Drugs For Pain Management

Nicolaski Lumbuun Faculty of Medicine Univ. Pelita Harapan

Case Study
A 20 yo cross country runner complains of pain in her foot. She runs more than 35 miles per week and has been having foot pain for almost 10 days. She ask you whether she should take aspirin, prednisolone or codein, or What should you do??

Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is always subjective pain 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 7th World Congress on Pain, 1993.)

Classification
Physiological
Nociceptive Neuropathic Psychological

Clinical
Acute Chronic Malignant

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. 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:

Neuropathic Pain
Abnormal processing of sensory input by the peripheral or central nervous system; treatment usually includes adjuvant analgesics. Centrally Generated Pain 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 the level of a spinal cord lesion reflects injury to the central nervous system. Peripherally Generated Pain Painful polyneuropathies: Pain is felt along the distribution of many peripheral nerves. Examples: diabetic neuropathy, alcoholnutritional neuropathy, and those associated with Guillain-Barr syndrome. Painful mononeuropathies: 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.

Tumor involvement of
the organ capsule that causes aching and fairly well-localized pain. Obstruction of hollow viscus, which causes intermittent cramping and poorly localized pain.

Sympathetically
maintained 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).

Pathophysiology
Pain: Involves four physiological processes: - Transduction - Transmission - Modulation - Perception

Pathophysiology
Noxious stimulus

NSAIDS release of inflammatory substances (PG, Hst, Srn, Brdks, Sub.P)

Transduction
(generation & electrical impulses)

Transmission

Pathophysiology
Opioids Transmission
(conduction by nerve fibers)

Opioids Modulation
(descending pathways)

Opioids Perception

Nerve pathways
Ascending Tracts Tract Signal function Dorsal columns
Vibration, tactile sensation, conscious proprioception

Spinocerebeller Spinothalamic (lateral and

anterior)

Proprioception
Pain, temperature, itch (lateral), crude touch (anterior) Pain Pain Pain (touch?) Pain

Spinoreticular Spinomesencephalic Spino-cervico-thalamic Spinohypothalamic

Pain( neuroexcitatory) transmitter:

Glutamate, Ach, NE, Srn, Substance P

Intervention for Pain

TENS = Transcutaneus Electric Nerve Stimulation

LA = Local Anesthesi

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

Drugs Intervention for Pain

1. Non-narcotics Simple analgetic (Paracetamol)/NSAIDs

2. Narcotics
3. Adjuvant analgesic or coanalgesics tricyclic antidepressants antiepileptics corticosteroids bisphosphonates

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

Classification of NSAIDs
Highly COX-1 Selective Relatively COX-1 selective Equally Selective Flurbiprofen, Ketoprofen Fenoprofen, Piroxicam Sulindac Aspirin, Ibuprofen, Ketorolac, Indomethacin, Naproxen, Oxaprosin, Tenoxicam, Tolmetin Diclofenac, Etodolac, Meloxicam, Nabumetone, Nimesulide Rofecoxib, Celecoxib, Etoricoxib, Valdecoxib,
Parecoxib, Lumiracoxib

Relatively COX-2 Selective Highly COX-2 Selective

Principles of Opioid 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 receptor antagonist

Receptor

Subtypes

Location

Function

delta ()

1, 2

Brain opontine nuclei oamygdala oolfactory bulbs odeep cortex

Brain ohypothalamus operiaqueductal gray oclaustrum spinal cord osubstantia gelatinosa

analgesia antidepressant effects physical dependence

Spinal analgesia Sedation Miosis Inhibition of ADH release

kappa ()

1, 2, 3

mu ()

1, 2, 3

brain ocortex (laminae III and IV) othalamus operiaqueductal gray

spinal cord osubstantia gelatinosa

1: Supraspinal analgesia physical dependence 2: respiratory depression miosis euphoria reduced GI motility physical dependence

Opiate receptor interactions

Drug mu Full Agonists Morphine Fentanyl Alfentanil Sufentanil Hydromorphone Methadone Meperidine Codeine Levorphanol Buprenorphine +++ ++++ +++ +++++ +++ +++ ++ + P Receptor kappa ++ delta + + ? + ++ ++

++
+++ +++ ++

Opiate receptor interactions

Drug Receptor kappa +++ +++ P

mu
Mixed agonist-antagonists Nalbuphine Pentazocine Nalorphine Antagonists Naloxone Naltrexone ---

delta

-----

Principles of Opioid Analgesic

Pharmacokinetics
Absorption : Most opioid
well absorbed, but have first pass metabolism effect. Interpatient variability making prediction of an effective oral dose difficult.
perfused such as the brain, lungs, liver, kidneys, and spleen.

Distribution : Highest concentrations in tissues that are highly 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

Table Common Opioid Analgesics

Generic Name Trade Name Approximately Oral:Parenteral Duration Maximum Equivalent Potency Ratio of Efficacy Dose (mg) Analgesia (hours) 10 1.5 10 60100 0.1 0.02 Titrated Titrated 23 30604
4 2

Morphine

Low Low Low High Medium Low Parenteral only Parenteral only Parenteral only High High Medium Medium Oral only Medium Parenteral only Low Parenteral only

45 45 34 46 24 11.5 11.5 0.250.75 0.05 45 34 46 34 45 34 36 48 34

3

High High High High High High High High High High Low Moderate Moderate Very low Moderate High High High

Hydromorphone Dilaudid Oxymorphone Methadone Meperidine Fentanyl Sufentanyl Alfentanil Remifentanyl Levorphanol Codeine Hydrocodone Oxycodone1,5 Propoxyphene Pentazocine Nalbuphine Buprenorphine Butorphanol Dolophine Demerol Sublimaze Sufenta Alfenta Ultiva LevoDromoran

Numorphan 1.5

510 Percodan Darvon Talwin Nubain Buprenex Stadol 4.56 601206 30506 10 0.3 2

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

Clinical Use of Opioids

Analgesia
Pain associated with cancer and other terminal illnesses must be treated aggressively, require continuous use of potent opioid analgesics tolerance & dependence. Administer opioid regularly (not PRN) if pain is present most of day. A regular dose at a scheduled time is more effective 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-induced increase in smooth muscle tone cause a paradoxical increase in pain. An increase in the dose of opioid is usually successful in providing adequate analgesia.

Clinical Use of Opioids

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

Clinical Use of Opioids

Cough
obtained at doses lower than for analgesia. Recently the use of opioid analgesics to allay cough has diminished largely because a number of effective synthetic compounds (eg. Dextrometorphan, noscapin) have been developed that are neither analgesic nor addictive.

Diarrhea
from almost any cause can be controlled with the opioid analgesics, but if diarrhea is associated with infection must not use. Now synthetic opioid with more selective gastrointestinal effects and few or no CNS effects, eg, diphenoxylate (Lomotil), loperamide are used.

Clinical Use of Opioids

Shivering
Although all opioid agonists have some propensity to reduce shivering, meperidine is reported to have the most pronounced antishivering properties. Meperidine blocks shivering through its action on subtypes of the 2 adrenoceptor vasoconstriction

Clinical Use of Opioids

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.

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 ordinary therapeutic 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 hours methadone 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

Opioid ADR Monitoring

Constipation
always prescribe laxatives

Nausea/Vomiting
Metoclopramide Ondansetron

Respiratory depression
Naloxone

Histamine release
Antihistamines

Principles of Opioid 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

Clinical Outcome in Pain management

Thank You
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