[2.1] Pain Medicines and Drugs used for Join Disorders

Pain

A subjective experience wherein there is a localized sensation and unpleasant quality of varying sensitivity.

Structural and tissue damage

This is what pain is usually associated with.

The Pain Pathway

This illustrates the 4-stage neural progression of nociceptive signals from peripheral tissue damage to cerebral processing.

1. Site of Injury

2. Spinal Cord

3. Brainstem

4. Cerebrum

These are the main stages of the Pain Pathway.

1. Fast, myelinated A-fibers

2. Slow, unmyelinated C-Fibers

3. Afferent nerve fiber

These are the key neural structures at the site of injury.

Fast, myelinated A-fibers

This conduct fast, acute pain signals.

Slow, unmyelinated C-Fibers

This conduct slow, persistent pain signals.

Afferent nerve fiber

This carries initial action potential away from site of injury.

1. Dorsal ganglion

2. Synapse

These are the key neural structures in the spinal cord.

Spinothalamic tract

This is the key neural structure involving histaminergic neurons.

Dorsal ganglion

This is where afferent fibers enter through the spinal cord.

Synapse

Afferent fibers form a ____ with secondary neurons.

Spinothalamic tract

This is where the afferent fiber ascends through after interacting with the secondary neurons.

1. Mid-pons

2. Reticular formation

These are the key neural structures in the brainstem.

Mid-pons

This is where ascending signals travel in the brainstem.

Reticular formation

This activates the autonomic alertness and immediate arousal.

1. Thalamus

2. Somatosensory cortex

3. Limbic System

These are the key neural structures in the cerebrum.

Thalamus

This serves as the central sensory relay station.

Somatosensory complex

This identifies pain location and severity.

Limbic System

This processes emotional and visceral responses to pain either mechanical or chemical in nature.

Nociceptors

Important specialized sensory nerve cells that detect potential or actual tissue-damaging stimuli and send threat signals to the spinal cord and brain.

Anti-pain medication

They generally regulate the response of these nociceptors.

1. Skin

2. Visceral

3. Joint

These are the main locations where nociceptors are found.

Mechanonociceptor

This nociceptor is activated by intense mechanical stimulation.

Chemo nociceptor

This nociceptor is activated by chemical mediators released during tissue damage (including prostaglandins and histamine).

Thermo nociceptor

This nociceptor is activated by mechanical and thermal stimuli.

Polymodal nociceptor

This nociceptor is activated by high intensity of stimuli of various types.

Silent nociceptor

This nociceptor is activated by mechanical stimulation after inflammation has set in.

1. Mechanonociceptor

2. Chemo-

3. Thermo-

4. Polymodal

5. Silent

   
   

These are the types of nociceptors present in the skin.

1. Mechanonociceptor

2. Chemo-

3. Thermo-

4. Silent

These are the types of nociceptors present in visceral locations.

1. Mechanonociceptor

2. Polymodal

3. Silent

These are the types of nociceptors present in joints.

1. Duration

2. Location

3. Intensity

4. Etiology

These are the basis for the types of pain.

1. Acute

2. Chronic

These types of pain are classified based on duration.

1. Mild

2. Moderate

3. Severe

These types of pain are classified based on intensity.

1. Nociceptive

2. Neuropathic

These types of of pain are classified based on etiology.

Acute Pain

This type of pain lasts for less than 3 months.

Chronic Pain

This type of pain lasts for 3-6 months.

Visual Analogue Scale (VAS)

A line from “no pain” (left) to “worst pain imaginable” (right); patient marks their pain level.

Numeric Rating Scale (NRS)

Patients rate pain on a 0-10 scale (0 = no pain, 10 = worst pain).

Verbal Rating Scale (VRS)

Type of pain measurement scale wherein the patient selects descriptive words.

Pediatric Scale

Type of pain measurement scale wherein visual faces showing expression from happy to crying and a patient points to a face to indicate their pain.

1. Intensity - how severe the pain is

2. Location - where the pain is on the body

3. Onset - sudden vs. gradual start

4. Duration - how long the pain lasts

5. Variation - continuous vs. intermittent patterns

6. Quality - how it feels

These are the parameters of pain needed to be considered when selecting appropriate pain medication or treatment plans.

Nonopioid ± Adjuvant

(e.g., Aspirin, Acetaminophen, NSAIDs)

This drug class can be used for mild pain according to the WHO Pain Ladder.

Opioid ± Nonopioid ± Adjuvant

(e.g., Codeine, Hydrocodone, Oxycodone)

This drug class can be used for moderate pain according to the WHO Pain Ladder.

Opioid ± Nonopioid ± Adjuvant

(e.g., Morphine, Hydrocodone)

This drug class can be used for severe pain according to the WHO Pain Ladder.

Inflammatory Mediators (Peripheral Sensitizers)

They start the cascade of biochemical processes for the body to recognize whenever there is a painful event. They also eventually get transmitted to the brain that will execute a response.

• Bradykinin

• Serotonin

• Nitric Oxide (NO)

• Neuropathic Growth Factors

• Histamine

• ATP

• Cytokines

• Neurogenic Factors (Substance P, Calcium Gene-related Peptide)

These are various chemical inflammatory mediators for pain.

• Prostaglandins

• Leukotrienes

These are lipid mediators produced from arachidonic acid at the site of injury that sensitize nociceptors and amplify inflammation and pain.

Phospholipase A2 (PLA2)

This is activated by cell injury or inflammatory stimuli, releasing arachidonic acid from membrane phospholipids.

COX-1 enzyme

This enzyme is constitutive (always expressed in normal tissue).

COX-2

This enzyme is inducible (upregulated at sites of inflammation) by cytokines, or bacterial lipopolysaccharides in bacterial infections.

COX-2 inhibition

With traditional NSAIDs, inhibiting this enzyme produces analgesic, antipyretic, and anti-inflammatory effects.

COX-1 inhibition

With traditional NSAIDs, inhibiting this enzyme causes GI irritation, impaired platelet function, and reduced renal function.

Loss of COX-1 protective effects

This occurs due to continuous traditional NSAID intake.

COX-2 inhibitors

This type of inhibitors selectively inhibit COX-2, so COX-1 functions are unaffected.

Analgesic

This brings relief of pain without loss of consciousness.

1. Non-narcotic

2. Narcotic

These are two types of analgesics.

1. Acetaminophen (Paracetamol)

2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

These are two major non-narcotic analgesics.

Paracetamol (British Approved Name)

Para-acetylaminophenol (APAP)

Other terms for Acetaminophen

Analgesic and antipyretic

These are the general properties/effects of acetaminophen.

• Inhibits PG synthesis in the brain by inhibiting COX

• Weakly inhibits peripheral PG, explaining its non-inflammatory action

What is the MOA of the analgesic property of acetaminophen?

• Produces antipyresis by inhibiting the temperature rising effects of interleukin-1 by preventing the increase in brain PGs

• Inhibits the hypothalamic heat-regulating center

What is the MOA of the antipyretic property of acetaminophen?

False: Acetaminophen has no significant anti-inflammatory activity and has no platelet function (thus why it is not considered as an NSAID).

True or False: Acetaminophen has significant anti-inflammatory activity.

• to relieve mild-to-moderate pain

• reduce fever

• alternative when aspirin is contraindicated

What are the indications for the use of acetaminophen?

• Skin rash

• Hyperpyrexia

• Renal tubular necrosis

• Blood dyscrasias (rare)

What are the adverse effects of acetaminophen use?

4000 mg

This is the maximum daily dose of acetaminophen for adults.

15 g

This is considered overdosage of acetaminophen for adults.

4 g

This is considered overdosage of acetaminophen for children.

20 g

At this dose, acetaminophen can be severely fatal.

NAPQI (N-acetyl-para-benzoquinoneimine)

This is a toxic metabolite responsible for hepatotoxicity, produced in severely fatal acetaminophen overdose.

Administration of sulfhydryl compounds (NAC, IV/Oral within 8 hrs of poisoning)

This is the treatment for severely fatal acetaminophen overdose.

Cholestyramine

Acetaminophen decreases the absorption of this drug used for the management of dyslipidemia.

Metoclopramide

Acetaminophen increases the absorption of this drug.

• Barbiturates

• Carbamazepine

• Hydantoincs

• Rifampicin

• Sulfinpyrazone

Acetaminophen decreases the effect of these drugs.

Warfarin

Acetaminophen increases the effect of this drug.

• High dosage

• ↑ risk of liver damage in chronic alcoholics

• ↑ risk of toxicity with other hepatotoxic drugs or those that induce microsomal enzymes (CRAPGPS)

These are potentially fatal drug-drug interactions.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

This class of drugs has antipyretic, analgesic, anti-inflammatory activities, and anti-platelet activities (4As).

Non-selectively and irreversibly inhibits COX-I and COX-II, inhibiting prostaglandin and thromboxane

What is the general MOA of NSAIDS?

Inhibit PG synthesis both peripherally and centrally through COX enzyme

What is the MOA for the analgesic and anti-inflammatory property of NSAIDs?

Same as APAP

• Produces antipyresis by inhibiting the temperature rising effects of interleukin-1 by preventing the increase in brain PGs

• Inhibits the hypothalamic heat-regulating center

What is the MOA for the antipyretic property of NSAIDs?

• Mild to moderate pain in general

• Acute pain for skeletal muscle or dental in origin

• Treat pain and inflammation associated with Osteoarthritis and Rheumatoid arthritis

• Chronic malignant pain (mild to moderate cancer pain), ineffective severe cancer pain 

• May be effective in managing pain due to bone metastases (depends on severity of pain)

What are the indications for the use of NSAIDs?

Acetylsalicylic acid (ASA)

This was isolated from the bark of the willow tree (Salix purpurea)

Aspirin

What is the more known term for acetylsalicylic acid?

• Antipyretic

• Anti-inflammatory

• Analgesic

• Anti-platelet

What are the general effects of aspirin?

Musculoskeletal disorders

Aspirin is a primary clinical application for the treatment of these kinds of disorders.

300 mg

Aspirin can cause prolongation of bleeding with as small as this dose.

Thromboembolic events

Aspirin can prevent these types of events due to its anti-platelet property.

Inhibits PGE synthesis from the hypothalamus

What is the MOA for the antipyretic and analgesic property of aspirin?

Inhibits peripheral PG synthesis

What is the MOA for the anti-inflammatory property of aspirin?

Irreversibly inhibits COX

What is the MOA for the anti-platelet property of aspirin?

• For headache, arthritis, dysmenorrhea

• Acute rheumatic fever

• Prophylaxis for thromboembolism, stroke, or myocardial infarction

• Reduce incidence of MI in men and women who have had a previous MI, angina pectoris

What are the indications of use for aspirin?

Aspirin

This is a first-line drug for the treatment of rheumatoid arthritis.

• Hypoprothrombinemia

• Vitamin K deficiency

• Hemophilia

Aspirin is contraindicated for patients with these conditions.

• Gastrointestinal

• Hepatic

• Renal

• Endocrine

• Pregnancy

• Respiratory

Adverse effects of aspirin generally involves these systems.

• Epigastric stress

• Irritation of gastric mucosal lining

• Stimulation of the Chemoreceptor Trigger Zone (CTZ)

• Dose-related gastric ulcerations

• Other ulcer-related symptoms (bleeding, exacerbation of peptic ulcer symptoms, erosive gastritis)

• Iron deficiency anemia (an ulcer-related symptom)

• Inhibition of PGI2 synthesis

What are the adverse gastrointestinal effects of aspirin?

Misoprostol

This is a Prostaglandin E1 analog that induces the production of bicarbonates and mucus, used as a treatment for NSAID-induced ulcer.

• Anicteric (mild and reversible)

• Dose-dependent hepatic injury

• Severe effects associated with encephalopathy (e.g., Reye’s syndrome)

• Hepatitis with cerebral edema

What are the adverse hepatic effects of aspirin?

Dose-dependent hepatic injury

This adverse effect of aspirin occurs in patients with connective tissue disorders.

As it is usually asymptomatic, elevated plasma transaminase levels are detected in the liver.

How is dose-dependent hepatic injury detected?

Use of aspirin or aspirin-containing medications during viral disease.

How can adverse effects of aspirin related to encephalopathy occur?