MSK exam 3 a

where can adjuvant analgesics work?

central, dorsal root ganglia, peripheral

what are adjuvant analgesics used for?

not primarily indicated for pain; used perioperatively to spare opioids

what types of pain are adjuvant analgesics used for?

centralized pain and neuropathic pain

what are examples of centralized pain?

fibromyalgia, ibs, and tension headaches

what are examples of central neuropathic pain?

ms, stroke, and spinal cord disease

what are examples of peripheral neuropathic pain?

dpn and cipn

what are the two gabapentinoids?

gabapentin and pregabalin

what are gabapentinoids structured like, and do they act on gaba?

structured like gaba, but unrelated to gaba receptors, synthesis, or metabolism

what do gabapentinoids bind?

alpha-2-delta-1 subunit of voltage-gated calcium channels in the cns

how do gabapentinoids reduce neuropathic pain?

decrease excitatory neurotransmitters such as glutamate and substance p

how are gabapentinoids dosed in pediatrics?

mg/kg; gabapentin is preferred because it has stronger pediatric data

what happens with gabapentinoid withdrawal?

tachycardia, confusion, diaphoresis, gi symptoms, and agitation

when does gabapentinoid withdrawal resolve after restarting therapy?

within 1–2 days

what is gabapentin's benefit-risk relationship?

nnt < nnh, so benefits are greater than risks

how does gabapentin cross the bbb?

through a saturable lat1 transporter, which can cause off-site adverse effects

is gabapentin metabolized?

no; it is renally excreted

when should gabapentin be adjusted?

in poor renal function

what is the gabapentin starting dose in young adults?

300 mg

what is the gabapentin starting dose over age 65?

100 mg

how is gabapentin titrated?

increase by 100 mg every 3–7 days

what is the maximum gabapentin dose?

2400 mg; higher doses have diminishing returns

how should gabapentin be taken with mg or al antacids?

take gabapentin 2 hours after the antacid

what are important gabapentin adverse effects?

peripheral edema, especially with heart failure, and respiratory depression

what is special about gralise?

extended-release gabapentin with once-daily dosing; take with fatty food

what is enacarbil?

an extended-release gabapentin prodrug

what can alcohol do with enacarbil?

enhance release of the active metabolite

can gabapentin formulations be interchanged?

no, formulations cannot be interchanged

what is pregabalin's benefit-risk relationship?

nnt > nnh, so risks are greater than benefits

what are pregabalin's pharmacokinetics?

linear pk with higher bioavailability

why does pregabalin have a fast onset?

strong receptor affinity

is pregabalin metabolized?

no; active drug is renally excreted

when should pregabalin be adjusted?

crcl <60 or hemodialysis

what is the maximum pregabalin dose?

600 mg/day, usually divided bid or tid

what are important pregabalin adverse effects?

peripheral edema, dizziness, and somnolence

what is the benefit-risk relationship for tcas?

nnt < nnh, so benefits are greater than risks

what is the moa of tcas?

inhibit 5ht and ne reuptake, block nmda and na channels, and have independent analgesia

how are tcas absorbed and distributed?

rapidly absorbed, albumin-bound, and widely distributed into extravascular tissues

how are tcas metabolized?

hepatically through cyp enzymes

how are tcas eliminated?

some renal elimination; enough to avoid in dialysis

what is the tca starting dose in young adults?

20 mg qhs

what is the tca starting dose over age 65?

10 mg qhs

how are tcas titrated?

increase weekly for 4–8 weeks

how should tcas be tapered?

over 2–4 weeks

what is the tca black box warning?

suicidal thoughts and behaviors

which tcas have stronger pediatric data?

amitriptyline and nortriptyline

what are the major tca adverse effects?

anticholinergic effects, lower seizure threshold, suicidality, and qt prolongation

why are tcas contraindicated with glaucoma, bph, and cv disease?

anticholinergic effects make them unsafe in these conditions

why does amitriptyline have more 5ht activity?

lower 5ht ki and a tertiary amine group

what happens to amitriptyline after demethylation?

it becomes nortriptyline in the liver and significantly inhibits 2c19

what are the major amitriptyline adverse effects?

anticholinergic effects, sedation, orthostatic hypotension, and weight gain

why does nortriptyline have more analgesia?

lower ne ki and a secondary amine group increase ne activity

how do nortriptyline interactions compare with amitriptyline?

fewer drug and cyp interactions

what is the major nortriptyline adverse effect?

weight gain

why does imipramine have more 5ht activity?

lower sert ki and a tertiary amine group

what happens to imipramine after demethylation?

it becomes desipramine and significantly inhibits 2c19

what are imipramine's major adverse effects?

weight gain and many other moderate adverse effects

why does desipramine have more analgesia?

lower ne ki and a secondary amine group increase ne activity

how do desipramine interactions and elimination compare with other tcas?

fewer drug and cyp interactions and more renal elimination

does desipramine have a significant adverse effect of concern?

no significant adverse effect of concern

what is the benefit-risk relationship for snris?

nnt < nnh, so benefits are greater than risks

what are important snri adverse effects?

insomnia, sexual dysfunction, hyponatremia, hypertension, and bleeding risk

how long should maois be washed out before starting an snri?

14 days due to serotonin syndrome risk

what proteins are snris highly bound to?

alpha immunoglobulin and albumin

how does smoking affect snri bioavailability?

smoking reduces bioavailability

which cyp enzymes produce active snri metabolites?

cyp1a2 and cyp2d6

which cyp enzyme may snris inhibit?

cyp2d6

when should snris be adjusted?

poor renal function, crcl <30, dialysis, or hepatic impairment

when should snris be avoided?

liver disease, cirrhosis, gfr <30, and chronic alcohol use

what is the snri starting dose in young adults?

30 mg

what is the snri starting dose over age 65?

20 mg

how are snris titrated?

increase by 20 mg every 2 weeks

what is the maximum snri dose?

60 mg/day

how should significant snri withdrawal be managed?

resume the previous dose and taper more gradually

when should snris be taken?

in the morning because they can be activating and cause insomnia

what should be avoided with snris because of premature release?

pudding

which snri has slightly more 5ht activity?

duloxetine

what is venlafaxine's primary activity?

primarily 5ht effects, with risk of serotonergic effects

which snri has equal 5ht and ne activity?

milnacipran

what is tramadol's mechanism?

mu agonist with weak ne and 5ht reuptake inhibition

what is ketamine's mechanism?

nmda antagonist with activity at other targets

what is important about ketamine's metabolism?

racemic r and s mixture is metabolized by cyp enzymes, creating ddi risk

what is lidocaine's role in pain?

class 1b antiarrhythmic that blocks sodium channels with anti-inflammatory and antihyperalgesic effects

who should avoid lidocaine for pain?

patients with heart arrhythmias or other cardiovascular issues

how is lidocaine metabolized and eliminated?

cyp3a4-mediated metabolism and renal clearance; up to 10% unchanged

why is lidocaine given by iv infusion?

it has a short half-life

what is the goal lidocaine serum level?

1 mcg/ml

when does lidocaine require more monitoring?

when symptomatic; symptoms include dizziness, metallic taste, tinnitus, hallucinations, low bp, and convulsion