DYSPNEA IN ADVANCED DISEASE

Porter Storey MD, FACP, FAAHPM

CONFLICT OF INTEREST DISCLOSURES - NONE

NOT FDA APPROVED (OFF – LABEL USES)

• Haloperidol for agitated delirium

• Lorazepam for sedation of the ventilated patient

• Clonazepam for anxiety• Trazodone for insomnia

• Morphine, oxycodone, hydromorphone, and fentanyl (sl or iv) for

• Cancer pain in children• Postoperative pain in

children• Delivery via PCA pump• Relief of dyspnea in

advanced disease

LEARNING OBJECTIVES

• At the conclusion of this talk, you should be able to:

1) Describe 4 components of the physiology of dyspnea,2) Explain 3 ways opioids may increase ventilatory efficiency, and3) Name several ways effective teamwork can help relieve dyspnea in advanced disease.

DYSPNEA

• Old Misinformation

• Must improve heart or lungs to help

• Opioids contraindicated

“HELP ME, I CAN’T BREATHE!”

Breast cancer with lung mets, radiation toxicity, pleural effusion, + pneumothorax

Worried about what this means

Now unable to work and support her children

Why me?

DAME CICELY SAUNDERS

“Total” Pain or BreathlessnessPhysical causes – often multiple,

e.g. airway obstruction, pleural effusion, CHF, PE, pneumothorax

Psychological – anxiety, depression

Social issues – isolation, angerFinancial – care costs, unable to

workSpiritual – meaning, purpose,

hopeStaff – efficiency, burnout, prof

mask

“TOTAL BREATHLESSNESS”

• End-stage COPD refusing oxygen and medications

• “I did this to myself!”• “I don’t deserve them.”

• Wife frantic• “Help us! He’s dying!”• Her diabetes out of control.

• Illegal immigrant with no insurance.

• Strong faith, but prayers not being answered now.

RESEARCH IN MULTIDIMENSIONAL DYSPNEA

Meek PM, Banzett R, et al. Eur Respir J. 2015 Jun; 45(6): 1681–1691.

RESEARCH IN PSYCHOLOGICAL ASPECTS OF RESPIRATORY DISEASE

• Likelihood of COPD hospitalization • Higher if more depression and anxiety

• Pooler A, Int J Chron Obstruct Pulmon Dis 2014;9:315-330.

• Higher if sleep and mental disorder• Ohayon MM, J Psychiatr Res 2014; epub

• Lower if self-management program utilized• Zwerink M, Cochrane database Syst Rev 2014: epub

• Dyspnea relief w acupuncture• Suzuki M Arch Intern Med 2012; 172 (11):878-86.• Romeo MJ, Explore (NY). 2015 Sep-Oct;11(5):357-62.

PROPOSED PHYSIOLOGY OF DYSPNEA

“A subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.”

American Thoracic Society 2012

OPIOIDS INCREASE EXERCISE TOLERANCE

• Opioid reduced breathlessness and increased exercise tolerance in severe COPD patients.

• Woodcock AA, NEJM 1981; 305:1611-1616.

• Oral morphine increased exercise tolerance in COPD pts by reducing breathlessness for a given level of ventilation and allowing an elevation in pCO2 so less ventilation required for a given workload.

• Light RW Am Rev Resp Dis 1989; 139:126-133.

PROPOSED MECHANISMS FOR OPIOIDS INCREASE IN VENTILATORY EFFICIENCY

• Reduced bronchoconstriction• Improved gas exchange due to higher CO2 and lower O2 concentrations

• Reduction in responses to hypoxia and hypercapnia• Reduction in the drive to breath• Reduction in total ventilation

• Less oxygen required at rest or to exercise • Vasodilation of pulmonary vasculature• Increased inspiration

• Attenuate limbic responses to dyspnea

RESEARCH ON OPIOIDS AND DYSPNEA

• Neuroimaging studies suggest that the emotion-related structures involved in pain and dyspnea are shared.

• Odonnell DE, Proc Am Thorac Soc 2007; 4(2):145–168.• Von Leupoldt A, Neuroimage 2009; 48(1):200-206.

• Morphine reduces dyspnea and hypercapnic response in lab• Less “air hunger” from increased partial pressure of

end-tidal CO2 w restricted ventilation• Effectiveness of morphine validates model of dyspnea• Banzett RB, Am J Respir Crit Care Med. 2011 Oct 15;184(8):920-7.

ENDOGENOUS OPIOIDS AND DYSPNEA• Opioid receptors are located throughout lungs but especially in

alveoli, where they can modulate respiratory function.• Zebraski SE, Life Sci 2000; 66: 2221-31.• Krajnik M, Pharmacol Rep 2010; 62(1):139-49.

• Endogenous opioids reduce dyspnea in exercising COPD pts.• Ayiyama Y, J Appl Physiol 1993; 74: 590—5.• Gifford AH, COPD 2011;8:160–166.

• Reduced dyspnea effects reversed with naloxone.• Mahler DA, Eur Resp J 2009; 33(4): 771-777.• Mahler DA, Gifford AH, et al. Chest. 2013 May;143(5):1378-85.

JOHN’S ISSUES

-Disabling dyspnea

-Widely metastatic lung cancer

-Newly divorced-Marginal insurance-Upset son-“This isn’t fair!”

JOHN NEEDS THE FULL TEAM!

SLOW-RELEASE MORPHINE FOR COPD DYSPNEA

• Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea.

• Abernethy AP1, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. BMJ. 2003 Sep 6;327(7414):523-8.

• 48 pts w COPD

• Randomized to 4 days of morphine SR 20mg or placebo + crossover

• 38 completed study

• Morphine associated with• Less dyspnea• Better sleep• Constipation

LONG-TERM MORPHINE SR FOR DYSPNEA

• Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study.

• Currow DC1, McDonald C, Oaten S, Kenny B, Allcroft P, Frith P, Briffa M, Johnson MJ, Abernethy AP J Pain Symptom Manage 2011 Sep;42(3):388-99.

• 83 patients (mean 75yo, 54% COPD)

• Given morphine SR 10mg daily,

• Non-responders increase by 10mg daily each week.

• 62% responded, for 70% dose was 10mg/d.

• Benefit maintained for 3 mo for 33%.

• Breathlessness significantly better, constipation worst side-effect (no respiratory depression or hospitalization due to morphine)

META-ANALYSES AND SYSTEMATIC REVIEWS

• Marciniuk DD, Managing dyspnea in patients with advanced chronic obstructive pulmonary disease: A Canadian Thoracic Society Guideline. Can Respir J 2011; 18(2).

• We recommend that oral (but not nebulized) opioids be used for the treatment of refractory dyspnea in the individual patient with advanced COPD. (Grade of recommendation 2C)

• Ben-Aharon I, Interventions for alleviating cancer-related dyspnea: a systematic review and meta-analysis. Acta Oncol 2012; 51(8):996-1008.

• Our systematic review and meta-analysis demonstrate a beneficial effect to opioids in alleviating cancer-related dyspnea, and no advantage for the use of oxygen.

From Marciniuk D, Goodridge D, Hernandez P, et al. Managing dyspnea in patients with advanced chronic obstructivepulmonary disease: A Canadian Thoracic Society clinical practice guideline. Can Respir J. 2011;18(2):69-78.258Reprinted with permission.

Canadian Thoracic Society Guidelines

Managing Dyspnea in Advanced COPD

MANAGEMENT OF DYSPNEA IN PATIENTS WITH ADVANCED LUNG OR HEART

DISEASE•  patients should be asked to rate the intensity of their breathlessness as part of a comprehensive care plan, opioids should be dosed and titrated for relief of dyspnea in the individual patient, 

Mahler DA, Chest. 2010 Mar;137(3):674-91.

American College of Chest Physicians

OPIOID FOR DYSPNEA – SAFETY?68yo with COPD and advanced lung cancer

Would be on O2 if stopped smoking

Dyspnea and pain at rest

Wants to stay home with his dog

Highest priority comfort

Safe to administer an opioid?

SC MORPHINE RELIEVES CANCER DYSPNEA

WITHOUT RESPIRATORY DEPRESSION• Open, uncontrolled trial

• in 20 terminal ca pts, 5mg or 2.5 x reg

• 95% reported less dyspnea• No change in respiratory rate or

effort• No change in arterial O2 sat or end-

tidal PaCO2.• Bruera E J Pain Symptom 1990; 5(6):

341-344.• Crossover Placebo Controlled Trial

• 10 consecutive ca pts on stable opioid

• Dose increased 50% (avg 34.5 mg sc)• Good relief, no resp depression• Bruera E Ann Intern Med 1993;

119:906.

• Randomized double-blind trial• 9 elderly cancer patients• Received either 5mg sc or 3.75mg

more than regular dose.• In 45 min sig lower mean dyspnea

by VAS & Borg scales• No changes observed in respiratory

effort or rate,• No change in O2 sats

• Mazzocato C, Ann Oncol. 1999; 10(12):1511-4.

HYDROMORPHONE EFFECTIVE FOR DYSPNEA WITHOUT RESPIRATORY

DEPRESSION• 14 palliative care patients with dyspnea• All treated with hydromorphone and carefully monitored• In 30 minutes, average dyspnea dropped 5.2 to 1.1 on

10 point scale• Respiratory rate decreased 39 to 35 breaths / min• peripheral oxygen saturation unchanged • transcutaneous arterial pressure of carbon dioxide

unchanged• Clemens KE, Support Care Cancer. 2008; 16(1):93-9.

OPIOIDS SAFE AND EFFECTIVE FOR DYSPNEA IN ADVANCED

• Cancer dyspnea• Bruera E, J Pain Symptom Manage

1990; 5(6):341-4.

• COPD• Abernethy AP, BMJ 2003; 325:523-

539.

• Idiopathic pulmonary fibrosis• Allen S, Palliat Med 2005; 19(2): 128-

30.

• Cystic Fibrosis• Pediatrics 1997 Aug;100(2 Pt 1):205-

9.

• Motor Neuron Disease / ALS• Amyotroph Lateral Scler 2010

Dec;11(6):562-4.

• CHF• J Palliat Med 2013 Mar;16(3):250-5

COMPONENTS OF RELIEF

Careful assessment for treatable causes

Teamwork to address non-physical issues

General measures, O2, fan, relaxation

Skillful use of opioid

WHICH OPIOID & HOW MUCH ?

• Dyspnea-related History• Severity, onset, associations, effective interventions?• Adequate trial of disease-modifying or supportive interventions?• Good response to past use of opioid? Side-effects?• Difficulties controlling use of nicotine, alcohol, sedatives, cannabis,

or opioids?

• Exam and lab studies• Extent of disease?• Signs of treatable complication (pneumonia, effusion, etc.)?• Signs of CNS or GI disease that might predispose patient to side-

effects?

BUILDING TRUST

Do your evaluation in a way that says,

“Gosh, I see you are having a tough time!”

“There is more we can do to help.”

“We are going to be here when you need us!”

START LOW, TITRATE REGULARLY IF NEEDED

• Starting dose will vary based on symptom severity, frailty, co-morbidities

• Outpatient with moderate symptoms, one possible beginning might be

• hydrocodone or oxycodone 2.5 to 5mg every 4-6 hours as needed• With regular use of laxative

• Inpatients with more severe symptoms may benefit from • parenteral doses of morphine or hydromorphone to get relief

quickly and determine effective dosing.• Remember sleepless patient, finally comfortable, can look

overmedicated • Family and staff require some educating also.• Don’t forget the laxative!

USE ORAL MEDS WHEN POSSIBLE

Patient trust in provider important for therapeutic success.

IV or SC much less painful than IM.

LIKE TREATING PAIN-Use regularly scheduled or slow-release medication for persistent symptom. (Drug must be in patient to prevent distress).

-Breakthrough medication short-acting and as needed. Titrate doses regularly for best balance of relief and side-effects.

-Don’t forget the laxative!

OPIOID PRESCRIBING CONCERNS

• Side-effects • Tolerance rapidly develops

to • Sedation• Confusion• Itching

• Tolerance rarely develops to • Constipation

• Addiction and Abuse• Little evidence that normal

people become addicts when opioids prescribed appropriately

• People with addiction problems (tobacco, alcohol, drugs) often develop advanced disease.

• Overdose Deaths at crisis levels

OPIOID OVERDOSE DEATHS

OPIOID OVERDOSE DEATHS

• Prescription painkiller overdoses - a public health crisis

• 116 million people in the US suffer from chronic pain.• 12 million Americans (age 12 or older) reported

nonmedical use of prescription painkillers in the past year.• Drug overdose has now surpassed traffic accidents as the

leading cause of unintentional injury in the US.• 75% of pharmaceutical overdose deaths due to opioid analgesics

like oxycodone, hydrocodone, and methadone.

• Prescription painkiller overdoses killed over 16,600 people in the US in 2010.

OPIOID OVERDOSE DEATHSDrug overdose death rates by state per 100,000 people

NON-MEDICAL OPIOID SOURCE

Free from friend or relative 54%

Prescribed by physician(s) 20%

Stolen from friend or relative 5%

Bought from friend or relative 11%

Bought from dealer 4%

Stolen, fake script, etc. 5%

MANAGING OPIOIDS IN PATIENTS WITH ADDICTION HISTORY

• Engagement – develop a therapeutic relationship

• Assessment • Misuse or abuse?• Dependence?• Physical and mental health• Motivation to change?• Focus on patient’s strengths

• Define Goals• Controlling Substance Use• Harm reduction

• Tools to consider• Colorado Prescription Drug

Monitoring Program• Opioid Agreement?• Slow-release preparations

only

JUANITA

-Osteosarcoma widelymetastatic to lungs-Pain and dyspnea severe

with activity-Family in crisis-Trying to be brave-Mother rarely gives the

hydrocodone,afraid “of addiction”

WHAT WOULD MAKE A DIFFERENCE NOW?

-On morphine SR 60mg every 12 hours

-Comfortable enough to really enjoy the pizza party for her friends.

ON HER FINAL DAY-Now on equivalent of morphine 180mg IV / hr

-Communicates with family that she is comfortable

-Able to eat some jello and smile at jokes.

-Dies quietly when Mom steps away from room.

THE FINAL HOURS OF LIFE

• Important to recognize• Patient with very advanced disease• Has been on a stable dose of symptom management medications• Now barely arousable, irregular respiration, mottled extremities

• Appropriate actions• Sit down with family• Sensitively discuss your concern that time may be short• Discuss with staff to make sure

• Symptoms remain under control• Patient and family not abandoned• Naloxone stays in the pharmacy where it belongs

REJECTING A LUNG TRANSPLANT-Transferred to inpatient hospice dyspneic, terrified, suicidal.

-Full team worked hard on complex psychosocial catastrophe.

-Now out enjoying the sunshine, greeted me with a smile, -On hydromorphone 1mg/hr sc + lorazepam

HOPE

• Hope can be measured on 5 point Likert scale• “I see light ahead”• “I feel better each day”

• Hope-fostering strategies• Symptom relief• Increase interpersonal connectedness• Lightheartedness, Courage• Serenity, Attainable aims• Uplifting memories• Affirmations of worth

• As patients were referred to a hospice service and approached the end of their lives, their scores increased.

• Herth K, J Adv Nurs 1990; 15:1250-1259.

• Buckley J, Herth K, Nurs Stand 2004; 19(10): 33-41.

THERE IS LOTS WE CAN DO TO HELP