No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
PhD thesis Sensitivity to capsaicin in skin and airways in patients with symptoms elicited by odorous chemicals
ResearchGate has not been able to resolve any citations for this publication.
Background: Multiple chemical sensitivity (MCS) is characterized by chemically induced symptoms from multiple organs. These symptoms occur in response to demonstrable exposure to chemically unrelated compounds at doses far below those known to cause harmful effects in the general population. Although the mechanism of this action remains unclear and no acceptable and well-documented treatment for MCS has yet been established, regarding neurogenic inflammation, it has been hypothesized that an increased density of C-fiber neurons is found in symptomatic tissues.
Methods: Using capsaicin, we examined the sensitivity of the cough reflex in patients with MCS and chronic cough (CC) and compared the findings with those in control subjects. Fifteen patients (four males, 11 females; mean (± SD) age 38.3±16.3 years) suffering from MCS and 29 patients (10 males, 19 females; mean age 46.4±15.9 years) who had cough symptoms lasting 4 weeks or longer and normal chest radiograph findings (CC) were enrolled in the present study. Twenty-nine healthy subjects (14 males, 15 females; mean age 37.9±9.5 years) who had no history of coughing during the previous 6 months and no chronic respiratory diseases were enrolled as controls. Subjects inhaled stepwise incremental concentrations of capsaicin (0.122-62.5 |imol/L) for 15 s. Inhalation was performed at 45 s intervals and the number of coughs per minute was counted. The provocation was terminated when the subject coughed five or more times. Ventilatory functions (forced vital capacity (FVC), forced expiratory volume in 1 s and the expiratory flow rate at 50 and 75% FVC (V50 and V25, respectively)) were also measured.
Results: No significant differences were observed in ventilatory function test findings between the three groups. The log concentration of capsaicin causing five or more coughs (C5) was 0.150±0.630, 0.611±0.691 and 1.120±0.612 | mol/L in MCS, CC and control subjects, respectively. The log C5 in MCS subjects was significantly lower than that in CC and control subjects.
Conclusions: Capsaicin is a cough-inducing agent in humans that possibly acts on non-myelinated C-fiber endings. The findings of the present study indicate that the mechanisms underlying MCS may originate in the sensory nervous system.
Contralateral responses to unilateral stimuli have been well described in animal models. These range from central sensitization to peripheral inflammatory responses. Our aim was to test for contralateral responses following unilateral intradermal capsaicin injection in man.
Three groups were investigated. A healthy volunteer group (1) was injected with capsaicin into the volar aspect of one forearm. A group of patients with RA (2) was also injected with capsaicin. A control group of healthy volunteers (3) was not injected with capsaicin. All groups were tested for hyperalgesia and allodynia every 10 min for 1 h following the injection using quantitative sensory testing.
A total of 9/14 healthy volunteers (Group 1) and 10/14 patients with RA (Group 2) demonstrated contralateral sensitization that subsided within 1 h following intradermal capsaicin injection. A total of 2/23 control subjects (Group 3) demonstrated positive responses with the monofilaments. The frequency of the contralateral responses in the experimental groups compared with the control group is significant (P < 0.05). The peak hyperalgesia was relatively delayed contralaterally compared with the ipsilateral side (35 min vs 15 min). The area of sensitization, where present, was reduced compared with the ipsilateral side (5-50%).
This is the first demonstration of a contralateral response following a unilateral stimulus in man. Bilateral neural pathways mediating contralateral responses may have a role in the pathophysiology of chronically painful or inflammatory diseases and a confounding influence on using the contralateral limb as a control experimentally. We did not find that a systemic inflammatory disease sensitized for this phenomenon.
Wind-up and secondary hyperalgesia both are related to central sensitization, but whereas the former is explained by homosynaptic facilitation, the latter is due to heterosynaptic facilitation. To investigate possible interactions between both types of facilitation, we tested for alterations of perceptual wind-up in the secondary hyperalgesic skin zone adjacent to a capsaicin injection with light touch (by a cotton wisp) and punctate stimuli (calibrated von Frey hairs and pin pricks). Temporal summation of pain sensation (perceptual wind-up) was only observed with a clearly noxious stimulus (pin prick) presented at a repetition frequency of 0.6 s(-1), but not 0.2 s(-1). Pain ratings to trains of pin pricks reached a plateau after 3-4 repetitions, which was 1.65 times the initial rating ('wind-up ratio'). Injection of capsaicin induced a tenderness to mechanical stimuli in adjacent uninjured skin (secondary hyperalgesia), including hyperalgesia to light touch (allodynia) and hyperalgesia to punctate stimuli. Hyperalgesia to punctate stimuli was characterized by a leftward shift of the stimulus response function, corresponding to a decrease in pain threshold and an increase of painfulness of suprathreshold stimuli by a factor of 3-4. After capsaicin, the difference between the ratings of the first and last stimuli of trains of pin pricks was increased, but the ratio was unchanged. This behavior is equivalent to an increase in effective stimulus intensity, and could be mimicked by increasing the pin prick force from 20 mN to 40 and 80 mN in normal skin. Thus, the leftward shift of the stimulus response function fully accounts for all alterations of pain sensitivity to punctate stimuli in the zone of secondary hyperalgesia. We conclude that when the gain of spinal transmission was changed in secondary hyperalgesia, the gain of wind-up remained unchanged. These findings indicate that secondary hyperalgesia (heterotopic facilitation) and wind-up of pain sensation (homotopic facilitation) are independent phenomena.
When one is studying the physiology of the cutaneous microcirculation there is a need for relevant non-invasive and versatile techniques. In this study we used a new optical device, the tissue viability imager (TiVi), to map changes in cutaneous microvascular concentrations of red blood cells during iontophoresis of vasoactive substances (noradrenaline (NA) and phenylephrine (Phe) for vasoconstriction and acetylcholine (ACh) and sodium nitroprusside (SNP) for vasodilatation). We aimed to present data both individually and pooled, using a four-variable logistic dose response model that is commonly used in similar in vitro vascular studies. The accuracy of the TiVi was also investigated by calculating the coefficient of variation and comparing it with similar tests previously done using laser Doppler imaging. Tests were also performed using the TiVi and LDPI simultaneously to further compare the two methods. Results showed that the TiVi is capable of quantifying vascular responses to iontophorised noradrenaline and phenylephrine without the need to increase background flow first. Fitting the TiVi data to the dose response model resulted in ED(50)-values with narrow confidence intervals and acceptable r(2) values. Mean ED(50)-values for the TiVi did not differ significantly from similar values obtained using laser Doppler. Results further seem to suggest that when the blood perfusion increases during vasodilatation in skin the initial phase relies mainly on an increase in red blood cell concentration whereas the further perfusion increase is due to an increase in red blood cell velocity.
To develop a methodology for translating the McGill Pain Questionnaire (MPQ) into a Danish version, and to make comparisons to studies of patients speaking other languages.
Finding suitable Danish adjectives using the same methodology as that in the original MPQ. Comparison of Danish descriptors to the words in the English version of MPQ. Survey in healthy subjects and patients with rheumatoid arthritis (RA) and fibromyalgia (F).
The general public and hospital outpatients.
A random sample of 186 healthy volunteers, 20 patients with rheumatoid arthritis and 41 patients with fibromyalgia.
Danish words translated as closely as possible to the descriptors in the original McGill Pain Questionnaire. A pain-assessment instrument making international pain description possible.
A Danish version of the McGill Pain Questionnaire was developed with scale values of Danish descriptors not differing more than 5 x SEM from the 'patient' words in the English version. The subdivision into classes and subclasses was respected. In the reliability experiment, the same rank values were found in 85% of subclasses. In a study using two experimental pain stimulus intensities, seven of 10 subjects obtained higher MPQ scores following the high-intensity stimulus. In the clinical study, the pain profiles of patients with RA and F in English, Italian, and Danish patients were almost the same.
The present methodology of translating the McGill Pain Questionnaire permits comparison of studies from English-speaking and non-English-speaking populations, thus facilitating international research exchange.
Self-reported information about health and mental health status and history on (a) three diverse samples of individuals who reported multiple chemical sensitivities syndrome (n = 60) and (b) one sample of the general population (n = 60) was collected by telephone interview. Subjects from the general population were selected randomly from the telephone directory and were matched for age, gender, and socioeconomic status with index subjects. Data on an additional 10 subjects with multiple chemical sensitivities syndrome were also available for comparison on many of the variables of interest. The four diverse groups of patients with multiple chemical sensitivities syndrome had very similar general and specific indices of illness and sensitivity to chemicals. Members of the general population reported mild sensitivity to chemicals, and even those with more sensitivity differed from the multiple chemical sensitivities syndrome groups with respect to number and types of symptoms reported, duration and frequency of response, and associated features. Multiple chemical sensitivities syndrome was associated consistently with only one psychiatric variable, elevated negative affect scores, which were correlated significantly with the presence of illness. Patients with multiple chemical sensitivities syndrome from the diverse samples had very similar characteristic features, despite whether they had or had not received treatment by clinical ecologists.
Chronic, nonproductive cough and cough associated with the use of angiotensin converting enzyme inhibitors, are more frequently observed in females as compared to males. To examine the influence of sex, age, height, weight and pulmonary function on airway cough sensitivity, cough threshold to inhaled capsaicin, an index of the airway cough sensitivity, was measured in 160 nonsmoking, nonatopic healthy subjects. Forty young males (aged 24 +/- 2 yrs) 40 young females (aged 22 +/- 2 yrs) 40 middle-aged males (aged 48 +/- 5 yrs) and 40 middle-aged females (aged 50 +/- 7 yrs) were studied. The cough threshold was defined as the lowest concentration of inhaled capsaicin causing five or more coughs. The cough threshold was 3-5 fold lower in females than in males both in young (p<0.001) and middle-aged (p<0.005) subjects. Cough threshold was weakly but significantly correlated to height, weight, forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) when all subjects were considered together but not when each group was considered separately. Multiple regression analysis revealed that sex difference was the significant predictive factor for the cough threshold in either age group. These results confirm that cough sensitivity is heightened in females and suggest that influence of height and pulmonary function on the cough threshold may have resulted from sex difference.
We have shown previously that female sex is a determinant of cough sensitivity to inhaled capsaicin, but the relationship between atopy and the cough sensitivity has not been examined. The capsaicin cough threshold, defined as the lowest concentration of capsaicin causing five or more coughs, nonspecific bronchial responsiveness, defined as the provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20), total immunoglobulin E (IgE) and specific IgEs to eight common aeroallergens (house dust 1, 2 and 6, Dermatophagoides pteronyssinus and D. farinae, Japanese cedar, ragweed and orchard grass) in the serum were measured in 71 nonsmoking, healthy young women aged 20.6+/-0.1 yrs (mean+/-EM). A structured interviewer-led questionnaire on allergic diseases revealed that one and six subjects had mild current and past asthma, respectively. These seven subjects were excluded from the data analysis. PC20 was significantly lower in 42 subjects showing a positive specific IgE than in 22 subjects showing a negative specific IgE to any of the eight allergens (p<0.05), while the capsaicin cough threshold was not significantly different between the subgroups. PC20 was significantly lower in subjects with positive specific IgE to Dermatophagoides and house dust, but not to the three kinds of pollen examined. It was confirmed that atopy indicated by specific immunoglobulin E to mite-related antigens, but not to pollen antigens, is associated with nonspecific bronchial responsiveness, and it is suggested that atopy is not a determinant of airway cough sensitivity in healthy, nonasthmatic subjects.
Syndrome of Multiple Chemical Sensitivities has been known since the middle of 80th of the last century. Although health professionals expressed their scepticism, they recommended the serious study of this problem by standard epidemiologic, clinical and laboratory methods. Later, the epidemiologic studies described higher frequency of the syndrome than it had been earlier suggested. The results verifying the hypothesis about the primary psychiatric initiation of the problems are controversial. The possible role of immunity systems dysfunction in the causality of the syndrome is still studied.
Background: Several studies have reported on extensive two-way overlaps found among chronic fatigue syndrome (CFS), fibromyalgia syndrome (FMS) and multiple chemical sensitivity syndrome (MCS) but none have yet reported on the overlap of all three. This study assesses the prevalence of pure MCS, MCS-CFS, MCS-FMS and the overlap of all three among 100 consecutive new patients evaluated for MCS in a private practice specializing in occupational and environmental medicine.
Methods: Sixty-eight females and 32 males diagnosed with MCS-based on a medical history of multiple chronic symptoms in multiple organs triggered by multiple chemical exposures at or below previously tolerated levels-were also evaluated for CFS and FMS using the diagnostic criteria of the US Centers for Disease Control and the American College of Rheumatology, respectively.
Results: Eighty-eight percent of the 100 MCS patients met criteria for CFS, 49% met criteria for FMS, and 47% met both. Slightly more male than female MCS patients had CFS: 91% vs. 87%; while FMS was more than twice as common among female MCS patients: 59% vs. 28%. The majority of women, 56%, met criteria for all three disorders, and an additional 31% had both MCS and CFS. This pattern was reversed in men, only 28% of whom had all three, compared to 63% with MCS and CFS but no FMS. MCS alone was diagnosed in only 10% of the women and 9% of the men. Even rarer was the overlap of MCS and FMS without any CFS, found in just 2 women.
Conclusions: At least in this clinic population, MCS seldom occurs alone. The enormous range of diagnostic overlaps reported here and in previous studies of various overlaps among CFS, FMS and MCS highlights the need to screen for all three disorders in studies of any one and to report results in these terms. We recommend this be made standard practice in both clinical settings and research protocols.
Fillingim and Maixner (Fillingim, R.B. and Maixner, W., Pain Forum, 4(4) (1995) 209–221) recently reviewed the body of literature examining possible sex differences in responses to experimentally induced noxious stimulation. Using a `box score' methodology, they concluded the literature supports sex differences in response to noxious stimuli, with females displaying greater sensitivity. However, Berkley (Berkley, K.J., Pain Forum, 4(4) (1995) 225–227) suggested the failure of a number of studies to reach statistical significance suggests the effect may be small and of little practical significance. This study used meta-analytic methodology to provide quantitative evidence to address the question of the magnitude of these sex differences in response to experimentally induced pain. We found the effect size to range from large to moderate, depending on whether threshold or tolerance were measured and which method of stimulus administration was used. The values for pressure pain and electrical stimulation, for both threshold and tolerance measures, were the largest. For studies employing a threshold measure, the effect for thermal pain was smaller and more variable. The failures to reject the null hypothesis in a number of these studies appear to have been a function of lack of power from an insufficient number of subjects. Given the estimated effect size of 0.55 threshold or 0.57 for tolerance, 41 subjects per group are necessary to provide adequate power (0.70) to test for this difference. Of the 34 studies reviewed by Fillingim and Maixner, only seven were conducted with groups of this magnitude. The results of this study compels to caution authors to obtain adequate sample sizes and hope that this meta-analytic review can aid in the determination of sample size for future studies.
Patients with multiple chemical sensitivity and eczema patients with airway symptoms elicited by odorous chemicals have enhanced cough reflex to capsaicin when applying the tidal breathing method. The aims of the present study were to test whether the capsaicin induced cough reflex was enhanced when applying the single breath inhalation method in similar groups of patients with symptoms related to odorous chemicals e.g. other persons wearing of perfume; and to investigate to what extent the reporting of lower airway symptoms influenced the cough reflex. Sixteen patients fulfilling Cullen's criteria for multiple chemical sensitivity and 15 eczema patients with airway symptoms elicited by odorous chemicals were compared with 29 age-matched, healthy controls. We measured C5--the capsaicin concentration causing five coughs or more--using the single breath inhalation test. No difference was found between groups in age, body mass index or pulmonary function. The median C5 were 129 micromol/L (control group), 48 micromol/L (multiple chemical sensitivity patients), 32 micromol/L (eczema patients). The reporting of lower airway symptoms from odorous chemicals was significantly (p<0.05) correlated to increased cough reflex sensitivity to capsaicin, independent of patient group or co-existence of asthma. The results suggest that the C5 is not reliable for diagnosing MCS but C5 can be used to verify presence of lower airway symptoms related to odorous chemicals.
We investigated whether persons with self-reported chemical sensitivity (CS) have an attention bias and enhanced sensitization to chemical exposure.
Chemosomatosensory, olfactory, and auditory event-related potentials (ERPs) were recorded from 21 CS subjects and 17 controls in attend and ignore conditions. Reaction times (RTs) and magnitude estimations of perceived intensity were collected in the attend condition. ERPs were averaged over attention conditions and during the first/second part of the testing.
ERP patterns indicated that CS subjects did not habituate to the same extent as the controls and had difficulties ignoring the chemical exposure. CS subjects had faster overall RT, and the perceived intensities for the chemosomatosensory stimuli did not decrease with time in the CS group, which was the case for the controls.
These results indicating attention bias and enhanced sensitization in CS suggest alterations in central, cognitive responses to chemical exposure.
Tissue Viability Imaging (TiVi) is an emerging bioengineering technology intended for two-dimensional mapping of skin erythema and blanching. Before TiVi can be effectively used in studies of diseased or damaged skin, the variability in normal skin red blood cell concentration (RBC(conc)) requires evaluation.
To demonstrate how TiVi maps spatial and temporal variations in normal skin RBC(conc) at the dorsal side of the hand at rest and during post-occlusive hyperemia.
Short-term and day-to-day variations in skin RBC(conc) were quantified at the dorsal side of the hand in four healthy volunteers at rest. In a separate study, the increase in skin RBC(conc) was recorded during post-occlusive hyperemia.
A lower skin RBC(conc) (179-184 TiVi units) was observed at the back of the hand and base of the thumb compared with areas adjacent to the nailfoldfold region of the fingers (190-213 TiVi units). The short-term variation (within 70 s) was <2% in all areas of the dorsal side of the hand, while day-to-day variations were in the range 5-7% in the back of the hand and up to 10% in areas adjacent to the nailfold region. In the post-occlusive hyperemia phase, up to a 60% increase in skin RBC(conc) was observed in the early part of the reactive hyperemia phase. This increase in skin RBC(conc) successively decreased but remained about 18% above the pre-occlusion level after 30 min.
Establishment of healthy skin RBC(conc) reference values is important for the design of versatile test procedures for assessment of skin damage caused by vibration tools, chemical exposure or peripheral vascular disease.
In the last decade, studies of transient receptor potential (TRP) channels, a superfamily of cation-conducting membrane proteins, have significantly extended our knowledge about the molecular basis of sensory perception in animals. Due to their distinct activation mechanisms and biophysical properties, TRP channels are highly suited to function in receptor cells, either as receptors for environmental or endogenous stimuli or as molecular players in signal transduction cascades downstream of metabotropic receptors. As such, TRP channels play a crucial role in many mammalian senses, including touch, taste and smell. Starting with a brief survey of sensory TRP channels in invertebrate model systems, this review covers the current state of research on TRP channel function in the classical mammalian senses and summarizes how modulation of TRP channels can tune our sensations.
Several indications suggest that supramedullary brain regions receive sensory information from the airways and provide motor control to the brainstem neurons that control coughing. However, the organization of this circuitry has not been described in any detail. In this short review we will discuss how state-of-the-art functional brain imaging techniques in humans and animals will enable unprecedented insights into the supramedullary brain regions that help control coughing. In addition we will describe the likely similarities between cough-related higher brain networks and those involved in the processing of other aversive sensory modalities, such as pain.
Unlabelled:
Neuropeptides released from axons of primary afferent nociceptive neurons are the key elements for the incidence of neurogenic inflammation and their release is associated with dorsal root reflexes (DRRs). However, whether the release is due to the triggering of DRRs and plays a role in inflammation-induced pain still remain to be determined. The present study assessed the role of calcitonin gene-related peptide (CGRP) in sensitization of primary afferent nociceptors induced by activation of transient receptor potential vanilloid-1 (TRPV(1)) after intradermal injection of capsaicin and determined if this release is due to activation of primary afferent neurons antidromically by triggering of DRRs. Under dorsal root intact conditions, primary afferent nociceptive fibers recorded in anesthetized rats could be sensitized by capsaicin injection, as shown by an increase in afferent responses and lowering of the response threshold to mechanical stimuli. After DRRs were removed by dorsal rhizotomy, the capsaicin-evoked sensitization was significantly reduced. In dorsal root intact rats, peripheral pretreatment with a CGRP receptor antagonist could dose-dependently reduce the capsaicin-induced sensitization. Peripheral post-treatment with CGRP could dose-dependently restore the capsaicin-induced sensitization under dorsal rhizotomized conditions. Capsaicin injection evoked increases in numbers of single and double labeled TRPV(1) and CGRP neurons in ipsilateral dorsal root ganglia (DRG). After dorsal rhizotomy, these evoked expressions were significantly inhibited.
Perspective:
These data indicate that the DRR-mediated neurogenic inflammation enhances sensitization of primary afferent nociceptors induced by capsaicin injection. The underlying mechanism involves antidromic activation of DRG neurons via upregulation of TRPV(1) receptors whereby CGRP is released peripherally.
The principle finding of the present study is that there are two types of mechanical hyperalgesia developing in human hairy skin following injurious stimuli. Mechanical hyperalgesia comprises a dynamic component (brush-evoked pain, allodynia) signalled by large myelinated afferents and a static component (hyperalgesia to pressure stimuli) signalled by unmyelinated afferents. While the static component is only found in the injured area, the dynamic component also extends into a halo of undamaged tissue surrounding the injury. The irritant chemicals, mustard oil or capsaicin, were applied transdermally in 20 subjects to a patch (2 x 2 cm) of hairy skin. Both substances evoked burning pain and hyperalgesia to mechanical stimuli. While stroking normal skin with a cotton bud was perceived only as touch prior to chemical stimulation, there was a distinctly unpleasant sensation afterwards. This component of mechanical hyperalgesia persisted for at least 30 min and was present in the skin exposed to the irritants (primary hyperalgesia) as well as in a zone of untreated skin surrounding the injury (secondary hyperalgesia) measuring 38 +/- 4 cm2 after capsaicin. Pressure pain thresholds dropped to 55 +/- 8% of baseline level after mustard oil and to 46 +/- 9% after capsaicin. However, this drop of thresholds was short-lived, lasting 5 min following mustard oil but persisting more than 30 min following capsaicin treatment. The reduction of pressure pain thresholds was only observed for treated skin areas, but not in the surrounding undamaged tissue from where brush-evoked pain could be evoked. When pressure pain thresholds were lowered, the pain had a burning quality which differed distinctly from the quality of brush-evoked pain. On-going burning pain and both types of mechanical hyperalgesia were critically temperature dependent. Mildly cooling the skin provided instant relief from on-going pain, abolished brush-evoked pain and normalized pressure pain thresholds. Rewarming resulted in a reappearance of on-going pain and hyperalgesia. The effect of a nerve compression block of the superficial radial nerve on these sensations was tested in 14 experiments. When the ability to perceive light touch had been abolished, there was also no touch-evoked pain, indicating that this component of mechanical hyperalgesia is mediated by large-diameter primary afferents. At a later stage of the block when the subjects' ability to perceive cold stimuli had also been lost, application of cool stimuli still eliminated on-going burning pain, suggesting that pain relief afforded by cooling the skin acts at the peripheral receptor level and not by central masking.(ABSTRACT TRUNCATED AT 400 WORDS)
We have evaluated the properties of capsaicin as a selective cough-inducing agent in healthy human subjects. Despite frequent coughing, the subjects could inhale repeated breaths of capsaicin aerosol during 60 s without difficulty. Cough started immediately on inhalation and was most intense during the first 30 s. Cough always disappeared promptly when the capsaicin inhalation was terminated. The cough response was well reproducible and concentration-dependent up to 10 microM; at higher concentrations there was a distinct plateau of the cough response. Specific airway conductance was not changed 3 min after 50 microM capsaicin. Capsaicin (> or = 10 microM) had a burning taste, but there were no visual signs of pharyngitis or laryngitis. Citric acid (nebulized solutions 0.125 to 32%) had a choking effect and could be administered only as single breaths. There was no correlation between the cough response to citric acid and to capsaicin. Inhaled lidocaine (20 and 80 mg from nebulized solutions) caused a dose-dependent inhibition of capsaicin-induced cough. Lidocaine suppressed citric acid-induced cough as effectively as capsaicin-induced cough. In conclusion, we have characterized capsaicin-induced cough and demonstrated that it can be a useful tool in the study of cough reactivity and for evaluation of antitussive agents in humans. Capsaicin may be complementary to citric acid and may offer experimental advantages over this traditional tussive stimulus.
Inhalation cough challenge has become an accepted method of investigating antitussive agents. It is, therefore, important to examine the degree of tachyphylaxis seen with repeated cough challenge. In addition, different types of challenge may reveal important differences in the neuronal pathways involved in the cough reflex. Citric acid, distilled water and capsaicin were examined to determine adaptation of the cough response during acute and long-term inhalation studies in healthy subjects. To study acute tachyphylaxis two separate one minute continuous inhalation challenges (n = 13) were performed. Long-term tachyphylaxis (n = 10) was examined using citric acid and capsaicin inhalation at 10 min intervals for 40 min, and at 4 and 6 h. Cross-tachyphylaxis to citric acid and capsaicin was examined in a separate randomized crossover study (n = 10). Highly significant adaptation occurred between the first and last 10 s of the one minute challenge with citric acid (90-100%) and distilled water (74-84%), but was less pronounced with capsaicin (37-49%, at 2 microM). Cough during the whole of the second test was significantly reduced for citric acid (50%). During long-term challenge cough was attenuated over 40 min both with citric acid (100 mM, p less than 0.05; 300 mM, p less than 0.001; 1 M, p less than 0.001) and with capsaicin (3 microM, p less than 0.01; 10, 30, 100 microM, p less than 0.001 each). With higher doses, tachyphylaxis was still present at 180 min with both citric acid (300 mM, p less than 0.05) and capsaicin (100 microM, p less than 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)
Cough may occur in association with excess bronchial secretions and may, therefore, be productive. However, in a proportion of patients the cough is non-productive and a possible association with an enhanced response of the cough reflex has been postulated. Using the irritant capsaicin, the sensitivity of the cough reflex was measured in 363 individuals. A questionnaire was used to divide subjects into three groups: Group A) non-coughing controls; Group B) subjects with non-productive cough; and Group C) subjects with productive cough. The group means (+/- 99% confidence interval (CI)) of the log capsaicin concentration causing two or more coughs (C2) for groups A, B, C were 0.98 (+/- 0.08), 0.64 (+/- 0.09) and 1.04 (+/- 0.23), respectively. The log capsaicin concentration causing five or more coughs (C5) for groups A, B, C were 1.78 (+/- 0.1), 1.16 (+/- 0.12) and 1.54 (+/- 0.25), respectively. Group B was significantly more sensitive to inhaled capsaicin than the other groups (p less than 0.01). No significant difference was observed between groups A and C. Some differences were found when subgroups were examined within groups B and C. In group B, patients with post-nasal drip were found to have a normal sensitivity of the cough reflex and were, therefore, different from the remainder of patients with non-productive cough. In group C, patients with bronchiectasis and current infection showed an increase in the sensitivity of their cough reflex. It is concluded that cough can occur in association with either excess mucus production leading to productive cough or an increase in the sensitivity of the cough reflex, possibly leading to non-productive cough.
To examine the sensitivity of different parts of the human respiratory tract to a tussive and bronchoconstrictor stimulus, randomized, standardized single breaths of capsaicin aerosols were inhaled by nine healthy, nonsmoking subjects. A small droplet aerosol (3.2 microns MMD) was inhaled slowly (0.25 L/s), and a large droplet aerosol (5.2 microns MMD) was inhaled rapidly (1.0 L/s) to optimize differences in deposition, which were assessed after inhalation of 99mTc-DTPA aerosols with similar characteristics. Both capsaicin aerosols (zero to 256 microM) produced a concentration-dependent cough response. The geometric means (95% Cl) for the concentrations causing two coughs (cough threshold) were 2.3 microM (1.1 to 4.9) and 8.7 microM (3.1 to 24.5) (p less than 0.02), respectively, with the small and large droplet aerosols. The concentrations causing five coughs were 5.5 microM (3.0 to 10.0) with the small droplet aerosol and 29.5 microM (8.3 to 104.7) with the large droplet aerosol (p less than 0.02). In contrast, FEV1, measured 2 min after the largest concentration of capsaicin, was not significantly altered by any of the two capsaicin aerosols. In each subject, a similar dose was deposited in the larynx with both aerosols, whereas the dose deposited in intrapulmonary airways was 2.3 times larger with the small droplet aerosol. This study confirmed that slow inhalation of a small droplet aerosol produced a more peripheral airway deposition than did rapid inhalation of a large droplet aerosol. The small droplet aerosol was four times more potent, and capsaicin-sensitive sensory neurons mediating cough seem, therefore, to be present in human intrapulmonary airways.(ABSTRACT TRUNCATED AT 250 WORDS)
1. Capsaicin, the algesic substance in chilli peppers, was injected intradermally in healthy human subjects. A dose of 100 micrograms given in a volume of 10 microliters caused intense pain lasting for a few minutes after injection and resulted in a narrow area of hyperalgesia to heat and a wide surrounding area of hyperalgesia to mechanical stimuli (stroking) lasting for 1-2 h. 2. Nerve compression experiments with selective block of impulse conduction in myelinated (A) but not in unmyelinated (C) fibres indicated that afferent signals in C fibres contributed to pain from capsaicin injection and to heat hyperalgesia, whereas conduction in afferent A fibres was necessary for the perception of mechanical hyperalgesia. 3. Electrical intraneural microstimulation normally eliciting non-painful tactile sensations was accompanied by pain when the sensation was projected to skin areas within the region of mechanical hyperalgesia induced by capsaicin injection. 4. The threshold for pain evoked by intraneural microstimulation was reversibly lowered and pain from suprathreshold stimulation was exaggerated during the period of mechanical hyperalgesia, regardless of lidocaine anaesthesia of the cutaneous innervation territory of the stimulated fibres. 5. The results indicate that hyperalgesia to stroking on a skin area surrounding a painful intradermal injection of capsaicin is due to reversible changes in the central processing of mechanoreceptive input from myelinated fibres which normally evoke non-painful tactile sensations.
1. Capsaicin, the potent algesic substance in chilli peppers, was applied topically to, or injected intradermally into or outside, the receptive fields of 14 C mechanoheat (polymodal) nociceptor units in awake humans. The nociceptor discharges were recorded using microelectrodes inserted into the peroneal nerve. Simultaneously, the subjects estimated the magnitude of pain as a function of time during the first 1.5-3 min after injection. Magnitude estimates of pain produced by heat and/or mechanical stimuli were also obtained before and after capsaicin in order to assess the magnitude of cutaneous hyperalgesia. 2. An injection within or adjacent to, but not greater than 4 mm outside, the receptive fields of C nociceptor units evoked discharges. The magnitude of pain and the mean discharge rate of the units were both maximal on injection, declining rapidly over the next 1-3 min, which indicates that these nociceptors contribute to the magnitude and duration of pain evoked by capsaicin injection. 3. Reduced or abolished excitability in C nociceptors after capsaicin injection within the receptive fields correlated with analgesia at the injection site. 4. Capsaicin injection produced a wide surround area of mechanical hyperalgesia, i.e. pain on gently stroking the skin or abnormally intense pain on punctate stimulation. Nevertheless, the injections did not lower the thresholds or enhance the responses to such mechanical stimuli of C nociceptor units with their receptive fields in this hyperalgesic area. 5. Topical application of capsaicin evoked on-going discharges in four units tested. Both nociceptor response thresholds and pain thresholds were lowered for heat from 45 to 35 degrees C. A newly developed weak response to stroking the skin in two units after capsaicin was accompanied by faint pain. 6. On-going activity in sensitized C nociceptors and concomitant pain were effectively reduced by cooling the skin in the receptive area. 7. It is concluded that activity in C mechanoheat (polymodal) nociceptors contributes to the magnitude and duration of pain evoked by intradermal injection of capsaicin. The after-effects of capsaicin on C nociceptor excitability depend on concentration: high concentration (by injection) leads to desensitization, whereas low concentration (by topical application) leads to sensitization. On-going discharges and lowered response thresholds to heat in these units after topical application of capsaicin correlates with background pain as well as lowered pain thresholds to heat of the affected skin (primary hyperalgesia). The unchanged responsiveness of C nociceptors in the skin well outside the injection area indicates that central rather than peripheral sensitization accounts for the observed mechanical hyperalgesia in this region (secondary hyperalgesia).
Neurogenic inflammation, due to release of neuropeptides from sensory nerves, has been demonstrated in airways of several species, particularly rodents, and may contribute to the inflammatory response in asthmatic airways. Tachykinins (substance P and neurokinin A) and calcitonin-gene-related peptide released from airway sensory nerves may cause bronchoconstriction, vasodilatation, plasma exudation and mucus secretion. Sensory nerves may become sensitised by inflammatory products and triggered by mediators such as bradykinin, resulting in exaggerated inflammation. The effects of tachykinins may be further amplified by loss of the major degrading enzyme, neutral endopeptidase, from epithelial cells. Several strategies for reducing neurogenic inflammation are possible.
1. Psychophysical studies were made, in humans, of the sensory characteristics and underlying mechanisms of the hyperalgesia (often termed "secondary hyperalgesia") that occurs in uninjured skin surrounding a local cutaneous injury. The hyperalgesia was characterized by lowered pain thresholds and enhanced magnitude of pain to normally painful stimuli. The "injury" was produced by a single intradermal injection of 10 microliters of 100 micrograms of capsaicin, the algesic substance in hot chili peppers. 2. On injection of capsaicin into the volar forearm, the subjects experienced intense burning pain, accompanied immediately by the formation of three areas of hyperalgesia surrounding the injection site. The largest mean area (55 cm2) was hyperalgesic to a normally painful punctate stimulation of the skin. Nested within this was an area of tenderness to gentle stroking (38 cm2) and a much smaller area of hyperalgesia to heat (2 cm2). An area of analgesia to pinprick, approximately 4 mm in diameter and centered on the injection site, developed within minutes and typically disappeared within 24 h. The hyperalgesia to heat and to stroking disappeared within 1-2 h, whereas the hyperalgesia to punctate stimuli, although gradually decreasing in area, lasted from 13 to 24 h. 3. The radial spread of the mechanical hyperalgesia (to punctate and stroking stimuli) away from the injury was dependent on neural activity and not produced, for example, by algesic substances transported away from the injury. The injection of capsaicin into a small area of anesthetized skin did not produce hyperalgesia in the surrounding, unanesthetized skin. Also, the hyperalgesia in normal skin readily crossed a tight arm band that blocked the circulation of blood and lymph. 4. The spread of mechanical hyperalgesia away from the injury was peripherally mediated via cutaneous nerve fibers because it was blocked by a thin mediolateral strip of cutaneous anesthesia placed 1 cm away from the capsaicin injection site. Hyperalgesia developed normally on the capsaicin side of the strip but not on the other side. 5. Heat stimulation of the skin that produced pain that was equivalent in magnitude and time course to that produced by an injection of capsaicin (10 micrograms) resulted in much smaller areas of mechanical hyperalgesia. It was postulated that there exist special chemosensitive primary afferent nerve fibers that are more effective in producing mechanical hyperalgesia than are the known thermo- and mechanosensitive nociceptive nerve fibers. 6. Once developed, the mechanical hyperalgesia became only partially dependent on peripheral neural activity originating at the site of injury.(ABSTRACT TRUNCATED AT 400 WORDS)
Psychophysical measurements of pain and mechanical hyperalgesia were obtained following different doses of capsaicin injected intradermally into the forearms of human subjects. Each subject received a 10 microliter injection of the vehicle and capsaicin doses of 0.01, 0.1, 1, 10 and 100 micrograms. The relationship between capsaicin dose and the magnitude and duration of pain was determined using the method of magnitude estimation. In addition to pain, capsaicin produced a flare and mechanical hyperalgesia. The area of flare and the area and time course of mechanical hyperalgesia were measured as a function of the dose of capsaicin. The magnitude and duration of pain, based on averaged responses of all subjects, increased as a negatively accelerating function of dose. The lowest dose of capsaicin to produce more pain than the vehicle was 0.1 micrograms. The area and duration of mechanical hyperalgesia also increased as a negatively accelerating function of dose. The lowest dose of capsaicin to produce an area of mechanical hyperalgesia was 0.1 micrograms. An area of hyperalgesia was present within seconds following injection. For doses of 10 and 100 micrograms, the area of hyperalgesia grew to reach a maximum within 5 and 7 min following the injection and gradually decreased, disappearing within 15 and 137 min, respectively. Capsaicin doses of 1, 10 and 100 micrograms produced successively greater areas of flare. The results demonstrate that humans can scale the magnitude of pain produced by capsaicin in a dose-dependent fashion. Further, the duration of pain, the area and duration of mechanical hyperalgesia, and the area of flare are dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanically induced vasodilatation or flare on the skin, known as dermatographia, is a common clinical observation in fibrositis syndrome and is thought to be a neurogenically mediated axon reflex response. In our study, mechanically and chemically induced flares were quantitated in 13 patients with fibrositis syndrome and 14 control subjects. There was a reduced threshold for chemically induced flare response and the area of flare was greater in patients compared to controls, although there was a wide range of responses in both groups. There was also a significant positive correlation between mechanically and chemically induced flares, and the number of tender points in all subjects correlated with the size of the chemically induced flare. We suggest that exaggerated neurogenic inflammatory responses in patients with fibrositis syndrome reflect increased activity of polymodal nociceptors of unmyelinated primary afferent nerves. This increased receptor activity may also contribute to the pain and tenderness experienced by these patients.
The flare response to noxious stimulation of the skin is mediated by polymodal nociceptors of C fiber primary afferent nerves. Topical application of capsaicin initiates a flare response and burning pain. In this study, the variability of capsaicin-induced flare and pain was assessed in 220 subjects. The major factors in flare response are body site and age; more severe reactions occur in more proximal sites and in younger subjects. Larger flares were shown to be associated with greater pain. Variability is probably due to differences in the structure and reactivity of the neurovascular unit as proposed in the Lewis model of the axon reflex. It may prove possible to assess polymodal nociceptor function using topical capsaicin in disease states that affect the peripheral terminals of primary afferent nerves.
Infrared thermography and video image analysis were used to compare the development of the neurogenic flare response in deep and superficial skin layers. Neurogenic vasodilatation was induced by injection or iontophoretic application of histamine. Thermograms were recorded every 10 s to evaluate the local warming reaction. Color-video image analysis was used for computerized delineation of the visible flare. Images derived from video analysis were superimposed to the thermograms after linear transformation. The thermal reaction started within 10 s simultaneously at 2-5 distinct spots after histamine application at distances of 4-25 mm from the application site while the flare reaction seemed to spread from the application site when it became visible after a delay often exceeding 20 s. The visible flare but not the warming reaction was suppressed by topically applied local anesthetic (EMLA). Warming at focal spots was also observed during post-occlusive hyperemia. About 70% of these spots were identical to those activated by histamine. The results indicate that the vascular axon reflex is differently organized in different layers of the skin.
To assess sensory function in skin overlying the joints of patients with rheumatoid arthritis, in relation to the pain and tenderness which commonly arises in structures not directly involved in the inflammatory process.
An intradermal injection of capsaicin 0.05 microgram in 10 microliters was made over the wrists and forearms of 40 patients with rheumatoid arthritis and 46 control subjects. Axon reflex vasodilatation was measured using laser Doppler flowmetry. Cholinergic sympathetic function was assessed by measuring axon reflex sweating induced by a single intradermal injection of nicotine 0.5 microgram in 0.1 ml.
Capsaicin induced axon reflex vasodilation over the wrists was found to decrease with age in normal subjects (r = -0.62, p < 0.001). In patients with rheumatoid arthritis, capsaicin induced axon reflex vasodilatation was significantly greater over the wrists, but not the forearms, when compared with age matched normal controls (p < 0.01). A minimal correlation between axon reflex vasodilatation and visual analogue pain score was apparent in the rheumatoid group (r = -0.37, p < 0.05). Nicotine induced sweating responses were similar in the rheumatoid and normal groups, and both showed a linear age related decline.
The results show a selective increase of capsaicin induced vasodilatation in skin overlying joints in patients with rheumatoid arthritis. This suggests that the activity of a sub-population of periarticular small sensory fibres is altered, which may explain, at least in part, some of the clinical findings in this disorder.
To assess the role of enhanced cough sensitivity in the pathogenesis of cough, we measured cough severity on a visual analogue scale (VAS) and capsaicin cough sensitivity (the concentration required to elicit two [C2] and five [C5] coughs) in 87 consecutive patients referred with chronic cough. Measurements were repeated after complete investigation and treatment, when patients were entered into one of four study groups: (1) treatment success (primary cause of cough successfully treated with elimination of the cough, n = 48); (2) primary treatment failure (treatment of potential primary cause of cough unsuccessful, n = 12); (3) cough treatment failure subgroup A (potential primary cause of cough identified and successfully treated but no improvement in cough, n = 8); and (4) cough treatment failure subgroup B (no potential primary cause of cough identified, n = 19). All patients in groups 3 and 4 were nonsmokers, had normal chest radiography and negative histamine challenge test, and failed to respond to intensive empirical treatment for rhinitis and gastroesophageal reflux. The VAS cough severity was lower and log C2 and C5 higher after treatment compared with initial values in the treatment success group but not in the other three groups. Enhanced sensitivity of airway nerves that mediate cough is important in the pathogenesis of nonproductive cough, and successful treatment is associated with a reduction in cough sensitivity. While enhanced sensitivity of airway nerves is usually present in patients with identifiable causes of chronic nonproductive cough, it is also found in other patients in whom the cause of cough is unknown.
Neurogenic inflammation as a pathway distinct from antigen-driven, immune-mediated inflammation may play a pivotal role in understanding a broad class of environmental health problems resulting from chemical exposures. Recent progress in understanding the mediators, triggers, and regulation of neurogenic inflammation is reviewed. Evidence for and speculations about a role for neurogenic inflammation in established disorders such as asthma, rhinitis, contact dermatitis, migraine headache, and rheumatoid arthritis are presented. The sick building syndrome and multiple chemical sensitivity syndrome have been defined as clinical entities in which exposure to chemical inhalants gives rise to disease. Current data on the existence of chemical irritant receptors in the airway and skin are discussed; neurogenic inflammation arising from stimulation of chemical irritant receptors is a possible model to explain many of the aspects of chemical sensitivities.
When skin-prick tests (SPTs) are used quantitatively, the circumference of the weal and/or the flare is outlined using a felt tip pen, and transferred to paper by adhesive tape. The aim of the study was to develop and validate a procedure, objectively and precisely determining these areas after transfer to paper. A system was developed enabling the drawing of the area of weal or flare to be read by a hand-held scanner and calculated on a personal computer. Areas in the 5-500 mm2 range could be determined with day-to-day and interoperator coefficients of variation (CVs) of 3.1% and 1.8%, respectively. Accuracy was determined in two ways: by correlation to cutting/weighing of four times enlarged SPT areas (r2 = 0.999, P < 0.001) and by measuring standardized areas (deviations less than intra-assay CV, i.e. 1-2%). For comparison, CV of alternative methods were also determined: eight different areas (9-76 mm2) were evaluated in quadruplicate using the SPT-scanner (CV = 1.4%), by cutting/weighing of paper (CV = 2.3%), by digitizing (CV = 4.4%) or by measuring longest and orthogonal diameters (CV = 13.6%). In conclusion, the scanning device and software provides an objective and reproducible procedure for rapid determination of SPT areas. When areas are determined by scanning, digitizing or cutting/weighing the variations in area determination becomes negligible compared to the variations of the entire skin test procedure.
A study was conducted to identify clinical diagnostic criteria that experts regarded as major for categorizing patients as having multiple chemical sensitivities (MCS) syndrome. A cross-sectional survey of 148 medical practitioners with an interest in, or familiarity with, the condition was performed scoreable questionnaires were returned by 60.1% of those surveyed. The following five criteria, all based on self-reports, were selected as major for diagnosing the syndrome by more than 50% of the respondents: (1) symptoms are reproducible with exposure; (2) condition is chronic; (3) low levels of exposure result in manifestations of the syndrome; (4) symptoms resolve with removal of incitants; and (5) responses occur to multiple, chemically unrelated substances. It is proposed that the major criteria accepted by the majority of survey respondents be used provisionally as the basis for categorizing cases in investigations of MCS syndrome.
Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.
This report reviews individual-related variables (age, sex, race, anatomical site, skin surface properties), intra- and interindividual variation (temporal, physical and mental activity, orthostatic effect, menstrual cycle/menopause), environment-related variables (light conditions, temperature) and various instrument-related variables that influence skin colour. CIE colorimetry (Minolta Chroma Meter) and spectrophotometric measurement (Derma Spectrometer) are considered. The guidelines give recommendations for measuring conditions and procedures.
Multiple Chemical Sensitivity (MCS), which may not be caused by chemicals at all, is a serious medical problem of unknown origin and uncertain etiology that raises many fundamental science and policy questions. Regulators, for example, are confronted with a dilemma: what, if anything, should be done to protect people from the scientifically uncertain health risks of exposures to extremely low levels of environmental chemicals. Regulatory agencies, such as the Environmental Protection Agency, do not have the luxury of waiting until conclusive scientific evidence is available before making a decision; however, our present lack of scientific understanding about MCS is so acute that it is not possible to ascertain whether the cause of MCS-related symptoms is chemical, biological, physical, psychosocial, or some combination thereof. Nevertheless, many MCS sufferers and advocates for the chemically induced hypothesis are clamoring for regulatory action to reduce putative health risks from very-low-level exposures to chemicals in the environment. Unless steps are taken to improve the quantity and quality of the existing scientific data base, we cannot, with any acceptable degree of certainty, evaluate the extent to which regulatory decisions about MCS are either protective of public health or cost-effective. This article examines how research can strengthen the scientific basis for risk-related decisions about MCS, and proposes a framework for establishing research directions and priorities. It is argued that high-priority research on MCS is distinguishable by four attributes: (1) results are valuable for risk-related decisions; (2) findings significantly advance scientific knowledge and understanding; and the hypothesis being tested is both (3) biologically plausible and (4) readily testable.
This paper summarizes the key features of the olfactory-limbic, neural sensitization model for multiple chemical sensitivity (MCS) and presents relevant data on chemically intolerant human subjects from laboratory studies using quantitative electroencephalography, polysomnography, neuropsychological tests, cardiovascular measurements, and blood markers. MCS is a poorly understood chronic, polysymptomatic condition in which some prior controlled research studies have failed to find evidence to differentiate active from placebo tests. Closer examination of past MCS research, however, reveals that studies have failed to incorporate the design and methodological approaches necessary to test for nonimmunological sensitization. Time-dependent sensitization (TDS) is a well-documented phenomenon in the pharmacology literature involving the progressive increase in a given response by the passage of time between the initial and subsequent exposures to a substance or a stressor. As in MCS, multiple, chemically unrelated agents can trigger TDS. Females time-sensitize more readily than do males. Pharmacological and nonpharmacological (stress) stimuli can cross-sensitize. Dopaminergic pathways in the brain and the hypothalamic-pituitary-adrenal axis are likely involved in TDS. Data on the symptomatology of MCS point to central nervous system involvement, including limbic regions that receive input from both olfactory (odor) and trigeminal (irritant) pathways. Limbic and mesolimbic brain regions are among the most sensitizable to repeated, intermittent environmental stimuli. Sensitizable individuals can show no difference or lesser responses to a test substance on initial exposure, but later exhibit much greater increases in responsivity on the next exposure after a period of days. For future research, it is essential to distinguish chemical intolerance symptoms such as derealization, sudden mood changes, musculoskeletal pain, menstrual dysfunction, and uncontrollable sleepiness from chemical phobia and avoidance behaviors. This model permits hypothesis-driven research on MCS and has major implications for interpretation of apparently positive and negative tests for "true" as opposed to "perceived" sensitivity to low levels of environmental chemicals.
A case history of the induction of asthma and chemical sensitivity in a 42-year-old registered nurse illustrates several of the characteristic features of multiple chemical sensitivity (MCS). This patient's problems started shortly after moving into a new home under construction, with associated chemical exposures. Other MCS patients report the onset of the condition with other chemical exposures such as those encountered at their places of work or use of pesticides at their residences. Patients often describe a spreading phenomenon of increasing intolerance to commonly encountered chemicals at concentrations well tolerated by other people. Symptoms usually wax and wane with exposures, and are more likely to occur in patients or families with preexisting histories of migraine or with classical allergies. Idiosyncratic medication reactions (especially to preservative chemicals) are common in MCS patients, as are dysautonomia symptoms (such as vascular instability) and poor temperature regulation. Myalgia and joint pains and food intolerance are common features as well. Contamination with xenobiotic chemicals is frequently found in these patients when they are tested. Reactive airways dysfunction syndrome is a recently identified condition that exhibits features of both asthma and chemical sensitivity. MCS patients frequently have patterns of neurotoxic brain metabolism that can be confirmed on single photo emission computed tomography imaging.
Patients reporting sensitivity to multiple chemicals at levels usually tolerated by the healthy population were administered standardized questionnaires to evaluate their symptoms and the exposures that aggravated these symptoms. Many patients were referred for medical tests. It is thought that patients with chemical sensitivity have organ abnormalities involving the liver, nervous system (brain, including limbic, peripheral, autonomic), immune system, and porphyrin metabolism, probably reflecting chemical injury to these systems. Laboratory results are not consistent with a psychologic origin of chemical sensitivity. Substantial overlap between chemical sensitivity, fibromyalgia, and chronic fatigue syndrome exists: the latter two conditions often involve chemical sensitivity and may even be the same disorder. Other disorders commonly seen in chemical sensitivity patients include headache (often migraine), chronic fatigue, musculoskeletal aching, chronic respiratory inflammation (rhinitis, sinusitis, laryngitis, asthma), attention deficit, and hyperactivity (affected younger children). Less common disorders include tremor, seizures, and mitral valve prolapse. Patients with these overlapping disorders should be evaluated for chemical sensitivity and excluded from control groups in future research. Agents whose exposures are associated with symptoms and suspected of causing onset of chemical sensitivity with chronic illness include gasoline, kerosene, natural gas, pesticides (especially chlordane and chlorpyrifos), solvents, new carpet and other renovation materials, adhesives/glues, fiberglass, carbonless copy paper, fabric softener, formaldehyde and glutaraldehyde, carpet shampoos (lauryl sulfate) and other cleaning agents, isocyanates, combustion products (poorly vented gas heaters, overheated batteries), and medications (dinitrochlorobenzene for warts, intranasally packed neosynephrine, prolonged antibiotics, and general anesthesia with petrochemicals). Multiple mechanisms of chemical injury that magnify response to exposures in chemically sensitive patients can include neurogenic inflammation (respiratory, gastrointestinal, genitourinary), kindling and time-dependent sensitization (neurologic), impaired porphyrin metabolism (multiple organs), and immune activation.
Rheumatoid arthritis (RA) is characterised by pain and tenderness not only over inflamed or damaged joints, but also over apparently normal tissues. Experimental models suggest that these features results from changes of sensitivity within both peripheral and central neurones, but direct evidence from human disease is lacking. At present, most clinical studies have evaluated overall pain experience rather than activity within components of the nociceptive pathway. Therefore, the aim of this study was to assess the use of a capsaicin-based technique to quantify changes of neuronal sensitivity in patients with RA. First 20 microliters of capsaicin in solution (0.03 mg/ml) was applied topically for 30 min to apparently normal skin on the forearm of control subjects and patients with RA. The subsequent development of mechanical hyperalgesia to pinprick stimuli was then measured at various time points using a 74.4-mN von Frey hair. The relationship between the area of hyperalgesia and a number of clinical measures was determined. Capsaicin-induced mechanical hyperalgesia was found to decline with age in normal subjects (r = 0.47, P < 0.01). The development of hypearlgesia had a similar time course in normal subjects and patients with RA. The maximum area of hyperalgesia, however, was substantially larger in 35 RA patients; 254.3 +/- 20.7 cm2, compared with 35 normal controls; 109 +/- 7.5 cm2 (P < 0.001). An association was apparent between hyperalgesic area and a composite score of joint tenderness (r = 0.47, P < 0.01), but not with overall pain score or a systemic marker of inflammation. These results provide evidence for enhanced sensitisation of a population of sensory fibres in RA. Peripheral sensory activity over the forearms of rheumatoid patients has previously been shown to be normal and the results suggest the presence of enhanced central mechanisms in this disorder. The correlation between capsaicin-induced hyperalgesia and joint tenderness in the RA patients implies that joint symptoms arise partially as a result of central, and not exclusively peripheral, factors. The study supports the use of capsaicin-based techniques to explore nociceptive mechanisms in clinical disorders characterised by chronic pain.
The more common occurrence in women of cough due to angiotensin-converting enzyme inhibitors raises the possibility of gender-related differences in the sensitivity of the cough reflex. Of two recent studies that evaluated cough response to inhaled capsaicin in normal subjects, one demonstrated heightened sensitivity of the cough reflex in women compared with men, while the other revealed no gender-related differences. To further investigate this question, we reviewed our experience with cough challenge testing in normal volunteers.
To compare cough reflex sensitivity in healthy adult female and male subjects.
Retrospective data analysis.
Academic medical center.
One hundred healthy volunteers (50 male, 50 female). Interventions: Subjects inhaled capsaicin in ascending, doubling concentrations until the concentration inducing five or more coughs (C5) was reached. In addition, the concentration inducing two or more coughs (C2; cough threshold) was measured. Results: Mean log C5 was significantly lower in women than in men: 1.02+/-0.09 (SEM) microM vs 1.41+/-0.08 microM, respectively (p=0.002). Log C2 (cough threshold) was also significantly lower in female subjects: 0.534+/-0.068 microM vs 0.870+/-0.065 microM in male subjects (p=0.00058).
Healthy women have a more sensitive cough reflex than do healthy men. The reasons for this significant gender difference remain to be elucidated, but may involve a heightened sensitivity, in women, of the sensory receptors within the respiratory tract that mediate cough.