Pain Management

An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage

Subjective

Affects > 100 million people in US
Chief complaint or is due to co-morbid condition
Now being recognized as a disease state rather than a condition
More than \$600 billion spent annually on pain, which includes direct and indirect costs

Anxiety/Depression

Impaired Sleep

Decreased Mobility

nociceptive pain is caused by physical damage or potential damage to the body while neuropathic pain is caused by damage to the nervous system.

Injury → Inflammation → Transduction Conduction → Modulation → Perception

Acute
Usually nociceptive
Improves over time and subsides once healing resolved
Commonly due to surgery, acute illness, trauma, labor, or medical procedures

Chronic
Persists from months to years
Can worsen over time
Cancer pain or non-cancer pain
Disease, treatment, diagnostic procedures

**Sign & Symptoms**

sharp, dull, shock like, tingling, shooting, radiating, fluctuating in intensity, vary in location

occurs in a timely relationship to noxious stimuli

Objective: ↑ BP, ↑ HR, diaphoresis, mydriasis, pallor
Can have no obvious physical signs

Subjective: Severity/intensity

**Sign & Symptoms**

Same as acute pain

Over time, the pain stimulus may cause symptoms that completely change

No temporal relation to noxious stimuli

Most have no obvious physical signs, but may have comorbid conditions due to pain (anxiety, depression, insomnia)

Subjective: Severity/intensity

Consider Vit D, TSH, Vit B12

Pain Experience- social, history

Physical Experience
Site of pain
Focus on musculoskeletal and nervous system
Cognitive function
Non-verbal pain behaviors

Functional Assessment

Diagnostic
Medical history/psychiatric history
Laboratory or radiographic evaluation is directed by the goals of care

3 = no pain, 12 = max pain

0 = no pain, 8 = max pain

Analgesia: Optimize pain relief
Acute: relieve or decrease intensity
Chronic: improving daily function
Activity: Optimize activities of daily living
Aberrant drug behavior: Avoid addiction-related outcomes
Adverse effects: Minimize adverse drug events (ADE)
Affect: Relationship between pain and mood

Education

Pharmacologic

Non-pharmacologic

Heat/ice therapy

Accupuncture

Psychological treatment cognitive behavioral therapy (CBT)

Electric nerve stimulation

Physical therapy and mobility

Surgery

Step 1 - non-opioid +/- adjuvant

Step 2 - non-opioid +/- weak opioid +/- adjuvant

Step 3 = Non-opioid +/- strong opioid +/- adjuvant

Use of more than one pharmacological class of analgesic medication targeting different receptors along the pain pathway with the goal of improving analgesia while reducing individual class-related side effects.

Acetaminophen (Tylenol)
Non-steroidal anti-inflammatory drugs (NSAID)

Systemic ketorolac is indicated for short-term (≤5 days) use in adults for treatment of moderately severe acute pain requiring opioid-level analgesia.

Topical agents
Local anesthetics
Regional anesthetics
Antispasmodic agents

Capsaicin cream
Depletes substance P in the periphery and down regulates the TRPV1 receptors

Higher concentration dose forms (ex: 8% patch) available for medical office use

Other agents considered may include: Bengay, Icy-Hot, etc

Overdose deaths remain a leading cause of injury-related death in the US

Increased deaths involving synthetic opioids (e.g., fentanyl) and stimulants (e.g., cocaine)
68,630 overdose deaths in 2020 (74.8% of all overdose deaths) involved opioids
82.3% of opioid-involved overdose deaths involved synthetic opioids

Natural and synthetic substances
Will determine risk for allergy
3 major types of opioid receptors: μ (mu) , delta and kappa
Most target μ-opioid receptors
Variable potency and formulations

Natural alkaloid - opiate
Pure μ-receptor agonist
Hypotension, pruritus
Avoid in renal disease (CKD, AKI)
Liver metabolism to **morphine-3-glucuronide** (M3G - inactive analgesic) and **M6G (active analgesic)**
Available for PO (IR and ER), IV, IM

- Start with immediate release (shorter duration of action); provides ability to titrate dose
- We do not start with ER products; reserved for opioid tolerant patients
- IV dosing - 2-4 mg IV
ER: MS contin(q8-12h), Kadian (q12h)

Semi-synthetic derivative of morphine (more potent)
Safer in renal and hepatic impairment
**Only available as PO (IR and ER)**

normally start with 5-10 mg; q4-6 hours for IR (still short acting)
ER: Oxycontin q12h
Often in combination with APAP
Associated with increased euphoria & abuse potential

No ceiling effect → you may see massive doses of opioids (does not mean it is wrong; tolerance)

Semi-synthetic derivative of morphine → 7 x more potent
Safer in renal and hepatic impairment
Liver metabolism to H3G (inactive)
Available for PO (IR and ER), IV, IM, SC

- PO IR start low because it is so potent
- IV (0.2, 0.3 mg) - very low doses q2-4h

ER: Exalgo (q24h)
Associated with increased euphoria & abuse potential

Natural alkaloid - opiate
Weak opioid
Available by itself and in combination with APAP
Metabolized by CYP 2D6
Causes more nausea

Semi-synthetic opioid
Available by itself and in combination with APAP and ibuprofen
New ER formulations:
Zohydro ER®
Hysingla ER®

Newest IV opioid - less respiratory depression & nausea
48 hour duration of use

Why switch?
Lack of efficacy
Intolerable side effects
Inability to use certain formulations
Moving to/from inpatient or outpatient
Availability
Cost or formulary issues

Does NOT take into account individual variability or incomplete cross tolerance
Generally calculate total daily dose and decrease by up to 50%
20-30% if pain well controlled
Take into account organ dysfunction

Dosing titrated to effect

Fully synthetic
μ receptor agonist and NMDA receptor antagonist
Reserved for opioid tolerant patients - more than 60 mg of MME/day for more than 7 days
Also used to treat opioid use disorder (OUD)
PK/PD highly variable (T½ up to 60 hours)
Equianalgesic dosing not recommended
Estimate % of TDD morphine-equivalent
QTc prolongation and cardiac arrhythmias ← inhibit cardiac potassium channels

Fully synthetic
100 x more potent than morphine
Reserved for opioid tolerant patients ≥60 mg of morphine daily x 7 days
Acute vs. chronic pain
- Acute - IV
- Chronic - topical (q72hours), buccal, SL, IN
— Avoid topical in fever or cachexia
- Safe in renal and hepatic impairment
dosing = mcg/hour

Weak μ receptor agonist and a weak serotonin-norepinephrine reuptake inhibitor
Schedule IV controlled substance
Used in neuropathic pain

μ receptor agonist and a norepinephrine reuptake inhibitor
Schedule II controlled substance
ER formulation indicated for diabetic peripheral neuropathy

MOA: μ-receptor antagonist
Quick onset/offset
Available: IV, IM, SC, IN
Caution in chronic opioid users
Unmask pain
Precipitate withdrawal

ADRs: pain, agitation, hypertension, nausea/vomiting, diarrhea
FDA approved IN formulation for EMS and caregivers to administer
Some states made it available OTC

Semi synthetic
20 - 50 x more potent
High-affinity binding to mu receptors → Partial mu agonist

- knocks off opioids already bound to the receptor

Weak kappa antagonist
Treatment of pain and OUD
Can precipitate withdrawal in chronic opioid users or OUD
Available: buccal, IM, SL, TD, SC

Not first line; normally adjunctive

NMDA receptor antagonist
Blocks glutamate
Low (subanesthetic) doses --> analgesia
Modulate central sensitization (refractory pain)
Attenuate opioid tolerance
Available as: PO, IN, IV, topical
ADR: nausea, vomiting, and psychomimetic effects

Damage to nerves outside of the brain or spinal cord (CNS)
Nerve compressed, injured, crushed or severed
Neuropathy or peripheral neuropathy (PN)
Often associated with certain disease states or trauma
Burning or shooting pain
Numbness or tingling in extremeties (hands or feet)

In the setting of diabetes without other causes of PN
~ 56% with DPN complain pain affects their quality of life (QOL)
Affects men and women equally

**Risk Factors**
Age
Duration of diabetes
Arterial hypertension
Impaired glucose tolerance
Obesity with low HDL and high TGs
Genetic factors

**Acute sensorimotor neuropathy**
Uncontrolled glycemic levels
Development of ketoacidosis

**Chronic sensorimotor neuropathy**
Most common form of PN
Symptoms include distal, symmetrical burning pain that involves the feet initially and gradually moves upward

Goals of therapy
Protect lower limbs from damage from sensory loss
Relieve pain to enhance the QOL and functionality
Opioids not recommended first line

Glycemic control
DPN pathogenesis -->Hyperglycemia and insulin deficiency
Glycemic control is one of the most effective treatments to slow progression of the disease and delay its onset

Structurally related to gamma-aminobutyric acid (GABA)
No direct GABA effects (GABA-A or -B)
No change in GABA degradation/uptake

Available only as PO
Dosing: 100 - 3600 mg/day
Requires renal dose adjustment
Potential for withdrawal when stopped abruptly
Not a controlled substance

Available only as PO
Dosing: 25- 600 mg/day
Requires renal dose adjustment
Potential for withdrawal when stopped abruptly
Controlled substance (C-V)

CNS or respiratory depression, dizziness, drowsiness

First line for most neuropathic pain syndromes
The onset of effect may be rapid

Tricyclics (TCAs)
Inexpensive and easily administered once daily
Anticholinergic adverse effects
Amitriptyline > nortriptyline
Orthostatic hypotension and urinary retention in elderly
May cause cardiac arrhythmias with higher doses

FDA approved for DPN
Dosing: 60-100 mg/day
Avoid use CrCl < 60 mL/min
Contraindicated in patients with liver disease or those who drink alcohol

No FDA approval for DPN
Use extrapolated from Duloxetine
Recommended dose reduction for renal or hepatic dysfunction

drowsiness, fatigue, nausea/vomiting, GI change(diarrhea, constipation), diaphoresis, weight loss

Used in various neuropathic pain syndromes
Post-herpetic neuralgia (PHN)
DPN

**Not used first line due to:**
Need for therapeutic drug monitoring
Carbamazepine (4-12 mcg/mL)
Administration two or three times daily
Caution with renal or hepatic impairment
Risk for drug-drug interactions

maybe in refractory cases; dexamethasone

- Post-Herpetic Neuralgia (PHN)

Varicella zoster is a virus --> chicken pox (varicella shingles) --> herpes zoster (HZ)
HZ develops secondary to reactivation of varicella virus from its latent state
PHN may occur 2 weeks after the presence of HZ and is the chronic form of the disease
Very debilitating pain
Control of pain is difficult
Risk factors: age, rash severity during acute phase, female, acute pain severity

Zoster (shingles) vaccine decreases incidence of HZ & PHN

Acute phase (shingles)
Acyclovir, famciclovir, and valacyclovir
Initiate within 72 hours
Equally effective in increasing rate of healing/decreasing pain
Prophylaxis data for PHN inconsistent
Symptomatic Tx - acetaminophen, NSAIDs, opioids
Corticosteroids relieve pain intensity, not duration

Topical Analgesics
5% lidocaine patch or 4% to 10% lidocaine cream
Effective in controlling PHN pain from allodynia
Safe due to minimal systemic absorption & no DDI

Capsaicin cream or high-concentration patch
Potential benefit in treating PHN
First application exacerbation of the burning sensation
Continued use desensitizes nerve root endings to decrease hyperalgesia

Genetic differences in pain transmission and response inter-individually
Differences also seen with genders, ages, ethnicity
Pharmacogenomic variability of analgesic response to both opioid and non-opioid analgesics
Qualitative genotyping
Help identify those who may require higher doses or may have greater toxicity

1. Consistent monitoring necessary for optimized therapy
2. Utilization of assessment tools (chronic pain)
3. Utilize 5 A’s (see Goals of Treatment slide) as an initial and continuous evaluation of therapy