The concentration of propoxyphene in the plasma and analgesia scores in postpartum patients

TOXICOL.QGYANDAPPLIEDPHARMACOLOGY19,498-503

The

Concentration Analgesia

(1971)

of Propoxyphene Scores in Postpartum

in the Plasma Patients

and

ROBERT L. WOLEN, CHARLESM. GRUBER,JR., ARTHURBAPTISTI,JR.,

AND NORMANE. SCHOLZ Lilly Laboratory for Clinical Research, Marion County General Hospital, and Eli Lilly and Company, Indianapolis, Indiana 46206 Received February 26, 1970

The Concentrationof Propoxyphenein the Plasmaand AnalgesiaScores in Postpartum Patients. WOLEN, ROBERT L., GRUBER, CHARLES M., JR., BAPTISTI, ARTHUR, JR., and SCHOLZ, NORMAN E. (1971). Toxicol. Appl. Pharmacol. 19,498-503. Equimolar quantitiesof 2 propoxyphenesaltswere administeredas singleoral dosesto womenreporting postpartum uterine cramping.The dosesincluded32,65, and 130mg of the hydrochloride and 50, 100,and 200mg of the napsylatesalt. Identical-appearingplacebocapsuleswereincluded. Both analgesiascoresand plasmaconcentrationswere determined.The correlation betweenthese2 measures of responsewasnot significant when all of the 336 pairs of individual observationswere included in the computation. Both responses wererelated to amount of drug ingested,and on this basisthe meansof the analgesiascoresand the concentrations in the plasmawere significantly correlated. In single-dose studies postpartum patients have proved receptive to oral analgesic medications. In the study discussedin this paper a single sample of venous blood was obtained from each postpartum patient at a prespecified interval following administration of propoxyphene. These data were usedin an attempt to correlate plasma concentration of propoxyphene with analgesic response. METHODS Postpartum patients with uterine cramping were assignedto treatment groups in a prespecified order. Differences among the treatment groups included the intensity of uterine cramping reported by the patient and the medication to be administered. Four intensities of pain were selected on an arbitrary basis. These were “a little,” “some,” “a lot,” and ?errible.” The medications were single oral dosesof 32, 65, and 130mg of propoxyphene hydrochloride’ and 50, 100, and 200 mg of propoxyphene napsylate.2 The molecular weights of propoxyphene hydrochloride and of propoxyphene napsylate are 375.92 and 565.7, respectively. The corresponding dosesused contained almost molar equivalents of propoxyphene. Instructions were given that all other analgesicsbe withheld for at least 4 hr before the test drugs were administered and for 8 hr afterward. All patients’ charts were examined for recorded doses of analgesic 1Propoxyphene hydrochlorideismarketedasDarvon”, a productof Eli Lilly andCompany. 2Propoxyphene napsylatehasthetrademarkDoloxene@‘, a productof Eli Lilly andCompany. 498

PROPOXYPHENE

CONCENTRATION

AND

ANALGESIA

499

medications. The data from those patients who obviously did not comply with the instructions to exclude all other analgesicswere not included in the analyses. The study was continued until equal numbers of patients with admissibledata were administered each dose of propoxyphene hydrochloride and propoxyphene napsylate at each initial pain intensity level. Twelve patients were included in every block, representing one of the 2 drugs, the 3 doses,and the 4 initial pain intensities. In addition an equal number of patients were given placebo at each initial pain intensity. Thus, the number of individual dosagesevaluated during the study was 336. Observations were madeprior to administration of the medication (0 hr) and at 1, 2, 3, 4, 6, and 8 hr after treatment. At each time interval the intensity of pain was evaluated according to the scaleused in blocking, with the addition of a category for “none.” At the sameintervals after medication, patients also estimated their relief (the degree to which their pain was eased).The relief estimateswere scored according to a similar scalein which the term “complete” was substituted for “terrible” as category 4. The analgesiascores used to evaluate effectiveness were determined by summing the pain-intensity-difference scoresand the estimate-of-relief scoresobtained at each point in time (Gruber and Baptisti, 1963).At the end of the 8th hr of observation, the subjects were asked whether they had experienced any of the following symptoms during the previous 8 hr: nausea, constipation, abdominal discomfort, headache, dizziness, drowsiness,nervousness,tremor, weakness,blurred vision, dry mouth, sweating,itching or others. If any were reported, the patients were askedto quantify the intensity of the symptom according to the same empirical scale as that used for pain intensity. In addition to thesesubjective data, a singlesampleof plasmawas obtained from each patient to determine the concentration of propoxyphene in the blood. The venipunctures were timed so that sampleswere obtained from 2 patients in each medicationpain-intensity block at each point in time after the 0 hr. The random preselection of the point in time for obtaining samplesof plasma offers an acceptable method for selecting subjective data from 1 time-point for each patient. These individual analgesiascores and the concentration of propoxyphene in the plasma obtained at the sametime were analyzed. The method for determination of plasma propoxyphene concentration is based on solvent extraction at neutral or near neutral pH values followed by purification and concentration of the extract. The extract is analyzed by gas chromatography using a short column with a liquid phaseof silicone gum rubber. Quantitation is possible through the inclusion of d-pyrroliphene hydrochloride (E-d-2-acetoxyl-1,2-diphenyl3-methyl-4-pyrrolidinobutane hydrochloride) as a mass internal standard which is carried through the extraction. The ratio of chromatographic peak heights of propoxyphene to pyrroliphene is compared to ratios derived from standard prepared in plasma and treated in the samemanner as the sample (Wolen and Gruber, 1968). RESULTS The data obtained during this study, relating to the total scoresfor eachpatient and to the scoresat the time the venipunctures were made, are reported by Gruber et al. (1971). In that report the authors indicate that (1) significantly more analgesia was reported following propoxyphene than placebo, (2) the increasein analgesiawas linearly related to the dosesof propoxyphene, (3) no significant differenceswere demonstrated between

500

WOLEN ET AL.

the napsylate and the hydrochloride salts, and (4) time of observation was a significant source of variation. The correlation coefficients at each point in time are the subject of this report. They were computed for several estimates of effectiveness and plasma concentrations (Table 1). All those coefficients involving plasma determinations are of a low order. TABLE CORRELATION

COEFFICIENTS WITH Two

I

OBSERVED IN POSTPARTUM PATIENTS PROPOXYPHENE DERIVATIVES

TREATED

Hour after oral dose of medication Parameters’ Intensity of pain vs. plasma cont. Relief of pain vs. plasma cont. Analgesia score vs. plasma cont. Total analgesia score vs. plasma cont. Relief of pain vs. intensity of pain Analgesia score vs. intensity of pain Total analgesia score vs. intensity of pain Analgesia score us. relief of pain Total analgesia score vs. relief of pain Total analgesia score US. analgesia score

1

2

3

4

6

8

0.06 0.13 0.06 0.07 0.64 0.87 0.48 0.94 0.45 0.50

0.16 0.17 0.18 0.08 0.65 0.90 0.55 0.92 0.59 0.63

0.14 0.24 0.21 0.14 0.64 0.91 0.77 0.90 0.80 0.87

0.21 0.27 0.27 0.09 0.64 0.89 0.67 0.92 0.65 0.73

0.16 0.29 0.26 0.28 0.74 0.90 0.81 0.96 0.80 0.86

0.07 0.11 0.10 0.02 0.69 0.88 0.64 0.95 0.60 0.67

E See Gruber and Baptisti (1963). 6.0

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0.0

130 .

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65

. Naps,

. Naps,

200

100 50

Lebo

0 Mean

I

I

50

104 Plasma

Concentration

I 150

J 2w

(pa/liter)

1. Mean analgesic responses and plasma concentrations in patients for various doses of propoxypbene hydrochloride (HCI) and propoxyphene napsylate (Naps) (r = 0.89). FIG.

PROPOXYPHENE

CONCENTRATION

AND

ANALGESIA

501

Thus, the correlations between the concentration of propoxyphene in the plasma and the measures of effectiveness for each dose seem to be unrelated at various points in time. However, the mean plasma level correlates with the mean analgesia score. This correlation is highly significant (Fig. 1). A similar relationship was not demonstrated for the undesirable-symptom scores (Fig. 2). 6.0

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200

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FIG. 2. Mean values for adverse reports and plasma concentrations in patients for various doses of propoxyphene hydrochloride (HCl) and propoxyphene napsylate (Naps) (r = 0.29).

DISCUSSION

Whenever a standard procedure is altered or an addition is made to an established format, unexpected results may be obtained. The addition of the plasma determinations in the clinical evaluation of analgesic drugs proved to be no exception. Three major findings were made. First, the patient is accepted in these studies as the experimental unit. Thus, the degrees of freedom in any analysis of variance are the same whether 1 or a series of observations are obtained on each subject. The decision to get 1 plasma sample from each mother (staggering the time-points at which they were obtained) provided a rule for selecting a single subjective estimate within the series obtained from each patient. When estimates of pain intensity difference, relief, and analgesia scores are obtained from different patients at staggered time intervals, these measures of effectiveness not only correlate with each other but also with the total analgesia scores obtained through the repeated observations of each patient. This suggests that it may not be necessary to observe each patient repeatedly throughout an 8-hr time period. One estimate from each patient may be sufficient.

502

WOLEN

ET AL.

Second, all patients’ charts were carefully examined to determine whether other analgesic medications were given regardless of instructions to the contrary. In such a case, that patient’s data were judged to be inadmissible and were not included. The dose given to that patient was repeated, but in a different mother. Nevertheless, when the plasmas were analyzed for propoxyphene, it became apparent that some patients had ingested propoxyphene which was not recorded on their charts. This was observed primarily in the plasmas obtained 6 or 8 hr after placebo administration. It could result from self-administration of the medication or from a relatively lenient attitude in providing medications by the ward personnel. The administration of the 2nd series of

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FIG. 3. A scatter diagram presenting the relationships between pairs of observations in patients. Note that plasma concentrations are plotted on a log scale with zero depicted by interval “1.”

medications was started after this source of bias was discovered. At that time, all medications containing propoxyphene were removed from the postpartum ward. Following this the occurrence of elevated propoxyphene concentrations in the plasma of patients given placebo was almost abolished. Thus, it is thought that the major problem was not self-administration. The clinical bias is a result of the patient’s “need” for relief. It tends to make the blank and low doses of the medication appear more effective than they really are. Since the source of bias is present in the clinical as well as in the plasma concentration data, correlation between these data remains valid; but there may be some loss of sensitivity in the measurement of differences among the doses of medication. Third, one patient displayed an unusual response to the medication on successive days. The concentrations of propoxyphene reported in her plasma were 1618 and 1470 pg/l. By chance, she had been administered propoxyphene hydrochloride 130 mg on both occasions, once for grade 3 pain and once for grade 4 pain. Again by chance, both plasma samples were obtained 2 hr after administration of the drug. These 2 plasma values were considerably larger than those reported for any other patient. Before this

PROPOXYPHENE

CONCENTRATION

AND

ANALGESIA

503

information was available the patient was discharged from the hospital and no followup was attempted. Since significant correlation between the pairs of individual analgesia scores and plasma determinations was not demonstrated, the data were stratified according to the medication administered. The correlation coefficients for patients administered 32, 65, or 130 mg of propoxyphene hydrochloride, 50,100, or 200 mg of propoxyphene napsylate, or placebo were 0.224, -0.022, 0.087, -0.069, -0.117, 0.244, and -0.231, respectively. The correlation within each of these subgroups was, therefore, not significant. Furthermore, similar analyses at each point in time failed to disclose a significant relationship. These correlation coefficients are presented in Table 1. One explanation for the lack of significant correlation between the pairs of individual analgesia and plasma determination values may be the wide variation in both components (Fig. 3). If enough data near the boundaries of the set of all possible analgesic responses could be obtained, correlation might be demonstrated. ACKNOWLEDGMENTS We wish to extend our thanks to Mrs. B. Forcum for interrogation of the patients and also to the staff of the Obstetrical Service for their attention to the details of patient care. REFERENCES C. M., JR., and BAPTISTI, A., JR. (1963).Estimatingthe acceptabilityof morphineand noracymethadolin postpartumpatients.C/in. PharmacoI. Ther. 4, 172-181. GRUBER, C. M., JR., WOLEN, R. L., and BAPTISTI, A., JR. (1971).Analgesiascoresastimed responsesfollowing oral administration of propoxyphene to postpartum patients. Toxicol. Appl. Pharmacol. 19, 504-511. WOLEN, R. L., and GRUBER, C. M., JR. (1968). Determination of propoxyphene in human GRUBER,

plasma

by gas chromatography.

Anal. Chem. 40, 1243-1246.