1. Pharmacotherapy of pain

2. Types of pain 1 Acute pain Chronic pain preventive function localised
has vegetative sympthomatology and doesn´t 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

3. Types of pain 2 Nociceptive Neuropatic Idiopatic Psychogenic somatic
superficial
deep
visceral (diffuse)
Neuropatic
central
deafferentational
peripherial
neuropaties
Idiopatic
Psychogenic

4. 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)

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

7. Analgesics/antipyretics

8. Paracetamol (Acetaminophen)
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 glucuronides and sulfates
In doses over 5 g/day can cause hepatal damage
In the world, approximately 200 different preparates containing paracetamol are being used
Antidote: N-acetylcysteine (mucolytic drug)

9. Metamizole (Dipyrone)
Derivate of pyrazolone
Mechanism of action: complex;  inhibition of a central COX-3 and activation of the opioidergic system and cannabinoid system
Has spasmolytic properties
Serious adverse effect: 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; short plasmatic half-life (i.v. metamizole - 14 min); elimination mostly through kidneys

10. Non-steroidal anti-inflammatory drugs (NSAIDs)

12. inducable / constitutional
Properties
Cyklooxygenase 1
Cyklooxygenase 2
Localisation
cytoplasmatic in ER
perinuclear
Regulation
constitutional
inducable / constitutional
Presence in tissues
GIT mucosa, renal parenchyma, endothelium, Tr
Mf, Mo, CNS, kidneys, uterus, seminiferous
Predicted function
Integrity of stomach mucosa, kidney perfusion, Tr function
Patogenesis of inflammation and genesis of pain

13. Non-steroidal anti-inflammatory drugs
Division according to COX selectivity:
Selective inhibitors of COX-1:
Acetylsalicylic acid (ASA)- in a dose of mg/day (secondary prevention if atherosclerosis)
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.

14. Acetylsalicylic acid (Aspirin)
in a dose of mg/day (secondary prevention if atherosclerosis)
in a dose of 500 mg (pain, fever)
high doses (antiinflammatory effect; high risk of gastrotoxicity)
not in children: Reye´s syndrome

15. 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 effect ...

16. NSAIDs – one of the most widely used drug groups→ their ADRs represent a serious medical / public health / economical problem there are big differences between various NSAIDs in the level risk of particular possible ADRs

17. 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, sleep disorders, dizziness, epileptic seizures...
other- hepatotoxicity, bleeding, provocation of asthmatic attack, Ray´s syndrom, prolonged childbirth, urticaria, decreased number of white blood cells...

18. 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

19. 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 approx. 18%, severe cases- roughly 1%

20. 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

21. Opioid analgesics
Dampen strong somatic and visceral pain – strongest analgesics, without roof effect, can cause addiction
Dampen algognostic (perception and localisation) and algothymic (psychical and emotional) part of pain
Strong agonists: morphine, fentanyl
Weak agonists: tramadol, codeine
Partial agonists: buprenorphine
Agonists/antagonists: butorfanol, pentazocine
Antagonists: naloxone, naltrexone

24. Pharmacological effects
Depressory
Analgesia
Depression of breathing
Antitussive effect
Decreased secretion and motility in the GIT – constipation
Sedation
Stimulatory
Vomiting
Miosis
Increased tonus of smooth muscles, sphincters
Induction of histamine release
Euphoria

25. 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

26. Morphine Prototypical opioid
Isolated from sap from unriped skulls of poppy (1803)
Fast resorption after p.o. application, bioavailability is 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

27. Fentanyl Synthetic derivate of phenylpiperidine
Strong agonist of  receptors
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 anestesiology
Big advantage – availability of fentanyl in the form of transdermal patches – „Durogesic“
The second most widely used opioid

28. 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

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