1. Pain and Analgesics Dr Ian Coombes, Judith Coombes, Dr Lisa Nissan
University of Queensland Schools of Medicine and Pharmacy
Safe Medication Practice Unit, Queensland Health
The University of Queensland

2. Outline What is pain Pain assessment Principles of Pain Management
Drug therapies
Neuropathic Pain and adjuvant therapy
Role of the Pharmacist / other health professionals

3. What patient factors do you need to consider?
You have been asked to recommend a patient’s analgesia including medication choice dose and duration…
What patient factors do you need to consider?
Prompt students to answer -
What is the relevance to them as junior prescribers?
You have the knowledge and want to show importance of recalling that knowledge in clinical situation
Safe Medication Practice Unit 3

4. What is Pain? A signaling system : mechanical and nerve
Unpleasant sensory & emotional experience – IASP
A perception : unlike taste or hearing
cannot define independent of person experiencing it
Only know in pain by statements & actions
Pain is what the patient says “hurts”

5. Psychological Factors
Noxious Stimulus,
Tissue Damage
Pain Sensation
Psychological Factors
Sex
Age
Cognitive Level
Previous Pain
Family Learning
Culture
Situational Factors
Expectation
Control
Relevance
Emotional Factors
Fear
Stress
Anxiety
Frustration

6. Acute pain (e.g. sprain, surgery)
Limited duration
related specifically to an event or trauma
bodies’ natural “healing” process
Palliative Care
components of both
e.g. incident pain,
disease progression
Chronic pain
pain persists beyond time of healing
often no specific pathology identified
 changes in the CNS
 development of NP
complex interplay physical +psychological
Often - sleep disturbances, fatigue, depression, social withdrawal, and self-esteem issues +++

7. Acute vs Chronic Acute Pain Chronic Pain Passive patient
Short term planning
“hands-on” Tx
Rest
PRN Tx (inc. Meds)
Resume usual life
Chronic Pain
Active patient
Long term planning
“hands-off” Tx
Activity
Regular Tx (inc.Meds)
Retraining, readjustment

8. Examples of acute pain Acute post operative pain Sprains and strains
Sports injuries
Period pain
Headaches
Toothache / dental

9. Types of chronic pain Chronic back or neck pain Total body pain
Chronic daily headaches
Musculoskeletal pain
Include: OA,RA, polymyalgia
Painful diabetic neuropathy (PDN)
Post-herpetic neuralgia (PHN)
Phantom limb pain

10. Cancer Pain – 4 sources Malignancy Treatment Pain Debility Unrelated
E.g. infiltration of tumor, fractures
Treatment Pain
E.g. radiotherapy, mucositis
Debility
E.g. bed sores
Unrelated
E.g. history of underlying lower back pain

11. Types of pain
mechanical
inflammatory
neuropathic

12. Two Main categories Nociceptive Pain Neuropathic Pain
Pain due to stimulation of superficial or deep tissue pain receptors as a result of injury or inflammation
Neuropathic Pain
Pain due to dysfunction or primary lesion in the central or peripheral nervous system

14. Goal to individualise analgesic therapy
Patient Assessment
Goal to individualise analgesic therapy
Assess patient characteristics:
indication for analgesia
age, sex, weight
culture
vital signs
allergies/ADRs
opioid tolerance
respiratory status
renal/hepatic function
other medical co-morbidities
mental state
other Rx
availability of oral/rectal routes
In adults, age rather than weight is a better predictor of opioid requirements (although there is large inter-patient variation)
Need to evaluate current analgesia (if applicable) - what patient was prescribed and what they are actually taking.
Look for other sources of analgesia e.g. PCA, site perfusion devices etc.
Titrate analgesia to patients needs – wide variability in patient response to pain (“emotional” experience)
respiratory status (sleep apnoea, chronic lung disease)
other Rx (e.g. antidepressants; analgesics; benzos)
Safe Medication Practice Unit 14

15. Assessment Pain History (LINDOCARRF) Location Intensity Nature
Duration
Onset, Offset
Concomitants
Aggravating
Relieving
Radiating
Frequency

16. Verbal Rating Scale: On a scale of 1-10 ….. How would you rate your pain? Sometimes add – “where 10 is the worst ever and zero is no pain”

21. Principles of Analgesic Prescribing
Analgesic Ladder
Adjuvants -
TCA
Anti-convulsants
Anti-arrhythmic
STEP 3
STEP 2
NSAID
Non-opioid (paracetamol)
Strong Opioid (morphine, oxycodone)
Adjuvant Medication
STEP 1
NSAID
Non-opioid (paracetamol)
Weak Opioid (codeine, tramadol)
Adjuvant Medication
NSAID
Non-opioid (paracetamol)
Adjuvant Medication

22. Paracetamol Analgesic, antipyretic, Act centrally (PGs)
Not useful as an anti-inflammatory
Few SE if taken at therapeutic doses
Onset of effect min
Dosing:
500 –1000mg QID Max 4g for adult

23. Paracetamol Should be 1st line therapy
minor, non-inflammatory pain
As effective as aspirin/NSAID in relieving acute pain
Similar antipyretic actions to aspirin, NSAID
No. 1 choice mild to moderate pain in children
May be given chronically:
1g QID, or for example in people with OA
ALTERNATE Extended release: 1330mg TDS 23

24. Paracetamol Dosing in Children - Often under dosed! Appropriate:
15mg/kg Q4H MAX 60mg/kg (community)
15mg/kg Q4H MAX 90mg/kg (hospital)
Can use in Combination with Ibuprofen
Careful with other OTC products
Esp. cough and cold medications
“cumulative paracetamol”

25. Side-effects major risk: is poisoning with overdose
Paracetamol can damage the liver (mainly OD)
Risk of toxicity  - dehydrated, malnourished, alcohol (chronic)
Common: N/V, dizziness, sedation
Less common: headache, skin rash
*NOTE: paracetamol & NSAID can be used together

26. How do they work? - NSAID v COX2
Arachidonic acid
Maintenance
Induced
COX-1
COX-2
NSAIDs
Coxibs
thromboxane / prostaglandins
prostaglandins
Primarily mediate
inflammation, pain & fever
Primarily support platelet function
Primarily protect GI mucosa

27. COXib Withdrawal 2004 Vioxx® withdrawn 2004   CV risk MOA CV risk
COX-2 is the main source of the prostacyclin PGI2
PGI2 acts in opposition to thromboxane
TXA2 generated by COX-1
PGI2 = anti-clotting (anti-thrombotic)
TXA2 = pro-clotting (pro-thrombotic)
Therefore, inhibiting COX-2   PGI2 synthesis  “pro-thrombotic” effect (TXA2)  risk of MI, stroke

28. Non-Steroidal Anti-inflammatory Drugs (NSAID)
Analgesic, antipyretic
Anti inflammatory - several days dosing
must dose constantly at least several days
prn not significant anti-inflammatory action
Onset of action / effect 30 – 60 min
difference in half-life and SE
NOTE:
elderly patients should not be on NSAID's with long half-lives
can be even more prolonged in elderly

29. NSAIDs- Adverse Effects
Side effects
Cautions
hypersensitivity/allergy
GI (GORD/PUD)
platelet inhibition
sodium retention, oedema
renal toxicity
hepatic toxicity
Platelet inhibition, but remember – COX-2 inhibitors INCREASE the risk of thrombotic events!
GI bleeding/ulceration – risk NOT reduced by use of enteric coated or rectal dosage forms.
Use a proton pump inhibitor to minimise risk of GORD/PUD
Safe Medication Practice Unit 29

30. NSAIDs- Adverse Effects
Side effects
Cautions
hypersensitivity/allergy
asthma
GI (GORD/PUD)
GI bleeding/ulceration
platelet inhibition
coagulation disorders
warfarin therapy
sodium retention, oedema
hypertension
cardiac failure
ACEI/ARA/diuretics
renal toxicity
renal impairment
gentamicin therapy
hepatic toxicity
hepatic impairment
Platelet inhibition, but remember – COX-2 inhibitors INCREASE the risk of thrombotic events!
GI bleeding/ulceration – risk NOT reduced by use of enteric coated or rectal dosage forms.
Use a proton pump inhibitor to minimise risk of GORD/PUD
Safe Medication Practice Unit 30

31. NSAIDs – Caution! Major cause of ADEs and hospital admissions
use lowest effective dose for shortest possible time
use paracetamol as alternative or to reduce NSAID dose
COX-2 inhibitors
similar adverse effects to non-selective
increase risk of thrombotic events (stroke; MI)!
little difference in efficacy between NSAIDs
avoid aspirin < 18 yrs in viral illness (Reye’s syndrome)
elderly - increased risk of adverse effects
Continue only if effective. Avoid if possible!
Little difference in efficacy between NSAIDs
(choice depends on individual response and tolerance)
children - no aspirin < 2 y.o. and avoid < 18 y.o. in viral illness (Reye’s syndrome)
elderly - increased risk of adverse effects (esp. in heart failure, GI ulceration; renal impairment)
Safe Medication Practice Unit 31

32. Where do Opioids Act?

33. How do Opioids Act? CNS and PNS
Interact with specific cell-surface receptors in
CNS and PNS
other tissues (GIT, immune cells, other tissues)   
2nd messenger
systems
G-proteins
G-protein

34. Pharmacological Effects of Opioid Agonists
Desired Action – analgesia
Unwanted actions
Analgesic tolerance
physical dependence
Respiratory depression
Nausea, vomiting sedation
Tolerance often develops

35. Other unwanted effects
Constipation
inhibition of GIT motility
slowing of oral-caecal transit times
Never forget laxatives
Endocrine effects
may alter male sex hormones in chronic dosing
Must monitor in chronic therapy
Neuro-excitatory SE
e.g. myoclonus, allodynia, seizures
very high doses
No tolerance

36. Opioids – Precautions hypotension, shock concomitant CNS depression
impaired respiration /↓ respiratory reserve
elderly
hepatic impairment
renal impairment
epilepsy/recognised seizure risk
biliary colic or surgery
hypotension, shock —reduced blood volume increases hypotensive risk.
impaired respiration/↓ respiratory reserve – respiratory depression.
elderly; infants ≤ 12 months
hypoxia; hypercapnia; cor pulmonale
acute/severe asthma; COPD
avoid opiates during acute asthma attack — opioids depress respiration and cough reflex and dry secretions
elderly (increased risk of cognitive impairment and falls) - ↓ dose
phaeochromocytoma - pressor response 2o to histamine release (no histamine release with fentanyl)
hepatic impairment - severe hepatic disease may precipitate coma (↓ dose)
renal impairment - active/toxic metabolites accumulate (↓ dose/use fentanyl or oxycodone)
epilepsy/recognised seizure risk - increased risk of seizure
head injury; metabolic disorders; EtOH/drug withdrawal; CNS infections; CNS depressants (eg. hypnotics) (CNS depression)
biliary colic or surgery (spasm of sphincter of Oddi)
Safe Medication Practice Unit 36 12

37. What are Opioids? Step 2 / 3 - Moderate to severe pain
Definite role in cancer + non-cancer pain
Mu, Kappa, Delta receptors
Many available
Typical SE profile
Nausea, Drowsiness, Respiratory Depression
Constipation, Sweating, Itch
Caution in hepatic and renal impairment

38. Opioids – what to do? Assess requirements – calculate dose
Conversion table as a guide (if on other opioids)
Can start on one Short Acting opioid and titrate
Conversion to SR / CR preparation when possible
Adding it up …..
If currently on multiple Tx - Use conversion table
E.g. convert all to oral morphine equivalent

39. Opioids – what to do? ******
Start low go slow …..
When converting between opioids
Reduce calculated total daily dose ~20-30%
Breakthrough (incident pain – esp. in cancer)
Calculate as: 1/6th – 1/12th of TDD
Or ~ 50% of the dose just given (if e.g. Q4H)

40. Oral Morphine equivalent
DRUG
DOSE x CONVERSION FACTOR
Pethidine (oral)
Pethidine (IV)
x 0.125
x 0.4
Methadone
x 1.5
Oxycodone
Buprenorphine
x 50
Codeine
x 0.16
Dextropropoxyphene
x 0.1
Morphine (IV)
Morphine (oral)
x 3
x 1
Oral Morphine equivalent
* 100mg tramadol ~ 60mg codeine ~ 10mg oral morphine

41. Adjust dose in renal impairment
Drug / action
Duration of action
Active metabolites
Adjust dose in renal impairment
Codeine (A)
3-4
Morphine
Yes
Dextropropoxyphene (A)
4-6
Nordextropropoxyphene (toxic)
Fentanyl (A)
0.5-2 (iv) No no
Hydromorphone
2-4
hydromorphone-3-glucuronide (H3G - toxic)
yes
Methadone (A)
Variable (>24hr)
Morphine (A)
2-3
CR/SR
12-24
morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G – toxic)
Oxycodone (A)
oxymorphone
Pethidine (A)
2–3
norpethidine (CNS +++)
yes; contraindicated
Tramadol (A)
3–6
desmethyl tramadol
Buprenorphine (partial agonist)
6–8
norbuprenorphine
Reference: AMH

42. Regular vs PRN Analgesia
regular analgesia is better in setting of continuous pain
PRN only if pain intermittent and unpredictable
in most settings, pain is predictable
problems with using only PRN analgesia
dose prescribed by Dr/administered by nurse
patients don’t ask for medication
inadequate or infrequent dosing → unrelieved pain
keeping up with pain is easier than catching up with pain
prn dose = 1/6 →1/12 total regular daily dose
In acute pain setting, regular is preferred over just PRN.
PRN prescribing is for when pain is possible but not predictable. In most post-op settings, pain is predictable.
Regular analgesia should be given and then PRN analgesics can be used to manage breakthrough pain.
A vicious cycle can occur if doctors don’t initially prescribing enough or adjust doses to individual patient needs:
nurses give lower dose (if range prescribed) and less frequently, because PRN is translated as “when requested by patient”.
patients don’t ask for medication because they don’t want to bother busy staff, so try to hold out.
patients not regularly assessed for pain
delays in administering analgesia promote anxiety in the patient and emotion is a part of the pain experience.
Unfounded fears of giving too much/overdose or causing addiction.
Evaluate PRN analgesic use and assess whether regular analgesia should be increased.
Safe Medication Practice Unit 42 5

43. Tramadol (Tramal) 1st - opioid effects similar to morphine (mu)
Centrally acting analgesic with a dual MOA
1st - opioid effects similar to morphine (mu)
Active Metabolite M1
M1 - 6x tramadol as analgesic, 200x binding
2nd - inhibit re-uptake of NA / 5-HT
descending pain inhibitory pathway
Hepatic Metab. Via CYP 2D6 (P450)
similar to codeine

44.  doses in renal and hepatic impairment
50 – 100mg 4-6 hrs (Max 400mg) or SR equiv.
Interactions:
SSRI, TCA, carbamazepine, MAOI, warfarin ( INR)
Can cause serotonin syndrome by itself!
Start low – go slow ……. Short term use only!
Start on IR then (switch to SR if appropriate)

45. More serious ADR’s with tramadol
Australian Adverse Drug Reactions Bulletin - Volume 22, Number 1, February 2003
NNT > / = 50% relief 3.5 (2.4 to 5.9)
NNH = 7.7 (4.6 to 20) 45

46. Neuropathic Pain
Pain or abnormal sensations due to a dysfunction of, or damage to, a nerve or group of nerves
primarily peripheral nerves, although pain due to CNS damage (“central pain”) may share these characteristics

47. Neuropathic Pain Can be due to a central or peripheral component
Opioids not particularly effective
Post Herpetic Neuralgia: acute herpes zoster
Phantom Limb Pain
Postoperative Pain
Diabetic neuropathy
May be lancinating (shooting, stabbing)
non-lancinating (dull, aching)
burning (dysesthesia)

48. TREATMENTS FOR NEUROPATHIC PAIN
Antidepressants
Anticonvulsants
Opioids
Topical
agents
Eg.
CBZ
Gabapentin
pregabalin
Eg.
Tramadol
oxycodone
Eg.
Lidocaine patch
Capsaicin
Eg.
Amitriptyline
Desipramine
paroxetine

49. Inflammatory e.g. rheumatoid arthritis
DRUGS
PAIN TYPE
Nociceptive
e.g. fracture
Neuropathic
eg neuralgia
Inflammatory e.g. rheumatoid arthritis
Paracetamol
Effective when taken regularly at max. dose
Less effective
Effective, but not
anti-inflammatory
Opioids
Effective
May be effective
(agent + dose)
(depends on dose)
NSAIDs
Not effective
TCAs, parenteral, local anaesthetics antiepileptic
Rarely used (clonidine may be effective as adjunct)
Rarely used (may be effective as adjunct)
Adapted from Table 3-1, Australian Medicines Handbook
Adapted from Table 3-1, Australian Medicines Handbook
Different pharmacological groups of analgesics effective for different types of pain.
Again, must take people through this in question and answer format.
Safe Medication Practice Unit 49

50. Things to think about when reviewing Prescriptions
Regular dosing of pain medications
Dosage form issues
Crushing, breaking SR/CR
Appropriate level of breakthrough medication
Managing SE
Importance of laxative use
Increasing needs ? More breakthrough
Interactions ….. Watch OTC / complementary

51. Monitoring – making it work
Frequent assessment is essential
Important to maintain communication with
Doctor, patients, carers
Nursing staff and pharmacist ……
Monitor for response to therapy
Include increase in need
Change in pain “type” or “origin”
Change in severity
ADR / SE
Esp. laxatives with opioids

52. Key Messages individualise analgesic therapy
choose analgesics judiciously
use multimodal analgesia
regular pain monitoring is critical to outcomes
regularly review and revise analgesic doses
adjust regular dose according to breakthrough usage
anticipate and manage analgesic-associated adverse events
avoid NSAIDs – major cause of morbidity/mortality!
avoid tramadol, dextropropoxyphene, pethidine

53. Questions?