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Chronic Pain - Coggle Diagram
Chronic Pain
Opioids
Tramadol
MOA: Mu opioid receptor agonist, inhibits reuptake of serotonin and norepinephrine
PK/PD/PGx
M: Demethylathin by 3A4 and 2D6, glucorinidation, sulfation
Active Metabolite via 2D6 (M1)
Immediate Release: Time to onset 1 hour, time to peak 2 to 3 hours
Extended Release: Time to peak 4 to 12 hours
Concentrations 20% higher in PM vs. EM (active metabolite 40% less)
ADR: dizziness, vertigo, rash, constipation
BBW
: Potential for addiction, abuse, and misuse. Risk of life-threatening respiratory depression (increases w/ concomitant use of BZD or other CNS depressants).
Regimen (Chronic Pain)
Initial Dose: 25 to 50 mg q6h prn (can titrate up to 50 to 100 mg q4h pen, max dose 400 mg/day)
Extended Release: 100 mg once daily (can titrate up by 100 mg every 5 days, max dose 300 mg/day)
Monitoring: Respiratory depression, constipation, random urine drug screen, pill counts
Duration: Indefinite, as clinically indicated
Warnings/Precautions
Concurrent BZDs (Respiratory depression)
CYP3A4 inducers/inhibitors, CYP2D6 inhibitors
Comorbid mental health conditions
Serotonin Syndrome
Suicide Risk
Thyroid Dysfunction
Obesity
Contraindications
Hypersensitivity
Peds <12
Acute/severe bronchospasm (asthma)
Respiratory Depression
Abuse/Misuse
MAOI w/in 14 days
DDIs: Respiratory depressants (alcohol, BZDs)
Special Pops:
Geriatrics (sedation/falls risk (Increased CMax and T1/2))
Renal Impairment: Decreased exctretion
Hepatic Impairment: IR: Decreased metabolism, ER: decreased exposure
Education
Constipation Prophylaxis
Naloxone Dispensing
Misuse/Abuse
Oxycodone
MOA
: Mu opioid receptor agonist; causes inhibition of ascending pain pathways, altering the perception & response to pain; produces generalized CNS depression
BBW
: Potential for addiction, abuse, and misuse. Risk of life-threatening respiratory depression (increases w/ concomitant use of BZD or other CNS depressants).
Dose
:
Opioid naive/not opioid tolerant: initial 10 mg PO Q12H. titrate by 25% - 50% of current dose every 1-2 days based on analgesic requirement and tolerance; use lowest effective dose for shortest duration necessary.
When discontinuing, do not stop abruptly for pts that are physically dependent. Consider > by no more than 10% to 25% every 2-4 weeks.If withdrawal sx occur, increase to previous dose and taper more slowly.
Monitoring
: Pain control, AEs, s/sx of respiratory depression, need for continued tx, s/sx of sedation or hypotension, s/sx of worsened seizure control; s/sx of addiction, abuse or misuse
PK/PD
: metabolized extensively by liver (substrate of CYP3A4/2D6, eliminated primarily by kidneys. Active metabolites: oxymorphone, noroxycodone, noroxymorphone.
AEs
:
Common
: pruritis, constipation, N/V, dizziness, HA, somnolence.
Serious
: severe hypotension, adrenal insufficiency, anaphylaxis, respiratory depression, withdrawal syndrome.
Special Pop
: Renal impairment (CrCl <60 mL/min) initiate/adjust conservatively, if <9 mg dose is needed, use alternative analgesic; Hepatic impairment initiate tx w/ 1/3 to 1/2 usual starting dose, if <9 mg is necessary, use an alternative analgesic; geriatric; concomitant CNS depressants
Education/Counseling
: ppx to prevent constipation recommended, do not drive or operate machinery until you know how this will affect you, may cause drowsiness/dizziness/N/V, watch for allergic rxn
Dosage forms
: oral capsule, oral solution, oral tablet (IR and ER)
Hydrocodone
MOA
- Binds to opioid receptors in the CNS - inhibition of ascending pain pathways; altering pain perception and response; produce generalized CNS depression
PK
-
A - N/A
D - 1,300 - 1,400 L ; protein binding - 36%
M - hepatic - via CYP2D6
E - Urine (~12% unchanged)
Regimen (Chronic Pain)
- Opioid naiive -
Hysingla ER
- initial 20 mg once daily; increase in increments of 10-20 mg every 3-5 days prn
Zohydro ER
- initial 10 mg Q12; increase in increments of 10 mg every 12 hours every 3-7 days
AEs
- Constipation, nausea, HTN, peripheral edema, headache, chills, sedation, anxiety, insomnia, dizziness, drowsiness, fatigue, depression, UTI,
Monitoring
- pain relief, respiratory and mental status, bp, bowel function, signs/symptoms of misuse, abuse, addition, hypogonadism, hypoadrenalism
BBW
- Addiction, misuse, abuse, REMs. life-threatening respiratory depression, accidental ingestion; neonatal opioid withdrawal syndrome, cytochrome p450 3A4 interaction, Risk from concomitant use with benzo + other CNS depressant, alcohol interaction (Zyhydro ER)
CI
- hypersensitivity, GI obstruction, significant respiratory depression, acute or severe bronchial asthma in unmonitored setting
Special Pop
- Renal/Hepatic impairment - reduce 50% of initial dose in moderate to severe and ESRD, pregnancy - opioid crosses placenta, breastfeeding - metabolite in breast milk, elderly - start with dose of lower range
Education/counseling
- swallow whole, ppx to prevent constipation, safe storage of drug, potential for misuse, abuse and addiction, allergic rxn, do not double up, may cause drowsiness, dizziness, N/V, headache, fatigue; do not operate machinery
Morphine
MOA
: Mu opioid receptor agonist; causes inhibition of ascending pain pathways, altering the perception & response to pain; produces generalized CNS depression
Dosing
General note
: Individualize dose by taking pt's prior analgesic tx experience and risk factors for addiction, abuse, & misuse; due to substantial inter-pt variability in relative potency. When converting, best to under-estimate pt's 24-hr oral morphine requirements.
Opioid naive:
IR formulations
: for conversion from parenteral to PO morphine, a dose ranging from 3-6 mg may be required for analgesia equivalent to parenteral morphine.
Arymo(R) **extended-release tablets
: initiate 15 mg PO Q8-12H, discontinue all other around-the-clock opioids upon initiation; when converting from other parenteral/oral non-morphine opioids, consider starting with 1/2 the estimated daily morphine requirement for initial dose, supplementing with IR mophine to manage inadequate analgesia. Titrate dose every 1-2 days. When discontinuing, taper slowly. Do not stop abruptly. Taper daily dose by 10% to 25% every 2-4 weeks.
BBW
: do not take with alcohol, potential for addiction, abuse, misuse, FDA-required REMS, life-threatening respiratory depression, neonatal opioid withdrawal syndrome, accidental ingestion, risk of medication errors (oral solution), risk with use of BZDs or CNS depressants, risk with neuroaxial administration
PK
D: low protein binding
M: conjugation to M6G and M3G
E: renal
DDI
: CNS depressants, alcohol, serotonergic agents, MAOIs, muscle relaxants, diuretics, anticholinergics, PGP inhibitors
Monitoring
: adequate pain control, AEs, s/sx of respiratory depression, need for continued tx, s/sx of sedation or hypotension, s/sx of worsened seizure control, s/sx of addiction, abuse or misuse.
Dosage forms
: IM solution, IV solution, oral capsule (ER), oral solution, oral tablet, rectal suppository
Hydromorphone
MOA: Mu opioid agonist
PK/PD/PGx
Bioequivalance between 8 mg IR tablet and liquid has been demonstrated
Rapidly absorbed, extensive first pass effect
Hepatic Metabolism
Glucoronidation (inactive metabolites
Onset: 15 to 30 min,
Peak: 30 to 60 min
Duration: 3 to 4 hours
BBW
: addiction, abuse, misuse, opioid REMS, life threatening resp depression, accidental ingestion, neonatal opioid withdrawal, medication error, concomitant use with benzo + other CNS depressants
ADR: rash, constipation, dizziness, bradychardia
Special Pops
Increased Cmax and AUC in renal and hepatic impairment
Monitoring: Respiratory depression, constipation, random urine drug screen, pill counts
DDIs: Respiratory depressants (alcohol, BZDs)
Regimen: 2 to 4 mg q4-6h
May need higher doses for those who have taken opioids previously
Chronic Pain, Dose that's 5 to 15% total daily usage can be given every 2 hours
Warnings/Precautions
Concurrent Respiratory Depressants
Hypotension
Mental Health Conditions
GI Narrowing
Obesity
Contraindications
Hypersensitivity
ER: Opioid non-tolerant patients, narrowing of GI
Education/counseling
- swallow whole, ppx to prevent constipation, safe storage of drug, potential for misuse, abuse and addiction, allergic rxn, do not double up, may cause drowsiness, dizziness, N/V, headache, fatigue; do not operate machinery
Skeletal Muscle Relaxants
Cyclobenzaprine
MOA: muscle relaxant similar to TCAs, reduce tonic somatic motor activity on alpha and gamma motor neurons
antispasmodic
indicated more for acute pain
PK
D: highly protein bound
M: extensively by via glucuronidation
E: renal
significantly better improvement of pain than with diazepam
Regimen
only use for up to 2 to 3 weeks
5 mg TID, but up to 7.5 or 10 mg TID
Special Populations
plasma concentration higher in elderly and poor liver function
elderly: start with 5 mg dose and titrate slowly (Beers Criteria)
not recommended to be used with moderate to severe liver impairment
no good trials with pregnant patients, not known if excreted in breastmilk, pediatric studies have not been conducted
Warnings
serotonin syndrome
risk of drug abuse and dependence
avoid in patients with acute narrow angle glaucoma
Contraindications
hypersensitivity, use of MAOIs currently or within 14 days of discontinuation, acute recovery phase of MI, arrhythmias, heart block, conduction disturbances, congestive heart failure, hyperthyroidism
hear-related contraindications due to similarity of cyclobenzaprine to TCAs and their effects on the heart
DDI: MAOIs, barbiturates, CNS depressants, alcohol, tramadol (increase risk of seizure)
ADR: drowsiness, dry mouth, fatigue, headache
Baclofen
Indicated for spasticity (5mg 1-3x daily - may increase by 5mg every 3 days based on tolerability and efficacy); off-label use for muscle spasms/musculoskeletal pain (5-10mg TID PRN)
MOA:
inhibition of reflexes at spinal cord level through hyperpolarization of primary afferent nerve fiber terminals
PK/PD:
>70% excreted through urine as unchanged drug; VD highly variable; absorption in GI tract is dose dependent
Withdrawal can occur (AMS, rebound spasticity, HTN, fever) mostly with intrathecal dosage form however 1-2 week titration for discontinuation of oral dosage form suggested; no specific contradindications
Special Populations
Able to pass through to fetuses, fetuses can experience withdrawal; Use with caution in elderly due to CNS effects; Renal dose adjustments <80 mL/min; no hepatic dose adjustments
Most common side effect is GI upset (N/V), CNS effects (confusion, dizziness)
Carisoprodol
PK
M: 2C19 to a barbiturate (potential for abuse and dependence)
E: renal
MOA: altered interneuronal activity in the spinal cord and descending reticular formation of brain, active metabolite has activity at GABAa receptors
Warnings: withdrawal can occur with abrupt discontinuation, respiratory depression, sedative so be careful when driving or operating machinery, abuse, dependence, seizures, CNS depression with overdosage
Regimen: 250 mg TID and at bedtime (up to 350) for up to 2 to 3 weeks
Contraindications: history of acute intermittent porphyria (effect on the nervous system), hypersensitivity
ADR: drowsiness, dizziness, headache
not really indicated for chronic pain
DDI: enhanced sedative effect with other CNS depressants
2C19 inhibitors and inducers
Special populations: transferred into breastmilk (monitor baby for sedation)
women have higher exposure to carisoprodol than males
has not been studied in children or elderly
PGX: reduced 2C19 activity may have increased exposure
Patient Education: may cause sedation, avoid alcohol and other CNS depressants, should only be used short term
Diazepam
Indicated as alternative treatment for muscle spasm/spasticity (2mg BID or 5mg QHS); not recommended as first-line use due to abuse potential/CNS depressant effects
BBW
risk with concomitant use with opioids; abuse, misuse, addiction potential; dependence and withdrawal reactions
MOA:
binds to benzo receptors on post-synaptic GABA neurons within the CNS enhancing the inhibitory effect of GABA on neuronal excitability due to increased permeability of chloride ions
PK/PD:
well absorbed (delayed/decreased when administered with high fat meal), hepatic metabolism by CYP3A4/2C19, highly bioavailable, t1/2 ~45 h, excreted in urine
Special Populations:
No renal/hepatic dose adjustments, use with caution in elderly (Beer's Criteria)
Most common side effect is drowsiness
Monitoring
HR, RR, BP, mental status, liver enzymes, CBC
Anticonvulsants
Gabapentin
MOA
: Exact mechanism unknown - involves inhibition of alpha-2 delta subunit of voltage gated calcium channel
Dose
: Postherpetic - IR - 300 mg once on day 1, 300 mg BID on day 2, 300 mg TID on day 3, then increase prn up to 1.8- 3.6 g/day in divided doses
ER - 300 mg daily; increase by 300 mg each day up to 900 mg once daily .
Off label - IR - 100-300 mg 1-3 times a day, increase baed on response and tolerability to target dose range of 300 mg - 1.2 g TID
ER - 300 mg at bedtime; increase dose based on response and tolerability to target dose of 900 mg - 3.6 mg daily
Dosage Forms:
Capsule, tablet, solution, blister pack (Gralise Starter)
CI:
Hypersensitivity to gabapentin or ingredients in formulation; pt with myasthenia gravis or myoclonus
ADR:
-
Significant
: CNS and respiratory depression, anaphylaxis, angiodema, SJS, neuropsychiatric effects, suicidal ideation and tendencies
Other
: Infection (viral), ataxia, dizziness, drowsiness, fatigue
PK
A: variable; dose dependent
D: Vd - 52-64L; CSF concentration ~ 20% plasma concentration; < 3 % protein binding
M: N/A
E: renal
DDI:
losartan, caffeine, phenytoin, mefloquine, MgOx, cimetidine, naproxen, sevelamer, morphine
Monitoring
: renal function, suicidality
Pearls
: Take at least 2 hours after taking antacid or magnesium; renal adjustment needed, none for hepatic
Indication
- postherpetic neuralgia; Neuropathic pain (off label)
Pregabalin
Indicated for fibromyalgia (75mg BID, may increase to 150mg BID after 1 week, max 450mg/day), and neuropathic pain (25-150mg/day in 2-3 doses, may increase weekly in 25-150mg increments, max 600mg/day in divided doses)
MOA:
Binds voltage gated calcium channels within CNS to modulate calcium influx at nerve terminals which inhibits excitatory neurotransmitter release (glutamate, NE, 5HT, Dopamine, SubP)
PK/PD:
effects may appear in first week of therapy, absorption decreased significantly when administered without food, high bioavailability, not protein bound, t1/2 ~6h, metabolism negligible, excreted in urine as unchanged drug
Special Populations
Use with caution in elderly (may cause respiratory depression), use with caution in patients with severe CVD, use with caution in patients with substance abuse history, no hepatic dose adjustments, renal dose adjustments <60 mL/min
Pearls:
Do not discontinue abruptly; taper over at least 1 week; delayed hypersensitivity can occur, risk of increased SI, CNS/respiratory depression risk
ADE:
angioedema is possible, may cause weight gain, peripheral edema, dizziness, drowsiness, xerostomia
Monitoring
Efficacy, degree of sedation, symptoms of myopathy, ocular disturbance, SI
Carbamazepine
MOA
: block voltage-gated Na channels and potentiate effects of GABA
Labeled Indication
: Neuropathic pain: Treatment of trigeminal or glossopharyngeal neuralgia
Off-Label:
Bipolar major depression; Maintenance treatment for bipolar disorder
Dose
: Initial: 200 to 400 mg/day, gradually increasing (over several weeks) in increments of 200 mg/day as needed. Maintenance dose: 600 to 800 mg/day; maximum dose: 1.2 g/day
AEs
: anemia or agranulocytosis, serious dermatological reactions (SJS/TEN) w/ Increased risk of HLA-B*1502 allele, hepatotoxicity, hyponatremia, multiorgan sensitivity reactions (DRESS), suicidal Ideation
DDIs
: strong CYP3A4 Inducer
decrease OCP
PK
:
Metabolism
: CYP3A4 (major)
autoinduction (3-5 weeks after Initiation)
Strong Inducer of CYP3A4
Elimination
: Urine 72% (1% to 3% as unchanged drug); feces (28%)
T1/2:
Initial: 25 to 65 hours; Extended release: 35 to 40 hours
BBW
: serious dermatologic effects (HLA-B*1502 allele), aplastic anemia/agranulocytosis
Dosage Forms
: capsule ER 12 h, suspension, tablet, chewable tablet, tablet ER 12 h
CI
: hypersensitivity to drug, bone marrow depression, within 14 days of MAOi, concomitant use of nefazodone, delavirdine, or other reverse transcriptase Inhibitors through CYP3A4
*teratogenic
*decrease OCP
*autoinduction thru CYP3A4
Monitoring
: Baseline and periodic: CBC with platelet count and differential, reticulocytes, serum iron, liver and renal function tests, urinalysis, BUN, serum sodium, ophthalmic exam including intraocular pressure
As appropriate: Lipid panel, serum carbamazepine levels, thyroid function tests; pregnancy test; observe patient for excessive sedation, especially when instituting or increasing therapy; signs of rash; HLA-B
1502 and HLA-A
3101 genotype screening prior to therapy initiation in patients with ancestry in genetically at-risk populations; suicidality
Toxic concentration: >15 mcg/mL; patients who require higher levels of 8 to 12 mcg/mL (SI: 34 to 51 micromole/L) should be watched closely
Topiramate
MOA
: Inhibits voltage-gated Na channels, Ca channels, blocks AMPA subtype of glutamate receptor, inhibits carbonic anhydrase, and Increases activity of GABA-A receptor
Labeled Indication
: seizure, migraine (prevention)
Off-Label
: Antipsychotic-induced weight gain; Binge eating disorder; Headache, cluster (prevention); Headache, short-lasting unilateral neuralgiform attacks (prevention); Tremor, essential
Dosage Forms
: capsule ER 24 h sprinkle, capsule ER 24 h, capsule sprinkle, tablet
CI
: Extended release: Recent alcohol use (ie, within 6 hours prior to and 6 hours after administration) (Trokendi XR only); patients with metabolic acidosis who are taking concomitant metformin (Qudexy XR only).
AEs
: glaucoma, metabolic acidosis, hyperammonemia and encephalopathy, kidney stones, oligohidrosis, hypo/hyperthermia, cognitive dysfunction, paresthesia, insomnia, weight loss
Monitoring
: Seizure frequency, hydration status; electrolytes (serum bicarbonate at baseline and periodically), serum creatinine; monitor for symptoms of acute acidosis and complications of long-term acidosis (nephrolithiasis, nephrocalcinosis, osteomalacia/osteoporosis, and reduced growth rates and/or weight in children); ammonia level in patients with unexplained lethargy, vomiting, or mental status changes; intraocular pressure, symptoms of secondary angle closure glaucoma; suicidality (eg, suicidal thoughts, depression, behavioral changes); weight and eating behaviors in patients with eating disorder symptoms or risk factors; sedation
DDIs
: CYP3A4 inducer, CYP2C19 Inihibitor
decrease OCP at doses > 200 mg
Dose
: Initial: 25 mg PO daily x 1 week. Titrate by 25-50 mg week. Target dose: 50 mg PO BID (migraine ppx) or 200-400 mg/day neuropathic pain
CrCl <70 mL/minute/1.73 m2: Reduce dose to 50% of normal dose and titrate more slowly.
Hemodialysis: 50 to 100 mg twice daily; administer a supplemental dose (50 to 100 mg) post-dialysis (Israni 2006). Topiramate is cleared by hemodialysis.
*decrease OCP at doses > 200 mg
PK
:
Excretion
: Urine (~70% as unchanged drug); may undergo renal tubular reabsorption
Metabolism
: CYP3A4 Inducer, CYP2C19 Inhibitor
Non-Pharm/CAM
Physical Therapy, formal exercise programs
Acupuncture, Tai Chi, Yoga
Mindfullness, meditation, relaxation, biofeedback
Weight loss, diet changes
Electroanalgesia (TENS)
NSAIDs
Celecoxib
Diclofenac (oral/topical)
ketorolac (oral/injectin)
SNRIs
Venlafaxine
Duloxetine
Milnacipran
Therapeutic Goals
Therapeutic Goal Monitoring
Effectiveness: Pain relief, adequate functionality, change in pain
Frequency based on ROA, duration of action, PK factors, concomitant therapies
Five A's (analgesia, activity, abhorrent drug behavior, adverse effects, affect)
Adverse Effects
Sedation, constipation (opioids)
Lack of objective monitoring parameters
Depends on type of pain present, should be tailored to specific patient and circumstances
Improve or maintain patients level of functioning
Decrease pain perception
Decrease use of medications (when possible)
Improve QOL
TCA
Amitriptyline
Nortriptyline