Department of Applied Pharmacy
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Pharmaceutical Care
Pain
Department of Applied Pharmacy
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 What is pain
 How is it treated
 Use of non-opiod analgetics
 Use of NSAIDs
 Use of opiod analgetics
Learning outcomes of today
Department of Applied Pharmacy
Analgesics in pharmacy
1. self-treatment (OTC drugs) - headache, teeth,
musculosceletal system
• Right analgesic doses
• Risks - Many different brand names, combinations
2. Rx analgesics - chronic pain – dispensing minimum
• Sustained-release tablets, TTS, sprays, sublingual
tablets – instructions for patients
• duplicate medications from various doctors
• overuse of analgesics, eg. NSA - GI risks
• opioids - documentation, risk of addiction, abuse
Department of Applied Pharmacy
Important:
• To communicate with the patient, ask questions
• Knowledge of OTC medicines, brand names,
including their risks
• Check combinations (Rx, OTC, different names)
• Know the limits of self-medicaiton
• The correct use of various analgesic medication
forms, their dosing schedules, adverse effects
Department of Applied Pharmacy
When send the patient to the physician?
• if the patient serious pain for the first time and the
cause of pain is not clear
• The pain lasts much longer and he suffers from a
variety of illnesses and uses a combination of
medication
• the pain is associated with some other disorder (back
pain with wounding and stool leakage, headaches with
difficulty in hand movement)
• similar pain but this time it is significantly stronger, it
has a different character, localization (it was blunt,
this time it is sharp, it is cut (it has back pain, but this
time it is significantly stronger)
Department of Applied Pharmacy
Pharmaceutical specifics
• Why sustained-release tablets, especially opioids?
• transdermal therapeutic system
• sublingual, bucal, nasal application
• Technologies, advantages and disadvantages?
• The technology principles
• Rules for proper dosage, application
• Dispensation minimum
• Prescription restrictions
Department of Applied Pharmacy
Therapy of pain:
• Analgesics
• Antidepressants (AD)
• Alpha 2-adrenergic agonist - clonidine
• Corticosteroids
• GABA agonists, and Anticonvulsants
• Local anesthetics
• Calcitonin
• Bisphosphonates
• Antispasmodics
Department of Applied Pharmacy
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 Pain is an unpleasant sensory, emotional and mental feeling
(experience) associated with accompanying psychic and
eventually vegetative reactions and behavioral change
 It is caused by tissue damage by disease, injury, surgery, heat..
 How much is the emotional part involved – depends on the
individual..
 pain is not just a nociceptic, but a complex biological and
psychological experience that also has a social connection
 a mechanism to preserve the individual → warns against the
consequences of the action that would lead to irreversible
damage of tissue
What is pain? - definition
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 How would you clasify pain?
 Nociceptive pain from pain receptors (twisted ankle)
 Neuropatic pain: from nervous system (trigeminal neuralgia,
postherpetic neuralgia)
 Pain with no apparent cause
Types of pain:
 Acute
 Chronic non-malignant
 Chronic - malignant
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 Lasts for a short period of time (hours, days, weeks)
 Warning function
 Usually localized, more acceptable
 Generally fast improvement
 Its cause can be determined
 First is to treat the cause
 The most important factor is the intensity and location of pain
 Is accompanied by adrenergic (stress) response
Acute pain
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 Initially stronger and faster-acting analgesic is chosen
 Note: Weak opioids do not have a stronger analgetic
effect than non-opioid analgesics! It was proven by
meta-analysis of clinical trials that it is true in acute pain
 “Step down„ model: we begin with a strong analgesic,
gradually reducing the dose and passing on weaker
analgesics.
Acute pain
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 Lasts for longer than 3 months
 Has no biologically useful function
 The goal of treatment is not necessarily a full
recovery, but modification condition of the patient
 Is accompanied by psychiatric disorders (eg.
depression, sleep disturbance)
Chronic pain
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 The aim of treatment for chronic pain is not necessarily a
full recovery of the individual, but the modification and
possible restoration of physical, mental and social health
 The "step up„ model: The procedure according to
analgesic ladder from the bottom up, gradual dose
increases + possible combination with other adjuvant
drugs.
Chronic pain
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Pain evaluation – visual analogy scale
3 times/a day (once daily)
„diary od pain“
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1) First step in mild to moderate pain
ibuprofen 200 mg
diclofenac (50) 25 mg
metamizol 500mg
(650-1000 mg ASA)
paracetamol 650-1000 mg or tramadol 75-100 mg
Pharmacotherapy Algorithm of routine short term pain
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2) Second degree in moderate to severe pain
ibuprofen 400 mg (up to 800 mg)
diclofenac 50 mg (up to 100 mg)
nimesulide 100 mg
analgesic combinations
tramadol do 400 - 600 mg/d
dihydrokodein (DHC) do 240mg/d
paracetamol 650 mg -1,000 mg + codeine 60 mg
paracetamol 650 mg + 75 mg tramadol
500 -1000 mg metamizole
Pharmacotherapy Algorithm of routine short term pain
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3) Third step - severe pain
Strong opioid (+ paracetamol)
oxycodone 10 - 20 mg
hydromorphone slow release 4-6mg
morphine 30 mg or more
fentanyl TTS 25-100 µg/h
buprenorphin TTS 35-140 µg/h
injection: morphine, pethidine
Pharmacotherapy Algorithm of routine short term pain
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 Paracetamol / acetaminophen - at therapeutic doses (ie up to
1000 mg after 4 h, up to 4 g daily) are among the relatively
safest painkillers. Importantly, however, give it a sufficient dose,
ie 650 - 1000 mg for an adult (fever – 500mg)
 Acetylsalicylic acid - as an analgesic has been mostly
superseded by other more effective and safer NSAIDs. MDD 4g
 Pyrazolone derivatives - for example, metamizole (500 - 1000
mg for an adult dose, 4000-6000 mg per day ) or propyfenazon.
They have a very good analgesic efficacy without serious
gastrointestinal risks. Rarely can cause dangerous blood
disorder (agranulocytosis) or anaphylactic shock reaction.
Their use is not recommended as first medication the election.
They are not suitable for chronic pain.
Anelgesics - Antipyretics
Department of Applied Pharmacy
Acetaminophen (paracetamol)
– no anti-inflammatory effects
– Fewer adverse effects than other nonopioid
analgesics
– Adverse effects
• Renal toxicity
• Risk for hepatotoxicity at high doses
– Increased risk with liver disease or chronic alcoholism
– risk for hepatic toxicity is minimized at doses below 4
grams per day
– No effect on platelet function
Department of Applied Pharmacy
Paracetamol – analgetic dose 1000mg !!!
• Single analgesic dose of paracetamol per os 10-15 mg/kg,
daily maximum of 60 mg/kg
• Note: Micromedex admits 10-15 mg / kg 5 times a day, in
adults 1 g at the earliest after 4 hours, but not more than
4 g daily (8 tablets)
• Dosage of paracetamol - based on patient's body weight
• > 50kg the dose of one 500mg tablet is inadequate
• 51-70 kg, 1.5 tablets (750mg)
• weight 71-100 kg needs 2 tablets (1000mg)
Department of Applied Pharmacy
Metamizol (dipyrone)
• 1000mg - highly potent analgetic dose
• ADR: rarely hematopoietic disorders leukopenia,
agranulocytosis, thrombocytopenia or haemolytic
anemia.
• probably on an immunological basis
• The drug was not authorised in the United States or the United
Kingdom. withdrawn from the market in most developed countries,
registered in Germany, France, Spain and eastern European
countries
• No case of agranulocytosis has been reported to SUKL
during its registration, which does not exclude its occurrence
www.sukl.cz
Department of Applied Pharmacy
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1. NSAIDs inhibit acute pain according to a meta-analysis with
the same probability as morphine!
2. The current findings suggest that the analgesic efficacy,
on average, not very different (for individual patients may
vary considerably).
3. The analgesic effect is dose dependent and is not typical for
them "ceiling effect" in effect.
4. A preferred feature is the minimum tolerance even after
prolonged use and the absence of physical dependence.
5. The combination of NSAIDs is not rational, and only increases
the ADRs
NSAIDs
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 Ibuprofen - GIT's gentlest traditional NSAIDs (at doses up to
1200 mg / day). It inhibits pain already in-the-counter dose of
200 mg. Dos. up to per day - 2400 mg (1200 mg).
 Diclofenac - differentiate products with normal and retarded
release. Dos. max per die - 150 mg.
 Piroxicam - is unlike other NSAIDs very long half-life
(approximately 50 h). Piroxicam has a high gastrointestinal risk.
Dos. up per day - 20 mg.
 Naproxen - has a longer half-life (about 13 h). Dos. up to per
day - 1000 mg.
 Ketoprofen - a high risk of gastrointestinal bleeding. Dos. max
for die - 300 mg.
 Indomethacin - a strong analgesic effect, a high risk of
gastrointestinal bleeding, not suitable for chronic use. Dos. max
for die - 200 mg short term.
NSAIDs
Department of Applied Pharmacy
Aceclofenac (Biofenac)
• used for over 20 years
• NSA with high selectivity to COX-2 - with low gastrotoxic
potential
• 100% bioavailability and up to 60% concentration in synovial fluid
• rapid onset of action and minimal risk of bleeding from GIT (except
coxibs)
• symptomatic treatment of pain and inflammation in osteoarthritis and
rheumatoid arthritis at doses of 200 mg (1 tbl) max 2 times daily
• and also in the form of a soluble suspension
• the effect of acute pain is lower (compared to other analgesics)
• 20x100mg por plv sol
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Dexketoprofen
• S - (+) - stereoisomer of ketoprofen
• is about a 30-fold more potent COX-1 inhibitor and about
100 times more potent COX-2 inhibitor then ketoprofen
• Faster onset of action, half-time 6 hours
• 25 mg each 8 hours. Total daily dose of max 75 mg
• short-term administration, low risk of ADRs
• musculoskeletal, postoperative, colic and tumor
pain, headache and dysmenorrhea
Doležal T.: dexketoprofenum, Remedia 2003
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 Nimesulide - a good analgesic effect, tbl. and effervescent drug
form
 ! It is not without gastrointestinal side effects.
 ! It was confirmed hepatotoxicity with prolonged use
 Dos. max for die - 200 mg (2 tablets)
 Meloxicam - designed primarily for rheumatic diseases, but
can be used for other pain. Dos. up per day - 15 mg, one tablet
a day
 Celecoxib - registered only for treatment of rheumatic pain.
 ! Cerebrovascular and cardiovascular ADRs.
 Dos. max for die - 400 mg.
Preferential COX-2 inhibitors
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meloxicam (Movalis and generic drugs)
• is indicated for short-term symptomatic treatment of
exacerbations of osteoarthritis and long-term symptomatic
treatment of rheumatoid arthritis
• significantly improves GIT tolerance over other NSAs
• KV risk comparable to that of non-selective NSAs
• Selectivity for COX2 at low doses (15mg)
• no significant drug interactions
• anti-inflammatory "specialist"
• there is no evidence of increased warfarin efficacy when taking
meloxicam
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nimesulid (Aulin, Nimesil)
• analgesic-antipyretic effect, anti-inflammatory
• preference for COX-2, little ADRs
• rapid onset of action
• CV risk comparable to that of non-selective NSAs
• Hepatotoxicity !!!! Contraindications:
– liver damage, abuse of alcohol and hepatotoxic substances
• 2007 - not to use more than 15 days
• 2009 - Confirmed + only as second-line medicine
• 2012 - treatment of acute pain and dysmenorrhoea
Department of Applied Pharmacy
Hepatotoxicity of NSAID
• Hepatotoxicity is a rare but potentially serious side
effect of NSAIDs? group effect ("class effect")
• It is an idiosyncratic type of hepatotoxicity
less hepatotoxicity
• Ibuprofen
• coxibs
higher hepatotoxicity
• nimesulide
• sulindac
• fluorobiprofen
• diclofenac
Department of Applied Pharmacy
Coxibs contraindications
• Active peptic ulcer or active bleeding into the GI tract.
• Pregnancy and breast-feeding
• Hepatic dysfunction of the liver (serum albumin <25 g / l or ChildPugh
score ≥ 10).
• Decreased renal clearance <30 ml / min.
• Children and adolescents up to 16 years of age.
• Inflammatory bowel disease.
• Patients with congestive heart failure (NYHA II-IV).
• Patients with hypertension whose blood pressure is permanently
elevated above 140/90
• Patients with ischemic heart disease
• peripheral arterial disease
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Cardiotoxicity of NSAID
• an increased risk of coronary events is a group effect of
NSAIDs
Cardiotoxic:
• Coxibs (celecoxib - Celebrex, etoricoxib - Arcoxia)
• Diclofenac
Less cardiotoxic:
• Naproxen
• Ibuprofen
Department of Applied Pharmacy
Opioid Therapy: Side Effects
• Common
– Constipation
– Somnolence, mental clouding
• Less common
– Nausea – Sweating
– Myoclonus – Amenorrhea
– Itch – Sexual dysfunction
– Urinary retention – Headache
• Physical dependence
• Tolerance
• Addiction
miosis (eye
pupil
constriction)
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 Tramadol - the advantage is a low risk of constipation, of
dependence
 ! ADRs - dizziness and nausea, psychological effect.
 Very good is the combination of paracetamol with tramadol.
 Dos. max per day - 600 mg.
 Codeine - is a weak analgesic, used almost only in combination,
preferably with paracetamol. antitussic
 Dos. max for die - 240 mg.
 Dihydrocodeine - its analgesic efficacy after oral administration is
similar to codeine. Maximum rational dos. for die - 360 mg.
 Pentazocine, nalbuphine - are intended for acute or of short pain,
are not suitable for chronic pain.
 These belong to so-called mixed agonist-antagonist.
 For this group of ceiling effect is applied (for further increasing the dose does not
increase the analgesic effect only side effects).
! Increased risk of psychological dependence.
Weak opioids
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N02A - opioid analgesics
• N02AA opium alkaloids
• morphine, hydromorphone, oxycodone,
dihydrocodeine
• N02AB Phenylpiperidine derivatives
• fentanyl
• N02AC Diphenylpropylamine derivatives
• N02AD Benzomorphan derivatives
• N02AE Derivatives of oripavine
• buprenorphine
• N02AF Morphine derivatives
• N02AX Other opioid analgesics
• tramadol (+ combination)
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N02AA Opium alkaloids
• N02AA01 Morphine
• N02AA02 Opium
• N02AA03 Hydromorphone
• N02AA05 Oxycodone
• N02AA08 Dihydrocodeine
• N02AA09 Diamorphine
• N02AA10 Papaveretum
• N02AA51 Morphine, combination
• N02AA58 Dihydrocodeine, combination
• N02AA59 Codeine, combinations except
psycholeptics
• N02AA79 Codeine, combinations with psycholeptics
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 Morphine - injectable form is suitable for the treatment of severe
acute pain.
p.o. forms with gradual release working 12 hours or up to 24 h are used for
chronic pain.
 Fentanyl – TTS (transdermal therapeutic system) is suitable for the treatment of
severe chronic pain. The advantage of treatment in the fentanyl TTS is
a very stable plasma concentrations.
 Buprenorphine - a partial agonist at μ receptors and an antagonist at
kappa receptors -TTS
 Pethidine - in comparison with morphine has lower spazmogennic
effect, it is preferable for acute colic pain. It has a shorter duration of
action (2 h) and is not suitable for chronic treatment!
 Unsuitable for the treatment of chronic pain results from psychomimetic
effect and increased risk of psychological dependence.
 Hydromorphone, oxycodone
Strong opioids
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N02AA01 Morphine
• Low (30%) availability after oral application
• Active metabolites
– M-6-G - analgesia, convulsions
– M-3-G - agitation, anxiety
• after. 30-60min, max 60-120min, 4-5hours
• Possible histamine release
• Constipation
• Individual pharmacokinetics
• - genetic polymorphism
MST continus
Vendal retard
(Sevredol tbl)
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N02AA03 Hydromorphone
• Semisynthetic derivative of morphine
• pure μ - agonist
• 4-6 times higher affinity for opioid receptors
• 2x better availability than morphine (over 60%)
• Half-time-2-3 hours
• Direct glucuronidation in the liver, an almost
pharmacologically inactive metabolite (hydromorphone-3-
glucuronide)
• Only 8% binding to plasma proteins
• Independence from CYP-450
• it could be the first choice opioid for cancer pain
• Similar to ideal opioid
• Palladone (12)
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Hydromorphone (Palladone cps)
• oral modified-release medicine containing hydromorphone
HCl
• gelatin capsule with pellets - biphasic drug release - fast initial
blood concentrations followed by sustained release
over 24 hours
• Twice a day after 12 hours
• The possibility of asymmetric dosing according to
the circadian rhythm of pain intensity
– Another dose for daily activity, other for night
Department of Applied Pharmacy
N02AA05 Oxycodone
• A strong μ1 and μ2 agonist
• Availability after p.o. administration of 60-80%
• Sweating, euphoria, confusion
• Slightly analgesically acting metabolites
• best of opioids for neuropathic pain
Department of Applied Pharmacy
N02AA05 Oxycodone
• Oxycontin (Mundipharma)
• Oxycodon Sandoz
• Oxycodon Ratiopharm
• AcroContin® biphasic absorption profile immediate
release of the drug over an hour and
prolonged effect for 12 hours.
• The GI fluid dissolves the coating of the tablet and
the initial dose of oxycodone (37%) is released
immediately after contact. GI fluid penetrates into
the matrix pores, dissolves the remaining drug
(62%), which slowly diffuses from the matrix pores
(t1 / 2 is 6.2 hours).
• pH independent release, constant throughout the
GIT
Department of Applied Pharmacy
Method of use - Sustained-release tablets
• Do not chew, do not divide, do not crush
• Palladone - can be opened – use pellets
• Use regularly at the same time of day, according to the dosing
schedule, by the hour
• If low efficacy, do not reduce the interval, increase the dose
• Rebound effect (discontinue slowly)
• Interactions: IMAO, alcohol, hypnotics
• Affecting the ability to drive car
• Adverse effects - respiratory depression, bradycardia, myosis,
somnolence, constipation
• Fluid intake, fiber, softening laxatives
• Prevention of orthostatic hypotension
Department of Applied Pharmacy
N02AB03 Fentanyl (TTS)
• is a synthetic opioid analgesic that exhibits high selectivity
to μ-subtype opioid receptors with about 100 times more
affinity than morphine
• Highly lipophilic, 100 times faster penetrates skin
than morphine
• Biotransformation occurs mainly in the liver via CYP3A4, an
ineffective metabolite
• High efficacy, selectivity and low incidence of side effects
• in patients with severe chronic pain
• The TTS form is an effective alternative to morphine, but is
only suitable for patients with a stable opiate dose
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Method of using TTS:
• Aply to skin without injury, not irritated, scarring, flat surface of the
trunk, or arms
• Skin without hair do not shave (microtrauma)
• Children - upper half of the back
• Clean, dry, intact skin
• Press for 30 seconds
• Do not cover with other patches
• Record the date and time of the application on the box
• Change the place of application - at the same place after 7 days
• After applying return to the pharmacy
• It is possible to bath, take a shower, swim, not long in warm water and
exposure to the sun
• Exposure to high temperatures (sauna, solarium, electric blankets)
fever
• The last dose of the tablet 12 hours after sticking the patch, the effect
persists for 12-17 hours after peeling ...
• Cut / not cut ?????
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Rescue medication
• Good efficacy
• Rapid onset of action
• Short duration of effect
• Good tolerability
• Easy to use
• Acceptable to the patient
• Available / affordable
Instanyl, Lunaldin, Breakyl, Effentora,
Department of Applied Pharmacy
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Adjuvant analgetics (AA)
Multi-effective AA - has adjuvant for most types of chronic pain.
Antidepressants (AD)
 I. generation - amitriptyline, clomipramine, dosulepin
 II. and III. generation - maprotiline, fluoxetine, paroxetine,
citalopram - are indicated in case of increased risk of AD first
generation.
 (AD III. Generation (SSRIs) have lower self-analgesic effect than
the AD first generation.)
Alpha2-adrenergic agonist - clonidine, tizanidine can be effective in
chronic refractory pain with sympathetic dysfunction
Corticosteroids - tend to have a supportive effect on some types of
chronic refractory pain
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Adjuvant analgetics (AA)
AA for neuropathic pain
GABA agonists, and Anticonvulsants - carbamazepine, valproic acid,
gabapentin (favorable safety profile, low incidence of drug
interactions and efficiency are factors for which gabapentin is now
listed as first choice anticonvulsant for neuropathic pain),
clonazepam
Local anesthetics - mexiletine, mesokain in slow infusion
Calcitonin, bisphosphonates - are effective for pain and sympathetic
maintained pain in osteoporosis
Antispasmodics - butylskopolamin
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Adjuvant analgetics (AA)
AA for musculoskeletal pain
Central muscle relaxants - can have an analgesic effect especially for
some types of acute back pain