Pla

sma c

once

ntr

ati

on

Time

PO: Cmax ~ 60 minutes(oxymorphone ~ 30 minutes )

SQ: Cmax ~ 30 minutes

IV: Cmax ~6 minutes

Pharmacologic administration curvesafter single opioid dose

PRN dosing interval based on time to Cmax:

1 mg hydromorphone iv Q 10 minutes prn

1 mg hydromorphone sq Q 15-30 minutes

Despite these efforts Fred continues to have uncontrolled pain.

How rapidly can you safely escalate his continuous infusion and his prn dose?

PRN dosing interval based on time to Cmax:

1 mg hydromorphone iv Q 10 minutes prn

1 mg hydromorphone sq Q 15-30 minutes

Despite these efforts Fred continues to have uncontrolled pain.

How rapidly can you safely escalate his continuous infusion and his prn dose?

Opioid infusionsDose escalation

Opioid infusionsDose escalation

Opioid infusionsDose escalationOpioid infusionsDose escalation

Adjust bolus dose by up to 100% at least every 30-60 minutes until effective

Adjust infusion rate by up to 100% based on prn need every 12-24 hours

Adjust bolus dose by up to 100% at least every 30-60 minutes until effective

Adjust infusion rate by up to 100% based on prn need every 12-24 hours

The pain crisisThe pain crisis

40 year old man with rectal cancer

S/P abdominoperineal resection

Wound dehiscence

Hospitalized for > 100 days

Daily c/o severe pain

Prescribed 2 mg hydromorphone q 1 hour prn pain

Uncertain how much he had actually been receiving

40 year old man with rectal cancer

S/P abdominoperineal resection

Wound dehiscence

Hospitalized for > 100 days

Daily c/o severe pain

Prescribed 2 mg hydromorphone q 1 hour prn pain

Uncertain how much he had actually been receiving

The pain crisisThe pain crisis

TimeHydromorphon

emg

Response

1300 2 None

1310 4 None

1315 4 None

1330 8 None

1342 8 None

1355 16 None

1415 16 Partial

1430 16 Good/Drowsy

Total 74 mg over 90 minutes

MethadoneMethadone

MethadoneMethadone

Dual effect

Mu-opioid receptor antagonist (analgesia)

NMDA antagonist (prevention/reversal of opioid tolerance)

Variable equianalgesic ratios

Dual effect

Mu-opioid receptor antagonist (analgesia)

NMDA antagonist (prevention/reversal of opioid tolerance)

Variable equianalgesic ratios

MethadoneMethadone

MethadoneMethadone

Dual affect

Mu-opioid receptor antagonist (analgesia)

NMDA antagonist (prevention/reversal of opioid tolerance)

Variable equianalgesic ratios

Variable metabolism

Half life 8 to 190 hours

Plethora of drug-drug interactions

Dual affect

Mu-opioid receptor antagonist (analgesia)

NMDA antagonist (prevention/reversal of opioid tolerance)

Variable equianalgesic ratios

Variable metabolism

Half life 8 to 190 hours

Plethora of drug-drug interactions

MethadoneMethadone

Potent

Effective

Cheap

Complicated

Dangerous

Potent

Effective

Cheap

Complicated

Dangerous

FentanylFentanyl

IV:Transdermal =2:1

Fentanyl IV: Morphine IV roughly 100:1

Transdermal absorption dependent on fat stores

IV:Transdermal =2:1

Fentanyl IV: Morphine IV roughly 100:1

Transdermal absorption dependent on fat stores

Side effectsSide effects

Constipation

Up to 80 % of patients

Requires stimulant laxatives

Does not abate with time

Counseling important

Nausea

Transient

Vestibular mediated

Responds to anticholinergic anti-emetics

Ondansetron is NOT an anticholinergic antiemetic

Educate patients

Constipation

Up to 80 % of patients

Requires stimulant laxatives

Does not abate with time

Counseling important

Nausea

Transient

Vestibular mediated

Responds to anticholinergic anti-emetics

Ondansetron is NOT an anticholinergic antiemetic

Educate patients

Side effectsSide effects

Pruritis

Transient, responds to antihistamines.

Histamine release is pharmacologic property of morphine

Often misinterpreted as allergic reaction

Urinary retention

Rare but potentially serious

Pruritis

Transient, responds to antihistamines.

Histamine release is pharmacologic property of morphine

Often misinterpreted as allergic reaction

Urinary retention

Rare but potentially serious

Side effectsSide effects

Sedation

Especially with initiation or dose increase

Usually resolves

More common with elderly, high dose, polypharmacy

Responds to

Adjuvants/dose reduction

Opioid rotation

Stimulants

Marked sedation requires evaluation

Sedation

Especially with initiation or dose increase

Usually resolves

More common with elderly, high dose, polypharmacy

Responds to

Adjuvants/dose reduction

Opioid rotation

Stimulants

Marked sedation requires evaluation

NeurotoxicityNeurotoxicity

Opioid neurotoxicityOpioid neurotoxicity

55 yo old woman with breast cancer

Pain initially controlled on dilaudid 10 mg/hour

Over the past 10 days pain has worsened despite increase in dilaudid to 50 mg/hr.

Patient is anxious, restless. Complains of pain “all over”

Pain elicited by gently stroking arm

Occasional twitching of chest wall and leg noted.

55 yo old woman with breast cancer

Pain initially controlled on dilaudid 10 mg/hour

Over the past 10 days pain has worsened despite increase in dilaudid to 50 mg/hr.

Patient is anxious, restless. Complains of pain “all over”

Pain elicited by gently stroking arm

Occasional twitching of chest wall and leg noted.

Opioid metabolismOpioid metabolism

Morphine is metabolized in the liver to:

Morphine-6 glucuronide (Active)

Morphine-3 glucuronide (Neuroexictory)

Excreted in the kidney

Morphine-3-glucuronide accumulates in renal failure, high dose and prolonged therapy, oliguria

Morphine is metabolized in the liver to:

Morphine-6 glucuronide (Active)

Morphine-3 glucuronide (Neuroexictory)

Excreted in the kidney

Morphine-3-glucuronide accumulates in renal failure, high dose and prolonged therapy, oliguria

Opioid neurotoxicityOpioid neurotoxicity

Increasing sensitivity to pain (hyperalgesia)

Worsening pain despite rapid opioid escalation

Pain becomes diffuse

Delirium, hallucinations

Allodynia, myoclonus, seizures

Increasing sensitivity to pain (hyperalgesia)

Worsening pain despite rapid opioid escalation

Pain becomes diffuse

Delirium, hallucinations

Allodynia, myoclonus, seizures

Opioid neurotoxicityOpioid neurotoxicity

Risk factors:

High dose

Morphine>hydromorphone>oxycodone, fentanyl, methadone

Renal failure

Oliguria

Can occur at any dose

Risk factors:

High dose

Morphine>hydromorphone>oxycodone, fentanyl, methadone

Renal failure

Oliguria

Can occur at any dose

Opioid neurotoxicityManagement

Opioid neurotoxicityManagement

Prevention, anticipation, early recognition

Assess urine output, magnesium level, electrolyte abnormalities

Hydration if otherwise appropriate

Opioid rotation at 25% equianalgesic dose

Add NMDA antagonist (ketamine or methadone)

Benzodiazepines/phenobarbital based on severity

Prevention, anticipation, early recognition

Assess urine output, magnesium level, electrolyte abnormalities

Hydration if otherwise appropriate

Opioid rotation at 25% equianalgesic dose

Add NMDA antagonist (ketamine or methadone)

Benzodiazepines/phenobarbital based on severity

Opioid refractory pain

Opioid refractory pain

Causes of opioid refractory pain

Causes of opioid refractory pain

Rapid progression cancer

New source of pain

Abscess

Occult fracture

Bladder outlet obstruction

Pain refractory to opioids (Neuropathic pain, skin ulceration)

Opioid related

Malabsorption,

Drug diversion

Toxicity

Fear, existential or spiritual pain

Delirium

Rapid progression cancer

New source of pain

Abscess

Occult fracture

Bladder outlet obstruction

Pain refractory to opioids (Neuropathic pain, skin ulceration)

Opioid related

Malabsorption,

Drug diversion

Toxicity

Fear, existential or spiritual pain

Delirium

Opioid refractory pain-Management

Opioid refractory pain-Management

Opioid rotation or dose escalation

Use of adjuvants, non-opioids

NMDA antagonists (Ketamine and/or methadone)

Address spiritual and psychologic concerns

Non-pharmacologic treatments

Interventional modalities, radiation therapy if appropriate

Consideration of palliative sedation

Opioid rotation or dose escalation

Use of adjuvants, non-opioids

NMDA antagonists (Ketamine and/or methadone)

Address spiritual and psychologic concerns

Non-pharmacologic treatments

Interventional modalities, radiation therapy if appropriate

Consideration of palliative sedation

Barriers to pain reliefBarriers to pain relief

Clinician related

Health care system related

Patient related

Clinician related

Health care system related

Patient related

Patient relatedPatient related

Reluctance to report

“The good patient”

Fear of not receiving chemotherapy

Reluctance to treat

Fears of tolerance

Fear of addiction

Stigma

Meaning of pain

Side effects

“A tradeoff between managing the pain and managing the consequences of managing the pain”

Reluctance to report

“The good patient”

Fear of not receiving chemotherapy

Reluctance to treat

Fears of tolerance

Fear of addiction

Stigma

Meaning of pain

Side effects

“A tradeoff between managing the pain and managing the consequences of managing the pain”

Supporting patient adherence

Supporting patient adherence

Normalize concerns

“Some patients worry about becoming addicted or the drug not working in the future when you need it. Are these of concern to you?”

Non-judgmental questioning:

“It must be really hard to take all these pills. How often, in the last week, have you found that you forget one or two?”

Educate and follow up on likely side effects

Normalize concerns

“Some patients worry about becoming addicted or the drug not working in the future when you need it. Are these of concern to you?”

Non-judgmental questioning:

“It must be really hard to take all these pills. How often, in the last week, have you found that you forget one or two?”

Educate and follow up on likely side effects

“Pain is a multifaceted phenomenon involving not only a tissue damage response but also psychological, social, spiritual and existential domains.

(Nessa Coyle, JPSM, 2004)

“Pain is a multifaceted phenomenon involving not only a tissue damage response but also psychological, social, spiritual and existential domains.

(Nessa Coyle, JPSM, 2004)