Opioids and Cancer: Current Understanding and Clinical Considerations.

Pain is one of the most common symptoms in patients with cancer. Pain not only negatively affects the quality of life of patients with cancer, but it has also been associated with reduced survival. Pain management is therefore a critical component of cancer care. Prescription opioids remain the first-line approach for the management of moderate-to-severe pain associated with cancer. However, there has been increasing interest in understanding whether these analgesics could impact cancer progression. Furthermore, epidemiological data link a possible association between prescription opioid usage and cancer development. Until more robust evidence is available, patients with cancer with moderate-to-severe pain may receive opioids to decrease suffering. However, future studies should be conducted to evaluate the role of opioids and opioid receptors in specific cancers.

RNA profiling of human dorsal root ganglia reveals sex differences in mechanisms promoting neuropathic pain.

Neuropathic pain is a leading cause of high-impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain-associated dorsal root ganglia. We sequenced 70 human dorsal root ganglia, and among these 50 met inclusion criteria for sufficient neuronal mRNA signal for downstream analysis. Our expression analysis revealed profound sex differences in differentially expressed genes including increase of IL1B, TNF, CXCL14 and OSM in male and CCL1, CCL21, PENK and TLR3 in female dorsal root ganglia associated with neuropathic pain. Coexpression modules revealed enrichment in members of JUN-FOS signalling in males and centromere protein coding genes in females. Neuro-immune signalling pathways revealed distinct cytokine signalling pathways associated with neuropathic pain in males (OSM, LIF, SOCS1) and females (CCL1, CCL19, CCL21). We validated cellular expression profiles of a subset of these findings using RNAscope in situ hybridization. Our findings give direct support for sex differences in underlying mechanisms of neuropathic pain in patient populations.

The µ-Opioid Receptor in Cancer and Its Role in Perineural Invasion: A Short Review and New Evidence.

Cancer is a significant public health problem worldwide. While there has been a steady decrease in the cancer death rate over the last two decades, the number of survivors has increased and, thus, cancer-related sequela. Pain affects the life of patients with cancer and survivors. Prescription opioids continue as the analgesic of choice to treat moderate-to-severe cancer-related pain. There has been controversy on whether opioids impact cancer progression by acting on cancer cells or the tumor microenvironment. The µ-opioid receptor is the site of action of prescription opioids. This receptor can participate in an important mechanism of cancer spread, such as perineural invasion. In this review, current evidence on the role of the µ-opioid receptor in cancer growth is summarized and preliminary evidence about its effect on the cross-talk between sensory neurons and malignant cells is provided.

Fadu head and neck squamous cell carcinoma induces hyperexcitability of primary sensory neurons in an in vitro coculture model.

Introduction: Currently, cancer pain is viewed as a process orchestrated by the release of pronociceptive molecules and the invasion of neural structures, referred to as perineural invasion (PNI). Cancer pain resulting from PNI is well-documented, but the mechanisms leading to peripheral sensitization because of tumor growth are not fully known. Methods: A retrospective study was used to examine how the use of anti-inflammatory medications affected preoperative pain in patients with oral squamous cell carcinoma cancer. We then used an in vitro coculture model in which dorsal root ganglion (DRG) neurons were incubated together with Fadu human head and neck squamous cell carcinoma cancer cells to explore how cancer cells affect the electrical membrane properties of sensory neurons. Results: We found that inflammation contributes to preoperative pain in patients with oral squamous cell carcinoma. After coculture with Fadu human head and neck squamous cell carcinoma cancer cells, we identified markers of inflammation in coculture media and found evidence of neuronal sensitization, including spontaneous activity, reduced current thresholds, depolarized resting membrane potential, and enhanced responses to current stimulation in human and rat DRG neurons. In rats, these effects were influenced by sex and age: neurons from young adult female rats were resistant to changes in neuronal activity, in contrast to neurons from older adult female rats or male rats of either age group. Conclusions: Pro-inflammatory substances released in cancer cell-DRG coculture promoted neuronal hyperexcitability and may contribute to cancer pain after PNI, and these effects may differ across age groups and sexes.

Studying human nociceptors: from fundamentals to clinic.

Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood-brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap.

Role of innate immunity in chemotherapy-induced peripheral neuropathy.

It has become increasingly clear that the innate immune system plays an essential role in the generation of many types of neuropathic pain including that which accompanies cancer treatment. In this article we review current findings of the role of the innate immune system in contributing to cancer treatment pain at the distal endings of peripheral nerve, in the nerve trunk, in the dorsal root ganglion and in the spinal dorsal horn.

Chemotherapy-induced peripheral neuropathy in a dish: dorsal root ganglion cells treated in vitro with paclitaxel show biochemical and physiological responses parallel to that seen in vivo.

The mechanisms underlying chemotherapy-induced peripheral neuropathy have yet to be fully elucidated, but primary afferent neurons have emerged as an especially vulnerable initiating pathophysiological target. An important recent study has also shown that the initial toxicity produced by paclitaxel in patients was highly predictive of long-term outcome. In this study, we therefore focused on defining the mechanisms of acute toxicity produced by paclitaxel treatment on primary sensory neurons under in vitro conditions. In primary rat dorsal root ganglion (DRG) culture with paclitaxel, an increase of pERK and pp38 was observed at 2 hours, and this was accompanied by an increase in expression and release of C-C chemokine ligand 2 (CCL2). There was no change in pJNK. The increase in pERK was sustained at 48 hours of exposure when the expression of TLR4, MyD88, and IL-6 was also increased. IL-6 and CCL2 were colocalized to TLR4-positive cells, and all these responses were prevented by coincubation with a TLR4 antagonist (LPS-RS). Whole-cell patch-clamp recordings revealed that DRG neurons developed spontaneous depolarizing fluctuations (DSFs) in membrane potential and hyperexcitability to current injection but no ectopic action potential activity at 24 and 48 hours of paclitaxel incubation. However, CCL2 applied to cultured neurons not only induced DSFs but also evoked action potentials. Evidence of oxidative stress and mitotoxicity was observed at 48 hours of exposure. These results closely parallel the responses measured in the DRG with paclitaxel exposure in vivo and so indicate that acute toxicity of paclitaxel on the DRG can be modelled using an in vitro approach.

Persistent and Chronic Postoperative Opioid Use in a Cohort of Patients with Oral Tongue Squamous Cell Carcinoma.

BACKGROUND: Recently, the concept of persistent postsurgical opioid use has been described for patients undergoing cancer surgery. Our hypothesis was based on the premise that patients with oral tongue cancer require high dosages of opioids before, during, and after surgery, and thus a large percentage of patients might develop persistent postsurgical opioid use. METHODS: After institutional review board approval, we conducted a retrospective study that included a cohort of patients with oral tongue cancers who underwent curative-intent surgery in our institution. Multivariable logistic regression models were fit to study the association of the characteristics of several patients with persistent (six months after surgery) and chronic (12 months after surgery) postoperative opioid use. RESULTS: A total of 362 patients with oral tongue malignancies were included in the study. The rate of persistent use of opioids after surgery was 31%. Multivariate analysis showed that patients taking opioids before surgery and those receiving adjuvant therapy were 2.9 and 1.78 times more likely to use opioids six months after surgery. Fifteen percent of the patients were taking opioids 12 months after surgery. After adjusting for clinically relevant covariates, patients complaining of moderate tongue pain before surgery and those taking opioids preoperatively had at least three times higher risk of still using these analgesics one year after surgery. CONCLUSIONS: Patients with oral tongue cancers have a high risk of developing persistent and chronic postsurgical opioid use.

Pioglitazone, a PPARγ agonist, reduces cisplatin-evoked neuropathic pain by protecting against oxidative stress.

Painful peripheral neuropathy is a dose-limiting side effect of cisplatin treatment. Using a murine model of cisplatin-induced hyperalgesia, we determined whether a PPARγ synthetic agonist, pioglitazone, attenuated the development of neuropathic pain and identified underlying mechanisms. Cisplatin produced mechanical and cold hyperalgesia and decreased electrical thresholds of Aδ and C fibers, which were attenuated by coadministration of pioglitazone (10 mg/kg, intraperitoneally [i.p.]) with cisplatin. Antihyperalgesic effects of pioglitazone were blocked by the PPARγ antagonist T0070907 (10 mg/kg, i.p.). We hypothesized that the ability of pioglitazone to reduce the accumulation of reactive oxygen species (ROS) in dorsal root ganglion (DRG) neurons contributed to its antihyperalgesic activity. Effects of cisplatin and pioglitazone on somatosensory neurons were studied on dissociated mouse DRG neurons after 24 hours in vitro. Incubation of DRG neurons with cisplatin (13 µM) for 24 hours increased the occurrence of depolarization-evoked calcium transients, and these were normalized by coincubation with pioglitazone (10 µM). Oxidative stress in DRG neurons was considered a significant contributor to cisplatin-evoked hyperalgesia because a ROS scavenger attenuated hyperalgesia and normalized the evoked calcium responses when cotreated with cisplatin. Pioglitazone increased the expression and activity of ROS-reducing enzymes in DRG and normalized cisplatin-evoked changes in oxidative stress and labeling of mitochondria with the dye MitoTracker Deep Red, indicating that the antihyperalgesic effects of pioglitazone were attributed to its antioxidant properties in DRG neurons. These data demonstrate clear benefits of broadening the use of the antidiabetic drug pioglitazone, or other PPARγ agonists, to minimize the development of cisplatin-induced painful neuropathy.

Inhibition of anandamide hydrolysis attenuates nociceptor sensitization in a murine model of chemotherapy-induced peripheral neuropathy.

Painful neuropathy frequently develops as a consequence of commonly used chemotherapy agents for cancer treatment and is often a dose-limiting side effect. Currently available analgesic treatments are often ineffective on pain induced by neurotoxicity. Although peripheral administration of cannabinoids, endocannabinoids, and inhibitors of endocannabinoid hydrolysis has been effective in reducing hyperalgesia in models of peripheral neuropathy, including chemotherapy-induced peripheral neuropathy (CIPN), few studies have examined cannabinoid effects on responses of nociceptors in vivo. In this study we determined whether inhibition of fatty acid amide hydrolase (FAAH), which slows the breakdown of the endocannabinoid anandamide (AEA), reduced sensitization of nociceptors produced by chemotherapy. Over the course of a week of daily treatments, mice treated with the platinum-based chemotherapy agent cisplatin developed robust mechanical allodynia that coincided with sensitization of cutaneous C-fiber nociceptors as indicated by the development of spontaneous activity and increased responses to mechanical stimulation. Administration of the FAAH inhibitor URB597 into the receptive field of sensitized C-fiber nociceptors decreased spontaneous activity, increased mechanical response thresholds, and decreased evoked responses to mechanical stimuli. Cotreatment with CB1 (AM281) or CB2 (AM630) receptor antagonists showed that the effect of URB597 was mediated primarily by CB1 receptors. These changes following URB597 were associated with an increase in the endocannabinoid anandamide in the skin. Our results suggest that enhanced signaling in the peripheral endocannabinoid system could be utilized to reduce nociceptor sensitization and pain associated with CIPN.