Tumor Necrosis Factor and Interleukin Modulators for Pathologic Pain States: A Narrative Review.

Chronic pain, a complex and debilitating condition, involves intricate interactions between central and peripheral inflammatory processes. Cytokines, specifically tumor necrosis factor (TNF) and interleukins (IL), are key mediators in the initiation and maintenance of chronic pain states. Sensory neurons expressing receptors for cytokines like TNF, IL-1, and IL-6 are implicated in peripheral sensitization, contributing to increased signaling of painful sensations. The potential of targeting TNF and IL for therapeutic intervention in chronic pain states is the focus of this review, with preclinical and clinical evidence supporting the use of TNF and IL modulators for pain management. The physiological and pathological roles of TNF in neuropathic pain is complex. Experimental evidence highlights the effectiveness of TNF modulation in mitigating pain symptoms in animal models and displays promising outcomes of clinical trials with TNF inhibitors, such as infliximab and etanercept. ILs, a diverse group of cytokines, including IL-1, IL-6, and IL-17, are discussed for their contributions to chronic pain through inflammation and peripheral sensitization. Specific IL modulators, such as secukinumab and tocilizumab, have shown potential in managing chronic neuropathic pain, as demonstrated in various studies and clinical trials. The pharmacokinetics, safety profiles, and challenges associated with TNF and IL modulators highlight the need for cautious medication monitoring in clinical practice. Comparative evaluations have revealed distinct efficacy and safety profiles among different cytokine modulators, emphasizing the need for personalized approaches based on the specific underlying causes of pain. Further research is necessary to elucidate the intricate mechanisms by which cytokines contribute to chronic pain, as well as to understand why they may affect pain differently in various contexts. Additionally, long-term safety profiles of cytokine modulators require more thorough investigation. This continued exploration holds the promise of enhancing our comprehension of cytokine modulation in chronic pain and shaping more potent therapeutic strategies for the future.

Peripheral Nerve Stimulation in Postoperative Analgesia: A Narrative Review.

PURPOSE OF REVIEW: Recent research has shown the effectiveness of peripheral nerve stimulators (PNS) in managing chronic pain conditions. Ongoing studies aim to explore its potential application in treating acute postoperative pain states. The purpose of this systematic review is to assess the role of PNS in providing relief for postoperative pain. RECENT FINDINGS: Clinical studies investigating the use of peripheral nerve stimulators (PNS) for analgesia following various surgeries, such as total knee arthroplasty, anterior cruciate ligament repair, ankle arthroplasty, rotator cuff repair, hallux valgus correction, and extremity amputation, have shown promising results. Lead placement locations include the brachial plexus, sciatic, femoral, tibial, genicular, perineal, sural, radial, median, and ulnar nerves. These studies consistently report clinically significant reductions in pain scores, and some even indicate a decrease in opioid consumption following PNS for postoperative pain. PNS involves the subcutaneous placement of electrode leads to target peripheral nerve(s) followed by delivery of an electric current via an external pulse generator. While the precise mechanism is not fully understood, the theory posits that PNS modulates electrical stimulation, hindering the signaling of nociceptive pain. PNS presents itself as an alternative to opioid therapy, holding promise to address the opioid epidemic by offering a nonpharmacologic approach for both acute and chronic pain states.

Novel Local Anesthetics in Clinical Practice: Pharmacologic Considerations and Potential Roles for the Future.

The treatment of pain, both acute and chronic, has been a focus of medicine for generations. Physicians have tried to develop novel ways to effectively manage pain in surgical and post-surgical settings. One intervention demonstrating efficacy is nerve blocks. Single-injection peripheral nerve blocks (PNBs) are usually preferred over continuous PNBs, since they are not associated with longer lengths of stay. The challenge of single injection PNBs is their length of duration, which at present is a major limitation. Novel preparations of local anesthetics have also been studied, and these new preparations could allow for extended duration of action of anesthetics. An emerging preparation of bupivacaine, exparel, uses a multivesicular liposomal delivery system which releases medication in a steady, controlled manner. Another extended-release local anesthetic, HTX-011, consists of a combination of bupivacaine and low-dose meloxicam. Tetrodotoxin, a naturally occurring reversible site 1 sodium channel toxin derived from pufferfish and shellfish, has shown the potential to block conduction of isolated nerves. Neosaxitoxin is a more potent reversible site 1 sodium channel toxin also found in shellfish that can also block nerve conduction. These novel formulations show great promise in terms of the ability to prolong the duration of single injection PNBs. This field is still currently in development, and more researchers will need to be done to ensure the efficacy and safety of these novel formulations. These formulations could be the future of pain management if ongoing research continues to prove positive effects and low side effect profiles.

Zolpidem: Efficacy and Side Effects for Insomnia.

PURPOSE OF REVIEW: Insomnia is a common type of sleep disorder defined by an ongoing difficulty initiating or maintaining sleep or nonrestorative sleep with subsequent daytime impairment. The sleep disturbances in insomnia usually manifest as difficulty in falling asleep, maintaining the continuity of sleep, or waking up too early in the morning well before the desired time, irrespective of the adequate circumstances to sleep every night. Insomnia can significantly impact daytime functioning resulting in decreased workplace productivity, proneness to errors and accidents, inability to concentrate, frequent daytime naps, and poor quality of life.The treatment of insomnia should involve a multi-disciplinary approach, focusing on implementing behavioral interventions, improving sleep hygiene, managing psychological stressors, hypnotic treatment, and pharmacological therapy. The most effective therapies utilize cognitive behavioral therapy in conjunction with pharmacotherapy to minimize the needed dose and any resulting side effects. Non-benzodiazepine hypnotics such as zolpidem, eszopiclone, zaleplon are the most used as adjunctive treatment. One of the most used of these hypnotics is zolpidem. However, zolpidem has a wide variety of adverse effects and has some special considerations noted in the literature. RECENT FINDINGS: Zolpidem has been associated with an increased risk of falls in hospitalized patients with an OR of 4.28 (P <0.001) when prescribed short-term for insomnia. The relative risk (RR) for hip fractures in patients taking zolpidem was described as 1.92 (95% CI 1.65-2.24; P<0.001), with hip fractures being the most commonly seen. A case series of 119 inpatients aged 50 or older demonstrated that a majority (80.8%) of ADRs were central nervous system (CNS)-related such as confusion, dizziness, and daytime sleepiness. A systematic review of 24 previous studies of sleepwalking associated with zolpidem demonstrated that the association was not dependent on age, dose, medical history, or even a history of sleepwalking at any time before zolpidem use. Suicide attempts and completion have been successfully linked with zolpidem use (OR 2.08; 95% CI 1.83-2.63) in patients regardless of the presence of comorbid psychiatric illness. There have been multiple cases reported of seizures following the withdrawal of zolpidem. Most cases have demonstrated that withdrawal seizures occurred in patients taking daily dosages of around 450-600mg/day, but some reported them as low as 160mg/day. Rebound insomnia has been a concern to prescribers of zolpidem. Sleep onset latency has been demonstrated to be significantly increased on the first night after stopping zolpidem (13.0 minutes; 95% CI 4.3-21.7; P<0.01). Women had a non-significantly higher mean plasma concentration than men after 8 hours for the 10mg IR (28 vs. 20 ng/mL) and the 12.5mg MR (33 vs. 28ng/mL). The FDA has classified zolpidem as a category C drug based on adverse outcomes seen in animal fetal development. In the mothers exposed to zolpidem, there was an increased incidence of low birth weight (OR = 1.39; P<0.001), preterm delivery (OR 1.49; P<0.001), small for gestational age (SGA) babies (OR = 1.34; P<0.001), and cesarean deliveries (OR =1.74; P<0.001). The rate of congenital abnormalities was not significantly increased with zolpidem (0.48 vs 0.65%; P = 0.329). SUMMARY: Insomnia is linked to fatigue, distractibility, mood instability, decreased satisfaction, and overall decreased quality of life. Optimal therapy can aid patients in returning to baseline and increase their quality of life. Zolpidem is a helpful drug for the treatment of insomnia in conjunction with cognitive-behavioral therapy. When prescribed to elderly patients, the dose should be adjusted to account for their slower drug metabolism. Still, zolpidem is considered a reasonable choice of therapy because it has a lower incidence of residual daytime sleepiness and risk of falls when compared to other drugs. The most concerning adverse effects, which are often the most publicized, include the complex behaviors that have been seen in patients taking Zolpidem, such as sleeping, hallucinations, increased suicidality, driving cars while asleep, and even a few cases of committing homicide. Even so, zolpidem could be a suitable pharmacological treatment for insomnia. Decisions for whether or not to prescribe it and the dosage should be made on a case-by-case basis, considering both the psychical and psychiatric risks posed to the patient with insomnia versus if the patient were to take zolpidem to treat their condition.

A Comprehensive Review of Novel Interventional Techniques for Chronic Pain: Spinal Stenosis and Degenerative Disc Disease-MILD Percutaneous Image Guided Lumbar Decompression, Vertiflex Interspinous Spacer, MinuteMan G3 Interspinous-Interlaminar Fusion.

Spinal stenosis is the compression of nerve roots by bone or soft tissue secondary to the narrowing of the spinal canal, lateral recesses, or intervertebral foramina. Spinal stenosis may have acquired or congenital origins. Most cases are acquired and caused by hypertrophy of the ligamentum flavum, enlarged osteophytes, degenerative arthritis, disk herniations, and various systemic illnesses. The ligamentum flavum (LF) is a highly specialized elastic ligament that connects the laminae of the spine and fuses them to the facet joint capsules. There are a number of treatment options available for spinal stenosis. Implants and surgical interventions have grown in popularity recently, and a number of these have been shown to have varying efficacy, including the minimally invasive lumbar decompression (MILD®), Vertiflex®, Coflex® Interlaminar Stabilization, and MinuteMan G3® procedures. Minimally invasive lumbar decompression (MILD®) is a minimally invasive outpatient procedure to treat spinal stenosis related to hypertrophied ligamentum flavum. The Superion® Interspinous Spacer, also known as Vertiflex®, is a titanium implant that is delivered percutaneously to relieve back pain caused by lumbar spinal stenosis. The MinuteMan® is a minimally invasive, interspinous-interlaminar fusion device planned for the temporary fixation of the thoracic, lumbar, and sacral spine, which eventually results in bony fusion. Based on our review of the available current scientific literature, the novel interventions for symptomatic lumbar spinal stenosis, such as the MILD® procedure and the Superion® interspinous spacer, generally appear to be safe and effective. There is a possibility in the future that these interventions could disrupt current treatment algorithms for lumbar spinal stenosis.

Novel Interventional Techniques for Chronic Pain with Minimally Invasive Arthrodesis of the Sacroiliac Joint: (INSITE, iFuse, Tricor, Rialto, and others).

Acute and chronic pain are public health issues that clinicians have been battling for years. Opioid medications have been a treatment option for both chronic and acute pain; however, they can cause unwanted complications and are a major contributor to our present opioid epidemic. The sacroiliac (SI) joint is a common cause of both acute and chronic low back pain. It affects about 15-25% of patients with axial low back pain, and up to 40% of patients with ongoing pain following lumbar fusion. Recent advances in the treatment of SI joint pain have led to the development of a wide variety of SI joint fusion devices. These fusion devices seek to stabilize the joints themselves in order that they become immobile and, in theory, can no longer be a source for pain. This is a minimally invasive procedure aimed to address chronic pain without subjecting patients to lengthy surgery or medications, including opioids with the potential for addiction and abuse. Minimally invasive SI fusion can be performed by a lateral approach (i.e., iFuse, Tricor) or posterior approach (i.e., CornerLoc, LinQ, Rialto). The posterior approach requires the patient to be in the prone position but allows for less disruption of muscles with entry. More data are necessary to determine which fusion system may be best for a particular patient. SI fusion devices are a promising way of treating chronic lower back pain related to the SI joint. This narrative review will discuss various types of SI fusion devices, and their potential use in terms of their safety and efficacy.