Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
Current Medical Research and Opinion
Vol. 6, No. 2, 1979
Post-operative analgesia with diflunisal
N. Papathiodossiou, M.D.
Curr. Med. Res. Opin., (1979) 6, 154.
Received: 2nd April 1979
Hbpital Pourtalas, Neuchitel, Switzerland
Summary A n open study was carried out in 196 consecutive patients who had undergone orthopaedic (103) or gjnaecological (93) surgical procedures to assess the effectiveness and tolerability o f a single dose of 500 mg dijlunisal in the relief of postoperative pain. Dijlunisal was given when patients first complained oj’ pain, and pain severity before and at intervals up to 6 hours after the dose was assessed using a 10-point analogue scale. The results showed that dijlunisal was both prompt and prolonged in its effect. No pain was reported after I hour in 138 (71 %) of the 196 patients, and after 6 hours only 13 ( 7 % ) still reported some pain. DiJIunisal was equally as effective in the two groups. Side-effects were reported in 13 ( 7 % ) patients but these were ones conzmonlyfound in the post-operative situation. Key words: Dijlunisal- analgesics, anti-inflammatory -pain, post-operative
Introduction The well-known dangers of the parenterally administered potent analgesics make them unsuitable for the routine treatment of pain after surgical procedures6 and, although aspirin and other such oral analgesis have been widely used, their usefulness has been somewhat limited by anticoagulant activity and their tendency to produce gastro-intestinal and other disturbing side-effects. The search has continued, therefore, to find an ideal analgesic for use in post-operative pain which is effective, safe and acceptable to the patient. Diflunisalt is a recently developed salicylic acid derivative which has been shown to have marked analgesic and anti-inflammatory activity.’ It differs from acetylsalicylic acid through the introduction of the difluorophenyl moiety and the elimination of the clinically and biologically labile 0-acetyl group (Figure 1). This structural difference confers several advantages on diflunisal. Unlike aspirin, it has no effect on platelet count, bleeding time or ADP- or collagen-induced platelet aggregation.12.14 This means no problems with post-operative bleeding induced by such mechanisms. In addition, diflunisal possesses considerably greater potency and longer duration of action than aspirin13 - a finding of real importance for a
t ‘Dolobid’, ‘Unisal’, trade marks, MSD 154
N. Papathdodossiou
Figure 1. Structural formula of diflunisal compared with that of aspirin Acetylsalicylic acid
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
COOH
prospective analgesic for post-operative pain. Furthermore, there is no evidence of dependency or addition problems. Diflunisal has been extensively studied in a variety of painful conditions.’-3. 5.9~10.15.16In view of these favourable reports it was decided to assess thesuitability of diflunisal for the management of post-operative pain in a number of our patients.
Patients and methods A total of 196 consecutive patients undergoing surgery at the Hdpital Pourtalts et Maternit6 in Neuchatel were studied. The first group of 103 patients (66 males and 37 females, mean age 39.9k13.3 years) consisted of those undergoing orthopaedic and trauma procedures such as osteotomies, arthrotomy of the knee, rectification of hallux valgus, amputations, arthroscopy, osteosynthesis, ablation of material, and meniscectomy. The second group comprised 93 women (mean age 36.8 f12.9 years) undergoing gynaecological operations such as curettage and biopsy of the breast or uterus. On complaining of post-operative pain, each patient was rated on a 10-point analogue scale (O=none to IO=unbearable). Two 250 mg diflunisal tablets were then prescribed and the pain severity ratings measured at 15 minutes, 30 minutes, 1, 2, 4, and 6 hours after this initial therapy. All observations were carried out by who also asked for and recorded any side-effects the same investigator (N.P.), possibly related to the medication.
Results Table I gives details of the duration of operations and the time after surgery when the patient first complained of pain and received analgesic therapy. Mean pain severity scores at baseline and at intervals up to 6 hours after the administration of diflunisal are given in Table 11, and Figures 2 and 3 show the percentage of patients with the different pain scores during the observation period. 155
Post-operative analgesia with diflunisal
Table I. patients
Duration of operations and time of first complaint of post-operative pain: number of
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
Time
Orthopaedic group (n= 103)
Gynaecological group (n =93)
Total (n=196)
62
Duration of operation (rnin) 5 to I5 16 to 30 31 to45 46 to 60 61 to 75 16 to 90 91 or over
I
55
37 25 I 15 5 7
20
51
15
40 8 16 6 7
Mean time
46.1
20.1
I 1 1
33.7
Time ofjirst complaint ofpost-operative pain (min) 120to 180 181 to210 21 1 to 240 241 to 270 271 to 300 301 to 330
9 21 56 9
Mean time
228.2
9 22 52 10
18
49 108 2
2
225.1
226.1
Table 11. Mean pain severity scores before and after a single 500 mg dose of diflunisal Assessment
Orthopaedic group
Gynaecological group
Baseline 15 min 30 min 1 hour 2 hours 4 hours 6 hours
2.9 2.3 1.4 0.8 0.4 0.3 0.2
2.3 1.6 0.8
0.4 0.2 0.1 0.1
No pain was reported after 1 hour in 138 (71 %) of the 196 patients, and after 6 hours only 13 (7%) patients still reported some pain. The results were equally as satisfactory in both groups of patients. Table I11 gives the time of last reported pain. Diflunisal was extremely well tolerated, and adverse reactions possibly related to drug therapy were noted only in 13(7 %)patients. Furthermore, all of the experiences reported - vomiting (l), nausea (4),dizziness (2), and sweating (6) - are commonly found in the post-operative situation. 156
N. Papathbdossiou
Figure 2. Percentage of patients with the different pain scores before and after treatment with a single 500 mg dose of diflunisal:103 orthopaedic patients Hmeline
A.jio. 15 miti Y
A.frc.i.30 t t i i i i t
Afie, I
lioiii.
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
lo04
-
. O o\
--
7-
20-
r
L
40 20
L 1 2 3 4 5 6
0
0
2 3 4 5 6
0 1 2 3 4 5 6
Pain severity score
Discussion Pharmacokinetic and metabolic studies' 3 have shown that diflunisal is well absorbed from the gastro-intestinal tract with peak plasma levels being reached within 2 to 3 hours. The initial plasma half-life observed following single oral doses of 125,250 and 500 mg ditlunisal is dose dependent, ranging from approximately 7.5 hours for the 125 mg dose to 11 hours for the 500 mg dose. The terminal slope (determined after plasma drug levels reached approximately 15 pg/ml) indicates a half-life of 7.5 to 8 hours in normal subjects. The theoretical clinical advantages of such properties are confirmed in the present study. Onset of analgesic action compared favourably with many other nonsteroidal, non-addictive analgesic agents, whereas duration of action was prolonged. Many non-steroidal anti-inflammatory/analgesicagents affect platelet function and blood coagulation via their inhibitory actions on the prostaglandin synthetase enzyme system,s particularly on the formation of thromboxane A2.' Exposure to aspirin impairs the ability of platelets to respond to aggregation stimuli for the life of the platelet, while indomethacin exerts a reversible inhibition of platelet aggrega157
Post-operative analgesia with diflunisal
Figure 3. Percentage of patients with the different pain scores before and after treatment with a single 500 mg dose of diflunisal: 93 gynaecological patients Illt.Cl//t.
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
I00
-, C
.Is.
._
, l,wt
1
1.i
00
i):tii\
A//t,t 30
//,I//\
A/LY
I
ll~llt,~
1
_I
a
C
Pain severity scorc
Table III. Time of last reported pain after a single 500 mg dose of diflunisal: number of patients Time
0rth opaedic group
Gynaecological group
Total
Baseline 15 min 30 min 1 hour 2 hours 4 hours 6 hours
3 28 32 19
15 66 57 25 16 4 13
Total
7
12 38 25 6 9
4 10
3
103
93
1%
tion. The effect of indomethacin disappears within 12 to 24 hours following termination of indomethacin treatment.’ 1 In contrast diflunisal, in single doses as high as 500 mg and in chronic dosage regimens up to and including 500 mg twice daily, causes no alteration in adenosine diphosphate (ADP)-induced platelet aggregation, platelet disaggregation or prothrombin and bleeding times.’ 2.14 Utilivng the standard 51 Cr-tagged red blood cell technique, a double-blind, crossover study4 158
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
N. Papatheodossiou
was carried out to measure gastro-intestinal blood loss after 500 mg diflunisal per day compared with that after an equianalgesic dose of aspirin (2.4 g per day). The results showed that, at this dosage regimen, diflunisal does not cause a statistically significant alteration in the rate of gastro-intestinal blood loss, but the equianalgesic dose of aspirin results in a significant increase(p
Current Medical Research and Opinion
Vol. 6, No. 2, 1979
Post-operative analgesia with diflunisal
N. Papathiodossiou, M.D.
Curr. Med. Res. Opin., (1979) 6, 154.
Received: 2nd April 1979
Hbpital Pourtalas, Neuchitel, Switzerland
Summary A n open study was carried out in 196 consecutive patients who had undergone orthopaedic (103) or gjnaecological (93) surgical procedures to assess the effectiveness and tolerability o f a single dose of 500 mg dijlunisal in the relief of postoperative pain. Dijlunisal was given when patients first complained oj’ pain, and pain severity before and at intervals up to 6 hours after the dose was assessed using a 10-point analogue scale. The results showed that dijlunisal was both prompt and prolonged in its effect. No pain was reported after I hour in 138 (71 %) of the 196 patients, and after 6 hours only 13 ( 7 % ) still reported some pain. DiJIunisal was equally as effective in the two groups. Side-effects were reported in 13 ( 7 % ) patients but these were ones conzmonlyfound in the post-operative situation. Key words: Dijlunisal- analgesics, anti-inflammatory -pain, post-operative
Introduction The well-known dangers of the parenterally administered potent analgesics make them unsuitable for the routine treatment of pain after surgical procedures6 and, although aspirin and other such oral analgesis have been widely used, their usefulness has been somewhat limited by anticoagulant activity and their tendency to produce gastro-intestinal and other disturbing side-effects. The search has continued, therefore, to find an ideal analgesic for use in post-operative pain which is effective, safe and acceptable to the patient. Diflunisalt is a recently developed salicylic acid derivative which has been shown to have marked analgesic and anti-inflammatory activity.’ It differs from acetylsalicylic acid through the introduction of the difluorophenyl moiety and the elimination of the clinically and biologically labile 0-acetyl group (Figure 1). This structural difference confers several advantages on diflunisal. Unlike aspirin, it has no effect on platelet count, bleeding time or ADP- or collagen-induced platelet aggregation.12.14 This means no problems with post-operative bleeding induced by such mechanisms. In addition, diflunisal possesses considerably greater potency and longer duration of action than aspirin13 - a finding of real importance for a
t ‘Dolobid’, ‘Unisal’, trade marks, MSD 154
N. Papathdodossiou
Figure 1. Structural formula of diflunisal compared with that of aspirin Acetylsalicylic acid
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
COOH
prospective analgesic for post-operative pain. Furthermore, there is no evidence of dependency or addition problems. Diflunisal has been extensively studied in a variety of painful conditions.’-3. 5.9~10.15.16In view of these favourable reports it was decided to assess thesuitability of diflunisal for the management of post-operative pain in a number of our patients.
Patients and methods A total of 196 consecutive patients undergoing surgery at the Hdpital Pourtalts et Maternit6 in Neuchatel were studied. The first group of 103 patients (66 males and 37 females, mean age 39.9k13.3 years) consisted of those undergoing orthopaedic and trauma procedures such as osteotomies, arthrotomy of the knee, rectification of hallux valgus, amputations, arthroscopy, osteosynthesis, ablation of material, and meniscectomy. The second group comprised 93 women (mean age 36.8 f12.9 years) undergoing gynaecological operations such as curettage and biopsy of the breast or uterus. On complaining of post-operative pain, each patient was rated on a 10-point analogue scale (O=none to IO=unbearable). Two 250 mg diflunisal tablets were then prescribed and the pain severity ratings measured at 15 minutes, 30 minutes, 1, 2, 4, and 6 hours after this initial therapy. All observations were carried out by who also asked for and recorded any side-effects the same investigator (N.P.), possibly related to the medication.
Results Table I gives details of the duration of operations and the time after surgery when the patient first complained of pain and received analgesic therapy. Mean pain severity scores at baseline and at intervals up to 6 hours after the administration of diflunisal are given in Table 11, and Figures 2 and 3 show the percentage of patients with the different pain scores during the observation period. 155
Post-operative analgesia with diflunisal
Table I. patients
Duration of operations and time of first complaint of post-operative pain: number of
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
Time
Orthopaedic group (n= 103)
Gynaecological group (n =93)
Total (n=196)
62
Duration of operation (rnin) 5 to I5 16 to 30 31 to45 46 to 60 61 to 75 16 to 90 91 or over
I
55
37 25 I 15 5 7
20
51
15
40 8 16 6 7
Mean time
46.1
20.1
I 1 1
33.7
Time ofjirst complaint ofpost-operative pain (min) 120to 180 181 to210 21 1 to 240 241 to 270 271 to 300 301 to 330
9 21 56 9
Mean time
228.2
9 22 52 10
18
49 108 2
2
225.1
226.1
Table 11. Mean pain severity scores before and after a single 500 mg dose of diflunisal Assessment
Orthopaedic group
Gynaecological group
Baseline 15 min 30 min 1 hour 2 hours 4 hours 6 hours
2.9 2.3 1.4 0.8 0.4 0.3 0.2
2.3 1.6 0.8
0.4 0.2 0.1 0.1
No pain was reported after 1 hour in 138 (71 %) of the 196 patients, and after 6 hours only 13 (7%) patients still reported some pain. The results were equally as satisfactory in both groups of patients. Table I11 gives the time of last reported pain. Diflunisal was extremely well tolerated, and adverse reactions possibly related to drug therapy were noted only in 13(7 %)patients. Furthermore, all of the experiences reported - vomiting (l), nausea (4),dizziness (2), and sweating (6) - are commonly found in the post-operative situation. 156
N. Papathbdossiou
Figure 2. Percentage of patients with the different pain scores before and after treatment with a single 500 mg dose of diflunisal:103 orthopaedic patients Hmeline
A.jio. 15 miti Y
A.frc.i.30 t t i i i i t
Afie, I
lioiii.
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
lo04
-
. O o\
--
7-
20-
r
L
40 20
L 1 2 3 4 5 6
0
0
2 3 4 5 6
0 1 2 3 4 5 6
Pain severity score
Discussion Pharmacokinetic and metabolic studies' 3 have shown that diflunisal is well absorbed from the gastro-intestinal tract with peak plasma levels being reached within 2 to 3 hours. The initial plasma half-life observed following single oral doses of 125,250 and 500 mg ditlunisal is dose dependent, ranging from approximately 7.5 hours for the 125 mg dose to 11 hours for the 500 mg dose. The terminal slope (determined after plasma drug levels reached approximately 15 pg/ml) indicates a half-life of 7.5 to 8 hours in normal subjects. The theoretical clinical advantages of such properties are confirmed in the present study. Onset of analgesic action compared favourably with many other nonsteroidal, non-addictive analgesic agents, whereas duration of action was prolonged. Many non-steroidal anti-inflammatory/analgesicagents affect platelet function and blood coagulation via their inhibitory actions on the prostaglandin synthetase enzyme system,s particularly on the formation of thromboxane A2.' Exposure to aspirin impairs the ability of platelets to respond to aggregation stimuli for the life of the platelet, while indomethacin exerts a reversible inhibition of platelet aggrega157
Post-operative analgesia with diflunisal
Figure 3. Percentage of patients with the different pain scores before and after treatment with a single 500 mg dose of diflunisal: 93 gynaecological patients Illt.Cl//t.
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
I00
-, C
.Is.
._
, l,wt
1
1.i
00
i):tii\
A//t,t 30
//,I//\
A/LY
I
ll~llt,~
1
_I
a
C
Pain severity scorc
Table III. Time of last reported pain after a single 500 mg dose of diflunisal: number of patients Time
0rth opaedic group
Gynaecological group
Total
Baseline 15 min 30 min 1 hour 2 hours 4 hours 6 hours
3 28 32 19
15 66 57 25 16 4 13
Total
7
12 38 25 6 9
4 10
3
103
93
1%
tion. The effect of indomethacin disappears within 12 to 24 hours following termination of indomethacin treatment.’ 1 In contrast diflunisal, in single doses as high as 500 mg and in chronic dosage regimens up to and including 500 mg twice daily, causes no alteration in adenosine diphosphate (ADP)-induced platelet aggregation, platelet disaggregation or prothrombin and bleeding times.’ 2.14 Utilivng the standard 51 Cr-tagged red blood cell technique, a double-blind, crossover study4 158
Curr Med Res Opin Downloaded from informahealthcare.com by University of British Columbia on 12/11/14 For personal use only.
N. Papatheodossiou
was carried out to measure gastro-intestinal blood loss after 500 mg diflunisal per day compared with that after an equianalgesic dose of aspirin (2.4 g per day). The results showed that, at this dosage regimen, diflunisal does not cause a statistically significant alteration in the rate of gastro-intestinal blood loss, but the equianalgesic dose of aspirin results in a significant increase(p
