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Synergistic effect of the interaction between curcumin and diclofenac on the formalin test in rats.


The association of non-steroidal anti-inflammatory drugs with certain plant extracts can increase antinociceptive activity, permitting the use of lower doses and thus limiting side effects. Therefore, the aim objective of the current study was to examine the effects of curcumin on the nociception and pharmacokinetics of diclofenac in rats. Antinociception was assessed using the formalin test. Diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection, and a reduction in formalin-induced flinching was interpreted as an antinociceptive response. Rats were treated with oral diclofenac (1-31 mg/kg), curcumin (3.1-100 mg/kg) or the diclofenac-curcumin combination (2.4-38.4 mg/kg). To determine the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (10 mg/kg) was studied in presence and the absence of curcumin (31 mg/kg). Diclofenac, curcumin, or diclofenac-curcumin combination produced an antinociceptive effect on the formalin test. [ED.sub.30] values were estimated for the individual drugs, and an isobologram was constructed. The derived theoretical [ED.sub.30] for the antinociceptive effect (19.2 mg/kg) was significantly different from the observed experimental [ED.sub.30] value (9.8 mg/kg); hence, the interaction between diclofenac and curcumin that mediates the antinociceptive effect was synergistic. Notwithstanding, the interaction does not appear to involve pharmacokinetic mechanisms, as oral curcumin failed to produce any significant alteration in oral diclofenac bioavailability. Data suggest that the diclofenac-curcumin combination can interact at the systemic level and may have therapeutic advantages for the clinical treatment of inflammatory pain.









Pain is a warning mechanism allowing the preservation of the integrity of the organism. However, under certain circumstances, pain does not longer have a beneficial effect and becomes a pathological process that requires treatment. Drugs used for pain relief, such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs), induce several adverse effects (O'Neil et al., 2012). A strategy that may allow an increase in analgesic drug efficacy and a reduction of adverse effects is combining drugs with different mechanism of action. Diclofenac is a NSAID prescribed for its anti-inflammatory and antipyretic effects, besides it has been shown to be effective in treating a variety of acute and chronic pains (Gan, 2010). Extensive research has shown that the pharmacological activity of diclofenac goes beyond COX inhibition, including multiple mechanisms of action (Bjorkman, 1995; Ortiz et al., 2003; Ortiz, 2012; Vellani et al., 2013). Even though diclofenac is an effective analgesic, the inhibition of COX enzymes can lead to a range of undesirable and sometimes fatal short-and long-term organ toxicities, including gastrointestinal ulceration, bleeding, nefro- and hepatotoxic effects (O'Neil et al., 2012). Therefore, several approaches have been adopted to reduce the risk of NSAID-induced complications; these include reducing the NSAID dose, switching to NSAIDs that are perceived to be less toxic, or the concomitant use of other drugs or plant extracts with minor toxicity and with analgesics effects.

In recent years curcumin (diferuloylmethane), the most abundant curcuminoid isolated from Curcuma longa L (Zingiberaceae) has demonstrated anti-inflammatory, immunomodulatory, hypolipidemic, antiviral, antiprotozoal, antifungal and antibacterial properties (Srinivas et al., 1992; Mesa et al., 2000; Chainani-Wu, 2003; Kohli et al., 2005). Furthermore, previous reports have demonstrated analgesic effects of curcumin in formalin-induced pain (De Paz-Campos et al., 2012; Mittal et al., 2009) and chronic constriction injury-induced neuropathic pain (Zhao et al., 2011). The mechanisms underlying the analgesic action of systemic curcumin have been suggested to be associated with suppression of brain nitrite and serum tumor necrosis factor [alpha] levels, activation of [K.sub.ATP] channels and the descending monoamine system coupled with opioid receptors (De Paz-Campos et al., 2012; Zhao et al., 2011). A recent study showed that the intrathecal administration of curcumin decreased inflammatory pain in rats (Han et al., 2012). Moreover, it appears that curcumin is able to improve the effect of subanalgesic doses of diclofenac in the formalin-induced orofacial pain in rats (Mittal et al., 2009). However, no information is available on the kind of interaction between diclofenac and curcumin. Therefore the main objective of the present work was to extend the observations on the interaction between curcumin and diclofenac and to determine if this interaction between these two drugs is pharmacodynamic or pharmacokinetic.

Materials and methods


Female Wistar rats aged 7-10 weeks (weight range; 180-200 g) from our own breeding facilities were used in this study. Efforts were made to minimize animal suffering and to reduce the number of animals used. Each rat was used in only one experiment and sacrificed in C[O.sub.2] chamber at the end of the experiment. All experiments followed the Guidelines on Ethical Standards for Investigation in Animals (Zimmermann, 1983), and the protocol was approved by the Institutional Animal Care and Use Committee (CINVESTAV, IPN).


Curcumin (>80% curcumin, [greater than or equal to]94% curcuminoid content), diclofenac and formaldehyde were purchased from Sigma-Aldrich, Saint Louis, MO, USA. Curcumin was suspended in a 0.5% carboxymethyl-cellulose (CMC). Diclofenac was dissolved in saline solution.

Isobolographic analysis study

Measurement of antinociceptive activity

Pain and antinociception were assessed using the paw formalin test, as previously described (Ortiz et al., 2003, 2012; Ortiz and Castaneda-Hernandez, 2008). Briefly, 50 p.1 of diluted formalin (1%) were injected subcutaneously (s.c) into the dorsal surface of the right hind paw, and the resulting flinching behavior was considered to be an expression of nociception. Certain groups of animals received an oral administration (p.o.) of vehicle or increasing doses of curcumin (3.1,10, 31 and 100 mg/kg) sixty min before the formalin insult. Other groups of rats were treated with diclofenac (1, 3.1, 10 and 31 mg/kg, p.o.) 15 min before formalin injection. Finally, the curcumin-diclofenac combination was also administered at increasing doses (2.4, 4.8, 9.6, 19.2 and 38.4 mg/kg p.o.). The oral volumes administered were 4ml/kg. Rats in all groups were observed for changes in behavioral or motor function that could have been induced by the treatments. The ability of the animals to stand and walk with a normal posture was assessed, but this was not quantified.

Data analysis

The time courses of the antinociceptive responses resulting from the administration of the individual drugs and the drug combinations were constructed by plotting the mean number of flinches as a function of time. The areas under the resulting curves (AUC) were calculated using the trapezoidal rule (Tallarida and Murray, 1981). AUC was calculated for the two phases of the assay and the percent of antinociception for each phase was calculated according to the following equation (Ortiz and Castaneda-Hernandez, 2008): Percent of antinociception = [([AUC.sub.vehicle] - [ compound])/ [AUC.sub.vehicle]] x 100.

Dose-response curves were constructed using least-squares linear regression, and the antinociceptive [ED.sub.30] [+ or -] standard error (SE) values were calculated according to Tallarida (2000). The interaction between curcumin and diclofenac was characterized by isobolographic analysis in which it was assumed that the combinations are comprised of equieffective dose of the individual component drugs (Berenbaum, 1989). Thus, from the dose-response curves of each individual agent, the dose resulting in 50% of the effect ([ED.sub.50]) could be determined. However, considering a maximal effect to be 100% of the total suppression of formalin-induced nociception, it appeared that diclofenac was incapable of exerting a 50% suppression of the nociceptive response; thus, the calculation of [ED.sub.50] in the antinociceptive effect was not feasible. Therefore, we estimated the antinociceptive [ED.sub.30] instead of the antinociceptive [ED.sub.50]. It has been demonstrated that [ED.sub.30] values are suitable for isobologram construction with several agents (Tallarida, 2000; Ortiz and Castaneda-Hernandez, 2008), including diclofenac (Jimenez-Andrade et al., 2003). Subsequently, a dose-response curve was obtained by concurrent delivery of two drugs (curcumin plus diclofenac) in a fixed-ratio mixture (1:1) that was based on the [ED.sub.30] values of each individual agent. To construct the experimental antinociceptive effect-dose curve each group of rats received one of the following dose of the combination: curcumin [ED.sub.30] (18.6 mg/kg) + diclofenac [ED.sub.30] (19.8mg/kg); curcumin [ED.sub.30]/2 (9.3 mg/kg) + diclofenac [ED.sub.30]/2 (9.9mg/kg); curcumin [ED.sub.30]/4 (4.65 mg/kg) + diclofenac [ED.sub.30]/4 (4.95mg/kg); curcumin [ED.sub.30]/8 (2.33 mg/kg) + diclofenac [ED.sub.30]/8 (2.48 mg/kg); or curcumin [ED.sub.30]/16 (1.16 mg/kg) + diclofenac [ED.sub.30]/16 (1.24 mg/kg). The experimental [ED.sub.30] value for the curcumin-diclofenac combination was calculated from this curve.

The theoretically additive effect of the antinociceptive [ED.sub.30] was estimated from the dose-response curves obtained by sole administration of each drug (i.e., considering that the effect observed with the combination is the result of the sum of the effects of each individual drug). This theoretical [ED.sub.30] value was then compared with the experimentally derived [ED.sub.30] value to determine whether there was a statistically significant difference (Tallarida, 2000). The theoretical and experimental [ED.sub.30] values of the combinations were also contrasted by calculating the interaction index. This was calculated as experimental [ED.sub.30]/theoretical [ED.sub.30]. If the value is close to 1, the interaction is additive. Values lower than 1 are an indication of the magnitude of supra-additive or synergistic interactions, and values higher than 1 correspond to sub-additive or antagonistic interactions (Berenbaum, 1989; Tallarida, 2000, 2001, 2002; Ortiz and Castaneda-Hernandez, 2008).

Statistical analysis

Dose-response data were analyzed by one-way analysis of variance (ANOVA) with Tukey's test post hoc comparison (Jimenez-Andrade et al., 2003; Ortiz and Castaneda-Hernandez, 2008). The statistical significance of differences between the theoretical additive [ED.sub.30] value and the experimental derived [ED.sub.30] value was determined using Student's t test (Jimenez-Andrade et al., 2003; Tallarida, 2000). An experimental [ED.sub.30] value that was significantly lower that theoretical additive [ED.sub.30] value was regarded as an indication of a synergistic interaction between curcumin and diclofenac. Statistical significance was considered to be achieved when p<0.05. The interaction index obtained was compared to unity using the Student's t test (Jimenez-Andrade et al., 2003).

Pharmacokinetic study

Blood sampling

Animals were lightly anesthetized with ethyl ether. Then, PE catheters (a combination of PE-10 and PE-50 was used; I.D. 0.28 mm, O.D. 0.61 mm; I.D. 0.58 mm, O.D. 0.965 mm, respectively; Clay Adams, Parsippany, NJ) were surgically implanted into the caudal artery for the collection of blood samples as reported previously (Leon-Reyes et al., 2008).

Pharmacokinetic study design

Rats received an oral dose of carboxymethylcellulose or curcumin (31 mg/kg) and 45 min later oral diclofenac (10 mg/kg) was administered. Blood samples (100 [micro]l) were drawn from rats immediately after administration of diclofenac and at 2.5, 5, 10, 15, 30, 60,120, 240,360, and 480 min.

Analysis of diclofenac

Blood concentrations of diclofenac were determined by a high-performance liquid chromatography (HPLC) method developed in our laboratory. Briefly, whole blood samples (100 [micro]l) were placed into 1.5 ml Eppendorf tubes, and spiked with 0.1 mg/ml of naproxen as internal standard (25 [micro]l). Proteins were then precipitated by the addition of 875 [micro]l of methanol (total volume in the tube was 1000 [micro]l). Then, the samples were vortexed at maximal speed for 1 min, and centrifuged at 14,000 rpm for 10 min. Finally, the supernatant was transferred to a clean tube and 60 [micro]l aliquots were injected into the chromatographic system (Leon-Reyes et al., 2008).

Pharmacokinetic and statistical analysis

Retention times were 2.5 and 3.5 min for naproxen and diclofenac, respectively. Calibration curves were constructed for diclofenac concentrations in blood ranging from 0.1 to 12 [micro]g/ml. A linear relationship (r = 0.9999) was obtained when peak-height ratios of diclofenac to the internal standard were plotted against diclofenac blood concentration. Coefficients of variation were always lower than 15%, whereas accuracy ranged from 90% to 100%. Pharmacokinetic parameters were determined directly by non-compartmental analysis (Leon-Reyes et al., 2008). Data are expressed as mean value [+ or -]SEM. Comparisons between diclofenac bioavailability parameters was carried out by the Student's t-test and a p value of <0.05 was considered statistically significant.


Systemic antinociceptive effect of curcumin and diclofenac

Administration of formalin produced a typical pattern of flinching behavior. Oral administration of diclofenac and curcumin induced a dose dependent antinociceptive effect during phase two (p < 0.05; Fig. 1) but not during phase one (p > 0.05; data not shown). These results were consistent with previous observations of our group on the effects of diclofenac (Ortiz et al., 2003) and curcumin (De Paz-Campos et al., 2012) in the paw 1 % formalin assay. None of the treatments produced a significant alteration of ambulation or motor activity. The [ED.sub.30] values for curcumin and diclofenac in the second phase of the 1% formalin assay were 18.6 [+ or -]2.0 mg/kg and 19.8 [+ or -] 4.5 mg/kg, respectively.

Antinociceptive interaction of curcumin and diclofenac after systemic administration

The combination of diclofenac and curcumin exhibited significant (p < 0.05) dose-dependent antinociceptive effect in the second phase of the formalin test (Fig. 2, upper panel). An isobologram was constructed with these data (Fig. 2, lower panel). It appears that the experimental [ED.sub.30] was significantly lower that the theoretical value (9.8 [+ or -]0.7 against 19.2 [+ or -]2.4 mg/kg, p < 0.05). Moreover, the experimental [ED.sub.30] is located below to the zerointeraction line of the isobologram that is the line corresponding to a purely additive interaction (Jimenez-Andrade et al., 2003; Wagner and Ulrich-Merzenich, 2009). The interaction index for the curcumin-diclofenac combination was 0.51 [+ or -]0.08, being statistically different from 1 (p < 0.05). All these data consistently suggest that the interaction observed after the systemic administration of curcumin and diclofenac is synergistic.

Pharmacokinetic of diclofenac in combination with curcumin

To establish the possible pharmacokinetic interaction between treatments, a single oral dose of diclofenac (10 mg/kg) was given and time-courses of blood diclofenac concentrations observed with or without co-administered curcumin were determined. The pharmacokinetic profiles are showed in Fig. 3. Diclofenac concentrations were similar in presence and absence of curcumin. There was no significant difference in diclofenac bioavailability parameters when the NSAID was given alone or combined with curcumin (Table 1).


It has been observed that curcumin, the most abundant curcuminoid in turmeric (Curcuma longa), is able to elicit antinociception in several experimental pain models after systemic (De Paz-Campos et al., 2012; Mittal et al., 2009; Tajik et al., 2007,2008) and intrathecal (Han et al., 2012) administration. Moreover, it has been recently reported that synthetic curcumin derivatives are effective against inflammatory and neuropathic pain in mice (Lee et al., 2013). Hence, it appears that curcumin may be clinically useful for the treatment of clinical pain and thus deserves further study.

The paw formalin test is a well-characterized experimental model of nociception and has been used by several groups to study curcumin antinociceptive effect (De Paz-Campos et al., 2012; Han et al., 2012; Tajik et al., 2007). This test shows two phases of nociception. The initial phase appears to result from immediate and intensive stimulation of afferent nerve fibers induced directly by formalin, while phase 2 is produced by peripheral inflammatory processes and central sensitization (Tjolsen et al., 1992; Henry et al., 1999). Tajik et al. (2007), as well as our group (De Paz-Campos et al., 2012) have reported that systemic curcumin was effective only in the second phase of the paw formalin test. Notwithstanding, Han et al. (2012) observed that curcumin was effective in both phases of the assay after intrathecal administration. Furthermore, systemic curcumin has also been studied in the orofacial formalin test, which also exhibits two phases of nociception. Curcumin was effective in the two phases of this assay (Mittal et al., 2009). It should be noted that, although in both, the paw and orofacial formalin tests the nociceptive insult is provoked by the same agent, there are differences between these two assays. Particularly, spinal mechanisms are involved in the paw, but not in the orofacial assay (Raboisson and Dallel, 2004). The available evidence hence suggests that the antinociceptive effect of curcumin involves several mechanisms of action, which can be activated depending on route of administration, bioavailability and disposition of the drug.

NSAIDs, such as diclofenac, are effective analgesic and anti-inflammatory agents. However, they are not free of adverse effects that limit their use (O'Neil et al., 2012). Hence, combinations of NSAIDs with other analgesic agents appear to be a suitable strategy to reduce NSAID exposure, favoring safety. It has been reported that curcumin potentiates the anti-inflammatory of aspirin and rofecoxib in the cotton pellet granuloma pouch model (Nandal et al., 2009). Mittal et al. (2009) studied the effect of intraperitoneal curcumin in the orofacial formalin test. They reported that curcumin was able to induce a dose-dependent antinociceptive effect on the two phases of the assay and that the addition of a subanalgesic dose of diclofenac was able to increase the effect of the lowest curcumin dose assayed. No further observation was reported. Hence, the purpose of the present study was to characterize the interaction between curcumin and diclofenac. It should be noted that the interaction between two analgesic agents can be additive, synergistic or antagonistic and can be the result of pharmacodynamic or pharmacokinetic mechanisms (Fletcher et al. 1997).

We observed that diclofenac, curcumin and the fixed-dose ratio combination of diclofenac and curcumin were able to produce a dose-dependent antinociceptive effect in the paw formalin test. Isobolographic analysis suggests that the curcumin-diclofenac interaction is synergistic. Our data, however, presents limitations. A complete isobolographic analysis should be performed using [ED.sub.50] values estimated form several fixed-ratio mixtures, i.e. 3:1, 2:1, 1:1,1:2,1:3 (Wagner and Ulrich-Merzenich, 2009). In the present study, [ED.sub.50] value could not be estimated as diclofenac did not achieve a 50% reduction of formalin-induced nociception. Hence, isobolograms were constructed using [ED.sub.30] values and the isobologram was constructed with a single point. This approach, although limited, allows to clearly appreciating that the interaction between curcumin and diclofenac is synergistic, as the actually observed [ED.sub.30] value is located below the additive dose line, and was significantly lower than that expected considering a purely additive interaction. Moreover, the interaction index was significantly lower than unity. This approach has allowed us to describe the synergistic interactions of several analgesic agents in several previous studies (Jimenez-Andrade et al., 2003; Ortiz and Castaneda-Hernandez, 2008).

The synergistic interaction may be due to an increase in the bioavailability of one or the two components of the combination. A drug may alter the bioavailability of a second drug by affecting absorption form the gastrointestinal tract, first pass metabolism and/or systemic clearance. Diclofenac bioavailability can be reduced by a variety of agents including colestipol, cholestyramine (Al-Balla et al., 1994) and aspirin (Todd and Sorkin, 1988), but can be increased by other drugs such as diosmin, likely by inhibition of CYP2C9 (Rajnarayana et al., 2007). In vitro studies have shown that curcumin and its decomposition products inhibit several recombinant cytochrome P450s, including CYP2C9 (Appiah-Opong et al., 2007). A recent study using microsomes showed that curcumin impairs diclofenac metabolism by CYP2C9 (Wang et al., 2014). However, our results show that despite a potentiation of the analgesic effect, curcumin does not produce any significant alteration in diclofenac bioavailability in vivo. Hence, a pharmacokinetic interaction leading to augmented diclofenac exposure can be ruled out.

The synergism between curcumin and diclofenac can be due to a pharmacodynamic interaction. It has been suggested that a synergistic interaction can be obtained when two drugs with different and complementary mechanisms of action are associated. It has been reported that curcumin is able to modulate TRPV1 (Lee et al., 2013), TRPA1 (Leamy et al., 2011) and ATP-sensitive potassium channels (De Paz-Campos et al., 2012), as well as the descending monoamine system and opioid receptors (Zhao et al., 2011). On the other hand, diclofenac, as all NSAIDs, inhibits prostaglandin synthesis at the site of injury (Bjorkman, 1995), but also exhibits additional mechanisms of action (Gan, 2010). It has been reported that diclofenac activates the nitric oxide (NO)-cyclic GMP-K+ channel pathway at the peripheral, spinal and systemic (Ortiz et al., 2003, 2012) levels, inhibits H+-gated channels and inhibits substance P release in sensory neurons (Vellani et al., 2013). Therefore, it is likely that the observed synergistic interaction between diclofenac and curcumin involves the participation of several of the mechanisms mentioned above. Elucidation of the exact mechanism of action of this interaction, however, requires further investigation. Other aspect of the curcumin-diclofenac interaction that was not addressed here is the effect of diclofenac on curcumin bioavailability, which is known to be quite low after oral administration (Pan et al., 1999).

The interaction observed in the present study suggests that the diclofenac-curcumin combination could be an inexpensive alternative to produce an effective analgesic activity, superior to that of diclofenac alone.


The authors wish to thank Lourdes Gonzalez-Flores and Marta Patricia Gonzalez-Garcia for technical assistance. Marco A. De PazCampos and Liliana Zazueta-Beltran received fellowships from CONACYT.


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Article history:

Received 3 December 2013

Received in revised form 15 April 2014

Accepted 27 June 2014

Marco A. De Paz-Campos (a), Mario I. Ortiz (b,c),*, Aracely E. Chavez Pina (d), Liliana Zazueta-Beltran (a), Gilberto Castaneda-Hernandez (a)

(a) Departamento de Farmacologia, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico. DF, Mexico

(b) Area Academica de Medicina del Instituto de Ciencias de la Salud, Universidad Autonoma del Estado de Hidalgo, Pachuca, Hidalgo, Mexico

(c) Universidad del Futbol y Ciencias del Deporte, San Agustin Tlaxiaca, Hidalgo, Mexico

(d) Laboratorio de Farmacologia, Seccion de Estudios Posgrado e Investigacion. Escuela Nacional de Medicina y Homeopatia Instituto Politecnico Nacional, Mexico, DF, Mexico

* Corresponding author at: Laboratorio de Farmacologia, Area Academica de Medicina del Instituto de Ciencias de la Salud, Universidad Autonoma del Estado de Hidalgo, Eliseo Ramirez Ulloa 400, Col. Doctores, Pachuca, Hidalgo 42090, Mexico. Tel.: +52 77 1717 2000x2361; fax: +52 77 1717 2000x2361.

E-mail address: (M.I. Ortiz).

Table 1

Pharmacokinetic parameters of diclofenac after single oral dose
of 10 mg/kg alone or in the presence of curcumin at 31 mg/kg
orally in rat.

Treatment       [C.sub.max]         [T.sub.max]         [AUC.sub.o-r]

Diclofenac      5.9 [+ or -] 1.6    16.9 [+ or -] 4.0   470.3 [+ or -]
  + vehicle                                             161.7
Diclofenac      4.8 [+ or -] 1.6    8.1 [+ or -] 1.7    493.3 [+ or -]
  + curcumin                                            91.2

The results for [C.sub.max]. [T.sub.max] and AUC are given
as mean [+ or -] SEM of six repetitions for each treatment.
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Author:De Paz-Campos, Marco A.; Ortiz, Mario I.; Pina, Aracely E. Chavez; Zazueta-Beltran, Liliana; Castane
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Oct 15, 2014
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