if it’s not one case it’s another! complex cases in …...6/5/2019 1 if it’s not one case...

6/5/2019

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If it’s not one case it’s another! Complex cases in

pain management

Mellar P. Davis, MD, FCCP, FAAHPM

Geisinger Medical Center

Paul A. Sloan, MD

University of Kentucky

Mary Lynn McPherson, PharmD, MA, MDE, BCPS

University of Maryland

Patient 1 • 73 year old man with chronic kidney disease stage III and severe peripheral vascular

disease (PVD) presents with left leg pain (7/10) and early gangrene left lateral foot and toes.

• The surgeon assesses the extent of disease and finds no surgical option and offers amputation.

• The patient refuses.

• You are consulted for pain and goals of care.

• How will you manage his pain?

• What is his prognosis?

Patient 1 - Epidemiology • Critical leg ischemia develops 500-1000/106

• Cardiovascular events occur more frequently than those with CAD

• Conservative management-mortality is 45% at 2 years, all cause mortality 50%

• Mortality worse than advanced colorectal, breast and prostate cancer

Norgren L 2007

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Patient 1 - Pain and Pathophysiology • Pain is caused by an distal axonopathy-neuropathic

• Secondary alterations in muscle and oxidative stress

• Pain is worse at night ( limb is no longer in a dependent position)

• Wakens patients from sleep

• Risk of phantom pain syndrome s/p amputation

Patient 1 - Palliation • Lumbar sympathectomy – inconclusive

• IV prostanoids > sympathectomy ( low grade evidence)

• Spinal cord stimulation - inconclusive

• Lidocaine IV> morphine – problems with portability

• Ketamine 0.6mg/kg > placebo ( NNT 5) - problems with portability and side effects

Sen I Cochrane Review 2018

Ubbin D 2013; Vahidi E 2015; Mitchell A 2002

Patient 1 - Palliation • Gabapentin- single arm, 15/17 responded (NRS 9/10 to 5/10 over 28 days)

• Buprenorphine added to epidural morphine/ local anesthetic in 2 RCT- improved pain > morphine alone, less morphine needed and better sleep

Aurilio B 2005 and 2009

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Patient 1 - Summary Palliation for pain

• Gabapentin

• Buprenorphine =/- spinal analgesia

• Ketamine IV

• Lidocaine IV

• IV prostanoids

• Lumbar sympathectomy

Laoire A 2017

Patient 2 • A 58 year old man with metastatic colon cancer to the liver is started on FOLFOX

chemotherapy which contains oxaliplatin.

• After each cycle he develops acute neuropathic like pain which is worsened when exposed to cold that lasts one week then gradually subsides.

• Your oncologist has started to refer all his patients with advanced gastrointestinal cancer to you as an integrated care model.

• The patient has had 2 cycles of chemotherapy and his major wish is that you do something to reduce his pain.

• What would you do?

Patient 2 - Acute Oxaliplatin Neurotoxicity

• Transient hypersensitivity to cold

• Exacerbated immediately after surgical procedures due to release of oxaliplatin from erythrocytes

• Channelopathy involving voltage gated sodium channels

• Pathophysiology includes oxidative stress

• Individualized risk through inherited variants of glutathione S-transferase genotype

Di Cesare Mannelli 2012; Grolleau F 2001

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Patient 2 - Venlafaxine • Serotonin norepinephrine reuptake inhibitor

• In therapeutic doses venlafaxine blocks sodium channels

Durand J 2003; Khalifa M 1999

Venlafaxine for Taxane and Oxaliplatin Acute Neuropathy- Retrospective Study

• D- Retrospective case controlled study

• P- 206 patients receiving oxaliplatin or taxane with NCI-CTCAE version 4.03 pain > 4/10

• Neuropathic Pain Symptom Inventory

• O- > 75% relief with subsequent chemotherapy

• Result- Relief with venlafaxine 45-58% vs 0% controls

• AE < 5%, nausea. Asthenia/somnolence

Kris T JSCC 2016

Patient 2 - Efficacy of Venlafaxine D - Case control retrospective study

P - Patients experiencing acute neurotoxicity from oxaliplatin, age <65, not a diabetic

I - Venlafaxine ER 75mg/d

O -Target 75% reduction in previously experienced pain, secondary Neuropathic Pain Symptom Inventory responses

Kris T 2016

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Patient 2 - Efficacy of Venlafaxine Results

• N = 84/477 treated

• Pain intensity NRS- 6.4 to 1.4 pre-post

• 75% relief ranged between 72-76% ( burning pain, pain triggered by cold, pins and needles pain)

Kus T 2016

Patient 2 - Efficacy with Venlafaxine D - RCT

P - Patients distressed by oxaliplatin neurotoxicity

I - Venlafaxine ER 50mg prior to oxaliplatin the 37.5mg bid days 2-11

C - Placebo

O - Neuropathic Pain Symptom Inventory days 1-5

Durand J 2012

Patient 2 - Efficacy with Venlafaxine • Results

• N=54 with 48 completed

• Median cycles 4-5

• Full relief of pain 31.3% vs. 5.3% ( placebo)

• Reduced oxaliplatin neurotoxicity 3 months after stopping therapy

Durand J 2012

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Patient 2

• In a randomized trial venlafaxine did not prevent acute neuropathy caused by oxaliplatin

Zimmermann C JSCC 2016

Patient 3 • A 57 year old man presents with muscle invasive rectal cancer and liver metastases.

• He is given a palliative course of radiation to the pelvis with capecitabine and then is started on FOLFOX chemotherapy.

• His obstipation and bleeding resolves but after 7 months of FOLFOX he develops rectal discomfort described as “ drilling” or “pressing” which intensifies with defecation.

• A repeat CT scan demonstrates persistent cancer in the rectum, improved liver metastases.

• There is stranding to the sacrum.

• A PET scan demonstrates persistent uptake in the rectum and perirectal tissues extending to but not invading his sacrum.

• He refuses a consideration of a colostomy.

• How would you manage his pain?

Patient 3 - Tenesmus • Relatively resistant to opioid therapy

• Opioids cause sphincter dysfunction and circular muscle contraction

• Refractoriness to opioid therapy is similar to pancreatic pain, decubitus ulcers, superficial skin ulcers and pain from shear injury

Hanks G 1991

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Pain 3 - Tenesmus • “Orphan” pain syndrome - found in 9/362 home palliative care patients

• Rarity means that the evidence base for managing the symptom is low and is dependent on case reports, case series and cohort studies

Mercadante S 2013

Patient 3 - Pathophysiology of Tenesmus • Smooth muscle contractions

• Tumor invasion of lumbar plexus

• Tumor induced inflammation which sensitizes afferents

Laoire A 2017

Patient 3 - Management of Tenesmus • Calcium channel blockers nifedipine and diltiazem -5 of 6 responses

• Methadone - 2 case reports

• Mexiletine - 5 patient reports

• Intrathecal and intrarectal bupivacaine

• Lumbar sympathectomy -10 of 12 responses

• Endoscopic laser therapy -21 of 26 responses and 4 of 8 responses

• Phenol neurolytic saddle block - 1 case report

Laoire A 2017

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Patient 3 - Traditional Therapies of Tenesmus • Benzodiazepines - no data

• Phenothiazines -no date

Other possible therapies without data

• Dicyclomine - muscle spasm

• Gabapentinoids - hypersensitivity or plexopathy

• Anticholinergics - muscle spasm

• Ketamine - neuropathic ( visceral)

Patient 4 • A 63 year old woman with a T2N2M0 base of tongue squamous cancer is undergoing

definitive radiation plus cisplatin 100mg/m2 every 3 weeks.

• By week 2 she has developed grade II mucositis with redness and thinning of the mucosa ( CTCAE-4th edition).

• By week 3 she develops superficial ulcers and desquamation and has difficulty swallowing.

• She is placed on magic mouth wash and morphine elixir 5 mg but complains the morphine burns and tastes bad and does little to help.

• She does not want a nasal feeding catheter and promises to work hard on swallowing.

• The oncology team is considering a PEG tube.

• She is an outpatient and wants to avoid hospitalization.

• You are asked to manage her pain

Patient 4 - Gabapentin for Mucositis • Gabapentinoids reduce alpha2-delta voltage gated calcium channel expression which

prevents surface expression of calcium channels

• Increases CNS GABA

• Prevents connectivity between insula cortex and other brain centers ( brain default modes)

• Reduces neuroinflammation

• Increases spinal cord norepinephrine

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Patient 4 - Gabapentin for Mucositis • Gabapentin doses as high as 2700 mg reduces mucositis caused by intensity

modulated radiotherapy (IMRT)

Bar Ad V 2010

Patient 4 - Gabapentin and Mucositis D - Retrospective analysis

P - 42 patients with H and N cancer undergoing IMRT plus chemotherapy plus PEG feeding (93%)

I - Gabapentin 600mg at hs increased over 1 week to 900mg tid plus oxycodone or fentanyl as needed

Bar Ad V 2010

Patient 4 - Gabapentin and Mucositis Results

• 90% received 2700mg gabapentin by the final week, average oxycodone 60mg/d ( 10-180)

• 5% developed mild dizziness

• Radiation interruption 2.5%

Bar Ad V 2010

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Patient 4 - Gabapentin and Mucositis • Bolus with the elixir - 900mg similar to managing perioperative acute pain

• Particularly helpful in those opioid tolerant

• Anti-anxiety, antiemetic, improved sleep and mood

Randomized Trial of Gabapentin for Mucositis

• D-RCT- pilot

• P- Head and Neck cancer undergoing chemoradiation (n=22)

• I- Gabapentin which was maintained at 900mg/d for 4 weeks post chemoradiation plus acetaminophen/opioids

• C- acetaminophen plus opioids

• O- VAS, total opioid dose, QOL (EORTC-QLQ-C30)

• Results- no difference in primary or secondary outcomes, QOL worse with gabapentin

Kataoka T Aus Nasus Larynx 2016

Discussion

• Dose ( 900mg/d)

• Small trial

• Combined with opioids versus single agent

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Patient 4 - Single Dose Gabapentinoid D - Sequential up and down dosing titration of pregabalin in a cross over RCT compared to placebo

P - Normal human subjects with capsaicin pain ( n=13)

I - Pregabalin 75mg, 150mg and up

C - Placebo

O - 30% reduction in spontaneous pain over placebo-secondary outcome secondary hyperalgesia, allodynia, heat allodynia, mechanical hyperalgesia

Wong W 2014

Patient 4 - Single Dose Gabapentinoid • Results

• ED50- 252mg (95%CI 194-310)

• Drowsiness 46%, euphoria 31%, dizziness 7%

• Response to spontaneous pain predicted responses to other pains

Wong W 2014

Patient 4 - Single Dose Gabapentinoid • This paper demonstrated the median single effective dose of pregabalin 250-300 mg

which translates to between 900 and 1200 mg of gabapentin. In patients with severe pain it is often frustrating to do the usual titration schema with gabapentinoids.

• In general I will give a single high dose of pregabalin 300 mg or gabapentin 900-1200 mg at night which both reduces pain and allows patients to sleep.

• If one gets a response than you can give divided doses the next day with an expectation of response. I have treated mucositis the same way.

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Patient 4 - Gabapentin the Ugly • Abuse potential

• A population nested case control study suggested increased mortality with the combination compared to opioids alone

< 900 mg/d OR 1.49

900-1800 mg/d OR 1.56

> 1800 mg/d OR 1.56

• Problems- no dose response relationship, differences between groups, limited payers, not propensity matched

Gomes T 2017

Patient 4 - Is there a preferred opioid? D - Noninferiority RCT

P - Opioid naïve H and N cancer patients undergoing radiation or radiochemotherapy (n=82)

I - Methadone 2.5mg bid and titrate, rescue IN or SL fentanyl

C - Fentanyl 12mcg/h and titrate, rescue IN or SL fentanyl

O -95% CI of 1 NRS (0-10), secondary pain interference, global perceived effect, HADS, EQ-5D, breakthrough, escalation index

Haumann J 2017

Patient 4 - Methadone vs. Fentanyl Results

• Methadone decreased pain severity 0.75 points over fentanyl (95% CI -0.21-1.71)- non-inferior to superior

• Decreased pain interference greater with methadone

• Opioid escalation less with methadone

• Global impression not different

• No difference in breakthrough rescue doses

Haumann J 2017

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Patient 5

• 54 year old woman; history of liposarcoma of abdomen. • Uncertain retroperitoneal lymph node, ?? recurrence. • Pain is mostly epigastric burning superficial pain following

abdominal surgery; rated 6/10. • Takes duloxetine for migraines. • Not taking opioids. • Works full time as hospital nurse.

• What can/should we try?

Patient 5

• 25 mg desipramine with improved pain relief, and improved sleep

• Adverse effect: increased dreaming

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Patient 5 – Ponderings

• ? Trial of opioids

• Other approaches

• ? Interaction of duloxitine and desipramine

Patient 6

• 66 year old woman; history of peritoneal carcinomatosis recently diagnosed.

• Hx Etoh abuse (none in 6 months by history); daily MJ for appetite.

• Hx gastritis.

• Hx abdominal pain thought to be related to gastritis, possibly exacerbated by recent chemotherapy, but same as chronic noncancer pain of many years duration.

• Pain relieved with hydrocodone 10 mg 3 times daily.

Patient 6

• ? Further screening

• ? Continue opioids

• ? Continue marijuana

• ? Change to nonopioid analgesic(s)

• ? What monitoring for follow up

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Definitions • Addiction

• Characterized by loss of control, continued use despite harm to self and others, compulsion to use, craving

• Physical dependence • Withdrawal symptoms upon sudden cessation of the drug

• Opioid misuse • Opioid use that is not medically sanctioned • e.g., dose escalation

• Opioid abuse • Nonmedical use of opioids • e.g., to get a high

• Compliance • Taking the medications as prescribed

Hale ME. J Opioid Manage 2016; 12: 139

Hydrocodone ER ADF -75% study completion - good pain scores

Hydrocodone ER ADF -44% study completion

Wen W. J Opioid Manage 2015; 11: 339

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Factors associated with risk of Opioid Use Disorder (addiction) from prescription opioid therapy

• History of substance use disorder

• Younger age

• Major depression

• Use of psychotropic medications

• Long-term prescription opioid therapy

• Daily opioid dose with long-term therapy

• Men more than women

Edlund MJ. Clin J Pain 2014; 30:557 Banta-Green CJ. Drug Alcohol Depend 2009; 104:34 Boscarino JA. Addiction 2010; 105:1776

Risk of Opioid Use Disorder (addiction) from prescription opioid therapy

• Estimates in primary care setting: 4% - 26% • 8% - Drug Alcohol Depend 2009; 104:34

• 26% - Addiction 2010; 105:1776

• 4% - J Pain 2007; 8:573

• Estimates in Pain Clinic setting: 3% - 14% • 3% - Pain Med 2003; 4:340

• 14% - Eur J Pain 2010; 14:1014

• 3% - Clin J Pain 2007; 23:287

• 7% - J Opioid Manage 2010; 6:385

Patient 7

• 30 year old woman; history of cervical cancer s/p surgery, chemo, and XRT.

• No known recurrence.

• Initial evaluation - ongoing chronic LBP along with pelvic pain.

• Rates pain at 10/10.

• Comes on oxycodone/acetaminophen TID.

• Does not seem in particular distress.


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Patient 7

• Urine drug testing: ? dipstick ? LCMS

• How to handle opioid diversion

• ? Ultra rapid metabolizer of oxycodone

• ? Is patient addicted to opioids

• ? Do we “fire” the patient

Patient 8 - Roger

•66 yr. old man; s/p maxillectomy for cancer of nose

•Chronic facial pain; as well as chronic LBP

•Oxycodone/Aceta 10 mg TID

•Because of inadequate analgesia; trial of methadone 10 mg. BID

•UDS inappropriate: positive for oxycodone, methadone, tramadol and buprenorphine

•Because of cancer history, trial of tramadol alone

•UDS then inappropriate:

•lab called: industrial strength tramadol level

with evidence of pill shaving

•No tramadol metabolite present

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OTA violation of CNMP Treatment

• Retrospective study over 6 month period; chronic pain patients

• 234 subjects

• 38% discharged from clinic for OTA violation

• 89% with inappropriate UDS

• Discharged a mean of 7.4 months after initial visit

• Of the UDS: most common (40%) was illicit drug use, MJ the most common drug

• Therefore: monitor UDS every patient, every visit

Summers P. J Opioid Manage 2015; 11:501

Larson MEM. J Opioid Manage 2015; 11:489

Oxycodone concentration in urine varies with the dose;

BUT - there is great variance and almost no relationship at the

more common doses of <64 mg/d

Patient 9

• 46 year old woman; history of head and neck cancer with previous treatment of surgery, chemotherapy and radiation therapy.

• No evidence of recurrence.

• No obvious red flags with long-term opioid therapy.

• Morphine ER 30 mg BID for some pain relief.

• Patient treated for several years.

• Then a letter arrives:

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Patient 9

“We are writing this letter to advise you that one of your patients is selling prescription drugs in our neighborhood. We have no doubt that she is involved in the illicit sale and distribution of the drugs that your clinic provides to her by legal prescription and we want it to stop. No one wants a drug dealer in their neighborhood. We have recently involved the Sherriff Department narcotic unit. I will be calling the Sherriff periodically for any update. If Dr. Sloan is not cooperative we will forward this letter to senior UK administration asking for an explanation.” Signed, “Concerned Neighbors” Copy to local Sherriff

Patient 9

• ? How to proceed

Patient 10

• 57 year old man, hx of squamous cell carcinoma of the right tonsil for 1 yr.

• Treatment with XRT and chemo.

• Neck pain constant and 8/10; but chronic 2 yr. knee pain at 9/10, prior ant cruciate ligament surgery no help.

• Prescribed oxycodone 5 mg BID.

• Admits purchasing on the street: Oxy 30s, Xanax and marijuana.

• PMH: depression, MVC with knee injury, disability, HTN.

• Referring physician will no longer prescribe opioids.

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Patient 10

• ? Further work up

• ? How to proceed

• ? Treatment

Patient 11

• 57 year old man with active liver cancer, diagnosed 1.5 yr. ago.

• Hx pancreatitis, alcohol abuse, legal issues (DUI), recent incarceration.

• Says he is dry for several months.

• Chronic abdominal pain which predates his cancer diagnosis.

• PMH: HTN, anxiety, depression, smoker, recent endovascular aortic repair.

• Prescribed oxycodone 10 mg. PRN, plus tramadol.

• Primary no longer wishes to write any opioids.


Patient 12

• 57 yr. old man with right lung cancer, dx 2012.

• Treatment with surgery, XRT and chemo. Paraspinous mets with recent XRT.

• Right anterolateral chest wall neuropathic pain.

• Also chronic low back pain.

• Taking gabapentin 300 TID, and morphine ER 400 mg BID.

• Treatment options?

• Candidate for neurolytic block?

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Patient 13

• 28 year old man with long history of jeuvanile rheumatoid arthritis

• Joint pain, mostly in the left forearm and wrist, and knees • On regular chemotherapy which helps control the disease and the

chronic pain • Long-term use of low-dose hydrocodone

• Routine office visit with urine dipstick is negative for opioids!

• Plan of action??

• 50 yr old man with 5 month history of MM, on daily chemotherpay. On CT scan lucent foci of cancer throughout the spine

• On methadone 20 mg TID and fentanyl patch 100mcg/hr • With side effects, would like to be off all oral/transdermal opioids • Plan of action??

Patient 15

• 50 yr old woman with recently resected mediastinal cancer of the thymus. Receiving XRT

• Pain is chest wall post-surgical neuropathic pain • On initial evaluation she denies taking opioids • Initial urine drug screen positive for oxycodone, hydrocodone and

buprenorphine • Plan of action??

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Prescription Opioid Withdrawal: Recommendations

• First: Document the reason(s) for withdrawal; including history, exam, lab, Rx monitoring, discussion with patient. Do not use the word detoxification.

• Consider an Opioid Taper Agreement • Outlines opioid taper plan

• Keep all appointments

• Agree to UDS

• Continue nonopioid therapy

• Stay with the one physician

• Plan if taper fails • ?New attempt at taper

• ?Consult with addiction medicine

• ?Consider opioid maintenance therapy

Berna C et al. Mayo Clin Proc 2015l 90:828-842

Washington State Agency Medical Director’s Group Interagency Guideline on Prescribing Opioids for Pain 2015. pages 36-39

Prescription Opioid Withdrawal: Recommendations

• Patient education: chronic pain is complex, opioids alone often fail to achieve analgesia, some patients have better pain relief after opioid discontinuation, consequences of noncompliance, will not abandon and CONTINUE to care for the patient, typically as outpatient

• Have a taper plan: (little data to support any option!) • Taper with patients’ opioid • 10% opioid dose reduction per week • 10% opioid dose reduction per day • 50% opioid dose reduction per 2 weeks • 50% opioid dose reduction per week • 25-50% opioid dose reduction every few days • For high dose, long-term opioid pain patients: ?slower taper such as 10% per 2 or 4 weeks • 75% opioid dose reduction per day (from addiction medicine and may require inpatient treatment) • Abstinence if history of illegal opioid diversion • Do NOT use ultra-rapid opioid detoxification methods

Jan 15, 2016

Nathan N. Anesth Analg 2017; 125:1428

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Patient 16

• Ms. Johnson is a 54 year old woman with advanced breast cancer.

• She was on home hospice care, receiving MS Contin 15 mg po q12h.

• She experienced a pain crisis, and was admitted to the hospice inpatient unit and started on a continuous infusion of IV hydromorphone, plus a bolus option.

• Several days later her pain is now well controlled, and she’s requiring about 10 mg IV hydromorphone in 24 hours to stay comfortable.

• The attending would like to send her BACK home on oral morphine.

• What dose do you convert her to?

Equianalgesic Opioid Dosing

*Not available in the US

Reprinted with permission from McPherson ML. Demystifying opioid conversion calculations: a guide for effective dosing, 2nd ed. Bethesda: ASHP; ©2018.

NOTE: Learner is STRONGLY encouraged to access original work to review all caveats and explanations pertaining to this chart.

2010 Equianalgesic Doses (mg)

Drug Parenteral Oral

Morphine 10 30

Fentanyl 0.1 NA

Hydrocodone NA 30

Hydromorphone 1.5 7.5

Oxycodone 10* 20



Morphine 10 25

Fentanyl 0.15 NA

Hydrocodone NA 25

Hydromorphone 2 5

Oxycodone 10* 20

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Equianalgesic Opioid Dosing

*Not available in the US

Reprinted with permission from McPherson ML. Demystifying opioid conversion calculations: a guide for effective dosing, 2nd ed. Bethesda: ASHP; ©2018.

NOTE: Learner is STRONGLY encouraged to access original work to review all caveats and explanations pertaining to this chart.



Morphine 10 30

Fentanyl 0.1 NA

Hydrocodone NA 30

Hydromorphone 1.5 7.5

Oxycodone 10* 20



Morphine 10 25

Fentanyl 0.15 NA

Hydrocodone NA 25

Hydromorphone 2 5

Oxycodone 10* 20

Parenteral to Oral Hydromorphone

• Largely determined by oral bioavailability (of oral hydromorphone) • Parab - 50.7 +/- 29.8%; Ritschel – 51.35 +/- 29.3%

• Do we need to evaluate conversion from oral to parenteral? • No, because conversion is determined primarily by BAB

• Secondarily by pharmacogenetics

• Clinical experience in large patient populations provide average guidance

• Best data is 1:2.5 (IV:oral)

PRESENTED BY:

McPherson Table Equianalgesic Doses (mg)


Hydromorphone 2 5

Biopharm & Drug Dispo, 1988;9(2):187-199. J Clin Pharm 1987;27(9):647-653.

Conversion Ratio from IV Hydromorphone to Oral Opioids in Cancer Patients

IV Hydromorphone → Oral Opioid

1 mg IV hydromorphone (< 30 mg/day) → Oral hydromorphone 2.5 mg

1 mg IV hydromorphone (> 30 mg/day) → Oral hydromorphone 2.1 mg

1 mg IV hydromorphone (< 30 mg/day) → Oral morphine 11.54 mg

1 mg IV hydromorphone (> 30 mg/day) → Oral morphine 9.86 mg

1 mg IV hydromorphone → Oral oxycodone 8.06

McPherson Table Equianalgesic Doses (mg)


Morphine 10 25

Hydromorphone 2 5

Oxycodone 10* 20

Reddy A et al. J Pain Symptom Manage 2017;54(3):280-288.

Reddy’s bottom line: I:2.5 (IV hydromorphone to oral hydromorphone)

1:10 (IV hydromorphone to oral morphine) 1:8 (IV hydromorphone to oral oxycodone)

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Morphine Hydromorphone

• Is it bidirectional? (IV HM to PO MS equal to PO MS to IV HM?)

• Study by Lawlor – SQ to SQ HM/MS and PO to PO HM/MS • Going from morphine to hydromorphone (same route) was 5:1 (M:HM)

• Going from hydromorphone to morphine (same route) was 3.7:1 (M:HM)

• Limitations of Lawlor study: • Data highly skewed and variable, not normally distributed

• Authors stated differences in direction were clinically insignificant and called for further research...in the meantime differences in M→HM and HM→M remain speculative

PRESENTED BY: Pain 1997;72(1-2):79-85.

How about oral MS to parenteral hydromorphone?

IV HM:PO MS - 1.5:30 IV HM:PO MS – 2:25 Coments

Switching from 10 mg IV HM per day to PO MS

A. Calculate 200 mg PO MS B. Calculate 125 mg PO MS New conversion more conservative, and it’s consistent with Reddy findings.

Switching from 200 mg PO MS per day to IV HM

C. Calculate 10 mg IV HM D. Calculate 16 mg IV HM New conversion seems more aggressive than older conversion ratio.

But wait! There’s more than one way to pluck a chicken! 200 mg oral morphine → 40 mg oral hydromorphone →

16 mg IV hydromorphone



Morphine 10 25

Hydromorphone 2 5

PRESENTED BY:

Which is my seat?

Don’t know!

I just got you

in the ball park!

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Patient 17

Ms. R. is a 43 year old woman with end-

stage cervical cancer.

She is admitted to hospice from the

hospital, on IV morphine 80 mg/hour

with a 20 mg bolus every 15 minutes

(uses about once an hour).

She is experiencing myoclonus, and the

hospice medical director prescribed lorazepam 2 mg po

q6h scheduled.

Two days after admission, the patient went on vacation for a

week to the ocean side vacation.

Patient 17

• When the patient returned from vacation, she was admitted directly back to the hospital.

• It was revealed that she spent most of her ocean side vacation in the local hospital complaining of increased pain and myoclonus.

• On returning home, she is now on IV morphine 130 mg/hour plus a 30 mg bolus, which she uses once or twice an hour, plus a continuous infusion of midazolam at 10 mg/hour. She continues to experiences significant myoclonus.

• Patient has a history of a prolonged QTc and refuses methadone therapy.

• Determine a plan that incorporate ketamine to treat Ms. R.

Opioid Therapy

• Cornerstone of therapy for the treatment of moderate to severe pain (cancer, non-cancer)

• Increased availability and comfort level in using opioids in recent years • Greater attention to pain management

• Better education

• Used earlier in disease process

• Used in higher doses

• Adverse effects of opioid • Usual – nausea, vomiting, constipation, pruritus, sleepy, confused

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What’s going on?

• A common clinical observation: • Opioid-requiring patients need a dosage increase to maintain adequate

analgesia

• Why?

Clin J Pain 2008;24:479-496

Dis

ease

Pro

gres

sio

n

Disease

Progression

Op

ioid

To

lera

nce

Opioid Tolerance

Op

ioid

-In

du

ced

Pai

n

Opioid- Induced

Pain (OIH)

CNS Adverse Effects of Opioids • Adverse effects of opioids on CNS (neurotoxicity - damage to nerve

cells) • Reduced level of consciousness (sedation, drowsiness, sleep disturbance)

• Adverse effects on thinking process and ability to reaction (cognitive impairment, psychomotor impairment, delirium, hallucinations, dreams, nightmares)

• Direct toxic effect on neurons (myoclonus, seizures, hyperalgesia and tolerance)

Clin J Pain 2008;24:479-496; A – OIH; B - Tolerance

Vicious Cycle of Opioid-Induced Neurotoxicity

http://palliative.info/pages/TeachingMaterial.htm

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Clinically…

• Increased sensitivity to pain stimulus (hyperalgesia)

• Worsening pain despite increasing doses of opioids

• Pain that becomes more diffuse, extending beyond the distribution of the pre-existing pain

Patient reports

• Any dose of an opioid, but particularly with high-dose morphine or hydromorphone, and in renal impairment/failure

• Pain elicited from ordinary nonpainful stimuli (e.g., stroking skin with cotton [allodynia])

• Presence of other manifestations of opioid-induced hyperexcitability: myoclonus, delirium, seizures

Provider observes

Morphine and Hydromorphone Active Metabolite Accumulation in Renal Failure

http://palliative.info/pages/TeachingMaterial.htm

Management of OIH

• Hydration if clinically appropriate

• Reduce the opioid dose • Consider use of an opioid-sparing coanalgesic

• Acetaminophen, NSAID

• Opioid rotation • Allows comparable analgesia at a lower equianalgesic dose • Fentanyl • Methadone

• NMDA receptor antagonist

• Ketamine (NMDA receptor antagonist)

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Ketamine protocol

• Indications for use:

• Neuropathic pain poorly responsive to opioids and adjunctive analgesics, particularly in patients with hyperalgesia/allodynia

• Somatic/visceral pain despite appropriately titrated opioid therapy

• Adverse effects to increasing doses of opioids (e.g., myoclonus, uncontrolled constipation, respiratory depression)

• Severe pain associated with wound care

• Adjunctive for analgesia

Ketamine protocol

• 2.5-5 mg administered over 1 minute

• Evaluate patient response over the next 15 minutes

IV/SQ dosing

• Reduce total daily opioid dose by 30%; reduce BZD

• Continue breakthrough opioid at previously prescribed dose

• Loading dose up to 10 mg

• Starting dose - 50 mg over 24 hours (e.g., 2 mg/hour)

• Increase dose by an additional 50 mg per 24 hours if needed

• Usual dosage range - 100-400 mg/24 hours

IV/SQ Infusion

Ketamine protocol

• Put injectable ketamine in fruit juice

• Reduce total daily opioid dose by 30%; reduce BZD

• Continue breakthrough opioid at previously prescribed dose

• Starting dose - 10-15 mg every 6 hours

• Dose titration - increase 10 mg per dose every 2-3 days

• Usual maximum dose - 50 mg every 6 hours

Oral dosing

• 2.5-5 mg by mouth 30 minutes prior to wound care/procedure

Oral ketamine for wound care

• Injectable ketamine in artificial saliva (20 mg [0.2 ml] with 5 ml saliva substitute

• 20 mg swish and SPIT solution

Topical ketamine for mucositis

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Ketamine protocol

• Oral dosing

• Use ketamine 100 mg/ml (10 ml vial)

• Dilute with 90 ml sterile water (or flavored syrup)

• Resulting solution is ketamine 10 mg/ml (100 ml total)

• Expires in 7 days; keep refrigerated

• Dose may be further diluted with orange juice, cola, etc. immediately before administration to mask bitter taste

• San Diego Hospice (used with permission); Adapted from Twycross R, Wilcock A, et al:

• Palliative Care Formulary, 2nd ed. Radcliffe Medical Press, United Kingdom, 2002, p. 291.

Patient 17

Begin ketamine 10 mg po q6h, mixed in orange juice

Empirically reduce morphine infusion by 30% to 90 mg/hour; keep bolus in place

Empirically reduce midazolam infusion by 50% to 5 mg/hour

Increase ketamine by 10 mg per dose every 2-3 days (while titrating morphine and midazolam down)

Patient 18 - What a pain in the butt!

• Case report from Nigeria – 34 yo man with anal cancer • Complained of extreme, nonradiating sharp pain within anal canal

• Morphine 20 mg q4h plus acetaminophen 500 q6h plus meloxicam 15 qd

• Radiation did not help pain

PRESENTED BY: Ali SK, Abdulkarim S. JPSM 2018;56(1):e1-e2

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Patient 18 - What a pain in the butt!

• Pain related to anal cancer – SO challenging to treat!

• Reports of intrathecal opioid therapy, calcium channel blockers for perineal pressure-like pain and tenesmus

• Opioids, steroids, lidocaine ointments

• Case report from Nigeria – 34 yo man with anal cancer • Complained of extreme, nonradiating shapr pain within anal canal

• Morphine 20 mg q4h plus acetaminophen 500 q6h plus meloxicam 15 qd

• Radiation did not help pain

• Rectal suppositories lidocaine 60 mg plus hydrocortisone 5 mg pr q12h

PRESENTED BY: Ali SK, Abdulkarim S. JPSM 2018;56(1):e1-e2

Patient 19

• BD is a 36 year old soldier with residual low back pain secondary to a work-related injury.

• BD’s sister-in-law is a nurse who suggests application of a topical adjuvant analgesic cocktail.

• Will this likely provide meaningful relief?

PRESENTED BY:

An

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Compounded Topical Pain Creams • Military treatment facility

• 399 patients with localized pain classified by their MD as neuropathic, nociceptive or mixed (back/butt; neck; limb; other location)

PRESENTED BY:

Group Compounded Product

1 – Neuropathic pain Ketamine, gabapentin, clonidine, lidocaine

2 – Nociceptive pain Ketoprofen, baclofen, cyclobenzaprine, lidocaine

3 – Mixed neuropathic/nociceptive

Ketamine, gabapentin, diclofenac, baclofen, cyclobenzaprine, lidocaine

4 – Placebo Placebo

Brutcher RE et al. Ann Int Med 2019;170:309-318.

Concentrations of ingredients

• Ketamine 10%

• Gabapentin 6%

• Clonidine 0.2%

• Lidocaine 2%

• Ketoprofen 10%

• Baclofen 2%

• Cyclobenzaprine 2%

• Diclofenac 3%

• Lipophilic base carrier

PRESENTED BY:

Apply to affected area 3 times per day.

Amount applied determined by size of the area (set by investigators – 4 rotations of

container for 5x5 area)

Magic Pain Cream

So WILL a little dab do ya?

• Primary outcome – average pain score 1 month after treatment • Positive categorical response was a reduction in pain score by > 2 points (0-

10) WITH a satisfaction score of > 3 on a 5-point satisfaction scale

• Data collected by phone by a trained, blinded investigator not involved in patient care • 1 month (24-40 days)

• 3 months (75-110 days)

• 399 started trial, 390 completed • 202 assigned to a study drug, 197 to placebo

PRESENTED BY:

Magic Pain Cream

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Drum roll please….

• No change in pain score at 1 month between drug and placebo for any group • Neuropathic pain – 0.1 point reduction in pain

• Nociceptive pain – 0.3 point reduction in pain

• Mixed pain – 0.3 point reduction in pain

• SF-36 measures did not differ between the groups

PRESENTED BY:

Patient 20 – What’s the sitch?

• Mrs. Gladson is a 78 year old woman diagnosed with end-stage hepatic cancer. She was admitted to hospice on MS Contin 15 mg po q12h with oral morphine solution 5 mg every 3 hours as needed for additional pain.

• Hospice RN reports patient is having a pain crisis; she is taking her MS Contin as directed and several doses of oral morphine solution with no relief at all.

• Patient rates pain as greater than a 10 on a 0-10 scale, family is insistent she be admitted to the hospice inpatient unit.

• She is transported to the inpatient unit, arriving at 6 pm. The attending on call is Dr. Doogie Howser (he’s so excited – this is his first position post-fellowship!).

• Dr. Howser calculates that the patient was receiving approximately 40 mg oral morphine in the past 24 hours, which he figures in about 16-mg IV morphine per day (0.6 mg/h)

• He orders a 2.5 mg IV morphine loading dose, and a continuous infusion at 1.2 mg/hour, with an order to titrate to comfort per nursing judgment.

What’s the sitch?

• The family stays with the patient and keeps the nurse informed as to the patient’s response to the morphine infusion.

• The family is concerned that she’s still complaining of pain that she rates as 9/10 at 8 pm, so the nurse increases the infusion to 3 mg/hour and the clinician bolus to 5 mg.

• At 10 pm the family reports the patient is still grimacing and crying out, so the nurse repeats the 5 mg IV morphine loading dose and increases the continuous infusion to 5 mg/hour

• The patient seems to settle down, and the family leaves around midnight.

• When the nurse checks on Mrs. Gladson at 3 am, she is nonresponsive, even to sternal rub.

• Her respiratory rate is 6 breaths/minute with periods of apnea. She has pinpoint pupils, and the nurse calls Dr. Howser in a panic.

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What’s wrong with this picture?

A. The family must have increased Mrs. Gladson’s infusion before they left

B. The nurse was trigger happy with the hourly clinician bolus

C. Dr. Howser incorrectly calculated the starting dose of morphine (bolus and infusion)

D. The infusion rate was titrated incorrectly (too quickly)


A. The family must have increased Mrs. Gladson’s infusion before they left B. The nurse was trigger happy with the hourly clinician bolus C. Dr. Howser incorrectly calculated the starting dose of morphine (bolus and

infusion) D. The infusion rate was titrated incorrectly (too quickly) The family didn’t do anything. The nurse gave the hourly bolus as ordered. Dr. Howser’s math was fine. That leaves us with – the order was inappropriate – “titrate to comfort??” The infusion started at 6 pm, increased at 8 pm and again at 10 pm. The patient is elderly and has a terminal illness, so her half-life of morphine is probably closer to 5 hours. To get to 87.5% or 93.75% of the way to steady-state it would take 15-20 hours, NOT 4 hours. The infusion was titrated way too aggressively, too quickly.


• We need to recognize the two issues at play here: • We need to FULLY appreciate the clinical impact of the

current continuous opioid infusion dose when it achieves a steady-state serum level (both therapeutic gain and potential toxicity) BEFORE we increase the dose (and make the situation worse, and that always seems to happen at 3 am when no one is really paying close attention); and

• We don’t want the patient to suffer with pain while we are waiting for the magical moment of steady-sate to make sure we haven’t overdosed the patient.

• Doogie, Doogie, DOOGIE…this is why we never let 14 year-olds be doctors – EVER!

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Answer is…

• “Why yes, I happen to look good in orange. Why do you ask?”

• “If you start an IV infusion of morphine at 2 mg/hour and order “titrate to comfort,” the consequences may beg the question how you look in orange.”

• Half-life of morphine • General population 2-3 hours

• Cancer patients 5 hours

• Liver impairment 8 or more hours

“Titrate to Comfort” is not a good look

Number t ½ % of Steady State Achieved

2 hour t ½ 3 hour t ½ 5 hour t ½ 8 hour t ½

1 50 2 3 5 8

2 75 4 6 10 16

3 87.5 6 9 15 24

4 93.75 8 12 20 32

5 96.875 10 15 25 40

J Pall Med 2007;10(6):1369-1394; Micromedex 2016

• More aggressive – increase continuous infusion in 8 -12 hours




1 50 2 3 5 8

2 75 4 6 10 16

3 87.5 6 9 15 24

4 93.75 8 12 20 32

5 96.875 10 15 25 40

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• Most aggressive – increase continuous infusion in 8 -12 hours

• More conservative – increase continuous infusion in 12-24 hours




1 50 2 3 5 8

2 75 4 6 10 16

3 87.5 6 9 15 24

4 93.75 8 12 20 32

5 96.875 10 15 25 40

Play it again Sam!

• Dr. Howser correctly calculated the patient’s home use of oral morphine (40 mg a day) and converted this to an IV infusion (0.6 mg/hour).

• Given patient’s severe pain he correctly doubled it to 1.2 mg/hour as a continuous infusion.

• He correctly ordered a clinician bolus (for the RN to give as often as hourly) (10-20% of the total opioid taken in the previous 24 hours [10% 16 mg IV morphine equivalent = 1.6 mg; 20% = 3.2 mg])

• He should NOT have ordered “titrate to comfort per nursing judgment” – should have given better guidance.

• “Administer 2.5 mg IV morphine now. Begin continuous morphine infusion at 1.2 mg/hour. Reassess pain every 30 minutes x 3 and repeat 2.5 mg IV bolus dose of morphine if pain decreased but not adequately controlled, or increase to 5 mg if pain unchanged or increased. If pain is not adequately controlled after 3-IV bolus doses, contact prescriber. Do not increase continuous infusion before 8 am (morning rounds).”

PRESENTED BY:

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if it’s not one case it’s another! complex cases in …...6/5/2019 1 if it’s not one case...

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