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THE INFLUENCE OF SURGICAL PROCEDURES, ANAESTHETICS AND ANALGESICS ON BODY WEIGHT AND FOOD AND WATER CONSUMPTION IN RATS AND MICE
Proceedings of the 4th International Congress of Veterinary Anaesthesia
THE INnUENCE OF SURGICAL PROCEDURES, ANAESTHETICS AND ANALGESICS ON BODY WEIGHT AND FOOD AND WATER CONSUMPTION IN RATS AND MICE.
J.H. Liles and PA. Flecknell Comparative Biology Centre, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH England Introduction The assessment of post-operative pain in animals remains highly subjective, despite attempts to introduce more objective scoring systems (Morton and Griffiths, 1985). It has been suggested that post-operative pain may result in a reduction in body weight and in food and water intake in animals (Morton and Griffiths, 1985; Leese et al., 1988,, Taylor, 1985; Wright et al.,
cycle was maintained. Animals underwent a 2 week period of acclimatisation to single housing prior to study. Effects of anaesthesia and a n a 1l e Anaesthesia was induced and maintained with halothane (3% induction, 2% maintenance) for 2Ll minutes at 09.00 h. Immediately following anaesthesia, rats received either buprenorphine 0.05 or 0.01 mg/kg sc, or bupivacaine 0.7 ml 0.125%. Groups of animals also received saline 0.3 ml rats, 0.15 ml mice.
1985; Yoxall, 1978) but there appear to be no controlled studies of the effects of surgical procedures on these variables. A series of investigations have been carried out to determine the changes which occur following surgery in rats and mice, and to assess whether these changes can be prevented or minimised by the admiiistration of analgesics. We have also investigated the effects of anaesthesia and administration of analgesics in normal animals.
Effects of surgery The surgical procedures were required to be undertaken as part of an unrelated research project. Anaesthesia was induced and maintained with halothane as described above. The first group of rats underwent craniotomy and implantation of electrodes under the skull, these rats had collars placed on them; a control group just underwent anaesthesia and placement of a collar. All rats received either buprenorphine 0.05 mg/kg SC or saline 0.3 ml SC post-operatively. The second group of rats underwent midline laparotomy followed by bile duct ligation. These rats received either saline 0 3 mls sc, Buprenorphine 0.05 mg/kg SC or a local infitration of Bupivacaine 0.7 ml of 0.125%. Mice received sternotomy followed by removal of the thymus gland, at the end of the period of anaesthesia, at approximately 3 pm, the animals received either saline 0.15 ml SC or buprenorphine 0.05 mg/kg SC this was repeated the following morning at 9 am.
Materials and Methods Body weight changes were recorded by weighing the animals between 9am and loam each day. Food and water consumption was monitored by weighing the animals' food hoppers and water bottles at the same time. Full details of the apparatus and methodology have been described previously (Flecknell and Liles, 1991).
Male Wistar outbred rats, or male Balb/c mice obtained from this Institute's S.P.F. unit were used in the study. Animals received a commercial pelleted diet (R&M Nol, S.D.S. Ltd.)and water ad libitum. Room temperature was maintained at 24l L 2" C and a 9 h : m light-dark 259
Proceedings of the 4th International Congress of Veterinary Anaesthesia
Statistical metho& Food and water consumption and body weight were compared within groups using Student’s paired t-test. The relative changes between groups were examined by calculating the ratio of the post-treatment intake to the pre-treatment intake. This ratio was compared between groups using Student’s t-test. Results Effects of anaesthesia and analoes’la Halothane anaesthesia followed by either 2 doses of saline or a single dose of buprenorphine 0.05 mg/kg SC or 0.01 mg/kg SC or bu-
pivacaine 0.7ml 0.125% produced a small fall in food and water intake in rats (Figure 1) and mice. The post-treatment food intake for the rats which received the higher dose of buprenorphine 0.05 mg/kg was significantly (Pc0.05) lower than the pre-treatment intake. Effects of sureid Drocedurek Following craniotomy, food and water intake in the buprenorphine treated rats did not differ significantly from the unoperated controls but was significantly (PcO.001) depressed in the rats which received saline (Figure 2). After laparotomy food intake was significantly (Pc0.05)lower than in unoperated controls for all three post-operative treatments (Figure 3). Water intake was significantly depressed in the saline (Pc0.05) and bupivacaine (P
In mice food and water intake was reduced following anaesthesia and the administration of buprenorphine, but was not depressed following anaesthesia and the administration of saline. However following sternotomy, saline treated mice had signiticantly (P
Proceedinas of the 4th International Conpress of Veterinalv Anaesthesia
Schmidt et al., 1985; Cowan et al., 1977, Steinfels and Cook, 1986, Hermansen et al., 1986; Wootton et al., 1988; Flecknell and Liles, 1990).
References
Cowan A., Doxey J.C. and Harry EJ.R. (1977) The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br. J. Pharm. 60, 547-554.
It is clear that buprenorphine, even at the relatively low dose rates used in the present study, has an effect at the higher dose rate (0.05 mg/kg), on food intake. The lower dose rate of buprenorphine (0.01 mg/kg) did not cause a significant reduction in food or water intake. Although the use of analgesics to alleviate postoperative pain is clearly desirable, the results of the present study indicate that opioids may have some adverse side-effects in rats. The reduction in food intake is clearly undesirable and emphasises the need to administer analgesics
Flecknell P A . and Ldes J.H. (1990) Assessment of the analgesic action of opioid agonist-antagonists in the rabbit. J. Ass. vet. Anaesth. (in press). Flecknell P A . and Ldes J.H. (1991) The effects of surgical procedures, halothane anaesthesia and nalbuphine on locomotor activity and food and water consumption in rats. Lab Anim. 25, 50-60. Hermansen K. Pedersen L.E. and Olesen H.O. (1986) The analgesic effect of buprenorphine, etorphine and pethidine in the pig: a randomised double blind cross-over study. Acta Pharmacol. et Toxicol. 59, 27-35.
only when pain is believed to be present.
All of the surgical procedures studied caused a reduction in food and water consumption and a loss of body weight, the magnitude of these changes could be reduced by treatment with buprenorphine. Bupivacaine appeared to have little effect, this may be due to an inappropriate dose being used or because this sort of analgesia is
Leese T., Husken PA. and Morton D.B. (1988) Buprenorphine analgesia in a rat model of acute pancreatitis. Surg. Res. Comm., 3, 5360, 1988.
inappropriate for the pain being experienced. Morton D.B. and Griffths P.H.M. (1985) Guidelines on the recognition of pain, distress and discomfort in experimental animals and a~ hypothesis for assessment. Vet. Rec. 116, 431-
The monitoring of food and water intake and body weight would appear to be a simple and useful means of assessing the adverse effects of surgical procedures. Further studies of the effects of a range of different surgical procedures are required, however, before any firm recommendations can be made concerning the use of these techniques for assessing pain or distress.
436.
Pircio A.W., Gylys JA, Cavanagh R.L.,Buynkki J.P. and Bierwagen M.E. (1976) The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic. Arch. Int. Pharmacodyn, 220,231-257.
Acknowledgements: This work was supported by
Schmidt W.K., Tam W.S., Shotzberger G.S., Smith D.H., Clark R. and Vernier V. (1985) Nalbuphine. Drug and Alcohol Dependence,
the Wellcome Trust.
261
Procccdinns of the 4th International Coneress of Vcterinalv Anaesthesia
14,339-362. Steinfels G. and Cook L. (1986) AntinoCiceptive profiles of Mu and Kappa opioid agonists in a rat tooth pulp simulation procedure. J. Pharm. Exp. Therapeutics. 236,111-117 Taylor P.M. (1985) Analgesia in the dog and the cat. In Practice 7,5-13. Wright E.M., Marcella KL. and Woodson J.F. (1985) Animal pain: evaluation and control. Lab Animals 14,20-30. Y o d A.T. (1W8) Pain in small animals - its recognition and control. J.SA.P. 19,423-438. Wootton R.,Cross G., Wood S. and West C.D. (1988) An analgesiometry system for use in rabbits with some preliminary data on the effects of buprenorphine and lofentanil. Lab. Anim. 22,217-222.
262
A
8 i
7
0
m
r
lr)
0
m
I
c\l c/)
I
0 0.l
0 0
T
7
0 a3
0
0
co
0
0
v
0
0 c\l
0
0 0 0
Fig 2: Relative depression i n food and uater intake i n r a t s follouing anaesthesia and analgesic administration. Values are mean
2 1SD of the r a t i o of food and
0.00
1.20'
Craniotom y Bupronorphino
S.lin0
Food intake
Craniotomy
. ,. .. , . . . . .
I Water intake
Unopotatod Bupranorphine
T
S8liDO
Unoper8ted
T
value = mean + S D
I
uater intake during the 24 hours follouing treatment t o the intake during 24 hours p r i o r t o treatment. indicates s i g n i f i c a n t difference ( ~ 0 . 0 5 ) f r a n halothane/saline control. HS3 = halothane/saline x 3; HBUT = halothane/butorphanol x 3; HS6 = halothane/saline x 6; HN6 = halothane/nalbuphine x 6.
a,
U L
0 .+
0
rC
a
0
v)
+
\
f l
L
a,
I
Q 0
.-C
+
U
Y
1.20
Saline
Laparotomy
Buprenorphine
Bupivacaine
I Control
halothane/nalbuphine x 6; NN6 = nephrectomy/nalbuphine x 6; HLOC= halothane/bupivicaine x 2; NLOC = nephrectomy/bupivicaine x 2.
F i g 3: R e l a t i v e depression i n food and water i n t a k e i n r a t s f o l l o w i n g u n i l a t e r a l nephrectomy. Values are mean 2 1SD o f the r a t i o o f food and uater intake during t h e 24 h w r s f o l l o u i n g treatment t o the intake d u r i n g 24 hours p r i o r t o treatment. indicates s i g n i f i c a n t d i f f e r e n c e (p
L
U
4-
.-0
0
+
a
0
v)
+
\
II
L
a,
I
0
CL
.-
+ t
Y U
Q,
Fig.
4
0.00
0.28
0.56
0.84
1.12
1.40
Saline
T
Buprenorphine
T
T
r Bupivacaine
EIl Control
aparotomy/control Water intake
Laparotomy
Wistar
0
c
I
0 c\1
I
Fig. 6
0
I
2
3
4
5
6
day
*
*
Saline post-op 0.15ml sc
n=20
post-op
day
= siguficantly different kxO.05) from me-op intake
v a l u e s are mean + SD
s t e r n o t o m y day
Buprenorphrne post-op O.OSmg/kg sc
Pre-op
.. .. ,..............,.,.
....,
ie effects of sternotomy on mouse food intake
THE INnUENCE OF SURGICAL PROCEDURES, ANAESTHETICS AND ANALGESICS ON BODY WEIGHT AND FOOD AND WATER CONSUMPTION IN RATS AND MICE.
J.H. Liles and PA. Flecknell Comparative Biology Centre, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH England Introduction The assessment of post-operative pain in animals remains highly subjective, despite attempts to introduce more objective scoring systems (Morton and Griffiths, 1985). It has been suggested that post-operative pain may result in a reduction in body weight and in food and water intake in animals (Morton and Griffiths, 1985; Leese et al., 1988,, Taylor, 1985; Wright et al.,
cycle was maintained. Animals underwent a 2 week period of acclimatisation to single housing prior to study. Effects of anaesthesia and a n a 1l e Anaesthesia was induced and maintained with halothane (3% induction, 2% maintenance) for 2Ll minutes at 09.00 h. Immediately following anaesthesia, rats received either buprenorphine 0.05 or 0.01 mg/kg sc, or bupivacaine 0.7 ml 0.125%. Groups of animals also received saline 0.3 ml rats, 0.15 ml mice.
1985; Yoxall, 1978) but there appear to be no controlled studies of the effects of surgical procedures on these variables. A series of investigations have been carried out to determine the changes which occur following surgery in rats and mice, and to assess whether these changes can be prevented or minimised by the admiiistration of analgesics. We have also investigated the effects of anaesthesia and administration of analgesics in normal animals.
Effects of surgery The surgical procedures were required to be undertaken as part of an unrelated research project. Anaesthesia was induced and maintained with halothane as described above. The first group of rats underwent craniotomy and implantation of electrodes under the skull, these rats had collars placed on them; a control group just underwent anaesthesia and placement of a collar. All rats received either buprenorphine 0.05 mg/kg SC or saline 0.3 ml SC post-operatively. The second group of rats underwent midline laparotomy followed by bile duct ligation. These rats received either saline 0 3 mls sc, Buprenorphine 0.05 mg/kg SC or a local infitration of Bupivacaine 0.7 ml of 0.125%. Mice received sternotomy followed by removal of the thymus gland, at the end of the period of anaesthesia, at approximately 3 pm, the animals received either saline 0.15 ml SC or buprenorphine 0.05 mg/kg SC this was repeated the following morning at 9 am.
Materials and Methods Body weight changes were recorded by weighing the animals between 9am and loam each day. Food and water consumption was monitored by weighing the animals' food hoppers and water bottles at the same time. Full details of the apparatus and methodology have been described previously (Flecknell and Liles, 1991).
Male Wistar outbred rats, or male Balb/c mice obtained from this Institute's S.P.F. unit were used in the study. Animals received a commercial pelleted diet (R&M Nol, S.D.S. Ltd.)and water ad libitum. Room temperature was maintained at 24l L 2" C and a 9 h : m light-dark 259
Proceedings of the 4th International Congress of Veterinary Anaesthesia
Statistical metho& Food and water consumption and body weight were compared within groups using Student’s paired t-test. The relative changes between groups were examined by calculating the ratio of the post-treatment intake to the pre-treatment intake. This ratio was compared between groups using Student’s t-test. Results Effects of anaesthesia and analoes’la Halothane anaesthesia followed by either 2 doses of saline or a single dose of buprenorphine 0.05 mg/kg SC or 0.01 mg/kg SC or bu-
pivacaine 0.7ml 0.125% produced a small fall in food and water intake in rats (Figure 1) and mice. The post-treatment food intake for the rats which received the higher dose of buprenorphine 0.05 mg/kg was significantly (Pc0.05) lower than the pre-treatment intake. Effects of sureid Drocedurek Following craniotomy, food and water intake in the buprenorphine treated rats did not differ significantly from the unoperated controls but was significantly (PcO.001) depressed in the rats which received saline (Figure 2). After laparotomy food intake was significantly (Pc0.05)lower than in unoperated controls for all three post-operative treatments (Figure 3). Water intake was significantly depressed in the saline (Pc0.05) and bupivacaine (P
In mice food and water intake was reduced following anaesthesia and the administration of buprenorphine, but was not depressed following anaesthesia and the administration of saline. However following sternotomy, saline treated mice had signiticantly (P
Proceedinas of the 4th International Conpress of Veterinalv Anaesthesia
Schmidt et al., 1985; Cowan et al., 1977, Steinfels and Cook, 1986, Hermansen et al., 1986; Wootton et al., 1988; Flecknell and Liles, 1990).
References
Cowan A., Doxey J.C. and Harry EJ.R. (1977) The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br. J. Pharm. 60, 547-554.
It is clear that buprenorphine, even at the relatively low dose rates used in the present study, has an effect at the higher dose rate (0.05 mg/kg), on food intake. The lower dose rate of buprenorphine (0.01 mg/kg) did not cause a significant reduction in food or water intake. Although the use of analgesics to alleviate postoperative pain is clearly desirable, the results of the present study indicate that opioids may have some adverse side-effects in rats. The reduction in food intake is clearly undesirable and emphasises the need to administer analgesics
Flecknell P A . and Ldes J.H. (1990) Assessment of the analgesic action of opioid agonist-antagonists in the rabbit. J. Ass. vet. Anaesth. (in press). Flecknell P A . and Ldes J.H. (1991) The effects of surgical procedures, halothane anaesthesia and nalbuphine on locomotor activity and food and water consumption in rats. Lab Anim. 25, 50-60. Hermansen K. Pedersen L.E. and Olesen H.O. (1986) The analgesic effect of buprenorphine, etorphine and pethidine in the pig: a randomised double blind cross-over study. Acta Pharmacol. et Toxicol. 59, 27-35.
only when pain is believed to be present.
All of the surgical procedures studied caused a reduction in food and water consumption and a loss of body weight, the magnitude of these changes could be reduced by treatment with buprenorphine. Bupivacaine appeared to have little effect, this may be due to an inappropriate dose being used or because this sort of analgesia is
Leese T., Husken PA. and Morton D.B. (1988) Buprenorphine analgesia in a rat model of acute pancreatitis. Surg. Res. Comm., 3, 5360, 1988.
inappropriate for the pain being experienced. Morton D.B. and Griffths P.H.M. (1985) Guidelines on the recognition of pain, distress and discomfort in experimental animals and a~ hypothesis for assessment. Vet. Rec. 116, 431-
The monitoring of food and water intake and body weight would appear to be a simple and useful means of assessing the adverse effects of surgical procedures. Further studies of the effects of a range of different surgical procedures are required, however, before any firm recommendations can be made concerning the use of these techniques for assessing pain or distress.
436.
Pircio A.W., Gylys JA, Cavanagh R.L.,Buynkki J.P. and Bierwagen M.E. (1976) The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic. Arch. Int. Pharmacodyn, 220,231-257.
Acknowledgements: This work was supported by
Schmidt W.K., Tam W.S., Shotzberger G.S., Smith D.H., Clark R. and Vernier V. (1985) Nalbuphine. Drug and Alcohol Dependence,
the Wellcome Trust.
261
Procccdinns of the 4th International Coneress of Vcterinalv Anaesthesia
14,339-362. Steinfels G. and Cook L. (1986) AntinoCiceptive profiles of Mu and Kappa opioid agonists in a rat tooth pulp simulation procedure. J. Pharm. Exp. Therapeutics. 236,111-117 Taylor P.M. (1985) Analgesia in the dog and the cat. In Practice 7,5-13. Wright E.M., Marcella KL. and Woodson J.F. (1985) Animal pain: evaluation and control. Lab Animals 14,20-30. Y o d A.T. (1W8) Pain in small animals - its recognition and control. J.SA.P. 19,423-438. Wootton R.,Cross G., Wood S. and West C.D. (1988) An analgesiometry system for use in rabbits with some preliminary data on the effects of buprenorphine and lofentanil. Lab. Anim. 22,217-222.
262
A
8 i
7
0
m
r
lr)
0
m
I
c\l c/)
I
0 0.l
0 0
T
7
0 a3
0
0
co
0
0
v
0
0 c\l
0
0 0 0
Fig 2: Relative depression i n food and uater intake i n r a t s follouing anaesthesia and analgesic administration. Values are mean
2 1SD of the r a t i o of food and
0.00
1.20'
Craniotom y Bupronorphino
S.lin0
Food intake
Craniotomy
. ,. .. , . . . . .
I Water intake
Unopotatod Bupranorphine
T
S8liDO
Unoper8ted
T
value = mean + S D
I
uater intake during the 24 hours follouing treatment t o the intake during 24 hours p r i o r t o treatment. indicates s i g n i f i c a n t difference ( ~ 0 . 0 5 ) f r a n halothane/saline control. HS3 = halothane/saline x 3; HBUT = halothane/butorphanol x 3; HS6 = halothane/saline x 6; HN6 = halothane/nalbuphine x 6.
a,
U L
0 .+
0
rC
a
0
v)
+
\
f l
L
a,
I
Q 0
.-C
+
U
Y
1.20
Saline
Laparotomy
Buprenorphine
Bupivacaine
I Control
halothane/nalbuphine x 6; NN6 = nephrectomy/nalbuphine x 6; HLOC= halothane/bupivicaine x 2; NLOC = nephrectomy/bupivicaine x 2.
F i g 3: R e l a t i v e depression i n food and water i n t a k e i n r a t s f o l l o w i n g u n i l a t e r a l nephrectomy. Values are mean 2 1SD o f the r a t i o o f food and uater intake during t h e 24 h w r s f o l l o u i n g treatment t o the intake d u r i n g 24 hours p r i o r t o treatment. indicates s i g n i f i c a n t d i f f e r e n c e (p
L
U
4-
.-0
0
+
a
0
v)
+
\
II
L
a,
I
0
CL
.-
+ t
Y U
Q,
Fig.
4
0.00
0.28
0.56
0.84
1.12
1.40
Saline
T
Buprenorphine
T
T
r Bupivacaine
EIl Control
aparotomy/control Water intake
Laparotomy
Wistar
0
c
I
0 c\1
I
Fig. 6
0
I
2
3
4
5
6
day
*
*
Saline post-op 0.15ml sc
n=20
post-op
day
= siguficantly different kxO.05) from me-op intake
v a l u e s are mean + SD
s t e r n o t o m y day
Buprenorphrne post-op O.OSmg/kg sc
Pre-op
.. .. ,..............,.,.
....,
ie effects of sternotomy on mouse food intake