Perioperative intravenous low-dose ketamine for neuropathic pain after major lower back surgery: A randomized, placebo-controlled study.

BACKGROUND: Chronic pain after major lower back surgery is frequent. We investigated in adults the effect of perioperative low-dose ketamine on neuropathic lower back pain, assessed by the DN4 questionnaire, 6 and 12 months after major lower back surgery. METHODS: In this single-centre randomized trial, 80 patients received intravenous ketamine 0.25 mg/kg preoperatively, followed by 0.25 mg kg-1  hr-1 intraoperatively, and 0.1 mg kg-1  hr-1 from 1 hr before the end of surgery until the end of recovery room stay; 80 controls received placebo. RESULTS: Preoperatively, 47.4% of patients in the ketamine group and 46.3% in the placebo group had neuropathic pain; 10% and 3.8%, respectively, were using strong opioids. At the end of the infusion, the median cumulative dose of ketamine was 84.8 mg (IQR 67.4-106.7) and the median plasma level was 97 ng/ml (IQR 77.9-128.0). At 6 months, 28.8% of patients in the ketamine group and 23.5% in the placebo group had neuropathic pain (absolute difference, 5.2%; 95% CI -10.7 to 21.1; p = .607). At 12 months, 26.4% of patients in the ketamine group and 17.9% in the placebo group had neuropathic pain (absolute difference 8.5%; 95% CI -6.7 to 23.6; p = .319). CONCLUSIONS: In this patient population with a high prevalence of neuropathic lower back pain undergoing major lower back surgery, a perioperative intravenous low-dose ketamine infusion did not have an effect on the prevalence of neuropathic lower back pain at 6 or 12 months postoperatively. SIGNIFICANCE: We were unable to show any analgesic benefit of a short-term perioperative ketamine infusion as an adjuvant to multimodal analgesia in patients with a high prevalence of neuropathic lower back pain undergoing major back surgery. Based on these data, the widespread opinion that ketamine is universally analgesic across different pain conditions must be challenged. PRIOR PRESENTATIONS: Abstract presentation at the annual congress of the Swiss Society of Anaesthesiology, 2016, Basel, Switzerland. CLINICAL TRIAL NUMBER AND REGISTRY URL: Registered by Dr Christoph Czarnetzki as principal investigator on February 20, 2008 at clinicaltrials.gov (NCT00618423).

Using venlafaxine to treat behavioral disorders in patients with autism spectrum disorder.

OBJECTIVE: To test the efficacy of venlafaxine at a dose of 18.75 mg/day on the reduction of behavioral problems such as irritability and hyperactivity/noncompliance in patients with intellectual disabilities and autism spectrum disorder (ASD). Our secondary hypothesis was that the usual doses of zuclopenthixol and/or clonazepam would decrease in the venlafaxine-treated group. METHODS: In a randomized double-blind study, we compared six patients who received venlafaxine along with their usual treatment (zuclopenthixol and/or clonazepam) with seven patients who received placebo plus usual care. Irritability, hyperactivity/noncompliance, and overall clinical improvement were measured after 2 and 8 weeks, using validated clinical scales. RESULTS: Univariate analyses showed that the symptom of irritability improved in the entire sample (p = 0.023 after 2 weeks, p = 0.061 at study endpoint), although no difference was observed between the venlafaxine and placebo groups. No significant decrease in hyperactivity/noncompliance was observed during the study. At the end of the study, global improvement was observed in 33% of participants treated with venlafaxine and in 71% of participants in the placebo group (p = 0.29). The study found that decreased cumulative doses of clonazepam and zuclopenthixol were required for the venlafaxine group. Multivariate analyses (principal component analyses) with at least three combinations of variables showed that the two populations could be clearly separated (p b 0.05). Moreover, in all cases, the venlafaxine population had lower values for the Aberrant Behavior Checklist (ABC), Behavior Problems Inventory (BPI), and levels of urea with respect to the placebo group. In one case, a reduction in the dosage of clonazepam was also suggested. For an additional set of variables (ABC factor 2, BPI frequency of aggressive behaviors, hematic ammonia at Day 28, and zuclopenthixol and clonazepam intake), the separation between the two samples was statistically significant as was the Bartlett's test, but the Kaiser­Meyer­Olkin Measure of Sampling Adequacy was below the accepted threshold. This set of variables showed a reduction in the cumulative intake of both zuclopenthixol and clonazepam. CONCLUSION: Despite the small sample sizes, this study documented a statistically significant effect of venlafaxine. Moreover, we showed that lower doses of zuclopenthixol and clonazepam were needed in the venlafaxine group, although this difference was not statistically significant. This was confirmed by multivariate analyses, where this difference reached statistical significance when using a combination of variables involving zuclopenthixol. Larger-scale studies are recommended to better investigate the effectiveness of venlafaxine treatment in patients with intellectual disabilities and ASD.

Central pain sensitization, COMT Val158Met polymorphism, and emotional factors in fibromyalgia.

UNLABELLED: Neurobiological evidence points to altered central nervous system processing of nociceptive stimuli in fibromyalgia. Enzymes like catechol-O-methyl-transferase (COMT) are involved in the elimination of catecholamines playing a possible role in central sensitization and pain. We used quantitative sensory testing to evidence central sensitization in fibromyalgia patients and test whether COMTVal158Met polymorphism, associated with a reduction in enzyme activity, plays a role in sensitized patients. Pain evaluation and quantitative sensory testing were performed including the spinal nociceptive flexion reflex, a physiologic correlate for the evaluation of central nociceptive pathways. Quality of life and distress questionnaires were used. A total of 137 fibromyalgia patients were assessed and compared to 99 matched controls. Central sensitization (nociceptive flexion reflex <27 mA) was present in 95/134 (71%) patients. Among them, COMT p.Val158Met polymorphism displayed a significant linear "genotype effect" (P = .033), with the Met/Met (mean = 17.8 ± 4.8 mA) and Val/Val (mean = 21.4 ± 4.6 mA) subgroups at the opposite ends of the nociceptive flexion reflex threshold (Met/Met vs Val/Val P = .015) and the Val/Met subgroup (mean = 19 ± 4.9 mA) in between (Val/Met vs Val/Val P = .041). Spontaneous moderate to severe pain was more likely to be associated with COMT Met/Met genotype. Patients showed important emotional distress compared to controls. In sensitized patients, the COMT Met/Met subgroup showed systematically-though not significantly-worse scores for all psychological variables. PERSPECTIVE: The association between COMT p.Val158Met polymorphism and central sensitization in fibromyalgia is essential as it refers to the severity of central sensitization and may be a risk factor for treatment outcome.

Dual reuptake inhibitor milnacipran and spinal pain pathways in fibromyalgia patients: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Investigations based on quantitative sensory testing have consistently shown evidence of allodynia in fibromyalgia syndrome (FMS) patients involving both the spinal and supraspinal pain regulatory systems. Functional imaging studies have demonstrated enhanced neural activities in pain-related brain areas as well as impairment of pain inhibition in the descending nociceptive regulatory system. A higher state of excitability of spinal nociceptive neurons as evidenced by lowered nociceptive flexion reflex R-III (NFR) threshold was reported for FMS patients. The NFR procedure has been shown to be a valuable tool to evaluate pharmacologically active therapeutic agents at the spinal level. OBJECTIVE: Serotonin-noradrenaline reuptake inhibitors have been shown to reduce pain in FMS patients possibly through descending monoaminergic pain pathways modulation. This randomized double-blind placebo-controlled trial assessed the pharmacodynamic activity of the dual-reuptake inhibitor milnacipran (MLN) at the spinal level by means of the objective spinal NFR. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: A single academic medical center, outpatient setting. METHODS: Seven-week exposure (100, 150, 200mg/day) in women fibromyalgia patients. Evaluation consisted of extensive quantitative sensory testing including determination of the NFR threshold, self-reported standard questionnaires investigating pain, visual analog scales, fibromyalgia impact, health-related quality of life, depression and anxiety questionnaires, as well as the Patient's Global Impression of Change (PGIC). Analysis of covariance adjusted for baseline value was used for all endpoints. RESULTS: Seventy-seven (39 placebo, 38 milnacipran all doses) out of 80 randomized patients were available for analysis. The absence of influence of MLN (any dose) on the NFR surprisingly contrasted with the dose-dependent analgesic effect observed in MLN-treated patients with an adjusted change difference of -18.4mm (-30.9; -5.8) in pain reduction between placebo and the maximum dosage (200 mg) MLN groups (P = 0.02). Unchanged depression and anxiety scores confirmed the predominant selectivity of the analgesic effect of MLN on nociceptive pain pathway. Self-reported questionnaires consistently reflected the positive effects of MLN on quality of life and psychological well-being. Odds ratio 5.1 for PGIC responders (i.e. much/very much improved) was significantly in favor of MLN (P = 0.04). CONCLUSION: Milnacipran has a predominantly supraspinal analgesic effect as evidenced by the significant clinical benefits and the absence of changes in the nociceptive spinal reflex threshold. Higher dose was associated with higher pain reduction. Reported analgesia was independent of patients' emotional status.

Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain.

BACKGROUND: There is some evidence that dextromethorphan (DM) is effective as a pre-emptive analgesic agent.  DM is mainly metabolized to dextrorphan (DOR) by CYP2D6 whose activity can be inhibited by pharmacologic intervention. OBJECTIVES: To investigate the efficacy of DM as a pre-emptive analgesic agent and describe the population pharmacokinetics in the presence of normal and poor CYP2D6 metabolism in acute post-operative pain. STUDY DESIGN: Double blind, randomized, placebo-controlled trial SETTING: Post-surgical analgesic consumption after knee ligament surgery, a setting of acute pain. METHODS: Forty patients were randomized to a single oral dose of 50 mg quinidine or placebo, administered 12 hours before 50 mg DM. Patients were genotyped for the major CYP2D6 and ABCB1 variants and phenotyped for CYP2D6 using urine DM/DOR metabolic ratios and blood samples for population pharmacokinetic modeling. RESULTS: Quinidine was effective in inhibiting CYP2D6 activity, with 2-fold reduction of DM to DOR biotransformation clearance, prolonged DM half-life, and increased DM systemic availability. Patients in the quinidine group required significantly less often NSAIDs than patients in the placebo group (35.3% vs. 75.0%, P = 0.022). The odds ratio for NSAID consumption in the placebo vs. quinidine group was 5.5 (95% confidence interval (CI) 1.3 - 22.7) at 48 hours after surgery. LIMITATIONS: While this study shows an impact of DM on pre-emptive analgesia and is mechanistically interesting, the findings need to be confirmed in larger trials. CONCLUSION: CYP2D6 inhibition by quinidine influenced the pre-emptive analgesic effectiveness of DM confirming that CYP2D6 phenotypic switch increases the neuromodulatory effect of oral dextromethorphan.

Psychological distress in fibromyalgia patients: a role for catechol-O-methyl-transferase Val158met polymorphism.

OBJECTIVE: Fibromyalgia (FM) has been related to biochemical alterations, central pain sensitization and psychological distress. Among genetic and environmental hypotheses, a role was suggested for catechol-O-methyl-transferase (COMT), a modulator in the metabolism of monoaminergic neurotransmitters. METHOD: This study compared the COMT Val158Met enzyme polymorphism (rs4680) of 198 FM patients to 99 pain-free controls. Psychological and functional aspects were assessed through investigating anxiety, depression, catastrophizing, perceived health, and functional status. RESULTS: The distribution of the COMT Val158Met polymorphism was similar in FM and controls. Out of 198 patients, 137 were able to stop medication before evaluation. In these patients, the COMT Val158Met genotype was associated with specific psychological profiles. The Met/Met subgroup scored systematically worse on all psychological and functional variables. All variables displayed a "genotype-trend effect" with the Met/Met and Val/Val subgroups at the two ends of the scores. Genotypes distribution in the 61 patients unable to stop medication was significantly different from that of patients able to stop medication and controls (p = .002 and p = .018, respectively) with an increase in the proportion of the Met/Met genotype associated to the lowest COMT activity. These results suggest a possible role of COMT Val158Met polymorphism in the psychological distress observed in FM. CONCLUSIONS: The association of COMT genotype with psychological distress may be of importance as identifying subgroups is a challenge in the diagnosis and treatment of fibromyalgia patients. This association may contribute to open new perspectives into the understanding of the pathophysiology of fibromyalgia and stress-related genes.

Influence of ABCB1 gene polymorphisms and P-glycoprotein activity on cyclosporine pharmacokinetics in peripheral blood mononuclear cells in healthy volunteers.

The calcineurin inhibitor cyclosporine is removed from lymphocytes by the drug efflux transporter P-glycoprotein (P-gp) encoded by the ABCB1 gene for which several single nucleotide polymorphisms (SNPs) have been identified. Of a total of 87 healthy volunteers genotyped for ABCB1 G2677T/A and C3435T SNPs, 10 GG-CC and 9 TT-TT individuals were selected and received a single oral dose of cyclosporine. Peripheral blood mononuclear cell (PBMC) ABCB1 mRNA expression, P-gp activity in CD4(+) and CD8(+) cells and the 24h cyclosporine pharmacokinetics in PBMCs and whole blood were determined. No correlation was observed between cyclosporine PBMC and whole blood levels (AUC(0-24), Spearman, r(S)=0.09, p=0.71). Intraindividual PBMC and whole blood levels followed parallel profiles that did not significantly differ with respect to t(max) (Wilcoxon, p=0.53) and t((1/2)) (p=0.49). Significant negative correlations between cyclosporine t((1/2)) in PBMCs and P-gp activity in CD4(+) (r(S)=-0.82, p=0.007) and CD8(+) (r(S)=-0.72, p=0.03) were observed among TT-TT subjects. Similarly, a negative correlation was detected in the GG-CC group between P-gp activity in CD4(+) and cyclosporine PBMC AUC(0-24) (r(S)=-0.69, p=0.03), as well as PBMC to whole blood AUC(0-24) ratio (r(S)=-0.60, p=0.07). Tested ABCB1 genotypes had no influence on cyclosporine pharmacokinetic parameters in PBMCs and whole blood. The haplotypes investigated were neither significantly correlated with PBMC ABCB1 mRNA expression nor with P-gp activity in CD4(+) and CD8(+). In conclusion, cyclosporine PBMC pharmacokinetics was influenced by P-gp activity and cyclosporine whole blood concentrations did not predict PBMC drug levels, suggesting that despite values in the therapeutic range, some subjects could have inadequate intracellular drug levels.

Pharmacokinetic and pharmacodynamic properties of buprenorphine after a single intravenous administration in healthy volunteers: a randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND: Buprenorphine is used as an analgesic for postoperative and chronic pain. The usual sublingual dose is 0.2 to 0.8 mg, and the usual parenteral dose is 0.3 mg for acute postoperative pain. The pharmacokinetic and related pharmacodynamic properties of buprenorphine at these doses have not been characterized. OBJECTIVE: The aim of this study was to assess the pharmacokinetic properties of buprenorphine 0.002 mg/kg IV (0.15 mg/70 kg) and its antinociceptive and psychomotor effects. METHODS: Healthy male volunteers received 0.002 mg/kg buprenorphine IV in a randomized, double-blind, placebo-controlled, crossover design. Blood samples were collected at 0.5, 1, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, and 8 hours for the determination of plasma concentrations. Pharmacokinetic parameters were estimated by a compartmental model using specialized software. Antinociceptive and psychomotor effects were determined for 8 hours. Quantitative sensory testing with thermal and electrical (nociceptive flexion RIII reflex) stimulations was performed. The cold pressor test was used to assess pain tolerance to a tonic, intense pain stimulation. Psychomotor performance was assessed by the digit symbol substitution test (DSST). Participants also rated sedation on an 11-point numeric scale (0 = none to 10 = severe). A selective liquid chromatography-tandem mass spectrometry assay was developed for the determination of buprenorphine; the limit of quantification was 0.05 ng/mL using a 0.25-mL plasma aliquot. Participants were instructed to report adverse effects, which were recorded for type, time of onset, seriousness, and duration. RESULTS: The study enrolled 12 participants, all of whom were white. Mean (SD) age was 26 (3.5) years, and mean weight was 67 (9) kg. None of the participants had a history of opiate abuse. Buprenorphine significantly increased the objective (nociceptive flexion RIII reflex) and subjective pain thresholds for >4 hours and pain tolerance (cold pressor test) for 2 hours. The mean (SD) RIII reflex threshold and subjective threshold at baseline were 31.6 (9.5) mA and 45.5 (22.3) mA, respectively. The maximum increases (mean [SD]) were +14.1 (17.5) mA for the RIII reflex (P = 0.02) and +24.2 (21.7) mA for the subjective threshold (P = 0.02), corresponding to mean (SEM) percentages of 53.7% (20.2%) and 74.7% (20.4%) of the baseline values, respectively. The maximum increases were observed at 120 minutes for both measures. The effect of buprenorphine on pain tolerance peaked at 30 minutes. Mean (SEM) latency before withdrawal of the hand was 69 (10) seconds, corresponding to a mean increase of 63.8% (14.4%) from baseline (P = 0.003). Buprenorphine had a significant effect on the DSST. The mean maximum decrease in the total number of symbols drawn was -6 (14.5%; P = 0.005) at 1 hour. The participants reported high levels of sedation: at peak effect (120 minutes), mean scores increased from 2.9 to 6.4 (SEM 0.7) (P = 0.005). Levels returned to baseline values by the end of the session, unlike for the nociceptive tests. The onset of effects occurred during the distribution phase for all the measures, and their duration was observed across a wide range of concentrations during the elimination phase. The most likely explanation for this finding is the high affinity of buprenorphine at mu-opioid receptors, and possibly distribution to the brain. Buprenorphine t(l/2) was 2.75 hours. A secondary peak in concentration was observed at 90 minutes, suggesting enterohepatic circulation of buprenorphine. A 2-compartment model adequately described buprenorphine pharmacokinetics. CONCLUSIONS: A clinically relevant analgesic dose of 0.002 mg/kg (0.15 mg/70 kg) of buprenorphine had a significant effect on nociception and psychomotor performance in these healthy male volunteers. A 2-compartment model satisfactorily characterized buprenorphine pharmacokinetics, and we found evidence of enterohepatic circulation.

Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors.

BACKGROUND: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation. RESULTS: Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function. CONCLUSIONS: QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.