William H. Forrest

The Effect of Sleep Plus Morphine on the Respiratory Response to Carbon Dioxide

Respiratory response curves were obtained in 4 subjects while awake, asleep, awake after morphine, and asleep after morphine. Sleep plus morphine produced a decrease in slope and a displacement to the right of the carbon dioxide response curve. A substantial effect of sleep plus morphine on the depression of respiration was demonstrated.

Relative analgesic potencies of morphine and hydromorphone in postoperative pain.

Because of discrepancies in the estimates of the relative analgesic potencies of hydromorphone and morphine, the drugs were compared in two four-point, double-blind bioassays. In the first study, hydromorphone, 1 and 2 mg, was compared with morphine, 5 and 10 mg, in 31 postoperative patients; in the second, hydromorphone, 0.5 and 1 mg, was compared with morphine, 5 and 10 mg, in 112 postoperative patients. Subjective responses to nurse-observer questions were used to quantitate analgesia for postoperative pain. Hydromorphone is more potent than commonly believed: approximately 0.9 to 1.2 mg is equianalgesic with 10 mg of morphine, with a similar incidence of side effects.

Hypnotic efficacy of diphenhydramine, methapyrilene, and pentobarbital

The antihistamines diphenhydramine and methapyrilene were compared with pentobarbital for hypnotic effect in two Veterans Administration Hospital populations using subjective‐response methods. In the first part of the study, 60 mg and 180 mg of pentobarbital were compared with 50 mg and 150 mg of diphenhydramine. A positive dose‐response relationship was obtained only for pentobarbital; neither dose of diphenhydramine was significantly different from 60 mg of pentobarbital for any response variable. In the second part of the study, 100 mg of pentobarbital, 50 mg of diphenhydramine, and 50 mg of methapyrilene were compared with placebo. One hundred mg of pentobarbital and 50 mg of diphenhydramine were significantly different from placebo, but 50 mg of methapyrilene was not.

Respiratory and subjective effects of d‐ and I‐pentazocine

The relative respiratory depressant potencies of the d‐ and l‐isomers of pentazocine were determined in a crossover study. The l‐isomer was found to be a potent respiratory depressant (13 mg. ≎ 10 mg. morphine). The response to 30 and 60 mg. of the d‐isomer did not differ significantly from placebo. The possibility that higher doses of d‐pentazocine might produce significant respiratory depression cannot be dismissed, however. Sub;ective effects similar to those produced by morphine were noted, although there appeared to be qualitative differences. Lightheaded and dreamy reactions were noted more frequently, for instance, after l‐pentazocine. Some effects, such as anxiety, were reported after d‐pentazocine while their opposites, stich as relaxation, were reported following administration of the l‐isomer.

The Interaction of Caffeine with Pentobarbital as a Nighttime Hypnotic

The Interaction of caffeine with pentobarbital taken for its hypnotic effect was studied in 42 medical and surgical patients. Each patient received the following medications orally: a lactose placebo; 250 mg caffeine; 100 mg pentobarbital; and 250 mg caffeine plus 100 mg pentobarbital. Hypnotic effects were determined by patient evaluation of sleep. Caffeine had an adverse effect on sleep, whereas pentobarbital was an effective hypnotic. Together, their effects appeared additive, and the 250 mg caffeine plus 100 mg pentobarbital combination was not distinguishable from the placebo.

Clinical and statistical methodology for cooperative clinical assays of analgesics

This paper describes a method for carrying out a cooperative clinical bioassay of analgesics. The method was developed in five Veterans Administration Hospitals. The patients were largely older men with acute postoperative pain. Procedures for collecting and recording data and for automatic data processing are discussed. Uniformity trial results with morphine are reported. These data indicate the magnitude of hospital differences, patient differences, differences due to order of administration, and differences due to morphine dose. The inherent variation in the assay is reported for various completely randomized complete‐block, crossover designs. The number of patients required for specified reliability of potency estimates is presented. Statistical techniques for analysis, particularly the pooling of results from hospitals, are discussed.

Respiratory effects of hydromorphone in man.

The respiratory depressant efJeets of hydromorphone, a potent analgesie, were compared with morphine in a randomized double‐blind erossover study in human volunteers. Using a rebreathing technique, earbon dioxide response curves were plotted automatically with a speeial‐purpose analog computer. The respiratory depressant relative potency of hydromorphone to morphine over the total observation period was found to be 7.99 with lower and upper 95 per cent confidence limits of 5.44 and 10.69. Based on the displacement of the respiratory response curve, approximately 1.25 mg of hydromorphone is equivalent to 10 mg of morphine in our population of volunteers. For peak respiratorll depression, 0.95 mg of hydromorphone is equivalent to 10 mgoj morphine

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.

Oral Zomepirac and Intramuscular Morphine in Postoperative Pain

In this double-blind, single dose, randomized four-cell study, 100 and 200 mg oral zomepirac were compared to 4 and 8 mg intramuscular morphine* in 104 patients with acute postoperative pain. Zomepirac was administered as the sodium salt dihydrate; 100 mg zomepirac is equivalent to 120 mg zomepirac sodium dihydrate. Each patient received simultaneously a dose of active drug in either oral or parenteral form with dummy capsules of lactose or dummy injections of normal saline as the alternate form (the double-dummy technique). Patients were entered into the study if less than 48

The Oral Hypnotic Bioassay of Hydroxyzine and Pentobarbital for Nighttime Sedation

H YDR0XYZINE, an antihistamine, is extensively used as a tranquilizing agent for preoperative medication,’ as a tranquilizer in intensive care and coronary care units,2 in combination with narcotic agents for analgesia and sedation in minor surgical procedures,3 as a psychoactive agent in the management of neuroses and psychoses,4 and as a sedative for women in labor.5 Since it has a wide margin of safety, its usefulness as a nighttime sedative was examined in this study.