I. Basic principles
The typical treatment scheme of cancer pain medication is the three-step medication principle proposed by the World Health Organization (WHO) in 1986, which has been proven to be effective after 20 years of practice and should continue to be promoted. However, due to the continuous emergence of new analgesic drugs, the present three-step drug regimen has been greatly improved from the original one. Some suggest that an intermediate level should be added between level II and level III, i.e., before using strong analgesic drugs in the last level, it is possible to add an intermediate level of drugs; some also suggest that the original level II drugs should be withdrawn and replaced by controlled-release tramadol, oxycodone, hydromorphone, fentanyl or morphine, while the Level III treatment is replaced with invasive treatment such as subarachnoid space implantation of analgesic pumps and continuous epidural or subcutaneous or intravenous drug administration, with an emphasis on interventional and minimally invasive treatments that can be interspersed throughout the treatment process.
The original analgesic ladder was to treat mild pain primarily with nonsteroidal anti-inflammatory analgesics (Class I), with weak opioids if pain persists or increases to moderate pain (Class II), and with strong opioids if pain continues to increase or is uncontrollable in moderate to severe pain (Class III), with additional analgesic adjuvants at each level of treatment to enhance analgesia (Figure 6-1 ). This means that not only the so-called weak opioids such as codeine or dihydrocodeine, but also non-opioid analgesics such as tramadol can be used. These drugs are collectively called medium-acting analgesics. Nowadays, there are many types of drugs used in the third step, so that there are more choices, so in recent years, the dosage of strong analgesics such as morphine has a tendency to decrease.
The popular application of the three-step principle has played an important role in promoting the use of opioids for cancer analgesia, and the outstanding achievement of benefiting the majority of patients is evident to all. The three-step principle emphasizes the administration of drugs by steps, while now it is more advocated that the principle of drug selection is to achieve maximum analgesic effect, minimum side effects, best function and highest quality of life; the three-step principle emphasizes the administration of drugs on time, while now it is more advocated that controlled slow-release drugs should be given for continuous or background pain, and fast-acting and strong immediate-release drugs should be added temporarily for outbreak pain; the three-step principle emphasizes oral administration, while now it is considered that Non-invasive drug delivery (transdermal and transmucosal drug delivery) is also the preferred method of drug delivery if it is convenient and satisfactory for patients to use and the effect is indeed; the three-step principle emphasizes individualized drug delivery, and opioid drugs have no capping effect, while it is now emphasized that the nature of pain should be distinguished whether it is injurious pain or neuropathic pain or mixed pain, and more attention should be paid to multimodal combined analgesia.
Severe pain
Class III Potent opioid analgesics
± analgesic adjuncts
Persistent or increasing pain
Moderate pain
Class II Weak opioid analgesics
± analgesic adjuvant
Persistent or increasing pain
Mild pain
Class I Non-steroidal anti-inflammatory analgesics
± analgesic adjuvant
Basic principles of three-stage ladder medication: According to the ladder medication administration method advocated by WHO, it is based on oral medication, which is convenient for patients to take medication by themselves and also easy to popularize, with the expectation of achieving elimination of pain in all cancer patients. For digestive tract tumors with swallowing difficulties, transrectal, dermal, sublingual and injectable administration can be used. Another important principle is to give the drug on time, that is, the drug should be given regularly according to the time effect of the drug, regardless of whether it is painful at that time, including at night, instead of giving the drug only when the pain occurs according to the usual habit of people, in order to maintain a stable blood concentration with analgesic effect, so as to prevent the onset of pain and achieve the ideal analgesic effect. Not only should the drug be given on time, it should also be given in sufficient quantity, and the way of giving the drug in small and gradual increments is not desirable. Another important principle is that the selected drug and the dose should be individualized, and the necessary adjuvants should be applied. Long-term application of opioids can produce drug resistance, and because of individual differences, the dose should be titrated (titration) and adjusted or changed at any time. Although opioids are the most effective analgesics available today, they are not ideal for bone metastatic pain and neuropethic pain. Therefore, opioids are not effective for all types of pain, and different drugs should be chosen for different causes of pain and different doses should be used for different individuals. The addition of adjuvant medications does not mean that opioids are ineffective or inefficient, but rather that the pharmacological properties of opioids dictate this.
The stepwise escalation from weak analgesics to strong analgesics is not set in stone, and a patient who presents with severe pain at the time of consultation should be treated with strong analgesics immediately. If the cancer invades or compresses the peripheral nerves, such as when the breast cancer involves the axilla and affects the brachial plexus, sudden tearing-like pain can occur, which is often difficult to control with strong opioids. Although these drugs are mainly used to treat epilepsy and are not analgesics, they are effective for neuropathic pain because they block voltage-dependent calcium channels, thereby inhibiting spontaneous action potential discharges in nerves. In some cases, when the dose of strong opioids has been increased to a very high level, and the pain is still difficult to be fully controlled due to the development of drug resistance or significant side effects, it is necessary to use interventional therapy, nerve blocks with nerve-destroying drugs such as ethanol or phenol, or nerve destruction by radiofrequency thermocoagulation, as well as the application of opioids in the spinal canal, which can achieve unexpected results. It has been suggested that the interventional treatment used at this time be called step IV. Whether it is the addition of a step between the II and III steps or the addition of the IV step, these suggestions indicate that the three-step treatment plan is improving as new analgesics continue to enter the market and new analgesic techniques continue to emerge, making its analgesic effects better and better. Although WHO’s call to eliminate cancer pain in the world in 2000 has not been achieved, it now seems that it is not a distant prospect.
II. Class I analgesic drugs
Non-steroidal anti-inflammatory drugs (NSAIDS) are mainly used for Class I analgesia, and there are many kinds of such drugs, including non-acidic drugs and acidic drugs in terms of chemical structure, such as acetaminophen (paracetamol) for the former and salicylic acid for the latter, such as aspirin and propionic acid. The former are salicylic acid such as aspirin, propionic acid such as ibuprofen, acetic acid such as indomethacin, pyrazolone such as phenylbutazone, xicam such as piroxicam and lornoxicam, and celecoxib such as celecoxib. celecoxib (celebrex), etc. The common mechanism of action of these drugs is to inhibit the prostaglandin synthesis enzyme, cyclooxygenase (COX), thus reducing the synthesis of prostaglandins, which are important inflammatory and pain-causing substances, so these drugs can exert anti-inflammatory and anti-nociceptive effects. NSAIDS are mainly used for the treatment of mild to moderate pain such as toothache, muscle pain, joint pain, headache, etc. In cancer pain treatment, they are mainly used as Class I step analgesics and Class II and III step adjuvants, and have better effect on bone metastasis pain.
The commonly used drugs are mainly as follows.
1.Aspirin Chemical name is acetylsalicylic acid, which is acidic. It is the NSAIDS with the longest history of application and has better effect on inflammatory joint pain such as rheumatoid arthritis and cancer bone metastasis pain, the latter is related to the osteolytic effect of prostaglandin E2 when it is involved in bone metastasis. For cancer pain treatment, the adult dose is 0.5~1.0g each time, once every 4~6 hours, preferably taken orally at mealtime, and taken together with antacids such as Gastrodin, which can reduce the acidic stimulation to the stomach and have the effects of local hemostasis and protection of gastric mucosa. Despite its good pain relief effect, the application of aspirin is limited by its side effects such as gastrointestinal reactions, gastrointestinal bleeding and inhibition of liver and kidney function. Patients with impaired hepatic or renal function, ulcerative, bleeding and allergic diseases should be considered as contraindications. Lepirin (lysine acetylsalicylate, lysine acetylsalicylate, lysampirin) is a compound salt of aspirin and lysine, because its dosage form has changed, so it is suitable for intramuscular injection or intravenous injection, the stimulation of the digestive tract is reduced, adults each time 0.9-1.8g, 1 to 2 times a day, the contraindications are the same as aspirin.
2, indomethacin commonly known as anti-inflammatory pain, the strongest analgesic effect in NSAIDS, but because of its side effect rate up to 30% to 50%, so generally not as antipyretic, analgesic long-term use. Changing to gel pills or suppositories can reduce its digestive side effects. Adults 25-50mg each time, 3-4 times a day, taken with meals.
3, acetaminophen (paracetamol, acetaminophen) commonly known as paracetamol, its antipyretic effect is similar to that of aspirin, but the analgesic and anti-inflammatory effect is slightly weaker. This is due to the strong role of this drug in inhibiting prostaglandin synthesis in the thalamus and the weak role in inhibiting prostaglandin synthesis in the periphery. It is a safer analgesic because it is less irritating to the gastrointestinal tract and has fewer side effects such as bleeding, so it is often used in the treatment of cancer pain. The usual dosage is 1g every 6 hours, and it generally has good therapeutic effect on mild to moderate pain, and sometimes it can also achieve good analgesic effect on severe pain, because although the intensity of the pain complained of is an important reference for choosing drugs, it is not necessarily the only indicator of which intensity analgesic to give. In terms of side effects, it should be noted that the drug’s GI, cardiac, renal and platelet adverse reactions are very mild, generally do not cause nausea and vomiting, no respiratory depression side effects, but the side effect that deserves attention is liver necrosis due to overdose, a single oral dose of 8-15g may have this serious complication, so the maximum daily dose should not exceed 4g. the drug and other NSAIDS drugs, the effect After the expected analgesic effect is achieved, increasing the dose can only increase the side effects and cannot enhance the analgesic effect. The recently introduced intravenous form is already in use in Europe and Australia. In view of its high safety and low incidence of adverse reactions when used in combination with other drugs, it has become a recognized first-order analgesic of choice or the first choice in combination with other drugs for combined analgesia.
Class II analgesic drugs
Class II analgesic drugs are mainly weak opioids such as codeine, which are often used in combination with acetaminophen. This is a reasonable combination because opioids are mainly central analgesics, while acetaminophen is mainly peripheral analgesics, and the combination of the two drugs has analgesic synergistic effect, which enhances the analgesic effect and makes it have the effect of cough suppression and antipyretic.
Commonly used Class II analgesic drugs mainly include the following.
1.Codeine is a weak opioid, the chemical structure of which is methylmorphine, and the finished product is its phosphate. Opioids containing codeine 0.5% to 1%, is a by-product of the manufacture of morphine. The formulation is codeine phosphate, with an oral bioavailability of about 35%. In vivo, only about 10% of codeine is demethylated and metabolized to morphine to exert analgesic effects, and the metabolic enzyme that converts codeine to morphine may vary greatly in different populations, and patients lacking this enzyme (CYP2D6) are poorly treated with codeine (see Chapter 5). The analgesic strength of codeine is equivalent to 1/12 of morphine, and the duration of analgesia is 3-5 hours. This drug has a strong cough suppressant effect and a weak sedative effect, and suppression of respiration rarely occurs. Like other opioids, this drug can relax smooth muscle, and thus also has the side effects of constipation and nausea, and can produce dependence (addiction) and cross-resistance with morphine for a long time. The usual dose is 60mg (2 tablets) per hour. If it is not effective, you should consider changing to a stronger analgesic, because the analgesic effect will not continue to be enhanced if the dose is increased. Nicoderm is a codeine phosphate extended-release agent with a 12-hour duration of action. It is usually taken twice a day, starting with 1 tablet (45mg) by mouth and gradually adjusting the dose until no pain is experienced. It should not be chewed when taken orally.
2. Dihydrocodeine (DHC contin) is a controlled-release tablet of dihydrocodeine tartrate, which reaches peak blood concentration in 1.6-1.8 hours after oral administration, with a plasma half-life of 3.5-4.5 hours and an effective analgesic time of 12 hours. 1~2 tablets per dose, once every 12 hours, must be swallowed whole. It is suitable for moderate pain.
3. paracetamol et codeine phosphate Each tablet contains 8.4mg of codeine phosphate and 300mg of acetaminophen, and aminoglutethimide II is codeine 15mg and acetaminophen 300mg. the advantage of compounding is to use its synergistic effect to enhance the analgesic effect. For general pain treatment, the usual dose for adults is 1 tablet per time, 3 times a day, and for cancer pain treatment, 1 to 2 tablets per time, every 4 to 6 hours. The side effects are mild, with occasional dizziness, sweating, nausea and drowsiness, which can be continued if not serious and disappear after stopping the drug.
In addition to codeine, dihydrocodeine or dextropropoxyphene (dextropropoxyphene) can also be compounded with acetaminophen to make tablets, the former is a semi-synthetic codeine derivative, oral and codeine equivalent, the latter’s analgesic effect is not stronger than aspirin or acetaminophen, but repeated administration of metabolite accumulation, analgesic efficacy and codeine equivalent. The two drugs do not have obvious advantages over codeine, so they are only used as a substitute for codeine when combined with acetaminophen.
4, tramadol (tramadol) This drug is combined with opioid receptors, but its affinity is very weak, so it is generally considered tramadol for non-opioid central analgesic drugs, usually not subject to the restrictions of narcotic drug prescription management, the use of more convenient. Tramadol is one of the new analgesics, and its mechanism of action combines weak opioid agonist properties with inhibition of spinal norepinephrine and 5-hydroxytryptamine uptake, thus affecting nociceptive transmission and exerting analgesic effects. The analgesic effect of this drug is stronger than codeine, but weaker than morphine, its addiction is not obvious, and can be regarded as an alternative to morphine, so some people advocate adding half level analgesia between level II and level III analgesia, that is, using tramadol, and then enter level III analgesia when it is not effective or the effect is not satisfactory. This drug takes effect in 20-30 minutes after oral administration, and the maintenance time is 3-6 hours. The peak effect is reached in 1-2 hours by intramuscular injection, and the analgesia lasts for 5-6 hours. Tramadol does not produce euphoria, and its sedative effect is slightly weaker than that of pethidine. Side effects include nausea and vomiting, dry mouth and sweating, dizziness, drowsiness and constipation, but the incidence is very low.
5, chimantin (tramcontin) for tramadol hydrochloride sustained release oral tablets (tramadol hydrochloride sustained release tablets), extended release can prolong the maintenance time of therapeutic concentration, reduce the fluctuation of blood concentration, so the interval between two doses should not be less than 8 hours, a single dose of 50 to The maximum daily dose is 400mg, and the dose can be slightly larger when treating cancer pain, with the same side effects as tramadol.
6.Meptazinol, commonly known as meptazinol, is one of the new analgesics, which has both opioid receptor agonist and antagonist effects. The common feature of these drugs is that the analgesic strength is not as strong as morphine, but the respiratory depression is lighter and dependence is rarely produced. The analgesic efficacy of this drug is comparable to that of dextropropoxyphene and acetaminophen combination (co-proxamol), and the side effects are similar to other analgesics.
7, pentazocine (pentazocine) trade name analgesic new, also for opioid receptor agonist-antagonist, analgesic strength is about 1/4 to 1/3 of morphine, that is, 30-40mg of this drug is equivalent to morphine 10mg, oral effect of 1 hour, the effect lasts about 3 hours, can also be used intramuscular, intravenous or subcutaneous administration. The usual dose is 50mg orally, 30mg by other means, once every 3-4 hours, side effects include dizziness, nausea, sweating, etc.
8, Aminophenotrimadol trade name and Tongan, 1 tablet containing acetaminophen 375mg, tramadol 37.5mg, has been proved that the two drugs to 8-12:1 ratio, can play a synergistic effect of analgesia, and the ratio of the two drugs if lower than 5:1 or higher than 12:1 will play an additive role. The onset and maximum effect of aminoglutethimide is about 17-25 minutes, and the maintenance time is 5-6 hours, which is significantly better than that of single drug, and the analgesic effect is significantly stronger than that of single drug because of the compound formula, and the incidence and severity of side effects are significantly reduced because of the reduced dose of two drugs. Aminotrimadol has been shown to be effective in postoperative acute mild to moderate pain, dental pain, post-fracture pain, post-muscle and joint injury pain and dysmenorrhea, and the drug is also used in chronic pain and flare-up pain treatment. Because of its high safety, it has special significance in the long-term treatment of bone, joint and muscle soft tissue pain, especially for chronic pain with mild inflammatory response such as osteoarthritis pain with good therapeutic effect.
IV. Class III analgesic drugs
When Class II analgesic drugs cannot control pain, it may not make sense to replace other drugs within Class II analgesic drugs for intense pain, although some patients may be effective with tramadol instead of codeine-based analgesic drugs. At this point, immediate escalation to a Class III potent opioid is indicated. Although there are a variety of drugs to choose from in this class, morphine is still the standard strong analgesic for other drugs, safe and effective in the conventional dose range, and inexpensive, this drug is under the control of poisonous and narcotic drugs, and the prescription should follow the policy set by the state.
1, morphine (morphine) morphine preparations have two kinds of hydrochloride and sulfate, its characteristics are shown in Table 18-1. sulfate for the bimolecular structure, thermal decomposition temperature is higher than the hydrochloride, water solubility and purity is slightly higher, slightly less impurities. Theoretically, sulfate has a more stable molecular structure, higher active ingredient and stronger analgesic effect, but from the viewpoint of clinical analgesic effect, there seems to be no significant difference between the two preparations. Commercially available preparations are mostly morphine hydrochloride, which is easier to make. When Class II analgesic drugs are ineffective, morphine should be used soon, usually in immediate release formulation, with a standard dose of 10 mg every 4 hours, to be taken at regular intervals. In order to avoid the trouble of taking medication at night, the dose can be doubled in the last dose before bedtime, and it is more convenient to use long-acting dosage form, which is taken once every 12 hours. Despite regular dosing, it is difficult to avoid sudden onset of pain, and another regular dose should be given in this case. If sudden pain occurs frequently, increase the dose of morphine or re-dose titration should be considered.
(1) Dose titration: The standard dose of morphine is 10mg every 4 hours at the beginning, but this dose is obviously insufficient for most patients, so careful dose titration is needed to adjust the dose to the appropriate dose for different patients. The patient’s pain response and side effects should be closely monitored as the dose is gradually increased. The typical titration method is to double the dose every 24-48 hours for the first few increments up to 40 mg every 4 hours, and then increase the dose by 50% each time thereafter. Intermediate doses are generally 40-60 mg every 4 hours, and some patients who require more than this dose should not be denied further dosing. The analgesic effect of morphine is different from that of NSAIDS, there is no capping effect, and the effect can be increased by increasing the dose. There is no clear limit to the maximum dose of morphine on the basis of gradual increment, and the principle is to achieve pain control. The method of intravenous titration can also be taken, that is, the beginning of the injection of morphine 1 ~ 2mg (has used opioids, opioids have produced tolerance to the first dose of 2 ~ 3mg), in the pain can not be stopped and up to the VAS score of 7 points or more, then every 10 ~ 20 minutes to repeat the above dose until the patient pain control, if the VAS score has been reduced to 6 points or less, the additional dose should be reduced by 1/2. 24 hours The oral dose of morphine is obtained by multiplying the intravenous dose by 3. Dose titration is the ideal method for individualized dosing.
(2) Side effects of morphine: Acute side effects include nausea, vomiting, constipation, drowsiness and cognitive impairment, which are described below.
(1) nausea and vomiting: the incidence of 30% to 40%, the mechanism of its occurrence is related to central chemoreceptor excitation and terminal smooth muscle relaxation. Anti-emetic drugs with mainly central effects such as droperidol and cyclizine are recommended for treatment. When ineffective, dopamine receptor antagonists such as domperidone and metoclopramide, which inhibit the chemosensitive zone of emetics, and 5-HT3 antagonists ondansetron and granisetron also have preventive and therapeutic effects.
(2) constipation: the application of opioids commonly have constipation, which is due to intestinal smooth muscle relaxation, the need to routinely give laxative prevention, oral senna (senna), bisacodyl or phenolphthalein (phenolphthalein, fruit guide) has the effect of stimulating intestinal peristalsis, liquid paraffin (liquid paraffin), honey or 50% glycerin rectal medication (corkage) can soften the stool, and the combination of the two is more effective. Severe cases need to use osmotic drug magnesium sulfate, in the intestine to form a certain osmotic pressure, so that the intestine accumulate water, stimulate intestinal peristalsis and cause diarrhea. Magnesium sulfate 20g, dissolved in water 400ml orally, about 2 to 4 hours to defecate, while needing to increase water intake.
(3) drowsiness and cognitive impairment: morphine has a significant sedative effect, in the elderly and even intramuscular injection 5 ~ 10mg in the pain relief can be drowsy for several hours. General drowsiness, the call can respond, and no adverse effects, no need to deal with. Cognitive disorders such as mental confusion, can be given neuroleptic drugs such as haloperidol treatment, but may aggravate its drowsy state, need to wait for its natural recovery. If drowsiness is more frequent during morphine administration, the dosage should be reduced or replaced by other opioids with lighter sedative effects such as methadone, fentanyl, etc.
4) Urinary retention: the incidence is less than 5%, which is due to increased bladder sphincter tone. It is treated with induction of urination, such as listening to the sound of water, rinsing the perineum, massage of the bladder area, and catheterization if necessary.
(5) respiratory depression: morphine has a significant inhibitory effect on respiration, the clinical manifestation is mainly the slowing down of respiratory rate, which is different from the intravenous anesthetic thiopental sodium (thiopental sodium), the latter’s inhibition of respiration is mainly the shallowing of respiration, but both make the minute ventilation volume decrease, ventilation volume is insufficient, and respiration completely stops in case of overdose. Although the inhibition of respiration by morphine is obvious, clinical cancer pain treatment is based on slowly increasing morphine doses to gradually reach larger doses. Due to the development of drug resistance and the strong stimulation of pain, there is usually no obvious respiratory depression despite the high dosage, so there is no need not to increase the dosage of morphine due to the concern of respiratory depression.
These side effects are inherent to opioids, and most of them coexist with their analgesic effects, and are not contraindications to continued use of the drug. Severe reactions need to be replaced by other analgesics or analgesic methods.
(3) Toxicity of morphine: long-term application of morphine and appropriate adjuvant drugs, side effects can be well controlled, especially when used orally on a regular basis, so it can be considered that morphine is a very safe analgesic for cancer pain. If morphine is overdosed, such as inaccurate dose titration, misuse of large dose or chemical or radiation therapy, the pain is reduced after tumor shrinkage, but the dose is not reduced, then there will be obvious drowsiness and cognitive impairment, as well as sweating and myoclonic jerking, etc. The dose can be reduced by 25%. Another possible hazard of prolonged application of morphine is that its metabolites are pharmacologically active and are excreted by the kidneys, which can easily accumulate in the body and lead to renal failure. Fentanyl is not excreted by the kidneys and can be used as an alternative to morphine in such cases. Another possible cause of drug accumulation is the shortening of the time interval when using morphine controlled-release dosage form, and the toxic reaction of morphine overdose caused by frequent dosing.
Acute morphine intoxication: Single application of morphine overdose can cause acute intoxication, mainly manifested by coma and respiratory arrest, along with a drop in blood pressure and convulsions due to hypoxia. Emergency treatment measures are endotracheal intubation, artificial respiration, blood volume replenishment, and maintenance of circulatory system stability. The specific opioid receptor antagonist naloxone (naloxone) has a good effect on resolving respiratory depression, and this drug has a short duration. It is advisable to administer 0.3-0.4 mg intravenously first, and then 0.6 mg intramuscularly or 5 μg/(kg?k[Niu Changming1] ) intravenously 15 minutes later. It should be noted that the nociception is restored at the same time as the respiration is restored.
2, morphine controlled release formulations long-acting morphine formulations, every 8, 12 or 24 hours to take a dose, very convenient for patients, its analgesic effect and every 4 hours with the immediate release formulations (immediate release), the same dose is also equivalent. The dose of morphine in the immediate release formulation is initially administered as a loading dose, and after the analgesic dose is determined, the controlled release formulation is used to maintain the dose. If the breakthrough pain occurs at long intervals, the dose of morphine should be given in a 4-hour dose of immediate release formulation, e.g., 12-hour 60 J controlled release formulation, then the breakthrough pain dose should be 20 J of immediate release formulation.
According to the release rate, drug dosage forms are classified as immediate release, extended release and controlled release. Immediate release formulations are common formulations, such as morphine oral tablets, which are rapidly released and absorbed after taking the drug, and the drug effect lasts for 3-4 hours; sustained release formulation is a transitional form of common and controlled release formulations, and its slow release mechanism is the addition of excipients in the formulation to prolong the release of the drug. The release rate of this dosage form is in line with the primary process of pharmacokinetics, that is, the drug is released in a certain proportion per unit of time, and therefore it is also called constant ratio release, so with the extension of time, the amount of drug release gradually decreases, the release rate gradually slows down, and the blood concentration decreases. Although the sustained release dosage form has a longer duration of action than the immediate release dosage form, it is still difficult to maintain a stable blood concentration. Oramorph SR (morphine sulfate tablets) and Chimantin (tramcontin, tramadol) are sustained release dosage forms. The controlled release dosage form consists of drug and carrier, the carrier of morphine sulfate controlled release tablets is ethyl cellulose and ethylene vinyl acetate copolymer, its release rate is in line with the zero-level process, that is, the carrier releases the drug in a certain amount per unit time instead of in a certain proportion, the amount of drug released is not related to the blood concentration and the amount of drug not released, so it is also called constant amount release, with the extension of time, the amount of drug released does not gradually decrease, and can It can maintain the stability of blood concentration for a long time. It can be seen that controlled release is a more advanced dosage form, and morphine sulfate controlled release tablets are of this kind. Doctors should pay attention to the above-mentioned dosage form characteristics when choosing the medication.
Currently, morphine sulfate controlled-release tablets (Methocarbamol, MS Contin) and morphine hydrochloride controlled-release tablets (Mefecam) are available for oral use. Although the onset of action is not rapid (about 1 hour), the effect lasts up to 12 hours, which is suitable for cancer pain patients who have been using opioid analgesics for a long time. The initial dose is 20-30J, taken once every 12 hours, and the dose will be increased depending on the pain relief effect until the pain is relieved. If a larger dose is needed, the dose can be increased by 25% to 50% each time according to the situation, or add non-steroidal anti-inflammatory analgesics, and for sudden pain it is appropriate to add immediate release morphine orally or intramuscularly injected morphine. Controlled-release preparations must be swallowed intact when taken orally, do not chew, and do not break. The adverse reactions and precautions for the use of morphine controlled-release preparations are the same as those for general morphine preparations.
3, oxycodone and its controlled release preparations oxycodone (oxycodone) that is hydroxydihydrocodeinone (hydroxydihydrocodeinone) for a morphine substitute, for moderate and severe pain, can be given orally, rectally or parenteral injection, equivalent analgesic dose and morphine, so the two drugs are easy to convert each other. Oxycodone is an analgesic drug used in the three-stage cancer pain treatment program from moderate pain in the second stage to severe pain in the third stage. It has no capping effect, and the analgesic effect is enhanced by increasing dose, and the side effects are less and milder than morphine. Oxycodone hydrochloride 5J and acetaminophen 500J make a compound combination called Tylenol, which is used for cancer pain 1 to 2 capsules each time, 3 times a day. This formulation can reduce the abuse of oxycodone alone and can enhance its analgesic effect. Oxycontin (oxycontin) is a combination of oxycodone hydrochloride immediate release dosage form and controlled release dosage form, thus making up for the slower onset of action of mescaline. 38% of the effective amount of this drug is immediate release, 62% is controlled release, the former is quickly released and absorbed, rapid onset of action, 1 hour after taking the drug to play a pain-relieving effect, effective analgesia can last for 12 hours, within a day to reach steady-state blood concentration. The initial dose is 10～40J, if drug resistance or pain aggravation occurs, the dose should be increased by 10%～30%, there is no clinical limit, the average dose is 60～105J (20～640J) per day, and the dose ratio of equivalent analgesic effect and mescaline is 1:2, suggesting that the analgesic effect of OxyContin is strong.
4.Other class III potent opioid analgesics
(1) pethidine (pethidine): also known as dolantin (dolantin), is the most used opioid analgesic, used for acute severe pain such as post-traumatic pain and post-operative pain with good effect, but not suitable for long-term treatment of cancer and other chronic pain. The reason is that the metabolite of pethidine, norethindrone, is neurotoxic, and its long half-life and slow metabolism make it easy to accumulate in long-term applications, which can produce toxic symptoms such as tremors, convulsions, muscle spasms, and even grand mal seizures. Pethidine has a short duration of action and needs to be used frequently. Its positive frequency effect can accelerate the heart rate and affect the heart function, and the negative inotropic effect can weaken the contraction of the heart muscle and decrease the blood pressure, and hypotension can occur. The above mentioned action characteristics and more side effects are not conducive to the long-term use of pethidine, so the application of pethidine should be excluded in the treatment of cancer pain.
(2) Methadone: It is a strong opioid that can replace morphine, with analgesic effects comparable to or slightly stronger than morphine, and longer duration of action than morphine, and has advantages for neuropathic pain and morphine-resistant pain. This drug has some NMDA receptor antagonistic properties and has an inhibitory effect on the uptake of 5-hydroxytryptamine and norepinephrine. Adults take it orally once in 6-8 hours, starting from 5-7.5J per dose, 3 times a day, and gradually adjust the dosage. The side effects are similar to morphine, and drowsiness and cognitive impairment can occur when the drug accumulates, then the interval between doses should be extended to 12 hours. Methadone has a long duration of action, weak drug resistance and dependence, and mild withdrawal symptoms, and can be used as an alternative detoxification treatment for morphine dependence.
(3) hydromorphone: the effect of this drug is stronger than morphine, equivalent analgesia is 20% of the dose of morphine, for patients who need large doses of morphine and more obvious side effects can be replaced with this drug, oral, rectal, parenteral injection are convenient.
(4) fenazosin (phenazocine): is a strong opioid analgesic alternative to morphine, 5J tablets and morphine 25J equivalent, side effects are similar to morphine, but the psychotropic effect is lighter.
(5) diacetylmorphine (diamorphine): that is, heroin (heroin), is a precursor of morphine, metabolized into morphine and 6-monoacetylmorphine in the body to play the analgesic effect. Because of its high lipid solubility, it is often abused because it can enter the central nervous system more quickly when administered parenterally. This drug is equivalent to morphine, with the advantage that it is easily soluble and can reach a concentration of 250 J/ml when injected subcutaneously, compared to 30 J/ml for morphine, which means that diacetylmorphine can be given in large doses in small volumes. Oral administration does not have more advantages than morphine.
(6) buprenorphine (buprenorphine): mainly for the treatment of moderate to severe pain, sublingual 0.2 to 0.8J, 15 to 45 minutes to take effect, maintain 6 to 8 hours, intramuscular or slow intravenous dose of 0.15 to 0.4J. This drug is an opioid receptor partial agonist, with a capping effect. Buprenorphine patch is now made, with long-acting nature, more convenient to use, less side effects.
(7) dihydroetorphine (dihydroetorphine): is by far the strongest analgesic, its analgesic potency in humans and different animals is about 1 000 ~ 12 000 times of morphine. The maintenance time is 3-4 hours for the former and 2-3 hours for the latter. It is effective in the treatment of severe cancer pain, but needs to be used in combination with tramadol or other adjuvants because of the short effective time. This drug has been used for detoxification of opioid dependence, because it itself can also produce dependence, patients have euphoria after application, and after stopping the drug, there is a soporific behavior, so eventually failed to become a withdrawal drug use.
(8) fentanyl and its transdermal patch: fentanyl (fentanyl, fentanil) is a semi-synthetic potent opioid analgesic, analgesic potency compared with morphine in the parenteral administration of 1:80, the action time of about 30 minutes. Sufentanil, alfentanil and remifentanil are all homologous drugs of fentanyl. Although they all have strong analgesic effects, they are not suitable for cancer pain treatment because of their short duration of action and the fact that they are all injectable, except for sudden pain in cancer. Fentanyl is highly lipid-soluble, so that it can be absorbed through the skin, and can be rapidly and widely distributed when administered transdermally, with an elimination half-life of up to 12 hours. Fentanyl has fewer and milder side effects than morphine. Patients with drowsiness and cognitive impairment with morphine are advised to switch to fentanyl transdermal patches, and constipation is less severe than morphine. The commercially available product is called duragesic, which is a transdermal extended-release form of fentanyl. This drug has four specifications, fentanyl content of 2.5J, 5.0J, 7.5J, 10.0J, its hourly release of 25μg, 50μg, 75μg, 100μg, in turn, can continue to release drugs for 72 hours, 25μg / h and about every 4 hours morphine 10 ~ 20J equivalent. The analgesic effect is produced 6-12 hours after pasting, and the steady-state blood concentration is reached in 12-24 hours, and the blood concentration decreases by 50% in 17 (13-22) hours after discontinuation. If the effect is unsatisfactory or if there is sudden pain, oral immediate release form or intramuscular morphine can be added, and after 3 days, the dose should be changed to a higher dose. The patching site should be in a flat area without hair on the trunk or upper limbs, clean and dry, and the patching site should be changed when renewing. If switching to other analgesics, the dose of the alternative drug should be increased gradually to avoid withdrawal reaction.
The side effects of fentanyl transdermal patch are the same as those of opioids, including nausea, vomiting, drowsiness, mental disorder, urinary retention, etc. The local skin may be itchy, and there may be insufficient ventilation or even respiratory depression in case of overdose, which should be alerted. The elderly and frail people should reduce the dosage, the absorption of fever is accelerated, and should be closely observed.
Transmucosal fentanyl ingot is now made, with a short rod to support it in the buccal mucosa, can be quickly absorbed to play a role in the accidental pain effect is very good. Recently, transdermal iontophoresis transdermal system (ITS fentanyl) has been applied to fentanyl patches, and the dose can be controlled by patient-controlled analgesia (PCA), with 40 μg of drug released in 10 minutes for each press of the patch, limited to 6 times/hour, and the effect of the whole patch can last for 24 hours, with indications for Cancer pain and post-surgical pain.