Anaesthesia, 1992, Volume 47, pages 1075-1077
Diclofenac for analgesia after Caesarean section
D. J. Bush, F R C A n a e s , Registrar, G. Lyons, F F A R C S , R. Macdonald, PhD, FFARCS, Consultants, Anaesthetic Department, S t James’s University Hospital, Beckett Street, Leeds LS9 7TF.
Summary
The analgesic eficacy of a single intramuscular dose of 75 mg diclofenac given after elective Caesarean section was studied in 50 women in a double-blind randomised manner using a patient-controlled analgesia system. The mean 18 h papavaretum consumption of the placebo group was significantly greater (91.4 mg compared to 61.4 m g ) . Subjective experience of pain and observed sedation were significantly greater in the control group up to 6 h after operation. Key words
Pain; postoperative, patient controlled analgesia. Analgesics; diclofenac.
Caesarean section is commonly associated with postoperative pain, but may be performed using regional anaesthestic techniques which can be modified to provide analgesia in the postoperative period with advantage [I]. Analgesia after general anaesthesia is usually provided by a parenteral opioid which may produce side effects such as nausea, sedation and respiratory depression. Patients are mobilised early after obstetric surgery [2] and might benefit from the addition of supplementary analgesia, which would reduce their opioid requirements and any drug-related side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, have been shown to reduce opioid requirements after orthopaedic [3], abdominal [4] and gynaecological [5] surgery and a lower incidence of respiratory depression and a reduction in pain scores have been claimed, with few adverse effects [4]. The analgesic effects of NSAIDs have not been investigated in patients after Caesarean section. The aim of the study was to assess the value of a single dose of diclofenac given intramuscularly after elective Caesarean section performed under general anaesthesia. Methods
Fifty patients of ASA grade 1 or 2 scheduled for elective Caesarean section under general anaesthesia gave verbal informed consent to this double-blind, randomised, controlled trial. Patients were not studied if they were known to have pre-eclampsia or contraindications to opioids or NSAIDs. Hospital ethics committee approval was obtained. Patients were visited before surgery and instructed in the use of the patient-controlled analgesia system. Premedication of ranitidine 150 mg orally the evening before and on the morning of surgery and 30 ml of 0.3 M sodium citrate were given by mouth immediately before anaesthesia. General anaesthesia was induced with a sleep dose of thiopentone and tracheal intubation was facilitated by suxamethonium 1 mg.kg- ’. Anaesthesia was maintained with isoflurane in nitrous oxide and oxygen. Footnore:
Preparations of papavaretum containing noscopine may n o longer be given to women of childbearing age (Ed).
Accepted 19 September 1991
The Ao, was 0.5 before delivery and 0.3 after. Atracurium 0.4 mg.kg-’ was used to maintain muscle relaxation. After delivery, syntocinon and papavaretum 0.3 mg.kg-’ were given, and atropine 1.2 mg and neostigmine 2.5 mg antagonised neuromuscular blockade after surgery. Patients were allocated at random to two groups who received either 75mg diclofenac (group A), or an equal volume of normal saline (group B), intramuscularly before discontinuing anaesthesia. The solutions were drawn up by an independent operator not involved in the study. Analgesia was provided by a patient-controlled analgesia system (PCAS) (Graseby Medical) set to deliver 3-5 mg boli of papavaretum, according to the patient’s weight, with a lockout time of IOmin, and no background infusion. The system was connected to the patient’s intravenous infusion by a unidirectional valve, and details of the requests for analgesia were recorded in real time by a dedicated thermal printer (Hewlett Packard 82162-A). Intramuscular antiemetic and additional opioid analgesia were available on demand. Each patient was visited at 6, 12 and 24 h after surgery when the correct use of the PCAS was confirmed and assessments of pain, nausea and sedation were recorded. The patients were asked to complete a 10 cm linear analogue scale (LAS) for pain [6]. Four-point verbal rating scores (VRS) were used to rate nausea (none, nausea, vomiting or repeated vomiting) and sedation (awake, drowsy, rousable or deep sleep). The study was terminated at 24 h or earlier if the patient was mobilised or the intravenous infusion was stopped. A four-point verbal rating scale was used a t the end of the study period to rate the overall severity of pain experienced (none, mild, moderate or severe). Specific enquiry about injection site discomfort was made. Results were analysed using the Northwick Park statistics package. Demographic data were compared using Student’s unpaired t-test; the Wilcoxon rank sum test was used for the LAS data and the Chi-squared test for the sedation and nausea VRS data. A p value of < 0.05 was considered to be significant. Results
Twenty-three patients received diclofenac (group A) and 25 normal saline (group B). Two patients were lost to the study because of missing data from the PCAS printer.
1076
Forum Table 1. Patient data (mean, SD).
Age; years Weight; kg Height; cm
Group A
Group B
26.8 (4.3) 72.0 (12.1) 157.3 (9.0)
28.3 (5.4) 67.2 (9. I ) 158.7 (6.9)
g
50-
f
40-
5
30-
C
I
5
Most patients were mobilised or had stopped intravenous therapy well before 24 h. Demographic data did not differ between groups (Table 1). No patients required additional rescue analgesia and there were no adverse effects to diclofenac. Cumulative papavaretum consumption was significantly greater at 18 h in group B (p < 0.05), mean (SD) 91.4 (23.4) mg, than in group A, mean (SD) 61.4 (30.2) mg (Fig. I). Analysis of papavaretum consumption in 6 hourly epochs revealed a significantly greater consumption in group B compared to group A in the 0-6 h epoch (p < 0.01) and in the 6-12 h epoch (p < 0.05). There was no difference in papavaretum consumption between the groups in the 12-18 h epoch (Fig. 2). Linear analogue scores for pain were significantly lower in the diclofenac group at 6 h, (p < 0.05); the median (interquartile range) score for group A was 0.5 (0.2-2.0)mm and for group B 2.0 (0.1-3.5)mm. There was no difference in the linear analogue scores for pain at 12 h; the median (interquartile range) for group A was 1.2 (0.2-3.6) mm and for group B I .5 (1 .I-3.4) mm. VRS for sedation were significantly lower in the group who received diclofenac at 6 h (p < 0.05) (Table 2). There were no differences between sedation scores by 12 h or between nausea scores at any time between the groups. Two patients in each group commented on mild discomfort at the site of injection, but there was no significant difference between the VRS for the overall severity of pain experienced during the study period. In the diclofenac group, 15 patients rated their pain as mild, and eight as moderate over the study period. Fourteen of the saline group rated their overall pain as mild and 1 1 as moderate. Discussion
This study demonstrates that the addition of a single dose of intramuscular diclofenac 75 mg given immediately after Caesarean section reduces papavaretum consumption by one third during the first 18 h, and in the first 6 h equal or superior analgesia was achieved with less sedation when diclofenac was given. These results agree with previous work which demonstrated that diclofenac reduces opioid requirements after hysterectomy and abdominal surgery [4, 51, procedures which represent a similar surgical insult to Caesarean section. However, diclofenac was less effective after cholecystectomy, where an upper abdominal
20: -
100
12- 18
6-12
0-6
Postoperative period ( h )
Fig. 2. Mean 6 hourly papaveretum consumption in the diclofenac ( 0 )and the placebo (H)groups. Bars represent SD *p < 0.05.
incision may represent a greater insult [7]. Plasma clearance of diclofenac takes about 4 to 5 h after intramuscular injection in healthy volunteers [8] and in our study most of the opioid-sparing effect occurred within the first few hours after the drug was given. This may explain why the reduction in pain and sedation scores were limited to the first 6 h and disappeared after this. We did not administer a further dose of diclofenac, which would have been necessary to continue the analgesia into the second half of our study, because we wished to minimise the number of intramuscular injections given to our patients and the absorbtion of the oral preparation of the drug could not be predicted so soon after abdominal surgery. There was no reduction in nausea in those of our patients who received diclofenac despite a reduced opioid consumption. This is not unexpected; many other factors have been shown to influence the incidence of postoperative nausea and vomiting in addition to peri-operative opioid [9]. The linear analogue pain scores were low in our study compared to the findings of others who investigated pain relief after Caesarean section [lo]. The explanation for this difference is unknown, but all our patients rated their pain, over the whole study period, as mild or moderate and mobilised rapidly. This observation confirms the effectiveness of PCA after Caesarean section, as previously demonstrated [I I]. It also suggests that opioid consumption during the study period provided an objective measure of the pain experienced. For this reason the reduced opioid consumption by the patients given diclofenac in our study indicates that this
Table 2. Assessment of severity of sedation and nausea (number of patients per category) *p < 0.05. Sedation 6h
12h
___
Group A* Group B* Group A Group B Awake Drowsy Rousable Asleep
17 4 2
14 4 2
10
11 3 I
0
12 8 2 3
3
Nausea
12h
6h Group A I
I
I
1
6
8
10
12
I 14
I
I
16
18
Time ofter injection ( h )
Fig. 1. Mean cumulative papavereturn consumption (mg) in the
placebo
( 0 ) and
the diclofenac (H)groups. Bars represent SD.
None Nausea Vomiting Repeated vomiting
12 6 5 0
Group B 14 9 I 1
Group A Group B 17
2 3 1
16 6 0 2
Forum drug has a worthwhile analgesic effect when given after Caesarean section. It has been suggested that giving NSAIDs before surgery begins may minimise the initiation of pain in the peripheral tissues and enhance their effectiveness as analgesics [ 121. We did not give diclofenac until after delivery because NSAIDs are known to induce premature closure of the ductus arteriosus when given in large doses to the mother before delivery. The breast milk of women treated with diclofenac contains extremely small amounts of the drug [13], a quantity not felt likely to represent a hazard to the infants of breast feeding mothers (personal communication, Geigy Pharmaceuticals). We did not attempt to measure diclofenac in breast milk, but there were no problems attributed to it in our mother's infants. We conclude that a single dose of 75 mg diclofenac given intramuscularly has a useful role in the provision of pain relief after Caesarean section performed under general anaesthesia. References [I] CARRIELES. Extradural, spinal or combined block for obstetric surgical anaesthesia. British Journal of Anaesthesia 1990; 65: 225-33. [2] WEBSTER NR, LYONSG, MACDONALLI R. Sleep and comfort after Caesarean section. Anaesthesia 1986; 41: 1143-5. [3] BUCHANANJM, HALSHAWJ, BALDESERAJ. POLLARDJK, POOLEP. Postoperative pain relief; a new approach: narcotics compared with non-steroidal anti-inflammatory drugs. Annal.7 of the Royal College of Surgeons of England 1988; 7 0 332-5.
1077
NBA, BURNSJ, BLYTHA, KENNY GNC, MCARDLE [4] HODSMAN H. The morphine sparing effects of diclofenac CS, ROTMAN sodium following abdominal surgery. Anaesthesia 1987; 4 2 1005-8. [5] CARLBORG L, LINWFFC, HELLMAN A. Diclofenac versus pethidine in the treatment of pain after hysterectomy. European Journal of Anaesthesiology 1987; 4: 241-7. M, HOGG MIJ. The [6] REVILLSI, ROBINSONJO, R ~ E N reliability of a linear analogue for evaluating pain. Anaesthesia 1976; 31: 1191-8. AD, FELL D. Failure of rectal diclofenac to [7] COLQUHOUN augment opioid analgesia after cholecystectomy. Anaesthesia 1989; 44: 57-60. [8] Rims W, STIERLIN H, DEGENP, FAIGLEJW, GERARDIN A, MOPPERT J, SALLMAN A, SCHMIDK, SCHWEIZER A, SULC M, THEOBALD W, WAGNER J. Pharmacokinetics and metabolism of the anti-inflammatory agent Voltaren. Scandanavian Journal of Rheumatology 1978; 7 (Suppl. 22): 17-29. [9] PALAZZOMGA, STRUNINL. Anaesthesia and emesis. I: etiology Canadian Anaesthetists' Society Journal 1984; 31: 178-87. [lo] BUNTING P, MCCONACHIE 1. Ilioinguinal nerve blockade for analgesia after Caesarean section. British Journal of Anaesthesia 1988; 61: 773-5. [ I 11 RAYBURN WF, GERANIS BJ, RAMADEl CR. WOODS RE, PATILB KD. Patient-controlled analgesia for post-Cesarean section pain. Obstetrics and Gynecology 1988; 7 2 136-9. [I21 DAHLJB, KEHLETH. Non-steroidal anti-inflammatory drugs: rationale for use in postoperative pain. British Journal of Anaesthesia 1991; 66: 703-12. M, HUSBYG . Antirheumatic drug treatment during [I31 OSTENSEN pregnancy and lactation. Scandanavian Journal of Rheumatology 1985; 1 4 1-7.
Diclofenac for analgesia after Caesarean section
D. J. Bush, F R C A n a e s , Registrar, G. Lyons, F F A R C S , R. Macdonald, PhD, FFARCS, Consultants, Anaesthetic Department, S t James’s University Hospital, Beckett Street, Leeds LS9 7TF.
Summary
The analgesic eficacy of a single intramuscular dose of 75 mg diclofenac given after elective Caesarean section was studied in 50 women in a double-blind randomised manner using a patient-controlled analgesia system. The mean 18 h papavaretum consumption of the placebo group was significantly greater (91.4 mg compared to 61.4 m g ) . Subjective experience of pain and observed sedation were significantly greater in the control group up to 6 h after operation. Key words
Pain; postoperative, patient controlled analgesia. Analgesics; diclofenac.
Caesarean section is commonly associated with postoperative pain, but may be performed using regional anaesthestic techniques which can be modified to provide analgesia in the postoperative period with advantage [I]. Analgesia after general anaesthesia is usually provided by a parenteral opioid which may produce side effects such as nausea, sedation and respiratory depression. Patients are mobilised early after obstetric surgery [2] and might benefit from the addition of supplementary analgesia, which would reduce their opioid requirements and any drug-related side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, have been shown to reduce opioid requirements after orthopaedic [3], abdominal [4] and gynaecological [5] surgery and a lower incidence of respiratory depression and a reduction in pain scores have been claimed, with few adverse effects [4]. The analgesic effects of NSAIDs have not been investigated in patients after Caesarean section. The aim of the study was to assess the value of a single dose of diclofenac given intramuscularly after elective Caesarean section performed under general anaesthesia. Methods
Fifty patients of ASA grade 1 or 2 scheduled for elective Caesarean section under general anaesthesia gave verbal informed consent to this double-blind, randomised, controlled trial. Patients were not studied if they were known to have pre-eclampsia or contraindications to opioids or NSAIDs. Hospital ethics committee approval was obtained. Patients were visited before surgery and instructed in the use of the patient-controlled analgesia system. Premedication of ranitidine 150 mg orally the evening before and on the morning of surgery and 30 ml of 0.3 M sodium citrate were given by mouth immediately before anaesthesia. General anaesthesia was induced with a sleep dose of thiopentone and tracheal intubation was facilitated by suxamethonium 1 mg.kg- ’. Anaesthesia was maintained with isoflurane in nitrous oxide and oxygen. Footnore:
Preparations of papavaretum containing noscopine may n o longer be given to women of childbearing age (Ed).
Accepted 19 September 1991
The Ao, was 0.5 before delivery and 0.3 after. Atracurium 0.4 mg.kg-’ was used to maintain muscle relaxation. After delivery, syntocinon and papavaretum 0.3 mg.kg-’ were given, and atropine 1.2 mg and neostigmine 2.5 mg antagonised neuromuscular blockade after surgery. Patients were allocated at random to two groups who received either 75mg diclofenac (group A), or an equal volume of normal saline (group B), intramuscularly before discontinuing anaesthesia. The solutions were drawn up by an independent operator not involved in the study. Analgesia was provided by a patient-controlled analgesia system (PCAS) (Graseby Medical) set to deliver 3-5 mg boli of papavaretum, according to the patient’s weight, with a lockout time of IOmin, and no background infusion. The system was connected to the patient’s intravenous infusion by a unidirectional valve, and details of the requests for analgesia were recorded in real time by a dedicated thermal printer (Hewlett Packard 82162-A). Intramuscular antiemetic and additional opioid analgesia were available on demand. Each patient was visited at 6, 12 and 24 h after surgery when the correct use of the PCAS was confirmed and assessments of pain, nausea and sedation were recorded. The patients were asked to complete a 10 cm linear analogue scale (LAS) for pain [6]. Four-point verbal rating scores (VRS) were used to rate nausea (none, nausea, vomiting or repeated vomiting) and sedation (awake, drowsy, rousable or deep sleep). The study was terminated at 24 h or earlier if the patient was mobilised or the intravenous infusion was stopped. A four-point verbal rating scale was used a t the end of the study period to rate the overall severity of pain experienced (none, mild, moderate or severe). Specific enquiry about injection site discomfort was made. Results were analysed using the Northwick Park statistics package. Demographic data were compared using Student’s unpaired t-test; the Wilcoxon rank sum test was used for the LAS data and the Chi-squared test for the sedation and nausea VRS data. A p value of < 0.05 was considered to be significant. Results
Twenty-three patients received diclofenac (group A) and 25 normal saline (group B). Two patients were lost to the study because of missing data from the PCAS printer.
1076
Forum Table 1. Patient data (mean, SD).
Age; years Weight; kg Height; cm
Group A
Group B
26.8 (4.3) 72.0 (12.1) 157.3 (9.0)
28.3 (5.4) 67.2 (9. I ) 158.7 (6.9)
g
50-
f
40-
5
30-
C
I
5
Most patients were mobilised or had stopped intravenous therapy well before 24 h. Demographic data did not differ between groups (Table 1). No patients required additional rescue analgesia and there were no adverse effects to diclofenac. Cumulative papavaretum consumption was significantly greater at 18 h in group B (p < 0.05), mean (SD) 91.4 (23.4) mg, than in group A, mean (SD) 61.4 (30.2) mg (Fig. I). Analysis of papavaretum consumption in 6 hourly epochs revealed a significantly greater consumption in group B compared to group A in the 0-6 h epoch (p < 0.01) and in the 6-12 h epoch (p < 0.05). There was no difference in papavaretum consumption between the groups in the 12-18 h epoch (Fig. 2). Linear analogue scores for pain were significantly lower in the diclofenac group at 6 h, (p < 0.05); the median (interquartile range) score for group A was 0.5 (0.2-2.0)mm and for group B 2.0 (0.1-3.5)mm. There was no difference in the linear analogue scores for pain at 12 h; the median (interquartile range) for group A was 1.2 (0.2-3.6) mm and for group B I .5 (1 .I-3.4) mm. VRS for sedation were significantly lower in the group who received diclofenac at 6 h (p < 0.05) (Table 2). There were no differences between sedation scores by 12 h or between nausea scores at any time between the groups. Two patients in each group commented on mild discomfort at the site of injection, but there was no significant difference between the VRS for the overall severity of pain experienced during the study period. In the diclofenac group, 15 patients rated their pain as mild, and eight as moderate over the study period. Fourteen of the saline group rated their overall pain as mild and 1 1 as moderate. Discussion
This study demonstrates that the addition of a single dose of intramuscular diclofenac 75 mg given immediately after Caesarean section reduces papavaretum consumption by one third during the first 18 h, and in the first 6 h equal or superior analgesia was achieved with less sedation when diclofenac was given. These results agree with previous work which demonstrated that diclofenac reduces opioid requirements after hysterectomy and abdominal surgery [4, 51, procedures which represent a similar surgical insult to Caesarean section. However, diclofenac was less effective after cholecystectomy, where an upper abdominal
20: -
100
12- 18
6-12
0-6
Postoperative period ( h )
Fig. 2. Mean 6 hourly papaveretum consumption in the diclofenac ( 0 )and the placebo (H)groups. Bars represent SD *p < 0.05.
incision may represent a greater insult [7]. Plasma clearance of diclofenac takes about 4 to 5 h after intramuscular injection in healthy volunteers [8] and in our study most of the opioid-sparing effect occurred within the first few hours after the drug was given. This may explain why the reduction in pain and sedation scores were limited to the first 6 h and disappeared after this. We did not administer a further dose of diclofenac, which would have been necessary to continue the analgesia into the second half of our study, because we wished to minimise the number of intramuscular injections given to our patients and the absorbtion of the oral preparation of the drug could not be predicted so soon after abdominal surgery. There was no reduction in nausea in those of our patients who received diclofenac despite a reduced opioid consumption. This is not unexpected; many other factors have been shown to influence the incidence of postoperative nausea and vomiting in addition to peri-operative opioid [9]. The linear analogue pain scores were low in our study compared to the findings of others who investigated pain relief after Caesarean section [lo]. The explanation for this difference is unknown, but all our patients rated their pain, over the whole study period, as mild or moderate and mobilised rapidly. This observation confirms the effectiveness of PCA after Caesarean section, as previously demonstrated [I I]. It also suggests that opioid consumption during the study period provided an objective measure of the pain experienced. For this reason the reduced opioid consumption by the patients given diclofenac in our study indicates that this
Table 2. Assessment of severity of sedation and nausea (number of patients per category) *p < 0.05. Sedation 6h
12h
___
Group A* Group B* Group A Group B Awake Drowsy Rousable Asleep
17 4 2
14 4 2
10
11 3 I
0
12 8 2 3
3
Nausea
12h
6h Group A I
I
I
1
6
8
10
12
I 14
I
I
16
18
Time ofter injection ( h )
Fig. 1. Mean cumulative papavereturn consumption (mg) in the
placebo
( 0 ) and
the diclofenac (H)groups. Bars represent SD.
None Nausea Vomiting Repeated vomiting
12 6 5 0
Group B 14 9 I 1
Group A Group B 17
2 3 1
16 6 0 2
Forum drug has a worthwhile analgesic effect when given after Caesarean section. It has been suggested that giving NSAIDs before surgery begins may minimise the initiation of pain in the peripheral tissues and enhance their effectiveness as analgesics [ 121. We did not give diclofenac until after delivery because NSAIDs are known to induce premature closure of the ductus arteriosus when given in large doses to the mother before delivery. The breast milk of women treated with diclofenac contains extremely small amounts of the drug [13], a quantity not felt likely to represent a hazard to the infants of breast feeding mothers (personal communication, Geigy Pharmaceuticals). We did not attempt to measure diclofenac in breast milk, but there were no problems attributed to it in our mother's infants. We conclude that a single dose of 75 mg diclofenac given intramuscularly has a useful role in the provision of pain relief after Caesarean section performed under general anaesthesia. References [I] CARRIELES. Extradural, spinal or combined block for obstetric surgical anaesthesia. British Journal of Anaesthesia 1990; 65: 225-33. [2] WEBSTER NR, LYONSG, MACDONALLI R. Sleep and comfort after Caesarean section. Anaesthesia 1986; 41: 1143-5. [3] BUCHANANJM, HALSHAWJ, BALDESERAJ. POLLARDJK, POOLEP. Postoperative pain relief; a new approach: narcotics compared with non-steroidal anti-inflammatory drugs. Annal.7 of the Royal College of Surgeons of England 1988; 7 0 332-5.
1077
NBA, BURNSJ, BLYTHA, KENNY GNC, MCARDLE [4] HODSMAN H. The morphine sparing effects of diclofenac CS, ROTMAN sodium following abdominal surgery. Anaesthesia 1987; 4 2 1005-8. [5] CARLBORG L, LINWFFC, HELLMAN A. Diclofenac versus pethidine in the treatment of pain after hysterectomy. European Journal of Anaesthesiology 1987; 4: 241-7. M, HOGG MIJ. The [6] REVILLSI, ROBINSONJO, R ~ E N reliability of a linear analogue for evaluating pain. Anaesthesia 1976; 31: 1191-8. AD, FELL D. Failure of rectal diclofenac to [7] COLQUHOUN augment opioid analgesia after cholecystectomy. Anaesthesia 1989; 44: 57-60. [8] Rims W, STIERLIN H, DEGENP, FAIGLEJW, GERARDIN A, MOPPERT J, SALLMAN A, SCHMIDK, SCHWEIZER A, SULC M, THEOBALD W, WAGNER J. Pharmacokinetics and metabolism of the anti-inflammatory agent Voltaren. Scandanavian Journal of Rheumatology 1978; 7 (Suppl. 22): 17-29. [9] PALAZZOMGA, STRUNINL. Anaesthesia and emesis. I: etiology Canadian Anaesthetists' Society Journal 1984; 31: 178-87. [lo] BUNTING P, MCCONACHIE 1. Ilioinguinal nerve blockade for analgesia after Caesarean section. British Journal of Anaesthesia 1988; 61: 773-5. [ I 11 RAYBURN WF, GERANIS BJ, RAMADEl CR. WOODS RE, PATILB KD. Patient-controlled analgesia for post-Cesarean section pain. Obstetrics and Gynecology 1988; 7 2 136-9. [I21 DAHLJB, KEHLETH. Non-steroidal anti-inflammatory drugs: rationale for use in postoperative pain. British Journal of Anaesthesia 1991; 66: 703-12. M, HUSBYG . Antirheumatic drug treatment during [I31 OSTENSEN pregnancy and lactation. Scandanavian Journal of Rheumatology 1985; 1 4 1-7.
