Parisa Gazerani, Pharm D, PhD

Faculty of Medicine, Aalborg University

gazerani@hst.aau.dk

Learning objectives

• The mechanisms of chronic pain and development of mechanism-oriented approach tailored to the individual patient

• The risk factors involved in pain chronification and importance of early and effective pain treatment in the prevention of chronic pain

• Endogenous modulation mechanisms in pain

• Main analgesics and mechanism of action

• Combining approaches in chronic pain management

Pain

“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”

International Association

for the Study of Pain (IASP), 2011.

Pain is a complex phenomenon

an individual and subjective experience

involves emotions, thoughts, and beliefs simultaneously

Nociceptors (sensory nerve fibers)

Aδ fibers (large, myelinated, fast)

C fibers (small, non-myelinated, slow)

Located in every tissue, including skin, bone and viscera

Nociceptors transmit signals via chemical messengers

Excitatory neurotransmitters (e.g. glutamate) enhance pain

Inhibitory neurotransmitters (e.g. GABA) modulate pain

CNS = central nervous system.

Peripheral

sensory nerve

fibers

Nociceptors

Spinal

cord

Dorsal

root

Aβ

A

C

GABA = γ-aminobutyric acid.

Knowledge of pain pathways is key in the understanding of pain

pathophysiology and the management of different types of pain

4

Nociceptive or inflammatory pain

CGRP = calcitonin gene-related peptide.

Pain caused by inflammation or tissue damage

Chemicals (e.g. prostaglandin,

substance P, histamine, bradykinin,

CGRP, neurokinin A) are generated

in the damaged area and trigger

nociceptors

Nociceptive pain may have multiple causes

Chemicals Nociceptors

Spinal cord

Neuropathic pain

Nerve damage

Pain caused by a lesion or disease of the somatosensory system

Surrounding

tissues remain

intact

5

Neuropathic pain may have multiple causes

Neuropathic pain and ion channels

● Sodium channels

Act as accelerator: generate

signals and allow them to pass

on

● Calcium channels

Act as a gear box: facilitate

● Potassium channels

Act as a brake: modulate

signals

transmission of pain signals

These mechanisms may be disrupted in neuropathic pain and

form targets for therapeutic intervention

6

Nociceptive pain and neuropathic pain can become chronic

To treat chronic pain effectively, it is important to understand the

underlying mechanism of the chronification process

Examples of chronic pain are

• Chronic nociceptive pain: osteoarthritis

• Chronic neuropathic pain: diabetic neuropathy

• Chronic nociceptive and neuropathic pain: chronic back pain and cancer

Chronic

back pain

Cancer

pain

7

Acute and chronic pain

Pain persistence

• Signals tissue damage

• Serves a protective function

• Signals increased nervous

system activity

• Resolves upon healing

Acute pain Chronic pain

• No longer serves a useful

purpose

• Persists beyond the expected

period of healing

• Secondary to physiological

changes in pain signaling and

detection

• Degrades health and function

2

Acute pain Chronic pain

Is a signal to the brain about a noxious

stimulus or ongoing tissue damage

Is uncoupled from the causative event

Intensity correlates with the triggering

stimulus

Intensity no longer correlates with

causal stimulus

Has a distinct warning and protective

function

Has lost its warning and protective function

Can be clearly located

Not felt in one place

Radiates in different areas

Is a serious comorbidity which has an

impact on clinical outcomes and

quality of life

Is a special therapeutic challenge

Is associated with a complex set of

physical and psychological changes

Acute and chronic pain

2

Chronification of pain: central sensitization

Central sensitization

• Decrease in neuronal threshold

Receptive fields expand

• Neurons may become

spontaneously active

Spinal cord is key in chronification of pain

• Persistent peripheral stimuli lead to central

sensitization

Spinal cord

8

Consequence of central

sensitization

• Allodynia

• Hyperalgesia

• Spontaneous pain

Central sensitization

• Reactivity nociceptive posterior horn neurons

(wind up)

• Mechanoreceptors (Aβ-fibers) obtain contact

to the nociceptive system

• Non-painful stimuli are recognized as painful

(allodynia)

Central sensitization

Chronification of pain

• May result from local tissue damage and inflammation

• Alteration of nociceptors by inflammatory mediators producing pain

sensitization

• Lasting activity of damaged nerve fibres leads to neuroplastic changes in

the CNS

10

CNS = central nervous system.

Mechanism of central sensitization

Repeated stimulation of pain pathways results in prolonged

activation of NMDA receptors

NMDA receptors

• In dorsal horn spinal cord

• It is stimulated by its excitatory neurotransmitter glutamate

Activated NMDA receptor

• Enhances pain and central sensitization

• Leads to wind-up and temporal summation

9 AMPA = ɑ-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; mGluR = metabotropic glutamate receptors; NMDA = N-methyl D-aspartate.

Consequences of central sensitization

• Rapidly enhanced and ongoing pain

• Greater area of pain

• Hyperalgesia

• Allodynia

Central sensitization leads to

• Enhanced release of neurotransmitters

• Amplified output to the brain

10

Disruption of limbic brain function

• Fear, anxiety

• Sleep disturbance

• Depression

Descending excitatory and inhibitory controls

● Descending pathways

Activate facilitatory neurons increase dorsal horn activity in spinal cord

Activate inhibitory neurons decrease dorsal horn activity in spinal cord

Failure of descending inhibition plays

a role in chronic pain conditions

● Central sensitization

Less effective descending inhibitory pathways

Hyperexcitable state in spinal cord

12

Endogenous pain modulation and mediators of pain

• At pre-synaptic level, neurotransmitters inhibit the release of excitatory neurotransmitters

• At post-synaptic level, these mediators cause hyperpolarization and thereby inhibit

neuronal activation

• Endorphins inhibit pain

signalling by acting on

opioid receptors

• Noradrenergic pathways

inhibit pain signalling

• 5-HT may either inhibit or

facilitate pain signalling

The sensation of pain can

be influenced by ON and

OFF cells in the rostral

ventromedial medulla

5

Disturbance in the balance between facilitation and inhibition of pain

may cause the development of chronic pain

Through the descending pathway, the brain responds to incoming pain

signals and modulates the experience of pain

Chemicals and channels involved in nociceptive processes

Different formulations can block chemical messages in nociceptive pain

• Local anaesthetics like lidocaine can non-selectively block ion channels

• NSAIDs and COX inhibitors can block the production of prostaglandins

14 COX = cyclooxygenase; NSAIDs = non-steroidal anti-inflammatory drugs.

Chemicals and channels involved in neuropathic processes

Treatment for neuropathic pain relate to abnormalities in the function of ion channels due to damaged nerves

• Carbamazepine and lidocaine target sodium channels

• Gabapentin and pregabalin target calcium channels

Opioid analgesia

The opioid system is the major inhibitory system related to pain,

via dampening of excitatory events

Activated opioid receptors open potassium channels, thereby

acting as a highly effective brake on (abnormal) electrical activity

produced by pain

Opioid receptors

are located in

both the pre-

synaptic and

post-synaptic

cleft

Opioid analgesia

Opioids

Spinal cord

C- and Aδ-

fibers

Pre-synaptic inhibition

• Transmission of pain

to spinal cord is

blocked

Post-synaptic inhibition

• Pain signal output of

the spinal cord is

modulated

18

Opioid receptors Type of receptor Endogenous opiod peptides Function

μ Endomorphins Opens K+

δ Enkephalins Opens K+

κ Dynorphin Closes Ca2+

ORL-1 Nociceptin Opens K+

μ-opioid

receptor

Endogeneous ligand Minimal pain inhibition

Drugs

• Morphine

• Codeine

• Fentanyl

• Pethidine

• Heroin

• Oxycodon

Significant pain

inhibition

Chronic pain: a disease in its own right

● Chronic pain is multifaceted and involves the interaction of Physical factors Psychological factors Social factors

● Pain management plan development based on Good physician-patient communication Jointly agreed goals

1

WHO recognizes pain as an important, global, public health concern

Chronic

pain

Acute

pain

Need for improved,

standardized

management

WHO = World Health Organisation

Physical and psychological burden of severe pain

3

Anxiety Appetite

disturbance

Reduced

mobility

Limited

social

functioning

Limited

workplace

functioning

Depression Disturbed

sleep

Reduced

quality of

life

The burden posed by severe and chronic pain is far-reaching

Questions: How would you re-assess this condition? Use all tools for pain assessments that you may need. What changes, if any, would you make to the current recommendations to her? What non-drug recommendations-plans would you implement? Apply all recommendation you can think of that can help Melinda’s situation.

Case: Melinda is a 45-year old office worker who re-presents to you with persistent lower back pain. She initially presented 3 weeks ago with acute onset severe pain after lifting a heavy box for which you recommended paracetamol. Her pain has improved but not resolved. Melinda’s lower back pain is “aching” in nature and it is diffuse, it radiates into her left buttock. Sitting for long periods and housework exacerbate her pain. She is worried that her back pain will get worse if she does too much. Melinda is not a good sleeper and does not eat well. Her excuse is stress and limitation of time that leads her to eat lots of canned food but she has no drug allergies. She often finds herself demotivated to take any sport activities on a regular basis in a nearby gym or joining walking club with her colleagues at work. She is a single mom, has 2 kids, and her mother recently passed away from a brain cancer. She is still recovering from her divorce and loss of an important family member. She does not have a large circle of friends and has started smoking regularly and heavy drinking during weekends. On examination she has diffuse tenderness of her lower back. Recent full blood count, liver and renal function tests were unremarkable.

https://www.youtube.com/watch?v=DkRnZNAnWfE

Incidence and costs of back pain

● Incidence of back pain – > 50,000 participants

– France, Germany, Italy, Spain, UK

– Severe pain: 3.5%

– Back pain: 66%

● Costs of back pain – 49 billion Euros per year (Germany)

– > 1300 Euros per patient

– More than 50% attributable to indirect

costs of back pain

– Highest indirect cost burdens of common

medical illnesses

66

52

32

18

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0

10

20

30

40

50

60

70

80

90

100

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rob

lem

Join

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in

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ck

Art

hritis

Surg

ery

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pro

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Fib

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4

Chronic back pain is the most frequently reported severe pain

Risk factors of back pain

5

The risk of back pain is

highest during the working

years, with a peak

between 30 and 39 years

Physical behavior • Lack of healthy exercise

• Sedentary lifestyle

Environmental factors • Vibrations

• Poorly designed furniture

Physical conditions • Weak trunk muscle

• Bad posture

Patient factors • Age

• Height

Psychological conditions • Stress

• Depression

• Fear of movement

Managing acute back pain

Physicians should always consider

the risks for acute pain becoming

chronic and persistent

16

● Physical

Stimulation to movement as soon as possible

Brief bed-rest/sick leave

Heat/cold application

Physical therapy

● Pharmacological

Analgesics

Co-analgesics

● Stimulation

Acupuncture

● Interventional/surgical treatment if other

methods unsuccessful

If there is no improvement in

2-4 weeks, the physician must

order futher tests

Managing chronic back pain

● Pharmacological e.g. Paracetamol, NSAIDs, weak opioids,

strong opioids, muscle relaxants, TCAs,

SNRIs and MOR-NRI

● Non-pharmacological e.g. controlled exercise therapy, relaxation

measures, ergotherapy, patient education,

behavioral therapy

● Interventional e.g. surgical

● Multi-modal, long term Individually oriented to the current

symptoms and to the pathophysiological

causes

Multimodal management to

● Help patients to self-manage their

condition

● Reduce pain and its impact

Physical and sport therapy • Active

• Medical training therapy

Psychological pain treatment • Relaxation techniques

• Pain coping strategies

Stimulation therapy • Spinal cord stimulation

Pharmacotherapy • Analgesics

• Co-analgesics

17

NSAIDs = non-steroidal anti-inflammatory drugs; MOR-NRIs = µ-opioid receptor-

norepinephrine reuptake inhibitors; SNRIs = selective noradrenaline reuptake inhibitors;

TCAs = tricyclic antidepressants; TENS = transcutaneous electrical nerve stimulation.

Non-medical, non-surgical therapy

Non-medical,

Non-surgical

therapy

• Core stability exercises

• Massages

• Chiropractic

• Physiotherapy

• Acupuncture

• Behavioral therapy

• Psychological pain

coping

• Strength training

and fitness

• Relaxation techniques

• Yoga

• Orthotic devices

The National Institute for Health and Clinical

Excellence (NICE) recommends 8 supervised,

physical and exercise sessions over 12 weeks

that can be combined with a psychological

treatment programme of management.

18

Red flags

Red flags to low back pain:

Trauma, cumulative trauma

Unexplained weight loss, insidious onset

Age > 50 years, especially women, and males with

osteoporosis or compression fracture

Unexplained fever, history of urinary or other infection

Immunosuppression, diabetes mellitus

History of cancer

Intravenous (IV) drug use

Prolonged use of corticosteroids, osteoporosis

Age > 70

Focal neurologic deficit(s) with progressive or disabling symptoms, cauda equina syndrome

Duration longer than 6 weeks

Prior surgery 12

Yellow flags

13

Yellow flags to low back pain identify psychosocial factors that increase the risk for developing or

perpetuating chronic pain and long-term disability

Psychosocial risk factors

Inappropriate attitudes and beliefs about back pain

Lifestyle habits

Smoking

Poor working conditions

Social class

Educations

Income

Coexisting disease

Cardio-respiratory diseases

Psychiatric diseases

Inappropriate pain behavior

Work-related problems or compensations issues

Emotional problems

Never forget the Multifaceted nature of chronic pain….

Chronic pain

Biological / physical factors

Psychological factors

Social factors

Biopsychosocial pain model

Risk factors for pain to become chronic vary,

but include

• Individual patient factors

• Environmental influences

• Psychosocial factors

• Inadequately-treated acute pain

Goals of chronic pain treatment

Patient and physician partnership

Reduction of pain and a combination of coping strategies

Individualized therapeutic aims

and goals of reverting/preventing pain chronification

Improved QoL and function

• The goals of chronic pain management differ from those of acute pain management

• Goals of chronic pain treatment include achieving a reduction in pain and changing

in the patient’s pain experience

5

Optimizing chronic pain management

In-depth and complete assessment of pain and pain-related impairments

Understanding of the underlying pathomechanisms and drivers of chronic pain

Good communication between patient and physician

Recognition and establishment of individual-patient treatment goals

Alignment of patient and physician expectations from treatment

Develop individualized therapy planning, evidence-based, multimodal or multi-mechanistic

pain management approach

8

Individual

treatment plan

Therapeutic

aims consensus Further diagnostic

evaluations

(as required)

• Lab tests

• Electrophysiology

• Imaging

• Nerve blocks

• Second opinion

Comprehensive clinical pain assessment

Physical examination Psychological

history or

psychosocial

case history /

diagnosis

(as required,

possible referral)

Explanation to

the patient

Diagnosis

Case history

• Pain history

• General medical

history

• Treatment history

• Psychosocial history

11

Pain case history and assessment

Intensity

• Apply rating

scales

Temporal

features

• Onset

• Duration

• Course

• Pattern

Location

• Focal

• Multifocal

• Generalized

• Referred

• Superficial

• Deep

Secondary

signs /

symptoms

• Neurological

deficit

• Hyperalgesia,

allodyna

Patient concept

• Purely somatic?

• Impact on activity /

quality of life

Character /

quality

• Aching

• Throbbing

• Stabbing

• Burning etc.

Impact of pain

• Use numerical and

multi-dimensional

tools

• Impact on physical

and mental function

• Impact on quality

of life

Influential

factors

• Aggravating factors

• Relieving factors

Associated

factors

• Mood

• Emotional distress

• Poor sleep

• Depression

Treatment

response

• Type of treatment

• Dosages

• Duration

• Side effects

• Reasons for

stopping

Key factors considered for chronic pain assessment

15

Importance of early and effective pain treatment

● Chronic pain may lead to intractable chronic pain states if not

efficiently treated

● Chronic pain is associated with brain atrophy

5–11% reduction in grey matter volume in chronic back pain patients vs

control subjects

● A failure to treat chronic pain effectively at an early stage can result

in the development of pain that is more difficult to treat

It is important in the clinical management of pain to identify,

early on, factors that may leat to unsuccessful treatments and

negative outcomes

6

Multimodal treatment strategies for chronic pain patients

Patient-physician

relationship and optimal

pharmacological treatment

Education of the patient and

relatives

Psychological therapy (relaxation, hypnosis, cognitive-

behavioral interventions)

Active physiotherapy and movement therapy (sports)

Peripheral stimulation and interventional

therapy (acupuncture,

spinal cord stimulation)

The aim of multimodal therapy is to help patients improve functionality

and to promote patient responsibility for managing disease

7

Pharmacological elements

Prostaglandin

synthesis

inhibitors

• NSAIDs

• Paracetamol

Pharmacotherapy

Opioid

analgesics

• Morphine

• Oxycodone

• Codeine

• Tramadol

Ion channel

blockers

• Lidocaine

Reuptake

inhibitors

• SSRIs

• SNRIs

• Pharmacological therapy should be seen as part of an integrated plan to:

• Improve physical and social functions

• Support a rehabilitative approach

• The choice should be based upon an analysis of the underlying pain

mechanisms

8

Pharmacological treatment of pain:

20

Pain character/symptoms Diagnosis

examples

Mechanisms Pain therapy with

medication

Affecting the muscular and

skeletal system/exertion-

dependent/local/tender/no

signs of inflammation

Arthrosis/myofascial

pain syndrome Nociceptive

Nociceptor

activation/reduced

endogenous pain inhibition

Non-

opioids/muslce

relaxants/MOR-

NRI

Opioids

Affecting the muscular and

skeletal system/exertion-

dependent/signs of

inflammation/local/pressing-

stabbing-probing

Activated

arthrosis/arthritis

Nociceptive/

inflammatory

Nociceptor activation and

sensitization/central

sensitization

NSAIDs/(glucocorticoids)/

opioids/MOR-NRI

Affecting the nervous

system/burning/shooting/

concomitant neurological

symptoms

Diabetic

polyneuropathy/

post-zoster

neuralgia

Neuropathic

Forming of new channels

and receptors/ectopic

impulse generation

(spontaneous activity)

Anticonvulsants (Na and Ca

channel blockers)/anti-

depressants (here above all

TCA)/MOR-NRI Central sensitization

Forming of new channels

and receptors/ectopic

impulse generation

(spontaneous activity)

Anti-depressants

(NSRIs)/opioids/topical

agents (lidocaine plaster,

topical capsaicin)

Multi-locular/no pathological

findings/hypersensitive to

pain/vegetative and/or mental

symptoms

Fibromyalgia

syndrome Dysfunctional

Reduced endogenous pain

inhibition and changed pain

processing

Anti-depressants (NSRIs)

MOR-NRI = µ-opioid receptor-norepinephrine reuptake inhibitor; NSAIDs = non-steroidal anti-inflammatory

drugs; SNRIs = selective noradrenaline reuptake inhibitors; TCAs = tricyclic antidepressants.

Rationale for pharmacotherapy

● Chronic pain

Often involves more than one mechanism

Seldom controlled by a single pharmacological principle

● Combining agents with different mechanisms of action increases the probability of

interrupting the pain signal (additive/synergistic effect)

● Use drugs with complementary pharmacokinetic profiles instead of a higher-dose single

agent treatment

● Methods of combining drugs include use of

Single, loose-drug combinations (e.g. oxycodone and pregabalin)

Fixed combination preparations (formulated to contain 2 agents, e.g. paracetamol/tramadol)

● Use of agents with more than one mechanism of action in a single molecule (e.g. tapentadol)

22

Warning:

• Certain agents are associated with risk of

severe side effects

• Some patients have treatment-related

adverse side-effects

Different types of pain

Nociceptive pain Neuropathic pain

Pain that arises from actual or threatened damage to non-neural

tissue and is due to the activation of nociceptors

Pain caused by a lesion or disease of the somatosensory

nervous system

Visceral Somatic Central Peripheral

Deep Superficial

Pain is not a homogenous sensory entity

12

Medications for different types of pain

Nociceptive pain Neuropathic pain

• Non-steroidal

anti-inflammatory drugs

(NSAIDs)

• Opioids

First-line medication:

• Antidepressants

• Anticonvulsants

• Topical agents

Second-line medication:

• Opioids

A combination

of treatment

Accurate diagnosis is vital in order to choose the appropriate therapy

13 NSAIDs = non-steroidal anti-inflammatory drugs

Understanding of pain mechanisms is important in the development of a mechanism-

oriented approach to treatment and to optimize choice and selection of pharmacological

modes of treatment

Multimodal pain management plan

Individualized pain treatment plan should be:

• Evidence-based

• Multimodal

• Multi-mechanistic

Pharmacological management Non-pharmacological management

Pharmacological management

should be driven mainly by the

underlying pathomechanisms and

not only by pain intensity

Maximum analgesia with minimum

adverse effects

Enhance functioning

Allow patients to feel more comfortable

Enable engagement in daily activities

The following should be integrated into the

overall pain management plan:

• Acupuncture

• TENS

• Physiotherapy

• Relaxation

• Learning of pain

• Stress coping strategies

17

TENS = transcutaneous electrical nerve stimulation.

Pain chronification – inflammation

• Local tissue damage and inflammation may cause chronic pain

• Persistent inflammatory mediators may alter pain sensitization

Neuronal plasticity allows neurons to modify their

• Properties

• Chemical profile

• Behaviour

• Sensitivity

8

Chronic pain

Inflammation Peripheral

sensitization

Central

sensitization

• Inflammatory compounds can increase

neuronal stimulation and nociceptor

sensitization

• Nociceptors become sensitive to normally

non-toxic stimuli

• Afferent C-fibres contribute to local

inflammation by releasing neuropeptides

• During peripheral sensitization, transmission in

afferent nociceptive neurons is increased

Pain chronification – peripheral sensitization

Chronic pain

Inflammation Peripheral

sensitization

Central

sensitization

CGRP = calcitonin gene related peptide.

9

Pain chronification – central sensitization

Chronic pain

Inflammation Peripheral

sensitization

Central

sensitization

• Central sensitization involves persistent activation of

spinal and supraspinal neurons

• Neurons may become spontaneously activated due

to reduced activation threshold or enlargement of

nociceptive fields

• Pain hypersensitvity occurs where pain perception is

no longer related to noxious peripheral stimuli

• Normal controls on pain processing is altered in

chronic pain NMDA = N-methyl D-aspartate.

10

Reduced noradrenergic and opioid pain inhibition

Noradrenergic and opioid pain inhibition

Suspended tonic noradrenergic

inhibition

• Changed net effect of

descending serotonergic

input from inhibition to

facilitation

Reduced expression of μ-

opioid receptors

• Reduced sensitivity of dorsal

horn neurons to inhibition by

opioids

When pain becomes chronic, shifts occur in the complex system

of control and modulation of pain

11

Pain management overview – mechanism

21

The choice of analgesic should be based on the pain mechanism

• Opioids

• Opioids

• Antidepressants

• Anticonvulsants

• Paracetamol/NSAIDs

• Paracetamol

• NSAIDs

Opioids Anticonvulsants Antidepressants Paracetamol/

NSAIDs

• Mainly effective

in managing

nociceptive pain

• Partially

effective in

relieving

neuropathic

pain

• Inhibit neuronal

excitation

• Stabilize nerve

membranes

• Mainly useful in

the

management of

neuropathic

pain

• Antidepressants

(TCAs, SNRIs

and SSRIs)

inhibit

neurotransmitte

r

• TCAs are

effective in

managing

neuropathic

pain, complex

regional

syndrome and

tension

headache

• SSRIs are less

effective than

SNRIs in pain

management

• Are used in

the

management

of acute pain

• Are effective

in relieving

nociceptive

pain

+

Analgesic synergy

Rationale for mechanism-oriented pharmacotherapy

Rationale for combining drugs

The agents together target multiple

mechanisms of chronic pain conditions,

addressing both nociceptive and neuropathic

components of pain

Opioidergic

Opioids

+ Offer potent analgesic

activity against nociceptive

components of pain

- Are less effective against

neuropathic pain

Monoaminergic

Antidepressants

(monoamine reuptake

inhibitors)

+ Offer activity against

neuropathic pain

components

Pain relief

23

Non-opioid analgesics in chronic pain

An analysis of pain medication-use in Europe revealed that:

96% of chronic pain patients were treated with analgesics not acting on the opioidergic

system

NSAIDs were the class of agent most frequently used

76% of chronic pain patients received NSAIDs as part of chronic pain treatment

In 70% of the cases, therapy had to be changed because of inadequate pain control

NSAIDs are not suited for long-term therapy for chronic pain because of

their mode of action and the potential for serious side effects

The EMA recommends that the lowest effective dosage and short-term use

of NSAIDs is to be preferred

12

Non-opioid analgesics

● Inhibition of the COX enzyme results in

inhibition of prostaglandin synthesis

● COX inhibitors

Non-acidic: paracetamol, metamizole

Acidic (NSAIDs): ibuprofen, diclofenac

● Non-selective NSAIDs act on COX-1 and

COX-2

● NSAIDs only act on nociceptive pain and

are not effective in chronic neuropathic

pain

● Side effects of NSAIDs can include

Gastrointestinal problems

Cardiovascular effects, including

myocardial infarction and stroke

Allergic reactions

Cholestatic hepatosis

Leukocytopenia and aplastic anaemia

NSAIDs must be used with

caution in older patients with

impaired renal function and heart

failure 11

Mechanism of analgesic action of

cyclooxygenase inhibitors

• Inflammatory states are often associated with

the production of prostaglandins, which are

important mediators of both peripheral (left)

and central (right) pain sensitization.

• In the periphery, prostaglandins produced by

inflammatory cells sensitize peripheral nerve

terminal prostaglandin (EP ) receptors,

making them more responsive to a painful

stimulus. In central pain pathways, cytokines

released in response to inflammation induce

prostaglandin production in the dorsal horn of

the spinal cord. These prostaglandins

sensitize secondary nociceptive neurons and

thereby increase the perception of pain.

• Nonsteroidal antiinflammatory drugs

(NSAIDs) block peripheral and central

sensitization mediated by prostanoids that

are released in inflammation.

Non-opioid analgesics

Paracetamol Widely used as an

analgesic and antipyretic

Metamizole Inhibitor of central

prostaglandin synthesis

Analgesic, antipyretic, anti-

inflammatory, and

antispasmodic effects

Side effects

Metamizole is associated

with risks such as allergic

agranulocytosis

Side effects

Paracetamol is associated

with risk of toxic liver

damage at high doses

13

https://www.youtube.com/watch?v=VY7xPVZc5Xs

Opioid analgesics

Weak opioids Opioids Strong opioids

• Do not have a narcotic,

or controlled-drug status

• Are often used in the

management of

musculoskeletal and

visceral pain

• Mainly effective in

managing nociceptive

pain

• Partially effective in

relieving neuropathic

pain

• Mainstay analgesic for

control of post-operative

pain and pain

associated with cancer

• Have a controlled-drug

status

The use of opioid-based analgesia should only be part of an overall plan for

management of chronic non-cancer pain

14

Opioids – natural ligands

Natural ligands for the opioid receptors are found in

● CNS

Limbic system

Thalamus

Hypothalamus

Striatum

● The spinal cord

Formatio reticularis

Substantia gelatinosa

● Peripherally

Natural ligands include neuropeptides such as

enkephalins, endorphins, and dynorphins

15

• Opioid receptors can be

of μ,κ or δ subtype

• Opioid drugs act mainly

via μ receptors

Opioids – mechanism of action

● At presynaptic level, opioid binding leads to

Reduced intracellular cAMP concentrations

Decreased calcium ion influx

Consequent inhibition of the release of excitatory

neurotransmitters

● At post-synaptic level, opioid binding leads to

Hyperpolarization of the neuronal membrane

Decreased probability of action potential

generation

Opioids reduce pain signal transmission, activate descending inhibitory

pathways and affect central pain processing

16

https://www.youtube.com/watch?v=AqDo4LiKz-c

Opioid-induced side effects

Common side effects of opioids: ● Nausea, vomiting

● Constipation

● Increased risk of respiratory depression

● Sedative/hypnotic effects

● Hypotension (orthostatic dysregulation)

● Decreased heart rate

● Cholestasis and micturnation disorders

● Urticaria

● Pruritus

● Bronchospasms in asthmatic patients

● Abnormal sensitivity to pain (hyperalgesia, allodynia)

17 http://drugabuse.com/featured/the-effects-of-opiates-on-the-body/

Reuptake inhibitors – tricyclic antidepressants (TCA)

Tricyclic antidepressants:

● Inhibit neuronal uptake of noradrenaline and serotonin (5-HT)

● Are effective in managing chronic pain conditions including

Neuropathic pain

Take 3–7 days for their analgesic effect to be seen

18

Main TCA side effects

● Anticholinergic effects

Dry mouth and nose

Disturbed vision

Constipation

Urinary retention

● Cardiovascular effects

Orthostatic hypotension

Palpitations

Tachycardia

Disturbed conduction

● Weight gain

● CNS effects

Dizziness

Sedation

Insomnia

Tremor

Convulsions

Change in appetite

● Impaired liver function

● Sexual dysfunction

● Anaphylactic reactions

● Drug-drug interactions

19

Selective serotonin and noradrenaline reuptake inhibitors

SNRIs

● Are not associated with side effects linked

with inhibition of adrenergic, cholinergic, or

histaminergic systems

● May be better tolerated than TCAs

● Have moderate efficacy in pain management

● Have an analgesic effect mainly due to

noradrenaline reuptake inhibition

● Are more effective in management of pain

than SSRIs, because 5-HT has both inhibitory

and facilitatory effects, and may thereby

enhance pain

Side effects

• Nausea

• Vomiting

• Constipation

• Somnolence

• Dry mouth

• Increased

sweating

• Loss of appetite

• Weakness

20

Anticonvulsants

66

• Effective in neuropathic

pain and recommended as

first-line analgesic in

neuropathic pain

conditions

• Binds to a subunit of

presynaptic voltage-

dependent calcium

channels

• Needs slow individual

titration

• Used and recommended

for first-line treatment in

neuropathic pain

conditions

• Provides its analgesic

effect by interacting with

N-type calcium channels

• Does not undergo hepatic

metabolism

• Has a low risk of drug-

drug interaction

• Blocks calcium and

sodium channels

• Is indicated for

neuropathic pain

conditions

• Is a liver enzyme inducer

• May be associated with

drug-drug interactions

Side effects

• Sedation

• Dizziness

• Ataxia

• Peripheral edema

• Nausea

• Weight increase

Side effects

• Dizziness

• Fatigue

• Nausea

• Vomiting

• Arrhythmia

• Double vision

• Pruritus

• Changes in blood parameters

21

Topical analgesics

22

NSAIDs

• Diclofenac

• Felbinac

• Ibuprofen

• Ketoprofen

• Piroxicam

• Naproxen

• Flurbiprofen

Lidocaine 5% medicated plaster

• Analgesia effect

• Acts locally directly at the area of pain

• Is indicated for neuropathic pain following a herpes zoster infection (post-

zoster neuralgia)

Mechanism of action

Mechanical protective component Pharmacological component

• Soft plaster: barrier against skin rubbing,

which provokes pain and allodynia

• Immediate cooling and soothing effect

• Lidocaine diffuses into the skin and blocks

over-excitable Na+-channels on damaged

nociceptors

• Stabilization of neuronal membrane potential

of A- and C-fibers, resulting in a reduction of

ectopic activity

• At the long-term, reduction of peripheral input

may counteract central sensitization

23

Other treatment options

24

Capsaicin

plaster

Tapentadol

• Overstimulates

TRPV1 channels

• Inhibits initiation

of pain

transmission in

the spinal cord

• Is a centrally

acting analgesic,

combining 2

mechanisms of

action

• μ-opioid receptor

agonism (MOR)

• Noradrenaline

reuptake

inhibition (NRI)

• Hence, belongs

to a new class

called “MOR-

NRI”

The use of two or more agents with differing mechanisms or multiple

modes of action increases the likelihood that pain signals will be

interrupted and pain is relieved

Rationale for combining analgesic agents

Analgesic efficacy

• Multiple mechanisms of action offer potential for synergistic analgesia

• Agents can be chosen with complementary pharmacokinetic profiles

Reduction of side-effects

Two or more agents can be used in lower doses to reduce the risk of treatment-related side effects

To tailor medication to the patients’ individual needs, physicians should be well-informed

about the patients’ pain level, functional status and the occurance of side effects

Example

• Elderly chronic pain patients often have other medical

conditions that require treatment and are thus at risk of

drug-drug interaction, e.g.

• NSAIDs can interfere with blood pressure-lowering

effects of ACE inhibitors

• NSAIDs are associated with increased bleeding risk

and would therefore not be suitable for patients with

cardiovascular disease receiving anticoagulant therapy

• Combining analgesics may reduce the required dose and

allows therapies to be chosen to fit the patients’ profile and

risk

The Vicious Circle: poor analgesia

Poor analgesia

Pharmacological treatment

Side effects

Dose

reduction

Poor

tolerability

Good

efficacy

Good

tolerability

Poor

efficacy

Dose increase

+ +

Patient struggles but stays / Patient drops out opioid rotation

• Low quality of life

• Inefficient pain management and higher costs in health care system

Adequate analgesia

26

Reason:

• Wrong substance /

wrong dose?

• Wrong diagnosis of

pain type or

components?

• Others?

The Vicious Circle: side effects

Poor analgesia

Pharmacological treatment

Side effects

Dose

reduction

Poor

tolerability

Good

efficacy

Good

tolerability

Poor

efficacy

Dose increase

+ +

Patient struggles but stays / Patient drops out opioid rotation

• Low quality of life

• Inefficient pain management and higher costs in health care system

Reason:

• Low tolerability?

• Interaction?

• Polymedication?

Adequate analgesia

27

Treatment algorithm

Pain assessment

and diagnosis

Establish NP cause

and treatment

Establish relevant

comorbidities

influencing NP

treatment

Doctor–patient

communication:

goals and treatment

explanation

Initiate therapy for

NP causing disease

First-line medication

for symptom

treatment

Patient evaluation

for non-

pharmacological

treatment

Pain and HR-QoL

reassessment (recurrent)

If

Substantial

pain

Partial

pain relief

No or inadequate

pain relief

Continue Add Other first-line

possibility?

Second- / third- /

fourth-line treatment

Switch

Yes

No

First-line medication for

symptom treatment

1 2 3 4

Stepwise approach to treating neuropathic pain

19 HR-QoL = health related quality of life

Treatment: first-line medication

Systemic treatment

Topical treatment

Antidepressants

Anticonvulsants

Local

analgesic

Secondary

amine TCAs

SNRIs

Calcium

channel 2-

ligands

Nortriptyline

Desipramine

Amitriptyline

Duloxetine

Gabapentin

Pregabalin

Lidocaine

patch

Amino

amide-type

20

TCAs = tricyclic antidepressants; SNRI = serotonin-norepinephrine reuptake inhibitor.

Treatment: second-line medication

Strong opioid

analgesics

Weak opioid

analgesics

Morphine

Oxycodone

Methadone

Fentanyl

Analgesics may be considered as first-line medication:

• If NP patients do not respond to other first line medications

• If patients have acute NP

• If patients have NP due to cancer

• If patients have episodic exacerbations of severe NP

• If prompt pain relief is required when titrating one of the first-line medications

Systemic

treatment

21

Tramadol

NP = neuropathic pain.

Treatment: third-line medication

Anti-

convulsants

Bupropion

Citalopram

Paroxetine

Carbamazepin

Lamotrigine

TCAs

SSRI

Oxcarbazepin

Topiramate

Valproic acid

Systemic

treatment

22

Anti-

depressant

SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Summary

Chronic pain is often multifactorial in nature and peripheral and central sensitization play a role in pain chronification

A multimodal approach is needed for management of a multifactorial pain and includes non-pharmacological and

pharmacological therapy

Multimodal therapy should be based on the underlying mechanisms of pain

Influencing factors on pain treatment need to be carefully considered

A mechanism-oriented approach to pain treatment, tailored to the individual patient, offers the best opportunity for pain

reduction and control

27

Questions: Do you put Melinda in any pain medications? In which ones? Why?

Case: go back to Melinda, please…. Melinda is a 45-year old office worker who re-presents to you with persistent lower back pain. She initially presented 3 weeks ago with acute onset severe pain after lifting a heavy box for which you recommended paracetamol. Her pain has improved but not resolved. Melinda’s lower back pain is “aching” in nature and it is diffuse, it radiates into her left buttock. Sitting for long periods and housework exacerbate her pain. She is worried that her back pain will get worse if she does too much. Melinda is not a good sleeper and does not eat well. Her excuse is stress and limitation of time that leads her to eat lots of canned food but she has no drug allergies. She often finds herself demotivated to take any sport activities on a regular basis in a nearby gym or joining walking club with her colleagues at work. She is a single mom, has 2 kids, and her mother recently passed away from a brain cancer. She is still recovering from her divorce and loss of an important family member. She does not have a large circle of friends and has started smoking regularly and heavy drinking during weekends. On examination she has diffuse tenderness of her lower back. Recent full blood count, liver and renal function tests were unremarkable.

https://www.youtube.com/watch?v=lIPPILw5dtc

References

Any Questions?