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

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

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

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?

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?

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 3.3-4.4 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

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

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

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

PRN Oral Opioid Equivalents Morphine 10-20 mg Oxycodone 10-20 mg Lortab®-5 2-4 tabs Lortab®-10 1-2 tabs Hydromorphone 2-4 mg Codeine 60-120 mg

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

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

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

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

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

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

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 24-48 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 24-48 hours important to monitor. Increased risk of nocturnal hypoxia the first 1-2 days.

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

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

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

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.

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?

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

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.

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

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

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.

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

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

Agents and Doses Metoclopramide 10-30 mg IM/IV/PO Q 4H PRN (60-100 mg/day on average) Droperidol 0.625 mg IV/IM Q 4H PRN Haloperidol 0.5-2 mg Q 6 H PRN Prochlorperazine 2.5-10 mg IV/IM/PO Q 4H PRN* Promethazine 6.25-25 mg IV/IM/PO/PR Q 4H PRN Chlorpromazine 25-100 mg IV/PO Q 4H PRN * Also have PR Option

Additional Agents Dexamethasone 4-8 mg IV/PO QD to QID Scopolamine patch 1.5 mg (up to 8 hours for effect) Dimenhydrinate 12.5-25 mg IV or 25-50 mg PO Q 4H PRN Meclizine 12.5-25 mg q 8 H PRN Trimethobenzamide 200 mg IM/PR Q 6H PRN

Serotonin(5HT3) Antagonists for General N/V Ondansetron 4 mg IV or 8 mg PO Granisetron 0.5 -1 mg IV/PO Dolasetron 12.5-25 mg IV or 50 mg PO All dosed one to two times daily

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

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

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

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

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

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

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

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

Results Are the Bottom Line

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