1. ANALGESICS

2. Pain Management What is pain?
A protective mechanism to warn of damage or the presence of disease
Part of the normal healing process
A protective mechanism to warn of damage or the presence of disease

3. Managing pain can be a challenge.
Every day the world nearly 4 million patients suffer from pain of different intensity: 10-15% of moderate pain, 30-40% of the average pain intensity, 60-80% of severe pain. Studies show that more than 30 million people in the world take NSAIDs daily , and that the complications of their reception, primarily gastrointestinal, constantly growing 3

4. I. Opioid (narcotic) analgesics
1. Agonists of opioid receptors – morphine hydrochloride, promedol, omnopon, fentanyl, codeine;
2. Agonists – antagonists and partial agonists of opioid receptors – pentazocin, buprenorphine.
II. Non-opioid analgesics and non steroidal anti-inflammatory drugs - NSAIDs
acetylsalicylic acid, paracetamol, analgin, indometacin, butadion, ibuprofen, pyroxicam, diclofenac-sodium, ketorolac, ketoprofen.
III. Substances with mixed mechanism of action (opioid and non-oioid components)
tramadole

5. The structures that take part in perception of pain: thalamus, hypothalamus, reticular formation, limbic system, occipital and frontal areas of cortex System which conducts and perceives pain - nociceptive
The structures that take part in perception of pain: thalamus, hypothalamus, reticular formation, limbic system, occipital and frontal areas of cortex
System which conducts and perceives pain - nociceptive

6. System which protects organism from pain – antinociceptive

7. Classification of Pain By Onset and Duration
Acute pain
Sudden in onset
Usually subsides once treated
Chronic pain
Persistent or recurring
Often difficult to treat

8. Major Sources of Pain Somatic body framework throbbing, stabbing
Area Involved
Characteristics
Treatment
Somatic
body framework
throbbing, stabbing
narcotics, NSAIDS
Visceral
kidneys, intestines, liver
aching, throbbing, sharp, crampy
Neuropathic
Nerves
burning, numbing, tingling
narcotics, NSAIDS,
antidepressants, anticonvulsants
Major Sources of Pain

9. OPIOID ANALGESICS

10. History of Opioids
Opium is extracted from poppy seeds (Papaver somniforum)
Used for thousands of years to produce:
Euphoria
Analgesia
Sedation
Relief from diarrhea
Cough suppression
Opium (poppy tears, lachryma papaveris) is the dried latex obtained from opium poppies (Papaver somniferum). Opium contains up to 12% morphine, an opiate alkaloid, like codeine, papaverine noscarpine (benzoisochinolon derivatives)

11. History cont’d
Used medicinally and recreationally from early Greek and Roman times
Opium and laudanum (opium combined with alcohol) were used to treat almost all known diseases
An opium-based elixir has been ascribed to alchemists of Byzantine times,. Around 1522, Paracelsus made reference to an opium-based elixir which he called, laudanum from the Latin word laudare meaning "to praise."

12. is the Greek god of dreams and sleep.
Morpheus
is the Greek god of dreams and sleep.
Friedrich Wilhelm Adam Sertürner, a German pharmacist, isolated Morphine from opium, in 1805.
Morpheus (pronounced /ˈmɔr.fjuːs/; Greek: "he who shapes [dreams]") is the Greek god of dreams and sleep. Morphine was isolated from opium in the early 1800’s and since then has been the most effective treatment for severe pain

13. History and Background
Invention of the hypodermic needle in 1856 produced drug abusers who self administered opioids by injection
Controlling the widespread use of opioids has been unsuccessful because of the euphoria, tolerance and physiological dependence that opioids produce

14. Subtypes of opiod receptors: mu, delta, kappa, epsilon, sigma
Opioid receptors
group of G-protein coupled receptors with opioids as ligands.
The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin.
Subtypes of opiod receptors:
mu, delta, kappa, epsilon, sigma
Opioid receptors are a group of G-protein coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin.

16. Opiod Receptor Activation
Response
Mu-1
Mu-2
Kappa
Delta
Sigma
Analgesia
Respiratory depression
Euphoria
Dysphoria
Decrease GI motility
Physical Dependence
Mania, hallucination

17. Morphine CNS Depressant effects Stimulate effects Analgesia
Indifference to surroundings
Mood and subjective effects
Depression of respiration
Cough centre
Temperature regulating centre
Vasomotor centre
CTZ (nausea, vimiting)
Edinger Wesphal nucleus
(III nerve –producing miosis)
Vagal centre (bradycardia)
Certain cortical areas and hippocampal

18. Morphine can be used as an analgesic to relieve:
pain in myocardial infarction
pain associated with surgical conditions, pre- and postoperatively (pre-anesthetic medication, balanced anesthesia, surgical analgesia)
pain associated with trauma, burns
severe chronic pain, e.g., cancer
pain from kidney stones, renal colic, ureterolithiasis, etc (pain may be valuable for diagnosis: should not be relived by analgesic unless proper assessment of the patient has been done)
traumas of thorax accompanied by cough (morphine depresses central links of coughing reflexes)

19. Acute left-ventricular cardiac failure
(cardiac asthma)
Reduce preload on heard due to vasodilatation
Tending to shift blood from pulmonary to systemic circuit; relieves pulmonary congestion and edema
Allays air hunger by depressing respiratory centre
Cuts down sympathetic stimulation by calming the patient ,

20. Applications in Dentistry
Narcotic (opioid) analgesics are extremely effective in reducing acute dental and postoperative pain.
The narcotic analgesics have established a niche for the treatment of pain in those situations where the NSAIDs are less effective.
Hydrocodone, oxycodone, codeine, and occasionally meperidine are the narcotics used to treat dental pain.

21. MORPHINE HYDROCHLORIDE
routes of administration
subcutaneously and intramuscularly
(analgesic action after min)
oral administration – presystemic elimination
( % enters general blood circulation)
sublingually – quick absorption
i.v. is indicated even in emergency
Epidural or intrathecal ( into the spinal canal ) injection produces segmental analgesia lasting 12 hours without affecting other sensory, motor or autonomic modalities
Duration of analgesic action – 4-6 hours
Maximum single dose of morphine is 0,02 g,
maximum daily dose – 0,05 g

22. Side effects of morphine
Respiratory depression
Vomiting (excitation of starting zone of vomiting center)
bradycardia (increasing of tone of n. vagus nuclei)
spasm of sphincters of gastro-intestinal tract accompanied by constipations
increasing of tone of smooth musculature of urinary and bile-excreting tracts (retentions of urination, bile stasis)
Decreasing of BP

23. CONTRAINDICATIONS FOR ADMINISTRATION OF MORPHINE
acute respiratory depression
renal failure (due to accumulation of the metabolites morphine-3-glucuronide and morphine-6-glucuronide)
chemical toxicity (potentially lethal in low tolerance subjects)
raised intracranial pressure, including head injury (risk of worsening respiratory depression)
Biliary colic
Precauntation
pain that accompanies chronic inflammatory pain
children before the age of 2 years

24. Tolerance
Tolerance is a diminished responsiveness to the drug’s action that is seen with many compounds
Tolerance can be demonstrated by a decreased effect from a constant dose of drug or by an increase in the minimum drug dose required to produce a given level of effect
Physiological tolerance involves changes in the binding of a drug to receptors or changes in receptor transductional processes related to the drug of action
This type of tolerance occurs in opioids

25. Addiction Physical dependence Physiological dependence
Withdrawal reactions

26. Tolerance and Dependence

27. Withdrawl Reactions Acute Action Withdrawl Sign Analgesia
Respiratory Depression
Euphoria
Relaxation and sleep
Tranquilization
Decreased blood pressure
Constipation
Pupillary constriction
Hypothermia
Drying of secretions
Reduced sex drive
Flushed and warm skin
Withdrawl Sign
Pain and irritability
Hyperventilation
Dysphoria and depression
Restlessness and insomnia
Fearfulness and hostility
Increased blood pressure
Diarrhea
Pupillary dilation
Hyperthermia
Lacrimation, runny nose
Spontaneous ejaculation
Chilliness and “gooseflesh”

28. OMNOPON contains mixture if opium alkaloids (48-50% morphine)
does not cause spasms of smooth musculature, as it contains alkaloids of isoquinoline raw
is used for analgesia according to all the indications of morphine hydrochloride, for example, colics

29. Promedol (trimeperidine)
produces similar effects to other opioids, such as analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal.
duration of analgesic action hours
moderate spasmolytic influence on smooth musculature of internal organs
stimulation of rhythmic contractions of uterus
can be used for analgesia
in case of pain syndrome connected with spasms of smooth musculature
Trimeperidine is an opioid analgesic that is an analogue of prodine (meperidine). It was developed in or around 1954 in the USSR during research into the related drug pethidine.

30. Fentanyl synthetic opioid analgesic of short action
analgesic activity is 300 times higher than of morphine
analgesic effect after intravenous introduction – after 1-3 min, lasts for min
used with neuroleptic droperidol (complex drug – “talamonal”) for neuroleptanalgesia
a form of analgesia achieved by the concurrent administration of a neuroleptic such as droperidol and an analgesic such as fentanyl. Anxiety, motor activity, and sensitivity to painful stimuli are reduced; the person is quiet and indifferent to surroundings

31. fentanyl transdermal system
should be used for long-term (chronic) pain requiring continuous narcotic pain
Is designed to release the drug into the skin at a constant rate ranging from 25 to 100 micrograms/h,

32. Codeine opium alkaloid
analgesic action is not strong, but anticough effect is considerable
administered as an anticough drug of central action
combination with non opiod analgesics
(eg. Paracetamol) is supra-additive

33. Pentazocin agonist-antagonist of opioid receptors
comparatively with morphine, it is a bit less dangerous in the aspect of addiction development
indicated in case of pain of medium intensity in such conditions like other opioid analgesics. In case of strong pain its administration is limited as in case of increasing of dose of the drug excitation appears
it can cause increasing of blood pressure and tachycardia that’s why it’s not advised to use in case of acute myocardium infarction
if it is administered for people with narcotic addiction manifestations of abstinence develop

34. Buprenorphine Partly agonist of mu-opioid receptors
Acts longer than morphine (approximately 6 hours)
Analgesic activity is higher than of morphine, that’s why it’s used in doses of 0,3-0,6 mg
In case of breathing depression, which it causes, naloxon is less effective since buprenorphine is slowly released from the connection with mu-receptors
Indicated for pain decreasing in the same situations as other narcotic analgesics
May be used for detoxication and supporting treatment of individuals who is addicted to heroine

35. Acute poisoning with opioid analgesics
Respiratory Depression
Euphoria
Relaxation and sleep
Tranquilization
Decreased blood pressure
Constipation
Pupillary constriction
Hypothermia
Drying of secretions
Flushed and warm skin

36. Triad in case poisoning with morphine
Acute miosis (Pinpoint pupils)
Cheyne Stokes respiration
deep tendon reflexes increased

37. Treatment of acute poisoning
Naloxon (antagonist of opioid receptors)
intravenously - 0,4-1,2 mg
general dose of naloxon should not overcome 10 mg
stomach lavage (for morphine enterohepatic circulation is typical) with 0,05-0,1% solution of potassium permanganate and 0,5 % tannin solution
suspension of g of activated charcoal
salt laxative agents (sodium sulfate)
forced diuresis
atropine sulfate
inhalation of carbogen (5-7 % СО2 and % O2)

38. NON-OPIOID ANALGESICS

39. Pharmacodynamic Effects
Analgesic
Antipyretic
Anti-inflammatory (except paracetamol)

40. Mechanism of action of non-opioid analgesics
depression of cyclooxygenases activity
decreasing of prostaglandins synthesis in peripheral tissues and in central nervous system
decreasing of sensitivity of nervous endings and depression of transmission of nociceptive impulses on the level of CNS structures
pain-relieving action of non-opioid analgesics is partly connected with their anti-inflammatory activity

42. Effects of COX Inhibition by Most NSAIDS
NSAIDs : anti-platelet—decreases ability of blood to clot

43. COX Enzyme:Prostaglandin Effects
COX-1: beneficial
COX-2: harmful
Peripheral injury site
Inflammation
Brain
Modulate pain perception
Promote fever (hypothalamus)
Stomach
protect mucosa
Platelets
aggregation
Kidney
vasodilation

44. Indications for administration of non-narcotic analgesics
headache
toothache
backache
neuralgias
pulled muscles
joint pain
dysmenorrhea
for potentiating of their action – combinations
paracetamol with codeine,
metamizol with dimedrol, metamizol with codeine

45. Applications in Dentistry
Toothache
Post extraction pain
Periodontitis
Neuritis
Stomatitis
Arthritis
Local usage as keratoplatic agents for hyperkeratosis, hyperesthesia
Although NSAIDs are the established drugs of first choice for the management of mild-to-moderate dental and postoperative pain, at times the oral narcotic analgesics must be used to treat the more severe intensities of pain.

46. Paracetamol (Acetaminophen)
analgesic and antipyretic drug
maximal effect if the drug is introduced orally – after 2 hours, lasts approximately for 4 hours
in case of durable administration of big doses – damaging of liver and kidneys, production of met-hemoglobin

47. Paracetamol (Acetaminophen) N-Acetyl-P-Aminophenol
Classification: analgesic, antipyretic, misc not an NSAID
Mechanism: inhibits prostaglandin synthesis via CNS inhibition of COX (not peripheral)- doesn’t promote ulcers, bleeding or renal failure; peripherally blocks generation of pain impulses,
inhibits hypothalamic heat-regulation center

48. Paracetamol
Tablets
Suppositories
Syrups
Soluble tablets
Capsules

49. PARACETAMOL

50. Pharmacokinetics: paracetamol
Metabolism: major and minor pathways
Half-life: 1-3 hours
Time to peak concentration: min
Treatment for overdose: Acetylcysteine

51. Paracetamol Liver Metabolism
1. Major pathway —Majority of drug is metabolized to produce a non-toxic metabolite
2. Minor pathway —Produces a highly reactive intermediate (acetylimidoquinone) that conjugates with glutathione and is inactivated.
At toxic paracetamol levels, minor pathway metabolism cannot keep up (liver’s supply of glutathione is limited), causing an increase in the reactive intermediate which leads to hepatic toxicity and necrosis

52. Acetylsalicylic acid Blocks irreversibly COX
As antipyretic and analgesic drug – 0,25 and 0,5 g per time
As an anti-inflammatory – 3-4 g per day (for arthritis, myocarditis, pleuritis, bronchitis etc.
As platelets inhibitor - for prophylaxis of thrombus-formation (in case of ischemic heart disease, thrombophlebitis etc.) – daily dose – mg

53. Pharmacokinetics: ASA
Absorption: from stomach and intestine
Distribution: readily, into most fluids/tissues
Metabolism : primarily hepatic
ASA contraindicated for use in children with viral fever –can lead to Reye’s Syndrome
Fatal overdose is possible
Similar pharmacokinetics for ibuprofen and related NSAIDs
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing hypoglycemia.[1] The exact cause is unknown, and while it has been associated with aspirin consumption by children with viral illness, it also occurs in the absence of aspirin use. 53

54. Analgin (metamizol-sodium)
It remained freely available worldwide until the 1970s, when it was discovered that the drug carries a small risk of causing agranulocytosis - a potentially fatal condition. Controversy remains regarding the level of risk. Several national medical authorities have banned metamizole either totally or have restricted it to be available only on prescription, while others have maintained its availability over the counter.

55. Analgesic and spasmolytic activity
Baralgin (maxigan, spazgan, spazmalgon, trigan) metamizol-sodium +pitophenon hydrochloride+pheniverinium bromide
Ampoules
tablets
suppositories
Analgesic and spasmolytic activity

56. Traditional and selective COX-2 inhibitors

58. for chronic pain syndrome
Ketorolak (ketanov)
according to analgesic activity it prevails over effect of acetylsalicylic acid, indometacin and equals to opioid analgesics
moderate anti-inflammatory, antipyretic and anti-aggregate effects
high effectiveness in case of pain in postoperative period, in oncology, during child delivery, traumas, colic
i/m, i/v, orally
NOT indicated
for chronic pain syndrome

59. Ketoprophen (ketonal)
strong analgesic, anti-inflammatory and antipyretic agent
administered in case of arthroses and arthritis, ancilizing spondilitis, pain of different genesis (after surgeries, in case of traumas, painful menstruations etc.)
administered orally, intramuscularly, in forms of suppositories and ointments

60. TRAMADOL Abuse potential is low Less respiratory depression
Analgesic activity is similar to the activity of morphine
Abuse potential is low
Less respiratory depression
Hemodynamic effects are minimal
In case of intravenous administration effect develops after 5-10 min, if administered orally – after min, action lasts for hours.
Tramadol possesses agonist actions at the μ-opioid receptor
and affects reuptake at the noradrenergic and serotonergic systems

61. ADMINISTRATION OF TRAMADOL
surgery, traumatology, gynecology, neurology, urology, oncology For all kinds of acute and chronic pain of moderate and considerable intensity, including neuralgias, postoperative, traumatic pain diagnostic and therapeutic interventions oncologic pathology

62. Thank you!
QUESTIONS?!