Propofol (Disoprivan, AstraZeneca AG, Zug, Switzerland) has long been considered to be nonanalgesic. However, accumulating evidence shows that propofol possesses modulatory action on pain processing ...and perception. In this study, the authors investigated the modulatory effects of propofol and a formulation similar to the solvent of propofol (10% Intralipid; Fresenius Kabi, Stans, Switzerland) on pain perception and central sensitization in healthy volunteers.
Fourteen healthy volunteers were included in this randomized, double-blind, placebo-controlled, crossover study. Intracutaneous electrical stimulation (48.8 +/- 25.8 mA) induced spontaneous acute pain (Numeric Rating Scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia were assessed regularly before, during, and after a 45-min target-controlled infusion (2 microg/ml) of propofol, the solvent 10% Intralipid, and saline.
During administration, propofol significantly decreased pain scores and areas of hyperalgesia and allodynia compared with both 10% Intralipid and saline (placebo-corrected mean Numerical Rating Scale score reduction by propofol: 38 +/- 28%). This difference disappeared shortly after cessation of the infusion. Thereafter, no significant group differences were observed in the Numerical Rating Scale score and the areas of hyperalgesia or allodynia. However, there was a trend to reduced hyperalgesia and allodynia after propofol treatment. Pharmacodynamic modeling regarding the analgesic effect of propofol showed an EC50 (half-maximum effect site concentration) of 3.19 +/- 0.37 microg/ml. Ten percent Intralipid was free of pain-modulatory effects in the authors' experiments.
Propofol showed short-lasting analgesic properties during its administration, whereas the solvent-like formulation 10% Intralipid had no effect on pain perception.
Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ‐opioid agonists, and ...the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full μ‐opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compound's favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for treating chronic cancer and noncancer pain.
Abstract Background Although opioids in general and remifentanil in particular have been shown to induce hyperalgesia, data regarding fentanyl are scarce. Thus, the authors investigated the effect of ...fentanyl dosing on pain perception and central sensitization in healthy volunteers using established pain models. Methods Twenty-one healthy, male volunteers were included in this randomized, double-blind, crossover study and received either intravenous low-dose (1 μg/kg) or high-dose (10 μg/kg) fentanyl. Pain intensities and hyperalgesia were assessed by intracutaneous electrical stimulation, and cold pressor pain was used as an additional measure of acute pain. The primary outcome was hyperalgesia from 4.5 to 6.5 h after fentanyl administration. Results A higher dose of fentanyl led to significantly decreased pain scores as measured by the numeric rating scale (0.83 units lower 95% CI, 0.63 to 1.02; P < 0.001) but increased areas of hyperalgesia (+30.5% 95% CI, 16.6 to 44.4%; P < 0.001) from 4.5 to 6.5 h after fentanyl administration. Allodynia did not differ between groups (+4.0% 95% CI, −15.4 to 23.5%; P = 0.682).The high dose also led to both increased cold pressor pain threshold (+43.0% 95% CI, 29.7 to 56.3%; P < 0.001) and tolerance (+32.5% 95% CI, 21.7 to 43.4%; P < 0.001) at 4.5 to 6.5h. In the high-dose group, 19 volunteers (90%) required reminders to breathe, 8 (38%) required supplemental oxygen, and 12 (57%) experienced nausea. Conclusions A higher dose of fentanyl increased hyperalgesia from 4.5 to 6.5 h in healthy volunteers while simultaneously decreasing pain scores.
BACKGROUND:Although opioids in general and remifentanil in particular have been shown to induce hyperalgesia, data regarding fentanyl are scarce. Thus, the authors investigated the effect of fentanyl ...dosing on pain perception and central sensitization in healthy volunteers using established pain models.
METHODS:Twenty-one healthy, male volunteers were included in this randomized, double-blind, crossover study and received either intravenous low-dose (1 μg/kg) or high-dose (10 μg/kg) fentanyl. Pain intensities and hyperalgesia were assessed by intracutaneous electrical stimulation, and cold pressor pain was used as an additional measure of acute pain. The primary outcome was hyperalgesia from 4.5 to 6.5 h after fentanyl administration.
RESULTS:A higher dose of fentanyl led to significantly decreased pain scores as measured by the numeric rating scale (0.83 units lower 95% CI, 0.63 to 1.02; P < 0.001) but increased areas of hyperalgesia (+30.5% 95% CI, 16.6 to 44.4%; P < 0.001) from 4.5 to 6.5 h after fentanyl administration. Allodynia did not differ between groups (+4.0% 95% CI, −15.4 to 23.5%; P = 0.682).The high dose also led to both increased cold pressor pain threshold (+43.0% 95% CI, 29.7 to 56.3%; P < 0.001) and tolerance (+32.5% 95% CI, 21.7 to 43.4%; P < 0.001) at 4.5 to 6.5h. In the high-dose group, 19 volunteers (90%) required reminders to breathe, 8 (38%) required supplemental oxygen, and 12 (57%) experienced nausea.
CONCLUSIONS:A higher dose of fentanyl increased hyperalgesia from 4.5 to 6.5 h in healthy volunteers while simultaneously decreasing pain scores.
Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain. Pathways that reduce synaptic inhibition in inflammatory and neuropathic pain states have been ...identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C-fiber) input to the spinal dorsal horn. We found that endocannabinoids, produced upon strong nociceptive stimulation, activated type 1 cannabinoid (CB₁) receptors on inhibitory dorsal horn neurons to reduce the synaptic release of γ-aminobutyric acid and glycine and thus rendered nociceptive neurons excitable by nonpainful stimuli. Our results suggest that spinal endocannabinoids and CB₁ receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain-controlling circuits.
Because the mechanism underlying the analgesic action of acetaminophen remains unclear, we investigated the possible interaction of acetaminophen with central serotonergic pathways. The effects of ...acetaminophen, tropisetron, the combination of both drugs, and saline on pain perception and central sensitization in healthy volunteers were compared. Sixteen healthy volunteers were included in this randomized, double-blind, placebo-controlled crossover study. Intracutaneous electrical stimulation (46.1
±
19.1
mA) induced acute pain (numeric rating scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia and allodynia were regularly assessed before, during, and after a 15-min infusion of acetaminophen, tropisetron, the combination of both drugs, and saline. Acetaminophen concentrations were measured to rule out any pharmacokinetic interaction. Both acetaminophen and tropisetron led to decreased pain ratings as compared to saline. However, when acetaminophen and tropisetron were administered simultaneously, the pain ratings were not affected. There was no significant difference in the evolution of the hyperalgesic and allodynic areas during the study period between the study groups (
P
=
.06 and
P
=
.33, respectively). Acetaminophen serum levels were not significantly different when associated with tropisetron (
P
=
.063), although we observed a trend toward lower acetaminophen concentrations when both drugs were concurrently administered. In summary, while the combination of acetaminophen and tropisetron showed no analgesic action, each drug administered alone led to decreased pain ratings as compared to saline.
In an electrically evoked human pain model, the combination of acetaminophen with tropisetron was free of any analgesic potential. However, when administered on its own, both acetaminophen and tropisetron were mildly analgesic.
Sodium channel blockers are known for reducing pain and hyperalgesia. In the present study we investigated changes in cerebral processing of secondary mechanical hyperalgesia induced by ...pharmacological modulation with systemic lidocaine. An experimental electrical pain model was used in combination with functional magnetic resonance imaging. After induction of pin-prick hyperalgesia lidocaine or placebo was administered systemically using a double-blinded design. A 2 x 2 factorial analysis was performed. The factors were (1) sensitization to pain (levels: pin-prick hyperalgesia and normal pin-prick pain) and (2) pharmacological modulation (levels: lidocaine and placebo). A main effect of (1) sensitization was found in bilateral secondary somatosensory cortex (S2), insula, anterior cingulate gyrus (ACC), medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (dlPFC), parietal association cortex (PA), thalamus and contralateral midbrain. A main effect of (2) pharmacological modulation was found in bilateral S2, insula, ACC, mPFC, dlPFC, PA, midbrain and contralateral primary motor cortex, and thalamus. Interaction of pharmacological modulation and sensitization to pin-prick pain with activity increase during hyperalgesia and placebo was found in mPFC, posterior cingulate gyrus and thalamus. However, only activity in mPFC was inversely correlated to area of hyperalgesia during placebo and antihyperalgesic treatment effect. Furthermore, the difference of mPFC activity during hyperalgesia and placebo versus hyperalgesia and lidocaine correlated inversely with the change of the weighted hyperalgesic area (as a factor of area and rated pain intensity). We conclude that activity in mPFC correlates inversely with individual extent of central hyperalgesia and predicts individual pharmacological antihyperalgesic treatment response.
The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with ...transdermal buprenorphine in chronic pain patients with end-stage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman
R
=
0.74;
P
<
0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 μg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.
OBJECTIVES:There is controversy about combining opioids with different receptor affinities. We assessed the analgesic and antihyperalgesic effects of the μ-agonist fentanyl and the partial ...μ-agonist/κ-antagonist buprenorphine in a human pain model, when given alone or in combination.
METHODS:Fifteen healthy male volunteers (22 to 35 y) were included in this randomized, double-blind, placebo-controlled, cross-over study. Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of secondary hyperalgesia. Pain intensities, measured on a numeric rating scale from 0 to 10, and the size of the hyperalgesic areas were assessed before, during, and after an intravenous infusion of 1.5 µg/kg fentanyl, 1.5 µg/kg buprenorphine, a combination of 0.75 µg/kg fentanyl and buprenorphine each, or saline 0.9%. Maximum effects of the treatments were compared by repeated measurement analysis of variance, and pharmacodynamic interaction models were fitted to the data.
RESULTS:Starting from a baseline value of numeric rating scale=6, the maximum reduction of pain intensity after correction for placebo effects was 43.9±22.2% after fentanyl, 35.0±23.0% after buprenorphine, and 39.4±20.8% after the combination (mean±SD, P=0.24). The maximum reduction of the hyperalgesic area was 38.3±39.0% for fentanyl, 34.4±32.7% for buprenorphine, and 30.0±53.8% for the combination (mean±SD, P=0.82). The time courses were best described by pharmacodynamic models assuming an additive interaction.
DISCUSSION:For the doses administered in this study, buprenorphine and fentanyl showed an additive interaction.
Abstract Topical application of lidocaine is an effective approach for treatment of post-herpetic neuralgia and other painful neuropathies. Lidocaine inhibits voltage-gated Na+ channels and it most ...likely reduces excitability of cutaneous sensory neurons which can be hyperexcitable or spontaneously active in states of neuropathic pain. However, lidocaine and other local anesthetics also exert a pronounced neurotoxicity and they activate the irritant receptors TRPV1 and TRPA1. In this randomized and double-blinded study, we explored the ability of lidocaine patches (5%) to alter sensory function and epidermal nerve fiber density in skin of healthy volunteers. As assessed by quantitative sensory testing, significantly elevated thresholds for touch, pin prick pain and mechanically induced wind-up were observed in skin treated with lidocaine patches. These effects reversed to baseline values within 2 days after termination of the treatment. Pressure pain and thresholds for heat and cold-induced pain were not affected by the lidocaine patch. A moderate but significant decrease in epidermal nerve fiber density was observed in skin blister roofs obtained after 42 days of treatment with lidocaine patches. The placebo patch did not induce any changes in sensory thresholds or nerve fiber density. In conclusion, lidocaine patches seem to have differential effects on sensory modalities in healthy skin. A degeneration of epidermal nerve fibers has previously been demonstrated for patches containing the TRPV1-agonist capsaicin and our findings suggest that this effect might also be relevant for lidocaine patches. These data warrant further studies on molecular mechanisms mediating a relief of neuropathic pain by topical lidocaine.
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