Pain Management- Drug Therapy

Presented by Robert A. Ancker, MD

Medical Director, Hospice of North Idaho

Module Objectives Review the role of acetaminophen and

NSAIDS in pain management Learn the difference between Psychological

vs. Physiological Dependence Learn the key pharmacological principles of

opioid analgesics and proper usage Learn the key opioid side effects Learn the indications and use of Relistor ® for

Opioid Induced Constipation

Pain Assessment1. Basic History

– When did it start?– Where is it?– What is the pain intensity? 0-10 scale– What does it feel like? (quality)

• Somatic – localized, achy, dull• Visceral – colicky, pressure, referred, diffuse• Neuropathic – burn, numb, radiate, hyperalgesia

– What makes the pain better or worse?

2. Analgesic History—Medications3. Analgesic History: Non-Pharmacological4. Impact and Meaning of Pain5. Pain Causality and Patient Goals

Visual Analog Scale (VAS)

Psychological vs. Physiological Dependence Psychological Dependence (Addiction)

– Compulsive use of drugs– Loss of control – Use in spite of harm– Occurs in only ~0.1% of chronic opioid patients – Drug seeking behavior: missed appointments, off-hours calls

for renewals, multiple physicians Physiological Dependence (Tolerance)

– Physical withdrawal Sx on abrupt discontinuation– Expect after 1 month of opioid use– Long term use results in tolerance & thus increased doses

(NORMAL)– Usually does not occur during acute pain management– Risk of MD directed addiction is NOT a concern in treating

cancer pain

Tolerance and Dependence

Tolerance is not an inevitable consequence of chronic opioids therapy- – RARE in cancer patients– Increased dose correlates with

disease progression Physical dependence is expected with

chronic therapy Do not confuse physical dependence

with ADDICTION (psychological dependence)

*Drayer et al. J Pain Symptom Manage 1999;17:434-40

Beware of the Pseudoaddict!!

Pseudoaddiction is .. The behavioral manifestations of

addiction that occur as a result of under treated pain– Moaning/crying when you enter the room– Clock watching– Frequent requests for more medication– Pain that seems “excessive” for the stimulus

Patient has no other history to suggest addiction– Behaviors cease with adequate pain treatment

Pseudoaddiction

May occur in the hospitalized patient, in pain, who has opioids ordered:– At inadequate potency or dose– At excessive dosing intervals– And when the behavior is reinforced by MD or RN

behavior that tends to limit opioid use:“you really shouldn’t be having this much pain”

“you have to wait another two hours for your next dose of medication”

Pain Type: Somatic – localized, achy, dull Visceral – colicky, pressure, referred,

diffuse Neuropathic – burn, numb, radiate,

hyperalgesia

Checkpoint

Classes of Analgesics

Non-opioids (NSAIDS, acetaminophen, aspirin, tramadol)

Opioids (morphine is the prototype) Adjuvant Analgesics (antidepressants,

anticonvulsants, steroids, others)

Analgesics for Mild Pain Acetaminophen NSAIDS/Aspirin Tramadol

Acetaminophen

Doesn’t affect stomach, kidney, platelets– But, it has no

inflammatory mediators– But, it has a ceiling

dose: 4 Grams/24 hours

– AND, is hepatotoxic in overdose

Why is Tylenol, the pain reliever recommendedby most doctors?

Checkpoint

What is the dose of acetaminophen (APAP) in the following preparations:

– Lorcet Plus ® = 650 mg APAP– Vicodin ES ® = 750 mg APAP– Ultracet ® = 325 mg APAP– Norco ® = 325 mg APAP

Acetaminophen toxicity Acetaminophen overdose is one the most

common causes of OTC drug poisoning in the United States.

More than 78,000 ER cases w/ 33,000 hospital admits per year of acetaminophen overdoses per report by the Consumer Products Safety Commission

About 300 deaths per year 50/50 accidental to intentional Leading cause of drug-induced liver failure in

the United States (Bartlett D 2004).

Bartlett D. Acetaminophen toxicity. J Emerg Nurs. 2004 Jun;30(3):281–3.

NSAIDs

Effective for relief of mild pain & have opioid dose-sparing effect

Pain relief via their anti-inflammatory effect by inhibiting prostaglandins, thus are very effective in relieving pain from bone mets.

Dosage: use patient response to determine effective dose

If max. dose achieved w/o pain relief try another drug from this same category

Route of Admin.: Use oral route; some suppositories available; Toradol via IM or IV

NSAIDs - toxicityHas significant end organ toxicity

– Should be used with great caution in the elderly

– ~16,500 deaths, ~100,000 hospitalizations annually due to adverse effects from NSAIDS

– ~3500 deaths from GI bleed Note! No NSAID has greater analgesic

efficacy compared to any other NSAID – However, patients may report greater effect from

a particular preparation

NSAIDs - toxicity Gastropathy Renal insufficiency Decreased platelet aggregation Hypersensitivity Hepatitis with some 2nd Generation NSAID’s reported to

have less GI toxicity– Maybe??– Vioxx® fiasco……

Tramadol (Ultram ®) A synthetic non-opioid(?) analog of codeine

– mu-receptor agonist – Weak inhibitor of serotonin, norepinephrine reuptake

Analgesic effect roughly equivalent to Tylenol #3 ®– Efficacy variable; has an analgesic ceiling

No anti-inflammatory effects Side effects similar to opioids at high dose-nausea,

confusion, dizziness, constipation Seizure risk Dependence may occur Not currently on a DEA schedule!

PDR.net. 2003: Ultram® (tramadol hydrochloride).Cherny NI. Opioid analgesics. Comparative features and prescribing guidelines. Drugs. 1996;51:714-37.

Opioid Pharmacology Opioid refers to

– Alkaloids derived from opium– Natural and synthetic agents whose actions are

mediated by selectively binding to opioid receptors in the brain/spinal cord and perhaps via peripheral opioid receptors

Receptor types include mu, delta, & kappa– Further divided into receptor subtypes, eg: mu1 & mu2

– The mu receptor is the dominant analgesic receptor, but other receptors play a role in analgesia for certain opioids

– There is no dose ceiling for pure agonists opioids, only for acetaminophen in combination products

Cherny NI. Drugs. 1996; 51:714-37.

Responses Mediated by Opioid Receptors

Adapted from: Cherny NI. Drugs. 1996; 51:714-37.

Receptor Response on activation

mu Analgesia, respiratory depression, miosis, euphoria, reduced GI motility

delta Analgesia

kappaAnalgesia, dysphoria, psychotomimetic effects, miosis, respiratory depression

Mu Receptor Activation of Opioids

Zuurmond WW, et al. Acta Anaesth Belg. 2002;53:196-201.Cherny NI. Drugs. 1996; 51:714-37. Walsh SL, et al. Clin Pharmacol Ther. 1994;55:569-80.

mu receptor site

morphine

FULL AGONIST activation of mu receptor

Stadol ®

PARTIAL AGONIST activation of mu receptor

mu receptor site

mu receptor site

naloxone

ANTAGONIST - Prevents or reverses activation of mu receptor

Mixed Agonist-Antagonists Claim to have less respiratory depressant

effects—not substantiated Claim to be less addicting—not substantiated Will potentiate withdrawal in patients being

treated with pure agonists– NEVER administer to a patient on a pure

agonist Have an analgesic ceiling Are psychotomimetic – can cause psychoses No real indication in end of life patients

Opioid pharmacology

Cmax after– PO 1 hr– SC, IM 30 min– IV 6 min

Half-life at steady-state – PO/PR/SC/IM/IV 3-4 hrs

. . . Opioid pharmacology

Steady state after 4-5 half-lives– Steady state after 1 day (24 hours)

Duration of effect of “immediate-release” formulations (except methadone)– 3-5 hours PO/PR– Shorter with parenteral bolus

Pla

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00 Half-life (t1/2)Half-life (t1/2) TimeTime

IVIV

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SC / IMSC / IM

CmaxCmax

OPIOIDS—Duration of Action

A. Ultra short

B. Short

C. Long

A. Ultra Short Acting Opioid Fentanyl

– IV has 50-100 x potency of morphine– transdermal– Transmucosal

Good role in Renal and/or Liver failure patients

B. Short Acting Opioids

Parenteral or Oral– morphine– hydromorphone

(Dilaudid ®)– meperidine (Demerol

®) – codeine

Oral only– oxycodone

(Percocet ®, Tylox ® , OxyIR)

– hydrocodone (Vicodin ® Lortab ®, Norco ®)

– propoxyphene (Darvon ®, Wygesic ®)

– Note: hydrocodone is only available as a combination product.

Oral dosing:– onset in 20-30 min– peak effect in 60-90 minutes– duration of effect 2-4 hours– Can be dose escalated or re-administered

every 2-4 hours for poorly controlled pain as long as the daily Acetaminophen dose stays < 4 grams

B. Short Acting Opioids

Opioid Combination Products

Opioids available as combination products with acetaminophen or aspirin

• Codeine; hydrocodone; oxycodone;

Typically used for• Moderate episodic (PRN) pain

– UOOB, BSC, ROM– May not need any med OR need PRE-MED

• Breakthrough pain in addition to a long-acting opioid – KEEP TRACK

Never prescribe more than one combination drug at any one time

Toxicity:– All the combination products can cause

opioid toxicities: nausea, sedation, constipation, etc.

– There is little published data that supports the use of one product over another in terms of toxicity; however …

– codeine is probably the most emetogenic opioid

How to Choose a Combination Product (cont)

Meperidine Shortest acting (only 2-3 hr duration) Weak potency;

– 300 mg po = 30 mg po morphine Converted to a long acting toxic

metabolite--a CNS stimulant– Tremor, myoclonus and seizure– Risk highest with prolonged use and

renal insufficiency

C. Long Acting Opioids Oral

– MS Contin®

– Oramorph SR®

– Oxycontin®

– methadone

Transdermal– Fentanyl Patch

(Duragesic®)

MS Contin® / Oxycontin® No clear benefit of one product over another

– MS Contin contains morphine– Oxycontin contains oxycodone– No difference in toxicity; No difference in

addiction potential All must be taken intact—they cannot be

crushed; they do not fit down GI tubes.– Exception: Kadian ®

All provide 8-12 hours of analgesia– Minimum dosing interval is q 8 hours– All provide onset of analgesia within 2 hours– All can be dose escalated every 24 hours

Transdermal Fentanyl Slow onset of action: 13-24 hours

– Duration of action: 48-72 hours Should only dose escalate q 3 days

– Fentanyl stays in circulation for up to 24 hours after patch removal

Place on hairless, non-irradiated skin No ceiling dose

Conversions from/to Transdermal Fentanyl (Duragesic®)

When converting fentanyl patches, published data suggest that a 25 mg patch is equivalent to 45-135 mg of oral morphine/24h.

However, clinical experience suggests that most patients will use the lower end of the range of morphine doses (i.e., for most patients 25 mcg is ≈ 50 mg of oral morphine/24h).

THUS, 24 hour total dose of oral morphine, divided by 2 = dose in micrograms of transdermal fentanyl;

Conversions from/to Transdermal Fentanyl (Duragesic®)

Example:• MS Contin® 30 mg q 12 = 60 mg MS/24

hours• 60 divided by 2 = 30; rounded to one 25 ug

Fentanyl Patch

Example:• Duragesic 50 mcg/hr = ~100 mg oral

morphine per day

Breakthrough Pain Patients on any long-acting med always

need a second, short-acting med, available for breakthrough pain

Take at least every 4 hours, preferably less

Guideline, dose of breakthrough opioid should be: 10-20% of 24 hour dose of analgesics

and made available q. 1-4 hours

Methadone Complex pharmacology Duration of action increases with

prolonged use from 4 hours to as much as 12 hours

Dose conversions to:from other opioids are complex—seek consultation

Least expensive potent opioid Does not need special DEA license to

use for pain; special license only needed if used as treat for substance abuse (methadone maintenance clinic)

Opioid Dose EscalationAlways increase by a percentage of the present dose

based upon patient’s pain rating and current assessment

Mild pain 1-3/10

25% increaseModerate pain4-6/10

25-50% increase Severe pain7-10/10

50-100% increase

Frequency of dose escalation The frequency of dose escalation (oral

opioids) depends on the particular opioid – Short acting oral: q 2-4 – Long acting oral, except methadone: q 24

hours– Methadone: q 4-6 DAYS– Transdermal fentanyl: q 72 hours

Parenteral Opioids IV is the route of choice if

access is available– There is no indication for IM opioids– All standard opioids can be given SQ, by either

bolus dose or by continuous infusion Can use a SQ button

– Change 2x/week– Limit 3ml/hr

PCA (basal rate plus a patient initiated dose) is an effective and well accepted modality; either IV or SQ

IV or SQ bolus doses have a shorter duration of action that oral doses; typically 1-3 hours

The peak effect from an IV bolus dose is 5-15 minutes

Dose escalation of parenteral opioids is the same as with oral—always by a percentage of the starting dose

Parenteral Opioids

6 8 10 12 14

Theoretical Relation Between Analgesic Drug Level, Dosing Interval, and Clinical Response

Pain

Analgesia

Sedation

Ferrante FM, et al. Anesth Analg. 1988;67:457-61.

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Time (hours)

Dose Dose Dose

Dose

Minimum analgesic concentration

IMPCA

IM=intramuscular; PCA=patient controlled analgesia

Equianalgesia Since all potent opioids produce analgesia by

the same pharmacological mechanism, they will produce the same degree of analgesia if provided in equianalgesic doses.

Thus, there is little basis to say, “morphine did not work, but hydromorphone did work”. Such a statement generally means that non-equianalgesic doses were used.

There is no dose ceiling. The word “potent” is irrelevant! Non-opioids are not included when

performing equianalgesic calculations.

EquianalgesiaCommon Conversions 10 po MS = 3.3 mg IV MS (3:1) 5 mg po Dilaudid = 1 mg IV Dilaudid (5:1) 10 mg po MS = 2.5 mg po Dilaudid® (4:1) 10 mg po MS = 10 mg po oxycodone ** 10 mg po MS = 10 mg po hydrocodone (!)

Note: Conversions factors are only a rough guide to approximate the correct dose.

** Controversial: some recommend 3:2 or 1.5:1 ratios for MS: oxycodone

Incomplete Cross-tolerance

If a switch is being made from one opioid

to another because of tolerance,

it is recommended to start the new opioid

at 50% of the equianalgesic dose

Opioids Side Effects Sedation, confusion, respiratory

depression Dizziness, dysphoria Nausea Constipation Itching, uticaria, bronchospasm

– NOT AN ALLERGY!!! Urinary retention Opioid hyperexcitability syndrome

– Hyperesthesia, myoclonus, seizure

Sedation / Respiratory Depression With increasing dose, all opioids lead

to a predictable sequence of CNS events:– Sedation with or without delirium then

• Further decrease consciousness then– Coma and respiratory depression

Respiratory Depression Risk Factors

– Renal insufficiency– Liver failure– Parenteral opioids; especially rapid dose

escalation in opioid naïve patients

– Severe pulmonary disease (CO2 retainers)

– Sleep apnea– Rapid dose escalation of transdermal

fentanyl or methadone

Naloxone (Narcan®) In palliative care, Narcan is only indicated

when:– **The goals of care are such that reversing CNS

depression is indicated**• ?? Intentional/accidental overdose

– And patients have decreased level of consciousness and decreased respirations

– Administer Narcan • 1 amp (0.4 mg) diluted in 9 ml saline• 1 ml per minute until level of consciousness improves

– CAUTION: may propagate a severe pain crisis!

Nausea and Vomiting Caused by stimulation of the CTZ

(chemoreceptor trigger zone) at base of 4th ventricle.– Nausea is not an allergy!!

Morphine and codeine are the most emetogenic opioids

Tolerance develops within 3-7 days for most patients

Standard anti-emetics can reduce symptoms

Itching and Urticaria Tolerance may or may not develop. Not life threatening

– not anaphylaxis, NOT AN ALLERGY!– does not mean that opioids can never be

used Drug treatment of symptoms is not very

effective (anti-histamines, steroids)– Trial of different opioids indicated as some

patients will itch with one product but not another

Constipation Multi-factorial cause Tolerance does not develop Start a bowel stimulant at the time

opioids are started– Senna or MOM good first choices

Goal is one BM qod, or what is “normal” for the patient

Relistor SQ

Methylnaltrexone Bromide

Relistor ®

12mg/0.6ml solution for SQ injection

Etiology of Opioid-Induced Constipation (OIC)

Opioids: suppress forward peristalsis raise sphincter tone increase fluid absorption reduce intestinal secretions

Largely mediated by peripheral mu ()-opioid receptors:

on myenteric and submucosal neurons in the gut

Gutstein HB, Akil H. Opioid Analgesics. Goodman and Gillman’s: The Pharmacological Basis of Therapeutics. 11th ed. New York: NY: McGraw-Hill; 2006. Schumacher MA, Basbaum AI, Way WL. Opioid analgesics & antagonists. Basic and Clinical Pharmacology. 10th ed. New York, NY: Lange Medical Books/McGraw-Hill; 2007.

Methylnaltrexone: Acts peripherally to directly counteract the

constipating effects of opioid analgesics in patients receiving palliative care who are not sufficiently responsive to laxatives1,2

– Brings prompt relief from OIC within 4 hrs1

– Reduces the need for enemas3 – Is generally well tolerated with most treatment-

emergent adverse events rated as mild or moderate in severity1

1. Thomas J et al. NEJM 2008;358:2332-432. Holzer Expert Opinion Investig Drugs 2007; 16(2): 181-1943. Wyeth Data on File MNTX02/2008

Dosing Schedule

Methylnaltrexone should be added to induce prompt bowel movement when response to laxative therapy has been insufficient

The usual administration schedule is one single dose every other day. Doses may also be given with longer intervals, as per clinical need.

Patients may receive two consecutive doses 24 hours apart, when there has been no response (bowel movement) to the dose on the preceding day

Local clinical guidelines may be taken into consideration

The recommended dose of Methylnaltrexone bromide is:

• 8 mg (for patients weighing 38‑61 kg) • 12 mg (for patients weighing 62‑114 kg)• Patients whose weight falls outside of the range should be dosed at 0.15mg/kg• The injection volume for these patients should be calculated:

Dose (ml) = patient weight (kg) x 0.0075

Methylnaltrexone SmPC July 2008, Wyeth Pharmaceuticals

Final comments…… BELIEVE THE PATIENT’S PAIN

COMPLAINTS & ESTABLISH REALISTIC PAIN RELIEF GOALS

TITRATE OPIOIDS TO PAIN RELIEF PROGRESSION OF THE DISEASE, NOT

TOLERANCE, IS THE USUAL CAUSE FOR DOSE INCREASES

CONSIDER PALLIATIVE CARE CONSULT FOR PAIN SYMPTOMS