Exam 5: Psych, Pain, SUD Flashcards
1
Q
Comorbidities of Bipolar Disorder
A
- alcohol and substance use common (50-60%)
- anxiety disorders are common and can significantly impact remission of mood episodes if left untreated or inadequately treated
2
Q
What mood pole is experienced most often in bipolar disorder and can lead to misdiagnoses?
A
Depression
3
Q
DSM-5 Classification of Bipolar I Disorder
A
≥ 1 manic episodes, depressive or hypomanic may have occurred
episodes generally last ≥ 1 week
4
Q
DSM-5 Classification of Bipolar II Disorder
A
major depressive and hypomanic episodes
hypomanic episodes generally lasts ≥ 4 days
5
Q
Target Symptoms of BPD: Mood
A
- euphoria, elation, happiness
- depression
- lability
- irritability
- hostility
- dissatisfaction
6
Q
Target Symptoms of BPD: Cognitive/Perceptual
A
- flight of ideas
- racing thoughts
- grandiosity
- delusions
- hallucinations
- ideas of reference
- fragmented thoughts
7
Q
Target Symptoms of BPD: Activity/Behavior
A
- pressured speech
- impulsivity
- insomnia
- aggression, outbursts, violence
- increased sexual dysfunction
- panic
8
Q
Pharmacotherapy Overview for BPD
A
- mood stabilizers are the foundation of acute and maintenance treatment
- 1st line: usually lithium or valproic acid
- atypical antipsychotics can also be used 1st line as monotherapy or in combination with lithium or valproic acid
- many patients will take polytherapy with mood stabilizers
9
Q
What is lithium associated with a decrease in?
A
- suicidality, especially in BPD
- narrow therapeutic index, evaluate if patient has a plan, and if it does involve overdose via pill ingestion
10
Q
Lithium Dosage Forms
A
some difference in lithium content, but use 1:1 conversion
11
Q
Therapeutic Level of Lithium for Acute Treatment
A
0.9-1.2 mEq/L
12
Q
Therapeutic Level of Lithium for Maintenance
A
0.6-0.9 mEq/L
13
Q
Therapeutic Level of Lithium for Toxicity
A
1.5 - >3.0 mEq/L
14
Q
When should you draw lithium levels?
A
draw trough serum concentration 72 hours after dose initiation, 12 hours after last dose
15
Q
Toxicities of Lithium
A
- GI
- ataxia
- coarse hand tremor
- AMS
- seizure
- lethargy
- confusion
- agitation
16
Q
Side Effects of Lithium
A
- fine hand tremor
- hypothyroidism
- polyuria
- polydipsia
- acne (upper body, chest)
- dry mouth
- weight gain
- ECG changes
- diabetes insipidous
17
Q
Teratogenic Effects of Lithium
A
- cardiac structural abnormality that requires surgery
- avoid in 1st trimester, use with caution in 2nd and 3rd trimester
- BPD gets worse in pregnancy, might need to increase dose
18
Q
Lithium Lab Monitoring
A
- SCr, BUN (almost entirely renally excreted)
- urine specific gravity
- Na, K, Ca
- ECG (especailly if age > 40 or cardiac risk factors)
- Thyroid Function (TSH, T4)
- Parathyroid hormone
- CBC w/ differential
- Weight
- Pregnancy Test
19
Q
How is lithium metabolized?
A
Mostly renally excreted
20
Q
Decreased Li Renal Clearance Causes
A
due to ACEi, ARBs, thiazides, NSAIDs, dehydration
21
Q
Increased Li Renal Clearance
A
lower Li levels
- caffeine
- osmotic diuretics
- loop diuretics
22
Q
Increased Li Excretion Causes
A
- lower Li levels
- sodium bicarb
- high sodium intake
23
Q
Toxicity Related to Na Depletion with Lithium
A
- thiazide diuretics
24
Q
Valproate Dosage Forms: ER
A
- ER dosage form is ~ 10-15% less bioavailable than delayed release dosage from
- 1:1 converstion, expect lower serum concentration with the ER dosage form, usually not clinically significant
25
Valproic Acid Syrup and Capsule Sprinkle Form
higher risk for GI ulcerations (usually esophageal)
26
Serum Levels for Efficacy w/ Valproate
- 80-125 mcg/mL associated with most efficacy in mania
- obtain level at least 96 hours (4 days) after first dose or dose increase
27
Valproic Acid in Pregnancy
- unsafe in any trimester of pregnancy
- obtain baseline pregnancy test
- use contraceptive
28
Valproic Acid and PCOS
- PCOS occurs in up to 50% of women
- may treat with metformin
- refer to endocrinologist
29
Valproic Acid Side Effects
- GI: anorexia, N/V/D, dyspepsia, ulceration
- throbocytopenia, platelet dysfunction
- teratogenic neural tube defects, enduring negative effects on IQ of offspring
- increased appetite, weight gain (~6-8 kg)
- hyperammonemia
30
Valproate Lab Monitoring
Baseline
- pregnancy test
- LFTs
- CBC w/differential
- Serum Ammonia if suspected hyperammonemia
31
Drug Interactions with Valproic Acid
- signficant concern with combo use with lamotrigine (increased lamotrigine serum concentration and increased risk of SJS
- drug dosing cut in half
32
Carbamazepine in BPD
- thrombocytopenia/hematologic effects
- induce nearly all CYP450 enzymes
33
Oxcarbazepine in BPD
- CYP450 3A4 inducer
- associated with hyponatremia
34
Lamotrigine in BPD
- not useful for acute treatment or for manic episodes
- 1st line treatment for DEPRESSIVE symptoms
35
Topiramate in BPD
- may cause weight loss
- heat intolerance/hypohidrosis
- metabolic acidosis and kidney stones
- possible teratogen
- DRESS
36
Antipsychotics in BPD
- atypicals (except brexpiprazole, clozapine, iloperidone, and paliperidone) are FDA approved for acute and/or maintenance treatment (manic/mixed episodes) with and without psychosis
37
Seroquel in BPD
- FDA approved for bipolar depression
- dose at least 300 mg/day
38
Abilifiy/Brexpiprazole in BPD
- FDA-approved for adjunctive treatment in depression in combination with antidepressants treatment
- may see increased use for bipolar disorder
39
Symbyax for BPD
- olanzapine/fluoxetine
- FDA-approved for bipolar depression and treatment-resistant depression
40
Latuda in BPD
- FDA approved for bipolar depression
41
Clinical Pearls: Antipsychotics in BPD
- atypical antipsychs may be used as monotherapy or can be used combo with other mood stabilizers (VA or Li)
- all monitoring parameters for metabolic syndrome and movement side effects apply when used for BPD
42
Treatment Considerations of BPD
- mood stabilizers treatment is long-term and considered to be maintenance treatment to reduce time to subsequent mood episodes
- suicide attempt risk is high in both poles of bipolar disorder, monitor closely, use lithium cautiously
43
Treatment in Pregnancy: BPD
- lithium, VA, carbamazepine and topiramate are known or possible teratogens
44
Antidepressants in Bipolar Disorder
- need to have maintenance mood stabilizer therapy in combo with antidepressant therapy
- will use serotenergic antidepressants to treat anxiety
45
Functions of Pain
- warning system (avoid injury)
- aid in repair (hypersensitivity)
- can be maladaptive (irreversible neuropathy)
46
Temporal Features of Pain
- onset
- duration
- course
- pattern
47
Intensity of Pain
- average
- least
- worst
- current pain
48
Location of Pain
- focal
- multifocal
- generalized
- referred
- superficial
- deep
- opioid induced hyperalgesia (generalized)
49
Quality of Pain
- inflammatory: throbbing, pulsating
- neuropathic pain: stabbing, shooting, burning
- visceral: squeezing
50
Pain Transmission
- trauma in the periphery will transmit signal to spinal cord (activation of PNS)
- activation of CNS at spinal cord
- spinal cord sends input to the brain
- processed in the brain
- descending modulation to the spinal cord
51
Temperature Sensitive Receptors and Channels (in the skin)
- transient receptor potential cation channel (TRP
- TRPV (vanniloid) = heat
- TRPM (melastatin) = cold
52
Acid Sensitive Ion Channel
ASIC activated by H+ and conducted by Na+
53
Chemical Irritant Sensitive Receptors and Channels involved in Pain Signaling
histamine
bradykinin
54
Reflex Upon Painful Stimuli
- bypasses CNS, goes right back toward the muscle
- transmission via afferent nerve to the spinal cord
- modulation back to muscle via efferent nerve
- does not go to brain!
55
Sodium Channels responsible for conduction of pain signal that are non-opioid
Nav1.1, Nav1.6, Nav1.7, Nav1.8
56
Neurotransmitter released at the end of afferent neuron
glutamate (conduction of pain in spinal cord)
57
A-beta fibers
- non-noxious (touch, pressure)
- innervate the skin (thicker myelin)
- faster (35-75 m/s)
58
A-gamma fibers
- pain, cold
- myelinated
- fast (2-35 m/s)
- first pain, reflex arc
- sharp prickly pain
59
C fibers
- pain, temp, touch, pressure, itch (polymodal)
- unmyelinated
- slow (0.5-2 m/s)
- second pain
- dull aching
60
Substance P's Role in Pain
- repeated stimuli reduces firing threshold
- increase expression of pain receptors via sensitization
- sunburn is a good example
61
Substance P MOA
- injury occurs at periphery
- substance P is released
- stimulates areas of the blood to degranulate mast cells
- vasodilation and release of bradykinin, prostaglandins, histamines (inflammatory markers)
- increase in receptors in the periphery to send more signals into the spinal cord
62
Neuropathic Pain Sensitization
- spontaneous afferent activity: possibly enhanced expression of sodium channel subtypes contributing to enhanced cellular excitability and generation of ectopic action potentials
- spinal sensitization leading to increased AMPA and NMDA expression and sensitivity
- A-beta afferent fibers that cause light touches to hurt due to cord sensitization
63
Neurotransmitters released in neuropathic pain signalling
- neuropeptides
- CGRP
- Substance P
64
_____ expression of opioid receptors in the brain stem along the _______ pathway
high, descending
65
Mu Opioid Expression Effects on Brain
- alter mood
- produce sedation
- reduce emotional reaction
66
Mu Opioid Receptor Expression on Brainstem
- increase activity of descending fibers
- decrease activity of input in ascending pathway via afferent neuron
67
Mu Opioid Receptor Expression on Spinal Cord
- inhibit vesicle release
- hyper-polarize post-synaptic membrane
68
Mu Opioid Receptor Expression on Periphery
- reduce activation of primary afferent
- modulate immune activity
69
What do Mu opioid receptors do?
influence ascending pathway and perceivement of pain
70
Amygdala and Pain
anticipates pain and reacts to perceived threats
71
Somatosensory Cortex and Pain
- registers which body part is in pain and the intensity of that pain
- less activity here when patients focus their attention away from their pain
72
Prefrontal Cortex and Pain
- processes pain signals rationally and plans action
- active when trying to consciously reduce pain
73
Right Lateral Orbitofrontal Cortex
- evaluates sensory stimuli and decides on response, particularly if fear is involved
- mindfulness meditation calms down this response
74
Opium contains which two types of Alkaloids
- phenanthrenes
- benzylisoquinolines
- opiates are only those opioids that are naturally occuring
75
Codeine SAR
3 position substitutions ether or ester produces decreased potency
76
Hydromorphone or Hydrocodone SAR
6 position increases activity
77
Oxycodone SAR
14 position OH has increased potency
78
Naloxone or Naltrexone SAR
N-allyl gives antagonists
79
Opioid SAR Overview
- 3 ring structure
- 3, 6, N position
- bulky group on N decreases potency
80
Where are peptides active?
endogenously
81
What are cleaved into more opioid subtype selective peptides?
large precursor proteins
82
Pro-opiomelanocortin (POMC)
cleaves beta-endorphin to Mu opioid
83
Preproenkephalin
- Leu-enkephalin --> delta opioid
- met-enkaphalin = mu and delta opioid
84
Preprodynorphin
- dynorphin --> kappa opioid
85
G protein coupled opioid receptor
- Family A peptide receptors
- Gi/o- coupled inhibition of cAMP production
- open GIRK potassium channels
- close calcium channels
86
Mu Opioid Receptors
- morphine
- endogenous opioid = endorphin
87
Kappa Opoid Receptors
- endogenous opioid = dynorphin
88
Delta Opioid Receptors
endogenous opioid = enkephalin
89
Nociceptin/Orphanin FQ Receptor
endogenous opioid = nociceptin
90
Sigma Receptors
not an opioid receptor
91
Opioid Receptor Signal Transduction
- presynaptic = inhibit calcium channel (Gi) decrease in neurotransmitter release
- postsynaptic = activate GIRK channel, efflux of K+ --> hyperpolarization
92
Endogenous peptides associated with Mu receptor
- beta-endorphins via POMC (endogenous morphine)
- component of runners high
93
Therapeutic Use of Mu
- analgesia (cancer pain, palliative, PCA)
- sedation
- antitussive (suppression of cough center in the medulla oblongata)
94
Opioid Induced Side Effects are mostly what?
on-target effects
95
Opioid Induced Side Effects
- respiratory depression in brain stem and pre-botzinger complex in the ventrolateral medulla
- constipation (GI tract)
- pruritus (itch) which is a side effect, not allergic response
- addiction
- urinary retention (opioid-induced ADH release)
- Nausea/Vomiting via chemoreceptor trigger zone in medulla
- miosis in oculomotor nerve (PAG)
96
Kappa opioid receptor endogenous peptide
- dynorphins natural ligand
- preprodynorphin
97
Kappa opioid receptor activation
- dysphoric
- aversive
- potential use for treatment of addiction by reducing dopamine release
- counterbalance mu opioid receptor effects
98
Delta opioid receptor endogenous ligand
- enkephalins
- proproenkephalin
99
Delta opioid receptor expression
- more dynamic expression
- intracellular
- externalized upon chronic stimuli
100
Role of Delta Opioid Receptor
- hypoxia/ischemia/stroke
- hibernation release of enkephalin like opioid
- reduce anxiety
- reduce depression
- treat alcoholism
- relief hyperalgesia, chronic pain
101
Side effect of delta opioid receptor
seizures
102
FDA approved delta opioids
None available
103
Opioid Site of Action
Ventral Tegmental Area and Nucleus Accumbens
104
Depressants can cause what neurotransmitter release
- dopamine release
105
Opioid MOA
- binds to mu receptor
- Gi signaling inhibits neurotransmitter release
- less GABA to activate GABAa
- less inhibition of dopamine neuron activity
- increase dopamine release
- increased activation of dopamine receptors in nucelus accubens
106
oral administration of opioids pk
- slow rise, long duration
- does not reach side effect region
107
Where is morphine absorbed?
- readily absorbed in GI
- first pass metabolism
108
Metabolism of Morphine/Phenanthrenes
- CYPD 2D6 and 3A4
- elimination T1/2 increased with liver disease
109
Morphine and Phenanthrenes undergo what type of metabolism?
- glucuronidation at 3' and 6' position
- morphine 6 glucuronide is still potent
110
Excretion of Morphine/PHenanthrenes
- glomerular filtration (renal)
- 90% excreted in 24h
111
Opioids that are prodrugs
- heroin
- codeine
- tramadol
112
CYP3A4 impact on opioid metabolism
- responsible for converting opioids to "nor" metabolites
- makes them less active
113
CYP 2D6 impact on opioid metabolism
- converts prodrug to active metabolite (morphine, hydromorphone, oxymorphone)
114
Which phenotype of 2D6 metabolizers is of high relevance
UM
- up to 50% higher plasma concentrations of morphine than EM when given codeine
- frequency 40% in North Africa
PM
- more common in caucasians
- no therapeutic effect from codeine
- same incidence of adverse effects
115
Use of Fentanyl
- 100x potent over morphine
- 50x potent over heroin
- used for palliative care breakthrough pain
116
Sufentanil, Remifentanil, Alfentainil
- agnoists
- anesthesia/sedation
- breakdown by plasma esterases due to ester linkage
117
Fentanyl Dosage Froms
- iv
- patch
- lollipop
118
Hydromorphone and Oxymorphone active metabolites
- no opioid active metabolites
119
Morphine use
- covered by medicare --> preferred over oxycontin
- extended release (MScontin)
- long acting, lower rush, M6G contribution to pain relief. risk for abuse if IV injected at once
120
Non-phenanthrene opioids
- tramadol
- meperidine
121
Tramadol use
- mild opiate anelgesic
- has SNRI properties (5HT/NE reuptake inhibitor, stimulates 5HT release)
- management of mild neuropathic pain
- painkiller used when you dont want to prescribe a stronger opioid
- schedule IV
122
Meperidine Use
- used to treat rigors (shivering)
- has toxic metabolite normeperidine (3A4)
- metabolite is devoid of analgesic activity
- neurotoxic causing nervousness, tremors, muscle twitches, and seizures
- renally excreted, do not use in patients with decreased renal function
123
Methadone MOA
block NMDA receptors
124
Methadone use
- primarily used for opioid dependence
- prolonged QTc
125
Opioids for Cough
- usually codeine
- DM has limited opioid activity (not scheduled)
126
Opioids for Diarrhea
- dephenoxylate with atropine
- Loperamide is strong pgp substrate (low BBB penetration)
- eluxadoline for IBS with diarrhea, mu/kappa agonist and delta antagonist
127
Pentazocine and Butorphanol
- k agonist
- partial agonist/antagonism at mu
- parenterally administered
- side effects include less dysphoria, hallucinations, increase in BP, HR
128
Nalbuphine
- full agonist at K
- antagonist at mu
- antagonism produces withdrawal
- parenterally administered
129
Buprenorphine
- partial mu agonist
- weak k agonist and gamma antagonist
- primary use in opioid replacement therapy
130
Prevention of constipation due to opioid use
Senna
- irritates colon
- cause fluid secretion/colonic contraction
Miralax
- stool softner via osmotic increase in GI water content
Docusate
- stool softener
131
opioid tolerance
- analgesic effects
- nausea
- urinary retention
- respiratory depression (biggest risk of death in withdrawn patients/users)
- euphoria
132
limited/no tolerance of opioid
- constipation
- itch
- miosis
133
Treatment for Opioid Dependence: Methadone
- full mu opioid receptor agonist (cross tolerance)
- provide relief from withdrawal
- slow acting (2-4 hours)
- accumulates with repeated dose
- + NDMA antagonist racemic mixture
134
Treatment for Opioid Dependance: Buprenorphine
- mu opioid receptor partial agonist
-blocks full agonist effect of heroin, oxycodone (antagonist)
- provides some activation (agonist) with less withdrawal
135
Subutex clinical pearl
abuse potential
136
suboxone clinical pearl
- partial blocks agonist effects when taken i.v.
- 4:1 bup:nx
137
Treatment for Opioid Dependance: Naltrexone
- intramuscular injection
- extended release
- once monthly
- decent oral bioavailability
- medium half life (4 hours)
- will cause withdrawal
- works better if patient has been drug free for 1 month or more
138
Naloxone and Naltrexone
- not interchangable
- naloxone: limited oral bioavailability/short half life
- naltrexone: PO
139
Treatment for Opioid Dependance: Narcan
- limited oral bioavailability
- rapid onset
- short half-life
- repeat every 2-5 minutes if not conscious
- one does is not enough
- presence of fentanyl and other opioids means even more doses
- causes strong withdrawal
140
Neonatal Abstinence Syndrome
- drug dependent
- causes serious withdrawal in the baby
- seizures may occur
- opioids can also be present in breast milk
- symptoms may begin 24-48 hours after birth or as late as 5 to 10 days
141
Nonpharmacological Treatment for Neonatal Abstinence Syndrome
- swaddling
- hypercaloric formula
- frequent feedings
- observations
- rehydration
142
pharmacological treatment of neonatal abstinence syndrome
- morphine diluted to 0.4 mg/mL
- sublingual buprenorphine
- methadone 0.05 to 1 mg/kg/dose every 6 hours
- morphine and buprenorphine linked with shorter hospital stay than methadone
- clonidine could be useful
143
Therapeutic Applications of NSAIDs
Analgesic
- chronic postsurgical pain
- potentailly inhibit bone healing
- myalgias
- inflammatory pain
- dysmenorrhea
Anti-inflammatory
- gout and hyeruricemia
- RA
- OA
- tendonitis and bursitis
Antipyretic
- feber
Prophylactic to reduce risk of MI
- aspirin
144
Three Phases of Inflammation
acute
- vasodilation leads to increased permeability
Subacute
- infiltration
chronic
- proliferation
145
Recruitment of Eicosanoids
- arachiodonic acid metabolites produce prostaglandins
- prostaglandins = heat, pain, reddness
- thromboxanes
- leukotrienes (swellign)
- cytokines (pain)
146
Aspirin
- irreversibly inhibits COX 1/2 by acetylation of COX
- frequently used as prophylactic for anti-coag
- no tolerance development to analgesic efffects
- reyes syndrome
147
Other NSAIDs
- competitive (reversible) inhibitors of COX 1/2
148
PK Properties of Aspirin/Salicylates
- rapidly absorbed
- delayed by presence of food
- distribution throughout most tissues and fluids and competes for protein binding sites
- salicylate half-life is 6-20 hours
- increased excretion with increased urinary pH (iv bicarb; pH trapping of aspirin in the urine)
149
Clinical Features of Salicylism/Aspirin Poisoning
- vertigo, tinnitus
- respiratory alkalosis caused by hyperventilation (moderate, adults)
- metabolic acidosis leading to lowering of blood pH (high dose or kids)
150
Treatment of Salicylism/Aspirin Poisoning
- reduce salicylate load by increasing urinary excretion (dextrose, sodium bicarb)
- trap in urine pKa of salicylate at 3.0
- correct metabolic imbalance
151
Arylpropionic Acids
- ibuprofen, naproxen
- Half life: Ibuprofen = 2 hr, naproxen = 14 hr
- better tolerated than aspirin
152
Diclofenac Therapeutic Use
- available as gel
- excellent alternative to ibuprofen and naproxen
- increased risk of peptic ulcer and renal dysfunction
- combined with misoprostol for chronic use
153
Indomethacin Therapeutic Use
- most potent reversible inhibitors of PG biosynthesis
- high incidence and severity of side effects long term
- acute gouty arthritis
154
Sulindac
- less toxic derivative of indomethacin
- still significant side effects
- RA
155
Enolic Acid NSAIDs
- use to treat arthritis
- great joint penetration
- least GI side effects
- at low doses, meloxicam is cox-2 selective
- long half life (20 hours meloxicam, 57 hours piroxicam)
156
Adverse Effects of NSAIDs
- inhibition of renal PGE2 synthesis can lead to increased sodium reabsorption, causing peripheral edema
- increased risk of bleeding due to transient inhibition of platelet aggregation
- inhibition of uterine motility (delaying preterm labor)
- GI distress/ulceration
157
Therapeutic Use of Acetaminophen
- highly effective as analgesic and antipyretic
- limited anti-inflammatory activity
- no GI toxicity
- acute overdose may lead to fatal hepatic necrosis
158
Adverse Effects of Acetaminophen
- more renal toxicity than aspirin and NSAIDS due to vasoconstriction by inhibition of PGE2
- dose dependent hepatic necrosis (limit 4 g/day)
- increase in toxic acetaminophen metabolites (NAPQI)
- treat with n-acetylcystemine to detoxify NAPQI
159
MOA of acetaminophen overdose
- APAP metabolized via glucuronidation and sulfation
- if those two pathways are overwhelmed, apap will. be metabolized by a third pathway via n-hydroxylation and rearrangement (cyp mediated)
- this creates NAPQI which has toxic reactions with proteins and nucleic acids
160
Side Effect Profile of Nonselective COX inhibitors
- reduce ulcers and GI bleeds
- withdrawn due to high chance of blood clots, stroke, and heart-attacks
- inhibition of cox-2 decreases PGI2, which increases platelet aggregation
161
NSAID contraindications
- chronic kidney disease
- peptic ulcer disease
- history of GI bleed
- CV risk (lowest risk is naproxen, highest is diclofenac)
- interfere with bone healing
- asthma exacerbations (cox 2 specific less likely)
162
Sodium Channel Blockers for local Pain
- lidocaine
- bupivacaine
- benzocaine
163
Lidocaine pearls
- local analgesia (dentistry)
- itch, burn
- 15 min onset, lasts 30-120 minutes
164
Bupivocaine pearls
- longer lasting (3.5 hour)
- epidural
165
Benzocaine pearls
- otc use
- oral ulcers
- ear pain
- esters have higher allergy risk
166
NaV1.7 Target
- severe neuropathic pain (GOF mutation)
- congenital insensitive to pain (LOF mutation)
- expressed in peripheral neurons (high in nociceptive neurons, low in cardiac muscles or CNS)
167
Psychiatric Drugs as Sodium Channel Blockers for Pain
- lamotrigine off label for peripheral neuropathy, migraine
- carbamazepine for tregminal neuralgia
- tricyclic antidepressants like amitriptyline
168
SNRI impact on pain
- increase NE levels
- can act on alpha 2 adrenergic receptors in the spinal cord (reflex arc)
- provide analgesia
169
Duloxetine use in pain
- diabetic pain
- fibromyalgia
- peripheral neuropathy
170
Venlafaxine use in pain
- off label diabetic neuropathic pain
- non-selective opioid effects
- naloxone reversible analgesia
- cardiac toxicity (NaV channels)
171
SNRIs lacking Sodium Channel Functionality
milancipran, tapentadol
172
CCBs as possible analgesics
- heart rate, blood pressure decrease
- diabetic neuralgia
- fibromyalgia, neuropathic pain
173
Gabapentin and Pregabalin use as CCBs
- alpha 2 gamma - CaV1, 2 selective blocking
- not metabolized
- no drug-drug interactions
- affect the Agamma/C fiber afferent neuron
- decrease glutamate, decreasing pain firing
174
Schedule 1
- no medical use
- high abuse potential
- safety not guaranteed
175
Schedule 1 drugs
- heroin
- marijuana
- THC
- LSD
- GHB
- psilocybin
- MDMA
176
Schedule II
- medical use
- high abuse potential
- large risk of dependence
177
Schedule II drugs
- cocaine
- Ritalin
- PCP
- morphine
- fentanyl
- oxycodone
- hydromorphone
178
Schedule III
- medical use
- moderate abuse and dependence
179
Schedule III drugs
- ketamine
- buprenorphine
- marinol
180
Schedule IV
- medical use,
- low abuse and dependence
181
Schedule IV drugs
- benzos
182
Opioids receptor target
mu
183
LSD, mushrooms receptor target
serotonin receptor (2A, 2C)
184
marijuana, K2, spice receptor target
cannabinoid receptors (CB1)
185
GHB receptor target
GABAb
186
Caffeine receptor target
adenosine receptors
187
Substances that act indirectly on G protein coupled receptors
- cocaine
- amphetamine
- mdma/ecstasy
- alcohol
188
Cocaine/Amphetamine MOA
- dopamine transporter
- noradrenaline, serotonin transporters
- release dopamine, serotonin, noradrenaline --> GPCRs
189
MDMA/Ecstasy MOA
monoamine transporters (dopamine, serotonin)
190
Alcohol MOA
- GABA channels
- 5HT3 channels
- NMDAR, nAchR, Kir3
- causes releaase of endogenous opioids
191
Substances of abuse that act on ion channels
- nicotine
- PCP, ketamine
- benzos, barbiturates
192
Nicotine MOA
- ionotropic acetylcholine receptors (Na)
- agonist
193
PCP/Ketamine MOA
- ionotropic NMDA receptor (Ca, Na - K)
- antagonist
194
Benzos/BBTs MOA
- ionotropic GABAa recpetors (Cl-)
- positive allosteric modulators
195
Frontal Cortex
decision making impulsivity
196
Striatum/SA
reward/value
197
Nucleus Accumbens
pleasure valuation
198
VTA
source of dopamine
199
Hippocampus
Memory/Learning
200
Dopamine hypothesis of addiction
- pleasurable events release dopamine
- PD only develop addiction during treatment
- DA important for assigning value to reward prediction error
- value provides the drug with an incentive salience
201
Limits of Dopamine Hypothesis
- dopamine not required for reward learning
- dissociation between liking and wanting
- tolerance to pleasurable effect, enhanced effect
- dopamine does not encode liking, but involved in making reward predictions and learning from the outcome/error
202
Glutamate Hypothesis of Addiction
- glutamate can increase dopamine activity in NAcc
- glutamate projects to the VTA
- destruction of this pathway reduces cocaine/morphine reward
- mGluR5 KO mice show reduced cocaine reward
- NMDA antagonist blocks acquisition of reinforcement learning
- intraNAcc AMPA injection causes relapse
- dopamine controls glutamate activity in amygdala
203
How does drug use impact neuronal plasticity
- long term potentiation
- persistent increase in synaptic strength following intense stimulation
- rewarding substances cause relative increase in glutamatergic AMPA receptors
204
Drug abuse defination
the use of a drug for a nontherapeutic effect
205
drug misuse defination
inappropriate, illegal, or excessive use of prescription or nonprescription drug
206
Substance use disorder criteria
- mild (2-3), moderate (4-5), severe (>6)
- cravings
- distracted
- causing problems in relationships
- giving up on activities
- tolerance
- withdrawal
207
physical dependence
- body needs more drug (tolerance)
- cellular adaptations upon repeated activation of receptors
- body withdraws without the drug
208
Dangerous Withdrawal Symptoms
- alcohol and tranquilizers
- grand mal seizures (also tramadol)
- hallucinations
- delirium tremens
209
psychological dependence
- addiction
- mental urge to take drug to function
- compulsive need/craving
- even in absence of withdrawal
210
drug is rewarding or produces positive reinforcement when:
the user feels pleasure/satisfaction
211
negative reinforcement
- reward by escaping negative/painful stimulus or event
- not same as punishment
212
respiratory depression
opioids, alcohol
213
cardiac arrhythmias, brain hemorage, stroke
stimulants
214
fatal seizures
withdrawal, choke on own vomit
215
PQRSTU
- palliative or precipitating factors
- quality of pain
- region of pain
- severity
- time related nature of pain
- impact of pain on you
216
objective assessment of pain
- dilated pupils
- paleness
- sweating
- tachycardia
- tachypnea
217
Acute pain
- < 3 months
- nociceptive (tissue)
218
chronic pain
- > 3 months
- neuropathic (nerve)
219
goals of therapy for non-malignant pain
- correct underlying cause of pain if possible
- minimize pain and symptoms for pain/injury
- improve QOL and activities of daily living
- limit pharmacotherapy side effects
220
non-pharm therapy for pain
- can be used in combination with analgesics
- correct the underlying cause
- exercise
- acupuncture
- massage
- heat or ice
- physical manipulation
221
WHO analgesic ladder: step 1
- non-opioid +/- adjuvant analgesic
222
WHO analgesic ladder: step 2
- opioid for mild-moderate pain
- + non-opioid
- +/- adjuvant analgesic
223
WHO analgesic ladder: step 3
- opioid for mod-severe pain
- + non-opioid
- +/- adjuvant analgesic
224
Non-opioid analgesics
- acetaminophen
- NSAIDS
225
adjuvant therapies
- gabapentinoids
- SNRIs
- TCAs
- muscle relaxants
- antiepileptics
- topical agents
226
Acetaminophen Uses
analgesics and antipyretic
227
Acetaminophen formulations
- tablet
- capsule
- chewable tablet
- liquid/gel
- IV solution
- suppository
228
Acetaminophen: Non-PO options?
YES
- suppository
- IV
229
Acetaminophen Dosing Adult
- 325 - 1000 mg PO Q4-6H PRN
- in liver disease, decrease max ≤ 2 g/day
230
Acetaminophen Dosing Children
- 10-15 mg/kg PO Q4H PRN
- max dose: 75 mg/kg/day or ≤ 3-4 g/day
231
Side Effects: APAP
- hepatotoxicity (acute liver liver failure most likely with ≥ 10 g dose)
232
APAP clinical pearls
- gold standard for OA due to fewer side effects in geriatric patients than NSAIDs
- education patients about max daily doses, including combo products
- injection is expensive
233
NSAIDs uses
analgesic, antipyretic, anti-inflammatory
234
NSAIDs side effects
- GI bleeding
- nephrotoxicity
- fluid retention
- increase CV events
235
NSAIDs clinical pearls
- take with food
- caution use in geriatric patients due to increased side effects (beers list)
- avoid systemic NSAIDs in patients with cardiac history (can use topical NSAIDs)
- avoid in severe liver disease or CKD
236
Aspirin Formulations
- chewable tablet
- tablet
- EC tablet
- capsule
- ER capsule
- suppository
237
Aspirin: Non-PO options
YES
- suppository
238
aspirin recommended dosing
- 325-1000 mg PO q4-6h prn (max 4 g/day)
239
aspirin clinical pearls
- avoid use for pain in patients taking blood thinners or anti-platelets
- some formulations available OTC
240
Reye's Syndrome association
associated with teens/children using aspirin when they have viral infections such as flu or chickenpox (with or without fever)
241
Ibuprofen available formulations
- capsule
- tablet
- chewable tablet
- suspension
- IV solution
242
Ibuprofen: Non-PO options?
YES
- IV solution
243
ibuprofen recommended dosing adult
200-800 mg PO q6-8h PRN (max 3200 mg/day)
244
ibuprofen recommended dosing pediatrics
- > 6months
- 5-10 mg/kg PO q4-6h prn
- max 40 mg/kg/day or 2400 mg, whichever is less
245
Diclofenac available formulations
- capsules
- tablet
- IV solution
- suppository
246
Diclofenac: Non-PO options?
YES
- topical gel
- suppository
- topical solution
- ophthalmic solution
- patch
247
Diclofenac recommended dosing
- 50 mg PO q8h or 2-4 g applied topically 4 times/day
248
diclofenac clinical pearls
- minimal systemic side effects with topical gel
249
Naproxen available formulations
- capsule
- tablet
- DR/ER tablet
- suspension
250
naproxen: Non-PO options?
NO
251
naproxen recommended dosing adults
220 mg - 500 mg po q6-12h (max 1000 mg/day)
252
Ketorolac available formulations
- tablet
- IV/IM solution
- nasal spray
- ophthalmic solution
253
ketorolac: Non-PO options?
YES
- IV/IM solution
- nasal spray
- ophthalmic solution
254
Ketorolac recommended dosing adult
15-30 mg IV q6h prn or 10 mg po q6h prn
255
ketorolac recommended dosing pediatric
0.5 mg/kg/dose IM/IV q6h prn
256
ketorolac clinical pearls
- max duration is 5 days
- increased risk of gi bleed when used longer
oral dosing is inteded as a continuation of IM or IV therapy
257
celebrex available formulation
- capsule
- oral solution
258
celebrex: Non-PO options?
no
259
celebrex recommended dosing
- 200 mg po bid
260
gabapentinoids uses
- fibromyalgia
- neuropathies
- post op pain
261
gabapentinoids available formulations
- tablets/capsule
- ER tablet
- liquid solution
262
gabapentinoids: Non-PO options?
- NO
263
recommended dosing: gabapentin
100-300 mg po TID (max 3600 mg/day)
264
recommended dosing: pregabalin
75 mg po bid (max 600 mg/day)
265
side effects of gabapentinoids
- sedation
- dizziness
- peripheral edema
266
gabapentinoids clinical pearls
- really dose adjusted
- titrate up dose to limit sedation
- use in combo to decrease requirements of other analgesics
- pregabalin is schedule V
267
SNRI uses
- fibromyalgia
- neuropathy
268
SNRI available formulatiosn
- capsule/tablet and in ER formulation
269
SNRI: Non-PO options?
NO
270
recommended dosing venlafaxine
- 37.5-75 mg po daily (max 225 mg/day)
271
recommended dosing duloxetine
30 mg po daily x 1 week, then increase to 60 mg po daily (max 60 mg/day)
272
Side Effects of SNRIs
- nausea
- headache
- hypertension
- sedation
- weakness
273
SNRI clinical pearls
- start low dose and titrate up to minimize side effects
- renally dose adjust venlafaxine
- avoid duloxetine for CrCl < 30 mL/min
274
TCA uses
- all off label
- fibromyalgia
- neuropathy
- migraine prophylaxis
275
TCA available formulations
- tablet (amitriptyline)
- capsule (nortriptyline)
- oral solution (nortriptyline)
276
TCA: Non-PO options?
NO
277
recommended dosing: TCA
- 10 mg po qhs (max 150 mg/day)
278
Side Effects: TCA
- anticholinergic side effects
- sedation
279
Clinical Pearls: TCA
- last line option for neuropathy and fibromyalgia due to side effects
280
Muscle Relaxants available formulations
- tablet/capsule (IR/XR)
- oral suspension (baclofen)
- parenteral solution (methocarbamol, baclofen)
281
muscle relaxants: Non-PO options?
YES
- parenteral solution for methocarbamol and baclofen
282
Side Effects: muscle relaxants
- sedation/drowsiness
- dizziness
- dry mouth
- vision changes
283
Muscle relaxants clinical pearls
- short term use (< 3 weeks)
- carisoprodol is schedule IV due to abuse potential
284
carbamazepine available formulations
- tablet
- ER capsule/tablet
- chewable tablet
- suspension
285
carbamazepine: Non-PO options?
no
286
recommended dosing of carbamazepine
- 200-400 mg PO daily in 2-4 divided doses (max 1200 mg/day)
287
Carbamazepine clinical pearls
- increased risk of hypersensitivity reaction in patient with HLA-B*1502
- auto induction of hepatic enzymes (levels will fall over first few weeks of use)
288
Lidocaine available formulations
- patch
- injection
- topical
289
recommended dosing: lidocaine
- apply 1 patch to affected area daily and remove 12 hours later (can vary by manufacturer)
290
side effects: lidocaine
- hypotension
- arrhythmia (minimal risk with patch)
291
lidocaine clinical pearls
- tachyphylaxis with continuous use
- 12 hour break between patches
- local effect, apply to site of pain
292
Capsacian available formulations
- cream, gel, lotion: apply 3-4 times per day
- patch: apply 1 patch to affected area daily and remove 8 hours later
293
capsacian side effects
- skin irritation and pain
294
capsacian clinical pearls
- do not get medicine into eyes (burning)
- wash hands after applying
- some formulations available OTC
295
Recommendations for Older Adults: Nonselective COX-2 NSAIDs, aspirin > 325 mg/day
- increased risk of GI bleeding or PUD
- can increase blood pressure and induce kidney injury
- use of ppi or misoprostol reduces but does not eliminate risk
- avoid short term scheduled use in combo with oral or parenteral steroids, anticoagulants, or antiplatelet agents unless other alternatives are not effective and patient can take a gi protective agent
296
Recommendations for Older Adults: Indomethacin and ketorolac
- increased risk of GI bleeding/PUD/AKI in older adults
- indomethacin has the most adverse effects, higher CNS effects
- avoid
297
Recommendations for Older Adults: Skeletal muscle relaxants
- poorly tolerated by older adults because some have anticholinergic adverse effects, sedation, and increased risk of fractures
- effectiveness at dosages toleraged by older adults is questionable
- this does not include baclofen or tizanidine
- avoid
298
Recommendations for Older Adults: SNRIs/TCAs/Carbamezpine
- may exacerbate or cause SIADH or hyponatremia
- monitor sodium levels closely when starting or changing dosages in older adults
- use with caution
299
Recommendations for Older Adults: opioids + benzo combo
- increased risk of overdose and adverse effect
- avoid
300
Recommendations for Older Adults: opioids + gabapentinoids combo
- increased risk of severe sedation related adverse events older adults including respiratory depression and death
- avoid
- except transitioning from opioid to gabapentinoid or using gabapentinoid to reduce opioid dose
301
Recommendations for Older Adults: anticholinergic and anticholinergic
- increased risk of cognitive decline, delirium, and falls or fractures
- TCA or muscle relaxant and other anticholinergic medication)
- avoid, minimize the number of anticholinergic drugs
302
Recommendations for Older Adults: antiepileptics, antidepressants, antipsychotics, benzos, z drugs, opioids, skeletal muscle relaxant combos
- increased risk of falls and fracture with concurrant use of three or more CNS active agents
- avoid concurrent use of three or more CNS active drugs
303
Naloxone (narcan) treatment of overdose
- opioid antagonist
- IV: 0.4-2 mg q2-3 min
- Nasal spray: 4 mg q2-3 minute alternate nostrils
- can precipitate withdrawal
304
Opioid Withdrawal onset
- Short acting (heroin): 8-24 hours after last use; duration 4-10 days
- long acting (methadone): 12-48 hours after last use; duration 10-20 days
305
opioid withdrawal treatment
- clonidine
- buprenorphine
- methadone
306
Side effects of opioids
- antitusive
- constipation
- n/v
- itching
- orthostatic hypotension
- urinary retention
- sedation
- respiratory depression
307
Codeine available formulations
- tablet
- cough syrup
308
Codeine metabolism
- CYP 2D6
- poor metabolizers will get no effect from codeine
- ultra rapid metabolizers can experience overdose, resulting in respiratory depression and death in children
- not recommended in breastfeeding mothers or children<12
309
Tramadol available formulations
- capsule ER 24 hr
- tablet IR and ER 24 hr
- oral solution
- combo products
310
tramadol clinical pearls
- risk of serotonin syndrome
- renally dose adjusted
- Use of CYP 3A4 inducers/inhibitors and 2D6 inhibitors with tramadol requires careful consideration of the effects on parent drug and metabolite
311
Morphine Available Formulations
- capsule ER 24 hr
- tablet IR and 12 ER
- oral solution
- solution for injection
- suppository
312
Morphine: non-PO option?
YES
313
Morphine clinical pearls
- itching more prominent compared to other opioids
- morphine and its metabolites are renally excreted and accumulate in renal dysfunction
- avoid in patients with ESRD or AKI
- boxed warning: avoid alcohol while taking ER capsules
- leads to increased morphine plasma levels and potentially fatal overdose
314
Hydromorphone available formulations
- IR and ER tablets
- oral solutions
- solutions for injection
- suppository
315
hydromorphone: non-PO available?
YES
- solution for injection
- suppositiory
316
hydromorphone clinical pearls
- US boxed warning about dosing errors when prescribing, dispensing
- oral solution: do not confuse mg and mL
- IV: do not confuse high potency (10 mg/mL) with other solutions
317
hydrocodone+apap available formulations
- oral solution
- ER tablet
- tablet
318
hydrocodone+apap clinical pearls
- counsel patients
- use with cyp 3A4 inhibitors may increase hydrocodone plasma concentrations
319
oxycodone available formulations
- tablet
- capsule
- oral solution
320
oxycodone clinical pearls
- counsel patients on apap use with combination
- ER capsule/tablets are abuse deterrent
- CYP 3A4 inhibitors may increase plasma concentrations
321
fentanyl available formulations
- buccal tablet
- sublingual liquid
- lozenge
- injectable solution
- patch
322
fentanyl: non-PO formulations?
YES
- IV
- Patch
323
fentanyl: clinical pearls
- Monitor patients receiving CYP 3A3 inhibitors or inducers
- can use in renal impairment
- less hypotension than morphine or hydromorphone at similar doses
- non-injectable forms are only indicated for patients who are opioid tolerant
- opioid tolerant is defined as taking morphine 60 mg per day (or equivalent) for at least 1 week
- doses are not converted from one fentanyl product to another on a mcg-per-mcg basis
324
fentanyl patch counseling
- apply one patch every 72 hours
- apply the patch tot he chest, back, flank, or upper arm
- do not cut the patches or use a patch that is torn or damage
- do not use the patch over broken skin
- do not let the patch get too warm while wearing
- your body will absorb too much medicine
325
methadone use
- last line treatment of chronic pain
- opioid detoxification
326
methadone available formulations
- oral solution
- injectable solution
- tablet
327
methadone clinical pearls
- US boxed warning: QTc prolongation
- US boxed warning: monitor patients receiving CYP 3A4 inhibitors or inducers
- long half life (8-59 hours)
328
meperidine available formulations
- injectable solution
- oral solution
- tablet
329
meperidine clinical pearls
- avoid in elderly, avoid in renal impairment, caution use in hepatic impairment
- monitor patients receiving cyp 3a4 inhibitors or inducers
- do not use within 14 days of MAOi
- metabolized by the liver into an active metabolite (accumulation of active metabolite can cause delirium and seizures)
- not commonly used due to adverse effects
330
potential side effects of opioid
- lower seizure threshold
- cause serotonon syndrome when used with other agents with serotonergic activity
- tramadol
331
Allergic Cross Reaction: Natural Opiates
- morphine and codeine
- YES, avoid in patients with allergy to other natural opiates and semi synthetic opioids
332
Allergic Cross Reaction: Semi Synthetic Opiates
- hydromorphone, oxycodone, oxymorphone, hydrocodone, buprenorphine
- YES, avoid in patients with allergy to other semi synthetic opioids and natural opiates
333
Allergic Cross Reaction: Synthetic Opioids
- fentanyl, methadone, meperidine, tramadol
- NO, can be used if patient has an allergy to another synthetic opioid, semi synthetic opioid, or natural opiate
334
Switching between opioids
- calculate daily consumption for each opioid
- convert each opioid to oral morphine
- add morphine doses together to get total daily oral morphine dose
- reduce the equal analgesic by 25-50%
- split total daily dose into appropriate dosing interval based on opioid selected (duration of action)
335
