Pain and Analgesics Pain and Analgesics

Dr Ian Coombes, Judith Coombes, Dr Lisa NissanUniversity of Queensland Schools of Medicine and

Pharmacy Safe Medication Practice Unit, Queensland Health

Dr Ian Coombes, Judith Coombes, Dr Lisa NissanUniversity of Queensland Schools of Medicine and

Pharmacy Safe Medication Practice Unit, Queensland Health

The University of Queensland

Outline

• What is pain

• Pain assessment

• Principles of Pain Management

• Drug therapies

• Neuropathic Pain and adjuvant therapy

• Role of the Pharmacist / other health professionals

You have been asked to recommend a patient’s analgesia including medication choice dose and duration…

What patient factors do you need to consider?

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”

Noxious Stimulus,Tissue Damage Pain Sensation

Psychological FactorsSexAge

Cognitive LevelPrevious Pain

Family LearningCulture

Situational Factors

Expectation

Control

Relevance

Emotional FactorsFear

StressAnxiety

Frustration

Acute pain (e.g. sprain, surgery) • Limited duration

• related specifically to an event or trauma

• bodies’ natural “healing” process

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 +++

Palliative Carecomponents of bothe.g. incident pain,

disease progression

Acute vs Chronic

• Acute 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

Examples of acute pain• Acute post operative pain

• Sprains and strains

• Sports injuries

• Period pain

• Headaches

• Toothache / dental

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

Cancer Pain – 4 sources

• Malignancy– 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

Types of pain

mechanical

inflammatory neuropathic

Two Main categories• Nociceptive 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

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

Assessment• Pain History (LINDOCARRF)

– Location – Intensity– Nature– Duration– Onset, Offset– Concomitants– Aggravating– Relieving– Radiating– Frequency

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”

Principles of Analgesic Prescribing

• Analgesic Ladder• Adjuvants -

– TCA– Anti-convulsants– Anti-arrhythmic

•NSAID

•Non-opioid (paracetamol)

•Adjuvant Medication

•NSAID

•Non-opioid (paracetamol)

•Weak Opioid (codeine, tramadol)

•Adjuvant Medication

•NSAID

•Non-opioid (paracetamol)

•Strong Opioid (morphine, oxycodone)

•Adjuvant Medication

STEP 1STEP 1

STEP 2STEP 2

STEP 3STEP 3

• Analgesic, antipyretic, Act centrally (PGs)

• Not useful as an anti-inflammatory

• Few SE if taken at therapeutic doses

– Onset of effect 30 - 60 min

• Dosing:

– 500 –1000mg QID Max 4g for adult

Paracetamol

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

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”

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

How do they work? - NSAID v COX2

Arachidonic acidArachidonic acid

COX-1COX-1 COX-2COX-2

thromboxane / prostaglandins prostaglandins

NSAIDs CoxibsCoxibs

Primarily support platelet function

Primarily protect GI mucosa

Maintenance Induced

Primarily mediate inflammation, pain & fever

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

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

NSAIDs- Adverse EffectsSide effects Cautions

• hypersensitivity/allergy

• GI (GORD/PUD)

• platelet inhibition

• sodium retention, oedema

• renal toxicity

• hepatic toxicity

NSAIDs- Adverse EffectsSide 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

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!

Where do Opioids Act?

Descending Inhibition

Brain

Nociceptors

Spinal Cord

DorsalHorn

Nociceptive primary afferent

Ascending Activation

Opioids

OpioidsDescending Inhibition

Brain

Nociceptors

Spinal Cord

DorsalHorn

Nociceptive primary afferent

Ascending Activation Descending Inhibition

Brain

Nociceptors

Spinal Cord

DorsalHorn

Nociceptive primary afferent

Ascending Activation

Opioids

Opioids

How do Opioids Act?

• Interact with specific cell-surface receptors in – CNS and PNS– other tissues (GIT, immune cells, other tissues)

2nd messenger systems

G-proteins G-protein

Pharmacological Effects of Opioid Agonists

• Desired Action – analgesia

• Unwanted actions– Analgesic tolerance– physical dependence

– Respiratory depression– Nausea, vomiting sedation

Tolerance often develops

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

Opioids – Precautions

hypotension, shock concomitant CNS depression impaired respiration /↓ respiratory reserve elderly hepatic impairment renal impairment epilepsy/recognised seizure risk biliary colic or surgery

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

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

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)

DRUG DOSE x CONVERSION FACTOR

Pethidine (oral)Pethidine (IV)

x 0.125x 0.4

Methadone x 1.5

Oxycodone x 1.5

Buprenorphine x 50

Codeine x 0.16

Dextropropoxyphene x 0.1

Morphine (IV)Morphine (oral)

x 3x 1

Oral Morphine equivalent

* 100mg tramadol ~ 60mg codeine ~ 10mg oral morphine

Drug / action Duration of action

Active metabolites Adjust dose in renal impairment

Codeine (A) 3-4 Morphine Yes

Dextropropoxyphene (A) 4-6 Nordextropropoxyphene (toxic) Yes

Fentanyl (A) 0.5-2 (iv) No no

Hydromorphone 2-4 hydromorphone-3-glucuronide (H3G - toxic)

yes

Methadone (A) Variable (>24hr)

No no

Morphine (A) 2-3

CR/SR

12-24

morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G – toxic)

yes

Oxycodone (A) 3-4

CR/SR

12-24

oxymorphone no

Pethidine (A) 2–3 norpethidine (CNS +++) yes; contraindicated

Tramadol (A) 3–6 desmethyl tramadol yes

Buprenorphine (partial agonist)

6–8 norbuprenorphine no Reference: AMH

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

Tramadol (Tramal)

• 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

• 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)

Reaction No. of reports Confusion 36 Hallucinations 30 Convulsions 26 Serotonin syndrome 20 Increase in blood pressure 14 Hypersensitivity reactions 12 Hepatic reactions 10 Warfarin interaction 5

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)

Neuropathic PainNeuropathic 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

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)

TREATMENTS FOR NEUROPATHIC PAIN

Antidepressants

Eg.AmitriptylineDesipramineparoxetine

Eg.Lidocaine patch

Capsaicin

Eg.Tramadol

oxycodone

Eg.CBZ

Gabapentinpregabalin

Topicalagents

OpioidsAnticonvulsants

DRUGS

PAIN TYPE

Nociceptivee.g. fracture

Neuropathiceg 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)

May be effective (depends on dose)

NSAIDs Effective Not effective Effective

TCAs, parenteral, local anaesthetics antiepileptic

Rarely used (clonidine may be effective as adjunct)

May be effective

Rarely used (may be effective as adjunct)

Adapted from Table 3-1, Australian Medicines Handbook

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

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

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

Questions?