Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2004. / Härtill 6 uppsatser.

Made available in DSpace on 2014-06-11T19:31:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-16Bitstream added on 2014-06-13T18:41:45Z : No. of bitstreams: 1 rondon_es_dr_jabo.pdf: 759675 bytes, checksum: 0a47e2de920daaecf1959b4694ea81db (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Em dois ensaios testou-se a eficácia da cetamina e do ifenprodil administrados preventivamente e por via subaracnóidea, no controle da hiperalgesia induzida (p 0,05). As provas farmacológicas utilizaram ratos Wistar em duas etapas: determinação da potência relativa e isobologramas. O estímulo hiperalgésico — injeção intraplantar de prostaglandina E2 - foi avaliado com um analgesímetro digital. Todos fármacos apresentaram ação anti-hiperalgésica com diferentes valores de EC50 crescentes nesta ordem: ifenprodil, cetamina S(+), cetamina racêmica e cetamina R(-). O ifenprodil potencializou a ação da cetamina e seus isômeros e foi potencializado pelo racemato e a forma S(+). Os resultados embasaram os ensaios clínicos. Nestes, oito cães foram utilizados para comparar o efeito anti-hiperalgésico do ifenprodil associado à cetamina racêmica com o uso isolado desta, durante 24 h após lesão cirúrgica incisional no coxim metatársico. Foram avaliados os escores de sedação e de claudicação; contagens da freqüência cardíaca e da respiratória; testes com filamentos de von Frey e medição da superfície de apóio plantar com planímetro nos tempos basal e 60, 90, 120, 180, 240, 480, 720 e 1440 min pós-trauma. A comparação entre grupos e ao longo do tempo revelou que os escores se mantiveram inalterados e as freqüências não variaram significativamente. Os testes de von Frey e com planímetro demonstraram diferenças significativas entre os protocolos. Concluiu-se que, ainda que o estímulo seja cirúrgico, o pré-tratamento com ifenprodil melhora a ação anti-hiperalgésica da cetamina racêmica nas primeiras 24 horas após a lesão. / In two different opportunities, it was tested the efficacy of cetamina and ifenprodil, administered preventively and by spinal route, in the control of induced hyperalgesia (P5 0.05). The pharmacological tests had used Wistar rats in two stages: determination of the relative power and isobolograms. The hyperalgesic stimulus — E2 prostaglandin intraplantar injection — was evaluated by electronic pressure meter. Ali the drugs had presented antihyperalgesic action with different ED50 values increasing in this order: ifenprodil, S(+) ketamine, racemic ketamine and R(-) ketamine. lfenprodil potentiated ketamine and its isomers action, and was potentiated by racemate and S(+) form. fie results had based the clinicai tests. In these, eight dogs had been used to compare the antihyperalgesic effect of ifenprodil associated with ketamine with the isolated use of ketamine during 24 hours after surgicai incision in the metatarsal pad. Sedation and claudication scores, respiratory and cardiac rates, von Frey filaments tests and the determination of plantar support area had been used in baseline and 60, 90, 120, 180, 240, 480, 720 and 1440 min after-trauma. The comparison between groups and throughout the time showed that lhe scores had kept unchanged and the rates had not varied significantly. The tests with von Frey filaments and with planimeter had demonstrated significant differences between the protocols. One concluded that, despite the stimulus is surgical, pretreatment with ifenprodil improves lhe antihyperalgesic action of racemic ketamine in the first 24 hours after the injury.

Resumo: Em dois ensaios testou-se a eficácia da cetamina e do ifenprodil administrados preventivamente e por via subaracnóidea, no controle da hiperalgesia induzida (p 0,05). As provas farmacológicas utilizaram ratos Wistar em duas etapas: determinação da potência relativa e isobologramas. O estímulo hiperalgésico - injeção intraplantar de prostaglandina E2 - foi avaliado com um analgesímetro digital. Todos fármacos apresentaram ação anti-hiperalgésica com diferentes valores de EC50 crescentes nesta ordem: ifenprodil, cetamina S(+), cetamina racêmica e cetamina R(-). O ifenprodil potencializou a ação da cetamina e seus isômeros e foi potencializado pelo racemato e a forma S(+). Os resultados embasaram os ensaios clínicos. Nestes, oito cães foram utilizados para comparar o efeito anti-hiperalgésico do ifenprodil associado à cetamina racêmica com o uso isolado desta, durante 24 h após lesão cirúrgica incisional no coxim metatársico. Foram avaliados os escores de sedação e de claudicação; contagens da freqüência cardíaca e da respiratória; testes com filamentos de von Frey e medição da superfície de apóio plantar com planímetro nos tempos basal e 60, 90, 120, 180, 240, 480, 720 e 1440 min pós-trauma. A comparação entre grupos e ao longo do tempo revelou que os escores se mantiveram inalterados e as freqüências não variaram significativamente. Os testes de von Frey e com planímetro demonstraram diferenças significativas entre os protocolos. Concluiu-se que, ainda que o estímulo seja cirúrgico, o pré-tratamento com ifenprodil melhora a ação anti-hiperalgésica da cetamina racêmica nas primeiras 24 horas após a lesão. / Abstract: In two different opportunities, it was tested the efficacy of cetamina and ifenprodil, administered preventively and by spinal route, in the control of induced hyperalgesia (P5 0.05). The pharmacological tests had used Wistar rats in two stages: determination of the relative power and isobolograms. The hyperalgesic stimulus - E2 prostaglandin intraplantar injection - was evaluated by electronic pressure meter. Ali the drugs had presented antihyperalgesic action with different ED50 values increasing in this order: ifenprodil, S(+) ketamine, racemic ketamine and R(-) ketamine. lfenprodil potentiated ketamine and its isomers action, and was potentiated by racemate and S(+) form. fie results had based the clinicai tests. In these, eight dogs had been used to compare the antihyperalgesic effect of ifenprodil associated with ketamine with the isolated use of ketamine during 24 hours after surgicai incision in the metatarsal pad. Sedation and claudication scores, respiratory and cardiac rates, von Frey filaments tests and the determination of plantar support area had been used in baseline and 60, 90, 120, 180, 240, 480, 720 and 1440 min after-trauma. The comparison between groups and throughout the time showed that lhe scores had kept unchanged and the rates had not varied significantly. The tests with von Frey filaments and with planimeter had demonstrated significant differences between the protocols. One concluded that, despite the stimulus is surgical, pretreatment with ifenprodil improves lhe antihyperalgesic action of racemic ketamine in the first 24 hours after the injury. / Orientador: Carlos Augusto Araújo Valadão / Coorientador: Carlos Amilcar Parada / Banca: Juan Carlos Duque Moreno / Banca: Silvana Lima Górniak / Banca: Stelio Pacca Loureiro Luna / Banca: Antonio de Queiroz Neto / Doutor

Ketamine is a dissociative anesthetic prescription drug and has been used for general anesthesia. The research surrounding this chemical compound has revealed conflicting evidence of its potential use in health care and addiction treatment. On one side, ketamine is a widespread drug of abuse associated with neurocognitive deficits and neurotoxicity, on the other side ketamine has recently been found to have a variety of potential uses, including but not limited to; antidepressant effects, reconsolidation of drug-related memories and disrupting maladaptive rumination. Ketamine’s ability to induce psychedelic and mystic experiences, reconsolidation of memories, antidepressant effects, and its ability to reduce cue-induced drug craving makes it a potentially useful tool in drug abuse therapy. Most of the negative side-effects of ketamine seem to be apparent at high doses and in frequent use but low doses and non-frequent use has a low risk of harm, therefore, careful consideration and extensive research are required before ketamine can be widely used in the public and in health care for treatment strategies. This thesis aims to explore the role of ketamine and its neurobiological effects in the treatment of addiction and depression.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A esquizofrenia à um transtorno psiquiÃtrico grave e, talvez, por isso, um dos mais pesquisados. Apesar dos importantes avanÃos realizados nos estudos sobre a fisiopatologia da doenÃa, durante o sÃculo passado, poucos benefÃcios foram significativos no tratamento pacientes. A elaboraÃÃo de novos modelos animais de esquizofrenia à uma ferramenta importante para a compreensÃo da fisiopatologia da doenÃa e para o desenvolvimento de novas terapias, uma vez que atà mesmo os antipsicÃticos atÃpicos nÃo mostraram os resultados esperados em relaÃÃo à melhora dos sintomas negativos e cognitivos. O objetivo desta pesquisa foi investigar os efeitos da cetamina no sistema nervoso central como um possÃvel agente em um modelo neurodesenvolvimental da esquizofrenia. Procurou-se determinar as alteraÃÃes de comportamento e estresse oxidativo pela administraÃÃo de cetamina neonatal, bem como a reversÃo e prevenÃÃo destes efeitos pelo tratamento com clozapina, um antipsicÃtico atÃpico. TambÃm realizou-se a avaliaÃÃo do sexo no desenvolvimento da esquizofrenia, dividindo as fÃmeas pelo ciclo estral, cujas fases apresentam concentraÃÃes altas e baixas de estrogÃnio, proestro e diestro, respectivamente, visto que estrogÃnio apresenta um efeito neuroprotetor. O delineamento experimental seguiu os critÃrios para determinar um modelo animal: a validade de face (onde se procura imitar o comportamento caracterÃstico da doenÃa no animal), validade do constructo (a fisiopatologia da doenÃa) e validade preditiva (se os medicamentos estabelecidos para a doenÃa sÃo capazes de inverter e prevenir os efeitos que a droga pesquisada induz). Os animais utilizados no protocolo experimental foram ratos Wistar, divididos em seis grupos e tratados com soluÃÃo salina ou cetamina intraperitoneal (i.p.) durante cinco dias (7Â- 11 dias apÃs o nascimento). Grupo 1 (machos tratados com soluÃÃo salina); Grupo 2 (fÃmeas tratadas com soluÃÃo salina) ; Grupo 3 (machos tratados com cetamina 2,5 mg/kg), Grupo 4 (fÃmeas tratadas com cetamina 2,5 mg/kg), grupo 5 (machos tratados com cetamina 5 mg/kg); Grupo 6 (fÃmeas tratadas com cetamina 5 mg/kg). Os testes de inibiÃÃo prÃ-pulso e y-maze (testes comportamentais) foram realizados na adolescÃncia (35 dias apÃs o nascimento), e repetidos na fase adulta (65 dias apÃs o nascimento). Na fase adulta, as fÃmeas foram divididas de acordo com o ciclo menstrual (diestro e de proestro) para observar a interferÃncia do estrogÃnio. No 66 dia apÃs o nascimento, os animais tratados com cetamina 5 mg/kg foram submetidos ao tratamento de reversÃo pela administraÃÃo de clozapina 10 mg/kg (i.p.), uma vez ao dia, durante 10 dias. ApÃs este perÃodo, os testes comportamentais e neuroquÃmicos (dosagem de BDNF e GSH) foram realizados. Os animais tratados com cetamina 2,5 mg/kg nÃo apresentaram qualquer diferenÃa significativa nos testes comportamentais realizados na fase adulta, quando comparados com os animais tratados com soluÃÃo salina, e, portanto, a dose escolhida para medir os outros parÃmetros foi de 5 mg/kg. O tratamento com cetamina 5 mg/kg reduziu significativamente os parÃmetros observados nos testes comportamentais, em machos e fÃmeas no diestro, na fase adulta. Os machos e as fÃmeas no diestro tambÃm apresentaram uma reduÃÃo significativa nos nÃveis de GSH. Os machos adultos tratados com cetamina 5 mg/kg apresentaram um aumento significativo de BDNF, enquanto que as fÃmeas no diestro os apresentaram uma reduÃÃo neste parÃmetro. As fÃmeas no proestro alcanÃaram um melhor desempenho em todos os testes. No protocolo de prevenÃÃo, o tratamento com clozapina 10mg/kg reverteu os efeitos da cetamina para os ensaios de inibiÃÃo prÃ-pulso e nos testes neuroquÃmicos, em machos e fÃmeas no diestro, tratados com cetamina 5 mg/kg. Os resultados observados nos testes comportamentais e neuroquÃmicas demonstraram que a cetamina induziu os parÃmetros da esquizofrenia, apresentando-se como uma nova ferramenta para a pesquisa de modelos animais esquizofrenia neonatal. O modelo desenvolvido conseguiu, pela primeira vez, mimetizar as diferenÃas entre as fases do ciclo estral dos animais, simulando o que acontece em humanos. / Schizophrenia is a severe psychiatric disorder, and maybe, because of this, one of the most researched. Despite the important advances achieved in the studies about the physiopathology of the disease during the last century, few benefits were significant in the treatment of these patients. The construction of new animal models of schizophrenia is an important tool for the comprehension of the physiopathology of the disease and the development of new therapies, since even the atypical antipsychotics did not show the expected results regarding the improvement of negative and cognitive symptoms. The objective of this research was to investigate the effects of ketamine in the central nervous system as a possible agent in a neurodevelopmental model of schizophrenia. We sought to determinate the behavioral changes and oxidative stress by the neonatal administration of ketamine, as well as the reversion and prevention of these effects by the treatment with clozapine, an atypical antipsychotic. We also conducted an analysis of the role of sex at the development of schizophrenia, dividing the females by the estrous cycle, that includes phases presenting high and low concentrations of estrogen, proestrus and diestrus, respectively, since estrogen presents a neuroprotective effect. The experimental design followed the criteria to determine an animal model: the face validity (where one seeks to mimic the characteristic behavior of the disease in the animal), construct validity (the physiopathology of the disease) and predictive validity (if the established medicines for the disease are able to reverse and prevent the effects that the researched drug induces). The animals used at the experimental protocol were Wistar rats, divided in six groups and treated with saline or ketamine intraperitoneal (i.p.) for five days (7th-11th day after birth). Group 1: (males treated with saline) Group 2 (females treated with saline); Group 3 (males treated with ketamine 2,5mg/kg); Group 4 (females treated with ketamine 2,5mg/kg); Group 5 (males treated with ketamine 5 mg/kg); Group 6 (females treated with ketamine 5 mg/kg).The tests of prepulse inhibition and y-maze (behavioral tests) were conducted in adolescence (35 days after birth), and repeated at the adult phase (65 days after birth). At the adult phase, the females were divided according with the estrous cycle (diestrus and proestrus) to observe the influence of estrogen. At the 66th day after birth, the animals trated with ketamine 5 mg/kg were submitted to a reversion treatment by clozapine 10 mg/kg i.p. once a day during 10 days. After this period, the behavioral and neurochemical (dosage of BDNF and GSH) tests were performed. The animals treated with ketamine 2,5 mg/kg did not show any significant difference in the behavioral tests conducted in the adult phase when compared with the animals treated with saline and, therefore, the dose selected to measure the other parameters was 5,0 mg/kg. The treatment with ketamine 5 mg/kg significantly reduced the parameters observed at the behavioral tests, both in adult males and females at the diestrus. The males and females at the diestrus also presented a significant reduction in the GSH levels. The adult males treated with ketamine 5 mg/kg presented a significant increase in BDNF, whereas the females at the diestrus presented a reduction in this parameter. The females at the proestrus achieved a better performance in all tests. In the prevention protocol, the treatment with clozapine 10mg/kg reverted the effects of ketamine in the tests of prepulse inhibition and in the neurochemical testes in males and females in the diestrus that were treated with ketamine 5 mg/kg.The results observed in the behavioral and neurochemical tests showed that ketamine induced the parameters of schizophrenia, presenting itself as a new tool available to the research of animal models of neonatal schizophrenia. The developed model succeeded for the first time in mimicking the differences between the phases of the estrous cycle of the animals, in a close approximation of what happens in humans

nÃo hà / A ketamina à usada principalmente como anestÃsico, produzindo um tipo de anestesia, denominada anestesia dissociativa que se caracteriza por um estado catalÃptico. Entretanto, o uso da ketamina nÃo tem sido restrito à prÃtica clÃnica e pesquisa, uma vez que, atualmente, tem sido utilizada como droga de abuso, visto produzir efeitos tanto alucinÃgenos quanto estimulantes. O objetivo deste estudo foi avaliar alteraÃÃes comportamentais tais como ansiedade e depressÃo em camundongos submetidos a diferentes tratamentos com ketamina (agudo, subcrÃnico e abstinÃncia de 24h), bem como investigar o envolvimento do estresse oxidativo em cÃrtex prÃ-frontal de camundongos apÃs tratamento agudo com ketamina. Trata-se de um estudo experimental, onde para avaliar as alteraÃÃes comportamentais (ansiedade e depressÃo) os camundongos foram tratados com ketamina agudamente ou subcronicamente (7 dias consecutivos), sendo realizados os modelos experimentais de Campo Aberto (TCA), Labirinto de Cruz Elevado (LCE), Nado ForÃado (TNF) e SuspensÃo da Cauda (TSC). Os animais tambÃm foram expostos a abstinÃncia de 24h apÃs o tratamento subcrÃnico e submetidos aos modelos experimentais supracitados. Para investigar o envolvimento do estresse oxidativo, os animais foram tratados agudamente com ketamina e utilizado o cÃrtex prÃ-frontal para avaliar atividade da catalase, nÃveis de glutationa, malonialdeÃdo e nitrito. Os resultados mostraram que no TCA houve aumento da atividade locomotora espontÃnea em todos os tipos de tratamento e em todas as doses utilizadas. No LCE o tratamento agudo, subcrÃnico e abstinÃncia de 24h com ketamina reduziu alguns parÃmetros nos braÃos abertos. No TNF e TSC, o tratamento agudo e subcrÃnico reduziu o tempo de imobilidade em todas as doses utilizadas. Enquanto na abstinÃncia de 24h houve aumento do tempo de imobilidade nas doses de 10 e 20 mg/kg. Quanto ao envolvimento do estresse oxidativo apÃs o tratamento agudo com ketamina em cÃrtex prÃ-frontal de camundongos notou-se um aumento significativo da atividade da catalase, dos nÃveis de malonildialdeÃdo e nitrito. Enquanto nos nÃveis de glutationa reduzida (GSH) observou-se uma diminuiÃÃo significativa. Conclui-se com o trabalho que o tratamento agudo e subcrÃnico causou efeito ansiogÃnico e antidepressivo. Enquanto que a abstinÃncia de 24h apÃs o tratamento subcrÃnico evidenciou um efeito ansiogÃnico e depressor. AlÃm das alteraÃÃes comportamentais, constata-se que o tratamento agudo com ketamina causa aumento do estresse oxidativo, indicando a ocorrÃncia de possÃveis lesÃes neurais em consequÃncia dessas alteraÃÃes. / Ketamine is mainly used as an anesthetic, producing a kind of anesthesia, called dissociative anesthesia characterized by a cataleptic. However, the use of ketamine has been restricted to clinical practice and research, since, currently, has been used as a drug of abuse, since both produce hallucinogenic effects as stimulants. The aim of this study was to evaluate behavioral changes such as depression and anxiety in mice subjected to different treatments with ketamine (acute, subchronic and withdrawal of 24), as well as investigate the involvement of oxidative stress in the prefrontal cortex of mice after acute treatment Ketamine. This is an experimental study to evaluate where behavioral changes (depression and anxiety) mice were treated with ketamine acutely or subcronicamente (7 consecutive days), being conducted experimental models of Open Field (TCA), Labyrinth of High Cross (LCE), Forced Swim (TNF) and Tail Suspension (TSC). The animals also were exposed to 24 hours of abstinence after treatment and subjected to subchronic experimental models above. To investigate the involvement of oxidative stress, the animals were treated acutely with ketamine and used the prefrontal cortex to evaluate the activity of catalase, glutathione, and nitrite malonialdeÃdo. The results showed that the TCA increased spontaneous locomotor activity in all types of treatment and at all doses used. In LCE treating acute and subchronic withdrawal 24h with ketamine reduced some parameters in the open arms. In TNF and TSC, acute and subchronic treatment reduced immobility time at all doses used. While the withdrawal of 24h was increased immobility time in doses of 10 and 20 mg/kg. Regarding the involvement of oxidative stress after acute treatment with ketamine in the prefrontal cortex of mice was noted a significant increase in catalase activity, levels of malondialdehyde and nitrite. While the levels of reduced glutathione (GSH) showed a significant decrease. It concludes with the work that the acute and subchronic treatment caused anxiogenic and antidepressant effects. While abstinence from 24h after treatment showed a subchronic effect anxiogenic and depressant. In addition to behavioral changes, it appears that acute treatment with Ketamine causes increased oxidative stress, indicating the possible occurrence of neural injuries as a result of these changes.

Major depressive disorder (MDD) is a widespread psychiatric disorder that affects millions of people worldwide and is hypothesized to occur due to impairments in several neurotransmitter systems, including the monoaminergic and glutamatergic neurotransmitter systems. Antidepressant medications targeting multiple monoamine neurotransmitters have been shown to be effective for the treatment of depression. Racemic amisulpride is an atypical antipsychotic that has been used at low doses to treat dysthymia, a mild form of depression, and functions as an antagonist at DA2/3, 5-HT2B, and 5-HT7 receptors. Recent preclinical studies have suggested that the S(+) isomer may be more critical for amisulpride’s antidepressant-like effects; however, this interpretation has not been fully characterized in comparison to the R(-) isomer. The glutamatergic system also has been shown to play a critical role in alleviating depression. Several studies have demonstrated that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces rapid and sustained antidepressant-like effects in clinical trials; however, few studies have examined the degree to which ketamine’s isomers contribute to antidepressant-like effects. Fully characterizing these differences in a preclinical model of depression may offer important insight into the role of these neurotransmitter systems on depression. The present study used a 72-sec differential-reinforcement-of-low-rate (DRL) task to assess the antidepressant-like effects of amisulpride, ketamine, and their isomers in mice. The DRL 72-sec task has shown to be a reliable and sensitive screen for drugs that possess antidepressant-like activity as reflected by an increase in the number of reinforcers, a decrease in the number of responses, and a right-ward shift in the interresponse time distributions (IRTs; i.e. the elapsed time between two successive responses). For comparison, the effects of the tricyclic antidepressant imipramine and the N-methyl-D-aspartate antagonist MK-801 as positive and negative controls, respectively, were determined. Consistent with previous findings, we hypothesized that amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, would produce antidepressant-like effects, and all formulations of ketamine would produce antidepressant effects. Racemic amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, produced an antidepressant-like effect, evidenced by a significant increase in the number of reinforcers and a significant decrease in the number of responses. Racemic ketamine and R(-)-ketamine significantly increased the number of reinforcers and decreased the number of responses, while S(+)-ketamine significantly increased the number of reinforcers, but did not decrease the number of responses (at the doses tested). Overall, these results indicate that the racemic formulations of amisulpride and ketamine, S(-)-amisulpride, and both ketamine isomers demonstrate antidepressant-like effects as assessed in the DRL task and may be useful in a clinical context. If either of the ketamine isomers can be shown to produce fewer psychotomimetic effects in humans, then the isomers may offer a significant clinical advantage over the parent compound ketamine. Regarding amisulpride, the present results demonstrate that the S(-) isomer, but not the R(+) isomer, possess antidepressant-like activity similar to racemic amisulpride.

No description available.

The objective of this study was to determine if administering epidural ketamine before or after the induction of a sodium urate crystal synovitis provides analgesia in dogs. In Part I, sixteen dogs were anesthetized with propofol (4 mg kg-1 intravenously). A sodium urate crystal synovitis was induced in the right stifle and allowed to develop for 12 hours. These dogs were again anesthetized with propofol and an epidural injection at the lumbosacral space of either ketamine (2 mg kg-1) or placebo (saline containing not more than 0.1 mg ml-1 benzethonium chloride) was performed. Analgesia was measured with a force platform and a numerical rating scale (NRS). Assessments were performed before and at 12, 14, 16, 18, 20 and 24 hours after the induction of synovitis. Vertical ground reaction forces were significantly decreased and numerical rating scale scores of total pain were significantly increased after the induction of synovitis in all dogs (p<0.05). No significant differences in ground reaction forces or total pain scores were measured between the ketamine and the control groups at any assessment period. In Part II, synovitis was induced in the right stifle as described in Part I. Epidural injections at the lumbosacral space followed immediately. Analgesia was assessed at 2, 4, 6, 8, and 12 hours after the epidural injection and the induction of synovitis. Dogs that received ketamine had significantly lower NRS scores two hours after treatment (p < 0.05). NRS scores did not differ between the two treatment groups at any other evaluation. Vertical ground reaction forces did not significantly differ between treatment groups at any assessment period. Results of this study indicate that ketamine, when administered epidurally at a dose of 2 mg kg-1 after the induction of a chemical synovitis, does not provide a significant level of analgesia. However, administration of ketamine immediately before the induction of synovitis resulted in a significantly decreased subjective pain score at two hours, but not at later evaluation periods. / Master of Science

Background: Chronic non-cancer pain (CNCP) is a prevalent condition, imposing significant burden on healthcare systems. Ketamine is suggested as a potential intervention for CNCP management. We conducted a systematic review and network meta-analysis to assess ketamine's effects in adults with CNCP. Methods: We searched Medline, Embase, CINAHL, and Cochrane CENTRAL up to January-2024 for randomized trials involving adults with CNCP, comparing ketamine with placebo, usual care, or other interventions. Reviewers independently assessed trial eligibility, extracted data, and evaluated risk-of-bias using the Cochrane tool. A random-effects network meta-analysis was performed. We assessed evidence certainty using GRADE. Results: We included 38 trials, with the following comparisons made between ketamine and placebo, using 0-10 VAS: At <30 minutes, ketamine may slightly reduce pain intensity (-1.32, 95% CI: [-1.73 to -0.90], low-certainty). At 1-3 hours follow-up, ketamine may slightly reduce pain intensity (MD: -1.25, (95% CI: [-1.76 to -0.74], low-certainty). At 3-to-7 days follow-up, ketamine may have little to no effect on pain intensity (MD: -1.34, 95% CI: [-2.29 to -0.39], low-certainty). At 3-to-5 weeks follow-up, ketamine likely results in no pain reduction (MD: -0.99, 95% CI: [-2.00 to 0.03], moderate-certainty). At beyond 5 weeks the evidence about ketamine pain reduction is very uncertain (MD: -1.09, 95% CI: [-1.86 to -0.32], very-low-certainty). Ketamine had no effect on physical functioning. Compared to placebo, ketamine may result in a slight increase in the risk of gastrointestinal adverse events (RR: 3.97, 95% CI: [2.18 to 7.22], RD: 12%, 95% CI: [5% to 25%], very-low-certainty), an increase in risk of dizziness (RR: 3.66, 95% CI: [1.25 to 10.74], RD: 11%, 95% CI: [1% to 40%], low-certainty), may increase the risk of fatigue, somnolence, and sedation (RR: 2.89, 95% CI: [1.84 to 4.53], RD: 27%, 95% CI: [12% to 50%], low-certainty), may increase of the incidence of dissociative symptoms (RR: 4.22, 95% CI: [2.20 to 8.10], RD: 17%, 95% CI: [6% to 37%], low- M.Sc. Thesis – Sara Moradi; McMaster University – Health Research Methodology iv certainty), and it may result in a slight increase in the risk of visual impairment (RR: 10.21, 95% CI: [2.86 to 36.42], RD: not evaluable, very-low-certainty). We did not have enough data to pool effect estimates for other outcomes. Conclusion: Ketamine may provide small but important benefit in CNCP patients at immediate-to-short follow-up, but it probably has little to no benefit at beyond 3-weeks. Ketamine is likely to provide similar benefits compared to alternative active interventions; however, these benefits may be associated with important side-effects. / Thesis / Master of Science (MSc)