Analgesics

One of the primary methods of pain control is the use of analgesics. Analgesics are among the most commonly used medications in society, along with the  antibiotics. Therefore, it is essential to accurately assess the principles of analgesic use and teach these principles to patients. It is an important fact that both physicians and pharmacists will contribute significantly during the process of teaching patients about the principles of analgesic use. Analgesics are medications used to achieve pain control in acute and chronic pain syndromes. The use of analgesics might be as ancient as human history itself.

Morphine - Opium and its derivatives, which are considered the ancestors of nonsteroidal anti-inflammatory drugs, such as salicylic acid (aspirin), have been used for 5000 years and 100 years respectively. In the past 50 years, numerous new drugs have been developed and utilized from both of these groups.

Unfortunately, analgesics are among the drugs that are commonly misused. The origin of this misuse lies in the lack of knowledge and understanding of both physicians and patients about this group of drugs. With the emergence of pain science in the last 20-30 years, the proper use of analgesics has improved.

Efforts aimed at the correct use of analgesics began within the framework of the World Health Organization (WHO) in the 1980s. In 1986, principles of analgesic use in cancer pain were published in a brochure.

With these principles published by the WHO, effective pain control is possible in about 80-85% of both cancer-related and non-cancer-related pains. The prerequisite for the proper use of analgesics is that the physician possesses detailed knowledge of the mechanism of action, effectiveness, side effects, drug interactions, and dosages of analgesics. Careful and thorough assessment is necessary to determine the origin, nature, and location of the pain, as well as the patient's age, general condition, other illnesses, and response to the intended medication.

Principles of Analgesic Use

Within this basic framework, the principles of analgesic use can be outlined as follows:

1. Oral administration should be the preferred route for the use of analgesics.

For patients with chronic pain who will use analgesics for an extended period, the simplest route is oral administration. This route, which requires no additional intervention in treatment, should be tried as a priority. Alongside oral administration, it is beneficial to pursue the use of the cheapest and most effective medication.

If the patient does not have problems such as difficulty swallowing, vomiting, or nausea, oral administration should definitely be preferred. If oral administration is not feasible, and if an appropriate form of the selected analgesic is available, alternative routes such as suppository, subcutaneous, or nasal routes should be considered.

2. The frequency of analgesic administration should be evaluated individually for each patient.

It has been emphasized multiple times that pain is a personalized experience. Even among patients with similar pain issues, there are significant differences in analgesic requirements. For example, the effectiveness of aspirin in treating cancer pain will differ from its effectiveness in relieving a simple bruise. The goal is to administer the most suitable dose with the least side effects. To find the ideal dose, the medication should be administered once, and the patient's needs should be compared with the drug's duration of action. The patient's cooperation is essential for achieving this.

The patient is asked to measure the duration of analgesic effect several times until the pain starts. A more careful dose adjustment is necessary for elderly patients.

3. Analgesics should be administered before the pain begins and at regular intervals.

One of the biggest mistakes in pain treatment with analgesics is administering them only after the pain has started. This is, in a way, starting pain treatment from scratch each time. An ideal analgesic treatment involves continuous pain control over 24 hours. This way, a vicious cycle does not occur in the patient, continuity of analgesia is ensured, and pain relief can be achieved with much lower doses of medication.

In other words, just like hypertension or diabetes medications are administered before blood pressure or blood sugar levels rise, analgesics should be administered before the pain level increases.

A traditional mistake is applying the 3x1 regimen based on meals. There is a 4-hour interval between breakfast and lunch, an 8-hour interval between lunch and dinner, and a 12-hour interval until morning. This implies extremely irregular administration of analgesics at 4-8-12-hour intervals. However, analgesics are medications with specific half-life times. Therefore, after determining the patient-specific dose and duration of action, analgesics should be administered at regular intervals considering the time when the analgesic effect will start.

4. Analgesics should be applied according to the stepwise principles.

One of the important factors in choosing analgesics is the severity of pain. The question of which analgesic to start with for pain of what intensity can be answered using the stepwise system developed by the WHO (World Health Organization) for cancer patients but can also be applied to other types of pain. The DST (Drug Selection Tool) has developed a three-step ladder system. In this system, analgesics are grouped by their strengths, ranging from the least potent to the most potent.

 

In the first step of analgesic therapy, aspirin and similar drugs, i.e., nonsteroidal anti-inflammatory drugs, are used. Additionally, secondary analgesics, such as antidepressants and muscle relaxants, can be added. When this step becomes insufficient, a transition is made to strong opioid derivatives, including morphine, and long-acting oral opioid derivatives. Weak opioids are discontinued at this stage. This three-step system developed by DST can be effective in 80-85% of patients. If this approach is not effective, interventional methods should be considered.

Patients who have never used analgesics should definitely start from the first step. A minimum of 24 hours must elapse for a step to be correctly assessed. Skipping steps in the stepwise system can lead to the emergence of certain side effects in patients. Therefore, it is necessary for the patient and their close relatives to carefully evaluate and for doctors to warn and educate them about this assessment.

Most patients try to evaluate these through reading the package inserts. There are unnecessary fears about analgesics among doctors, patients, and their families. These fears particularly develop against morphine and similar drugs.

Classification of Analgesics

Analgesics are classified into two groups: centrally acting and regionally acting.

Regional Acting Analgesics

With the discovery of aspirin from willow leaves by Hoffman in 1853, a significant breakthrough was made in the field of regional acting analgesics. The first example of this group, also known as nonsteroidal anti-inflammatory agents, is aspirin. However, hundreds of similar drugs have been developed later.

Pharmacology Nonsteroidal anti-inflammatory agents are used to treat mild to moderate pain, fever, inflammatory conditions such as rheumatic fever, rheumatoid arthritis, osteoarthritis, chronic pain, and cancer pain (especially with bone metastases).

Principles of Use

1. Should be used cautiously in conditions like gastritis and ulcers.
2. Should be used cautiously in individuals with clotting disorders.
3. Should not be used during pregnancy unless necessary. When used, risks should be considered, and they should not be used for labor pain.
4. Should not be used in individuals who have previously developed an allergy to the drug or experienced shortness of breath.
5. Patients' responses to nonsteroidal anti-inflammatory drugs vary. A patient who does not benefit from one agent or cannot tolerate it may be successfully treated with another agent.
6. Aspirin and other nonsteroidal anti-inflammatory drugs should not be used together. This is because there is not much therapeutic advantage, and especially the gastrointestinal side effects increase.
7. These drugs should not be used above the specified dose. Because of a phenomenon called ceiling effect, using more does not provide more pain relief. In other words, if a drug that needs to be taken twice a day is taken six times, it only increases the stomach-irritating effect, not the pain-relieving effect.

Main Side Effects These drugs have many side effects, so they should not be used arbitrarily. Side effects of nonsteroidal anti-inflammatory drugs include:

1. Gastrointestinal system
2. Kidneys
3. Cardiovascular system
4. Liver
5. Blood
6. Allergy and skin rashes
7. Respiratory system
8. Gastrointestinal System: Can affect the gastrointestinal system with varying severity. It can lead to nausea, vomiting, heartburn, diarrhea, constipation, abdominal pain, ulcers, perforation of the stomach, and bleeding. Age, smoking, coffee, alcohol use, gender, and corticosteroid use can increase the gastrointestinal side effects of these drugs. To prevent this, gastroprotective drugs can be used.
9. Effects on Kidneys: Acute kidney failure, chronic kidney failure can develop. Elderly patients using these drugs should be extremely careful.
10. Cardiovascular System: High blood pressure, heart failure can occur.
11. Effects on Liver: Liver failure can develop. In chronic treatment, liver tests should be performed, especially in the first 8 weeks.
12. Blood: Decrease in platelet count, which is responsible for blood clotting, and anemia can occur. The antiplatelet effect of nonsteroid drugs is not clinically significant; they are used in antithrombotic treatment.
13. Hypersensitivity Reactions: Aspirin and similar drugs can cause allergies, respiratory distress, and reactions similar to shock. Allergic skin rashes can occur. Itching may occur.
14. Effects on Respiratory System: Rarely, respiratory distress can develop. If unnoticed, respiratory failure may develop.

Clinical Use Regional analgesics can be used for headaches, dental pain, cancer pain, metastasis, postoperative pain, trauma, back pain, migraines, dysmenorrhea, and conditions such as rheumatoid arthritis, gout, ankylosing spondylitis, tendinitis, epicondylitis, and osteoarthritis. Unlike centrally acting analgesics, they do not cause addiction, tolerance, respiratory depression, or drowsiness. However, nonsteroidal analgesics have a ceiling effect. The ceiling effect refers to not experiencing a greater analgesic effect beyond a certain dose, while the intensity of side effects increases. For example, the analgesic ceiling for aspirin is around 650 mg/mL, and as the dose increases, the analgesic effect does not increase, but the severity of unwanted effects increases. Therefore, when using nonsteroid drugs, attention should be paid to this ceiling effect. Because they have different half-lives, it is possible to switch from one drug to another.

Centrally Acting Analgesics Opioid Analgesics

Naming Opioid analgesics like morphine and similar drugs are often referred to as "narcotic analgesics." This is a misnomer that has persisted from the past and is not easily erased. The term "narcotic" in Greek means drowsiness or numbness. At one point, it was used for almost all drugs that induce drowsiness.

In this sense, cocaine is also included in this group. However, cocaine stimulates the central nervous system. Moreover, the term "narcotic" is also used for addictive drugs.

The term "opiate" was originally used for naturally occurring and semi-synthetic drugs derived from morphine, while the term "opioid," meaning morphine-like, started being used with the synthesis of fully synthetic morphine-like drugs.

Today, the term "opioid" encompasses all drugs similar to morphine, whether natural, semi-synthetic, or fully synthetic. However, in many places, the terms "opiate" and "opioid" are used interchangeably.

History

There are many drugs today with effects similar to morphine. These can be natural, semi-synthetic, or fully synthetic. Despite all these drugs, morphine still retains its importance as an analgesic. Morphine was isolated from opium by Sertürner in 1803. Opium, also known as poppy, is obtained by scratching the not fully mature seed capsules of the Papaver somniferum plant, resulting in the release of a white liquid that darkens upon contact with air and becomes a gum-like substance.

Opium gum contains more than 20 substances. Among them, codeine, which has analgesic properties, was isolated by Robiquet in 1832.

Mechanisms of Action

 Opioids exert their effects by binding to their unique receptors or sensors. Drugs like morphine and its derivatives easily affect various parts of the body, such as the gastrointestinal system, lungs, nose, subcutaneous tissue, and muscles. A more recent approach is delivering them directly to the spinal cord region to achieve a much stronger effect.

In a person without pain, when therapeutic doses of morphine are administered, nausea, vomiting, dysphoria, apathy, and decreased physical activity can occur. The response of individuals in pain is different. Opioid analgesics alter the perception of pain and the reaction to it. Patients often report that they still feel the pain but no longer perceive it as an unpleasant sensation. Opioids prevent the transmission of painful stimuli to the central nervous system.

Euphoria/Dysphoria: Opioid drugs create pleasant feelings in painful individuals or addicts by relieving anxiety and discomfort. In normal individuals, they cause dysphoria characterized by restlessness and fatigue.

Sedation: Although drowsiness and clouded consciousness are common, memory loss is very rare. While opioids more frequently induce sedation in the elderly, waking up from sleep is easy. Synthetic opioids cause sedation less frequently and result in mild drowsiness.

Respiratory Impairment: Opioids can suppress the respiratory centers in the brainstem in a dose-dependent manner.

Suppression of Cough Reflex: Among opioid analgesics, codeine is the most potent suppressor of the cough reflex.

Nausea and Vomiting: They induce nausea and vomiting by stimulating the nausea center in the brainstem.

Gastrointestinal System: Opioid analgesics often cause constipation.

Urinary System: Morphine and similar drugs can cause temporary difficulty in urination.

Fear of Morphine and Dependency: Opio-phobia and Addiction Understanding morphine addiction requires correct definitions of certain concepts. Generally, terms like tolerance and addiction are used interchangeably, which is incorrect.

Tolerance: It is when a drug loses its initial effect after being used for a period of time. This is a completely normal phenomenon.

Physical and Psychological Dependence: Repeated use of opioids, at different levels, can lead to physical dependence. Stopping the drug can cause withdrawal symptoms like runny nose, yawning, tremors, frequent breathing, fever, muscle pain, vomiting, diarrhea, etc. The onset of these symptoms depends on the severity of physical dependence. Withdrawal symptoms in morphine users appear about 6-10 hours after the last dose, peak within 36-48 hours, and usually subside after 5 days. To prevent withdrawal symptoms, the dose should not be reduced by more than one-fourth, and discontinuation should not be sudden.

Psychological dependence is an increased desire to use the drug. This is usually the feared outcome. Due to this fear, both doctors and patients try to avoid using drugs sufficiently. Not providing adequate medication to a patient in pain facilitates the development of psychological dependence. In research conducted by the World Health Organization on 40,000 patients, it was found that psychological dependence developed in patients in pain, but only four cases were identified.

Clinical Use Pain: The belief that morphine and similar drugs are effective for all types of pain is incorrect. While opioids are beneficial for severe and persistent pain, they are not as effective for sharp, intermittent pain. The type of pain should be carefully selected. They can be used for chronic pain associated with cancer and other severe illnesses.

Shortness of Breath: Morphine is useful for shortness of breath caused by heart failure and pulmonary edema.

Cough: Cough reflex can be suppressed with a dose lower than that required for analgesia. However, today more effective, non-addictive drugs are used as cough suppressants.

Diarrhea: Opioids can be used to effectively prevent all types of diarrhea, especially infection-related diarrhea.

Secondary Analgesics       

Secondary analgesics refer to a concept that encompasses drugs from diverse pharmacological groups, which have primary uses other than pain relief but are known to be beneficial in certain pain syndromes. These drugs are either directly effective as pain relievers or enhance the effects of other analgesics.

In this group, there are various drugs such as antidepressants, tranquilizers, muscle relaxants, drugs that affect the central nervous system and are generally used in epilepsy treatment, corticosteroids, and many others. These drugs are used for pain control outside their primary indications. For instance, aspirin is not only used as a pain reliever but also for its blood-thinning effects.

Medicine  is increasingly benefiting from drugs in this group. In many situations where well-known pain relievers like morphine and aspirin are not effective, secondary analgesics in this group demonstrate greater effectiveness. Hence, these drugs are sometimes referred to as the next generation of pain relievers.