Involvement of nitric oxide signaling mechanisms underlying opioid tolerance

326 p.This work focuses on the study of neuropharmacological mechanisms underlying opioid tolerance, in particular, the involvement of NO signalling pathways. Opioids are potent drugs used for pain relief. However, their therapeutic potential is limited as their long-term use leads to the development of tolerance to their analgesic effects. Opioid tolerance is a complex phenomenon and the underlying mechanisms have not been fully elucidated. Understanding the ways in which tolerance can be attenuated would be a significant advantage in the therapeutic use of these agents. The noradrenergic nucleus locus coeruleus (LC) contains a high-density of MORs and it has been extensively used as a model to explore the cellular and molecular mechanisms underlying opioid tolerance. In this regard, there is substantial evidence showing the involvement of mu-opioid receptor (MOR) desensitization in the development of tolerance.The signaling messenger nitric oxide (NO) has been widely recognized to play pivotal roles in the regulation of multiple physiologic and pathophysiological processes. It is produced from L-arginine by the enzymatic action of NO synthase (NOS). The main target of NO is the enzyme soluble guanylyl cyclase (sGC), which catalyzes the formation of 3'5'-cyclic guanosine monophosphate (cGMP). This second messenger activates a number of effectors, such as the cGMP-dependent protein kinase (PKG). NO also reacts with oxygen derivatives to produce reactive oxygen and nitrogen species (ROS), such as the powerful oxidant molecule peroxynitrite. NO modulates opioid actions, as it was found to be involved in Met5-enkephalin (ME)-induced MOR desensitization in vitro and in the neuronal adaptations occurring in vivo during morphine tolerance. We carried out four studies to explore the role of NO and its downstream signaling pathways (sGC/cGMP and ROS) in the adaptations triggered by different opioid agonists both in vitro and in vivo

validation of analgesic effects of naloxone and refeeding

학위논문(박사) -- 서울대학교대학원 : 자연과학대학 뇌인지과학과, 2021.8. 오석배.만성통증은 전 세계적으로 빈번하게 발병하는 질병 중 하나이다. 중증도 이상의 만성통증을 치료하기 위해서는 마약성 진통제가 주로 사용된다. 하지만 마약성 진통제는 외상으로부터 기인하는 통증에는 효과적이나 그 외의 만성통증을 치료하는 데에는 한계가 있는 것으로 알려져 있다. 마약성 진통제의 오남용이나 중독은 심각한 사회문제로 급부상하고 있으며 큰 경제적 손실을 야기한다. 특히 미국에서는 2019년에 마약성 진통제 과다 복용으로 인한 사망자 수가 5만여명에 달했을 정도로 심각한 사회문제로 자리잡고 있다. 따라서 마약성 진통제를 대체할 치료법 개발이 필수적이다. 이에 본 논문에서는 마약성 진통제를 대체할 만성통증 치료 방법을 살펴보았다. 첫 번째 장에서는 약물학적 치료에 중점을 두고 연구하였다. 만성통증은 뇌의 오피오이드 시스템(opioid system)을 변화시키고 이로 인해 통증이 악화되는 것으로 알려져 있다 본 연구에서는 complete Freund adjuvant (CFA)라는 약물을 주사하여 염증성 만성통증을 유발한 쥐의 측좌핵(側坐核)(nucleus accumbens)과 편도체 (扁桃體) (central nucleus of amygdala)에서 카파 오피오이드 시스템(kappa opioid system)이 강화되고 뮤 오피오이드 시스템(mu-opioid system)이 억제됨을 추가로 보여주었다. 이어서 불특정 오피오이드 수용체의 길항제 (antagonist)인 나록손 (naloxone) (10 mg/kg)을 주사했을 때 자발통이 감소되는 것을 확인하였다. 카파 오피오이드 수용체의 길항제인 nor-BNI를 주사하였을 때에도 자발통이 감소하였다. 마지막으로 나록손과 nor-BNI를 뇌의 측좌핵과 편도체에 직접 주사했을 때 역시 자발통이 줄어드는 것을 확인하였다. 이를 통해 오피오이드의 길항제가 만성통증을 치료하는데 효과적임을 확인하였다. 만성통증은 심리적, 인지적 요소가 관련 되어있어 약물만으로는 치료가 어렵다. 따라서 두 번째 장에서는 비약물학적 만성통증 치료방법에 대하여 연구하였다. 운동부족, 스트레스, 수면부족, 불규칙한 섭식행동과 같은 비건전한 생활습관은 만성통증과 밀접한 관련이 있다고 알려져 있다. 그 중에서도 섭식습관 개선은 모두가 쉽게 접근할 수 있는 방법으로 이번 장에서는 섭식습관 개선을 통한 만성통증 치료에 초점을 두고 연구하였다. 현재까지 많은 연구들이 24 시간 단식과, 24 시간 단식 후 2 시간 재섭취가 진통효과를 나타낼 수 있음을 보여주었다. 24시간 단식으로 인한 진통효과의 기전은 밝혀져 있지만 24시간 단식 후 2시간 재섭취의 진통효과의 기전은 아직 밝혀지지 않고 있어 본 연구에서는 그 기전을 찾는 것을 목표로 하였다. 첫째로, 염증성 만성통증 상황에 측좌핵(側坐核)(nucleus accumbens)의 외피(外皮)(shell)와 뇌섬엽 (腦島葉) (insular cortex)의 앞쪽부분에서 신경활동이 증가했음을 확인하였다. 만성통증 상황에 뇌섬엽 앞부분에서 측좌핵 껍질로 신호를 전달하는 신경세포의 활성이 증가되고 재섭취 후에는 그 활성이 다시 감소되는 것을 확인하였다. 나아가 화학유전학 기법을 이용하여 이 회로를 억제하였을 때 만성통증이 감소하고, 이 회로를 활성화하였을 때 재섭취로 인하여 생겼던 진통 반응이 사라지는 것을 추가로 확인함으로써 24시간 단식 후 2시간 재섭취로 인한 진통 기전에는 뇌섬엽 앞부분과 측좌핵의 외피간의 신경회로가 관여하고 있다는 것을 알 수 있었다. 이 논문은 마약성 진통제 사용을 줄이며 부작용 없이 만성통증을 치료하는 약물학적, 비약물학적 방법에 대하여 소개한다.Chronic pain is a major public health problem worldwide that is highly prevalent. Among the available pharmacological treatments, opioids are widely used to treat moderate-to-severe chronic pain. Although these drugs are important tools for treating acute postoperative and traumatic pain, their comparative effectiveness and usefulness for chronic pain are questioned. Also, the misuse and addiction to opioids is a serious national crisis that affects public health as well as social and economic welfare. Surprisingly, in 2019, nearly 50,000 people in the United States died from opioid-involved overdoses. Therefore, exploring alternative effective treatments for chronic pain is important to decrease or eliminate opioid use. Hence, in this thesis, I aimed to explore the non-opioid treatments for chronic inflammatory pain. In the first chapter, I focused on non-opioid pharmacological management. Alteration of the opioid system in the brain is known to exacerbate chronic pain. Hence, I focused on reversing the altered brain opioid system with pain chronification. In this chapter, using the Complete Freund’s adjuvant-induced (CFA) chronic inflammatory pain animal model, I showed that the kappa opioid system was enhanced, and the mu-opioid system was suppressed within the nucleus accumbens (NAc) and the central nucleus of the amygdala (CeA), but not in other brain areas. Systemic administration of a general opioid antagonist (naloxone, 10 mg/kg), or a kappa-opioid receptor antagonist (norbinaltorphimine, nor-BNI 10 mg/kg) reduced spontaneous pain behavior in the CFA model. Furthermore, microinjection of both naloxone and nor-BNI into the NAc and CeA also significantly reduced spontaneous chronic pain behavior. Since chronic pain has emotional and cognitive features, there is a limit to control pathological pain through pharmacological treatment. Therefore, I aimed to study the non-pharmacological treatment of chronic pain in chapter 2. Lifestyle factors such as physical inactivity, stress, poor sleep, and an unhealthy diet are associated with chronic pain. Among them, feeding behavior modification is accessible for every patient. Hence, I focused on managing chronic pain via feeding behavior modification in this chapter. Accumulating evidence showed an analgesic effects of fasting and refeeding after 24 hr fasting. However, while brain circuits mediating fasting-induced analgesia have been identified, the underlying mechanism of refeeding-induced analgesia is still elusive. Hence, I sought to explore the underlying mechanism of refeeding-induced analgesia in this chapter. I demonstrated that the neural activities in the nucleus accumbens shell (NAcS) and anterior insular cortex (aIC) were increased in chronic inflammatory pain conditions, which was reversed by refeeding. I also found that refeeding reduced the enhanced excitability of aIC – NAcSD2R projecting neurons in this CFA model. Besides, chemogenetic inhibition of aIC–NAcSD2R neural circuit suppressed chronic pain behavior while activation of this circuit. Altogether, my thesis provides an alternative non-opioid treatment option for managing chronic pain without causing significant side effects, which may allow the reduction of opioid use.Contents 6 List of figures 7 Background 9 Purpose 24 CHAPTER 1:Naloxone-induced analgesia mediated by central kappa opioid system in chronic inflammatory pain 25 Abstract 26 Introduction 28 Materials and Methods 30 Results 34 Discussion 38 CHAPTER 2: Anterior insular-nucleus accumbens pathway controls refeeding-induced analgesia under chronic inflammatory pain condition 50 Abstract 51 Introduction 52 Materials and Methods 54 Results 61 Discussion 83 General discussion 89 References 92 국문초록 105박

Involvement of nitric oxide signaling mechanisms underlying opioid tolerance

326 p.This work focuses on the study of neuropharmacological mechanisms underlying opioid tolerance, in particular, the involvement of NO signalling pathways. Opioids are potent drugs used for pain relief. However, their therapeutic potential is limited as their long-term use leads to the development of tolerance to their analgesic effects. Opioid tolerance is a complex phenomenon and the underlying mechanisms have not been fully elucidated. Understanding the ways in which tolerance can be attenuated would be a significant advantage in the therapeutic use of these agents. The noradrenergic nucleus locus coeruleus (LC) contains a high-density of MORs and it has been extensively used as a model to explore the cellular and molecular mechanisms underlying opioid tolerance. In this regard, there is substantial evidence showing the involvement of mu-opioid receptor (MOR) desensitization in the development of tolerance.The signaling messenger nitric oxide (NO) has been widely recognized to play pivotal roles in the regulation of multiple physiologic and pathophysiological processes. It is produced from L-arginine by the enzymatic action of NO synthase (NOS). The main target of NO is the enzyme soluble guanylyl cyclase (sGC), which catalyzes the formation of 3'5'-cyclic guanosine monophosphate (cGMP). This second messenger activates a number of effectors, such as the cGMP-dependent protein kinase (PKG). NO also reacts with oxygen derivatives to produce reactive oxygen and nitrogen species (ROS), such as the powerful oxidant molecule peroxynitrite. NO modulates opioid actions, as it was found to be involved in Met5-enkephalin (ME)-induced MOR desensitization in vitro and in the neuronal adaptations occurring in vivo during morphine tolerance. We carried out four studies to explore the role of NO and its downstream signaling pathways (sGC/cGMP and ROS) in the adaptations triggered by different opioid agonists both in vitro and in vivo

The role of the gut microbiome and microbial metabolism in mediating opioid-induced changes in the epigenome

The current opioid pandemic is a major public health crisis in the United States, affecting millions of people and imposing significant health and socioeconomic burdens. Preclinical and clinical research over the past few decades has delineated certain molecular mechanisms and identified various genetic, epigenetic, and environmental factors responsible for the pathophysiology and comorbidities associated with opioid use. Opioid use-induced epigenetic modifications have been identified as one of the important factors that mediate genetic changes in brain regions that control reward and drug-seeking behavior and are also implicated in the development of tolerance. Recently, it has been shown that opioid use results in microbial dysbiosis, leading to gut barrier disruption, which drives systemic inflammation, impacting the perception of pain, the development of analgesic tolerance, and behavioral outcomes. In this review, we highlight the potential role of microbiota and microbial metabolites in mediating the epigenetic modifications induced by opioid use

New insights into enhancing morphine analgesia : from glia to pharmacokinetics

Opioid analgesics are effective in relieving acute and chronic pain. However, adverse effects and the development of opioid dependence and tolerance may restrict the use of opioids and result in inadequate pain relief. The effects of four structurally and functionally different drugs already on the market, ibudilast, atipamezole, spironolactone, and ketamine, were studied in coadministration with morphine, the prototypical mu-opioid receptor agonist. Experiments were conducted using thermal and mechanical tests of nociception in male Sprague-Dawley rats. Morphine tolerance was produced during four days by subcutaneous or intrathecal delivery of morphine. Drug and metabolite concentrations were measured using high-pressure liquid chromatography-tandem mass spectrometry. The objective of the thesis study was to search for potential drugs to augment morphine antinociception and prevent opioid tolerance. Ibudilast, a phosphodiesterase and macrophage inhibitory factor inhibitor, had transient sedative effects, but it restored the antinociceptive effect of morphine in morphine-tolerant rats after single and repeated administration. It did not prevent the development of opioid tolerance. Atipamezole, an alpha-2-adrenoceptor antagonist used for the reversal of sedation in animals during anesthesia, was effective in augmenting intrathecal morphine antinociception in both opioid-naïve and opioid-tolerant animals. These effects were observed at doses lower than those required for the antagonism of alpha-2-adrenoceptors. In subcutaneous administration, low doses of atipamezole did not influence morphine antinociception. The mineralocorticoid receptor antagonist spironolactone dose-dependently enhanced morphine antinociception. This effect was mediated via the increased access of morphine to the central nervous system by the inhibition of the efflux protein P-glycoprotein. Spironolactone did not inhibit the metabolism of morphine to the pronociceptive metabolite morphine-3-glucuronide, and it did not prevent the development of opioid tolerance. The effects of ketamine in augmenting opioid analgesia in tolerance are thought to result from a beneficial pharmacodynamic interaction. When acute ketamine was administered to rats under chronic morphine treatment, the brain concentrations of morphine, ketamine and norketamine were increased compared with the situation where either morphine treatment or acute ketamine were administered alone. The results indicate a potentially beneficial pharmacokinetic interaction between the two drugs. The results of the thesis study demonstrate that ibudilast and atipamezole modulate nociception at systemic and spinal levels in preclinical models of pain, and they may prove advantageous as an adjuvant to opioid therapy. Spironolactone had a pharmacokinetic interaction with morphine, leading to increased morphine concentrations in the central nervous system. Ketamine, a drug used for the treatment of opioid tolerance in cancer patients, may undergo previously unrecognized beneficial pharmacokinetic interactions with morphine.Opioidit, morfiinin kaltaiset kipulääkkeet, ovat tehokkaimpia lääkkeitä etenkin akuutin kivun hoidossa. Haittavaikutukset ja opioideille muodostuva toleranssi eli sietokyvyn lisääntyminen saattavat kuitenkin rajoittaa opioidien käyttöä ja johtaa epätyydyttävään kivun lievitykseen pitkittyneessä kivussa. Tässä tutkimuksessa tarkasteltiin neljää sekä rakenteellisesti että toiminnallisesti erilaista lääkettä, ibudilastia, atipametsolia, spironolaktonia ja ketamiinia, kokeellisissa opioidihoidon rottamalleissa. Tutkimuksessa käytettiin ihmisillä käytettävien kiputestien kaltaisia kuuman ja mekaanisen kivun väistötestejä sekä sedaatiota ja koordinaatiota mittaavia testejä. Opioidihoidon eri vaiheita mallinnettiin aina akuutista kerta-annosta nelipäiväiseen opioditoleranssimalliin. Opioideja ja tutkimuslääkkeitä annettiin joko nahanalaisesti tai suoraan aivo-selkäydinnesteeseen tutkimusmallista ja -lääkkeestä riippuen. Lääkkeiden ja niiden hajoamistuotteiden pitoisuuksia mitattiin kromatografialla. Tutkimuksen tarkoituksena oli etsiä uusia lääkehoitomahdollisuuksia opioidihoidon tehostamiseksi ja etenkin opioidien vasteen palauttamiseksi. Astmalääke ibudilastia on tutkittu usean neurologisen sairauden hoitoon mahdollisen keskushermoston gliasolujen patologisen aktivaation estäjänä. Sillä oli rottamallissa lievä sedatiivinen vaikutus, mutta se palautti tehokkaasti morfiinin kipua lievittävän vasteen opioiditoleranssissa. Se ei kuitenkaan estänyt opioiditoleranssin kehittymistä. Ibudilastin vaikutusmekanismi vaatii lisäselvityksiä. Alfa-2-reseptoreiden estäjä atipametsolia käytetään eläinlääkkeenä anestesian jälkeisessä eläinten herätyksessä. Aivo-selkäydinnesteeseen annettuna atipametsoli lisäsi morfiinin antinosiseptiivista vastetta sekä akuutissa yhteisannossa morfiinin kanssa sekä opioiditoleranssimallissa. Nämä vaikutukset havaittiin hyvin pienillä annoksilla atipametsolia. Nahan alle annosteltuna vastaavaa yhteisvaikutusta morfiinin kanssa ei havaittu. Nesteenpoistolääkkeenä käytetty spironolaktoni lisäsi morfiinin antinosiseptiivista vaikutusta sekä akuutissa yhteisannossa että toleranssimallissa. Pitoisuustutkimuksissa havaittiin spironolaktonin lisäävän morfiinin keskushermostopitoisuuksia. Tämä vaikutus välittyi todennäköisesti lääkeainekuljetusproteiini P-glykoproteiinin estovaikutuksen kautta. Spironolaktoni ei ehkäissyt opioiditoleranssin kehitystä. NMDA-reseptorin estäjä ketamiinin on ajateltu palauttavan opioidien vastetta reseptorien kautta välittyvien farmakodynaamisten yhteisvaikutusten kautta. Lääkkeiden pitoisuusmittauksissa havaittiin, että morfiinitoleranteilla rotilla morfiinin, ketamiinin ja norketamiinin keskushermostopitoisuudet olivat yhteisannossa lisääntyneet huomattavasti verrattuna tilanteeseen, jossa lääkkeitä annettiin yksinään. Ketamiinin hyödyllinen vaikutus opioiditoleranssissa saattaa siis osittain perustua myös farmakokineettiseen yhteisvaikutukseen

The Impact Of Advanced Age On Morphine Anti-Hyperalgesia And The Role Of Mu Opioid Receptor Signaling In The Periaqueductal Gray Of Male And Female Rats

Opioids are among the most potent and widely used drugs for the management of chronic pain. Chronic pain is exceedingly prevalent in individuals over 65 years of age but is under-managed in this population, due in part to a lack of knowledge regarding the suitable dosing of opioids for chronic pain management. The present experiments first seek to characterize the impact of advanced age on opioid potency in male and female rats using intraplantar Complete Freund\u27s adjuvant (CFA), a clinically relevant model of inflammatory pain. We report that advanced age and sex alter morphine modulation of persistent inflammatory pain, specifically, morphine potency was highest in adult male rats (2mos), with a 2-fold rightward shift in the dose-response curve for aged males (18mos), and females regardless of age. These findings suggest that opioids have decreased anti-hyperalgesic potency in aged rodents compared to adults, prompting us to determine the neural mechanisms underlying this attenuated response. Morphine-induced analgesia is mediated primarily via binding to μ-opioid receptors (MOR) within the midbrain periaqueductal gray (PAG), a critical site for descending pain modulation. The present studies use cellular and pharmacological techniques to examine MOR binding and signaling within the PAG. The data in this thesis thoroughly characterize the impact of advanced and biological sex on PAG MOR expression, binding, and signaling within the PAG in the presence of chronic inflammatory pain, and thus have significant implications for pain management in the aged population. These studies contribute to our understanding of how advanced age and sex alter morphine anti-hyperalgesia and enhance our knowledge of age- and sex-induced changes in PAG MOR signaling. Our findings identify novel therapeutic targets to improve opioid signaling in the aged brain and develop effective chronic pain management strategies

Electrophysiological characterisation of neuronal components of cold sensitivity

Aberrant cold sensitivity is apparent in several neuropathies of peripheral and central origin, and is poorly treated by currently available drugs. In an attempt to understand the mechanisms of cold evoked hyperalgesia and analgesia, these studies examined the dual pro- and anti-nociceptive roles of TRPM8, a cold temperature gated channel, and the role of calcium channels within cold sensitive pathways through a combination of in vivo electrophysiology, behavioural measures and gene ablation. Blocking TRPM8 with novel antagonists revealed lamina V/VI neuronal responses to innocuous and noxious cold stimulation were conserved in naïve rats. However, under neuropathic conditions inhibition of TRPM8 decreased neuronal responses to innocuous and noxious cold stimuli. This corresponded with an attenuation of behavioural hypersensitivity to innocuous cooling. Remarkably, systemically activating TRPM8 with a novel agonist resulted in identical neuronal and behavioural effects in neuropathic rats. Menthol is known to relieve various pain conditions as well as inducing hyperalgesia. Unlike in human subjects, menthol fails to induce central sensitisation in naïve rats, whereas in neuropathic rats topical menthol exerts some similar effects to the systemically dosed TRPM8 agonist. Gene ablation identifies a role of α2δ-1, an auxiliary calcium channel subunit, in cold and mechanical sensory pathways, likely dependent on impaired trafficking of calcium channels. Furthermore, α2δ-1 knockout mice exhibit a delay in the development of neuropathic like behaviours after injury. In neuropathic rats, systemic and spinal delivery of an activation state dependent Cav2 antagonist suppresses neuronal responses to mechanical stimuli but reveals no change in channel function within cold sensitive pathways. These findings expand the understanding of the neural basis of cold sensitivity and demonstrate TRPM8 is not essential to all forms of cold transduction in naïve rats, and that both inhibiting and activating TRPM8 have similar selective modality related inhibitory effects on cold transduction in neuropathic rats

Mechanisms of pain processing: spinal protein translation in the rat

The word ‘pain’ is described by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Shifts in pain thresholds and responsiveness are an expression of neural plasticity, a process whereby changes in the nervous system modulate the response to a given stimulus. It is widely believed that this process may contribute to chronic pain. Forms of long-term plasticity specifically require protein synthesis and such mechanisms are widely believed to be cellular counterparts of long-term memory. Relevant to mammalian pain nociceptors is the realisation that messenger ribonucleic acid (mRNA) in dendrites, axons, axon terminals as well as cell bodies, is essential for long-term synaptic plasticity and may therefore be important in pain processing. The protein kinase mammalian target of rapamycin (mTOR) is a key regulator of protein translation and can be specifically inhibited by the drug rapamycin and the rapamycin analogue cell cycle inhibitor (CCI)-779 (CCI-779). This was investigated in rats under physiological conditions and also pathophysiological conditions relevant to clinical pain syndromes i.e. persistent pain-like states. A variety of techniques were utilised: in vivo electrophysiology was used to obtain extracellular single unit recordings of spinal cord lamina V wide dynamic range (WDR) neurones that respond to innocuous and noxious stimuli to peripheral sites i.e. the rat hind paw; behavioural studies were used to assess the progression of pain-like states and assess the effects of rapamycin/CCI-779 on this behaviour and immunohistochemistry was used to visualise active components of rapamycin-sensitive protein translation pathways at the spinal level. In addition, the dependence of these spinal mechanisms on descending serotonergic pathways from higher brain centres was investigated pharmacologically by selectively activating or blocking serotonergic spinal 5-HT3 receptors. These pathways have already been proven to be pivotal in the maintenance of persistent pain-like states. The results suggest that mTOR has a continuous role in maintaining persistent pain-like states via rapid local protein translation, which can be influenced by descending facilitatory controls from higher centres in the brain

Ketamine for postoperative pain in adults

Suboptimal postoperative pain management increases complication rates and health care costs, and is a risk factor for chronic postoperative pain. Opioids have been the pharmacological cornerstone in postoperative pain management but adverse effects may limit their use. Multimodal analgesia combines different pain treatment modalities, aiming to reduce pain intensity, decrease opioid consumption and opioid-related adverse effects. Low-dose ketamine modulates molecular and cellular mechanisms behind pain and mitigates the development of opioid tolerance. The optimal dosing regimen of ketamine, and timing of dosing have not been established. The aim of the research was to evaluate the efficacy and tolerability of perioperative intravenous (IV) ketamine in adult patients when used for adjunct analgesia. The thesis constitutes of a Cochrane review (130 RCTs, 8341 patients) and two prospective, randomized, placebo-controlled and double- blinded clinical trials on adult patients undergoing spinal fusion surgery (198 patients and 100 patients, respectively). The RCTs compared two different intraperative IV infusions of S- ketamine with placebo and three different doses of S-ketamine added to an IV oxycodone patient-controlled analgesia (PCA). Perioperative IV ketamine reduced postoperative opioid consumption over 24 h and 48 h by 19%. With two different doses of intraoperative IV S-ketamine in lumbar fusion surgery, differences with placebo in 48 h oxycodone consumption were not significant. S-ketamine added to oxycodone IV-PCA in a ratio 0.75:1 reduced oxycodone need by 25% 24 h postoperatively. Postoperative pain intensity after perioperative IV ketamine administration was approximately 20% lower bot at rest and during movement. The degree of pain relief was greater following thoracic, major orthopedic, and major abdominal surgery. Both intraoperative S-ketamine infusions decreased pain scores significantly only at 4th postoperative hour after lumbar fusion surgery. A significant beneficial effect in mean change in pain intensity during the first 24 h after lumbar fusion surgery was achieved when the S-ketamine:oxycodone ratio in an IV-PCA was 0.75:1. All studies showed that perioperative IV ketamine and S-ketamine did not induce significant CNS adverse events. Approximately 5% of patients receiving perioperative IV ketamine experienced CNS adverse events, compared to 4% of controls. Perioperative IV ketamine reduced PONV from 27% with placebo to 23% with ketamine. Differences in the occurrence of PONV were nonsignificant in patients undergoing lumbar fusion surgery when S-ketamine was administered either as intraoperative infusions or as an adjunct with oxycodone IV-PCA. Conclusions: Ketamine and S-ketamine reduce postoperative pain intensity and opioid consumption especially in operations that are likely to induce more intense pain. Administration via IV-PCA in the postoperative period should be favoured over infusions after lumbar fusion surgery. Ketamine and S-ketamine cause negligible adverse events.Riittämätön kivunhoito leikkauksen jälkeen lisää haittatapahtumien esiintyvyyttä, viivästyttää potilaan kuntoutumista ja kasvattaa terveydenhuollon kustannuksia. Huonosti hoidettu leikkauksenjälkeinen kipu on myös pitkittyneen kivun merkittävä riskitekijä. Välitön leikkauksenjälkeinen kivunhoito on perustunut pitkälti opioideihin. Opiodien käyttöön liittyy kuitenkin merkittäviä haittavaikutuksia, jotka voivat rajoittaa niistä saatavaa hyötyä. Multimodaalinen kivunhoito yhdistää erilaisia kivunhoidon keinoja. Käytännössä multimodaalisen kivunhoidon tavoite on vähentää leikkauksenjälkeisen kivun voimakkuutta, vähentää opioidinkulutusta ja opioideihin liittyvien haittavaikutusten esiintymistä, nopeuttaa toipumista sekä parantaa potilaan kokemusta kivunhoidosta. Ketamiini on N-metyyli-D-aspartaatti (NMDA) -reseptorin antagonisti. Sen on havaittu pienellä annoksella vaimentavan kivun synnyn, opioiditoleranssin ja opioidien aiheuttaman hyperalgesian taustalla olevia mekanismeja. Ketamiinia on tutkittu kivunhoidossa laajasti, mutta sen ihanteellinen annostelu ja annosteluajankohta ovat vielä vakiintumatta. Väitöskirjatutkimuksen tavoitteena oli selvittää perioperatiivisen (leikkauksen alussa, leikkauksenaikana, leikkauksen jälkeen annostellun) laskimonsisäisen ketamiinin tehoa leikkauksenjälkeisen kivun hoidossa aikuisilla keskittyen erityisesti S-ketamiinin käyttöön lannerangan luudutusleikkauksen yhteydessä. Lisäksi halusimme selvittää, onko ketamiinin vaikutus annosriippuvainen, ja arvioida sen ihanteellista annosteluajankohtaa leikkauksenjälkeisen kivun hoidon kannalta. Lisäksi arvioimme pieniannoksisisen ketamiinin siedettävyyttä kivunhoidossa. Väitöskirja koostui Cochrane-kirjallisuuskatsauksesta meta-analyyseineen (osatyö I) sekä kahdesta prospektiivisesta, satunnaistetusta, kaksoissokkoutetusta, lumekontrolloidusta kliinisestä tutkimuksesta (osatyöt II ja III). Cochrane-katsauksen perusteella perioperatiivinen laskimonsisäinen ketamiini vähensi leikkauksenjälkeistä kipua ja opiodinkulutusta kohtalaisesti (noin 20 %). Ketamiinin vaikutus oli suurempi tilanteissa, joissa leikkauksenjälkeinen kipu oli kovaa. Kliinisten tutkimustemme perusteella leikkauksenaikainen S-ketamiini-infuusio ei tuonut merkittävää hyötyä lannerangan luudutusleikkauksen jälkeisen kivun hoidossa (osatyö II), mutta kun S-ketamiini annosteltiin yhdessä oksikodonin kanssa lannerangan luudutusleikkauksen jälkeen ns. kipupumpun kautta (opioid PCA; opioid patient-controlled analgesia; opiodien itseannostelu), S-ketamiinin kipua lieventävä ja oksikodonin kulutusta vähentävä vaikutus oli merkittävä 24 h kohdalla leikkauksen jälkeen (osatyö III). Sekä Cochrane-katsauksen että kliinisten tutkimusten tulosten perusteella ketamiinin ihanteellinen annosteluajankohta vaikuttaisi olevan leikkauksenjälkeisessä vaiheessa. Kliinisistä tutkimuksista saamiemme tulosten perusteella lannerangan luudutusleikkauksen jälkeisen kivun hoidossa tulisi suosia oksikodonin ja S-ketamiinin yhdistelmää PCA:n kautta annosteltuna (osatyöt II ja III). Oksikodonin ja ketamiinin ihanteellinen annostelusuhde vaikuttaisi olevan 1: 0.75 (osatyö III). Perioperatiivisesti annosteltu laskimonsisäinen ketamiini ei lisännyt keskushermostohaittavaikutusten esiintymistä. Leikkauksenjälkeisen pahoinvoinnin ja oksentelun riski jopa väheni hieman