Reinhard Sittl

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.

Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: A multicenter, randomized, double-blind, placebo-controlled trial

BACKGROUND Buprenorphine is a potent opioid analgesic that is available in sublingual and parenteral formulations. A new formulation, buprenorphine transdermal delivery system (TDS), has been developed. OBJECTIVE The aim of this study was to compare the analgesic efficacy and tolerability of the 3 available dosages of buprenorphine TDS (35.0, 52.5, and 70.0 microg/h) with placebo. METHODS This was a randomized, double-blind, placebo-controlled, multicenter study. Patients with chronic, severe pain related to cancer or other diseases and inadequately controlled with weak opioids were randomized to receive buprenorphine TDS 35.0, 52.5, or 70.0 microg/h or placebo patch for up to 15 days. A new patch was applied every 72 hours, for a total of 5 patches. All patients were permitted rescue analgesia with sublingual buprenorphine tablets (0.2 mg) as required for breakthrough pain. RESULTS A total of 157 patients (86 women, 71 men; mean [SD] age, 58.7 [11.8] years) were initially enrolled in the study. Buprenorphine TDS was associated with significantly higher response rates than was placebo at the 35.0- and 52.5-microg/h dosages (36.6% and 47.5%, respectively, vs 16.2%; P=0.032 and P=0.003, respectively) and a numerically higher response rate at 70.0 microg/h (33.3%), although this difference did not reach statistical significance. Patients treated with buprenorphine TDS experienced a 56.7% reduction in use of sublingual rescue analgesic during the study compared with an 8% reduction with the placebo patch. A total of 43.5% of patients treated with buprenorphine TDS reported good or complete pain relief compared with 32.4% in the placebo group. Pain intensity decreased in a dose-dependent manner with buprenorphine TDS, and the duration of sleep uninterrupted by pain was improved by the end of the study. More than three fourths (78.8%) of patients in the placebo and buprenorphine TDS groups reported at least 1 adverse event (AE) during the study. The most common AEs were central nervous system and gastrointestinal symptoms. The majority of treatment-related AEs were mild or moderate in intensity and were typical of those occurring at the beginning of therapy with a strong opioid. CONCLUSIONS Buprenorphine TDS was shown to be an effective analgesic against chronic, severe pain in this study population. Patients treated with this new formulation of buprenorphine showed improved duration of sleep and reduced need for additional oral analgesics.

Intraarticular Morphine Analgesia in Chronic Pain Patients with Osteoarthritis

Controlled clinical studies have shown that local administration of morphine can significantly relieve acute postoperative pain.This analgesic effect is long-lasting (up to 48 h) and is mediated by peripheral opioid receptors. Experimental evidence shows that analgesic effects of peripheral opioids and the density of opioid receptors on peripheral sensory nerves increase with the duration of painful inflammatory processes. This study examines the analgesic effects of 1 mg of morphine injected into the arthritic knee joints of two groups of chronic pain patients (n = 23) suffering from osteoarthritis. Using a randomized, double-blind cross-over design, patients received either an intraarticular injection of morphine and intravenous saline (Group A, n = 13) or an intraarticular injection of saline and intravenous morphine (Group B, n = 10) during Phase I. Seven days later, patients crossed over to the opposite treatment (Phase II). During Phase I, intraarticular morphine resulted in significantly greater pain relief than intraarticular saline, and this effect was present at rest as well as during movement. The analgesic effect was surprisingly long-lasting and extended into Phase II, a carry-over effect that prevented the analysis of Phase II. No side effects were reported. The treatment of arthritic pain by peripherally acting opioids may be a promising alternative to currently available medications that have serious side effects. (Anesth Analg 1997;84:1313-7)

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.

Transdermal buprenorphine in clinical practice--a post-marketing surveillance study in 13,179 patients.

ABSTRACT Objective: The objective of this post-marketing surveillance study was to collect effectiveness and safety data on the labelled use of buprenorphine transdermal patches (Transtec*) under routine clinical conditions. * Transtec is a registered trademark of Grünenthal GmbH, Aachen, Germany Research design and methods: For this open, observational study, patients with moderate to severe cancer or non-cancer pain requiring treatment with an opioid analgesic were recruited at hospitals, outpatient clinics and general practitioners’ practices in Germany. Buprenorphine transdermal patches (35 µg/h, 52.5 µg/h or 70 µg/h) were prescribed at physicians’ discretion in accordance with the products Summary of Product Characteristics (SmPC). Patients assessed their pain relief as ‘very good’, ‘good’, ‘satisfactory’, ‘poor’ or ‘no effect’. Investigators were instructed to report all adverse events throughout the observation period. On completion, effectiveness and tolerability were evaluated for the overall study population, cancer and non-cancer patients, and patients < 70 years and ≥ 70 years. Other analyses assessed pain relief with respect to previous opioid treatment and increased patch strength, and in patients who remained on their original dose. The total observation time was 9 months, and the average individual documented treatment time was 60.8 days. Results: A total of 13 179 patients were evaluated; 3690 (28%) with cancer pain and 9489 (72%) with non‐cancer pain. The most frequent diagnoses in non‐cancer patients were musculoskeletal disorders (77%) and neuropathy (23%). In the great majority of cases (78%), treatment was started with the 35 µg/h patch. The initial dose needed to be increased subsequently only in about 18% of subjects. Buprenorphine transdermal patches provided effective, sustained and dose-dependent analgesia in patients with cancer and non‐cancer pain, irrespective of the patients’ age or pain syndromes. Whereas good or very good pain relief was documented only for 6% of the patients with the initial assessment, this percentage increased to 71% at the first follow‐up and 80% at the final assessment. Fewer than 5% of subjects discontinued treatment owing to unsatisfactory pain relief. Altogether, adverse events were documented for 2874 patients (22%), whereas a relationship with transdermal buprenorphine (adverse drug reactions) was assumed for only 10% (2220 adverse drug reactions in 1330 patients). The tolerability profile was as expected for an opioid and did not vary to a relevant extent with either the patients age or the cause of pain (cancer or non‐cancer). No evidence emerged of any previously unknown side effects. Conclusions: Buprenorphine transdermal patches are well tolerated and effective in the treatment of chronic cancer and non‐cancer pain, irrespective of the patients’ age. There was no clinically relevant development of tolerance.

Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans

&NA; In contrast to an expected preventive analgesic effect, clinical observations suggest that intraoperatively applied opioids can induce postoperative hyperalgesia. We tested the development of post‐infusion hyperalgesia in a newly developed experimental model of electrically induced pain and secondary mechanical hyperalgesia. In a double‐blind, placebo controlled, cross‐over study, 13 subjects received either saline placebo, remifentanil (0.05 or 0.1 &mgr;g/kg/min) or naloxone (0.01 mg/kg). Remifentanil dose‐dependently reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level (p<0.01 and p<0.05, respectively). Naloxone infusion similarly resulted in increased pain (anti‐analgesia) (p<0.001) and mechanical hyperalgesia (p<0.01). Increased pain ratings following withdrawal of remifentanil significantly correlated to anti‐analgesia evoked by the &mgr;‐opioid antagonist naloxone (p<0.01) and was of similar magnitude, suggesting inhibition of endogenous opioids as an underlying mechanism. In contrast, hyperalgesia after remifentanil was more pronounced than hyperalgesia after naloxone administration and did not correlate to the observed anti‐analgesic effects, suggesting the involvement of additional receptors systems other than the endorphin system.