Costs of Implementing Electronic Context Factor Assessments and Patient-reported Outcomes in Pain Clinic Settings.

BACKGROUND: The Healing Encounters and Attitudes Lists (HEALs) patient-reported measures, consisting of 6 separate context factor questionnaires, predict patients' pain improvements. Our Patient-centered Outcomes Research Initiative-funded implementation project demonstrated success in using HEAL data during clinic consultations to enhance patient engagement, improve patient outcomes, and reduce opioid prescribing. OBJECTIVE: We aimed to determine the resources needed for additional sites to implement HEAL to improve pain care treatment. RESEARCH DESIGN: An observational study from March 1 to November 30, 2021, assessing implementation cost data from invoices, time and salary requirements for clinic personnel training, estimates of non-site-based costs, and one-time resource development costs. SUBJECTS: Unique patients eligible to complete a HEAL survey (N=24,018) and 74 clinic personnel. MEASURES: The Stages of Implementation Completion guided documentation of preimplementation, implementation, and sustainment activities of HEAL pain clinic operations. These informed the calculations of the costs of implementation. RESULTS: The total time for HEAL implementation is 7 months: preimplementation and implementation phases (4 mo) and sustainment (3 mo). One hour of HEAL implementation involving a future clinical site consisting of 2 attending physicians, 1 midlevel provider, 1 nurse manager, 1 nurse, 1 radiology technician, 2 medical assistants, and 1 front desk staff will cost $572. A 10-minute time increment for all clinic staff is $95. Total implementation costs based on hourly rates over 7 months, including non-site-based costs of consultations, materials, and technology development costs, is $28,287. CONCLUSIONS: Documenting our implementation costs clarifies the resources needed for additional new sites to implement HEAL to measure pain care quality and to engage patients and clinic personnel.

Comparison of test-retest reliability of BOLD and pCASL fMRI in a two-center study.

BACKGROUND: The establishment of test-retest reliability and reproducibility (TRR) is an important part of validating any research tool, including functional magnetic resonance imaging (fMRI). The primary objective of this study is to investigate the reliability of pseudo-Continuous Arterial Spin Labeling (pCASL) and Blood Oxygen Level Dependent (BOLD) fMRI data acquired across two different scanners in a sample of healthy adults. While single site/single scanner studies have shown acceptable repeatability, TRR of both in a practical multisite study occurring in two facilities spread out across the country with weeks to months between scans is critically needed. METHODS: Ten subjects were imaged with similar 3 T MRI scanners at the University of Pittsburgh and Massachusetts General Hospital. Finger-tapping and Resting-state data were acquired for both techniques. Analysis of the resting state data for functional connectivity was performed with the Functional Connectivity Toolbox, while analysis of the finger tapping data was accomplished with FSL. pCASL Blood flow data was generated using AST Toolbox. Activated areas and networks were identified via pre-defined atlases and dual-regression techniques. Analysis for TRR was conducted by comparing pCASL and BOLD images in terms of Intraclass correlation coefficients, Dice Similarity Coefficients, and repeated measures ANOVA. RESULTS: Both BOLD and pCASL scans showed strong activation and correlation between the two locations for the finger tapping tasks. Functional connectivity analyses identified elements of the default mode network in all resting scans at both locations. Multivariate repeated measures ANOVA showed significant variability between subjects, but no significant variability for location. Global CBF was very similar between the two scanning locations, and repeated measures ANOVA showed no significant differences between the two scanning locations. CONCLUSIONS: The results of this study show that when similar scanner hardware and software is coupled with identical data analysis protocols, consistent and reproducible functional brain images can be acquired across sites. The variability seen in the activation maps is greater for pCASL versus BOLD images, as expected, however groups maps are remarkably similar despite the low number of subjects. This demonstrates that multi-site fMRI studies of task-based and resting state brain activity is feasible.

Hierarchical clustering by patient-reported pain distribution alone identifies distinct chronic pain subgroups differing by pain intensity, quality, and clinical outcomes.

BACKGROUND: In clinical practice, the bodily distribution of chronic pain is often used in conjunction with other signs and symptoms to support a diagnosis or treatment plan. For example, the diagnosis of fibromyalgia involves tallying the areas of pain that a patient reports using a drawn body map. It remains unclear whether patterns of pain distribution independently inform aspects of the pain experience and influence patient outcomes. The objective of the current study was to evaluate the clinical relevance of patterns of pain distribution using an algorithmic approach agnostic to diagnosis or patient-reported facets of the pain experience. METHODS AND FINDINGS: A large cohort of patients (N = 21,658) completed pain body maps and a multi-dimensional pain assessment. Using hierarchical clustering of patients by body map selection alone, nine distinct subgroups emerged with different patterns of body region selection. Clinician review of cluster body maps recapitulated some clinically-relevant patterns of pain distribution, such as low back pain with radiation below the knee and widespread pain, as well as some unique patterns. Demographic and medical characteristics, pain intensity, pain impact, and neuropathic pain quality all varied significantly across cluster subgroups. Multivariate modeling demonstrated that cluster membership independently predicted pain intensity and neuropathic pain quality. In a subset of patients who completed 3-month follow-up questionnaires (N = 7,138), cluster membership independently predicted the likelihood of improvement in pain, physical function, and a positive overall impression of change related to multidisciplinary pain care. CONCLUSIONS: This study reports a novel method of grouping patients by pain distribution using an algorithmic approach. Pain distribution subgroup was significantly associated with differences in pain intensity, impact, and clinically relevant outcomes. In the future, algorithmic clustering by pain distribution may be an important facet in chronic pain biosignatures developed for the personalization of pain management.

Identifying Predictors of Recommendations for and Participation in Multimodal Nonpharmacological Treatments for Chronic Pain Using Patient-Reported Outcomes and Electronic Medical Records.

OBJECTIVE: High-quality chronic pain care emphasizes multimodal treatments that include medication and nonpharmacological treatments. But it is not clear which patients will participate in nonpharmacological treatments, such as physical therapy or mental health care, and previous research has shown conflicting evidence. METHODS: We used the Patient Outcomes Repository for Treatment (PORT) registry, which combines patient-reported outcomes data with electronic medical records. In this retrospective observational study, we performed two separate multinomial regression analyses with feature selection to identify PORT variables that were predictive of 1) recommendation of a nonpharmacological treatment by the provider and 2) patient participation in nonpharmacological treatments. Two hundred thirty-six patients were recommended (REC) or not recommended (NO REC) a nonpharmacological treatment, and all REC patients were classified as participating (YES) or not participating (NO) in the recommendations. RESULTS: Female gender and a diagnosis of Z79 "Opioid drug therapy" were significant positive and negative predictors of nonpharmacological treatment recommendations, respectively. Schedule II opioid use at initial presentation and recommendations for rehabilitation therapy were significant predictors of nonparticipation. CONCLUSIONS: Patients using opioids are less likely to be recommended nonpharmacological treatments as part of multimodal chronic pain care and are less likely to participate in nonpharmacological treatments once recommended. Males are also less likely to be recommended nonpharmacological treatments. Patients referred for rehabilitation therapies are less likely to comply with those recommendations. We have identified patients in vulnerable subgroups who may require additional resources and/or encouragement to comply with multimodal chronic pain treatment recommendations.

Use of a Long-Acting Opioid Microsphere Formulation to Overcome Difficulties in Swallowing Pain Medication.

PURPOSE: Xtampza ER® (XER) is a long-acting oxycodone formulation which was designed to be abuse-deterrent and to overcome capsule-swallowing issues. This pilot study evaluated the effectiveness of XER at reducing swallowing difficulty while providing effective analgesia in the setting of chronic pain. SUBJECTS AND METHODS: Eleven subjects with chronic pain who reported pill-swallowing difficulty were enrolled in a 6-week uncontrolled open-label pilot study in which their prescribed daily opioid medication was converted to XER. Swallowing difficulty, pain intensity, opioid satisfaction, and secondary indicators of pain response were recorded for subjects throughout the study. RESULTS: Both swallowing difficulty and opioid satisfaction (XER vs baseline opioid) improved significantly over the 6-week study period (p < 0.05), while pain intensity ratings demonstrated no significant change. No significant change was noted in any of the secondary pain, mental health, or physical function measures after conversion to XER compared to baseline. CONCLUSION: Subjects experienced improvement in both swallowing and opioid medication satisfaction after conversion to XER with no significant change in pain intensity and related measures.

Comparative Effectiveness of Embedded Mental Health Services in Pain Management Clinics vs Standard Care.

OBJECTIVE: Embedded behavioral medicine services are a common component of multidisciplinary chronic pain treatment programs. However, few studies have studied whether these services are associated with improved treatment outcomes. METHODS: Using a retrospective, matched, two-cohort study design, we examined patient-reported outcomes (PROs), including Patient-Reported Outcomes Measurement Information System pain, mental health, and physical function measures, collected at every clinic visit in every patient. Changes from baseline through 12 months were compared in those receiving embedded Behavioral Medicine in addition to usual care to a Standard Care group seen in the same pain practice and weighted via propensity scoring. RESULTS: At baseline, Behavioral Medicine patients had worse scores on most pain, mental health, and physical health measures and were more likely to be female, a member of a racial minority, and have lower socioeconomic status. Regardless of having a worse clinical pain syndrome at baseline, at follow-up both Behavioral Medicine (N = 451) and Standard Care patients (N = 8,383) showed significant and comparable improvements in pain intensity, physical function, depression, and sleep disturbance. Behavioral Medicine patients showed significantly greater improvements in their global impressions of change than the Standard Care patients. CONCLUSIONS: Despite worse pain and physical and psychological functioning at baseline, Behavioral Medicine patients showed improvements comparable to patients not receiving these services. Further, Behavioral Medicine patients report higher global impressions of change, indicating that embedded mental health services appear to have the additive value of amplifying the benefits of multimodal pain care.

Using formative evaluation methods to improve clinical implementation efforts: Description and an example.

Formative evaluation, a rigorous assessment process to identify potential and actual influences on the implementation process, is a necessary first step prior to launching any implementation effort. Without formative evaluation, intervention studies may fail to translate into meaningful patient care or public health outcomes or across different contexts. Formative evaluation usually consists of qualitative methods, but may involve quantitative or mixed methods. A unique aspect of formative evaluation is that data are shared with the implementation team during the study in order to adapt and improve the process of implementation during the course of the study or improvement activity. In implementation science, and specifically within formative evaluation, it is imperative that a theory or conceptual model or framework guide the selection of the various individual, organizational or contextual factors to be assessed. Data from these theory-based constructs can translate into the development and specification of implementation strategies to support the uptake of the intervention. In this article, we describe different types of formative evaluations (developmental, implementation-focused, progress-focused, and interpretive), and then present a formative evaluation case study from a real-world implementation study within several academic pain clinics, guided by the Theory of Diffusion of Innovation.

Circadian entrainment by food and drugs of abuse.

Circadian rhythms organize behavior and physiological processes to be appropriate to the predictable cycle of daily events. These rhythms are entrained by stimuli that provide time of day cues (zeitgebers), such as light, which regulates the sleep-wake cycle and associated rhythms. But other events, including meals, social cues, and bouts of locomotor activity, can act as zeitgebers. Recent evidence shows that most organs and tissues contain cells that are capable of some degree of independent circadian cycling, suggesting the circadian system is broadly and diffusely distributed. Within laboratory studies of behavior, circadian rhythms tend to be treated as a complication to be minimized, but they offer a useful model of predictable shifts in behavioral tendencies. In the present review, we summarize the evidence that formed the basis for a hypothesis that drugs of abuse can entrain circadian rhythms and describe the outcome of a series of experiments designed to test that hypothesis. We propose that such drug-entrained rhythms may contribute to demonstrated daily variations in drug metabolism, tolerance, and sensitivity to drug reward. Of particular importance, these rhythms may be evoked by a single episode of drug taking, strengthen with repeated episodes, and re-emerge after long periods of abstinence, thereby contributing to drug abuse, addiction, and relapse.

A narrative review of data collection and analysis guidelines for comparative effectiveness research in chronic pain using patient-reported outcomes and electronic health records.

Chronic pain is a widespread and complex set of conditions that are often difficult and expensive to treat. Comparative effectiveness research (CER) is an evolving research method that is useful in determining which treatments are most effective for medical conditions such as chronic pain. An underutilized mechanism for conducting CER in pain medicine involves combining patient-reported outcomes (PROs) with electronic health records (EHRs). Patient-reported pain and mental and physical health outcomes are increasingly collected during clinic visits, and these data can be linked to EHR data that are relevant to the treatment of a patient's pain, such as diagnoses, medications ordered, and medical comorbidities. When aggregated, this information forms a data repository that can be used for high-quality CER. This review provides a blueprint for conducting CER using PROs combined with EHRs. As an example, the University of Pittsburgh's patient outcomes repository for treatment is described. This system includes PROs collected via the Collaborative Health Outcomes Information Registry software and cross-linked data from the University of Pittsburgh Medical Center EHR. The requirements, best practice guidelines, statistical considerations, and caveats for performing CER with this type of data repository are also discussed.

Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator.

Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin-positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1-an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems-we report that the compound is able to reverse 'manic-like' behavior in two mouse models: amphetamine-induced hyperactivity and ClockΔ19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockΔ19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockΔ19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockΔ19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania.

Chronic Stress Induces Brain Region-Specific Alterations of Molecular Rhythms that Correlate with Depression-like Behavior in Mice.

BACKGROUND: Emerging evidence implicates circadian abnormalities as a component of the pathophysiology of major depressive disorder (MDD). The suprachiasmatic nucleus (SCN) of the hypothalamus coordinates rhythms throughout the brain and body. On a cellular level, rhythms are generated by transcriptional, translational, and posttranslational feedback loops of core circadian genes and proteins. In patients with MDD, recent evidence suggests reduced amplitude of molecular rhythms in extra-SCN brain regions. We investigated whether unpredictable chronic mild stress (UCMS), an animal model that induces a depression-like physiological and behavioral phenotype, induces circadian disruptions similar to those seen with MDD. METHODS: Activity and temperature rhythms were recorded in C57BL/6J mice before, during, and after exposure to UCMS, and brain tissue explants were collected from Period2 luciferase mice following UCMS to assess cellular rhythmicity. RESULTS: UCMS significantly decreased circadian amplitude of activity and body temperature in mice, similar to findings in MDD patients, and these changes directly correlated with depression-related behavior. While amplitude of molecular rhythms in the SCN was decreased following UCMS, surprisingly, rhythms in the nucleus accumbens (NAc) were amplified with no changes seen in the prefrontal cortex or amygdala. These molecular rhythm changes in the SCN and the NAc also directly correlated with mood-related behavior. CONCLUSIONS: These studies found that circadian rhythm abnormalities directly correlate with depression-related behavior following UCMS and suggest a desynchronization of rhythms in the brain with an independent enhancement of rhythms in the NAc.

Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2.

BACKGROUND: Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood. METHODS: We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing. RESULTS: Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. CONCLUSIONS: Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.

Folate receptor-targeted multimodality imaging of ovarian cancer in a novel syngeneic mouse model.

A new transplantable ovarian tumor model is presented using a novel folate receptor (FR) positive, murine ovarian cancer cell line that emulates the human disease and induces widespread intraperitoneal (i.p.) tumors in immunocompetent mice within 4-8 weeks of implantation. Tumor development was monitored using a new positron emission tomography (PET) FR-targeting reporter with PET/computerized tomography (PET/CT) and fluorescence molecular tomography (FMT) using a commercial FR-targeting reporter. Conventional structural magnetic resonance imaging (MRI) was also performed. Adult female C57BL/6 mice were injected i.p. with 6 × 10(6) MKP-L FR+ cells. Imaging was performed weekly beginning 2 weeks after tumor induction. The albumin-binding, FR-targeting ligand cm09 was radiolabeled with the positron emitter (68)Ga and used to image the tumors with a small animal PET/CT. The FR-reporter FolateRSense 680 (PerkinElmer) was used for FMT and flow cytometry. Preclinical MRI (7 T) without FR-targeting was compared with the PET and FMT molecular imaging. Tumors were visible by all three imaging modalities. PET/CT had the highest imaging sensitivity at 3-3.5 h postadministration (mean %IA/g mean > 6) and visualized tumors earlier than the other two modalities with lower kidney uptake (mean %IA/g mean < 17) than previously reported FR-targeting agents in late stage disease. FMT showed relatively low FR-targeted agent in the bladder and kidneys, but yielded the lowest anatomical image resolution. MRI produced the highest resolution images, but it was difficult to distinguish tumors from abdominal organs during early progression since a FR-targeting MRI reporter was not used. Nevertheless, there was good correlation of imaging biomarkers between the three modalities. Tumors in the mouse ovarian cancer model could be detected using FR-targeted imaging as early as 2 weeks post i.p. injection of tumor cells. An imaging protocol should combine one or more of the modalities, e.g., PET/CT or PET/MRI for optimal tumor detection and delineation from surrounding tissues.

The role of clock in ethanol-related behaviors.

Mice with a mutation in the Clock gene (ClockΔ19) exhibit increased preference for stimulant rewards and sucrose. They also have an increase in dopaminergic activity in the ventral tegmental area (VTA) and a general increase in glutamatergic tone that might underlie these behaviors. However, it is unclear if their phenotype would extend to a very different class of drug (ethanol), and if so, whether these systems might be involved in their response. Continuous access voluntary ethanol intake was evaluated in ClockΔ19 mutants and wild-type (WT) mice. We found that ClockΔ19 mice exhibited significantly increased ethanol intake in a two-bottle choice paradigm. Interestingly, this effect was more robust in female mice. Moreover, chronic ethanol experience resulted in a long-lasting decrease in VTA Clock expression. To determine the importance of VTA Clock expression in ethanol intake, we knocked down Clock expression in the VTA of WT mice via RNA interference. We found that reducing Clock expression in the VTA resulted in significantly increased ethanol intake similar to the ClockΔ19 mice. Interestingly, we also discovered that ClockΔ19 mice exhibit significantly augmented responses to the sedative effects of ethanol and ketamine, but not pentobarbital. However, their drinking behavior was not affected by acamprosate, an FDA-approved drug for the treatment of alcoholism, suggesting that their increased glutamatergic tone might underlie the increased sensitivity to the sedative/hypnotic properties of ethanol but not the rewarding properties of ethanol. Taken together, we have identified a significant role for Clock in the VTA as a negative regulator of ethanol intake and implicate the VTA dopamine system in this response.

Behavioral characteristics and pharmacological manipulations of a nicotine-entrainable circadian oscillator.

Chronic daily administration of nicotine and other drugs of abuse has been found to entrain pre- and post-drug circadian locomotor activity episodes that oscillate on a 24-h schedule and persist for several days after administration ceases. This drug-entrainable oscillator system could conceivably lead to circadian rhythms of drug seeking and drug use in human drug addicts. The present study (1) characterizes the ability of daily nicotine administration to entrain circadian wheel-running activity episodes in rats across a range of doses, lighting schedules, and food access; and (2) tests whether pre- and post-nicotine episodes can be altered through pharmacological manipulations. Adult female rats were housed in wheel boxes for 35-60 d, and both wheel-running and feeding-related behaviors were measured continuously. Following acclimation, nicotine or saline was administered for 16-24 d, and the rats were left undisturbed for several test days to observe the persistence of nicotine-entrained activity. The results showed that nicotine dose-dependently entrains wheel-running activity, and the highest dose of 1.0 mg/kg produces robust pre- and post-nicotine circadian activity episodes under constant, fixed, and variable light/dark schedules. In the pharmacological manipulation experiment, nicotine-entrained rats were administered one of seven pharmacological treatments (varenicline, mecamylamine, acamprosate, topiramate, naltrexone, SB-334867, or bupropion) in place of the nicotine injection for 2 d, and the rats were not disturbed for four subsequent days. Most of the treatment drugs significantly reduced post-nicotine activity episodes, but only three treatments affected pre-nicotine episodes: the µ- and κ-opioid receptor antagonist naltrexone, the orexin-1 receptor antagonist SB-334867, and the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid)/kainate antagonist topiramate. These results show that chronic daily nicotine administration is a robust zeitgeber that dose-dependently entrains a nonphotic oscillator system that includes opioid, orexin, and glutamate pathways.

Differential effects of chronic social stress and fluoxetine on meal patterns in mice.

Both chronic stress and antidepressant medications have been associated with changes in body weight. In the current study, we investigate mechanisms by which stress and antidepressants interact to affect meal patterns. A group of mice was subjected to the chronic social defeat stress model of major depression followed by fluoxetine treatment and was subsequently analyzed for food intake using metabolic cages. We report that chronic social defeat stress increases food intake by specifically increasing meal size, an effect that is reversed by fluoxetine treatment. In an attempt to gain mechanistic insight into changes in meal patterning induced by stress and fluoxetine, fasting serum samples were collected every 4h over a 24-h period, and acyl-ghrelin, leptin, and corticosterone levels were measured. Chronic stress induces a peak in acyl-ghrelin levels just prior to the onset of the dark phase, which is shifted in mice treated with fluoxetine. Taken together, these results indicate that stress increases food intake by decreasing satiation, and that fluoxetine can reverse stress-induced changes in meal patterns.

Effects of multiple daily nicotine administrations on pre- and post-nicotine circadian activity episodes in rats.

Administration of a single daily dose of nicotine has been shown to entrain circadian activity episodes both preceding and following the administration time that persist for several days after drug administration ceases. The present study tested the effects of multiple daily nicotine administrations on circadian activity episodes in adult female rats kept under constant light and rate-limited food access. Eight rats received 7 separate 7-day nicotine injection series, each followed by a 3-day test phase without injections. Subcutaneous nicotine was administered once a day during the 1st and 7th series, twice daily during the 2nd and 6th series, three times daily during the 3rd and 5th series, and four times daily during the 4th series. To control the cumulative daily dose throughout the study, 1.0 mg/kg nicotine was evenly divided among the injections within a single day. Pre- and post-administration effects of nicotine declined across the day, and significant entrainment of both pre- and post-nicotine episodes occurred for only one daily injection in each series. Additionally, post-nicotine episodes showed a different dose-response curve than the pre-nicotine episodes: post-nicotine wheel turns increased as the dose decreased, whereas pre-nicotine wheel turns remained relatively constant as the dose changed. These results provide evidence that nicotine-induced circadian entrainment to a single administration time does occur when the drug is administered multiple times a day, and pre- and post-nicotine circadian episodes are mediated at least partially by separate mechanisms.

Fentanyl, but not haloperidol, entrains persisting circadian activity episodes when administered at 24- and 31-h intervals.

Administration of several drugs of abuse on a 24-h schedule has been shown to entrain both pre-drug (anticipatory) and post-drug (evoked) circadian activity episodes that persist for several days when the drug is withheld. The present study tested the entrainment effects of fentanyl, an opioid agonist with a noted abuse liability, and haloperidol, an anti-psychotic dopamine antagonist without apparent abuse liability. Adult female Sprague-Dawley rats housed under constant light in cages with attached running wheels received repeated low, medium, or high doses of either fentanyl or haloperidol on a 24-h administration schedule followed by a 31-h schedule (Experiment 1) or solely on a 31-h schedule (Experiment 2). The results showed that all three doses of fentanyl entrained both pre-drug and post-drug episodes of wheel running when administered every 24h, and the combined pre- and post-fentanyl activity episodes persisted for at least 3 days when the drug was withheld during test days. On the 31-h schedule, fentanyl produced an "ensuing" activity episode approximately 24h post-administration, but failed to produce an anticipatory episode 29-31h post-administration. In contrast, haloperidol injections failed to produce both pre-drug episodes on the 24-h schedule and circadian ensuing episodes on the 31-h schedule, and post-haloperidol suppression of activity appeared to mask the free-running activity rhythm. Taken together, these results provide additional evidence that drugs of abuse share a common ability to entrain circadian activity episodes.

Pre- and post-nicotine circadian activity rhythms can be differentiated by a paired environmental cue.

Previous studies have shown that addictive drugs presented daily at fixed times produce circadian (oscillator-driven) anticipatory and evoked activity rhythms in rats. Other studies have shown that environmental cues paired with addictive drugs produce tolerance to drug effects and elicit craving behavior when presented without the drug. The present study tested these circadian entrainment and paired-cue conditioning effects together. This study compared the ability of daily nicotine and saline injections at different fixed times to entrain pre-injection (anticipatory) and post-injection (evoked) circadian activity rhythms in two groups of female Sprague-Dawley rats. One group (Paired) had an environmental cue (a tone) paired with the effects of the nicotine injection, and the second group (Unpaired) had the tone paired with the effects of the saline injection. The rats were housed singly for 56 days in chambers with attached wheels under constant dim light and rate-limited food access. During three separate injection phases, nicotine and saline were administered daily at different fixed times, and the tone was presented at the second injection time. Three multi-day test phases examined circadian activity (a) without injections or tone, (b) with the tone alone at normal and novel times, and (c) with the tone absent and with injections occurring at normal and at novel times. The results showed that nicotine entrained both pre- and post-injection circadian oscillators, and the nicotine-paired tone interfered with pre-injection anticipatory activity.

Drugs of abuse can entrain circadian rhythms.

Circadian rhythms prepare organisms for predictable events in the 24 h day. These rhythms are entrained by a variety of stimuli. Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse. Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues. Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms. We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse. We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states. This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward. These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.