Research Article Analgesic Efficacy of the Combination Metamizol+Morphine After Subchronic Treatment in Rats Adriana Miriam Domínguez Ramírez
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- Bu səhifədəki naviqasiya:
- Adriana Miriam Domínguez Ramírez, 1,2 * Gloria Patricia Hernández Delgadillo, 3 Rosa Ventura Martínez
- INTRODUCTION
- MATERIALS AND METHODS Experimental Animals
- Measurement of Analgesic Activity
- Study Design
- Data Presentation and Statistical Evaluation
- ACKNOWLEDGMENTS
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260 RAMÍREZ ET AL. © 2001 Wiley-Liss, Inc. DRUG DEVELOPMENT RESEARCH 51:260–267 (2000) DDR
ABSTRACT
In the present study, the analgesic efficacy and the possible development of tolerance pro- duced by the combination metamizol+morphine (562.3:5.6 mg/kg) during subchronic treatment (6 and 12 days) in arthritic rats using the PIFIR model was evaluated. This combination of metamizol+morphine produced the maximum analgesic efficacy (AUC E = 353.4 ± 24.7 au) when compared with morphine 5.6 mg/kg (AUC E = 196.6 ± 35.3 au), metamizol 562.3 mg/kg (AUC E = 262.8 ± 10.2 au), and morphine 10 mg/ kg (AUC E
± 31.0 au) given in a single dose. The results were essentially the same when the combination was administered for 6 (AUC E = 325.4 ± 13.1 au) or 12 days (AUC E = 354.5 ± 9.6 au). In addition, the duration of the effect was longer when the combination metamizol+morphine was adminis- tered either in single or subchronic treatment. Development of tolerance to the analgesic effect was ob- served after 6 and 12 days of morphine administration. However, the analgesic effect produced by the metamizol+morphine combination remained constant (near 100%) during both subchronic treatments. The present data demonstrate that metamizol significantly attenuates the development of tolerance to mor- phine. The mechanism involved in this effect of metamizol remains to be determined. Drug Dev. Res. 51:260–267, 2000. © 2001 Wiley-Liss, Inc. Key words: synergism; analgesia; tolerance; pharmacodynamic interaction Strategy, Management and Health Policy Venture Capital Enabling
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Opioids and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used to treat pain. Among opioid agents, morphine is still the drug of choice. Narcotic an- algesics represent the primary prescription for severe acute pain, such as that following acute myocardial inf- arction, renal and biliary colic, extensive surgical proce- dures, burns, and other traumas [Cherny, 1996; Carr and Goudas, 1999], as well as moderate to severe chronic pain associated with malignancies [Cherny, 1996; Rodríguez et al., 1994; WHO, 1996]. Although morphine is very useful as an analgesic, its clinical application in chronic pain is limited by the rapid development of tolerance [Johnstone and Smith, 1992; Trachtenberg, 1994]. An- other disadvantage of opioids is their short duration of action, which requires frequent administration. In most cases, this leads to the use of high doses that are associ- ated with severe adverse side effects such as respiratory depression [Cherny, 1996; Hill et al., 1990; Jaffe and Martin, 1990]. On the other hand, NSAIDs are effective and long- acting agents but their adverse side effects at high doses *Correspondence to: Adriana Miriam Domínguez Ramírez, M.Sc., Departamento Sistemas Biológicos, Universidad Autónoma Metropolitana, Xochimilco, Calzada del Hueso #1100, Colonia Villa Quietud, C.P. 04960 México, D.F. Received 19 April 2000; accepted 9 October 2000
METAMIZOL+MORPHINE TREATMENT IN RATS 261
limit their degree of analgesia. For instance, a number of studies have demonstrated mucosal damage in 50–57% of arthritis patients treated with long-term NSAID therapy. Also, gastric and duodenal ulcers are present in 10–30% of all patients taking NSAIDs. The incidence of serious complications increases with age, especially in those older than 65 years [Pearson and Kelberman, 1996; Singh et al., 1996]. In order to increase the analgesic effects of drugs and to reduce their unwanted side effects, combinations of low doses of analgesic drugs that act through different pharmacological mechanisms have been employed ex- tensively. This may result in an overall potentiation of the analgesic effect. In this regard, some combinations of opioid drugs with NSAIDs have been proposed [Bentley and Head, 1987; Calimlim et al., 1976; López- Muñoz et al., 1993b]. Nevertheless, information on the real benefits of such combinations in preclinical and clini- cal studies is still scarce. In previous studies we have shown the potential therapeutic benefits of combinations of metamizol (MET) with morphine (MOR) in arthritic rats [López-Muñoz et al., 1994; López-Muñoz, 1994] using the “pain-induced functional impairment in the rat” model (PIFIR) [López- Muñoz et al., 1993a]. In addition to its usefulness for evalu- ating the analgesic efficacy of individual drugs, PIFIR represents a valid model to determine the efficacy of their combinations [López-Muñoz et al., 1993b, 1995; López- Muñoz, 1995; López-Muñoz and Salazar, 1995]. Thus, the combination of MET+MOR (562.3:5.6 mg/kg, s.c.) produced the “maximum analgesic effect” (MAE) of 24 different combinations tested [López- Muñoz, 1994]. This is a significant finding given the high analgesic efficacy of the combination as compared to that exerted by the individual components. Furthermore, the probability of potential side effects is remarkably lower than expected from equally efficacious doses of the indi- vidual drugs. As pointed out above, one of the major disadvan- tages encountered during long-term treatment, i.e., chronic, therapy with morphine and other opioid drugs is the development of tolerance. In this case, the combi- nation MET+MOR that produced MAE in a single dose (acute treatment) represents an alternative choice since the dose of morphine in the combination is small. There- fore, it may be expected that the development of toler- ance could be diminished. It also may be expected that as the toxic profiles of both drugs differ, adverse side ef- fects would be avoided or diminished when low doses of both drugs are administered in combination, either as single or multiple doses. In this sense, it is necessary to demonstrate that, in addition to the pronounced efficacy of the combination of MAE in single dose, along with the absence of untoward effects, its characteristics re- main constant during subchronic treatment. This is of great importance in the clinical situation, especially for chronic treatment of pain. The aims of the present study were to evaluate the analgesic efficacy and the development of tolerance pro- duced by the combination MET+MOR of MAE (562.3:5.6 mg/kg) during subchronic treatment (6 and 12 days) in arthritic rats using the PIFIR model. In addi- tion, we compared these results with those obtained af- ter administration of the individual components of the combination, MET (562.3 mg/kg) and MOR (5.6 mg/kg), after single and 6 and 12 days administration. MATERIALS AND METHODS Experimental Animals Analgesia experiments were performed using fe- male Wistar rats [Crl: (WI)BR] (weight, 180–200 g) from the breeding facilities of CINVESTAV-IPN, México. All experimental procedures followed the recommendations of the Committee for Research and Ethical Issues of the International Association for the Study of Pain [Covino et al., 1980] and the guidelines on ethical standards for investigations of experimental pain in animals [Zimmer- mann, 1983], and were carried out according to a proto- col approved by the local animal Ethics Committee. The number of experimental animals was kept to a minimum. They were kept in an animal room at a constant tem- perature of 22 ° C, with a 12/h alternating light/dark cycle. Twelve hours before experiments, food was withheld but animals had free access to water. All experiments were performed during the light phase and animals were used only once. Compounds Uric acid was obtained from Sigma Chemical Co. (St. Louis, MO) and metamizol (MET) was obtained from Hoescht (Mexico City, Mexico). Morphine hydrochloride (MOR) was obtained from Mexican Secretariat of Health (Mexico City, Mexico). MET and MOR were dissolved in saline solution and administered subcutaneously. The doses mentioned in the text refer to the salts of substances. Measurement of Analgesic Activity Pain was induced and the analgesic effects of MET (562.3 mg/kg), MOR (5.6 mg/kg) and the combination MET+MOR (562.3:5.6 mg/kg) were measured in the PIFIR model, as previously described [López-Muñoz et al., 1993a]. Rats received an intraarticular injection of 0.05 mL of 30% mineral oil-suspended uric acid in the knee joint of the right hindlimb under light anesthesia with ether. An electrode was immediately fastened to each hindpaw between the plantar pad. Rats were allowed to recover from anesthesia and then placed on a stainless- steel cylinder, 30-cm diameter. The cylinder was rotated 262 RAMÍREZ ET AL. at 4 rev/min, which forced the rats to walk. The variable measured in this method was the time of contact between each of the rat hindpaws and the cylinder. When the elec- trode placed on the animal’s paw made contact with the cylinder floor, a circuit was closed and the time that cir- cuit remained closed was recorded. The cylinder was rotated for 2-min periods, during which time recordings were made, allowing the rats to rest for 28 min between recording periods. Animals did not show any visible sign of severe discomfort, such as licking, rearing, biting, shak- ing, or vocalization. After the uric acid injection, rats de- veloped a progressive dysfunction of the injured limb. This was recorded as a decreased time of contact between the right hindpaw and the cylinder. Data are expressed as the functionality index (FI%), i.e., the time of contact of the injured right limb divided by the time of contact of the control left limb, multiplied by 100. After approxi- mately 2 h the FI was zero; that is, the injected limb made no contact with the cylinder. This time was considered time zero for measurements of analgesia and rats received the analgesic agents. Recordings were carried out for the next 4 h. Recovery of FI was considered the expression of the analgesic effect. For the purpose of the study, in- ducing nociception in the experimental animals was unavoidable. However, care was taken to avoid unneces- sary suffering. At the end of the experiment the rats were immediately sacrificed.
Animals were randomly distributed in three sets in which the analgesic effects produced by either MET (562.3 mg/kg), MOR (5.6 mg/kg), and the combination of MET+MOR (562.3:5.6 mg/kg) were studied after single dose (acute treatment) or after a 6-day and 12-day treat- ment (subchronic treatments). The schedule of dose treat- ment administration is shown in Table 1. The analgesic effect of a single dose of 10 mg/kg of MOR was also studied. This dose was considered a con- trol, as it has previously been demonstrated to produce MAE in the PIFIR model. Drugs were dissolved in saline solution (0.9% NaCl) and administered s.c. to animals pre- viously injected with uric acid. Pain was induced the day after completing the number of administrations, i.e., on the 7th day for the 6-day treatment group or the 13th day for the 12-day treatment group. FI was determined in all groups at 0 and after administration of the compounds, at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, and 4 h.
Data are expressed as the percent of the function- ality index (FI%) (i.e., the time of contact of the injured right hindlimb divided by the time of contact of the con- trol left hindlimb multiplied by 100). The curves of time course (TC) were constructed by plotting FI(%) vs. time (h), and the maximal observed effect (E max
) was directly determined from these plots. The cumulative antinoci- ceptive effect during the entire observation period (4 h) was determined as the area under the time course curve (AUC). The area under the effect-against-time curve (AUC
E ) was estimated by the trapezoidal method rule [Rolland and Tozer, 1989]. Analgesic activity and toler- ance development during subchronic treatments were evaluated using these two pharmacodynamic parameters. E max is considered an indicator of analgesic efficacy and AUC
E as an overall expression of the analgesic action during the entire observation period and, hence, consid- ering both the intensity and the duration of effect [López- Muñoz et al., 1993a]. Additionally, analgesic effect at the end of the experiment (duration of effect) was estimated by the observed effect at 4 h after the administration of the drug(s) (E 4h ).
mean ± SEM of eight animals. The AUC E , E
max , and E
4h values obtained from data for the analgesic effects pro- duced by the combination under different treatments were compared with those obtained either by MET or MOR (assayed separately) by ANOVA followed by the Student-Newman-Keuls test. Significant differences be- tween means were indicated by P ≤ 0.05. RESULTS Intraarticular injection of uric acid induced a com- plete dysfunction of the right hindlimb in 2 h, correspond- ing to an FI% of zero. Rats which received vehicle did not show any significant recovery of the FI during the 4- h observation period. Temporal courses (TCs) of the an- algesic effect (FI% vs. time plots) obtained after acute s.c. administration (single dose) of MOR (5.6 mg/kg), MET (562.3 mg/kg), and the combination MET+MOR of MAE (562.3:5.6 mg/kg), are shown in Figure 1. MOR (5.6 mg/kg s.c.) induced an increase in FI which reached a maximum of about 70% (E max ) in an hour and then showed a gradual decrease to about 45% at 4 h. MET (562.3 mg/kg s.c.) produced an E max of about 80% at 0.75 h. Thereafter, the time course of the effect remained prac- tically constant during the 4-h experimentation period, TABLE 1. Schedule Treatment Sets
I II III MOR MET
MET+MOR (5.6 mg/kg) (562.3 mg/kg) (562.3:5.6 mg/kg) 1 Acute treatment Acute treatment Acute treatment (one dose) (one dose) (one dose) 2 6 Days 6 Days 6 Days
treatment treatment treatment 3 12 Days 12 Days 12 Days
treatment treatment treatment
METAMIZOL+MORPHINE TREATMENT IN RATS 263
with a negligible decrease at about 2.5 h. The FI at the end of the experiment was around 70%. The combina- tion of MET+MOR (562.3:5.6 mg/kg) was able to induce a rapid and significant recovery of the FI, reaching an E max
of about 100% at 0.75 h and this effect was main- tained until the end of the experiment (4 h). As a conse- quence of the difference in duration and E max
of the drugs administered alone and that of the combination, there was a marked difference in the AUC E (Table 2). The com- bination MET+MOR (562.3:5.6 mg/kg) yielded an AUC E of 353.4 ± 24.7 area units (au), whereas MET and MOR alone gave values of 262.8 ± 10.2 and 196.6 ± 35.3 au, respectively. Significant differences were found for AUC E (F cal = 88.9); E max (F
cal = 4.23) and E 4h (F
cal = 9.49) be- tween treatments. In addition, all these parameters showed statistical differences when the values obtained for the combination MET+MOR were compared to those of MOR (5.6 mg/Kg) and MET (562.3 mg/Kg), for pairwise multiple comparison by Student-Newman-Keuls method (Table 2). These results were comparable to those previ- ously reported under the same circumstances [López- Muñoz et al., 1994]. TCs of the two components MOR, MET, and the combination MET+MOR after a 6-day subchronic treat- ment are shown in Figure 2. Clearly, the analgesic effect is markedly diminished in the case of MOR (5.6 mg/kg), so a rapid development of tolerance was observed. The E max obtained in this case was only about 40% of FI at 0.75 h, with about a 50% reduction when compared with a single dose of MOR 5.6 mg/kg sc. The effect wore off rapidly, reaching a value of zero at 2.5 hr. On the other hand, the recovery of FI after chronic administration of MET (562.3 mg/kg) following a six-day treatment was practically the same as that obtained with a single dose of the same compound, producing an FI recovery of about 90% at 0.75 h (E max
), and this effect reached a value of about 76% at 4 h after administration. After subchronic Fig. 1. Temporal courses of the antinociceptive effects (analgesia) ob- served expressed as the recovery of functionality index (FI%) against time (h), after s.c. administration of a single dose of the combination of MET+MOR (562.3:5.6 mg/Kg) of MAE and of the individual compo- nents MET (562.3 mg/kg) and MOR (5.6 mg/kg) (CONTROLS). Data rep- resent the mean ± SEM of eight rats. TABLE 2. Pharmacodynamic Parameters Obtained From Temporal Courses of the Analgesic Effect Observed With the Combination Metamizol+Morphine (562.3:5.6 mg/kg) in Comparison to Metamizol (562.3 mg/kg) and Morphine (5.6 mg/kg) in Acute and Subchronic Treatments (6 and 12 days) in Rats Global efficacy Treatment AUC
E (%h)
T max
(h) E max (FI %) E 4h (FI %) Acute
MOR 10 mg/kg 316.6 (31) a 1.25
98.1 (7.7) 53.9 (14.1) N.K. n.s. b N.K. n.s. N.K. <.05 MOR 5.6 mg/kg 196.6 (35.3) 1.00
67.5 (7.9) 45.6 (13.6) N.K. P < .05 N.K. <.05 N.K. <.05 MET 562.3 mg/kg 262.8 (10.2) 0.75
77.9 (2.6) 67.2 (4.4) N.K. P < .05 N.K. <.05 N.K. <.05 MET+MOR 562.3:5.6 mg/kg 353.4 (24.7) 0.75
97 (9.5) 96.1 (4.8) 6 days MOR 5.6 mg/kg 49.6 (14.3) 0.75
37.9 (10.4) 0.2 (0.1) N.K. P < .05 N.K. <.05 N.K. <.05 MET 562.3 mg/kg 313.4 (14.5) 0.75
88.3 (4.4) 76.7 (7.3) N.K. n.s. N.K. n.s. N.K. n.s. MET+MOR 562.3:5.6 mg/kg 325.4 (13.1) 1.00
93.5 (4.1) 89 (3.9)
12 days MOR 5.6 mg/kg 56.6 (10.9) 0.75
42.1 (8.1) 2.6 (1.6) N.K. <0.05 N.K. <.05 N.K. <.05 MET 562.3 258.8 (23.7) 0.75
75.1 (10.7) 75.1 (10.7) N.K. <0.05 N.K. <.05 N.K. n.s. MET+MOR 562.3:5.6 mg/kg 354.5 (9.6) 1.00
100.6 (3.9) 83.5 (4.7) a Data represents the mean ± SEM of eight rats. b N.K. = significance for differences found in pairwise multiple comparison by Student-Newman-Keuls method (combination of MAE vs. individual components).
264 RAMÍREZ ET AL. treatment for six days, the combination produced an FI recovery of about 90% at 0.75 h, and the effect remained at this level after 4 h. In this case, the global effect reached by the combination rendered an AUC E of 325.4 ± 13.1 au while MOR (5.6 mg/kg) and MET (562.3 mg/ kg) gave an AUC E of 49.6 ± 14.3 and 313.4 ± 14.5 au, respectively (Table 2). In this case, significant differences were found in AUC E (F
cal = 124.2), E max (F
= 19.6), and E
4h (F
cal = 16.2). Particularly, differences were es- tablished when the combination MET+MOR was com- pared with MOR (5.6 mg/Kg), while values obtained for MET were similar to those of the combination of MAE and no differences for MET were found by the Student- Newman-Keuls method. In addition, the cumulative analgesic efficacy obtained with the combination MET+MOR after subchronic treatment (6 days) was similar to that obtained by a single dose of MOR (10 mg/ kg) AUC E
± 31.0 au, while the duration of the effect observed with the combination was longer than the one obtained by a single dose of 10 mg/kg of MOR and showed significant differences (Table 2). TCs of analgesic activity for the individual compo- nents MOR (5.6 mg/kg), MET (562.3 mg/kg), and the combination of both MET+MOR (562.3:5.6 mg/kg) af- ter a 12-day subchronic treatment are shown in Figure 3. The advantages of the combination MET+MOR over the individual components is clearly demonstrated. MOR only improved an FI recovery of about 40% and its effect rapidly diminished to zero at about 2.5 h; MET produced only an FI recovery of about 75% at the same time and this effect remained at the same level until the end of the experiment (4 h). On the other hand, the analgesic effect reached by the combination of MET+MOR was about 100% and this effect remained constant for 2.5 h. After this time, the effect diminished gradually and reached a value of about 85% at 4 h. The AUCE after 12 days of treatment was 56.6 ± 10.9 au for MOR, 258.8 ± 23.7 au
for MET and 354.5 ± 9.6 au for the combination of MET+MOR (562.3:5.6 mg/kg). ANOVA showed that sta- tistical differences between treatments exist, as indicated by differences in AUC E (F cal = 90), Emax (F cal = 12.9), and E 4h (F cal = 15.5). When the values obtained for AUC E ,
max , for MET an MOR (5.6 mg/Kg) given alone were compared by the Student-Newman-Keuls method, sig- nificant differences were also found. Differences for the duration of the effect, as evaluated by E 4h , were also found for MOR (5.6 mg/Kg). The analgesic effects shown by the combination after acute and subchronic treatments were also com- pared with those observed after the s.c. administration of an equiefficacious dose of morphine (10 mg/kg) (single dose). These data are included in Table 2. The global analgesic (AUC E ) elicited by the combination was equiva- lent to the one observed after administration of 10 mg/kg morphine. Moreover, in the case of morphine (10 mg/kg) the duration of the effect was shorter and diminished to about 50% of the initial effect at the end of the experi- ment. On the contrary, the effect produced by the com- bination under study remained over 80% of FI during the duration of the experiment, either after acute or subchronic treatment for 12 days. These results confirmed the utility of the combination under the present experi- mental conditions and highlight the benefits of the com- bination MET+MOR vs. the individual treatments.
The aim of the present study was to assess the anal- gesic efficacy and development of tolerance produced by the combination MET+MOR of MAE (562.3:5.6 mg/ Fig. 2. Temporal courses of the antinociceptive effects (analgesia) ob- served after the s.c. administration of MET (562.3 mg/kg), MOR (5.6 mg/kg), and the combination MET+MOR of MAE (562.3:5.6 mg/kg) during 6 days of subchronic treatment. Data represent the mean ± SEM
of eight rats. Fig. 3. Temporal courses of the antinociceptive effects (analgesia) ex- pressed as recovery of functionality index (FI%) against time (h) after the s.c. administration of the two components MET (562.3 mg/kg), MOR (5.6 mg/kg), and the combination MET+MOR of MAE (562.3:5.6 mg/kg) dur- ing 12 days of subchronic treatment. Data represent the mean ± SEM of
eight rats. METAMIZOL+MORPHINE TREATMENT IN RATS 265
Kg) after subchronic treatment in arthritic rats using the PIFIR model. Data obtained after administration of the combination under acute and subchronic (6 and 12 days) treatments were compared with those of the individual components, MET (562.3 mg/kg) and MOR (5.6 mg/kg). It was hypothesized that this design could show the po- tential antinociceptive usefulness arising from the inter- action of analgesic drugs that act through different mechanisms. This was visualized as a potentially supe- rior approach for the chronic treatment of pain. The combination MET+MOR (562.3:5.6 mg/Kg) was selected on the basis of previous studies in rats showing its ability to produce MAE between 24 different combina- tions under single administration protocols [López- Muñoz, 1994]. In the present study, these results were confirmed, as the cumulative analgesic efficacy (repre- sented as the AUC E ) for the combination MET+MOR was significantly higher (P < 0.05) than the one shown by the individual components when administered at the same dose used in the combination (Fig. 1). The combination of centrally and peripherally act- ing analgesics has theoretical justification because these compounds work through different mechanisms. MOR and other opioid drugs interact with µ opioid receptors and produce analgesia via the same mechanism as en- kephalin. In addition, morphine can interact with opioid receptors located in supraspinal structures activating the supraspinal system [Martin, 1984; Jaffe and Martin, 1990; Lipp, 1991]. Several lines of evidence support a role for activation of bulbospinal noradrenergic and serotoner- gic inhibitory pathways [Yaksh, 1979; Yeomans et al., 1992; Kawamata et al., 1993]. In addition, morphine has a di- rect effect on inflammatory hyperalgesic states [Loren- zetti and Ferreira, 1982, 1985]. Ferreira [1993] proposed that a downregulation of pain receptors by injection of morphine or acetylcholine may be due to the activation of the arginine-nitric oxide-cGMP pathway [Duarte et al., 1990; Ferreira et al., 1991]. On the other hand, MET is a pyrazolone derivative which is often classified as a peripherally acting drug, as its major metabolites act as COX inhibitors [Brogden, 1986; Brune and Alpermann, 1983]. However, metamizol is much more effective as an antipyretic and analgesic than as an antiinflammatory agent in vivo, and it has also been shown to have central analgesic effects [Neugebauer et al., 1994]. Furthermore, it has been reported that the analgesic effect of MET involves activation of the argin- ine-nitric oxide-cGMP pathway in addition to prostag- landin synthesis inhibition [Duarte et al., 1992; Lorenzetti and Ferreira, 1985; López-Muñoz et al., 1996]. Experi- mental evidence supports the hypothesis that metamizol and aminophenazone (two pyrazolone derivatives) pro- duce central antinociceptive effects by activating path- ways discarded from the PAG and exerting an inhibitory effect on nociceptive impulse transmission at the spinal level [Carlsson et al., 1986, 1988; Carlsson and Jurna, 1987]. This might provide an explanation for the high analgesic efficacy of MET observed after major abdomi- nal surgery. It has also been shown to produce a great analgesic efficacy when compared to morphine at doses as high as 2 g every 8 h in cancerous patients [Rodríguez et al., 1994]. It has also reduced the frequency of admin- istration of MOR after major abdominal surgery [Rockemann et al., 1996]. The great analgesic efficacy of MET in such types of pain might provide an explanation for the synergistic effect observed with the MET+MOR combination in the present study. No attempt was made to investigate the mechanism(s) involved in the poten- tiation of the analgesic effects produced by MET and MOR during single or subchronic treatment. Further experiments are required to elucidate these mechanisms. Additionally, the analgesic effects observed with the com- bination MET+MOR may also depend on the global pharmacodynamic/pharmacokinetic interactions between the components, either after acute or subchronic admin- istration. Possible mechanism(s) of pharmacokinetic in- teractions remain to be determined. It is well known that in addition to several adverse side effects, one of the major disadvantages of MOR and other opioid drugs under chronic treatment is the devel- opment of tolerance [Cherny, 1996; Johnstone and Smith, 1992]. Development of tolerance to MOR was confirmed in the present study and it occurred even when a small dose was used (5.6 mg/kg) in subchronic treatments. In contrast to the tolerance effects found with MOR alone, tolerance was not developed when the drugs were ad- ministered together, even after 12 days of treatment. This is of great importance as, in most instances, clinical treat- ment of chronic pain involves the use of long-term anal- gesic treatments. Thus, in this case it might be expected that an adequate combination for MET+MOR could be an alternative treatment with fewer side effects arising from the opioid component. Nevertheless, the potential clinical usefulness of the combination in an adequate ra- tio of doses must be evaluated in future studies. No attempt was made in relation to the mechanism implicated in the inhibition of tolerance development to the antinociceptive effect of the drugs (MET and MOR) when they were administered together. It might be pos- sible that, although a marked (MOR) or negligible toler- ance effect (MET) could be present with both components, i.e., given alone, the synergism observed with the anal- gesic effects of both drugs when they act together is pre- dominant over any other adverse effect. Several mechanisms have been proposed to explain the develop- ment of tolerance. Although repeated administration of MOR almost certainly leads to biochemical changes at the receptor level, and possibly its transduction systems, 266 RAMÍREZ ET AL. some of the most interesting aspects of morphine toler- ance have come from studies implicating both the NMDA and the nitric oxide systems [Bhargava, 1994; Pasternack et al., 1995]. Inhibition of NOS, the enzyme that gener- ates NO, blocks the appearance of MOR tolerance [Babey et al., 1994; Bhargava and Zhao, 1996]. In this case, as mentioned above, it has been demonstrated that the argi- nine-nitric-oxide-cGMP pathway is involved in the antinociceptive activity of metamizol. It has also been mentioned that some drugs such as metamizol or diclofenac cause a direct downregulation of nociceptors already switched “on” during inflammation [Ferreira, 1993]. So it might be expected that these could repre- sent levels of interaction that lead to the inhibition of tolerance development to the analgesic effect of MOR. Nevertheless, further studies are needed to confirm any of these hypotheses. The present results demonstrate that MET significantly attenuates tolerance development to MOR by modulating the pharmacological process respon- sible for tolerance development. It is likely that the analgesic effect will be modi- fied, depending on the type of pain and its intensity. The PIFIR model involves, in addition to inflammation, a type of pain very similar to the clinical situation encountered with gout. Thus, it is plausible to suggest that the combi- nation MET+MOR of MAE could have potential thera- peutic usefulness in the treatment of gout. In such cases, care must be taken when extrapolating findings obtained with the PIFIR and other preclinical models to clinical situations of pain. Further studies are necessary to deter- mine the real benefits in similar clinical situations in humans. The potential usefulness of the combination employed in this method to treat other types of pain also remains to be determined. Our findings show an enhanced analgesic effect and a diminished effect of tolerance development after subchronic treatment as the result of the adequate com- bination of MET and MOR, and indicate that the study of combinations of analgesic drugs in humans will be very important and constitute a superior approach in the treat- ment of chronic pain.
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