Intradiscal quantitative chemical exchange saturation transfer MRI signal correlates with discogenic pain in human patients.

Low back pain (LBP) is often a result of a degenerative process in the intervertebral disc. The precise origin of discogenic pain is diagnosed by the invasive procedure of provocative discography (PD). Previously, we developed quantitative chemical exchange saturation transfer (qCEST) magnetic resonance imaging (MRI) to detect pH as a biomarker for discogenic pain. Based on these findings we initiated a clinical study with the goal to evaluate the correlation between qCEST values and PD results in LBP patients. Twenty five volunteers with chronic low back pain were subjected to T2-weighted (T2w) and qCEST MRI scans followed by PD. A total of 72 discs were analyzed. The average qCEST signal value of painful discs was significantly higher than non-painful discs (p = 0.012). The ratio between qCEST and normalized T2w was found to be significantly higher in painful discs compared to non-painful discs (p = 0.0022). A receiver operating characteristics (ROC) analysis indicated that qCEST/T2w ratio could be used to differentiate between painful and non-painful discs with 78% sensitivity and 81% specificity. The results of the study suggest that qCEST could be used for the diagnosis of discogenic pain, in conjunction with the commonly used T2w scan.

Battlefield pain management: A view of 17 years in Israel Defense Forces.

BACKGROUND: Pain control in trauma is an integral part of treatment in combat casualty care (CCC). More soldiers injured on the battlefield will need analgesics for pain than those who will need lifesaving interventions (LSI). It has been shown that early treatment of pain improves outcomes after traumatic injury, whereas inadequate treatment leads to higher rates of PTSD. The purpose of this article is to report the Israel Defense Forces Medical Corps (IDF-MC) experience with point of injury (POI) use of analgesia. METHODS: All cases documented in the IDF Trauma Registry (ITR) between January 1997 and December 2014 were examined. All cases of POI pain medications were extracted. Data collection included mechanism of injury, wound distribution, pain medication administered, mortality, and provider type. RESULTS: Of 8,576 patients, 1,056 (12.3%) patients who had at least one documented pain management treatment were included in this study. Demographics of the study population included 94.2% men and 5.8% women with a median age of 21 years. Injury mechanisms included 40.3% blast injuries (n = 426) and 29% gunshot injuries (306). Of 1,513 injured body regions reported, 52% (787) were extremity wounds (upper and lower), 23% (353) were truncal wounds, and 17.7% (268) were head and neck injuries. A total of 1,469 episodes of analgesic treatment were reported. The most common types of analgesics were morphine (74.7%, 1,097 episodes), ketamine (9.6%, 141 episodes), and fentanyl (13.6%, 200 episodes). Of the patients, 39% (413) received more than one type of analgesic. In 90.5% of cases, analgesia was administered by a physician or a paramedic. Over the span of the study period (1997-2014), types of analgesics given by providers at POI had changed, as fentanyl was introduced to providers. A total of 801 LSIs were performed on 379 (35.9%) patients receiving analgesia, and no adverse events were found in any of the casualties. CONCLUSION: Most casualties at POI did not receive any analgesics while on the battlefield. The most common analgesics administered at POI were opioids and the most common route of administration was intravenously. This study provides evidence that over time analgesic administration has gained acceptance and has been more common place on the battlefield. Increasingly, more casualties are receiving pain management treatment early in CCC along with LSIs. We hope that this shift will impact CCC by reducing PTSD and overall morbidity resulting from inadequate management of acute pain.

Local Resiniferatoxin Induces Long-Lasting Analgesia in a Rat Model of Full Thickness Thermal Injury.

OBJECTIVE: Opioid-based analgesics are a major component of the lengthy pain management of burn patients, including military service members, but are problematic due to central nervous system-mediated side effects. Peripheral analgesia via targeted ablation of nociceptive nerve endings that express the transient receptor potential vanilloid channel 1 (TRPV1) may provide an improved approach. We hypothesized that local injection of the TRPV1 agonist resiniferatoxin (RTX) would produce long-lasting analgesia in a rat model of pain associated with burn injury. METHODS: Baseline sensitivities to thermal and mechanical stimuli were measured in male and female Sprague-Dawley rats. Under anesthesia, a 100 °C metal probe was placed on the right hind paw for 30 seconds, and sensitivity was reassessed 72 hours following injury. Rats received RTX (0.25 µg/100 µL; ipl) into the injured hind paw, and sensitivity was reassessed across three weeks. Tissues were collected from a separate group of rats at 24 hours and/or one week post-RTX for pathological analyses of the injured hind paw, dorsal spinal cord c-Fos, and primary afferent neuropeptide immunoreactivity. RESULTS: Local RTX reversed burn pain behaviors within 24 hours, which lasted through recovery at three weeks. At one week following RTX, decreased c-Fos and primary afferent neuropeptide immunoreactivities were observed in the dorsal horn, while plantar burn pathology was unaltered. CONCLUSIONS: These results indicate that local RTX induces long-lasting analgesia in a rat model of pain associated with burn. While opioids are undesirable in trauma patients due to side effects, RTX may provide valuable long-term, nonopioid analgesia for burn patients.

Tetrodotoxin suppresses thermal hyperalgesia and mechanical allodynia in a rat full thickness thermal injury pain model.

Burn injuries have been identified as the primary cause of injury in 5% of U.S. military personnel evacuated from Operations Iraqi Freedom and Enduring Freedom. Severe burn-associated pain is typically treated with opioids such as fentanyl, morphine, and methadone. Side effects of opioids include respiratory depression, cardiac depression, decrease in motor and cognitive function, as well as the development of hyperalgesia, tolerance and dependence. These effects have led us to search for novel analgesics for the treatment of burn-associated pain in wounded combat service members. Tetrodotoxin (TTX) is a selective voltage-gated sodium channel blocker currently in clinical trials as an analgesic. A phase 3 clinical trial for cancer-related pain has been completed and phase 3 clinical trials on chemotherapy-induced neuropathic pain are planned. It has also been shown in mice to inhibit the development of chemotherapy-induced neuropathic pain. TTX was originally identified as a neurotoxin in marine animals but has now been shown to be safe in humans at therapeutic doses. The antinociceptive effects of TTX are thought to be due to inhibition of Na(+) ion influx required for initiation and conduction of nociceptive impulses. One TTX sensitive sodium channel, Nav1.7, has been shown to be essential in lowering the heat pain threshold after burn injuries. To date, the analgesic effect of TTX has not been tested in burn-associated pain. Male Sprague-Dawley rats were subjected to a full thickness thermal injury on the right hind paw. TTX (8 µg/kg) was administered once a day systemically by subcutaneous injection beginning 3 days post thermal injury and continued through 7 days post thermal injury. Thermal hyperalgesia and mechanical allodynia were assessed 60 and 120 min post injection on each day of TTX treatment. TTX significantly reduced thermal hyperalgesia at all days tested and had a less robust, but statistically significant suppressive effect on mechanical allodynia. These results suggest that systemic TTX may be an effective, rapidly acting analgesic for battlefield burn injuries and has the potential for replacing or reducing the need for opioid analgesics.

State of the science review: Advances in pain management in wounded service members over a decade at war.

The pain conditions and comorbidities experienced by injured service members and the challenge of pain management by the military medical system offer a unique opportunity to inform pain management and medical research. In this article, acute and chronic pain issues, current treatment options and limitations, as well as novel approaches to pain management are discussed within the context of combat casualty care, from the battlefield to hospitalization and rehabilitation. This review will also highlight the current pain management limitations that need to be addressed in future clinical and basic science research to improve care for our nation's injured service members.

Sex differences in serotonin enhancement of capsaicin-evoked calcitonin gene-related peptide release from human dental pulp.

Serotonin (5HT) is a pronociceptive mediator in the periphery, and evidence implicates involvement in trigeminal pain processing. However, the mechanism(s) by which 5HT modulates trigeminal nociceptors remains unclear. Trigeminal pain can be evoked by the transient receptor potential V1 channel (TRPV1), which is expressed by nociceptive trigeminal neurons and induces release of proinflammatory calcitonin gene-related peptide (CGRP). In our preclinical models, 5HT evoked thermal hyperalgesia and enhanced calcium influx and CGRP release from the TRPV1 population of trigeminal nociceptors. Whether this occurs in humans is unknown. As dental pulp is densely innervated by trigeminal nociceptors, routine tooth extractions offer a unique opportunity to examine whether 5HT enhances CGRP release from human nociceptors. Pulpal tissue was collected from 140 extracted molar teeth from men and women, and basal release samples were collected before treatment with saline or 5HT 100µmol/L. CGRP release was then stimulated with the TRPV1 agonist capsaicin 1µmol/L and quantitated by enzyme immunoassay. Additional samples were collected for Western blots to examine 5HT receptor expression. We report that 5HT induced a significant increase in capsaicin-evoked CGRP release, and that this enhancement was observed only in female dental pulp, with no effect of 5HT on male dental pulp. The greatest amount of CGRP release occurred in dental pulp from women in the luteal phase of the menstrual cycle. These results indicate that 5HT enhances capsaicin-evoked CGRP release from human trigeminal nociceptors in a sexually dimorphic manner providing a mechanistic basis for prevalence of trigeminal pain disorders in women.

Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons.

Cannabinoid receptor antagonists have been utilized extensively in vivo as well as in vitro, but their selectivity has not been fully examined. We investigated activation of sensory neurons by two cannabinoid antagonists - AM251 and AM630. AM251 and AM630 activated trigeminal (TG) sensory neurons in a concentration-dependent fashion (threshold 1 µM). AM251 and AM630 responses are mediated by the TRPA1 channel in a majority (90-95%) of small-to-medium TG sensory neurons. AM630 (1-100 µM), but not AM251, was a significantly more potent agonist in cells co-expressing both TRPA1 and TRPV1 channels. We next evaluated AM630 and AM251 effects on TRPV1- and TRPA1-mediated responses in TG neurons. Capsaicin (CAP) effects were inhibited by pre-treatment with AM630, but not AM251. Mustard oil (MO) and WIN55,212-2 (WIN) TRPA1 mediated responses were also inhibited by pre-treatment with AM630, but not AM251 (25 uM each). Co-treatment of neurons with WIN and either AM630 or AM251 had opposite effects: AM630 sensitized WIN responses, whereas AM251 inhibited WIN responses. WIN-induced inhibition of CAP responses in sensory neurons was reversed by AM630 pre-treatment and AM251 co-treatment (25 µM each), as these conditions inhibit WIN responses. Hindpaw injections of AM630 and AM251 did not produce nocifensive behaviors. However, both compounds modulated CAP-induced thermal hyperalgesia in wild-type mice and rats, but not TRPA1 null-mutant mice. AMs also partially regulate WIN inhibition of CAP-induced thermal hyperalgesia in a TRPA1-dependent fashion. In summary, these findings demonstrate alternative targets for the cannabinoid antagonists, AM251 and AM630, in peripheral antihyperalgesia which involve certain TRP channels.

TRPA1-mediated responses in trigeminal sensory neurons: interaction between TRPA1 and TRPV1.

The transient receptor potential (TRP)A1 channel is involved in the transduction of inflammation-induced noxious stimuli from the periphery. Previous studies have characterized the properties of TRPA1 in heterologous expression systems. However, there is little information on the properties of TRPA1-mediated currents in sensory neurons. A capsaicin-sensitive subset of rat and mouse trigeminal ganglion sensory neurons was activated with TRPA1-specific agonists, mustard oil and the cannabinoid WIN55,212. Mustard oil- and WIN55,212-gated currents exhibited marked variability in their kinetics of activation and acute desensitization. TRPA1-mediated responses in neurons also possess a characteristic voltage dependency with profound outward rectification that is influenced by extracellular Ca(2+) and the type and concentration of TRPA1-specific agonists. Examination of TRPA1-mediated responses in TRPA1-containing cells indicated that the features of neuronal TRPA1 are not duplicated in cells expressing only TRPA1 and, instead, can be restored only when TRPA1 and TRPV1 channels are coexpressed. In summary, our results suggest that TRPA1-mediated responses in sensory neurons have distinct characteristics that can be accounted for by the coexpression of the TRPV1 and TRPA1 channels.