Analgesia scores as timed responses following oral administration of propoxyphene to postpartum patients

TOXICOLOGY

AND

APPLIED

Analgesia Administration

PHARMACOLOGY

19, 50‘+-511 (1971)

Scores as Timed Responses Following of Propoxyphene to Postpartum

Oral Patients

CHARLESM. GRUBER,JR., ROBERTL. WOLEN,AND ARTHUR BAPTISTI,

JR.

Lilly Laboratory for Clinical Research and Department of Obstetrics and Gynecology, Marion County General Hospital, Indianapolis, Indiana 46206 Received February 26, 1970

AnalgesiaScoresasTimed Responses Following Oral Administration of Propoxypheneto PostpartumPatients.GRUBER, CHARLES M., JR., WOLEN, ROBERT L., and BAPTISTI, ARTHUR, JR. (1971). Toxicol. Appl. Pharmacol. 19,504-511.Two propoxyphenesalts,the hydrochloride and the napsylate, were administeredin equimolar quantitiesas singleoral dosesto women reporting postpartum uterine cramping. The double-blind dosesincluded 32, 65, and 130mg of the hydrochloride and 50, 100, and 200 mg of the napsylatesalt. Identical-appearingplacebocapsuleswereincluded.Grouping the patients according to the intensity of pain treated and assigning paired patients to different treatment groupswasan important part of the procedure. The results(analgesiascores)indicate a linear dose-response over this range and no significant differencesbetweenthe propoxyphene salts. Postpartum patients have proved receptive to single-dosestudies with oral analgesic medications. A continuous program has, therefore, been established using these patients to evaluate various analgesic drugs. In the present study, total and interval analgesiascoreswere used to determine the effectivenessand timed-response to equimolar dosesof propoxyphene napsylate’ and propoxyphene hydrochloride.* METHODS The methods employed have been described previously (Baptisti et al., 1971). To summarize, postpartum patients with uterine cramping were given single oral dosesof propoxyphene napsylate or propoxyphene hydrochloride before breakfast. Twelve patients received each doseof the test medications at each of the 4 initial pain intensities. An equal number of patients at each pain level were given placebo. Thus, the total number of treatments during the study was 336. Subjective data concerning pain intensity and relief were collected at 0, 1,2,3,4,6, and 8 hr after treatment and were recorded on a report form. In addition to these data, interval analgesiascoreswere determined for 2 patients in each medication-pain-intensity block at each observation time after the 0 hr. Plasma sampleswere collected at the sameprespecified times as the interval score data and are evaluated as to their propoxyphene concentration by Wolen et al. (1971). ’ Propoxyphenenapsylatehasthe trademarkDoloxenem, a productof Eli Lilly andCompany. 2Propoxyphene hydrochlorideismarketedasDarvon@,a productof Eli Lilly andCompany. 504

ANALGESIA

SCORES

AS TIMED

505

RESPONSES

The venipunctures were timed so that samples were obtained from 2 patients in each medication-pain-intensity block at each observation time after the 0 hr. At the end of the 8th hr of observation, the subjects were asked whether they had experienced other symptoms during the study, and whether these symptoms were drug-related. Standard statistical methods (means, variance analysis, confidence limits, common slopes, and relative potency) were employed to analyze the data (Cochran and Cox, 1950; Dixon and Massey, 1951). RESULTS

Analgesia scoresusedto evaluate effectivenesswere determined by summing the painintensity-difference scoresand the estimate-of-relief scores obtained at each point in time (Gruber and Baptisti, 1963).The data relating to both the total and interval scores for eachpatient are summarizedin Table 1. Variance analysesof thesedata are presented

TOTAL ANALGESIA INITIAL

TABLE 1 SCORES FOR PROPOXYPHENE SALTSAT PAIN

INTENSITIES

Total analgesiascores Initial pain intensity Dosage Medication”

-

Blank Hydrochloride

(mg)

0 32 65 130 50

Napsylate

100

200

Total

-

1 a little

2

3

4

some

a lot

terrible

Total

179

143

231

201

240 231 236 156 266 244

187 228 197 189 256 289

249 262 235 212 180 224

133 259 371 259 261 290

754 809 980 1039 816 963 1047

1552

1489

1593

1774

6408

Interval analgesiascores Initial pain intensity Medication Blank Hydrochloride Napsylate

Dosage (ms) 0 32 65 130 50 100 200

Total a Hydrochloride

= propoxyphene

1

2

3

4

Total

31 32 41 45 32 39 41

18 39 39 44 31 49 51

35 36 48 52 30 24 34

30 17 38 55 37 51 46

114 124 166 196 130 163 172

261

271

259

274

1065

hydrochloride;

napsylate

= propoxyphene

napsylate.

18

308

3222.8

39825.0 45380.3 43047.8

Total Error for main effects

335 326

3 6

df

534.9 1797.6

ss

Initial pain (I) Medication (M) Hour of measurement(H) Primary interactions MxI MxH IxH Secondaryinteraction Within blocks

Sourceof variance

132.0

129.3

179.0

178.3 299.6

MS

Total score

1.38

1.35 2.26

F

0.05

PC

VARIANCE ANALYSES OF ANALGESIA SCORES

TABLE 2

4136.27 1776.10

5.28 5.53

335 321

5.87 8.06 5.46

0.65 18.63 73.91 6.32 5.62

MS

168

(30) (15) 90

176.16 120.94 491.29 886.50

&

3 6 5

df

1.94 111.77 369.53 398.31 101.21

ss

Interval score

1.11 1.52 1.03

3.52 13.48 1.14 1.06

F

0.05 0.001

PC

$ u ? 3 G “9 3

ur g 3

?

8 P

z

ANALGESIA

SCORES

AS TIMED

507

RESPONSES

in Table 2. Medication effects appear in Table 3, and the analyses in Table 4. In addition, the data at each point in time were examined. These evaluations indicate that (1) significantly more analgesia was reported following propoxyphene than placebo, (2) the increase in analgesia was linearly related to the dosage of propoxyphene, and (3) no significant differences were demonstrated between the napsylate and the hydrochloride salts. TABLE TOTAL

ANALGESIA

SCORES

3 FOR

PROPOXYPHENE

SALTS

Dosage(mg) Medication”

32-50

65-100

130-200

Total

1039 1047 2086

2828 2826 5654

Total analgesia scores

Hydrochloride Napsylate Totalb

809

980 963

816 1625

1943

Interval analgesia scores

Hydrochloride Napsylate Total’ o Hydrochloride b The total c The total

for for

= propoxyphene the placebo-treated the placebo-treated

124 130

166 163

196 172

254

329

368

hydrochloride; group was group was

napsylate

= propoxyphene

486 465 951 napsylate.

754. 114.

Figure 1 presents a summary of the dose-responsedata for both total and interval analgesiascores.In each set of data the common slopelinesare separatedby an interval compatible with the difference in molecular weight. Thus, the 2 salts are equi-analgesic on an equimolar basis. Extrapolation of the lines downward to intersect the one representing the placebo level of action indicates that this experimental method should not be expected to differentiate between 20 mg of propoxyphene hydrochloride, 30 mg of propoxyphene napsylate, and placebo. Analysis of the interval data, wherein 1 observation time waspreselectedfor each patient, allows an expanded evaluation of time effects. This is possiblebecausethesescoresare independent of each other. This analysis (Table 2) indicates that the time of measurementis a significant primary source of variance. However, the interaction between medication and the time of observation (M x H) is not significant, suggestingthat the saltsmay not have significantly different time effects. A specific analysisof the interaction between salt and time (S x T) was done. The mean square for the 5 degreesof freedom for this source of variance equals 28, the F value is 2.19 and P > 0.05. Reports of symptoms other than pain included those which could not be attributed to the medication. (For a list of symptoms, seeTable 3 of Gruber et al., 1971). Such reports volunteered by the patients were few in number and did not influence the interpretation of the data. An analysis basedon the number of adversereports made by each patient was almost identical to the one basedon scores.In the analysis of the scoresfor

Hydrochloride us.napsylate Low vs. high dose Middle vs. low + high dose Interaction propoxyphene x dose Blank vs. propoxyphene Error for main effects

Sourceof variance

633.4 43047.8 326

1

2

53.2

4.1

df 1 1 1

~.

4

53.2 2.1 633.4 132.0

0.1 1106.9

MS

4.79

8.38

F

0.05

0.01

PC

ss

1.53 67.68 2.25 4.95 35.36 1776.10

OFMEDICATIONEFFECTS

Total score

ANALYSIS

0.1 1106.9

ss

VARIANCE

TABLE

1

2

1 1 1

321

df

67.68 2.25 2.28 35.36 5.53

1.53

MS

Interval score

6.39

12.23

F

0.02

0.001

P<

$

?

$ 3 3 “k-

5

“2

3

s 8 3

ANALGESIA

SCORES

AS TIMED

RESPONSES

509

FIG. 1. Mean analgesic scores based on total scores (A) and on interval scores (B). The lines are based on common slopes for each of the 2 estimates of effectiveness. HCl = propoxyphene hydrochloride; Naps = propoxyphene napsylate.

other symptoms (Table 5) no significant medication effects were demonstrated. However, a linear relationship between the intensity of uterine cramping at 0 hr and the total “other-symptom” scoresis present. This finding is similar to that of Baptisti et al. (1971) and indicates that patients who report more intense cramping also report other discomforts to be of greater magnitude. DISCUSSION

The data obtained at all points in time for each patient are very similar to those reported in other studies using propoxyphene in postpartum patients. Baptisti et al. (1971) included larger but overlapping doses,and Gruber et al. (1971) administered the propoxyphene salts with and without aspirin. The principal findings observed in all 3 reports are as follows : (1) Analgesia scoresfollowing placebo were significantly lower than thosefollowing propoxyphene; (2) Analgesia scoresfollowing propoxyphene were directly proportional to the log of the dose; and (3) Patients who complained of more intense initial pain also reported a greater number of adverse responses.

510

GRUBER, JR., WOLEN, AND BAPTISTI, JR.

TABLE 5 TOTAL “OTHER-SYMPTOM" SCORESAND VARIANCE ANALYSIS FOR PROPOXYPHENE SALTS AT INITIAL PAIN INTENSITIES

Initial pain intensity Medication” Placebo Hydrochloride Napsylate

Dosage (mg> 32 65 130 50 100 200

Total Sourceof variance Initial pain Linear Quadratic Cubic Medications HCI vs. napsylate High vs. low dose Middle dosevs. meanof low and high Interaction dosex salt Blank vs. propoxyphene Interaction pain x medication Within blocks Total Error

1 48 41 46 45 34 36 27 277 Sumof squares

2

3

4

Total

52 53 58 52 53 37 65 370

48 50 56 49 47 75 78 403

66 66 68 65 38 76 81 460

214 210 228 211 172 224 251 1510

Degreesof freedom

209.68 (1) (1) 71.53 (7, (1)

173.78 3985.00 4439.99 4158.78

(1) (2) (1) 18 308 335 326

Mean square F value 69.89 201.62 3.85 4.20 11.92 0.01 33.33 6.25 31.40 0.07 9.65 12.93

5.48 15.81

P-c

0.001 0.001

2.57 2.46

12.75

uHydrochloride= propoxyphenehydrochloride;napsylate.= propoxyphenenapsylate Analysis of the analgesia scores obtained at the same intervals as venipunctures indicates, in addition to the above, that significant differences in the response to the salts over time were not present. This is in opposition to the report by Baptisti et al. (1971) and by Sunshine et al. (1971), but is in accord with the results of Gruber et al. (1971). The napsylate salt may produce significantly more analgesia at 6 and 8 hr (Baptisti et al., 1971), but the low magnitude of differences between the saltsmay result in an inability to demonstrate this difference consistently. The medications were not associatedwith significant differences in reports of adverse effects. This finding also is dissimilar to the study by Baptisti et ai. (1971), in which fewer complaints and lower “other-symptom” scores were associated with the napsylate. Again, theseestimatesare difficult to make when acceptabletherapeutic doses are used. These inconsistent findings must be expected unlessvery large numbers of patients are included. In the studiesthat have been reported, the napsylate salt has not been found to be lesseffective or more toxic than equimolar dosesof the hydrochloride sa!t of propoxyphene.

ANALGESIA

SCORES

AS TIMED

RESPONSES

511

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 A., JR., GRUBER, C. M., JR., and SANTOS, E. L. (1971). The effectiveness and sideeffect liability of propoxyphene hydrochloride and propoxyphene napsylate in patients with postpartum uterine cramping. Toxicol. Appl. Pharmacol. 19, 519-527. COCHRAN, W. G., and Cox, G. M. (1950).Experimental Designs, pp. 55-59,103-106,146-151, 396-399. Wiley, New York. DIXON, W. J., and MASSEY, F. J., JR. (1951). introdtrction to Stafisfical Analysis, pp. 119-152. McGraw-Hill, New York. GRUBER, C. M., JR., and BAPTISTI, A., JR. (1963).Estimatingthe acceptabilityof morphineand noracymethadolin postpartum patients. Clin. Pharmacol. Ther. 4, 172-181. GRUBER, C. M., JR., BAPTISTI, A., JR., and KIPLINGER, G. F. (1971).Relief of postpartum uterinecrampingwith propoxypheneand aspirin. Toxicol. Appl. Pharmacol. 19,546-553. SUNSHINE, A., LASKA, E., SLAFTA, J., and FLEISCHMAN, E. (1971). A comparative analgesia study of propoxyphene hydrochloride, propoxyphene napsylate, and placebo. Toxicol. Appl. Pharmacol. 19, 5 12-518. WOLEN, R. L., GRUBER, C. M., JR., BAPTISTI, A., JR., and SCHOLZ, N. E. (1971).Theconcentration of propoxyphenein the plasmaand analgesiascoresin postpartumpatients. Toxicol. BAPTISTI,

Appl. Pharmacol.

19, 498-503.