Browsing by Subject "CANCER PAIN"

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  • Lilius, Tuomas O.; Viisanen, Hanna; Jokinen, Viljami; Niemi, Mikko; Kalso, Eija A.; Rauhala, Pekka V. (2018)
    Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-d-aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of 7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6-hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high-performance liquid chromatography-tandem mass spectrometry. Ketamine (10 mg/kg), but not 6-hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6-hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6-hydroxynorketamine were doubled by morphine pre-treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co-administration of 6-hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6-hydroxynorketamine brain concentrations were increased after co-administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6-hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.
  • Lilius, Tuomas; Jokinen, V.; Neuvonen, M. S.; Niemi, Mikko; Kalso, E. A.; Rauhala, P. V. (2015)
    Background and Purpose The 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 Approach Morphine minipumps (6mg center dot day(-1)) induced tolerance during 5 days in Sprague-Dawley rats, after which s.c. ketamine (10mg center dot 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 Results In morphine-naive rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90min after administration) lasting up to 150min. 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-naive 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 Implications The 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.
  • Kress, Hans-Georg; Ahlbeck, Karsten; Aldington, Dominic; Alon, Eli; Coaccioli, Stefano; Coluzzi, Flaminia; Huygen, Frank; Jaksch, Wolfgang; Kalso, Eija; Kocot-Kepska, Magdalena; Mangas, Ana Cristina; Margarit Ferri, Cesar; Morlion, Bart; Mueller-Schwefe, Gerhard; Nicolaou, Andrew; Perez Hernandez, Concepcion; Pergolizzi, Joseph; Schaefer, Michael; Sichere, Patrick (2014)
  • Viisanen, Hanna; Lilius, Tuomas O.; Sagalajev, Boriss; Rauhala, Pekka; Kalso, Eija; Pertovaara, Antti (2020)
    Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid. is not yet known. Ketamine, an N-methyl-o-aspartate (NMDA) receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid-tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone. NEW & NOTEWORTHY Morphine and oxycodone are two clinically used strong opioids. Chronic treatment with oxycodone as well as morphine can lead to analgesic tolerance and paradoxical hyperalgesia. Here we show that an N-methyl-n-aspartate receptor-dependent pronociceptive change in discharge properties of rostroventromedial medullary neurons controlling spinal nociception has an important role in antinociceptive tolerance to morphine but not oxycodone. Interestingly, chronic oxycodone did not induce pronociceptive changes in the rostroventromedial medulla.
  • Miettinen, Teemu; Kautiainen, Hannu; Mantyselka, Pekka; Linton, Steven J.; Kalso, Eija (2019)
    Chronic pain patients enter treatment with different problem profiles making careful assessment a necessity for more individualized treatment plans. In this cross-sectional study we assigned 320 patients entering tertiary multidisciplinary pain treatment into four categories based on whether they scored low or high on the activity and the affective pain interference dimensions of the Brief Pain Inventory (BPI). To determine whether this categorization system delineates issues that should be assessed further, the categories were compared with ANOVA and MANOVA analyses on three domains: variables affecting physical well-being (body mass index, exercise, substance use), psychological resources (mood), and painspecific psychological factors (pain anxiety, pain acceptance). The results indicated that subjects who scored low on both interference dimensions compared similarly in weight: mean Body Mass Index (BMI) 27.0 (SD 6.0) kg/m(2), and exercise: mean of 2.4 (SD 1.7) exercising sessions over 20 minutes per week, to the general population, had no depressive symptoms on average: mean Beck Depression Index II (BDI-II) score 11.7 (SD 7.5), and had the most favorable psychological reactions to pain relative to the other categories: mean total Pain Anxiety Symptoms Scale-20 (PASS-20) score 36.4 (SD 17.9). In contrast, when interference was high on activity, more physical well-being problems were evident e.g. weight: mean BMI 31.0 (SD 7.3) kg/m(2), diminished exercise: mean of 1.5 (SD 1.6) exercising sessions per week, and avoidance behavior: mean PASS-20 Escape/Avoidance subscale 3.7 (95% CI: 1.7 to 5.8) scores higher in comparison to activity interference remaining low. With high affective interference, more depressive symptoms: mean BDI-II score 17.7 (SD 7.3), and more cognitive pain anxiety: mean PASS-20 Cognitive Anxiety subscale 2.8 (95% CI 0.7 to 4.8) scores higher in comparison to affective interference remaining low, emerged. Having high interference on both dimensions indicated accumulated risks for reduced physical well-being: mean BMI 29.9 (SD 6.1) kg/m(2), mean of 1.2 (SD 1.7) exercising sessions per week, mood problems: mean BDI-II 20.3 (SD 10.6), and negative psychological reactions to pain: mean total PASS-20 score 53.2 (18.4). The results suggest that low interference on both dimensions may allow assessment with only physician consultations, while high interference on either dimension may call attention to distinct issues to be addressed with the help of a physiotherapist or a psychologist, whereas high interference on both dimensions highlights the need for a full multidisciplinary assessment.
  • Kuusniemi, Kristiina; Pöyhiä, Reino (2016)
    This paper is a summary of presentations on postoperative pain control by the authors at the 2014 PainForum meeting in People's Republic of China. Postoperative pain is often untreated or undertreated and may lead to subsequent chronic pain syndromes. As more procedures migrate to the outpatient setting, postoperative pain control will become increasingly more challenging. Evidence-based guidelines for postoperative pain control recommend pain assessment using validated tools on a consistent basis. In this regard, consistency may be more important than the specific tool selected. Many hospitals have introduced a multidisciplinary acute pain service (APS), which has been associated with improved patient satisfaction and fewer adverse events. Patient education is an important component of postoperative pain control, which may be most effective when clinicians chose a multimodal approach, such as paracetamol (acetaminophen) and opioids. Opioids are a mainstay of postoperative pain control but require careful monitoring and management of side effects, such as nausea, vomiting, dizziness, and somnolence. Opioids may be administered using patient-controlled analgesia systems. Protocols for postoperative pain control can be very helpful to establish benchmarks for pain management and assure that clinicians adhere to evidence-based standards. The future of postoperative pain control around the world will likely involve more and better established APSs and greater communication between patients and clinicians about postoperative pain. The changes necessary to implement and move forward with APSs is not a single step but rather one of continuous improvement and ongoing change.