Fixed combination tramadol/paracetamol as an effective and safe option for long-term pain treatment even in polymorbid patients

Dangerous Overuse of NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very popular among patients for acute and chronic pain treatment due to their good efficacy and minimal occurrence of tolerance even with long-term administration. However, this leads to their overuse as they are mistakenly perceived as 'completely harmless' drugs—unlike opioids, where patients usually fear potential dependence.

NSAIDs do have an important place among analgesics, but they should be used only short-term, because regular or long-term administration can be associated with serious and potentially fatal adverse effects (AEs)—gastrointestinal (GI), cardiovascular (CV), or damage to the kidneys and liver. Given the growing trend of self-medication and the considerable 'creativity' of Czech patients who often do not adhere to the recommended dosages or combine prescribed medications with over-the-counter products, the risk of overdose, drug interactions, and adverse side effects of pain therapy increases further.

The potential toxicity of NSAIDs is clinically significant, especially in the older population with polypharmacy, who represent the majority of users of these analgesics. It is risky to use them concurrently with corticosteroids, antiaggregants, anticoagulants (including direct-acting—DOACs/formerly NOACs), and, of course, other NSAIDs. Therefore, especially in geriatric patients, it is recommended to favor paracetamol, opioids, or their combinations over systemically used NSAIDs.

Exaggerated Fears of Opioids? Caution and Individualization Are Key

Opioids, on the other hand, can be considered relatively safe analgesics as their administration is not associated with toxicity to parenchymal organs, hematopoiesis, or interference with the coagulation system. They are thus suitable, for example, for polymorbid patients. Of course, caution must be exercised with higher dosages and rapid increases in doses by the patient, and individualization of therapy is key in these cases.

The main AEs of opioids that need to be considered are constipation, respiratory depression, disruption of sleep architecture, or the development of physical dependence. Despite these drugs having various adverse effects, practically none of them, with adequate therapeutic management, endanger the patient's life.

One way to minimize these risks as much as possible is to use the lowest possible doses of tramadol potentiated by paracetamol. Tramadol is a weak opioid, and its AEs occur much less frequently than with strong opioids. In any case, it is always necessary to consider the individual benefit and risks of treatment for each patient and strive for active risk management. Appropriate guidelines include the 'Methodological Guidelines for Pain Pharmacotherapy' and other recommended procedures from professional associations.

Changing Approach to Analgesic Combinations

The World Health Organization (WHO) establishes three levels of pain pharmacotherapy according to its intensity, with adjuvant drugs, most commonly antidepressants and anticonvulsants, added to the primary analgesic suitable for each level.

In recent years, there has also been a change in the approach to indicating combined analgesics. While they were previously recommended for acute and postoperative pain therapy—since the components used, although potentiated in analgesic effect, exhibited significant organ toxicity or led to long-term abuses difficult to divert—combined analgesics have now come to the forefront. This has been made possible primarily by fixed combinations of active substances that have synergistic or additive effects, allowing for the advantageous reduction of the dose of individual components.

Thus, in small doses allowing safe use several times a day, fixed combinations include acetylsalicylic acid (ASA), paracetamol, codeine, caffeine, and tramadol.

Not All Tramadol is the Same

For example, tramadol monotherapy, especially in higher doses, is risky because beyond a certain analgesic ceiling, it primarily leads to psychological dependence. Consequently, it is necessary to switch tramadol to another preparation in time, use adjuvant medication, or, in the progression of the painful state, transition to strong opioids. Particularly dreaded is the potentially life-threatening serotonin syndrome, which occurs if high doses of tramadol are combined with antidepressants. Conversely, in the small doses of tramadol most often used in combination preparations, serotonin syndrome practically does not occur.

Tramadol is currently available on the market in fixed combination with paracetamol and NSAIDs, and in these limited doses (37.5 mg tramadol/325 mg paracetamol), it represents a gentle analgesic that, even with longer medication, does not cause serious AEs. On the contrary, it is much safer during prolonged use than the chronic use of classic NSAIDs. It can also be a rescue medication during the long-term use of other analgesics (including opioids) and often the first choice for mild to moderate pain in the elderly and polymorbid patients. In these situations, even with longer use, there are no risks of AEs or abuses, organ safety is multiple times higher than with chronic NSAID medication and the risk of GI complications is minimized.

(esr)

Sources:
1. Vranová V. Treatment of chronic pain—a risk analysis of pain treatment with nonsteroidal anti-inflammatory drugs and tramadol in fixed combination with paracetamol. Pharmacotherapeutic Review 2023; 8 (5): 1–2.
2. Kozák J. Commentary. Pharmacotherapeutic Review 2023; 8 (5): 2–4.