“Worse than torture”

88 y/o with dementia FAST 7-C who is a nursing home resident under hospice. Consult was made because of uncontrolled agitation despite being on lorazepam and haldol. When I arrived I heard the patient screaming from the end of the hallway. Inside the room was the wound care nurse standing in front of a scared, screaming patient who looked like somebody who saw evil. She had a 4 cm by 8 cm non-healing vascular ulcer on the dorsum of her left foot. Prior to dressing changes, she receives lorazepam +/- haldol. She is also on Lortab 5/500 mg q 4 hours prn for pain. She received 1 tablet the past 24 hours.

25-50 % have chronic pain syndromes 30 % of Nursing home patients did not

receive analgesics despite daily complaints of pain and another 16 % only received acetaminophen

Age and female sex were predictors of under-treatment for pain

Not recognizing the importance of pain Prejudices about pain Fears of abuse and addiction Unpleasant experiences with pain

therapy (intolerable side effects: nausea, drowsiness, fatigue, constipation)

Regulatory restrictions Insufficient knowledge of

pharmacological therapy

Chronic neurobiological disorder Genetic, psychological and social

components Characterized by an impaired ability to

control drug use and continued use despite recurrent problems related to self administration.

Arises when pain is inadequately managed, and the response of the medical staff is to use this as evidence for the diagnosis of drug addiction

May result from as needed dosing schedules with inadequate potency, and longer than appropriate dosing intervals

Adequate pain control results to resolution of aberrant behavior and improved functioning

Tobacco – 35% Cocaine – 23% Alcohol – 17% Marijuana – < 10%

Opioids – less than 1%

46 year old male with recurrent, progressive head and neck cancer with excruciating neoplasm related pain on the right ear, jaw, and mouth. Pain is between 8/10 to 10/10. Breakthrough pain is spontaneous. Never had relief for a year The local interventional pain physician placed him on Fentanyl 100 mcg 72 hours and oxymorphone 10 mg q 4 hours. He uses 6 to 8 doses of Subsys 1600 mcg gives him relief for 3 to 4 hours. He uses 6 doses per day. He gets significant pain relief when he gets IV morphine in the oncology clinic. He is depressed, anxious, grouchy, and sleep deprived. Weight continues to drop despite a PEG. There are no curative or life prolonging treatments available for his cancer. PPS=40 %. He is hospice appropriate but wife is still in denial.

75% of dying patients will require strong opioids

13% will require dose reduction, 44% require dose escalation, 44% unchanged

60% will be able to swallow and 40 % will require another route of administration

More than 50% will have new pain 10% to 20% will die with excruciating pain

Physical functioning Appetite loss Pain

EORTC Clinical Groups. Lancet Oncology. September 2009

The best pain medication is one that will control pain without any adverse effects

There is considerable inter-individual variability in response to each opioid

Opioids have a very wide effective dose range

Dose titration until adequate pain control is achieved or intolerable adverse effects manifest

Is there a maximum dose

Trajectory of the disease process and pain syndrome

Co-morbid condition Socio-economic factors Knowledge and experience in using

specific opioids Genetic factors Life expectancy

Always continue or convert chronic stable dose of home opioid analgesic. Be creative. May combine po with iv or transdermal with iv

There is incomplete cross tolerance among opioids. Because of this when converting stable doses use 75% of conversion dose if pain is fairly controlled

If pain is uncontrolled you may use 100% of conversion dose

Patient should be given a breakthrough or rescue dose for incidental or acute on chronic pain

Breakthrough dose is 10 to 15 % of 24 hour stable dose

Or 30% to 50% of q 4 hour dose Find that dose that will control

excruciating pain

Morphine Morphine POPO

33

1 1

HydromorHydromorphone IVphone IV

11

55

11

2020

HydromorHydromorphone POphone PO

11

22

11

88

55

11

MethadonMethadone POe PO

11

22

11

6 to 12 6 to 12

22

11

OxycodonOxycodone POe PO

1.51.5

11

11

22

1010

1 1

44

1 1

33

11

11

22

OxymorpOxymorphonehone

11

1111

3355

1144

33

Morphine Morphine IVIV

Morphine Morphine POPO

HydromorHydromorphone IVphone IV

HydromorHydromorphone POphone PO

MethadonMethadone POe PO

OxymorpOxymorphonehone

Fentanyl 25 mcg patch=45 mg oral morphine

100 mcg IV fentanyl=10 mg IV morphine

Fentanyl 100 mcg q 72 hours = 180 mg oral morphine per 24 hours

Opana 10 mg = 30 mg oral morphine x 6 doses = 180 mg oral morphine

Subsys 1600 mcg x 6 doses = no available conversion data = 1,440 to 2,880 mg oral morphine

Methadone 10 mg/ml, 20 mg q 6 hours sublingual

Roxanol 20 mg/ml 4 to 8 ml q 1 hour prn per peg for breakthrough pain. Instruction was given to try 4, 5, 6, 7, 8 ml and take note what dose will control breakthrough pain

Subsys 1600 mcg q 4 hours prn for breakthrough pain

Gabapentin 300 mg tid Dexamethasone 4 mg bid

20% to 40% of variable drug efficacy caused by phenotypic variations

Genetics is involved in drug metabolism. It causes differences to drug response› Extensive or normal metabolizers› Poor metabolizers› Ultra rapid metabolizers› Intermediate metabolizers

Phase 1 metabolism by the cytochrome P450 pathway (oxidation or hydrolysis)› CYP 3A4=metabolizes 90% of all drugs

Methadone, Fentanyl, Buprenorphine, Oxycodone, Tramadol

CYP 2D6=Codeine, Hydrocodone

Phase 2 metabolism by conjugation (glucurodination)› Morphine, Hydromorphone, Oxymorphone› Little or no pharmacokinetic drug-drug interaction› Pharmacodynamic drug-drug interactions are

possible (additive effect with benzodiazepine

CYP 3A4› Tramadol→M1 (Q-desmethytramadol)› Fentanyl→Norfentanyl› Oxycodone→Noroxycodone

CYP 2D6› Codeine→Morphine› Oxycodone→Oxymorphone› Hydrocodone→Hydromorphone (90%) and

Norhydrocodone(via CYP 3A4)

Codeine Morphine Hydromorphone Tramadol Oxycodone

Fentanyl Oxymorphone Methadone

Methadone Fentanyl

Saw the patient weekly 2nd visit, patient was smiling and said he

has not had relief for 1 year until he saw me His dose was titrated to

› Methadone 20 mg q 4 hours sublingually› Roxanol 5 ml q 1 hour prn averaging 4 doses per

day› Subsys 1600 mcg was not stopped. He

averaged 0 to 2 doses per day He survived for 5 months with good pain

control until the last 4 days of life

Related to initial use and intolerance - the opioid naïve patient› Delirium, drowsiness, respiratory

depression etc. Related to chronic high dose opioid use Other adverse effect different from the

first two› Persistent myoclonus, persistent

drowsiness, persistent delirium (persistent neurotoxicity)

52 y/o male with metastatic lung cancer. Severe back, bilateral hip, and chest wall pain due to multiple bone metastasis. Had palliative XRT. Morphine controlled release titrated to 400 mg TID. On Morphine IR 30 mg, 2 to 3 tabs q 2 hours prn for breakthrough. Pain was controlled until he had his first chemotherapy. Had nausea and vomiting that led to dehydration. He developed confusion, generalized pain and some myoclonus. Discussed case with Oncologist. Syndrome can be due to terminal phase but………

Morphine was stopped. Had aggressive hydration therapy. Methadone 5 mg q 6 hours was given (20% of conversion) and Dilaudid 4 mg po q 2 hours prn for breakthrough. Mental status improved, pain was perfectly controlled, and myoclonus resolved. He completed his palliative chemotherapy and survived for 8 months with good quality of life. He signed up with hospice 2 months before he passed away due to progressive weakness and onset of terminal delirium.

Disturbance of consciousness and defects in attention, orientation, and memory.

The patient is disoriented and cannot focus, sustain, or shift attention. He or she is unable to remember well or cannot use language without disorganization.

This disability fluctuates over hours and days. The key finding of fluctuating consciousness sets

delirium apart from dementia, and disorientation sets it apart from functional psychiatric disorders.

In dementia, cognition is impaired despite the patient's alert state and ability to pay attention. In functional psychiatric disorders, patients may have delusions and hallucinations, but their orientation to time and place are not typically impaired.

Due to prolonged use of opiates It occurs when there is a progressive

lack of response to a drug requiring increased dosing

Higher doses of opiates are required to elicit same amount of analgesia or anti-nociception

Can occur with other drugs including opioids

Hyperalgesia and allodynia Myoclonus Confusion (delirium) Related to but different from tolerance Has been observed and documented in

literature since 19th century (Observed by Albutt in 1870)

Results from prolonged opiate exposure Occur at a certain critical opioid dose NMDA plays central role in it’s

development Causes sustained neuroplastic changes

in the spinal cord Results into up-regulation of spinal

dynorphin and CGRP (proposed mechanism)

Methadone› Mu agonist and NMDA antagonist› A racemic mixture in which the d-isomer is

the NMDA antagonist› Displays incomplete cross tolerance

properties› Anecdotal reports show improvement or

control of OIH when reducing opioid dose and adding low dose methadone

Can be used to treat OIH Methadone can relieve opioid

withdrawal Due to long half life there are fewer

variations in plasma levels Standard of treatment for opioid

dependence for over 40 years Methadone can also cause OIH?

1. Chu L.F. Analgesic tolerance without demonstrable opioi-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain. Pain 2012;153(8): 1583-1592

2. Crews, K.R. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for codeine therapy in the context of Cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharm & Therapeutics 2012; 91(2): 321-326

3. DuPen, A. et al. Mechanisms of opioid induced tolerance and hyperalgesia. Pain Man Nurs 2007; 8(3): 113-121

4. Greenberg, D.B. Preventing Delirium at the End of Life: Lessons From Recent Research. Prim Care Companion J Clin Psychiatry 2003; 5(2): 62–67

5. Ferrari A. et al. Methadone-metabolism, pharmacokinetics and interactions. Pharmacol Res 2004; 50(6): 551-559

6. Hanks, G. et al. Oxford Textbook of Palliative Medicine. Oxford University Press Inc., New York, 2010

7. Hutchinson, R.M. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol 2003; 57(3): 287-297

8. Lee, M. A comprehensive review of opioid –induced hyperalgesia. Pain Physician 2011; 14: 145-161

9. Smith, H.S. Opioid Metabolism. Mayo Clin Proc. 2009; 84(7):613-624