Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis: comparison with paracetamol

Abstract

Both the analgesic drugs tramadol and paracetamol are widely used for the symptomatic therapy of osteoarthritis (OA). The aim of this double-blind, randomised study in patients with knee OA was to compare their effects on synovial fluid concentrations of interleukin (IL)-6 and substance P (SP). Moreover, we evaluated plasma and synovial fluid concentrations of tramadol and its active metabolite (O-desmethyl-tramadol, M1) after oral treatment with this drug. Twenty patients were enrolled. A group of 10 patients received tramadol (50 mg three times a day), and another group of 10 patients were treated with paracetamol (500 mg three times a day) for 7 days. Both drugs significantly reduced the intensity of joint pain. The synovial fluid concentrations of SP were significantly reduced only by the treatment with tramadol. In this group of patients, IL-6 synovial fluid concentrations were slightly, but not significantly, decreased. Paracetamol did not significantly change the synovial fluid concentrations of SP and IL-6. After oral administration, a considerable amount of tramadol was measurable in synovial fluid. Both in plasma and synovial fluid the concentrations of M1 were markedly lower than those of tramadol, with a T/M1 ratio of 14.7±4.6 and 9.3±3.9, respectively. These data demonstrate that the activity of tramadol may involve the modulation of inflammatory mediators. Moreover, they indicate that after oral treatment with tramadol, both the parent drug and its active metabolite can penetrate into synovial fluid.

Introduction

Tramadol hydrochloride (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride has become a drug of increasing interest due to its success in the management of several types of pain in humans [1], [2]. However, its pharmacological profile is not completely understood [3], [4], [5]. The early preclinical studies detected an affinity of tramadol for μ-opioid receptors [6]. However, it has been frequently noted that the affinity of tramadol for these receptors is too weak to account for the strong analgesic effects of this drug. Subsequently it has been demonstrated that the M1 metabolite of tramadol (O-desmethyl-tramadol) shows higher affinity for opioid receptors than the parent drug, and may contribute to its pharmacological effects [7], [8], [9]. However, the relative contribution of this metabolite in humans remains to be established. In addition, tramadol is able to inhibit the neuronal reuptake of serotonin and noradrenaline [3], [4]. We have previously demonstrated that tramadol exerts some anti-inflammatory effects in animals [10]. Moreover, we demonstrated that the anti-inflammatory action of tramadol is not related to a direct inhibitory effect on the formation of prostanoids [11].

In the last few years evidence has accumulated that opioid receptors in the periphery may inhibit nociception in inflammation, and that opioid drugs can induce analgesic effects in patients with osteoarticular pain also by interacting with opioid receptors located in the joint [12], [13], [14], [15].

It is increasingly clear that a number of mediators of the nervous, immune, and endocrine systems interact in the initiation and perpetuation of arthritic lesions. In this context, a pro-inflammatory and pro-algesic action is exerted by the neuropeptide substance P (SP), which can be released in the joint by primary sensory afferent fibers activated by mechanical, thermal and chemical stimuli [16]. Moreover, the synovial tissue lining the joint contains infiltrating immune cells and activated fibroblast that produce several pro-inflammatory cytokines [17]. In particular, interleukin-6 (IL-6) has been demonstrated to be linked to tissue erosion, its levels in the synovial fluid seem to correlate with the stage of OA, and its concentrations are modified by pharmacological treatments aimed at reducing OA pain [18]. Thus, the question arises on the possibility that tramadol-induced anti-inflammatory effects might involve SP and/or IL-6, and that such action might be relevant in order to better explain the analgesic effect of this drug in several clinical conditions of articular pain.

The analgesic drug paracetamol represents the first-line pharmacological therapy for OA [19]; however, it is well known that this drug does not exert anti-inflammatory effects. Moreover, it has been demonstrated that in some patients affected by OA, the pain is inadequately controlled with paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) [20], [21]. In these circumstances, tramadol can be considered for use as analgesic.

For all the above cited reasons, we considered it of interest to compare the effects of tramadol and paracetamol on joint pain, and on synovial fluid concentrations of IL-6 and SP in patients with knee OA and synovial effusion. Moreover, we evaluated for the first time plasma and synovial fluid concentrations of both tramadol and its M1 active metabolite after treatment with tramadol by oral route.