Potential mediators of improvement in painful chemotherapy-induced peripheral neuropathy via a web-based cognitive behavioural intervention.

PURPOSE: Preliminary evidence suggests that a self-guided cognitive and behaviourally-based pain management intervention (PROSPECT) is effective for chronic painful chemotherapy-induced peripheral neuropathy (CIPN), but its mechanism of action is unknown. The purpose of this secondary analysis was to explore if changes in anxiety, depression, sleep-related impairment, or fatigue mediated improvements in worst pain following PROSPECT in individuals with chronic painful CIPN. METHODS: Sixty participants were randomized to receive self-guided cognitive behavioural pain management (access for eight weeks) or treatment as usual. A seven-day worst CIPN pain diary and the PROMIS measures of anxiety, depression, fatigue, and sleep-related impairment were administered pre/posttest (eight-weeks). Causal mediation analysis was used to quantify mediators of worst pain improvement. RESULTS: None of the hypothesized mediators had a statistically significant effect on worst pain (n=38). IMPLICATIONS: Further research is needed to identify potential mediators of pain intensity that can be targeted by specific cognitive behavioural strategies to improve painful CIPN severity.

Prazosin as an Adjuvant to Increase Effectiveness of Duloxetine in a Rat Model of Oxaliplatin-Induced Peripheral Neuropathy.

OBJECTIVES: Duloxetine, the only American Society of Clinical Oncology (ASCO) treatment recommended for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors, is not effective for 40% of survivors. This study examined the ability of a duloxetine-prazosin combination to prevent the development of allodynia and hyperalgesia in a rat model of oxaliplatin-induced peripheral neuropathy (OPIN). METHODS: Female (n = 24) and male (n = 41) rats were started on duloxetine (15 mg), prazosin (2 mg), or a duloxetine-prazosin combination one week prior to administration of the chemotherapy drug, oxaliplatin, and continued the duloxetine-prazosin combination for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments over the course of the study. RESULTS: Overall percent paw withdrawal for rats that received the duloxetine-prazosin combination was significantly lower in female (p < .001 for both conditions) and male (p = .029 for allodynia; p < .001 for hyperalgesia) than those that received water. No significant posttreatment differences were found for allodynia or hyperalgesia between rats treated with duloxetine and rats that received the duloxetine-prazosin combination in either sex. CONCLUSIONS: These finding provide preliminary evidence that a duloxetine-prazosin combination can prevent the posttreatment development of allodynia and hyperalgesia in both male and female rats; however, the results suggest that the duloxetine-prazosin combination is no more efficacious than duloxetine alone in preventing chronic OIPN. IMPLICATIONS FOR NURSING PRACTICE: The profession of nursing is built on clinical practice supported by scientific research. The current study addressed the clinical practice problem of prevention and management of painful OIPN, which is a priority area in oncology nursing.

Effectiveness of Duloxetine on Oxaliplatin-induced Allodynia and Hyperalgesia in Rats.

Development of painful oxaliplatin-induced peripheral neuropathy (OIPN) is a major problem in people who receive oxaliplatin as part of cancer treatment. The pain experienced by those with OIPN can be seriously debilitating and lead to discontinuation of an otherwise successful treatment. Duloxetine is currently the only recommended treatment for established painful OIPN recommended by the American Society of Clinical Oncology, but its preventative ability is still not clear. This study examined the ability of duloxetine to prevent signs of chronic OIPN in female (n = 12) and male (n = 21) rats treated with the chemotherapeutic agent oxaliplatin. Using an established model of OIPN, rats were started on duloxetine (15 mg) one week prior to oxaliplatin administration and continued duloxetine for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments. Significant posttreatment differences were found for allodynia in female (p = .004), but not male rats. Duloxetine was associated with significant differences for hyperalgesia in both female (p < .001) and male (p < .001) rats. These findings provide preliminary evidence of the preventative effects of duloxetine on both oxaliplatin-induced allodynia and hyperalgesia in male and female rats, with a difference noted in response between the sexes.

The McGill Pain Questionnaire as a multidimensional measure in people with cancer: an integrative review.

First published in 1975, the McGill Pain Questionnaire (MPQ) is an often-cited pain measure, but there have been no systematic reviews of the MPQ in cancer populations. Our objective was to evaluate the MPQ as a multidimensional measure of pain in people with cancer. A systematic search of research that used the MPQ in adults with cancer and published in English from 1975 to 2009 was conducted. Twenty-one articles retrieved through computerized searches and nine studies from manual searches met the criteria. Review of the 30 studies demonstrated that pain intensity (n = 29 studies) and pain quality (n = 27 studies) were measured more frequently than pain location, pattern, and behavior parameters. Measuring cancer pain using the MPQ provided insights about disease sites, magnitude of pain, and effectiveness of treatment and intervention. Additionally, the MPQ data informed speculations about pain mechanisms, emotional status, overall sensory pain experience, changes in pain over time, and alleviating and aggravating behaviors/factors. Findings supported the MPQ as an effective multidimensional measure with good stability, content, construct, and criterion validity and showed sensitivity to treatment or known-group effects. The MPQ is a valid, reliable, and sensitive multidimensional measure of cancer pain. Cancer pain is a subjective complex experience consisting of multiple dimensions, and measuring cancer pain with the MPQ may help clinicians to more fully understand whether those dimensions of cancer pain influence each other. As a result, clinicians can provide better and effective cancer pain management.

Pain, Sleep, and Health-Related Quality of Life after Multidisciplinary Intervention for Chronic Pain.

Multidisciplinary pain-management programs have the potential to decrease pain intensity, improve health-related quality of life (HRQOL), and increase sleep quality. In this longitudinal prospective cohort study, the aim was to investigate the long-term effects of multidisciplinary pain rehabilitation interventions in Iceland. More precisely, we (a) explored and described how individuals with chronic pain evaluated their pain severity, sleep, and HRQOL at pre-treatment and at one-year follow-up and (b) examined what predicted the participants' one-year follow-up HRQOL. Seventy-nine patients aged 20-68 years, most of whom were women (85%), responded. The participants scored their pain lower at one-year follow-up (p < 0.001). According to their response, most of them had disrupted sleep, mainly because of pain. One year after the treatment, more participants slept through the night (p = 0.004), and their HRQOL increased. Higher pre-treatment mental component summary (MCS) scores and having pursued higher education predicted higher MCS scores at one-year follow-up, and higher pre-treatment physical component summary (PCS) scores predicted higher PCS scores at one-year follow-up. Sleep problems, being a woman, and having children younger than 18 years of age predicted lower MCS scores at one-year follow-up. These findings are suggestive that patients should be examined with respect to their mental status, and it could be beneficial if they received some professional support after completing the intervention.

Pain Rehabilitation's Effect on People in Chronic Pain: A Prospective Cohort Study.

Multidisciplinary long-term pain rehabilitation programs with a team of healthcare professionals are an integrated approach to treat patients with chronic non-malignant pain. In this longitudinal prospective cohort study, we investigated the long-term effects of multidisciplinary pain rehabilitation on the self-reported causes of pain, pain self-management strategies, sleep, pain severity, and pain's interference with life, pre- and post-treatment. Eighty-one patients, aged 20-69 years, with chronic pain responded. The two most frequently reported perceived causes of pain were fibromyalgia and accidents. The difference in average self-reported pain severity decreased significantly at one-year follow-up (p < 0.001), as did pain's interference with general activities, mood, walking ability, sleep, and enjoyment of life. At one-year follow-up, participants (21%) rated their health as good/very good and were more likely to state that it was better than a year before (20%). No change was found in the use of pain self-management strategies such as physical training at one-year follow-up. The intervention was effective for the participants, as reflected in the decreased pain severity and pain interference with life.

Breaking the vicious circle: Experiences of people in chronic pain on the pain rehabilitation journey.

Aim: To explore the lived experience of individuals' in chronic pain of participating in a pain rehabilitation programme in Iceland. Design: Phenomenological research. Method: The Vancouver School of Doing Phenomenology. Eleven participants were interviewed. Results: The overarching theme was as follows: "the journey of breaking the vicious circle of chronic pain." Before the programme, the participants felt they were in survival mode, trying to survive each day; they were stuck in a vicious circle of chronic pain, simultaneously trying to ease and conceal the pain. Reaching out for professional help was a turning point. While attending the programme, participants began deconstructing their old ways of dealing with chronic pain. After completing the programme, they were still reconstructing their daily lives. In conclusion, pain rehabilitation programmes can be the first step towards breaking the vicious circle of chronic pain.

Pain condition and sex differences in the descending noradrenergic system following lateral hypothalamic stimulation.

The lateral hypothalamus (LH) is known to modulate nociception via the descending noradrenergic system in acute nociception, but less is known about its role in neuropathic pain states. In naïve females, LH stimulation produces opposing effects of α-adrenoceptors, with α2-adrenoceptors mediating antinociception, while pronociceptive α1-adrenoceptors attenuate the effect. Whether this opposing response is seen in neuropathic conditions or in naïve males is unknown. We used a mixed factorial design to compare male and female rats with chronic constriction injury (CCI) to naïve rats, measured by Total Paw Withdrawal (TPW) responses to a thermal stimulus. Rats received one of three doses of carbachol to stimulate the LH followed by intrathecal injection of either an α1- or an α2-adrenoceptor antagonist (WB4101 or yohimbine, resp.) or saline for control. Overall, naïve rats showed a more pronounced opposing alpha-adrenergic response than CCI rats (p < 0.04). Naïve male and female rats demonstrated antinociception following α1-adrenoceptor blockade and hyperalgesia following α2-adrenoceptor blockade. Male CCI rats also showed dose dependent effects from either WB4101 or yohimbine (p < 0.05), while female CCI rats had significant antinociception from WB4101 (p < 0.05), but no effect from yohimbine. These results support the idea that peripheral nerve damage differentially alters the descending noradrenergic modulatory system in male and female rats, and notably, that female CCI rats do not show antinociception from descending noradrenergic input. These findings are suggestive that clinical therapies that recruit the descending noradrenergic system may require a different approach based on patient gender.

An NK1 receptor antagonist microinjected into the periaqueductal gray blocks lateral hypothalamic-induced antinociception in rats.

Substantial data are accumulating that implicate the lateral hypothalamus (LH) as part of the descending pain modulatory system. The LH modifies nociception in the spinal cord dorsal horn partly through connections with the periaqueductal gray (PAG), an area known to play a central role in brainstem modulation of nociception. Early work demonstrated a putative substance P connection between the LH and the PAG, but the connection is not fully defined. To determine whether LH-induced antinociception mediated by the PAG is neurokinin1 (NK1) receptor-dependent, we conducted behavioral experiments in which the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of lightly anesthetized female Sprague-Dawley rats (250-350 g) and antinociception was obtained on the tail flick or foot withdrawal tests. Cobalt chloride (100 nM), which reversibly blocks synaptic activation, blocked LH-induced antinociception. In another set of experiments, the specific NK1 receptor antagonist L-703,606 (5 microg) was microinjected in the PAG following LH stimulation with carbachol abolished LH-induced antinociception as well. Microinjection of cobalt chloride or L-703,606 in the absence of LH stimulation had no effect. These behavioral experiments coupled with earlier work provide converging evidence to support the hypothesis that antinociception produced by activating neurons in the LH is mediated in part by the subsequent activation of neurons in the PAG by NK1 receptors.

Lateral hypothalamic-induced alpha-adrenoceptor modulation occurs in a model of inflammatory pain in rats.

Previous work from our lab showed that stimulation of the lateral hypothalamus (LH) produces analgesia (antinociception) in a model of thermal nociceptive pain. This antinociceptive effect is mediated by alpha2-adrenoceptors in the spinal cord dorsal horn. However, a concomitant, opposing hyperalgesic (pro-nociceptive) response also occurs, which is mediated by alpha1-adrenoceptors in the dorsal horn. Antinociception predominates but is attenuated by the pronociceptive response. To determine whether such an effect occurs in a model of inflammatory pain, we applied mustard oil (allyl isothiocyanate; 20 microl) to the left ankle of female Sprague-Dawley rats. We then stimulated the LH using carbamylcholine chloride (carbachol; 125 nmol). The foot withdrawal latencies were measured. Some rats received intrathecal alpha-adrenoceptor antagonists to determine whether the opposing alpha-adrenoceptor response was present. Mustard oil application produced hyperalgesia in the affected paw, while the LH stimulation increased the foot withdrawal latencies for the mustard oil paw as compared to the control group. Following carbachol microinjection in the LH, WB4101, an alpha1-adrenoceptor antagonist, produced significantly longer foot withdrawal latencies compared to saline controls, while yohimbine, an alpha2-antagonist, decreased the foot withdrawal latencies from 10 min postinjection (p < .05). These findings support the hypothesis that the LH-induced nociceptive modulation is mediated through an alpha-adrenoceptor opposing response in a model of inflammatory pain.

A Systematic Review: Mindfulness Intervention for Cancer-Related Pain.

Moderate-to-severe pain is a common problem experienced by patients with cancer. Although analgesic drugs are effective, adverse side effects are common and some analgesic drugs are addictive. Nonpharmacological treatment may be a way to treat cancer pain without causing negative side effects. Mindfulness is used as an effective nonpharmacological treatment to improve quality of life (QoL) and to address psychological problems including distress, anxiety, stress, and depression. However, the effect of mindfulness on pain severity has not been sufficiently investigated. Therefore, a systematic review was undertaken to describe the effectiveness of mindfulness interventions for pain and its underlying pathophysiologic mechanisms. The search was conducted in PubMed, Ovid MEDLINE, and CINAHL and included only empirical studies published from 2008 to 2017. Search terms included mindfulness, mindfulness-based intervention, meditation, cancer, pain, and cancer-related pain. Six studies met the search criteria. These studies tested several types of intervention including mindfulness-based stress reduction, mindfulness-based cognitive therapy, meditation with massage, and mindful awareness practices. Study outcomes include improved pain severity, anxiety, stress, depression, and QoL. However, most studies reviewed were conducted in the United States and Denmark. Further research is needed to test culturally appropriate mindfulness interventions to reduce pain.

Lateral hypothalamic-induced antinociception may be mediated by a substance P connection with the rostral ventromedial medulla.

Stimulation of the lateral hypothalamus (LH) produces antinociception modified by intrathecal serotonergic receptor antagonists. Spinally-projecting serotonergic neurons in the LH have not been identified, suggesting that the LH innervates brainstem serotonergic neurons in the rostral ventromedial medulla (RVM), known to modify nociception in the spinal cord dorsal horn. To determine whether substance P (SP) plays a role in LH-induced antinociception mediated by the RVM, we conducted an anatomical experiment using retrograde tract tracing combined with double label immunocytochemistry and found that neuron profiles immunoreactive for SP in the LH project to the RVM. To further identify a functional connection between SP neurons in the LH and the RVM, the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of female Sprague-Dawley rats (250-350 g) and antinociception was obtained on the tail flick or foot withdrawal tests. Cobalt chloride (100 nM) was then microinjected in the RVM to block synaptic activation of spinally-projecting RVM neurons. Within 5 min of the cobalt chloride injection, the antinociceptive effect of carbachol stimulation was blocked. In another set of experiments, the specific NK1 receptor antagonist L-703,606 (5 microg) was microinjected in the RVM following LH stimulation with carbachol and abolished LH-induced antinociception as well. Microinjection of cobalt chloride or L-703,606 in the absence of LH stimulation had no effect. These anatomical and behavioral experiments provide converging evidence to support the hypothesis that antinociception produced by activating neurons in the LH is mediated in part by the subsequent activation of spinally-projecting neurons in the RVM.

Commonly used preclinical models of pain.

Pain cuts across gender, age, and disease and is the most common reason people seek health-related treatment. Certain pain states do not respond to standard therapies, leaving nurses with few options to successfully care for patients in pain. Preclinical studies use many models to investigate the mechanisms and treatments for pain states similar to those encountered in humans. Within Cervero and Laird's conceptual framework of experimental pain, the authors present several commonly used preclinical models. Phase 1 pain models measure responses to a brief, controlled stimulus that minimizes tissue damage. Phase 2 pain models use topical or injected irritants, which cause inflammation and persistent pain that change peripheral and central neuronal responses. Phase 3 pain models produce neuropathic pain through partial or complete ligation of peripheral nerves. The use of preclinical models of pain can lead to the development of better pharmacological and nonpharmacological therapies that enhance nursing practice.

Anatomical evidence for lateral hypothalamic innervation of the pontine A7 catecholamine cell group in rat.

Substantial behavioral evidence exists to support the idea that the lateral hypothalamus (LH) makes axonal connection with spinally-projecting noradrenergic neurons of the A7 catecholamine cell group in the pons. Through this putative projection, the LH modulates nociception via α1- and α2-adrenoceptors in the dorsal horn. We used double-label immunocytochemistry to demonstrate that axons from the LH labeled with the anterograde tracer biotinylated dextran amine (BDA) appose tyrosine hydroxylase-immunoreactive (TH-ir) neuron profiles in the A7 area. Other pontine areas labeled with BDA included the dorsomedial tegmental area, the pontine reticular nucleus, oral part, the caudal aspect of the dorsal raphe, the periaqueductal grey and the A6 area. To confirm the findings of the brightfield experiment, we used confocal microscopy to identify axons from the LH labeled with the anterograde tracer Fluoro-Ruby co-localized with TH-ir dendrites and cell bodies in the A7 cell group. These findings provide an anatomical substrate for behavioral studies in which stimulation of the LH modifies nociception in the spinal cord via norepinephrine.

Self-Guided Online Cognitive Behavioral Strategies for Chemotherapy-Induced Peripheral Neuropathy: A Multicenter, Pilot, Randomized, Wait-List Controlled Trial.

The purpose of this pilot, parallel, randomized controlled trial was to examine the efficacy of a self-guided online cognitive and behaviorally-based pain management intervention (Proactive Self-Management Program for Effects of Cancer Treatment [PROSPECT]) to reduce "worst" pain for individuals with chronic painful chemotherapy-induced peripheral neuropathy (CIPN). Secondary outcomes included "average" pain, nonpainful CIPN symptom severity, impression of change, and pain interference. Sixty patients with chronic painful CIPN were recruited from 5 outpatient academic and community cancer centers. Patients were randomized in a 1:1 ratio to receive either 8 weeks of PROSPECT or usual care. A 7-day electronic "worst" pain intensity diary and standardized measures of pain interference, nonpainful CIPN symptom severity, impression of change, and "average" pain were administered pre/post intervention. Postintervention mean scores were evaluated between groups using analysis of covariance adjusting for baseline. Individuals who received the PROSPECT intervention (n = 19) had significantly greater improvements in "worst pain" compared with individuals receiving usual care (n = 19; P = .046, d = .58). There were no significant differences in mean scores between groups for the secondary outcomes (n = 42). A larger, adequately powered study testing the PROSPECT intervention is needed to determine if improvements in pain may be sustained, evaluate the effect of the intervention on the secondary outcomes, and identify mediators of pain intensity-related improvement. PERSPECTIVE: This study explores the efficacy of an 8-week online cognitive behavioral pain management intervention for chronic painful CIPN. Intervention use resulted in greater improvements in "worst" pain than usual care alone. The findings provide preliminary support for the efficacy of a nonpharmacological intervention for chronic painful CIPN.

Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain.

No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A-mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right nonligated paws (p < .05). Rats were given carbachol in the LH followed by intrathecal injection of the orexin-1 (OX1) receptor antagonist SB-334867, which blocked LH-induced antinociception compared with control groups (p < .05) in the left paw, but not in the right paw. These findings support the hypothesis that LH stimulation produces antinociception in rats with thermal hyperalgesia from neuropathic pain via an orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.

The challenge of chronic pain.

Chronic pain is a complex problem with staggering negative health and economic consequences. The complexity of chronic pain is presented within Cervero and Laird's model that describes three phases of pain, including pain without tissue damage, pain with tissue damage and inflammation, and neuropathic pain. The increased afferent input in phases 2 and 3 of chronic pain produces marked changes in primary afferents, dorsal root ganglia, and spinal cord dorsal horn. These changes promote the symptoms of chronic pain, including spontaneous pain, hyperalgesia, and allodynia. Increased afferent input also evokes supraspinal input to the dorsal horn, including biphasic innervation from the ventromedial medulla and A7 catecholamine cell group, that promotes hyperalgesia and allodynia. More rostral brain structures, such as the lateral hypothalamus, amygdala, and hippocampus, may also play a role in chronic pain. Although much has been discovered about the multiple pathological mechanisms involved in chronic pain, further research is needed to fully comprehend these mechanisms.

Antinociception from lateral hypothalamic stimulation may be mediated by NK(1) receptors in the A7 catecholamine cell group in rat.

Stimulation of the lateral hypothalamus (LH) produces antinociception that is modified by intrathecal alpha-adrenergic antagonists. Spinally-projecting noradrenergic neurons in the LH have not been identified, suggesting that the LH may innervate brainstem noradrenergic neurons, such as the A7 catecholamine cell group in the dorsolateral pontine tegmentum, that modify nociception at the level of the spinal cord dorsal horn. Recently we demonstrated in neuroanatomical studies that substance P-immunoreactive neurons in the LH project the A7 area. To identify a functional connection between substance P neurons in the LH and the A7 cell group, the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of female Sprague-Dawley rats and antinociception was obtained on the tail flick or foot withdrawal test. Cobalt chloride (100 nM) was then microinjected near the A7 cell group to block synaptic activation of spinally-projecting A7 neurons, which were identified using tyrosine-hydroxylase immunoreactivity. Within 5 min of the cobalt chloride injection, the antinociceptive effect of carbachol stimulation was blocked. In another set of experiments, the NK(1) receptor antagonist L-703-606 (5 microg) was microinjected near the A7 cell group following LH stimulation with carbachol. L-703-606 also abolished LH-induced antinociception. These results support the conclusion that antinociception produced by activating substance P neurons in the LH is mediated in part by the subsequent activation of spinally-projecting noradrenergic neurons in the A7 cell group.