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Current Opinion in Supportive and... Jun 2020The treatment of cancer-induced bone pain (CIBP) has been proven ineffective and relies heavily on opioids, the target of highly visible criticism for their negative... (Review)
Review
PURPOSE OF REVIEW
The treatment of cancer-induced bone pain (CIBP) has been proven ineffective and relies heavily on opioids, the target of highly visible criticism for their negative side effects. Alternative therapeutic agents are needed and the last few years have brought promising results, detailed in this review.
RECENT FINDINGS
Cysteine/glutamate antiporter system, xc, cannabinoids, kappa opioids, and a ceramide axis have all been shown to have potential as novel therapeutic targets without the negative effects of opioids.
SUMMARY
Review of the most recent and promising studies involving CIBP, specifically within murine models. Cancer pain has been reported by 30-50% of all cancer patients and even more in late stages, however the standard of care is not effective to treat CIBP. The complicated and chronic nature of this type of pain response renders over the counter analgesics and opioids largely ineffective as well as difficult to use due to unwanted side effects. Preclinical studies have been standardized and replicated while novel treatments have been explored utilizing various alternative receptor pathways: cysteine/glutamate antiporter system, xc, cannabinoid type 1 receptor, kappa opioids, and a ceramide axis sphingosine-1-phosphate/sphingosine-1-phosphate receptor 1.
Topics: Animals; Antiporters; Bone and Bones; Cancer Pain; Cannabinoids; Disease Models, Animal; Humans; Mice; Receptor, Cannabinoid, CB1; Receptors, Opioid, kappa; Sphingosine-1-Phosphate Receptors
PubMed: 32349095
DOI: 10.1097/SPC.0000000000000496 -
The European Journal of Neuroscience Feb 2014Disorders of the skeleton are one of the most common causes of chronic pain and long-term physical disability in the world. Chronic skeletal pain is caused by a... (Review)
Review
Disorders of the skeleton are one of the most common causes of chronic pain and long-term physical disability in the world. Chronic skeletal pain is caused by a remarkably diverse group of conditions including trauma-induced fracture, osteoarthritis, osteoporosis, low back pain, orthopedic procedures, celiac disease, sickle cell disease and bone cancer. While these disorders are diverse, what they share in common is that when chronic skeletal pain occurs in these disorders, there are currently few therapies that can fully control the pain without significant unwanted side effects. In this review we focus on recent advances in our knowledge concerning the unique population of primary afferent sensory nerve fibers that innervate the skeleton, the nociceptive and neuropathic mechanisms that are involved in driving skeletal pain, and the neurochemical and structural changes that can occur in sensory and sympathetic nerve fibers and the CNS in chronic skeletal pain. We also discuss therapies targeting nerve growth factor or sclerostin for treating skeletal pain. These therapies have provided unique insight into the factors that drive skeletal pain and the structural decline that occurs in the aging skeleton. We conclude by discussing how these advances have changed our understanding and potentially the therapeutic options for treating and/or preventing chronic pain in the injured, diseased and aged skeleton.
Topics: Anabolic Agents; Analgesics; Animals; Bone and Bones; Humans; Musculoskeletal Pain; Neuralgia; Nociceptive Pain
PubMed: 24494689
DOI: 10.1111/ejn.12462 -
Biological & Pharmaceutical Bulletin 2021Temporomandibular disorder (TMD) is an oral dentofacial disease that is related to multiple factors such as disordered dental occlusion, emotional stress, and immune... (Review)
Review
Temporomandibular disorder (TMD) is an oral dentofacial disease that is related to multiple factors such as disordered dental occlusion, emotional stress, and immune responses. In the past decades, tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, has provided valuable insight into the pathogenesis of TMD, particularly in settings associated with inflammation. It is thought that TNF-α participates in the pathogenesis of TMD by triggering immune responses, deteriorating bone and cartilage, and mediating pain in the temporomandibular joint (TMJ). Initially, TNF-α plays the role of "master regulator" in the complex immune network by increasing or decreasing the production of other inflammatory cytokines. Then, the effects of TNF-α on cells, particularly on chondrocytes and synovial fibroblasts, result in pathologic cartilage degradation in TMD. Additionally, multiple downstream cytokines induced by TNF-α and neuropeptides can regulate central sensitization and inflammatory pain in TMD. Previous studies have also found some therapies target TMD by reducing the production of TNF-α or blocking TNF-α-induced pathways. All this evidence highlights the numerous associations between TNF-α and TMD; however, they are currently not fully understood and further investigations are still required for specific mechanisms and treatments targeting specific pathways. Therefore, in this review, we explored general mechanisms of TNF-α, with a focus on molecules in TNF-α-mediated pathways and their potential roles in TMD treatment. In view of the high clinical prevalence rate of TMD and damage to patients' QOL, this review provides adequate evidence for studying links between inflammation and TMD in further research and investigation.
Topics: Bone and Bones; Cartilage; Chondrocytes; Cytokines; Fibroblasts; Humans; Inflammation; Musculoskeletal Pain; Temporomandibular Joint; Temporomandibular Joint Disorders; Tumor Necrosis Factor-alpha
PubMed: 34853262
DOI: 10.1248/bpb.b21-00154 -
British Journal of Clinical Pharmacology Jun 2019Disorders of the skeleton are frequently accompanied by bone pain and a decline in the functional status of the patient. Bone pain occurs following a variety of injuries... (Review)
Review
Disorders of the skeleton are frequently accompanied by bone pain and a decline in the functional status of the patient. Bone pain occurs following a variety of injuries and diseases including bone fracture, osteoarthritis, low back pain, orthopedic surgery, fibrous dysplasia, rare bone diseases, sickle cell disease and bone cancer. In the past 2 decades, significant progress has been made in understanding the unique population of sensory and sympathetic nerves that innervate bone and the mechanisms that drive bone pain. Following physical injury of bone, mechanotranducers expressed by sensory nerve fibres that innervate bone are activated and sensitized so that even normally non-noxious loading or movement of bone is now being perceived as noxious. Injury of the bone also causes release of factors that; directly excite and sensitize sensory nerve fibres, upregulate proalgesic neurotransmitters, receptors and ion channels expressed by sensory neurons, induce ectopic sprouting of sensory and sympathetic nerve fibres resulting in a hyper-innervation of bone, and central sensitization in the brain that amplifies pain. Many of these mechanisms appear to be involved in driving both nonmalignant and malignant bone pain. Results from human clinical trials suggest that mechanism-based therapies that attenuate one type of bone pain are often effective in attenuating pain in other seemingly unrelated bone diseases. Understanding the specific mechanisms that drive bone pain in different diseases and developing mechanism-based therapies to control this pain has the potential to fundamentally change the quality of life and functional status of patients suffering from bone pain.
Topics: Age Factors; Analgesics; Animals; Bone and Bones; Central Nervous System Sensitization; Chemoreceptor Cells; Humans; Longevity; Mechanoreceptors; Musculoskeletal Pain; Pain Perception; Pain Threshold; Quality of Life; Risk Factors; Sympathetic Nervous System
PubMed: 30357885
DOI: 10.1111/bcp.13801 -
Molecular Pain 2020Bone cancer pain is common in patients with advanced cancers as tumor metastasizes to bone. The inefficient clinical treatment severely reduces quality of life of bone...
BACKGROUND
Bone cancer pain is common in patients with advanced cancers as tumor metastasizes to bone. The inefficient clinical treatment severely reduces quality of life of bone cancer pain patients. During the pain status, activated spinal astrocytes and microglia release various inflammatory cytokines, resulting in spinal inflammation and the development of neuron sensitization. Scorpion is the dry body of Buthus martensii Karsch and is often used for various pain management in clinical practice. However, its function on bone cancer pain is unclear.
METHODS
We investigated the effects of intragastric administration of scorpion on bone cancer pain induced by left tibial cavity injection of Walker 256 cells. Nociceptive behavior was measured using the von Frey filaments test and the spontaneous ambulatory pain score. The bone destruction was assessed by tibial radiographs. Expression of spinal cord astrocyte marker glial fibrillary acidic protein and microglial marker Iba1 was monitored by Western blot assay and immunofluorescence. Tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β was detected by real-time polymerase chain reaction. The proliferation of Walker 256 cells was evaluated by CCK8 assay.
RESULTS
Intragastric administration of scorpion reduced bone cancer pain behavior and relieved bone destruction, accompanied by decreased expression of spinal glial fibrillary acidic protein and Iba1 protein level and TNF-α, IL-6, and IL-1β mRNA level. Besides, scorpion inhibited proliferation of Walker 256 cells in a dose- and time-dependent manner.
CONCLUSION
Our results demonstrate that scorpion produces an analgesic effect in a rat model of bone cancer pain via inhibiting bone destruction and activation of spinal cord astrocytes and microglia.
Topics: Animals; Astrocytes; Behavior, Animal; Biological Products; Bone Neoplasms; Bone and Bones; Cancer Pain; Cell Line, Tumor; Female; Hyperalgesia; Inflammation; Interleukin-1beta; Interleukin-6; Mammary Neoplasms, Animal; Neoplasm Transplantation; Neuroglia; Rats; Rats, Sprague-Dawley; Scorpions; Spinal Cord; Stomach; Tumor Necrosis Factor-alpha
PubMed: 32052691
DOI: 10.1177/1744806920909993 -
Orphanet Journal of Rare Diseases May 2012One of the most common complications of fibrous dysplasia of bone (FD) is bone pain. Usual pain killers are often of inadequate efficacy to control this bone pain. The... (Review)
Review
One of the most common complications of fibrous dysplasia of bone (FD) is bone pain. Usual pain killers are often of inadequate efficacy to control this bone pain. The mechanism of bone pain in FD remains uncertain, but by analogy with bone tumors one may consider that ectopic sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers also occur in the dysplastic skeleton. Bone pain has been reported in up to 81% of adults and 49% of children. It affects predominantly the lower limbs and the spine. The degree of pain is highly variable and adults reports more pain than children. Bisphosphonates have been shown to reduce bone pain in uncontrolled studies. Their influence on bone strength remains unknown. In a randomized trial testing alendronate, bone pain was not significantly improved. Another trial assessing the effect of risedronate is ongoing. Possible future therapies include tocilizumab, denosumab and drugs targeting nerve growth factor and its receptor TrkA.
Topics: Alendronate; Antibodies, Monoclonal, Humanized; Bone Neoplasms; Bone and Bones; Fibrous Dysplasia of Bone; Humans; Nerve Fibers; Pain; Pain Management; Pain Measurement; Self Report; Sensory Receptor Cells
PubMed: 22640953
DOI: 10.1186/1750-1172-7-S1-S3 -
Frontiers in Endocrinology 2023
Topics: Humans; Bone Neoplasms; Bone and Bones; Bone Marrow Diseases
PubMed: 37564977
DOI: 10.3389/fendo.2023.1256406 -
The Journal of Clinical Investigation May 2006Skin and bone - what comes to mind at hearing this phrase? While certainly a metaphor for disease, it also defines two very different tissues, one a flexible and... (Review)
Review
Skin and bone - what comes to mind at hearing this phrase? While certainly a metaphor for disease, it also defines two very different tissues, one a flexible and contiguous outer covering, the other a morphologically diverse hard tissue distributed at over 200 sites in the body. As the accompanying series of Reviews highlights, these tissues are indeed diverse, but there are also surprising similarities. Skin is the interface between the internal organs and the environment, and as such plays a crucial role in the body's defense mechanism. The skin and its many appendages are responsible for functions as diverse as epidermal barrier and defense, immune surveillance, UV protection, thermoregulation, sweating, lubrication, pigmentation, the sensations of pain and touch, and, importantly, the protection of various stem cell niches in the skin. Bone serves a number of purposes: it provides protection for vital organs, a lever for locomotion, a reservoir for calcium, and the site of adult hematopoiesis. The tissue is composed of osteoblasts, osteoclasts, and their individual precursors plus a complex mixture of mesenchymal, myeloid, and lymphoid cells in the marrow space. Finally, the endothelial microenvironment provides nutrition and is a conduit for the influx and emigration of cells that impact bone biology in several important ways. This Review series guides the reader through these various facets of 2 diverse, yet interdependent, tissues.
Topics: Animals; Bone and Bones; Humans; Models, Anatomic; Models, Biological; Skin; Skin Physiological Phenomena
PubMed: 16670754
DOI: 10.1172/JCI28605 -
Inflammopharmacology Oct 2013Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP),... (Review)
Review
Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP), satisfactory relief of intractable pain in patients with advanced bony metastases is challenging for the clinicians because currently available analgesic drugs are often limited by poor efficacy and/or dose-limiting side effects. Rodent models developed in the past decade show that the pathobiology of PCIBP comprises elements of inflammatory, neuropathic and ischemic pain arising from ectopic sprouting and sensitization of sensory nerve fibres within PCa-invaded bones. In addition, at the cellular level, PCIBP is underpinned by dynamic cross talk between metastatic PCa cells, cellular components of the bone matrix, factors associated with the bone microenvironment as well as peripheral components of the somatosensory system. These insights are aligned with the clinical management of PCIBP involving use of a multimodal treatment approach comprising analgesic agents (opioids, NSAIDs), radiotherapy, radioisotopes, cancer chemotherapy agents and bisphosphonates. However, a major drawback of most rodent models of PCIBP is their short-term applicability due to ethical concerns. Thus, it has been difficult to gain insight into the mal(adaptive) neuroplastic changes occurring at multiple levels of the somatosensory system that likely contribute to intractable pain at the advanced stages of metastatic disease. Specifically, the functional responsiveness of noxious circuitry as well as the neurochemical signature of a broad array of pro-hyperalgesic mediators in the dorsal root ganglia and spinal cord of rodent models of PCIBP is relatively poorly characterized. Hence, recent work from our laboratory to develop a protocol for an optimized rat model of PCIBP will enable these knowledge gaps to be addressed as well as identification of novel targets for drug discovery programs aimed at producing new analgesics for the improved relief of intractable PCIBP.
Topics: Adjuvants, Pharmaceutic; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone Neoplasms; Bone and Bones; Combined Modality Therapy; Disease Models, Animal; Drug Therapy, Combination; Humans; Male; Nociceptive Pain; Pain Management; Prostatic Neoplasms
PubMed: 23918298
DOI: 10.1007/s10787-013-0183-7 -
Reumatismo Jun 2014The pain of osteoarthritis (OA) has multifaceted etiologies within and outside the joint. It is believed to be driven by both nociceptive and neuropathic mechanisms, as... (Review)
Review
The pain of osteoarthritis (OA) has multifaceted etiologies within and outside the joint. It is believed to be driven by both nociceptive and neuropathic mechanisms, as well as abnormal excitability in the pain pathways of the peripheral and central nervous system. Inflammation in the joint triggers a cascade of events that leads to peripheral sensitization, increased sensitivity of nociceptive primary afferent neurons, and hyperexcitability of the nociceptive neurons in the central nervous system. Pain receptors have been found in the synovium, ligaments, capsule, subchondral bone and surrounding tissues, with the exception of articular cartilage. The bone-related causes of pain in OA include subchondral microfractures, bone stretching with elevation of the periosteum due to osteophyte growth, bone remodeling and repair, bone marrow lesions, and bone angina caused by decreased blood flow and increased intra-osseous pressure. Central factors alter pain processing by setting the gain in such a way that, when a peripheral input is present, it is processed against a background of central factors that can enhance or diminish the experience of pain. As a complex phenomenon with a strong subjective component, pain can also be influenced by the nature of the underlying disease, personal predisposition (biological and psychological), and environmental and psychosocial factors. This review examines the current literature regarding the sources and mechanisms of pain in OA.
Topics: Afferent Pathways; Bone and Bones; Cartilage, Articular; Central Nervous System Sensitization; Cost of Illness; Diagnostic Imaging; Humans; Musculoskeletal Pain; Neuralgia; Neuropeptides; Nociceptors; Osteoarthritis; Overweight; Pain Perception; Posterior Horn Cells; Prevalence; Radiography; Synovial Fluid
PubMed: 24938198
DOI: 10.4081/reumatismo.2014.766