Relief of postpartum uterine cramping with propoxyphene and aspirin

TOXICOLOGY

AND APPLIED PHARMACOLOGY19,546-553

Relief

of Postpartum Propoxyphene

(1971)

Uterine Cramping and Aspirin

with

CHARLES M. GRUBER, JR., ARTHUR BAPTISTI, JR., AND GLENN F. KIPLINGER Lilly Laboratory for Clinical Research and Department of Obstetrics and Gynecology, Marion County General Hospital, Indianapolis, Zndiana 46206 Rereived January 7, 1970

Relief of Postpartum Uterine Cramping with Propoxyphene and Aspirin. GRUBER, C. M., JR., BAPTISTI, ARTHUR, JR., andKIPLINGER, GLENN F. (1971). Toxicoi. Appl. Pharmacol. 19, 546-553.Two propoxyphenesalts, the hydrochloride and the napsylate, were administered in equimolar quantities ascapsulesto womenprofessingpostpartum uterine cramping. The dosesusedwere6.5and 130mg of the hydrochloride and 100and 200mg of the napsylate.Enteric-coatedaspirintablets,in dosesof 325and 650mg, were also included in the study, as were identical-appearingplacebocapsulesand tablets. Single oral dosesconsistingof 1 capsuleand 2 tablets weregiven with the double-blindcontrol so that equalnumbersof patients were treated with each of the 15 medicationcombinations. Responses in proportion to the dosefollowed the administrationof propoxypheneand of aspirin. Largedosesof both analgesicsin combinationwereassociatedwith responses lessthan expectedfrom the sumsof the responses to thesesame dosesgiven separately.This phenomenonmay result from a plateaueffect associatedwith maximum response.A relationship betweendosageand possiblesideeffectswas not demonstrated. Postpartum patients with pain have beenemployed assubjectsfor the determination of the efficacy of analgesicdrugs for many years. Among the reasonsfor the selection of thesepatients are the following: (1) age-young adults, (2) well being-healthy except for postdelivery state; (3) availability-abundant in certain hospitals, (4) interestusually willing to participate; and (5) route-able to accept oral medication. Two reports involving propoxyphene (Lasagna and De Kornfeld, 1958; Prockop et al., 1960),led to our interest in postpartum patients. Our first studiesusingthesepatients (Gruber et al., 1961, 1962) shed light on problems occurring in the investigation of orally administered analgesics.In these early studies propoxyphene and aspirin were administered alone and in combination without a clear demonstration of a doseresponseor additive effects. In a third attempt to involve postpartum patients at Marion County General Hospital in an evaluation of oral analgesicmedications (Gruber and Baptisti, 1963), an oral dose of 60 mg of morphine sulfate was shown to be significantly different from placebo. With this minor encouragement the program has been continued. Data recently accumulated concerning the effectiveness of capsules of propoxyphene hydrochloride’ and ’ Propoxyphene

hydrochloride

is marketed

as Darvon 546

@, a product

of Eli Lilly

and Company.

ANALGESIA

WITH

PROPOXYPHENE

propoxyphene napsylate,2 and an experimental summarized in the present report.

AND

547

ASPlRlN

enteric-coated

aspirin

tablet3 are

METHODS

The method usedis identical to that reported previously by Baptisti et al. (1971). In summary, postpartum patients professing uterine cramping were given singleoral doses of test medication before breakfast. If they participated on more than 1 day, no attempt was made at cross-over. They were questioned at 0, 1,2,3,4,6, and 8 hr after treatment. Records were kept on a report form. Parallel studies with 4 groups of patients, each reporting a different grade of pain before treatment (“a little,” “some,” “ u lot,” or “terrible”) were undertaken. In each of thesestudies,patients were randomly assignedto one of 15treatment groups, representing 15 dosagecombinations of propoxyphene, aspirin, and placebo (Table 1). Thus, 60 blocks of 5 patients each, or 300 patients in all, were included in the study. Each of the medications consisted of 2 tablets and 1 capsulein order to maintain the double-blind feature of the study. Some patients complained of excessivepain before the 8 hr of observation were completed. The assumption was made that the pain would continue at this level for the remainder of the period; therefore, to avoid missingdata, the analgesiascore for the last observation prior to administration of a routine analgesicwas inserted at each subsequent time period. Observations for symptoms other than pain (“other symptoms”) were made before the second analgesicwas given, RESULTS

The relationships between intensity of pain treated and the analgesicresponseto the medication are presentedin Table 1. Both the intensity of initial pain and the medication given are significant (P c 0.001) sourcesof variance, although their interaction is not. This indicates that the medications have similar effects at all pain levels. The medication effects are summarized in Table 2. The error term for the analysis of thesedata, asin Table 1, is the mean square for the within-blocks variance plus the pain intensity-medication interaction variance. The orthogonal contrasts indicate that the analgesic responseto aspirin has a significant (P < 0.001) slope and is approximately linear to the dose. Similar results (P < 0.05) are demonstrated by the orthogonal contrasts associatedwith propoxyphene. The 2 salts of propoxyphene, when given in equimolar quantities, are almost identical; analysis of covariance on the intensity of pain treated provides identical medication variances and an almost identical error variance. This similarity is true of the other analysesreported below. The significant interaction between aspirin and propoxyphene in the analysis of variance suggeststhe presenceof either potentiation or antagonism in the analgesia associatedwith these drugs. As the dose of and the responseto propoxyphene increase, the associatedresponseto aspirin decreases(Fig. 1). This apparent antagonism may result from an artificial plateau inherent in the experimental design. Data-time-point curves for the enteric-coated aspirin preparations are presented in Fig. 2. Analyses similar to that reported for the totals of the analgesiascoreswere carried ? Propoxyphene napsylate has the trade name Doloxene &, a product of Eli Lilly and Company. ’ The aspirin used in the form of experimental enteric-coated tablets prepared by Eli Lilly and Company. 19

548

GRUBER, JR., BAPTISTI, JR., AND KIPLINGER TABLE

1

TOTAL ANALGESIA SCORESAND VARIANCE ANALYSISFOR MEDICATIONSAT INITIAL PAIN INTENSITIES AFTER TREATMENT WITH PROPOXYPHENE AND ASPIRIN

.-

Total analgesiascores Initial pain intensity

Medication (mg) Aspirin HCI” Nap” 0

0

0

325 650 325 650 325 650

65 65 65 130 130 130

325 650 325 650

100 100 100 200 200 200

Total

1 a little

2 some

63 83 129 114 90 133 111 120 126 98 104 108 103 107 109 1598

106 123 158

3

4

a lot

terrible

Total

99 125 199 110 120 169 186 189 194 150 144 160 180 181 150 2356

376 435 637 460 462 624 554 532 615 502 509 505 571 595 569

108 104 151 137 147 162 134 127 162 129 127 113 139 161 168 2069

99 105 160 123 96 133 125 134 124 149 146 142 1923

7946

Variance analysis Sourceof variance Initial pain Medication Interaction Within blocks Total Error

Sum of squares

Degreesof Mean freedom square ~- .- ..--.

3977 3982

2199 23003

33161 25202

3 14 42 240 299 282

1325.7 284.4 52.4 95.8

F

value 14.85 3.19

PC 0.001 0.001

89.4

’ Hydrochloridesaltof propoxyphene. bNapsylatesaltof propoxyphene. out at various time points. In these analyses no significant effect was associatedwith aspirin at 1 hr, but analgesiawas indicated with the 650-mg doseat 6 and 8 hr. Data-time-point curves for the propoxyphene dosesare shown in Fig. 3. Analyses of the data at each time-point demonstrate a significant responseto propoxyphene at 1 hr, but not at 6 or 8 hr. This may be related to a prompt releaseand absorption of the drug from the capsulesand to the plateau effect resulting from the action of the aspirin at the final 2 observations.

ANALGESIA

WITH

PROPOXYPHENE

TABLE TOTAL

ANALGESIA

AND

2

SCORES FOR MEDICATION AND ORTHOGONAL CONTRASTS Total

analgesia

0

Total

Napsylate

0

65

130

100

200

Total

376 435 637 1448

460 462 624 1546

554 532 615 1701

502 509 505 1516

571 595 569 1735

2463 2533 2950 7946

Sum of Source

of variance

squares

Degrees freedom

of

1387

Aspirin

0 US. 6.50 mg 325 mg vs. (0 + 650 mg)/2 1015

1580 25202

ct (1) (1) (1) 8 282

0

analgesia

response

of patients

to aspirin

F value

PC

7.77 13.24 2.25 2.84

0.001

6.54

0.05

4.65 2.21

0.05 0.05

0.001 0.05

650

325 mg. of Aspirin

Mean square

693.50 1185.84 200.68 253.75 0.06 582.81 17.06 415.36 197.50 89.36

(1)

Propoxyphene Salt (HCl vs. napsylate) Dose (high vs. low) Dose x salt interaction 0 vs. drug Interaction Error

FIG. I. Mean of propoxyphene.

OF THEIR

(mg)

HCI

32.5 650

AN ANALYSIS

scores

Propoxyphene

Aspirin 0-d

549

ASPIRIN

per Dose

alone and in the presence

of low and high doses

The scoresfor each of the sideeffects included in the checklist appear in Table 3; no other complaints were volunteered by these patients. If all 20 patients administered 1 medication reported a “terrible” intensity of each of the 12 symptoms on the list, a

550

GRUBER,

JR.,

BAPTISTI,

JR.,

AND

KIPLINGER

maximum score of 960 would be achieved. All values were 10 “/; of this maximum score. The table indicates that the complete blank was associated with lower scores than were most of the other drugs. The total scores for symptoms other than pain were, therefore,

FIG. 2. Mean analgesia scores of patients after aspirin alone and in combination with propoayphene HCl (65 or 130 mg) or propoxyphene napsylate (100 or 200 mg). The various dosage combinations appear in Table 2. These are the mean responses at each point in time and have the same relationship as the row totals in Table 2. TABLE SCORES FOR “OTHER

Medication (mg) ____ ---Aspirin HCP Nap” 0 325 650 325 650 325 650 325 650 325 650 Total

0

0

65 65 65 130 130 130 100 100 100 200 200 200

SYMPTOMS”

3

AFTER TREATMENT AND ASPIRIN

WITH

PROPOXYPHENE

Other symptoms” 1 1 2 0 5 3 1 1 3 7 2 2 3 2 2 4 38

9 10

11 12 Total

4 6 5 8 16 2 2 8 3 1 7 11 8 21 3 3 2 1 1 6 0 4 18 2 2 5 1 11 18 5 5 10 2 2 9 1 5 12 17 5 2 10 2 4 14 1 5 7 4 19 3 0 9 1 0 5 7 8 32 2 0 11 2 6 17 27 4 1 8 1 8 5 3 4 4 19 17 3 3 12 6 8 6 6 5 17 2 0 6 2 9 7 29 5 3 6 6 4 11 3 7 16 4 20 2 0 8 4 3 5 9 18 27 2 2 4 0 10 7 9 10 32 2 2 5 1 2 9 4 7 18 3 1 4 4 63 115 103 136 320 42 23 107 35

7 1 63 3 I 63 39 0 0 9 0 77 13 0 87 10 3 63 4 0 72 9 1 90 87 8 1 4 1 59 8 1 91 72 5 0 82 6 4 6 0 86 62 5 1 97 14 1093

2

3

4

5

6

7

8--

a Code for other symptoms: 1, nausea: 2, feeling of constipation; 3, abdominal distress; 4. headache; 5, dizziness; 6, drowsiness; 7, nervousness; 8, tremor; 9. weakness; 10, blurred vision; 11. sweating: 12, itching. b Hydrochloride salt of propoxyphene. c Napsylate salt of propoxyphene.

ANALGESIA WITH PROPc)XYPHENE AND ASPIRIN

551

Dose of Propoxyphene

FIG. 3. Analgesia scores of patients after 65 and 130 mg of propoxyphene HCI and 100 and 200 mgof propoxyphene napsylate, alone and in combination with 325 and 650 mg of aspirin. The various dosage combinations appear in Table 2. These are the mean responses at each point in time and have the same relationship as the column totals in Table 2.

TABLE TOTAL “OTHER AT INITIAL PAIN

SYMPTOM” INTENSITIES

4

SCORES AND VARIANCE ANALYSIS FOR MEDICATIONS AFTER TREATMENT WITH PROPOXYPHENE AND ASPIRIN

Total “other Aspirin

Medication HCl”

0 325 650 325 650 325 650

(mg)

0

Napb

1

0

8 12 11 15 25 11 27 12 14 6 15 15 21 18 15 225

65 65 65 130 130 130 100 100 100 200 200 200

325 650 325 650 Total

Source of variance Initial pain Medication Interaction Within blocks Total Error a Hydrochloride

salt of propoxyphene.

Sum of squares 45.93 152.29 464.22 3278.40 3940.84 3742.62

symptom”

scores

Initial pain intensity 2 3 19 17 4 9 16 18 22 35 25 23 21 11 22 26 11 279

30 13 7 19 25 19 13 16 31 9 23 35 25 19 20 304

4 6 21 17 34 21 15 10 27 17 21 32 11 14 23 16 285

Variance analysis Degrees of Mean freedom square 3 15.31 14 10.87 42 11.05 240 13.66 299 282 13.27 b Napsylate salt of propoxyphene.

Total 63 63 39 77 87 63 72 90 87 59 91 72 82 86 62 1093

F value 1.15

552

GRUBER,

JR.,

BAPTISTI,

JR.,

TABLE TOTAL“~THER

AND

KIPLINGER

5

SYMPTOM”SCORES FOR MEDICATIONSAND THEIR ORTHOGONAL CONTRASTS

Total “other-symptom” Propoxyphene

AN ANALYSIS

OF

scores (mg)

HCl

Napsylate

Aspirin 0-w)

0

65

130

100

200

Total

0 325 650 Total

63 63 39 165

77 87 63 227

72 90 87 249

59 91 72 222

82 86 62 230

353 417 323 1093

Source of variance Aspirin 0 vs. 650 mg 325 mg vs. (0 + 650 mg)/2 Propoxyphene Salt (HCl vs. napsylate) Dose (high vs. low) Dose x salt interaction 0 vs. drug Interaction Error

Sum of squares

Degrees of freedom

46.11 t:, (1) 66.82

39.36

ct (1) (1) (1) 8 282

Mean square 23.05 4.50 41.69 16.70 2.40 3.75 0.81 59.85 4.92 13.27

Fvalue

PC

1.73 3.13 1.25

4.51

0.05

examined and are reported in Tables 4 and 5. This evaluation gives someevidence that propoxyphene may have contributed to the symptom complex (P < 0.05); however the biphasic responseto increasing dosesof aspirin leads one to question these results. No differences in symptom scoresbetween the propoxyphene salts or dosesof propoxyphene are apparent. Patients who professed “a lot”or “terrible” pain reported significantly (P < 0.05) more “other symptom” discomfort than did those with “a little” or “some” initial pain. Other studies support this finding (Baptisti et al., 1971; Gruber et al., 1971). DISCUSSION

The inclusion of 2 quite different medications, capsulesof propoxyphene and entericreleasetablets of aspirin, in a singletrial was prompted by a desireto study an insoluble propoxyphene salt, propoxyphene napsylate, and a new enteric coating. The appearance of a significant interaction in the analysis of the total of the analgesiascoresand of the 6th hr analgesiascoressuggests,in retrospect, that this may not have been a wise decision. However, becauseof a delay related to gastric emptying, absorption of aspirin would not be expected during the 1st hr. This assumption is supported by the data presented. Propoxyphene at 1 hr was associatedwith a significant dose-responserelationship. The delay in absorption and relatively long duration of action of aspirin were in evidence at 6 and 8 hr when the effects of the propoxyphene were negligible. These

ANALGESIA

WITH

PROPOXYPHENE

AND

ASPIRIN

553

features support the contention that this experimental model is sufficiently sensitive to assay the effects of the drugs alone as well as in combination. Although the intensity of pain treated did not apparently influence the total side effects variance (Table 3), the patients who professed “u lot” or “terrible” pain also reported significantly higher “other-symptom” scoresthan did thosewith lower intensities of pain. This suggeststhat patients differ in their sensitivity to pain and to other discomforts, or at least that differences in interpretation occur although similar physical situations may be present. This is not a new idea; however, it is supported by the findings of this experimental model. The analgesiareported by patients with more intenseinitial pain wasgenerally greater than that reported by patients professing lessintense pain. This finding indicates the need to analyze these patients asseparategroups; i.e., by “biocking” on the intensity of pain treated. Both aspirin and propoxyphene had approximately the samedegree of effectiveness in patients reporting more intense pain as in those reporting less intense initial discomfort, suggesting effectiveness of both of these nonnarcotic analgesicsin various intensities of postpartum pain. The analgesiaassociatedwith both aspirin and propoxyphene was directly proportional to the dose. The possibility of designing trials to determine or evaluate potentiation of effects using postpartum patients is suggestedby this study. Propoxyphene was effective at 1 hr but not at 6 or 8 hr after administration; enteric-coated aspirin was ineffective at 1 hr but was associatedwith analgesiaat 6 and 8 hr. This method, therefore, is sensitive to both the immediate and delayed effects of orally administered analgesicmedications and offers an opportunity to assaythe usual doseswhen given alone or in combination. ACKNOWLEDGMENTS Wewishto extendour thanksto Mrs. B. Forcum for interrogation of the patientsand alsoto the staff of the Obstetrical Servicefor their attention to the detailsof patient care. REFERENCES BAPTISTI,A., JR., GRUBER, C. M., JR., and SANTOS, E. L. (1971).The effectivenessand sideeffect liability of propoxyphenehydrochloride and propoxyphenenapsylatein patientswith postpartum uterine cramping. Toxicol. Appl. Pharmacol. 19, 519-527. GRUBER, C. M., JR.,andBAPTISTI,A., JR.(1963).Estimatingthe acceptability of morphineand noracymethadolin postpartum patients. Clin. Pharmacol. Ther. 4, 172-181. GRWBER, C. M., JR., Doss,J., BAPTISTI,A., JR.,and CHERNISH, S. M. (1961).The useof postpartum patientsin evaluating analgesicdrugs. Clin. Pharmacol. Ther. 2, 429-440. GRUBER, C. M., JR.,BAPTISTI,A., JR.,and CHERNISH, S. M. (1962).Comparativeevaluationof analgesicagentsin postpartum patients: oral dextro propoxyphene,codeine,and meperidine. Anesth. Analg. (Cleveland) 41, 538-544. GRUBER, C. M., JR., WOLEN,R. L., and BAPTISTI,A., JR. (1971).Analgesiascoresas timed responses following oral administrationof propoxypheneto postpartumpatients. Toxicol. Appl. Pharmacol.

19, 504-511.

LASAGNA,L., and DE KORNFELD, T. J. Annual report on analgesictesting,presentedat the 19th meetingof the Committeeon Drug Addiction and Narcotics, National Research Council, March 29-30, 1958. PROCKOP, L. D., ECKENHOFF, J. E., and MCELROY,R. C. (1960).Evaluation of dextropropoxyphene,codeineand acetylsalicylic compound. Obstet. Gynecol. 16, 113-l 18.