How to Keep The Patient in Pain Sleeping at Night

(and you awake in the morning )

Barry Bass

University Center for Pain Medicine

UTHSC, Houston

Pain Management

For

Objectives

• To identify types of pain• To clarify principles of pain assessment• To clarify the basic principles of prescribing• To discuss the basic pharmacological principles of opioid

and adjuvants used in pain management• To discuss the practical application of drugs used in

analgesic therapy with emphasis on patient safety , risk benefit comparisons and cost containment

Acute Pain

An unpleasant reaction/sensation secondary to tissue damage

Acute Pain

• Corresponds to the degree of injury• Is self limiting• Serves a purpose• Responds to conventional therapy• Attracts sympathy and concern from

family and caregivers• Minimal affective response• Treatment is cost effective• Good outcomes

Chronic Pain

• Outlasts the initial injury• Subjective exceeds the objective findings• Poor response to conventional therapy• Serves no beneficial purpose• Poor response from family and care givers• Cost ineffective therapy• Accompanied by major psycho-social co-

morbidity• High incidence of substance abuse

Definition of Persistent (Chronic) Pain

• Any pain that – Persists beyond the expected time after a

physical or emotional injury

– Subjective complaints are magnified

– Pain is out of proportion to clinical signs

– Is accompanied by severe psycho-social issues

– Responds poorly to conventional therapy

PAIN

SUFFERING

DEPRESSION

LOSS OF FUNCTION

DRUG ABUSE

FINANCIAL LOSS

DOMESTIC DISRUPTION

Persistent Pain

Scope of The Problem

• One in four Americans has persistent pain• Commonest reason for PCP office visits• Over 50% of Cancer patients have severe pain• 60% of the elderly have persistent pain• Commonest cause of disability• Health care costs related to persistent pain is

$100 billion and rising rapidly• Lost work hours secondary to persistent pain

can double the costs• Rising rate of substance abuse

The Good

The Bad

The Ugly

ACUTE PAIN

Persistent nociceptive Pain

Neuropathic Pain

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Who Gets Persistent Pain ?

• Systemic disease– Diabetes mellitus– hypothyroidism– HIV/AIDS– Hepatitis C– Malignancy– Neurological disease….ALS, MS– Rheumatoid related syndromes

• Obesity• Psychiatric co-morbidity

Types of Persistent Pain

• Nociceptive– Musculo skeletal– Joint– Ligamentous– Visceral

• Neuropathic– Central– Somatic– Sympathetic

• Psychogenic• Mixed

Neuropathic Pain Pain secondary to

biochemical and structural changes within the central and peripheral nervous system.

Pain Transduction

Pain conduction

Pain processing

Pain perception

Pain expression

Pain Assessment

• The pain itself– Intensity– Radiation– Type– Relieving exacerbating factors

• Functional assessment• Behavioral assessment• Medication usage

Pain Assessment• Characterize the pain

• Characterize the disease, relationship between pain and disease and potentially treatable etiologies

• Clarify syndromes and infer pathophysiology

• Determine need for urgent therapy

• Identify other needs

• Develop a therapeutic strategy

Pain Intensity Rating Scales• Visual Analogue Scale (VAS)

No painNo pain ----------------------------------- ----------------------------------- Worst painWorst pain

• Categorical Scale

None (0) Mild (1 None (0) Mild (1 – 4) Moderate – 4) Moderate (5 (5 – 6) Severe – 6) Severe (7 – 10(7 – 10) )

• Numerical Rating Scale

-------------------------------------------------------------------------------------- 00 No painNo pain

1010Worst pain Worst pain imaginableimaginable

(Cleeland, 1991; Jacox et al, 1994)

Red Flags in Pain Assessment• Poor function• Pain always a 10 out of 10• Behavioral co morbidity• Obsession with drugs• Altercations with staff• Focus on particular medications• Multiple admissions for pain therapy• Frequent ER visits• Illegal drug usage• Alcohol and tobacco abuse• Poor motivation

Guidelines in Pain Therapy

• Assess the pain frequently• Pain assessment must be dynamic and not static• Be pre-emptive• Be mechanistic• Use around the clock therapy (ATC)• Treat and assess breakthrough pain aggressively• Where possible use oral route• Consider age, previous drug usage, hepato- renal

function• Monitor for abuse• Monitor and treat side effects• Be cost effective

Neuro -Physiology of Pain

TRANSDUCTION

PERCEPTION

EXPRESSION

CONDUCTION

CONDUCTION Descending Modulation

Decrease inflammatory response. NSAIDS, local anesthetics, steroids

Decrease conduction gabapentin, carbamazepine,local anesthetics, opioids

Prevent centralization

cox2,opioids, ketamine,alpha 2 agonists.

Increase inhibition.. Amitryptiline venlafaxine, clonidine

Modify expression..anxiolytics

Mechanistic Approach To Therapy

Mechanistic Approach to Drug Therapy in Persistent Pain

• Decrease peripheral sensitization

• Delay or block conduction

• Suppress automaticity

• Inhibit central amplification

• Increase descending inhibition

• Modify central perception

• Modify expression

The Opioids

Cancer Pain……… Palliation

Non Malignant Pain………Rehabilitation

Efficacy of Opioids in Persistent Pain States

• Nociceptive pain

• Visceral pain

• Neuropathic pain

WHO Analgesic “Ladder” for Cancer Pain

WHO 3-StepWHO 3-StepAnalgesic Analgesic

LadderLadder

Proposed 4th StepProposed 4th Step

Deer T, Winkelmuller W, Erdine S, et al. Intrathecal therapy for cancer and nonmalignant pain: patient selection and patient management. Neuromodulation 1999;2:55-66.

Freedom from Pain

Intrathecal Opioid Delivery

Pain persisting or increasing

Step 3Opioid for moderate to severe pain

± Nonopioid ± Adjuvant

Pain persisting or increasing

Step 2Opioid for mild to moderate pain

± Nonopioid ± Adjuvant

Pain persisting or increasing

Step 1± Nonopioid± Adjuvant

Pain

Breakthrough Pain

• End of dose

• Pathological

• Incidental

• Tolerance

Principles of Breakthrough Pain Therapy

• Should not exceed 25% of the daily dose

• Should stay within the therapeutic window

• Should have minimal side effects

• Should not be randomly escalated

• If needed more than 4 hrly. Increase ATC.

• Assess for abuse vs tolerance

Opioids Used for Pain Management• Morphine Sulphate• Hydromorphone (Dilaudid)• Demerol• Fentanyl• Methadone• Buprenorphine• Pentazocine• Oxycodone (Roxycodone, Tylox, Percocet)• Hydrocodone (vicodin, lortab, Norco)• Propxyphene ( Darvon, Darvocet)• Codeine

Strong Opioids

Partial agonists

Weak

opioids

Routes of Administration• Intravenous

– PRN nurse administered

– PCA

• Oral – PRN

– Around the clock

• Transdermal• Rectal• Transmucosal……oral or nasal• Neuraxial

– Intrathecal

– epidural

20 minutes

The PRN Scenario

The PCA

PHARMACOKINETIC GOALS

HOURS

PAIN

NO PAIN

SIDE EFECTS

Indications for PCA

• Moderate to severe pain requiring opioids

• Pain anticipated to last >10-12 hours

• Patients willing to control their analgesia

• Patient able to understand PCA

• Oral route is not appropriate

• Procedural pain

Choice of Opioid in PCA

• Depends on:– Allergies– Renal function– Liver function– History of abuse– Individual response– Previous surgical history

• Cost consideration

Loading Dose

• Morphine 50 g/kg q 10 minutes– 80 kg = 50 X 80 = 4,000 g = 4 mg

• Fentanyl 0.5 g/kg q 5 minutes– 80 kg = 0.5 X 80 = 40 g

• Hydromorphone 10 g/kg q 10 minutes– 80 kg = 10 X 80 = 800 g = 0.8 mg

Maintenance Dose

• Morphine 25 g/kg q 10 minutes– 80 kg = 25 X 80 = 2,000 g = 2 mg

• Fentanyl 0.25 g/kg q 5 minutes– 80 kg = 0.25 X 80 = 20 g

• Hydromorphone 5 g/kg q 10 minutes– 80 kg = 5 X 80 = 400 g = 0.4 mg

III. PCA

• Morphine 1 mg / ml (5 mg/ml)

• Fentanyl 10 g/ml (50 g/ml)

• Hydromorphone 0.2 mg/ml (1 mg/ml and 5 mg/ml)

• Meperidine 10 mg/ml

The Demand Dose with PCA

• <0.5 mg MS is associated with poor analgesia• >2 mg MS associated with over sedation• Excessive demands

– Poor pain relief or change in medical status

– Pump failure

– Patient confusion…………..elderly

– Family interference………..elderly and children

– Inappropriate patient use…….abuse

• Adjust bolus dose if poor pain relief with >4 demands per hour

• With line occlusion alarm set for 3 failed demands

The Lockout Interval

• Time interval to assure full effect and to minimize sedation…..a safety feature

• Too long a lockout will reduce the effectiveness of the PCA

• Too short a lockout will increase risk of sedation

• Lockout of 7 -11 minutes for morphine• Lockout of 6-10 minutes for

hydromorphone• Lockout 5-8 minutes for fentanyl Ginsberg. Pain.1995:62:95

The Lockout Interval

• Time interval to assure full effect and to minimize sedation…..a safety feature

• Too long a lockout will reduce the effectiveness of the PCA

• Too short a lockout will increase risk of sedation

• Lockout of 7 -11 minutes for morphine• Lockout of 6-10 minutes for hydromorphone• Lockout 5-8 minutes for fentanyl Ginsberg. Pain.1995:62:95

Basal Infusions with PCA• Infusion will continue regardless of

sedation level• Responsible for most instances of over-

sedation ..1-3% cf. <0.5% with demand • Removes the feed back loop• Does not offer improved pain relief • Does not offer improved sleep• No difference in number of demands• Does increase total opioid delivered• Increased risk of programming errors• Only to be used if patient is opioid tolerant

with knowledge of daily requirements

Rudolph.Anes.Analg.1999.89:1226

Inadequate Analgesia with PCA

• Check– Demands– The machine– The IV– The lesion being treated

• Abuse potential

Inadequate Analgesia with PCA• Increase the bolus dose• Decrease the lockout• Educate the patient• Start basal infusion• Change the route• Change the opioid• Add an adjuvant

– Antidepressant– Anticonvulsant– Anti inflammatory

• Treat the lesion

Extreme Caution with Basal Infusion

• Children• Elderly• OSA disease• Morbidly obese• Hypovolemia• Renal impairment……….when using morphine

and Demerol.• Inexperienced nursing staff• With concurrent epidural infusion

Etches. Can. J. Anes. 1994.41:125

Continuous Infusion

• Not routine• Start an infusion if:

– Inadequate analgesia over >6 hours

– Opioid-tolerant patient

• Infusion rate based on hourly use over previous 6 hours– Opioid-naïve 25-50% of hourly requirement

– Opioid-tolerant 50-75% of hourly requirement

PCA Dosing in Children

Drug/Potency PCA dose Basal

Morphine/1

Hydromorphone

Fentanyl/20

10-20mcg/kilo 5-30mcg/kilo/hr

2-6mcg/kilo 1-6mcg/kilo/hr

0.5-1mcg/kilo 0.25mcg/kilo/hr

Used in children over the age of 6 years

Lockout 6-10 minutes

(Dilaudid/5

Patient Education PCA

• Assess patient competency• Allay fears regarding addiction• Press the button before pain is intolerable• Family not to press the button• Nurses not to press button• Do not clock watch• Hit button whenever you want• Reassure fears of sedation

Meperidine…….Demerol• Short acting

• Toxic metabolites

• Metabolites with long half life >12 hrs

• Increased risks in renal failure

• High addiction potential

• Expensive

• High incidence of caregiver diversion

• Gradually being phased out

Normeperidine Toxicity

420 (37)

(260-540)

370 (66)

(46-1100)

350 (52)

(59-1080)

170 (18)

(75-380)

Rate of admin. (mg/day)

5.9 (1.0)

(3-10)

6.7 (1.9)

(1-30)

8.0 (1.2)

(1-22)

1.2 (0.1)

1-2

Days of administration

8/29/92019N

Myoclonus/ Grand mal

Tremors/ Twitches

Shaky Feelings

Asympto-maticPatient Group

Kaiko RF et al, Ann Neurol 1983;13(2):180-5

Equianalgesic Dosing

Drug Oral po Oral SR durn IV im peak

Morphine

demerolfentanyl

dilaudid

hydrocodone

oxycodone

methadone

30

200/1

2-4/2

10/1

10/1

20/2

30-60

10

Half life

10

100

0.1

0.5

8

/130

145

30

1

2-3

unpred

2 mins

2-3

4-5

3-4

15-30

3-5

3-4

3-4

3-4

6-8

2-3

.5-1

Opioid Equivalencies/ Conversions

Drug oral factor* durationPARENTERAL

MSO4 10 mg 30mg 3 3-4hrs

Oxycodone -------- 15-20 --- 3-4 hrs

Methadone 10MG 20mg 2 4-8 hours

Dilaudid 1.5 mg 7.5 mg 5 2-3 hours

codeine 130 mg 200mg 1.5 3-4 hourshydrocodone ------- 10-20mg --- 3-4 hours

propoxyphene 50-100Tramadol 50-100

3-4 hours3-7 hours

------------

-----------

Conversion to Oral

• Calculate total daily requirement with PCA• Convert to IV morphine• Convert to Oral morphine• Convert to alternate opioid• 75 % as ATC 25% as rescue• Factor in incomplete cross tolerance especially

with oxycodone and Methadone

Prior to Oral Conversion

• Patient able to tolerate oral fluids

• Oral therapy started prior to removal of PCA

• Pain control predictable and stabilized

• IV to oral conversion calculated

• Side effects under control

• multimodal therapy started to be used

Ginsberg B, Anesthes & Analgesia 1998

PCA to Oral Oxycodone Conversion Table

10 –15 mg40 mg1400 g16 mg80 mg

10 –15 mg40 mg1200 g14 mg70 mg

10 –15 mg30 mg1000 g12 mg60 mg

10 –15 mg30 mg800 g10 mg50 mg

5-10 mg20 mg650 g8 mg40 mg

5-10 mg10 mg500 g6 mg30 mg

5-10 mg0< 300 g< 4 mg< 20 mg

24-hour opioid

Oxycodone IR (q 3h prn)

OxyContin

Q 12 hFentanylHydro-

morphoneMSO4

Oral Opioid Comparison

• Long track record

• Avoids “M” word

• No toxic metabolites

• ? immune function

• Formulations

– Immediate release

– Combinations

Acetaminopheno Ibuprofen

• Long track record

• Avoids “M” word

• No toxic metabolites

• ? immune function

• Formulations

–Immediate release

–Sustained release (Fall 2001)

• Long track record

• Avoids “M” word

• No toxic metabolites

• ? immune function

• Formulations

–Immediate release

–Controlled release

HydrocodoneHydromorphoneOxycodone

Example of Conversion

• Total morphine for 24 hours on PCA= 60mg

Want to convert to Oxycodone.

60 mgm of MS IV( x 3) = 180 mgm oral.

To convert to oxycodone x by 1.5 = 120 mg oxycodone

75% as ATC = 90 mg = 40 mg Q 12 , but factor in 50% less for ICT = 20 mg q 12 hourly

25% as rescue = 30 mg or 5 mg Q 4-6 hourly PRN

Long Acting Opioids for ATC

• MS Contin 15,30,60 mgm

• Oxycontin 10,20,40,60,80 mgm

• Methadone 5, 10, 20 mgm

• Fentanyl patch 25, 50,75,100 mcg

Methadone (Dolophene)

• Long acting• Lower addiction potential• Cheap• Lower tolerance profile• For the opioid addict• No active or toxic metabolites• No renal excretion• No dependence on hepatic function• Long elimination half life• 8-12 hour analgesic action

Methadone

• Start of at lowest dosage

• 5 mgm Q 12 hourly

• Warn patient about dangers of PRN

• Increase only after 72 hours if needed

• If indicated increase to 5 mg Q 8 hourly

• Increase to 10 or 7.5 mg slowly

• Strongly advise against iv administration

Oxycodone

• High bioavailability compared to MSO4

• No toxic metabolites• Less tolerance

compared to MSO4• Higher incidence of

euphoria• Expensive• No “M” word

The Fentanyl Patch

• Indications for use– Around the clock delivery of opioids

– Allergy to long acting oral opioids

– Severe nausea and vomiting

– Unable to swallow

– Severe constipation

• Beware– Opioid naïve

– Febrile patient

– Elderly

– Drug abuser

One 25 mcg/h transdermal

fentanylpatch/3 days

(72 hours)

Conversion Chart for Starting Dose of Transdermal Fentanyl

(Adapted from Duragesic PI, 2001)

Fixed-combination short-acting opioids (6/day):

–Lorcet 5 mg/500 mg–Lortab 5 mg/500 mg–Percocet 5 mg/325 mg–Percodan 5 mg/325 mg–Tylenol + Codeine 30 mg/325 mg–Tylox 5 mg/500 mg–Vicodin 5 mg/500 mg

Long-acting opioids(2/day):– OxyContin 20 mg– MS Contin 30 mg

Multiple patches may be used for doses exceeding 100 mcg/h. Doses up to 6oo mcg/h have been evaluated in clinical trials.

Renal Failure

• Methadone

• Dilaudid

• Oxycodone

• Hydrocodone

• Morphine

• Fentanyl

• Demerol

NEUROTOXICITY

SEDATION

TOLERANCE

Liver Failure

• Methadone

• Dilaudid

• Oxycodone

• Hydrocodone

• Morphine

• Fentanyl

• Demerol

All pretty much OK, but halve dose

Side Effects of Opioids

• Nausea

• Sedation

• Constipation

• Pruritus

• Myoclonus

• Sweating

Dependence

• Physical dependence

• Psychological dependence

• Pseudo addiction

Recognizing the Addict

• Refuses drug screen• Focus on narcotics• Wants demerol or fentanyl• Wants Xanax and soma• Hourly or daily escalations• Conflicts with care givers• Family issues• Obvious stigmata

Strength Licit Retail Illicit Retail

10 mgm $1.25 $5-10

2o mgm $2.30 $10-20

40mgm $4.0 $25-40

80mgm $6.0 $65-80

160 mgm $14 $100-200

Cincinatti Police Department

50c to $1.5 per milligram oxycodone

Non Opioid Adjuvants

• Antidepressants

• Anticonvulsants

• Anti-inflammatories

• Acetominophen

• Tramadol

Acetaminophen

Guidelines• Short-term

– < 4 gm / day

• Long-term– < 3.2 gm /day

– < 2.4 gm /day, elderly, debilitated

OH

NHCOCH3

Acetominophen Content

Tylenol 160 325 500 650

Tylenol liquid 80 160 500

Tylenol drops 80 100

Tylox 500

Vicodin 500 750

Lortab 500 650

Norco 325

zydone 400

Wygesic 650

Tricyclic Antidepressants: Adverse Effects

• Commonly reported AEs (generally anticholinergic):– blurred vision– cognitive changes– constipation– dry mouth– orthostatic hypotension– sedation– sexual dysfunction– tachycardia– urinary retention

• Desipramine

• Nortriptyline

• Imipramine

• Doxepin

• Amitriptyline

FewestAEs

Most AEs

Caveats With the Antidepressants

•Start at lowest dose available

•Escalate slowly…every 10 -14 days

•Slow weaning, over a week

•Beware of drug interactions

•Check for

•Glaucoma

•Prostatic obstruction

•Heart block

Drug Interactions With Antidepressants

• Coumadin• Alcohol ( cold medications)• Appetite suppressants• Quinolone antibiotics• Antihistamines• Tramadol• Anti epileptics • Bronchodilators

The Anti Epileptic Drugs

• Carbamazapine (Tegretol)• Gabapentin (Neurontin)• Oxcarbezapine (Trileptal)• Topiramate ( Topramax)• Zonisamide ( Zonergan)• Levetiracetam( Keppra)• Lamotragine ( Lamictal)• Valproate ( Depakote)

Gabapentin in Neuropathic Pain Disorders

• FDA approved for postherpetic neuralgia• Anticonvulsant: uncertain mechanism• Limited intestinal absorption• Usually well tolerated; serious adverse effects rare

– dizziness and sedation can occur

• No significant drug interactions• Peak time: 2 to 3 h; elimination half-life: 5 to 7 h• Usual dosage range for neuropathic pain up to 3,600

mg/d (tid–qid)*

*Not approved by FDA for this use.

Suggestions with Gabapentin

• Start as low as possible…..100 mgm q HS• Increase slowly by 100 mgm every three days• Caution regarding driving• Increase to 1200 mgm and assess pain relief• If > 50% relief, wait two weeks and reassess• Increase to maximum of 3600 mgm• Do not exceed 1200 mgm in elderly• Elixir in children mgm/kilo

Selective COX-2

Inhibitor

The Arachidonic Acid Cascade and COX-1 and COX-2 Inhibition

X XTraditional NSAID X

Arachidonic acid

Needleman P, et al. J Rheumatol. 1997;24: 6-8.Simon LS, et al. J Clin Rheumatol. 1996;2:135-40.

COX-1 COX-2

Body Homeostasis• Gastric integrity• Renal function• Platelet function

InflammationPain

COX-2–Specific Inhibitors

Generic Name Brand Name Approval Year

Celecoxib Celebrex® 1998

Rofecoxib Vioxx® 1999

Valdecoxib

Paracoxib

Etoricoxib

Bextra® 2001

The COX 2 Inhibitors

• Rofecoxib 25-50 mg daily (Vioxx)

• Celecoxib 100-200mg daily (Celebrex)

• Valdecoxib 10-20 mg daily (Bextra)

• Etrocoxib

• Paracoxib (iv use)

Contra Indications to COX2 Therapy

• Previous side effects with COX2 inhibitors• Allergy to sulpha drugs• History of previous GI bleed• pregnancy• History of perforated gastric ulcer• Esophageal varices• Bronchospastic disease• Renal dysfunction• Coronary artery disease needing aspirin• Congestive heart failure

The Muscle Relaxants

• Most act by central mechanisms

• Most produce sedation

• Most have anticholinergic side effects

• Some are highly addictive

• Most produce little local relaxation

The Muscle Relaxants

• Centrally acting relaxants– Metaxalone(Skelaxin)– Cyclobenzaprine (Flexeril)– Methocarbamol (Robaxin)– Carisprodol (Soma)

• GABA agonists– Alprazolam (Xanax)– Diazepam (Valium)– Lioresal (Baclofen)

• Alpha 2 agonists– Tizanidine ( Zanaflex)

Beware of sedation, addiction and anticholinergic side effects

The Muscle Relaxants

• Centrally acting relaxants– Metaxalone(Skelaxin)– Cyclobenzaprine (Flexeril) 10mg and max at 40mg– Methocarbamol (Robaxin)– Carisprodol (Soma) highly addictive

• GABA agonists– Alprazolam (Xanax) highly addictive– Diazepam (Valium) high abuse potential– Lioresal (Baclofen) 10 mg daily and max at 40mg.

• Alpha 2 agonists– Tizanidine ( Zanaflex) 2mg q hs and escalate to 8mg

Case Example

•45 y.o. female with sickle cell disease

•Admitted with severe back and left hip pain

•Frequent visits to the ER for pain. Gets demerol

•Takes Soma, Xanax and Vicodin for pain

•History of cocaine, tobacco and THC abuse

•Hb 5gms, severe muscle spasm lower back, decreased ROM left hip.

•Placed on demerol 25-50 mg iv q 2 hourly PRN, Vicodin 10/500 tabs 1-2 q 4-6 hrly.

•Continual demands for more demerol and yelling at nurses

Take Home Message• Identify the pain generator• Identify and treat underlying disease(diabetes, HIV,

Depression)• Assess before you treat• Start low and go slow• Use rational poly-pharmacy, but not shotgun Rx.• Factor in age, hepato-renal function• Monitor for abuse and document• Identify and treat side effects early• Be cost effective• Communicate with patient and family• Obtain pain service consult when you feel necessary

Hermann Acute Pain Service

713-606-7100 Pager

713-704-3010 0ffice

Good Luck and Thank You for Your Attention

Questions?