Cell-Based Therapies for Rotator Cuff Injuries: An Updated Review of the Literature.

This review focuses on non-surgical treatment options for rotator cuff injuries and highlights the potential of mesenchymal stem cells (MSCs) as a potential regenerative approach. MSCs, sourced from various tissues like bone marrow and adipose tissue, exhibit promising mechanisms in vitro, influencing tendon-related gene expression and microenvironment modulation. Animal studies support this, showcasing MSCs' ability to reduce inflammation, improve tissue remodeling, and enhance repaired tendon strength. Human trials, while varied and limited, suggest that MSCs might lower retear rates and enhance post-repair outcomes, but randomized controlled trials yield mixed results, emphasizing the necessity for standardized investigations. Ultimately, while cell-based therapies demonstrate an excellent safety profile, more rigorous clinical trials are necessary to determine their efficacy in improving patient outcomes and achieving lasting structural changes in rotator cuff injuries.

The Use of Scrambler Therapy in Treating Chronic Pain Syndromes: A Systematic Review.

BACKGROUND: Scrambler therapy (ST) is a noninvasive method of transcutaneous neuromodulation that has 510(K) clearance from the United States Food and Drug Administration for treating acute pain, postoperative pain, and intractable chronic pain. Since its inception, ST has been used to treat many chronic pain syndromes in a variety of patient populations. We synthesized the available literature for ST to delineate its overall evidence basis. MATERIALS AND METHODS: We performed a systematic review based on conventional Preferred Reporting Items for Systematic Reviews and Meta-Analyses methods by surveying multiple data sources from January 1950 through October 2021. Two review authors, independently and in a standardized, unblinded fashion, conducted a systematic review to identify relevant studies and extract the necessary outcome measures. A conservative search strategy was implemented to identify all ST studies for the treatment of chronic pain syndromes. Primary outcome parameters collected were analgesic benefit, adverse effects, and other metrics such as sensorimotor testing. RESULTS: A total of 21 studies met the final criteria for study inclusion and comprised randomized controlled trials (n = 8), prospective observational studies (n = 10), and retrospective cohort studies (n = 3). Nearly all the reported studies explored the use of ST for the treatment of neuropathic pain, with chemotherapy-induced peripheral neuropathy being the most studied condition. Most studies were limited by small cohorts but reported ST being safe, well tolerated, and providing clinically meaningful pain reduction. The duration of posttreatment follow-up ranged from ten to 14 days (concordant with completion of typical ST protocols) to three months. Secondary benefits such as medication reduction and improvement of sensory and motor symptoms were noted by some studies. CONCLUSIONS: ST is regarded as a safe intervention with potential for significant analgesic benefit for neuropathic pain conditions. Although the available evidence is most robust for treating chemotherapy-induced peripheral neuropathy, ST has also been shown to be effective in treating other neuropathic pain syndromes. Evidence for ST use in nociceptive pain conditions is limited but appears promising. The favorable safety profile and increasing evidence basis for ST warrant more extensive recognition and consideration for use in clinical care.

Double-Spin Leukocyte-Rich Platelet-Rich Plasma Is Predominantly Lymphocyte Rich With Notable Concentrations of Other White Blood Cell Subtypes.

Purpose: To comprehensively characterize a double-spin leukocyte-rich platelet-rich plasma (LR-PRP) formulation and to compare it with whole blood (WB) by quantitatively assessing platelet and WB cell subtype concentrations in each. Methods: Prospective human ex vivo analysis with 12 healthy adult men with ages ranging from 25 to 31 was performed in a controlled laboratory setting. The main outcome measure was the leukocyte profile of human LR-PRP. Results: In LR-PRP, lymphocytes were the predominant WB cell type (11.94 ± 2.97 × 103 cells/µL) followed by neutrophils (3.72 ± 1.28 × 103 cells/µL). The mean cumulative percentage of granulocytes was 23% ± 8% and agranulocytes was 77% ± 18%. There was a significant difference observed between granulocyte and agranulocyte percentage within both WB (P = .004, [95% CI: (7%,31%)]) and LR-PRP (P < .0001, [95% CI: (42%,66%)]) groups. In addition, there was a significant difference observed between the WB and LR-PRP granulocyte percentages (P < .0001, [95% CI: (29%,43%)]) and between the WB and LR-PRP agranulocyte percentages (P < .0001, [95% CI: (30%,42%)]). Conclusions: Our study found that LR-PRP is predominantly lymphocyte rich with notable concentrations of other WB cell subtypes, including neutrophils, monocytes, eosinophils, basophils, and large unstained cells. While these subtypes are not routinely reported, they may play a role in modulating the local inflammatory environment. We also found significant differences in WB cell subtype concentrations between WB and LR-PRP. Clinical Relevance: PRP has been routinely used in many clinical practices without clear indications for its use and lacks standardization in its formulation. This study provides a comprehensive characterization of a broadly used PRP, LR-PRP, and further characterizes subtypes of WBC cells present in LR-PRP that have not been previously reported. Comprehensively reporting these subtypes in clinical trials of PRP is crucial to understanding how these cells participate in PRP's therapeutic potential. This type of data can help standardize future PRP formulations and improve patient outcomes.

Intrathecal Baclofen Monotherapy and Polyanalgesia for Treating Chronic Pain in Patients with Severe Spasticity.

PURPOSE OF REVIEW: Intrathecal drug delivery is a well evidenced strategy for the treatment of many chronic pain syndromes. While opioids, anesthetics, and ziconotide are the most commonly used agents, intrathecal baclofen (ITB), which is indicated to treat spasticity, is also thought to have some analgesic properties that are poorly understood. These analgesic benefits have been reported with ITB use in treating patients with central neurological disorders who suffer from severe spasticity and chronic pain. Our review aims to characterize ITB's effects on pain, function, and quality of life in patients with severe spasticity. We performed a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. The primary outcome parameters were analgesic relief and functional improvements. Secondarily, quality of life and adverse effects were also recorded. RECENT FINDINGS: After an initial survey identified 393 studies, 20 studies met final inclusion criteria. Of these, 16 utilized ITB monotherapy and 4 utilized ITB polyanalgesia. Overall, there was a paucity of high-powered studies. Mean titrated ITB doses ranged from 140 to 627.9 µg daily. Nineteen studies reported improved pain and spasticity. Seven studies reported improved functional outcomes and quality of life. Our results show that ITB may be an effective agent in treatingfor the treatment of chronic pain in patients with severe spasticity independent of its spasmolytic effects. Although this evidence was largely derived from studies lacking clearly defined outcomes of pain relief, ITB is reasonable to consider for concurrent spasticity and pain management. Well-designed studies are still needed to characterize ITB's analgesic efficacy when used in patients with severe spasticity.

Combination Intrathecal Drug Therapy Strategies for Pain Management.

BACKGROUND: Numerous combination intrathecal drug therapy (CIDT) strategies exist and are utilized for varying pain syndromes, typically when monotherapy dose escalation or medication alternation is deemed untenable or unfeasible. Unfortunately, the supportive evidence basis for the use of these strategies and specific drug combinations is generally lacking and unclear, with many medications being used for off-label indications. OBJECTIVE: In this manuscript, we provide a robust exploration and analysis of the literature to provide an evidence-based narrative for the use of CIDT strategies in regard to clinical indications, pharmacologic parameters, specific drug combinations, safety profiles, and future directions. STUDY DESIGN: Narrative review. METHODS: This was an evidence based narrative performed after extensive review of the literature. RESULTS: Variances in intrathecal pharmacokinetics and pharmacodynamics are utilized advantageously with CIDT strategies to achieve improved analgesic benefit; however, appropriate use may be limited by increased or compounded risk of adverse effects. The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors, including a lack of standardized dosing. The most evidenced CIDT strategies include polyanalgesia with morphine-ziconotide, opioid-clonidine, and morphine-bupivacaine. Notably, in addition to pain relief, morphine-bupivacaine has been shown to decrease early opioid escalation requirements. LIMITATIONS: The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors including a lack of standardized dosing. CONCLUSIONS: CIDT strategies and polyanalgesia combinations can be effective for treating various patient populations with chronic pain. The appropriate use of these strategies may be limited by increased or compounded risk of adverse effects, both of which are highly patient and scenario dependent. Therefore, practitioners should maintain a particularly low threshold of suspicion for adverse effects in patients with CIDT such that safety profiles associated with this therapy can be favorably maintained.

Microfragmented Adipose Tissue With Adjuvant Platelet-Rich Plasma Combination Therapy for Partial-Thickness Supraspinatus Tear.

A 50-year-old male presented with acute, sharp, right shoulder pain. Ultrasound of the right shoulder revealed a partial thickness tear of the supraspinatus. After conservative management failed to provide any relief, he was treated with microfragmented adipose tissue (MFAT) injection followed by platelet-rich plasma (PRP) at 14 weeks. At the 28-week follow-up, he showed significant improvement in pain and mobility with a resolution of the tear on ultrasound. While PRP has been shown to confer some protection against retears, very few studies have investigated the efficacy of MFAT use in rotator cuff pathology. In this case, we used a combination of MFAT and PRP to successfully treat a partial thickness supraspinatus tear. These agents may function in a synergistic manner, with MFAT providing a cell scaffold and PRP modulating the cellular environment to optimize healing. Further studies are needed to better understand the mechanism of this treatment modality in treating similar conditions.

Radiotherapy-Specific Chronic Pain Syndromes in the Cancer Population: An Evidence-Based Narrative Review.

While radiation therapy is increasingly utilized in the treatment paradigm of many solid cancers, the chronic effects of radiation therapies are poorly characterized. Notably, understanding radiation-specific chronic pain syndromes is paramount given that the diagnosis and management of these conditions can serve to prevent long-standing functional impairments, optimize quality of life, and even allow for continued radiotherapy candidacy. These radiation-specific chronic pain phenomena include dermatitis, mucositis, enteritis, connective tissue fibrosis, lymphedema, and neuropathic pain syndromes. It is necessary to maintain a low threshold of suspicion for appropriately diagnosing these conditions as there exists a variance in when these symptoms arise after radiation. However, we present key epidemiological data delineating vulnerable cancer populations for each pain syndrome along with the available evidence for the management for each specific condition.

Dorsal Root Ganglion Stimulation for the Treatment of Non-Complex Regional Pain Syndrome Related Chronic Pain Syndromes: A Systematic Review.

BACKGROUND: While the majority of indications and approvals for dorsal root ganglion stimulation (DRGS) are for the refractory management of complex regional pain syndrome (CRPS), emerging evidence has suggested that DRGS may be favorably used for a plethora of other chronic pain phenomena. Consequently, we aimed to characterize the use and efficacy of DRGS for these non-CRPS-related chronic pain syndromes. MATERIALS AND METHODS: A systematic review of clinical studies demonstrating the use of DRGS for non-CRPS-related chronic pain syndromes. The literature search was performed using PubMed, Cochrane Library, and CINAHL plus across August and September 2020. RESULTS: A total of 28 reports comprising 354 total patients were included in the analysis. Of the chronic pain syndromes presented, axial low back pain, chronic pelvic and groin pain, other peripheral neuropathies, and studies with multiple concomitant pain syndromes, a majority demonstrated >50% mean pain reduction at the time of last follow-up following DRGS. Physical function, quality of life (QOL), and lesser pain medication usage also were repeatedly reported to be significantly improved. CONCLUSIONS: DRGS continues to lack supportive evidence from well designed, high level studies and recommendations from consensus committee experts. However, we present repeated and consistent evidence from lower level studies showing success with the use of DRGS for various non-CRPS chronic pain syndromes in reducing pain along with increasing function and QOL from one week to three years. Due to such low-level, high bias evidence, we strongly encourage the continuation of high-level studies in order to provide a stronger foundation for the use of DRGS in non-CRPS chronic pain patients. However, it may be reasonable and appropriate to evaluate patients for DRGS candidacy on a case-by-case basis particularly if they manifest focal pain syndromes refractory to noninterventional measures and may not be ideal candidates for other forms of neuromodulation.

Hydrodissection as a therapeutic and diagnostic modality in treating peroneal nerve compression.

A 51-year-old man presented with pain in the region of his left patellar tendon and fibular head. He had previously undergone three L5 epidural steroid injections and physical therapy without relief. Prior magnetic resonance imaging was significant only for fat pad impingement, and electromyography and nerve conduction studies were negative. Ultrasound demonstrated an enlarged peroneal nerve suggestive of peroneal nerve entrapment. Three ultrasound-guided hydrodissection procedures offered symptomatic improvement and identified an area posterior to the fibular head that was unable to be hydrodissected, indicating scar tissue causing peroneal nerve compression. The patient was referred for peroneal nerve decompression at the area of entrapment with complete symptom relief. This case is unique in describing the ability of hydrodissection to identify nerve compression not visualized with other diagnostic tests.

Transient therapy-related surge in serum tumor biomarkers: characterizing behavior and postulating its biologic role.

A phenomenon of serum tumor biomarker surge or flare that ensues shortly after initiating cancer therapy and that may precede the actual therapeutic response-related decline is poorly understood and remains under-appreciated. However, it may have a significant clinical implication as it could be misinterpreted in clinical practice as therapeutic failure and lead to a premature discontinuation of potentially effective therapy. Therefore, in the present study, attempts have been made to understand the behavior of this phenomenon with respect to a reported median incidence, duration, and its relationship to clinical response. The results of these analyses suggest a significantly lower incidence of this phenomenon with carcinoembryonic antigen (CEA) as determined in colorectal cancer and prostate specific antigen (PSA) in prostate cancer as compared to the other biomarkers studied (p=0.006). Furthermore, regardless of the type of biomarker or the extent of its incidence, a therapy-related initial surge appears to correlate with eventual response to therapy. Although, the biologic significance of this phenomenon is currently elusive, two distinct hypothesis-generating cases with CEA and alpha-fetoprotein (AFP) are presented that, if supported by further research, would provide insights into the role of a biomarker surge in overall tumor growth control by cancer therapy.