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"American Academy of Orthopaedic Surgeons clinical practice guideline on the treatment of osteoarthritis of the knee, 2nd edition." has been saved, and will be accessible from the My NGC page.
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This is the current release of the guideline.
This guideline updates a previous version: American Academy of Orthopaedic Surgeons (AAOS). Treatment of osteoarthritis of the knee (non-arthroplasty). Rosemont (IL): American Academy of Orthopaedic Surgeons (AAOS); 2008 Dec 6. 263 p.
Note from the National Guideline Clearinghouse: This guideline references a drug(s) for which important revised regulatory and/or warning information has been released.
Osteoarthritis of the knee
Note: This guideline provides only treatment recommendations that are less invasive alternatives to knee replacement.
Adults (ages 19 years and older) who have been diagnosed by a physician with osteoarthritis of the knee and are undergoing treatment
Note: This guideline does not address patients diagnosed with rheumatoid arthritis, osteoarthritis of other joints, or other inflammatory arthropathies.
Note: No recommendation for or against use could be made for the following interventions: use of physical agents (including electrotherapeutic modalities); manual therapy; use of a valgus directing force brace (medial compartment unloader); acetaminophen, opioids, or pain patches; intraarticular corticosteroids; growth factor injections and/or platelet rich plasma; arthroscopic partial meniscectomy.
Note: The following interventions were considered but not recommended: acupuncture, lateral wedge insoles, glucosamine and chondroitin, hyaluronic acid, needle lavage, arthroscopy with lavage and/or debridement, free-floating (un-fixed) interpositional device.
Study Selection Criteria
The American Academy of Orthopaedic Surgeons (AAOS) developed a priori article inclusion criteria that are the group's "rules of evidence" for the systematic review and meta-analyses. Articles that did not have the selection characteristics were not eligible to be included as evidence for purposes of this guideline.
To be included an article had to meet the following selection criteria:
AAOS did not incorporate systematic reviews, meta-analyses, or other guidelines not specified by the guideline workgroup to avoid including studies that did not meet the AAOS's own criteria for selection. Rather, the AAOS research analyst recalled individual studies if the abstracts suggested that they might constitute evidence for one of the recommendations and also searched the bibliographies of published systematic reviews for any additional studies that potentially supplemented AAOS evaluation.
See the original guideline document for discussion on the outcomes considered and the effects of treatments in terms of the minimal clinically important improvement (MCII).
Literature Searches
The AAOS research analyst began the systematic review with a comprehensive search of the literature. Articles considered were published prior to May 2012 in four electronic databases; PubMed, EMBASE, CINAHL, and The Cochrane Central Register of Controlled Trials. The medical librarian conducted the search using key terms determined from the work group's preliminary recommendations.
The work group supplemented the electronic search with a manual search of the bibliographies of all retrieved publications, recent systematic reviews, and other review articles for potentially relevant citations. Recalled articles were evaluated for possible inclusion based on the study selection criteria and were summarized for the work group who assisted with reconciling possible errors and omissions.
The study attrition diagram in Appendix IV of the original guideline document provides a detailed description of the numbers of identified abstracts recalled and selected studies that were evaluated in the systematic review of this guideline. The search strategies used to identify the abstracts are contained in Appendix V of the original guideline document.
A total of 218 articles were considered for recommendations.
Appraising Evidence Quality and Applicability
The American Academy of Orthopaedic Surgeons (AAOS) determines quality based on a priori research questions and uses an automated numerical scoring process to arrive at final ratings. Extensive measures are taken to determine quality ratings so that they are free of bias.
AAOS evaluates the quality of evidence separately for each outcome reported in every study using research design domains suggested by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) work group members and others. The GRADE evidence appraisal system is used in the Cochrane Collaboration and has been developed for studies evaluating matched control groups. AAOS incorporates a coding scheme adaptable to all research designs that involves incremental increases for:
Each of the above quality domains is rated for possible flaws based on up to four indicator questions that define them. See Appendix VI in the original guideline document for a discussion of the American Academy of Orthopaedic Surgeons (AAOS) appraisal system. Domains are considered "flawed" if one indicator is coded "No" or at least two defining questions are "Unclear." The Statistical Power domain is considered flawed if sample size is too small to detect at least a small effect size of 0.2.
If there are flawed domains then the evidence quality is downgraded according to the reductions shown in the table below. As an example, the evidence reported in a randomized controlled trial (RCT) for any given outcome is rated as "High" quality if zero or one domain is flawed. If two or three domains are flawed, the rating is reduced to "Moderate." If four or five domains are flawed, the quality of evidence is downgraded to "Low." The quality of evidence is reduced to "Very Low" if six or more domains are flawed. As indicated above, very low quality evidence is not included in this AAOS guideline.
Relationship between Quality and Domain Scores for Interventions
The following flaws are so detrimental that AAOS appraises the evidence as "Very Low" quality regardless of the computed domain scores.
Quality is one of two dimensions that determines the strength of the final recommendations.
AAOS rates the applicability (also referred to as "generalizability" or "external validity") of each outcome reported in the studies. As with quality, applicability ratings are based on pre-established indicators that are coded and scored algorithmically. Applicability is rated as "High," "Moderate," or "Low," based on the number of domains that are flawed. A study is rated "High" if none of the domains are flawed, "Low" if all of the domains are flawed, and "Moderate" in all other cases.
Relationship between Applicability and Domain Scores for Interventions
AAOS's applicability appraisal system is derived from the PRECIS instrument originally intended for randomized controlled trials but also appropriate for other types of research design. It is comprised of 10 questions that are divided into four domains. The defining characteristics and domains are presented in Table 3 of the original guideline document.
Best Evidence Synthesis
When determining the best available evidence, the American Academy of Orthopaedic Surgeons (AAOS) first includes the highest-strength studies available for the outcomes examined. If there are two or more high-strength studies, the recommendation grade is strong. In this case, moderate- and low-strength evidence do not influence the grade of the recommendation. If there is one high- or at least two moderate-strength studies, the recommendation grade is moderate. If there is one moderate- or at least two low-strength studies, the recommendation grade is limited. Inconclusive recommendation grades are assigned when there is one low-strength study, no evidence, or contradictory findings. In this case, the rules for using expert opinion are not applicable so consensus recommendations are not appropriate. Consensus based recommendations are established only when the strength of the evidence would otherwise be inconclusive and the rules for consensus recommendations apply. See the section on Consensus Recommendations in the original guideline document (page 21).
Statistical Methods
Network Meta-analysis
During evidence appraisal of this guideline Bayesian network meta-analyses (also known as mixed treatment comparisons analysis) of randomized controlled trials were performed to ascertain the comparative effectiveness of analgesic treatments not directly compared in the literature, as explained below. For all interventions connected in one network by pairwise relationships, if there is no direct evidence about two analgesics but they are each compared to the same reference treatment then their relative effectiveness can be estimated based on their computable effects with the common comparator. Both direct and indirect comparisons contribute to the totality of evidence for selecting the best choices of treatment. The mixed treatment comparisons analysis follows methodology described by Lu and Ades using Winbugs version 1.4.
Network meta-analysis assumes that randomization within the individual trials is maintained. Additionally, it is appropriate when interactions and covariates that affect trial AB have similar effects on trial AC, and the same indirect effect BC could be obtained as if it had been evaluated as a true direct effect (i.e., third arm of the randomized controlled trial [RCT]). Breaking randomization and permitting effect modifying heterogeneity leads to biased estimates of the indirect comparisons. Consistency, the second important assumption, helps to produce interpretable results along with the similarity requisite. Similarity is required of the treatment effects among studies; consistency addresses the potential for significant variability between the direct and indirect comparisons.
Network meta-analysis requires statistical consistency between the direct and indirect pairwise effects. The work group uses the "back calculation" method as described by Dias et al. summarized as follows. Indirect effect BC is calculated as the difference between direct effects AB and AC and evaluated against the direct effect estimation for BC. The z-statistic for the difference between the direct and indirect effects of BC is compared to a standard normal distribution to test the null hypothesis evaluating consistency. If statistical significance is found, then the model is interpreted as having questionable reliability and is excluded from the data analysis. The results of the tests of statistical consistency between the direct and indirect comparisons of the pairs of analgesics examined in this guideline indicated that the consistency assumption was met; the output summary can be found in Appendix XIII of the original guideline document.
Network meta-analysis is based on multiple pairwise comparisons across at least three RCTs that connect at least three interventions where there is at least one closed loop (i.e., common comparator; direct comparison). It is an extension of traditional meta-analysis that incorporates a process where the outcome of a given comparison can affect the next outcome requiring the convergence of Markov chains that is based on this type of sampling. A total of k-1 parameters are estimated that allow for multiple pairwise comparisons across a range of k distributions. The results are assessed by examination of trace plots that graphically display the values a parameter took during the runtime of the chain. In general, for each network model the work group performed 100,000 iterations of which the first 50,000 were discarded as "burn in" pre-convergence iterations. Occasionally models required 100,000 burn-in pre-convergence iterations, which resulted in a total of 150,000 iterations.
Placebo Data Regression Analysis
Inclusion Criteria
As part of the studies included in the full guideline, articles that met inclusion criteria for a supplementary osteoarthritis of the knee placebo project were also recalled. Selection criteria included:
Because of differences in inclusion criteria between the placebo data project and the full guideline, some articles were included only in the placebo study while others were a part of both. As an example, sample size ≥30 was not a selection criterion for the regression analysis but it was for the full guideline.
AAOS searched placebo controlled trials relevant to all the recommendations for the following outcomes: Western Ontario and McMaster Universities Index (WOMAC) pain, stiffness, function, and total subscales, Visual Analogue Scale (VAS) pain, Short Form (SF)-36 role-physical and mental subscales, and the Lequesne Index. The only data available examined the treatment efficacy of osteotomy using the VAS; so only placebo controlled trials that measured change in VAS pain following osteotomy were incorporated.
Statistical Analysis
Data from 48 articles were extracted to predict differences between baseline and treatment scores in the experimental and placebo groups of two case series designed studies. Prais-Winsten regression analysis was conducted using STATA's XTP CSE command used specifically with panel data affected by heteroskedasticity and autocorrelation. Since each observation represented study-level averages of Visual Analog Scale (VAS) pain scores, the regression was weighted by size of the study samples.
The initial regression model predicted change in VAS pain using pretreatment score, age, percent female, follow up duration in weeks, multicenter study (0 = yes, 1 = no), and allowance for concomitant treatment (0 = no, 1 = yes) as independent variables. Blinding was not used as a predictor variable because patients were masked to the treatment assignments in all but one of the studies.
Refer to the "Methods" section in the original guideline document for more information, including a section on Minimal Important Difference (MID) Units.
The work group met for the introductory meeting on April 25, 2010 to establish preliminary recommendations and search terms for the guideline's systematic review. A two-day final meeting convened on August 25-26, 2012 where members voted on final recommendations following a review of the evidence, wrote the rationales, and approved the methodological contents of the guideline.
Formulating the Preliminary Recommendations
Based on their expert views of what works best, with whom, and under what circumstances, the work group's preliminary recommendations establishes the focus of the systematic review and determines the contents for the final conclusions. All preliminary recommendations are worded in the affirmative direction.
Modifications to the preliminary recommendations are not permitted between the introductory and final work group meetings. Only editing in accordance with the best available evidence and AAOS rules for wording recommendations based on evidence strengths are adopted. Modifications that require new literature searches or are not evidence-based are also not permitted.
Full Disclosure Information
The work group's preliminary recommendations are represented in this guideline and the empirical studies that the analysts examined are cited. The American Academy of Orthopaedic Surgeons (AAOS) has always striven for total transparency in the guideline development process.
Defining the Strength of the Recommendations
Judging the strength of evidence is only one step in the process of arriving at the final grade of a guideline recommendation. The overall strength is also based on clinical appropriateness, volume of the evidence, benefit versus potential harm to the patient's well-being, magnitude of treatment effects, and available data on critical outcomes.
It is highly unlikely that future evidence will overturn a recommendation supported by numerous high strength randomized controlled trials that show a large treatment effect. There is a greater likelihood for future evidence to contradict recommendations that are based on a small number of case series. Since RCTs tend to have higher scientific merit, they are usually associated with higher evidence strengths than case series studies.
When determining strength, AAOS staff first assigns a preliminary grade for each recommendation that reflects the quality and applicability ratings as well as volume of the evidence. Work group members then modify the preliminary recommendation strengths using the "Form for Assigning Strength of Recommendation (Interventions)" shown in Appendix VI of the original guideline document. See the "Rating Scheme for the Strength of the Evidence" field for the possible grades, definitions, and implications that can be assigned to recommendations.
Consensus Recommendations
Consensus recommendations are based on expert opinion. While they are prudent in certain instances, their liberal use can cause a source of bias. When the AAOS uses consensus-based recommendations, they follow the procedures described by the U.S. Preventive Services Task Force (USPSTF). In their view, there are only two circumstances that warrant their use. The first is in the case of procedures that have virtually no associated harm, are of relatively low cost, and reflect routine clinical care. The second pertains to medical interventions that potentially prevent loss of life or limb.
In making consensus-based recommendations, work group members consider:
The AAOS employs additional rules to manage the potential bias that may influence consensus recommendations. First, the rationale cannot contain references to studies that are not a part of the systematic review. Excluded articles are not viewed as evidence. Second, the final recommendation must use the language shown in Table 5 of the original guideline document that eliminates stating "we recommend," "we suggest," or "the practitioner might" to avoid confusion with the evidence-based recommendations. Third, the rationale must address any apparent discrepancies in logic with other recommendations. For example, if a guideline does not endorse an intervention in some instances but the work group has nevertheless issued a consensus-based recommendation, the rationale must explain the reason for the discrepancy in decisions.
When a recommendation is equivocal (i.e., when the recommendation reads "we are unable to recommend for or against"), the explanation why cannot contain an implied recommendation. For example, in the case of a new device, drug, or procedure, the work group may not incorporate such statements as, "Although treatment X appears to be promising, there is currently insufficient evidence to recommend for or against its use." The italicized phrase implies effectiveness in treatment X when "not being able to recommend for or against" implies that effectiveness remains undetermined.
Voting on the Recommendations
The recommendations and their strengths are voted on using the nominal group technique. AAOS presents the details in Appendix VIII of the original guideline document. Voting is conducted by secret ballot; work group members are blinded to the responses of the other members. If there is significant disagreement, negotiation takes place and is followed by up to an additional three rounds of voting. If the disagreements cannot be resolved, the applicable recommendation is not adopted. Lack of agreement is a reason some grades might be labeled "Inconclusive."
Formal vote by work group members was used to approve all of the recommendations. Only the work group chair is required to approve the rationales with the editing support of staff unless the evidence grade is consensus. However, the rationales for this guideline were approved by the entire work group. All components of consensus recommendations require formal vote.
Grade of Recommendation
The recommendation grades are based on the strengths of evidence and express the confidence one can have in the final recommendations. Grades reflect how likely it is current findings will be replicated in future studies. They are assigned as "Strong," "Moderate," or "Limited."
The American Academy of Orthopaedic Surgeons (AAOS) bases evidence grades on the quality and applicability ratings, whether or not the studies report critical outcomes, and potential harm to patients. More specifically, they begin by setting the strength as equal to the quality of available evidence. High quality evidence is preliminarily rated as "Strong," moderate quality as "Moderate," and low quality as "Limited." The ratings are downgraded if the evidence is: 1) of "Low" applicability; 2) inconsistent (comprised of studies with discrepant findings or a high degree of heterogeneity in the meta- or network meta-analyses); 3) based on only one study; or, 4) lacking "critical" outcomes. Preliminary recommendation grades are adjusted upward if the evidence is of "High" applicability or if the intervention is associated with decreased likelihood of catastrophic harm (i.e., possible loss of life or limb). In the present guideline, reducing potential harm is the reason that the evidence strength of one recommendation was raised.
Wording of the Final Recommendations
To prevent bias in the way recommendations are worded, the AAOS uses specific predetermined language stems that are governed by the evidence strengths. The format of guideline language is shown in the Table below.
AAOS Guideline Language
*Consensus recommendations are made only if specific criteria are met. See the "Consensus Recommendations" section in the "Description of the Methods Used to Formulate Recommendations" field.
Recommendation Strengths, Descriptions, and Clinical Implications
A formal cost analysis was not performed and published cost analyses were not reviewed.
Peer Review
Following the final meeting, the guideline draft undergoes peer review for additional input from external content experts. Written comments are provided on the structured review form (see Appendix IX of the original guideline document). All peer reviewers are required to disclose their conflicts of interest.
To guide who participates, the work group identifies specialty societies at the introductory meeting. Organizations, not individuals, are specified.
The specialty societies are solicited for nominations of individual peer reviewers approximately six weeks before the final meeting. The peer review period is announced as it approaches and others interested are able to volunteer to review the draft. The chair of the American Academy of Orthopaedic Surgeons (AAOS) committee on Evidence Based Quality and Value reviews the draft of the guideline prior to dissemination.
Some specialty societies (both orthopaedic and non-orthopaedic) ask their evidence-based practice (EBP) committee to provide review of the guideline. The organization is responsible for coordinating the distribution of AAOS materials and consolidating their comments onto one form. The chair of the external EBP committees provides disclosure of their conflicts of interest (COI) and manages the potential conflicts of their members.
The AAOS asks for comments to be assembled into a single response form by the specialty society and for the individual submitting the review to provide disclosure of potentially conflicting interests. The peer review stage gives external stakeholders an opportunity to provide evidence-based direction for modifications that they believe have been overlooked. Since the draft is subject to revisions until its approval by the AAOS Board of Directors as the final step in the guideline development process, confidentiality of all working drafts is essential.
The clinical practice guidelines manager drafts the initial responses to comments that address methodology. These responses are then reviewed by the work group chair and vice-chair, who respond to questions concerning clinical practice and techniques. The director of the Department of Research and Scientific Affairs provides input as well. All comments received and the initial drafts of the responses are also reviewed by all members of the work group. All changes to a recommendation as a result of peer review are based on the evidence and undergoes majority vote by the work group members via teleconference. Final revisions are summarized in a detailed report that is made part of the guideline document throughout the remainder of the review and approval processes.
The AAOS believes in the importance of demonstrating responsiveness to input received during the peer review process and welcomes the critiques of external specialty societies. Following final approval of the guideline, all individual responses are posted on the AAOS Web site with a point-by-point reply to each non-editorial comment. Reviewers who wish to remain anonymous notify the AAOS to have their names de-identified; their comments, AAOS responses, and their COI disclosures are still posted.
Review of the Treatment of Osteoarthritis of the Knee guideline was requested of 19 organizations and 18 external content experts were nominated to represent them. Sixteen individuals returned comments on the structured review form (see Appendix X of the original guideline document).
Public Comment
After modifying the draft in response to peer reviewers' input, the guideline is circulated for a 30-day public comment period. Public commentators consist of members of the AAOS Board of Directors (BOD), Council on Research and Quality (CORQ), Board of Councilors (BOC), and Board of Specialty Societies (BOS). The guideline draft is customarily sent to the AAOS BOD and CORQ for requested commentary whereas members of the BOC and BOS are solicited in advance for their interest and receive materials upon request. Additionally, a copy of this guideline is placed online (in a dropbox) and notices are sent to all members of the BOC and BOS instructing them on access during the Public Comment period.
If warranted and based on evidence, the guideline draft is modified in response to the public comments by the AAOS clinical practice guidelines unit and work group members. Changes that are made are summarized, and those who provide comment are informed of the revisions that result from their review. As indicated above and similar to peer review modifications, changes following the public comment period must be based on the evidence. They are detailed in a summary sheet that accompanies the document throughout the final approval process.
During the public comment period, 42 stakeholders returned the structured review form commenting on the clinical practice guideline (see Appendix X of the original guideline document).
The AAOS Guideline Approval Process
The work group submits the final guideline for approval by the Committee on Evidence-Based Quality and Value, Council on Research and Quality, and Board of Directors. These decision-making bodies are described in Appendix II of the original guideline document and are not designated to modify the contents. Their charge is to approve or reject its publication by majority vote.
Definitions of the strength of recommendations (Strong, Moderate, Limited, Inconclusive, and Consensus) are provided at the end of the "Major Recommendations" field.
Note from the American Academy of Orthopaedic Surgeons (AAOS): This summary of the AAOS clinical practice guideline "Treatment of Osteoarthritis of the Knee" contains a list of the evidence-based treatment recommendations and includes only less invasive alternatives to knee replacement. Discussion of how and why each recommendation was developed and the evidence report are contained in the full guideline from the AAOS Web site . Readers are urged to consult the full guideline for the comprehensive evaluation of the available scientific studies (see the "Availability of the Companion Documents" field). The recommendations were established using methods of evidence-based medicine that rigorously control for bias, enhance transparency, and promote reproducibility.
Conservative Treatments
Recommendation 1
The work group recommends that patients with symptomatic osteoarthritis of the knee participate in self-management programs, strengthening, low-impact aerobic exercises, and neuromuscular education; and engage in physical activity consistent with national guidelines.
Strength of Recommendation: Strong
Recommendation 2
The work group suggests weight loss for patients with symptomatic osteoarthritis of the knee and a body mass index (BMI) ≥25.
Strength of Recommendation: Moderate
Recommendation 3A
The work group cannot recommend using acupuncture in patients with symptomatic osteoarthritis of the knee.
Recommendation 3B
The work group is unable to recommend for or against the use of physical agents (including electrotherapeutic modalities) in patients with symptomatic osteoarthritis of the knee.
Strength of Recommendation: Inconclusive
Recommendation 3C
The work group is unable to recommend for or against manual therapy in patients with symptomatic osteoarthritis of the knee.
Recommendation 4
The work group is unable to recommend for or against the use of a valgus directing force brace (medial compartment unloader) for patients with symptomatic osteoarthritis of the knee.
Recommendation 5
The work group cannot suggest that lateral wedge insoles be used for patients with symptomatic medial compartment osteoarthritis of the knee.
Recommendation 6
The work group cannot recommend using glucosamine and chondroitin for patients with symptomatic osteoarthritis of the knee.
Pharmacologic Treatments
Recommendation 7A
The work group recommends nonsteroidal anti-inflammatory drugs (NSAIDs; oral or topical) or Tramadol for patients with symptomatic osteoarthritis of the knee.
Recommendation 7B
The work group is unable to recommend for or against the use of acetaminophen, opioids, or pain patches for patients with symptomatic osteoarthritis of the knee.
Procedural Treatments
Recommendation 8
The work group is unable to recommend for or against the use of intraarticular (IA) corticosteroids for patients with symptomatic osteoarthritis of the knee.
Recommendation 9
The work group cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee.
Recommendation 10
The work group is unable to recommend for or against growth factor injections and/or platelet rich plasma for patients with symptomatic osteoarthritis of the knee.
Recommendation 11
The work group cannot suggest that the practitioner use needle lavage for patients with symptomatic osteoarthritis of the knee.
Surgical Treatments
Recommendation 12
The work group cannot recommend performing arthroscopy with lavage and/or debridement in patients with a primary diagnosis of symptomatic osteoarthritis of the knee.
Recommendation 13
The work group is unable to recommend for or against arthroscopic partial meniscectomy in patients with osteoarthritis of the knee with a torn meniscus.
Recommendation 14
The practitioner might perform a valgus producing proximal tibial osteotomy in patients with symptomatic medial compartment osteoarthritis of the knee.
Strength of Recommendation: Limited
Recommendation 15
In the absence of reliable evidence, it is the opinion of the work group not to use the free-floating (un-fixed) interpositional device in patients with symptomatic medial compartment osteoarthritis of the knee.
Strength of Recommendation: Consensus
None provided
The type of supporting evidence is specifically stated for each recommendation (see the "Major Recommendations" field).
Effective treatment of osteoarthritis of the knee in adults
Individuals with osteoarthritis of the knee often complain of joint pain, stiffness, and difficulty with purposeful movement. The aim of treatment is to provide pain relief and improve the patient's functioning. Most interventions are associated with some potential for adverse outcomes, especially if invasive or operative. Potential harms of treatment include adverse effects of medications and complications of surgical procedures.
Contraindications vary widely by procedure. Reducing risks improves treatment efficacy and is accomplished through collaboration between patient and physician.
Guideline Dissemination Plans
The primary purpose of this guideline is to provide interested readers with comprehensive documentation about the work group recommendations and the process followed to develop them. All guidelines are available at the American Academy of Orthopaedic Surgeons (AAOS) Web site .
Shorter versions of the guideline are available in other venues. Publication of a guideline is typically announced during an Academy press release, and published in articles authored by the work group in the Journal of the American Academy of Orthopaedic Surgeons and AAOS Now. Most guidelines are also showcased at the AAOS Annual Meeting on Academy Row and as part of the Committee Scientific Exhibits.
Selected guidelines are disseminated by webinar, website, radio, briefings and continuing education. Examples include an online module for the Orthopaedic Knowledge Online website, radio media tours, media briefings, and AAOS' continuing medical education (CME) curriculum and Resource Center.
Other dissemination efforts outside of the AAOS include submission to the National Guideline Clearinghouse and to the Guidelines International Network database, as well as distribution at the annual meetings of other medical specialty societies.
Not applicable: The guideline was not adapted from another source.
The American Academy of Orthopaedic Surgeons funded this clinical practice guideline without any financial support from outside commercial sources.
American Academy of Orthopaedic Surgeons (AAOS) Treatment of Osteoarthritis of the Knee Guideline Work Group
Work Group Members: David Jevsevar, MD, MBA (Chair), Saint George, UT; Gregory Alexander Brown, MD PhD (Co-Chair), Park Nicollet Clinic-Meadowbrook, Department of Orthopaedic Surgery, St Louis Park, MN; Dina L. Jones, PT, PhD, West Virginia University Department of Orthopaedics, Morgantown, WV; Elizabeth G. Matzkin, MD, Tufts – New England Medical Center Department of Orthopaedics, Boston, MA; Paul Manner, MD, FRCSC, University of Washington, Seattle WA; Pekka Mooar, MD, Philadelphia, PA; John T. Schousboe, MD PhD, University of Minnesota, Consultant Rheumatologist, Park Nicollet Health Services, Adjunct Assistant Professor, Division of Health Policy and Management, Minneapolis MN; Steven Stovitz, MD, University of Minnesota, Sports Medicine and Family Practice, Department of Family Medicine and Community Health, Minneapolis, MN
Guidelines Oversight Chair: Michael J. Goldberg, MD, Seattle Children's Hospital & Regional Center, Seattle, WA
Guidelines Oversight Vice Chair: James O. Sanders, MD, University of Rochester, Department of Orthopaedics, Rochester, NY
Council on Research and Quality: Kevin J. Bozic, MD, MBA (Chair), University of California, San Francisco, San Francisco, CA
American Academy of Orthopaedic Surgeons (AAOS) Staff: William R Martin, III MD, AAOS Medical Director, Rosemont, IL; Deborah S. Cummins, PhD, Director of Research and Scientific Affairs, Rosemont, IL; Patrick Donnelly, MA, Lead Research Analyst; Anne Woznica, MLS, Medical Librarian
Former AAOS Staff: Patrick, Sluka MPH; Janet L Wies, MPH; Kevin Boyer MPH; Charles M Turkelson, PhD; Sharon Song, PhD
In accordance with American Academy of Orthopaedic Surgeons (AAOS) policy, all individuals whose names appear as authors or contributors to this clinical practice guideline provided full disclosure of and were vetted for potential conflicts of interest prior to the introductory meeting.
Refer to Appendix XII in the original guideline document for individual work group members' conflicts of interest.
Electronic copies: Available from American Academy of Orthopaedic Surgeons Web site .
Print copies: Available from the American Academy of Orthopaedic Surgeons, 6300 North River Road, Rosemont, IL 60018-4262. Telephone: (800) 626-6726 (800 346-AAOS); Fax: (847) 823-8125; Web site: www.aaos.org .
The following is available:
None available
This NGC summary was completed by ECRI Institute on April 8, 2009. The information was verified by the guideline developer on May 4, 2009. This summary was updated by ECRI Institute on July 31, 2013. The updated information was verified by the guideline developer on August 31, 2013. This summary was updated by ECRI Institute on September 18, 2015 following the U.S. Food and Drug Administration advisory on non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI Institute on June 2, 2016 following the U.S. Food and Drug Administration advisory on Opioid pain medicines.
This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions. For more information, please contact AAOS Department of Research and Scientific Affairs, 6300 North River Road, Rosemont, IL 60018; Phone: (847) 823-7186; Fax: (847) 823-8125.
The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.
All guidelines summarized by NGC and hosted on our site are produced under the auspices of medical specialty societies, relevant professional associations, public or private organizations, other government agencies, health care organizations or plans, and similar entities.
Guidelines represented on the NGC Web site are submitted by guideline developers, and are screened solely to determine that they meet the NGC Inclusion Criteria which may be found at http://www.guideline.gov/about/inclusion-criteria.aspx.
NGC, AHRQ, and its contractor ECRI Institute make no warranties concerning the content or clinical efficacy or effectiveness of the clinical practice guidelines and related materials represented on this site. Moreover, the views and opinions of developers or authors of guidelines represented on this site do not necessarily state or reflect those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or hosting of guidelines in NGC may not be used for advertising or commercial endorsement purposes.
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However, the order may not go as far as the United Nations wants. U.N. officials say all Afghan soldiers should leave Kabul, something Interior Minister Younus Qanooni says isn't going to happen.
In an interview with The Associated Press, Qanooni said soldiers now in Kabul were ordered to their barracks. But at least three large military complexes are within the city limits.
Under the U.N.-brokered agreement that resulted in creation of Afghanistan's interim government, all Afghan soldiers were to be out of Kabul when international peacekeeping forces arrived in the capital. The first peacekeepers came to Kabul in December.
The pact was meant to avoid a return of the factional fighting that killed thousands of Afghans in the early 1990s.


text:
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RATINGS: 347 WEIGHTED AVG: 4.24/5 SEASONAL: Special IBU: 60 EST. CALORIES: 402 ABV: 13.4%
Barrel Aged Barleywine. 11% ABV, 60 IBUs. Loosely based off our 2000th brew at our production facility,we revived this hybrid American / English Barley Wine for a special treat. Coming out of the tanks we aged it in barrels previously used for Bourbon County Rare Stout (Pappy Van Winkle 23 Year) to add another layer of complexity.
Note: The original release of this beer (2010) was done in regular bourbon barrels. The 2011 and bottle release saw the use of the barrels formerly used for Bourbon County Rare. We are not seperating these as I do not believe the bottles will clarify this. The original release also saw an 11% ABV, with the bottling seeing closer to 13.4%
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I traded several reels of beautiful bean footage for this Three Phase image. I hope it was worth it.
Crenshaw intended to make this out of macaroni pasta, but went with pixels instead.
"Stay puft" is DeathCab's personal mantra.
We clear up the BREXIT for confused Americans wondering why the global economy is collapsing this time.
BEEP! BOOP! ZAP! Video games aren't for my dad anymore! Because he's dead.
Insanely twisted and messed up stick figure families... holy sh*t...
with a slight motion of his hands, he appeared to remove and then reattach his thumb repeatedly
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Get a phu&king science degree and you will know how to test them.<quoted text>
Without testable hypotheses and repeatable results , all you have is personal opinion, and an ignorant faith based one at that.
Atheism requires as much faith as religion?
There are 255502 comments on the Webbunny tumblelog story from Jul 18, 2009, titled Atheism requires as much faith as religion?. In it, Webbunny tumblelog reports that:Atheism requires as much faith as religion? bearvspuma : The only problem with this rationalization is that ita s assuming all athiests are so because theya re intelligent in the ways of science and reasoning and all people that believe in a form of god are unintelligent.
Join the discussion below, or Read more at Webbunny tumblelog.
"Darwin died for your sins"
Since: Aug 08
#157366 Feb 28, 2013
Since: Mar 11
#157367 Feb 28, 2013
1000 years ago you would be screaming the earth was flat.
"Fear is the Mind-Killer"
Since: Jun 08
#157368 Feb 28, 2013
Are you making fun of immigrants? That's racist.
"Fear is the Mind-Killer"
Since: Jun 08
#157369 Feb 28, 2013
Yes there are. Plenty of evidence.
So Christians cannot defend their own sources? How else could they? You are accusing them of lying, being biased?
Think about that logically.
If the events DID happen ... how else is it to be reported? By those that witnessed it. And if they witnessed it, then they would be convinced that Jesus was God, and that it was all true.
What you are really saying if that you do not trust all the thousands of people during that time period of telling the truth. You are saying you don't trust people. You are saying they are primitive, and superstitious, and backwards. That is what you are saying.
And that tells me that you are a very bad person, and very contemptuous, and that you, yourself, cannot ever be trusted. If you do not see the folly of your own utterly irrational mind and total lack of logic ... the very notion that those that had been there 2000 years ago are not qualified to tell the truth, but you are? You know better than all those people back then?
Please, I dare you to rationalize your position. I dare you.
"Fear is the Mind-Killer"
Since: Jun 08
#157371 Feb 28, 2013
It's not evidence unless it's real. And without a time machine, it's as real as it's going to be.
Real enough to change the world.
"Fear is the Mind-Killer"
Since: Jun 08
#157372 Feb 28, 2013
Being outside of time and knowing everything in one great singularity does not negate free will.
Logic fail. And old argument since ancient times that fools like you keep falling for.
Nor are you a theologian. God's plans does not mean we cannot go against those plans. We do all the time.
The real scary part is that you fail logical thought so profoundly, that you do not take your own folly to its conclusion. If we did not have free will, then we are nothing more than machines. Why should we love God if we are machines? Love can only be freely given, not compelled by force.
Fail on all counts. Did you even think before you posted? Or is this just something someone else told you and you passed it along?
Since: Mar 11
#157373 Feb 28, 2013
Jesus Ben Strada an Egyptian sorcerer messiah who had followers did some magic tricks and guess what? We have secular evidence for him. Actual secular historians documented him. Yet this Jesus of Nazareth fellow who raised several dead Jewish prophets and walked into Jerusalem with them didn't get anyone's attention? Not one word? Even his own so called followers couldn't be bothered to write about him for decades later?
A cheesy Egyptian magician gets noticed but your Jesus doesn't? His own followers couldn't be bothered?
"Fear is the Mind-Killer"
Since: Jun 08
#157374 Feb 28, 2013
The complexity of the universe and life is the absolute scientific argument for design. It has been posted in journals since before they had journals. Are you so daft that you think science is only a recent event in the human experience?
Do you have any scientific journals that provide a valid argument for this all being an accident?
You do not even understand Christianity at all. If death is final, that would be far easier than being a Christian. Fear of death is no motivator at all, my friend. It is fear that it will never end that is the whole point.
Good grief, you are a moron.
"You have it partially correct, humanity that is subjected to "religion" are universally stupid and obviously superstitious."
Then you argue against evolution. It is evolution, the very essence of natural selection, and that we are among the top 1% of all living things on earth. But you say we are collectively morons?
You'd better get your story straight. Either we are evolved, and therefore the most highly advanced species ever in the long chain of events ... or we are actually a dumb species because of Adam and Eve's fall.
Which is it?
"Fear is the Mind-Killer"
Since: Jun 08
#157375 Feb 28, 2013
You did not offer an answer to the question at hand. Here it is again:
"What you are really saying if that you do not trust all the thousands of people during that time period of telling the truth. You are saying you don't trust people. You are saying they are primitive, and superstitious, and backwards. That is what you are saying.
And that tells me that you are a very bad person, and very contemptuous, and that you, yourself, cannot ever be trusted. If you do not see the folly of your own utterly irrational mind and total lack of logic ... the very notion that those that had been there 2000 years ago are not qualified to tell the truth, but you are? You know better than all those people back then?"
How do you plead for such contempt and disrespect to all those men and women 2000 years ago?
Since: Mar 11
#157376 Feb 28, 2013
Why thousands of people? Give their names. Give secular proof they existed. Show their writings. Hurry up now give the names of these people and secular proof they existed and documented as you claim. It ain't the gospels or anything in the NT because not a word of that was written until 50-70 years later.
Nazareth didn't even exist until the second century.
The Jesus and the adulterous woman isn't placed in the myth until the year 1100!!
Your faith is built on a hollow lie.
"Sweden more democratic thanUSA"
Since: Jun 12
Nykvarn, Sweden
#157377 Feb 28, 2013
and my relatives killed commies that tried to steal our land
"Sweden more democratic thanUSA"
Since: Jun 12
Nykvarn, Sweden
#157378 Feb 28, 2013
to only have freedom to choose between different religions isn't a freedom
"Ignore the trolls"
Since: Oct 08
Southampton, UK
#157379 Feb 28, 2013
It isn't a matter of "telling the truth" or otherwise, it is a matter of perception of that truth in a given time period. The bible sought to explain what at the time was unexplainable and put in in the context of faith. It is not a book of science, nor can it "prove" anything. It is a book of faith. Nothing wrong in that, until people attempt to use it to prove something. Then, it falls down. And given that Christianity is a minority religion in the world, why must the Jews, or the Muslims, or the Hindus or all the other myriad of faiths be wrong and the bible be right?
The bible is selective - if you study the texts left out of the bible (which are numerous - it was drawn together many years after Jesus's death by men who did not know him), the mis-translations that have occurred from the Greek, the re-writes that have been undertaken, it has to be a book of faith: no other explanation exists for its survival. It is not to denegrate men of less than 2000 years ago to suggest that their vision of the religion was less than perfect. Half of the New Testament is Paul's, not Jesus's word.
"Sweden more democratic thanUSA"
Since: Jun 12
Nykvarn, Sweden
#157380 Feb 28, 2013
and Nazism and fascism ....
"Fear is the Mind-Killer"
Since: Jun 08
#157381 Feb 28, 2013
Secular proof they existed?
World history and the rise of Christianity as a major movement.
Then prove it is based on a lie, and that this movement was born from liars. It should be easy. I am not the one calling thousands of people liars that witnessed various events in the first century AD.
You are.
"Darwin died for your sins"
Since: Aug 08
#157382 Mar 1, 2013
But nobody, not one single person, wrote anything down while he was supposedly alive. If he was such an important figure SOMEBODY would have figured out how to get his works written down at the time. I'm sure there were scrobes that would have done it.
"Fear is the Mind-Killer"
Since: Jun 08
#157383 Mar 1, 2013
No, it's a matter of telling the truth. Perception doesn't matter, and never will. The world does not changed based on perceptions, but facts. Water can be channeled into aqueducts, that is a fact, not a perception.
Christianity is not based on soft, fuzzy ideas. It either is based on facts, or it is not. Either Jesus was God, or he was a lying fraud and very dangerous. There is no perception, there are just facts.
No, it is not a book of science. It is a TESTIMONY of what was witnessed then, and preserved for future generations, like any other book. Who are you, 2000 years later, to accuse the witnesses and writers of lying and fraud?
If it means so little to you, then I accuse your ancestors of being pedophiles and gas chamber operators. Now ... defend them, or they are guilty. Prove your ancestors did not operate the gas chambers, or rape children. Prove it!
You really don't see it, do you?
"Darwin died for your sins"
Since: Aug 08
#157384 Mar 1, 2013
should be <scribes>
"Darwin died for your sins"
Since: Aug 08
#157385 Mar 1, 2013
What world history?
Christianity as a movement? That's an argumentum ad populam. Sorry.
Nobody is calling the people liars. What they believe is most likely not true. Willfully ignorant for refusing to investigate the sources of what they wanted to believe? IMO yes.
"Fear is the Mind-Killer"
Since: Jun 08
#157386 Mar 1, 2013
To the second part of your post.
Faith means to be persuaded by reason. It is a Greek word, and you are the one mistranslated it today, in this age when faith now means to accept something without evidence. That is not at all what faith meant in the Greek language, which only rational thought was allowed to accept such a bizarre and outrageous claim as Jesus made.
Selective? Indeed, just as any collection of books are selected today. You don't just collect all the stories and assume they are all correct. They SELECTED with great care the ones that made sense. The REJECTED books were not lost, they are still with us, they are just not considered inspired works. You have no understanding of the selection process that was done VERY scientifically and with great care.
And what was Jesus going to write? Nothing he said made any SENSE until after the Resurrection, and He was gone. Obviously, and logically, that was left to us to DOCUMENT THE EVENT AFTER THE FACT. Just like any crime scene, you wait, you investigate, you take your time, you are careful, and then you write your conclusions.
It is absolutely to degenerate men 2000 years ago. It is to show the utmost disrespect and loathing for people JUST LIKE YOU that where THERE WHEN IT HAPPENED, and gave ORAL testimony just like countless cultures have for thousands of years.
To say that oral tradition is a lie is to call people liars, pure and simple. Yet, to satisfy all the naysayers like yourself in the first few centuries, they wrote it down ... and still people like you come along with total contempt for all humanity.
Do you have any idea what God meant when He said to love thy neighbor? Yeah, that meant to trust one another ... it is the lack of TRUST that is tearing this world apart, and has always teared this world apart
You are the reason Jesus had to come. The distrustful, paranoid, and frightened. What are you afraid of?
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text:
Minn. officer accused of posting about protesters resigns
He made on Facebook urged drivers to run over protesters
Associated Press
ST. PAUL, Minn. — A St. Paul police officer has resigned a month after a post he made on Facebook urged drivers to run over protesters who rallied against the police killings of two black men in the Twin Cities last year.
The St. Paul Police Department said Wednesday that Sgt. Jeff Rothecker has resigned his position with the department, effective immediately. The police statement said no additional details were available.
Rothecker had apologized earlier for the post. He was put on leave while the Police Department investigated.
The St. Paul Pioneer Press reported the social media message said, "Run them over," and told people how to avoid being charged with a crime if they struck someone during the Martin Luther King Day march and rally on a bridge linking St. Paul and Minneapolis.
Copyright 2016 The Associated Press
Copyright Associated Press. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
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|Publication number
|Publication type
|Application number
|Publication date
|Mar 12, 1991
|Filing date
|May 5, 1989
|Priority date
|Jun 27, 1986
|Fee status
|Also published as
|Publication number
|Peter Fankhauser
|Original Assignee
|Ciba-Geigy Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (5), Referenced by (16), Classifications (24), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a continuation of application Ser. No. 063,889 filed on June 19, 1987 now abandoned.
Topical application of drugs is often indicated whenever the dosage form for oral or some other kind of parenteral administration leads to lack of tolerance, risks, or side-effects. Thus topical application to the skin is preferred if the drug is to act systemically, by-passing the gastrointestinal tract.
Pharmaceutical compositions for topical application on the basis of an oil-in-water emulsion containing diethylammonium-2-(2,6-dichloroanilino)phenyl acetate as active ingredient are disclosed in DE-A 3 336 047.
It is the object of the present invention to provide a pharmaceutical composition for topical application containing diclofenac or a salt thereof, which composition is distinguished by enhanced penetration properties and resorption.
This object is achieved with the pharmaceutical composition of this invention, which comprises the following components:
(a) diclofenac or a pharmaceutically acceptable salt thereof,
(b) a compound of formula ##STR1## wherein R1 is C9 -C19 alkyl and R2 and R3 are C1 -C4 alkyl, or wherein R1 is attached to one of the substituents R2 or R3 and, together with said substituent, is C5 -C7 alkylene, and the other substituent R2 or R3 is C10 -C20 alkyl, which compound enhances the permeability of component (a), and, optionally,
(c) a paraffin which is suitable for topical application and is liquid at body temperature, and/or
(d) further excipients suitable for percutaneous delivery.
A pharmaceutically acceptable salt of diclofenac, o-(2,6-dichloroanilino)phenylacetic acid, is in particular an alkali metal salt, e.g. the sodium or potassium salt, an acid addition salt with an amine, e.g. a mono-, di- or tri(C1 -C4 alkyl)amine, such as diethylamine or triethylamine, a hydroxy(C1 -C4)alkylamine such as ethanolamine, a (hydroxy-C2 -C4 alkyl)-di(C1 -C4 alkyl)amine such as dimethylethanolamine, or a quaternary ammonium salt, e.g. the tetramethylammonium salt or chlorine salt of diclofenac.
The compound of formula I has permeability enhancing properties in the pharmaceutical composition of this invention and is able to increase the rate of flux of diclofenac or salt thereof through the skin per unit of time.
In a compound of formula I, R1 is preferably straight chain C9 -C19 alkyl, e.g. n-nonyl, n-undecyl, n-tridecyl, n-pentadecyl, n-heptadecyl or n-nonadecyl.
If R1 is C9 -C19 alkyl, then R2 and R3 are preferably methyl.
R1 and R2 or R1 and R3 may also be attached to each other and together form an azacycloalkanone heterocycle. In this case, R1 and R2 or R1 and R3 together are C5 -C7 alkylene, preferably straight chain C5 -C7 alkylene, e.g. n-hexylene or n-heptylene, preferably n-pentylene; and the substituent R2 or R3 which is not attached to
R1 is preferably straight chain C10 -C20 alkyl containing an even number of carbon atoms, e.g. n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl or n-eicosyl.
In preferred compounds of formula I, R1 is n-undecyl and R2 and R3 are methyl (N, N-dimethyllauroylamide), or R1 and R2 or R1 and R3 are attached to each other together are n-pentylene, and form the azacycloheptan-2-one heterocycle which is substituted at the nitrogen by R3 or R2 defined as C10 -C20 alkyl, e.g. n-dodecyl, and is e.g. 1-n-dodecylazacycloheptan-2-one (Azone�, ex Nelson Corp.).
Paraffins which are suitable for topical application and liquid at body temperature are in particular purified clear, oily, tasteless and odourless mixtures of saturated aliphatic or cycloaliphatic hydrocarbons, e.g. low viscosity or viscous paraffin or VASELINE� petroleum jelly (Cheseborough Manuf. Co.).
The preferred paraffin is viscous paraffin with a boiling point above 300� C. and having the density and viscosity values indicated in standard pharmacopeias, e.g. DAB, OeAB, Helv., USP or CF, e.g. 0.865-0.890 and ≧120�20 cP (DAB 7, OeAB 9), 0.845-0.905 and ≧38.1 cSt (37.8� C.-USP XIX), 0.865-0.895 and ≧40 cP (Helv. VI) or 0.860-0.885 and ≧37 cSt (0� C.-CF 65), as well as having the purity standards and maximum limits for impurities prescribed in the above pharmacopeias.
Preferred excipients for percutaneous delivery are those which are suitable for the preparation of creams, ointments, gels, pastes or foams containing c. 0.5 to 5% of drug and, in particular, for the preparation of transdermal therapeutic systems.
Creams are water-in-oil emulsions. For the oily phase it is preferred to use fatty alcohols, e.g. lauryl, cetyl or stearyl alcohol, fatty acids, e.g. palmitic or stearic acid, liquid or solid waxes, e.g. isopropyl myristate, natural or partially synthetic fat, e.g. cocosyl triglyceride, hardened oils, e.g. hydrogenated ground nut oil or castor oil, or fatty acid partial esters of glycerol, e.g. glycerol monostearate or glycerol distearate. Suitable emulsifiers are surface-active compounds with mainly hydrophilic properties, e.g. nonionic surfactants, e.g. fatty acid esters of polyalcohols or adducts thereof with ethylene oxide such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tween�, ICI), and also polyoxyethylene fatty alcohol ethers or fatty acid esters, or anionic surfactants such as alkali metal salts of fatty alcohol sulfates, e.g. sodium lauryl sulfate, sodium acetyl sulfate or sodium stearyl sulfate, which are normally used in the presence of the fatty alcohols, e.g. cetyl alcohol or stearyl alcohol. To the aqueous phase are added e.g. humectants, e.g. polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives, perfumes and the like.
Ointments are water-in-oil emulsions. Component (c) is used as oily phase, preferably low viscosity paraffin to which preferably a fatty alcohol or an ester thereof, e.g. cetyl alcohol, or a wax alcohol, or wool wax is added to enhance the hydrophilic properties. Suitable emulsifiers are lipophilic substances such as sorbitan fatty acid esters (Span�, ex Atlas), e.g. sorbitan oleate and/or sorbitan isostearate. Additives for the aqueous phase include humectants such as polyalcohols, e.g. glycerol, propylene glycol, sorbitol and/or polyethylene glycol, as well as preservatives, perfumes and the like.
Ointments may also be anhydrous and contain, as base, component (c), in particular low viscosity paraffin, and also the cited natural or partially synthetic fats, e.g. cocosyl triglyceride, hardened oils, e.g. hydrogenated ground nut oil or castor oil, fatty acid partial esters of glycerol, e.g. glycerol monostearate and glycerol distearate, silicones e.g. polydimethylsiloxanes such as hexamethyl disiloxane or octamethyltrisiloxane, as well as e.g. the fatty alcohols, for improving the hydrophilic properties mentioned in connection with the water-containing ointments, and emulsifiers and/or other additives.
In the case of gels, a distinction is made between aqueous gels, anhydrous gels or gels of low water content which consist of swellable, gel-forming material. Transparent hydrogels based on inorganic or organic macromolecules are particularly suitable. Macromolecular inorganic components with gel-forming properties are mainly water-containing or water-absorbing silicates such as aluminium silicates, e.g. bentonite, magnesium/aluminium silicates, e.g. Veegum� (Vanderbilt Exp. Corp.) or colloidal silica, e.g. Aerosil� (Degussa). Typical examples of macromolecular organic components are natural, semi-synthetic or synthetic polymers. Natural and semi-synthetic polymers are derived e.g. from polysaccharides containing different carbohydrate components, e.g. cellulose, starch, tragacanth, gum arabic, agar-agar, gelatin, alginic acid and the salts thereof, e.g. sodium alginate and derivatives thereof, lower alkyl cellulose, e.g. methyl cellulose or ethyl cellulose, carboxy-lower alkyl cellulose or hydroxy-lower alkyl cellulose, e.g. carboxymethylcellulose or hydroxypropyl cellulose. The components of synthetic, gel-forming polymers are e.g. unsaturated substituted aliphatic compounds such as vinyl alcohol, vinyl pyrrolidone, acrylic acid or methacrylic acid. Examples of such polymers are derivatives of polyvinyl alcohol, e.g. polyviol, polyvinyl pyrrolidones such as Kollidon� (BASF) or Polyplasdon� (General Aniline), polyacrylates and polymethacrylates such as Rohagit S� (Rohm and Haas). Customary additives such as preservatives or perfumes can be added to the gels.
Pastes are creams or ointments containing the above mentioned constituents and secretion-absorbing powder components such as metallic oxides, e.g. titanium dioxide or zinc oxide, and also talcum and/or aluminium silicates which serve to bind moisture or secretions.
Foams are applied e.g. from pressurised containers and are liquid oil-in-water emulsions in aerosol form for which halogenated or non-halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g dichlorodifluoromethane or dichlorotetrafluoroethane or alkanes, e.g. propane or butane, are used as propellants. Fatty alcohols, e.g. cetyl alcohol, fatty acid esters, e.g. isopropyl myristate, and/or other waxes, are used as the oily phase. Suitable emulsifiers are e.g. mixtures of emulsifiers having mainly hydrophilic properties, for example polyoxyethylene sorbitan fatty acid esters (Tween�), with emulsifiers having mainly lipophilic properties, e.g. sorbitan fatty acid esters (Span�). Foams also contain conventional additives such as preservatives and the like.
Transdermal therapeutic systems (TTS) are preferred to such topical agents for percutaneous delivery, as such systems permit the continuous release of active ingredient through the skin over a prolonged period of time ranging from about 24 hours to one week, in contrast to gels or ointments which have to be applied repeatedly during the day. With the aid of transdermal therapeutic systems it is possible to administer constant amounts of drug per unit of time and thus to achieve a uniform systemic action.
Suitable transdermal therapeutic systems which may be applied are for example those disclosed in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,797,494 and 4,064,084, preferably the systems disclosed in DE-A 26 04 718 and in U.S. Pat. Nos. 4,031,984 and 4,262,003, or described by H. Asche in Schweiz. Rundschau Med. (Praxis) 74, No. 11, 257-260 (1985), e.g. matrix or monolith systems or membrane-controlled systems. In this connection it must be emphasised that such application is not limited to the transdermal therapeutic systems disclosed and described in the aforementioned publications. The preferred transdermal therapeutic system disclosed in DE-A 26 04 718 is a system in the form of a patch that releases the drug, e.g. diclofenac sodium, transdermally so that side-effects are avoided, in an initial dose of c. 10 to 200 μg/cm2 of skin and then at a rate of c. 0.3 to 5 μg/h, such that the drug concentration in the plasma remains approximately constant.
In membrane-controlled systems the patch can consist of multi-layer laminates which form the following layers viewed from the application surface:
(a) a protective backing layer; a gel-like mineral oil/polymeric hydrocarbon drug reservoir (b) which contains the flux enhancer and which provides the source of constant drug release; a membrane (c) which partly controls the constant rate of drug release; and (d) a gel-like mineral oil/polymer hydrocarbon layer which contains the drug and which acts as source of the initial dose; as well as further adhesive with which the patch is affixed to the skin after removal of a protective peel strip.
Polymeric hydrocarbons are used in the reservoirs of the above described transdermal therapeutic systems, e.g. polymers containing aliphatic, cycloaliphatic-aliphatic or aliphatic-aromatic molecules, e.g. polypropylene, polybutylene, polybutylethylene, polypropylethylene or polystyrene.
The gel-like mineral oil/polymeric hydrocarbon drug reservoir (b) contains the drug, e.g. Voltaren�, partly dissolved and partly undissolved, homogeneously dispersed in a gel-like mixture consisting of mineral oil having a viscosity of about 10 to 100 cP at 25� C., a polymeric hydrocarbon, e.g. polyisobutylene, and the flux enhancer, e.g. 1-n-dodecylazacycloheptan-2-one. The mixture of mineral oil and polymeric hydrocarbon also acts as adhesive and holds the patch together. The mineral oil is further used as vehicle for the drug, which has only limited solubility in mineral oil (c. 2 mg/ml). The maximum concentration of drug in the reservoir layer are chosen such that the mineral oil is substantially saturated with the drug during the entire release period of the patch.
The next layer of the multi-layered laminate is a semipermeable layer (c), e.g. a microporous membrane, the pores of which are filled with the above vehicle and which controls the rate at which the drug is released to the skin. The flux of drug through the semipermeable layer and the contact surface area of the membrane must be chosen such that the drug is released to the skin from the reservoir layer at substantially constant rate in the range from c. 0.3 to 5 μg/h. The semipermeable membrane is made from polymeric materials through which the drug can diffuse. Polymers suitable for making such membranes are described in the publications previously referred to, e.g. polypropylene, polyacrylates, polyvinyl chloride, polyester, siliconated polyester laminates, cellulose acetate, cellulose nitrate, polyacrylonitrate, copolymers of ethylene with other monomers, e.g. vinyl acetate, or organopolysiloxane rubber.
The adhesives layer (d) of the laminate is composed substantially of the same materials as layer (b) described above, contains the drug, e.g. diclofenac sodium, and releases an initial dose of the drug when the system is applied to the patient. With the aid of the strongly adhesive layer (d), consisting e.g. of polyisobutylene adhesive material, the patch is affixed to the skin after a protective peel strip, e.g. aluminium foil, has been removed.
The present invention preferably relates to a pharmaceutical composition comprising
(a) a pharmaceutically acceptable salt of diclofenac,
(b) a compound of formula I, wherein R1 is n-undecyl and R2 and R3 are methyl (N,N-dimethyllauroylamide), or wherein R1 is attached to one of the substituents R2 and R3 and together with said substituent is n-pentylene, and the nitrogen is substituted by R3 or R2 defined as n-dodecyl (1-n-dodecylazacycloheptan-2-one),
(c) viscous paraffin suitable for topical application, and, optionally,
(d) further excipients suitable for percutaneous delivery.
Most preferably, the invention relates to a pharmaceutical composition comprising
(a) the sodium, potassium or diethylammonium salt of diclofenac,
(b) N,N-dimethyllauroylamide or 1-n-dodecylazacycloheptan-2-one,
(c) a viscous mineral oil suitable for topical application, and, optionally,
(d) further excipients suitable for percutaneous delivery.
The pharmaceutical compositions of this invention can be used as formulations for topical application, in particular for transdermal therapeutic systems for the treatment of painful conditions, inflammatory conditions and/or rheumatic diseases in warm-blooded species (humans and animals). They can be applied in daily doses of c. 25-200 mg of drug by means of transdermal therapeutic systems.
The invention also relates to a process for the preparation of said pharmaceutical compositions, which comprises mixing components (a), (b) and optionally (c) and/or (d) in the intended amounts and further processing the mixture so obtained to topical formulations, e.g. creams, ointments, gels, pastes or foams or, in particular, to transdermal therapeutic systems.
The invention further relates to a process for enhancing the permeability of diclofenac or a pharmaceutically acceptable salt thereof in topical formulations, which process comprises the use of a compound of formula ##STR2## wherein R1 is C9 -C19 alkyl and R2 and R3 are C1 -C4 alkyl, or wherein R1 is attached to one of the substituents R2 or R3 and, together with said substituent, is C5 -C7 alkylene, and the other substituent R2 or R3 is C10 -C20 alkyl, and, optionally, of a liquid paraffin suitable for topical application and/or further excipients suitable for percutaneous delivery as base for topical formulations containing diclofenac or a pharmaceutically acceptable salt thereof.
Diclofenac and the salts thereof are known (q.v. Merck Index 1983, N. 3066).
Compounds of formula I are known. The use of compounds of formula I, wherein R1 is C9 -C19 alkyl and R2 and R3 are C1 -C4 alkyl, as penetration agents for achieving a systemic action is known (q.v. U.S. Pat. No. 4,031,894).
The use of compounds of formula I, wherein R1 is attached to one of the substituents R2 or R3 and the other substituent R2 or R3 is C10 -C20 alkyl, as penetration agents for topical application, is disclosed in U.S. Pat. No. 3,989,816.
The use of these compounds, especially of 1-dodecylazacycloheptan-2-one, as penetration agents for achieving a systemic action of drugs for topical application, is disclosed in U.S. Pat. No. 4,405,616.
The invention is illustrated by the following Examples.
1. Materials
1.1. diclofenac sodium (puriss.)
1.2. 1-n-dodecylazacycloheptan-2-one
1.3. N,N-dimethyllauroylamide
1.4. mineral oil (puriss.)
2. Procedure
A piece of pig epidermis measuring c. 3�3 cm was put into a diffusion cell in accordance with the method described by T. J. Franz, J. Invest. Dermatol. 64, 190-195 (1975). The lower acceptor compartment was filled with an isotonic buffer solution of pH 7.4, while the upper donor compartment was filled respectively with
(a) a supersaturated solution or suspension (c. 5%) of diclofenac sodium in mineral oil (vehicle),
(b) a supersaturated solution or suspension of diclofenac sodium in the vehicle with the addition of the flux enhancer 1-n-dodecylazacycloheptan-2-one,
(c) a supersaturated solution or suspension of diclofenac sodium in the vehicle with the addition of the flux enhancer, dimethyllauroylamide.
The permeabilities were measured for each sample over a period of 24 hours after 3, 6 and 24 hours respectively. The concentration of diclofenac sodium in the acceptor compartment of the diffusion cell was determined by HPLC. The amount of diclofenac permeated through the epidermis from the beginning of the test per cm2 (cumulative permeation) as well as the flux of diclofenac over the elapsed interval of time per cm2 and hour were computed from the concentrations. The following values were obtained:
TABLE______________________________________ Concentr of flux cumulative enhancer permeation Flux [% by 0-24 h [μg/cm2 � h] weight] [μg/cm2 ] 0-3 h >24 h______________________________________(a) vehicle -- 36 2.5 1.4 + diclofenac sodium --(b) 1-n-dodecylaza- 5 240 20 5 cycloheptan-2-one + vehicle + diclofenac sodium 20 11300 19 610(c) dimethyllauroyl- 5 2800 43 140 amide + vehicle + diclofenac sodium 20 7100 27 360______________________________________
A circular piece of sintered polypropylene, 1 mm thick and 3.6 mm in diameter, and having an average pore size of 5 μm and a relative pore volume of 20%, is affixed to the centre of a polyester sheet (Mylar�) coated with medicinal silicone adhesive (ex Dow Corning) and having a thickness of 20 μm and a diameter of 5.5 cm. In a vacuum cabinet, 200 mg of the following mixture are applied and air-blasted into the porous sheet:
4 g of diclofenac sodium
16 g of 1-n-dodecylazacycloheptan-2-one
80 g of low viscosity paraffin oil
0.1 g of Tween� 80
To prepare the mixture, the diclofenac sodium is ground in a glass bead mill (Dynomill�) to a particle size of less than 1 μm.
A 10 cm2 sachet is prepared from polyester/polyethylene composite film and, as backing film, porous polypropylene (Celanese�) as control membrane by heat sealing along the circumference. The sachet is filled with 250 mg of the mixture of Example 2 by puncturing it at the edge with an injection syringe and the puncture is heat sealed. The system containing the mixture is applied to the skin by means of a medicinal plaster.
25 g of diclofenac sodium are suspended in 100 g of 1-n-dodecylazacycloheptan-2-one and the suspension is ground in a glass bead mill to a particle size of less than 1 μm. This suspension is mixed in a heated kneader at 80� C. with 100 g of polyisobutylene with a molecular weight of 5,000,000 and 225 g of polyisobutylene with a molecular weight of 30,000. The mixture is pressed to sheets 1 mm thick which are covered on one side with 20 μm polyester backing layer and on the other with 20 μm siliconised polyester to be removed before use. Transdermal systems measuring 10 cm2 are cut from the laminates.
25 g of diclofenac sodium are suspended in 100 g of dimethyllauroylamide and, as in Example 4, processed with polyisobutylene to a plastic material. Sheets 1 mm and 0.1 mm thick are pressed separately from this material. Porous polypropylene sheeting is impregnated with dimethyllauroylamide and the following layers are laminated: a 20 μm polyester sheet as protective film, a 1 mm sheet as reservoir, an impregnated polypropylene sheet as control membrane, a 0.1 mm sheet as contact adhesive surface with initial dose, and a 20 μm siliconised polyester sheeting as peel strip. Transdermal systems measuring 10-40 cm2 are cut from this laminate.
Three flat teflon sachets measuring 2.5 cm2 with sealing edge are each affixed to the intact skin of the thorax (total area: 7.5 cm2) of 2 test persons. Each sachet is filled with a formulation comprising 10 mg of diclofenac sodium, 10 mg of 1-n-dodecylazacycloheptan-2-one and 30 mg of silicone oil (total of 30 mg of diclofenac sodium), and is left for 24 hours at its application site. Urine is collected at intervals of 0-5, 5-10, 10-24 and 24-48 hours and analysed for excreted drug.
An average flux of diclofenac sodium of 0.35 μg/cm2 19 24 h is computed from the excretion.
|Cited Patent
|Filing date
|Publication date
|Sep 29, 1969
|Jan 26, 1971
|Gelgy Chemical Corp
|Substituted derivatives of 2-anilinophenylacetic acids and a process of preparation
|Jun 19, 1975
|Nov 2, 1976
|Nelson Research & Development Company
|Vehicle composition containing 1-substituted azacycloheptan-2-ones
|May 20, 1982
|Sep 20, 1983
|Nelson Research & Development Company
|Penetration enhancers for transdermal drug delivery of systemic agents
|Mar 26, 1987
|Oct 10, 1989
|Maraho Co., Ltd.
|Percutaneous absorption preparation
|Title not available
|Citing Patent
|Filing date
|Publication date
|Mar 16, 1993
|Dec 20, 1994
|Sano Corporation
|Composition and method for transdermal delivery of diclofenac
|Dec 22, 1993
|Dec 12, 1995
|The Regents Of The University Of California
|Preventing and treating elevated intraocular pressure associated with administered or endogenous steroids using non-steroidal cyclooxygenase inhibitors
|Jun 7, 1995
|Feb 4, 1997
|Regents Of The University Of California
|Methods for the cyto-protection of the trabecular meshwork
|Nov 21, 1995
|Sep 9, 1997
|Davis; Roosevelt
|Transdermal therapeutic formulation
|Jun 7, 1995
|Oct 7, 1997
|University Of California
|Method for the treatment of a trabecular meshwork whose cells are subject to inhibition of cell division
|Apr 8, 1999
|Sep 19, 2000
|L.A.M. Pharmaceuticals Llc
|Topical drug preparations
|Sep 25, 1998
|Apr 20, 2004
|Samyang Corporation
|Transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, and the manufacturing method thereof
|Jun 10, 2009
|May 8, 2012
|Hisamitsu Pharmaceutical Co., Inc.
|Method for avoiding crystallization of anti-inflammatory agent in plaster formulation
|Jun 11, 2014
|Apr 21, 2015
|James Blanchard
|Gel for topical delivery of NSAIDs to provide relief of musculoskeletal pain and methods for its preparation
|Apr 17, 2001
|Aug 7, 2003
|Yasuhiro Ikeura
|Patch containing anti-inflammatory agent
|Dec 16, 2005
|May 4, 2006
|Luo Eric C
|Hydroxide-releasing agents as skin permeation enhancers
|Jun 10, 2009
|Oct 15, 2009
|Hisamitsu Pharmaceutical Co., Inc.
|Patch containing anti-inflammatory agent
|Nov 9, 2009
|Feb 25, 2010
|Tokuhon Corporation
|Analgesic anti-inflammatory patches for topical use
|Aug 1, 2008
|Apr 21, 2011
|Beiersdorf Ag
|Cosmetic emulsifier combination
|Jun 15, 2012
|Jan 24, 2013
|Epifarma Srl
|Patch containing diclofenac and thiocolchicoside
|Nov 4, 2013
|May 8, 2014
|Zydus Technologies Limited
|Stable transdermal pharmaceutical drug delivery system comprising diclofenac
|U.S. Classification
|514/567, 514/825, 514/916
|International Classification
|Cooperative Classification
|European Classification
|Dec 21, 1990
Owner name: CIBA-GEIGY CORPORATION, 444 SAW MILL RIVER RD., AR
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:CIBA-GEIZY AG;REEL/FRAME:005552/0384
Effective date: 19901207
|Oct 18, 1994
|Maintenance fee reminder mailed
|Mar 12, 1995
|Lapse for failure to pay maintenance fees
|May 23, 1995
|Expired due to failure to pay maintenance fee
Effective date: 19950315


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Driving an armored personnel carrier in the Norwegian military might become a lot more like playing a video game in the near future. The army there has developed a way for APC drivers to use Oculus Rift virtual reality goggles to make piloting the heavy vehicles significantly easier.
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Laura Dare Baby Girls Rosebud Sleeper w/ Bonnet Preemie-NewbornAn absolutely precious sleeper for your baby girl by Laura Dare.
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Petroleum Geo-Services (PGS), in cooperation with TGS, has returned for the third year to East Canada to complete acquisition of a previously announced 2D MultiClient survey offshore Newfoundland using the PGS GeoStreamer acquisition technology. The 2013 program will acquire additional data over approximately 16,000 line km of the Northeast Newfoundland Slope.
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