Janna Hilligoss

The Effect of Echinacea (Echinacea purpurea Root) on Cytochrome P450 Activity in Vivo

Echinacea is a widely available over‐the‐counter herbal remedy. Tinctures of echinacea have been shown to inhibit cytochrome P450 (CYP) in vitro. The effect of echinacea (Echinacea purpurea root) on CYP activity in vivo was assessed by use of the CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and midazolam (hepatic and intestinal CYP3A).

The interaction between St John's wort and an oral contraceptive

The popular herbal remedy St Johns wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives. Therefore we evaluated the effect of St Johns wort on thedisposition and efficacy of Ortho‐Novum 1/35 (Ortho‐McNeil Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone).

Research to Encourage Exercise for Fibromyalgia (REEF): Use of Motivational Interviewing Design and Method

Fibromyalgia (FM), defined as the presence of both chronic widespread pain and the finding of 11/18 tender points on examination, is an illness associated with major personal and societal burden. Supervised aerobic exercise is an important treatment modality to improve patient symptoms. Unfortunately, adherence to an exercise regimen after a structured supervised program is disappointingly low. Since FM is a chronic illness, studies are needed to test strategies that would enhance exercise adherence in these individuals. Individuals who are able to adhere to exercise almost always maintain the symptomatic benefits of exercise. The objective of this paper was to describe the protocol of the Research to Encourage Exercise for Fibromyalgia (REEF). REEF is a randomized attention-controlled trial that seeks to test the efficacy of 6 sessions of telephone delivered motivational interviewing (MI) that targets exercise adherence to improve FM-relevant clinical outcomes (i.e., physical function and pain severity). The trial has recently completed enrolling 216 subjects, and randomization has resulted in well-balanced groups. Details on the study design, MI program, and treatment fidelity are provided in the paper. Outcome assessments at week 12, week 24 and week 36 will test the immediate, intermediate and long-term effects of exercise-based MI on adherence (as measured by the Community Health Activities Model Program for Seniors/CHAMPS and accelerometer) and clinical outcomes. When completed, REEF will determine whether exercise-based MI could be utilized as a management strategy to sustain the clinical benefits of exercise for FM.

Research to encourage exercise for fibromyalgia (REEF): Use of motivational interviewing, outcomes from a randomized-controlled trial

Objectives:Regular exercise is associated with important benefits in patients with fibromyalgia (FM). Unfortunately, long-term maintenance of exercise after a structured program is rare. The present study tested the efficacy of Motivational Interviewing (MI) to promote exercise and improve symptoms in patients with FM. Methods:A total of 216 patients with FM were randomized to 6 MI sessions (n=107) or an equal number of FM self-management lessons (education control/EC, n=109). Co-primary endpoints were an increase of 30 minutes in moderate-vigorous physical activity and improvement in the Fibromyalgia Impact Questionnaire (FIQ)-Physical Impairment score, assessed at pretreatment, posttreatment, and 3-month and 6-month follow-up. Secondary outcomes included clinically meaningful improvements in FIQ score, pain severity ratings, and a 6-minute walk test. Results:There were no significant treatment group differences in either co-primary endpoint at 6-month follow-up. However, more MI participants than controls exhibited meaningful improvements in FIQ score at 6-month follow-up (62.9% vs. 49.5%, P=0.06). Compared with EC participants, MI participants also displayed a larger increment in their 6-minute walk test (43.9 vs. 24.8 m, P=0.03). In addition, MI was superior to EC in increasing the number of hours of physical activity immediately postintervention and in reducing pain severity both immediately after the intervention and at 3-month follow-up. Conclusions:Despite a lack of benefits on long-term outcome, MI seems to have short-term benefits with respect to self-report physical activity and clinical outcomes. This is the first study in FM that explicitly addresses exercise maintenance as a primary aim. Clinical Trial Registration:NCT00573612.

Cytochrome P450 3A5 Genotype is Associated with Verapamil Response in Healthy Subjects

We hypothesized that CYP3A5 genotype contributes to the interindividual variability in verapamil response. Healthy subjects (n=26) with predetermined CYP3A5 genotypes were categorized as expressers (at least one CYP3A5*1 allele) and nonexpressers (subjects without a CYP3A5*1 allele). Verapamil pharmacokinetics and pharmacodynamics were determined after 7 days of dosing with 240 mg daily. There was a significantly higher oral clearance of R‐verapamil (165.1±86.4 versus 91.2±36.5 l/h; P=0.009) and S‐verapamil (919.4±517.4 versus 460.2±239.7 l/h; P=0.01) in CYP3A5 expressers compared to nonexpressers. Consequently, CYP3A5 expressers had significantly less PR‐interval prolongation (19.5±12.3 versus 44.0±19.4 ms; P=0.0004), and had higher diastolic blood pressure (69.2±7.5 versus 61.6±5.1 mm Hg; P=0.036) than CYP3A5 nonexpressers after 7 days dosing with verapamil. CYP3A5 expressers display a greater steady‐state oral clearance of verapamil and may therefore experience diminished pharmacological effect of verapamil due to a greater steady state oral clearance.

MCP-1 and IL-8 as pain biomarkers in fibromyalgia: a pilot study.

OBJECTIVE Although fibromyalgia (FM) is traditionally a non-inflammatory condition, emerging data also suggest that FM has an immunologic component. Previous studies have reported that peripheral blood concentrations of two chemokines (i.e., interleukin-8 [IL-8] and monocyte chemotactic protein-1 [MCP-1]) were elevated in FM patients compared with normal controls. We sought to determine the longitudinal relationships of changes in the levels (picogram/mL) of IL-8 and MCP-1 with changes in the severity of FM-related pain. DESIGN Secondary data analysis of a cohort of 16 FM subjects who provided blood samples at two time points: week 1 and week 12. Setting.  Urban rheumatology clinic practices. PATIENTS Individuals who met the American College of Rheumatology 1990 criteria for FM. OUTCOME MEASURES Changes from week 1 to week 12 of the following variables: Brief Pain Inventory (BPI) pain severity and plasma concentrations of IL-8 and MCP-1. RESULTS   Change in BPI pain severity was significantly associated with changes in IL-8 and MCP-1 plasma concentrations. Specifically, for each unit increase in the change of BPI pain severity, IL-8 increased by 2.5 pg/mL (P = 0.03) and MCP-1 increased by 9.4 pg/mL (P = 0.006). None of the covariates (i.e., body mass index, medications, severity of depression, and overall FM burden) were significantly associated with either chemokines. CONCLUSION   Although preliminary, our findings raise the hypothesis that IL-8 and MCP-1 may be involved in the pathogenesis of FM. If replicated in a larger study, IL-8 and MCP-1 may assist in determining prognosis and in monitoring of treatment response.

Combining cognitive-behavioral therapy and milnacipran for fibromyalgia: A feasibility randomized-controlled trial.

Objectives:To evaluate the feasibility of a randomized-controlled trial and to obtain estimates of the effects of combined cognitive-behavioral therapy (CBT) and milnacipran for the treatment of fibromyalgia. Methods:Fifty-eight patients with fibromyalgia were randomized to 1 of the 3 treatment arms: (1) combination therapy (n=20); (2) milnacipran+education (n=19); and (3) placebo+CBT (n=19). Patients received either milnacipran (100 mg/d) or placebo. Patients also received 8 sessions of phone-delivered CBT or educational instructions, but only from baseline to week 9. Assessments were conducted at baseline, week 9, and 21. The primary endpoints were baseline to week 21 changes in weekly average pain intensity and physical function (SF-36 physical function scale). Results:Compared with milnacipran, combination therapy demonstrated a moderate effect on improving SF-36 physical function (SE=9.42 [5.48], P=0.09, effect size=0.60) and in reducing weekly average pain intensity (mean difference [SE]=−1.18 [0.62], P=0.07, effect size=0.67). Compared with milnacipran, CBT had a moderate to large effect in improving SF-36 physical function (mean difference [SE]=11.0 [5.66], P=0.06, effect size=0.70). Despite the presence of concomitant centrally acting therapies, dropout rate was lower than anticipated (15% at week 21). Importantly, at least 6 out of the 8 phone-based therapy sessions were successfully completed by 89% of the patients; and adherence to the treatment protocols was >95%. Conclusions:In this pilot study, a therapeutic approach that combines phone-based CBT and milnacipran was feasible and acceptable. Moreover, the preliminary data supports conducting a fully powered randomized-controlled trial.Clinical Trial Registration: NCT01038323.

Association of Nociceptive Responsivity With Clinical Pain and the Moderating Effect of Depression

UNLABELLED The role of central sensitization (CS) in clinical pain reported by FMS patients is unclear. In this report, we sought to establish evidence of a prospective association between clinical pain and an objective measure of spinal nociception (nociceptive flexion reflex [NFR] threshold) and explore whether depression moderates this relationship. We collected measures that included the NFR threshold (in the range of 0-60 milliamperes (mA); a lower threshold represents greater nociceptive responsivity) and clinical variables (ie, Fibromyalgia Impact Questionnaire (FIQ)-total, FIQ-pain, depression and current pain intensity) at 3 time points (baseline, weeks 6 and 12). Using linear mixed effects models, clinical variables were treated as time-varying covariates. Across time, current pain intensity [estimate -1.79 mA (.8), P = .03] and the presence of depression [estimate -6.30 mA (3.2), P = .059] were significantly associated with NFR threshold. The interaction of current pain intensity and depression was also significantly associated with NFR threshold. Specifically, the relationship between current pain intensity and NFR threshold was present in the nondepressed group but not in the depressed group (estimate -3.9 versus .07, P = .01). Both FIQ-total and FIQ-pain were not associated with NFR threshold. In conclusion, higher level of clinical pain intensity correlated with greater nociceptive responsivity, and that depression moderated this association. PERSPECTIVE Given that clinical pain correlated with nociceptive responsiveness, our findings support the mechanistic role of CS in fibromyalgia. If replicated in larger studies, NFR threshold may serve as a biomarker of clinical pain in nondepressed fibromyalgia patients. Also, our results may have future implication for treatment of FMS with and without comorbid depression.

Mast Cell Stabilizer (Ketotifen) in Fibromyalgia: Phase 1 Randomized Controlled Clinical Trial.

Objectives:Compared with pain-free controls, patients with fibromyalgia (FM) have more mast cells in the skin. Whether mast cells are involved in the pathogenesis of FM is unclear. We sought to determine the effects of a mast cell stabilizer (ketotifen) on FM symptoms. Materials and Methods:Fifty-one FM patients were randomized to daily oral ketotifen 2 mg bid (n=24) for 8 weeks or placebo (N=27). Mean age of patients was 51.2 years (SD=8.4); 88% were female and 88% were white; 22% were taking concomitant opiates; and mean pressure pain sensitivity (range, 0 to 20) was 10.0 (0.4). At study entry, the weekly average pain intensity was 6.4 (1.1) and the mean score on the Revised Fibromyalgia Impact Questionnaire-Revised was 66.8 (14.0). Results:We found no statistically significant treatment group differences from baseline in either group for the 2 primary measures: weekly average pain intensity (ketotifen −1.3 [1.9] vs. placebo −1.5 [1.9], P=0.7); and Fibromyalgia Impact Questionnaire-Revised score (−12.1 [19.5] vs. −12.2 [18.1], P=0.9). No secondary outcome measures (Brief Pain Inventory pain intensity and pressure pain sensitivity) reached statistical significance; results did not differ in the intent-to-treat and completer analyses. Other than transient sedation (6 [28.6%] vs. 1 [4.0%]), ketotifen was well tolerated. Discussion:The study results question whether skin mast cells play a major role in the pathogenesis of FM. However, given the role of mast cells in peripheral and central nociception, and the minimal side effects of ketotifen, a randomized clinical trial using increasing doses of ketotifen may be warranted.

Effect of CYP3A5 genotype on the extent of CYP3A inhibition by verapamil

To evaluate the effect of CYP3A5 genotype on the extent of CYP3A inhibition by verapamil (VER) and to examine the effect of VER on intestinal and hepatic CYP3A activity in vivo.