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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
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Pain Management
For
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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
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Acute Pain
An unpleasant reaction/sensation secondary to tissue damage
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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
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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
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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
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PAIN
SUFFERING
DEPRESSION
LOSS OF FUNCTION
DRUG ABUSE
FINANCIAL LOSS
DOMESTIC DISRUPTION
Persistent Pain
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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
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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
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Types of Persistent Pain
• Nociceptive– Musculo skeletal– Joint– Ligamentous– Visceral
• Neuropathic– Central– Somatic– Sympathetic
• Psychogenic• Mixed
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Neuropathic Pain Pain secondary to
biochemical and structural changes within the central and peripheral nervous system.
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Pain Transduction
Pain conduction
Pain processing
Pain perception
Pain expression
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Pain Assessment
• The pain itself– Intensity– Radiation– Type– Relieving exacerbating factors
• Functional assessment• Behavioral assessment• Medication usage
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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
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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)
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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
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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
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Neuro -Physiology of Pain
TRANSDUCTION
PERCEPTION
EXPRESSION
CONDUCTION
CONDUCTION Descending Modulation
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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
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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
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The Opioids
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Cancer Pain……… Palliation
Non Malignant Pain………Rehabilitation
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Efficacy of Opioids in Persistent Pain States
• Nociceptive pain
• Visceral pain
• Neuropathic pain
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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
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Breakthrough Pain
• End of dose
• Pathological
• Incidental
• Tolerance
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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
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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
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Routes of Administration• Intravenous
– PRN nurse administered
– PCA
• Oral – PRN
– Around the clock
• Transdermal• Rectal• Transmucosal……oral or nasal• Neuraxial
– Intrathecal
– epidural
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20 minutes
The PRN Scenario
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The PCA
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PHARMACOKINETIC GOALS
HOURS
PAIN
NO PAIN
SIDE EFECTS
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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
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Choice of Opioid in PCA
• Depends on:– Allergies– Renal function– Liver function– History of abuse– Individual response– Previous surgical history
• Cost consideration
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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
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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
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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
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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
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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
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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
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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
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Inadequate Analgesia with PCA
• Check– Demands– The machine– The IV– The lesion being treated
• Abuse potential
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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
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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
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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
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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
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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
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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
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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
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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
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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
------------
-----------
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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
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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
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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
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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
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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
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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
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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
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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
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Oxycodone
• High bioavailability compared to MSO4
• No toxic metabolites• Less tolerance
compared to MSO4• Higher incidence of
euphoria• Expensive• No “M” word
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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
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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.
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Renal Failure
• Methadone
• Dilaudid
• Oxycodone
• Hydrocodone
• Morphine
• Fentanyl
• Demerol
NEUROTOXICITY
SEDATION
TOLERANCE
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Liver Failure
• Methadone
• Dilaudid
• Oxycodone
• Hydrocodone
• Morphine
• Fentanyl
• Demerol
All pretty much OK, but halve dose
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Side Effects of Opioids
• Nausea
• Sedation
• Constipation
• Pruritus
• Myoclonus
• Sweating
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Dependence
• Physical dependence
• Psychological dependence
• Pseudo addiction
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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
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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
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Non Opioid Adjuvants
• Antidepressants
• Anticonvulsants
• Anti-inflammatories
• Acetominophen
• Tramadol
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Acetaminophen
Guidelines• Short-term
– < 4 gm / day
• Long-term– < 3.2 gm /day
– < 2.4 gm /day, elderly, debilitated
OH
NHCOCH3
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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
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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
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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
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Drug Interactions With Antidepressants
• Coumadin• Alcohol ( cold medications)• Appetite suppressants• Quinolone antibiotics• Antihistamines• Tramadol• Anti epileptics • Bronchodilators
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The Anti Epileptic Drugs
• Carbamazapine (Tegretol)• Gabapentin (Neurontin)• Oxcarbezapine (Trileptal)• Topiramate ( Topramax)• Zonisamide ( Zonergan)• Levetiracetam( Keppra)• Lamotragine ( Lamictal)• Valproate ( Depakote)
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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.
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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
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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
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COX-2–Specific Inhibitors
Generic Name Brand Name Approval Year
Celecoxib Celebrex® 1998
Rofecoxib Vioxx® 1999
Valdecoxib
Paracoxib
Etoricoxib
Bextra® 2001
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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)
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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
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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
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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
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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
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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
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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
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Hermann Acute Pain Service
713-606-7100 Pager
713-704-3010 0ffice
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Good Luck and Thank You for Your Attention
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Questions?