J. Filitz

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.

Supra-additive effects of tramadol and acetaminophen in a human pain model.

&NA; 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 37.5 mg 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.

Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine.

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.

Medial Prefrontal Cortex Activity Is Predictive for Hyperalgesia and Pharmacological Antihyperalgesia

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 × 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.

Interaction of fentanyl and buprenorphine in an experimental model of pain and central sensitization in human volunteers.

Objectives:There is controversy about combining opioids with different receptor affinities. We assessed the analgesic and antihyperalgesic effects of the &mgr;-agonist fentanyl and the partial &mgr;-agonist/&kgr;-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.

Analgesic andantihyperalgesic properties of single doses of oral morphine in a human pain model: 14AP6–9

Background and Goal of Study: Current discussions on opioids focus on dose adjustment as well as on a reasonable choice of analgesics meeting the therapeutic requirements of different pain states. The distinct property of reducing symptoms of sensitisation contributes to the choice of pharmacological treatment. This study examined the analgesic and antihyperalgesic properties of three different doses of oral morphine with major attention to the antihyperalgesic potency of morphine in general and the efficiency of dose escalation. Materials and Methods: After approval of the local ethics committee, 20 healthy male volunteers (age: 38.6 ± 1.6 ys) undergoing 4 sessions in a randomized cross-over design were enrolled in this double-blind and placebo-controlled study. Transcutaneous electrical stimulation induced spontaneous acute pain (NRS = 6 of 10) and stable areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the areas of hyperalgesia were determined over 180 min at regular intervals before and after a single oral dose of either morphine (15 mg, 30 mg or 60 mg) or placebo. The effect was assessed as percentage reduction compared to baseline. Statistical analysis (RM-ANOVA, Tukey test) was performed on the maximum and on the integral (AUC) of the effect. Results and Discussion: For pain rating, the maximum effects as well as the AUCs were significantly larger for each morphine dose as compared to placebo, whereas there were no significant differences between the three morphine doses (table 1). For the hyperalgesic areas, there was no significant impact of any oral dose of morphine compared to placebo, neither for the maximum effect nor for the AUC of the effect (table 1).

652 SUPRA-ADDITIVE EFFECTS OF TRAMADOL AND ACETAMINOPHEN IN A HUMAN PAIN MODEL

Background and Goal of Study: Combination of analgesic drugs with different pharmacological properties 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 (paracetamol) alone and in combination in an experimental pain model in humans. Materials and Methods: After approval of the local ethics committee, 20 healthy volunteers were enrolled in this double-blind and placebocontrolled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6±16.2mA) induced spontaneous acute pain (NRS= 6 of 10) and stable 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 10 minutes lasting intravenous infusion of acetaminophen (650mg), tramadol (75mg), a combination of both (325mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Results and Discussions: Tramadol led to a maximum pain reduction of 12% with no antihyperalgesic properties. In contrast, acetaminophen led to a weaker pain reduction (8%), but sustained antihyperalgesic effects. The combination of both analgesics at half doses led to a supraadditive pain reduction of 14% (Fig., Isobole for 14% pain reduction) and enhanced antihyperalgesic effects as compared to single administration of acetaminophen. Conclusions: Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. The results might act as a rationale for combining both analgesics.