Background It has been assumed that the analgesic and anti-inflammatory effects of diclofenac (DIC) are directly related to drug blood concentrations and, therefore, the time course of the intensity of the response is parallel to that of circulating drug levels. There is evidence, however, that DIC effects last for several hours even if the drug is no longer detectable in the circulation.¹ It has also been suggested its analgesic action explained in part, by a peripheral mechanism.² If such is the case, DIC response depends on its concentration at the injury site, rather than in plasma. Therefore, a formulation yielding a quick-slow release should show an improved efficacy, as it will allow a rapid drug transfer to the effect compartment, as well as a prolonged presence of DIC in its site of action.³

Objectives The purpose of this work was to examine the anal-gesic efficacy of diclofenac-cholestyramine (DC) a formulation with a quick-slow release profile,⁴ compared to diclofenac-sodium (DS) in patients with osteoarthrosis (OA). Additionally, we further investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of DIC in rats, after systemic and local administration, to yield a rational basis to the clinical observations.

Methods The analgesic effect of DC (b.i.d.) and DS (50 mg t.i.d.) was assayed in 126 patients with OA under a randomised double-blind design. Pain intensity was estimated by means of a visual analogue scale. The PK-PD relationship for DIC was deter-mined in rats using the pain-induced functional impairment model⁵ by the effect compartment approach.³ The local antinociceptive effect (ANE) of DIC was studied in rats injured by a plantar injection of 1% formalin in a hind paw,⁶ and direct drug injection at the injury.

Results Both treatments exhibited a similar analgesic efficacy after 12 weeks. This was observed despite the fact that DS was given t.i.d. while DC was given b.i.d. at a lower daily dose. No significant differences in tolerability were detected. Therefore, clinical results strongly suggest that DC exhibits an improved PK-PD profile. Such assumption was supported by animal studies. Local administration of DIC in formalin-injured rats resulted in a significant ANE compared to saline. This effect was restricted to the local level, as drug injection in the contralateral paw was ineffective. PK-PD modelling in the rat showed that there is no direct link between DIC ANE and its blood concentrations. However, the effect could be related to drug effect-site concentrations, being consistent with the observation of a local effect. Computer gene-rated simulations showed that a quick-slow release profile, such as that of DC, allows an optimised DIC transfer to the effect compartment and a prolonged response.

Conclusion DC, a formulation with a quick-slow release profile, exhibits good clinical efficacy and tolerability. PK-PD modelling shows that the quick-slow release profile optimises DIC transfer to its site of action and thus improves the pharmacological response.

References

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5. Granados-Soto, et al. J Pharm Pharmacol. 1992;44:741

6. Islas-Cadena, et al. J Pharmacol Toxicol Methods 1999;42:87