Reference values for nerve conduction studies of the peroneal, tibial, and sural nerve derived from a large population-based cohort: Associations with demographic and anthropometric characteristics-The Maastricht study.

INTRODUCTION/AIMS: Nerve conduction studies (NCSs) are widely used to support the clinical diagnosis of neuromuscular disorders. The aims of this study were to obtain reference values for peroneal, tibial, and sural NCSs and to examine the associations with demographic and anthropometric factors. METHODS: In 5099 participants (aged 40-79 years) without type 2 diabetes of The Maastricht Study, NCSs of peroneal, tibial, and sural nerves were performed. Values for compound muscle action potential (CMAP) and sensory nerve action potential amplitude, nerve conduction velocity (NCV), and distal latency were acquired. The association of age, sex, body mass index (BMI), and height with NCS values was determined using uni- and multivariate linear regression analyses. RESULTS: Detailed reference values are reported per decade for men and women. Significantly lower NCVs and longer distal latencies were observed in all nerves in older and taller individuals as well as in men. In these groups, amplitudes of the tibial and sural nerves were significantly lower, whereas a lower peroneal nerve CMAP was only significantly associated with age. BMI showed a multidirectional association. After correction for anthropometric factors in the multivariate analysis, the association between sex and NCS values was less straightforward. DISCUSSION: These values from a population-based dataset could be used as a reference for generating normative values. Our findings show the association of NCS values with anthropometric factors. In clinical practice, these factors can be considered when interpreting NCS values.

Cardiovagal baroreflex sensitivity, blood pressure and blood pressure variability - the Maastricht study.

OBJECTIVE: Low baroreflex sensitivity (BRS) has been hypothesized to underlie high blood pressure (BP) and greater BP variability on the longer term, but evidence is scarce. In addition, these associations may differ by sex and (pre)diabetes. Therefore, we investigated whether cardiovagal BRS is associated with short- to mid-term mean BP and BP variability, and differs according to sex and (pre)diabetes. METHODS: Cross-sectional data from the population-based Maastricht study (age 60 ±â€Š8 years, 52% men), where office ( n  = 2846), 24-h ( n  = 2404) and 7-day BP measurements ( n  = 2006) were performed. Spontaneous BRS was assessed by cross-correlating systolic BP and instantaneous heart rate. We used linear regression with adjustments for age, sex, BP or BP variability, and cardiovascular risk factors. RESULTS: With regard to BP, 1-SD (standard deviation) lower BRS (-5.75 ms/mmHg) was associated with higher office, 24-h and 7-day systolic BP (2.22 mmHg [95% confidence interval [CI]: 1.59; 2.80], 0.95 mmHg [0.54; 1.36], and 1.48 mmHg [0.99; 1.97], respectively) and diastolic BP (1.31 mmHg [0.97; 1.66], 0.57 mmHg [0.30; 0.84], and 0.86 mmHg [0.54; 1.17], respectively). Per 1-SD lower BRS, these associations were stronger in women (0.5-1.5 mmHg higher compared to men), and weaker in those with type 2 diabetes (1-1.5 mmHg lower compared to normal glucose metabolism). With regard to BP variability, BRS was not consistently associated with lower BP variability. CONCLUSIONS: Lower cardiovagal BRS is associated with higher mean BP from the short- to mid-term range, and not consistently with BP variability. The associations with mean BP are stronger in women and weaker in those with type 2 diabetes.

Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: The Maastricht Study.

BACKGROUND: Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures. METHODS: In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders. RESULTS: Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation. CONCLUSIONS: Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.

Associations of cells from both innate and adaptive immunity with lower nerve conduction velocity: the Maastricht Study.

INTRODUCTION: Distal sensorimotor polyneuropathy (DSPN) is common in people with diabetes but is also found in pre-diabetes. Peripheral nerve myelin damage, which can be assessed by reduced nerve conduction velocity (NCV), is an essential feature of DSPN. Emerging evidence indicates that the development of DSPN may involve the activation of the immune system. However, available studies have mainly investigated circulating immune mediators, whereas the role of immune cells remains unclear. Therefore, we aimed to test whether leukocyte subsets are associated with NCV. RESEARCH DESIGN AND METHODS: This cross-sectional study analyzed data from 850 individuals (of whom 252 and 118 had type 2 diabetes and pre-diabetes, respectively) of the Maastricht Study. NCV was measured in the peroneal and tibial motor nerves and the sural sensory nerve and summed to calculate a standardized NCV sum score. Associations between percentages of leukocyte subsets and NCV sum scores were estimated using linear regression models adjusted for demographic, lifestyle, metabolic and clinical covariates. RESULTS: After adjustment for covariates, higher percentages of basophils and CD4+ T cells were associated with lower NCV (p=0.014 and p=0.005, respectively). The percentage of CD8+ T cells was positively associated with NCV (p=0.022). These associations were not modified by glucose metabolism status (all pinteraction >0.05). No associations were found for monocytes, eosinophils, neutrophils, lymphocytes, total T cells, Treg cells and B cells. CONCLUSIONS: The associations of basophils, CD4+ and CD8+ T cells with NCV suggest that cell types from both innate and adaptive immunity may be implicated in the development of DSPN.

Cardiometabolic risk factors as determinants of peripheral nerve function: the Maastricht Study.

AIMS/HYPOTHESIS: We aimed to examine associations of cardiometabolic risk factors, and (pre)diabetes, with (sensorimotor) peripheral nerve function. METHODS: In 2401 adults (aged 40-75 years) we previously determined fasting glucose, HbA1c, triacylglycerol, HDL- and LDL-cholesterol, inflammation, waist circumference, blood pressure, smoking, glucose metabolism status (by OGTT) and medication use. Using nerve conduction tests, we measured compound muscle action potential, sensory nerve action potential amplitudes and nerve conduction velocities (NCVs) of the peroneal, tibial and sural nerves. In addition, we measured vibration perception threshold (VPT) of the hallux and assessed neuropathic pain using the DN4 interview. We assessed cross-sectional associations of risk factors with nerve function (using linear regression) and neuropathic pain (using logistic regression). Associations were adjusted for potential confounders and for each other risk factor. Associations from linear regression were presented as standardised regression coefficients (ß) and 95% CIs in order to compare the magnitudes of observed associations between all risk factors and outcomes. RESULTS: Hyperglycaemia (fasting glucose or HbA1c) was associated with worse sensorimotor nerve function for all six outcome measures, with associations of strongest magnitude for motor peroneal and tibial NCV, ßfasting glucose = -0.17 SD (-0.21, -0.13) and ßfasting glucose = -0.18 SD (-0.23, -0.14), respectively. Hyperglycaemia was also associated with higher VPT and neuropathic pain. Larger waist circumference was associated with worse sural nerve function and higher VPT. Triacylglycerol, HDL- and LDL-cholesterol, and blood pressure were not associated with worse nerve function; however, antihypertensive medication usage (suggestive of history of exposure to hypertension) was associated with worse peroneal compound muscle action potential amplitude and NCV. Smoking was associated with worse nerve function, higher VPT and higher risk for neuropathic pain. Inflammation was associated with worse nerve function and higher VPT, but only in those with type 2 diabetes. Type 2 diabetes and, to a lesser extent, prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were associated with worse nerve function, higher VPT and neuropathic pain (p for trend <0.01 for all outcomes). CONCLUSIONS/INTERPRETATION: Hyperglycaemia (including the non-diabetic range) was most consistently associated with early-stage nerve damage. Nonetheless, larger waist circumference, inflammation, history of hypertension and smoking may also independently contribute to worse nerve function.

An improved qEEG index for asymmetry detection during the Wada test.

The Wada test is commonly used to evaluate language and memory lateralization in candidates for epilepsy surgery. The spatial Brain Symmetry Index (BSI) quantifies inter-hemispheric differences in the EEG. Its application has been shown to be feasible during Wada testing. We developed a method for the quantification of EEG asymmetry that matches visual assessments of the EEG better than BSI. Fifty-three patients' EEG data, with a total of 85 injections were analyzed. In a step-wise, data-driven manner, multiple electrode and frequency band combinations were evaluated. Eventually, BSI, calculated using only the frontal electrodes F3 and F4, was combined with a temporal measure of delta power in the central electrodes, C3 and C4, into a new measure: cBSI. Using the area under the ROC curve (AUC), we showed that cBSI performs significantly better relative to BSI (median AUC 0.98 versus 0.96, p=0.0015, Wilcoxon signed rank test). Our results showed that asymmetry detection was significantly improved by combining temporal with spatial qEEG measures. In the future, our combined qEEG measure could allow for a more objective way of monitoring EEG asymmetry, thereby increasing the feasibility of using EEG as a monitoring tool during the Wada test. Future studies should, however, validate our cBSI method in real time in the operating room or radiology suite.

Assessment of dynamic cerebral autoregulation and cerebral carbon dioxide reactivity during normothermic cardiopulmonary bypass.

Despite increased risk of neurological complications after cardiac surgery, monitoring of cerebral hemodynamics during cardiopulmonary bypass (CPB) is still not a common practice. Therefore, a technique to evaluate dynamic cerebral autoregulation and cerebral carbon dioxide reactivity (CO2R) during normothermic nonpulsatile CPB is presented. The technique uses continuous recording of invasive arterial blood pressure, middle cerebral artery blood flow velocity, absolute cerebral tissue oxygenation, in-line arterial carbon dioxide levels, and pump flow measurement in 37 adult male patients undergoing elective CPB. Cerebral autoregulation is estimated by transfer function analysis and the autoregulation index, based on the response to blood pressure variation induced by cyclic 6/min changes of indexed pump flow from 2.0 to 2.4 up to 2.8 L/min/m(2). CO2R was calculated from recordings of both cerebral blood flow velocity and cerebral tissue oxygenation. Cerebral autoregulation and CO2R were estimated at hypocapnia, normocapnia, and hypercapnia. CO2R was preserved during CPB, but significantly lower for hypocapnia compared with hypercapnia (p < 0.01). Conversely, cerebral autoregulation parameters such as gain, phase, and autoregulation index were significantly higher (p < 0.01) during hypocapnia compared with both normocapnia and hypercapnia. Assessing cerebral autoregulation and CO2R during CPB, by cyclic alteration of pump flow, showed an impaired cerebral autoregulation during hypercapnia.

Optimizing temperature threshold testing in small-fiber neuropathy.

INTRODUCTION: We examined optimization of a temperature threshold testing (TTT) protocol for patients with suspected small-fiber neuropathy (SFN) to lessen the burden for both patients and technicians, without sacrificing accuracy. METHODS: Data from 81 patients with SFN (skin biopsy and TTT abnormal) and 81 without SFN (skin biopsy and TTT normal) were used. Warm, cold, and heat pain sensation thresholds were determined bilaterally on the thenar eminence and foot dorsum by methods of limits and levels. Diagnostic accuracy was determined for various sensory modality combinations through comparative corresponding area under the receiver-operator characteristic curves. RESULTS: Assessment of warm and cold thresholds in all extremities by the method of levels showed the best discriminatory ability (area under the curve 0.95, sensitivity 84.2%, specificity 93.8%). CONCLUSIONS: These assessments are suggested for TTT examination in possible SFN patients. By applying this combination, the time needed for TTT can be reduced, maintaining diagnostic accuracy.

Contact heat evoked potentials: normal values and use in small-fiber neuropathy.

INTRODUCTION: Contact heat evoked potentials (CHEPs) may be an objective, non-invasive diagnostic tool in small-fiber neuropathy (SFN). This study establishes normal CHEP values and examines their applicability in SFN patients. METHODS: Standardized CHEPs were administered at the wrist and ankle. The N2 and P2 latencies and N2 -P2 peak-peak amplitude were recorded by electroencephalography. We examined healthy subjects (n = 97), stratified by age and gender, and SFN patients with abnormal intraepidermal nerve fiber density (n = 42). CHEP reproducibility and interobserver values were also investigated. RESULTS: CHEP normative values were determined. There was a 9-16% increase in latency per centimeter of height with increasing age. Amplitudes were higher in women than men, and decreased (17-71%) with aging. Test-retest reproducibility and interobserver values were >0.61 and >0.96, respectively. CHEPs were abnormal in 73.8% of the patients. CONCLUSION: In this study we have established normal values, reliability, and clinical applicability of CHEPs in SFN.

Increased contact heat evoked potential stimulation latencies in responders to spinal cord stimulation for painful diabetic polyneuropathy.

OBJECTIVES: To analyze sensory characteristics and small nerve fiber function in patients suffering from painful diabetic polyneuropathy (PDP) and compare outcomes in responders and nonresponders to SCS treatment. METHODS: Fifteen patients with intractable PDP in the legs were recruited. If trial stimulation resulted in clinically relevant pain relief, a pulse generator was implanted and pain scores were measured after 12 months. Sensory characteristics (modified Inflammatory Neuropathy Cause and Treatment [md-INCAT] sum score) and small nerve fiber function (contact heat evoked potentials, CHEPs) were measured before implantation (D1), and CHEP measurement was repeated after two weeks of trial stimulation (D2). Outcomes in responders (N = 10) and nonresponders (N = 5) to SCS treatment were compared. Data were analyzed using nonparametric statistics. RESULTS: At one year, clinically relevant pain relief was achieved in 10 out of 15 patients. The md-INCAT score did not differ between SCS responders and nonresponders (8.0 vs. 5.0; p = 0.59). No differences were found in CHEP outcomes at D1 vs. D2, except for dorsal forearm P2 latency, and the correlation between D1 and D2 CHEP outcomes was high. Volar N2 forearm latency (0.492 vs. 0.434; p < 0.01), dorsal forearm N2 latency (0.518 vs. 0.453; p = 0.04), and dorsal forearm P2 latency (0.660 vs. 0.589; p = 0.04) were increased in SCS responders as compared with SCS nonresponders. CONCLUSIONS: From this small-scale clinical pilot study we conclude that forearm CHEP latencies are increased in PDP patients who respond to SCS therapy as compared with SCS nonresponders. Before the CHEP latency can be used as a predictor of SCS outcome in PDP patients, a large-scale study is needed.

Visually evoked blood flow responses and interaction with dynamic cerebral autoregulation: correction for blood pressure variation.

Visually evoked flow responses recorded using transcranial Doppler ultrasonography are often quantified using a dynamic model of neurovascular coupling. The evoked flow response is seen as the model's response to a visual step input stimulus. However, the continuously active process of dynamic cerebral autoregulation (dCA) compensating cerebral blood flow for blood pressure fluctuations may induce changes of cerebral blood flow velocity (CBFV) as well. The effect of blood pressure variability on the flow response is evaluated by separately modeling the dCA-induced effects of beat-to-beat measured blood pressure related CBFV changes. Parameters of 71 subjects are estimated using an existing, well-known second order dynamic neurovascular coupling model proposed by Rosengarten et al., and a new model extending the existing model with a CBFV contributing component as the output of a dCA model driven by blood pressure as input. Both models were evaluated for mean and systolic CBFV responses. The model-to-data fit errors of mean and systolic blood pressure for the new model were significantly lower compared to the existing model: mean: 0.8%±0.6 vs. 2.4%±2.8, p<0.001; systolic: 1.5%±1.2 vs. 2.2%±2.6, p<0.001. The confidence bounds of all estimated neurovascular coupling model parameters were significantly (p<0.005) narrowed for the new model. In conclusion, blood pressure correction of visual evoked flow responses by including cerebral autoregulation in model fitting of averaged responses results in significantly lower fit errors and by that in more reliable model parameter estimation. Blood pressure correction is more effective when mean instead of systolic CBFV responses are used. Measurement and quantification of neurovascular coupling should include beat-to-beat blood pressure measurement.

Temperature threshold testing: a systematic review.

The diagnosis of small fiber neuropathy (SFN) has been recently defined as typical symptoms due to small nerve fiber dysfunction accompanied by reduced intra-epidermal nerve fiber density (IENFD) or abnormal temperature threshold testing (TTT). Guidelines have been published for the assessment of IENFD. However, international guidelines for TTT are lacking. This paper presents a systematic literature review on reported TTT methods and provides recommendations for its future use in studies evaluating patients. A total of 164 papers fulfilled pre-defined requirements and were selected for review. Over 15 types of instruments are currently being used with a variety of methodological approaches for location, stimulus application, and sensation qualities examined. Consensus is needed to standardize the use of TTT as a diagnostic and follow-up tool in patients.

Baroreflex function is reduced in Alzheimer's disease: a candidate biomarker?

The baroreflex (BR) reflects autonomic blood pressure control. Alzheimer's disease (AD) affects the autonomic system. Detailed properties of BR in AD are unknown. We hypothesized that BR is reduced in AD, and is influenced by autonomic effects of cholinesterase inhibitors (ChEI). BR was determined in 18 AD patients, 11 patients with mild cognitive impairment (MCI) and 19 healthy control subjects. In AD, BR was measured again after ChEI treatment. Receiver operating characteristic analysis was used to define a BR cutoff value, which was then tested in an independent validation sample of 16 AD, 18 MCI, and 18 control subjects. BR was lower in AD compared with MCI (p < 0.05) and in MCI compared with healthy control subjects (p < 0.01). Receiver operating characteristic analysis between AD and healthy control subjects yielded a sensitivity of 89% and a specificity of 94%. ChEI treatment increased BR with 66% (p < 0.01). BR was reduced in AD and increased after treatment with ChEI. BR might be a good biomarker to further explore the link between cardiovascular disease and AD.

Dynamic cerebral autoregulation in subjects with Alzheimer's disease, mild cognitive impairment, and controls: evidence for increased peripheral vascular resistance with possible predictive value.

Cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). We hypothesized that cerebral autoregulation is impaired in patients with AD compared to subjects with mild cognitive impairment (MCI) and controls. Dynamic cerebral autoregulation (dCA) was investigated in 17 AD patients, 19 MCI subjects, and 20 controls (C). Groups were matched for age, gender, and level of education. Electrocardiogram and non-invasive finger arterial blood pressure were measured and transcranial doppler ultrasonography was used to measure cerebral blood flow velocity in right and left middle cerebral artery (MCA). Cerebrovascular resistance index (CVRi) was also computed. dCA in supine position was quantified based on spontaneous blood pressure variations by computation of the linear transfer function between arterial blood pressure and MCA cerebral blood flow velocity. dCA gain and phase were evaluated for different frequency bands. Results were also evaluated using a 3-parameter windkessel model (WKM). CVRi was significantly higher in AD (2.9 ± 0.2) compared to both MCI (2.3 ± 0.1, p = 0.02) and C (2.1 ± 0.1 mmHgs/cm, p = 0.002). Five MCI patients who converted to AD during the course of the study also had higher CVRi compared to non-converters (2.8 ± 0.6 versus 2.1 ± 0.5 mmHgs/cm, p < 0.05). No significant differences in dCA gain and phase were found. In terms of the WKM approach, in the order C→MCI→AD groups showed about equal arterial resistance and peripheral compliance, but increased peripheral vasculature resistance (26 ± 2 versus 36 ± 3 mmHgs/ml in C resp. AD, p = 0.004). In conclusion, AD patients compared to MCI patients and controls have increased CVRi, whereas dCA parameters do not seem to differentiate AD patients. For MCI patients, CVRi might have predictive value in developing AD.

Dynamic cerebral autoregulation: different signal processing methods without influence on results and reproducibility.

Cerebral autoregulation controls cerebral blood flow under changing cerebral perfusion pressure. Standards for measurement and analysis of dynamic cerebral autoregulation (dCA) are lacking. In this study, dCA reproducibility, quantified by intraclass correlation coefficient, is evaluated for different methodological approaches of transfer function analysis (TFA) and compared with multimodal pressure flow analysis (MMPF). dCA parameters were determined in 19 healthy volunteers during three 15-min lasting epochs of spontaneous breathing. Every spontaneous breathing epoch was followed by 5 min of paced breathing at 6 cycles/min. These six measurements were performed in both a morning and an afternoon session. Analysis compared raw data pre-processing by mean subtraction versus smoothness priors detrending. The estimation of spectral density was either performed by averaging of subsequent time windows or by smoothing the spectrum of the whole recording. No significant influence of pre-processing and spectral estimation on dCA parameters was found. Therefore, there seems to be no need to prescribe a specific signal-processing regime. Poor reproducibility of gain and phase was found for TFA as well as for MMPF. Based on reproducibility, no preference can be made for morning versus afternoon measurements, neither for spontaneous versus paced breathing. Finally, reproducibility results are not in favour of TFA or MMPF.

Improvement of small fiber neuropathy in a sarcoidosis patient after treatment with infliximab.

We describe a patient with severe small fiber neuropathy (SFN) accompanied by autonomic involvement, who was experimentally treated with infliximab, an anti-tumour necrosis factor-alpha (TNF-alpha) therapy. Six months after this treatment was started his symptoms completely resolved. Until now they did not return. Repeated temperature threshold testing (TTT) as well as cardiovascular autonomic function test clearly improved after one year therapy. This case reveals two important issues. First, it shows that SFN seems not an irreversible disorder, even in severe cases. Second, TNF-alpha may be a crucial cytokine in the pathogenesis of SFN in sarcoidosis and eventually also in other immune mediated inflammatory diseases.

Association of small fiber neuropathy with cardiac sympathetic dysfunction in sarcoidosis.

BACKGROUND AND AIM: Recently we found that small fiber neuropathy (SFN) occurs frequently in sarcoidosis. Autonomic dysfunction may be a feature of SFN. Since cardiac autonomic dysfunction has been identified as a strong predictor of morbidity and mortality, recognition of cardiac autonomic involvement is of clinical relevance. It was hypothesised that SFN might be related to cardiac sympathetic denervation in sarcoidosis. METHODS: In the present study 45 consecutive sarcoidosis patients (13 without SFN assessed by thermal threshold testing (TTT), 32 with SFN (abnormal TTT) were enrolled. To rule out bias due to myocardial ischemia, cases with abnormal Thallium (201Tl) perfusion scintigraphy were excluded (n = 2). Cardiovascular autonomic function testing (Ewing tests) and 123I-MIBG (metaiodobenzylguanidine) scintigraphy were used to assess cardiac autonomic function. Further cardiac diagnostic work-up included ECG, Holter recording and echo Doppler cardiography. RESULTS: Mild to moderate heterogeneity of 123I-MIBG uptake regional in the myocardium was demonstrated in a substantial number of the studied sarcoidosis population, especially in those with SFN (abnormal TTT). Mean inferior-anterior ratios were 0.85+/-0.17 (SFN) and 1.0+/-0.17 (no SFN; p = 0.003), respectively. Four out of the 14 cases with abnormal MIBG scintigraphy and SFN showed an abnormal Ewing test. CONCLUSION: Cardiac sympathetic dysfunction assessed by use of 123I-MIBG myocardial scanning appeared to be heterogeneous in sarcoidosis patients and dependent on the presence or absence of SFN. MIBG scintigraphy may be of additional value in the management and follow-up of sarcoidosis patients. Future study is warranted to explore possible prognostic and therapeutic implications of these findings in sarcoidosis.

Expectations of analgesia do not affect spinal nociceptive R-III reflex activity: an experimental study into the mechanism of placebo-induced analgesia.

The purpose of this study was to investigate whether placebo analgesia is mediated by the release of beta-endorphin. In addition to subjective pain reports, we included an objective physiological parameter of nociception reflected by the opioid sensitive nociceptive R-III reflex. Placebo consisted of strong suggestions of pain relief and an intravenous injection of saline. Forty minutes after placebo, either the opioid antagonist naloxone or saline was administered intravenously without subjects noticing (hidden). Sixty healthy males, aged 18-30 years, voluntarily participated in this study. Subjects were randomized into one of four groups: group 1 received placebo and hidden naloxone, group 2 received hidden naloxone only, group 3 received placebo and hidden saline and group 4 received hidden saline only. Pain was induced by electrical stimulation of the sural nerve and evaluated with a visual analogue scale (VAS). In addition, changes in the magnitude of the nociceptive R-III reflex activity were assessed. We determined to what extent R-III reflex activity and subjective pain reports were decreased by placebo and we investigated whether these placebo-induced changes in reflex activity and subjective pain reports were naloxone reversible. Furthermore, we measured the degree of association between pain relief as measured on VAS and changes in R-III reflex activity. Finally, the role of beta-endorphin was assessed by measuring plasma endorphin levels before and after the administration of placebo. This study could not demonstrate a placebo effect as measured on VAS and R-III responses. The administration of placebo did not appear to have an effect on the release of beta-endorphins. Consistently, the antagonizing effects of naloxone were negligible. A subgroup analysis of those who did show a placebo response as indicated on the VAS did not support the supposition that beta-endorphin is released due to placebo suggestion. It is suggested that intensified stimuli and a more effective procedure to induce placebo analgesia (e.g. conditioning) may produce a proper placebo effect.