• Nonopioid Analgesics
• Opioid Analgesics
• Adjuvant Analgesics

Nonopioid Analgesics include drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and dipyrone.

Opioid Analgesics or narcotic analgesics include drugs such as morphine, codeine, tramadol, and tapentadol.

Adjuvant Analgesics include drugs such as GABA agonists, neuroleptics, muscle relaxants, and anticholinergics.

Depending on the mechanism of action and usage, analgesics can be further divided into the following subcategories:

• Nonsteroidal Anti-Inflammatory Drugs
• Cox-2 Inhibitors
• Opioid Analgesics
• CGRP Inhibitors
• Miscellaneous Analgesics
• Adjuvant Analgesics

1. What Is the Mechanism of Action of Analgesics?

1.1. What Are Nonsteroidal Anti-Inflammatory Drugs?

NSAIDs are a group of drugs used to relieve pain, reduce inflammation, and fever by targeting the two cyclooxygenases (COX) enzymes, COX-1, and COX-2, responsible for the production of prostaglandins from the fatty acid arachidonic acid in the body [1].

Prostaglandins are lipid compounds that have hormone-like effects and are found in all tissues of our human body.

They are synthesized (produced) by the walls of the blood vessels and involved in the regulation of smooth muscle contraction and relaxation, including those of the blood vessels, uterus, gastrointestinal tract, and urinary bladder.

For example, prostaglandins are responsible for the vasoconstriction and vasodilatation of blood vessels.

They are also involved in inflammation through their role as proinflammatory mediators during the acute phase of inflammation.

Additionally, prostaglandins induce fever through their action on the thermoregulatory center in the hypothalamus.

Another function is associated with their role in platelets aggregation during coagulation, and therefore, are also involved in thrombosis (formation of blood clots in the blood vessels).

Thus, NSAIDs by inhibiting the enzymes COX-1 and COX-2, prevent the production of prostaglandins resulting in pain relief, reduction of inflammation, and fever, and prevention of thrombosis.

The most known NSAIDs are aspirin (acetylsalicylic acid), ibuprofen (Advil, Nurofen, Motrin), and naproxen (Aleve, Naprosyn).

• What Are NSAIDs Used to Treat?

NSAIDs are used for the relief of mild-to-moderate pain in conditions and disorders such as headaches, migraines, toothache, menstruation, muscle strains and sprains, rheumatoid arthritis, and osteoarthritis.

1.2. What Are Cox-2 Inhibitors?

COX-2 inhibitors are also NSAIDs used to relieve pain, reduce inflammation, and fever; however, these drugs selectively target COX-2, while the other NSAIDs target both COX-1 and COX-2.

The advantage of the COX-2 inhibitors is their reduced side effects on the gastrointestinal tract when compared with the other NSAIDs. However, some concerns were raised about the safety of some COX-2 drugs.

COX-2 inhibitors include drugs such as celecoxib (Celebrex) and rofecoxib (Vioxx), which were withdrawn from the market.

• What Are COX-2 Inhibitors Used to Treat?

Cox-2 inhibitors are used for the relief of mild-to-moderate pain in conditions and disorders such menstruation, hereditary polyps of the colon, ankylosing spondylitis, rheumatoid arthritis, and osteoarthritis.

1.3. What Are Opioid Analgesics?

Opioid analgesics or narcotic analgesics are used for the relief of moderate-to-severe acute or chronic pain.

This class of analgesics includes drugs such as morphine, codeine, tramadol, and tapentadol.

These drugs relieve pain through their binding to the opioid receptors (e.g., mu receptors) found in the brain, spinal cord, peripheral nerves, and gastrointestinal tract [2].

The increased prescriptions of opioid analgesics resulted in less effective therapy, and substance abuse [3].

• What Are Opioid Analgesics Used to Treat?

Opioid analgesics are used for the relief of mild-to-moderate pain associated with cancer, and for palliative care or end-of-life care. However, due to their oversubscription, they have been used for the relief of all types of pain.

1.4. What Are CGRP Inhibitors?

CGRP Inhibitors are drugs that relieve pain by targeting a peptide in the peptide known as Calcitonin gene-related peptide (CGRP) [4].

CGRP is stored in neurons of the brain, spinal cord, and peripheral nervous system, where it is involved in the transmission of pain.

CGRP Inhibitors include monoclonal antibodies that bind specifically to CGRP and block its action, including eptinezumab (Vyepti), galcanezumab (Emgality), and fremanezumab (Ajovy) and monoclonal antibodies that bind to the CGRP receptor such as erenumab (Aimovig).

• What Are CGRP Inhibitors Used to Treat?

CGRP Inhibitors are used to treat patients with frequent, episodic, or chronic migraine headaches.

1.5. What Are Miscellaneous Analgesics?

Miscellaneous Analgesics are a separate class of analgesics as they belong to neither nonsteroidal anti-inflammatory drugs (NSAIDs) nor opioid analgesics.

They include analgesics such as acetaminophen (Paracetamol, Tylenol), ziconotide, and dipyrone. However, in the United States, only acetaminophen and ziconotide are available.

• What Are Miscellaneous Analgesics Used to Treat?

Acetaminophen (Paracetamol, Tylenol) is used for reducing fever and relieving mild-to-moderate pain associated with conditions and disorders such as headaches, migraines, toothache, muscle strains, and sprains, rheumatoid arthritis, and osteoarthritis.

Ziconotide relieves severe pain by blocking N-type voltage-gated calcium channels found in the dendrites and nerve terminals and is involved in neurotransmission and pain transmission.

Dipyrone (Metamizole) is used as a pain killer, spasm reliever, and anti-inflammatory agent for the relief of acute and chronic forms of pain, high fever, acute injury, colic, and cancer pain; however, metamizole is banned in many countries including the United States.

1.6. Adjuvant Analgesics

Adjuvant analgesics are drugs that are not considered analgesics but are used for neuropathic pain, musculoskeletal pain, or cancer pain.

This group of drugs includes antidepressants, α₂-adrenergic agonists, corticosteroids, neuroleptics, muscle relaxants, and anticholinergics [2].

2. Do Analgesics Reduce Inflammation?

Analgesic drugs such as NSAIDs and COX-2 inhibitors are used to relieve pain and reduce fever, and inflammation.

The mechanism of action involves the inhibition of the production of the proinflammatory peptide prostaglandins.

3. Is Analgesic Good for Fever?

Analgesic drugs such as NSAIDs and COX-2 inhibitors are used to relieve pain and reduce inflammation, and fever.

The mechanism of action involves the inhibition of the production of prostaglandins which induce fever through their action on the thermoregulatory center in the hypothalamus.

4. Is Ibuprofen an Analgesic?

Ibuprofen (Advil, Nurofen, Motrin) is a nonsteroidal anti-inflammatory drug used to relieve pain, reduce inflammation, and fever by targeting COX-1, and COX-2 enzymes, responsible for the production of prostaglandins.

Conclusion

Analgesics are used for pain relief, and for the reduction of inflammation and fever. They are differently used depending on the severity of the pain; however, their oversubscription or misuse can result in disorders affecting the gastrointestinal tract (e.g., NSAIDs) or drug abuse (e.g., opioid analgesics).

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The hypothalamus works like a thermostat for the body and maintains the temperature in the range of 97.7-99.5 °F (36.5-37.5 °C) [1].

• What Is Hypothermia?

Hypothermia is when the body temperature is lower than 95 °F (35.5 °C).

• What Is Fever?

Hyperthermia is when the body temperature is higher than 99.5 °F (37.5 °C).

• What Is Hyperpyrexia?

Hyperpyrexia is when the temperature is higher than 104 °F (40 °C).

1. How Does the Hypothalamus Regulate Body Temperature?

The Hypothalamus regulates body temperature (Thermoregulation) through 3 mechanisms: Afferent sensing, central sensing, and efferent responses [2].

• Afferent Sensing

Afferent sensing is associated with temperature sensors known as thermoreceptors that are distributed throughout the body.

Thermoreceptors are sensory nerve endings that are part of the nervous system. They are categorized into receptors for warmth detection and receptors for cold detection [3].

Receptors for warmth detection are known as C fibers, while receptors for cold are known as Aδ fibers.

• Central Control

This part is controlled by the hypothalamus which receives information about the body temperature from the thermoreceptors.

• Efferent Responses

Efferent responses are automatic responses to changes in the temperature such as sweating, vasoconstriction (narrowing of the vessels), vasodilatation (dilatation of the vessels), and shivering [4].

2. What Hormone Controls Body Temperature?

The hypothalamus is the part of the brain that controls body temperature; however, heat is internally generated by the metabolisms (energy production) of the different organs of the body where thyroid hormones such as thyroxine (T4), and triiodothyronine (T3) play an essential role.

3. Does Low Body Temperature Indicate Thyroid Problems?

A low body temperature is not necessarily due to problems with the thyroid; however, increased sensitivity to cold is one of the symptoms of hypothyroidism [5].

4. What Time of Day Is Body Temperature the Highest?

The highest body temperature was reported to be an early evening at 6 pm [6].

5. What Factors Affect Body Temperature?

Temperature fluctuations can be associated with the following factors:

• Age

Older individuals (more than 60 years old) have a lower temperature mean (average) compared to those individuals less than 60 years old [1] [7].

• Sex

Women have a slightly lower temperature than men [1]. However, during pregnancy and ovulation, this temperature increases, while it is lower at the start of the menstrual cycle.

• Circadian Rhythms

The body temperature is highest at 6 pm in the evening and lowest at 3 am in the morning [6].

• Physical activity

During physical activity and exercise the body generates a significant amount of heat due to the intense energy consumption.

• Meals

There is an increase in the body s metabolism meals which leads to an increase in the temperature of the body.

• Fever

Fever is due to infections such as a virus or bacteria, heat exhaustion, and inflammation (e.g., rheumatoid arthritis).

• Medications

Antibiotics and blood pressure or seizures can increase the body temperature.

6. What Vitamins Help with Body Temperature?

Vitamins B1, B2, B3, B5, and B7 (Biotin) are directly involved in the metabolic conversion of food into energy necessary for the maintenance of body temperature.

7. Can Mental Stress Cause Fever?

Some individuals, especially young women, develop a high fever when they are exposed to emotional events which cause stress. This type of fever is known as psychogenic fever [8].

8. What Are the Disorders of Body Temperature?

Disorders of the body temperature include any disorders that can cause a fever or hypothermia.

8.1. What Causes Fever?

Fever is mainly caused by sepsis, however, inflammation, and medications can also contribute to fever.

8.1.1. What is Sepsis?

During sepsis, fever is caused by exogenous pyrogens (e.g., pathogens) or endogenous pyrogens such as cytokines that interact with an area of the brain known as the organum vasculosum of the lamina terminalis (OVLT) or supraoptic crest.

The activation of the OVLT results in the increase in the synthesis of molecules known as prostanoids which are involved in inflammation (e.g., prostaglandins and prostacyclins) and in vasoconstriction (thromboxanes).

Prostanoids act by slowing down the activity of the warm sensitive neurons of the hypothalamus leading to an increase in the temperature [9].

8.1.2. Is Fever Associated with Inflammation?

Inflammation is a natural event that occurs following tissue damage or infections that results in swelling, redness, heat, and pain.

During inflammation, several inflammatory mediators are released by the cells involved in wound healing or in fighting infections.

These mediators are also pyrogenic (causing fever) and may act in a similar way to that of the sepsis pyrogenic mediators.

In some cancer patients fever also appears to be mediated by the same mechanism as that of sepsis [10].

8.1.3. Which Drugs Induce fever?

Some pharmacological drugs can cause heat loss from the peripheries, directly damage tissues, interfere with the hypothalamus central temperature regulation, stimulate an immune response, or have pyrogenic properties [9].

• Antimicrobial agents such as beta-lactam antibodies and sulphonamides.
• Volatile anesthesic agents
• Anti-depressants such as SSRI
• Opioids such as fentanyl
• Central nervous system stimulants such as amphetamines and cocaine
• Psychedelics such as lysergide
• Anticholinergic agents such as bronchodilators and ephedrine
• Anti-emetics such as cyclizine
• Synthetic cathinones such as bupropion

8.1.4. What Is Endocrine fever?

Hyperthyroidism is associated with the increase in body temperature due to the increase in the secretion of the thyroid hormones, thyroxine (T4), and triiodothyronine (T3) that play an essential role in the metabolisms (energy production) of the different organs of the body [10].

8.2. What Causes Hypothermia?

There are several disorders and medications that cause hypothermia:

8.2.1. What Disorders Cause Hypothermia?

Some disorders can affect the body capacity to regulate core temperature:

• Hypothyroidism
• Diabetes
• Anorexia Nervosa
• Poor Nutrition
• Spinal Cord Injuries
• Severe Arthritis
• Stroke
• Parkinson Disease

8.2.2. What Medications Cause Hypothermia?

Changes in body temperature can be caused by the following drugs:

• Sedatives
• Antipsychotics
• Narcotic Pain Medications
• Antidepressants

8.3. Heart-Related Illness

In chronic heart failure, there is an alteration in the balance between heat production and heat loss but also an increased risk of ischemia or stroke that can damage the brain and also affect the metabolism [11].

Conclusion

The body temperature is controlled by the hypothalamus through mechanisms that involve afferent sensing, central control, and efferent responses. Any factors that disturb the normal functioning of these mechanisms lead to a change in the body’s temperature.

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