Parisa Gazerani

The effects of Botulinum Toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental human model of trigeminal sensitization

Abstract The trigeminovascular system is involved in migraine. Efficacy of Botulinum Toxin type A (BoNT‐A) in migraine has been investigated in clinical studies but the mechanism of action remains unexplored. It is hypothesized that BoNT‐A inhibits peripheral sensitization of nociceptive fibers and indirectly reduces central sensitization. We examined the effect of intramuscular injection of BoNT‐A on an experimental human model of trigeminal sensitization induced by intradermal capsaicin injection to the forehead. BoNT‐A (BOTOX®) or saline was injected intramuscularly in precranial, neck and shoulder muscles to 32 healthy male volunteers in a double blind‐randomized manner. Intradermally capsaicin‐induced pain, flare and secondary hyperalgesia were obtained before and 1, 4 and 8 weeks after the above treatments. A significant suppressive effect of BoNT‐A on pain, flare and hyperalgesia area was observed. The pain intensity area was significantly smaller in BoNT‐A group (9.16 ± 0.83 cm × s) compared to saline group (15.41 ± 0.83 cm × s) (P = 0.011). The flare area was also reduced significantly in BoNT‐A group (29.81 ± 0.69 cm2) compared to saline group (39.71 ± 0.69 cm2) (P < 0.001). Similarly, the mean area of secondary hyperalgesia was significantly smaller in BoNT‐A group (4.25 ± 0.91 cm2) compared to saline group (7.03 ± 0.91 cm2) (P = 0.040). Post hoc analysis showed significant differences across the trials with a remarkable suppression effect of BoNT‐A on capsaicin‐induced sensory and vasomotor reactions as early as week1 (P < 0.001). BoNT‐A presented suppressive effects on the trigeminal/cervical nociceptive system activated by intradermal injection of capsaicin to the forehead. The effects are suggested to be caused by a local peripheral effect of BoNT‐A on cutaneous nociceptors.

Subcutaneous Botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin.

Abstract The present human study aimed at investigating the effect of subcutaneous administration of Botulinum toxin type A (BoNT/A) on capsaicin‐induced trigeminal pain, neurogenic inflammation and experimentally induced cutaneous pain modalities. Fourteen healthy males (26.3 ± 2.6 years) were included in this double‐blind and placebo‐controlled trial. The subjects received subcutaneous BoNT/A (22.5 U) and isotonic saline in the mirror sides of their forehead. Pain and neurogenic inflammation was induced by four intradermal injections of capsaicin (100 μg/μL) (before, and days 1, 3 and 7 after treatments). The capsaicin‐induced pain intensity, pain area, the area of secondary hyperalgesia, the area of visible flare and vasomotor reactions were recorded together with cutaneous heat, electrical and pressure pain thresholds. BoNT/A reduced the capsaicin‐induced trigeminal pain intensity compared to saline (F = 37.9, P < 0.001). The perceived pain area was smaller for the BoNT/A‐treated side compared to saline (F = 7.8, P < 0.05). BoNT/A reduced the capsaicin‐induced secondary hyperalgesia (F = 5.3, P < 0.05) and flare area (F = 10.3, P < 0.01) compared to saline. BoNT/A reduced blood flow (F1,26 = 109.5, P < 0.001) and skin temperature (F1,26 = 63.1, P < 0.001) at the capsaicin injection sites compared to saline and its suppressive effect was maximal at days 3 and 7 (P < 0.05, post hoc test). BoNT/A elevated cutaneous heat pain thresholds (F = 17.1, P < 0.001) compared to saline; however, no alteration was recorded for electrical or pressure pain thresholds (P > 0.05). Findings from the present study suggest that BoNT/A appears to preferentially target Cfibers and probably TRPV1‐receptors, block neurotransmitter release and subsequently reduce pain, neurogenic inflammation and cutaneous heat pain threshold.

A human experimental capsaicin model for trigeminal sensitization. Gender-specific differences.

&NA; Migraine is much more common in women (18%) than in men (6%). Menstrual migraine in female migraineurs also varies from 7 to 19%. The main goals of the present study were (1) to investigate gender specific differences in an experimental capsaicin model of trigeminal sensitization (a proposed mechanism of migraine) and (2) to explore the influence of menstrual cycle phases. Twenty‐eight healthy female and male volunteers were studied. Capsaicin (100 μg/0.1 ml) was injected intradermally to the forehead. Pain intensity and distribution together with the visual flare and allodynic area (central sensitization) were assessed for females (during their menstrual and luteal phases) and for males. Pain area significantly changed across the menstrual cycle with 19.2±2.0 cm×min at menstrual and 16.4±0.9 cm×min at luteal phase (P<0.001). The area was significantly larger in both phases for females compared to males (14.2±1.3 cm×min, P<0.0001). Flare area at menstrual phase (69.2±4.2 cm2) was significantly (P<0.0001) larger than luteal phase (58.6±2.1 cm2). Females, in both phases, showed larger flare area compared to males (44.9±3.6 cm2, P<0.0001). Area of brush‐evoked allodynia was also larger at the menstrual phase compared to the luteal phase (P<0.0001) and males (P<0.0001). A significant difference was found in the capsaicin‐evoked pain distribution with a greater response in menstrual phase compared to the luteal phase (P<0.01) and men (P<0.0001). Capsaicin induced trigeminal sensitization and evoked gender specific sensory and vaso‐motor responses, with menstruating females generally showing the strongest manifestations. The model may be further applied to explore mechanisms of human trigeminal sensitization.

Sex-related differences in pain

This article provides an overview of sex-related differences in musculoskeletal pain and the role sex hormones and response to analgesic drugs may play in these differences. Some common pain conditions that include temporomandibular disorders, rheumatoid arthritis, fibromyalgia syndrome and tension-type and migraine headaches, show fairly marked sex-related differences in their occurrence, however, with the exception of rheumatoid arthritis, these pain conditions are also characterized by a lack of understanding of their basic underlying pathophysiology. The association of pain symptoms of these musculoskeletal pain conditions with the reproductive cycle of women is strongly suggestive of a role of the estrogens and/or progesterones, the main female sex hormones, in sex-related differences in pain. Nevertheless, an alternative suggestion that testosterone, the major male sex hormone, protects men from these chronic musculoskeletal pain conditions, has also been made. Indeed, emerging evidence suggests that both male and female sex hormones may contribute to the marked sex-related differences in the occurrence of certain musculoskeletal pain conditions. Men and women also appear to differ in response to pain treatment with certain analgesic drugs. The mechanistic basis for these sex-related differences is not entirely understood but sex hormones are thought to be one of the influencing factors. An improved understanding of mechanisms which underlie sex-related differences in musculoskeletal pain and response to analgesic drugs should permit improved pain management strategies for male and female musculoskeletal pain patients in the clinical setting.

Effects of subcutaneous administration of glutamate on pain, sensitization and vasomotor responses in healthy men and women

Abstract The present study aimed to investigate if (1) subcutaneous injection of glutamate induces pain, sensitization and vasomotor responses in humans and (2) if sex differences exist in these responses. Thirty healthy volunteers (men‐15 and women‐15) were included. Each subject received four subcutaneous injections (0.1 ml; glutamate 100, 10, 1 mM and isotonic saline 0.9%) into the forehead skin in two sessions separated by one week. Assessments of pain intensity (VAS), quality, distribution; area of pinprick hyperalgesia; pressure pain threshold (PPT) at the injection site; surface skin temperature and local blood flow were performed at predetermined time points. The highest concentration of glutamate evoked the highest pain intensity, the longest duration of pain and the largest pain area under the VAS–time curve (P < 0.001) in both men and women, although responses in women were larger than in men (P < 0.05). The face‐chart pain area was the largest for the highest concentration of glutamate (P < 0.001) and women drew a larger pain area than men (P = 0.024). The area of pinprick hyperalgesia was the largest for glutamate 100 mM (P < 0.001) and women indicated a larger area than men (P < 0.001). Concentration‐dependent local vasomotor responses were found following the subcutaneous injection of glutamate but there was no sex difference in this effect. Glutamate 100 mM significantly reduced the PPT values (P < 0.001) without sex‐related differences. The present study demonstrates for the first time that subcutaneous injection of glutamate evokes pain, vasomotor responses and pinprick hyperalgesia in human volunteers and that there are sex‐related differences in some of these responses.

Botulinum neurotoxin type A (BoNTA) decreases the mechanical sensitivity of nociceptors and inhibits neurogenic vasodilation in a craniofacial muscle targeted for migraine prophylaxis

&NA; The mechanism by which intramuscular injection of BoNTA into the craniofacial muscles decreases migraine headaches is not known. In a blinded study, the effect of BoNTA on the mechanical and chemical responsiveness of individual temporalis muscle nociceptors and muscle neurogenic vasodilation was investigated in female rats. Mechanical threshold was measured for 3 h following intramuscular injection of BoNTA or vehicle, and for 10 min after a subsequent injection of the algogen glutamate. Injection of BoNTA significantly increased the mechanical threshold of muscle nociceptors without altering the muscle surface temperature and blocked glutamate‐induced mechanical sensitization and neurogenic vasodilation. None of these effects were reproduced by pancuronium‐induced muscle paralysis. Western blot analysis of temporalis muscles indicated that BoNTA significantly decreased SNAP‐25. Measurement of interstitial glutamate concentration with a glutamate biosensor indicated that BoNTA significantly reduced glutamate concentrations. The mechanical sensitivity of muscle nociceptors is modulated by glutamate concentration through activation of peripheral NMDA receptors. Immunohistochemical experiments were conducted and they indicated that half of the NMDA‐expressing temporalis nerve fibers co‐expressed substance P or CGRP. Additional electrophysiology experiments examined the effect of antagonists for NMDA, CGRP and NK1 receptors on glutamate‐induced effects. Glutamate‐induced mechanical sensitization was only blocked by the NMDA receptor antagonist, but muscle neurogenic vasodilation was attenuated by NMDA or CGRP receptor antagonists. These data suggest that injection of BoNTA into craniofacial muscles acts to decrease migraine headaches by rapidly decreasing the mechanical sensitivity of temporalis muscle nociceptors through inhibition of glutamate release and by attenuating the provoked release of CGRP from muscle nociceptors.

The impact of ethnic differences in response to capsaicin-induced trigeminal sensitization

&NA; Ethnic differences in the experience of pain, pain‐related health care utilization and pain‐reducing activities have been reported. Thus, evaluating of such variations is important in clinical and experimental pain. Since clinical pain is greatly influenced by disease‐specific factors (severity, duration, type and treatment), evaluating ethnic differences in experimental pain models may not only provide some information about underlying mechanisms but also may predict or explain group differences in clinical pain. Migraine prevalence within ethnic populations is varied. Capsaicin injection to the forehead of healthy volunteers induces the state of an experimental trigeminal sensitization, which is one of the proposed mechanisms of migraine. The aim of the present study was to investigate ethnic differences between Caucasians and South Indians in this model of trigeminal sensitization. Thirty‐two healthy male volunteers (16 South Indians and 16 Danish Caucasians) were included. Capsaicin (100 μg/0.1 ml) was injected intradermally to the right forehead skin. Pain sensitivity, secondary hyperalgesic area, and pressure pain threshold were assessed. Overall, the model showed significant greater pain responses in South Indians (8.75±1.25 cm pain intensity and 9.33±2.32 cm2 hyperalgesic area) compared to Caucasians (6.25±1.95 cm pain intensity and 6.25±1.41 cm2 hyperalgesic area). The model may provide important information for further clinical research, e.g. migraine or differences in mechanisms underlying trigeminal sensitization.

Botulinum toxin type A reduces histamine‐induced itch and vasomotor responses in human skin

Background  Clinical evidence has revealed the antipruritic effect of botulinum toxin type A (BoNT/A). BoNT/A is believed to be effective against itch as it inhibits the release of acetylcholine as well as some other substances that may be involved in itch.

Pressure pain thresholds assessed over temporalis, masseter, and frontalis muscles in healthy individuals, patients with tension-type headache, and those with migraine: a systematic review

Abstract A systematic review was conducted to identify and summarize the available scientific literature addressing pressure pain threshold (PPT) values over the temporalis, masseter, and frontalis muscles in healthy humans, patients with tension-type headache (TTH), and those with migraine both in males and females. Six relevant medical databases for the literature search were included: PubMed, Web of Science, Cochrane, CINAHL, BioMed Central, and Embase. The search strategy was performed applying 15 keywords (eg, pressure pain threshold, temporalis muscle, tension type headache, pressure algometer) and their combinations. A total of 156 articles were identified, and 40 relevant articles were included. The main outcomes of the systematic review were extracted, and it was demonstrated that the PPT values in general were lower in patients compared with healthy subjects, and this was especially noted for temporalis in both females (migraine: 231.2 ± 38.3 kPa < TTH: 248.4 ± 39.3 kPa < healthy: 282.1 ± 70.8 kPa) and males (migraine: 225.5 ± 61.2 kPa < TTH: 264.2 ± 32.5 kPa < healthy: 314.8 ± 63.3 kPa). The masseter muscle seemed to be more sensitive than the other 2 muscles, in both females (healthy: masseter 194.1 ± 62.7 kPa < frontalis 277.5 ± 51.1 kPa < temporalis 282.1 ± 70.8 kPa) and males (healthy: masseter 248.2 ± 48.4 kPa < temporalis 314.8 ± 63.3 < frontalis 388 kPa). Females had lower PPT values than those of males in temporalis, masseter, and frontalis muscles. This work is the first to systematically review the scientific literature addressing PPT values over craniofacial muscles of healthy subjects, patients with TTH, and those with migraine to provide the PPT value ranges. Based on these findings, a set of guidelines was established to assist future studies including PPT assessments over craniofacial muscles.

Botulinum Toxin Type A as a Therapeutic Agent against Headache and Related Disorders

Botulinum neurotoxin A (BoNT/A) is a toxin produced by the naturally-occurring Clostridium botulinum that causes botulism. The potential of BoNT/A as a useful medical intervention was discovered by scientists developing a vaccine to protect against botulism. They found that, when injected into a muscle, BoNT/A causes a flaccid paralysis. Following this discovery, BoNT/A has been used for many years in the treatment of conditions of pathological muscle hyperactivity, like dystonias and spasticities. In parallel, the toxin has become a “glamour” drug due to its power to ward off facial wrinkles, particularly frontal, due to the activity of the mimic muscles. After the discovery that the drug also appeared to have a preventive effect on headache, scientists spent many efforts to study the potentially-therapeutic action of BoNT/A against pain. BoNT/A is effective at reducing pain in a number of disease states, including cervical dystonia, neuropathic pain, lower back pain, spasticity, myofascial pain and bladder pain. In 2010, regulatory approval for the treatment of chronic migraine with BoNT/A was given, notwithstanding the fact that the mechanism of action is still not completely elucidated. In the present review, we summarize experimental evidence that may help to clarify the mechanisms of action of BoNT/A in relation to the alleviation of headache pain, with particular emphasis on preclinical studies, both in animals and humans. Moreover, we summarize the latest clinical trials that show evidence on headache conditions that may obtain benefits from therapy with BoNT/A.