By W. Hamlar. Iowa State University.

Proponents of these ineffectual 33 procedures initially reported 40% excellent buy viagra soft 50 mg on line, 30% good and 30% poor responses generic viagra soft 50 mg fast delivery. New procedures or drugs are initially heavily advocated by clinicians but the interventions may have decreased efficacy over time. For example, the healing rate for cimetidine across over 50 controlled trials for peptic ulcer disease began decreasing in the 1980s while the response rate to a newer agent, ranitidine, remained stable across trials in the Complementary therapies in neurology 250 23 same time period. On the subtle end of the clinician bias spectrum is a study where subjects following a third molar dental extraction were told they would receive intravenous fentanyl, placebo or naloxone. There were two time periods for the study, one when the clinicians were told there were the three arms and the other where the clinicians were told there were only two arms, naloxone and placebo. Patients receiving placebo had more pain relief when their clinicians thought they were in a three-arm trial possibly getting fentanyl than when the clinical staff thought they were only in a two-arm trial with just placebo and 34 naloxone. Another study of the placebo analgesic response following dental extraction found differences in the analgesic effect in subjects who received morphine by hidden infusion administered by a person in an adjacent room and subjects who received morphine injection by a preprogrammed infusion pump. The precise cues that patients 35 may have perceived that caused these differences could not be identified. Clinicians may also have expectancies related to disease or condition that could alter the reliability 36 of clinical rating scales. Use of sham acupuncture may elicit some of the same physiological responses as usual acupuncture. Placebo arms in many clinical trials have some clinical interactions that may include explanations for the illness. As noted above, simply being in a study may actually be a treatment as it relates to the Hawthorne effect. Another issue that relates to placebo effect and perhaps should be considered part of the placebo effect is self-efficacy. Treatment regimens that actively engage the patient to have some sense of control over their disease process may produce better outcomes than those that are less actively engaging to the patient. There are usually not adequate control groups for self-management therapies and studies that clearly differentiate positive 11 expectancy from self-management are lacking. Despite these many, significant confounding issues that cloud the literature on the 26,27,37 placebo effect, it is clear from the studies described in this chapter that the placebo effect exists, and we even know some of the underlying neurobiological mechanisms. The ensuing discussion will include factors that influence the expectancy, such as aspects of the treatment, clinician-patient interaction and conditioning as well as possible mediators of the placebo effect (Figure 1). CLINICAL ASPECTS Factors that contribute to placebo effects are presumably culturally dependent; the studies discussed here are predominantly from Europe and North America. A clinician in a white coat with a syringe may produce nonspecific beneficial effects in some people but presumably would not produce similar effects in a person living in a rural, undeveloped country who has never been exposed previously to either a white coat or a syringe. Placebo effect: clinical perspectives and potential mechanisms 251 Factors related to treatment There have been many factors related to aspects of the treatment that impact placebo effects. Much of the early literature centered around physical aspects of tablets and 38 capsules. Other studies have suggested that capsules are perceived to be stronger than 40,42 40 tablets and possibly larger pills stronger than smaller pills. In a systematic review of 51 duodenal ulcer trials totaling over 3300 patients, the 4-week healing rate among those receiving placebo was 44. In addition to physical factors relating to the placebo, the brand name or overt symbolic association may be important. In a study of 407 chronic headache sufferers, subjects were given aspirin or placebo dispensed in either a highly publicized brand name container or a generic bottle. As expected, subjects who received aspirin reported more decrease in headaches than those receiving placebo. Also, subjects receiving their medication in a brand name container did significantly better than those receiving medication in a generic container. This brand name benefit was observed in subjects who received placebo as well as those who received aspirin, and in subjects who were regular 45 users of the name brand as well as those who were not. Injections elicit a stronger placebo effect than oral medications and surgery is best of all in terms of eliciting placebo effects. An early paper on hypertension treatment found that parenteral administration of placebo had a greater effect than oral administration of 46 placebo. In a formal systematic review of sumatriptan trials including over 1800 Complementary therapies in neurology 252 Figure 1 Components of the placebo effect (or the meaning response) that alter expectancy, which then may affect the underlying pathophysiology or the health/outcome markers directly. These effects are possibly mediated through psychoneuroimmune, neuroendocrine, autonomic nervous system or other neural activities patients, there was a higher response to subcutaneous placebo (32. There is a suggestion that medical devices may elicit stronger placebo effects than medications but, as Kaptchuk and colleagues concluded, well-designed experiments to evaluate this are not readily 48 available. The whole issue of clinician biases, necessity of blinded trials and placebo effect was Placebo effect: clinical perspectives and potential mechanisms 253 dramatically raised by classic studies that evaluated internal mammary artery ligation for treatment of angina. After several publications and increasing clinical use of the internal mammary artery ligation, randomized, controlled trials were performed comparing the surgical technique of internal mammary artery ligation to simple incision and exposure of 49,50 the artery without ligation. The studies found no difference between the two surgical groups in the outcome measures and the procedure was abandoned shortly afterwards. In a recent trial of arthroscopic surgery for osteoarthritis of the knee, there was no difference in pain improvement between those getting actual procedures and those simply receiving incisions and 51 sutures. However, all three groups had a significant decline in their pain compared to their baseline. There are ethical issues related to sham surgery as a control arm in clinical trials 55 but, despite objections by some, it appears reasonable to many researchers and 56,57 oversight groups. It could be argued that, given the potential benefit of sham surgery, the sham surgery should not be considered to have no potential benefit to the research subject, although this viewpoint would be controversial. Patient attributes There are many factors related to the patient that impact on placebo effects.

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Phosphorylation of cardiac cal- Coupled Receptors cium-channel proteins increases the probability of channel opening during Signal transduction at G-protein-cou- membrane depolarization cheap 100 mg viagra soft amex. It should be pled receptors uses essentially the same noted that cAMP is inactivated by phos- basic mechanisms (A) cheap viagra soft 50 mg with amex. Inhibitors of this enzyme to the receptor leads to a change in re- elevate intracellular cAMP concentra- ceptor protein conformation. This tion and elicit effects resembling those change propagates to the G-protein: the of epinephrine. However, a relation exists lipid phosphatidylinositol-4,5 bisphos- between receptor types and G-protein phate into inositol trisphosphate (IP3) types (B). IP3 promotes of individual G-proteins are distinct in release of Ca2+ from storage organelles, terms of their affinity for different effec- whereby contraction of smooth muscle tor proteins, as well as the kind of influ- cells, breakdown of glycogen, or exocy- ence exerted on the effector protein. Diacylglycerol GTP of the GS-protein stimulates adeny- stimulates protein kinase C, which late cyclase, whereas G! In this manner, K+ channels can be ceptors for dopamine, histamine, serot- activated (e. Major effector proteins for G-pro- tein-coupled receptors include adeny- late cyclase (ATP! Numerous cell functions are regulated by cellular cAMP concentra- tion, because cAMP enhances activity of protein kinase A, which catalyzes the transfer of phosphate groups onto func- tional proteins. Elevation of cAMP levels inter alia leads to relaxation of smooth muscle tonus and enhanced contractil- ity of cardiac muscle, as well as in- creased glycogenolysis and lipolysis (p. G-Protein-mediated effect of an agonist DAG Gs+ - Gi Facilitation P of ion ATP P P channel cAMP opening IP3 Ca2+ Protein kinase A Transmembrane Activation ion movements Phosphorylation Phosphorylation of functional proteins of enzymes Effect on: e. G-Proteins, cellular messenger substances, and effects Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. This procedure is, of course, feasible on- Many drugs exhibit a linear relationship ly if supramaximal dosing is not asso- between plasma concentration and ciated with toxic effects. However, the though the plasma level may fluctuate same does not apply to drugs whose greatly during the interval between elimination processes are already suffi- doses. Under these conditions, tration, cannot be described in terms of a smaller proportion of the dose admin- a simple exponential function. This means that the time course of the effect exhib- its dose dependence also in the pres- ence of dose-linear kinetics (C). In the lower dose range (example 1), the plasma level passes through a concentration range (0! The respective time cours- es of plasma concentration and effect (A and C, left graphs) are very similar. However, if a high dose (100) is applied, there is an extended period of time dur- ing which the plasma level will remain in a concentration range (between 90 and 20) in which a change in concentra- tion does not cause a change in the size of the effect. The effect declines only when the plasma level has returned (below 20) into the range where a change in plasma level causes a change in the in- tensity of the effect. Drug-Receptor Interaction 69 1,0 Concentration 10 Concentration 100 Concentration 0,5 5 50 t12 t12 t12 0,1 1 10 Time Time Time Dose = 1 Dose = 10 Dose = 100 A. Concentration-effect relationship 100 Effect 100 Effect 100 Effect 50 50 50 10 10 10 Time Time Time Dose = 1 Dose = 10 Dose = 100 C. Dose dependence of the time course of effect Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. In addition, a drug may also cause The above forms of hypersensitivity unwanted effects that can be grouped must be distinguished from allergies in- into minor or “side” effects and major or volving the immune system (p. Despite ap- rise to complaints or illness, or may propriate dosing and normal sensitivity, even cause death. For in- a higher dose than is required for the stance, the anticholinergic, atropine, is principal effect; this directly or indirect- bound only to acetylcholine receptors of ly affects other body functions. In excessive doses, it leptic, is able to interact with several inhibits the respiratory center and different receptor types. The dose de- is neither organ-specific nor receptor- pendence of both effects can be graphed specific. The distance between both DRCs tivity can often be avoided if the drug indicates the difference between the does not require the blood route to therapeutic and toxic doses. This margin reach the target organ, but is, instead, of safety indicates the risk of toxicity applied locally, as in the administration when standard doses are exceeded. This holds true for both With every drug use, unwanted ef- medicines and environmental poisons. In order to prescribing a drug, the physician should assess the risk of toxicity, knowledge is therefore assess the risk: benefit ratio. If certain body functions develop hyperreactivity, unwanted effects can occur even at nor- mal dose levels. Increased sensitivity of the respiratory center to morphine is found in patients with chronic lung dis- ease, in neonates, or during concurrent exposure to other respiratory depress- ant agents. The DRC is shifted to the left and a smaller dose of morphine is suffi- cient to paralyze respiration. Adverse Drug Effects 71 Decrease in Effect Respiratory depression pain perception Decrease in (nociception) Nociception Respira- Morphine tory overdose Safety activity Morphine margin Dose A. Adverse drug effect: overdosing Increased Effect sensitivity of respiratory Safety center margin Normal dose Dose B. Adverse drug effect: lacking selectivity Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved.

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Pain is minimum purchase viagra soft 100 mg overnight delivery, although point tenderness usually can be elicited over the acromioclavicular joint viagra soft 50 mg without a prescription. The roentgenogram is negative ini- tially, but later it may show subperiosteal calcification about the dis- tal end of the clavicle. Roentgenograms reveal the clavicle riding higher than the acromion, but to an extent that is usually less than the width of the clavicle, even while downward stress is applied to the arm. Whenever an acromioclavicular-joint injury is suspected, stress roentgenograms of both shoulders with a 10- to 15-pound weight suspended from each wrist should be included in the work-up. Pain and tenderness are noted over the acromiocla- vicular joint and usually over the distal third of the clavicle and cora- coid process. Deformity is obvious, and the distal end of the clavicle is easily palpable and ballotable. On the roentgenogram, the distal end of the clavicle is above the superior surface of the acromion, and the distance between the clavicle and coracoid process is increased. Special mention should be made of posterior displacement of the distal end of the clavicle. The mechanism of injury is usually a direct blow on the distal end of the clavicle; however, the injury may result from a fall on the posterosuperior aspect of the shoulder. This condition frequently is missed because, even on stress roentgenograms, the clavicle may not show an upward displacement. The treatment of ªcompleteº acromioclavicular dislocations remains contro- versial. However, since the treatment for the majority of type IV, V, and VI injuries is operative, it seems reasonable and practical to remove them from all-inclusive type III category and to create an expanded, more accurate classification system. Type II A moderate force to the point of the shoulder is severe enough to rup- ture the ligaments of the acromioclavicular joint (Fig. The scapula may rotate medially, producing a widening of the acromioclavicular joint. There may be a slight, relative upward displacement of the distal end of the clavicle sec- ondary to a minor stretching of the coracoclavicular ligament. In a ªclassicº type III injury, the acromioclavicular and coracoclavicular ligaments are disrupted (Fig. The distal clavicle appears to be displaced superiorly as the scapu- la and shoulder complex droop inferomedially. Type III Variants Most often, complete separation of the articular surfaces of the distal clavicle and acromion is accompanied by complete disruption of the ac- romioclavicular and coracoclavicular ligaments. Children and adoles- cents occasionally sustain a variant of complete acromioclavicular dislo- cation. Radiographs reveal displacement of the distal clavicular meta- physic superiorly with a large increase in the coracoclavicular inter- space. These injuries are most often Salter-Harris type I or II injuries in which the epiphysis and intact acromioclavicular joint remain in their anatomical locations while the distal clavicular metaphysis is displaced superiorly through a dorsal longitudinal rent in the periosteal sleeve. The importance of recognizing this injury is that the intact coracoclavi- cular ligaments remain attached to the periosteal sleeve. Nonoperative management most often results in healing of the clavicular fracture and thus reestablishment of the integrity of the coracoclavicular ligaments. Those authors who recommend surgical repair in selected instances em- phasize the importance of repairing the dorsal rent in the periosteal sleeve. A second variation of the type III injury involves complete separation of the acromioclavicular articular surfaces combined with a fracture of the coracoid process. The mech- anism of injury for this ªtriple lesionº is a simultaneous bowl to the ac- romion and forcible elbow flexion against resistance. Both operative and nonoperative methods of treatment have been de- scribed for combined acromioclavicular dislocation and coracoid pro- cess fracture with intact coracoclavicular ligaments. However, we have encountered instances in which the coracoid frag- ment contains a significant position of the glenoid fossa. The conjoined tendon rotates the coracoid process and glenoid inferolaterally and can result in significant displacement. Type IV Posterior dislocation of the distal end of the clavicle, or type IV acro- mioclavicular dislocation, is relatively rare. The clavicle is posteriorly displaced into or through the trapezius muscle as the force applied to the acromion drives the scapula anteriorly and inferiorly (Fig. Posterior clavicular displacement may be so severe that the skin on the posterior aspect of the shoulder becomes tented. The literature concern- ing posterior acromioclavicular dislocations consists mostly of small se- ries and case reports. When this injury does occur it is most often a posterior or type IV acromioclavicular dislocation associated with an anterior sternoclavicular dislocation. This underlies the importance of a thorough evaluation of any patient with acromioclavicular joint injury with particular reference paid to the sternoclavicular joint. Type V Type V acromioclavicular dislocation is a markedly more severe version of the type III injury. When combined with su- perior displacement of the clavicle owing to unopposed pull of the ster- nocleidomastoid muscle, the severe downward droop of the extremity produces a grotesque disfiguration of the shoulder. Type VI Inferior dislocation of the distal clavicle or type VI acromioclavicular dislocation, is an exceedingly rare injury.

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