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Palliative Care Symptom Guide Table of Contents

General Principles of Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Select Opiate Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Equianalgesic Dosing (Opioid conversion) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Patient Controlled Analgesia (PCA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Opioid Dosing in Renal or Hepatic Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Guidelines for Naloxone Administration and Patient Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7-8Nausea and Vomiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9-10Constipation and Bowel Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-12Delirium Diagnosis (CAM-ICU and the ICDSC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13-14Delirium: Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15-16Depression: Screening Tools and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-19End of Life Care: Symptom Management Treatment of Dyspnea and Pain at the End of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Oral Secretions at the End of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Palliative Care and Pain Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

July 2013

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Pain Scale

No Pain Worst Pain ImaginableNone = 0; Mild = 2 .5; Moderate = 5; Severe = 7 .5; Excruciating = 10

General Principles of Pain Management1. Assess pain using a standardized pain scale. Pain is a subjective feeling: ask the patient using the above 0-10 scale. If the patient is cognitively impaired, use the Abbey

pain scale. (See page 2.) Frequency of assessment: at the time of the initial interview, every eight hours, and PRN (at least every two hours when pain is severe).2. In opiate naive patients, start with short-acting opioids (morphine, hydromor-

phone, and oxycodone) to control acute, moderate to severe pain. Never use long-acting opioids to control acute pain.

3. When titrating or changing opiate dose, start by calculating the previous day’s Oral Morphine Equivalent (OME).a. Since all potent opioids produce analgesia by the same mechanism, they

will produce the same degree of analgesia if provided in equianalgesic doses (see equanalgesic table).

b. Rectal=oralc. SQ=IM=IV

4. Determine if the dose is adequate for the pain and dose adjust. a. Titrate at least every 24 hours when the pain is moderate and as often as every

four hours when using IV opioids and the pain is severe. b. Increase dose 25-50% for moderate pain and 50-100% for severe pain.5. Determine the opiate that will be used and dose adjust for incomplete

cross tolerance. a. The only reason to change from one opiate to another is side effects or

renal failure. b. When rotating opiate, decrease the dose 25-50% to correct for incomplete cross

tolerance.

6. Determine the route the opiate will be given. a. IM should never be given.7. Determine the dosing schedule. a. For non-opiate naive patients, use long-acting pain medicine for ongoing pain, not

prn; for opiate naive patients use only prn until you have a sense of how much medicine the patient needs.

b. Give 66-75% of patient’s stable daily OME as long acting. c. Consider a pca if the pain requirements are rapidly increasing or unknown.8. Determine break through dose (for acute pain in patient with otherwise

controlled pain). a. Use the same opiate for short- and long-acting pain when possible. b. 5-15% of total daily long acting opiate dose every 3 hr prn.9. Manage opiate side effects. Constipation must be treated prophylactically

(see page 6).10. Determine whether co-analgesics would help.

1 2 3 4 5 6 7 8 9 100

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PHARMACISTS WILL NOT MAKE SUBSTITUTIONS OR CORRECTIONS FOR OPIATES. IF SCRIPTS ARE NOT WRITTEN EXACTLY (e.g., CORRECT DRUG, DOSE, AND SCHEDULE), THEY WILL NOT BE FILLED.SELECT NON-INJECTABLE OPIOID PRODUCTS

Drug Formulation/Strength (mg/mg) (8)Anexsia (hydrocodone/acetaminophen) (4,6) Tabs 5/325 (scored), 5/500 (scored), 7 .5/325, 7 .5/650 (scored), 10/660 (scored)Empirin with Codeine (codeine/aspirin) (4,6) Tabs 30/325 (#3), 60/325 (#4)Lorcet (hydrocodone/acetaminophen) (3,4) Tabs 7 .5/650 (scored), 10/650 (scored) Caps 5/500Lortab (hydrocodone/acetaminophen) (3,4) Tabs 2 .5/500, 5/500 (scored), 7 .5/500 (scored), 10/500 Elixir 7 .5/500 per 15 mLNorco (Hydrocodone/acetaminophen) (3,4) Tabs 5/325, 7 .5/325, 10/325Percocet (oxycodone/acetaminophen) (3,4) Tabs 2 .5/325, 5/325, 7 .5/325, 7 .5/500, 10/325, 10/650 Percodan (oxycodone/aspirin) (4) Tabs 5/325 Roxicet (oxycodone/acetaminophen) (4) Tabs 5/325 Caps 5/500 Oral Solution 5/325 per 5 mLTylenol with Codeine (codeine/acetaminophen) (3) Tabs 15/300 (#2), 30/300 (#3), 60/300 (#4) Oral Solution 12/120 per 5 mLVicodin (hydrocodone/acetaminophen) (3,4) Tabs 5/300, 7 .5/300 (ES), 10/300 (HP)Vicoprofen (hydrocodone/ibuprofen) (6) Tabs 7 .5/200Zydone (hydrocodone/acetaminophen) (4,6) Tabs 5/400, 7 .5/400, 10/400

Drug Short Acting (mg) Long Acting (mg)Morphine Tabs (15, 30 mg) Caps (15, 30 mg) MS Contin Tabs (q12hr) (15, 30, 60, 100, 200 mg) MSIR Oral Solution (10 mg/5 mL, 20 mg/5 mL) Oramorph SR Tabs (q12hr) (15, 30, 60, 100 mg) MSIR, Roxanol Oral Concentrate (100 mg/5mL) (1) Kadian Caps (q12hr or q24hr) (10, 20, 30, 40, 50, 60, 70, 80, 100, 130, 150,200mg) (2, 5) Supp (5, 10, 20, 30 mg) Avinza Caps (q24hr) (30, 60, 90, 120 mg) (2, 5)Oxycodone Roxicodone Tabs (5, 15, 30 mg) OxyIR Caps (5 mg) OxyContin Tabs (q12hr) (10, 15, 20, 30, 40, 60, 80 mg) Roxicodone Oral Solution (5 mg/5 mL) OxyFAST, Oxydose, Roxicodone Intensol Oral Concentrate (20 mg/mL) (1,6) Hydromorphone Dilaudid Tabs (2, 4, 8 mg) (8 mg brand-name scored) Exalgo Tabs (q24h) (8, 12, 16, 32 mg) (Dilaudid) Dilaudid Oral Solution (5 mg/5 mL) Supp (3 mg) Codeine Tabs (15, 30, 60 mg) Solution or Elixir (15 mg/5 mL) Fentanyl See note (7) Duragesic Transdermal Patch (12 .5, 25, 50, 75, 100 mcg/hr)Oxymorphone Opana (5, 10 mg) Opana ER (5, 7 .5, 10, 15, 20, 30, 40 mg)

SELECT COMBINATION OPIOID PRODUCTS

(1) Orders for concentrated oral opioid solutions must include drug name and strength (e.g. 100 mg/5mL) to avoid confusion with other oral solutions. (2) Data supporting safe use with enteral feeding tubes (must use size 16 French or larger). See Kadian prescribing information and UPMC PUH SHY online formulary (Avinza) for product-specific instructions. (3) Maximum daily dose of acetaminophen is 4 grams in patients with normal liver function. (4) Many other brand name products contain similar combinations of opioids. (5) Formulary restricted. (6) Non-formulary. (7)Prescribers must complete Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) (8) As of Fall 2008, all combination opiates with more than 325 mg of acetaminophen will be non-formulary.

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Oral and Parenteral Opioid Analgesic Equivalencies and Relative Potency of Opioids as Compared with Morphine*When converting from one opioid to another, you should use 50–75% of the equivalent dose . Allow for incomplete cross-tolerance between dif-ferent opioids (may need to titrate up rapidly and use PRN dose to ensure effective analgesia for the first 24 hours) . Avoid IM injections because of inconsistent absorption and patient discomfort .

*These are rough approximations; individual patients may vary . ** Equivalency for a one time dose of IV Fentanyl only . For Fentanyl patch conversion, see box below .1) Meperidine is not a first-line opioid . Avoid in patients with renal dysfunction . Contraindicated with MAOIs . Please see UPMC Meperidine

Guidelines before prescribing .2) Parenteral opioid: onset of action, 5 minutes; peak, 15 min .

3) Oral opioid: onset of action, 15–30 minutes; peak, 45–60 min .

Please refer to APS Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain (2003); American Pain Society (APS) Guideline for the Management of Cancer Pain in Adults and Children (2005).

Opioid Agonists Parenteral mg (2) Oral mg (3) Duration of Effect Morphine 10 30 3–4 hours Oxycodone 20–30 3–4 hours Hydromorphone 1 .5 7 .5 3–4 hours Meperidine (1) (not recommended) 75 300 3 hours Fentanyl (4) 0 .1** 1–2 hours Codeine 130 200 3–4 hours Hydrocodone 25–30 Oxymorphone 1 10 3–6 hours

TWENTY-FOUR HOUR ORAL MORPHINE EQUIVALENT DIVIDED BY 2 IS EQUAL TO FENTANYL PATCH DOSE IN MCG/HR.IV FENTANYL DOSE/HR=TRANSDERMAL FENTANYL DOSENOTE: PATCH TAKES 12–24 HRS TO ACHIEVE FULL EFFECT. WHEN REMOVING A PATCH, REMEMBER THE ANALGESIC EFFECT CAN STILL LAST 24 HRS.

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Patient Controlled Analgesia (PCA)The following are suggestions for the PCA order for adults . Like all opioid orders, doses must be individualized .

Use the preprinted PCA order form for all new PCA orders and dose changes. EDUCATE FAMILIES NOT TO PRESS THE PCA BUTTON!

*Opioid tolerant and chronic/cancer pain patients may require higher doses and continuous infusions.

1.PCA alone is a maintenance technique. Patients should receive loading doses (delivered through the infuser) that are titrated to achieve an adequate level of analgesia (pain score less than or equal to 4/10).

2.Quantity delivered when button is pressed. Reduce doses by 30-50% in elderly and patients with liver disease. Do not increase dose based on increased body weight; this is especially important in patients with Obstructive Sleep Apnea. Dosing depends on the patient—young vs. elderly/opioid naive vs. tolerant.

3.How frequently demand dose can be activated. Patient must be able to

press the button and be able to comprehend instructions on when to press the button. In the elderly, consider a longer lockout interval.

4.The hour limit should not be less than the available total hourly patient administered dose. Bolus doses and the continuous infusion are included in the one-hour dose limit count.

5.Not recommended for patients who are opioid naive, the elderly, patients with altered mentation, or with Obstructive Sleep Apnea, COPD, or asthma.

6.Morphine is generally the opioid of choice. Hydromorphone is preferred in patients with impaired renal function.

If pain unrelieved following administration of loading dose(s), increase loading dose by 50% and titrate to pain score less than or equal to 4/10.

Loading Starting Patient Lockout One-hour Dose Continuous infusion dose(s) (1) Administered Dose* (2) Interval (3) Limit (optional) (4) rate in mg/hr (5) Morphine (6) Opioid naive: 1 mg 8 –20 min . 7–10 mg 2-4 mg q 15 min Elderly (>70 yrs .) 0 .5 mg 8 –20 min . 4– 6 mg 2mg q 20 min . titrated to pain relief Hydromorphone Opioid naive: 0 .2 mg 8 –20 min . 0 .7–1 .4 mg (Dilaudid) 0 .2–0 .3 mg q 15 min Elderly (>70 yrs .) Elderly: 0 .1 mg 8 –20 min . 0 .4–0 .6 mg 0 .2mg q 20 min titrated to pain relief

When indicated, calculate based on

intermittent PCA use or previous opioid

requirement .

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Opioid Dosing in Renal or Hepatic DysfunctionGiven the paucity of pharmacokinetic and pharmacodynamic data of opioids in renal failure, it is difficult to advocate for specific analgesic treatment algorithms . However, the following guide has been proposed for the initial dosing of the safer opioids in renal failure .

• CreatinineClearance>50mL/min:normaldosing. •CreatiningClearance<10mL/min:50%ofnormal• CreatinineClearanceof10-50mL/min:75%ofnormal.

Opioid name Recommendation CommentsCodeine Not recommended Causes profound toxicity which can be delayed and may occur after trivial dosesFentanyl Considered safe Has no active metabolicsHydromorphone Use with caution Considered safe in dialysis patientsMeperidine Not recommended Accumulation of normeperidine can cause seizuresMethadone Considered safe No active metabolites; has several other precautionsMorphine Not recommended Rapid accumulation of nondialyzable metabolites that are neurotoxic, avoid long acting preparationsOxycodone Use with caution Can accumulated resulting in CNS toxicity and sedationOxymorphone Use with caution May accumulate resulting in respiratory depression and oversedation

Opioid name Recommendation CommentsCodeine Not recommended Impaired conversion of codeine to the active compound, morphine, in the liver to be active

Fentanyl Considered safe Pharmacokinetics were not altered in patients with cirrhosis. With continued use, recovery time after termination of infusion may be longer

Hydromorphone Use with caution Risk of accumulation of parent drug due to decreased conversion to metabolites and decreased elimination. Recommended to decrease dose by 50% of the usual amount.

Meperidine Not recommended Accumulation of toxic metabolite, normeperidine, may cause CNS toxicity Methadone Not recommended Risk of accumulation with severe liver disease.

Morphine Use with caution Recommended to decrease frequency of administration and dosage because of decreased clearance and increased t1/2 and oral bioavailability

Oxycodone Use with caution Risk of accumulation of parent drug due to decreased conversion to metabolites and decreased elimination.Recommended to reduce dose by 1/2 to 1/3 of the usual amount and avoid in severe cirrhosis

Oxymorphone Not recommended Contraindicated in moderate to severe liver dysfunction. Recommend 1/2 of the usual dose in mild hepatic impairment

References:Arnold RM, Verrico P, and Davison SN. Opioid Use in Renal Failure #161. J Palliat Med. 2007. 10(6):1403.Gina Carbonara, PharmD. Opioids in Patients with Renal or Hepatic Dysfunction. Practical Pain Management Volume 8, Issue 4

General Opioid safety recommendations in renal insufficiency:

General Opioid safety recommendations in hepatic insufficiency:

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Guidelines for Naloxone Administration and Patient Monitoring1. Nurses may administer naloxone without a physician’s order

when patients who have received an opioid meet the following criteria: (a)SedationScale=3(Somnolent;Difficulttoarouse),(b)RR<8 OR OxygenSaturation<92%andRR<12

2. If the criteria listed above are met, stop the administration of the opioid (including fentanyl patches) and benzodiazepines .

3. Provide oxygen via face mask STAT.

4. Method for naloxone administration: Naloxone 0.04 mg IV q 1 minute until a change in alertness is observed. Dilute 0 .4mg naloxone (one ampule) with NSS to a total volume of 10ml (1 ml = 0 .04 mg) in a 10 ml syringe .

5. Notify the primary physician and/or house staff of the need to immediately evaluate the patient. If the house staff does not arrive within five minutes or if the nurse assesses the need, a “Condition C” should be called .

6 Titrate the prescribed naloxone until the patient is responsive. The half-life of naloxone (ONE HOUR) is shorter than the half-life of opioid agonists . Naloxone administration should not cause pain to return or precipitate opioid withdrawal. If a response is not obtained after one ampule of naloxone (10 cc of diluted solu-tion) is administered, examine the patient for alternate causes of sedation and respiratory depression. For assistance with further naloxone dosing, please contact the Toxicology Treatment Program (412-647-7000) .

7. Re-evaluate the events leading to the need for naloxone administration. In cases where the prescribed opioid dosing was too high, reassess the therapeutic plan for pain management . Consider decreasing the opioid dose by 50%. Resume opioid administration when the patient is easily aroused, is beginning to experience pain, and after the RR increases to > 9 .

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Non Pharmacologic and Indirect Measures for Treatment of InsomniaInsomnia is most often secondary and attributable to underlying medical or psychological conditions, medications or other substances that interfere with sleep or poor sleep environment.

Non-pharmacologic Components Evidence

Good sleep hygiene behaviors Stable bedtimes and rising times, no nappingRegular daytime light exposureQuiet dark room at night; no TV while trying to sleepFamily should place familiar items in the patient’s roomAvoid evening intake of caffeine, nicotine, alcohol, and diureticsMinimize nighttime procedures and noiseMinimize administration of steroids, beta blockers, psychostimulants at nighttimeMaintain adequate nutritionNo heavy exercise/ bright lights before bedtimeEncourage a 30 min relaxation period before bedtime

Can improve time to onset of sleep and total sleep time

Treating underlying disorders and symptoms Use of BIPAP for obstructive sleep apneaManage pain, dyspnea, nausea and vomitingLook for heart failure, gastroesophageal reflux and chronic obstructive pulmonary disease

Some patients report difficulty becoming accustomed to sleeping with the BiPAP mask on, this therapy can dramatically improve symptoms

Address spiritual concerns Directly address a patient questions, spiritual concerns, worries, and fearsCan request for pastoral care or psychologist input

Other measures such as sleep restriction, cognitive behavioral therapy and biofeedback with progressive muscle relaxation are implemented as outpatient therapies usually under the guidance of a specialistReferences:1. Wilson JF. In the clinic. Insomnia Ann Intern Med. 2008 Jan 1;148(1):ITC13-1-ITC13-16.2. UPMC Presbyterian Shadyside, Pharmacy & Therapeutics Committee Drug Use and Disease State Management Program: Therapeutic Approaches to Acute Insomnia in Hospitalized Patients.3. M Miller; R Arnold. Fast Fast Fact and Concept #104: Non-pharmacological Therapy for Insomnia. End-of-Life/Palliative Education Resource Center (www.eperc.mcw.edu). Accessed April 15, 2013

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Pharmacologic treatments for insomnia:Class

Drug (Generic name)

Starting po dose Onset of action T max T1/2 Glucuronidation* Comments

BZDs Temazepam 15-30 mg,Elderly:7.5 mg 30 min-1 hr 1.4 hrs 3-18 hrs Y Daytime sedation, anterograde amnesia, falls, rebound insomnia are found with all. rebound insomnia was not reported in studies of Non BZDs.Agitation, disorientation, headache have been reported with Non-BZDs. Zolpidem Is also associated with complex sleep behaviors (sleep driving, sleep eating) but may occur more with concomitant alcohol and antidepressants

Lorazepam 1 mg Elderly:0.5 mg 30 min 0.5-3 hrs 12 hrs Y

Oxazepam 15 mg No Data 2-3 hrs 3-9 hrs Y

Non-BZDs** Zolpidem 10 mg.Elderly: 5 mg No Data 1.6 hrs 2.5 hrs N

Zaleplon 10 mg Elderly: 5 mg No Data 1 hr 1 hr N

Eszopiclone 2-3 mg Elderly: 1-2 mg No Data 1 hr 6 hrs N

Antidepressant Trazodone 25-100 mg No Data 0.5-2 hrs 7.1 hrs N Not FDA approved. Is an automatic substitution for diphenhydramine for use in insomnia in elderly

BZDs: Benzodiazepines, Non-BZDs: Non-Benzodiazepines*Only intermediate half life benzodiazepines are recommended for pharmacologic treatment of insomnia. Those with non-oxidative (glucuronidation) metabolism are preferred in the elderly. Oxidation for all except Zaleplon is via the cytochrome P450 pathway**UPMC preferredOther sedating antidepressants such as Tricyclics, Mirtazapine are not recommended for the treatment of pure insomnia without underlying depression because of higher incidence of anticholinergic and cardiac conduction side effects.For Restless Legs Syndrome, start Pergolide at a dose of 0.05 mg and increase to 0.2-0.5 mg taken in divided doses before bedtime). Side effects of pergolide include abdominal pain, nasal stuffiness, nightmares, and recurrence of symptoms earlier in the day. Other dopamine agonists such as bromocriptine, pramipexole, and ropinirole can also be used. If poorly tolerated, benzodiazepine agents, opiates or gabapentin may be used.

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Nausea and Vomiting: TreatmentMechanism-based therapy involves the following steps:1. A complete history and physical including oropha-

ryngeal, abdominal, rectal and neurological exams2. Consider labs: BUN/Cr, Na, LFT’s, amylase/lipase,

Ca, drug levels3. Consider imaging: flat plate of the abdomen to

assess for constipation, Abdominal CT to evaluate for obstruction, Head CT/MRI

4. Determine which receptors are mediating the symptoms (see below)

5. Choose an antiemetic to block the implicated recep-tors (see next page)

Pathophysiology of nausea and vomiting. Nausea and vomiting are triggered by activation of one of four main pathways:1 . Chemoreceptor Trigger Zone (CTZ): Main receptors:

D2, 5HT3, NK12. Cortex: Main receptors are in the vomiting center.3. Vestibular apparatus: Main receptors: Ach, H14. Peripheral pathways: Mediates nausea from trigger-

ing of GI/visceral chemoreceptors (local toxins) and mechanoreceptors (stretch). Enterochromaffin cells release 5HT3 when damaged (ie by chemotherapy or radiation) which activates local 5HT3 receptors.

These four pathways send signals to the vomiting center

(main receptors: H1, Ach, 5HT2) which triggers nausea and vomiting when thresholds are reached.If nausea is persistent, severe or refractory:• Schedule antiemetics around the clock, not PRN• Choosesecondandthirdantiemeticswhichworkon

different receptors.• ConsiderPalliativeCareconsultforsecondandthird

line therapiesIN ADDITION TO USING ANTIEMETICS, ALWAYS TREAT ANY REVERSIBLE CAUSES (medications, anxiety, constipation, hypercalcemia, thrush, increased ICP, GERD, pain)ALWAYS EVALUATE FOR CONSTIPATION AND PERFORM A RECTAL EXAMAvoid use of promethazine because of adverse effects including sedation and respiratory depressionAvoid benzodiazepines unless the nausea is from anxiety because they can sedate the patient and increase risk of aspirationFor nausea associated with vomiting, give antiemetics via the IV route until symptoms are controlledEvaluate for clinical signs of bowel obstruction (persis-tent nausea briefly relieved by vomiting, abdominal pain, distended abdomen, obstipation)If bowel obstruction, consider surgery and/or GI consults for possible surgical repair or venting PEG tube

Consider palliative care consult for medical management of bowel obstruction.References:Wood GJ, Shega JW, Lynch B, Von Roenn JH. Management of intractable nausea and vomiting in patients at the end of life “I was feeling nauseous all of the time…nothing was working.” JAMA. 2007;298(10): 1196-1207.

Receptors:D2: Dopamine type 2 receptor, 5HT3: 5-hydroxytrypta-mine type 3 receptor, 5HT2: 5-hydroxytryptamine type 2 receptor, Achm: muscarinic acetylcholine receptor, H1: histamine type 1 receptor, NK1: Neurokinin type 1 receptor

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Drug (Generic Name)

Receptoractivity

Common ClinicalIndications Dosage/Route Cost Comments/

Side Effects

Haloperidol D2 Opioid Induced N/V 0.5-4 mg PO or SQ or IV Q6h $ IV has less EPS compared to PO

Metoclopramide Peripheral D2 Impaired GI motility Opioid Induced N/V

5-20 mg PO or SQ or IV AC and HS $ EPS, esophageal spasm,and colic inGI tract obstruction

Prochlorperazine D2 Opioid Induced N/V N/V of unknown etiology

5-10 mg PO or IV every 6 h or 25mg PR Q6h

$ EPS and sedation

Scopolamine Ach, H1 Motion induced N/V 1.5 mg Transdermal patch every 3 d $ Dry mouth, blurred vision, ileus, urinary retention, and confusion

Ondansetron 5HT 3 Chemotherapy or radiation induced N/V

4-8 mg PO as a pill or dissolvable tablet or IV every 4-8 h

$$ Headache, fatigue, and constipation

Dexamethasone Decrease ICP N/V related to Increased ICP

4-8 mg QAM or BID, PO (as pill or liquid) and IV

$ Agitation, Insomnia, Hyperglycemia

N/V: Nausea/Vomiting

Nausea and Vomiting: Treatment

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Medication Onset of action Usual starting dosage Site and Mechanism of ActionOsmotic laxatives

Lactulose 24-48 hr 15-30 ml q12-24 hr Colon; osmotic effect

Polyethylene Glycol 48-96 hr 17g (1tbsp) powder in 8oz water q24 hr GI tract; osmotic effect

Sorbitol 24-48 hr 15-30 ml q12-24 hr, max 150 ml/d Colon; delivers osmotically active molecules to the colon

Saline Laxatives*

Magnesium citrate 30 min-3 hr 120-240 ml x1; 10 oz q24 hr Small and large bowel; attracts and retains water in the bowel lumen

Magnesium hydroxide (MOM) 30 min-3 hr 30 ml q12-24h Colon; osmotic effect & increased peristalsis

Stimulant laxatives

Bisacodyl 6-10 hr 5-15 mg x1 Colon; stimulates peristalsis

Bisacodyl (PR) 15 min-1 hr 10 mg x1 Colon; stimulates peristalsis

Senna 6-10 hr 2 tabs qhs Colon; stimulate myenteric plexus, alters water and electrolyte secretion

Surface laxatives

Docusate 24-72 hr 100 mg q12-24 hr Small and large bowel; detergent activity; softens feces

Constipation and Bowel Protocol

Bulk laxatives alone are not useful in the treatment of opiate induced constipation*Avoid use of MOM and related products (including sodium phosphate enema products) in patients with renal dysfunction because of risk of hyperphosphatemiaReference: Reuben DB, Herr KA, Pacala JT, et al. Geriatrics at Your Fingertips 2009, 11th edition. New York: The American Geriatrics Society; 2009

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Constipation and Bowel Protocol (page2)

BOWEL REGIMEN: With few exceptions, all patients on opioid therapy need an individualized bowel regimen. When and effective regimen is found it must be continued for the duration of the opioid therapy. If a patient has not been on a bowel regimen, the step 1 regimen should be started. If there is no response in 24 hours, move to the next step. At any given time, if there has been no bowel movement in four or more days, a sodium phosphate or mineral oil enema should be administered. If this is not effective, a high colonic tap water enema should be administered. Be aware of the possibility of bowel obstruction or fecal impaction. A digital rectal exam should be performed prior to starting a bowel regimen and if no BM for 4 days.

Other drugs that can exacerbate constipation: anticholinergics (tricyclic antidepressants, scopolamine, oxybutinin, promethazine, diphenhydramine), lithium, verapamil, bismuth, iron, aluminium, calcium salts.

Opiod Antagonists to treat refractory constipation: Methylnaltrexone (MNTX) is a quaternary amine which does not cross the blood brain barrier to cause reversal of opioid analgesia or withdrawal. Use of oral naloxone for constipation has been associated with these effects. MNTX is approved for use in patients who have been on a steady opioid regimen for 2 weeks and laxative regimen for 3 days. Greater than 50% of patients will have a bowel movement within 4 hours of being given the dose by subcutaneous injection. In general, it is recommended that oral and rectal laxative regimens should have been tried, prior to utilizing MNTX. Pts with fecal ostomy bags and PD catheters were excluded from the studies. There is a dosing order set in the EMR.

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Delirium: Diagnosis DSM-IV criteria for delirium include four components: A . Acute onset, over hours to days .B . Behavioral disturbance, marked by a reduced clarity in the patient’s

awareness of the environment, with impaired ability to focus, sustain, or shift attention . The patient may be agitated, irritable, and emotionally labile, OR drowsy, quiet, and withdrawn .

C . Consciousness level fluctuates over the course of the day . D . Different from dementia, delirium cannot be accounted for by a patient’s

preexisting, established, or evolving dementia . Delirium is conceptualized as a reversible illness, except in the last 24–48 hours of life .

1 . Delirium occurs in at least 25–50% of hospitalized cancer patients, and in a higher percentage of patients who are terminally ill . Delirium increases the risk of in-hospital and six-month mortality .

2 . Differential diagnosis: D: Drugs (opioids, anticholinergics, sedatives, benzodiazepines, steroids, chemo- and immunotherapies, some antibiot-ics); E: Eyes and Ears (poor vision and hearing, isolation); L: Low flow states (hypoxia, MI, CHF, COPD, shock); I: Infections; R: Retention (urine/stool), Restraints; I: Intracranial (CNS metastases, seizures, subdural, CVA, hypertensive encephalopathy); U: Under-hydration, Under-nutrition, Under-sleep; M: Metabolic disorders (sodium, glucose, thyroid, hepatic, deficiencies of vitamin B12, folate, niacin, and thiamine) and Toxic (lead, manganese, mercury, alcohol) .

3 . Routinely screen for delirium, and monitor delirious patients frequently .

AssessmentAsk family or friends of patient

Patient is easily distracted . Abnormal Digit Span: Inability to repeat a series of five digits (start with reading aloud a string of two random digits, then increase) and Vigilance A: At least two errors (read aloud in neutral normal tone a list of 10 letters with four A’s . Patient taps when A is read) . Rambling or irrelevant conversation, unclear or illogical flow of ideas, or topic switching, or ask patient’s family . Ask: 1) Can a rock float? 2) Are there fish in the sea? 3) Is one pound more than two pounds? 4) Do you use a hammer to pound a nail? 5) Command say to patient, “Hold up this many fingers .” (Examiner holds two fingers in front of patient .) Next, do the same thing with the other hand (not repeating holding up the number of fingers) .

Hyper-alert, drowsy, stuporous, or unarousable

Feature1 . Acute onset and fluctuating course

AND 2 . Inattention

PLUS3 . Disorganized thinking >2 errors

OR4 . Altered level of consciousness

Confusion Assessment Method (CAM) ICU for the Diagnosis of DeliriumDiagnosis positive with 1 and 2, plus 3 or 4

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Delirium: Diagnosis The scale is completed based on information collected from each item over an 8 hour shift or the previous 24 hours. Obvious manifestation of an item = 1 pointNo manifestation of an item or no assessment possible = 0 point

Patient evaluation Day 1 Day 2 Day 3 Day 4 Day 5

Altered Level of consciousness

If A or B do not complete patient evaluation for the period

Inattention

Disorientation

Hallucinations-delusion-psychosis

Psychomotor agitation or retardation

Inappropriate speech or mood

Sleep/wake cycle disturbance

Symptom fluctuation

Total ScoreLevel of consciousness: A: no response No score B: response to intense and repeated stimulation (loud voice and pain) No score C: Response to mild or moderate stimulation 1 D: normal wakefulness 1 E: exaggerated response to normal stimulation 1Inattention: Difficulty in following a conversation or instructionsDisorientation: Any obvious mistake in time, place, personHallucinations, delusion or psychosis: Overt clinical manifestation of hallucination or behavior related to hallucination or delusionPsychomotor agitation or retardation: Hyperactivity requiring restraints or drugs, clinically noticeable psychomotor slowingInappropriate speech or mood: Disorganized or incoherent or inappropriate speech. Inappropriate display of emotion related to events of situationSleep/wake cycle disturbance: Sleeping <4 hours or waking frequently at night (not initiated by staff or loud environment), sleeping during most of the daySymptom fluctuation: Fluctuation of any item over 24 hoursReference: See www.icudelirium.org for more information

The Intensive Care Delirium Screening Checklist (ICDSC)

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Delirium: Treatment Rule out other medical causes of delirium . Review medications, and discontinue or decrease anticholinergic and/or benzodiazepine doses . Check for drug-drug interactions . Rotate opioids, reduce doses by 25% if possible, and avoid meperidine .

Benzodiazepines are NOT effective in treating delirium, may worsen delirium, and should be used cautiously only as adjunct therapy with neuroleptics when relief of agitation is required .

Neuroleptics are used for treatment of delirium . Haloperidol is the standard neuroleptic for treatment of delirium . Risperidone, olanzapine, and quetiapine are atypical neuroleptics, generally with fewer side effects . All neuroleptics can cause QT prolongation .

Supportive care to prevent and reduce delirium includes frequent orientation (well-lit rooms, caregivers, calendars, clocks, communication), therapeutic activities (patient mobilization 3x/day when possible), non-pharmacologic sleep aids (see page 12), treatment of hearing and vision problems, treatment of incontinence, and volume repletion . Confusion increases the risk of falls . Pay attention to patient safety . Constant supervision (sitter) may be more beneficial than restraints or sedation .

Table 2: Drugs used for treatment of delirium in the hospital setting

Generic name(Common brandname)

Starting dose

Dosing interval

Max q24hdose

Formulations EPS Anti-cholinergic

Sedation Comments**

Haloperidol(Haldol®)

0 .5-1 mg(2 mg in ICU*)

0 .5-1 hour forurgentsymptoms .Otherwise Q6Hor Q8H

20 mg 0 .5, 1, 2, 5, 10 mgtablets . Available asoral solution and asan injectableproduct .

+++ + ++ IV has less EPScompared to PO .***

(continued)

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Abbreviations: EPS: extrapyramidal symptoms; IM: intramuscular; IV: intravenous; ODT: oral disintegrating tablet; SQ: subcutaneous .Definition: †Sundowning: Onset of confusion in the elderly that typically begins in the evening*Refer to the UPMC Presbyterian Shadyside “Acute Agitation Management” order set .** The FDA has determined that the use of antipsychotic medications in the treatment of behavioral disorders in elderly patients with dementia is associated with increased mortality . This risk appears to be highest during the first two weeks of use .*** Use IV haloperidol with caution in patients with prolonged QT interval . Increased risk of arrhythmia and sudden death exists with high IV doses .

Generic name(Common brandname)

Starting dose

Dosing interval

Max q24hdose

Formulations EPS Anti-cholinergic

Sedation Comments**

Risperidone(Risperdal®)

0 .25-1 mg BID or up to Q6HPRN

6 mg 0 .25, 0 .5, 1, 2, 3,4 mg tablets .Available as ODT (not for 0 .25)

++ + + Caution withrenal failure .

Olanzapine(Zyprexa®)

2 .5-10 mg

Debilitatedor elderly:2 .5 mg .

DAILY

IM: Q2H

20 mg 2 .5, 5, 7 .5, 10, 15,20 mg tablets .Available as ODT (5, 10,15 & 20 mg)and IM injection

+ +++ ++ Patients with hypoactivedelirium, >70yearsCNS malignancymay not respond well .

Quetiapine(Seroquel®)

12 .5- 50 mg

BID 800 mg 25, 50, 100, 200,300, 400 mg tablets

+ ++ +++ Start DAILY at 4pm forsundowning† and then time subsequent, additional dosesbased on symptoms .

Aripiprazole(Abilify®)

5-15 mg Q AM 30 mg 2, 5, 10 . 15, 20,30 mg . Available asIM and oral solution . Available as ODT (10 & 15 mg)

++ + ++ Useful for hypoactivedelirium . Can cause insomnia if given at night

Delirium: Treatment

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Depression: Screening Tools and TreatmentA shorter screening test for depression is to ask:

1 . Are you feeling either depressed or hopeless most of the time over the last 2 weeks?

2 . Have you found little brings you pleasure or joy over the last 2 weeks?

From: R Arnold . Fast Fact and Concept #146: Screening for Depression in Palliative Care . End-of-Life/Palliative Education Resource Center (www .eperc .mcw .edu) . 2005

Spiritual Distress Screen—A Quick Screen

1 . Ask “Are you at peace?”

2 . If the answer is no, ask the patient if he/she would like to see a chaplain .

Source: Archives of Internal Med 2006:166:101-5 .

Some select antidepressants are listed in the table next page:

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Category Generic(Common Brand Name)

Starting PO dose(depression)*

Dosinginterval

Therapeuticdose/day range*

Generic(Y/N)

Formulations (mg)

SSRIs Citalopram(Celexa®)

10-20 mg DAILY 10-60 mg Y 10, 20, 40 (tablets)10 mg/5 mL (solution)

Escitalopram(Lexapro®)

5-10 mg DAILY 10-20 mg N 5,10, 20 (tablets)5 mg/5 mL (solution)

Sertraline(Zoloft®)

25-50 mg DAILY 50-200 mg Y 25, 50, 100 (tablets)100 mg/5 mL (solution)

SNRIs Venlafaxine(Effexor®)

75 mg/day divided BID-TID 150-375 mg Y 25, 37 .5, 50, 75, 100 (tablets)

Venlafaxine XR(Effexor XR®)

37 .5-75 mg DAILY 75-225 mg N 37 .5, 75, 150 (capsules)

Duloxetine(Cymbalta®)

20 mg BID 30-60 mg N 20, 30, 60 (delayed-released capsules)

Stimulants Methylphenidate(Ritalin®)

2 .5-5 mg BID 8a,12p 5-40 mg (fordepression)

Y 5, 10, 20(tablets)

Commonly used antidepressants: dosing, formulations

Abbreviations: CR, SR, XL, XR: sustained-release products SSRIs: Serotonic Specific Reuptake Inhibitors, SNRIs: Serotonin Norepinephrine Reuptake InhibitorsOthers: Use the following w/caution in renally impaired patients: all SNRIs, all formulations of buproprion and mirtazapineUse the following w/caution in hepatically impaired patients: All SSRIs, methylphenidate, all SNRIs and bupropion*The therapeutic dose/day range varies from the minimum efficacious dose up to the maximum tolerated or daily recommended amounts . Maximum daily doses are dependent upon indication for use and should only be used as a guide . Initial doses should be low in elderly patients and increased gradually . Doses of up to 300 mg of venlafaxine XR have been used in practice, but are not FDA-approved . The doses for methylphenidate can be higher than 20mg but are generally not recommended .

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Drug (Commonbrand name)

Cost perday*

Anticholinergic Insomnia GI Distress Comments**

Citalopram(Celexa®)

<$ + + ++ Mild to moderately activating, few drug interactions .

Escitalopram(Lexapro®)

$ + +++ ++ t1/2 similar to Sertraline and Citalopram

Sertraline(Zoloft®)

$ -- + +++ Moderately activating .

Venlafaxine(Effexor®)

$$ + +++ +++ Dual serotonin/norepinephrine action at doses of 150-225mg which is effective in neuropathic pain and is mildly activating . On switching from thevenlafaxine XR to venlafaxine, the shorter half life of venlafaxine requires frequent dosing to reach the same dose of venlafaxine XR .Use with caution in patients with hypertension .

Venlafaxine XR(Effexor® XR)

$$$$ + +++ ++

Duloxetine(Cymbalta®)

$$$$ ++ ++ ++ FDA-approved for diabetic neuropathy and off-label use for urinary incontinence . Do not use in patients with liver dysfunction . Use caution in patients with seizure disorder .

Methylphenidate(Ritalin®)***

<$ -- +++ + Energizing, may increase appetite .

Commonly used antidepressants: costs, side effects, comments

Abbreviations: ODT: oral disintegrating tablet; t1/2: half-life .*Cost per day of a typical daily dose was calculated based on generic products when available . Cost data was extrapolated from www .drugstore .com .**Activating antidepressants tend to cause insomnia .***Not FDA-approved for treatment of depression . Differences in arrythmogenicity are not clinically relevant among these groups .

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Treatment of Dyspnea and Pain at the End of Life 1 . The following guidelines are for “comfort measures” patients

ONLY . See CPOE CMO order sets .

• “Titratetocomfort”medicationordersarenotacceptable.Parameters for drug dosing and titration must be included on all written and electronic care sets .

2 . Opioid naive patient (all doses are for morphine):

• Loadingdose:2–5mgIVpush.

• Ifdistressnotrelievedin15minutesafterinitialloadingdose,give bolus equal the loading dose increased by 50 percent . If severe distress persists repeat the dose every 15 minutes until comfortable .

• Forincreasedpain/distressgiveextrabolusdose/sequaltothelast given bolus dose every 30 minutes as needed .

• Ifusingmorethan2bolusdosesover6-hourperiod,considerstarting a continuous infusion . To calculate the continuous infusion rate divide the total dose over last 6 hours by 6 .

3 . Non-naive patients:

• Forpatientswhohavebeentakingopioidpainmedicationswithin last 24 hours calculate the equianalgesic parenteral dose of morphine for the last 24 hrs (see page 4 for opioid equivalencies) .

• Dividethetotal24hourIVmorphinedoseby24todetermineinitial hourly infusion rate (mg/hour, IV) . Start continuous infusion at this rate .

• Ifpatientinpain/distressuseloadingdose=hourly infusion rate .

• Ifdistressnotrelievedin15minutesafterinitialloadingdoseorthe patient in increased pain/distress, administer the loading dose increased by 50 percent and repeat every 15 minutes until comfortable .

• Ifusingmorethantwobolusdosesover6-hourperiod,deter-mine new continuous infusion rate by recalculating total dose given over last 6 hours and dividing it by 6 .

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Oral Secretions at the End of Life As the level of consciousness decreases in the dying process, patients lose their ability to swallow and clear oral secretions . As air moves over the secretions, the resulting turbulence produces noisy ventilation with each breath, described as gurgling or rattling noises . Death rattle is a good predictor of near death; one study indicated the median time from the onset of death rattle to death was 16 hours .

Non-pharmacological treatments: Position the patient on their side or in a semi-prone position to facilitate postural drainage . Reassure family about noise; can compare to snoring .

While there are no evidence-based guidelines, the standard of care is to use muscarinic receptor blockers (anti-cholinergic drugs) .

*Use atropine ophthalmic drops .Tertiary amines which cross the blood-brain barrier (all but glycopyrrolate) cause CNS toxicity (sedation, delirium) . Source: K Bickel; R Arnold . Fast Fact and Concept #109: Death Rattle and Oral Secretions, 2nd Edition . End-of-Life/Palliative Education Resource Center (www .eperc .mcw .edu) 2003 .

Drug (Trade Name) Route Starting Dose Onset

hyoscyamine hydrochloride Scopolamine Transdermal 1 (~1 mg/3 days) 12 hrs .

hyoscyamine sulfate Levsin Drops, Tabs (oral) 0 .125 mg 30 min .

glycopyrrolate Robinul Pills (oral) 1 mg 30 min .

glycopyrrolate Robinul Injection (SC, IV) 0 .2 mg 1 min .

atropine Atropine Injection 0 .1 mg 1 min .

atropine multiple Sublingual* 1 gtt (1%) 30 min

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UPMC Palliative Care and Pain Treatment Resources (area code 412)Inpatient Supportive and Palliative Care ServicesPUH/MUH Supportive & Palliative Care Service 647-7243, pager: 8511Shadyside Supportive & Palliative Care Service 647-7243, pager: 8513Magee Womens Hospital of UPMC Supportive and Palliative Care Service 647-7243, pager: 8510Children’s Hospital of Pittsburgh of UPMC Supportive Care Program 692-3234VA Palliative Care Program Inpatient and oncology: 688-6000 Ext. 816178; or pager - 645-2345 Geriatric palliative care: pager - 958-0215

Inpatient Medical Ethics ServicesPUH/MUH Medical Ethics 647-7243, pager: 2881Shadyside Medical Ethics 263-8347

Pain Treatment ServicesPUH/MUH Chronic Pain Service 647-4991Shadyside Chronic Pain Service 665-8030, after hours call 665-8031PUH/MUH Acute Interventional Perioperative Pain Service (AIPPS) 647-7243, pager: 7246 (PAIN)Shadyside Acute Interventional Perioperative Pain Service (AIPPS) 692-2333

Outpatient ServicesUPMC Hillman Cancer Center’s Cancer Pain and Supportive Care Program 692-4724UPMC Heart and Vascular Institute’s Advanced Heart Failure Clinic 647-6000Magee Women’s Cancer Center 641-4530Magee Gynecologic Cancer Program 641-5411 or 641-5566Benedum Geriatric Center Supportive Care Clinic 692-4200Renal Supportive Care Clinic 802-3043Magee - Chronic non malignant/spine/muscular skeletal pain (outpatient) 901-2891UPMC Presbyterian Pain Medicine (outpatient) 692-2234St. Margaret Pain Medicine (outpatient) and Chronic Pain Service 784-5119 (outpatient) or 784-4000 (Hospital Operator)

Family Hospice and Palliative Care 572-8800

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Questions or comments regarding this information, contact Robert Arnold, MD (rabob@pitt.edu), 692-4834, pager 2322. This information provided by the UPMC Supportive and Palliative Care Program is merely in the form of recommendations and does not replace the service of a physician. Author: Mamta Bhatnagar, MD with Lisa Podgurski, MD; Susan Skledar, RPh, MPH; Peg Verrico, RPh; and Robert Arnold, MD. This pain card was made possible with the assistance of Kimberly L. Gottschalk, MBA and the generous support of the UPMC Palliative and Supportive Institute. Produced in cooperation with the University of Pittsburgh. UMC90239-0413

•Psychological or spiritual counseling for patients and their families•Discharge planning and interface with local hospices•Bereavement services in the event of death•Outpatient palliative care follow-up

Indications for Palliative Care Referral:•Pain in patients with life-limiting illness•Management of other symptoms such as nausea, vomiting, shortness of breath, delirium •Negotiating goals of treatment or end-of-life decision making•Family support for a patient with a life-limiting illness

VERSION 9 .0 PAIN CARD