David L. Lipschitz

Opioid Pharmacotherapy for Chronic Non-Cancer Pain in the United States: A Research Guideline for Developing an Evidence-Base

UNLABELLED This document reports the consensus of an interdisciplinary panel of research and clinical experts charged with reviewing the use of opioids for chronic noncancer pain (CNCP) and formulating guidelines for future research. Prescribing opioids for chronic noncancer pain has recently escalated in the United States. Contrasting with increasing opioid use are: 1) The lack of evidence supporting long-term effectiveness; 2) Escalating misuse of prescription opioids including abuse and diversion; and 3) Uncertainty about the incidence and clinical salience of multiple, poorly characterized adverse drug events (ADEs) including endocrine dysfunction, immunosuppression and infectious disease, opioid-induced hyperalgesia and xerostomia, overdose, falls and fractures, and psychosocial complications. Chief among the limitations of current evidence are: 1) Sparse evidence on long-term opioid effectiveness in chronic pain patients due to the short-term time frame of clinical trials; 2) Insufficiently comprehensive outcome assessment; and 3) Incomplete identification and quantification of ADEs. The panel called for a strategic interdisciplinary approach to the problem domain in which basic scientists and clinicians cooperate to resolve urgent issues and generate a comprehensive evidence base. It offered 4 recommendations in 3 areas: 1) A research strategy for studying the effectiveness of long-term opioid pharmacotherapy; 2) Improvements in evidence-generation methodology; and 3) Potential research topics for generating new evidence. PERSPECTIVE Prescribing opioids for CNCP has outpaced the growth of scientific evidence bearing on the benefits and harms of these interventions. The need for a strong evidence base is urgent. This guideline offers a strategic approach to creating a comprehensive evidence base to guide safe and effective management of CNCP.

Investigating efficacy of two brief mind–body intervention programs for managing sleep disturbance in cancer survivors: a pilot randomized controlled trial

PurposeAfter completing treatment, cancer survivors may suffer from a multitude of physical and mental health impairments, resulting in compromised quality of life. This exploratory study investigated whether two mind–body interventions, i.e., Mind–Body Bridging (MBB) and Mindfulness Meditation (MM), could improve posttreatment cancer survivors’ self-reported sleep disturbance and comorbid symptoms, as compared to sleep hygiene education (SHE) as an active control.MethodsThis randomized controlled trial examined 57 cancer survivors with clinically significant self-reported sleep disturbance, randomly assigned to receive MBB, MM, or SHE. All interventions were conducted in three sessions, once per week. Patient-reported outcomes were assessed via the Medical Outcomes Study Sleep Scale and other indicators of psychosocial functioning relevant to quality of life, stress, depression, mindfulness, self-compassion, and well-being.ResultsMixed effects model analysis revealed that mean sleep disturbance symptoms in the MBB (p = .0029) and MM (p = .0499) groups were lower than in the SHE group, indicating that both mind–body interventions improved sleep. In addition, compared with the SHE group, the MBB group showed reductions in self-reported depression symptoms (p = .040) and improvements in overall levels of mindfulness (p = .018), self-compassion (p = .028), and well-being (p = .019) at postintervention.ConclusionsThis study provides preliminary evidence that brief sleep-focused MBB and MM are promising interventions for sleep disturbance in cancer survivors. Integrating MBB or MM into posttreatment supportive plans should enhance care of cancer survivors with sleep disturbance. Because MBB produced additional secondary benefits, MBB may serve as a promising multipurpose intervention for posttreatment cancer survivors suffering from sleep disturbance and other comorbid symptoms.Implications for Cancer SurvivorsTwo brief sleep-focused mind–body interventions investigated in the study were effective in reducing sleep disturbance and one of them further improved other psychosocial aspects of the cancer survivors’ life. Management of sleep problems in survivors is a high priority issue that demands more attention in cancer survivorship.

Two sessions of sleep-focused mind-body bridging improve self-reported symptoms of sleep and PTSD in veterans: A pilot randomized controlled trial.

OBJECTIVE Sleep disturbance is highly prevalent among veterans. As an alternative to sleep medications with their undesirable side effects, nonpharmacological mind-body interventions may be beneficial for sleep management in primary care. The aim of this pilot study was to investigate whether a novel mind-body intervention, mind-body bridging (MBB), focusing on sleep, could improve self-reported sleep disturbance and comorbid symptoms in veterans. METHODS This pilot study was a randomized controlled trial at the Veterans Affairs Salt Lake City Health Care System in which 63 veterans with self-reported sleep disturbance received MBB or an active sleep education control. Both interventions were conducted in two sessions, once per week. Patient-reported outcomes included the following: primary-Medical Outcomes Study (MOS) Sleep Survey, MOS Short Form-36V; secondary-Center for Epidemiological Studies-Depression, PTSD Check List-Military, Five-Factor Mindfulness Questionnaire. RESULTS At both Week 1 (1 week after the first session) and post-intervention assessments, while sleep disturbance decreased in both groups, MBB performed significantly better than did the control group. Furthermore, self-reported PTSD symptoms improved in MBB, while they remained unchanged in the control. Overall mindfulness increased in MBB, while it remained unchanged in the control. CONCLUSIONS This study provides preliminary evidence that a brief sleep-focused MBB could be a promising intervention for sleep and potentially other comorbid symptoms (e.g., PTSD). MBB could help patients develop awareness skills to deal with sleep-related symptoms. Integration of MBB into primary care settings may enhance care of patients with sleep disturbance and co-morbid symptoms.

Trends in funding for research on pain: a report on the National Institutes Of Health grant awards over the years 2003 to 2007.

UNLABELLED In recent years, the National Institutes of Health (NIH) has experienced unprecedented reductions in its customary annual budget increases. Consequently, researchers, health care policy planners and others have a pressing need for accurate information on NIH funding patterns. We created a unique and objective system for compiling, classifying, and analyzing data on NIH grant awards and funding for research on pain, nausea, and dyspnea using naïve observers, cross-validation by multiple raters, and face validation by experts. We present results of our method and analyses for the period from 2003 to 2007. Following a 12% increase from 2003 to 2004, funding for pain research fell by 9.4% per year on average over the next 3 years. The percent of the total NIH budget going to support pain research increased to 0.78% in 2004 but fell to 0.61% in 2007. A piecewise regression model confirmed the declining trend represented a significant fit to the data (R(2)=0.98, p=0.024). Separate breakdowns by Institutes showed similar patterns. Analyses of nausea and dyspnea research support revealed small but steady increases over the same period. Declining support for pain research disproportionate to decreases in the NIH budget signals a need for measures to promote funding for meritorious applications. PERSPECTIVE Results of 5 year trends in numbers of grants and funding for research in pain, nausea, and dyspnea by the NIH show overall declines for pain but slight increases for nausea and dyspnea. Declining support for pain research that exceeds the reductions in the total NIH budget signals a need for measures to increase pain research funding.

Central Blockade of Oxytocin Receptors During Late Gestation Disrupts Systemic Release of Oxytocin During Suckling In Rats

There is evidence that the central oxytocin system is activated and undergoes reorganization before parturition. The present study was designed to determine the effects of central oxytocin receptor blockade during late gestation on parturition, pup growth, and oxytocin release during suckling. Female Sprague‐Dawley rats were implanted on gestation day 12–14 with Alzet® osmotic minipumps containing an oxytocin receptor antagonist (d(CH2)5, Tyr (Me)2, Orn8–vasotocin; OT‐X) or artificial cerebrospinal fluid (VEH), which was infused into the third cerebral ventricle. Pumps were removed within 24 h of parturition. Daily maternal body weight and food intake were monitored during gestation and lactation. The length of gestation, duration of parturition, pup number, litter weight and interbirth interval were recorded. Subsequently, pup number and litter weights were recorded daily until lactation day 10 or 11, when maternal and pup behaviour, and plasma oxytocin concentration before and during suckling were measured. Central oxytocin blockade had no effect on the timing of parturition, maternal behaviour, litter size, still births, or litter weights at birth. However, beginning on day 3 of lactation, average weights of litters of OT‐X females were significantly lower than litters of VEH‐treated females. Furthermore, while basal plasma oxytocin concentrations, oxytocin increases in response to suckling and dam/pup interactions did not differ between groups, a significant delay in suckling‐induced systemic oxytocin release was observed in OT‐X females. Finally, OT‐X dams weighed less than VEH dams during the postpartum observation period, although food intakes were similar. These data suggest that central actions of oxytocin during late gestation are necessary for the normal timing of systemic release of oxytocin during suckling, normal pup weight gain, and maintenance of maternal body weight.

Central blockade of oxytocin receptors during mid-late gestation reduces amplitude of slow afterhyperpolarization in supraoptic oxytocin neurons

The neurohypophysial hormone oxytocin (OT), synthesized in magnocellular paraventricular (PVN) and supraoptic (SON) nuclei, is well known for its effects in lactation. Our previous studies showed that central OT receptor (OTR) binding is increased during gestation and that blockade of central OTRs, specifically during mid-late gestation, causes a delay in OT release during suckling and reduces weight gain in pups, suggesting decreased milk delivery. In the present study, we tested whether central OTR blockade during late gestation disrupts the gestation-related plasticity in intrinsic membrane properties. Whole cell current-clamp recordings were performed in OT neurons from pregnant rats (19-22 days in gestation) that were infused with an OTR antagonist (OTA) or artificial cerebrospinal fluid (aCSF) and from virgin rats infused with aCSF into the third ventricle via an osmotic minipump beginning on days 12-14 of gestation. The amplitudes of both Ca(2+)-dependent afterhyperpolarizations (AHPs), an apamin-sensitive medium AHP (mAHP) and an apamin-insensitive slow AHP (sAHP), were significantly increased during late gestation in control pregnant animals. However, the amplitude of the sAHP from pregnant rats treated with the OTA was significantly smaller than that of pregnant control rats and similar to that of virgins. These results indicate that the diminished efficiency in lactation due to OTR blockade may be partly a result of an altered sAHP that would shape OT bursting. These findings suggest that central actions of OT during late gestation are necessary for programming the plasticity of at least some of the intrinsic membrane properties in OT neurons during lactation.

Feasibility and Acceptability of a Tai Chi Chih Randomized Controlled Trial in Senior Female Cancer Survivors

Objective. The purpose of this randomized controlled trial (RCT) was to examine the feasibility and acceptability of a Tai Chi Chih (TCC) intervention in senior female cancer survivors with physical functioning limitations, and its effects on health-related quality of life (QOL). Design. This was a two-armed, parallel group, RCT with 12-weeks of Tai Chi Chih or Health Education Control. Methods. Sixty-three senior (M age = 67 years, SD = 7.15) female cancer survivors (83% breast cancer, stages I-III) with physical functioning limitations (SF-12 Health Survey role-physical & physical functioning subscales) were randomized to 12-weeks of TCC or Health Education control (HEC). Primary outcomes were feasibility and acceptability. Secondary outcomes included health-related QOL (SF-36 Health Survey), and participants’ qualitative feedback on the intervention. Results. Retention (TCC = 91%; HEC = 81%) and class attendance (TCC = 79%; HEC = 83%) rates, and satisfaction levels for both study arms were high, but did not significantly differ from one another. At one-week post-intervention, none of the SF-36 scores differed between the TCC and HEC groups. Within-group analyses revealed significant improvements in the mental component summary score in TCC (p = 0.01), but not in HEC. Qualitative analyses indicated that the TCC group felt they received mental and physical benefits, whereas HEC group reported on social support benefits and information received. Conclusion. The TCC intervention was found to be a feasible and acceptable modality for senior female cancer survivors. Future, larger definitive trials are needed to clarify TCC dosage effects on QOL in this vulnerable population.

Neurochemical bases of plasticity in the magnocellular oxytocin system during gestation

The central and systemic release of oxytocin (OT) has been well documented during parturition and lactation. In preparation for the demands of these events, the magnocellular hypothalamic neurons of the central OT system undergo a variety of biochemical, molecular, electrophysiological, and anatomical adaptations during gestation. However, the mechanisms responsible for these changes have not been well established. A number of neurochemical mediators have been implicated in contributing to the plasticity in the OT magnocellular system during gestation, including ovarian hormones, as well as central neurotransmitters, such as glutamate, gamma-amino butyric acid (GABA), and central neurosteroids, e.g., allopregnanolone. In addition, several lines of evidence suggest that central OT release and subsequent OT receptor stimulation may contribute to adaptations of the OT system during gestation, and may be necessary for its subsequent functioning during lactation. Here, we review evidence for involvement of the neurochemical systems implicated in contributing to adaptations that occur in the OT system during the course of gestation.

An Exploratory Study of the Effects of Mind-Body Interventions Targeting Sleep on Salivary Oxytocin Levels in Cancer Survivors

Cancer survivors experience high levels of distress, associated with a host of negative psychological states, including anxiety, depression, and fear of recurrence, which often lead to sleep problems and reduction in quality of life (QOL) and well-being. As a neuropeptide hormone associated with affiliation, calmness, and well-being, oxytocin may be a useful biological measure of changes in health outcomes in cancer survivors. In this exploratory study, which comprised a subset of participants from a larger study, we evaluated (a) the feasibility and reliability of salivary oxytocin (sOT) levels in cancer survivors and (b) the effects of 2 sleep-focused mind–body interventions, mind–body bridging (MBB) and mindfulness meditation (MM), compared with a sleep hygiene education (SHE) control, on changes in sOT levels in 30 cancer survivors with self-reported sleep disturbance. Interventions were conducted in 3 sessions, once per week for 3 weeks. Saliva samples were collected at baseline, postintervention (~1 week after the last session), and at the 2-month follow-up. In this cancer survivor group, we found that intra-individual sOT levels were fairly stable across the 3 time points, of about 3 months’ duration, and mean baseline sOT levels did not differ between females and males and were not correlated with age. Correlations between baseline sOT and self-report measures were weak; however, several of these relationships were in the predicted direction, in which sOT levels were negatively associated with sleep problems and depression and positively associated with cancer-related QOL and well-being. Regarding intervention effects on sOT, baseline-subtracted sOT levels were significantly larger at postintervention in the MBB group as compared with those in SHE. In this sample of cancer survivors assessed for sOT, at postintervention, greater reductions in sleep problems were noted for MBB and MM compared with that of SHE, and increases in mindfulness and self-compassion were observed in the MBB group compared with those in SHE. The findings in this exploratory study suggest that sOT may be a reliable biological measure over time that may provide insight into the effects of mind–body interventions on health outcomes in cancer survivors.

Investigating impacts of incorporating an adjuvant mind-body intervention method into treatment as usual at a community- based substance abuse treatment facility: A pilot randomized controlled study

Treatment of substance use/misuse (SUM) continues to pose a difficult challenge. This exploratory pilot study evaluated whether a novel mind–body intervention program called “Mind–Body Bridging” (MBB) could be an effective short-term adjuvant intervention for managing SUM and coexisting symptoms in women undergoing residential and outpatient substance use treatment in a community setting. Thirty-eight women attending a local substance abuse (SA) facility were recruited and randomly assigned to either (a) treatment as usual (TAU) or (b) MBB and TAU. The MBB program consisted of 20 sessions and lasted for 10 weeks. Participants were asked to complete a set of self-report questionnaires designed to assess drug/alcohol cravings, impact of past trauma, depression, sleep disturbance, mindfulness, self-compassion, and well-being. They completed the questionnaires at three time points: preintervention, midintervention (after the fifth week), and postintervention. MBB + TAU significantly reduced drug/alcohol cravings, trauma-related thinking, and disturbed sleep in comparison with TAU. Furthermore, MBB + TAU significantly increased mindfulness, self-compassion, and well-being in comparison with TAU. MBB for SUM appears promising as a complementary adjuvant intervention, warranting future larger scale randomized controlled trials of MBB for SUM populations. SUM is a difficult condition to treat and manage clinically, especially given the multiple comorbid conditions that frequently affect those with SUM. In the search to develop effective adjuvant interventions for SUM, the present pilot study suggested that adding MBB to standard SUM treatment in community-based settings could enhance therapeutic efficacy and quality of care.