Quiz 3

Question 1

3 types of pain

Answer 1

• nociceptive pain: produced by injury
  -neuropathic pain: involves nerve
  -psychogenic pain: related to psychological disorder

Question 2

Two different types of afferent neurons that are activated in response to noxious stimuli

Answer 2

1. A delta fibers – sharp, intense, well localized discomfort
2. C fibers – dull, burning, diffuse type of pain

Question 3

Chemical Mediators in Pain

Answer 3

Neurotransmitters and Chemicals involved in pain transmission:
· Substance P
· NMDA (N-methyl-d-aspartate)
· Nitrous Oxide
· Bradykinin
· Prostaglandins
· Neurokinin A
· Glutamate
· GABA
Neurotransmitters and Chemicals involved in blocking pain transmission:
· 5-HT (Serotonin)
· Enkephalins
· Norepinephrine

Question 4

Pharmacologic Treatment for Pain

Answer 4

· Opioids
· Anti-inflammatory Agents (NSAIDs)
· Acetaminophen
· Others

Question 5

Mu receptor

Answer 5

most responsible for analgesia and euphoria and most ADRs.
Use is typically reserved for when non-opioid treatments have failed or in terminally ill patients

Question 6

Opioids
Schedule II Narcotics

Answer 6

· Morphine
· Fentanyl
· Oxycodone
· Hydrocodone
· Methadone
· Hydromorphone
· Codeine (alone)

Question 7

ADRs for opioids

Answer 7

· Respiratory depression
· Bradycardia
· Emesis
· GI slowing
· Pruritus
· Dependence

Question 8

Methadone:

Answer 8

Unique Features:
· Also have SNRI (serotonin and norepinephrine reuptake inhibitors) activity
· May be tolerated in patients with allergy to other opioids
· Only long acting opioid available in a liquid formulation

Safety:
· Long and variable half-life (usual 15-60 hours, but up to 120 hours)
· Respiratory depressant effect starts later and lasts longer
· Associated with QT prolongation and arrhythmias

Drug Interactions (CYP450):
· Drugs that prolong the QT Interval
· Drugs that cause sedation
· Drugs that increase serotonin levels

Assessment:
· Risk of substance abuse
· Urine drug screen
· Risk of arrhythmias (baseline EKG)

Risk Factors:
· Electrolyte imbalance (hypokalemia, hypomagnesemia)
· Hepatic impairment
· Structural heart disease

Dose low and slow!
Use in opioid naïve patients not recommended

Question 9

Other Opioids

Answer 9

Schedule III opioids
· Codeine with acetaminophen
Schedule IV opioids
· Tramadol
- Risk of Serotonin syndrome
- Do not take with alcohol
Schedule V opioids
· Phenergan with codeine

Question 10

Opioid Partial Agonists:

Answer 10

Buprenorphine (Sublocade): Opioid partial agonist
· High affinity (strength with which a drug binds to a receptor) for μ receptor but lower efficacy (ability of the drug to produce a response when the above complex is formed).

Suboxone:(buprenorphine/naloxone) Opioid agonist – antagonist
· Naloxone is an opioid antagonist
· Naloxone helps prevent overdose

Butorphanol :
is an Agonist of κ opiate receptors, partial agonist of μ opiate receptors
Uses:
· Labor and delivery
· Pre-op medication
· Adjunct to anesthesia

Question 11

Opioid Antagonists:

Answer 11

**Naloxone – ANTIDOTE:
· Reverses opioid effects (respiratory depression and coma) in overdose situations
· Competes and displaces opioids at opioid receptor sites
- Highest affinity for μ receptor
· Intranasal or Intramuscular

Low-Dose Naltrexone (LDN):
· May exert analgesic, antioxidant, or anti-inflammatory effects through upregulation of endogenous opioids
* Usual dose: 0.5 to 4.5 mg/day
Uses:
* Alcohol use disorders
* Opioid use disorders
Unlabeled uses:
* Chronic fatigue
* Complex regional pain syndrome
* Fibromyalgia
* MS
Common Side effects:
vivid dreams, headache, nausea

Risk of unintentional opioid overdose

Question 12

Opioids: Adverse Effects

Answer 12

Adverse effects are extremely common and potentially severe.
· CNS
· Peripheral effects

CNS effects
· Respiratory Depression – can be life threatening – even at usual doses
· Sedation
· Vomiting
· Cognitive impairment is worse during first few days of treatment and within first few hours after administration
· Tolerance increases over time to the CNS effects

Peripheral Effects:
· Constipation
· Urinary Retention
· Bronchospasm (due to possible histamine release)
· Tolerance to constipation DOES NOT develop over time
· Most patients are on a stool softener/laxative routinely
· Pruritus - Some opioids trigger histamine release from mast cells

Question 13

Opioids: Tolerance and Dependence

Answer 13

Separate from psychological dependence (addiction)
Physical Dependence and Tolerance – PREDICTABLE
· Patients will need an increased dose over time to maintain same effect
· Withdrawal symptoms can start 6-10 hours after dose is missed (with chronic use)
- Symptoms: anxiety, irritability, diarrhea, tachycardia, vomiting
- Peak within 24 to 72 hours
- Physically dependent but not necessarily psychologically dependent

Question 14

Heroin

Answer 14

Also known as diamorphine
· Converted rapidly to morphine
· Greater lipid solubility
· Shorter duration of action
What does this mean for a patient using heroin?
· Activation of µ receptors leads to release of dopamine
· Pleasurable feelings reinforce the behavior and lead to repeat drug use
· After routine use, will need to continue use to feel “normal” and avoid withdrawal

Question 15

Therapeutic Concerns with Opioids

Answer 15

Recently started on opioids:
· Drowsiness
· Dizziness
· Impaired cognitive function
· Respiratory depression
Until tolerance occurs
· Caution when ambulating or operating car/heavy machinery
· Wait to make important decisions until full cognitive function returns
Fentanyl patches
· Do not use heat therapy on patch

Therapy is best given when opioid has reached peak effect (once tolerance to drowsiness has developed)

Question 16

Anti-inflammatory Agents

Answer 16

Aspirin
· Irreversibly blocks cyclooxygenase (COX) 1 and 2 (blocking the production of prostaglandins)
· Anti-inflammatory effects
· Reduces fever
· Reduces pain (at higher doses)
· Anti-thrombotic effects by blocking the production of thromboxane A2 (lower doses)

ADRs/Therapeutic Concerns
- GI problems
o Bleeding and ulcers
o Diarrhea
o N/V (nausea and vomiting)
o Take with food

Renal Impairment
o Prostaglandins important for renal blood flow
o Can cause acute renal failure
- Reye’s Syndrome (rare, but serious condition that can cause liver swelling and other things) – encephalitis when given to children with viral infections.
DO NOT GIVE TO CHILDREN UNDER 12

Question 17

Topical NSAIDs

Answer 17

Diclofenac Gel 1%
· Available OTC
· Mild OA pain
· Hand, Knee joints
Do not combine with oral NSAID
Apply 2 or 4 grams to no more than 2 joints, 4 times per day
· Use dosing card
· 4 grams to lower extremities
· 2 grams to upper extremities

Side Effects/ADRs of NSAIDs
· Stomach Upset
· Gastritis
· Stomach Ulcers
· Bruising
· Increased Risk for Bleeding (Increases Bleeding Time) w/ COX-1 Selective
· Possible increase in HTN (High Blood Pressure)
· Chance for acute renal failure

Question 18

Acetaminophen (APAP)

Answer 18

Inhibits prostaglandin synthesis in CNS and inhibits COX-3 enzyme
· Found in brain, spinal cord and heart in murine and canine species
· Fever Reducer
· Weak peripheral anti-inflammatory
· Analgesic
· Standard in osteoarthritis treatment when NSAIDs can no longer be tolerated
** don’t jump to Tylenol right away for anti-inflammatory needs- stick with NSAIDs for that.
At a normal therapeutic dose, free of adverse effects
Can be used for prolonged period of time

ADRs
· With high doses (>3000mg/24 hours) and/or in combination with alcohol
- Liver and kidney damage

Signs and Symptoms of APAP toxicity
o Nausea
o Vomiting

Antidote: Acetylcysteine

Question 19

Therapeutic Concerns for Anti-inflammatory Agents

Answer 19

NSAIDs and high blood pressure/renal issues/cardiac disease
· Can make antihypertensive medications less effective
· Reduces aspirin effectiveness if taken before aspirin in patients with cardiac disease
· Can elevate blood pressure
If both low-dose aspirin and NSAIDs are to be given, give aspirin first 2 hours prior to NSAID to maintain cardio protective effect

Main Concern
· Bruising and Bleeding
· GI effects (diarrhea, nausea, vomiting)
Beware of duplicate therapy with prescription NSAID and over-the-counter NSAID or multiple products containing same medication
· Ex: Nyquil – has acetaminophen – count all mg’s in 24 hrs from ALL products
Other:
* Skeletal muscle relaxants
* Cyclobenzaprine (sig. Sedation, increased fall risk in elderly, steroid injections)

Question 20

Neuropathic Pain

Answer 20

Disease or injury to the peripheral or central nervous system
Disease states associated with neuropathic pain
· Diabetes
· Immune deficiencies
· Shingles
· Trauma
· Multiple Sclerosis
· Ischemic issues
· Cancer

Symptoms of neuropathic pain:
· Burning, shock-like, aching, shooting
Can be related to nerve compression or and increased sensitization of A delta and C fibers
· Other mechanisms as well

Question 21

Treatment of Neuropathic Pain

Answer 21

Typically, more than 1 drug will be needed
· Antidepressants
· Anticonvulsants
· Topical Agents

Antidepressants
Tricyclics – amitriptyline, imipramine
· Pain related insomnia
· Side effects: Dry mouth, urinary retention, blurred vision, orthostasis (similar to anticholinergics)

SNRI’s (serotonin-norepinephrine reuptake inhibitors) - duloxetine, venlafaxine
· Comorbid depression
· Side effects: Hypertension
Analgesia occurs at lower doses than those used for depression

Anticonvulsants
Gabapentin – commonly used agent for neuropathic pain
· Structurally related to GABA and appears to affect the release of excitatory neurotransmitters
Pregabalin – Controlled substance
· Inhibits excitatory neurotransmitter release
· Side effects: sedation, dizziness, weight gain, edema
Carbamazepine
· Side effects: sedation, dizziness, weight gain, edema

Question 22

Topical Options

Answer 22

Lidocaine
– topical anesthetic to help with pain and itching associated with vasodilation
· Patch and Ointment
· May apply up to 3 patches, on for 12 hours, off for 12 hours

Capsaicin
– topical cream and patch, induces release of substance P(in chili pepper)
· Patch applied in clinic every 3 months (up to 4 areas for 60 minutes)
· Concern that long-term use may damage epidermal nerve fibers
· Cream – applied 4 times daily
- Not for PRN use, need to use consistently for effect
- Burning sensation, wear gloves while applying

Opioids-
Tapentadol
* Specifically indicated for diabetic peripheral neuropathy
* Has some effect on norepinephrine
Oxycodone
* Pose herpetic neuralgia
* Post stroke pain

Low quality evidence
Concerns about misuse and abuse

Cannabinoids-
* Dronabinol
Off label use for central neuropathic pain in MS

Question 23

Treatment of neuropathic pain:

Answer 23

Natural Products:
Folic Acid
Vitamin B6
Vitamin B12
Deficiency may lead to neuropathy
* Consider ruling out a deficiency
B Vitamins improve microvascular function and reduce oxidative stress

Question 24

Rheumatoid Arthritis

Answer 24

Progressive inflammatory disorder affecting the joints

Cause and mechanism remain unknown

Likely Autoimmune

Question 25

Pathophysiology of Rheumatoid Arthritis

Answer 25

In synovial fluid, prevalence of T lymphocytes in the inflamed joint and pro-inflammatory cytokines
- Cytokines are proteins that work as intercellular messengers for immune system
- Produced in response to other cytokines and are also activated in response to specific stimuli
· Cytokines in joint:
- TNFα +++
- IL-1β +++
- IL-6 ++
- IL-8 ++
- IL-10 ++
- IL-15 +
- Others

Symptoms of RA
· Inflammation and swelling of joints
· Over time – destruction of ligaments and tendons surrounding joints – leading to joint deformity
· Fatigue
· Weakness
· Low-grade fevers
· Joint pain – commonly symmetrical
· Stiffness – particularly the hands

Rheumatoid Arthritis (RA) Treatment
· DMARDs (Disease-modifying anti-rheumatic drugs)
· TNF inhibitors
· Corticosteroids
· NSAIDs
Early in treatment
Symptomatic relief
Do not prevent joint destruction

Question 26

Pathophysiology of Rheumatoid Arthritis

Answer 26

In synovial fluid, prevalence of T lymphocytes in the inflamed joint and pro-inflammatory cytokines
- Cytokines are proteins that work as intercellular messengers for immune system
- Produced in response to other cytokines and are also activated in response to specific stimuli
· Cytokines in joint:
- TNFα +++
- IL-1β +++
- IL-6 ++
- IL-8 ++
- IL-10 ++
- IL-15 +
- Others

Symptoms of RA
· Inflammation and swelling of joints
· Over time – destruction of ligaments and tendons surrounding joints – leading to joint deformity
· Fatigue
· Weakness
· Low-grade fevers
· Joint pain – commonly symmetrical
· Stiffness – particularly the hands

Rheumatoid Arthritis (RA) Treatment
· DMARDs (Disease-modifying anti-rheumatic drugs)
· TNF inhibitors
· Corticosteroids
· NSAIDs
Early in treatment
Symptomatic relief
Do not prevent joint destruction

Question 27

DMARDS (disease modifying anti-rheumatic drugs)

Answer 27

· Used to attempt to alter progression of disease

Methotrexate (Gold Standard)
· Impairs DNA synthesis
· ADRs: stomatitis (mouth sores), anorexia, abdominal cramping
· Given once weekly
· Chemotherapeutic agent at higher doses
* May be compared with folic acid

Leflunomide
· Immunosuppressant
Hydroxychloroquine
* Antimalarial agent
* Requires routine eye exams.

Sulfasalazine
· Immunosuppressant

TNF inhibitors
· Bind and inactivate TNFα (Tumor Necrosis Factor-alpha) – one of the major inflammatory cytokines found in RA synovial fluid
- Etanercept (SQ) - monotherapy or in combo with methotrexate
- Adalimumab (SQ) –monotherapy or in combo with methotrexate
- Infliximab (IV) - indicated for use with methotrexate
- Certolizumab (SQ) - monotherapy or in combo with methotrexate
- Golimumab (SQ) – indicated for use with methotrexate
· All have the potential for wide-spread infection
· Most common is reactivation of latent tuberculosis
· Risk of cancer

Janus Kinase Inhibitors (JAK Inhibitors)
· Inhibits the JAK Enzyme, which plays a role in cytokine signaling and is lined to joint and tissue inflammation
- Baricitinib
- Tofacitinib
- Upadacitinib

· Monotherapy or combination with methotrexate
· Oral agents given once or twice daily
· Monitor lipids, liver, and kidney function

Other biologic response modifiers:
* T cell stimulation Modulator
* B lymphocyte-depleting agent
* Interleukin-6 antagonist
* Interleukin-1 Antagonist
*All have the potential for widespread infection
* Most common is reactivation of latent TB
* Risk of cancer

Question 28

Corticosteroids

Answer 28

Prednisone
– used to suppress immune function and reduce inflammation
· Interferes with inflammatory cell adhesion
· Impairs leukotriene and prostaglandin synthesis by blocking Phospholipase A2
· Impairs transport of immune complexes
· Makes antigens susceptible to phagocytosis
· Inhibits the release of immune cytokines through blocking transcription factors
· Depresses bone marrow cells
· Catabolic (break down) effect on all types of supportive joint tissue

Immune System Depression
* Prednisone needs to be weaned over time

Side Effects of Corticosteroids
Short Term:
· Increase Blood Sugar
· Weight gain
· Bruising
· Insomnia
Long term:
· Osteoporosis
· Muscle wasting
· Tendon Rupture
· Thin skin
· Poor wound healing

Question 29

Therapeutic Concerns with RA

Answer 29

· Immunosuppression – prone to infection
· Fatigue
· Look for easy bruising, signs of infection, skin rashes (often indicates drug toxicity), lowered exercise tolerance
· Encourage hydration
- Helps decrease possibility for renal toxicity

Question 30

Gout Treatment

Answer 30

Treatment involves treating inflammation and lowering uric acid level to prevent exacerbations
· Acute flares:
- NSAIDs – Indomethacin
- Opioids
- Corticosteroids
- Colchicine – for acute attacks – prevents activation, degranulation, and migration of neutrophils that are responsible for some of the gout symptoms
- Prophylaxis- urate lowering
- Consider in patients with the following:
Greater than one Tophi (crystalline deposits)
* Radiographic damage to bones from gout
- Allopurinol – long term treatment by inhibiting xanthine oxidase (enzyme responsible for converting hypoxanthine into xanthine into uric acid)
***Blocks uric acid synthesis – major interaction with warfarin

· Non-pharmacologic Treatment:
- Hydration
- Ice
- Elevation
- Rest
- Relax – stress can worsen gout
· Dietary Modifications
- Limit purines (red meats, asparagus, shellfish)
- Limit high fructose corn syrup
- Limit alcohol

Question 31

Osteoarthritis – (Not Rheumatoid Arthritis)

Answer 31

Characterized by cartilage degeneration, subchondral bone thickening, osteophytes, and bone cysts
Usually weight bearing joints affected but can affect smaller joints

Treatment:
· Acetaminophen (preferred)
· NSAIDs – decline in use due to GI and cardio effects
· Hyaluronan – injection of a component of synovial fluid into the joints
· Glucosamine and Chondroitin – building blocks for cartilage synthesis
· Intra-articular corticosteroids (triamcinolone and methylprednisolone)
· Topical NSAIDs
· Capsaicin – from hot chili pepper plant WASH HANDS AFTER USE OR WEAR GLOVES
* ARNICA (CONTROVERSIAL)

Question 32

Fibromyalgia

Answer 32

Widespread pain primary symptom
· Also, fatigue, poor sleep, depression, anxiety, cognitive impairment

Nonpharmacologic treatment is key

Choose pharmacotherapy that is effective on multiple symptoms:
· TCAs – target pain, sleep and possibly fatigue
- Amitriptyline, nortriptyline
· SNRIs – Pain, sleep, depression/anxiety
- Duloxetine, venlafaxine, milnacipran
· GABA – pain, possibly sleep
- Gabapentin, pregabalin