Cancer-Related Pain: Understanding Genetic Influences and Determining Implications for Practice.

Pain can be highly variable and unpredictable. Genetics may be key to identifying pain mechanisms that control the intensity, duration, and physiologic response in individuals with chronic pain. Pharmaco-genomics and precision medicine are permitting advances in pain control with analgesic drugs that have increased effectiveness and lead to decreased side effects. Knowledge of genetic variations related to how and why patients experience pain will aid in identifying those at risk, provide a better understanding of the phenomenon of pain, and possibly lead to innovative therapies to control pain.

Bioinformatic Analysis of Potential Biomarkers for Spinal Cord-injured Patients with Intractable Neuropathic Pain.

BACKGROUND: Neuropathic pain is one of the common complications after spinal cord injury (SCI), affecting individuals' quality of life. The molecular mechanism for neuropathic pain after SCI is still unclear. We aimed to discover potential genes and microRNAs (miRNAs) related to neuropathic pain by the bioinformatics method. METHODS: Microarray data of GSE69901 were obtained from Gene Expression Omnibus (GEO) database. Peripheral blood samples from individuals with or without neuropathic pain after SCI were collected. Twelve samples from individuals with neuropathic pain and 13 samples from individuals without pain as controls were included in the downloaded microarray. Differentially expressed genes (DEGs) between the neuropathic pain group and the control group were detected using the GEO2R online tool. Functional enrichment analysis of DEGs was performed using the DAVID database. Protein-protein interaction network was constructed from the STRING database. MiRNAs targeting these DEGs were obtained from the miRNet database. A merged miRNA-DEG network was constructed and analyzed with Cytoscape software. RESULTS: In total, 1134 DEGs were identified between individuals with or without neuropathic pain (case and control), and 454 biological processes were enriched. We identified 4 targeted miRNAs, including mir-204-5p, mir-519d-3p, mir-20b-5p, mir-6838-5p, which may be potential biomarkers for SCI patients. CONCLUSION: Protein modification and regulation of the biological process of the central nervous system may be a risk factor in SCI. Certain genes and miRNAs may be potential biomarkers for the prediction of and potential targets for the prevention and treatment of neuropathic pain after SCI.

[Interindividual variation of pharmacokinetic disposition of and clinical responses to opioid analgesics in cancer pain patients].

Use of prescription opioids for cancer pain according to the World Health Organization analgesic ladder has been accepted in Japan. Although oxycodone and fentanyl are commonly used as first-line analgesics, a few clinical reports have been published on interindividual variations in their pharmacokinetics and clinical responses in cancer patients. (1) Some factors relating to CYP2D6, CYP3A, ATP-binding cassette sub-family B member 1 (ABCB1), and opioid receptor mu 1 (OPRM1) involve oxycodone pharmacokinetics and sensitivity in humans. The relations between their genetic variations and clinical responses to oxycodone are being revealed in limited groups. In our study, the impact of genetic variants and pharmacokinetics on clinical responses to oxycodone were evaluated in Japanese populations. (2) Opioid switching improves the opioid tolerance related to the balance between analgesia and adverse effects. Some patients have difficulty in obtaining better opioid tolerance in recommended conversion ratios. The activities of CYP3A, ABCB1, and OPRM1 contribute to the interindividual variations in clinical responses to fentanyl in cancer patients. However, the variations in opioid switching remain to be clarified in clinical settings. In our study, genetic factors related to interindividual variations in clinical responses in opioid switching to fentanyl were revealed in Japanese populations. In this symposium review, the possibility of approaches to personalized palliative care using opioids based on genetic variants of CYP2D6, CYP3A5, ABCB1, and OPRM1 is discussed.

Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors?

OBJECTIVES: Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness. SETTING: 17 hospice/palliative care services (tertiary services) in 11 European countries. PARTICIPANTS: 2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment. PRIMARY OUTCOME MEASURES: The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588). SECONDARY OUTCOME MEASURES: The same measures for people on oxycodone (n=402) or fentanyl (n=429). RESULTS: SNPs not in Hardy-Weinberg equilibrium or with allele frequencies (<5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the ß-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone. CONCLUSIONS: This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy.

Clinical and genetic factors related to cancer-induced bone pain and bone pain relief.

OBJECTIVE: The study objective was to evaluate whether there are clinical or genetic differences between patients with cancer-induced bone pain (CIBP) and patients with non-CIBP, and, in the CIBP group, in those with good versus poor opioid response. MATERIALS AND METHODS: A total of 2,294 adult patients with cancer who were receiving opioids for moderate or severe pain were included in the European Pharmacogenetic Opioid Study. Pain intensity and pain relief were measured using the Brief Pain Inventory. Linkage disequilibrium of 112 single nucleotide polymorphisms was evaluated in 25 candidate genes, and 43 haplotypes were assessed. Correlations among demographical factors, disease-related factors, genetic factors, CIBP, and pain relief were analyzed by logistic regression models corrected for multiple testing. Patients with bone metastases and bone/soft tissue pain were defined as having prevalent bone pain (CIBP population). This population was compared with patients who had other types of cancer pain (non-CIBP). RESULTS: A total of 577 patients (26.2%) had CIBP, and 1,624 patients (73.8%) had non-CIBP. Patients with CIBP had more breakthrough cancer pain episodes (64.2% vs. 56.4%, p = .001), had significantly higher pain interference in "walking ability in the past 24 hours" (p < .0001), used more adjuvant drugs (84.1% vs. 78.3%, p = .003), and had a higher, albeit nonsignificant, median overall survival (3.8 vs. 2.9 months, p = .716) than patients with non-CIBP. None of the examined haplotypes exceeded p values corrected for multiple testing for the investigated outcomes. CONCLUSION: Patients with CIBP who were taking opioids had a clinical profile slightly different from that of the non-CIBP group. However, no specific genetic pattern emerged for CIBP versus non-CIBP or for responsive versus nonresponsive patients with CIBP.

T-type calcium channels: functional regulation and implication in pain signaling.

Low-voltage-activated T-type Ca(2+) channels (T-channels), especially Cav3.2 among the three isoforms (Cav3.1, Cav3.2, and Cav3.3), are now considered to play pivotal roles in processing of pain signals. Cav3.2 T-channels are functionally modulated by extracellular substances such as hydrogen sulfide and ascorbic acid, by intracellular signaling molecules including protein kinases, and by glycosylation. Cav3.2 T-channels are abundantly expressed in both peripheral and central endings of the primary afferent neurons, regulating neuronal excitability and release of excitatory neurotransmitters such as substance P and glutamate, respectively. Functional upregulation of Cav3.2 T-channels is involved in the pathophysiology of inflammatory, neuropathic, and visceral pain. Thus, Cav3.2 T-channels are considered to serve as novel targets for development of drugs for treatment of intractable pain resistant to currently available analgesics.

Medullary sponge kidney.

PURPOSE OF REVIEW: After it was first described in 1939, medullary sponge kidney (MSK) received relatively little attention. This was because it was believed to have a low prevalence and because it was considered a benign condition. Studies in recent years have been changing these convictions however, hence the present review. RECENT FINDINGS: Insight has been obtained on the genetic basis of this disease, supporting the hypothesis that MSK is due to a disruption at the 'ureteric bud-metanephric mesenchyme' interface. This explains why so many tubular defects coexist in this disease, and particularly a distal tubular acidification defect of which the highly prevalent metabolic bone disease is one very important consequence. In addition to the typical clinical phenotype of recurrent stone disease, other clinical profiles have now been recognized, that is, an indolent, almost asymptomatic MSK, and a rare form characterized by intractable, excruciating pain. SUMMARY: Findings suggest the need for a more comprehensive clinical characterization of MSK patients. The genetic grounds for the condition warrant further investigation, and reliable methods are needed to diagnose MSK.

Microglia and intractable chronic pain.

Many pathological processes within the central nervous system are mediated by complex interactions between neurons and resident glial cells. In the case of painful peripheral neuropathy, spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. Purinergic signaling has been shown to be at the center of this reactivity, and here we review recent mechanistic advances describing the importance of microglial P2 receptors and their interactions with neuronal populations in the development of neuropathic pain.

Targeted drug delivery to the peripheral nervous system using gene therapy.

Gene transfer to target delivery of neurotrophic factors to the primary sensory afferent for treatment of polyneuropathy, or of inhibitory neurotransmitters for relief of chronic pain, offers the possibility of a highly selective targeted release of bioactive molecules within the nervous system. Preclinical studies with non-replicating herpes simplex virus (HSV)-based vectors injected into the skin to transduce neurons in the dorsal root ganglion have demonstrated efficacy in reducing-pain related behaviors in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer, and in preventing progression of sensory neuropathy caused by toxins, chemotherapeutic drugs or resulting from diabetes. Successful completion of the first phase 1 clinical trial of HSV-mediated gene transfer in patients with intractable pain from cancer has set the stage for further clinical trials of this approach.

The transition from acute to chronic post surgical pain.

All chronic pain was once acute, but not all acute pain becomes chronic. The transition of acute postoperative pain to chronic post surgical pain is a complex and poorly understood developmental process. The manuscript describes the various factors associated with the transition from acute to chronic pain. The preoperative, intraoperative and postoperative surgical, psychosocial, socio-environmental and patient-related factors and the mechanisms involved are discussed and preventive (or limitation) strategies are suggested. In future, the increasing understanding of genetic factors and the transitional mechanisms involved may reveal important clues to predict which patients will go on to develop chronic pain. This may assist the development of appropriate interventions affecting not only the individual concerned, but also ultimately the community at large.

A new Nav1.7 sodium channel mutation I234T in a child with severe pain.

Dominant gain-of-function mutations that hyperpolarize activation of the Na(v)1.7 sodium channel have been linked to inherited erythromelalgia (IEM), a disorder characterized by severe pain and redness in the feet and hands in response to mild warmth. Pharmacotherapy remains largely ineffective for IEM patients with cooling and avoidance of triggers being the most reliable methods to relieve pain. We now report a 5 year old patient with pain precipitated by warmth, together with redness in her hands and feet. Her pain episodes were first reported at 12 months, and by the age of 15-16 months were triggered by sitting as well as heat. Pain has been severe, inducing self-mutilation, with limited relief from drug treatment. Our analysis of the patient's genomic DNA identified a novel Na(v)1.7 mutation which replaces isoleucine 234 by threonine (I234T) within domain I/S4-S5 linker. Whole-cell voltage-clamp analysis shows a I234T-induced shift of -18 mV in the voltage-dependence of activation, accelerated time-to-peak, slowed deactivation and enhanced responses to slow ramp depolarizations, together with a -21 mV shift in the voltage-dependence of slow-inactivation. Our data show that I234T induces the largest activation shift for Na(v)1.7 mutations reported thus far. Although enhanced slow-inactivation may attenuate the gain-of-function of the I234T mutation, the shift in activation appears to be dominant, and is consistent with the severe pain symptoms reported in this patient.

Down-regulation of Toll-like receptor 4 gene expression by short interfering RNA attenuates bone cancer pain in a rat model.

BACKGROUND: This study demonstrates a critical role in CNS innate immunity of the microglial Toll-like receptor 4 (TLR4) in the induction and maintenance of behavioral hypersensitivity in a rat model of bone cancer pain with the technique of RNA interference (RNAi). We hypothesized that after intramedullary injection of Walker 256 cells (a breast cancer cell line) into the tibia, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. RESULTS: We assessed tactile allodynia and spontaneous pain in female Sprague-Dawley (SD) rats after intramedullary injection of Walker 256 cells into the tibia. In a complementary study, TLR4 small interfering RNA(siRNA) was administered intrathecally to bone cancer pain rats to reduce the expression of spinal TLR4. The bone cancer pain rats treated with TLR4 siRNA displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines compared with controls. Only intrathecal injection of TRL4 siRNA at post-inoculation day 4 could prevent initial development of bone cancer pain; intrathecal injection of TRL4 siRNA at post-inoculation day 9 could attenuate, but not completely block, well-established bone cancer pain. CONCLUSIONS: TLR4 might be the main mediator in the induction of bone cancer pain. Further study of this early, specific, and innate CNS/microglial response, and how it leads to sustained glial/neuronal hypersensitivity, might lead to new therapies for the prevention and treatment of bone cancer pain syndromes.

Electroconvulsive stimulation (ECS) increases the expression of neuropeptide Y (NPY) in rat brains in a model of neuropathic pain: a quantitative real-time polymerase chain reaction (RT-PCR) study.

OBJECTIVES: Electroconvulsive shock therapy (ECT) has been widely used as an effective and established treatment for refractory depression and schizophrenia. Some reports have shown that ECT is also effective for treating refractory neuropathic pain. DESIGN: In a rat model of neuropathic pain produced by chronic constrictive injury (CCI) of the sciatic nerve, thermal hyperalgesia, and mechanical allodynia were observed from day 2 after surgery. An electroconvulsive shock (ECS) was administered to rodents once daily for 6 days on days 7-12 after CCI operation using a pulse generator. Thermal and mechanical stimulation tests were performed to assess pain thresholds. Real-time polymerase chain reaction was used to measure the gene expression levels for 5HT(1A)R, 5HT(2A)R, neuropeptide Y (NPY), and GABAA(alpha1)R in the brain. RESULTS: After ECS, the latency to withdrawal from thermal stimulation was significantly increased; however, pain withdrawal thresholds in response to mechanical stimulation were not significantly changed. Expression ratios of NPY were significantly greater after ECS. CONCLUSION: Symptoms of neuropathic pain improved and expression of NPY in the brain was increased in CCI model rats after ECS, suggesting that changes in the expression of NPY in the brain may be related to the mechanism of action of ECT in treating neuropathic pain.

DRD3 Ser9Gly polymorphism is related to thermal pain perception and modulation in chronic widespread pain patients and healthy controls.

UNLABELLED: Experimental studies showed that dopamine influences pain perception in healthy volunteers. Dopamine dysfunctions have been linked to the physiopathology of fibromyalgia (FM), which is associated with hyperalgesia and deficient pain inhibition. We sought to investigate the relationships between catecholamine-related polymorphisms [dopamine-D(3) receptor (DRD3) Ser9Gly and catechol-O-methyltransferase (COMT) Val158Met] and thermal pain measures in healthy subjects and FM patients. Seventy-three subjects (37 FM patients and 36 controls) participated in this study. Thermal pain thresholds (TPTs) were measured using a Peltier thermode. Inhibitory systems were elicited using a thermal tonic pain stimulation administered before and after activation of the diffuse noxious inhibitory controls (DNIC) by means of a cold-pressor test. Genetic analyses were performed using polymerase chain reaction. Regression analyses were performed across and within groups. FM was associated with lower TPTs and deficient pain inhibition. DRD3 Ser9Gly polymorphism predicted (1) DNIC efficacy across groups and (2) thermal TPTs in FM patients. COMT Val158Met and thermal pain measures were not related. These preliminary results suggest that the DRD3 Ser9Gly polymorphism influences DNIC efficacy and TPTs and that this latter relationship is present only in FM patients. Two core psychophysical features of FM appear to be significantly influenced by limbic dopamine functioning. PERSPECTIVE: This experimental study is the first to relate DNIC and TPTs to a functional polymorphism of limbic dopamine-D3 receptors. As lowered pain thresholds and deficient pain inhibition are 2 core features of fibromyalgia, these preliminary results may help identify a subgroup of FM patients who require closer medical attention.

Refractory migraine and chronic migraine: pathophysiological mechanisms.

Despite increased understanding of primary headaches and their treatment, the underlying causes of refractory migraine remain unknown. This note considers potential genetic, structural, functional and pharmacological factors that could contribute to this relatively intractable condition. Further understanding of refractory migraine will require the use of medical imaging technologies, clinical experimental medicine studies on novel pharmacological agents and astute observations in clinical practice to direct potential novel therapeutic approaches.

Molecular epidemiology, cancer-related symptoms, and cytokines pathway.

The Human Genome Project and HapMap have led to a better appreciation of the importance of common genetic variation in determining cancer risk, created potential for predicting response to therapy, and made possible the development of targeted prevention and therapeutic interventions. Advances in molecular epidemiology can be used to explore the role of genetic variation in modulating the risk for severe and persistent symptoms, such as pain, depression, and fatigue, in patients with cancer. The same genes that are implicated in cancer risk might also be involved in the modulation of therapeutic outcomes. For example, polymorphisms in several cytokine genes are potential markers for genetic susceptibility both for cancer risk and for cancer-related symptoms. These genetic polymorphisms are stable markers and easily and reliably assayed to explore the extent to which genetic variation might prove useful in identifying patients with cancer at high-risk of symptom development. Likewise, they could identify subgroups who might benefit most from symptom intervention, and contribute to developing personalized and more effective therapies for persistent symptoms.

Variable response to opioid treatment: any genetic predictors within sight?

The aim of this literature review is to summarize and discuss the available evidence for a relationship between polymorphisms in human genes and variability in opioid analgesia and side effects among patients treated for moderate or severe pain. The evidence supporting a role of certain alleles, genotypes or haplotypes in modulation of opioid analgesia is derived from a limited number of studies, a limited number of genes and a limited number of opioids. Although several interesting candidates have emerged as potentially relevant factors, only for one polymorphism, the prevalent 118A>G of the micro-opioid receptor, the accumulated evidence is sufficient to suggest a clinically relevant effect for an opioid used for moderate or severe pain. Still the data are valid only at the group level and cannot be used to predict treatment outcome in individual patients. Only a few of the symptoms often seen as opioid adverse effects in palliative care, such as nausea, vomiting, constipation and sedation, have been associated with genetic variants in various genes, but the results have been based on case reports, healthy volunteers or post-operative patients. So far, there is no clear evidence that genetic markers can be used to predict opioid efficacy or adverse effects in palliative care patients. This reflects the general lack of studies performed in the context of palliative care, the lack of sufficiently scaled studies and the lack of international standards for the assessment of subjective symptoms.

Refractory migraine and chronic migraine: pathophysiological mechanisms.

Migraine is a complex disorder of the brain whose mechanisms are only now being unravelled. It is common, disabling, and economically costly. Brain imaging has suggested a role for the brainstem. While the disorder is almost certainly inherited, the degree to which this contributes to a treatment refractory state is not clear. Indeed, no specific structural or pharmacological explanation can be seen from the data as they have been generated. It is clear that patients with more frequent headache are very likely to go on to even more frequent headache, but again these data are complex. A challenge going forward is to establish the biology of these very challenging patients who undoubtedly have substantial disability.