Residual analgesic effects of morphine in 55 four-period crossover analgesic studies

Subjective response data from 55 postoperative pain studies were examined for the residual analgesic effects of morphine. The studies were planned as four-period crossover designs for four treatments. Each patient received 5 and 10 mg of morphine and two doses of a test preparation. Two measures of analgesia were used: Sum of the Pain Intensity Difference (SPID) and Total Pain Relief (TOTPAR). To facilitate analysis, two two-period groups were defined. Morphine data for periods 1 and 2 were designated as group A, and morphine data for periods 3 and 4 were designated as group B. Residual analgesic effects were 0.12 for both SPID and TOTPAR in group A and were 0.65 and 0.17 for SPID and TOTPAR, respectively, in group B. In these 55 studies, there was no evidence of significant residual analgesic effects. Thus the crossover design is an appropriate method for the evaluation of selected parenteral analgesics in the postoperative pain model.     

Using baseline measurements in the two-period crossover clinical trial

In a clinical trial designed to compare the efficacy of two treatments, use can be made of the two-period crossover design, in which each patient is randomly assigned to receive both treatments in one of two sequences. A restriction of its utilization involves the issue of carryover effect, otherwise known as sequence effect or treatment by period interaction. Carryover effects can sometimes be eliminated by using baseline measurements taken at the beginning of each period just prior to treatment. We examine this approach of using baseline measurements in this setting and find that there are many circumstances in which, in spite of eliminating carryover, the use of baseline measurements provides a less powerful test of treatment effect and a less precise estimate of the treatment difference.     

Crossover design in pharmacy research.

OBJECTIVE: Reports of pharmacy research using crossover designs were reviewed to determine if the studies adequately consider interaction effects and use appropriate statistical analyses. DATA SOURCES: All crossover studies published in DICP, The Annals of Pharmacotherapy during 1988 and 1989 were analyzed. STUDY SELECTION: Reports of crossover studies were included only if at least two treatments were applied in a different order to two or more groups of subjects. DATA EXTRACTION: The principal characteristics of crossover studies and the critical design variables were listed and each study analyzed according to these variables. The critical design variables included consideration of period, sequence, and carryover effects as well as the presentation of data by groups and the use of multivariate statistical analysis. The analysis was conducted independently by each author and conflicts were discussed until consensus was obtained. RESULTS: A total of 11 crossover studies were identified: 6 were bioavailability trials, 3 were treatment comparisons, and 2 had multiple objectives. The possibility of period, sequence, or carryover effects was less with bioavailability studies than with treatment comparisons. Only 1 study presented data by group and only 4 studies used multivariate analysis. CONCLUSIONS: The crossover design appears more appropriate for bioavailability trials than for treatment trials in pharmacy research. Analysis of data from crossover designs could be improved by presenting the data for each treatment group and using multivariate statistical analysis.     

Double-Blind Study of Belladonna-Ergotamine-Phenobarbital for Interval Treatment of Recurrent Throbbing Headache

SYNOPSIS
In a double-blind study comparing crossover and parallel group designs, 55 patients with recurrent throbbing headache were given either belladonna-ergotamine-phenobarbital (BEP) or placebo for headache prophylaxis. Analysis of the crossover design showed BEP to be significantly more effective than placebo in reduction of headache severity and overall effectiveness. During BEP treatment, patients had less days during which medications for relief of headache symptoms were required. Although there were period effects favoring BEP, no significant differences between treatments were observed in the parallel design. The greater variability in the parallel portion of the study precluded demonstration of statistical significance with this number of patients. The crossover design indicates that BEP offers benefits in the prophylaxis of recurrent throbbing headache, without serious or frequent side effects.     

Crossover and noncrossover designs in four-point parallel line analgesic assays

Fifty-nine analgesic investigations designed as four-point parallel line crossover assays were examined. Sum of pain intensity differences (SPID) and total pain relief (TOTPAR) were the subjective response measures. Separate analyses with four-point crossover data and first-dose data (noncrossover) allowed comparison within each study of these two approaches. The crossover analysis allows for removal of the subject component of variance, which in these studies was a substantial fraction of the error variance (0.49 for SPID; 0.56 for TOTPAR). For this type of study, 2.4 times as many subjects would have to be recruited in a noncrossover design to obtain precision equivalent to that of the crossover design. Thus efficiency considerations argue for the crossover design in cases in which a treatment carryover effect may be assumed to be negligible.     

Crossover studies with continuous variables: power analysis.

The crossover design is a sensitive means of determining the efficacy of new drugs because it eliminates between-subject variability. However, if the response in the first period carries on into the second (carryover effect) or if time factors cannot be kept constant in a lengthy crossover (time effects), its statistical power may be jeopardized. This may be equally true if a negative correlation exists between treatment responses. We recently demonstrated that the crossover design with binary variables is a powerful method even if correlation between treatment responses is negative. Power analysis of crossover trials with continuous variables has not been explicitly studied. Using the Scheffé model for the assessment of treatment effect, carryover effect, and time effect, we drew power curves of hypothesized crossover studies with different levels of correlation between drug response. We demonstrate that the sensitivity of testing is largely dependent on the levels of correlation between drug response. When positive, we have a great deal of sensitivity with which to test treatment effect and little sensitivity to test carryover or time effect. When negative, the opposite is observed. The correlation level in a crossover comparison is a major determinant of the sensitivity of testing. Treatments from one class with one mode of action frequently have a positive correlation and should be particularly considered for crossover comparisons. With treatment comparisons of totally different classes of drugs/modes of action, the opposite is true. It is hoped that this work affects the design of future crossover trials.     

A critique of recent research on the two-treatment crossover design

A critical review is provided of recent articles on two-treatment crossover trials that purport to provide solutions to the problems caused by the existence of differential carryover effects. Included in the review are papers suggesting that extra-period designs be employed in which treatments follow themselves, that the bias caused by a difference between the carryover effects may sometimes be ignored, that changes from baseline be analyzed, and that a series of preliminary tests using baseline values be performed. The validity of many of these suggestions is shown to depend on whether mathematical assumptions that are generally unverifiable are satisfied. The two-period crossover design is recommended only when prior experience suggests that its assumptions are likely to be satisfied.     

Effects of acupuncture as a treatment for hyperventilation syndrome: a pilot, randomized crossover trial

BACKGROUND: Sustained and subtle hyperventilation can result in a wide variety of symptoms, leading to a chronic condition that has been termed hyperventilation syndrome (HVS). Treatment options include physiotherapy, in the form of breathing retraining (BR), but additional approaches aim to reduce the anxiety that is recognized as being a frequent component of this condition. OBJECTIVES: The aim of this study was to evaluate whether acupuncture is an appropriate treatment for HVS to reduce anxiety, and whether a crossover trial is an appropriate study design to evaluate acupuncture in this condition. DESIGN: A single-blind crossover trial was carried out comparing the effects of 4 weeks (30 minutes twice weekly) acupuncture and BR on patients with HVS. SUBJECTS: Ten (10) patients diagnosed with HVS were recruited to the trial and randomized into two groups. Both groups received acupuncture and BR with a washout period of 1 week. OUTCOME MEASURES: The primary outcome measure used was the Hospital Anxiety and Depression (HAD) Scale. Other outcome measures used were the Nijmegen questionnaire and Medical Research Council Dyspnea scale. RESULTS: The results showed statistically significant treatment differences between acupuncture and breathing retraining, in favor of acupuncture. Reductions were found in the HAD A (anxiety) (p = 0.02) and Nijmegen (symptoms) (p = 0.03) scores. There was no statistical evidence of any carryover effects. However, when graphically examining individual anxiety scores, in those who received acupuncture first, there was a reduction in anxiety levels which persisted through the washout period, suggesting that there may have been some carryover effect from this treatment. CONCLUSIONS: This study suggests that acupuncture may be beneficial in the management of HVS in terms of reducing anxiety levels and symptom severity. However, there may be some carryover effect, after acupuncture treatment, which went undetected because the small sample size. This preliminary study provides the basis for a larger, sufficiently powered and methodologically sound trial.     

脑通治疗血管性痴呆对定向力、语言、记忆力、回忆、注意力5个因子疗效的对照研究

目的评价脑通治疗血管性痴呆(VD)的疗效。方法对确诊为VD患者48例,随机分成2组,服用脑通组24例,对照组24例,根据简易精神状态检查表(MMSE)总分及定向力、记忆力、语言、回忆、注意力及计算力5个因子分评定疗效。结果脑通组2周疗效略优于对照组;MMSE总分值大于对照组,治疗8周后明显优于对照组,对重症痴呆患者也有一定的疗效,副作用较轻。结论脑通是治疗VD的有效药物,对各期痴呆均有疗效,而且副作用小。     

A randomised clinical trial of the effect of informed consent on the analgesic activity of placebo and naproxen in cancer pain

To determine whether informed consent in a therapeutic trial modifies the analgesic effect of naproxen and placebo, we conducted a prospective, randomised, single dose, placebo-controlled trial. Patients were randomly selected to receive or not information concerning the study. All patients included were then given a single dose of naproxen and placebo according to a crossover, double-blind design. Forty-nine patients with mild or moderate cancer pain which did not need narcotic analgesics entered the study. Twenty-five received both treatments without any information and constituted the uninformed group. Twenty-four had a complete information about the trial; six refused to participate. The 18 others constituted the informed-consent group. Visual analogue scales of pain before and 30, 60, 120 and 180 min after the intake of naproxen and placebo were recorded. As an analgesic, naproxen was more effective than placebo in both groups of patients (p = 0.001). For naproxen as well as for placebo, the analgesic effect was better in the informed-consent group compared to the uninformed group (p = 0.012). The difference in therapeutic activity between naproxen and placebo was moderately higher in the uninformed patients (p = 0.08). We concluded that, in contrast with parallel studies, giving information in a crossover, placebo-controlled trial may increase the apparent efficacy of both the tested agent and the placebo, and decrease the perceived difference the two.     

Tetrodotoxin for moderate to severe cancer pain: a randomized, double blind, parallel design multicenter study

Cancer pain is a serious public health issue and more effective treatments are needed. This study evaluates the analgesic activity of tetrodotoxin, a highly selective sodium channel blocker. This randomized, placebo-controlled, parallel design study of subcutaneous tetrodotoxin, in patients with moderate or severe unrelieved cancer pain persisting despite best available treatment, involved 22 centers across Canada. The design called for tetrodotoxin administered subcutaneously over Days 1-4 with a period of observation to Day 15 or longer. All patients could enroll into an open-label extension efficacy and safety trial. The primary endpoint was the proportion of analgesic responders in each treatment arm. Eighty-two patients were randomized, and results on 77 were available for analysis. There was a nonstatistically significant trend toward more responders in the active treatment arm based on the primary endpoint (pain intensity difference). However, analysis of secondary endpoints, and an exploratory post hoc analysis, suggested there may be a robust analgesic effect if a composite endpoint is used, including either fall in pain level, or fall in opioid dose, plus improvement in quality of life. Most patients described transient perioral tingling or other mild sensory phenomena within about an hour of each treatment. Nausea and other toxicities were generally mild, but one patient experienced a serious, adverse event, truncal and gait ataxia. This trial suggests tetrodotoxin may potentially relieve moderate to severe, treatment-resistant cancer pain in a large proportion of patients, and often for prolonged periods following treatment, but further study is warranted using a composite primary endpoint.     

Crossing controls to treatment in repeated-measures trials

For repeated-measures trials with continuous outcomes in which one group is designated as control and the other treatment, it is sometimes advantageous to add the treatment to the control group in the last periods of the design rather than to continue with control conditions throughout the repeated measures. Many circumstances preclude crossing patients who were initially administered a test treatment back to control conditions so that a full crossover design is not possible. Maintaining the treatment in the treatment group while crossing controls over to treatment in the last periods can result in greater efficiency in estimating a treatment effect that is constant over measures than continuing with control conditions. In contrast, crossing controls is less efficient for estimating a slope parameter for the treatment effect. Equations are provided for both treatment-effect models to determine loss or gain in efficiency from crossing controls. The information from the measures in which controls are crossed to treatment decreases variances of other estimators of interest, such as subgroup-by-treatment interaction effects, stepped or quadratic changes in treatment effect, and interpatient random treatment-effect variance and covariances. Exploration of various models for changes in treatment effect over measures showed that the efficiency of crossing controls depended on the model. This sensitivity to model means that the practical and statistical advantages of crossing controls over to treatment only sometimes outweigh those of the traditional continued-control design.     

Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy

Tricyclic antidepressants have been reported to relieve the paresthesiae associated with peripheral neuropathies of many etiologies. We designed a randomized, double-blind, placebo-controlled, crossover trial to establish the efficacy of nortriptyline in the treatment of cis-diamminedichloroplatinum (CDDP)-induced paresthesiae. The study included 51 evaluable patients with CDDP-induced peripheral neuropathy and painful paresthesiae. The study consisted of two 4 week phases, separated by a 1 week 'wash-out' period, in which patients received escalating dosages of either placebo or nortriptyline. The target maximum dose of nortriptyline was 100 mg/day. Each patient filled out pre-randomization and then weekly questionnaires assessing paresthesiae severity, hours of sleep, quality of life, and adverse effects over the 9 week study. No significant differences in paresthesia were observed in the first treatment period between nortriptyline and placebo (means of 49 and 55 respectively on a 0-100 point scale, P=0.78). Although some evidence of a modest effect in favor of nortriptyline was observed during the second treatment period (about one patient in five got a 10-point reduction in pain from drug above placebo effect), this occurred in the presence of a strong carryover effect. Linear models analysis and Bayes methods confirmed that the effect of nortriptyline on paresthesia was modest at best. Hours of sleep increased in the nortriptyline phase (P=0.02). There was no significant difference in measures of quality of life and the effect of paresthesiae on patients' daily activities between nortriptyline and placebo. There was no major toxicity associated with nortriptyline, but dry mouth, dizziness, and constipation were more common with nortriptyline. In summary, nortriptyline failed to demonstrate strong evidence of any effect on paresthesia or pain. The presence of a potential effect which appeared in the second period of the crossover design is questionable due to the observed carryover effect. Cross-validation sensitivity analysis of results support the conclusion that nortriptyline provides modest improvement at best over placebo in terms of chemotherapy-related neuropathy.     

Analysis of a crossover clinical trial by permutation methods

An initially balanced crossover design is analyzed by permutation rather than parametric methods in order to obtain exact distribution-free significance levels, thus controlling type I error and increasing power. The analysis is first restricted to those subjects who completed all nine periods. Next, it is extended to those who successfully completed two of the three blocks of treatments or six periods. Finally, we show how these distribution-free results may be extended to any number of treatment sequences and treatments in a balanced crossover design.     

Rapid onset of effect of sodium alginate on gastro-oesophageal reflux compared with ranitidine and omeprazole, and relationship between symptoms and reflux episodes

The objective of the open, randomised, four-period crossover study was to compare the time of onset of effect of sodium alginate (SA), omeprazole, ranitidine and control, based on oesophageal and intragastric pH and to determine any correlation between reflux symptoms and episodes in volunteers suffering from occasional gastro-oesophageal reflux. SA showed extensive prevention of acid exposure in the oesophagus compared with other treatments during the first hour. Overall, SA was more effective than control or omeprazole and comparable with ranitidine. There was little evidence of association between 'oesophageal' symptoms and reflux episodes, but associations between 'gastric' symptoms and acidity in the oesophagus, fundus and corpus were apparent. For an immediate reduction in gastro-oesophageal reflux into the oesophagus and gastric acidity during the first hour, SA was significantly superior to control, ranitidine and omeprazole. Ranitidine showed a superior effect from 2 h, consistent with its pharmacological mode of action.     

Clinical Trials: Design Flaws Associated with Use of a Placebo

BACKGROUND: The placebo arm of a trial, although it controls for psychological placebo effects and natural history of a disease and facilitates effective blinding, is susceptible to bias just like the true treatment arm is. The placebo arm of a trial may even be particularly vulnerable to specific types of bias. The present article focuses on design flaws associated with the use of a placebo. RESULTS: (1) Placebo-controlled trials using mortality rather than morbidity as the end point may have both ethical and statistical problems. (2) Bias may affect placebo data to a larger extent than active treatment data. (3) Trials may provide an atmosphere of exaggerated placebo effects and, consequently, inadequate power to determine differences between placebo and active treatment groups. (4) A biased placebo period due to carryover effect is a common problem of controlled trials with a crossover or self-controlled design. (5) Adjustment for asymmetries between placebo and treatment group in a parallel-group trial is inappropriate if such asymmetries are not completely independent on the main variables of the study. (6) Samples may not be representative when a large number of patients inappreciative of a possible treatment with placebo refuse randomization. CONCLUSIONS: It is emphasized that routinely accounting for design flaws associated with use of placebo may further improve the powerful method of controlled clinical trials.     

A comparative outcome study of body awareness therapy,feldenkrais, and conventional physiotherapy for patients with nonspecific musculoskeletal disorders: changes in psychological symptoms,pain, and self-image

Patients with nonspecific musculoskeletal disorders are often remitted for physiotherapy treatment in primary care. The rehabilitation effects for this patient group are generally poor and many of the treatment methods used have not been scientifically evaluated. The purpose of this study is to compare treatment effects of Body Awareness Therapy, Feldenkrais, and conventional individual treatment with respect to changes in psychological distress, pain, and self-image in patients with nonspecific musculoskeletal disorders. A total of 78 patients, 64 females and 14 males, with nonspecific musculoskeletal disorders were recruited consecutively to the different treatment groups in a quasiexperimental design. The patients were measured three times during the study period: before the interventions, after six months, and after one year. The results showed significant positive changes over time in all three treatment groups with regard to reduced psychological distress, pain, and improved negative self-image. There were few significant differences among the groups but effect-size analysis indicated that the group treatments using Body Awareness Therapy and Feldenkrais might be more effective than conventional treatment.     

The clinical efficacy of reflexology in nursing home residents with dementia

OBJECTIVE: This experimental, repeated-measures, crossover design study with nursing home residents examined the efficacy of reflexology in individuals with mild-to-moderate stage dementia. Specifically, the study tested whether a weekly reflexology intervention contributed to the resident outcomes of reduced physiologic distress, reduced pain, and improved affect. SETTING: The study was conducted at a large nursing home in suburban Philadelphia. SAMPLE: The sample included 21 nursing home residents with mild-to-moderate stage dementia randomly assigned to two groups. INTERVENTIONS: The first group received 4 weeks of weekly reflexology treatments followed by 4 weeks of a control condition of friendly visits. The second group received 4 weeks of friendly visits followed by 4 weeks of weekly reflexology. OUTCOME MEASURES: The primary efficacy endpoint was reduction of physiologic distress as measured by salivary alpha-amylase. The secondary outcomes were observed pain (Checklist of Nonverbal Pain Indicators) and observed affect (Apparent Affect Rating Scale). RESULTS: The findings demonstrate that when receiving the reflexology treatment condition, as compared to the control condition, the residents demonstrated significant reduction in observed pain and salivary alpha-amylase. No adverse events were recorded during the study period. CONCLUSIONS: This study provides preliminary support for the efficacy of reflexology as a treatment of stress in nursing home residents with mild-to-moderate stage dementia.     

Nimodipine, a New Calcium Antagonist, in the Prophylactic Treatment of Migraine

SYNOPSIS
The prophylactic effect of the calcium antagonist nimodipine was assessed in a double-blind placebo controlled parallel design study in 60 patients. After a drug-free interval of two weeks, placebo or nimodipine were given for 13 weeks each. The dose of nimodipine was 40 mg t.i.d. Ten patients (eight on placebo, two on nimodipine) withdrew because of therapeutic failure. In the 50 patients who completed the trial there was a significant beneficial effect in the nimodipine treated group, with regard to number of migraine attacks and duration during the last two months of treatment. Side effects were negligible.