Comparison of opioid rotation on pain, symptoms, and daily opioid dose in a supportive care clinic.

BACKGROUND: Opioid rotation (OR) is used to decrease patients' cancer-related pain and mitigate opioid-induced adverse effects. There is limited evidence regarding its effect on symptoms and morphine equivalent daily dose (MEDD). The objective of this study was to investigate the effects of OR on pain scores, Edmonton Symptom Assessment Score (ESAS), and MEDD in patients with cancer. METHODS: Retrospective observational study in an outpatient supportive care clinic using a within-subject design to analyze data collected over 34 months. Study included 676 patients with 217 rotations identified in 128 patients at supportive care clinic at a National Cancer Institute (NCI) Cancer Center. OR were identified and analysis compared the pre-visit data with the subsequent post-visit data following OR using paired t-tests. Primary endpoints included pain scores, total ESAS, and MEDD for OR and these endpoints were compared amongst rotations to specific opioid analgesics. RESULTS: Following OR, there was a statistically significant reduction in mean pain scores from 6.25 at the pre-visit to 5.75 following OR. Of the 194 ORs, 29.90% were successful in reducing patients' pain by either 30% or by 2-points. Only rotations to morphine, oxycodone, and methadone correlated with significant decreases in pain scores. Overall, OR did not correlate with significant changes in ESAS or MEDD. Only rotations to methadone correlated with a significant reduction in MEDD. CONCLUSIONS: These findings suggest OR is associated with decreased pain scores without increasing MEDD. Of the agents compared, only rotations to methadone correlated with both a significant reduction in pain scores and in MEDD.

Comparison of chemotherapy effects on mechanical sensitivity and food-maintained operant responding in male and female rats.

Chemotherapies of varying classes often cause neuropathy and debilitating chemotherapy-induced neuropathic pain sufficient to limit treatment and reduce quality of life for many patients battling cancer. There are currently no effective preventive or alleviative treatments for chemotherapy-induced neuropathic pain. Preclinical models have been developed to test candidate chemotherapy-induced neuropathic pain treatments; however, studies using these models rarely provide direct comparisons of effects of different chemotherapies or assess the degree to which chemotherapies produce clinically relevant signs of pain-depressed behavior. Male and female Sprague-Dawley rats received four injections of vehicle, paclitaxel, oxaliplatin, vincristine, or bortezomib on alternate days. Mechanical hypersensitivity, body weight, and food-maintained operant responding were evaluated before, during, and for up to 42 days after initiation of treatment. Morphine potency and effectiveness to reverse chemotherapy-induced effects were also evaluated. All four chemotherapies produced dose-dependent and sustained mechanical hypersensitivity in all rats. Vincristine and oxaliplatin produced transient weight loss and decreases in food-maintained operant responding in all rats, whereas paclitaxel and bortezomib produced lesser or no effect. At 4 weeks after treatment, operant responding was depressed only in paclitaxel-treated males. Morphine reversed mechanical hypersensitivity in all rats but failed to reverse paclitaxel-induced depression of operant responding in males. We conclude that chemotherapy treatments sufficient to produce sustained mechanical hypersensitivity failed to produce sustained or morphine-reversible behavioral depression in rats. Insofar as pain-related behavioral depression is a cardinal sign of chemotherapy-induced neuropathic pain in humans, these results challenge the presumption that these chemotherapy-dosing regimens are sufficient to model clinically relevant chemotherapy-induced neuropathic pain in rats.

Lack of paclitaxel effects on intracranial self-stimulation in male and female rats: comparison to mechanical sensitivity.

Paclitaxel is a cancer chemotherapy with adverse effects that include peripheral neuropathy, neuropathic pain, and depression of behavior and mood. In rodents, hypersensitive paw-withdrawal reflexes from mechanical stimuli serve as one common measure of paclitaxel-induced pain-related behavior. This study tested the hypothesis that paclitaxel would also depress rates of positively reinforced operant responding as a measure of pain-related behavioral depression. Male and female Sprague-Dawley rats were equipped with electrodes targeting the medial forebrain bundle, trained to lever press for electrical brain stimulation in an assay of intracranial self-stimulation (ICSS), and treated with four injections of varying paclitaxel doses (0.67, 2.0, or 6.0 mg/kg/injection×4 injections on alternate days). Mechanical sensitivity, body weight, and ICSS were evaluated before, during, and for 3 weeks after paclitaxel treatment. Paclitaxel doses sufficient to produce mechanical hypersensitivity did not reliably depress ICSS in male or female rats. Moreover, the degree of behavioral suppression in individual rats did not correlate with mechanical sensitivity. Paclitaxel treatment regimens commonly used to model chemotherapy-induced neuropathic pain in rats are not sufficient to depress ICSS.

Opposing effects of dopamine D1- and D2-like agonists on intracranial self-stimulation in male rats.

Dopamine acts through dopamine Type I receptors (comprising D1 and D5 subtypes) and dopamine Type II receptors (comprising D2, D3, and D4 subtypes). Intracranial self-stimulation (ICSS) is 1 experimental procedure that can be used to evaluate abuse-related effects of drugs targeting dopamine receptors. This study evaluated effects of dopamine receptor ligands on ICSS in rats using experimental procedures that have been used previously to examine abused indirect dopamine agonists such as cocaine and amphetamine. Male Sprague-Dawley rats responded under a fixed-ratio 1 schedule for electrical stimulation of the medial forebrain bundle, and frequency of stimulation varied from 56-158 Hz in 0.05 log increments during each experimental session. Drug potency and time course were determined for the D1 ligands A77636, SKF82958, SKF38393, fenoldopam, and SCH39166 and the D2/3 ligands sumanirole, apomorphine, quinpirole, PD128907, pramipexole, aripiprazole, eticlopride, and PG01037. The high-efficacy D1 agonists A77636 and SKF82958 produced dose-dependent, time-dependent, and abuse-related facilitation of ICSS. Lower efficacy D1 ligands and all D2/3 ligands failed to facilitate ICSS at any dose or pretreatment time. A mixture of SKF82958 and quinpirole produced a mixture of effects produced by each drug alone. Quinpirole also failed to facilitate ICSS after regimens of repeated treatment with either quinpirole or cocaine. These studies provide more evidence for divergent effects of dopamine D1- and D2-family agonists on ICSS procedure in rats and suggest that ICSS may be a useful complement to other approaches for preclinical abuse potential assessment, in part because of the reproducibility of results. (PsycINFO Database Record