Eija Kalso

Helsinki University Central Hospital, Helsinki, Uusimaa, Finland

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Publications (149)727.38 Total impact

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    ABSTRACT: Background Oxycodone is increasingly being used in combination with pregabalin. Pregabalin use is prevalent in opioid-dependent individuals. A high number of deaths caused by the co-use of gabapentinoids and opioids occur. It is not known whether pregabalin affects concentrations of oxycodone or morphine in the central nervous system.Methods Effects of pregabalin on acute oxycodone or morphine-induced antinociception, tolerance and sedation were studied using tail-flick, hot plate and rotarod tests in male Sprague–Dawley rats. Concentrations of pregabalin, opioids and their major metabolites in the brain were quantified by mass spectrometry.ResultsIn the hot plate test, morphine (2.5 mg/kg, s.c.) caused antinociception of 28% maximum possible effect (MPE), whereas pregabalin (50 mg/kg, i.p.) produced 8–10% MPE. Co-administration of pregabalin and morphine resulted in antinociception of 63% MPE. Oxycodone (0.6 mg/kg s.c.) produced antinociception of 18% MPE, which increased to 39% MPE after co-administration with pregabalin. When pregabalin 10 mg/kg was administered before oxycodone (0.6 mg/kg, s.c.) or morphine (2.5 mg/kg), only the effect of oxycodone was potentiated in the tail-flick and the hot plate tests. Brain concentrations of the opioids, their major metabolites and pregabalin were unchanged. Pregabalin co-administration (50 mg/kg, i.p., once daily) did not prevent the development of morphine tolerance.Conclusions Pregabalin potentiated antinociceptive and sedative effects of oxycodone and morphine in acute nociception. Co-administration of pregabalin with the opioids did not affect the brain concentrations of oxycodone or morphine. Pregabalin did not prevent morphine tolerance.
    European journal of pain (London, England) 05/2015; DOI:10.1002/ejp.728 · 3.22 Impact Factor
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  • Survey of Anesthesiology 04/2015; 59(2):98-99. DOI:10.1097/01.SA.0000461276.90838.5a
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    ABSTRACT: Movement accuracy is ensured by interaction between motor, somatosensory, and visual systems. In complex regional pain syndrome (CRPS), this interaction is disturbed. To explore CRPS patients' visual perception of actions, we investigated how these patients evaluate the applied force in observed hand actions of another person. Nineteen patients suffering from unilateral upper-limb CRPS and 19 healthy control subjects viewed six different videos of left- and right-hand actions. They were asked to evaluate the applied force in each hand action, as well as their subjective sensations of unpleasantness and pain during the observation. The patients overestimated the force applied in the videos: the ratings were two times as large as in the control subjects for actions performed with the hand corresponding to the patients' affected hand, and 1.5 times as large for actions corresponding to their healthy hand. The control subjects considered the stimuli neutral and painless, whereas the patients rated them unpleasant. Moreover, the patients felt increased pain during viewing actions performed with the hand corresponding to their affected side. The overestimation of force was related to the elicited unpleasantness and pain, but not to the patients' muscle strength. We propose that the overestimation of force is explained both by the pain elicited by the observation and by the abnormal sensorimotor integration that is associated with perception of increased effort. This visually elicited unpleasantness and painfulness may promote avoidance of viewing own actions, further impairing the patients' motor performance. © 2015 European Pain Federation - EFIC®
    European journal of pain (London, England) 03/2015; DOI:10.1002/ejp.669 · 3.22 Impact Factor
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    ABSTRACT: Low-dose ketamine is a lucrative therapeutic approach in cancer pain, perioperative treatment of pain, and management of treatment-resistant depression. The analgesic potency of its main metabolite norketamine is thought to be one third that of ketamine. However, few studies exist on the pharmacokinetics of orally administered S-ketamine. In our study, 11 healthy volunteers received S-ketamine 0.25 mg/kg orally and 0.125 mg/kg intravenously. S-ketamine and norketamine concentrations were measured up to 23.5 h post-dose. A population pharmacokinetic model was built to describe S-ketamine and norketamine pharmacokinetics. A three-compartment model for both S-ketamine and norketamine best described the data. To accommodate for the extensive formation of norketamine after oral S-ketamine, a separate presystemic absorption-phase component was included in addition to its systemic formation. The oral bioavailability of S-ketamine was low, 8 % (11 % interindividual variability), and its clearance was high, 95 L/h/70 kg (13 % interindividual variability). Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S-ketamine. Given that the analgesic effect of S-ketamine is due to both S-ketamine and norketamine, relatively small oral doses of S-ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain.
    European Journal of Clinical Pharmacology 03/2015; 71(4). DOI:10.1007/s00228-015-1826-y · 2.70 Impact Factor
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    ABSTRACT: Background Patients with widespread unilateral chronic pain associated with recurrent herpes simplex virus (HSV) infections show functional and/or structural changes in the insula, anterior cingulate cortex, frontal and prefrontal cortices, as well as the thalamus, suggesting central dysfunction of the pain system in these patients. Central pain has been associated with attenuated laser-evoked cortical responses. We aimed to clarify whether the observed deficient activation of these areas to acute nociceptive stimuli is due to a lesion at a lower level of pain processing pathways.Methods We explored the functional integrity of the ascending nociceptive pathways by recording the cortical-evoked responses to noxious laser stimulation using magnetoencephalography and electroencephalography in eight patients (age 41–51 years, mean 46) with recurrent HSV infections and a history of chronic, spontaneous, widespread unilateral pain, and in nine age-matched healthy control subjects.ResultsThe cortical-evoked fields of the HSV patients originating from the secondary somatosensory and posterior parietal cortices, as well as the evoked potentials recorded from the midline, did not differ from those of the control subjects, indicating functionally intact ascending nociceptive pathways.Conclusions The present results show that our patients with chronic hemibody pain do not show signs of spinothalamic tract lesion. This indicates normal processing of sensory aspects of painful stimuli, while higher pain processing areas show altered activation. We conclude that normal laser-evoked magnetic fields (LEF) or laser-evoked potentials (LEP) may not exclude central pain condition.
    European journal of pain (London, England) 01/2015; DOI:10.1002/ejp.642 · 3.22 Impact Factor
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    ABSTRACT: Background and PurposeThe effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal.Experimental ApproachMorphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry.Key ResultsIn morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed.Conclusions and ImplicationsThe ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans.
    British Journal of Pharmacology 10/2014; 172(11). DOI:10.1111/bph.12974 · 4.99 Impact Factor
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    ABSTRACT: Context Measuring opioid concentrations in pain treatment is warranted in situations where optimal opioid analgesia is difficult to reach. Objectives To assess the usefulness of oral fluid (OFL) as an alternative to plasma in opioid concentration monitoring in cancer patients on chronic opioid therapy. Methods We collected OFL and plasma samples from 64 cancer patients on controlled-release (CR) oral morphine, CR oral oxycodone or transdermal (TD) fentanyl for pain. Samples were obtained on up to five separate days. Results A total of of 213 OFL and plasma samples were evaluable. All patients had detectable amounts of the CR or TD opioid in both plasma and OFL samples. The plasma concentrations of oxycodone and fentanyl (determination coefficient R2 = 0.628 and 0.700, respectively), but not morphine (R2 = 0.292), were moderately well correlated to the daily opioid doses. In contrast to morphine and fentanyl (mean OFL/plasma ratio 2.0 and 3.0, respectively), the OFL oxycodone concentrations were significantly higher than the respective plasma concentrations (mean OFL/plasma ratio 14.9). An active transporter could explain the much higher OFL versus plasma concentrations of oxycodone compared with morphine and fentanyl. Conclusion OFL analysis is well suited for detecting the studied opioids. For morphine and fentanyl, an approximation of the plasma opioid concentrations is obtainable, whereas for oxycodone, the OFL/plasma concentration relationship is too variable for reliable approximation results.
    Journal of Pain and Symptom Management 09/2014; DOI:10.1016/j.jpainsymman.2014.09.004 · 2.74 Impact Factor
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    ABSTRACT: Most clinically used opioids are mu-opioid receptor agonists. Therefore, genetic variation of the OPRM1 gene that encodes the mu-opioid receptor is of great interest for understanding pain management. A polymorphism 118A>G (rs1799971) within the OPRM1 gene results in a missense mutation and affects the function of the receptor. We studied the association between the 118A>G polymorphism and oxycodone analgesia and pain sensitivity in 1,000 women undergoing breast cancer surgery. Preoperatively, experimental cold and heat pain sensitivities were tested. Postoperative pain was assessed at rest and during motion. I.v. oxycodone analgesia was titrated first by a research nurse and on the ward using a patient-controlled analgesia device. The primary endpoint was the amount of oxycodone needed for the first state of adequate analgesia. For each patient, the 118A>G polymorphism was genotyped using Sequenom MassArray. The association between this variant and the pain phenotypes was tested using linear regression. The 118A>G variant was associated significantly with the amount of oxycodone requested for adequate analgesia (P=0.001, β=0.016). Collectively, oxycodone consumption was highest in individuals having the GG genotype (0.16 mgkg(-1)), lowest for the AA genotype-group (0.12 mg kg(-)¹), and moderate for the AG genotype-group (0.13 mg kg(-)¹). Furthermore, the G allele was associated with higher postoperative baseline pain ratings (P=0.001, β=0.44). No evidence of association with other pain phenotypes examined was observed.
    Journal of Pain 09/2014; 15(12). DOI:10.1016/j.jpain.2014.09.002 · 4.22 Impact Factor
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    ABSTRACT: This review evaluates trials of antidepressants for acute and chronic postsurgical pain.
    Anesthesiology 09/2014; 121(3):591-608. DOI:10.1097/ALN.0000000000000307 · 6.17 Impact Factor
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    ABSTRACT: We describe the frequency, duration, clinical characteristics, and radiologic correlates of central poststroke pain (CPSP) in young ischemic stroke survivors in a prospective study setting.
    Neurology 08/2014; 83(13). DOI:10.1212/WNL.0000000000000818 · 8.30 Impact Factor
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    ABSTRACT: Are antiepileptic drugs associated with reduced pain intensity in patients with neuropathic pain or fibromyalgia?
    JAMA The Journal of the American Medical Association 07/2014; 312(2):182-3. DOI:10.1001/jama.2014.6336 · 30.39 Impact Factor
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    ABSTRACT: Background and aims Thoracotomies can cause severe pain, which persists in 21–67% of patients. We investigated whether NSAID + intravenous patient-controlled analgesia (IV-PCA) with morphine is an efficacious alternative to thoracic epidural analgesia (TEA). We also wanted to find out whether an extended controlled pain management protocol within a clinical study can decrease the incidence of persistent post-thoracotomy pain. Methods Thirty thoracotomy patients were randomized into 3 intervention groups with 10 patients in each. G1: preoperative diclofenac 75 mg orally + 150 mg/24 h IV for 44 h, then PO; G2: valdecoxib 40 mg orally + parecoxib 80 mg/24 h IV for 44 h, then PO. IV-PCA morphine was available in groups 1 and 2 during pleural drainage, and an intercostal nerve block at the end of surgery was performed; G3: paracetamol + patient controlled epidural analgesia (PCEA) with a background infusion of bupivacaine with fentanyl. After PCA/PCEA oxycodone PO was provided when needed. These patients were contacted one week, 3 and 6 months after discharge. Patients (N = 111) not involved in the study were treated according to hospital practice and served as a control group. The control patients’ data from the perioperative period were extracted, and a prospective follow-up questionnaire at 6 months after surgery similar to the intervention group was mailed. Results The intended sample size was not reached in the intervention group because of the global withdrawal of valdecoxib, and the study was terminated prematurely. At 6 months 3% of the intervention patients and 24% of the control patients reported persistent pain (p < 0.01). Diclofenac and valdecoxib provided similar analgesia, and in the combined NSAID group (diclofenac + valdecoxib) movement-related pain was milder in the PCEA group compared with the NSAID group. The duration of pain after coughing was shorter in the PCEA group compared with the NSAID + IV-PCA group. The only patient with persistent pain at 6 months postoperatively had a considerably longer duration of pain after coughing than the other Study patients. The patients with mechanical hyperalgesia had more pain on movement. Conclusions Both PCEA and NSAID + IV-PCA morphine provided sufficient analgesia with little persistent pain compared with the incidence of persistent pain in the control group. High quality acute pain management and follow-up continuing after discharge could be more important than the analgesic method per se in preventing persistent post-thoracotomy pain. In the acute phase the measurement of pain when coughing and the duration of pain after coughing could be easy measures to recognize patients having a higher risk for persistent post-thoracotomy pain. Implications To prevent persistent post-thoracotomy pain, the extended protocol for high quality pain management in hospital covering also the sub-acute phase at home, is important. This study also provides some evidence that safe and effective alternatives to thoracic epidural analgesia do exist. The idea to include the standard “as usual” care patients as a control group and to compare them with the intervention patients provides valuable information of the added value of being a study patient, and deserves further consideration in future studies.
    Scandinavian Journal of Pain 07/2014; DOI:10.1016/j.sjpain.2014.07.001
  • Clinical Neurophysiology 06/2014; 125:S311. DOI:10.1016/S1388-2457(14)51025-5 · 2.98 Impact Factor
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    ABSTRACT: This article presents general considerations discussed at an IMMPACT consensus meeting regarding proof-of-concept (POC) clinical trials and major POC trial designs and their advantages and limitations when used to evaluate chronic pain treatments. Abstract Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine if a treatment is likely to be efficacious for a given indication and thus if it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge of designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and cross-over designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs including (1) N-of-1 designs, (2) enriched designs, (3) adaptive designs, and (4) sequential parallel comparison designs are summarized and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.
    Pain 05/2014; DOI:10.1016/j.pain.2014.05.025 · 5.84 Impact Factor
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    ABSTRACT: Abstract Twenty years ago, the main barriers to successful cancer pain management were poor assessment by physicians, and patients' reluctance to report pain and take opioids. Those barriers are almost exactly the same today. Cancer pain remains under-treated; in Europe, almost three-quarters of cancer patients experience pain, and almost a quarter of those with moderate to severe pain do not receive any analgesic medication. Yet it has been suggested that pain management could be improved simply by ensuring that every consultation includes the patient's rating of pain, that the physician pays attention to this rating, and a plan is agreed to increase analgesia when it is inadequate. After outlining current concepts of carcinogenesis in some detail, this paper describes different methods of classifying and diagnosing cancer pain and the extent of current under-treatment. Key points are made regarding cancer pain management. Firstly, the pain may be caused by multiple different mechanisms and therapy should reflect those underlying mechanisms - not simply based on pain intensity, as recommended by the WHO three-step ladder. Secondly, a multidisciplinary approach is required which combines both pharmacological and non-pharmacological treatment, such as psychotherapy, exercise therapy and electrostimulation. The choice of analgesic agent and its route of administration are considered, along with various interventional procedures and the requirements of palliative care. Special attention is paid to the treatment of breakthrough pain (particularly with fast-acting fentanyl formulations, which have pharmacokinetic profiles that closely match those of breakthrough pain episodes) and chemotherapy-induced neuropathic pain, which affects around one third of patients who receive chemotherapy. Finally, the point is made that medical education should place a greater emphasis on pain therapy, both at undergraduate and postgraduate level.
    Current Medical Research and Opinion 05/2014; 30(9):1-0. DOI:10.1185/03007995.2014.925439 · 2.37 Impact Factor
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    ABSTRACT: Pregabalin (PRG) and gabapentin (GBP) are used in the treatment of neuropathic pain and epilepsy, and PRG also in generalized anxiety disorder. There is increasing evidence that PRG possesses considerable abuse potential. PRG may have a higher addiction potential than GBP due to its rapid absorption and faster onset of action. Our objective is to estimate the proportion of all PRG- and GBP-related fatalities attributable to PRG and GBP abuse. We investigated all medico-legal death cases in Finland in which PRG or GBP was found in postmortem toxicology during 2010-2011. PRG was found in 316 cases and GBP in 43 cases. Drug abuse was associated with 48.1% of the PRG and 18.6% of the GBP findings. PRG poisoning accounted for 10.1% of all PRG cases and GBP poisoning for 4.7% of all GBP cases. In the drug abuser cases, PRG poisoning represented 19.1%, and GBP poisoning 12.5%. The median blood concentration of PRG was 15mg/L in the abuser group and 5.8mg/L in the other cases. For GBP, these concentrations were 12mg/L and 8.3mg/L, respectively. In the PRG abuser group, 91.4% of cases showed concomitant opioid use, while in the rest of these cases neither alcohol nor opioids were detected, but other central nervous system acting drugs were found in each abuser case. In the GBP abuser group, 87.5% of cases showed concomitant opioid use. PRG abuse with high doses is increasingly common and can be fatal when combined with opioids.
    Forensic Science International 05/2014; 241C:1-6. DOI:10.1016/j.forsciint.2014.04.028 · 2.12 Impact Factor
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    ABSTRACT: This is an update of a Cochrane review entitled 'Carbamazepine for acute and chronic pain in adults' published in Issue 1, 2011. Some antiepileptic medicines have a place in the treatment of neuropathic pain (pain due to nerve damage). This updated review considers the treatment of chronic neuropathic pain and fibromyalgia only, and adds no new studies. The update uses higher standards of evidence than the earlier review, which results in the exclusion of five studies that were previously included. To assess the analgesic efficacy of carbamazepine in the treatment of chronic neuropathic pain and fibromyalgia, and to evaluate adverse events reported in the studies. We searched for relevant studies in MEDLINE, EMBASE and CENTRAL up to February 2014. Additional studies were sought from clinical trials databases, and the reference list of retrieved articles and reviews. Randomised, double blind, active or placebo controlled trials (RCTs) investigating the use of carbamazepine (any dose, by any route, and for at least two weeks' duration) for the treatment of chronic neuropathic pain or fibromyalgia, with at least 10 participants per treatment group. Participants were adults aged 18 and over. Two study authors independently extracted data on efficacy, adverse events, and withdrawals, and examined issues of study quality. Numbers needed to treat for an additional beneficial effect (NNT) or harmful effect (NNH) with 95% confidence intervals (CIs) were calculated from dichotomous data.We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts, at least 200 participants in the comparison, at least 8 weeks' duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that was considered very likely to be biased or used outcomes of limited clinical utility, or both. Ten included studies (11 publications) enrolled 480 participants with trigeminal neuralgia, diabetic neuropathy, and post stroke pain. Nine studies used a cross-over design, and one a parallel group design. Most of the studies were of short duration, lasting four weeks or less.No study provided first or second tier evidence for an efficacy outcome. Using third tier evidence, carbamazepine generally provided better pain relief than placebo in the three conditions studied, with some indication of pain improvement over mainly the short term, but with poorly defined outcomes, incomplete reporting, and in small numbers of participants. There were too few data in studies comparing carbamazepine with active comparators to draw any conclusions.In four studies 65% (113/173) of participants experienced at least one adverse event with carbamazepine, and 27% (47/173) with placebo; for every five participants treated, two experienced an adverse event who would not have done so with placebo. In eight studies 3% (8/268) of participants withdrew due to adverse events with carbamazepine, and none (0/255) with placebo. Serious adverse events were not reported consistently; rashes were associated with carbamazepine. Four deaths occurred in patients on carbamazepine, with no obvious drug association. Carbamazepine is probably effective in some people with chronic neuropathic pain, but with caveats. No trial was longer than four weeks, had good reporting quality, nor used outcomes equivalent to substantial clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.
    Cochrane database of systematic reviews (Online) 04/2014; 4(12):CD005451. DOI:10.1002/14651858.CD005451.pub3 · 5.94 Impact Factor
  • Clinical Toxicology 04/2014; 52(4):329-329. · 3.12 Impact Factor
  • Eija Kalso
    Scandinavian Journal of Pain 04/2014; DOI:10.1016/j.sjpain.2014.02.006

Publication Stats

6k Citations
727.38 Total Impact Points

Institutions

  • 1998–2015
    • Helsinki University Central Hospital
      • • Department of Oncology
      • • Department of Clinical Pharmacology
      Helsinki, Uusimaa, Finland
  • 1991–2015
    • University of Helsinki
      • • Institute of Biomedicine
      • • Faculty of Pharmacy
      • • Institute of Clinical Medicine
      • • Division of Pharmacology and Toxicology
      • • Department of Anaesthesia
      Helsinki, Uusimaa, Finland
  • 2013
    • University of Oxford
      Oxford, England, United Kingdom
    • University of Turku
      • Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine
      Turku, Western Finland, Finland
  • 2011
    • Central Hospital Central Finland
      Jyväskylä, Province of Western Finland, Finland
  • 2004
    • Turku University Hospital
      Turku, Province of Western Finland, Finland
    • Hospital District for Helsinki and Uusimaa
      Helsinki, Southern Finland Province, Finland
  • 2003
    • Haukeland University Hospital
      • Department of Anesthesia and Intensive Care
      Bergen, Hordaland Fylke, Norway
  • 1997
    • Åbo Akademi University
      • Department of Biology
      Turku, Province of Western Finland, Finland