Drugs for Pain Management Rev 2011

7/28/2019 Drugs for Pain Management Rev 2011

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Drugs For Pain

Management

Nicolaski Lumbuun

Faculty of Medicine

Univ. Pelita Harapan


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Case Study A 20 yo cross country runner complains

ofpain in her foot. She runs more than

35 miles per week and has been havingfoot pain for almost 10 days. She ask

you whether she should take aspirin,

prednisolone or codein, or

What should you do??


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Pain

An unpleasant sensory and emotional experienceassociated with actual or potential tissue damage.

Pain is always subjectivepain is what the

patients says it is. So, All pain management is base on individual

perceptions & response

Many persons would rather be dead than unloved,abandoned and too often, left in pain.

(Margaret Somerville Death of Pain: Pain, Suffering and Ethics. Proceedings of the 7thWorld Congress on Pain, 1993.)


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Classification

Physiological

Nociceptive

Neuropathic

Psychological

Clinical

Acute

Chronic

Malignant


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Two Major Types of Pain

Nociceptive Pain

Normal process of stimuli that damages normal tissues

or has the potential to do so if prolonged; usually

responsive to nonopioids and/or opioids.

Neuropathic Pain

Abnormal processing of sensory input by the peripheral

or central nervous system; treatment usually includes

adjuvant analgesics.

Somatic Pain

Arises from bone, joint,

muscle, skin, or connective

tissue. It is usually aching

or throbbing in quality and

is well localized.

Visceral Pain

Arises from visceral

organs, such as the GI tract

and pancreas. This may be

subdivided:

Tumor involvement ofthe organ capsule that

causes aching and fairly

well-localized pain.

Obstruction of hollowviscus, which causes

intermittent cramping and

poorly localized pain.

Centrally GeneratedPain

Deafferentation pain:Injury to either the

peripheral or central

nervous system.

Examples: Phantom pain

may reflect injury to the

peripheral nervous system;burning pain below thelevel of a spinal cord lesion

reflects injury to the

central nervous system.

Sympatheticallymaintained pain:

Associated with

dysregulation of the

autonomic nervous system.

Examples: May include

some of the pain associated

with reflect sympathetic

dystrophy/causalgia

(complex regional pain

syndrome, type I, type II).

Peripherally GeneratedPain

Painfulpolyneuropathies: Pain is

felt along the distribution

of many peripheral nerves.

Examples: diabeticneuropathy, alcohol-

nutritional neuropathy, and

those associated withGuillain-Barr syndrome.

Painfulmononeuropathies:

Usually associated with a

known peripheral nerve

injury, and pain is felt at

least partly along the

distribution of the

damaged nerve. Examples:nerve root compression,

nerve entrapment,

trigeminal neuralgia.


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Pathophysiology

Pain:

Involves four physiological processes:

- Transduction

- Transmission

- Modulation

- Perception


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Noxious stimulusNSAIDSrelease of inflammatory substances

(PG, Hst, Srn, Brdks, Sub.P)

Transduction

(generation & electrical impulses)

Transmission

Pathophysiology


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Opioids Transmission(conduction by nerve fibers)

Opioids Modulation

(descending pathways)

Opioids Perception

Pathophysiology


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Nerve pathways

Ascending TractsTract Signal function

Dorsal columnsVibration, tactile sensation, conscious

proprioception

Spinocerebeller Proprioception

Spinothalamic (lateral andanterior)

Pain, temperature, itch (lateral), crude

touch (anterior)

SpinoreticularPain

Spinomesencephalic Pain

Spino-cervico-thalamic Pain (touch?)

Spinohypothalamic Pain


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Pain( neuroexcitatory)transmitter:

Glutamate, Ach, NE,Srn, Substance P


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Intervention for Pain

LA = Local Anesthesi

TENS = Transcutaneus Electric Nerve Stimulation


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Medical management of pain

WHO Ladder

1. Mild pain

NSAID + adjuvant

2. Moderate pain

weak narcotic +

NSAID + adjuvant

3. Severe pain strong narcotic +

NSAID + adjuctant

4. Regional analgesia


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Drugs Intervention for Pain

1. Non-narcotics

Simple analgetic (Paracetamol)/NSAIDs

2. Narcotics3. Adjuvant analgesic or coanalgesics

tricyclic antidepressants

antiepileptics corticosteroids

bisphosphonates


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NSAIDs

Principally have same mechanism of action

Pharmacokinetics (route of administration,

concomitance disease like peptic ulcers,impairment of kidney or liver)

Issue of side effects cox selectivity

Drug-drug interaction, drug-disease interaction


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Highly COX-1 Selective Flurbiprofen, Ketoprofen

Relatively COX-1 selective Fenoprofen, PiroxicamSulindac

Equally Selective Aspirin, Ibuprofen,Ketorolac, Indomethacin,Naproxen, Oxaprosin,Tenoxicam, Tolmetin

Relatively COX-2 Selective Diclofenac, Etodolac,

Meloxicam, Nabumetone,Nimesulide

Highly COX-2 Selective Rofecoxib, Celecoxib,

Etoricoxib, Valdecoxib,Parecoxib, Lumiracoxib

Classification of NSAIDs


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Principles ofOpioid Analgesic

Pharmacodynamic - Intrinsic Effect

Receptor :

(Mu), (Delta), and (Kappa), (Sigma)?

Full agonists, partial agonists, and antagonists

Example :

Morphine is a full agonist at the opioid receptor

Codeine functions as a partial receptor agonist

Naloxone, a strong receptorantagonist

Receptor Subtypes Location Function


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Receptor Subtypes Location Function

delta () 1, 2 Brain

opontine nuclei

oamygdala

o

olfactory bulbsodeep cortex

analgesia

antidepressant

effects

physical dependence

kappa () 1, 2, 3 Brain

ohypothalamus

operiaqueductal gray

o

claustrumspinal cord

osubstantia gelatinosa

Spinal analgesia

Sedation

Miosis

Inhibition ofADHrelease

mu () 1, 2, 3 brain

ocortex (laminae III and

IV)othalamus

operiaqueductal gray

spinal cord

osubstantia gelatinosa

1:

Supraspinalanalgesia

physical dependence2:

respiratory depression

miosis

euphoria

reduced GI motility

physical dependence
http://en.wikipedia.org/wiki/Delta_Opioid_receptorhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Ponshttp://en.wikipedia.org/wiki/Amygdalahttp://en.wikipedia.org/wiki/Olfactory_bulbshttp://en.wikipedia.org/wiki/Cerebral_cortexhttp://en.wikipedia.org/wiki/Analgesiahttp://en.wikipedia.org/wiki/Antidepressanthttp://en.wikipedia.org/wiki/Physical_dependencehttp://en.wikipedia.org/wiki/Kappa_Opioid_receptorhttp://en.wikipedia.org/wiki/Kappa_Opioid_receptorhttp://en.wikipedia.org/wiki/Kappa_Opioid_receptorhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Periaqueductal_grayhttp://en.wikipedia.org/wiki/Claustrumhttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Substantia_gelatinosahttp://en.wikipedia.org/wiki/Sedationhttp://en.wikipedia.org/wiki/Miosishttp://en.wikipedia.org/wiki/Antidiuretic_hormonehttp://en.wikipedia.org/wiki/Mu_Opioid_receptorhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Cerebral_cortexhttp://en.wikipedia.org/wiki/Thalamushttp://en.wikipedia.org/wiki/Periaqueductal_grayhttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Substantia_gelatinosahttp://en.wikipedia.org/wiki/Supraspinalhttp://en.wikipedia.org/wiki/Supraspinalhttp://en.wikipedia.org/wiki/Analgesiahttp://en.wikipedia.org/wiki/Physical_dependencehttp://en.wikipedia.org/wiki/Respiratory_depressionhttp://en.wikipedia.org/wiki/Respiratory_depressionhttp://en.wikipedia.org/wiki/Miosishttp://en.wikipedia.org/wiki/Euphoriahttp://en.wikipedia.org/wiki/Gastrointestinal_tracthttp://en.wikipedia.org/wiki/Physical_dependencehttp://en.wikipedia.org/wiki/Physical_dependencehttp://en.wikipedia.org/wiki/Gastrointestinal_tracthttp://en.wikipedia.org/wiki/Euphoriahttp://en.wikipedia.org/wiki/Miosishttp://en.wikipedia.org/wiki/Respiratory_depressionhttp://en.wikipedia.org/wiki/Physical_dependencehttp://en.wikipedia.org/wiki/Analgesiahttp://en.wikipedia.org/wiki/Supraspinalhttp://en.wikipedia.org/wiki/Substantia_gelatinosahttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Periaqueductal_grayhttp://en.wikipedia.org/wiki/Thalamushttp://en.wikipedia.org/wiki/Cerebral_cortexhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Mu_Opioid_receptorhttp://en.wikipedia.org/wiki/Antidiuretic_hormonehttp://en.wikipedia.org/wiki/Miosishttp://en.wikipedia.org/wiki/Sedationhttp://en.wikipedia.org/wiki/Substantia_gelatinosahttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Claustrumhttp://en.wikipedia.org/wiki/Periaqueductal_grayhttp://en.wikipedia.org/wiki/Hypothalamushttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Kappa_Opioid_receptorhttp://en.wikipedia.org/wiki/Kappa_Opioid_receptorhttp://en.wikipedia.org/wiki/Kappa_Opioid_receptorhttp://en.wikipedia.org/wiki/Physical_dependencehttp://en.wikipedia.org/wiki/Antidepressanthttp://en.wikipedia.org/wiki/Analgesiahttp://en.wikipedia.org/wiki/Cerebral_cortexhttp://en.wikipedia.org/wiki/Olfactory_bulbshttp://en.wikipedia.org/wiki/Amygdalahttp://en.wikipedia.org/wiki/Ponshttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Delta_Opioid_receptor


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Opiate receptor interactions

Drug Receptor

mu kappa deltaFull Agonists

Morphine +++ ++ +

Fentanyl ++++ +

Alfentanil +++ ?

Sufentanil +++++ +

Hydromorphone +++ ++

Methadone +++ ++

Meperidine ++ ++

Codeine +

Levorphanol +++ ++

Buprenorphine P +++


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Opiate receptor interactions

Drug Receptor

mu kappa delta

Mixed agonist-antagonists

Nalbuphine --- +++Pentazocine - +++

Nalorphine - P

AntagonistsNaloxone --- - -

Naltrexone --- - -


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Principles ofOpioid Analgesic

PharmacokineticsAbsorption : Most opioid well absorbed, but have first pass

metabolism effect. Interpatient variability making prediction of an

effective oral dose difficult.

Distribution : Highest concentrations in tissues that are highlyperfused such as the brain, lungs, liver, kidneys, and spleen.

Metabolism Phase 2 Metabolism (conjugation with glucuronid) : morphine

Phase 1 & 2 : heroin, remifentanil

Phase 1 : meperidine, fentanil, alfentanil, sulfentanil, codein

Excretion : Mainly in the urine, only a small portion in faeces


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Table Common Opioid AnalgesicsGeneric Name Trade

Name

Approximately

Equivalent

Dose (mg)

Oral:Parenteral

Potency Ratio

Duration

of

Analgesia

(hours)

Maximum

Efficacy

Morphine 1 10 Low 45 High

Hydromorphone Dilaudid 1.5 Low 4

5 High

Oxymorphone Numorphan 1.5 Low 34 High

Methadone Dolophine 10 High 46 High

Meperidine Demerol 60100 Medium 24 High

Fentanyl Sublimaze 0.1 Low 11.5 High

Sufentanyl Sufenta 0.02 Parenteral only 11.5 High

Alfentanil Alfenta Titrated Parenteral only 0.250.75 High

Remifentanyl Ultiva Titrated2

Parenteral only 0.053

High

Levorphanol Levo-Dromoran

23 High 45 High

Codeine 30604 High 34 Low

Hydrocodone 4 510 Medium 46 Moderate

Oxycodone1,5 Percodan 4.56 Medium 3

4 Moderate

Propoxyphene Darvon 601206

Oral only 45 Very low

Pentazocine Talwin 30506

Medium 34 Moderate

Nalbuphine Nubain 10 Parenteral only 36 High

Buprenorphine Buprenex 0.3 Low 48 High

Butorphanol Stadol 2 Parenteral only 3

4 High


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Clinical Use of Opioids

For a patient in acute severe pain, opioid analgesic

is usually considered a primary part of the overall

management plan.

Determining : route of administration (oral, parenteral, intrathecal)

duration of drug action

ceiling effect (maximal intrinsic activity)

duration of therapy

potential for adverse effects

patient's past experience with opioids


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Analgesia Pain associated with cancer and other terminal illnesses

must be treated aggressively, require continuous use ofpotent opioid analgesics tolerance & dependence.

Administer opioid regularly (not PRN) if pain is presentmost of day. A regular dose at a scheduled time is moreeffective in achieving pain relief than dosing on demand.Use controlled release preparation (morphine (MST continus),fentanyl patch transdermal)

severe pain of renal and biliary colic the drug-inducedincrease in smooth muscle tone cause a paradoxicalincrease in pain.An increase in the dose of opioid isusually successful in providing adequate analgesia.


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Acute Pulmonary Edema The relief produced by intravenous morphine

Sugessted mechanism of morphine :

reduced anxiety

reduced cardiac preload (reduced venous tone)

afterload (decreased peripheral resistance)

Morphine can be particularly useful when treating painful

myocardial ischemia with pulmonary edema


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Cough obtained at doses lower than for analgesia.

Recently the use of opioid analgesics to allay cough hasdiminished largely because a number of effectivesynthetic compounds (eg. Dextrometorphan, noscapin)have been developed that are neither analgesic noraddictive.

Diarrhea

from almost any cause can be controlled with the opioidanalgesics, but if diarrhea is associated with infectionmust not use.

Now synthetic opioid with more selective gastrointestinaleffects and few or no CNS effects, eg, diphenoxylate

(Lomotil

), loperamide are used.


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Shivering

Although all opioid agonists have some

propensity to reduce shivering, meperidine is

reported to have the most pronounced anti-shivering properties.

Meperidine blocks shivering through its action

on subtypes of the 2 adrenoceptor

vasoconstriction


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Applications in Anesthesia Frequently used as premedication before anesthesia and surgery

Also used intraoperatively both as adjuncts to other anesthetic

agents and, in high doses (eg, 0.020.075 mg/kg of fentanyl), as a

primary component.

Also be used as regional analgesics by administration into the

epidural or subarachnoid spaces of the spinal column have

demonstrated long-lasting analgesia with minimal adverse effects

(epidural administration of 35 mg of morphine, followed by slow

infusion through a catheter placed in the epidural space).

Epidural application of morphine might selectively produce

analgesia without impairment of motor, autonomic, or sensory

functions. Currently is favored ???

In rare cases, chronic pain management surgically implant a

programmable infusion pump connected to a spinal catheter for

continuous infusion of opioids or other analgesic compounds.


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Adverse Effects of Opioid

Tolerance & Dependence A strong agonist is associated w/ more severe withdrawal sign & symptoms

Tolerance develops most readily when large dose are given at short intervals.Generally manifest after 2-3 weeks of frequent exposure to ordinarytherapeutic doses.

Physical Dependence signs and symptoms : rhinorrhea, chills, gooseflesh (piloerection), hyperventil,

hypertherm, mydriasis, musc ach, vomit, diarrhea, anxiety

time of onset, intensity, duration depend on the drug.

morphine/heroin start within 610 hours after. Peak effects at 3648 hours,after that most of the signs and symptoms gradually subside.

meperidine, the withdrawal syndrome largely subsides within 24 hoursmethadone several days to reach the peak of symphtom, and last as 2 weeks

Psychologist Dependence euphoria, indifference to stimuli, and sedation (iv) promote compulsive use


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Opioid ADR Monitoring

Constipation always prescribe laxatives

Nausea/Vomiting

Metoclopramide

Ondansetron

Respiratory depression

Naloxone

Histamine release

Antihistamines


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Principles ofOpioid Analgesic Use

in Acute and Cancer Pain

Individualize route, dosage, and schedule

Administer analgesics regularly (not PRN) if

pain is present most of day Become familiar with dose / time course of

several strong opioids

Give infants / children adequate opioid dose Follow patients closely, particularly when

beginning or changing analgesic regimens


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Clinical Outcome in Pain management


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Drugs for Pain Management Rev 2011