Andrew Moore

Single dose oral paracetamol (acetaminophen) for postoperative pain

BACKGROUNDnParacetamol (acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the relief of mild and moderate pain arising from headache, musculoskeletal conditions and dysmenorrhoea. A prior Cochrane systematic review concluded that paracetamol is also effective for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way.nnnOBJECTIVESnTo assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain.nnnSEARCH STRATEGYnWe searched the Cochrane Library (Issue 3, 2002), the trials register of the Cochrane Pain, Palliative and Supportive Care group (November 2002); MEDLINE (1966 to May 1996); PubMed (1996 to August 2001); EMBASE (1980 to 1996); the Oxford Pain Relief Database (1950 to 1994); and reference lists of articles in order to update an existing version of the review.nnnSELECTION CRITERIAnRandomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults.nnnDATA COLLECTION AND ANALYSISnTwo reviewers independently assessed trial quality and extracted data. The area under the pain relief versus time curve was used to derive the proportion of patients with paracetamol or placebo experiencing least 50% pain relief over four to six hours using validated equations. The number-needed-to-treat (NNT) was calculated using 95% confidence intervals. Information on adverse effects was also collected.nnnMAIN RESULTSnForty-seven reports that enrolled 4186 patients (2561 patients were treated with a single oral dose of paracetamol and 1625 with placebo) met the inclusion criteria and were included in the analyses. The NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 325 mg NNT 3.8 (2.2 to 13.3); 500 mg NNT 3.5 (2.7 to 4.8); 600/650 mg NNT 4.6 (3.9 to 5.5); 975/1000 mg NNT 3.8 (3.4 to 4.4); and 1500 mg NNT 3.7 (2.3 to 9.5). Sub-group analysis showed no significant differences between smaller and larger trials, or lower and higher quality trials. Drug-related study withdrawals were rarely reported. Studies reported a variable incidence of adverse effects that were generally mild and transient. There were no statistically significant differences in the frequency of reported adverse effects between paracetamol 975/1000 mg and placebo.nnnREVIEWERS CONCLUSIONSnSingle doses of paracetamol are effective analgesics for acute postoperative pain and give rise to few adverse effects.

Evidence for Endoscopic Ulcers as Meaningful Surrogate Endpoint for Clinically Significant Upper Gastrointestinal Harm

BACKGROUND & AIMSnSurrogate endpoints are biomarkers intended to substitute for a clinical endpoint. Are endoscopic ulcers a useful surrogate endpoint for a biological progression to clinical endpoints of ulcer complications (perforation, ulcers, and bleeds), hospital admission, or death?nnnMETHODSnReview of randomized trials, meta-analyses, clinical outcomes trials, and observational studies.nnnRESULTSnNo large study examined both endoscopic and clinical endpoints. Endoscopic ulcers and clinically significant ulcer complications were affected in the same direction and to about the same extent in 4 distinct circumstances: (1) by risk factors-age, previous history of symptomatic ulcer or bleeding, Helicobacter pylori, aspirin; (2) in studies of antiulcer treatments with differing modes of action, especially in relation to nonsteroidal anti-inflammatory drug toxicity, and Helicobacter pylori infection; (3) in studies evaluating ulcer complications with Cox-2 selective drugs and nonsteroidal anti-inflammatory drugs; and (4) in studies of interventions in patients with high risk of recurrent ulcer bleed needing nonsteroidal anti-inflammatory drug therapy. All study designs showed consistent and reproducible effects on gastrointestinal ulcer complications paralleling endoscopy.nnnCONCLUSIONSnConsistent and plausible findings from disparate populations and designs make endoscopic ulcers a strong candidate for surrogacy, though direct progression from endoscopic ulcers to ulcer complications cannot be demonstrated. Large outcome studies are needed to establish the power of the surrogacy, absolute risk of clinical outcomes, and to identify the totality of risks and benefits of new pharmacologic therapies.

Individuals, averages, and evidence based medicine

In asking “Does this work for you?”1 Christakis finds the heart of evidence based medicine—“the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.”2 The individual approach can also reconcile clinical trial results with the demands of clinical practice: “managers and trialists may be happy for treatments to work on average; patients expect their doctors to do better than that.”3nnThat not all patients …

Luteinizing Hormone-Releasing Hormone for Induction of Follicular Maturation and Ovulation in Women with Infertility and Amenorrhea *

Five patients with primary infertility and secondary amenorrhea who did not respond to clomiphene with a gonadotropin or estrogen surge were treated with 500 mug of luteinizing hormone, follicle-stimulating hormone-releasing hormone (LH-RH), self-administered subcutaneously every 8 hours for 14 days. Of four patients who responded to this treatment, three showed follicular maturation, ovulation, and menses, although the luteal phase was deficient; in the fourth patient, follicular maturation and menses occurred without evidence of ovulation. For their second course of treatment these four patients were given LH-RH with the addition of human chorionic gonadotropin when the urinary estrogen levels indicated follicular maturation. All four patients responded with ovulation, an adequate luteal phase, and menses, without clinical indication of ovarian hyperstimulation. These results suggest that LH-RH may be a better alternative to human menopausal gonadotropin in the treatment of anovulatory infertility.

Opioids in non-cancer pain--a critical read of Cicero et al.

Cicero et al. [1] describe the pattern of opioid use in an insured Missouri population in 2004. The issue of opioid use in chronic non-cancer pain is politically and legally fraught, so the topic is important to us as readers of Pain. Our concerns are on the one hand that we should not harm patients with an inappropriate opioid prescription, harm particularly in the sense of dependence, and on the other hand that patients continue to have access to effective and appropriate analgesia. Denial of that access by knee-jerk legislation is a clear and present danger, but can be avoided if we have better outcome data to make our case. To that extent this paper is important because it brings new data to our attention. We need however to be confident that the data are robust, because the fact of its publication in Pain can be perceived as an endorsement, and that information may then be used by policymakers in the ongoing debate. We need to be confident that the information is internally valid and only then, with confirmed internal validity, is it legitimate to extrapolate it to our own practice. If the information is not internally valid then we should not be extrapolating from it. The authors have ‘cut’ the data in several ways, acute and chronic dosing, weak and strong opioids and by gender. The acute and chronic dosing were defined as one prescription for less than ten days drug supply in the study calendar year, and 180 or more days drug supply, respectively. As the authors say, these definitions differ from the 5 days or fewer used for acute and more than 5 days for chronic which one reads elsewhere. This difference may contribute to some of the disparities below which are worrying. The weak opioids were defined as propoxyphene, codeine and tramadol, and strong opioids as ‘‘hydrocodone, oxycodone, fentanyl, morphine and other more potent opioids”. This definition is unclear because it does not tell us how combinations of, for example, a step 3 opioid such as oxycodone combined with acetaminophen were handled. The definition implies that that particular combination would have been classified as strong (step 3), because it contained oxycodone, whereas for most of us such a combination would be step 2 rather than step 3. Indeed textbooks pre-1990 refer to oxycodone as a weak opioid (step 2) because it was available only (in the USA) as combination products. These problems in the definition of weak and strong may also contribute to the worrying disparities between these data and other published work. The problems in the paper by Cicero et al. are:

Reply to Drs. Schwartzman, Kirkpatrick and colleagues

To the Editor: It is egregious enough that the reviewers got their facts wrong in their recent commentary published in PAIN. It is even worse that they then use their misstatements of fact to support their assertion that ketamine should not be a recognized option offered to patients with intractable CRPS that is unresponsive to other treatment modalities [1]. Intravenous ketamine is indicated by the Food and Drug Administration in the United States to control pain related to diagnostic and surgical procedures, and to supplement low-potency analgesic agents. IV ketamine has not been approved by the FDA to treat any specific medical condition. Ketamine has a safety record lasting over 30 years. Schwartzman and colleagues published a randomized-controlled trial to determine the safety and efficacy of ketamine in the treatment of intractable CRPS on an outpatient basis [3]. We hope that the following information will help Bell and Moore to a better understanding.

Capítulo 30 – AINE y Coxib: Uso clínico

Los analgesicos simples, como el paracetamol y los farmacos antiinflamatorios no esteroideos (AINE), son clinicamente muy efectivos. La introduccion de farmacos antiinflamatorios no esteroideos inhibidores de la ciclooxigenasa-2 (Coxib), que inhiben selectivamente la ciclooxigenasa (Cox)-2 ha proporcionado una gran cantidad de datos sobre seguridad y eficacia. Aunque existen diferencias entre la eficacia de los AINE y el paracetamol, la eficacia entre los AINE clasicos y los Coxib es similar, tanto en dosis unicas utilizadas para tratar el dolor posquirurgico agudo como en el tratamiento cronico de afecciones musculoesqueleticas, como la osteoartritis. Las dosis mas altas de AINE producen un numero necesario de pacientes para tratar (NNT) para lograr el 50% de alivio del dolor cercano a 1, que representa el NNT teoricamente perfecto. Las principales diferencias se encuentran en su perfil de seguridad. Los AINE y los Coxib pueden provocar hemorragia gastrointestinal, y a dosis terapeuticas pueden acelerar la insuficiencia renal o la insuficiencia cardiaca congestiva. Si los AINE orales se toman durante por lo menos 2 meses, el riesgo de una ulcera endoscopica es de 1 entre 5, el de una ulcera sintomatica esta alrededor de 1 entre 70, el de una ulcera sangrante de 1 entre 150, y el de muerte por ulcera sangrante es de 1 entre 1.300. Los Coxib reducen el riesgo de hemorragia gastrointestinal comparados con los AINE. En la terapia cronica con AINE el odds ratio para la insuficiencia renal aguda es de 1,6 a 2,0. El riesgo de insuficiencia cardiaca congestiva es dos veces mas alto en la terapia cronica con AINE, y aumenta hasta casi 20 veces en pacientes con antecedentes de riesgo. Los Coxib no reducen los riesgos de insuficiencia renal o cardiaca en comparacion con los AINE. El paracetamol es seguro en dosis terapeuticas, pero es algo menos efectivo. Este equilibrio entre la eficacia y la seguridad es fundamental para el uso optimo de los farmacos en todas las areas terapeuticas.

AINE y Coxib

Los analgesicos simples, como el paracetamol y los farmacos antiinflamatorios no esteroideos (AINE), son clinicamente muy efectivos. La introduccion de farmacos antiinflamatorios no esteroideos inhibidores de la ciclooxigenasa-2 (Coxib), que inhiben selectivamente la ciclooxigenasa (Cox)-2 ha proporcionado una gran cantidad de datos sobre seguridad y eficacia. Aunque existen diferencias entre la eficacia de los AINE y el paracetamol, la eficacia entre los AINE clasicos y los Coxib es similar, tanto en dosis unicas utilizadas para tratar el dolor posquirurgico agudo como en el tratamiento cronico de afecciones musculoesqueleticas, como la osteoartritis. Las dosis mas altas de AINE producen un numero necesario de pacientes para tratar (NNT) para lograr el 50% de alivio del dolor cercano a 1, que representa el NNT teoricamente perfecto. Las principales diferencias se encuentran en su perfil de seguridad. Los AINE y los Coxib pueden provocar hemorragia gastrointestinal, y a dosis terapeuticas pueden acelerar la insuficiencia renal o la insuficiencia cardiaca congestiva. Si los AINE orales se toman durante por lo menos 2 meses, el riesgo de una ulcera endoscopica es de 1 entre 5, el de una ulcera sintomatica esta alrededor de 1 entre 70, el de una ulcera sangrante de 1 entre 150, y el de muerte por ulcera sangrante es de 1 entre 1.300. Los Coxib reducen el riesgo de hemorragia gastrointestinal comparados con los AINE. En la terapia cronica con AINE el odds ratio para la insuficiencia renal aguda es de 1,6 a 2,0. El riesgo de insuficiencia cardiaca congestiva es dos veces mas alto en la terapia cronica con AINE, y aumenta hasta casi 20 veces en pacientes con antecedentes de riesgo. Los Coxib no reducen los riesgos de insuficiencia renal o cardiaca en comparacion con los AINE. El paracetamol es seguro en dosis terapeuticas, pero es algo menos efectivo. Este equilibrio entre la eficacia y la seguridad es fundamental para el uso optimo de los farmacos en todas las areas terapeuticas.

Métodos de estudio terapéutico

Si se siguen algunas reglas, los estudios clinicos de dolor agudo y cronico pueden lograr un alto nivel de precision. En este capitulo se discuten las diferentes formas de estudiar el dolor, como pueden disenarse este tipo de estudios y como se analizan los resultados.

AINE y Coxib: Uso clínico

Los analgesicos simples, como el paracetamol y los farmacos antiinflamatorios no esteroideos (AINE), son clinicamente muy efectivos. La introduccion de farmacos antiinflamatorios no esteroideos inhibidores de la ciclooxigenasa-2 (Coxib), que inhiben selectivamente la ciclooxigenasa (Cox)-2 ha proporcionado una gran cantidad de datos sobre seguridad y eficacia. Aunque existen diferencias entre la eficacia de los AINE y el paracetamol, la eficacia entre los AINE clasicos y los Coxib es similar, tanto en dosis unicas utilizadas para tratar el dolor posquirurgico agudo como en el tratamiento cronico de afecciones musculoesqueleticas, como la osteoartritis. Las dosis mas altas de AINE producen un numero necesario de pacientes para tratar (NNT) para lograr el 50% de alivio del dolor cercano a 1, que representa el NNT teoricamente perfecto. Las principales diferencias se encuentran en su perfil de seguridad. Los AINE y los Coxib pueden provocar hemorragia gastrointestinal, y a dosis terapeuticas pueden acelerar la insuficiencia renal o la insuficiencia cardiaca congestiva. Si los AINE orales se toman durante por lo menos 2 meses, el riesgo de una ulcera endoscopica es de 1 entre 5, el de una ulcera sintomatica esta alrededor de 1 entre 70, el de una ulcera sangrante de 1 entre 150, y el de muerte por ulcera sangrante es de 1 entre 1.300. Los Coxib reducen el riesgo de hemorragia gastrointestinal comparados con los AINE. En la terapia cronica con AINE el odds ratio para la insuficiencia renal aguda es de 1,6 a 2,0. El riesgo de insuficiencia cardiaca congestiva es dos veces mas alto en la terapia cronica con AINE, y aumenta hasta casi 20 veces en pacientes con antecedentes de riesgo. Los Coxib no reducen los riesgos de insuficiencia renal o cardiaca en comparacion con los AINE. El paracetamol es seguro en dosis terapeuticas, pero es algo menos efectivo. Este equilibrio entre la eficacia y la seguridad es fundamental para el uso optimo de los farmacos en todas las areas terapeuticas.