Supra-additive effects of tramadol and paracetamol in a human pain model

Department of Anesthesiology, University Hospital Erlangen, Krankenhausstrasse 12, D-91054 Erlangen, Germany.
Pain (Impact Factor: 5.21). 07/2008; 136(3):262-70. DOI: 10.1016/j.pain.2007.06.036
Source: PubMed


The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.

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    • "In contrast, it may be a quite powerful inhibitor of hyperalgesia of the secondary hyperalgesia type, which is related to a heterosynaptic mechanism of spinal central sensitization. This corroborates previous findings in an intracutaneous electrical hyperalgesia model [22], [23] and reports on the efficacy of acetaminophen on laser-evoked pain in panretinal photocoagulation [58] and mechanical experimental pain involving hyperalgesia to blunt pressure 109. "
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    ABSTRACT: This study tested a modified experimental model of heat-induced hyperalgesia, which improves the efficacy to induce primary and secondary hyperalgesia and the efficacy-to-safety ratio reducing the risk of tissue damage seen in other heat pain models. Quantitative sensory testing was done in eighteen healthy volunteers before and after repetitive heat pain stimuli (60 stimuli of 48°C for 6 s) to assess the impact of repetitive heat on somatosensory function in conditioned skin (primary hyperalgesia area) and in adjacent skin (secondary hyperalgesia area) as compared to an unconditioned mirror image control site. Additionally, areas of flare and secondary hyperalgesia were mapped, and time course of hyperalgesia determined. After repetitive heat pain conditioning we found significant primary hyperalgesia to heat, and primary and secondary hyperalgesia to pinprick and to light touch (dynamic mechanical allodynia). Acetaminophen (800 mg) reduced pain to heat or pinpricks only marginally by 11% and 8%, respectively (n.s.), and had no effect on heat hyperalgesia. In contrast, the areas of flare (-31%) and in particular of secondary hyperalgesia (-59%) as well as the magnitude of hyperalgesia (-59%) were significantly reduced (all p<0.001). Thus, repetitive heat pain induces significant peripheral sensitization (primary hyperalgesia to heat) and central sensitization (punctate hyperalgesia and dynamic mechanical allodynia). These findings are relevant to further studies using this model of experimental heat pain as it combines pronounced peripheral and central sensitization, which makes a convenient model for combined pharmacological testing of analgesia and anti-hyperalgesia mechanisms related to thermal and mechanical input.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Tramadol/paracetamol 37.5/325 mg provided similar efficacy to that of codeine/paracetamol 30/300 mg in patients with chronic back pain and similar analgesia to hydrocodone/paracetamol 10/650 mg in patients with postoperative dental pain [15] [16]. The combination acts synergistically and guarantees the rapid onset of paracetamol and the prolonged analgesic effect of tramadol good tolerability [6] [23] [24]. "
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    ABSTRACT: Background: Tramadol/paracetamol is a fixed-dose combination prescribed for the relief of moderate to severe pain. The combination acts synergistically and guarantees the rapid onset of paracetamol and the prolonged analgesic effect of tramadol with good tolerability. These drugs are often used in various formulations in the treatment of patients with postoperative pain, e.g. after stomach resection. Gastrectomy leads to pathophysiological changes within the alimentary tract, which may affect the process of drug absorption. The aim of the research was an analysis of the pharmacokinetics of tramadol/paracetamol from effervescent and conventional tablets in patients after total gastrectomy. Methods: The research was carried out on patients after gastrectomy with Roux-en-Y reconstruction. The patients received two tramadol/paracetamol fixed-dose combination tablets in a single orally administered dose of 75/650 mg (2 × 37.5/325 mg). The patients were subjected to one of the two study drug group with: I. effervescent tablet (ET) (n = 14; mean [SD] age, 63.4 [10.1] years; weight, 75.5 [15.3]kg; and BMI, 26.0 [4.6]kg/m(2)) and II. conventional tablet (CT) (n = 12; mean [SD] age, 66.8 [7.7] years; weight, 79.8 [17.8]kg; and BMI, 27.4 [5.3]kg/m(2)). Blood samples were collected within 10 h after the drug administration. The plasma concentrations of tramadol and paracetamol were measured with validated HPLC (high-performance liquid chromatography) method with UV detection. Results: The comparison of the paracetamol and tramadol C(max) ratio for the ET group with that of the CT group gave ratios of 1.16 [90% confidence interval (CI) 1.06, 1.27] and 0.86 (90% CI 0.72, 1.02), respectively. The comparison of the paracetamol and tramadol AUC(0-t) ratio for the ET group with that of the CT group showed ratios of 0.99 (90% CI 0.88, 1.10) and 1.00 (90% CI 0.82, 1.22), respectively. The comparison of the difference for the effervescent and conventional formulation gave an estimated decrease in t(max) of 0.5 h for paracetamol and 0.13 h for tramadol. Conclusions: In view of the changes in the pharmacokinetics of paracetamol and tramadol in the patients after gastric resection for both formulations compared the conventional tablet seems to be more appropriate due to the comparable rate of absorption of both substances, higher concentrations of tramadol and comparable exposure to paracetamol.
    Full-text · Article · Feb 2014 · Pharmacological reports: PR
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    • "Analgesic synergy of fixed-dose combination products for pain relief in humans has, to our knowledge, so far only been demonstrated for tramadol/paracetamol [84]. Details concerning the experience with this combination are given below for individual indications. "
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    ABSTRACT: The family practitioner plays an important role in the prevention, diagnosis, and early management of chronic pain. He/she is generally the first to be consulted, the one most familiar with the patients and their medical history, and is likely the first to be alerted in case of inadequate pain control or safety and tolerability issues. The family practitioner should therefore be at the center of the multidisciplinary team involved in a patient’s pain management. The most frequent indications associated with chronic pain in family practice are of musculoskeletal origin, and the pain is often multimechanistic. Fixed-dose combination analgesics combine compounds with different mechanisms of action; their broader analgesic spectrum and potentially synergistic analgesic efficacy and improved benefit/risk ratio might thus be useful. A pain specialist meeting held in November 2010 agreed that the fixed-dose combination tramadol/paracetamol might be a useful pharmacological option for chronic pain management in family practice. The combination is effective in a variety of pain conditions with generally good tolerability. Particularly in elderly patients, it might be considered as an alternative to conventional analgesics such as NSAIDs, which should be used rarely with caution in this population.
    Full-text · Article · Apr 2013
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