MD, Geoff Clarke, FCB, Tim Grattan, FCB, Angelika Beisel, Christian Mueller, MD, Ulrike Werner, PhD, Gerd Kobal, MD, and Kay Brune, MD A cetaminophen (paracetamol) is a nonopioid, non-NSAID (nonsteroidal anti-inflammatory drug) analgesic that is widely used as an over-the-counter drug for the treatment of mild to moderate pain. The mechanism of action is not yet clarified but may involve inhibition of cerebral prostaglandin synthesis 1-3 and central serotonergic or opioidergic pathways. [4][5][6] Caffeine is a common adjuvant to analgesic drugs. 7,8 The mechanism of its putative analgesia-enhancing effect remains unclear. Caffeine is thought to produce competitive antagonism at adenosine receptors, 9,10 induce changes of the pharmacokinetics of acetaminophen, 11,12 and induce changes in mood, 13 all of which may lead to enhancement of the analgesic action of acetaminophen.The aim of this study was to investigate the analgesic activity of 1000 mg acetaminophen compared with caffeine alone and the combination of both using an experimental human pain model. To define caffeine actions, subjective and objective pain assessments and pharmacokinetic evaluations were included in this study. The pain model used is based on evoked cortical potentials and pain ratings following specific stimulation of nasal nociceptors with gaseous carbon dioxide (CO 2 ), 14,15 and it is also based on pain ratings after tonic painful stimulation of the nasal mucosa with dry air of controlled flow and temperature. 16 This model has been applied successfully to quantify the activity of several nonopioid 15,[17][18][19][20][21][22][23] METHODS SubjectsThe study was approved by the ethics committee of the University of Erlangen-Nuremberg. It was conducted according to the Declaration of Helsinki on biomedical research involving human subjects (Somerset West amendment). Twenty-four subjects were enrolled (12 men, 12 women, aged 18-45 years [median, 26 years]), all within ±20% of their ideal body weight (men: median weight, 75 kg; range, 67-86 kg; women: median weight, 57 kg; range, 51-66 kg). All were found to be healthy by routine clinical examination and laboratory tests at the beginning and end of the study. Oral contraceptives were the only medication allowed during the study. ProtocolThis was a single-center, 4-way crossover, randomized, placebo-controlled, double-blind study. Each subject received a single dose of 1000 mg acetaminophen (Panadol), 130 mg caffeine, 1000 mg acetaminophen plus 130 mg caffeine (Panadol Extra), or placebo, taken with 150 mL of water, after fasting for 6 hours. Subjects remained fasted but were allowed to drink water during the study period. The washout periods between drug administrations were at least 6 days.On each study day, participants were subjected to 5 periods of phasic pain lasting for 20 minutes each and applied at baseline and at 20, 40, 90, and 180 minutes after receiving medication. During a stimulus period, 16 stimuli of 60% v/v CO 2 and 32 stimuli of 70% v/v CO 2 were delivered to the left ...

The purpose of this investigation was to study the dissolution behavior of paracetamol and ibuprofen in the presence of a range of selected potential excipients. First, a pH-solubility profile was generated for both drugs, and the effect of changing hydrodynamic conditions on the intrinsic dissolution rate was investigated. It was established that both drugs dissolved according to the diffusion-layer model. Paracetamol solubility (approximately 20.3 mg mL(-1)) did not vary from pH 1.2-8.0, corresponding to the in vivo range in the gastrointestinal tract. Ibuprofen had an intrinsic solubility of approximately 0.06 mg mL(-1), and pK(a) was calculated as 4.4. Second, the effects of selected potential excipients (lactose, potassium bicarbonate, sodium bicarbonate, sodium chloride, and tartaric acid) were evaluated by measuring the effect of the inclusion of each additive in the dissolution medium on drug solubility, drug intrinsic dissolution rate, and solution viscosity. The results were evaluated using the diffusion-layer model, and it was determined that for paracetamol, the collected data fitted the model for all the excipients studied. For ibuprofen, it was found that there were differences between the excipients that raised the solution pH above the pK(a) to those that did not. For the excipients raising the pH above the pK(a), the effect on intrinsic dissolution rate was not as high as that expected from the change in drug solubility. It was postulated that this might be due to lack of penetration of the excipient into the drug boundary layer microenvironment. Formulators may calculate the effect of adding an excipient based on solubility increases but may not find the dissolution rate improvement expected.

The primary objective of this four-way crossover study was to compare the concentration-time profile of paracetamol from a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with a conventional paracetamol tablet (P), in a panel of 28 fed and fasted healthy volunteers. The results demonstrated that paracetamol was absorbed more rapidly from tablets containing sodium bicarbonate compared to conventional tablets, as indicated by a shorter tmax in both the fed and fasted state and a higher Cmax in the fasted state. The two formulations were bioequivalent with respect to area under curve (AUC). Food did not affect the extent of absorption from either formulation, as indicated by AUC, however, food did reduce the rate of absorption from both formulations, as indicated by a longer tmax and a lower Cmax. Metabolic activation of paracetamol to its oxidation metabolites, as assessed by combined partial clearances to subsequent secondary metabolites cysteine and mercapturic acid conjugates, indicated that the two formulations were bioequivalent in this respect.

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