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Proteolytic enzymes in oral surgery
Proteolytic enzymes in oral surgery
G. Donald Magnes, D D S , C h ic a g o
In f la m m a tio n m u s t o c c u r b e fo re th e h e a lin g p rocess in a w o u n d c a n b e g in . . E xcessive in fla m m a t io n , h o w e v e r, d e la y s h e a lin g . I n f l a m m a tio n
and
o th e r c o m p lic a tio n s o f s u rg ic a l
p ro c e d u re s , su ch as e d e m a , th e r e fo r e , sh o u ld b e m in im iz e d fo r b o th p h y s ic a l a n d p syc h o lo g ic a l reasons. T h e a u t h o r , in a d o u b le -b lin d c o n tro lle d s tu d y , n o te d th e e f fe c ts o f d e n ta l s u rg ic a l
p ro c e d u re s
w hen
24
p a tie n ts
used
e it h e r a p la c e b o o r p ro te o ly tic e n z y m e s e x tr a c te d fro m C a r ic a p a p a y a . m a jo r s y m p to m
In e a c h o f th e
c a te g o rie s — e d e m a ,
in fla m
m a tio n , p a in , a n d tris m u s — th e e n z y m e s w e re s u p e rio r to th e p la c e b o in p ro v id in g a d e q u a te re lie f, e n a b lin g e a r ly re s o lu tio n o f w o u n d re p a ir a n d a lle v ia tin g m a n y p h y s ic a l a n d p sy c h o lo g ic a l sy m p to m s. n if ic a n t ly
e f f e c t iv e
T h e e n z y m e s w e re s ig in
75
per
cent
of
th e
p a tie n ts , c o m p a re d w it h th e 4 p e r c e n t e f f e c tiv e n e s s p ro d u c e d by th e p la c e b o .
The healing process in a deep open wound re sulting from extraction of a tooth is probably 1420
similar to that in any deep open wound. Certain local factors, however, attend the healing of the alveolus after extraction that are not encountered elsewhere. The presence of saliva, the elimina tion of a tooth in the bone, and the shape of the wound are involved. With all open wounds, healing occurs from the base out. The initial stage involves spontane ous hemorrhage and the formation of a clot. Wounds on the mucous membrane, because of the moist surface, will not permit the adherence of a scab and, for this reason, are slower to heal than those that occur on a dry flat surface. In flammation, although it may not be readily observ able, must and does occur before the healing process can begin. Excessive inflammation, al though it does not produce complete stoppage of repair as does sepsis, does prolong and delay the process of healing. Some point between the two extremes represents the ideal situation; thus, every effort should be made to limit the degree of inflammation in order to promote rapid wound repair. For some time, I have employed in dental surgery the proteolytic enzymes extracted from Carica papaya*, with what appears to be. better than average results. In order to confirm the validity of these ob servations, a double-blind, controlled, compara tive study was initiated to determine the effect of these proteolytic enzymes on edema, inflam mation, pain, and trismus.
Table 1 ■ Diagnoses and surgical procedures Case no.
Diagnoses
Surgical procedures
P la c e bo group
1 2 3 4 5 6 7 8 9 10 11 12
Impacted lower right cuspid Mesial impacted upper left third molar Impacted lower left bicuspid Impacted upper left third molar Badly broken down upper right second bicuspid Acute secondary cellulitis Lower immediate denture Tumor, palatal area Impacted upper right bicuspid "Subm erged" deciduous tooth Impacted upper right third molar Fibrous "b a n d y" frenum
Surgical flap, bone removed, tooth removed. Surgical flap, tooth elevated out. Surgical flap, bone removed, tooth removed. Surgical flap, bone removed, tooth removed. Surgical flap, bone removed, tooth removed. Root canal therapy. Extractions; bone trim. Tumor surgically removed, flap closed. Surgical flap, bone removed, tooth removed, Surgical removal of tissue, bone, and tooth. Surgical flap, bone removed, tooth removed. Frepectomy.
Papase group 13 14 15 16 17 18 19 20 21 22 23 24
Impacted lower right bicuspid Bicuspid palatal impaction Fibrous "b a n d y " frenum Lingually impacted left lateral Fibrous "b a n d y " frenum Multiple extractions Badly broken down upper first molar Pericoronitis Large tumor of mandibular anterior ridge Impacted upper left third m olar Badly broken down upper right first molar Badly broken down upper left second molar
Procedure Twenty-four patients from 7 to 62 years old (average age, 27 years) were included in the study. There were six women and ten men; six girls and two boys. The diagnosis and surgical procedure for each patient are shown in Table 1. Each patient was assigned a coded bottle of pills and was instructed to take 1 tablet every hour from the time of completion of the surgical pro cedure to the next morning. Thereafter, 1 tablet was to be taken 4 times daily for the next 4 days. The coded bottles of tablets, which were identical in appearance, contained either placebo tablets or proteolytic enzymes from Carica papaya. The placebo was identical to the tablet containing the enzymes, except that it did not contain the active ingredient. Neither the investigator nor the patient was aware of which bottle contained the active medication, and the code was not dis closed until the study was completed. The amount of edema, inflammation, pain, and trismus present was noted for each patient at the time of the first and second follow-up visits, and each was recorded as being less than usual, usual, or greater than usual, with variations within the less-than-usual and greater-than-usual classifications. Evidence of side effects was also noted. All procedures were performed by the
Surgical flap, bone removed, tooth removed. Surgical flap, bone removed, tooth removed. Frenectomy. Surgical flap, tooth elevated out. Frenectomy. Extraction of upper teeth, insertion of denture. Surgical flap, bone removed, tooth removed. Surgical removal of flap. Tumor removed, stitches placed involving lower lip. Surgical flap, bone removed, tooth removed. Surgical flap, tooth sectioning. Surgical flap, tooth sectioning.
author, thereby eliminating any variables that might have resulted from having more than one individual performing the dental surgery.
O verall results At completion of the study, 12 patients had re ceived the placebo, and 12 patients had received the proteolytic enzymes. The first follow-up visit averaged 1.16 days after the surgical procedure for both the placebo and active-drug groups. Ten patients in both groups were seen the day after the procedure, and two patients in both groups were seen the second day after the pro cedure. The second follow-up visit was an aver age of 3.58 days later for the placebo group and 3.25 days later for the proteolytic enzyme group, making a difference in favor of the placebo group of three-tenths of a day. For practical purposes, however, the time of the first visit and the time of the second visit for the two groups were con sidered comparable. In the placebo group, there were 37 symptoms to be measured at both the first and second fol low-up visits (edema, 12; inflammation, 12; pain, 12, and trismus, 1), making a total of 74 symp toms to be measured for the two visits. In the proteolytic enzyme group there were 38 symp toms to be measured at the first visit (edema, 1421
Table 2 ■ Overall results— all symptoms
Less than usual Patient
First visit
Second visit
Between less than usuat and usual (first) visit)
Between usual and greater than usual
Usual
Greater than usual
First visit
Second visit
First visit
Second visit
First visit
Second visit
l,P 1 l/E P,T l/E l/P P l/E l/P l/P 1 P
l,E,P l/E l/E
E
P E
p E E
1,E(P (T
P
l/E,P/T
Placebo group 1 2 3 4 5 6 7 8 9 10 11 12
E
E E
l,E
1 P l/P l/P
1 P
E P E E E/P T,E
l/P P 1 P
E E l/E E l/E E,P l/E
Papase group 13 14 15 16 17 18 19 20 21 22 23 24
l,E,P,T 1,E l,£,P,T l/E,P l,E,P l,E l,E,P, l/E !,E l,E
l,E,P,T l,E,P,T l,E,P l,E,P E l/E l,E l/E l/E E
l/E,P P l/E,P
P P
1/E,P
l/P P P P P l/P
P
I = in flam m atio n; E = edema; P = pain; T = trismus.
12; inflammation, 12; pain, 12, and trismus, 2) and 39 to be measured at the second visit (tris mus in one additional patient at time of second visit only), making a total of 77 symptoms to be measured (Table 2).
placebo group. For the proteolytic enzyme group, at the end of the second follow-up visit it was less than usual, 24 out of 39 (62 per cent); usual, 15 out of 39 (38 per cent), and greater than usual, 0 out of 39 (0 per cent) (Table 2).
■ Results according to each visit: In measuring all symptoms at each visit, it was found that at the time of the first follow-up visit, only 2 symp toms (both edema) out of 37 (5 per cent) in the placebo group were less than usual in sever ity, whereas 27 out of 38 (71 per cent) were less than usual in severity in the proteolytic enzyme group. In the “usual severity” category, there were 21 symptoms out of 37 (57 per cent) in the placebo group compared with 10 symptoms out of 38 (26 per cent) in the proteolytic enzyme group. In the greater-than-usual-severity category there were 14 symptoms out of 37 (38 per cent) in the placebo group compared with 1 symptom out of 38 (3 per cent) in the enzyme group. At the time of the second follow-up visit, the number of symptoms in each severity classifica tion was less than usual, 2 out of 37 (5 per cent); usual, 17 out of 37 (46 per cent), and greater than usual, 18 out of 37 (49 percent) for the
■ Results of combined visits: Combining the first and second visits for each group, the number of symptoms in the less-than-usual-severity, usualseverity, and greater-than-usual-severity classifi cations was 4 out of 74 (5 per cent), 38 out of 74 (52 per cent), and 32 out of 74 (33 per cent), respectively, for the placebo group, and 51 out of 77 (66 per cent), 25 out of 77 (33 per cent), and one out of 77 (1 per cent), re spectively, for the proteolytic enzyme group. These differences in percentage in each classi fication show the superiority of the results ob tained by the patients who received the proteoly tic enzymes. This finding was especially true of the differences in percentages in the less-thanusual-severity category— 5 per cent in the placebo group compared with 66 per cent in the pro teolytic enzyme group, and the differences in the greater-than-usual severity category— 43 per cent in the placebo group compared with 1 per cent in the enzyme group. These differences were sta tistically significant (P = < 0.05).
1422 ■ JA D A , Vol. 72, June
1966
Table 3 ■ Edema and inflammation Placebo follow-up
Edema Almost absent Almost absent to less than usual Less than usual Less than usual to usual
Papase
First visit
Second visit
First visit
Patients %
Patients %
Patients
follow-up Second visit
%
Patients %
3 3 3 1
25 25 25 8
2 3 5 0
17 25 41 0
17
2
17
2
17
8 15 8 8
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 0
0 0 1 0
0 0 8 0
3 0 7 0
25 0 58 0
2 0 6 0
17 0 51 0
75
7
58
2
17
4
33
8 8 8 0
0 3 1 Q
0 26 8 0
0 0 0 0
O 0 0 0
0 0 0 0
0 0 0 0
0 0 2 1
0 0 17 8
0 0 1 0
0 0 8 0
Usual
1
8
2
Usual to greater than usual Greater than usual Greater than usual to severe Severe
Ì 6 0 1
8 51 0 8
1 6 1 1
Almost absent Almost absent to less than usual Less than usual Less than usual to usual
0 0 0 0
0 0 0 0
Usual
9
Usual to greater than usual Greater than usual Greater than usual to severe Severe
1 1 1 0
Inflammation
■ Results according to individual patients: Ex amination of the results by individual patient shows that in the placebo group not a single patient had all his symptoms in the less-thanusual-severity category. Even when measuring 2 out of 3 or 3 out of 4 symptoms, only one patient (8 per cent) could be included. One patient (8 per cent) had all his symptoms in the usual category, and five (42 per cent) had 2 out of 3 symptoms in this classification. Only one patient (8 per cent) had all symptoms in the greater-than-usual category, and four (33 per cent) had 2 out of 3 symptoms in this cate gory. In the proteolytic enzyme group, four patients (33 per cent) had all symptoms in the less-thanusual category, which is a statistically significant difference at the 0.05 level of confidence (P = < 0.05); five (42 per cent) had 2 out of 3 or 3 out of 4 in the less-than-usual category, and three (25 per cent) had the majority o f symp toms in the usual category. None of the patients had the majority of symptoms in the greater-thanusual classification.
Results according to individual symptoms ■ Edema: In 25 per cent of the placebo group, at the time of the first follow-up visit, edema was less than usual. It was usual or greater than
usual in 75 per cent, with 8 per cent usual and 67 per cent greater than usual (Table 3). In the proteolytic enzyme group, the amount of edema was less than usual in 83 per cent (ten) of the patients (P = < 0.01), and usual in 17 per cent (two). In none of the patients in this group was the edema greater than usual. At the time of the second follow-up visit, edema was less than usual in 8 per cent of the patients, usual in 17 per cent, and greater than usual in 75 per cent of the patients in the placebo group. In the proteolytic enzyme group, edema was less than usual in 83 per cent (P = < 0.01) and usual in 17 per cent. In none of the patients was it greater than usual at the time of the second follow-up visit. ■ Inflammation: As may be observed from Table 3, none of the patients in the placebo group ex perienced less than the normally expected de gree of inflammation; it was usual or greater than usual in 100 per cent of the patients at the time of the first follow-up visit. In direct contrast, none of the patients in the proteolytic enzyme group experienced greater than usual inflammation. The degree of inflam mation was less than usual in 83 per cent (ten patients) and usual in 17 per cent (two pa tients), a statistically significant difference (P = <
0 .01 ) .
M agnes: PR O T EO LY T IC E N Z Y M E S IN O R A L S U R G E R Y ■ t423
Table 4 ■ Pain and trismus Placebo follow-up
Symptom
Papase follow-up
First visit
Second visit
First visit
Second visit
Patients %
Patients %
Patients %
Patients %
Pain Almost absent Almost absent to less than usual Less than usual Less than usual to usual
0 0 0
0
75
67
0
Usual Usual to greater than usual Greater than usual Greater than usual to severe Severe
0 0
26
0
58 8
0
0
0 0
17
0
26
17
0 0 0
67
0 0 0 0
Trismus Almost absent Alm ost absent to less than usual Less than usual Less than usual to usual Usual Usual to greater than usual Greater than usual Greater than usual to severe Severe
At the time of the second follow-up visit, only one patient in the placebo group had less in flammation than normally would have been ex pected. In the proteolytic enzyme group, 68 per cent (eight patients) had less than the usual amount ( P = < 0.01). In the placebo group, 92 per cent of the patients had the usual or greater than usual amount of inflammation, with 58 per cent being usual and 34 per cent being greater than usual. In the proteolytic enzyme group, 33 per cent of the patients experienced the usual amount of inflammation. None of the patients in the enzyme group had a greater than usual amount. ■ Pain: In the placebo group, 75 per cent of the patients had the usual amount of pain, and 25 per cent had greater than usual pain. In none of the patients was it less than usual at the time of the first visit. In the proteolytic enzyme group, it was less than usual in 33 per cent (P = < 0.05), usual in '58 per cent, and greater than usual in 8 per cent (Table 4). At the time of the second follow-up visit, pain was usual in 67 per cent (eight patients) and greater than usual in 34 per cent (four patients) of the patients in the placebo group. In the proteolytic enzyme group, pain was less than usual in 33 per cent of the patients and usual in 67 per cent of the patients. In none was it greater than usual at the time of the second 1424 ■ JA D A , Vol. 72, Ju n e
1966
follow-up visit, a statistically significant differ ence (P = < 0.05). ■ Trismus: In the placebo group, trismus was present in only one patient and was of the de gree usually expected at the time of the first and second visits. In the proteolytic enzyme group, trismus was present in two patients at the time of the first visit and was less than usual in one and usual in the other. At the time of the second visit, trismus was present in three patients and was usual in one and less than usual in two (Table 4). There were no side effects in either the placebo or proteolytic enzyme group.
Discussion Although inflammation is necessary for wound repair, it is in excess of what is required when it is clinically visible. The varied and compli cated processes involved in inflammation and repair preclude the inclusion of a discussion here. Excessive inflammation and swelling prevent the removal of tissue debris and necrotic material. Then, the natural barriers against invasion of bacteria are often prevented from functioning, and antibiotic therapy becomes advisable. It has been observed in this study and in an analysis of previous experience that antibiotic therapy
can usually be eliminated when inflammation and accompanying edema are maintained at a min imum. Keeping this minimum is important to the dentist from the standpoint of obtaining a successfully completed procedure and early heal ing of the operative site. It is probably equally important to the patient, from both a psycho logical and a physical standpoint. Preoperative anxiety, concern about oral de formity, or temporary loss of function of involved areas contribute to psychic trauma. The physical aspect is comprised of reactions to anesthetics and postoperative complications, such as pain, bleeding, temporary loss of functional parts, and oral deformity. Various combinations of psychic and physical symptoms can have a devastating effect on the patient-dentist relationship. For tunately, much of the psychic trauma can be eliminated by the dentist; the physical symptoms are more difficult to overcome. All surgical procedures are attended by some trauma, but it is the degree of trauma that is the deciding factor. This degree of trauma will depend primarily on the skill of the surgeon and the operative procedure to be carried out. In most instances, however, even after “gentle” surgical technic, pain will be one of the major postoperative factors involved. Pain is a difficult factor to measure. It was observed in this study, however, that pain was limited to the usual intensity or was less than usual in intensity in 96 per cent of the patients in the proteolytic enzyme group; whereas, with the placebo group, it was usual or greater than usual in intensity in 100 per cent of the patients. This finding is in agreement with the fact that there was considerably less edema and inflam mation in the enzyme-treated patients. Control of edema and inflammation can do much for the patient. Esthetically, he will not have facial swelling or deformity. Physiologically, too, he will benefit, with earlier reestablishment of the function that was impaired or lost. The extraction of teeth and the subsequent insertion of dentures
will be possible at an earlier date with less diffi culty for the patient and, indirectly, the dentist. The results obtained in this study confirm the advantages of proteolytic enzymes: They act as adjunctive therapy in the control of edema and inflammation, and they reduce, indirectly, asso ciated pain during the postsurgical period. Conclusions A double-blind controlled study to determine the effectiveness of proteolytic enzymes to con trol edema, inflammation, and pain resulting from oral dental surgical procedures showed the pro teolytic enzymes to be significantly effective in 75 per cent of the patients as compared with 4 per cent effectiveness produced by the placebo. In each of the major symptom categories, the enzymes were superior to the placebo in pro viding adequate relief: 83 per cent compared with 16 per cent in edema; 75 per cent compared with 4 per cent in inflammation, and 33 per cent compared with 0 per cent in pain, all statistically significant in favor of the proteolytic enzyme. It is thus concluded that proteolytic enzymes (Papase) are a safe and effective adjunctive therapy in the control and reduction of edema, inflammation, and pain associated with induced trauma resulting from oral surgical procedures. They enable early resolution of wound repair and are of considerable benefit in alleviating many of the physical and psychological symptoms that confront the patient. Proteolytic enzymes (Pa pase) are in no way a substitute for good oral surgical procedure, but certainly have proved to be a helpful adjunct for postoperative unevent fulness. Doctor Magnes' address is 1700 W . Lawrence Ave., Chicago. * Papase (proteolytic enzym es), W arner-Chilcott Lab oratories, Morris Plains, N .J. Each green, peppermintflavored tablet contains a standardized amount of an extract of proteolytic enzymes from Carica papaya, with 10,00(. W arner-Chilcott Units of enzyme activity.
Magnes: PR O T E O LY T IC E N Z Y M E S IN O R A L SU R G E R Y ■
1425
REVIEW OF DENTAL RESEARCH
S in c e
1 9 5 5 , th e C o u n c il on D e n ta l R esearch
e a c h y e a r h as p re s e n te d a re v ie w o f re s e a rc h
show n in th e ta b le below . The
C o u n c il
is g r a t e f u l
to C a rl
J.
S ta rk ,
d e v e lo p m e n ts in s e le c te d a re a s o f in te re s t to
m e m b e r o f th e C o u n c il on D e n ta l
d e n tis tr y .
w h o h as se rv ed as e d ito r o f th e s e review s fo r
T h e p a tte r n f o r th e s e re p o rts w as
m o d ifie d in 1 9 6 5 so t h a t m o s t to p ic s c a n be
th e p a s t 3 y e a rs .
re p e a te d e v e ry th ir d y e a r .
th a t
T w o c a te g o rie s o f
th e
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R e s e a rc h ,
I t w as u n d e r his g u id a n c e
fo rm a t
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d e v e lo p e d
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re v ie w a r tic le s w ill d e v ia te fro m th e sc h e d u le.
th ro u g h h is e f fo r ts t h a t a c o h e re n t re v ie w o f
F irs t, b e c a u s e o f th e c u r r e n t in te re s t, a re v ie w
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T h e C o u n c il is a ls o g r a t e f u l to A n th o n y A . R iz z o , T h e o d o r R o se b u ry , P a r k e r E. M a h a n ,
to p ic s
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" S p e c ia l"
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S ec o n d ,
be
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d e n tis tr y w ill
s p e c ia liz e d
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W.
S ta n fo rd ,
Roy T .
D u ro c h e r,
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t ic u la r ly t im e ly b u t p ro b a b ly w ill n o t be re
L. D o u g la s , a n d D o n a ld E. O re fo r p re p a rin g
p e a te d in 3 ye ars.
re view s in t h e ir re s p e c tiv e s p e c ia ltie s fo r th e
T h e f o r m a t , as in tro d u c e d la s t y e a r , is as
Category
Published in this issue
1 9 6 6 re view s o f d e n ta l re se arc h .
To be published in 1967
To be published in 1968
Disease-related
Periodontal disease
Oral pathology exclusive of caries and periodontal disease
Dental caries
Basic science
Microbiology Physiology Dental materials
Embryology & genetics Pharmacology & therapeutics Behavioral & social science
Anatomy Radiation biology Biochemistry
C lin ical science
Clinical dentistry
Clinical dentistry
Clinical dentistry
Special
Preventive dentistry
To be selected
To be selected
1426
G. Donald Magnes, D D S , C h ic a g o
In f la m m a tio n m u s t o c c u r b e fo re th e h e a lin g p rocess in a w o u n d c a n b e g in . . E xcessive in fla m m a t io n , h o w e v e r, d e la y s h e a lin g . I n f l a m m a tio n
and
o th e r c o m p lic a tio n s o f s u rg ic a l
p ro c e d u re s , su ch as e d e m a , th e r e fo r e , sh o u ld b e m in im iz e d fo r b o th p h y s ic a l a n d p syc h o lo g ic a l reasons. T h e a u t h o r , in a d o u b le -b lin d c o n tro lle d s tu d y , n o te d th e e f fe c ts o f d e n ta l s u rg ic a l
p ro c e d u re s
w hen
24
p a tie n ts
used
e it h e r a p la c e b o o r p ro te o ly tic e n z y m e s e x tr a c te d fro m C a r ic a p a p a y a . m a jo r s y m p to m
In e a c h o f th e
c a te g o rie s — e d e m a ,
in fla m
m a tio n , p a in , a n d tris m u s — th e e n z y m e s w e re s u p e rio r to th e p la c e b o in p ro v id in g a d e q u a te re lie f, e n a b lin g e a r ly re s o lu tio n o f w o u n d re p a ir a n d a lle v ia tin g m a n y p h y s ic a l a n d p sy c h o lo g ic a l sy m p to m s. n if ic a n t ly
e f f e c t iv e
T h e e n z y m e s w e re s ig in
75
per
cent
of
th e
p a tie n ts , c o m p a re d w it h th e 4 p e r c e n t e f f e c tiv e n e s s p ro d u c e d by th e p la c e b o .
The healing process in a deep open wound re sulting from extraction of a tooth is probably 1420
similar to that in any deep open wound. Certain local factors, however, attend the healing of the alveolus after extraction that are not encountered elsewhere. The presence of saliva, the elimina tion of a tooth in the bone, and the shape of the wound are involved. With all open wounds, healing occurs from the base out. The initial stage involves spontane ous hemorrhage and the formation of a clot. Wounds on the mucous membrane, because of the moist surface, will not permit the adherence of a scab and, for this reason, are slower to heal than those that occur on a dry flat surface. In flammation, although it may not be readily observ able, must and does occur before the healing process can begin. Excessive inflammation, al though it does not produce complete stoppage of repair as does sepsis, does prolong and delay the process of healing. Some point between the two extremes represents the ideal situation; thus, every effort should be made to limit the degree of inflammation in order to promote rapid wound repair. For some time, I have employed in dental surgery the proteolytic enzymes extracted from Carica papaya*, with what appears to be. better than average results. In order to confirm the validity of these ob servations, a double-blind, controlled, compara tive study was initiated to determine the effect of these proteolytic enzymes on edema, inflam mation, pain, and trismus.
Table 1 ■ Diagnoses and surgical procedures Case no.
Diagnoses
Surgical procedures
P la c e bo group
1 2 3 4 5 6 7 8 9 10 11 12
Impacted lower right cuspid Mesial impacted upper left third molar Impacted lower left bicuspid Impacted upper left third molar Badly broken down upper right second bicuspid Acute secondary cellulitis Lower immediate denture Tumor, palatal area Impacted upper right bicuspid "Subm erged" deciduous tooth Impacted upper right third molar Fibrous "b a n d y" frenum
Surgical flap, bone removed, tooth removed. Surgical flap, tooth elevated out. Surgical flap, bone removed, tooth removed. Surgical flap, bone removed, tooth removed. Surgical flap, bone removed, tooth removed. Root canal therapy. Extractions; bone trim. Tumor surgically removed, flap closed. Surgical flap, bone removed, tooth removed, Surgical removal of tissue, bone, and tooth. Surgical flap, bone removed, tooth removed. Frepectomy.
Papase group 13 14 15 16 17 18 19 20 21 22 23 24
Impacted lower right bicuspid Bicuspid palatal impaction Fibrous "b a n d y " frenum Lingually impacted left lateral Fibrous "b a n d y " frenum Multiple extractions Badly broken down upper first molar Pericoronitis Large tumor of mandibular anterior ridge Impacted upper left third m olar Badly broken down upper right first molar Badly broken down upper left second molar
Procedure Twenty-four patients from 7 to 62 years old (average age, 27 years) were included in the study. There were six women and ten men; six girls and two boys. The diagnosis and surgical procedure for each patient are shown in Table 1. Each patient was assigned a coded bottle of pills and was instructed to take 1 tablet every hour from the time of completion of the surgical pro cedure to the next morning. Thereafter, 1 tablet was to be taken 4 times daily for the next 4 days. The coded bottles of tablets, which were identical in appearance, contained either placebo tablets or proteolytic enzymes from Carica papaya. The placebo was identical to the tablet containing the enzymes, except that it did not contain the active ingredient. Neither the investigator nor the patient was aware of which bottle contained the active medication, and the code was not dis closed until the study was completed. The amount of edema, inflammation, pain, and trismus present was noted for each patient at the time of the first and second follow-up visits, and each was recorded as being less than usual, usual, or greater than usual, with variations within the less-than-usual and greater-than-usual classifications. Evidence of side effects was also noted. All procedures were performed by the
Surgical flap, bone removed, tooth removed. Surgical flap, bone removed, tooth removed. Frenectomy. Surgical flap, tooth elevated out. Frenectomy. Extraction of upper teeth, insertion of denture. Surgical flap, bone removed, tooth removed. Surgical removal of flap. Tumor removed, stitches placed involving lower lip. Surgical flap, bone removed, tooth removed. Surgical flap, tooth sectioning. Surgical flap, tooth sectioning.
author, thereby eliminating any variables that might have resulted from having more than one individual performing the dental surgery.
O verall results At completion of the study, 12 patients had re ceived the placebo, and 12 patients had received the proteolytic enzymes. The first follow-up visit averaged 1.16 days after the surgical procedure for both the placebo and active-drug groups. Ten patients in both groups were seen the day after the procedure, and two patients in both groups were seen the second day after the pro cedure. The second follow-up visit was an aver age of 3.58 days later for the placebo group and 3.25 days later for the proteolytic enzyme group, making a difference in favor of the placebo group of three-tenths of a day. For practical purposes, however, the time of the first visit and the time of the second visit for the two groups were con sidered comparable. In the placebo group, there were 37 symptoms to be measured at both the first and second fol low-up visits (edema, 12; inflammation, 12; pain, 12, and trismus, 1), making a total of 74 symp toms to be measured for the two visits. In the proteolytic enzyme group there were 38 symp toms to be measured at the first visit (edema, 1421
Table 2 ■ Overall results— all symptoms
Less than usual Patient
First visit
Second visit
Between less than usuat and usual (first) visit)
Between usual and greater than usual
Usual
Greater than usual
First visit
Second visit
First visit
Second visit
First visit
Second visit
l,P 1 l/E P,T l/E l/P P l/E l/P l/P 1 P
l,E,P l/E l/E
E
P E
p E E
1,E(P (T
P
l/E,P/T
Placebo group 1 2 3 4 5 6 7 8 9 10 11 12
E
E E
l,E
1 P l/P l/P
1 P
E P E E E/P T,E
l/P P 1 P
E E l/E E l/E E,P l/E
Papase group 13 14 15 16 17 18 19 20 21 22 23 24
l,E,P,T 1,E l,£,P,T l/E,P l,E,P l,E l,E,P, l/E !,E l,E
l,E,P,T l,E,P,T l,E,P l,E,P E l/E l,E l/E l/E E
l/E,P P l/E,P
P P
1/E,P
l/P P P P P l/P
P
I = in flam m atio n; E = edema; P = pain; T = trismus.
12; inflammation, 12; pain, 12, and trismus, 2) and 39 to be measured at the second visit (tris mus in one additional patient at time of second visit only), making a total of 77 symptoms to be measured (Table 2).
placebo group. For the proteolytic enzyme group, at the end of the second follow-up visit it was less than usual, 24 out of 39 (62 per cent); usual, 15 out of 39 (38 per cent), and greater than usual, 0 out of 39 (0 per cent) (Table 2).
■ Results according to each visit: In measuring all symptoms at each visit, it was found that at the time of the first follow-up visit, only 2 symp toms (both edema) out of 37 (5 per cent) in the placebo group were less than usual in sever ity, whereas 27 out of 38 (71 per cent) were less than usual in severity in the proteolytic enzyme group. In the “usual severity” category, there were 21 symptoms out of 37 (57 per cent) in the placebo group compared with 10 symptoms out of 38 (26 per cent) in the proteolytic enzyme group. In the greater-than-usual-severity category there were 14 symptoms out of 37 (38 per cent) in the placebo group compared with 1 symptom out of 38 (3 per cent) in the enzyme group. At the time of the second follow-up visit, the number of symptoms in each severity classifica tion was less than usual, 2 out of 37 (5 per cent); usual, 17 out of 37 (46 per cent), and greater than usual, 18 out of 37 (49 percent) for the
■ Results of combined visits: Combining the first and second visits for each group, the number of symptoms in the less-than-usual-severity, usualseverity, and greater-than-usual-severity classifi cations was 4 out of 74 (5 per cent), 38 out of 74 (52 per cent), and 32 out of 74 (33 per cent), respectively, for the placebo group, and 51 out of 77 (66 per cent), 25 out of 77 (33 per cent), and one out of 77 (1 per cent), re spectively, for the proteolytic enzyme group. These differences in percentage in each classi fication show the superiority of the results ob tained by the patients who received the proteoly tic enzymes. This finding was especially true of the differences in percentages in the less-thanusual-severity category— 5 per cent in the placebo group compared with 66 per cent in the pro teolytic enzyme group, and the differences in the greater-than-usual severity category— 43 per cent in the placebo group compared with 1 per cent in the enzyme group. These differences were sta tistically significant (P = < 0.05).
1422 ■ JA D A , Vol. 72, June
1966
Table 3 ■ Edema and inflammation Placebo follow-up
Edema Almost absent Almost absent to less than usual Less than usual Less than usual to usual
Papase
First visit
Second visit
First visit
Patients %
Patients %
Patients
follow-up Second visit
%
Patients %
3 3 3 1
25 25 25 8
2 3 5 0
17 25 41 0
17
2
17
2
17
8 15 8 8
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 0
0 0 1 0
0 0 8 0
3 0 7 0
25 0 58 0
2 0 6 0
17 0 51 0
75
7
58
2
17
4
33
8 8 8 0
0 3 1 Q
0 26 8 0
0 0 0 0
O 0 0 0
0 0 0 0
0 0 0 0
0 0 2 1
0 0 17 8
0 0 1 0
0 0 8 0
Usual
1
8
2
Usual to greater than usual Greater than usual Greater than usual to severe Severe
Ì 6 0 1
8 51 0 8
1 6 1 1
Almost absent Almost absent to less than usual Less than usual Less than usual to usual
0 0 0 0
0 0 0 0
Usual
9
Usual to greater than usual Greater than usual Greater than usual to severe Severe
1 1 1 0
Inflammation
■ Results according to individual patients: Ex amination of the results by individual patient shows that in the placebo group not a single patient had all his symptoms in the less-thanusual-severity category. Even when measuring 2 out of 3 or 3 out of 4 symptoms, only one patient (8 per cent) could be included. One patient (8 per cent) had all his symptoms in the usual category, and five (42 per cent) had 2 out of 3 symptoms in this classification. Only one patient (8 per cent) had all symptoms in the greater-than-usual category, and four (33 per cent) had 2 out of 3 symptoms in this cate gory. In the proteolytic enzyme group, four patients (33 per cent) had all symptoms in the less-thanusual category, which is a statistically significant difference at the 0.05 level of confidence (P = < 0.05); five (42 per cent) had 2 out of 3 or 3 out of 4 in the less-than-usual category, and three (25 per cent) had the majority o f symp toms in the usual category. None of the patients had the majority of symptoms in the greater-thanusual classification.
Results according to individual symptoms ■ Edema: In 25 per cent of the placebo group, at the time of the first follow-up visit, edema was less than usual. It was usual or greater than
usual in 75 per cent, with 8 per cent usual and 67 per cent greater than usual (Table 3). In the proteolytic enzyme group, the amount of edema was less than usual in 83 per cent (ten) of the patients (P = < 0.01), and usual in 17 per cent (two). In none of the patients in this group was the edema greater than usual. At the time of the second follow-up visit, edema was less than usual in 8 per cent of the patients, usual in 17 per cent, and greater than usual in 75 per cent of the patients in the placebo group. In the proteolytic enzyme group, edema was less than usual in 83 per cent (P = < 0.01) and usual in 17 per cent. In none of the patients was it greater than usual at the time of the second follow-up visit. ■ Inflammation: As may be observed from Table 3, none of the patients in the placebo group ex perienced less than the normally expected de gree of inflammation; it was usual or greater than usual in 100 per cent of the patients at the time of the first follow-up visit. In direct contrast, none of the patients in the proteolytic enzyme group experienced greater than usual inflammation. The degree of inflam mation was less than usual in 83 per cent (ten patients) and usual in 17 per cent (two pa tients), a statistically significant difference (P = <
0 .01 ) .
M agnes: PR O T EO LY T IC E N Z Y M E S IN O R A L S U R G E R Y ■ t423
Table 4 ■ Pain and trismus Placebo follow-up
Symptom
Papase follow-up
First visit
Second visit
First visit
Second visit
Patients %
Patients %
Patients %
Patients %
Pain Almost absent Almost absent to less than usual Less than usual Less than usual to usual
0 0 0
0
75
67
0
Usual Usual to greater than usual Greater than usual Greater than usual to severe Severe
0 0
26
0
58 8
0
0
0 0
17
0
26
17
0 0 0
67
0 0 0 0
Trismus Almost absent Alm ost absent to less than usual Less than usual Less than usual to usual Usual Usual to greater than usual Greater than usual Greater than usual to severe Severe
At the time of the second follow-up visit, only one patient in the placebo group had less in flammation than normally would have been ex pected. In the proteolytic enzyme group, 68 per cent (eight patients) had less than the usual amount ( P = < 0.01). In the placebo group, 92 per cent of the patients had the usual or greater than usual amount of inflammation, with 58 per cent being usual and 34 per cent being greater than usual. In the proteolytic enzyme group, 33 per cent of the patients experienced the usual amount of inflammation. None of the patients in the enzyme group had a greater than usual amount. ■ Pain: In the placebo group, 75 per cent of the patients had the usual amount of pain, and 25 per cent had greater than usual pain. In none of the patients was it less than usual at the time of the first visit. In the proteolytic enzyme group, it was less than usual in 33 per cent (P = < 0.05), usual in '58 per cent, and greater than usual in 8 per cent (Table 4). At the time of the second follow-up visit, pain was usual in 67 per cent (eight patients) and greater than usual in 34 per cent (four patients) of the patients in the placebo group. In the proteolytic enzyme group, pain was less than usual in 33 per cent of the patients and usual in 67 per cent of the patients. In none was it greater than usual at the time of the second 1424 ■ JA D A , Vol. 72, Ju n e
1966
follow-up visit, a statistically significant differ ence (P = < 0.05). ■ Trismus: In the placebo group, trismus was present in only one patient and was of the de gree usually expected at the time of the first and second visits. In the proteolytic enzyme group, trismus was present in two patients at the time of the first visit and was less than usual in one and usual in the other. At the time of the second visit, trismus was present in three patients and was usual in one and less than usual in two (Table 4). There were no side effects in either the placebo or proteolytic enzyme group.
Discussion Although inflammation is necessary for wound repair, it is in excess of what is required when it is clinically visible. The varied and compli cated processes involved in inflammation and repair preclude the inclusion of a discussion here. Excessive inflammation and swelling prevent the removal of tissue debris and necrotic material. Then, the natural barriers against invasion of bacteria are often prevented from functioning, and antibiotic therapy becomes advisable. It has been observed in this study and in an analysis of previous experience that antibiotic therapy
can usually be eliminated when inflammation and accompanying edema are maintained at a min imum. Keeping this minimum is important to the dentist from the standpoint of obtaining a successfully completed procedure and early heal ing of the operative site. It is probably equally important to the patient, from both a psycho logical and a physical standpoint. Preoperative anxiety, concern about oral de formity, or temporary loss of function of involved areas contribute to psychic trauma. The physical aspect is comprised of reactions to anesthetics and postoperative complications, such as pain, bleeding, temporary loss of functional parts, and oral deformity. Various combinations of psychic and physical symptoms can have a devastating effect on the patient-dentist relationship. For tunately, much of the psychic trauma can be eliminated by the dentist; the physical symptoms are more difficult to overcome. All surgical procedures are attended by some trauma, but it is the degree of trauma that is the deciding factor. This degree of trauma will depend primarily on the skill of the surgeon and the operative procedure to be carried out. In most instances, however, even after “gentle” surgical technic, pain will be one of the major postoperative factors involved. Pain is a difficult factor to measure. It was observed in this study, however, that pain was limited to the usual intensity or was less than usual in intensity in 96 per cent of the patients in the proteolytic enzyme group; whereas, with the placebo group, it was usual or greater than usual in intensity in 100 per cent of the patients. This finding is in agreement with the fact that there was considerably less edema and inflam mation in the enzyme-treated patients. Control of edema and inflammation can do much for the patient. Esthetically, he will not have facial swelling or deformity. Physiologically, too, he will benefit, with earlier reestablishment of the function that was impaired or lost. The extraction of teeth and the subsequent insertion of dentures
will be possible at an earlier date with less diffi culty for the patient and, indirectly, the dentist. The results obtained in this study confirm the advantages of proteolytic enzymes: They act as adjunctive therapy in the control of edema and inflammation, and they reduce, indirectly, asso ciated pain during the postsurgical period. Conclusions A double-blind controlled study to determine the effectiveness of proteolytic enzymes to con trol edema, inflammation, and pain resulting from oral dental surgical procedures showed the pro teolytic enzymes to be significantly effective in 75 per cent of the patients as compared with 4 per cent effectiveness produced by the placebo. In each of the major symptom categories, the enzymes were superior to the placebo in pro viding adequate relief: 83 per cent compared with 16 per cent in edema; 75 per cent compared with 4 per cent in inflammation, and 33 per cent compared with 0 per cent in pain, all statistically significant in favor of the proteolytic enzyme. It is thus concluded that proteolytic enzymes (Papase) are a safe and effective adjunctive therapy in the control and reduction of edema, inflammation, and pain associated with induced trauma resulting from oral surgical procedures. They enable early resolution of wound repair and are of considerable benefit in alleviating many of the physical and psychological symptoms that confront the patient. Proteolytic enzymes (Pa pase) are in no way a substitute for good oral surgical procedure, but certainly have proved to be a helpful adjunct for postoperative unevent fulness. Doctor Magnes' address is 1700 W . Lawrence Ave., Chicago. * Papase (proteolytic enzym es), W arner-Chilcott Lab oratories, Morris Plains, N .J. Each green, peppermintflavored tablet contains a standardized amount of an extract of proteolytic enzymes from Carica papaya, with 10,00(. W arner-Chilcott Units of enzyme activity.
Magnes: PR O T E O LY T IC E N Z Y M E S IN O R A L SU R G E R Y ■
1425
REVIEW OF DENTAL RESEARCH
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T h e f o r m a t , as in tro d u c e d la s t y e a r , is as
Category
Published in this issue
1 9 6 6 re view s o f d e n ta l re se arc h .
To be published in 1967
To be published in 1968
Disease-related
Periodontal disease
Oral pathology exclusive of caries and periodontal disease
Dental caries
Basic science
Microbiology Physiology Dental materials
Embryology & genetics Pharmacology & therapeutics Behavioral & social science
Anatomy Radiation biology Biochemistry
C lin ical science
Clinical dentistry
Clinical dentistry
Clinical dentistry
Special
Preventive dentistry
To be selected
To be selected
1426