The more prevalent opioid use has created many opioid use disorders, characterized by large doses, craving for opioids, and anxiety if no opioid.
Acetaminophen APAP (Tylenol PO, Ofirmev IV)
MOA: inhibits synthesis of prostaglandin (PG) in CNS and peripherally block pain impulse generation. No anti-inflammation effects like NSAIDs.
SE: liver damage. Max: 3-4g/day, accumulation of a metabolite damages liver.
Antidote: N-acetylcysteine (NAC, IV form Acetadote), restore intracellular glutathione (a powerful reducing agent for oxidative stress in the body); NAC smells like rotten egg and causes nausea.
Pediatric dose: 10-15 mg/kg; Infant drop 80mg/0.8ml (more concentrated than children's 160mg/5ml!) This is against our logic, why is that? Fever in infants is more severe than in children, therefore, needs more attention and a stronger dose to reduce the fever and prevent deterioration.
Well tolerated in the elderly, first line in osteoarthritis (largely a non-inflammatory condition).
Phenacetin (acetophenetidin) is metabolized to APAP; it is a pain and fever-reducing drug, ban is imposed by FDA due to kidney damage in chronic use.
MOA: binds reversibly to COX-1 and 2, inhibits prostaglandin synthesis; Has anti-inflammatory property.
SE: GI risk (bleeding and ulceration), water retention and ↑ BP (vasoconstriction of efferent nephrons ↓renal clearance by reducing the flow to glomerulus from, which lead to edema in extremities), ↑CV risk (MI and stroke, except aspirin, use is contraindicated after CABG surgery (use an antiplatelet such as ASA).
Take with food to reduce GI risk (risk is higher in non-selective NSAIDs especially ketorolac and piroxicam, and lower in COX2-selective). 1st line in treating NSAID-induced ulcer: proton pump inhibitors (PPIs) such as omeprazole.
Do not use NSAID in the 3rdtrimester of pregnancy (premature closure of ductus arteriosus), however, IV NSAID (indomethacin) is useful in newborn to close a patent ductus arteriosus (PDA: a shunt that allows blood from the right ventricle to bypass the fetus’s non-functioning lungs, connects the main pulmonary artery to the proximal descending aorta), if PDA does not close on its own after birth.
Diclofenac: greater risk of hepatotoxicity compared to other NSAIDs; + misoprostol = Arthrotec.
Indomethacin: commonly used in gout flare; High risk of CNS side effects, avoid in psychotic disease and GI toxicity (these side effects suggest lipophilic propensity of this drug).
Ketorolac: Always start IV/IM and continue orally, max 5 days (Due to its serious adverse effect); Cannot be given intrathecal or epidural due to its alcohol content (solution contains 10% alcohol); May inhibit aggregation of platelet, thus increase risk of bleeding.
DI: decrease renal clearance of many drugs by reducing blood flow to glomerulus (e.g: ↑ the level of Li and methotrexate leads to toxicity); additive bleeding risk; avoid using with other nephrotoxic drugs (vasoconstriction of nephrons lower their clearance and can lead to more toxicity).
↓GI risk compared to traditional NSAIDs, but ↑CV risk.
Aspirin (ASA)
MOA: ASA binds irreversibly to COX 1 and 2.
SE: Risk of GI bleeding (stop before surgery), dyspepsia, avoid ASA in less than 16 years old (Reye’s syndrome: edema in brain); Overdose can be present as tinnitus, caution use with other ototoxic agents (vancomycin); Photosensitivity.
Commonly used as anti-platelet. 81mg. Occasionally 325mg.
Misoprostol
MOA: Prostaglandin analog, replaces gut-protective prostaglandin, reduce the risk of GI damage (ulcer) from NSAID.
SE: May cause diarrhea, cramping.
It is also one of the drugs used in gynecological abortive treatment.
+ diclofenac = Arthrotec to treat arthritis.
Opioids
Drugs: Oxymorphone (Opana), Hydromorphone (Dilaudid, Exalgo), Morphine (MS Contin, Roxanol), Oxycodone (Oxycontin CR). All are schedule II.
Signs of overdose: Respiratory depression, pale & clammy face, limp body, blue or purple fingernails or lips, pinpoint pupils, vomiting or gurgling noises, cannot be awakened from sleep, unable to speak, very little or no breathing, slow or no heartbeat, "Death rattle": exhaled breath with a labored sound coming from the throat. This is a sign that the patient needs emergency resuscitation.
No ceiling effect, high dose opioids should be rotated with other opioids to reduce tolerance.
If allergy (symptoms: difficulty breathing, severe drop in BP, rash, swelling of face lips), chose fentanyl, meperidine, methadone, tramadol.
Commonly cause histamine-induced skin rash (is not an allergy, pre-treat with antihistamine).
Constipation: can be treated with methylnaltrexone (Relistor, an opioid antagonist), an opioid laxative (“-sto-“).
Common opioids
Morphine: Metabolized in liver and excreted with active metabolite via kidney. morphine +naltrexone (Embeda ER).
Fentanyl: Chronic pain management, not for opioid naïve patients nor acute PRN use (80-100 times more potent than morphine, wow!) only for those maintained with 60mg MME for at least a week.
Apply 1 patch every 3 days, no PRN dosing. Slow onset, patch effect can be seen 24 hrs, do not stop other analgesic at first. Dispose patch in toilet.
Contact prescriber if you see fentanyl patches for acute pain (acute back pain, post-op pain, broken bone, etc.) Be vigilant and always confirm opioid tolerance. Patients on fentanyl patch are at higher risk of overdosing.
Dispose patch in toilet (avoid risk of exposure to children and pets).
Oxycodone
Avoid used with 3A4 inhibitors. "OP" formulation contains polyethylene oxide to deter abuse, substance form a gel when mixing with water.
+ ASA = Percodan; + APAP = Endocet or Percocet.
Methadone
Methadone can't be dispensed by a pharmacy for the treatment of opioid dependence (only through addiction clinic). However, it can be dispensed for management of pain as long as the prescription says "for pain".
Variable half-life, hard to dose safely.
Carries a risk of QT prolongation, ↓ testosterone and lead to sexual dysfunction.
Codeine
CYP2D6 is involved in the conversion of opioids (codeine, hydrocodone, oxycodone and tramadol) to active metabolites.
Codeine is largely a prodrug, metabolized by CYP2D6 to morphine.
Patients who are CYP2D6 deficient are less likely to respond to codeine, the addition of a CYP2D6 inhibitor will not result in any change in the concentrations of the substrate.
For ultra-rapid metabolizers, caution with medications inhibit CYP 2D6 (fluoxetine, paroxetine, quinidine), which can lead to increased conversion of codeine to morphine, and can be dangerous.
Other C-II opioids
Meperidine: the metabolite normeperidine is renally cleared, if accumulate can cause CNS toxicity including seizure. No longer recommended due to CNS toxicity; Serotonergic (wash-out period with MOAI).
Nalbuphine (Nubain): Treat severe pain, given before or during surgery.
Propoxyphene (Darvon, +APAP=Darvocet): Less potent compare to other opioids, BBW: accidental death, withdrew from market.
Opioid conversion
Calculate daily dose of the new drug and reduce dose at least 25% (safer to go lower starting a new drug, you can always titrate up doses), and always have a BTP (breakthrough pain med, IR).
Calculating the Morphine Milligram Equivalent (MME), avoid >/= 90 MME per day. Overdose cases are more likely in patients dosed above this threshold. Some patients in real life take way over the recommended MME for years, their body has developed adaptation to larger doses. The practitioner may initiate conversation and suggest tapering down doses gradually.
Step 1: Calculate the total daily milligram of the opioid, E.g., Oxycodone 10mg Take 1 tablet every six hours as needed. Total daily dose = 40mg.
Step 2: Multiply the total daily mg by the estimated conversion factor. E.g., The conversion factor for oxycodone is estimated at 1.5; 40mg x 1.5 = 60 mg MME.
Step 3: Round down the dose to avoid the risk of overdose.
The above conversion factors seem a lot since we already need to memorize massive materials, fortunately, it does not make sense for them to hard test you on these specific multipliers. Most institutions already have a conversion chart handy, so it is helpful to just have a general idea of relative strength and save your precious memory somewhere else, e.g.: morphine (1) is stronger than codeine (0.15), and equally potent to hydrocodone.
MOA: block the analgesic action of opioids and the pleasure response of endorphins.
Naloxone: acts within minutes and lasts for about an hour because of rapid metabolism. This makes it ideal for opioid overdose rescues (antidote).
Who needs naloxone? Recommend for patients on > 50 mg/day MME (fentanyl 25 mcg/hr), opioid patients who also take benzos, have COPD or asthma, history of overdose or substance abuse. Emphasize calling 911 and follow-up care. Repeat naloxone 2 to 3 min if needed (opioids last longer than blocking agent, may need repeating dose).
Naltrexone acts slowly and lasts longer, and cannot treat overdoses. It is used to block cravings for both opioids and alcohol (naloxone cannot), it only helps people who are addicted to opioids to have less craving.
Vivitrol: used for alcohol and opioid dependence, once a month IM; naltrexone + morphine = Embeda.
In treating alcoholism, avoid alcohol: very serious reaction can happen.
Buprenorphine (Subutex, C-III)
Long-acting opioid agonist, reduce withdraw symptoms and opioid craving, may discourage opioid use by binding to mu receptor.
BBW: QT prolongation.
Suboxone (buprenorphine/naloxone) is used as an alternative to methadone.
Butran patch: apply once a week.
Require special DEA license starting "X" (APRN and NP can be licensed too).
SE: Anticholinergic effect, sedation/CNS depression (they are CNS depressants).
IV succinylcholine (Anectine): ultra-short acting used during surgery.
Tizanidine: short acting, interact with Cipro, level increase 1000%.
Benzos such as diazepam can also be used as muscle relaxant, e.g: Diastat rectal in seizure treatment.
DI: avoid use with other CNS depressants (alcohol, BZDs, hypnotics, opioids), and CNS stimulants such as ADHD drugs amphetamine (cancelling each other, the combo should alert you red flag for drug abuse).
Lidocaine patch (Lidoderm): 12-hrs on, 12-hrs off, can be cut into smaller pieces; pro-arrhythmic (Class I-b), caution in patients receiving antiarrhythmic drugs.
Which of the following is a caution with the use of tramadol?
Bradycardia
GI bleeding
HTN
Hyperglycemia
Seizures
Which of the following is a common effect of narcotic or opioid analgesics?
Constipation
Diarrhea
Hypertension
Tachycardia
which of the following should be avoided in PUD? (Select ALL that apply.)
Diflunisal
Indomethacin
Ketorolac
Ibuprofen
Cyclobenzaprine
Which of the following medications is contraindicated in a patient with sulfa allergy?
Elavil
Celecoxib
Meperidine
Hydromorphone
Which of the following medications may be used to treat neuropathic pain? (Select ALL that apply.)
Acetaminophen
duloxetine
Gabapentin
Ibuprofen
Ketorolac
Which of the following formulations are available for oxycodone? (Select ALL that apply.)
CR tablet
IR tablet
IV injection
Oral solution
Which of the following is FDA approved for the treatment of fibromyalgia?
A.Gabapentin
B.Ketorolac
C.Morphine
D.Pregabalin
Which of the following NSAIDs is available as an IM injection formulation?
A.Celecoxib
B.Ibuprofen
C.Ketorolac
D.Naproxen
Which of the following is associated with methadone use?
A.Diarrhea
B.GI bleeding
C.Hyperkalemia
D.Hypertension
E.QTc prolongation
Targiniq ER is indicated to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Which of the following component provides abuse-deterrent property to Targiniq ER?
Buprenorphine
Oxycodone
Naltrexone
Naloxone
Methadone
Which of the following statements regarding CYP2D6 poor metabolizers (PM) is/are TRUE? (Select ALL that apply.)
CYP2D6 poor metabolizers are usually carriers of at least one *1 allele.
CYP2D6 poor metabolizers demonstrate unusually high morphine concentrations following codeine administration.
CYP2D6 poor metabolizers have polymorphisms that result in an allele with supra-enzymatic activity.
CYP2D6 poor metabolizers will form fewer metabolites through the CYP2D6 pathway than extensive metabolizers.
A CYP2D6 poor metabolizer is a phenotype that can be predicted by a patient’ s genotype.
Which of the following is the most likely clinical outcome in a CYP2D6 poor metabolizer being treated for pain?
Hallucinations associated with hydrocodone
Failed pain management with codeine
Respiratory depression with oxycodone
Failed pain management with hydromorphone
None of the above
A 72-year-old woman with osteoporosis and a history of multiple vertebral fractures presents with intolerance to both alendronate and risedronate due to dyspepsia and esophageal irritation. She has followed administration instructions closely but continues to complain of bothersome side effects and indicates that she will no longer consider taking the medications. Her medical history is significant for chronic heart failure and history of venous thromboembolism (× 2). Current medications include calcium, vitamin D, lisinopril, digoxin, furosemide, and rivaroxaban. Which of the following is the most appropriate therapy for her osteoporosis?
Ibandronate
Teriparitide
Denosumab
Raloxifene
An 80-year-old woman is diagnosed with osteoarthritis of the right hand. Her medical history is significant for of peptic ulcer disease (PUD), hypertension, and hyperlipidemia. Which is the most appropriate therapy recommendation?
A.Glucosamine sulfate 500 mg by mouth three times daily
B.Naproxen 500 mg by mouth twice daily
C.Diclofenac 1% gel topically four times daily
D.Duloxetine 60 mg by mouth once daily
A 62-year-old man with hyperlipidemia, allergic rhinitis, and a history of PUD with an upper gastrointestinal bleed 2 years ago is diagnosed with osteoarthritis of the knee. He has tried maximum-dose, scheduled acetaminophen with insufficient pain relief. Current medications include atorvastatin and loratadine. Which is the best recommendation for the management of this patient’ s osteoarthritis of the knee?
Naproxen
Naproxen plus esomeprazole
Intraarticular corticosteroid
Diclofenac topical gel
Tramadol is associated with increased risk of seizures and should be used with caution in patients with a history of seizure.
Constipation is common side effects associated with opioid analgesics, which are often treated with stimulant laxatives to provide relief to the patient. Opioid analgesics may also be associated with hypotension and bradypnea.
A B C D are NSAIDs and should not be used if a patient has PUD or a history of GI bleeding. If an NSAID must be used, a COX-2 selective inhibitors would be preferred.
Use of celecoxib is contraindicated in a patient with a sulfa allergy.
Duloxetine, gabapentin may be used to treat neuropathic pain. Neuropathic pain does not respond well to acetaminophen or NSAIDs.
Oxycodone is available in IR, CR tablet, and oral concentrate. It is not available for IV, IM, or subcutaneous injection.
Pregabalin (Lyrica) is FDA approved for the treatment of fibromyalgia. Other treatment of fibromyalgia includes duloxetine (Cymbalta) and milnacipran (Savella).
Ketorolac is available as an IV/ IM formulation.
Methadone is known to prolong QT interval and should not be used together with other agents that prolong the QTc interval. Methadone is associated with constipation (not diarrhea), hypokalemia (not hyperkalemia), and hypotension (not hypertension). Traditional NSAIDs (such as ibuprofen) are known to cause GI bleeding.
Naloxone. Targiniq ER = Oxycodone/Naloxone. Naloxone is used to reverse the effects of opioid overdose.
A CYP2D6 poor metabolizer is a phenotype that can be predicted by a patient’ s genotype. A poor metabolizer (PM) has diminished CYP2D6 activity, resulting in fewer active metabolites. The *1 allele refer to the wild-type allele, and homozygotes (two *1 alleles) is considered extensive metabolizers, one *1 allele is thought to be intermediate metabolizer, but not poor metabolizers. Morphine is a metabolite formed via CYP2D6 of codeine. Supra-enzymatic activity describes an ultra-rapid metabolizer phenotype, not a PM; a phenotype is the observable characteristic and can be affected by genetic and environmental factors.
The prodrug codeine has minimal analgesic effectiveness. It exerts its analgesic effect through activation to morphine by CYP2D6. A poor metabolizer would have negligible morphine concentrations and would lack an effective response from codeine.
Denosumab is used in postmenopausal female patients at high risk of fracture (prior fractures) that failed alternate therapy options. Raloxifene is a SERM, and is contraindicated with a history of venous thromboembolism. Teriparatide would be an appropriate for a history of fracture but it interacts with digoxin, ↑ risk of digoxin toxicity.
1st line for osteoarthritis of the hand: topical and oral NSAIDs, topical capsaicin, and tramadol. The guidelines do not recommend glucosamine. For patients > 75, topical NSAIDs are preferred. Although duloxetine is a second-line option, this agent is not recommended before trying topical NSAIDs and is not preferred in OA of the hand.
Patients with a history of a GI bleed >1 year ago should receive an NSAID + PPI (B or a COX2 selective NSAID. According to the ACR 2012 guidelines, oral NSAIDs such as naproxen are the first-line option following inadequate response to maximum dose APAP. Duloxetine, tramadol, and intraarticular injections are reserved for patients with NSAID nonresponse or NSAID contraindications. Diclofenac topical gel is reserved for NSAIDs contraindication or > 75 y/o.
