Harald Olsen

Drug-related Information Generates Placebo and Nocebo Responses That Modify the Drug Response

OBJECTIVE Administration of the muscle relaxant carisoprodol and placebo was crossed with information that was agonistic or antagonistic to the effect of carisoprodol. It was investigated whether information alone induced physiological and psychological responses, and whether information modified the response to the drug. METHODS Half of the subjects received capsules containing 525 mg carisoprodol together with information that the drug acted in a specific way (Groups Relaxant/C, Stimulant/C, and No Information/C). The other half of the subjects received lactose (Groups Relaxant/L, Stimulant/L, and No Information/L). Dependent variables were blink reflexes and skin conductance responses, subjective measures of tension and sleepiness, and serum carisoprodol and meprobamate concentrations. Recordings were made between 15 and 130 minutes after administration of the capsules. RESULTS The Stimulant/L group reported more tension compared with the other two groups, and carisoprodol increased tension even more in the Stimulant/C group. The Relaxant/C group displayed higher levels of carisoprodol serum concentration compared with the other groups that received carisoprodol. CONCLUSIONS Reported tension was modulated in the direction suggested by the stimulant information. The effect of carisoprodol on tension was also modulated by stimulant information. Increased carisoprodol absorption in the group that received relaxant information could be a mechanism in the placebo response.

Adverse Drug Reactions in Current Antihypertensive Therapy: a General Practice Survey of 2586 Patients in Norway

The objective of this study was to determine the frequency and profile of adverse reactions to antihypertensive drugs in an unselected group of drug-treated hypertensive patients. A questionnaire-based survey was carried out among 2586 drug-treated hypertensive patients who attended a general practitioner for clinical control. Adverse drug reactions reported spontaneously, upon general inquiry, upon specific questioning and as evaluated by a physician were used as the main outcome measures. The study shows that the percentage of patients who reported adverse drug reactions spontaneously, upon general inquiry and upon specific questioning were 16%, 24% and 62% respectively. Users of diuretics reported the lowest frequency of adverse reactions, whereas users of beta-blockers reported the highest frequency. In 7% of the patients, the adverse drug reactions were of such a nature that the physicians considered discontinuing the treatment. As a conclusion, the reported frequency of adverse drug reactions in antihypertensive treatment is high, but with significant differences between the various drug groups. Monotherapy is connected with far fewer adverse drug reactions than combination therapy.

Blood pressure levels in treated hypertensive patients in general practice in Norway

The aim of this study was to examine the blood pressure (BP) levels in patients treated for essential hypertension in 1816 patients in general practice in Norway. The study was based on an optical readable questionnaire filled out by the physician including information about systolic (S) and diastolic (D) BP, gender, age, body weight, smoking habits and all pharmaceutical treatment given. Sixty-four per cent of the patients were treated with one antihypertensive drug. Only 22.3% of the women and 30.7% of the men (p < 0.05) had BP 140/90 mmHg. When BP < 160/95 was used as criterion for BP control, the fraction of patients was 50%. The fraction of patients with DBP 80 mmHg was 26% in the whole group of patients. DBP 90 mmHg was achieved in 74% and SBP 140 mmHg in 30% of the patients. The BP control was less in women and in patients above 60 years of age. Patients on combination therapy were no better controlled than those on monotherapy. Based on our results, the proportion of hypertensive patients on drug treatment with insufficient BP control is too high. Efforts should be made to improve the medical treatment of hypertension in general practice in Norway.

PHARMACOLOGICAL CLASSICAL CONDITIONING IN HUMANS

Two groups, each with five healthy male volunteers, received pairings of a distinct environment, the laboratory, with administrations of the muscle relaxant carisoprodol (CSP group), or pairings of the same environment with administrations of an inactive agent (control group). The control group received carisoprodol at home. This procedure was in effect in three sessions, each spaced 1 week apart. The CSP group received an inactive agent in the fourth session, and the control group received carisoprodol. The administration procedure was hypothesized to constitute a conditioned stimulus (CS) in the CSP group. The results showed that carisoprodol decreased blink reflex amplitude and duration. However, increased blink reflex amplitude was seen in the CSP group when the inactive agent was administered, which is opposite to the effect of carisoprodol. This indicates that a drug‐antagonistic conditioned response was elicited by the CS in the CSP group. Moreover, blink reflex amplitude was increased in the CSP group compared to the control group when carisoprodol was administered, indicating that the antagonistic conditioned response decreased the effect of carisoprodol. The results suggest a role for antagonistic conditioned responses in human drug tolerance.

The effect of carisoprodol on performance on repeatedly administered neuropsychological tests

The present double‐blind experiment investigated whether the muscle relaxant carisoprodol affected performance on three neuropsychological tests. Our results showed no effect of carisoprodol on test scores, suggesting no cerebral affection of carisoprodol in humans. There were no changes in skin conductance responses after carisoprodol administration, indicating that the arousal level was not affected. However, there was significant improvement in test scores across days for all tests, indicating that test scores improved with practice.

Lack of evidence of increased lethality due to propoxyphene overdose in the presence of ethanol in male wistar rats

The primary purpose of the present investigation was to evaluate if the presence of ethanol increased lethality induced by propoxyphene. A secondary aim was to study the effect of naloxone on propoxyphene lethality alone, and on the concomitant administration of propoxyphene and ethanol. Male Wistar rats (210–330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats, received either of the following drug treatments: Propoxyphene, ethanol + propoxyphene, naloxone + propoxyphene, and naloxone + ethanol + propoxyphene respectively. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. Some animals died despite naloxone administration, possibly due to a nonopioid cardiotoxic effect of propoxyphene or its metabolite. An increase in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain, and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. In the animals which died, the highest P/N ratio was observed in brain tissue and the lowest in heart muscle. Despite the pharmacokinetic data obtained in this investigation indicating impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene-induced lethality. This is also contrary to suggestions from previous studies. Our results demonstrate that at least in one species and at one dose ratio (ethanol/propoxyphene) ethanol might reduce the lethality caused by propoxyphene alone. This suggests some kind of antagonism between the two drugs, probably in the central nervous system.