Thesis (MBA)--Stellenbosch University, 2012. / Analgesics are the medication most-generally used by modern society. The pain management market has therefore experienced substantial growth over the last few years. This research report aims to provide a critical review of pain management in the pharmaceutical market in South Africa, in order to establish and evaluate the most significant growth factors. This research report provides an overview of the history of pain, the basic physiology of pain and pain classification systems. There are three categories of analgesics - opioid analgesics, non-opioid analgesics and adjuvant analgesics. These categories of analgesics have been analysed according to the most generally-used MIMS pharmacological classification system referring to the analgesic therapeutic classes. These are narcotic analgesics, analgesics and antipyretics, combination analgesics, others such as tramadol and musculo-skeletal agents which consist of NSAIDs and COX inhibitors. Growth over the last four years (from August 2009 to July 2012) will be determined by analysing data per molecule, per product and per manufacturer. Splits between branded and generic drugs will also be analysed. Top prescribers by healthcare professionals will be examined, analysing scripting data from ImpactRx, which covers 85% of the private market data nationally. There are currently approximately 41 analgesic molecules in the assessed pain market which has produced 738 analgesic products. The analgesic market (worldwide and in South Africa) has seen the launch of only a few new drugs. New molecules of the same drug class or family have been launched, but in effect they can be viewed as mere line extensions with claimed reduction in side effects, advanced delivery times or improved efficacy. Two new molecules have been launched in the South African market in the narcotic analgesic class, (oxycodone and hydromorphone), however these molecules have been available internationally for years. Accelerated growth of the pain management market has mainly been met by combination analgesics, which in essence are not new, but rather a combination of different active ingredients or new drug delivery systems. The impact of product withdrawals on market share is also evaluated. The development and acceptance of generics are highlighted as key contributing factors in the growth of the analgesic market. Important to note is that generics often compete in their own generic market share. This may be the reason why the generic market does not show a significant increase over branded products. Another significant trend evident in the increased acceptance of generics, is that manufacturers, in order to keep market share, may choose to produce their own generic medication after their branded products patent has expired. Pain is one of the main reasons why patients seek medical attention and it is the physician’s ethical responsibility to treat patients and provide them with effective pain relief medication. The WHO analgesic ladder as a guideline for treating pain has proven to be effective after 25 years in practice. It is forecasted that an increase in the narcotic analgesic class will be noted. Pain is heavily undertreated worldwide and in South Africa, Increased awareness, education, new advanced research and knowledge may help to address this dilemma.

The thesis deals with comparing the postoperative analgesia with a focus on pacients after hip replacement surgery at the intensive care units. The quantitative study realized at the Fakultní nemocnice v Motole and Nemocnice Třebíč during November 2012 and February 2013. The main task of the theoretical part is to analyze the current trends in the field of post- operativeanalgesia by the patients undergoing hip joint surgery as well as the explanation the basicconcepts of this issue and overviewing the international postoperative pain treatments. The practical part is an objective comparison the postoperative analgesia byselected patients at the Fakultní nemocnice v Motole and Nemocnice Třebíč determined by questionnaire. The results of the questionnaire are processed into graphical representation and subsequently evaluated. The work serves to clarify the overall issue of post-operative analgesia. The focus is mainly on ensuring the quality of postoperative analgesia, the financial requirements administered analgesics and the possible complications associated with the use of analgesic therapy. Key words: Analgesia, pain, hip surgery, visual analogue scale, analgesics

The thesis focuses on the history of pain treatment from the beginning of humanity to present days. It aims to provide a comprehensive overview of the research development, creation of theories and struggling of a man with the pain, an unpleasant sensory perception, without which the mankind would most probably not survive. From the skeletal remains we learn about pain-killing practices among primitive people who were, besides various potions, charms, spells and rituals, able to use even the trepanation techniques. We find that people in ancient times apparently understood the pain caused by traumatic mechanisms but they could not handle the pain caused by some internal disorder. Early findings about the treatment of pain were thus linked to the nature. People used plants with narcotic and analgetic effects e. g. opium, cannabis, mandrake and physical quantities such as pressure, heat, cold or even shocks generated by electric fish. Over the time they improved this knowledge and reached for new findings. This thesis presents also ideas and creation of theories of pain provided by thinkers and scholars across centuries. Works from antiquity had apparently the biggest and the longest lasting influence on pain and medical problematics. From historical sources we read that new discoveries in medicine...

INTRODUÇÃO:Pacientes em ventilação mecânica (VM) são freqüentemente submetidos ao uso prolongado e/ou a doses elevadas de opióides, que durante a retirada podem causar abstinência dificultando o desmame da VM. Objetivo: testar a hipótese de que a introdução da metadona enteral na fase de desmame da sedação e analgesia em pacientes adultos graves sob VM diminui o tempo de desmame da VM. MÉTODOS: Estudo prospectivo, randomizado, controlado e duplo-cego, realizado entre abril de 2005 e outubro de 2009, em quatro Unidades de Terapia Intensiva (UTIs) de adultos de Joinville, SC. Foram randomizados 75 pacientes que apresentavam critérios para desmame da VM e estavam em uso de fentanil por mais de cinco dias consecutivos ou infusão ³ 5 g/kg/h por 12 horas. Os pacientes foram randomizados em dois grupos: Grupo Metadona (GM) e Grupo Controle (GC). Nas primeiras 24 horas após a inclusão os dois grupos receberam 80% da dose original do fentanil. Ao GM administrou-se metadona via enteral (10 mg cada 6 horas), e ao GC administrou-se placebo via enteral. Após as primeiras 24 horas acrescentou-se infusão intravenosa de solução salina (placebo) no GM, enquanto o GC recebeu infusão de solução intravenosa de fentanil. Em ambos os grupos, a solução venosa foi reduzida em 20% a cada 24 horas. Episódios de intolerância à retirada de opióide foram medicados com suplementação de opióide. Os grupos foram comparados entre si avaliando-se o tempo de desmame da VM, tempo de VM, permanência na UTI e permanência hospitalar. RESULTADOS: Dos 75 pacientes randomizados, sete foram excluídos e 68 foram analisados: 37 no GM e 31 no GC. Entre o início do desmame e a extubação, observou-se maior probabilidade de antecipação da extubação no GM, porém a diferença não foi significativa (Hazard Ratio: 1,52 (IC 95% 0,87 a 2,64; p = 0,11). Analisando-se o intervalo entre a randomização e o quinto dia do desmame da VM, a probabilidade de sucesso de desmame foi significativamente maior no GM (Hazard Ratio: 2,64 (IC 95%: 1,22 a 5,69; p < 0,02). Dentre os 54 pacientes que completaram o desmame da VM (29 do GM e 25 do GC), o tempo de desmame da VM foi significativamente menor no GM (Hazard Ratio: 2.06; IC 95% 1.17 a 3.63; p < 0.004). Não houve diferença entre os grupos com relação ao tempo de VM, permanência na UTI e permanência hospitalar. CONCLUSÃO: a introdução da metadona enteral na fase de desmame da sedação e analgesia de pacientes adultos graves sob VM resultou na diminuição do tempo de desmame da VM / INTRODUCTION: Patients on mechanical ventilation (MV) are often subjected to prolonged use and / or high doses of opioids, which when removed can cause withdrawal syndrome and to difficult weaning from MV. Objective: to test the hypothesis that the introduction of enteral methadone in weaning from sedation and analgesia in critically ill adult patients on MV decreases the time of weaning from MV. METHODS: Prospective, randomized, controlled, double-blind trial, conducted between April 2005 and October 2009 in ICUs of four hospitals in Joinville, SC. We randomized 75 patients who met the criteria for weaning from MV and were using fentanyl for more than 5 consecutive days or infusion ³ 5 g/ kg / h for 12 hours. Patients were randomized into two groups: Methadone group (MG) and Control Group (CG). At first 24 hours both groups received 80% of the original dose of fentanyl and received, additionally, enteral methadone (10mg qid) or enteral placebo. After the first 24 hours, MG: received enteral methadone (10mg qid) and intravenous placebo. CG received enteral placebo and intravenous fentanyl. In both groups, the blinded intravenous solutions were reduced by 20% of the original dose, every 24 hours. Episodes of intolerance opioid withdrawal were treated with supplemental opioid. The groups were compared by evaluating the time of weaning from MV, duration of MV, ICU and hospital stay.RESULTS: Of 75 randomized patients, 7 were excluded and 68 were analyzed: 37 at MG and 31 in CG. Between the beggining of weaning and extubation, there was a greater probability of anticipation of extubation in the MG, but the difference was not significant. (Hazard Ratio: 1,52 (IC 95% 0,87 a 2,64; p = 0,11). Analyzing the interval between randomization and the fifth day of weaning from MV, the probability of successful weaning was significantly higher in GM (Hazard Ratio: 2,64 (IC 95%: 1,22 a 5,69; p < 0,02). Within the 54 patients who completed the weaning from MV (29 on the MG and 25 on the CG), weaning time from MV was significantly less in the MG (Hazard Ratio: 2.06; IC 95% 1.17 a 3.63; p < 0.004). There was no difference between the two groups with respect the duration of MV, length of ICU stay and hospital stay. CONCLUSÃO: the introduction of enteral methadone in weaning from sedation and analgesia of critically ill adult patients on MV decreased the time of weaning from MV

Submitted by Eunice Novais (enovais@uepg.br) on 2017-08-17T19:02:15Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) FABIANA FERNANDES MADALOZZO COPPLA.pdf: 8129839 bytes, checksum: 555584401fddabd5299b0abdea4be4de (MD5) / Made available in DSpace on 2017-08-17T19:02:15Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) FABIANA FERNANDES MADALOZZO COPPLA.pdf: 8129839 bytes, checksum: 555584401fddabd5299b0abdea4be4de (MD5) Previous issue date: 2017-06-28 / Introdução: A Sensibilidade dental (SD) induzida pelo clareamento é altamente prevalente. A combinação de opioides e analgésicos não opioides pode proporcionar um melhor efeito analgésico. Objetivos: Avaliar o efeito da associação de paracetamol / codeína administrado pré e pós-operatoriamente sobre o risco e a intensidade da SD induzida pelo clareamento dental. Métodos: Realizou-se um ensaio clínico randomizado paralelo, triplo cego, com 105 pacientes saudáveis os quais receberam um placebo ou uma associação de paracetamol / codeína. A primeira dose de (paracetamol 500 mg / codeína 30 mg) ou placebo foi administrada 1 h antes do clareamento em consultório (peróxido de hidrogénio 35%) e doses extras foram administradas a cada 6 h durante 48 h. A SD foi avaliada utilizando duas escalas: 0-10 escala visual analógica VAS e uma escala de classificação numérica NRS 0-4 em diferentes períodos: durante o clareamento, 1 h até 24 h, 24 h até 48 h pós clareamento. A cor foi mensurada antes e um mês após o clareamento dental com uma escala de cores visuais Vita Classical, Vita Bleachedguide 3D-Master e espectrofotômetro Vita Easyshade (Vita Zahnfabrik). O risco absoluto de SD foi avaliado pelo teste exato de Fisher. Os dados da intensidade SD com escala NRS dos dois grupos foram comparados com os testes de Mann- Whitney e Friedman, enquanto que os dados da escala VAS foram avaliados por meio de ANOVA dois fatores de medidas repetidas. As alterações de cor entre os grupos foram comparadas utilizando teste t de Student (α = 0,05). Resultados: Não foram observadas diferenças significativas entre os grupos quanto ao risco e intensidade de SD. O risco absoluto total de SD foi de aproximadamente 96%. Uma alteração de cor de quase 5 unidades da escala de cor visual Vita Classical foi detectada em ambos os grupos, que foram estatisticamente semelhantes (p> 0,05). Conclusão: O uso da associação paracetamol / codeína pré e pós clareamento de consultório não reduz o risco e a intensidade da SD induzida pelo clareamento. Implicações clínicas: O uso de um fármaco analgésico opioide não foi capaz de prevenir SD decorrente de clareamento dental em consultório. / Background: Bleaching-induced TS is highly prevalent. The combination of Opioids and non opioids analgesics may provide a better analgesic effect. Objective: To evaluate the effect of the combination of paracetamol / codeine administered before and postoperatively on the risk and intensity of TS induced by dental whitening. Methods: A triple-blind, parallel, randomized clinical trial was conducted with 105 health patients who received either a placebo or an association of codeine/acetaminophen. The first dose of Tylex® 30 mg (acetaminophen 500 mg/codeine 30 mg) or placebo was administered 1 h before the in-office bleaching (35% hydrogen peroxide), and extra doses were administered every 6 h for 48 h. The TS was recorded using two scales: 0-10 visual analog scale and a 0-4 numeric rating scale in different periods: during bleaching, 1 h up to 24 h, 24 h up to 48 h postbleaching. The color was measured before and one month after dental bleaching with a visual shade guide Vita Classical, Vita Bleachedguide 3D-Master and spectrophotometer Vita Easyshade (Vita Zahnfabrik). The absolute risk of TS was evaluated by Fisher’s exact test. Data of TS intensity with NRS scale of the two groups were compared with Mann-Whitney and Friedman tests, while data from the VAS scale were evaluated by two-way repeated measures ANOVA. The color changes between groups were compared using a Student t-test (α = 0.05). Results: No significant differences between the groups were observed in the risk and intensity of TS. The overall absolute risk of TS was approximate 96%. A color change of nearly 5 shade guide units of the Vita Classical was detected in both groups, which were statistically similar (p > 0.05). Conclusion: The use of acetaminophen/codeine association pre and post in-office bleaching does not reduce the risk and intensity of bleaching-induced TS. Practical Implications: The use of an opioid analgesic drug was not capable to prevent TS arising from in-office dental bleaching.

As anêmonas do mar utilizam um rico complexo protéico para capturar suas presas e para se defender de predadores. A peçonha, destes animais, contem neurotoxinas com ação em canais iônicos específicos e hemolisinas que atuam formando poros em membranas. No entanto, pouco se conhece sobre a atividade biológica de substâncias de baixo peso molecular isoladas da peçonha destes animais. Bunodosina 391 (BDS 391), um composto de baixo peso molecular isolado da peçonha da anêmona do mar Bunodosoma cangicum, apresenta atividade antinociceptiva periférica. Ensaios farmacológicos mostraram que a ação do BDS 391 é mediada pela ativação de receptores serotoninérgicos, histaminérgicos e pela abertura de canais de potássio. É interessante observar que o BDS 391 apresenta similaridade estrutural a 5-HT e histamina, o que torna de especial interesse a detecção do efeito antinociceptivo periférico para este composto. Os resultados obtidos nesse estudo poderão favorecer o melhor conhecimento sobre a fisiopatologia da dor e de seu controle, bem como o desenvolvimento de novos fármacos. / Animal toxins are directed against a wide variety of pharmacological targets, making them an invaluable source of ligands for studying the signaling pathways of pain and its control. Sea anemone venoms contain many biologically active compounds such as cytolysins (1820 kDa) and ion channel modulators (35 kDa). In addition, low molecular weight compounds have been isolated and identified in these venoms; however few studies have been carried out in order to determine the biological activity of such compounds. BDS 391 is a low molecular weight and non-peptidic compound purified from the Brazilian sea anemone Bunodosoma cangicum venom. Studies on the structure of BDS 391 have demonstrated that this compound is composed of a bromoindole group connected to histidine. Our recent data have indicated that BDS 391 administered by intraplantar route into the rat hind paw induces potent peripheral analgesia in models of acute and chronic pain. These study can to contribute to the better characterization of the pain pathway and your control.

Increased opioid analgesic (OA) prescribing has been associated with increased risk of prescription opioid diversion, misuse, and abuse. States established prescription drug monitoring programs (PDMPs) to collect and analyze electronic records for dispensed controlled substances to reduce prescription drug abuse and diversion. PDMP data can be used by prescribers for tracking patient’s history of controlled substance prescribing to inform clinical decisions. The studies in this dissertation are focused on the less utilized potential of the PDMP data to enhance public health surveillance to monitor OA prescribing and co-prescribing and association with opioid overdose mortality and morbidity. Longitudinal analysis of OA prescribing and evaluation of the effect of recent policies and opioid prescribing guidelines require consensus measures for OA utilization and computational tools for uniform operationalization by researchers and agencies. Statistical macros and computational tools for OA utilization measures were developed and tested with Kentucky PDMP data. A set of covariate measures using mortality and morbidity surveillance data were also developed as proxy measures for prevalence of painful conditions justifying OA utilization, and availability of heroin and medication treatment for opioid use disorder. A series of epidemiological studies used the developed OA measures as outcomes, and adjusted for time-varying socio-demographic and health care utilization covariates in population-averaged statistical models to assess longitudinal trend and pattern changes in OA utilization in Kentucky in recent years. The first study, “Trends and Patterns of OA Prescribing: Regional and Rural-Urban Variations in Kentucky from 2012 to 2015,” shows significant downward trends in rates of residents with OA prescriptions. Despite the significant decline over time, and after accounting for prevalence of injuries and cancer, the rate of dispensed OA prescriptions among residents in Kentucky Appalachian counties remained significantly higher than the rest of the state. The second study, “Population-Level Measures for High-Risk OA Prescribing: Longitudinal Trends and Relationships with Pain-Associated Conditions,” shows significant reduction in high-risk OA prescribing (e.g., high daily dosage, long-term use, concurrent prescriptions for OA and benzodiazepines) from 2012 to 2016, significantly positive associations between high-risk OA prescribing and cancer mortality rates with no substantial change in the association magnitude over time, and declining strengths of positive associations between high-risk OA prescribing and acute traumatic injuries or chronic non-cancer pain over the study period. The third study, “A Reciprocal Association between Longitudinal Trends of Buprenorphine/Naloxone Prescribing and High-Dose OA Prescribing,” indicates a significant reciprocal relationship between high-dose OA prescribing and buprenorphine/ naloxone prescribing, and a clinically meaningful effect of buprenorphine/naloxone prescribing on reducing OA utilization. The results from the studies advanced the understanding of the epidemiology of opioid use and misuse in Kentucky, and identified actionable risk and protective factors that can inform policy, education, and drug overdose prevention interventions. The developed operational definition inventory and computational tools could stimulate further research in Kentucky and comparative studies in other states.

Ovariohysterectomy and castration are common surgical procedures in small animal practice that can result in clinically significant postoperative pain. One way of controlling postoperative pain is administration of a single analgesic or a combination of different classes of analgesics prior to the onset of noxious stimuli. A constraint to the perioperative use of traditional opioids and non-steroidal anti-inflammatory drugs (NSAIDs) is their undesirable side effects. In this series of experiments, the preventive (pre-emptive) analgesic efficacy of two popular human analgesics, tramadol (an ?atypical? opioid) and parecoxib (a NSAID with selective COX-2 inhibition) was evaluated in dogs. Initially, the efficacy and renal safety of parecoxib, tramadol and a combination of parecoxib, tramadol and pindolol (a -adrenoceptor blocker and 5-HT1A/1B antagonist) were screened in anaesthetised healthy dogs. These analgesics increased the dogs? nociceptive threshold to mechanical stimuli, without causing significant alterations in the dogs? glomerular filtration rate (GFR) estimated by plasma iohexol clearance. Subsequently, the efficacy of tramadol was compared with morphine, in dogs undergoing ovariohysterectomy or castration. The Glasgow composite measure pain scale-short form score (CMPS-SF) and changes in intraoperative electroencephalogram (EEG) responses were used to assess the efficacy of analgesics. Of the three treatment groups (preoperative morphine, 0.5 mg kg-1; preoperative tramadol, 3 mg kg-1; a ?combination? of preoperative low-dose morphine, 0.1 mg kg-1, and postoperative tramadol 3 mg kg-1), dogs given the ?combination? had significantly lower pain scores after ovariohysterectomy. In castrated dogs, preoperative tramadol (3 mg kg-1) and morphine (0.5 mg kg-1) were tested and no significant difference in the CMPS-SF score were observed between them. Changes in EEG variables were not specific between the treatment groups in ovariohysterectomised dogs. Finally, the efficacy of test drugs was evaluated against acute noxious electrical stimulation in anaesthetised dogs, using EEG. Median frequency of the EEG, a reliable indicator of nociception, increased significantly in tramadol and parecoxib groups, compared to morphine, after electrical stimulation. These studies demonstrated that tramadol and parecoxib can produce analgesia in dogs with insignificant side effects. The efficacy of tramadol appears to vary with the type of noxious stimulus. A complete prevention of noxious input by administration of analgesics pre- and post-operatively could have important clinical applications.

Drug use and misuse by young people is a problem and concern in the Australian and Australian Capital Territory (ACT) communities. There are concerns regarding illicit and licit drugs but licit drug use has been identified as the major area of concern. Young people in the ACT reflect the drug use/misuse patterns and trends of other states. Commonly used drugs by young people are alcohol, tobacco, cannabis and analgesics. Strategies to address the problem of drug use/misuse by young people include intervention and community drug education programs. Peer drug education (as an example of community drug education), trains young people as peer educators to implement drug education programs with younger age groups. A case study analysis based on qualitative, naturalistic and new paradigm research is the research method used in this thesis. An eclectic model of drug education including key components from a variety of drug education models provides a comprehensive overview of peer drug education. The literature review showed the complexity of influences on drug use/misuse. These influences relate to individual, peer, parental and family, community and societal factors. Peer drug education is generally recognised as an effective drug education strategy. Peer drug education programs (Triple T: Teenagers Teaching Teenagers) were conducted in the ACT from 1988-1990. Reports documenting these programs (including evaluation data) and a literative review are the main data analysed for the case study. The case study analysis of five ACT peer drug education programs and one interstate program showed the key planning issues for effective peer drug education were: collaborative decision making as a central concept; detailed planning and liaison with target groups; established structures within schools and communities to support the trained peer educators; team work and small group work as intrinsic and extrinsic factors within the program; clarification of responsibilities and roles of all personnel involved in the program; and facilitators/leaders with attributes and qualities that encourage peer drug educators as social change agents. Analysis of data from the case study reports showed young people can be effective peer drug educators. Residential programs are preferred over non-residential programs. Peer drug education programs are effective in both school and community agencies. The literature review and analysis of reports also indicated that peer drug education needs to focus on establishing positive norms in groups of young people. Collaborative decision making and positive role modelling assist in the establishment of these norms. Peer drug education links to the wider changes occurring in education and health settings. Peer drug education is about collaborative decision making, social justice, development of key competencies and social change. This thesis confirmed the complexity and dynamic nature of peer drug education and there were many questions raised for further research from the literature review and analysis of program reports.

Ovariohysterectomy and castration are common surgical procedures in small animal practice that can result in clinically significant postoperative pain. One way of controlling postoperative pain is administration of a single analgesic or a combination of different classes of analgesics prior to the onset of noxious stimuli. A constraint to the perioperative use of traditional opioids and non-steroidal anti-inflammatory drugs (NSAIDs) is their undesirable side effects. In this series of experiments, the preventive (pre-emptive) analgesic efficacy of two popular human analgesics, tramadol (an ?atypical? opioid) and parecoxib (a NSAID with selective COX-2 inhibition) was evaluated in dogs. Initially, the efficacy and renal safety of parecoxib, tramadol and a combination of parecoxib, tramadol and pindolol (a -adrenoceptor blocker and 5-HT1A/1B antagonist) were screened in anaesthetised healthy dogs. These analgesics increased the dogs? nociceptive threshold to mechanical stimuli, without causing significant alterations in the dogs? glomerular filtration rate (GFR) estimated by plasma iohexol clearance. Subsequently, the efficacy of tramadol was compared with morphine, in dogs undergoing ovariohysterectomy or castration. The Glasgow composite measure pain scale-short form score (CMPS-SF) and changes in intraoperative electroencephalogram (EEG) responses were used to assess the efficacy of analgesics. Of the three treatment groups (preoperative morphine, 0.5 mg kg-1; preoperative tramadol, 3 mg kg-1; a ?combination? of preoperative low-dose morphine, 0.1 mg kg-1, and postoperative tramadol 3 mg kg-1), dogs given the ?combination? had significantly lower pain scores after ovariohysterectomy. In castrated dogs, preoperative tramadol (3 mg kg-1) and morphine (0.5 mg kg-1) were tested and no significant difference in the CMPS-SF score were observed between them. Changes in EEG variables were not specific between the treatment groups in ovariohysterectomised dogs. Finally, the efficacy of test drugs was evaluated against acute noxious electrical stimulation in anaesthetised dogs, using EEG. Median frequency of the EEG, a reliable indicator of nociception, increased significantly in tramadol and parecoxib groups, compared to morphine, after electrical stimulation. These studies demonstrated that tramadol and parecoxib can produce analgesia in dogs with insignificant side effects. The efficacy of tramadol appears to vary with the type of noxious stimulus. A complete prevention of noxious input by administration of analgesics pre- and post-operatively could have important clinical applications.