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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 2days 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 42days 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. [ABSTRACT FROM AUTHOR]

Objective: Pleural tubes after coronary artery bypass graft (CABG) surgery usually cause pain resulting interalia in an impact of postoperative breathing. Therefore, the influence of intrapleural lidocaine application through special double-lumen chest tubes with respect to pain relief and lung function was investigated and compared with placebo., Methods: In this study, 40 patients who underwent CABG got intrapleural injection either with 2% lidocaine ( n  = 20) or placebo (0.9% saline solution) ( n  = 20) on the first 2 days after surgery. Pain was measured by pain intensity numeric rating scale (NRS) (0 = no pain; 10 = the most intense pain) and lung function by portable spirometer., Results: On the first postoperative day (POD1), mean pain reduction was NRS 1.9 for the lidocaine group with an improvement of the forced expiratory volume in 1 second (FEV1) of 0.51 L. Similar results were shown on the second postoperative day (POD2) with a decreased pain level of mean NRS 1.65 and an FEV1 improvement of 0.26 L. In comparison, results of the placebo group showed no significant pain reduction, neither on the POD1 (NRS 0.35; p  = 0.429) nor on the POD2 (NRS 0.55; p  = 0.159). Also, there was no significant influence of FEV1 after placebo on the POD1 (FEV1 = 0.048 L; p  = 0.70) or on the POD2 (FEV1 = 0.0135 L; p  = 0.925)., Conclusion: Intrapleural application of lidocaine is a safe and feasible method to reduce drainage-related pain and improving lung function after CABG., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: After surgical procedures, anesthesia itself may affect pain perception. Particularly, there is increasing evidence that opioids not only have analgesic effects but also provoke pronociceptive changes, that is, opioid-induced hyperalgesia. We investigated the effect of different anesthetic regimens on pain processing in volunteers using a transdermal electrical pain model. In this model, stimulation of epidermal nerve fibers representing mainly peptidergic C-nociceptors leads to secondary hyperalgesia and habituation to the stimulus., Methods: Forty-eight healthy volunteers underwent conditioning noxious stimulation (CS) over 5 days. On day 2, the volunteers were randomized into 4 groups: control group (no anesthesia) and 3 groups receiving anesthesia before CS in anesthetic doses: propofol (P), propofol/remifentanil (PR), and propofol/remifentanil/S-ketamine (PRK). Quantitative sensory testing was performed on days 1 through 5 and on day 22., Results: In every group, CS was associated with short- and long-term habituation to the electrical stimulus. Repetitive CS resulted in unmodified short-term sensitization with stable areas of hyperalgesia. Although the PR group showed a trend toward increased areas of hyperalgesia on day 2, no significant differences were detectable between the groups. In contrast, anesthesia resulted in decreased intensity of the electrically evoked pain on day 2. Finally, the mechanical pain threshold before CS on day 5 was increased in all groups and remained elevated 3 weeks after the first CS, consistent with a long-term antinociceptive effect after CS., Conclusions: The results suggest a short-term analgesic effect of general anesthesia. Furthermore, the conditioning stimulation over several days induced differential modulation of pro- and antinociceptive systems., (© 2015 World Institute of Pain.)

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.

Patients with opioid pretreatment can be divided into different groups.While patients after successful drug addiction treatment with or without drug replacement therapy usually not require an extensive perioperative pain therapy, patients with persistent chronic pain and patients with an existing opioid addiction regularly are challenging for the anesthetist. Important pathophysiological issues among the patients include opioid tolerance, opioid-induced hyperalgesia (OIH) as well as acute withdrawal symptomes. Pharmakokinetic properties of the opioid seems to be crucial the manifestation of an acute withdrawal syndrome following opioid administration, and thus the use of remifentanil has frequently been reported to induce withdrawal symptoms. While all established anesthetic procedures can be applied, regional anesthetic techniques should be included whenever possible. A common misstake when treating patients with a history of opioid abuse is an unwarranted restraint in using opioids. In patients with a ongoing opioid abuse, it may be efficient to apply methadone or buprenorphine even prior to surgery. While pregabalin and gabapentin are first line therapeutics for treatment of neuropathic pain, they also seem to be effective co-analgesics in patients suffering from chronic pain and undergo surgery. A similar statement applies to clonidine and dexmedetomidine, which probably induce analgesia by activation of the descending antinociceptive noradrenergic system. The intraoperative administration of S-ketamine is recommended for patients who either already have developed opioid tolerance or suffer from neuropathic pain, and by which postoperative pain is high and was already shown to be poorly adjusted. Other therapeutic options such as intraoperative administration of magnesium or lidocaine may be promising approaches., (© Georg Thieme Verlag Stuttgart · New York.)

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., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: Propofol showed short-lasting analgesic properties during its administration, whereas the solvent-like formulation 10% Intralipid had no effect on pain perception.

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 gamma-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.

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 combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.

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 microg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.

Unlabelled: We investigated naloxone effects in a model of electrically induced pain and hyperalgesia. In a double-blind, placebo-controlled, cross-over study, 15 volunteers underwent four 150-minute sessions of high-current-density electrical stimulation of their forearms. After 60 minutes, naloxone or placebo was given intravenously (increasing plasma concentrations of 0.1, 1, and 10 ng/mL; 30 minutes each) in 3 of the 4 sessions. Pain ratings and areas of mechanical hyperalgesia were assessed at regular intervals during all sessions. The low doses of naloxone did not cause any significant change of pain rating of areas of hyperalgesia. In terms of intrasession effects, pain ratings and areas of hyperalgesia significantly decreased during the sessions to 62% (pain rating), 70% (area of punctuate hyperalgesia), and 82% (area of allodynia) of the initial values. Naloxone (10 ng/ml) reversed these decreases. In terms of between-session effects, the time course of pain ratings remained constant from session to session. In contrast, the areas of punctate hyperalgesia successively decreased to 60% of initial value at the fourth repetition. The session effect was not reversed by naloxone. High-current-density electrical stimulation provokes central sensitization, but in addition inhibitory systems are activated that are only partly naloxone-sensitive., Perspective: Endogenous inhibitory systems are of major importance for clinical pain conditions, but are not reflected in traditional human pain models. Here we show activation of a naloxone-sensitive short-term and a naloxone-insensitive long-term inhibitory system in a new model of electrically induced pain and hyperalgesia.