1. Management of Acute Pain, Nausea, and Emesis
Joseph Bubalo PharmD, BCPS, BCOP
Oncology Clinical Pharmacy Specialist
Assistant Professor of Medicine

2. Acute Pain and Nausea Management Overview
Assessment
Therapeutic options
Monitoring/management

3. Pain Assessment
History of past pain medication use as well as history of recreational or substance abuse activity, including alcohol.
List of current medications (RX and OTC) and supplements (herbal, nutritional, homeopathic, etc)
Allergy/sensitivity History

4. Pain Assessment
Location – find all locations and intensity at each. Get an overall pain score.
Character – sharp, dull, aching, constant, intermittent, burning, etc.
Frequency and pattern.
Severity.
Has it changed or what makes it better/worse?
Known etiology?

5. Pain Assessment
What have they tried (pharmacologic and non-pharmacologic) and what were the results?
Therapy, dose, duration, how results were evaluated.
What are the patient’s expectations/goals?
Initial evaluation and follow-up must be done a bedside
Follow-up over time – is a change new pain as opposed to not enough drug?

6. Opioid Agonists Drug Onset (min) Peak (h) Duration Half-life(h)
Dose Interval(h)
Codeine
IM 10-30
PO 30-60
0.5-1
4-6
3-4
3-6
Fentanyl
IM 7-15
IV 3-5
0.1
1-2
1.5-6
0.5-2
Hydrocodone
10-20
4-8
Hydromorphone
PO 15-30
2-4
Methadone
IV 10-20
Acute 4-6
Chronic >8
15-30
6-12
Morphine
PO 15-60
IV <5
PO 0.5-1
IV 0.3
Oxycodone
PO 10-15

7. Equianalgesic Interchange
Agent
IM/IV/SQ
Oral
Morphine 10
30(60)
Oxycodone
N/A 30
Hydromorphone
1.5
7.5
Methadone
1-10
2-20
Fentanyl
0.1
N/A-Actiq*
Hydrocodone
Codeine
120
200
Meperidine 75
300

8. Routes of Administration
Oral
Rectal
Transdermal
Sublingual/Buccal
Intramuscular
Intravenous
Subcutaneous
Spinal

9. PRN IV Opioid Equivalents
Morphine 4 mg
Hydromorphone 0.5 mg
Fentanyl 40 mcg
Meperidine – no longer used at OHSU

10. PRN Oral Opioid Equivalents
Morphine mg
Oxycodone mg
Lortab® tabs
Lortab® tabs
Hydromorphone 2-4 mg
Codeine mg

11. Analgesic Therapeutics
Start at “normal dose”
Base frequency on severity of pain, patient tolerance, pharmacokinetics
If chronic analgesics minimum of 25-30% of chronic dose for breakthrough to achieve efficacy
Titrate to therapeutic dose and lengthen interval as analgesia occurs
Consider adjuvants and co-analgesics

12. Duration of Therapy
Based upon etiology …the expected duration of pain will vary
Somatic, abdominal, neuropathic
Fixed pain course?
Acute pain – Subsides over an “expected” period of time
Acute exacerbation of chronic pain
Return to baseline or titrate to new baseline

13. Renal and Hepatically Impaired Patient
Choose agent with fewest active metabolites
Dose to effect than titrate slowly at increased intervals
Agents of choice - hydromorphone, oxycodone, and fentanyl
Contraindicated agents – meperidine, propoxyphene

14. The Opioid Naive Assess type and duration of pain
Analgesic doses used thus far and response/side effects
PCA OK, but no basal
Frequent reassessment
Most at risk: small, elderly, organ compromised

15. Opioid Tolerant Chronic pain patient Recreational user
Figure 24 hour usage
Base rescue dosing at 10% of 24 hour use or 25-30% of incremental dose at the normal interval
Assess bowel function

16. PCA Guide
Initial basal may be used to replace chronic dosing otherwise leave off during initial assessment period
Breakthrough frequency generally 6, 10, or 15 minutes
Choices – Morphine 1 mg = hydromorphone 0.2 mg = fentanyl 10 mcg
Give range to allow titration for more effective dosing
Naloxone part of protocol orders

17. PCA Safety Issues PCA by proxy Patient education Monitoring
For appropriate analgesia
To prevent oversedation
Videogame thumb
Monitoring
Pain, alertness, vitals Q 4H-rate/quality of respirations first hours.
Product selection
Pt Ed – Be sure patient is capable of operating a PCA and knows they don’t have to keep pushing the button if they are comfortable. Products available are hydromorphone, MS, and fentanyl. Respirations, heart rate, and blood pressure the first hours important to monitor. Increased risk of nocturnal hypoxia the first 1-2 days.

18. Adjuvants/Coanalgesics
Laxatives
NSAIDs
Anti-anxiety
Antiemetics
Hypnotics
Muscle relaxants
Local anesthetics
Consider additive side effects and potential to exacerbate co-morbidities

19. Opioid Side Effects
Respiratory depression – titration rate based on analgesic need, reduce dose if cause of pain relieved. Rare after 3-4 days.
Constipation
Itching – Antihistamines or change agent. True allergy rare
Nausea – Antiemetics, take with food, change agent or route
Hallucinations – Change agent or route
Sedation – Rule out other causes, change agent, add stimulant
Urinary retention – Change agent or add bethanacol

20. General Management of Nausea and Vomiting
Sick
Expulsion
Hurl
Puke
Retching
Spew
Honk
Ralph Ow
Vomito
Gag
General Management of Nausea and Vomiting
Upchuck
Heave
Spit Up
Regurgitation
Upset Stomach
Blow
Chunks
Oh- mandarin, vomito- spanish, Ow - cantonese
Barf
Emesis
Hyperemesis
Disgorgement
Throw up OH

21. The First Emesis?
feb 2002, Fossilized "dinosaur" vomit has been discovered in a quarry in Peterborough. Scientists believe the vomit, estimated to be 160 million years old, gives vital clues to the feeding habits of ichthyosaurs, marine reptiles that lived at the same time as the dinosaurs.
Detailed analysis has revealed the remains of dozens of belemnites - an ancient sea creature - within the fossilized substance.
Peter Doyle has studied the prehistoric vomit Professor Peter Doyle, of the University of Greenwich, believes the belemnite shells contained in the vomit indicate that they were regurgitated.
The process is shared by the modern-day sperm whale.
Professor Doyle said: "It is highly unlikely that these shells passed through the ichthyosaur's intestines and were excreted as droppings because they would have damaged the soft tissue of the reptile's internal organs.
"The only alternative is that the shells were vomited out in much the same way that modern-day sperm whales regurgitate the indigestible beaks of squid."
Chronic indigestion
Further examination has revealed distinctive etching marks on the shells.
These are believed to have been caused by the digestive fluids from the gut of the ichthyosaur.
Ichthyosaurs swam in the ocean when dinosaurs walked on land.
They appeared slightly earlier than dinosaurs (250 million years ago) and lived until about 90 million years ago.
Professor Doyle said: "The Peterborough belemnite shells have revealed acid etching marks, proving that they had been eaten by a predator.
"The fact that most of these belemnites were juveniles reinforces our view that they did not die of old age."
The research team believes the acid etching marks provide the first hard evidence that ichythosaurs vomited the inedible parts of shellfish to avoid internal damage and chronic indigestion.

22. Assessment of N/V GI status – Obstructed or not
Frequency – nausea/emesis
Volume – emesis and contents
Timing – Proximate cause, worse in AM/PM?
Hydration status?

23. Assessment Associated Factors Undigested food
Neurologic signs/headache
Electrolyte abnormalities
New medications (include OTC, supplements, etc)
Therapy – drugs, radiation, chemo,
Phobias, anxieties, anticipatory habits
Patient expectations

25. Cerebrum Motion/spaceH1, M, 5HT1a Emetic center 5HT3, D2, M, NK1
Sensory input (pain, smell, sight)
Cerebrum
Memory, fear, dread
Motion/spaceH1, M, 5HT1a
Inner ear
Emetic center
Nucleus tractus solitarious (NTS)
5HT3, D2, M, H1, NK1
Chemoreceptor Trigger Zone (area postrema)
5HT3, D2, M, NK1
CNS
Periphery
Vagal and sympathetic afferents
Pharynx
Blood brain Barrier
GI tract
5HT3, SP
Blood born toxins
Local irritants
Calcium causes an exocytic release of serotonin from enterochromaffin cells in the GI tract, possibly as a result of free radical generation. The release serotonin activates vagal afferent receptors which stimulate the CNS. 5HT3 receptors are also in the area postrema, NTS, subnucleus gelatinosus, the lower densities of the vagus. Substance P is co-localized with serotonin in the enterochromaffin cells of the GI tract.

26. Etiologies Drug/treatment Induced Disease related
Opioids, supplements, antibiotics, cytotoxics, NSAIDs, SSRI, radiation (to GI, CNS)
Disease related
Gastric irritation/obstruction, constipation, electrolyte/metabolic factors, increased intracranial pressure, vestibular disturbances
Psychological Factors
Anxiety, fears, phobias, sights, odors
Metabolic – uremia, hypercalcemia, hyponatremia, ketosis

27. Therapy/Drug Selection Issues
Drug affinity for probable cause (receptors, pharmacodynamics, etc)
Available routes of administration
Side effect profile
Patient Contraindications
Treat underlying condition if possible

28. Major “Antiemetic” Drug Classes
Serotonin (5-HT3) receptor antagonists
Dopamine (D2) receptor antagonists
Neurokinin 1 antagonists (NK1a)
Substituted benzamides (metoclopramide)
Steroids
Benzodiazepines (BZ)
Cannabinoids
Histamine (H1) receptor antagonists
Muscarinic receptor antagonists
The 5-HT3 receptor antagonists have been available in the US since 1991 and represent the largest therapeutic advance in the control of chemotherapy-induced emesis.
Lorazepam, a benzodiazepine, is used to control anxiety, induce amnesia, and decrease the stress of receiving chemotherapy; antiemetic activity has been suggested for this drug.*
Cannabinoids are used in the treatment of CIE; however, their use is limited by the many CNS side effects caused by these agents including sedation, mood changes, memory loss, euphoria, and hallucinations
Dopamine receptor antagonists (including the phenothiazines, the butyrophenones, and domperidone) may produce extrapyramidal side effects, they have been used to prevent CIE, radiotherapy-induced emesis, and postoperative nausea and vomiting (PONV).
Histamine H1 receptor antagonists are used to treat postoperative vomiting and motion sickness.
Muscarinic receptor antagonists include scopolamine (hycosine) and atropine, both of which are used to control PONV and motion sickness.
Pyridoxine (vitamin B6) has been used to treat pregnancy-associated nausea and vomiting and radiotherapy-induced emesis, but its efficacy has never been clearly established.
Steroids, such as dexamethasone and methylprednisolone, are used to control CIE; their antiemetic mechanism of action is unknown, but it may be mediated through inhibition of prostaglandin synthesis
Substituted benzamides, such as metoclopramide, are used to treat CIE; at high does, they may produce extrapyramidal side effects.
*This indication is not approved by the FDA for use in the United States.

29. Agents and Issues
Metoclopramide – GI stasis or lower sedation level needed
Dexamethasone – inflammatory component, cerebral edema, additive effect needed
Octreotide - Bowel obstruction in terminal disease or those who fail anticholinergics
Benzodiazepines – anxiety, phobias, learned behaviors

30. Agents and Issues
Phenothiazines – Broadly active, especially in combination
Haloperidol, droperidol – similar to phenothiazines in spectrum of activity
Meclizine, dimenhydrinate, scopolamine – vestibular component
Hyoscyamine – for nausea secondary to excess bronchial or gastric secretions
Serotonin antagonists – Drug of last resort

31. Agents and Doses
Metoclopramide mg IM/IV/PO Q 4H PRN ( mg/day on average)
Droperidol mg IV/IM Q 4H PRN
Haloperidol mg Q 6 H PRN
Prochlorperazine mg IV/IM/PO Q 4H PRN*
Promethazine mg IV/IM/PO/PR Q 4H PRN
Chlorpromazine mg IV/PO Q 4H PRN
* Also have PR Option

32. Additional Agents Dexamethasone 4-8 mg IV/PO QD to QID
Scopolamine patch 1.5 mg (up to 8 hours for effect)
Dimenhydrinate mg IV or mg PO Q 4H PRN
Meclizine mg q 8 H PRN
Trimethobenzamide 200 mg IM/PR Q 6H PRN

33. Serotonin(5HT3) Antagonists for General N/V
Ondansetron
4 mg IV or 8 mg PO
Granisetron
mg IV/PO
Dolasetron
mg IV or 50 mg PO
All dosed one to two times daily

34. Additional Routes Sub Q
Metoclopramide, octreotide, haloperidol, dexamethasone, scopolamine
Don’t give Sub-Q (cause irritation and erosions)
Chlorpromazine, diazepam, prochlorperazine, promethazine, hydroxyzine
Sublingual
Lorazepam, hyoscyamine, haloperidol

35. Is Droperidol Evil?
03/01 UK’s Medicine Control Agency reviews QT issues and Janssen Dc’s Droleptan® and injectable droperidol after risk benefit assessment
FDA reviews drug and receives 273 reports for 11/97-12/01 with many being duplicates
Majority of events occurred at doses > 10 mg
10 deaths, 18 cardiac arrests, 6 cases of QTc prolongation and 3 of torsades de pointes reported at doses < 2.5mg in 30 years
10 Serious case reports at doses < 1.25 mg, none of which showed a causal relationship
Horowitz BZ, et al Academy of Emergency Medicine 2002;9(6);615-8

36. Droperidol Effects Normal QTc is 440 msec males and 450 msec females
Prolonging QTc more than 500 msec or 60 msec increases the risk for dysrhythmia
QT prolongation  fatal arrhythmia/ cardiac arrest
0.1, 0.175, and 0.25 mg/kg doses equivalent in a 70 kg adult to 7, 12.25, and 17.5 mg caused a 37, 44, and 59 msec QTc prolongation respectively.
Before 2001 warning for doses > 25 mg causing sudden death if at risk for cardiac dysrythmias
Lischke V, et al Anesthesia and Analgesia 1994;79:983-6

37. Droperidol May be evil … However
Droperidol is associated with QTc prolongation
This temporal and dose dependent association has not been proven to be related to torsades de pointes in any type of randomized or controlled setting
Case reports suggest that rare cardiac events may be associated with droperidol administration but none are causally associated with it’s use
Analogous situations exist with other medications including haloperidol, cyclobenzaprine, and 5HT3 antagonists

38. Droperidol Recommendations
Ongoing safety monitoring should occur
Avoid use with other agents which prolong the QT interval, change target drug metabolism, or in patients with known cardiac dysrhythmias
Consider ECG monitoring if elevated doses are required or use is indicated in a patient with known risk factors
Use the minimum effective dose
Consider alternative agents if doses > 5mg are indicated
Kao LW et al Annals of Emergency Medicine 2003;41:546-58

39. Combinations D2 Antagonist 5HT3 Antagonist Other Metoclopramide
Prochlorperazine
Haloperidol
Droperidol
Promethazine
5HT3 Antagonist
Ondansetron
Other
Dexamethasone
Lorazepam
Dronabinol
Dimenhydrinate
Diphenhydramine
Meclizine
Scopolamine
Hyoscyamine
Trimethobenzamide

40. NonPharmacologic Approaches
Decrease Milk products
Clear liquid diet
Bland diet
Decrease sources of smell (cold and room temperature food)
Manage anxiety
Distraction techniques, guided imagery
NG tube

41. Other Issues Multiple agents common Ginger, Peppermint oil Hydration
Acupressure
Marijuana

42. Results Are the Bottom Line

43. Thank you!