NSG 533 Advanced Pharmacology Exam 2

pain

the most common symptom prompting patients to visit primary care providers. More than 80% of patients who visit physicians report pain. Often remains under treated.

nociceptive pain

pain from a normal process that results in noxious stimuli being perceived as painful. Explained by ongoing tissue injury.

thermal, mechanical and chemical nociceptors that engage "withdrawal" reflex followed by inflammatory response to protect injured tissue

functional pain

pain sensitivity due to an abnormal processing or function of the central nervous system in response to normal stimuli

neruopathic pain

Pain caused by lesions or other damage to the nervous system.

Diabetic peripheral neuropathy

progressive deterioration of nerve function that results in loss of sensory perception

acute pain

is pain that occurs as a result of injury or surgery, under 3 months. Poorly treated acute pain can cause psychological stress and compromise the immune system. Somatic acute pain is an injury to skin, bone, joint, muscle and connective tissue. Visceral pain involves injury to nerves on internal organs. Treat aggressively. Examples: cut hand, menstrual cramps.

chronic pain

can be intermittent or persistent, more than 3 months. Main affects include a) effects on physical function b) psychological changes c) social consequences and d) societal consequences. Usually involving life threatening diseases such as cancers, aids, progressive neurological diseases, end stage organ failure, dementia. Management should be multimodal with cognitive interventions, physical manipulations, pharmacological agents, surgical interventions, and regional or spinal anesthesia.

chronic malignant pain

Painn is associated with a progressive life-threatening disease like cancer, aids, neurologic diseases, end stage organ failure, and dementia. Goal is pain alleviation and prevention. Dependence or addiction is not a concern. Pain not associated with life threatening disease and lasting more than 6 months beyond the healing period is referred to as "chronic nonmalignant pain."

What are some non-pharmacological approaches to pain?

imagery, distraction, relaxation, psychotherapy, biofeedback, cognitive behavioral therapy, support groups, and spiritual counseling. Physical therapy, heat, cold, water, ultrasound, TENS, massage and therapeutic exercise.

WHO 3 step analgesic ladder

* 1- nonopioid

* 2 - opioid for mild to moderate pain

* 3 - opioid for moderate to severe pain

WHO first step pain ladder

mild pain/nonopioid analgesics such as NSAIDS or acetaminophen w/ or w/out adjuvants (such as pregablin) .. "soreness." Med examples: apap 1000mg q 6hrs, ibu600mg q6 hrs

NSAIDs

Non-steroidal anti-inflammatory drugs. associated with several clinically significant contraindications and drug interactions. NSAIDS are equally effective in analgesia, antipyretic and anti-inflammatory effects. Choice should include STEPS (simplicity, tolerability, evidence, price, safety). If patient fails therapy with an agent from one class of NSAIDs, use of an agent from another class is reasonable.

COX2 inhibitors

Celecoxib (Celebrex) selective agents (celecoxib) have ideal indication in patients with high risk for GI bleed, high intolerance of non-selective NSAIDS, or treatment failure with non-selective agents. NSAIDs are of minimal value in neuropathic pain. NSAIDs produce a flat dose response curve (celling effect) with higher doses providing no greater efficacy than moderate doses.

Acetaminophen

Tylenol. blocks PG synthesis in CNS, inhibits peripheral pain impulses. APAP does not interfere with COX 1 or COX2 and thus has no anti-inflammatory benefits.

WHO pain ladder step 2

moderate pain: weak opioids (hydrocodone, codeine, tramadol) w/ or w/out nonopioid analgesics w/ or w/out adjuvants "every time I do something, it hurts" med examples: apa325mg + cod 60mg q4 hrs

WHO pain ladder step 3

severe and persistent pain, potent opioids (morphine, tapentadol, oxycodone, hydromorphone, fentanyl, w/ or w/out non-opioid analgesics and with or without adjuvants "no matter what I do it hurts, theres a bone sticking out of my skin!" Examples; morphine 10mg q4 hrs, hydromorphone 4mg q4 hr

What is the mechanism of NSAIDs and precautions to use?

NSAIDS are either nonselective (inhibit cox 1 and cox 2) or selective (inhibit cox 2). Cox 2 inhibition is responsible for anti-inflammatory effects. - Cox 1 contributes to increased GI and renal toxicity assoc with nonselective NSAIDS. Use with caution in patients with dyspepsia, peptic ulcers, bleeding, and patients taking corticosteroids. Nephrotoxicity can occur in the elderly. A boxed warning is now required for prescription nonselective NSAIDs and Celecoxib due to the increase risk of cardiovascular events and GI bleeding. Generally pts prescribed NSAIDS will need PPI's.

Managment for NSAID risks

Pts more pre-disposed to GI toxicity if pre-existing ulcer or dyspepsia, H Pylori infection, older age, and some concurrent medications increase risk. Management options for GI side effects include taking with food or milk, Switch to different NSAID with better safety profile, COX2 selective agent (celecoxib) and/or gastroprotection (H2RA, PPI, misoprostol

Celecoxib

is recommended for patients at increased risk of gastrointestinal bleeding / ulcer who require a NSAID -Side effects can also include htn, and worsening asthma symptoms.

Tordol (Ketorolac)

40mg, max 5 days.. huge bleeding risk beyond that!

When are NSAIDs indicated and is one NSAID better / safer than another in a given patient?

Useful for mild to moderate pain that are mediated by prostaglandins (RA, menstrual cramps, and postsurgical pain). Works well for pain assoc with bone metastasis. Will dose escalation provide greater benefits (i.e. is there a ceiling effect)? Higher doses produce no greater efficacy than moderate doses.

What is the mechanism of acetaminophen?

Blocks prostaglandin synthesis in the CNS and block pain impulses in the periphery.

When is APAP indicated and are there precautions / restrictions / limitations to use or in dosing (you MUST know maximum daily doses in general population and older adults)?

Apap does NOT have anti-inflammatory properties. It is used for mild to moderate pain and as an antipyretic. - Considered first line for low back pain and osteoarthritis. Causes a hypoprothrombinemic response to warfarin in patients receiving 2000 mg/day. Hepatotoxicity has been reported with excessive use especially in patients with hepatitis or chronic alcohol use. - All providers and patients should be aware of the maximum daily doses of APAP and be conscious of the fact APAP can be found in many products in combination with other medications.... -Max dose for patients with normal renal + hepatic function if 4000mg/day -Max dose for elderly is 3000mg/ day. Reduce dose 50% to 75% in patients with renal or hepatic dysfunction.

*Practice question: What would you be concerned with regarding the first patient's use of Vicodin in terms of the dose Acetaminophen?

In elderly patients, it is recommended not to exceed 3,000mg per day of Acetaminophen.

How does spectrum of use differ from NSAIDs?

Also used as an antipyretic

What is meant by an adjuvant analgesic and when would they be appropriate? Provide examples of medications in this class

Adjuvant analgesics are drugs that have indications other pain but are useful as monotherapy or in combination with other drugs. Examples: diabetic neuropathy, post hepatic neuralgia, fibromyalgia.... Common adjuvants are antiepileptic drugs, antidepressants, antiarrhythmic drugs, local anesthetics, capsaicin, NMDA antagonists, clonidine, and muscle relaxants.

Diabetic peripheral neuropathy treatment

Duloxetine (Cymbalta) 60mg daily; Pregabalin (Lyrica) 50mg TID or 100mg TID.

Practice question: What medication could you recommend for a diabetic patient in pain that could also be used to help treat depression?

SNRIs; either Duloxetine or venlafaxine have been successfully used in diabetic peripheral neuropathy.*

Postherpetic Neuralgia (PHN)

Gabapentin (Neurotonin) 300mg TID up to 3600mg; Pregabalin 75mg BID or 50mg TID. May be increased to 100mg TID; Lidocaine (Lidoderm Patch) up to 3 patiches over site. 12 hours on, 12 hours off.

Practice question: In addition, be sure to understand which non-opioid medications you would use for a patient with neuropathic pain

Gabapentin, pregabalin, transdermal lidocaine, or TCAs. (pg 580).

Fibromyalgia treatment

Duloxetine 30mg daily up to 60mg. Pregabalin 75mg TID up to 300mg-450mg

What is the mechanism of opioids and common adverse effects?

Stimulate opioid receptors in the CNS. Pure agonists like Morphine bind to receptors to produce analgesia that increase with dose without ceiling effect. They block pain, not treat the cause of pain. The opioids exert their analgesic efficacy by stimulating opioid receptors Mu (μ), kappa (κ), and delta (δ)

u receptor

(Mu (μ) produces the effects of analgesia. - The μ2-receptor is also associated with other effects such as "sedation, reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation"

Opioid side effects and management

Common adverse effects include sedation, nausea, and constipation. Sedation and nausea are common when starting therapy and increasing doses. Constipation is managed by stimulant laxatives like senna or bisacodyl and stool softeners like docusate sodium. Tolerance to respiratory depression develops rapidly with repeated doses. If serious, give Naloxone. Opioids can be rotated to achieve a better balance of analgesia and treatment-limiting adverse effects

Managing opioid side effects continued

excessive sedation: reduce dose by 25% or space them out longer/ increase dosing interval. -constipation; laxative/stool softener. Constipation - TOLERANCE DOES NOT DEVELOP TO THIS SIDE EFFECT. Because constipation is a predictable effect of opioid therapy, providers should advise patients to begin using laxatives prophylactically when initiating treatment. -N/v: zofran, hydroxyzine, diphenhydramine, compazine. -Gastroparesis; metoclopramide. -Vertigo; meclizine. -Urticaria/itching: diphenhydramine. -Cns irritability: DC opioid, treat with benzo -Respiratory depression: mild: reduce dose by 25%. Moderate/severe: narcan 04.mg-2mg iv q 2-3 minutes, may need to repeat q hour.

Provide reasonable alternatives to a given opioid in the event of a true allergy (anaphylactic

Itching /rash is a side effect, not an allergy! Mixed agonist and antagonist such as methadone, tramadol, or fentanyl can be used in place of Morphine if a true allergy exists. Treat with epinephrine and steroids initially and d/c opioid

Allergenicity

- For a patient with a true allergy to codeine (or related compound), the risk of cross-reactivity with another opioid can be reduced if an analgesic from a different chemical class is used. Cross allergenicity of compounds in the same column: Example - If a patient has a true documented allergy to fentanyl, then hydromorphone might be a reasonable alternative. If allergic to fentanyl, hydromorphone, pentazocine, or codeine can be used instead.

*practice question: If a patient has a true allergy to Morphine, what opioid, if any, could you try instead?

True opioid allergies are rare. When a true allergy is present, an agent from another opiate class should be used. For example, a patient with a true opiate allergy could receive fentanyl (pg. 579)*

Opioid tolerance

Tolerance - A state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more opioid effects over time. The issue of adjusting for incomplete cross tolerance is for those who are defined as being opioid tolerant. The FDA specifically defines this as "The FDA defines a patient as opioid tolerant if for at least 1 week he or she has been receiving oral morphine 60 mg/day; transdermal fentanyl 25 mcg/hour; oral oxycodone 30 mg/day; oral hydromorphone 8 mg/day; oral oxymorphone 25 mg/day; or an equianalgesic dose of any other opioid

What is meant by equianalgesic doses and the concept of incomplete cross tolerance and opioid rotation? Perform a manual conversion taking the concepts into account.

Use when converting one opioid to another. First step is to calculate the patients total daily dose based on the regularly scheduled dose and the total amount of rescue dose needed in 24 hrs. This is then converted to morphine-dosing equivalents. Total daily morphine dose is then used to calculate the daily dose if the new opioid.

Headache red flags

"SNOOP T"

S = Systemic Symptoms or Illnesses

* Fever

* Anticoagulation

* Pregnancy

* Cancer

N = Neurologic Signs/Symptoms

* Impaired mental status

* Neck stiffness

* Seizures

* Focal neurologic deficits

O = Onset

* Sudden, abrupt, or split-second

* New onset and progressive headache, especially

in middle age >50 yr (giant cell arteritis)

O = Other associated conditions

* Following head trauma

* Awakens patient from sleep

* Jaw claudication

* Scalp tenderness

* Worse with exercise, sexual activity, or valsalva

P = Prior headache history

* Different pattern

* Rapidly progressing in severity/frequency

T = Triggered headache (e.g. by valsalva activity, exertion, or sexual intercourse)

How does IHS classify migraine headaches (w or w/o aura) and cluster headaches:

Primary headaches are migraines, tension-type, cluster, and other trigeminal autonomic cephalgias. Oral NSAIDs and combination analgesics with caffeine: first-line treatment choices for mild to moderate attacks or severe attacks that have responded in the past to similar treatment Triptans - First line therapy for moderate to severe migraines, especially when nonspecific (including OTCs (e.g. Excedrine Migraine)) medications are ineffective. Use for migraines with predictable pattern (Example: menstrual cycle). Triptans can be tried in patients unresponsive to NSAIDs, but generally not considered to standard of practice

practice question: What could you use in the treatment of acute migraine symptoms? A

APAP, ASA or combination products with caffeine for mild to moderate migraines, for moderate to severe migraine; triptans are first line. (pg 588)*

Triptan contraindications

pts with Ischemic heart disease (CAD, history of MI, angina)

pts with strokes, PVD, uncontrolled HTN

avoid triggers like cheese, caffeine, alcohol

Ergotamines (anti-migraine)

-ERGOT-

Ex. dihydroergotamine, ergotamine

Moderate to severe migraine attacks. Usually considered after other treatment failures. -Contraindicated among patients with/at risk for CAD, stroke, PVD, uncontrolled HTN, liver/kidney disease, strong inhibitors of CYP3A4, pregnancy (category X)

When are opioids used for headaches

Reserved for moderate to severe infrequent headaches "Last resort" due to contraindication or failed response to conventional therapies.

Prophylactic therapy for migraines

Goal: reduce frequency, severity, duration of migraines and improve responsiveness to therapy

Agents

• Beta blockers (propranolol, atenolol, metoprolol)

• Antidepressants (amitriptyline, notriptyline,

imipramine, doxepin)

• Anticonvulsants (divalproex sodium, topiramate, gabapentin)

• Calcium channel blockers (verapamil)

Used if a person has a high number of migraine days per month and/or if acute treatments aren't effective

There is no commonly accepted indication for starting prophylactic treatment, but should be considered when quality of life, business duties, or school attendance are severely impaired, frequency of attacks ≥ 2 per month, migraine attacks do not respond to acute drug treatment, frequent, very long, or uncomfortable auras occur.

*Practice question: What could you use for prophylaxis of migraines?

Beta-blockers if not contraindicated (or CCB), low-dose TCAs (amitriptyline, venlafaxine), and antiepileptics (topiramate, valproic acid, and divalproex sodium). (pg 590-591)

Beta-blockers (e.g. propranolol)

Ideal for healthy patients or comorbid hypertension, angina, or anxiety. avoid in reactive airway disease, heart block, bradycardia, asthma.

TCAs (e.g. nortriptyline, amitryptiline)

Good choice for patients with comorbid depression or insomnia. avoid in urinary retention, BPH, glaucoma or where anticholinergic effects are problematic.

Anticonvulsants (e.g. valproate, topirimate)

Good choice for patients with comorbid seizure disorder or manic-depressive illness. many drug-drug interactions

CCBs (e.g. verapamil)

generally considered second or third line for migraine headaches, but first line for prophylaxis of cluster type headache

*Practice question: What class of prophylaxis for migraines should be avoided in asthmatics?

Beta Blockers would usually be a medication used in the prophylaxis of migraines, but this would not be the best choice in an asthmatic. (Inderal, propranolol is contraindicated). (pg 591-591)*

Migraine headaches with aura:

Criteria symptoms are visual, sensory, speech/and or language, brainstem, retinal... Symptoms last 5-60 minutes, one symptom Is unilateral, the aura is accompanied or followed by headache within 60 minutes. 2x or more of these criteria met can increase rx of stroke.

Migraine headaches w/o aura:

pain interrupts or worsens with activity, unilateral pain, pulsating pain, moderate-severe intensive, n/v, photophobia, phonobia.. 5+ more of these symptoms can increase rx of stroke

Cluster headaches

lacrimation(tears), nasal congestion/rhinorrhea, eyelid edema, forehead of facial sweating/ flushing, sensation of fullness in the area, miosis and/or ptosis, duration of pain 15-180 minutes, frequency of attacks are every other day up to 8 or more a day. Can have 10 or more attacks, lasts up to 7 days... At least 5+ more of these symptoms can increase rx of stroke.

headache diary

: Keeping detailed records of HA to provide additional insight about triggers and how to avoid them. It also helps identify patterns and track characteristics of HA.

Migraine triggers

Altered sleep patterns

Skipping meals

Overexertion

Weather change

Stress or relaxation from stress

Hormonal changes (menstrual periods)

Excess afferent stimulation (bright lights, strong smells)

Chemicals (alcohol or nitrates)

Headache red flags

• New onset sudden and/or severe pain • Stereotyped pain pattern worsens • Systemic signs (fever, weightloss, accelerated HTN) • Focal neurologic symptoms (other than typical visual or sensory aura) • Papilledema • Cough (exertion or Valsalva triggered headache) • Pregnancy or postpartum • Patients with cancer, HIV, other infectious or immunodeficiency • Seizures

Migraine management

Short-term goal is to provide rapid pain relief and allow the pt to resume their normal activities. Long-term goals are to prevent headache recurrences and to diminish headache severity. Early abortive treatment is the rule... Prophylaxis for headache disorders Is indicated if headaches are frequent or severe if significant disability occurs, if pain relieving medications are used frequently, or if adverse events occur with acute therapies.

maximum daily dose of APAP in older adults

3000 mg in older adults and less than 2,000 mg a day in frail patients or those over 80 years of age who consume alcohol or with impaired liver function.

Acetaminophen Hepatotoxicity

-Hepatic injury starts 24 to 72 hours after ingestion

-Injury possible with high therapeutic doses-pts with preexisting liver disease

-Injury possible with high therapeutic doses in malnutrition & alcoholics

-Can result in hepatic failure and in some instances death

Occurs in doses greater than 4 grams per day.

adjuvant analgesics

used to treat chronic pain that is neuropathic in nature. Examples: Gabapentin, lidocaine for post-herpetic neuralgia, duloxetine for diabetic peripheral neuropathy. TCAs for trigeminal neuralgia.

u1 receptor

produces the effects of analgesia

Opioids use

moderate/severe pain, pre-operative to sedate and ease anxiety, intra-op analgesia.

Severe acute pain, moderate to severe cancer pain, moderate to severe chronic non-malignant and severe neuropathic pain (third or fourth line) has gained more acceptance in recent years.

Initiation of Therapy Objective:

to find the medication that provides the best pain relief with the fewest adverse events.

Intermittent pain treatment

begin with short acting opioids

morphine, oxycodone, hydrocodone

Q4-6hrs

Continuous pain

Long-acting agents are recommended

CR morphine

Methadone

Use short acting agents to determine starting point

Opioid Side Effects

- Euphoria

- Sedation

- Respiratory Depression

- Miosis

- Nausea and Vomiting

- Constipation

- Pruritis (Itching)

Sedation and opioids

During the initial period of opioid therapy, patients should be cautioned against driving or other activites that could be dangerous if sedation develops

Opioid sedation interventions

Reduce dose 25% or increase interval

Caffeine 100-200mg PO q 6hrs

Methlyphenidate 5-10 mg PO 1-3x/day

Dextroamphetamine 5-10mg PO 1-3x / day

Modafanil 100-200 mg PO daily

respiratory depression

slow, weak respirations at a rate of fewer than 12 per minute.

most serious adverse effect of opioid therapy. Mild RD decrease dose by 25%. Severe RD / administer naltrexone stat

hydroxyzine, diphenhydramine, Ondansetron

nausea / emesis

dose 25-100mg PO/IM q 4-6 PRN

dose 25-50mg PO/IM q 6 PRN

dose 4-8 mg PO TID

Prochlorperazine (Compazine)

Antiemetic

Dose 5-10 mg PO/IM q6 PRN

25mg PR BID

Haloperidol (Haldol)

An antipsychotic drug thought to block receptor sites for dopamine, making it effective in treating the delusional thinking, hallucinations and agitation commonly associated with schizophrenia.

Can be used as an antiemetic n dose of 0.5-1mg PO q6-8 hrs. PRN.

Metoclopramide

Reglan

Antiemetic

Dose 10-20 mg PO q6 PRN

Granisteron

2mg PO daily

Palonosetron

300 mcg/kg IV

addiction

A primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations

physical dependence

A state of adaptation that is manifested by a drug class-specific withdrawal syndrome produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Tolerance

A state of adaptation in which exposure to a drug induces changes that result in diminution of one or more opioid effects over time

opioid tolerant patients

Patients who are taking, for 1 week or longer, at least:

60 mg oral morphine/day or

25 mcg transdermal fentanyl/hour or

30 mg oxycodone/day or

8 mg oral hydromorphone/day or

25 mg oral oxymorphone or

An equianalgesic dose of any other opioid

Aberrant drug-related behavior

A behavior outside the boundaries of the agreed on treatment plan which is established as early as

possible in the doctor-patient relationship

drug abuse

any use of an illegal drug, or the intentional self-administration of a medication for non-medical purposes

Naloxone (Narcan)

opiate antagonist, reverses opioid induced respiratory depression. Opioid antagonist the treatment of opioid agonist-induced respiratory depression and known / suspected overdose of opioid.

Reverses both toxic and clinical effects of opioids.

naltrexone indication

For Alcoholism and Opioid/Opiate addiction (Anti-Craving Drug) weight loss, neuropathic pain

Diabetic neuropathy treatment

1. TCA 2. duloxetine 3 anticonvulsant (gabapentin, pregabalin)

Consider duloxetine and or pregabalin as the initial approach.

Given the risk for addiction, avoid the use of opiates including tepentadol or tramadol.

Naratriptan

Onset 1-3 hrs half life 70%

Almotriptan

Eletriptan

Frovatriptan

Naratriptan

Rizatriptan

Sumatriptan

Zolmitriptan

Triptans

Onset 1-3 hours

half-life 2-6 hours other than Frovatriptan with a half-life of 26 hours

Ergotamine MOA

5-HT2b (Vasculature), 5-HT2d (Trigeminal) inhibition-->Vasoconstriction. Used for moderate to severe migraine attacks. Usually considered after other treatment failures.

Lasmiditan

5-HT1F agonist being developed for potential use as treatment of migraine -reduced vasocontriction effects. Selective serotonin 1F receptor agonist that lacks vasoconstrictor activity

Lasmiditan adverse effects

dizziness, paresthesia, somnolence, fatigue and nausea. Serotonin syndrome: has occurred in patients receiving Lasmiditan alone.

CGRP antagonists

• Calcitonin-gene-related peptide (CGRP)

Indications: Acute Migraine

MOA: Blocks protein (CGRP) involved in trigeminovascular pain transmission to the CNS and neurogenic vasodilation

Treatment Acute Migraine. Used in patients with either insufficient response or contraindication to treatment with triptans.

Migraine prophylaxis indications

>=2 migraines per month.

Severe and prolonged migraines.

Medication used to treat migraines >=2x per week on a regular basis.

Standard analgesics or triptans contraindicated or ineffective.