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Background Naloxone has a high affinity for the µ-opioid receptor and acts as a competitive antagonist, thus reversing the effects of opioids. Naloxone is often administrated intravenously, but there is a growing interest in the intranasal route in treating patients with opioid overdose, and in reversing effects after therapeutic use of opioids. As administration is painless and no intravenous access is needed, the intranasal route is especially useful in children. Aim The aim of this study was to investigate the uptake of naloxone 0.4 mg/ml during the first 20 min after administration as a nasal spray in a pediatric population, with special focus on the time to achieve maximum plasma concentration. Methods Twenty children, 6 months-10 years, were included in the study. The naloxone dose administered was 20 µg/kg, maximum 0.4 mg, divided into repeated doses of 0.1 ml in each nostril. Venous blood samples were collected at 5, 10, and 20 min after the end of administration. Results All patients had quantifiable concentrations of naloxone in venous blood at 5 min, and within 20 min, peak concentration had been reached in more than half of the children. At 20 min after intranasal administration, the plasma naloxone concentrations were within the range of 2-6 nanogram/ml. Conclusion This study confirms the clinical experience that the rapid effect of naloxone after intranasal administration in children was reflected in rapid systemic uptake to achieve higher peak plasma concentrations than previously reported in adults.

The objective of this randomized double blind cross-over trial was to determine if patients with severe cancer-related pain and inadequate response to systemic opioids prefer intrathecal (IT) pain relief with a combination of bupivacaine and morphine or bupivacaine only. Adult patients with cancer-related pain (n = 23) scheduled for IT analgesia at the Pain Center at the Karo-linska University Hospital Solna, Stockholm, Sweden, were included. The optimal individual flow rate of IT bupivacaine (2 mg/mL) in addition to bolus doses was titrated and maintained for 4 days. Morphine (1 mg/mL) was added to bupivacaine either on day 2 or 4 according to a randomization protocol. Expression of pain relief preference for morphine instead of control (bupivacaine only) was the primary outcome. Secondary outcomes were difference in pain intensity, pain relief, total use of bupivacaine per 24 hours and number of requested bolus doses. Eight patients dropped out during the 4-day study period for reasons not related to the trial. IT bupivacaine significantly decreased median (interquartile range) pain intensity from 5 (3 - 7) at baseline (before catheter insertion) to 1 (0 - 1) (p = 0.0001; Wilcoxon test). Only 1 patient of 15 with 4-day data expressed any preference for morphine. The addition of IT morphine did not result in any significant change of pain intensity, pain relief score, total use of bupivacaine per 24 hours, or number of requested bolus doses. Conclusion These results suggest that patients with cancer-related pain treated with high doses of systemic opioids, may start IT treatment with an optimal dose of IT bupivacaine without morphine. .

Background The use of opioids in non-cancer-related pain following skeletal trauma is controversial due to the presumed risk of dose escalation and dependence. We therefore examined the pattern of opioid prescriptions, that is, those actually dispensed, in patients with femoral shaft fractures. Methods We analysed data from the Swedish National Hospital Discharge Register and the Swedish Prescribed Drug Register between 2005 and 2008. Results We identified 1471 patients with isolated femoral shaft fractures. The median age was 75 (16–102) years and 56% were female. In this cohort, 891 patients (61%) received dispensed opioid prescriptions during a median follow-up of 20 months (interquartile range 11–32). In the age- and sex-matched comparison cohort (7339 individuals) without fracture, 25% had opioid prescriptions dispensed during the same period. The proportions of patients receiving opioid analgesics at 6 and 12 months after the fracture were 45% (95% CI 42–49) and 36% (32–39), respectively. The median daily morphine equivalent dose (MED) was between 15 and 17 mg 1–12 months post-fracture. After 3 months, less than 5% used prescription doses higher than 20 mg MED per day. Older age (≥ 70 compared with < 70 years) was a significant predictor of earlier discontinuation of opioid use (Hazard ratio [HR] 1.9). Conclusion A notable proportion of patients continued to receive dispensed prescriptions for opioids for over 6 months (45%) and more than a third of them (36%) continued treatment for at least 12 months. However, the risk of dose escalation seems to be small in opioid-naive patients.

Background Epidurals may be challenging in neonatal patients due to technical difficulties relating to insertion and the risk of local anaesthesia toxicity. The use of wound catheters with an infusion of local anaesthetic has been shown to be well tolerated in adults and older children. There are few data concerning wound catheter techniques in neonatal patients. Objectives The primary aim of this study was to analyse plasma levels of levobupivacaine associated with continuous wound infiltration via a catheter following neonatal surgical procedures. Secondary parameters, including the quality of postoperative analgesia and wound healing, were also noted. Design A prospective, observational study. Setting Paediatric ICU at the Karolinska University Hospital, Stockholm, Sweden, from March 2008 to December 2010. Patients Twenty newborn infants (median weight 3.48 kg) scheduled for major abdominal or thoracic surgery were included. Exclusion criteria were known or suspected hepatic dysfunction. Before skin closure, a subcutaneous catheter was inserted into the wound followed by a 0.5 mg kg(-1) bolus of levobupivacaine (0.125%, 0.4 ml kg(-1)) through the catheter. A continuous infusion was started 20 to 30 min later at a rate of 0.2 mg kg(-1)h(-1) (0.16 ml kg(-1) h(-1)). Main outcome measures Plasma concentrations of levobupivacaine (total and unbound) at 12, 24, 48 and 72 h postoperatively. Morphine consumption, pain scores and wound healing were also analysed. Results Median concentrations of unbound and total levobupivacaine at 72 h were 0.018 and 1.305 μg ml(-1), respectively. In 18 out of 20 infants [90%; 95% confidence interval (CI) 68.3 to 98.8], the unbound plasma concentration of levobupivacaine remained relatively stable and below 0.05 μg ml(-1) throughout the 72 h observation period. Pain scores and morphine consumption levels were low. All wounds except one healed within 10 days. Conclusion The studied infusion regimen was associated with plasma levels of levobupivacaine well below those associated with toxicity. Adequate wound healing, low pain scores and a reduced need for opioids were also noted.

Background Local infiltration analgesia (LIA) with local anaesthetic (ropivacaine), a nonsteroidal anti-inflammatory drug (ketorolac) and epinephrine after lower extremity arthroplasty has gained increasing popularity during the last decade. This method has certain advantages, which include minimal systemic side effects, faster post-operative mobilization, earlier post-operative discharge from hospital and less opioid consumption. However, information regarding plasma concentrations of ketorolac after LIA mixture is insufficient to predict the risk of renal impairment in patients subjected to arthroplasty. Aim To determine the maximal plasma concentration and the exposure of ketorolac during the first 30 h following LIA in hip arthroplasty. Methods Thirteen patients scheduled for primary total hip arthroplasty with LIA (ropivacaine 200 mg, ketorolac 30 mg and epinephrine 0.5 mg in a volume of 106 ml) were included. Plasma concentration of ketorolac was quantified by liquid chromatography-mass spectrometry. In addition, we assessed the effect of increasing age and decreasing glomerular filtration rate on the maximal plasma concentration and the total exposure to ketorolac during 30 h. Results The range of the maximal plasma concentration, 0.3–2.2 mg/l, was detected 30 min–4 h after completing the infiltration. Similar plasma levels have been reported after intramuscular injection of the same dose of ketorolac to healthy elderly volunteers. Conclusion Exposure to ketorolac after LIA may be comparable to an intramuscular injection of the same dose. Decision of dose reduction should be based on clinical assessment of risk factors.

Background Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. In an earlier study, we have examined the pharmacokinetic properties in children in different age groups but have not focused on neonates. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in neonates. Methods Fifteen full-term neonates (eight females) from 37 gestational weeks at birth and scheduled for elective surgery were included in the trial. Their median age was 3 days (range 1–18 days). Ketobemidone hydrochloride was administered as a single intravenous bolus dose, and ketobemidone concentrations were measured by liquid chromatography-mass spectrometry over 10 h. Pharmacokinetic parameters were calculated with standard compartmental methods. Results The median (range) values for ketobemidone clearance, apparent volume of distribution, volume of central compartment, distribution half-life and elimination half-life were 0.46 (0.23–0.84) l/h/kg, 4.64 (3.50–7.31) l/kg, 1.71 (0.16–3.47) l/kg, 2.85 (1.04–10.78) min and 7.26 (3.5–11.3) h. Conclusion Compared with our previous study in children older than 1 year of age, the elimination of ketobemidone appeared to be slower in full-term neonates. Despite a low pharmacokinetic variability of ketobemidone as observed in the present neonatal patient population, we recommend individualizing the dose of ketobemidone based on observations of analgesic efficacy.

IntroductionChronic pain and the pattern of opioid use after skeletal fractures has been a neglected topic in pain medicine. Pelvic and in particular acetabular fractures represent some of the most troublesome injuries for patients with a high incidence of chronic pain after fracture. We examined the long-term opioid analgesic use among patients with acetabular fractures and analysed if potential risk factors would predict a prolonged opioid therapy.Patients and methodsData were extracted from medical databases such as the Swedish National Hospital Discharge Register and the National Pharmacy Register. The study period was 2005–2008. Kaplan–Meier analysis constructed the cumulative opioid consumption with 95% confidence intervals (CI). Cox multiple-regression model was used to study risk factors for a prolonged opioid prescription after admission for fracture. An age- and sex-matched control group was included for comparisons.ResultsWe identified 1017 patients with isolated acetabular fractures. The proportion of dispensing opioids for these patients was 39%, which was 7 times higher than in the age- and sex-matched non-fracture controls (n=5077). The median follow-up time was 14 (interquartile range [IQR] 5–24) months. Most patients with opioid use after fracture were male (60%) and the median age was 76 (IQR 61–85) years. The leading mechanism of injury was fall on the same level (52%). At 6 and 12 months after fracture, 41% (95% CI 36–47) and 33% (28–39) were still treated with opioids. The multiple Cox regression-analysis (adjusted for age, sex, type of treatment, and mechanism of injury) revealed that younger patients (age

Numerous in vitro studies suggest that inflammation is associated with enhanced release of substance P (SP) in the dorsal horn. To test the hypothesis that inflammation increases the evoked concentration of SP in the intact animal, we used in vivo microdialysis with a highly sensitive radioimmunoassay to monitor SP-like immunoreactivity (SP-LI) in the dorsal horn. Seven days after the induction of persistent unilateral inflammation with hindpaw injection of complete Freund's adjuvant, perfusion of the microdialysis probe with 10 microM capsaicin (a concentration which failed to induce SP-LI release in rats without inflammation) induced a significant increase of microdialysate SP-LI. Inclusion of an NMDA antagonist in the perfusion fluid completely blocked this capsaicin-evoked SP release. Administration of a five-fold higher dose of capsaicin did not further increase SP release. These results in a rat model of chronic arthritis suggest that persistent inflammatory signaling facilitates capsaicin-evoked SP release in the dorsal horn in vivo.

In this study, we determined the plasma concentration of ropivacaine by liquid chromatography-mass spectrometry for 30 hours after local infiltration analgesia in 15 patients with elective hip arthroplasty. The 95% upper prediction bound of maximal unbound plasma concentration of ropivacaine was 0.032 mg/L. Side effects sufficient to stop an IV infusion have been reported at arterial concentrations of 0.34 to 0.85 mg/L. Alpha-1-acid glycoprotein did not correlate with the fraction of unbound ropivacaine during the first 24 hours after local infiltration analgesia. No signs or symptoms of systemic local anesthetic toxicity were observed. The Clopper-Pearson 95% upper confidence limit for adverse signs was 0.218.

The aim of the present in vivo microdialysis study was to determine the possible contribution of N -methyl- d -aspartate (NMDA) or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors to capsaicin-induced release of substance P-like immunoreactivity (SP-LI) in the dorsal horn of the rat. Perfusion of a microdialysis probe with capsaicin (50 or 100 μM) induced a significant eight-fold increase of the extracellular SP-LI level. The capsaicin (50 μM)-evoked release of SP-LI was blocked by spinal administration of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (D-APV; 5 mM), but not by the AMPA/KA antagonist 6-nitro-7-sulphamoylbenzo[ f ]quinoxaline-2,3-dione disodium (NBQX; 0.5 mM). In contrast, the SP-LI release induced by 100 μM capsaicin could not be prevented by D-APV (10 mM) or NBQX (0.5 mM). The data suggest that the spinal SP-LI release induced by a moderate concentration of capsaicin is in part dependent on the release of glutamate acting on NMDA receptors.

OBJECTIVE The aim of the present study is to monitor the extracellular gamma-aminobutyric acid (GABA) levels in the lumbar dorsal horn of allodynic rats, which respond to spinal cord stimulation (SCS) with a normalization of the tactile withdrawal threshold. In addition, we monitored the GABA levels in nonresponding and sham-stimulated rats. METHODS Partial constriction injury of the sciatic nerve was performed, and a permanent electrode for SCS was inserted into the spinal canal. The response to SCS was assessed with von Frey hairs in awake animals. Later, microdialysis was performed in the dorsal horn of the spinal cord under halothane anesthesia. The concentration of GABA in the microdialysate was assessed by high-performance liquid chromatography. RESULTS Extracellular GABA levels in rats with sciatic nerve lesions and allodynia (2.3 +/- 0.5 nmol/L) were significantly lower (P < 0.001) than in control rats with intact sciatic nerves (8.1 +/- 1.0 nmol/L), whereas only slightly decreased GABA levels (5.7 +/- 1.1 nmol/L) were detected in nonallodynic rats with sciatic nerve lesions. In the allodynic rats, which respond to SCS by a normalization of the tactile withdrawal threshold, significantly (P < 0.001) increased GABA levels (6.7 +/- 2.3 nmol/L) were detected after SCS. In contrast, neither the allodynic rats, which did not respond to SCS, nor the sham-stimulated allodynic rats displayed increased GABA levels in response to stimulation. CONCLUSION Our results indicate that the development of allodynia, a common symptom in neuropathic pain states, may be linked to a decreased spinal release of GABA. We suggest that an SCS-induced release of GABA could be important for the suppression of allodynia observed in rats after SCS. Similar mechanisms could also be involved in the SCS-induced alleviation of pain in patients with peripheral neuropathy.

The mechanism underlying the beneficial effect of electrical stimulation of the posterior surface of the spinal cord in chronic pain states are unknown. The prolonged pain relief following a short stimulation period is believed to imply the activation of long-lasting neurochemical processes, mainly in the spinal cord, but possibly also involving other parts of the central nervous system. Previous studies have demonstrated that substance P and serotonin are released in the cat dorsal horn during spinal cord stimulation (SCS) with electrical parameters similar to those used in the clinic. However, gamma-aminobutyric acid (GABA) has also been hypothesized to play a role in the effect of SCS, but there have been no studies of the possible effects of SCS on GABA release. The authors applied SCS to anesthetized rats and monitored the extracellular concentration of GABA in the lumbar dorsal horns by microdialysis and a sensitive reverse-phase high-performance liquid chromatography technique. After 30 minutes of SCS, the GABA level increased significantly (by almost 270%) in comparison with the basal level recorded before stimulation, from 3.6 +/- 1.0 nmol/L to 13.1 +/- 2.2 nmol/L (mean +/- the standard error of the mean; P < 0.05). The peak release was delayed and appeared in the 30-minute fraction collected after stimulation. Also, perfusion of the dialysis probes with potassium (100 mmol/L) induced an increase of the GABA level. In control experiments without electrical stimulation, slowly decreasing GABA levels were observed throughout the experiments. The present results may suggest an involvement of GABA in the mechanism of SCS-induced pain relief.(ABSTRACT TRUNCATED AT 250 WORDS)

Pain after total knee arthroplasty (TKA) is difficult to control. A recently developed and increasingly popular method for postoperative analgesia following knee and hip arthroplasty is Local Infiltration Analgesia (LIA) with ropivacaine, ketorolac and epinephrine. This method is considered to have certain advantages, which include administration at the site of traumatized tissue, minimal systemic side effects, faster postoperative mobilization, earlier postoperative discharge from hospital and less opioid consumption. One limitation, which may prevent the widespread use of LIA is the lack of information regarding plasma concentrations of ropivacaine and ketorolac. The aim of this academically initiated study was to detect any toxic or near-toxic plasma concentrations of ropivacaine and ketorolac following LIA after TKA. Methods Forty patients scheduled for primary total knee arthroplasty under spinal anaesthesia, were randomized to receive either local infiltration analgesia with a mixture of ropivacaine 300 mg, ketorolac 30mg and epinephrine or repeated femoral nerve block with ropivacaine in combination with three doses of 10mg intravenous ketorolac according to clinical routine. Plasma concentration of ropivacaine and ketorolac were quantified by liquid chromatography–mass spectrometry (LC–MS). Results The maximal detected ropivacaine plasma level in the LIA group was not statistically higher than in the femoral block group using the Mann–Whitney U-test (p = 0.08). However, the median concentration in the LIA group was significantly higher than in the femoral block group (p < 0.0001; Mann–Whitney U-test). The maximal plasma concentrations of ketorolac following administration of 30mg according to the LIA protocol were detected 1 h or 2 h after release of the tourniquet in the LIA group: 152–958 ng/ml (95% CI: 303–512 ng/ml; n = 20). The range of the plasma concentration of ketorolac 2–3 h after injection of a single dose of 10mg was 57–1216 ng/ml (95% CI: 162–420 ng/ml; n = 20). Conclusion During the first 24 h plasma concentration of ropivacaine seems to be lower after repeated femoral block than after LIA. Since the maximal ropivacaine level following LIA is detected around 4–6 h after release of the tourniquet, cardiac monitoring should cover this interval. Regarding ketorolac, our preliminary data indicate that the risk for concentration dependent side effects may be highest during the first hours after release of the tourniquet. Implication Femoral block may be the preferred method for postoperative analgesia in patients with increased risk for cardiac side effects from ropivacaine. Administration of a booster dose of ketorolac shortly after termination of the surgical procedure if LIA was used may result in an increased risk for toxicity.

Background: Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in children because these properties have not been reported previously. Methods: Thirty children, newborn to 10 years, scheduled for elective surgery were included in the trial. Ketobemidone hydrochloride was administered as a single intravenous bolus dose and ketobemidone and norketobemidone concentrations were measured by LC-MS over 8 h. Pharmacokinetic parameters were determined using compartmental methods. Results: Six children were excluded from pharmacokinetic analysis because of incomplete blood sampling. The values of ketobemidone clearance (l/h/kg) given as median (range) were 0.84 (0.29–3.0) in Group A (0–90 days), 0.89 (0.55–1.35) in Group B (1–2.5 years) and 0.74 (0.50–0.99) in Group C (7–10 years). The corresponding values for apparent volume of distribution (l/kg) were 4.4 (3.7–6.9) (Group A), 2.6 (2.0–5.6) (Group B) and 3.9 (2.7–5.0 (Group C), and for elimination half-life (h) 3.0 (1.4–8.9) (Group A), 2.0 (1.2–4.7) (Group B) and 3.7 (2.4–6.9) (Group C), respectively. In the two neonates the elimination half-life was almost 9 h. The metabolite norketobemidone did not reach levels above the limit of quantification (0.07 ng/ml) in any of the patients. Conclusion: The pharmacokinetic parameters of ketobemidone in children older than 1 month appear to be similar to those in adults. Because of the large interindividual variability of the pharmacokinetics in neonates, further studies especially in this age group are warranted.

Background: Tramadol is used as an analgesic in post-operative pain treatment. Intravenous tramadol is often combined with morphine to achieve better pain relief and less side-effects after orthopaedic surgery. However, the available evidence is insufficient to support this combination. For this reason, we conducted the present non-commercial, randomized, double-blind clinical trial. Method: Sixty-three patients with osteoarthritis of the knee, selected for primary total knee arthroplasty (TKA), were randomized to receive saline or tramadol 100 mg/ml intravenously every 6 h during the first post-operative day (total, 400 mg/24 h). All patients had access to morphine via a patient-controlled analgesia (PCA) pump. Results: Neither during the 6 h after the first dose nor during the first post-operative day could we detect any statistically significant difference with regard to pain intensity, sedation and nausea between patients treated with tramadol and the placebo group. However, the withdrawal rate caused by insufficient pain relief was greater in the tramadol group (7/31) than in the saline group (2/32). This difference did not reach statistical significance. In the group of patients who remained in the study for 24 h (‘per protocol’), those randomized to receive tramadol had a significantly (P < 0.05) lower morphine consumption (20 mg or 31%) than the placebo group. Conclusion: Our study does not support the combination of tramadol and morphine via PCA for post-operative pain relief after primary TKA. In addition, our study indicates that morphine via PCA as the sole means of post-operative analgesia does not provide sufficient pain relief after TKA. Thus, other means of post-operative analgesia should be used following TKA.

Opioid-induced hyperalgesia is characterized by hypersensitivity to innocuous or noxious stimuli during sustained opiate administration. Microinjection of lidocaine into the rostral ventromedial medulla (RVM), or dorsolateral funiculus (DLF) lesion, abolishes opioid-induced hyperalgesia, suggesting the importance of descending pain facilitation mechanisms. Here, we investigate the possibility that cholecystokinin (CCK), a pronociceptive peptide, may drive such descending facilitation from the RVM during continuous opioid administration. In opioid-naive rats, CCK in the RVM produced acute tactile and thermal hypersensitivity that was antagonized by the CCK2receptor antagonist L365,260 or by DLF lesion. CCK in the RVM also acutely displaced the spinal morphine antinociceptive dose-response curve to the right. Continuous systemic morphine elicited sustained tactile and thermal hypersensitivity within 3 d. Such hypersensitivity was reversed in a time-dependent manner by L365,260 in the RVM, and blockade of CCK2receptors in the RVM also blocked the rightward displacement of the spinal morphine antinociceptive dose-response curve. Microdialysis studies in rats receiving continuous morphine showed an approximately fivefold increase in the basal levels of CCK in the RVM when compared with controls. These data suggest that activation of CCK2receptors in the RVM promotes mechanical and thermal hypersensitivity and antinociceptive tolerance to morphine. Enhanced, endogenous CCK activity in the RVM during sustained morphine exposure may diminish spinal morphine antinociceptive potency by activating descending pain facilitatory mechanisms to exacerbate spinal nociceptive sensitivity. Prevention of opioid-dose escalation in chronic pain states by CCK receptor antagonism represents a potentially important strategy to limit unintended enhanced clinical pain and analgesic tolerance.

Stimulation of spinal serotonin (5-HT) 2A/2C receptors has previously been reported to lead to either a pro-nociceptive or an anti-nociceptive response. Behavioral data have indicated that the pro-nociceptive effect is related to the release of substance P (SP). The aim of this in vivo microdialysis study was to investigate if stimulation of spinal 5-HT 2A/2C receptors by the selective agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) induces spontaneous or capsaicin-evoked increase in the release of SP-like immunoreactivity (SP-LI) in the rat dorsal horn. A dose of capsaicin (25 μM in the perfusion medium administered for 30 min), which did not lead to a significant release of SP-LI on its own, induced a significant increase of greater than 4-fold of the SP-LI level following spinal application of 50 nmol DOI. Higher (500 nmol) or lower (5 nmol) doses of DOI failed to induce a similar effect. In rats with a peripheral inflammation, induced by carrageenan, capsaicin (25 μM) induced a non-significant increase of SP-LI. A significant 8-fold increase of the SP-LI level was detected following administration of 50 nmol DOI in combination with capsaicin. The effect of DOI, which was completely prevented by co-administration of the 5-HT 2A receptor antagonist ketanserin in control animals without peripheral inflammation, was only partly blocked in animals with carrageenan induced peripheral inflammation. In conclusion, stimulation of 5-HT 2A/2C receptors facilitates the capsaicin-evoked release of SP-LI in the dorsal horn in both animals with and without carrageenan-induced unilateral inflammation. The observation that the highest dose of DOI failed to induce SP-LI release may be due to an inhibitory postsynaptic action at this dose.

The anticonvulsant drug gabapentin has been demonstrated to alleviate symptoms of painful diabetic neuropathy as well as other types of neuropathic pain. The aim of the present study was to investigate the effect of gabapentin in a recently developed mouse model of peripheral neuropathy. This model is based on a photochemical ischemic lesion of the sciatic nerve generated by laser-induced activation of the photosensitizing dye erythrosin B. Following laser irradiation of the sciatic nerve for 2, 5, or 10 min, tactile allodynia was observed during at least 3 weeks. The degree of allodynia was most marked following 10 min of irradiation. Subcutaneous administration of gabapentin [175-300 micromol/kg ( approximately 30-51 mg/kg), cumulative doses, at 1-h intervals] significantly reversed tactile allodynia induced by 10-min laser irradiation. The maximal dose of gabapentin increased the withdrawal threshold from approximately 0.55 to approximately 1.85 g (i.e., about 77% of the threshold in normal animals, approximately 2.4 g). Gabapentin did not affect the tactile withdrawal threshold in intact animals. A dose of gabapentin (100 micromol/kg, sc) that had no effect on allodynia was found to significantly reduce the pain behavior during phase 2 of the formalin test. The present study demonstrates that systemic administration of gabapentin suppresses both allodynia induced by an ischemic lesion of the sciatic nerve and pain behavior in the formalin test.

Previous studies indicate that an increased release of cholecystokinin (CCK) in response to morphine administration may counteract opioid-induced analgesia at the spinal level. In the present study we used in vivo microdialysis to demonstrate that systemic administration of antinociceptive doses of morphine (1-5 mg/kg, s.c.) induces a dose-dependent and naloxone-reversible release of CCK-like immunoreactivity (CCK-LI) in the dorsal horn of the spinal cord. A similar response could also be observed following perfusion of the dialysis probe for 60 min with 100 microM but not with 1 microM morphine. The CCK-LI release induced by morphine (5 mg/kg, s.c.) was found to be calcium-dependent and tetrodotoxin-sensitive (1 microM in the perfusion medium). Topical application of either the L-type calcium channel blocker verapamil (50 microg) or the N-type calcium channel blocker omega-conotoxin GVIA (0.4 microg) onto the dorsal spinal cord completely prevented the CCK-LI release induced by morphine (5 mg/kg, s.c.). Our data indicate that activation of L- and N-type calcium channels is of importance for morphine-induced CCK release, even though the precise site of action of morphine in the dorsal horn remains unclear. The present findings also suggest a mechanism for the potentiation of opioid analgesia by L- and N-type calcium channel blocking agents.

Most of the previous experimental studies on the antinociceptive effects of electrical spinal cord stimulation (SCS) have focused on short-lasting effects mainly depending on spinal mechanisms. However, patients treated with SCS for chronic pain often report pain relief exceeding the period of stimulation for several hours. The long lasting effect of SCS might not only involve spinal, but also supraspinal mechanisms. A supraspinal region of major importance for the coordination of descending pain inhibition is the periaqueductal grey matter (PAG). The aim of the present microdialysis study, performed in awake freely moving rats, was to investigate if repeated SCS (two 30 min periods separated by a 90 min resting period) alters the extracellular neurotransmitter concentrations in the ventrolateral PAG. In a first series of experiments significantly decreased (−30%; P n = 7) γ-aminobutyric acid (GABA) levels were detected immediately after the second SCS session. Neither the concentration of serotonin nor that of substance P-like immunoreactivity (SP-LI) was affected by SCS. The decrease of GABA after two SCS sessions was confirmed in a second series of experiments (−30%; P n = 7). No spontaneous decline of GABA was observed in sham-stimulated animals ( n = 6). The glutamate concentration was also determined in this latter series of experiments and a significant decrease (−23%; P n = 5) was observed after the second SCS session. As GABA-neurons in the PAG exert a tonic depressive effect on the activity in descending pain inhibitory pathways, a decreased extracellular GABA level in this region, as detected following repeated SCS, might indicate an increased pain inhibition.

Electrical spinal cord stimulation (SCS) is an important method in the treatment of certain chronic pain syndromes which are difficult to manage with conventional techniques. The indications for this procedure have gradually narrowed to neuropathic pain states, especially those of peripheral origin, ischaemic pain due to peripheral vascular disease, and treatment-resistant angina pectoris. In spite of the clinical use of this method for more than 20 years, the mechanisms underlying the pain alleviating effect remain largely unknown.