PAIN Flashcards
Define pain
an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage
What is critical to understand in a patient experiencing pain?
A reported pain experience must be respected
Describe the biopsychosocial model of pain
Pain affects all aspects of one’s life
Reduced quality of life and general health
Mental and emotional health
Increased risk of suicide
Problems with cognitive function, such as reduced processing speed, selective attention, memory, and executive functioning
School/work absence and reduced productivity
Increased disability and inactivity
Decreased social connections and supports
Increased health care utilization
What are the classifications of pain?
Describe the differences in acute pain and chronic pain?
a) Duration
b) Organic Cause
c) Relief of Pain
d) Tx Goal
e) Dependance/Tolerance to Meds
f) Psychological Component of Pain
e) Environmental/familty issues
f) Depression
g) Insomnia
Define Nociceptive Pain?
Arises from damage to body tissue; typical pain one experiences as a result of injury, disease, or inflammation
Usually described as sharp, aching, or throbbing pain
e.g., burning your hand on a hot stovetop (tissue damage = adaptive)
Define neuropathic pain
Arises from direct damage to the nervous system itself, usually peripheral nerves but can also originate in central nervous system
Usually described as burning or shooting/radiating, the skin might be numb, tingling, or extremely sensitive – even to light touch (allodynia)
e.g., post-herpetic neuralgia (i.e. shingles pain)
Define nociplastic pain
Arises from a change in the way sensory neurons function, rather than from direct damage to the nervous system; sensory neurons become more responsive (sensitization)
Usually described similar in nature to neuropathic pain
e.g., fibromyalgia (no tissue damage = maladaptive)
NiciceptivePain: Describe the difference between somatic and viscerail pain
Describe the nocicpetive pain pathophysiology
Describe nocicpetive pain transduction
Describe nocicpetive pain conduction
Describe nocicpetive pain transmission
A-δand C-nerve fibers synapse in various layers (laminae) of the spinal cord’s dorsal horn
Release excitatory neurotransmitters (e.g. glutamate, substance P)
N-type voltage-gated calcium channels regulate the release of these excitatory neurotransmitters
Pain signals reach brain through various ascending spinal cord pathways (including spinothalamic tract)
Thalamus acts as relay station within brain
Pathways ascend and pass impulses to higher cortical structures for further pain processing
Describe nociceptive pain perception.How does this occur?
Pain becomes a conscious experience
Occurs in higher cortical structures
Physiology of perception is not well understood
Cognitive and behavioural functions can modify pain
Relaxation, distraction, meditation may ↓ pain
Depression, anxiety ↑ pain
Describe nociceptive pain modulation
Howis neuropathic pain different from nocipetive pain?
Different from nociceptive pain
No noxious stimuli
Result of damage or abnormal functioning of the PNS +/- CNS
Difference between peripheral and central neuropathic pain
Describe the pathophysiology of nociplastic pain
Acute Pain Duration and Cause
Typically < 3-6 months
Due to tissue damage signaling harm or potential for harm
Serves a useful purpose (adaptive)
Often due to an identifiable cause
Common causes: surgery, acute illness, trauma, labour, medical procedures
What typoes of pain are acute pain? Issue with long-term pain?
Usually nociceptive, sometimes neuropathic
May outlive its biologic usefulness and have negative effects
Poorly treated, can increase risk of chronic pain syndromes, including nociplastic pain (maladaptive)
General Presentation of acute pain
Sx of Acute Pain
Signs of acute pain
Lab Tests and Diagnosis of Acute Pain
How can acute pain be assesed?
Pain management is most effective when validated and accurate pain assessments are carried out
Self-rated pain intensity scales
Adult: visual analogue or numerical rating scale
Child: Faces scale (Bieri or Wong-Baker)
Observational tools
If unable to communicate
PAINAD (dementia), FLACC (>2 months), CHEOPS (>1yr), PACSLAC (dementia)
Red flags for referral of back pain
Algorithm for Pain Assesment
Acute Pain Goals of TX
Primary goal depends on type of pain present and should be tailored to individual patient and circumstance
Acute pain: achieve level of pain relief that allows patient to attain certain functional goals (usually = get back to normal function) → cure
Realistic pain reduction = may be possible to fully eliminate pain, unlike in chronic pain
Prevent or minimize ADEs
Improve quality of life
Non-Pharm Strategies Acute Pain
There is a difference between active and passive strategies – (active – movement, relaxation) – EMPHASIZE active strategies, tend to work the best
Passive strategies should not be used alone (someone doing something to you – acupuncture, meds are passive strategies, massage) – Needs to be combined with active
Pharm Tx Overview of Acute Pain
Acet Moa
Believed to inhibit prostaglandins in the CNS and work peripherally to block pain impulse generations
Minimal effect on peripheral prostaglandin synthesis (no anti-inflammatory activity)
Acet Place in TX
Reduction of fever (1st line)
Mild-moderate acute pain
Pediatric moderate pain
Dementia (more aggressive, self it changes anything for them)
Acet A/e
Liver toxicity
Overdose
May increase systolic BP (~3-4mmHg)
Rare neutropenia and thrombocytopenia
Acet C.I
Acetaminophen-induced liver disease
Hypersensitivity to acetaminophen, or any component of the formulation
Acet Cautions
Acetaminophen is one of the most frequent causes of accidental poisoning in infants and toddlers
Hepatotoxicity has occurred in patients receiving high or excessive doses with therapeutic intent
Some patients may be more susceptible to acetaminophen hepatotoxicity (e.g., chronic alcohol use, those with liver disease, or those who are malnourished or taking other hepatotoxic drugs)
Acet Dosing of AVilable Formulations
NSAID MOA
Non-Selective:
Inhibit cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in ↓ formation of prostaglandin precursors
Antipyretic, analgesic, and anti-inflammatory properties
COX-2 Inhibitors (Coxibs):
Inhibit prostaglandin synthesis by ↓ the activity of the enzyme, COX-2, which results in ↓ formation of prostaglandin precursors
Antipyretic, analgesic, and anti-inflammatory properties.
Do not inhibit COX-1 at therapeutic concentrations
NSAID Place in TX
Mild to moderate pain (osteoarthritis, acute & chronic low back pain)
Dysmenorrhea-induced pain
Fever (only ibuprofen and naproxen)
C.I. NSaids
CKD (CrCl < 40mL/min)
Hyperkalemia
Cirrhosis/ Liver impairment
GI Ulcer (duodenal/ peptic) + IBD
Uncontrolled Heart Failure
MI
Thrombocytopenia
Transplant
A/E NSAIDs
Dyspepsia
Edema
GI Bleed
N/V
Phototoxic Reaction
CNS : Dizziness, drowsiness, headache, tinnitus, confusion (especially in the elderly & with indomethacin). CNS effects may be dose related.
Minor or serious skin rashes, pruritus
COX-2 selective – similar efficacy & renal/CV toxicity to other NSAIDS, but less GI risk
NSAID CAutions
Asthma
CVD, HTN
Risk of bleeding increases perioperatively; discontinue pre-surg
ASA MOA
Irreversibly inhibits COX-1 and COX-2 enzymes via acetylation which decreases formation of prostaglandin precursors
Antipyretic, analgesic, and anti-inflammatory properties
Place in TX ASA
Mild-moderate pain (short term use)
Reduction of fever
ASA Dosing
< 300mg/d: reduce platelet aggregation
300-2400mg/d: antipyretic and analgesic (325-650mg po q4h prn)
2400-4000mg/d: anti-inflammatory
Max: 4g/day
C.I. ASA
Hypersensitivity to NSAIDs, anaphylaxis
CKD (CrCl < 40mL/min)
GI Ulcer
A/E ASA
Same as NSAIDS
Cautions of ASA
Concurrent antiplatelet and/or anticoagulant therapy
Risk of Reye syndrome in children
Toxic in overdose (tinnitus, vertigo, hyperventilation, respiratory alkalosis, hyperthermia, coma, death)
Describe Peripheral PG Synthesis
ASA Dose
325-650 mg PO q4-6h (PRN)
Max: 4000 mg/day
Diclofenac DOse
50 mg PO BID; 75- 100 mg SR PO daily (PRN)
Max: 100 mg/day (Dose-relaed)
Ibuprofen Dose
TC: 200-400 mg PO q4-6h (PRN) (max 1200 mg/day)
Rx: 600 mg PO q6h (PRN) (max 2400-3200 mg/day)
Children up to 12 years of age: 4-10 mg/kg/dose q6-8h; max = 40mg/kg/day
Ketorlac Dose
10 mg PO QID (PRN)
Max: 40 mg/d, 5 days limit (↑ GI bleed risk)
Naproxen Sodium ()OTC)
125 – 500 mg PO BID (PRN)
Max: 1500 mg/day
NAproxen Base Dose
250-500 mg PO BID (PRN)
Max: 1000 mg/day
Cardiac Risk of NSaids.. ASA?
Thromboxane A2 produced by the COX-1 pathway on activated platelets is platelet aggregating and vasoconstricting
Prostacyclin produced by the COX-2 pathway in nearby smooth muscle cells is a platelet inhibitor and vasodilating
ASA, as a non-reversible COX inhibitor (COX-1 > COX-2), inhibits platelet aggregation even at low doses and is cardioprotective
Cox-2 Inhibitors and Cardiac Risk
Selective COX-2 inhibitor NSAIDs “tip the balance” in favour of:
vasoconstriction
platelet aggregation
thrombosis
Other non-selective NSAIDs have varying cardiac risk depending on specificity for COX-1 and COX-2
ASA and NSAID Interaction and MAnagement
ASA, Aspirin, Naproxen D.I.
Ibubrofen and naproxen have higher affinity for Cox enzymes (take this before or at same time with ASA) – Ibu and naproxen will bind to platlets reversibley (will lose effect)
Sperate them out
Give advil, wait 2 hours and then give ASA – ASA can get on the platelets and inhibit them
Cardiac vRisk of Avilable NSAID’s and MAngement
Which NSAID is the most cardiac neutral
Naproxen
How do NSAID’s excaerbate HF and increase blood pressure?
How do NSAID’s pose a GI Risk?
Prostaglandins produced by the COX-1 pathway increase GI mucosal blood flow, mucous and bicarbonate production, and epithelial growth
NSAIDS inhibit COX-1 which leads to
↓ prostaglandins
↓ gastroduodenal mucosal protection
↑ GI ulcer risk
Management of GI Risk of NSAIDs
Consider misoprostol or PPI (add-on or combo product):
Arthrotec 75 (50/75mg diclofenac + 200 mcg misoprostol), generic
Formulary
Max diclofenac is 100 mg a day; may need to adjust dose
Vimovo (375/500 mg naproxen + 20 mg esomeprazole)
Non-formulary
Risk Classification of GI Toxicity of NSAID’s
Recommendations for prevention of NSAID complications
Renal Risk: How do NSAIDS cause it?
Prostaglandins (PGE2, PGI2) produced by the COX-1 and COX-2 pathways are vasodilating
NSAIDs inhibit COX-1 and COX-2 which leads to
vasoconstriction of afferent renal arteriole
↓ ability for kidneys to regulate blood flow
Risk Factors for Renal Dysfx NSAIDs
Age ≥70
Pre-existing renal disease
Volume depletion (diuretics)
Combined use with ACEI or ARB (dilate efferent arteriole)
Heart failure
Cirrhosis
Long-term history of NSAID use
Managemnet of Renal Risk NSAIDs
Avoid in CKD (CrCl < 40 mL/min)
Monitor creatinine, urea within 3-7 days after initiating therapy
Celecoxib Advantages
Main attractive feature is the selective COX-2 inhibition
COX-1 primarily involved in homeostatic bodily functions
Maintains normal lining of the GI tract
Maintains blood patency (hemostasis)
COX-2 primarily involved with pain and inflammation
Selective COX-2 inhibition spares the inhibition of COX-1
↓ the risk of GI complications (e.g., GI bleeding)
minimal platelet effect
↑ cardiac/serious events with celecoxib > 200mg/day
Celecoxib DoseAdjustments and Renal Risk
Dose adjustments recommended for elderly and CYP2C9 metabolizers
CYP2C9 poor metabolizers, reduce initial dose by 50%
Carries similar renal risk as non-selective NSAIDs
Celecoxib Dosing
Acute pain:
Celecoxib 400mg PO as a single dose on the first day, followed by 200mg PO once daily (up to 7 days); max dose = 400mg/day for up to 7 days
Other indications:
Dose ranges from 100-200mg PO once daily to twice daily (max dose = 200 or 400mg per day, depending on indication)
Dose-related ↑ in serious CV events (e.g., MI) detectable at doses of celecoxib 200mg BID (400mg/d) or more
NSAID/COXIBS D.I.
↓ anti-HTN effect: ACE-I, ARB, beta-blocker, thiazides
↑ toxicity of: lithium, methotrexate, steroids, tenofovir, warfarin
↑ risk of GI bleed: warfarin, heparin, corticosteroids, SSRI
↑ nephrotoxicity: ACE-I, ARB, diuretics
↓ efficacy of ASA antiplatelet effect if co-administered
Preganancy and NSAIDs
Pregnancy: do not recommend in general
Preconception: query block implantation
1st trimester: malformations, miscarriage
2nd trimester: low dose PRN
3rd trimester: closes ductus arteriosus
Low dose ASA has some pregnancy-related indications (generally avoid higher pain doses)
Should be discussed with obstetrician and/or primary care provider
Low dose for prevention of pre-eclampsia, thromboprophylaxis for positive antiphospholipid antibody test or with confirmed antiphospholipid syndrome
Lactation and NSAID’s
Lactation: may consider agents with short half life (can get into the breast milk)
Ibuprofen, diclofenac
Muscle Relaxantas Examples and MOA
Centrally-acting drugs via heterogeneous mechanisms
Methocarbamol (sedative skeletal muscle relaxation)
Baclofen (centrally acting in spinal cord relief of spasticity)
Cyclobenzaprine (similar to TCA in structure and adverse effects drug interactions)- ANTICHOLINERGIC
Tizanidine (alpha2-adrenergic agonist (like clonidine) hypotension)
Little/no actual relaxant effect on tissues ?misnomer
Effect linked to sedation and resultant central relaxation?
Muscle Relxants Place in TXand Duration
Might consider for spasms (acute low back pain)
No evidence that they are more effective than acetaminophen/NSAIDs
Limit use to < 1-2 weeks
C.I. Muscle Relxants
Age > 65 years old (although commonly seen in practice)
Cautions of Muscle Relxants
++ CNS adverse effects (drowsiness, impaired cognition, falls)
Hepatic toxicity (esp. with Tylenol)
Hypotension (tizanidine)
Risk usually > benefit, esp. in chronic treatment
Dose Muscle RElxants
Baclofen 5-20 mg TID
Cyclobenzaprine 5-10 mg TID
Methocarbamol (combo with ASA/acetaminophen/ibuprofen)
Step-wise APproach WHO LAdder
Analgesic LAdder RXFiles
Pain In specific Populations:
a) Acute on Chronic
b) Incident
c) Frail Elderly
d) Hepatic Dysfx
5. Renal Dysfx
6. Prgenancy
7. Post-operative
When to refer for acute pain
Use of acetaminophen/NSAIDs for self-medication of pain should generally not exceed 10 days in adults or 5 days in children, unless directed by a prescriber
Chronic Pain Duration and Differentiation
Pain lasting > 3 months
Difference between Chronic cancer pain vs. chronic non-cancer pain
What can chronic pain lead to? Sx?
Can lead to a chronic pain syndrome (symptoms/consequences of chronic pain)
Fatigue, ↓ activity, deconditioning
Depressed mood, substance use, suicidal ideation/attempt/completion
Social & financial stress (marital/family/friends, absenteeism, treatment cost)
Chronic Pain Etyiology. Can the exact cause be identified?
Often “mixed” pain etiologies (3 categories; overlap between)
Often exact cause cannot be identified
What is chronic secondary pain? Includes?
Chronic Secondary Pain:
Diagnosed when pain originally emerges as a symptom of another underlying health condition
May persist even after the underlying condition has been treated, in which case it is considered a disease in its own right
Includes the following sub-diagnoses:
Chronic cancer pain, chronic post-surgical or post-traumatic pain, chronic neuropathic pain, chronic secondary headache, chronic secondary visceral pain, and chronic secondary musculoskeletal pain
Chronic Primary Pain Definition
Chronic Primary Pain:
Persists or recurs for longer than 3 months, and
Is associated with significant emotional distress (e.g., anxiety, anger, frustration, depressed mood) and/or significant functional disability (interferes with activities of daily living (ADLs) and participation in social roles), and
The symptoms are not better accounted for by another diagnosis
Gneral Presentation of NEuroptahic Pain
Severity may be out of proportion to the degree or severity of the pathology or initial nerve injury
Ongoing nerve damage from persisting factors (e.g., poorly controlled diabetes) can worsen or spread pain over time
Sx of Neuropathic PAin
Constant or pulsating pain (shock-like, burning, buzzing, stinging, itching, shooting, radiating [AKA radiculopathy if shooting from lower back down leg(s])
Hypersensitivity to external (e.g., hot/cold, touch) or internal (e.g., anxiety) stimuli
Hyperalgesia: exaggerated pain by normally painful stimulus
Allodynia: pain caused by normally nonpainful stimulus
Signs of Neuropathic PAin
↓ pinprick sensitivity threshold measured with weighted needles
↓ vibratory sense measured using tuning fork
Slowed peripheral nerve conduction on nerve conduction studies (can be very painful)
LAb Tests of Neuropathic PAin
Pain is always subjective
Handheld screening devices (e.g. tuning fork) and nerve conduction studies may be used
No specific lab tests but some non-specific tests can indicate nerve conduction issues (e.g. HbA1c, vitamin D, TSH, B12)
History +/- diagnostic proof of past trauma (e.g. CT) may be helpful in diagnosis etiology
Nociplastic Pain Gneral
Can appear to have no noticeable suffering to complete writhing over pain for all waking hours
Note mental/emotional factors influence pain perception
↓ pain threshold by anxiety, depression, fatigue, anger, fear vs. ↑ pain threshold by rest, mood elevation, sympathy
Nociplastic Pain Sx
Symptoms may change throughout the day or over time (often occur without a temporal association to an obvious noxious stimuli)
Nociplastic PAin Signs,Comorbid Conditions and Tx
In most cases, no obvious signs
Some conditions specific (e.g., CRPS - redness, swelling, hair or nail changes in one limb)
Comorbid conditions very commonly present (e.g. insomnia, depression, anxiety) - not always
Outcome of treatment often unpredictable
Nociplastic Pain Lab Tests
Pain is always subjective
No specific lab tests but history +/- diagnostic proof of past trauma (e.g., CT) may be helpful in diagnosing etiology
No positive lab/diangnostic test for diagnosisng nociplastic pain
General labs may be considered (e.g., vitamin D, TSH, B12)
Diagnosis of Nociplastic PAin. Common diagnoses?
Best diagnosed based on patient description/history
Common diagnoses: chronic widespread pain syndrome (fibromyalgia), CRPS, TMJ disorder
Best pain management uses the….
What is first line for chronic pain?
Non-Pharm
1st line for pain
Essential to long-term success in chronic pain
Individualized recommendations and patient education is key!
Goal of Chronic Pain
target: functional goals, not complete resolution of pain
Role of Continuing Pharmacotx from Acute to Chronic Back LPAin
Acetaminophen
Does not appear effective, is not recommended by guidelines
If patient finds benefit, use lowest effective dose (consider max 3200mg/day)
PRN/adjunct use for acute on chronic pain
First choice for people with dementia due to effectiveness in this population and safety
NSAIDs
May be effective for some to manage chronic inflammation causing pain
Lowest effective dose, shortest duration (reassess as risks may > benefits over time)
Non-selective and COX-2 inhibitor comparable efficacy, must consider individualized risk vs benefit
Naproxen and ibuprofen less CV risk
Celecoxib less GI risk (or pair NSAID with PPI or misoprostol if risk factors for bleeding ulcer)
PRN/adjunct use for acute on chronic pain
Muscle Relaxants
No role in chronic pain unless concurrent spasticity (e.g., MS)
Short term use only (< 2 weeks) for acute low back pain
Again, may cause more of a sedative effect than actual relaxant effect
Other AGnets for Chronic Low BAck PAin
Duloxetine (SNRI) – Health Canada indication
Moderate evidence for benefit in non-neuropathic chronic low back pain
Especially makes sense if concurrent neuropathic symptoms/radiculopathy (i.e., sciatica) or depression or anxiety
Tricyclic antidepressants – not enough evidence for/against
Might be helpful if comorbidities (e.g. chronic migraine, insomnia)
Certainity of Evidence of TX Options in Chronic. Low BAck Pain
Treatment of Low BAck PAin Algorithm(Evidence of Benefit)
Chronic Low BAck Pain Summary
Exercise has consistently been shown to meaningfully improve pain scores and usually improves function, quality of life, and mental health as well
Other “non-pharms” like spinal manipulation and psychotherapy (CBT) have evidence of benefit
Long term NSAID use should be reassessed frequently (~q6-12 months) to ensure benefit still > risks/harms
Duloxetine may be worth considering, may be especially helpful if concurrent GAD, MDD, neuropathic pain
Acetaminophen use is not supported by evidence, but may be trialed
Low BAck Pain Summary of Pharmacotx
Neuropathic Pain TX Summary
2017 Stepwise Approach for Neuropathic PAinn
Evidence of Pharmacotx in Neuropathic Pain
2022 TX of Neuropathic Pain
Physical activity less role in neuropathic role – still want to encourage; just may be less benefit than seen in osteoarthritis and chronic low back pain
Neuropathic PAin Guidance Bottom Line
Consider the patient as a whole and their other medical conditions can you pick a medication that can do “double duty”
Bottom line: inquire about and explore the patient’s medication history and enable them to make the choice
Diabetic Neuropathy TX
Post-Herpetic Neuralgia TX
Trigeminal Neuralgia Tx.AE, D.I.?
Examples of Gabapentinoids
(gabapentin, pregabalin)
MOA of Gabepentinoids
Block release of excitatory neurotransmitters by binding to specific calcium channels in the CNS (Structurally similar to GABA but NO effect on GABA neurotransmission)
Other indications of gabpentinoids
Alcohol withdrawal, anxiety, intractable hiccups, chronic pruritis, focal seizures, restless legs syndrome, perimenopausal vasomotor symptoms
Gabapentinoids 1/2 life and elimination
5-7 hours (TID-QID dosing)
Excretion is proportional to renal function so dose adjust in renal impairment to avoid accumulation!
A/e of Gabapentinoids
Dizziness/drowsiness (30%), H/A, N/V, mood changes
Tremor, nystagmus, ataxia, peripheral edema (8%), weight gain (2-3%)
D.I. Gabapentinoids
No relevant metabolism/CYP effects to consider
CNS depressants and anticholinergics (pharmacodynamic interactions)
Serotonergic agents or potentiators (e.g., mirtazapine, opioids)
Gabapentin Elimination, Bioavilability and Dosing Considerations
100% renal elimination, no hepatic metabolism
Gabapentin bioavailability is inversely proportional to dose due to saturable absorption, pregabalin has regular PK
Taper off to decrease risk of seizures/withdrawal syndrome
Approx. dose conversion factor gabapentin:pregabalin ~ 6:1
How long does it take to see effect of gabapentinoids? How should they be titrated?
Gabapentin: Take weeks to see effect
Gabapentinoids can be increased every 3-7 days (1-2 weeks for tolerance) – Can taper quickly (more quickly than medications)
TCA Examples
amitriptyline [prodrug], nortriptyline [active metabolite], ?desipramine
TCA MOA
Inhibit the reuptake of serotonin and norepinephrine, block sodium channels, block N-methyl-d-aspartate (NMDA) agonist–induced hyperalgesia
Other Indications of TCA’s
Depression, insomnia, migraine prophylaxis, interstitial cystitis, IBS, sialorrhea
t1/2 TCA’s
13-36 hours (once daily dosing HS)
A/E TCA’s.C.I?
Anticholinergic ADEs (dry eyes, dry mouth, constipation, urinary retention), postural hypotension, sedation, confusion, QT prolongation (baseline ECG if older than 40 or at risk of sudden cardiac death)
Contraindications: MAOI use in past 7 days, severe liver impairment
D.I. TCA’s
CYP2D6 substrates (major) – amitriptyline
CNS depressants and anticholinergics (pharmacodynamic interactions)
Serotonergic agents or potentiators (e.g., mirtazapine, opioids)
Antiplatelets, NSAIDs (↑ risk of bleeding ulcer)
Bupropion – may lower seizure threshold
Carbamazepine – may lower serum concentration of TCAs
Cyclobenzaprine – TCA-like structure risk > benefit, ?duplication of therapy
TCA Dose, Which agent, and Titration
Much lower dose required for pain than depression (1/3 to 1/5 antidepressant dose)
Amitriptyline has been more studied but nortriptyline generally better tolerated
Start at low dose and titrate up slowly, especially in older adults
Taper off to prevent withdrawal
Which TCA has less s/e?
Notriptylline has less s/e than amitriptyline
Titration of TCA’s
Increase every 7 days, 2 weeks to ases stolerbaility, 4 weeks as a trial
SNRI Examples
(duloxetine, venlafaxine [prodrug], desvenlafaxine [active metabolite])
MOA of SNRI
Inhibit the reuptake of serotonin and norepinephrine at neuronal junctions
Duloxetine also has weak inhibition of dopamine reuptake
Other indications of SNRI’s
Depression, anxiety, migraine prophylaxis, PMDD, perimenopausal vasomotor symptoms
**duloxetine has some moderate evidence also for chronic low back pain and knee OA
t1/2 and excretion of SNRI
12 hours (longer in older women) – delayed release particles
Excreted in urine so longer t1/2 in renal impairment (also hepatic impairment for venlafaxine and desvenlafaxine)
A/e SNRI’s.Ci?
Drowsiness, sedation, constipation, nausea,
hypotension (esp. duloxetine in older women predisposed)
OR increased HR/BP (esp. venlafaxine),
hyponatremia (duloxetine)
Contraindication: MAOI use in past 7 days
D.I. SNRI
Duloxetine: CYP2D6 inhibitor (moderate) (e.g., will increase aripiprazole, risperidone levels)
Venlafaxine: CYP2D6 inhibitor (weak)
Serotonergic agents or potentiators (e.g., mirtazapine, opioids)
Antiplatelets, NSAIDs (↑ risk of bleeding ulcer)
Smoking (↓ serum concentration of duloxetine)
TAper and VEnlafaxine Consideration
Venlafaxine inhibits norepinephrine reuptake only at doses ≥ 225mg
Taper off to prevent withdrawal (FINISH)
Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, and Hyperarousal (anxiety/agitation)
SNRI’s traget the…..
Targeting the descending pathway here
How long should SNRI’s be trailed? Where do they work?
Targeting the descending pathway here
- Give 4 weeks of trial
Neuropathic PAin Considerations
Encourage lifestyle interventions and “non-pharms”, when appropriate
CBT, mindfulness, TENS, acupuncture, mirror therapy, hypnosis, aromatherapy, weighted blankets and other comfort measures, etc.
↑ dose q1-2weeks to minimize adverse effects and assess response
Gabapentin and pregabalin may be titrated faster than this
Generally takes up to 6 weeks once titrated to target/tolerable dose for full analgesic effect of the agent for neuropathic pain
Fibromylagia is what type o0f pain?
Nociplastic
Fibromyalgia Diagnosis
What is fibormyalgia not?
a made-up diagnosis
a diagnosis of exclusion
a mental health or psychosomatic disorder
Fibromyalgia SUmmary of Pharmacotx
Pharmacotx Considerations in Nociplastic PAin
Exercise is the most effective treatment, better than any drug
Mind-based treatments also essential
Consider similar approach to comparing non-opioid options indicated for neuropathic pain
Pregabalin, amitriptyline (low dose), duloxetine
Fluoxetine may be considered for CWPS/FM (help on anxiety as symptoms)
Opioids should be avoided in almost all scenarios (can cause hyperactive pain)
Cannabis might be considered if concurrent sleep disturbance, may modulate pain
Opiods vs opiates
Opiod Receptors
Opiod Indications
Opiod Dose acute Pain
Opiod Naieve
Opiod Use Strategies
Chronic Pain Opiods Advatages/Disadvatages
Space Trial Findings
When are IR opiod products used? What is there duration?
Used for acute pain, breakthrough pain, or when initiating someone on chronic therapy
Duration ~4-6 hours
How often are sustained release opiods dosed? Who are these used in?
Q12 hours formulations (q8hrs in select patients)
Q24 hours formulations
Not for acute; harder to take away when initiated, higher doses
Buccal Opiods
Very short duration (fast in, fast out)
Fentora® (fentaNYL) effervescent tablet
Very long duration (due to slow dissociation from receptor)
Suboxone® tablet & film (buprenorphine - with naloxone)
Suppository Opiods Duration
Duration ~4 hours
Supeudol® (oxyCODONE)
Transdermal Opiods Duration
Q72 hours formulation (q48hrs in select patients) – fentanyl patch
Qweekly formulation - Butrans® (buprenorphine) patch
What opiods are avilable in injections?
morphine, hydromorphone, codeine, fentanyl, Sublocade® (buprenorphine subQ monthly)
Difference between IV and Oral
Iv s twice as potent
When should a control released product not be used?
CONTROLLED RELASE – Never acute pain or on an as needed basis
What is the reference compound for opiods?
Morphine
“Natural” opioid = opiate
“Reference” opioid
Use for conversion factor calculations
Morphine Metabolism
Metabolized into two primary compounds (excreted in urine)
Morphine-6-glucuronide
Active analgesic
Morphine-3-glucuronide
Not active as an analgesic, CNS stimulation
Morphine Monitoring
Monitor closely (or avoid) if CrCl <20-30 mL/min
Accumulation of metabolites may lead to toxicity
Monitor for CNS toxicity (confusion, ↓ LOC), if occurs change to alternative opioid
If long-term opioid required consider alternative in patients with CKD
Codeine Comparison to Morphine and MEQ
Much less potent than morphine
MEQ= 0.15
200mg of oral codeine ≈ 30mg of oral morphine
Codeine Metabolism.Issue with metabolism?
Prodrug - Converted to morphine in the body via CYP2D6
Conversion required for analgesic effect
~10% of population is deficient in CYP2D6 = no pain relief
Ultra-rapid metabolizers = ↑ adverse drug effects
Due to higher morphine exposure
Codeine Drug Interactions and CAutions
Potential drug interactions with agents that inhibit CYP2D6 = less pain control
Caution in breastfeeding/chestfeeding
rapid metabolizers ↑ morphine toxicity risk in infant
CAse STudy of Codeine
CYP2D6 metabolism of codeine to morphine is a minor pathway of codeine metabolism (<10%)
Ultra-rapid metabolizers have higher conversion to morphine
Case describes codeine toxicity due to ultrarapid CYP2D6 metabolism, CYP3A4 inhibition, renal failure
Codeine C.I.
Contraindications:
< 12 years old, < 18 years old post op tonsillectomy and/or adenoidectomy
What formulations of codeine are avilable?
Available by itself or in combination with acetaminophen and caffeine (other combo products available)
ANti-tussive Dose of Codeine
Antitussive at dose > 15mg q4-6h
Oxycodone MEQ
~1.5x more potent than morphine
20mg of oral oxycodone ≈ 30mg of oral morphine
Oxycodone Metabolism
Metabolized by CYP3A4 (major) and 2D6 (minor) to active metabolites
↑ ADE if ultra-rapid metabolizer
Avilable Formulation of Oxycodone
OxyContin
Brand discontinued in 2012; route easily altered
Crushed, chewed, snorted, injected
OxyNeo
Bioequivalent to OxyContin
Formulation is different
Forms a viscous gel when wet
Difficult to break the tablets
If broken, the broken pieces still retain some controlled release formulation
Oxycodone Combo Products
acetaminophen 325mg and oxycodone 5mg (brand name formerly Percocet)
ASA 325mg and oxycodone 5mg (brand name formerly Percodan)
Targin (oxycodone + naloxone)
Naloxone = “opioid antagonist that competes and displaces opioids at opioid receptor sites, including gut opioid receptors, which counteracts opioid-induced constipation” - Limited evidence, no better than opiod with laxative
Hydromorphone MEQ. A good option when….
Synthetic opioid
5 times more potent than morphine
1mg of oral hydromorphone ≈ 5mg of oral morphine
Good option if require an opioid in renal impairment
Tramadol MOA
Dual mechanism of action
Mu receptor agonist
Inhibits serotonin and norepinephrine reuptake
Tramadol MEQ
Binding affinity for mu receptor is ~600 times less than morphine
100mg of oral tramadol ≈ 10-20mg of oral morphine (rough estimate)
Tramadol Metabolism
Prodrug - Metabolized to active metabolite via CYP2D6
O-desmethyl tramadol
Tramadol Risks
↑ risk of seizures, serotonin syndrome (more likely), hypoglycemia, QT prolongation
Tapentadol
Tapentadol – More potent than tramadol, but less potent than morphine
Tramadol and Tapentadol Dosing Unique
Max recommended dose – sertonergic and norepeinephrine effects
Fentanyl MEQ. With the formulation avialble of fentanyl, how is this converted?
Much more potent than morphine (~100x)
25mcg/hour patch ≈ 100mg of oral morphine
This is a DAILY equivalent
This does NOT mean 100mg of morphine equivalency is released per hour
LOTS of controversy regarding this conversion
Conversion is safe when converting from opioid to fentanyl patch BUT
Conversion is aggressive when converting from fentanyl patch to other opioid (TABLE NOT MEANT TO BE USED )
Fentanyl Patch USed for….
Option for those who cannot take oral medications & who are opioid-tolerant
Opiod Tolerance Definition
someone taking 60 MEQ for a week to be opiod tolerant
How often is the fentanyl patch dosed?
Dosing schedule of q72hours
Considered convenient
Also may be considered/inconvenient, ?forgetfulness
Fentanyl Metabolites
No known active metabolites
Option for patients with renal impairment
Fentanyl patch not suitable for….
Diaphoresis
Morbid obesity
Ascites
Cachexia (wasting of the body)
Also parenteral formulation
If patch touches skin during application?
If gel from the patch contacts your skin (e.g., hands) during the application procedure, wash with water only and not soap, as soap will increase the absorption of the patch through the skin
What dose of the patch should be used for alterations? Fentanyl Patch Alterations
Use the 12mcg/hr patch for dosing titrations / tapers
If required, can cover half of the area of a patch with an occlusive dressing/barrier
NOT officially recommended
Area covered is the patch-skin interface (do not cover the whole patch- ↑ absorption, risk of toxicity)
Matrix membrane patch = technically could be cut
NOT officially recommended, inaccurate dosing
Monograph indicates the patch should not be cut
Methadone MOA
Potent mu (μ) opioid receptor agonist and an NMDA (N-methyl-D-aspartate) receptor antagonist
NMDA mechanism plays a role in prevention of opioid tolerance, potentiation of analgesic effects, & neuropathic pain treatment
Methadone Half Life and Riskwith half-life? When should dose adjustments be made?
Long and variable half-life: ~10-60 hours (24-190hrs for some)
Potential for accumulation and overdose
Do not increase dose more frequently than q3-5days
Methadone:How long does the analgesia last for? How often is it dosed?
Observed duration of analgesia 6-12 hours
Usually dosed q8h for pain (occasionally q6-12h). Differs from once daily dosing for opioid use disorder.
Is methadone equivalent to other opiods? Caution in? Can metahdone equivalence be converted to other opiods?
Equianalgesic potency compared to other opioids is unpredictable
Caution in severe hepatic failure, hepatitis, concurrent antiretroviral use
Various published guidelines to convert morphine methadone but not from methadone other opioids
Methadone Renal Impairment
Useful in renal impairment because inactive metabolites are excreted in the urine and feces
Methadone Risksand Management of Risk
Risk of QTc prolongation
Initiating prescribers should generally obtain an ECG at baseline
Additional ECG if:
dose >100mg
after every ↑ of 20 mg
unexplained dizziness or fainting
Initiation of additional QT prolongation medication
↑ risk of serotonin syndrome when combined with serotonergic drugs
Methadone: Why should dose adjustments only be made every 5 days? What ahppens if you stop it abruptly?
Slow onset = progression of respiratory depression is insidious (come on before you know it)
24 h t1/2; serum levels will ↑ with each dose until steady state is reached (4-5 half lives)
= ↑ risk of overdose and death
Prescribers should not increase dose more frequently than every 5 days
Physiological dependence physical and psychological withdrawal symptoms if discontinued abruptly
Buprenorphine for Pain Formulations, Dose and Titration
Buprenorphine (BuTrans)
Patch formulation for persistent, moderate pain
Non-formulary
Applied q7days
Opioid naïve patients
Start with 5mcg/hr q7d
Can increase after 7 days (no sooner than 3)
Max. 20mcg/hr
Buprenorphine Roptation from Other Opiods
Buprenorphine dose in BuTrans is relatively low (even at max of 20mcg/hr)
Can only convert relatively low doses (< 90 MEQ) of other opioids to Butran patch
- More than 90 MEQ cannot switch to patch – use buprenorph/naloxone sublingual
Buprenorphin MOA. Advantages?
Receptor Interactions: mu-partial agonist, delta & kappa antagonist
Analgesia, decreased opioid-induced hyperalgesia & tolerance
Better safety profile
May cause less anxiety & depression
Buprenorphine t1/2.Benefits?
High affinity, slow dissociation, long elimination half-life (~37hrs subling tab)
More consistent serum concentrations, can alleviate end-of-dose withdrawal
Flexibility in dosing schedules
Buprenorphine Metabolism.Renal and Hepatic Dysfx?
Metabolism: CYP3A4 substrate (major)
Safe in decreased renal function
Relatively safe with hepatic dysfunction (may ↓ dose if severe impairment)
Opiod Contraindications
Allergy
Co-administration of a drug capable of inducing drug-drug interaction
Active diversion of controlled substances
Opiod Alllergy. Management
Rare
A/e of Opiods
Sedation
Respiratory depression
Constipation
Nausea
Miosis (pinpoint pupils)
Itching / rash (pseudoallergy)
histamine release from cutaneous mast cells, not a true allergic or immunoglobulin-E (IgE) or T-cell response (see last slide)
Too much opiods – miosis
Withdrawl – pupils get wider
Do patients develop tolerance to opiod adverse effects? When does this occur?
Patients will develop tolerance to all adverse effects of opioids except constipation and miosis (pin-point pupils)
Tolerance to respiratory depression:
Tolerance to respiratory depression can be lost quickly within 1 -2 days of no opioids high risk for overdose if return to previous dose!
Tolerance to sedation:
Begins after 3 to 4 days
May take up to 10 days
Highly variable, may never resolve
Long-term Side Effecrs of Opiods
General adverse effects of opioids (develop over the longer term, even as short as weeks):
Hypogonadism
Sleep apnea
Opioid-induced hyperalgesia
Opioid tolerance
Opioid dependence, opioid use disorder
Risk of opioid toxicity (overdose) multifactorial
Opiod Drug Interactions
Hypogonadism Mechanism of OPIODS
Opioids influence the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis
Morphine has been reported to cause a strong, progressive↓ in the plasma cortisol level
Opioids interfere with the modulation of hormonal release, including:
an ↑ in prolactin
a ↓ in luteinizing hormone, follicle-stimulating hormone, testosterone, and estrogen
Testosterone depletion has been demonstrated in people with opioid (heroin) use disorder and in patients receiving methadone maintenance therapy
The collective effects of the hormonal changes may lead to ↓ libido and drive; aggression; amenorrhea or irregular menses; and galactorrhea
Sleep Apnea Opiods
Patients on long-term sustained-release opioids show a distinctive pattern of sleep-disordered breathing called central sleep apnea that is different from the disturbances usually observed in people with obstructive sleep apnea (OSA)
The oxygen desaturation is more severe and respiratory disturbances are long during NREM sleep
Opioids may complicate underlying sleep apnea and make continuous positive airway pressure (CPAP) therapy less effective
Opiod Tolerance.What can it result in?
May have decreased effect over time
Withdrawal-mediated pain is becoming increasingly understood
Mechanism still unclear
May result in end-of-dosing interval increase in pain
Beyond underlying pain severity
Opiod Induced Hyperalgesia.What is its mechanism?
↑ sensitivity to pain
Even after one month of opioid therapy in patients with chronic pain, hyperalgesia has been documented
Opioid-induced hyperalgesia appears to be more likely with higher doses of opioid, for longer periods of time
Mechanism of OIH is unclear but speculated to be related to NDMA receptor sensitization, increased glutamate release, and immune cell changes (e.g., microglial and glial cells)
Opiod Induced Hyperalgesis Management
Consider dose reduction (tapering), opioid rotation (account for cross-tolerance), rotation to buprenorphine or methadone
Risk of opiod use disorder associated with:
History of substance use disorder (SUD),
Taking opioids for >90 days, or
Taking higher doses (>120 MED)
Opiod USe Disorder Screening
POMI
Score > 2 = positive screen
COMM
Score > 9 = positive screen
Opiod USe Disorder MAngement
Signs of Overdose
Difficulty
walking
talking
staying awake
Blue lips or nails
Very small pupils
Cold and clammy skin
Dizziness and confusion
Extreme drowsiness
Choking, gurgling, or snoring sounds
Slow, weak or no breathing
Inability to wake up, even when shaken or shouted at
Response to Overdose
If you think someone is overdosing, call 9-1-1 ASAP
Give naloxone (if available)
An overdose is always an emergency
Naloxone may wear off before overdose completely resolved
Additional doses may be required
Always call for help
Naloxone mOA
Binds the same sites as opioids in the brain (more tightly)
Displaces opioid
Antagonist at receptor
Restores breathing within about 2 to 5 min when it has been dangerously slowed or stopped due to opioid use
Admin Naloxone
IM:
Can be given through clothing into the muscle of the upper arm or upper leg
Cautions of NAloxone
Can cause opioid withdrawal in those with opioid dependence
Benefit > risk
Effects wear off after 30- 90 min, so overdose may return
Especially if patient was taking long-acting opioid (e.g. methadone)
Management of acute on chronic pain
Challenging due to opioid tolerance & potential hyperalgesia
Educate patient
Pain relief aimed at acute pain
Maintain analgesia for underlying pain condition
May use short acting opioids for new ACUTE pain
May require 2-3x higher dose than an opioid naïve patient
Use adjuvant analgesics
Acetaminophen, NSAIDs, ketamine, gabapentinoids
Return to prior analgesic dose when acute pain resolved
