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.Yuen H Kwok, James E Swift, Parisa Gazerani, Paul Rola

The comorbidities of dysmenorrhea: a clinical survey comparing symptom profile in women with and without endometriosis

Purpose: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. The frequency of 14 associated symptoms both within and outside the pelvis was determined. Patients and methods: Symptom questionnaires were completed by 168 women with dysmenorrhea, allocated to three groups based on their diagnostic status for endometriosis confirmed (Endo+), endometriosis excluded (Endo−), or endometriosis diagnosis unknown (No Lap). Those with endometriosis confirmed were further divided into current users (Endo+ Hx+) and non-users of hormonal treatments (Endo+ Hx–). Users of hormonal treatments were further divided into users (Endo+ Hx+ LIUCD+) and non-users (Endo+ Hx+ LIUCD–) of a levonorgestrel-releasing intra-uterine contraceptive device (LIUCD). The frequency and number of symptoms within groups and the effect of previous distressing sexual events were sought. Results: Women with and without endometriosis lesions had similar symptom profiles, with a mean of 8.5 symptoms per woman. Only 0.6% of women reported dysmenorrhea alone. The presence of stabbing pelvic pains was associated with more severe dysmenorrhea (P=0.006), more days per month of dysmenorrhea (P=0.003), more days per month of pelvic pain (P=0.016), and a diagnosis of migraine (P=0.054). The symptom profiles of the Endo+ Hx+ and Endo+ Hx– groups were similar. A history of distressing sexual events was associated with an increased number of pain symptoms (P=0.003). Conclusion: Additional symptoms are common in women with dysmenorrhea, and do not correlate with the presence or absence of endometriosis lesions. Our study supports the role of central sensitization in the pain of dysmenorrhea. The presence of stabbing pelvic pains was associated with increased severity of dysmenorrhea, days per month of dysmenorrhea, days per month of pelvic pain, and a diagnosis of migraine headache. A past history of distressing sexual events is associated with an increased number of pain symptoms

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-1β 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-1β released into the supernatant was measured with ELISA. Significantly increased IL-1β 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.Yuen H. Kwok, Mark R. Hutchinson, Melanie G. Gentgall, Paul E. Rola

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-1β 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-1β release by PBMCs and spinal cord tissues (n = 42; 6 rats per group). Statistical models were subsequently developed using the IL-1β 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.Yuen H. Kwok, Jonathan Tuke, Lauren L. Nicotra, Peter M. Grace, Paul E. Rolan, Mark R. Hutchinso

Why do we still not know whether refractive error causes headache? Towards a framework for evidence-based practice.

In this paper, we systematically review the available experimental and clinical evidence concerning the causation of headache by refractive error. Despite the apparent belief of both medical and optometric professionals that provision of an appropriate correction may alleviate various types of headache, there is little if any robust evidence in support of this position. We identify four serious methodological and theoretical difficulties with studies to date, which currently render it impossible to assess the relationship between refractive error and headache. The provision by the International Headache Society of the diagnostic category "headache associated with refractive error" is called into question. Five research questions are posited in the form of a framework for the development of evidence-based practice in optometry and the treatment of headache

Chronic tension-type headache is associated with impaired motor learning

Background: Supraspinal activity-dependent neuroplasticity may be important in the transition from acute to chronic pain. We examined neuroplasticity in a cortical region not considered to be a primary component of the central pain matrix in chronic tension-type headache (CTTH) patients. We hypothesised that neuroplasticity would be exaggerated in CTTH patients compared to healthy controls, which might explain (in part) the development of chronic pain in these individuals. Methods: Neuroplasticity was examined following a ballistic motor training task in CTTH patients and control subjects (CS). Changes in peak acceleration (motor learning) and motor-evoked potential (MEP) amplitude evoked by single-pulse transcranial magnetic stimulation were compared. Results: CTTH patients showed significantly less motor learning on the training task than CS (mean acceleration increase 87% CTTH, 204% CS, p.05). Conclusions: These findings suggest a deficit in use-dependent neuroplasticity within networks responsible for task performance in CTTH patients which might reflect reciprocal influences between primary motor cortex and interconnected pain processing networks. These findings may help explain the positive effects of facilitatory non-invasive brain stimulation targeting motor areas on chronic pain and help elucidate the mechanisms mediating chronic pain. © 2013 International Headache Society

Demographic summary.

<p>Data were collected from medical and family history. Data are expressed as mean ± S.E.M. One-way ANOVA and Student's t-test was used to determine significant differences (P-values shown).</p

TLR 2 agonist stimulation caused significant enhanced release of IL-1β in chronic pain patients.

<p>Isolated white cells obtained from chronic pain sufferers on opioids (□), chronic pain sufferers not on opioids (•) and pain-free controls (▴) were stimulated with a range of Pam3CSK4 (TLR2) concentrations (13 pg·ml⁻¹ to 1 µg·ml⁻¹) to generate the response curves and resulted in significant group differences (P<0.0001). Error bars on graphs represent standard error of the mean.</p

TLR 7 agonist stimulation allowed the differentiation between chronic pain patients and pain-free participants.

<p>Isolated white cells obtained from chronic pain sufferers on opioids (□), chronic pain sufferers not on opioids (•) and pain-free controls (▴) were stimulated with a range of imiquimod (TLR7) concentrations (50 pg·ml⁻¹ to 100 µg·ml⁻¹) to generate the response curves and resulted in group differences (P = 0.0048). Error bars on graphs represent standard error of the mean.</p

TLR 4 agonist stimulation caused significant enhanced release of IL-1β in chronic pain patients.

<p>Isolated white cells obtained from chronic pain sufferers on opioids (□), chronic pain sufferers not on opioids (•) and pain-free controls (▴) were stimulated with a range of LPS (TLR4) concentrations (6 pg·ml⁻¹ to 10 µg·ml⁻¹) to generate the response curves and resulted in significant differences (P = 0.002). Error bars on graphs represent standard error of the mean.</p