Pain therapy

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Fixed combination of tramadol plus paracetamol to the effective

By combining analgesics with different starting points, pain therapy can be optimized. The fixed combination of tramadol and acetaminophen offers synergistic effects. It causes less side effects with the same analgesic activity than with the treatment with the monosubstances. The fixed combination (Zadiar) is indicated for the treatment of moderately severe to severe pain and should come to the market in spring 2003.

In pain therapy, the treatment concepts are changing. Monotherapy is no longer an incontrovertible doctrine, because useful combination analgesics can have advantages. Because the sensible combination of different starting points in the pain control, an effective pain relief can be mediated with significantly lower drug concentration of the individual substances and thus with a lower risk of side effects.

Combinations are useful if it is possible to achieve an additive or even a synergistic and therefore superadditive effect by mutual reinforcement of the action of the monosubstances. Other potential goals include widening the spectrum of activity, and improving compliance and application security through lower revenue.

A prerequisite for the rational development of fixed combination preparations, however, is to find partners with suitable pharmacological properties, the dosage of which must be well coordinated and the clinical efficacy must be documented in controlled studies.

Synergistic effects

An example of how synergistic effects are possible under such conditions is provided by the two active ingredients paracetamol and tramadol, which have been widely used as analgesics in pain therapy for many years, and in the coming year by Grünenthal GmbH as a fixed combination for pain therapy be introduced to the market. The product contains 37.5 mg tramadol and 325 mg paracetamol and is indicated for the treatment of moderate to severe pain.

It uses the different mechanisms of pain relief of the two components, as well as the different kinetic properties. Because while paracetamol provides rapid onset of pain relief (less than 20 minutes) due to its rapid onset of action, the prolonged duration of action of tramadol (over five hours) also ensures long-lasting analgesia.

At the selected dose ratio, which has been shown to be particularly effective in the studies and has been chosen from a clinical point of view, there is at the same time an increase in activity compared with the two individual components. This is shown in a study in 462 patients with lumbago or osteoarthrosis, who were randomized to double-blind treatment for four weeks with either tramadol plus paracetamol or a combination of codeine and paracetamol.

The patients were able to freely titrate the dose of their medication until pain was relieved. An equally good pain relief was achieved with the combination of tramadol / paracetamol as with the comparator medication, but the side effect profile was clearly more favorable. The study participants complained in particular less often about drowsiness and also less often about constipation.

Opioid-saving effect

In a second study, the tramadol / acetaminophen combination was studied in 119 patients with subacute back pain and compared with tramadol 50 mg. The patients received the respective medication double-blind randomized for ten days, whereby they could also titrate the dosage to freedom from pain.

The tramadol / acetaminophen combination showed the same level of effectiveness as tramadol alone, with a clear tramadol-sparing and therefore opioid-sparing effect. Because the tramadol dose was in the combination group on average 165 mg and in the control group on average 214 mg.

The difference explains the significantly lower opioid-typical side effects in the verum group. Especially accompanying reactions such as nausea and vomiting, drowsiness, constipation and sweating were clearly stated as a side effect. The fixed combination thus proved to be significantly more compatible with the sole administration of opioid with comparable pain relief.


Tramadol is commonly given for severe pain, but five to ten percent of patients do not respond to the painkilling medicine. A genetic test that can be used to identify this patient group already exists, but it takes too long for the daily routine of the clinic and is expensive. Scientists at a clinic in Caen, France have now developed a faster and cheaper test. It is based on the determination of a conversion product of tramadol called O-demethyltramadol or ODT short.

The background: Tramadol must first be activated in the body to actually effective ODT. This is usually done in the liver using a specific enzyme. If this is missing, the activation – and thus the pain relief – stops. To identify the patients who lack the enzyme, the researchers found a simple and effective way: 24 hours after administering the analgesic, they determine the ratio of ODT to tramadol in the blood. If it is less than 0.1, this indicates that the patient is not responding to tramadol. The enzyme also plays a role for other drugs.