Latest generation synthetic opioids

The latest generation of synthetic opioids as an alternative to true opiates:

Tramadol hydrochloride (tramal, tradol, etc.) is a synthetic opioid analgesic, referring to analgesics of average strength. Tramadol oral administration is characterized by high bioavailability, which is important for long-term treatment of chronic pain syndrome. The coefficient of its bioavailability (analgesic effect) when administered orally is 0.7 with respect to the subcutaneous route of administration. This is high compared with other opioids. For morphine, it is 0.1, for codeine and pentazocine – 0.2. When ingestion, tramadol is rapidly and almost completely (90%) absorbed with reaching the maximum concentration in the blood 2 hours after taking the capsules (drops). According to experimental and clinical data, tramadol in analgesic doses does not affect breathing, systemic and pulmonary circulation, almost does not violate the motility of the gastrointestinal tract, urinary and biliary tract, does not cause physical and mental dependence when used in analgesic doses. Tramadol is not listed in the Drugs Convention under international control and is not subject to special registration as a drug.

Tramadol is presented in various non-invasive dosage forms. There are capsules (50 mg), drops (20 drops = 50 mg), suppositories (100 mg), injection solution in ampoules of 50 and 100 mg. There is a new dosage form – the tablets of the prolonged action of tramal retard and tramundin on 100, 150 and 200 mg.

Tramal is prescribed for moderate chronic pain syndrome with the ineffectiveness of previous therapy with non-narcotic analgesics of the 1st stage in combination with adjuvant drugs. The initial single dose of tram is from 50 to 100 mg, daily – from 200 to 400 mg.

For the tram-retard, a single dose is doubled and amounts to 100-200 mg, due to a delayed release of the active substance by about half compared with the usual tram. In this case, the daily dose does not differ from the dose of tram capsules.

Analgesic effect of tram develops in 25-45 minutes. after taking the capsules and lasts from 3.5 to 6 hours. The action of the tablets of tramal retard develops a little later – after 20-60 minutes, but lasts 2 times longer. Longer and stable analgesic effect of tramal retard reduces the number of doses of the drug to 2-3 per day against 3-5 when treated with ordinary tram.

Against the background of effective analgesia with tramal cancer, the quality of life in patients with cancer improves – night sleep, mood, and daytime physical activity improves.

It must be emphasized that the success of tramadol therapy is determined by the correct assessment of the intensity and type of chronic pain syndrome. As practice shows, tramadol is highly effective in somatic and visceral chronic pain syndrome of moderate intensity and ineffective in strong chronic pain syndrome, especially with a neuropathic component.

When using candles, approximately 1/3 of the patients had symptoms of local irritation of the rectal mucosa (tenesmus, pain). To reduce these phenomena, it is necessary to introduce candles to a sufficient depth (beyond the sphincter, into the cavity of the rectal ampulla). Approximately half of the patients at the beginning of therapy have various side effects: transient sedation (drowsiness), dizziness, nausea, vomiting, etc. Tablets of trauma-retard are similar in frequency and nature of side effects to tram capsules, and during the transition to a prolonged preparation patients do not appear or diminish, and in part appear or increase, which may be due to different conditions of absorption of these dosage forms.

Most patients prefer to continue therapy with tramal, despite the side effects, which, as a rule, can be avoided by observing short-term bed rest (30-40 min) after taking the first dose of tram. These symptoms gradually disappear within a few days of therapy and do not bother patients, including those of old age. In general, the incidence and severity of side effects during prolonged therapy with tramal compared with morphine is much lower.

All of the above allows us to consider tramadol hydrochloride as the means of choice in the treatment of chronic pain syndrome of moderate intensity (stage 2 pharmacotherapy) due to its high efficiency, good tolerability, the absence of severe side effects, various non-invasive dosage forms, and drug safety. This drug is convenient and safe for self-sustaining use by cancer patients at home. In order to avoid failures, tramadol should not be prescribed for chronic pain syndrome of high intensity, which shows stronger opioids. A consistently good result of tramadol therapy is achieved when it is prescribed in a timely manner to patients in whom the 1st-stage drugs no longer provide complete pain relief, and the intensity of the pain syndrome increases from mild to moderate, but has not reached a strong one.

Prosidol – a new domestic synthetic opioid agonist – a derivative of phenylpiperidine, which has the qualities necessary in the treatment of chronic pain.

Prosidol is available in several dosage forms: a solution of 1% for injection in 1 ml ampoules, tablets for oral administration of 0.025 g (25 mg) and buccal tablets of 0.02 g (20 mg).

The initial single dose of buccal prosidol (stage I) is 20 mg, daily 100 mg. The analgesic effect develops 5-25 minutes after the first dose and lasts 1-6 hours, i.e. the onset and duration of analgesia are very individual, depending on the characteristics of the chronic pain syndrome and, probably, the absorbability of the drug.

It should be noted that in terms of the onset of analgesia, prodid of buccal surpasses almost all existing opioids in non-invasive dosage forms, approaching by this indicator only to buprenorphine sublingual. Its action comes 1.5-2 times faster than tram capsules, 3 times faster than MCT tablets, 2 times faster than prosidol tablets for internal use. However, it is inferior to all these drugs for the duration of action, so the number of maintenance doses is 4-6 times a day.

Analysis of adverse symptoms of therapy with prosidol buccal showed that they do not differ in character from those observed with other opioids, but are less pronounced. When using prosidol, there were no cases of respiratory failure and changes in blood circulation indices.

Prosidol is an effective narcotic analgesic of medium strength and medium duration of action for the treatment of chronic pain syndrome of moderate intensity. Prosidol can be considered as an additional (intermediate between 2nd and 3rd steps) analgesic, which expands the possibilities of treatment of chronic pain syndrome. Its advantages over other opioids in patients with chronic pain syndrome are minimal side effects, good tolerability of seriously ill patients, the presence of various dosage forms, including two non-invasive – oral tablets and buccal.

The disadvantage of prosidol in the treatment of chronic pain is a relatively short-term effect (3-5 hours), so the number of its techniques can reach 5-8 per day.

Buprenorphine is widely used to treat chronic high-intensity pain syndrome. It is presented in two dosage forms: 0.2 mg sublingual tablets and injection solution in ampoules of 0.3 and 0.6 mg (1 and 2 ml, respectively).

An analgesic dose of buprenorphine will vary from 0.6 to 2.0 mg per day.

After taking the sublingual buprenorphine tablet, the reduction of pain begins in the 15th minute, and the maximum effect develops after an average of 30 minutes and continues to 7

hours). In terms of the speed of development of analgesia, buprenorphine is close to prosidol buccal and tramal and significantly exceeds the MCT-continus, which is implemented only by the end of 1 hour from the moment of taking the tablets. By the duration of its action, buprenorphine is about 1.5 times as much as tramal and 2–2.5 times asylum, but inferior to morphine sulfate.

Dosing of buprenorphine is not difficult and can be done without mandatory personal monitoring of the patient, who can take buprenorphine at home. It is enough to instruct the patient or his relatives on the selection of the optimal single and daily doses. A single dose is easily determined by sequential administration of 0.2 mg tablets under the tongue. In case of insufficient analgesia after taking 1 tablet, after 40 minutes, you should take the 2nd and in the absence of side effects, if necessary with the same interval, the 3rd and 4th.

As a rule, it is possible to predict the magnitude of the optimal dose of buprenorphine in a particular patient, depending on the intensity of pain, the type and dosages of the previous analgesic. For example, if buprenorphine is prescribed against the background of insufficient efficacy of tram in a daily dose of 400-600 mg, then a single analgesic dose of buprenorphine may not exceed 0.2 mg (up to 0.4 mg), and the daily dose will be 0.6-1.2 mg. If prodidol in a dose of more than 300 mg per day does not relieve pain, the daily analgesic dose of buprenorphine can reach 2.0-3.0 mg.

Butorphanol tartrate (stadol, moradol, beforal) is a synthetic opioid antagonist agonist, phenanthrene derivative, similar in structure to nalorphine. The drug is completely absorbed when administered intravenously and intramuscularly, the action occurs respectively after 10 and 30-40 minutes. When ingested, the bioavailability of butorphanol is low (17%) due to its metabolism in the liver.

When administered parenterally, butorphanol at a dose of 2 mg is equivalent to morphine at a dose of 10 mg, i.e. its analgesic activity is higher than morphine. It is superior to the analgesic effect of pentazocine.

The ability of butorphanol to cause withdrawal after prolonged use is regarded as minimal. With prolonged therapy with butorphanol, its sudden cessation causes less pronounced withdrawal symptoms than morphine and other true opiates. Butorphanol does not have a significant effect on the vital functions of the body. Respiratory depression under the influence of an analgesic dose of butorphanol 2–4 mg is much less pronounced than with the use of an equivalent dose of morphine (10–20 mg), and the degree of respiratory depression practically does not increase with a further increase in dose, which distinguishes butorphanol from true opiates. Respiratory depression caused by butorphanol is easily eliminated by naloxone. Butorphanol does not inhibit myocardial contractility, does not cause, unlike morphine, a statistically significant decrease in systemic arterial pressure, but leads to increased pressure in the pulmonary artery and pulmonary vascular resistance, which should be borne in mind and caution should be used when prescribing the drug to patients with chronic pathology of the heart, lungs, pulmonary hypertension. Unlike morphine-like analgesics, butorphanol does not increase the tone of the smooth muscles of the gastrointestinal tract, urinary or biliary tract and does not cause dyskinesia of these organs.

Like other opioids, butorphanol is not devoid of side properties, often associated with analgesia. The main one is the sedative effect observed, according to different authors, in 1 / 3-1 / 2 patients. Less commonly, nausea, dizziness, and dysphoria occur. Butorphanol does not possess nephro- and hepatotoxic properties, but since it is metabolized in the liver, its use in hepatic insufficiency should be avoided.

Butorphanol is not one of the opioids widely used in the treatment of chronic pain in cancer patients, but in some cases it may be useful for this purpose, in particular, for

Butorphanol tartrate (stadol) is available in 2 mg ampoules and is intended for intravenous and intramuscular administration. In the US, the drug is also available as a nasal spray.

The analgesic effect of butorphanol begins on average after 25 minutes and lasts 7 hours, i.e. the number of injections is 3-4 per day. Subcutaneous administration is preferred, in which, unlike intramuscular and intravenous administration, side effects are less pronounced due to more gradual absorption and action.

Treatment of chronic pain with butorphanol can be carried out for a rather long time and with a good result in the majority of patients, but failures are possible due to its psychomimetic side effects. The injectable dosage form of butorphanol is not optimal because of its invasiveness, especially at home. The advantage of butorphanol over most other opioids is its drug safety.

Relative indications for the treatment of chronic cancer pain may have two other opioid antagonist agonists: pentazocine and nalbuphine.

Pentazocine (talvin, fortral) is a synthetic derivative of benzomorfan. It causes analgesia, sedation, unsharp respiratory depression and, in contrast to butorphanol, impaired intestinal motility.

Pentazocine is a medium-strength analgesic. It is inferior in terms of analgesia to other members of the class of antagonist agonists (butorphanol and nalbuphine), significantly inferior to buprenorphine and morphine, but exceeds tramal and codeine.

Pentazocine is characterized by low toxicity, used in injection solution (30 mg in 1 ml) and injected intramuscularly or subcutaneously. The possibilities of this analgesic make it possible to apply it in cases when the transition from moderate to severe pain begins, i.e. when the action of analgesics of the 2nd stage (tramal, codeine) becomes inadequate. If these previous analgesics were used at the maximum dose (for example, tramal 400-500 mg / day) and did not achieve a reduction in pain, then a single dose of pentazocine may be 60-90 mg, and a daily dose of 180-360 mg. If pentazocine is prescribed for moderate pain syndrome, then the initial single dose should not exceed 30 mg, and the daily dose should be 90 mg.

Patients usually tolerate treatment with pentazocine at moderate doses (up to 200 mg / day), but often it is accompanied by transient sedation, and sometimes nausea. With large doses, dysphoria (unusual emotional experiences) and visions may occur. In these cases, if it is not possible to preserve analgesia and eliminate side effects by lowering the dose, pentazocine is replaced by another analgesic.

Experience shows that, in terms of analgesia, pentazocine roughly corresponds to the domestic proedidol, but the latter favorably differs from it by its convenient non-invasive dosage form and the absence of psychomimetic effects.

Nalbuphine (nubain) is a semisynthetic derivative of the opium alkaloid thebaine.

Unlike butorphanol and pentazocine, nalbuphine has almost no effect on heart activity and blood circulation, and does not increase pressure in the pulmonary artery system. Due to this, it can be applied without restriction in patients with arterial hypertension and coronary heart disease.

Nalbuphine favorably differs from opiates and most antagonist agonists with minimal side effects that are not dangerous. In about 40% of cases, analgesic doses of nalbufine cause sedation and in 3-6% of cases nausea, dizziness, headache, dry mouth.

Despite a number of beneficial qualities (good analgesic effect, minimal side effects, negligible probability of drug dependence), the use of nalbuphine in chronic pain in cancer patients, although possible, has limitations.

Nalbuphine can be prescribed with the ineffectiveness of opioids of the 2nd stage (tram, codeine), which in some patients with somatic or visceral pain can give a long lasting good result in the absence of significant side effects. The initial analgesic dose is usually 10-15 mg, the duration of its action is 4-6 hours.

the process of long-term therapy, the maximum single dose can reach 60 mg, and daily – 400 mg. With neuropathic pain, full analgesia does not occur. It may be useful in case of intolerance to other opioids, since it has the lowest side effects. Enhancing its effect can be achieved by combining with adjuvant agents.

The use of opioids in the pharmacotherapy regimen for chronic pain in cancer patients should first of all be considered in three main aspects: firstly, from the point of view of their analgesic properties, which determine the level of therapy at which they can be used; secondly, in terms of the mechanism of their action on opioid receptors and possible antagonistic relationships with other opioids, to which indications may arise in the process of developing pain syndrome; thirdly, in terms of patient tolerance to therapy.

With moderate pain (Stage 2), not only classical opiate codeine can be successfully applied, but also an alternative to the opioid tramadol, which has several important advantages: various dosage forms (capsules, retard tablets, drops, suppositories, solution for injections), good tolerability, improving the quality of life of incurable patients, minimal likelihood of constipation, complicating codeine therapy, drug safety and, as a result, lack of need for special accounting and the possibility of discharge as usual prescription form. Treatment with tramadol is safe for seriously ill patients and can be used at home without special medical supervision.

At the present stage, it is advisable to recognize tramadol as the main analgesic of the 2nd stage instead of codeine due to its obvious advantages. Indications for codeine or other analgesics of the 2nd stage with less favorable properties (dextropropoxyphene, tilidine) can occur in rare cases with individual intolerance to tramadol.

The optimal means of the 3rd stage, should be considered an agonist of m-receptor buprenorphine, characterized by a powerful analgesic effect, close to the action of morphine and characterized by such beneficial properties as a universal non-invasive dosage form (sublingual tablets) and less pronounced side effects, which allows you to assign it to patients at home without prior selection of doses.

In developed by Moscow in them. Herzen’s scheme for the pharmacotherapy of chronic pain in cancer patients, morphine as the most powerful long-acting drug, has a final place after buprenorphine, which, despite the possibility of long-term successful therapy, has a limit of use due to its inherent plateau phenomenon in doses above 3-5 mg / day . In the absence of an increase in the analgesic effect of buprenorphine, with an increase in its doses to the indicated limits, it is necessary to switch to morphine, the doses of which in the course of long-term therapy may, if necessary, be increased tenfold with respect to the initial analgesic dose. In incurable patients, this is a significant advantage of morphine, and if we proceed from the pharmacological characteristics of morphine, the progressive increase in its analgesic dose during the treatment of chronic pain reflects the properties typical for true drugs – tolerance (addiction) and dependence.

Taking into account the above features of various opioid analgesics, an optimal sequential treatment regimen for increasing chronic pain in cancer patients has been developed.

Taking into account the existing gradation of the intensity of pain (mild, moderate, strong and the strongest), it is logical that in the treatment of increasing pain there are 4 stages corresponding to the four levels of pain intensity. The proposed modification of the traditional 3-step scheme is characterized not only by increasing the “ladder” by one step, but also by replacing, moving and introducing additional components. It is important that all opioids of the 2-4th stages of the new scheme have the properties of m-receptor agonists and do not interfere with each other’s actions.

The essence of the modification is to replace codeine with tramadol in the 2nd stage (moderate pain); in the use of prosidol as an intermediate between the 2nd and 3rd steps; in the replacement of the 3rd stage (severe pain) with morphine buprenorphine and in the transfer to the 4th stage of morphine as a means against the most severe pain. Such a set and such a sequence of use of opioids with the properties most beneficial for each stage of therapy increase the patient’s chances of getting full pain relief and improving the quality of life during the entire period of pain. If, during the course of pain therapy, the patient is undergoing a course of anticancer treatment (radiation or chemotherapy), leading to a reduction or elimination of the pain syndrome, it is possible, “going down the stairs”, to switch to less powerful analgesics or even cancel them, which should not be done abruptly in order to avoid withdrawal, which, as shown above, is most pronounced in morphine and prosidol. If a patient has been receiving morphine for a long time because of very severe pain, which has dramatically decreased or even stopped after a special antitumor therapy, it is more rational to switch to buprenorphine, which will soften the manifestations of morphine withdrawal. It is better that the initial dose of buprenorphine, even in the case of a high previous dose of morphine (above 100 mg / day), does not exceed 2-3 mg per day, and subsequently as a result of a gradual reduction of the dose by 0.2 mg daily (1 tablet) after 2 weeks in the absence of pain, buprenorphine can be reversed, which does not lead to withdrawal symptoms. The ability of buprenorphine to alleviate morphine withdrawal is an additional argument in favor of including this valuable opioid in the pharmacotherapy regimen for chronic pain.

If, after a course of antitumor therapy, the pain did not stop, but decreased to moderate or weak, after replacing morphine with buprenorphine, they switch to tramadol or non-narcotic analgesics of the 1st stage.