Estimation of Dietary Capsaicinoid Exposure in Korea and Assessment of Its Health Effects.

The consumption of capsaicinoids, the active components in chili peppers, has been associated with both positive and negative health effects, and the level of capsaicinoid exposure may be an important determinant. Dietary capsaicinoid exposure was estimated using a previously developed database for capsaicinoid content and a 24-h dietary recall dataset obtained from the Korea National Health and Nutrition Examination Survey. The estimated consumption level was evaluated to determine its potential effects on weight reduction and gastrointestinal distress. The estimated daily mean capsaicinoid intake was 3.25 mg (2.17 mg capsaicin), and most Koreans consumed 1-30 mg of capsaicinoids (0.67-20 mg capsaicin) in a day. No adverse effect of capsaicin consumption was reported other than abdominal pain. For long-term repeated consumption, 30 mg may be the maximum tolerable dose. However, the effects on body weight or energy balance were inconsistent in 4-12 week clinical studies conducted with various capsaicin doses (2-135 mg), which was likely due to the complex interplay between capsaicin dose, study length, and participant characteristics. Therefore, the capsaicin consumption of most Koreans was below the levels that may cause adverse effects. However, more long-term studies for the dose range of 2-20 mg are required to further characterize capsaicin's health benefits in Koreans.

Capsaicin 8% dermal patch in clinical practice: an expert opinion.

INTRODUCTION: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. AREAS COVERED: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. EXPERT OPINION: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the 'defunctionalization' of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient's response to treatment.

Assessment of Pharmacology, Safety, and Metabolic activity of Capsaicin Feeding in Mice.

Capsaicin (CAP) activates transient receptor potential vanilloid subfamily 1 (TRPV1) to counter high-fat diet (HFD)-induced obesity. Several studies suggest that CAP induces the browning of white adipocytes in vitro or inguinal white adipose tissue (iWAT) in vivo. However, there is a lack of data on the dose-response for CAP to inhibit HFD-induced obesity. Therefore, we first performed experiments to correlate the effect of various doses of CAP to prevent HFD-induced weight gain in wild-type (WT) mice. Next, we performed a subchronic safety study in WT mice fed a normal chow diet (NCD ± CAP, 0.01% in NCD) or HFD ± CAP (0.01% in HFD) for eight months. We analyzed the expression of adipogenic and thermogenic genes and proteins in the iWAT from these mice, conducted histological studies of vital organs, measured the inflammatory cytokines in plasma and iWAT, and evaluated liver and kidney functions. The dose-response study showed that CAP, at doses above 0.001% in HFD, countered HFD-induced obesity in mice. However, no difference in the anti-obesity effect of CAP was observed at doses above 0.003% in HFD. Also, CAP, above 0.001%, enhanced the expression of sirtuin-1 and thermogenic uncoupling protein 1 (UCP-1) in the iWAT. Safety analyses suggest that CAP did not cause inflammation. However, HFD elevated plasma alanine aminotransferase and creatinine, caused iWAT hypertrophy and hepatic steatosis, and CAP reversed these. Our data suggest that CAP antagonizes HFD-induced metabolic stress and inflammation, while it does not cause any systemic toxicities and is well tolerated by mice.

[Capsaicin Cutaneous Patch: a Cost-consequences Study in a French University Hospital]. / Étude coût-conséquences sur la capsaïcine en patch cutané dans un CHU français.

INTRODUCTION: The capsaïcine 8% cutaneous patch (Qutenza®) was recently approved for the management of patients with peripheral neuropathic pain (PNP). Considering its limited clinical efficacy data, its improvement of medical benefit was determined to be 5 which was insufficient to support its reimbursement in addition to diagnosis related groups'tarifs. Nevertheless its commercialization was associated with a marked interest considering the unmet therapeutic needs for patients with PNP. OBJECTIVES: Our objectives were to assess the effectiveness, the safety, and the economic impact of Qutenza® in real-life conditions. METHODS: An observational cost-consequences study was launched under the aegis of the Drug Committee of our hospital. Medical charts and prescriptions of all patients who received at least one patch application were analyzed. Effectiveness and safety were assessed after 12-week and 24-week of follow-up. The economic impact was measured within the Hospital and Health Insurance perspective and with limitation to direct costs. RESULTS: From March 2012 to October 2013, 91 patients (54.3 ± 14.1 years; 52.7% of male) received at least one application. The average follow- up duration was 188.3 ± 86.4 days. The PNP etiologies were mainly post-surgery (42.9%) and post-traumatology (20.8%). A therapeutic response (decrease of ENS score of least 30%) after 12 weeks and 24 weeks was observed in 27.9% and 37.1% of patients respectively. The SF-36 mental score was significantly improved. The safety profile was good. The application of the patch resulted in incremental costs of 154 euros per hospital stay without impact on outpatient-prescription drug expenditures. CONCLUSION: This study confirms the interest of Qutenza® for heavily pretreated, refractory patients with PNP. The clinical profile of responders has to be further investigated in large observational studies.

Assessment of the feasibility of high-concentration capsaicin patches in the pain unit of a tertiary hospital for a population of mixed refractory peripheral neuropathic pain syndromes in non-diabetic patients.

BACKGROUND: High-concentration-capsaicin-patches (Qutenza®) have been put on the market as a treatment for peripheral neuropathic pain. A minimum infrastructure and a determinate skill set for its application are required. Our aim was to assess the feasibility of treatment with high-concentration-capsaicin-patches in clinical practice in a variety of refractory peripheral neuropathic pain syndromes in non-diabetic patients. METHODS: Observational, prospective, single-center study of patients attended to in the Pain Unit of a tertiary hospital, ≥ 18 year-old non-responders to multimodal analgesia of both genders. The feasibility for the application of capsaicin patch in clinical practice was evaluated by means of the number of patients controlled per day when this one was applied and by means of the times used for patch application. RESULTS: Between October 2010 and September 2011, 20 consecutive non-diabetic patients (7 males, 13 females) with different diagnoses of refractory peripheral neuropathic pain syndromes, with a median (range) age of 60 (33-88) years-old were treated with a single patch application. The median (range) number of patients monitored per day was not modified when the capsaicin patch was applied [27 (26-29)] in comparison with it was not applied [28 (26-30)]. The median (range) total time to determine and mark the painful area was 9 (6-15) minutes and of patch application was 60 (58-65) minutes. No important adverse reactions were observed. CONCLUSION: High-concentration-capsaicin-patch treatment was feasible in our unit for the treatment of a population with refractory peripheral neuropathic pain. The routine of our unit was not affected by its use.

Assessment of pain and itch behavior in a mouse model of neurofibromatosis type 1.

UNLABELLED: Neurofibromatosis type 1 (NF1) is characterized primarily by tumor formation in the nervous system, but patients report other neurological complications including pain and itch. Individuals with NF1 harbor 1 mutated NF1 allele causing heterozygous expression in all of their cells. In mice, Nf1 heterozygosity leads to hyperexcitability of sensory neurons and hyperproliferation of mast cells, both of which could lead to increased hypersensitivity and scratching in response to noxious and pruritic stimuli. To determine whether Nf1 heterozygosity may increase pain and itch behaviors independent of secondary effects of tumor formation, we used mice with a targeted, heterozygous Nf1 gene deletion (Nf1±) that lack tumors. Nf1± mice exhibited normal baseline responses to thermal and mechanical stimuli. Moreover, similar to wild-type littermates, Nf1± mice developed inflammation-induced heat and mechanical hypersensitivity, capsaicin-induced nocifensive behavior, histamine-dependent or -independent scratching, and chronic constriction injury-induced cold allodynia. However, Nf1± mice exhibited an attenuated first phase of formalin-induced spontaneous behavior and expedited resolution of formalin-induced heat hypersensitivity. These results are not consistent with the hypothesis that Nf1 heterozygosity alone is sufficient to increase pain and itch sensation in mice, and they suggest that additional mechanisms may underlie reports of increased pain and itch in NF1 patients. PERSPECTIVE: This study assessed whether Nf1 heterozygosity in mice increased hypersensitivity and scratching following noxious and pruritic stimuli. Using Nf1± mice lacking tumors, this study finds no increases in pain or itch behavior, suggesting that there is no predisposition for either clinical symptom solely due to Nf1 heterozygosity.

Assessment of pain response in capsaicin-induced dynamic mechanical allodynia using a novel and fully automated brushing device.

BACKGROUND: Dynamic mechanical allodynia is traditionally induced by manual brushing of the skin. Brushing force and speed have been shown to influence the intensity of brush-evoked pain. There are still limited data available with respect to the optimal stroke number, length, force, angle and speed. Therefore, an automated brushing device (ABD) was developed, for which brushing angle and speed could be controlled to enable quantitative assessment of dynamic mechanical allodynia. OBJECTIVES: To compare the ABD with manual brushing using capsaicin-induced allodynia, and to investigate the role of stroke angle and speed on pain intensity. METHODS: Experimental dynamic mechanical allodynia was induced by an intradermal injection of capsaicin (100 µg) into the volar forearm of 12 healthy, male volunteers. Dynamic mechanical allodynia was rated on a 10 cm visual analogue scale (VAS) after each set of strokes at angles of 30°, 60° and 90° with speeds of 17 mm/s, 21 mm/s and 25 mm/s for each angle. A two-way ANOVA with repeated measures was performed to assess the influence of brushing parameters. To evaluate test-retest reliability, Bland-Altman 95% limits of agreement, including a coefficient of repeatability and an intraclass correlation coefficient (ICC), were determined. RESULTS: The angle and speed exhibited a significant impact on pain intensity (P<0.001 and P<0.015, respectively). Post hoc analysis showed that the highest pain intensity was recorded with an angle of 30° regardless of brushing speed. The ABD demonstrated superior test-retest reliability (coefficient of repeatability = 1.9 VAS; ICC=0.91) compared with manual brushing (coefficient of repeatability = 2.8 VAS; ICC=0.80; P<0.05). The most reliable combination of parameters (coefficient of repeatability = 1.3 VAS; ICC=0.97) was an angle of 60° and a speed of 21 mm/s. CONCLUSIONS: A controlled, automatic brushing method can be used for quantitative investigations of allodynic reactions, and is more reliable for quantitative assessment of dynamic mechanical allodynia compared with traditional manual brushing.

Assessment of the reproducibility of intradermal administration of capsaicin as a model for inducing human pain.

The reproducibility and tolerability of intradermal (i.d.) administration of capsaicin as a method for eliciting human pain was assessed in healthy male volunteers (n = 12). The primary endpoints for assessing pain were spontaneous pain response and areas of allodynia, pinprick hyperalgesia and neurogenic inflammation. These were recorded before, immediately after, and at regular intervals following each of four doses (250 microg) of capsaicin (two per trial day). Within- and between-subject variability to the technique was assessed by measuring the maximum recorded values (max), time to maximum value (t(max)) and area under the curve (AUC(0-1 h)) of each of the endpoints. Tolerability to the technique was addressed by recording adverse events. Reproducibility of the i.d. capsaicin model was demonstrated for each type of capsaicin-induced pain. Following each dose, the magnitude and profile of response and overall AUC values were similar for each parameter although some decrease in pinprick hyperalgesia was observed over time. For spontaneous pain, evidence of a period effect was observed in mean AUC data, with values increasing following the second dose of each trial day. This effect was confounded by the possibility of an arm effect, with the non-dominant arm appearing to be more sensitive to pain than the dominant arm. The data were not sufficient to confirm the existence of these effects. Between-subject variability and within-day, within-subject variability accounted for most of the variability observed in the trial. By optimising study design to eliminate these sources of variability, it was estimated that spontaneous pain and the area of allodynia would be the least variable endpoints. A positive correlation was found between the area of allodynia and area of pinprick hyperalgesia (r(2) = 0.835). Overall, the model was well tolerated with no reports of adverse events. We conclude that the tolerability profile, and variability of i.d. capsaicin-induced pain is acceptable for pharmacological profiling of novel anti-nociceptive agents, with limited number of subjects.

Evaluation of a quantitative clinical method for assessment of sensory skin irritation.

Sensory skin irritation refers to the myriad of symptomatic complaints (e.g., sting and burn) frequently associated with inflammatory skin conditions or skin intolerance to various chemicals or finished products. Sensory irritation is an important factor in consumer acceptance of the products that they buy and use; however, from a safety testing and risk assessment standpoint, it has been difficult to evaluate. Recently, methods have been developed to more quantitatively assess sensory irritation using a semantically-labeled scale of sensation intensity, the labeled magnitude (LM) scale. Using this device, studies were conducted to determine if test subjects' perceptions of recalled or imagined sensory responses (from a series of survey questions) were related to their actual sensory reactivity to chemical challenge. Subjects were presented with 15 skin sensation scenarios of varying intensities and asked to record their self-perceived recalled or imagined responses using the LM scale. Individual and mean responses to each of the 15 survey questions were compared within and across studies. Considerable variation was seen between subjects' responses to the questions, particularly for questions pertaining to stronger stimuli (e.g., scalding water or skin lacerations). There was also little consistency seen in the pattern of individual responses across the questions. However, among 4 different study populations, the group mean scores for each of the 15 survey questions showed a high degree of consistency. Also, in spite of the variability in perceived responses to the recalled/imagined skin sensations, statistically significant dose-response and time-response patterns were observed in chemical (lactic acid and capsaicin) challenge studies. In one capsaicin study, a direct relationship was observed, among 83% of the study subjects, between the mean recall intensity scores and actual responses to subsequent capsaicin challenge. This pattern was not seen in a lactic acid challenge study. However, a similar relationship was seen in this study if only recall stimuli related to sting-type responses were included in the analysis. Hence, use of recall/imagined skin sensation perception data for prediction of actual reactivity to chemical probes may have screening utility depending on the survey questions used. On the whole, the LM scale is of practical use for quantifying subjective sensory irritation responses. Combined with evolving noninvasive instrumental and bioassay procedures for identifying biophysical or inflammatory markers of sensory irritation, better methods are on the horizon for improving our sensory skin irritation testing and risk assessment capabilities.