation contribute to the deterioration of both bone and muscle.

Evidence suggests that bone and muscle communicate through biochemical signals, such as myokines (from muscle) and osteokines (from bone), and through mechanical interactions. Therefore, interventions targeting one tissue may also benefit the other.

Standard management typically includes physical activity and sufficient intake of calcium, vitamin D, and protein. However, emerging research suggests that novel supplements, such as hydroxymethylbutyrate (HMB), creatine, probiotics, prebiotics, and compounds that influence bile acid metabolism, may offer additional benefits.

These may include lowering inflammation, reducing fall risk, and enhancing muscle mass and strength.

The gut–bone–muscle axis highlights the impact of gut microbiota on osteosarcopenia. Arrows indicate interactions. ↑ indicates an increase; ↓ indicates a decrease. (created in https://BioRender.com).

Creatine and Osteosarcopenia

Creatine is a compound vital for energy production, especially in muscles and the brain. While the body produces some creatine, dietary sources, mainly fish and meat, are essential. Older adults often consume less creatine, making supplementation a potentially beneficial option.

Research indicates that creatine, particularly when combined with resistance training, enhances muscle mass, strength, and function in older individuals, thereby reducing fall risk and improving mobility.

Creatine also supports bone health by enhancing osteoblast activity and reducing bone breakdown; however, recent studies suggest no significant increase in bone mineral density in older adults. It may instead influence bone geometry and strength indirectly through muscle gain.

Combining creatine with protein, branched-chain amino acids (BCAAs), or vitamin D has been shown to provide additional benefits for muscle health in some studies. However, there is currently no research on the synergy between creatine and prebiotics, probiotics, or HMB in older adults. The review specifically notes that studies of combined supplementation (such as creatine plus HMB or creatine plus probiotics) have not been conducted in older populations.

HMB’s role in age-related muscle and bone loss

HMB, a metabolite of the amino acid leucine, has gained interest for its potential to support muscle health in older adults. It enhances muscle protein synthesis and reduces breakdown, potentially helping to preserve muscle mass during periods of inactivity or illness.

Supplementation up to three grams a day is considered safe, but research findings are mixed. Some studies have shown that HMB improves hand grip strength and muscle quality, particularly with prolonged use of more than 12 weeks. However, the effects on skeletal muscle mass and physical performance remain inconsistent, and most trials demonstrate only small or non-significant effects on muscle mass.

Most evidence is not available for community-dwelling older adults; few studies have been conducted, and the effects are modest, with statistical significance primarily observed for hand grip strength, rather than mass or performance.

Evidence for HMB’s role in bone health is limited to animal studies, with no randomized controlled trials in humans. HMB may work synergistically with other supplements, such as vitamin D, creatine, protein, and probiotics, to enhance muscle growth and development outcomes. However, results vary by population and supplement combinations. The review also notes the need for further research on the combined effects of HMB with other agents in older adults.

Prebiotics and probiotics target the gut-muscle-bone axis

Prebiotics (non-digestible fibers) and probiotics (live beneficial microbes) may influence muscle and bone health by modulating the gut microbiota. Together, as synbiotics, they enhance microbial balance and promote anti-inflammatory effects.

Aging-related changes in gut microbiota are associated with sarcopenia and osteoporosis through mechanisms that involve nutrient absorption, insulin sensitivity, inflammation, and immune regulation.

The gut–muscle axis suggests that microbiota influence muscle strength and metabolism, while the gut–bone axis shows impacts on bone density through immune modulation, hormone production, and gut barrier function.

Probiotics, such as Lactobacillus and Bifidobacterium, may improve muscle function and mass; however, well-designed clinical trials in older adults are limited. The review specifies that only one study in mildly frail adults over 70 years showed improvement with L. plantarum; most evidence for probiotic effects in older people is based on animal models or mixed-age populations. Similarly, certain prebiotics have been shown to enhance bone health in animal models. Human data for older adults are scarce and strain-specific. Gut-derived metabolites also affect bone remodeling. Though mostly safe, probiotics may rarely cause infections in vulnerable individuals, including bacteremia or liver abscess. The summary could better contextualize the complexity of gut-derived metabolites, bile acids, and their roles within the gut–bone–muscle axis, as discussed in the review.

Conclusions

This review highlighted emerging nutritional supplements as promising strategies for managing osteosarcopenia in older adults.

These supplements are generally safe and well-tolerated, with creatine showing the strongest evidence for improving muscle and indirectly supporting bone health, especially when combined with exercise and other nutrients, such as protein and vitamin D.

HMB may enhance muscle strength, though results are inconsistent. Probiotics and prebiotics offer potential through modulation of the gut microbiota, but their effects vary by individual and bacterial strain.

Overall, these interventions show promise, but further research is needed to optimize their use and identify target populations.

Kampala, Uganda — Uganda said Thursday that it would use 200,000 doses of the Hepatitis B vaccine donated by Gavi, the Vaccine Alliance, to immunize newborns.

Rose Akuno, Hepatitis program coordinator at the Ministry of Health, told Xinhua by telephone that the vaccination campaign, scheduled for August, aims to prevent and control new Hepatitis B infections among newborns in the East African country.

According to ministry data, about 2.7 million adults and 230,000 children — roughly 6 percent of Uganda’s population — remain critically infected with the virus.

Akuno said that all newborns, whether born in health facilities or at home, should be vaccinated within the first 24 hours of birth. “The mothers should ensure the newborns receive this vaccine to prevent and protect them from Hepatitis B,” she said.

The donation from Gavi is expected to arrive in the country later this month or early next month, according to the Health Ministry.

Akuno said that Uganda faces significant funding challenges in the fight against Hepatitis B, with only three million U.S. dollars allocated to the program.

In 2022, an estimated 1,250 Ugandans died of the disease, according to the World Health Organization.

Hepatitis B can cause chronic infection and puts people at high risk of death from cirrhosis and liver cancer, according to the Ministry of Health. It spreads through contact with the blood or other body fluids of an infected person. ∎

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