Ceiling effect

In some pharmacotherapy studies, psychotherapy exposure has been minimized, on the basis of concern that psychotherapy may produce a ceiling effect on improvement in drug or alcohol use, making medication effects difficult to detect. However, a recent meta-analysis revealed that psychosocial interventions, in fact, may enhance pharmacotherapeutic effects (Hopkins et al. 2002). In this review we have also noted instances where psychosocial and medication treatments have had beneficial additive effects. Minimization of psychotherapy in pharmacotherapy trials may be counterproductive, because psychosocial therapies that encourage the patient to remain engaged in treatment may positively affect patients adherence to the medication regimen, a factor that has an effect on alcohol treatment outcomes (Chick et al. 2000 Volpicelli et al. 1997). 

This class produces analgesia and has a ceiling effect on respiratory depression and lower abuse potential than morphine. However, psychotomimetic responses (e.g., hallucinations and dysphoria with pentazocine), a ceiling analgesic effect, and the propensity to initiate withdrawal in opioid-dependent patients have limited their widespread use. 

Respiratory depression At the usual adult dose of 10 mg/70 kg, nalbuphine causes respiratory depression approximately equal to that produced by equal doses of morphine. However, nalbuphine exhibits a ceiling effect increases in dosage beyond 30 mg produce no further respiratory depression. Respiratory depression induced by nalbuphine can be reversed by naloxone. Administer nalbuphine with caution at low doses to patients with impaired respiration (eg, from other medication, uremia, bronchial asthma, severe infection, cyanosis, or respiratory obstructions). 

Ethacrynic acid is chemically distinct from the thiazides and furosemide but ceiling effect is similar. It is a phenoxyacetic acid derivative that also contains an adjacent ketone and methylene group. 

Butorphanol tartrate is a weak partial p-receptor agonist, 3.5-5 times as potent as morphine. The incidence of psychotomimetic effects is relatively low. The recommended doses are 1-4 mg intramuscularly every 3-4 h or 0.5-2 mg intravenously. Respiratory depression produced by butorphanol 2 mg IV is similar to that of 10 mg morphine. However, there is a ceiling effect for respiratory depression, and near-maximum depression occurs after 4 mg in normal adults. In healthy volunteers, butorphanol 0.03-0.06 mg-kg-1 produces no significant cardiovascular changes. However, in patients with cardiac disease, progressive increases in cardiac index and pulmonary artery pressure occur, and butorphanol should be avoided in patients with recent myocardial infarction. Butorphanol is metabolised mainly in the liver to inactive metabolites. The terminal half-life is 2.5-3.5 h. 

Nalbuphine hydrochloride is structurally related to oxymorphone and naloxone. It is approximately equipotent with morphine. Nalbuphine is metabolised in the liver to inactive metabolites. The plasma terminal half-life is approximately 5 h. The onset of analgesia is within 2-3 min of intravenous administration and 15 min after intramuscular injection, and lasts 3-6 h with an adult dose of 10 mg. With equi-analgesic doses, similar degrees of respiratory depression to that of morphine occur up to a dose of approximately 0.45 mg-kg-1. With higher doses a ceiling effect occurs. Sedation, possibly mediated by K-receptor activation, occasionally occurs. The incidence of psychotomimetic side effects is lower than with pentazocine. The abuse potential is low, but is can cause withdrawal symptoms in opioid-dependent subjects. It has occasionally been used to reverse opioid-induced respiratory depression. 

For a patient in severe pain, the administration of an opioid analgesic is usually considered a primary part of the overall management plan. Determining the route of administration (oral, parenteral, neuraxial), duration of drug action, ceiling effect (maximal intrinsic activity), duration of therapy, potential for adverse effects, and the patient s past experience with opioids all should be addressed. One of the principal errors made by physicians in this setting is failure to adequately assess a patient s pain and to match its severity with an appropriate level of therapy. Just as important is the principle that following delivery of the therapeutic plan, its effectiveness must be reevaluated and the plan modified, if necessary, if the response was excessive or inadequate. 

Pharmacologically, the effects of these drugs resemble those of opioid agonists. All four have analgesic potency equal to or greater than morphine and. like morphine, they cause respiratory depression. A ceiling effect is reached, however, above which increased doses do not increase respiratory depression or do not produce proportionally greater depression. 

Ceiling effect The point at which no further increase in response occurs as a drug dose is progressively increased this effect is represented by a plateau on the drug s dose-response curve (SYN maximal efficacy). 

Maximal efficacy The maximum response a drug can produce the point at which the response does not increase even if the dosage continues to increase (SYN ceiling effect). 

There are several MWT variants with respect to trial duration. This variation stems from the fact that the MWT can be adapted to a variety of situations depending on the degree of sleepiness and motivational characteristics of the population to be studied. As examples, with extremely somnolent subjects such as patients with narcolepsy, a shorter trial duration, say 20 min, can be used with minimal ceiling effects. In individuals who are only moderately sleepy (say, MSLT sleep latencies in the 6-10 min range), as opposed to extremely sleepy (say, MSLT sleep latencies in the 0-5 min range), MWT trial durations of 30 min or 40 min are needed to reduce problems with ceiling effects (15-17). 

Several methods of terminating an MWT trial can be chosen depending on the subject population and the purposes of the test. It is true that such protocol variability can limit comparability of data from study to study. However, variability within a particular subject population can actually be reduced by the judicious selection of MWT protocol parameters so that ceiling effects are minimized and incentives to comply with instructions are optimized. Possible trial termination rules include the following ... 

A chemical instability which can be distinguished based on the gel effect or Trommsdorff effect, or on the ceiling effect. The influence of the gel effect on stability depends on its location. For example, if it occurs entirely within the screws, the increases in viscosity and reaction rate will stabilize the process, but if it occurs close to the die it will mainly affect viscosity in the die, which leads to destabilization. The ceiling effect will generally decrease the reaction speed, and therefore it will be negative for the stability of the process. 

In such cases, we recommend that parametric statistics be applied to the latency data as long as a minimum of 4 animals show convulsions, to avoid score bias by inclusion of floor and ceiling effects. 

Passive avoidance procedures are essentially procedures for detecting impairing effects of test substances. It is more difficult to demonstrate cognition enhancement because of ceiling effects. In terms of safety pharmacology, this is not a major drawback as impairment represents the major cognitive risk. 

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