Tramadol hydrochloride (Tramal)
In recent years, a synthetic central-acting analgesic of the last generation — tramadol hydrochloride (Tramal) — has been widely used to treat moderate and severe pain of various origins. This drug (the fourth most commonly prescribed analgesic in the world) is used to treat both oncological and non-oncological pain in 70 countries of the world . A large database has now been accumulated on the use of this original drug. Analysis of these data gives grounds to draw the attention of practitioners dealing with acute and chronic pain syndromes of high intensity to the basic principles of the use of tramadol hydrochloride in rheumatology.
Tramadol refers to analgesics of moderate strength due to weak opioid and secondary non-opioid effects. The uniqueness of the dual mechanism of action of tramadol is explained by the fact that part of its molecules activate the analgesic m-opioid receptors. At the same time, the affinity of tramadol to these receptors is 6 thousand times weaker than that of morphine; therefore, the narcotic potential of this drug is minimal. The second part of the tramadol molecules simultaneously activates non-opioid analgesic systems – inhibits the reuptake of serotonin or norepinephrine in the nerve synapses. Due to the activation of non-opioid noradrenergic and serotonergic systems, tramadol inhibits the transmission of pain impulses at the spinal level. The effect of each mechanism of action is rather weak, but in general there is not just a summation, but a multiple increase in the general anesthetic effect. It is the synergism of the two mechanisms of action of tramadol that makes it highly effective. The low affinity of tramadol to opiate receptors explains the fact that in recommended doses tramadol does not cause respiratory depression and blood circulation, impaired motility of the gastrointestinal tract (constipation) and urinary tract, with long-term use does not lead to the development of drug dependence.
In various rheumatic diseases, tramadol hydrochloride was studied using controlled (including double-blind) randomized trials. It was shown that the drug relieves severe and moderate pain in the treatment of osteoarthritis of large joints to the same extent as diclofenac or meloxicam, without causing side effects inherent in NSAIDs. The drug was highly effective for pain in the lower back, reliably reduced pain in rheumatoid and other arthritis, as well as some systemic diseases of the connective tissue. Especially effective was the long-term (4–6 months) treatment of fibromyalgia in doses of 100–200 mg, which made it possible to achieve not only a complete relief or reduction to a minimum of pain, but also the disappearance of functional disorders, improvement of the patient’s psychological state and restoration of working capacity. Available in the literature data allow us to recognize tramadol as a fairly convenient analgesic for the correction of various manifestations of acute and chronic pain of moderate and strong intensity not only in oncology, but also in rheumatology.
Recently, tramadol hydrochloride has been recognized as an alternative in the treatment of musculoskeletal pain, especially in patients with moderate to severe pain, who are not helped or who have contraindications to the administration of paracetamol, NSAIDs or weak opioids. In September 2000, the American College of Rheumatology gave new recommendations for the treatment of osteoarthritis of the knee and hip joints, according to which, in particular, acetaminophen and NSAIDs are prescribed for weak and moderate pains, and tramadol can be recommended for moderate to severe pain.
Analysis of the literature and the experience of the staff of the Institute of Rheumatology allows you to determine the indications for use of tramadol in rheumatic diseases. Analgesic therapy with tramadol may be useful in patients with moderate or severe pain, when the ongoing antirheumatic therapy has insufficient analgesic effect, in particular:
- in case of exacerbation of pain syndrome in the presence of NSAIDs, when increasing the dose of the latter is undesirable (gastropathy, peptic ulcer or 12 duodenal ulcer);
- in patients receiving glucocorticosteroids, since the use of tramadol does not increase the risk of developing serious gastrointestinal disorders;
- with complications of specific treatment – bone fractures against osteoporosis, with the development of aseptic bone necrosis;
- with the increase of pain on the background of the development of systemic manifestations – polyneuropathy, vasculitis and other vascular disorders, accompanied by “ischemic” pain;
- at accession of associated diseases (herpes zoster);
- with intolerance to NSAIDs;
- patients who are contraindicated NSAIDs;
- with temporary need to strengthen analgesic therapy, for example, in the selection or cancellation of basic therapy.
Thus, the main principle of using tramadol hydrochloride is to use it as an additional means in order to increase the effectiveness of pain relief and the safety of antirheumatic therapy.
Tramadol is usually prescribed to patients with rheumatic diseases for a relatively short period of time (from 2-3 weeks to several months) or with courses for periods of increased pain. More long-term tramadol is used in cases where other means are ineffective, and surgical treatment is contraindicated, for example, for aseptic bone necrosis or irreversible deformities in osteoarthritis. It should be noted that in oncological practice, the drug is used for a long time, for 2-3 years, without the development of addiction (ie, it retains an analgesic effect and does not lead to the development of withdrawal syndrome).
Daily doses of tramadol range from 50 to 300 mg / day. Usually, 100–200 mg / day was enough to achieve good pain relief for rheumatic diseases. The principles of dosing are presented in table 2.
It should be remembered that Tramal is a potent drug, therefore, for the treatment of non-oncological pain, exceeding the daily dose above 400 mg is contraindicated.
The use of retard tablets (100 mg 1-2 times a day) is as effective as other forms in equivalent doses. The retard form is convenient to use due to the slow release of the active substance (approximately double compared with the usual form of release of tramadol). 100 mg retard tablets provide constant pain control for 12 hours due to the even release of tramadol hydrochloride. Due to the maintenance of a stable level of the drug in plasma, its high efficiency is maintained. Due to the absence of peak plasma concentrations, there is a more favorable side effect profile.
Of particular interest are the results of the successful combined use of tramadol and NSAIDs, allowing not only to achieve an adequate analgesic effect with minimal adverse reactions, but also to reduce the dose of NSAIDs. Adding tramadol helps well with the ineffectiveness of peripheral analgesics. In rheumatoid arthritis, additional therapy with tramadol in case of insufficient analgesic effect of NSAIDs significantly reduces the indices of pain and reduces functional insufficiency. It is important that tramadol can be combined with paracetamol, traditional NSAIDs and specific COX-2 inhibitors. The drug has no side effects characteristic of NSAIDs and can be used in patients with drug gastropathy, with gastric ulcer, as well as liver, heart and kidney failure.
Successful analgesia with the use of medium doses of tramal and NSAIDs can be partially explained by their interaction with the central nervous system. In the experiment, a new mechanism of interaction between NSAIDs and opioids in the terminals of the central neuron was demonstrated. It turned out that endogenous opioids that bind to m-receptors inhibit the release of neurotransmitters, stimulating the activity of phosphorylase – 2 (Fig. 3). Phosphorylase-2 includes the arachidonic acid cascade, as a result of which not only COX-2 activation occurs (followed by the synthesis of pro-inflammatory prostaglandin E2), but also activation of lipo-oxygenases (LOG). In the process of conversion of lipoxygenases, active metabolites are formed, in particular, 12 – LOG. The latter lead to increased activity of voltage-dependent positively charged potassium channels. This inhibits the release of the GABA neurotransmitter from the GABA – ergic nerve terminal. The result of this chain of reactions is the “emancipation” of the descending antinociceptive system and, accordingly, the reduction of pain. These results are interesting in terms of possible combinations of centrally acting analgesics, NSAIDs and specific inhibitors of LOG.
Tramadol is a safe drug, since its analgesic doses do not lead to a violation of vital functions. In about half of the cases, tramadol does not produce any side effects. At the same time, side effects of varying severity — sedation, dizziness, nausea and vomiting, loss of appetite, dry mouth, and constipation — often encourage patients to stop treatment. According to various authors who have used tramadol in rheumatology, the cancellation occurs in 10-25% of cases. The main reason is the development of vertigo. In most cases, the side effects of tramadol gradually disappear during the first days of therapy. Slow, for 2-3 days, increasing the dose (dose titration) at the beginning of therapy helps to avoid unpleasant consequences while taking this drug. Nausea and vomiting, if necessary, can be stopped with antiemetic agents (metoclopramide). Very rarely, with the appointment of high doses of the drug or while taking antidepressants or antipsychotics at the same time, seizures may develop. With caution, use the drug at risk of seizures, with epilepsy – only for health reasons. Contraindications for the appointment of Tramal are hypersensitivity to opiates, acute alcohol poisoning, hypnotics, analgesic and psychotropic drugs (i.e. agents acting on the nervous system). It is impossible to appoint Tramal simultaneously with MAO inhibitors and for two weeks after their cancellation.
Experimental and clinical studies have shown that the ability to cause mental and physical dependence in tramadol is practically absent. In the practice of European clinicians who have used this drug since the late 1970s, tramadol abuse has been very rare. So, for the first 14-year period of its use, the number of reports of abuse of tramadol (when calculated per million prescribed doses) was 0.23, which is 40 and 30 times lower than when using dihydrocodeine and codeine phosphate in equivalent doses. In this regard, Tramal is not included in the Convention on Drugs under international control, and is not subject to special accounting as a narcotic analgesic. All forms of Tramal, including Tramal – Retard, are included in the “List of Potent Drugs” and are written out on the prescription form 148 / y.
An interesting experience with tramadol hydrochloride was accumulated in the USA in 1995–99. Summary data on a low risk of drug dependence allowed to introduce the drug to the market as unrecognized. Recommendations not to give the drug the accounting status were prepared by the Special Committee on Drug Dependence Control after studying the clinical and epidemiological data obtained after using this drug for 20 years in Europe. According to these data, the dependence was rare, despite the fact that the drug has an affinity for m-receptors. In 70 countries, for 20 million patients who were prescribed tramadol, 200–300 individuals with addiction were identified, i.e. 1.0–1.5 cases per 100,000 treated with the drug. In the United States, there is “under-treatment of pain” in the population, i.e., as in other countries, a large number of patients report that their pain is not cropped enough. At the same time, there is a widespread reluctance among prescribing doctors to prescribe analgesics to be taken into account because of the fear of addiction. In such a situation, an effective analgesic with a weak opioid effect and a low risk of developing dependence could be very helpful. However, recognition of non-accounting status was stipulated by the creation of a special accounting program and verification of the frequency of drug dependence by an independent screening committee, which was supposed to identify all cases of abuse of this drug. The post-marketing research program consisted of the systematic collection and scientific study of cases suspicious of the development of drug dependence in populations at high risk of development. An active search for such cases was carried out through the “Key infomant network” computer program for physicians working with patients with drug dependence and by collecting spontaneous cases of drug dependence through the FDA MedWatch system. At the same time, methods were developed to account for the number of patients to whom the drug was prescribed. The degree of dependence development was determined monthly by calculating the risk – benefit ratio, i.e. dependence on 100,000 patients who received the drug. The results obtained for 3 years of research of the drug after its launch on the market indicate that the degree of development of drug dependence was low. During the first 18 months of familiarization of doctors with the drug, the frequency of dependence was the highest and reached a maximum – about 2 cases per 100,000 patients who received the drug, but over the next 2 years there was a significant decrease in the frequency of dependence development (p = 0.011), reaching less than 1 case per 100,000 patients in the past 18 months. The overwhelming number of cases of drug dependence development (97%) was found among individuals who had a drug dependence on other substances in the history. The results suggest that the decision not to include tramadol hydrochloride in the list of accounting drugs in the United States was legitimate and that the post-marketing research program created effectively detected cases of dependence. Analyzing the experience of using Tramal in the United States, it is possible to determine such a contraindication to its intended use as a medical dependence in history. With extreme caution should be prescribed the drug in risk groups for drug dependence, treatment should be carried out for a short time under constant medical supervision.
Being a potent opioid agent, the drug requires a responsible attitude on the part of the doctor in the treatment of non-oncological pain. At the same time, the considered drug expands the arsenal of anesthetics in the treatment of moderate and severe chronic pain syndromes in diseases of the musculoskeletal system. Used according to strict indications, it can reduce the suffering of the patient and provide him with a decent quality of life.