Wolfgang Koppert

Short-term infusion of the μ-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal

&NA; Numerous animal studies suggest that acute and chronic exposure to opioids can be associated with the development of hyperalgesia, i.e. an increased sensitivity to noxious stimuli. Hyperalgesia has been documented during withdrawal and on occasion while animals were still exposed to opioids. A pivotal role in the genesis of opioid‐associated hyperalgesia has been attributed to a pain facilitating system involving the N‐methyl‐d‐aspartate (NMDA)‐receptor. In humans little direct evidence documents opioid‐associated hyperalgesia, albeit observational data suggest that such hyperalgesia may be relevant in a clinical context. This study used a double blind, randomized, crossover and placebo‐controlled design to test in opioid‐naïve, healthy human volunteers whether hyperalgesia would develop within 30 min of stopping a 90‐min infusion with the &mgr;‐opioid agonist remifentanil, and whether co‐administration of the NMDA‐receptor antagonist S‐ketamine would prevent such hyperalgesia. We found that a skin area with pre‐existing mechanical hyperalgesia was significantly enlarged after stopping the remifentanil infusion. However, the pain response to heat assessed in regular skin was not different before and after the infusion of remifentanil. Co‐administration of the NMDA‐receptor antagonist S‐ketamine abolished observed enlargement of the hyperalgesic skin area. This study provides direct evidence in humans that short‐term administration of an opioid can enhance hyperalgesia as observed during withdrawal and points to a potential role of the NMDA‐receptor system in mediating such a hyperalgesic response. This study also points to a differential susceptibility of different pain modalities for the expression of hyperalgesia associated with opioid administration.

Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans.

Background Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the &mgr;-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the &agr;2-receptor agonist clonidine. Methods Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 ± 16.8 mA, mean ± SD) induced acute pain (numerical 11-point rating scale: 5–6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 &mgr;g · kg−1 · min−1 and S-ketamine at 5 &mgr;g · kg−1 · min−1 over a period of 30 min, respectively; clonidine infusion at 2 &mgr;g/kg for 5 min). Results Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings. Conclusions Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the &agr;2-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.

Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery

Sodium channel blockers are approved for IV administration in the treatment of neuropathic pain states. Preclinical studies have suggested antihyperalgesic effects on the peripheral and central nervous system. Our objective in this study was to determine the time course of the analgesic and antihyperalgesic mechanisms of perioperative lidocaine administration. Forty patients undergoing major abdominal surgery participated in this randomized and double-blinded study. Twenty patients received lidocaine 2% (bolus injection of 1.5 mg/kg in 10 min followed by an IV infusion of 1.5 mg · kg−1 · h−1), and 20 patients received saline placebo. The infusion started 30 min before skin incision and was stopped 1 h after the end of surgery. Lidocaine blood concentrations were measured. Postoperative pain ratings (numeric rating scale of 0–10) and morphine consumption (patient-controlled analgesia) were assessed up to 72 h after surgery. Mean lidocaine levels during surgery were 1.9 ± 0.7 &mgr;g/mL. Patient-controlled analgesia with morphine produced good postoperative analgesia (numeric rating scale at rest, ≤3; 90%–95%; no group differences). Patients who received lidocaine reported less pain during movement and needed less morphine during the first 72 h after surgery (103.1 ± 72.0 mg versus 159.0 ± 73.3 mg; Student’s t-test; P < 0.05). Because this opioid-sparing effect was most pronounced on the third postoperative day, IV lidocaine may have a true preventive analgesic activity, most likely by preventing the induction of central hyperalgesia in a clinically relevant manner.

A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S(+)-ketamine, and lidocaine.

Background The authors used the analgesics alfentanil, S (+)-ketamine, and systemic lidocaine to examine a new human model of experimental pain and hyperalgesia. Methods Transcutaneous electrical stimulation at a high current density (5 Hz, 67.5 ± 6.6 mA) was used to provoke acute pain (numeric rating scale, 5 of 10), stable areas of secondary mechanical hyperalgesia to pin prick (43.6 ± 32.1 cm2), and light touch (27.5 ± 16.2 cm2) for 2 h. Alfentanil, S (+)-ketamine, and lidocaine were applied for 20 min in a double-blind, placebo-controlled, crossover design in 12 subjects using target controlled infusions. Results In the placebo session, pain ratings and areas of hyperalgesia were stable during the stimulation period, which facilitated the assessment of analgesic effects. Alfentanil effectively inhibited electrically evoked pain and reduced pin prick hyperalgesia and allodynia during its infusion. S (+)-ketamine–induced inhibition of secondary hyperalgesia was more pronounced and lasted for the whole experimental protocol. Therapeutic levels of systemic lidocaine showed only marginal analgesic effects, but lasting antihyperalgesic effects. Conclusions A new model of electrically induced pain and hyperalgesia was established, which enabled assessment of the time course of analgesic and antihyperalgesic effects with high temporal resolution and minimum tissue damage and which was further validated by use of common intravenous anesthetics.

Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model

&NA; Different mechanisms were proposed for opioid‐induced analgesia and antihyperalgesia, which might result in different pharmacodynamics. To address this issue, the time course of analgesic and antihyperalgesic effects of intravenous (i.v.) and sublingual (s.l.) buprenorphine was assessed in an experimental human pain model. Fifteen volunteers were enrolled in this randomized, double‐blind, and placebo controlled cross‐over study. The magnitude of pain and the area of secondary hyperalgesia following transcutaneous stimulation were repetitively assessed before and up to 150 min after administration of (1) 0.15 mg buprenorphine i.v. and placebo pill s.l., (2) 0.2 mg buprenorphine s.l. and saline 0.9% i.v. or (3) saline 0.9% i.v. and placebo pill s.l. as a control. The sessions were separated by 2 week wash‐out periods. For both applications of buprenorphine the antihyperalgesic effects were more pronounced as compared to the analgesic effects (66±9 vs. 26±5% and 43±10 vs. 10±6%, for i.v. and s.l. application, respectively). This contrasts the pattern for the intravenous administration of pure μ‐receptor agonists in the same model in which the antihyperalgesic effects are weaker. The apparent bioavailability of buprenorphine s.l. as compared to buprenorphine i.v. was 58% with a 15.8 min later onset of antinociceptive effects. The half‐life of buprenorphine‐induced analgesic and antihyperalgesic effects were 171 and 288 min, respectively. In contrast to pure μ‐receptor agonists, buprenorphine exerts a lasting antihyperalgesic effect in our model. It will be of major clinical interest whether this difference will translate into improved treatment of pain states dominated by central sensitization.

Low-dose lidocaine reduces secondary hyperalgesia by a central mode of action

Abstract Sodium channel blockers are approved for intravenous administration in the treatment of neuropathic pain states. Preclinical studies have suggested antihyperalgesic effects on the peripheral as well as the central nervous system. The objective of this study was to determine mechanisms of action of low‐dose lidocaine in experimental induced, secondary hyperalgesia. In a first experimental trial, participants (n=12) received lidocaine systemically (a bolus injection of 2 mg/kg in 10 min followed by an intravenous infusion of 2 mg kg−1 h−1 for another 50 min). In a second trial, a modified intravenous regional anesthesia (IVRA) was administered to exclude possible central analgesic effects. In one arm, patients received an infusion of 40 ml lidocaine, 0.05%; in the other arm 40 ml NaCl, 0.9%, served as a control. In both trials capsaicin, 20 &mgr;g, was injected intradermally and time course of capsaicin‐induced pain, allodynia and hyperalgesia as well as axon reflex flare was determined. The capsaicin‐induced pain was slightly reduced after systemic and regional application of the anesthetic. The area of pin‐prick hyperalgesia was significantly reduced by systemic lidocaine, whereas the inhibition of hyperalgesia was absent during regional administration of lidocaine. In contrast, capsaicin‐induced flare was significantly decreased after both treatments. We conclude that systemic lidocaine reduces pin‐prick hyperalgesia by a central mode of action, which could involve blockade of terminal branches of nociceptors. A possible role for tetrodotoxin resistant sodium channels in the antihyperalgesic effect of low‐dose lidocaine is discussed.

Spinal Endocannabinoids and CB1 Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization

Plastic Pain Perception Drugs and endocannabinoids acting on cannabinoid (CB) receptors have potential in the treatment of certain types of pain. In the spinal cord they are believed to suppress nociception, the perception of pain and noxious stimuli. Pernia-Andrade et al. (p. 760) now find that endocannabinoids, which are released in spinal cord by noxious stimulation, may promote rather than inhibit nociception by acting on CB1 receptors. Endocannabinoids not only depress transmission at excitatory synapses in the spinal cord, but also block the release of inhibitory neurotransmitters, thereby facilitating nociception. Noxious stimulation releases endocannabinoids in the spinal cord that may promote, rather than inhibit, the perception of pain. 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.

Evidence and consensus-based German guidelines for the management of analgesia, sedation and delirium in intensive care--short version.

Targeted monitoring of analgesia, sedation and delirium, as well as their appropriate management in critically ill patients is a standard of care in intensive care medicine. With the undisputed advantages of goal-oriented therapy established, there was a need to develop our own guidelines on analgesia and sedation in intensive care in Germany and these were published as 2nd Generation Guidelines in 2005. Through the dissemination of these guidelines in 2006, use of monitoring was shown to have improved from 8 to 51% and the use of protocol-based approaches increased to 46% (from 21%). Between 2006–2009, the existing guidelines from the DGAI (Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin) and DIVI (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin) were developed into 3rd Generation Guidelines for the securing and optimization of quality of analgesia, sedation and delirium management in the intensive care unit (ICU). In collaboration with another 10 professional societies, the literature has been reviewed using the criteria of the Oxford Center of Evidence Based Medicine. Using data from 671 reference works, text, diagrams and recommendations were drawn up. In the recommendations, Grade “A” (very strong recommendation), Grade “B” (strong recommendation) and Grade “0” (open recommendation) were agreed. As a result of this process we now have an interdisciplinary and consensus-based set of 3rd Generation Guidelines that take into account all critically illness patient populations. The use of protocols for analgesia, sedation and treatment of delirium are repeatedly demonstrated. These guidelines offer treatment recommendations for the ICU team. The implementation of scores and protocols into routine ICU practice is necessary for their success.

The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in humans.

&NA; Non‐steroidal antiinflammatory drugs (NSAIDs) are known to induce analgesia mainly via inhibition of cyclooxygenase (COX). Although the inhibition of COX in the periphery is commonly accepted as the primary mechanism, experimental and clinical data suggest a potential role for spinal COX‐inhibition to produce antinociception and reduce hypersensitivity. We used an experimental model of electrically evoked pain and hyperalgesia in human skin to determine the time course of central analgesic and antihyperalgesic effects of intravenous parecoxib and paracetamol (acetaminophen). Fourteen subjects were enrolled in this randomized, double blind, and placebo controlled cross‐over study. In three sessions, separated by 2‐week wash‐out periods, the subjects received intravenous infusions of 40 mg parecoxib, 1000 mg paracetamol, or placebo. The magnitude of pain and areas of pinprick‐hyperalgesia and touch evoked allodynia were repeatedly assessed before, and for 150 min after the infusion. While pain ratings were not affected, parecoxib as well as paracetamol significantly reduced the areas of secondary hyperalgesia to pinprick and touch. In conclusion, our results provide clear experimental evidence for the existence of central antihyperalgesia induced by intravenous infusion of two COX inhibitors, parecoxib and paracetamol. Since the electrical current directly stimulated the axons, peripheral effects of the COX inhibitors on nociceptive nerve endings cannot account for the reduction of hyperalgesia. Thus, besides its well‐known effects on inflamed peripheral tissues, inhibition of central COX provides an important mechanism of NSAID‐mediated antihyperalgesia in humans.

Opioid-induced Mast Cell Activation and Vascular Responses Is Not Mediated by μ-opioid Receptors: An in Vivo Microdialysis Study in Human Skin

Activation of mast cells and the systemic release of histamine is a common side effect of opioids. Nevertheless, fentanyl and its derivatives show only a slight activation of mast cells with a subsequent liberation of histamine and tryptase. In this study, we used intradermal microdialysis to assess whether this stimulatory effect of opioids on mast cells depends on the activation of opioid receptors. This new approach allowed us to measure the dose-dependent release of histamine and tryptase from mast cells and the subsequent vascular and sensory effect without systemic side effects in volunteers. The opiate codeine and the synthetic opioids meperidine, fentanyl, alfentanil, sufentanil, remifentanil, buprenorphine, and the opioid antagonist naloxone were tested. Only codeine and meperidine induced mast cell activation with the release of tryptase and histamine, leading to protein extravasation, flare reactions, and itch sensations. Because naloxone did not attenuate these effects, it is unlikely that &mgr;-opioid receptors are involved in the activation of mast cells.