A general practice intervention for people at risk of poor health outcomes: the Flinders QUEST cluster randomised controlled trial and economic evaluation.

OBJECTIVE: To determine whether a multicomponent general practice intervention cost-effectively improves health outcomes and reduces health service use for patients at high risk of poor health outcomes. DESIGN, SETTING: Clustered randomised controlled trial in general practices in metropolitan Adelaide. PARTICIPANTS: Three age-based groups of patients identified by their general practitioners as being at high risk of poor health outcomes: children and young people (under 18 years), adults (18-64 years) with two or more chronic diseases, and older people (65 years or more). INTERVENTION: Enrolment of patients with a preferred GP, longer general practice appointments, and general practice follow-up within seven days of emergency department and hospital care episodes. Intervention practices received payment of $1000 per enrolled participant. MAIN OUTCOME MEASURES: Primary outcome: change in self-rated health between baseline and 12-month follow-up for control (usual care) and intervention groups. SECONDARY OUTCOMES: numbers of emergency department presentations and hospital admissions, Medicare specialist claims and Pharmaceutical Benefits Scheme (PBS) items supplied, Health Literacy Questionnaire scores, and cost-effectiveness of the intervention (based on the number of quality-adjusted life-years [QALYs] gained over 12 months, derived from EQ-5D-5L utility scores for the two adult groups). RESULTS: Twenty practices with a total of 92 GPs were recruited, and 1044 eligible patients participated. The intervention did not improve self-rated health (coefficient, -0.29; 95% CI, -2.32 to 1.73), nor did it have significant effects on the numbers of emergency department presentations (incidence rate ratio [IRR], 0.90; 95% CI, 0.69-1.17), hospital admissions (IRR, 0.90; 95% CI, 0.66-1.22), Medicare specialist claims (IRR, 1.00; 95% CI, 0.91-1.09), or PBS items supplied (IRR, 0.99; 95% CI, 0.96-1.03), nor on Health Literacy Questionnaire scores. The intervention was effective in terms of QALYs gained (v usual care: difference, 0.032 QALYs; 95% CI, 0.001-0.063), but the incremental cost-effectiveness ratio was $69 585 (95% CI, $22 968-$116 201) per QALY gained, beyond the willingness-to-pay threshold. CONCLUSIONS: Our multicomponent intervention did not improve self-rated health, health service use, or health literacy. It achieved greater improvement in quality of life than usual care, but not cost-effectively. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617001589370 (prospective).

Toll-Like Receptor Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhea.

PURPOSE: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC). PATIENTS AND METHODS: Fifty-six women aged 16-35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL-1ß) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs. RESULTS: The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI -4.69, -0.09) increase in IL-1ß release when compared with pain-free participants across both days. CONCLUSION: This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea.

A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine.

BACKGROUND: Chronic migraine (CM) is problematic, and there are few effective treatments. Recently, it has been hypothesized that glial activation may be a contributor to migraine; therefore, this study investigated whether the potential glial inhibitor, ibudilast, could attenuate CM. METHODS: The study was of double-blind, randomized, placebo-controlled, two-period crossover design. Participants were randomized to receive either ibudilast (40 mg twice daily) or placebo treatment for 8 weeks. Subsequently, the participants underwent a 4-week washout period followed by a second 8-week treatment block with the alternative treatment. CM participants completed a headache diary 4 weeks before randomization throughout both treatment periods and 4 weeks after treatment. Questionnaires assessing quality of life and cutaneous allodynia were collected on eight occasions throughout the study. RESULTS: A total of 33 participants were randomized, and 14 participants completed the study. Ibudilast was generally well tolerated with mild, transient adverse events, principally nausea. Eight weeks of ibudilast treatment did not reduce the frequency of moderate to severe headache or of secondary outcome measures such as headache index, intake of symptomatic medications, quality of life or change in cutaneous allodynia. CONCLUSION: Using the current regimen, ibudilast does not improve migraine with CM participants.

Glial Attenuation With Ibudilast in the Treatment of Medication Overuse Headache: A Double-Blind, Randomized, Placebo-Controlled Pilot Trial of Efficacy and Safety.

BACKGROUND: Medication overuse headache (MOH) is a condition bordering between a chronic pain condition and a substance dependence disorder. Activation of immunocompetent glial cells in the central nervous system has been linked to both pathological pain and drug addiction/reward. Preclinically, ibudilast attenuates glial activation and is able to reduce neuropathic pain and markers of substance dependence. We therefore hypothesized ibudilast would reduce headache burden and opioid analgesic requirements in patients with opioid overuse headache. OBJECTIVE: To determine if treatment with ibudilast provides a greater reduction in headache index than placebo in MOH patients consuming opioids. METHODS: Participants with MOH who were using opioids were randomized via computer-generated code to ibudilast 40 mg or placebo twice daily for 8 weeks in a double-blind, parallel groups study. Before randomization participants completed a 4-week baseline headache diary. During treatment, headache diary data collection continued and participants attended 4 study visits during which quantitative sensory testing was performed. Blood samples for immune biomarker analyses were collected before and after treatment in a subgroup of participants. RESULTS: Thirty-four participants were randomized, 13 of 15 randomized to ibudilast and 17 of 19 randomized to placebo completed treatment. Ibudilast was generally well-tolerated with mild, transient nausea reported as the most common adverse event (66.7% vs 10.5% in placebo group). Results are shown as mean (SD). At the end of treatment no differences in the primary outcome average daily headache index (placebo 62 [44] vs ibudilast 77 [72] groups, difference -15, CI -65 to 35 h × numerical rating scale), or secondary outcomes headache frequency (placebo 23 [8.1] vs ibudilast 24.5 [6.2], difference -1.5, CI -7.7 to 4.8 days/month) and opioid intake (placebo 20.6 [43] vs ibudilast 19 [24.3], difference 1.6, CI -31.5 to 34.8 mg morphine equivalent) were observed between placebo and ibudilast groups. CONCLUSIONS: Using the current dosing regimen, ibudilast does not improve headache or reduce opioid use in patients with MOH without mandated opioid withdrawal. However, it would be of interest to determine in future trials if ibudilast is able to improve ease of withdrawal during a forced opioid down-titration when incorporated into an MOH detoxification program.

TLR 2 and 4 responsiveness from isolated peripheral blood mononuclear cells from rats and humans as potential chronic pain biomarkers.

BACKGROUND: Chronic pain patients have increased peripheral blood mononuclear cell Interkeukin-1ß production following TLR2 and TLR4 simulation. Here we have used a human-to-rat and rat-to-human approach to further investigate whether peripheral blood immune responses to TLR agonists might be suitable for development as possible systems biomarkers of chronic pain in humans. METHODS AND RESULTS: Study 1: using a graded model of chronic constriction injury in rats, behavioral allodynia was assessed followed by in vitro quantification of TLR2 and TLR4 agonist-induced stimulation of IL-1ß release by PBMCs and spinal cord tissues (n = 42; 6 rats per group). Statistical models were subsequently developed using the IL-1ß responses, which distinguished the pain/no pain states and predicted the degree of allodynia. Study 2: the rat-derived statistical models were tested to assess their predictive utility in determining the pain status of a published human cohort that consists of a heterogeneous clinical pain population (n = 19) and a pain-free population (n = 11). The predictive ability of one of the rat models was able to distinguish pain patients from controls with a ROC AUC of 0.94. The rat model was used to predict the presence of pain in a new chronic pain cohort and was able to accurately predict the presence of pain in 28 out of the 34 chronic pain participants. CONCLUSIONS: These clinical findings confirm our previous discoveries of the involvement of the peripheral immune system in chronic pain. Given that these findings are reflected in the prospective graded rat data, it suggests that the TLR response from peripheral blood and spinal cord were related to pain and these clinical findings do indeed act as system biomarkers for the chronic pain state. Hence, they provide additional impetus to the neuroimmune interaction to be a drug target for chronic pain.

Increased responsiveness of peripheral blood mononuclear cells to in vitro TLR 2, 4 and 7 ligand stimulation in chronic pain patients.

Glial activation via Toll-like receptor (TLR) signaling has been shown in animals to play an important role in the initiation and establishment of chronic pain. However, our ability to assess this central immune reactivity in clinical pain populations is currently lacking. Peripheral blood mononuclear cells (PBMCs) are an accessible source of TLR expressing cells that may mirror similarities in TLR responsiveness of the central nervous system. The aim of this study was to characterize the IL-1ß response to various TLR agonists in isolated PBMCs from chronic pain sufferers (on and not on opioids) and pain-free controls. Venous blood was collected from 11 chronic pain sufferers on opioids (≥ 20 mg of morphine / day), 8 chronic pain sufferers not on opioids and 11 pain-free controls. PBMCs were isolated and stimulated in vitro with a TLR2 (Pam3CSK4), TLR4 (LPS) or TLR7 (imiquimod) agonist. IL-1ß released into the supernatant was measured with ELISA. Significantly increased IL-1ß expression was found in PBMCs from chronic pain sufferers (on and not on opioids) compared with pain-free controls for TLR2 (F((6, 277)) = 15, P<0.0001), TLR4 (F((8, 263)) = 3, P = 0.002) and TLR7 (F((2,201)) = 5, P = 0.005) agonists. These data demonstrate that PBMCs from chronic pain sufferers were more responsive to TLR agonists compared with controls, suggesting peripheral cells may have the potential to become a source of biomarkers for chronic pain.