Pharmacotherapy of pain

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Pharmacotherapy of pain
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Types of pain 1

• Acute pain
• preventive function
• localised
• has vegetative sympthomatology and doesnt cause
  severe psychological changes
• clearly defined beginning and ending
• analgesics are usually effective in treatment

• Chronic pain
• without preventive function
• lasts 3-6 months
• often associated with severe psychological
  changes
• without clearly defined beginning
• malignant (caused by cancer)or non-malignant

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Types of pain 2

• Nociceptive
• somatic
• superficial
• deep
• visceral (diffuse)
• Neuropatic
• central
• deafferentational
• peripherial
• neuropaties
• Idiopatic
• Psychogenic

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Therapy of pain

• Analgesics and co-analgesics
• Non-opioid analgesics
• Analgesics/antipyretics
• Non-steroidal anti-inflammatory drugs
• (NSAIDs)
• Opioid analgesics
• Natural (morphine, dihydrocodeine)
• Synthetic (fentanyl, buprenorphine)
• Co-analgesics (Antidepressants, Anxiolytics,
  Myorelaxants, Anticonvulsives, Neuroleptics,
  Glucocorticoids, Anesthetics, ?2
  sympaticomimetics, H1 antihistamines)

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Non-opioid analgesics

• Analgesics/antipyretics
• aspirin (acetylsalicylic acid- ASA)
• paracetamol (USA- acetaminophen)
• metamizole (textbooks from the US say its an
  NSAID)
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Non-selective inhibitors of COX-1 and COX-2
  (ibuprofen, diclofenac, ASA)
• Preferential inhibitors of COX-2 (nimesulide,
  meloxicam)
• Selective inhibitors of COX-2 (celecoxib,
  rofecoxib (dereg.))

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• Analgesics/antipyretics

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Paracetamol

• Derivate of anilin
• Mechanism of action unknown, possibly
• inhibition of COX-3 (variant of COX-1) in CNS
• Good absorption from GIT
• Biological half life - 1,5-3 h 
• Only a small percentage of the drug binds on
  plasma proteins (10)
• Elimination through the kidnies in the form of
  glukuronides and sulfates
• In doses over 5 g/day can cause hepatal damage
• In the world, approximately 200 different
  preparates containing paracetamol are being used.

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Metamizole

• Derivate of pyrazolone
• Synonyms Noramidopyrín, Dipyrón
• has spasmolytic properties.
• Serious adverse effect is depression of bone
  marrow leading to agranulocytosis.
• Good absorption in the case of both peroral and
  rectal administration.
• More than 50 binds onto plasmatic proteins
• Plasmatic halflife is short (i.v. metamizole - 14
  min)
• Elimination- mostly through kidnies.

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• Non-steroidal anti-inflammatory drugs
• (NSAIDs)

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Non-steroidal anti-inflammatory drugs
Division according to COX selectivity
Selective inhibitors of COX-1 Acetylsalicylic acid (ASA)- in a dose of 30- 300 mg/day
Non-selective inhibitors of COX Acetylsalicylic acid- in a dose of 500 mg/day or more, ibuprofen, diclofenac, ketoprofen, tiaprofen, indomethacin and many more
Preferential inhibitors of COX-2 nimesulide, meloxicam etc.
Selective inhibitors of COX-2 celecoxib, rofecoxib, etoricoxib, valdecoxib etc.
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Effects of NSAIDs

• Analgesic effect
• Antipyretic effect
• Antiflogistic effect (mainly higher doses)
• Antiaggregatory effect (not every NSAID, most
  important is ASA because of irreversible blocade
  of COX-1- be careful with combination of ASA for
  anti-aggregation and other NSAIDs- mostly
  ibuprofen)
• Other effects- for example reduced incidence of
  some tumors (for example colorectal carcinoma),
  uricosuric effekt ...

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NSAIDs one of the most widely used drug
groups? their ADRs represent a serious medical /
public health / economical problemthere are big
differences between various NSAIDs in the level
risk of particular possible ADRs
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Adverse effects of NSAIDs

• GIT- erosions and ulcers of the gastric mucosa
  (also in other localisations in the GIT), nausea,
  vomitus, meteorism, diarrhoea, constipation...
  (mainly inhibition of COX-1)
• kidney- reduction of glomerular filtration,
  retention of Na and fluids, edema, hyperkaliemia,
  kidney failure, interstitial nephrits...
  (inhibition of COX-1 and 2)
• CVS- thrombotic events, increase of blood
  pressure, heart failure... (mainly COX-2 (mostly
  in thrombotic events))
• CNS- cephalea, weakness, sleap disorders,
  dizziness, epileptic seizures...
• other- hepatotoxicity, bleeding, provocation of
  asthmatic attack, Rays syndrom, prolonged
  childbirth, urticaria, decreased number of white
  blood cells...

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Gastrointestinal ADRs

• most serious ? production of prostaglandins in
  the gastric mucosa ? peptic ulcer (most often in
  the stomach and duodenum the mucosa can get
  damaged by NSAIDs also in other places in the
  GIT)
• roughly 25 of chronic NSAID users might develop
  erosions and ulcers, in 2-4 perforation or
  bleeding can occure

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Kidney ADRs

• Decreased production of prostanoids ? negative
  effect on the perfusion of the kidneys,
  glomerular filtration, excretion of sodium
  and water and on production of renin ?
  circulation overload, oedemas, hypertension
  hyperkalemia in severe cases symptoms of acute
  kidney failure
• serious complication interstitial nephritis
  (immunological reasons)
• Incidence of kidney ADRs is poughly 18, severe
  cases- roughly 1

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Cardiovascular ADRs

• Increased blood pressure- mostly in hypertensive
  patients treated with antihypertensives (mainly
  ACEIs, ARBs, beta blockers), there are big
  differences between various NSAIDs
• Development/worsening of heart failure- the risk
  is highest during the first weeks of treatment,
  mainly in patients with preexisting congestive
  heart failure possibly 19 of all cases of
  congestive heart failure could be caused (at
  least partially) by NSAID therapy
• Thrombotic events- acute myocardial infarction,
  stroke, thromboembolic disease

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Opioid analgesics

• Dampen strong somatic and visceral pain
  strongest analgesics, without roof effect, can
  cause addiction
• Dampen algognostic (perception and localisation)
  and algotymick(psychical and emotional) part
  of pain

• Strong agonists morphine, fentanyl
• Weak agonists tramadol, codeine
• Partial agonists buprenorphine
• Agonists/antagonists butorfanol, pentazocine
• Antagonists naloxone, naltrexone

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Pharmacological effects

• Stimulatory
• Vomiting
• Miosis
• Increased tonus of smooth muscles, sphincters
• Induction of histamine release
• Euphoria

• Depressory
• Analgesia
• Depression of breathing
• Antitussive effect
• Decreased secretion and motility in the GIT
  constipation
• Sedation

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Adverse effects of opioids

• Neuropsychiatric
• Sedation, clouded consciousness, euphoria, sleep
  disorders
• Cardiopulmonal
• Depression of breathing, Bronchoconstriction
  (high doses) Orthostatic hypotension,
  Bradycardia (high doses)
• Gastrointestinal
• Nausea, vomiting, constipation, gastrointestinal
  or gallbladder colics
• Urinary system
• Retention of urine
• Endocrine
• Decreased levels of testosterone, problems with
  menstrual cycle
• Allergic and immunologic
• Pruritus, immunosupression

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Morphine

• Prototypical opioid
• Isolated from sap from unriped skulls of poppy
  (1803)
• Fast resorption after p.o. application,
  bioavailabilityis only 30 (significant first
  pass effect)
• Most common adverse effects- nausea, vomiting,
  constipation, gallbladder and uretral spasms
• Depression of breathing is the most common cause
  of death in case of intoxication.
• Most common signs of intoxication
  unconstiousness, bradypnoea a miosis

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Fentanyl

• Synthetic derivate of phenylpiperidine
• Strong agonist of ? receptors
• 80-100 times more potent than morphine
• Lipophilic character rapid onset of action,
  but the effect lasts only for a short time
• Contraindicated in pregnancy
• Derivates of fentanyl- sufentanyl and alfentanyl
  are used in anesteziológii
• Big advantage availability of fentanyl in the
  form of transdermal patches Durogesic
• The second most widely used opioid

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Tramadol

• Atypical opioid
• Intermediate analgesic effect
• High bioavailability is an advantage.
• In therapeutic doses lacks most of the adverse
  effects of opioids.
• The most common adverse effects are sweating,
  nausea and dry mouth.
• Suitable for treatment of mild to severe pain in
  adults and children.
• Available in different drug forms.
• It is cheap.

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In case of long term treatment, analgesics should
be administered regularly, not only when the
patient feels pain.