Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers.

BACKGROUND: Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(-)-ketamine isomers, or esketamine, containing just the S(+)-isomer. METHODS: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 µg kg-1 min-1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point. RESULTS: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. CONCLUSIONS: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(-)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms. CLINICAL TRIAL REGISTRATION: NTR 5359.

Esketamine counters opioid-induced respiratory depression.

BACKGROUND: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression. METHODS: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO2-chemosensitivity, or both. RESULTS: Remifentanil reduced isohypercapnic ventilation (end-tidal PCO2 6.5 kPa) by approximately 40% (from 20 to 12 litre min-1) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO2 sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO2 sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO2 sensitivity. The remifentanil concentration that reduced ventilatory CO2 sensitivity by 50% (C50) was doubled at an esketamine concentration of 127 (84-191) ng ml-1 [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression. CONCLUSIONS: Esketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO2 chemosensitivity.

An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers.

Background: There is a clinical need for potent opioids that produce little or no respiratory depression. In the current study we compared the respiratory effects of tapentadol, a mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and oxycodone, a selective mu-opioid receptor agonist. We hypothesize that tapentadol 100 mg has a lesser effect on the control of breathing than oxycodone 20 mg. Methods: Fifteen healthy volunteers were randomized to receive oral tapentadol (100 and 150 mg), oxycodone 20 mg or placebo immediate release tablets in a crossover double-blind randomized design. The main end-point of the study was the effect of treatment on the ventilatory response to hypercapnia and ventilation at an extrapolated end-tidal PCO2 of 7.3 kPa (55 mmHg, VE55); VE55 was assessed prior and for 6-h following drug intake. Results: All three treatments had typical opioid effects on the hypercapnic ventilatory response: a shift to the right coupled to a decrease of the response slope. Oxycodone 20 mg had a significantly larger respiratory depressant effect than tapentadol 100 mg (mean difference -5.0 L min-1, 95% confidence interval: -7.1 to -2.9 L min-1, P<0.01), but not larger than tapentadol 150 mg (oxycodone vs. tapentadol 150 mg: P>0.05). Conclusions: In this exploratory study we observed that both tapentadol and oxycodone produce respiratory depression. Tapentadol 100 mg but not 150 mg had a modest respiratory advantage over oxycodone 20 mg. Further studies are needed to explore how these results translate to the clinical setting.

Effect of subanaesthetic ketamine on plasma and saliva cortisol secretion.

BACKGROUND: The commonality between chronic conditions that are treated with low-dose ketamine, such as specific chronic pain conditions, depression, and post-traumatic stress disorder, can be found in relation to the stress system, particularly the hypothalamus-pituitary-adrenal axis. In this study we assess the effect of ketamine on the stress system by measuring plasma and saliva cortisol production during and following exposure to low-dose ketamine. METHODS: In a double-blind, randomized, placebo-controlled study, the influence of subanaesthetic ketamine (0.29 mg kg(-1) h(-1) for 1 h, followed by 0.57 mg kg(-1) h(-1) for another hour) was studied with repeated plasma and saliva cortisol samples in 12 healthy male volunteers. A pharmacokinetic-pharmacodynamic model was used to describe the circadian rhythm-dependent ketamine-induced production of cortisol. RESULTS: The endogenous mean baseline cortisol production was 7.9 (SE 1.5) nM min(-1). Consistent with the circadian rhythm, cortisol production decayed by 1.25 nM min(-1) h(-1). Ketamine doubled the cortisol production at a concentration of 165 (SE 35) ng ml(-1). The salivary cortisol concentration closely mirrored the plasma concentration and was exponentially related to the plasma concentration with, at 100 ng ml(-1) ketamine, a saliva:plasma ratio of 0.036 (se 0.006). CONCLUSIONS: Ketamine has an appreciable effect on cortisol production. This may impact on critical physiological and psychological functions. CLINICAL TRIAL REGISTRATION: This study was registered in the Dutch Trial Register under number NTR2717 at www.trialregister.nl.

Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy.

BACKGROUND: Tapentadol is an analgesic agent for treatment of acute and chronic pain that activates the µ-opioid receptor combined with inhibition of neuronal norepinephrine reuptake. Both mechanisms are implicated in activation of descending inhibitory pain pathways. In this study, we investigated the influence of tapentadol on conditioned pain modulation (CPM, an experimental measure of endogenous pain inhibition that gates incoming pain signals as a consequence of a preceding tonic painful stimulus) and offset analgesia (OA, a test in which a disproportionally large amount of analgesia becomes apparent upon a slight decrease in noxious heat stimulation). METHODS: Twenty-four patients with diabetic polyneuropathy (DPN) were randomized to receive daily treatment with tapentadol sustained-release (SR) [average daily dose 433 (31) mg] or placebo for 4 weeks. CPM and OA were measured before and on the last day of treatment. RESULTS: Before treatment, none of the patients had significant CPM or OA responses. At week 4 of treatment, CPM was significantly activated by tapentadol SR and coincided with significant analgesic responses. CPM increased from 9.1 (5.4)% (baseline) to 14.3 (7.2)% (placebo) and 24.2 (7.7)% (tapentadol SR, P<0.001 vs placebo); relief of DPN pain was also greater in patients treated with tapentadol than placebo (P=0.028). Neither placebo nor tapentadol SR treatment had an effect on the magnitude of the OA responses (P=0.78). CONCLUSIONS: Tapentadol's analgesic effect in chronic pain patients with DPN is dependent on activation of descending inhibitory pain pathways as observed by CPM responses. CLINICAL TRIAL REGISTRATION: The study was registered at trialregister.nl under number NTR2716.

High-inspired oxygen concentration further impairs opioid-induced respiratory depression.

BACKGROUND: Hyperoxaemia depresses the output of peripheral and central chemoreceptors. Patients treated with opioids often receive supplemental oxygen to avert possible decreases in oxygen saturation (Sp(O2)).We examined the effect of a single dose of remifentanil in healthy volunteers inhaling room air vs air enriched with 50% oxygen. METHODS: Twenty healthy volunteers received i.v. 50 mg remifentanil (infused over 60 s) at anormoxic (N) or hyperoxic (FI(O2) 0.5, H) background on separate occasions. Minute ventilation (Vi), respiratory rate (RR), end-tidal PC(O2), and Sp(O2) were collected on a breath to-breath basis. The occurrence of apnoea was recorded. RESULTS: During normoxia, remifentanil decreased Vi from 7.4 (1.3) [mean (SD)] to 2.2 (1.2) litre min 21 (P,0.01), and during hyperoxia from 7.9 (1.0) to 1.2 (1.2) litre min 21 (P,0.01; H vs N: P,0.001). RR decreased from 13.1 (2.9) to 6.1 (2.8) bpm during N (P,0.01) and from 13.2 (3.0) to 3.6 (4.0) bpm during H (P,0.01; H vs N: P,0.01). During normoxia, Sp(O2) decreased from 98.4 (1.5) to 88.6 (6.7)% (P,0.01), while during hyperoxia, Sp(O2) changed from 99.7 (0.7) to 98.7 (1.0)% (P,0.001). Apnoea developed in two subjects during normoxia and 10 during hyperoxia. CONCLUSIONS: Respiratory depression from remifentanil is more pronounced in hyperoxia than normoxia as determined from minute ventilation, end-tidal PC(O2), and RR. During hyperoxia, respiratory depression may be masked when measuring Sp(O2) as pulse oximetry remains in normal values during the first minutes of respiratory depression.

Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study.

BACKGROUND: Descending inhibition of pain, part of the endogenous pain modulation system, is important for normal pain processing. Dysfunction is associated with various chronic pain states. Here, the effect of ketamine and morphine on descending inhibition is examined using the conditioned pain modulation (CPM) paradigm in chronic neuropathic pain patients. METHODS: CPM responses were obtained in 10 adult neuropathic pain subjects (two men/eight women). All subjects had peripheral neuropathy as defined by abnormal quantitative sensory testing. The effects of S(+)-ketamine (0.57 mg kg(-1) h(-1) for 1 h) and morphine (0.065 mg kg(-1) h(-1) for 1 h) were tested in a randomized, placebo-controlled double-blind study. CPM was measured at baseline and 100 min after the start of treatment and was induced by immersion of the leg into a cold-water bath. The test stimulus was a 30 s static thermal stimulus to the skin of the forearm. RESULTS: Without treatment, no CPM was detectable. Treatment with ketamine, morphine, and placebo produced CPM responses of 40.2 (10.9)%, 28.5 (7.0)%, and 22.1 (12.0)%, respectively (for all treatments, CPM effect P<0.05), with no statistical difference in the magnitude of CPM among treatments. The magnitude of CPM correlated positively with the magnitude and duration of spontaneous pain relief. CONCLUSIONS: The observed treatment effects in chronic pain patients suggest a role for CPM engagement in analgesic efficacy of ketamine, morphine, and placebo treatment.

Opioid-induced respiratory depression in paediatrics: a review of case reports.

Opioids remain the cornerstone of modern-day pain treatment, also in the paediatric population. Opioid treatment is potentially life-threatening, although there are no numbers available on the incidence of opioid-induced respiratory depression (OIRD) in paediatrics. To get an indication of specific patterns in the development/causes of OIRD, we searched PubMed (May 2012) for all available case reports on OIRD in paediatrics, including patients 12 yr of age or younger who developed OIRD from an opioid given to them for a medical indication or due to transfer of an opioid from their mother in the perinatal setting, requiring naloxone, tracheal intubation, and/or resuscitation. Twenty-seven cases are described in 24 reports; of which, seven cases were fatal. In eight cases, OIRD was due to an iatrogenic overdose. Three distinct patterns in the remaining data set specifically related to OIRD include: (i) morphine administration in patients with renal impairment, causing accumulation of the active metabolite of morphine; (ii) codeine use in patients with CYP2D6 gene polymorphism associated with the ultra-rapid metabolizer phenotype, causing enhanced production of the morphine; and (iii) opioid use in patients after adenotonsillectomy for recurrent tonsillitis and/or obstructive sleep apnoea, where OIRD may be related to hypoxia-induced enhancement of OIRD. Despite the restrictions of this approach, our analysis does yield an important insight in the development of OIRD, with specific risk factors clearly present in the data.

[Pain in cancer]. / Pijn bij kanker.

Patients with cancer often experience pain that significantly interferes with their daily life. In this review paper the authors discuss the different aspects of cancer pain by answering different questions regarding cancer pain. Items that are discussed include measurement of pain, medical and interventional pain treatment, side effects, opioid tolerance and addiction and barriers that preclude proper treatment of pain. The conclusion of this review paper is that the treatment of cancer pain is complex and warrants a multidisciplinary team effort with a central role for the patient.

Validation of a novel respiratory rate monitor based on exhaled humidity.

BACKGROUND: Postoperative monitoring of ventilation is largely restricted to the measurement of haemoglobin-oxygen saturation and respiratory rate (RR) derived from the ECG. measurement is inadequate when used with supplemental oxygen and ECG-derived RR is subject to artifacts. A new monitor measures RR by quantifying the humidity of exhaled air (respiR8(®)). METHODS: The accuracy of the system was tested using a breathing simulator. In healthy volunteers, the respiR8(®) monitor was compared with two other methods of measuring RR: capnometry and counting of thoracic breathing movements. The ability of the monitor to track changes in RR resulting from the infusion of 2.5 µg kg(-1) fentanyl was assessed and compared with RR measured from a validated flow measurement system. The RR in 50 postoperative patients measured with the respiR8(®) was compared with that derived from the ECG. RR values were compared by population-based Bland-Altman analyses. RESULTS: The respiR8(®) monitor was accurate in the range required in clinical practice. There was a close agreement between RR from respiR8(®), capnometry, and manual counting of respiratory movements without bias (limits of agreement ±1 bpm). The respiR8(®) monitor was well able to accurately track RR changes from fentanyl. In postoperative patients, RR from respiR8(®) and ECG had a bias of 1.7 (5.7) bpm due to greater RR values observed from the ECG due to artifacts. CONCLUSIONS: The respiR8(®) gives an accurate measurement of RR and is useful in postoperative care.

Comparison of neuromuscular block measured by compressomyography at the upper arm and electromyography at the adductor pollicis muscle in obese and non-obese patients: An observational study.

STUDY OBJECTIVE: Quantitative neuromuscular monitoring is traditionally evaluated at the adductor pollicis muscle. By contrast, the TOF-Cuff compressomyograph evaluates neuromuscular block (NMB) at the upper arm. However, compressomyography has not been fully validated against other monitoring entities. This study evaluates the agreement between NMB measured by compressomyography at the upper arm and electromyography at the adductor pollicis muscle during various levels of neuromuscular block in patients with and without obesity. INTERVENTIONS: NMB was measured at the upper arm by compressomyography (TOF-Cuff) and by electromyography (GE-NMT) at the adductor pollicis. DESIGN: Prospective, multicenter, observational study. SETTING: Secondary and tertiary care hospitals' operating theatres. PATIENTS: 200 non-obese and 50 obese patients. MEASUREMENTS: During onset and offset of deep (post-tetanic-count 1-15 twitches), moderate (Train-of-Four-count 1-3 twitches) and shallow (Train-of-Four-ratio 0.01-1.0) depths of NMB were measured in obese and non-obese patients. The bias and limits of agreement of both devices were calculated using a Bland-Altman analysis for repeated measurements. Data obtained during spontaneous recovery (i.e. without the use of reversal agents) were used in the primary analyses. MAIN RESULTS: Data from enrolled patients yielded 942 paired post-tetanic-counts, 1175 paired train-of-four-counts and 1574 paired train-of-four ratios during spontaneous recovery. In non-obese patients, mean bias (95% CI) between the two devices was 3.405 (2.294 to 4.517) during deep NMB; -0.023 (-0.205 to 0.160) during moderate NMB and 0.312 (0.287 to 0.338) during shallow NMB. In obese patients, bias was -0.170 (-2.872 to 2.531); 0.178 (-0.202 to 0.558); 0.384 (0.299 to 0.469) for deep, moderate and shallow NMB respectively. CONCLUSIONS: There is variable disagreement between the level of NMB measured at the upper arm by compressomyography and at the adductor pollicis muscle measured by electromyography, throughout the various stages of NMB in obese and non-obese patients. Recovery of NMB on compressomyography preceded recovery on electromyography, which may have consequences for reversal and extubation decisions in clinical practice.

[Postoperative opioid overdose due to patient-controlled analgesia by proxy]. / Postoperatieve overdosering morfine door familielid.

Patient-controlled analgesia (PCA) is a popular and efficacious form of postoperative pain relief that, however, is not without complications. Here we describe a 73-year-old Somalian male patient that underwent abdominal surgery and received intravenous morphine PCA for postoperative pain relief. Due to his inability to speak the native language, his son served as interpreter. On the day after surgery, the patient was found unresponsive by the nursing staff with an oxygen saturation of 91%. He was treated with naloxone and transferred to a medium care facility. The son indicated that he had operated the PCA system at regular intervals over the last 12 hours. The dangers of PCA and PCA by proxy in particular are discussed. In this case, the language barrier, and possibly cultural differences and health illiteracy may have contributed to the PCA by proxy.

Safety of sugammadex for reversal of neuromuscular block.

Introduction: Sugammadex is a modified cyclodextrin that is able to reverse neuromuscular block induced by aminosteroidal neuromuscular blocking drugs. Compared to reversal with neostigmine, it reverses neuromuscular block quicker and more predictable and without cholinergic side effects. However, there have been concerns about sugammadex ability to bind other drugs and its effects on QT interval and clotting times. In addition, sugammadex might induce hypersensitivity reactions more frequently than initially anticipated. This review summarizes current evidence with regard to these and other safety aspects of sugammadex. Areas covered: This review provides an overview of the efficacy of sugammadex in various patient populations, evaluates potential interactions with other drugs and discusses adverse effects and reactions that have been reported in the literature. Expert opinion: Sugammadex quickly reverses aminosteroid neuromuscular block with less side effects compared to neostigmine. As such, it has the potential to significantly reduce the incidence of residual neuromuscular block and to improve postoperative pulmonary outcome. Current safety concerns mainly focus on hypersensitivity reactions and cardiac arrhythmias. Although the absolute risk for these events is low, ongoing vigilance and research in this area are needed.

Waterijs na een operatie vermindert opiaatbehoefte.

OBJECTIVE To evaluate the effect of an ice-lolly on acute postoperative pain. DESIGN Randomised prospective intervention study. METHOD A total of 100 patients scheduled for an elective laparoscopic cholecystectomy were recruited to participate in the study. Patients were randomised to receive either an ice-lolly or no treatment after arrival at the post-anaesthesia care unit. The analgesic requirements (opioid and non-opioid), pain scores, and the presence of nausea and vomiting were registered on the post- anaesthesia care unit and ward during the first 24 hours after surgery. This study is registered in the Nederlands Trial Register under number NTR5335. RESULTS In the post-anaesthesia care unit, pain scores did not differ between patients who received an ice-lolly and those who did not. The opioid requirements of patients who had consumed an ice-lolly were significantly lower than those of the patients who had not (cumulative piritramide dose: 4.9 (SD 4.2) with ice-lolly vs. 6.6 (SD 4.0) without ice-lolly mg; P = 0.04). Furthermore, patients who did not receive an ice-lolly required more additional pain relief with non-opioid analgesics than patients who had been given an ice- lolly (31% vs. 10%; P = 0.01). Combining all administered opioid and non-opioid analgesics into one analgesic composite score showed that patients who received an ice-lolly required significantly fewer analgesics in the post-anaesthesia care unit than patients who had not been given an ice-lolly (2.2 (SD 1.7) vs. 2.9 (SD 1.8); P = 0.03). No differences between the groups in pain scores or use of analgesics were observed on the ward in the first 24 hours postoperatively. CONCLUSION The postoperative consumption of an ice-lolly reduces postoperative opioid and non-opioid analgesic requirements in the post- anaesthesia care unit. Conflict of interest and financial support: none declared.

A randomized controlled trial and novel mathematical analysis of the analgesic effect of oxycodone versus paracetamol orodispersible tablets.

BACKGROUND: For effective treatment of acute pain, a rapid onset of action is important. Here we quantify the antinociceptive profile of an orodispersible oxycodone tablet (OOT) in a randomized, double-blind, active comparator (paracetamol orodispersible tablet, POT), crossover study design in a population of healthy volunteers. METHODS: Twelve female volunteers were randomized to receive 20 mg OOT and 500 mg POT sublingually on two occasions. The electrical pain threshold (EPTh), electrical pain tolerance (EPTol) and pressure pain threshold (PPT) were obtained at regular intervals for 5 h. Time-response data were analysed with a longitudinal pharmacodynamic model characterized by rate constants for analgesia onset (kON ), offset (kOFF ), potency parameter (EFF) and validated with a bootstrap analysis. Values are the median (95% CI) as derived from the bootstrap analysis. RESULTS: OOT produced a rapid increase in response values. For electrical pain analgesia onset, t½kON , 44 (25-67) versus analgesia offset, t½kOFF , 156 (63-552) min, p < 0.01. For pressure pain, t½kON equalled t½kOFF : 30 (16-48) min. OOT was most potent on EPTol: EFF 0.95 (0.39-1.71), p < 0.01, with similar potencies on EPTh, 0.43 (0.19-0.87) and PPT, 0.40 (0.21-0.67). Paracetamol displayed 14% of the analgesic efficacy of oxycodone. CONCLUSIONS: The analgesic effect of orodispersible oxycodone was successfully quantified using a mathematical model of analgesia evolution. This method allows quantification of a variety of responses times from sparse data sets. Response times as defined by a 30% increase in response thresholds varied significantly among end points: EPTol 15 min, PPTh 18 min and EPTh 41 min.

Differences in telomerase expression by the CD1a+ cells in Langerhans cell histiocytosis reflect the diverse clinical presentation of the disease.

Langerhans cell histiocytosis (LCH) is a disease characterized by an uncontrolled clonal proliferation of Langerhans cells, whose aetiology is still unclear. The clonal nature of LCH could support the hypothesis that it is a neoplastic disease with unlimited growth potential. One requirement for unlimited proliferation is the maintenance of telomere length. In a group of 70 patients, we set out to investigate whether a telomere maintenance mechanism is indeed active in LCH cells. This work showed that LCH cells from all restricted skin LCH lesions (6/6) expressed telomerase as assessed by human telomere reverse transcriptase (hTERT) immunohistochemistry, whereas LCH cells from the majority of the bone lesions analysed did not express hTERT (26/34). Interestingly, in contrast to the solitary bone lesions, LCH cells from lesions of multi-system patients always expressed telomerase (11/11), regardless of the lesional site. In situ telomeric repeat amplification protocol (TRAP) assays performed on different lesional sites showed that this telomerase was active. In addition, the telomere length of LCH cells from a hTERT-positive skin multi-system lesion was long and homogeneous when compared to that in the LCH cells from hTERT-negative bone single-system LCH lesions, which was heterogeneous in length. No evidence for an alternative lengthening of telomeres mechanism was found in hTERT-negative lesions. The difference in telomerase expression and telomere length at the different lesional sites and in biopsies from patients with solitary versus multi-system disease appears to reflect the diverse clinical presentation and course of this disease. The results from this study have important implications for understanding the nature of this disease.