Article: Concerns on Tramadol Overprescription

 Pain

The question of the correct use or not of tramadol cannot be considered in the abstract, but has to be seen in the whole vision of pain treatment. And this, in turn, requires refreshing some important features of pain. First of all, its importance: it has a great prevalence^2,4 and it is the most common reason for seeking medical care⁶.  Second, something that is often forgotten: pain is not a disease, but a symptom⁷. However, drug treatments are only focused on their relief, and they have important side effects. Finally, the definition⁸ of pain is very subjective: “An unpleasant sensory and/or emotional experience,
associated with actual or potential tissue damage, or
described in terms of such damage.”

Although they share medicines, the different types of pain have different treatments. Neuropathic pain is usually difficult to treat, and normaly, different medicines have to be tested until the one that best suits the patient is found. Tramadol is licensed for this use, and thus, should be used when necessary. This, according to the National Institute for Health and Clinical Excellence  guideline⁹, is as third line treatment.  The recommendations from International Association for the Study of Pain are similar¹⁰.

However, the recommendations for acute pain are not so well defined, so important differences are found between guidelines:  Tramadol’s recommended use (in combination with paracetamol) varies from first¹¹ to third¹² line treatment. This  lack of consensus increases the risk of doctor´s preferences to prevail over evidence based treatment. Moreover, the WHO pain relief ladder¹³, initially developed for cancer pain but now widely used, opens the door to the use of tramadol both as a weak opioid in step 2 or as adjuvant in any¹¹.

Tramadol’s mechanism of action 

The pharmaceutical industry, with last years’ aggressive marketing and highly promotion of opidoids¹⁴ is behind the overdiagnosis and thus, overprescription of opioids, which has been mainly reported in the United States⁵. In tramadol’s case, pharmaceutical companies took advantage of tramadol’s “special” mechanism of action, and contributed to spread the idea of a drug with opioids’ effectiveness but with little of their side effects.

It is indeed true that tramadol is different from other opioids:  Apart from its weak opioid agonist action it releases serotonin and inhibits the reuptake of noradrenaline¹⁵. Incidentally, point out the confusion created since not everybody describes this drug as a weak opioid. Opioids in persistent non-cancer pain² and British Pain Society’s Opioids for persistent pain: good practice ¹⁶, place the tramadol, incorrectly, among the strong opioids.

Being weak agonist does not mean that it will not have the adverse effects of the opioids, and, since it is known, these are not trivial. In addition, it is worth remembering that the 80% of patients taking opioids will experience at least one adverse effect¹⁶.  Tramadol’s release of serotonine and the inhibition of reuptake of noradrenalin contribute to the relief of pain, but they are, in turn, source of additional interactions, as it will be later seen.

Effectiveness comparison

Drug’s first acid test is the efficacy they show. A good tool for that is the table 1, taken from the Oxford league table of analgesics¹⁷. This table is based on randomised, double-blind, single-dose studies in patients with moderate to severe acute pain and shows the number of patients that need to be given the active drug (NNT) to achieve at least 50% pain relief in one patient compared with a placebo over a 4 to 6 hour treatment period.

Although, fortunately, tramadol hardly ever is prescribed instead of paracetamol, it is never bad to remember why this should continue to be like that: it is just less effective (and has more side effects). It has also to be noted that ibuprofen is one of the most effective in the whole table, but its side effects¹⁸ make it.

More tricky is to decide which combination is better:  paracetamol + tramadol or  paracetamol + codeine. Table’s data have the drawback that the paracetamol dose in the combination is different, this is, there is not paracetamol 1000 + tramadol 100 to check against the paracetamol 1000 + codeine 60.  With the available data what can be said is that there seem to be no big differences in effectiveness. Other sources support this idea:  paracetamol 325mg + tramadol 37.5mg can be as effective as parecetamol 300 + codeine30¹⁹.

Side effects and interactions comparison

If similar in effectiveness, the next step is to look at the side effects of the different drugs. Since both codeine and tramadol are opioids, they share this kind of drug’s side effects^2,16,20,21: sedation, dizziness, nausea, vomiting, constipation, respiratory depression, tolerance and physical dependence. However, tramadol has fewer of the opioids’ typical side effects^15,22,23: less respiratory depression, less constipation and less addition potential²⁴. This has lead to postulate its use for chronic pain^15,24, but as for the rest of opioids data demonstrating sustained analgesic efficacy in the long term are lacking¹⁶. Anyhow, there are other reasons for not recommending it as first line treatment for chronic pain.

Opioids interact with quite a lot of drugs, and in this point tramadol and codeine are similar. However, tramadol has its own particular interactions^22,23, numerous and important:

• enhances antiocoagulant effect of coumarins
• increases serotonergic effects when given with duloxetine, mirtazapine or venlafaxine. This may lead to serotonergic syndrome¹⁰.
• increases risk of CNS toxicity when given with SSRIs or triciclics.
• increases risk of convulsions when  given with antipsychotics.
• possibly increases risk of convulsions when given with atomoxetine.
• its effects are reduced by carbamacepine
• its effects are possibly antagonized by ondansetron

Moreover, withdrawal problemsmay occur even after short period of doses and with modified release formulations¹⁶. All this drawbacks may explain why a French study²⁵ on the reporting rate of adverse drug reactions(ADR) of  dextropropoxyphene, tramadol and codeine (combined with paracetamol)  it was found that although the rate of deaths due to ADRs did not differ among the three combinations, “the rate and ‘seriousness’ of reported ADRs were the highest with tramadol+paracetamol and the lowest with codein+paracetamol”.

Definitely, the interaction point tips the balance to in favour of using codeine (with paracetamol) as first option.

What pharmacist can do?

The idea of writing an article came from what I said in the first paragraph: my surprise at how frequently is tramadol prescribed in the hospital where I am.  More astonishing even is that hospital’s joint phormulary²⁶ states it only for patients that do not tolerate the adverse effects of other opioids or paracetamol. Unfortunately, this is seldom the cause of its prescription.

Therefore, there is need of not only good guideline; this information has to reach the doctors. Pharmacists should remind them the evidence and to query when recommendations are not followed. We have an important role to play in this chapter of the evidence based medicine, and we may have to do even more, since we might have double dose of tramadol in the near future²⁷.

Table 1