J Int Med Res (1979) 7, 240
Analgesic Combinations with Orphenadrine in Oral Post-Surgical Pain Leo Winter, Jr, DDS, FRSM and Arthur Post, DDS, 405 Park Avenue, New York, New York 10022, USA
Two hundred male and female patients underwent a variety of oral surgical procedures and were treated cifterwards in four test groups. They took a combination of orphenadrine (25 mg) and acetaminophen (325 mg), either drug alone, or placebo. A double-blind study design was used. All patients had moderately severe baseline pain intensity; post-treatment pain relief was recorded at 30 minutes, one, two, four and six hours. A back-up analgesic (codeine-ASA) was made available ifneeded. Pain intensity difference (PID) and sums of pain intensity difference (SPID) were calculated using established analgesic study techniques. Statistical analyses indicated better analgesic efficacy in both PID and SPID scoresfor the orphenadrine-acetaminophen combination over the three other treatments. This was evident at 30 minutes and continued through the sixth hour. Each active drug, in turn, was also significantly better throughout than placebo for pain relief Sub-groups in each treatment regimen required additional pain reliefprior to six hours, with significantly more placebo than orphenadrine-acetaminophen patients needing remedication. Side-effect incidence was very low and randomly distributed among thefour groups.
Introduction It is generally agreed that drug hazards roughly approximate analgesic efficacy, and that treating severe rather than mild pain therefore entails greater risk. As new potent analgesics are exceedingly rare, combinations of existing drugs is perceived as a logical way to attain greater clinical efficacy without concomitant increases in risk factors. Beaver (1975) has reviewed extensively this burgeoning field, pointing out both the advantages and disadvantages. The principal drawback is that most 0300-0605(79(030240-07 $02·00
combinations offer no demonstrable advantage, either in safety or efficacy, over the single drug used alone. Indeed, there is even greater need for pharmacological understanding in formulating such combination products because our knowledge of drug interaction is still far from complete. Where adequate pharmacodynamic knowledge exists, however, pairing of drugs with different sites of action may provide some clinical advantage. The goal, as Grotto, Dikstein & Sulman 1965 note is not merely an additive but rather an augmentative synergism between analgesic drugs.
© Cambridge Medical Publications Limited
L Winter and A Post
In this context, a combination of orphenadrine" and acetaminophen't" has much to commend itt. Orphenadrine is an effective muscle relaxant (Gold 1978a, Kaufman 1977, Gold 1978b) with a supraspinal locus of action (Ginzel 1966); it also possesses clinically useful analgesic properties alone (Gold 1978b, Fry 1977, Batterman 1965) and in combination with other compounds (Birkeland & Clawson 1968, Trevo, Petaja & Lepisto 1976). Moreover, it is safe; extremely high doses have been taken (e.g, 70 mg/kg) without causing death or permanent injury (Bennett & Kohn 1976). Acetaminophen, too, is an ideal component of combination formulations. Its site of analgesic action, thought to be peripheral, is not clearly established (KochWeser 1976), but its antipyretic effect is due to a direct action on hypothalamic heat-regulating centres. On a milligram-to-milligram basis, numerous controlled clinical trials have shown equipotency with aspirin (Beaver 1965), without the latter's tendency to gastric irritation (Davison et a11966, DiPalma 1976) or alterations of haemostatic mechanisms (Koch-Weser 1976, Mielke et at 1976). The drug has no irritant effect on topical application to the buccal mucosa (Beaver 1965). A recent study by Winter/Holder l of the same orphenadrine-acetaminophen combination used in this study reveals safety and bioavailability with multiple doses. Clinical evaluation by Mok § demonstrates its efficacy in patients with severe post-operative pain. In view of the comment by Koch-Weser (1976) that no amount of acetaminophen will control severe pain of any origin, the statistical findings of the Mok study are doubly interesting. They, along with our own data described below, suggest enhanced analgesia when these two drugs are taken together.
"Citrate salt of -dimethylaminoethyl-2-methylbenzhydryl ether **N-acetyl-para-aminophenol f Supplied by Riker Laboratories Inc., Northridge, CA9l324, USA tSubmitted for publication §Personal communication
241 Materials and Methods Study design was double-blind non-crossover. Entering patients with moderately severe pain following oral surgery were randomly assigned to one of four possible treatment regimens. By this means, the combination product was compared to each component drug and to placebo. Two hundred male and female patients aged 18 to 65 years completed this study after having one of the following surgical procedures under general, local or combination anaesthesia: I. Multiple extractions 2. Single boney impaction 3. Multiple boney impactions 4. Singletissue impaction 5. Multiple tissue impactions 6. Alveolectomy Patients who met the entrance criteria of no known hypersensitivity to any of the test drugs or a state of pregnancy, were fully informed as to the nature and scope of the study. Informed consent was obtained. Coded drug packets were given, along with a reporting card. Patients recorded pain intensity following test medication at 30 minutes, one, two, four and six hours. If this treatment was insufficient to control pain, a back-up analgesic (codeine-ASA) was made available for use; time of use of the latter was also noted. Adverse reactions to test drugs were also indicated on the reporting forms. Prior to taking these drugs, no other analgesics were to have been used for at least three hours. Test medications consisted of single doses of the following:
Orphenadrine/acetaminophen 25 mg/325 mg Orphenadrine-25 mg Acetaminophen-325 mg Placebo Pain intensity was scored by assigning numerical values as follows: moderately severe = 4, moderate = 3, mild = 2, and none = I At each of the five post-medication observations, patients recorded their pain intensity score. From these data, pain intensity difference (PID) was calculated by subtracting present pain from baseline pain. Mean group scores were calculated as sums of pain intensity difference (SPID) after the method of Laska et al (1967).
242
The Journal ofInternational Medical Research
Table 1 Patient allocations for treatment groups for each dental procedure
Treatment groups Procedure
Orphenadrine/ acetaminophen
Orphenadrine
Acetaminophen
Placebo
Single tissue impaction Multiple extractions Single boney impaction Multiple boney impactions Multiple tissue impactions Alveolectomy Combinations
10 (20)* 1 (02) 12 (24) 10 (20) 3 (06) 10 (20) 4 (08)
4 (08) 1 (02) 21 (42) 3 (06) 6 (12) 9 (18) 6 (12)
6 (12) 1 (02) 21 (43) 10 (20) 2 (04) 6 (12) 3 (06)
8 (16) 3 (06) 13 (25) 5 (10) 6 (12) 12 (23) 4 (08)
"Per cent
Table 2 Type of anaesthesia used in each treatment group
Treatment groups
Anaesthesia
Orphenadrine/ acetaminophen
Orphenadrine
Acetaminophen
Placebo
General Local Combination
19 (38)· 24 (48) 7 (14)
16 (32) 27 (54) 7 (14)
\8 (37) 22 (45) 9 (18)
\5 (29) 28 (55) 8 (16)
"Per cent
Table 3 Pain intensity difference (PID) scores"
Treatment groups Time (hr)
Orphenadrine/ acetaminophen
Orphenadrine
Acetaminophen
Placebo
0·5 1·0 2·0 4:0 6·0
2·12 2·54 2·46 2·38 2·34
1·58 1·80 1·82 1·72 1·72
\·59 \·69 1·63 1·57 1·55
1· 10 1·14 )·08 0·9\ 0·92
"Baseline pain 'minus pain intensity at each observation
L Winter and A Post
243
Data in each treatment regimen were In order to secure a uniform baseline for subsequently evaluated for statistically statistical evaluation of the pain intensity significant differences using analysis of difference (PIO) scores, all patients had variance and the Newman-Keuls multiple moderately severe initial pain. The pattern of comparison test. The 95% level of confidence response to treatment was established as early was accepted throughout as indicative of as the 30 minute observation (Table 3). At this clinically meaningful pain relief. point the combination drugs provided greater pain relief at a statistically significant level Results (p < 0·01) over orphenadrine, acetaminophen Two hundred and thirty-one patients were and placebo. Further, both active drugs taken entered into this study with an overall attrition alone were better than placebo (p < 0·05). of 13·5%, thus ending with 200 completed and This pattern of response was maintained acceptable patients. These 200 patients were throughout the full six-hour observation then randomly assigned to one of the four period, the only change being in statistical treatment groups. In terms of surgical validation of the single drugs over placebo procedures performed there was some from 95% to 99% confidence level by one unevenness of randomization only in those hour. Respective time-effect curves for each undergoing treatment for single boney treatment group are shown in Figure 1. impactions (Table 1); otherwise, distribution Analysis of the sums of pain intensity was adequate. The same might be said for differences (SPIO) revealed that composite distribution according to the type of group scores corroborate PIO data and attest anaesthesia used (Table 2), another factor to the sensitivity of the analgesic model used attesting to the adequacy of randomization (Table 4). SPIO score for the combination followed. product was better than each of the other three
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Analgesic Combinations with Orphenadrine in Oral Post-Surgical Pain Leo Winter, Jr, DDS, FRSM and Arthur Post, DDS, 405 Park Avenue, New York, New York 10022, USA
Two hundred male and female patients underwent a variety of oral surgical procedures and were treated cifterwards in four test groups. They took a combination of orphenadrine (25 mg) and acetaminophen (325 mg), either drug alone, or placebo. A double-blind study design was used. All patients had moderately severe baseline pain intensity; post-treatment pain relief was recorded at 30 minutes, one, two, four and six hours. A back-up analgesic (codeine-ASA) was made available ifneeded. Pain intensity difference (PID) and sums of pain intensity difference (SPID) were calculated using established analgesic study techniques. Statistical analyses indicated better analgesic efficacy in both PID and SPID scoresfor the orphenadrine-acetaminophen combination over the three other treatments. This was evident at 30 minutes and continued through the sixth hour. Each active drug, in turn, was also significantly better throughout than placebo for pain relief Sub-groups in each treatment regimen required additional pain reliefprior to six hours, with significantly more placebo than orphenadrine-acetaminophen patients needing remedication. Side-effect incidence was very low and randomly distributed among thefour groups.
Introduction It is generally agreed that drug hazards roughly approximate analgesic efficacy, and that treating severe rather than mild pain therefore entails greater risk. As new potent analgesics are exceedingly rare, combinations of existing drugs is perceived as a logical way to attain greater clinical efficacy without concomitant increases in risk factors. Beaver (1975) has reviewed extensively this burgeoning field, pointing out both the advantages and disadvantages. The principal drawback is that most 0300-0605(79(030240-07 $02·00
combinations offer no demonstrable advantage, either in safety or efficacy, over the single drug used alone. Indeed, there is even greater need for pharmacological understanding in formulating such combination products because our knowledge of drug interaction is still far from complete. Where adequate pharmacodynamic knowledge exists, however, pairing of drugs with different sites of action may provide some clinical advantage. The goal, as Grotto, Dikstein & Sulman 1965 note is not merely an additive but rather an augmentative synergism between analgesic drugs.
© Cambridge Medical Publications Limited
L Winter and A Post
In this context, a combination of orphenadrine" and acetaminophen't" has much to commend itt. Orphenadrine is an effective muscle relaxant (Gold 1978a, Kaufman 1977, Gold 1978b) with a supraspinal locus of action (Ginzel 1966); it also possesses clinically useful analgesic properties alone (Gold 1978b, Fry 1977, Batterman 1965) and in combination with other compounds (Birkeland & Clawson 1968, Trevo, Petaja & Lepisto 1976). Moreover, it is safe; extremely high doses have been taken (e.g, 70 mg/kg) without causing death or permanent injury (Bennett & Kohn 1976). Acetaminophen, too, is an ideal component of combination formulations. Its site of analgesic action, thought to be peripheral, is not clearly established (KochWeser 1976), but its antipyretic effect is due to a direct action on hypothalamic heat-regulating centres. On a milligram-to-milligram basis, numerous controlled clinical trials have shown equipotency with aspirin (Beaver 1965), without the latter's tendency to gastric irritation (Davison et a11966, DiPalma 1976) or alterations of haemostatic mechanisms (Koch-Weser 1976, Mielke et at 1976). The drug has no irritant effect on topical application to the buccal mucosa (Beaver 1965). A recent study by Winter/Holder l of the same orphenadrine-acetaminophen combination used in this study reveals safety and bioavailability with multiple doses. Clinical evaluation by Mok § demonstrates its efficacy in patients with severe post-operative pain. In view of the comment by Koch-Weser (1976) that no amount of acetaminophen will control severe pain of any origin, the statistical findings of the Mok study are doubly interesting. They, along with our own data described below, suggest enhanced analgesia when these two drugs are taken together.
"Citrate salt of -dimethylaminoethyl-2-methylbenzhydryl ether **N-acetyl-para-aminophenol f Supplied by Riker Laboratories Inc., Northridge, CA9l324, USA tSubmitted for publication §Personal communication
241 Materials and Methods Study design was double-blind non-crossover. Entering patients with moderately severe pain following oral surgery were randomly assigned to one of four possible treatment regimens. By this means, the combination product was compared to each component drug and to placebo. Two hundred male and female patients aged 18 to 65 years completed this study after having one of the following surgical procedures under general, local or combination anaesthesia: I. Multiple extractions 2. Single boney impaction 3. Multiple boney impactions 4. Singletissue impaction 5. Multiple tissue impactions 6. Alveolectomy Patients who met the entrance criteria of no known hypersensitivity to any of the test drugs or a state of pregnancy, were fully informed as to the nature and scope of the study. Informed consent was obtained. Coded drug packets were given, along with a reporting card. Patients recorded pain intensity following test medication at 30 minutes, one, two, four and six hours. If this treatment was insufficient to control pain, a back-up analgesic (codeine-ASA) was made available for use; time of use of the latter was also noted. Adverse reactions to test drugs were also indicated on the reporting forms. Prior to taking these drugs, no other analgesics were to have been used for at least three hours. Test medications consisted of single doses of the following:
Orphenadrine/acetaminophen 25 mg/325 mg Orphenadrine-25 mg Acetaminophen-325 mg Placebo Pain intensity was scored by assigning numerical values as follows: moderately severe = 4, moderate = 3, mild = 2, and none = I At each of the five post-medication observations, patients recorded their pain intensity score. From these data, pain intensity difference (PID) was calculated by subtracting present pain from baseline pain. Mean group scores were calculated as sums of pain intensity difference (SPID) after the method of Laska et al (1967).
242
The Journal ofInternational Medical Research
Table 1 Patient allocations for treatment groups for each dental procedure
Treatment groups Procedure
Orphenadrine/ acetaminophen
Orphenadrine
Acetaminophen
Placebo
Single tissue impaction Multiple extractions Single boney impaction Multiple boney impactions Multiple tissue impactions Alveolectomy Combinations
10 (20)* 1 (02) 12 (24) 10 (20) 3 (06) 10 (20) 4 (08)
4 (08) 1 (02) 21 (42) 3 (06) 6 (12) 9 (18) 6 (12)
6 (12) 1 (02) 21 (43) 10 (20) 2 (04) 6 (12) 3 (06)
8 (16) 3 (06) 13 (25) 5 (10) 6 (12) 12 (23) 4 (08)
"Per cent
Table 2 Type of anaesthesia used in each treatment group
Treatment groups
Anaesthesia
Orphenadrine/ acetaminophen
Orphenadrine
Acetaminophen
Placebo
General Local Combination
19 (38)· 24 (48) 7 (14)
16 (32) 27 (54) 7 (14)
\8 (37) 22 (45) 9 (18)
\5 (29) 28 (55) 8 (16)
"Per cent
Table 3 Pain intensity difference (PID) scores"
Treatment groups Time (hr)
Orphenadrine/ acetaminophen
Orphenadrine
Acetaminophen
Placebo
0·5 1·0 2·0 4:0 6·0
2·12 2·54 2·46 2·38 2·34
1·58 1·80 1·82 1·72 1·72
\·59 \·69 1·63 1·57 1·55
1· 10 1·14 )·08 0·9\ 0·92
"Baseline pain 'minus pain intensity at each observation
L Winter and A Post
243
Data in each treatment regimen were In order to secure a uniform baseline for subsequently evaluated for statistically statistical evaluation of the pain intensity significant differences using analysis of difference (PIO) scores, all patients had variance and the Newman-Keuls multiple moderately severe initial pain. The pattern of comparison test. The 95% level of confidence response to treatment was established as early was accepted throughout as indicative of as the 30 minute observation (Table 3). At this clinically meaningful pain relief. point the combination drugs provided greater pain relief at a statistically significant level Results (p < 0·01) over orphenadrine, acetaminophen Two hundred and thirty-one patients were and placebo. Further, both active drugs taken entered into this study with an overall attrition alone were better than placebo (p < 0·05). of 13·5%, thus ending with 200 completed and This pattern of response was maintained acceptable patients. These 200 patients were throughout the full six-hour observation then randomly assigned to one of the four period, the only change being in statistical treatment groups. In terms of surgical validation of the single drugs over placebo procedures performed there was some from 95% to 99% confidence level by one unevenness of randomization only in those hour. Respective time-effect curves for each undergoing treatment for single boney treatment group are shown in Figure 1. impactions (Table 1); otherwise, distribution Analysis of the sums of pain intensity was adequate. The same might be said for differences (SPIO) revealed that composite distribution according to the type of group scores corroborate PIO data and attest anaesthesia used (Table 2), another factor to the sensitivity of the analgesic model used attesting to the adequacy of randomization (Table 4). SPIO score for the combination followed. product was better than each of the other three
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