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On the other hand prednisone 20 mg sale allergy shots duration, absence The duration of a trial will be influenced by whether or of a washout means a true 'baseline' is not achieved purchase cheap prednisone online allergy medicine germany, assum- not a placebo group is included. The longer the duration, ing that there has been some degree of response and or the more difficult to justify the retention of patients on adverse effects from the prior treatment. The use of a con- placebo, and the higher the dropout rate, the less useful are current placebo group in the treatment trial mitigates these the data. The type, dosage, and half-life of prior treatments is generally variable. The modal time frame of response has will influence how long a washout is necessary to prevent to be factored into trial design in order to allow estimates potential withdrawal effects from influencing baseline rat- of statistical power. Whether or not a washout takes place (and how long for example, most patients will experience at least half of it is) can have implications for assessing the effects of subse- the ultimate degree of improvement within the first 4 to 6 quent treatment. The effects of withdrawal are neither con- weeks (assuming that there was not an inordinately long sistent nor predictable, which complicates establishment of titration phase). In many studies a significant drug effect is an appropriate baseline. For example, agitation is likely to respond more adjustment is associated with poorer outcome, and may be rapidly than delusions or thought disorder. In addition, an indicator of those patients in whom early neurodevelop- there may be a subgroup of patients who are slower to re- mental abnormalities or prodromal symptoms were more spond, and for such patients longer trials may be needed. If a between-drug comparison of the full extent of response Comorbid psychiatric disorders should be evaluated and is ultimately important, then much longer trials are needed documented. As more and more on overall response to psychotropic medications, common domains of outcome are of interest in clinical trials (such comorbid conditions should be studied at some point to as primary negative symptoms or cognitive dysfunction in help assure generalizability and to inform clinical practice. Estimates of expected degrees of improve- be an important outcome measure in appropriate popula- ment in various domains will be critical for statistical power tions. In studying antipsychotic medications it is important to document the presence and severity of any preexisting The Role Of Placebos movement disorders in order to have an adequate baseline assessment and to ensure that a preexisting condition (or The decision as to whether or not to use a placebo in short- withdrawal effect) is not attributed to subsequent treatment. It is beyond the scope of this 'regulatory' requirements, investigators, institutional re- chapter to discuss this in great detail, but patients should view boards, patients and families, and other interested par- be able to describe and explain in their own words the re- ties. There are a number of important arguments that can search in which they are agreeing to participate, its goals, be made against the routine use of a placebo in clinical its experimental aspects, and its potential risks and benefits. Rothman and Michels (3) argue that when an effective 540 Neuropsychopharmacology: The Fifth Generation of Progress treatment exists for a particular disease, the use of a placebo active treatment. This is a difficult question to adequately is inappropriate on both logical and ethical bases. However, address; however, there have been some attempts to examine the argument suggests that the use of a placebo is appropri- the consequences, both short- and long-term, of receiving ate in cases when an effective treatment is not available. Overall, there problem remains in how to define effectiveness. The use of do not appear to be demonstratable deleterious effects of the term effective in this context is not necessarily identical to participating in short-term trials (6,7). The issue of lengthy the current use of effectiveness as differentiated from efficacy. If we define response tion of untreated psychosis is associated with poor outcome. In the case of outcome (8), but the effect was no longer evident in long- severe deficit symptoms or in patients who have proven term follow-up (9). Short-term clinical trials usually involve refractory to other drugs, the issue is less clear. Therefore, it is important to A particular problem arises when response to a proven recognize potential differences in consequences between effective treatment (or so-called gold standard) can vary brief delays and relatively long delays in treatment. Lavori enormously from trial to trial and in some cases be rather (5) argues that because assessments in placebo-treated pa- low, or when response to a placebo is generally high (4). The field would certainly benefit from more intent- already available, the question should not be is the new drug to-treat analyses as well as long-term follow-up of patients superior to placebo but rather is the new drug superior to who were involved in placebo-controlled trials. Unfortunately, given the nature Designs involving the treatment of patients who have of the diseases and the adverse effects associated with some failed on other treatments are another challenge. One could psychotropic drugs, a new drug could be superior in one argue that placebo controls are more acceptable in this con- domain and inferior in another, while being a very valuable text because there is no effective treatment. However, it is addition to the therapeutic armamentarium. The use of pla- usually the case that these patients have demonstrated some cebo controls can still be important to determine whether benefit from standard, albeit inadequate, treatment. There- or not in some domains a drug is inferior, but still better fore, the appropriate comparison would be the new treat- than a placebo, or whether its inferiority in one domain is ment versus standard treatment, with the only outcome of such that it would change the overall effectiveness equation. To provide an example, suppose drug A were somewhat The decision as to whether or not to use placebo or active less effective than drug B in controlling acute symptoms, controls or both in a particular trial is not an easy one. At the same There are complex issues that need to be considered, and time, drug B was associated with serious side effects that it is hoped that further knowledge involving the determi- might result in a substantial number of patients discontinu- nants of heterogeneity in response will facilitate more ra- ing the medication within a short period of time. Before approving drug A, we would want to be harm and not withhold effective treatment is a critical issue. Extensive use of rescue medication can make it diffi- (5) has emphasized, the data sets available from current cult to accurately assess the drug effect (even though use of placebo-controlled trials are usually 'heavily truncated, dif- rescue medication can be a telling outcome in and of itself). Here, too, carried forward (LOCF)' and that 'the interpretation of rates of utilization can be an important outcome measure, positive results in the context of badly truncated data re- yet at the same time the additional medication might have quires unverifiable assumptions, external to the observed other undesirable effects (e. To some extent, patient receives a potentially active compound and if re- this results from unfounded assumptions that we have good sponse occurs, crossover to a placebo takes place. If response data on dose-response relationships with drugs that have does not occur, the placebo phase is not required. In addi- cebo phase in this context helps to determine whether or tion, dosage requirements will vary depending on the popu- not the response to medication was a true drug effect or lation. For example, in schizophrenia, first-episode patients not. It is argued that this design has the advantage of each in general respond to lower doses than multiepisode pa- patient serving as his or her own control, allowing all pa- tients, and acute treatment usually requires higher doses tients to eventually receive active medication and increasing than maintenance treatment. Another design that is being increasingly utilized is the The applicability of this design varies depending on the adjunctive or add-on strategy. This is particularly useful nature of the disorder being studied, the time course of when subjects with partial or inadequate response are the response, and the vulnerability to relapse or symptom exac- focus of interest. Rather than switching participants from erbation once active treatment is replaced by a placebo. For the unsatisfactory treatment to a new treatment, partici- example, this design may be more informative in rapid cy- pants are randomized to an added placebo or added experi- cling bipolar patients (11) than in the context of an acute mental treatment. In this approach, no drug withdrawal is treatment trial in other disorders. Also, this trial does not necessary and the question of interest is whether or not the eliminate exposure to a placebo.
Although diseases such as schizophrenia have been charac- terized by a broad array of biologic abnormalities cheap prednisone 20mg without prescription allergy relief èíñòðóêöèÿ, there are as yet no well-validated biological classification systems that Effectiveness Research have proven to be useful in clinical trials or in drug develop- Increasing attention has been focused on the fact that tradi- ment order prednisone 10 mg without prescription allergy drops for eyes. This may be largely due to lackof systematic effects tional randomized clinical trials often include highly se- in this direction rather than an absence of potentially in- lected patients who may not be representative of the popula- formative relationships. As new medications are used in routine clinical diverse perspectives ranging from neuroimaging to pharma- practice, there is often a considerable gap in the knowledge cogenomics, it is just a matter of time before biological base needed to inform decision making. For example, many classification becomes a critical ingredient in this context. In addition, a variety of concerns including of psychotropic medications. In The more knowledge available about pharmacokinetics and designing assessment batteries, it is important to choose metabolism (including activity of metabolites) before large- instruments with proven reliability and validity as well as scale clinical trials are designed, the better. Understanding instruments that are likely to be sensitive to the kind of potential relationships between blood levels and therapeutic treatment effect being measured. Meaningful clinical effects response as well as adverse effects can be very helpful in should be identified with specific measures of change in optimizing treatment outcome. However, relevant data are order to ensure that the sample size provides adequate statis- often inadequate before critical decisions about dose and tical power. If more attention were given to As increasing numbers of assessments are employed, it these issues earlier, clinicians would have to struggle less is also important to recognize the burden created for patients with establishing appropriate treatment strategies. Careful thought should go into selecting the in brain imaging have set the stage for useful investigation most informative measures and planning a data analysis pro- during early stages of drug development; however, here, too, gram with a priori primary and secondary hypotheses. PROBLEMS IN ASSESSMENT Clinicians value the availability of different delivery methods for psychotropic medications, given the challenges Because psychiatric disorders are often complex, multifa- of both acute and long-term treatment. Oral, liquid, intra- ceted diseases and some key symptoms are purely subjective, muscular, and long-acting forms should be developed and the techniques used for assessment can be critical. Informa- tested in clinical trials as early as possible. Different clinical tion regarding psychopathology is most frequently obtained trial designs may be necessary with different preparations from direct patient interview and observation, though infor- intended for different levels of acuity or phases of treatment. Patient report can be impeded by intentional kinetic and pharmacodynamic issues, the better. It is not uncommon enormous variability in drug absorption and metabolism, for psychiatric patients to reveal more psychopathology as randomly assigning patients to different plasma levels of they begin to respond to treatment than they did prior to interest can be a powerful tool in establishing dose-response its initiation. The reliability and validity of different sources relationships and optimum dosing guidelines. Though more of information in assessing specific domains have not been difficult than the standard trial, such studies are feasible, adequately studied. In many trials assessors who are not but rarely done (24). Although these ratings can be sensi- tive to treatment effects, it is likely that a person who has ASSESSMENT OF THERAPEUTIC EFFECTS ongoing contact with the patient in a treatment context AND CLINICAL CHANGE will provide a more accurate assessment. Here, too, research comparing different rater allocation strategies would be There are many established instruments for the assessment helpful in determining which is most valid and cost-effec- of psychopathology in clinical trials. It is critical to have the same rater evaluating the patient instruments have been utilized for many years. Despite establishing there continues to be a dearth of new scale development. As new drugs are devel- for a given assessment should be determined by the goals oped with potentially different spectrums of activity, it in the study. In general, when rating psychopathology, the would be useful to have new scales designed to be sensitive previous weekis a reasonable time frame. This is particularly appropri- likely to accurately recall specific symptoms that are more 40: Issues in Clinical Trial Designs 545 remote in time. The time frame used for a particular assess- trial designs to better address the full range of public health ment does not need to coincide with the interval between issues. In a long-term trial it is not necessary to rate patients weekly. But when they are assessed, the previous weekcan be the focus of the assessment. Improvement of phase III psychotropic drug trials by intensive phase II work. Neuropsychopharmacology 1991;4: ASSESSMENT OF ADVERSE EXPERIENCES 251â€“257. Antipsychotic-induced The two major goals of drug developmentâ€”to enhance weight gain: a comprehensive research synthesis. Am J Psychiatry therapeutic efficacy and to improve tolerabilityâ€”go hand 1999;156(11):1686â€“1696. The placebo control in clinical trials (a view from the clinical signs and symptoms of psychiatric illnesses. Biol Psychiatry 2000;47: ance and determining the overall benefit-to-riskratio. Does short term placebo In general, the methods for detecting adverse events have treatment of chronic schizophrenia produce long term harm? Br been given far less attention than the methods for evaluating Med J 1986;293:726â€“728. The long-term effects of placebo accurately estimating the incidence of adverse effects. Biol Psychiatry 1999;46: clinical trials rely on patient self-report, with some specific 1092â€“1105. Duration of psychosis queries or rating scales used to assess known adverse effects and outcome in first episode schizophrenia. Predictors of relapse many adverse events, there is a concern that detailed, specific following response to first episode schizophrenia or schizoaffec- queries across a broad range of possible symptoms will result tive disorder. Placebos, active control groups, and in the elicitation of far more symptoms than an unstruc- the unpredictability paradox. Statistical ap- A methodologic comparison study (27) suggested that proaches to trial durations in episodic affective illness. Psychiatry the general elicitation of adverse events is more practical Res 1998;78:71â€“87. A case study of an and appropriate for routine clinical trials than a comprehen- adaptive clinical trial in the treatment of outpatients with depres- sive and lengthy interview. Control, dose- response study of sertindole and haloperidol in the treatment of take inhibitor (SSRI) antidepressants. There is a strong argument for the use of data and safety 15. Antiepileptic drugs, clinical trials, and the market- monitoring boards when large and/or long-term studies are place. Methodological issues in maintenance therapy clinical trials. Fluphenazine versus placebo CONCLUSION in patients with remitted, acute first episode schizophrenia.
Additionally discount prednisone master card allergy shots not effective, positive pregnant women are given zidovudine before deliv- MacCoun provided a template for integrating harm reduc- ery (69) buy prednisone 40mg otc allergy symptoms sore joints. HIV can also be transmitted by breast-feeding, tion with prevalence reduction (discouraging the engage- and thus infant formula feeding is recommended for babies ment in drug use) and quantity reduction (encouraging the of HIV-positive mothers, except in some developing coun- reduction in frequency or extent of drug use) (76). Thor- With regard to opioids, much of the health-related harm ough washing of infants born to HIV-infected mothers im- from their improper or illicit use is secondary to elements Chapter 105: Treatment of Opioid Addiction 1515 other than the substances themselves (77). Funds saved from these hygienic methods of administration and poor injection cost reductions have often not been invested in outpatient technique are typically more serious than the constipation treatment. A good example is the VA, which administers or other side effects of the drugs themselves, acute overdoses the largest network of substance abuse treatment programs notwithstanding. With regard to opioid addiction treat- in the United States. Since the application of managed care ment, medications such as methadone, LAAM, and bupre- policies, the overall amount spent on substance abuse treat- norphine, among others (including supervised heroin sub- ment declined by 41%, from $597 million in 1993 to $351 stitution) used for maintenance agonist treatment, may be million in 1999. Measured as a percentage of overall VA considered harm reduction measures. All have the potential health care costs, specialized substance abuse care decreased to reduce morbidity, mortality, and crime associated with from 4. However, in this sense they are no differ- VA health care expenditures increased 10% between 1993 ent from other medical therapies such as those used for the and 1999 (85). Most of these reductions were achieved by treatment of hypertension, diabetes, or asthma. The result has been an overall reduction cates that these types of programs may have beneficial effects in the total number of veteran patients treated and in the in numerous areas, including a reduction in the spread of amount of drug counseling provided. As a result, no new blood-borne infectious disease such as hepatitis and HIV, methadone programs were opened in the VA despite the and acting as a conduit to more comprehensive drug-abuse recent increase in heroin addiction, evidence of waiting lists treatment services (78). In one study (79), the initiation for methadone treatment, and cities (such as Portland, Ore- and continuation of syringe exchange program participation gon) with serious heroin problems but no agonist mainte- among high-risk injection drug users were independently nance programs in spite of recent increases in heroin over- associated with a cessation of syringe sharing. Not all that changes in resource allocation have caused programs findings have been positive, however. In a study designed to become vulnerable to service disruptions, poor morale, to assess the association between risk behaviors and HIV burnout, and reduced motivation and quality of perfor- seroprevalence and incidence among injection drug users, mance and characterized by failures to maintain service lev- risk elevations for HIV associated with needle exchange pro- els in accord with the mandates of law (86). However, an examination of to integrate medical and psychiatric services into agonist potential bias in nonrandomized comparisons (82) sug- maintenance programs. Thus, both old and new pharmaco- gested that injection drug users participating in needle ex- therapies for opioid addiction described earlier are un- change programs at a given point may include a high pro- derused in the VA, the largest substance abuse treatment portion of persons whose pattern of drug use puts them system. There is every indication that penetration of these at greater risk for blood-borne viral infections. Further, a new treatments into the opiate treatment field at large has prospective cohort study found no evidence of a causal asso- also been slow. Harm reduction related to psychoactive substance abuse has gone through numerous stages. The current phase has SUMMARY been described as the development of an integrated public health perspective for all drugs in which a multifaceted, New pharmacotherapies, behavioral therapies, and treat- strategic approach is taken (84). The direction of this ap- ment strategies are being developed for opioid addiction. As described earlier, various treatments can be combined to IMPACT OF MANAGED CARE produce better patient outcomes. However, the overall ef- fect of these developments on addiction treatment and pub- Efforts to control costs by managed care have resulted in a lic health is very dependent on funding support, which has marked reduction in use of inpatient or residential treat- become a serious problem. Parity legislation may help to 1516 Neuropsychopharmacology: The Fifth Generation of Progress solve funding problems and result in the expansion of treat- 19. Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone ment to meet patient needs, but the details of how and treatment for in-patient opiate detoxification. Drug Alcohol De- when more investment in substance treatment may occur pend 1998;50:227â€“232. The development of dose methadone in a 180-day heroin detoxification program. J medications for the treatment of opiate and cocaine addictions: issues Subst Abuse Treat 1994;11:225â€“232. Methadone transition treat- of Medicine, National Academy Press, 1995. Effective medical treatment of opiate Int J Addict 1995;30:387â€“402. The effectiveness of methadone maintenance treat- ton, DC: American Psychiatric Association, 1999:251â€“269. A 24â€“h inpatient detoxification treatment fied and dissatisfied patients on methadone maintenance treat- for heroin addicts: a preliminary investigation. Safety of anesthesia: a prospective study in methadone, heroin, codeine, buprenorphine: ceiling for cardio-respiratory effects at high IV and morphine addicts. High risk of ultrashort noninva- trial of buprenorphine as a treatment for opioid dependence. A multisite efficacy evalua- no apparent benefit but suppression of thyroid hormones and tion of a buprenorphine/ naloxone product for opiate dependence risk of pulmonary and renal failure. Ultra-rapid opiate nance treatment for opiate dependence: a multicenter, random- detoxification using deep sedation with or midazolam: short- and ized clinical trial. A controlled comparison levomethadyl acetate, buprenorphine, and methadone as treat- of buprenorphine and clonidine for acute detoxification from ments for opioid dependence. Abuse of prescriptionÂ´ lization and rapid-taper protocol for the detoxification of opioid medicines in southwestern France. Preliminary assessment of a 10â€“day rapid detoxifica- 34. Dependent opioid tion programme using high dosage buprenorphine. Eur Addict users assessed for methadone treatment in Otago: patterns of Res 1998;4:29â€“31. Comparing the subjective, psy- opioid detoxification in a primary care setting: a randomized chomotor and physiological effects of intravenous buprenorphine trial. Double blind randomized con- stabilized, opiate-dependent volunteers. Psychopharmacology trolled trial of lofexidine versus clonidine in the treatment of 1999;141:37â€“46. Randomised double-blind comparison of opiate receptors by naltrexone. J Nucl Med 1988;29:1207â€“ of lofexidine and clonidine in the out-patient treatment of opiate 1211. Randomized double-blind compari- cebo-controlled pilot study to evaluate the efficacy and safety of son of lofexidine and methadone in the in-patient treatment of oral nalmefene HCl for alcohol dependence.
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