Spinal miRNA-124 regulates synaptopodin and nociception in an animal model of bone cancer pain.

Strong breakthrough pain is one of the most disabling symptoms of cancer since it affects up to 90% of cancer patients and is often refractory to treatments. Alteration in gene expression is a known mechanism of cancer pain in which microRNAs (miRNAs), a class of non-coding regulatory RNAs, play a crucial role. Here, in a mouse model of cancer pain, we show that miR-124 is down-regulated in the spinal cord, the first relay of the pain signal to the brain. Using in vitro and in vivo approaches, we demonstrate that miR-124 is an endogenous and specific inhibitor of synaptopodin (Synpo), a key protein for synaptic transmission. In addition, we demonstrate that Synpo is a key component of the nociceptive pathways. Interestingly, miR-124 was down-regulated in the spinal cord in cancer pain conditions, leading to an up-regulation of Synpo. Furthermore, intrathecal injections of miR-124 mimics in cancerous mice normalized Synpo expression and completely alleviated cancer pain in the early phase of the cancer. Finally, miR-124 was also down-regulated in the cerebrospinal fluid of cancer patients who developed pain, suggesting that miR-124 could be an efficient analgesic drug to treat cancer pain patients.

Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol.

BACKGROUND: Ziconotide is a new analgesic agent administered intrathecally. It is challenging to use and can induce several and sometimes serious adverse events. A low initial dosage followed by slow titration may reduce serious adverse events. OBJECTIVE: To determine whether a low starting dosage of ziconotide, followed by slow titration, decreases the incidence of major adverse events associated with ziconotide when used for intractable cancer pain. STUDY DESIGN: Observational cohort study. SETTING: Three French cancer centers. METHODS: Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy (more than 200 mg/d of oral morphine equivalent) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine, ropivacaine, and clonidine. RESULTS: Seventy-seven patients were included. Adverse events were recorded in 57% of them; moderate adverse events occurred in 51%. Adverse events required treatment discontinuation in 7 (9%) including 5 (6%) for whom a causal role for ziconotide was highly likely; among them 4 (5%) were serious. All patients experienced a significant and lasting decrease in pain intensity (by 48%) in response to intrathecal analgesic therapy that included ziconotide. LIMITATIONS: Limitations include the nonrandomized, observational nature of the study. Determining the relative contributions of each drug to adverse events was difficult, and some of the adverse events manifested as clinical symptoms of a subjective nature. CONCLUSIONS: The rates of minor and moderate adverse events were consistent with previous reports. However, the rate of serious adverse events was substantially lower. Our study confirms the efficacy of intrathecal analgesia with ziconotide for relieving refractory cancer pain. These results indicate that multimodal intrathecal analgesia in patients with cancer pain should include ziconotide from the outset in order to provide time for subsequent slow titration.

[Interventional radiology procedures in the treatment of bone metastasis]. / Traitement des métastases osseuses par radiologie interventionnelle.

Over the last ten years, there has been much development in the treatment of bone metastases using percutaneous image-guided interventional radiology procedures. They are helpful in the management of patients resulting in stabilization of bone lysis in order to achieve additional biomechanical stability and in significant symptomatic relief. Vertebroplasty consisting in an injection of an acrylic cement into a structurally weakened or destructed bone plays a major role in the management of specific bone weakening. Advances have been made also with the application of thermoablation procedures to bone tumors (radiofrequency ablation, cryotherapy). Since conservative treatment with analgesics is often insufficient and the analgesic effect of radiation therapy is delayed and sometimes ineffective, these image-guided procedures play a beneficial role in the management of bone metastases and need more evaluation.